WO2009124553A2 - Use of hypothermia inducing drugs - Google Patents

Use of hypothermia inducing drugs Download PDF

Info

Publication number
WO2009124553A2
WO2009124553A2 PCT/DK2009/000092 DK2009000092W WO2009124553A2 WO 2009124553 A2 WO2009124553 A2 WO 2009124553A2 DK 2009000092 W DK2009000092 W DK 2009000092W WO 2009124553 A2 WO2009124553 A2 WO 2009124553A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
phosphate
phenyl
optionally
Prior art date
Application number
PCT/DK2009/000092
Other languages
French (fr)
Other versions
WO2009124553A3 (en
Inventor
Uno Jakob Weber
Jacob Gotfredsen
Original Assignee
Neurokey A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neurokey A/S filed Critical Neurokey A/S
Publication of WO2009124553A2 publication Critical patent/WO2009124553A2/en
Publication of WO2009124553A3 publication Critical patent/WO2009124553A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of compounds for the induction of hypothermia for the prophylaxis and treatment of ischemia.
  • Ischemia is the lack of oxygenated blood flow to various body parts and may result from apoplexia, cardiac arrest and asphyxia.
  • Ischemia is the lack of oxygenated blood flow to various body parts and organs.
  • Cerebral ischemia is an ischemic condition where the brain or parts of the brain do not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various serious diseases such as stroke and cardiac arrest, or the result of arterial obstruction such as strangulation. Severe or prolonged cerebral ischemia will result in unconsciousness, brain damage or death.
  • hypothermia counteracts ischemic brain damage by several mechanisms: 1. Ischemia induces opening of the blood-brain barrier, a process that seems to be very sensitive to brain temperature [15]. This is evident from studies of tracers and their migration across the blood-brain barrier, in which hypothermia attenuates extravasation several hours after ischemia [16] and prevents vasogenic oedema [17]. 2. Reperfusion after brain ischemia results in the production of free radicals, which causes peroxidation and destruction of membrane lipids [18]. Hypothermia prevents the production of free radicals such as hydroxyl and nitric oxide during reperfusion after brain ischemia [19;20]. 3.
  • Amino acids such as glutamate, aspartate, and glycine, act as excitotoxic neurotransmitters by over stimulation of neurons in the vicinity of ischemic damage, which causes further injury. Hypothermia lowers the release and may even cause a more rapid reuptake of these transmitters [21-24]. Re- lease of excitotoxic neurotransmitters might also cause progressive neuronal death in the penumbra in stroke patients [22], and hypothermia after cerebral ischemia could attenuate this process.
  • hypothermia By lowering of neutrophil and microglial activation after ischemia, hypothermia also has an anti-inflammatory effect [30;31].
  • Apoptosis and DNA changes are crucial stages in delayed neuronal death after transient cerebral ischemia [32].
  • Hypothermia directly inhibits apoptosis [33] and may also increase endogenous production of the anti-apoptotic protein Bcl-2 [34].
  • Hypothermia may even have effects at the DNA level: A slight lowering of brain temperature results in less DNA fragmentation [35] and less apoptosis [36].
  • hypothermia Induction of hypothermia by lowering of the core temperature of the body has been attempted by mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel.
  • mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel.
  • these mechanical inducers of hypothermia have been shown to have considerable unwanted side effects. These side effects include shivering, serious infections and lung puncture. Shivering causes an increased exertion of the heart of the patient, and this will in some cases result in ischemia of the heart and thereby increased morbidity and mortality.
  • a pharmaceutical composition comprising a compound capable of inducing hypothermia would not only solve the problem of preventing the effects of ischemia, but also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.
  • Leker et al. [37] described that the cannabinoid HU-210 did provide hypothermia and protection against ischemic damages in Sprague-Dawley rats. However, Leker et al. observed hemodynamic and behavioural side effects due to the treatment in the rats, such side effects precluding the drug used in humans.
  • Another reason for the variation observed may be the less than 100 % homology in cannabinoid receptors of the various species.
  • hypothermia in animals having a body weight of 300 g differs significantly from induction of hypothermia in humans having an average body weight of 70-75 kg, i.e. a 250-fold difference in body weight and thus volume that has to be reduced in temperature when inducing hypothermia.
  • Cannabinoid-containing drugs have been administered to humans for the treatment of pain, however no reports of significant hypothermia observed in humans during such treatment has been described.
  • the present inventors have found that it is possible to medically induce hypothermia in human beings by administration of a cannabinoid.
  • the present invention relates to the induction of hypothermia in humans in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising a compound capa- ble of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue ischemia and anoxia.
  • the inventors have found that such hypothermic effects can be obtained in humans as a result of compounds such as cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors.
  • the present invention discloses the use of a compound for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof.
  • a kit of parts comprising the medicament as herein disclosed is yet an aspect of the present invention.
  • Figure 2 Plot of diastolic blood pressure.
  • FIG. 3 Plot of temperature curves (Example 18; study 1) Dihydrocapsaicin.
  • Figure 4 Plot of temperature curves (Example 18; study 2) Dihydrocapsaicin.
  • Figure 5 Plot of temperature curves (Example 18; study 3) Dihydrocapsaicin.
  • Figure 7 Plot of temperatur.e curves (Example 18; study 5) HU-210.
  • a cannabinoid receptor agonist is a cannabinoid or a cannabimimetic compound.
  • Antagonist A cannabinoid receptor antagonist is a substance capable of inhibiting the effect of a cannabinoid receptor agonist.
  • Alcohol A class of organic compounds containing one or more hydroxyl groups (OH).
  • OH hydroxyl groups
  • Alicyclic group means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
  • Aliphatic group in the context of the present invention, the term "aliphatic group” means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.
  • Alkyl group means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like.
  • Alkenyl group means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as a vinyl group.
  • Alkvnyl group means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds.
  • Amphiphil substance containing both polar, water-soluble and nonpolar, water- insoluble groups.
  • Aromatic group the term "aromatic group” or "aryl group” means a mono- or poly- cyclic aromatic hydrocarbon group.
  • Cannabinoid Compound capable of binding to a cannabinoid receptor and isolated from or identical to a compound isolated from an organism such a plant or animal. In the present context any compound capable of binding a cannabinoid receptor.
  • Cannabimimetic Compound capable of binding to a cannabinoid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a cannabinoid receptor.
  • Cyclic group means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.
  • Cycloalkenyl means a monovalent unsaturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkenyl, lower alkoxy, lower haloalkoxy, alkenylthio, halo, haloalkenyl, hydroxyalkenyl, nitro, alkoxycarbonenyl, amino, alkenylamino, alkenylsulfonyl, arylsulfonyl, alkenylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkenylaminocarbonyl, aryla
  • Cycloalkyl means a monovalent saturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylamino- sulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino.
  • Cationic group A chemical group capable of functioning as a proton donor when a compound comprising the chemical group is dissolved in a solvent, preferably when dissolved in water.
  • Form a ring means that the atoms mentioned are connected through a bond when the ring structure is formed.
  • Group (Moiety / substitution) as is well understood in this technical area, a large degree of substitution is not only tolerated, but is often advisable. Substitution is anticipated on the materials of the present invention.
  • group and “moiety” are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not allow or may not be so substituted.
  • group when the term "group” is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with O, N, or S atoms, for example, in the chain as well as carbonyl groups or other conventional substitution.
  • alkyl group is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc.
  • alkyl group includes ether groups, haloal- kyls, nitroalkyls, carboxyalkyls, hydroxyalkyls, sulfoalkyls, etc.
  • alkyl moiety is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like.
  • heterocyclic group means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulphur, etc.).
  • Heterocyclyl means a monovalent saturated cyclic radical, consisting of one to two rings, of three to eight atoms per ring, incorporating one or two ring heteroatoms (chosen from N, O or S(O) 0 - 2 , and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino,
  • Heteroaryl means a monovalent aromatic cyclic radical having one to three rings, of four to eight atoms per ring, incorporating one or two heteroatoms (chosen from nitrogen, oxygen, or sulphur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, aryl- aminocarbonyl, alkylcarbonlamino and arylcarbonylamino.
  • hypothermia Lowering of the body temperature below normal level.
  • Ischemia Restriction in blood supply with resultant dysfunction or damage of tissue.
  • Ischemic tissue damage Tissue damage due to ischemia.
  • Moieties of a particular compound cover group(s) or part(s) of said particular compound.
  • Pharmaceutical composition or drug, medicament or agent refers to any chemical or biological material, compound, or composition capable of inducing a desired therapeutic effect when properly administered to a patient.
  • Some drugs are sold in an inactive form that is converted in vivo into a metabolite with pharmaceutical activ- ity.
  • the terms "pharmaceutical composition” and “medicament” encompass both the inactive drug and the active metabolite.
  • Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.
  • the principle of the present invention is the use of cannabinoids and/or cannabimimetic compounds for induction of hypothermia, such as for alleviating the effects of ischemia, such as but not limited to tissue damaging effects of ischemia.
  • Ischemia is the reduction or abolition of blood supply to a tissue.
  • the associated deficiency of oxygen and nutrients may lead to cell death (necrosis) in areas of the affected tissue.
  • the damage induced by the lack of oxygenated blood in the brain occurs in two stages. First cellular metabolism is arrested due to lack of oxygen and some cells and tissue will die within minutes as a consequence hereof. Secondly a cascade of processes such as apoptosis is initiated and continues up to 12 hours after the event that initially induced the ischemic state has been abolished.
  • the tissue damaged by the second cascade can be crucial and cause greater harm to the individual than the primary damage happening within the first minutes of ischemia.
  • the current invention is aimed at correcting ischemia of the brain thereby minimizing the damage to the central nervous system.
  • the invention does so by administering a drug to induce hypothermia in patients.
  • the hypothermic effect is presumed to counteract ischemic damage by several mechanisms in the brain: Prevention of the blood-brain-barrier disruption that happens soon after ischemic onset that allows oedema formation from extravasation; Diminishing of the oxygen-based free-radical production that results from activation of microglia and other cell types; Reduction of the excitotoxic-neurotransmitter release that over- stimulates neighbouring neurons; Lowering of the metabolic rate and subsequent energy depletion; and anti-inflammatory action.
  • Ischemia may occur under various circumstances; of special relevance to the present invention are the circumstances relating to cardiovascular diseases, asphyxia and traumatic brain injuries.
  • the compound of the present invention is administered to prevent or treat or treat and prevent tissue damaging effects subsequent or in conjunction with ischemia.
  • Cardiovascular disease is the most common cause of death and of physical as well as mental impairment in the developed world. A similar development is seen in the rest of the world as it emulates the lifestyle of the Western hemisphere with its fatty diets, lack of exercise and increasing average lifespan.
  • cardiovascular diseases myocardial infarction, acute coronary syndrome, cardiac arrest and stroke, but many less common cardiovascular diseases may be equally detrimental to the individual affected. These less common diseases include among others arterial aneurism, subarachnoid haemorrhage, arteriosclerosis or atherosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • arteriosclerosis or atherosclerosis arteriosclerosis or atherosclerosis
  • angina pectoris hypertension
  • hypercholesterolemia cardiac arrhythmia
  • cardiomegaly cardiomyopathy
  • heart valve regurgitation heart valve stenosis
  • Myocardial infarction (heart attack) is a result of an atherosclerotic plaque slowly building up in the inner lining of a coronary artery which then suddenly ruptures, partially or totally occluding the artery and preventing blood flow.
  • Cardiac arrest is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively.
  • Brain damage is likely to occur after 3-4 minutes without medical intervention, except in cases of hypothermia.
  • Stroke is an acute neurological injury, lasting more than 24 hours, in which the blood supply to a part of the brain is interrupted, either by a clot in the artery or if the artery bursts.
  • Arterial aneurism is a localized ballooning of an artery by more than 50% of the diameter of the vessel.
  • Aneurysms most commonly occur in the arteries at the base of the brain and in the aorta. This bulge in an artery carries the risk of bursting and leading to internal hemorrhage. The larger an aneurysm becomes, the more likely it is to burst.
  • Subarachnoid haemorrhage (SAH) is bleeding into the subarachnoid space surrounding the brain, i.e., the area between the arachnoid and the pia mater. It may arise due to trauma or spontaneously, and is a medical emergency, which can lead to death or severe disability even if recognized and treated in an early stage.
  • Arteriosclerosis is a disease in which arterial walls harden over years or decades as a result of the formation of collagen and cal- cium deposits.
  • Atherosclerosis is the most common subgroup of arterioscleosis, and is characterised by a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells ('foam cells') and promoted by low density lipoproteins (LDL; plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macro- phages by functional high density lipoproteins (HDL).
  • Hypertension or high blood pressure is a medical condition wherein the blood pressure is chronically elevated.
  • Hypercholesterolemia is the presence of high levels of cholesterol in the blood.
  • Arrhythmia is a group of conditions in which the muscle con- traction of the heart is irregular or is faster or slower than normal. Some arrhythmias are life threatening medical emergencies that can cause cardiac arrest and sudden death. Cardiomegaly is a medical condition wherein the heart is enlarged. It can often be associated with other serious medical conditions. Cardiomyopathy is the deterioration of the function of the myocardium (i.e., the actual heart muscle). Peo- pie with cardiomyopathy are at risk of arrhythmia and/or sudden cardiac death.
  • Heart valve regurgitation also known as heart valve insufficiency, is the abnormal leaking of blood through heart valves.
  • Heart valve stenosis is a heart condition caused by the incomplete opening of a heart valve, typically the aortic valve or the mitral valve, impairing blood flow through the heart.
  • Each of the cardiovascular diseases mentioned, as well as others not mentioned, may cause ischemia of organs. This ischemia, whether of the brain, heart or other organs, may lead to death or impairment if not treated rapidly.
  • cardiovascular diseases such as, but not limited to: myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hyperten- sion, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • the medicament is for the treatment or prophylaxis of ischemia due to cardiac arrest, myocardial infarction, acute coronary syndrome, stroke, arterial aneu- risms, sub-arachnoid haemorrhage or angina pectoris.
  • Sudden cardiac arrest victims may be subjected to early CPR, early defibrillation and early advanced care. Further tests and treatments may include cardiac catheterization, electrophysiologic tests, coronary artery bypass surgery, balloon angio- plasty or PTCA, antiarrhythmic medicine, implantable cardioverter / defibrillator, implantable pacemaker and heart transplant.
  • acute treatment may include clot-busters (e.g. tPA) or surgical intervention (e.g. aneurysm clipping, and endovascular procedures such as insertion of "coils”).
  • clot-busters e.g. tPA
  • surgical intervention e.g. aneurysm clipping, and endovascular procedures such as insertion of "coils”
  • Preventive treatment includes the administration of anticoagulants/anti-platelet. It may furthermore include carotid endarterectomy and angioplasty and/or stents.
  • Patients suffering a heart attack may have one or several treatments and procedures done to survive and diagnose the condition: These include resuscitation (early CPR, early defibrillation, early advanced care), thrombolysis, coronary angioplasty (also known as Percutaneous Transluminal Coronary Angioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation), and coronary artery bypass graft surgery (CABG).
  • resuscitation early CPR, early defibrillation, early advanced care
  • thrombolysis also known as Percutaneous Transluminal Coronary Angioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation
  • PTCA Percutaneous Transluminal Coronary Angioplasty
  • PCI Percutaneous Coronary Interventions
  • Balloon Angioplasty and Coronary Artery Balloon Dilation Balloon Angioplasty and Coronary Artery Balloon Dilation
  • Asphyxia is a common cause of death and of physical as well as mental impairment in perinatals, neonatals or newborns, children and adults of all ages.
  • WHO World Health Organization
  • the perinatal period commences at 22 completed weeks (154 days) of gestation (the time when birth weight is normally 500 g), and ends seven completed days after birth or delivery.
  • the neonatal period is most often and herein defined as four weeks after birth; regardless of whether or not birth occurs prematurely.
  • a premature infant is born after a gestation period of less than the normal time (about 266 days in the human).
  • Asphyxia can be divided into perinatal asphyxia and non-perinatal asphyxia.
  • Perinatal asphyxia is the medical condition resulting from deprivation of oxygen to a newborn infant long enough to cause apparent harm. It results most commonly from a drop in maternal blood pressure or interference during delivery with blood flow to the infant's brain, but may also stem from umbilical cord entanglement. This can occur due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation. Extreme degrees of asphyxia can cause cardiac arrest and death. Hypoxic damage can occur to most of the infant's organs, but brain damage is of most concern and perhaps the least likely to quickly and completely heal. In severe cases, an infant may survive, but with damage to the brain manifested as developmental delay and spasticity.
  • the compound is administered to the infant while it resides within the uterus and/or birth canal, i.e. as soon as asphyxia is determined.
  • Asphyxia may be determined for ex- ample by measuring the pH of the blood of the infant.
  • Non-perinatal asphyxia is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. Common causes hereof include drowning, strangulation and exposure to toxic gasses.
  • Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs most sensitive to hypoxia first, such as the brain, hence resulting in cerebral hypoxia. The absence of effective remedial action will very rapidly lead to unconsciousness, brain damage and death.
  • Treatment by administration of the cannabinoid receptor agonists defined in this patent may be carried out in conjunction with test and treatments of diseases and accidents including asphyxia (perinatal asphyxia, and non-perinatal asphyxia includ- ing, but not limited to, drowning, strangulation and exposure to toxic gasses).
  • diseases and injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
  • Traumatic brain injury also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage.
  • TBI can result from a closed head injury or a penetrating head injury.
  • Parts of the brain that can be damaged include the cerebral hemispheres, cerebellum, and brain stem.
  • Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain.
  • Outcome can be anything from complete recovery to permanent disability or death. Ischemia is a significant factor contributing to the neurological damage frequently seen in patients suffering from TBI.
  • Treatment by administration of the cannabinoid receptor agonists defined in this patent may also be carried out in conjunction with test and treatments in relation to traumatic head injury (closed head injury or penetrating head injury). Such injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
  • Fever also known as pyrexia, or a febrile response
  • Fever is a frequent medical symptom that describes an increase in especially internal body temperature to levels above normal. Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, meaning that the temperature is raised by the body in a controlled manner. Fever is a symptom of many different diseases such as infectious diseases, immunological diseases, cancers, metabolic disorders and more.
  • Hyperpyrexia is an extreme degree of fever, where the set body temperature is elevated greater than or equal to 41 degree Celsius. Such a high temperature is considered a medical emergency and requires immediate medical attention.
  • Hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production or insufficient thermoregulation, or both. Hyperthermia may be caused by heat- or sunstroke, exposure, dehydration and more.
  • a special variant of hyperthermia is malignant hyperthermia which may arise due to administration of general anesthesia. It is an object of the present invention to provide a compound for the induction of hypothermia and/or lowering of body temperature in an individual with an elevated body temperature, such as an individual suffering from fever, hyperpyrexia and/or hyperthermia.
  • hypothermia in an individual in whom the initial temperature prior to treatment is above the normal temperature for said individual.
  • Such an individual may be an individual suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other. It is common that individuals suffering from a heart attack or stroke e.g. suffering from ischemia develop a fever and it is an object of the present invention to reduce the fever and induce hypothermia in such an individual.
  • An Individual otherwise suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other may benefit by administration of the compound of the present invention to reduce the elevated temperature to normal; that is to within 35 to 39 degree Celsius, such as to within 35.5 to 38.5 degree Celsius, such as to within 36 to 38 degree Celsius, such as to within 37 degree Celsius +/- 0.6 degree Celsius, or to reduce their body temperature further to hypothermic levels as described above.
  • An individual with elevated body temperatures may have any temperature considered to be above normal, which is any temperature above 36 degree Celsius.
  • the temperature of the individual in need of treatment according to the present invention may thus be a temperature of above 36 degree Celsius, such as above 36.5 degree Celsius, such as above 37 degree Celsius, such as above 37.5 degree Celsius, such as above 38 degree Celsius, such as above 38.5 degree Celsius, such as above 39 degree Celsius, such as above 39.5 degree Celsius, such as above 40 degree Celsius, such as above 40.5 degree Celsius, such as above 41 degree Celsius such as above 41.5 degree Celsius such as above 42 degree Celsius, such as above 42.5 degree Celsius, such as above 43 degree Celsius, such as above 43.5 degree Celsius and higher.
  • the outcome of several types of surgery is improved if the individual undergoing the surgery is placed under hyperthermia prior to or during the surgery.
  • Examples of such operations are neurosurgeries, thorax surgeries and especially cardiac surger- ies.
  • the lowering of the body temperature slows down the metabolic rate and thus reduces the need for e.g. oxygen during the surgery thus giving more time to the surgeon to perform complicated procedures.
  • the compound of the present invention is preferably administered pre-operatively. It is also an aspect of the invention to provide a compound for the induction of hypothermia in an individual in need of surgery prior to and/or during transportation of said individual.
  • a specific procedure in which it is of interest to lower the body temperature is in the case of organ transplants, where it is beneficial that the organs to be transplanted are cooled prior to removal and especially prior to and during transport before transplantation into the recipient. It is furthermore of interest for the preservation of or- gans, tissues, and cells that hypothermia may be induced in these by induction of hypothermia in the individual from which these are taken. Either prior to or after removal, stasis (very low or no detectable metabolic rate) may be induced by further administration of the compounds of the present invention.
  • hypothermia is the lowering of the core temperature of the body below normal level. Normal body temperature in an adult human measured rectally over 24 hours is 37 degree Celsius +/- 0.6 degree Celsius and is thus variable between individuals, and over time within the individual. Hypothermia as a medical condition is usually defined as the effects seen on the body once the core temperature drops below 35 degree Celsius. It may become critical, if the body temperature falls below 32 0 C. In the present application hypothermia is defined as the lowering of the core body temperature below normal levels. This implies that any temperature below the normal core body temperature of the specific individual with its natural variations at the given point in time of the day, or period, herein is defined as being hypothermic. In particular, hypothermia is a temperature below 35.5 0 C, such as below 35 0 C, such as below 34.5 0 C, such as below 34.0 0 C.
  • Body temperature may be measured by a variety of means; by mercury, electronic or plastic strip thermometers on different areas of the body such as the forehead, mouth, armpit, ear or rectum. It is presently understood, that the temperature referred to in the present application is the core body temperature, and that some of the above methods of measurement will indicate a different temperature than the core temperature.
  • induction of hypothermia in an individual can follow a predictable course and be responsive to the dose in which the compound capable of inducing hypothermia is administered.
  • the induction of the hypothermic condition may be rapid or slow depending on the situation of the individual in need of treatment. Also depending on the severity of the ischemic condition, it is of interest to provide a medicament for retaining the individual in the hypothermic state for variable durations of time.
  • a single compound may be used depending on dosage within a range of temperatures or for the induction of hypothermia to a specific temperature.
  • a combination of compounds may furthermore be used for an initial rapid decrease in core body temperature, and the subsequent maintenance of the reached temperature over a prolonged period. It is furthermore beneficial if the hypothermic state can be reversed in a rapid and controlled fashion either slowly or rapidly depending on the status of the individual.
  • the compound is capable of inducing hypothermia to any range of temperatures between 37 and 31 degree Celsius, such as between 36.5 and 31.5 degree Celsius, such as between 36 and 32 degree Celsius, such as between 35.5 and 32.5 degree Celsius, such as between 35 and 33 degree Celsius, such as between 34.5 and 33.5 degree Celsius.
  • the ranges may furthermore be between 37 and 34 degree Celsius, such as between 36.5 and 34.5 degrees, such as 36 and 35 degrees, alternatively between 34 and 31 degree, such as between 33.5 and 31.5 degree, such as 33 and 32 degree Celsius, alternatively between 36 and 33 degree or 35 and 32 degree Celsius.
  • the compound of the present invention is capable of inducing hypothermia in the range of between 36 to 32 degree Celsius, more preferably between 35 and 33 degree Celsius.
  • the temperature range or specific temperature a given compound is capable of inducing is herein also referred to as the target temperature of the combination of compounds and/or the medicament comprising the combination of compounds.
  • the core body temperature of an individual with about 10 degree Celsius or less such as 9 degree Celsius, 8 degree, 7 degree, 6 degree, 5 degree, 4 degree, 3 degree, 2 degree or 1 degree Celsius.
  • about 10 degree is meant 10 +/- 0.5 degree Celsius and likewise for 9 degree and so on.
  • the temperature is lowered with 5 degree Celsius or less, such as 4 degree, 3 degree, 2 degree or 1 degree Celsius.
  • the target temperature may be of greater interest than the specific amount of degrees of reduction in core body temperature a given compound or combination of compounds may induce.
  • the core body temperature of the individual may already be decreased prior to treatment due to reduced blood flow.
  • the temperature of the individual may be between 35 and 36 degree Celsius. Therefore the compound of the present invention may not only induce hypothermia in regards to lowering the core body temperature a certain amount of degrees, the compound or combination of compounds of the present invention are furthermore capable of reaching a predetermined target temperature.
  • the target temperature of the compounds or combination of compounds of the present invention is: 32 to 34 degree Celsius
  • the person in need of the hypothermic treatment e.g. the administration of a compound of the present invention suffers from ischemia, or is in need of surgery such as neurosurgery or cardiac surgery, e.g. the compound is administered pre-operatively.
  • Celsius such as between +/-0.3 degree Celsius, such as between +/- 0.2 degree Celsius, or such as between +/- 0.1 degree Celsius.
  • An aspect of the present invention regards the treatment of an individual in need thereof by the use of a compound of the present invention for the induction of hypothermia.
  • the individual in need of the treatment is an individual suffering from conditions that are benefitted by the induction of hypothermia and/or reduction in body and/or brain temperature.
  • Such an individual include but are not limited to: an individual suffering from or at risk of suffering from ischemia, elevated body temperatures due to fever, hyperthermia, hyperpyrexia, malign hyperpyrexia or are in need of treatment, such as but not limited to surgery, wherein the outcome of the procedure or the procedure itself is benefitted by a reduction in temperature of the individual undergoing the treatment and/or surgery.
  • Cannabinoids and cannabimimetic compounds are a group of chemicals which activate the body's cannabinoid receptors, CB1 and CB2. Before other types were discovered, the term referred to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological ef- fects. Cannabinoids are generally grouped into five classes based mainly on chemical composition and in part on origin:
  • the eicosanoids also referred to as endocannabinoids are produced in the bodies of humans and other animals 2.
  • Classical cannabinoids a group which includes natural cannabinoids found in larger or smaller amounts in the hemp plant Cannabis sativa.
  • Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence. Cannabinoids and cannabimimetic compounds (CB1/CB2 agonists) have furthermore received interest as putatively neuroprotective substances.
  • CB1/CB2 agonists cannabimimetic compounds
  • Cannabinoids are generally termed such due to their ability to bind one or more of the cannabinoid receptors CB1 and CB2.
  • CB1 and CB2 cannabinoid receptors
  • CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
  • CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the antiinflammatory and possible other therapeutic effects of cannabis.
  • hypothermia the behavioural effects, including hypothermia, seen when introducing animals to cannabinoids seems to be due to other factors besides CB1 receptor stimulation [37;40]. Inducing hypothermia by cannabinoids is therefore not solely equivalent to stimulating the CB1 receptor. Furthermore, there is evidence in the literature for other receptors than CB1 and CB2 as recipients of the cannabinoid ligands.
  • the receptors to which the cannabinoids and cannabimimetic compounds of the present invention may bind includes, apart from CB1 and CB2: a third CB receptor, herein termed CB3, GABA (gamma-aminobutyric acid) receptors, the NMDA (N- methyl-D-aspartate) receptor, the 5-HT(1 A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR) and TRPV1 (transient receptor potential vanilloid 1). It is furthermore within the scope of the invention that the compounds of the invention may bind CB1 , CB2 or CB3 co-receptors. Compounds capable of bind- ing any of the above-mentioned receptors thus fall within the scope of the present invention.
  • cannabinoids of this application are, based on their structure, categorized as follows: classic cannabinoids, non-classic cannabinoids, aminoalkylindoles, eicosanoids (endogenous cannabinoids) and other compounds that fall out of the classification. Compounds belonging to any of these categories fall within the scope of the present invention.
  • the compounds of the invention are capable of inducing hypothermia in an individual.
  • the compounds of the invention are capable of binding a cannabinoid receptor.
  • R is a chemical bond or a chemical moiety as defined in the above.
  • R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, heteroaryl-(C 1-4 )-alkyl, heterocyclyl-(C 1 .
  • any of the compounds may carry one or more phosphate groups bound as phosphate esters.
  • the present invention concerns the use of a compound such as a classic or non- classic cannabinoid comprising the general formula (I):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 .
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO 2 , phosphate,
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halo- gen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 . 4 )-alkyl, heterocyclyl-(C 1 .
  • R4 is selected from the group of: C, H, S, N, O, optionally substituted with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl- (C 1 . 4 )-alkyl, heteroaryl-(C 1-4 )-alkyl, heterocyclyl-(C 1 .
  • the present invention concerns the use of a compound comprising the general formula (I) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C 1-CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or more times with methyl, diheterocycle, lower alcohol, alkyl or phosphate, when R4 is C, H, N,
  • the present invention concerns the use of a compound comprising the general formula (I) wherein R1 is C, optionally substituted with H, OH, OCH 3 or phosphate, when R2 is C substituted with C, O, OSO 2 , alkyl such as (C 3 -C 11 ) any of which may be further substituted with methyl, dimethyl, alkyl such as (C 1 -C x ), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted with C, ethyl, phosphate, alkyl such as (C 1 -C 2 ) wherein C 2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate when R4 as defined in claim 8 is C, (C1 -C8) any C of which may bond with R3 and optionally is substituted with R
  • the present invention also concerns the use of a compound such as a classic or non-classic cannabinoid comprising the general formula (II):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alky!, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 . 4 )-alkyl, heterocyclyl-(C 1 .
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phos- phate, heterocycloalkyl, cycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO 2 , phosphate
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 .
  • R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halo- gen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 . 4 )-alkyl, heterocyclyl-(C 1 .
  • R3 is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, phenyl, optionally substituted with OH, methyl, dimethyl any of which may connect with R3 and more preferably is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn and -
  • R5 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl,
  • the present invention concerns the use of a compound comprising the general formula (II) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C1-CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 thus forming a ring, when R4 is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, or
  • the present invention concerns the use of a compound comprising the general formula (II) wherein R1 is C, optionally substituted with H, OH, OCH 3 or phosphate when R2 is C substituted with C, O, OSO 2 , alkyl such as (C 3 -C 8 ) any of which may be further substituted with methyl, dimethyl, alkyl such as (C 1 -C x ), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is O, OH, NH, optionally connecting with R4, when R4 is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn, when R5 is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH2OH and wherein x is an integer of from 1 to 15.
  • R2 An additional element of importance for especially CB1 receptor recognition is the side chain of R2. It is preferably a lipophilic carbon chain comprising from 1 to 15 carbon atoms, preferably from 3 to 1 1 carbon atoms. It may have any number and type of substituents, especially methyl and/or dimethyl groups. The methyl groups are preferably close to the phenol group, as this appears to induce the greatest effect of the drug. Interestingly, it appears that shorter side chains increase the intensity and decrease the duration of the activity of the compounds.
  • the present invention concerns the use of a compound such as an eicosanoids or other cannabinoid compound comprising the general formula (III):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 . 4 )-alkyl, heterocyclyl-(C 1 .
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halo- gen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 ⁇ )-alkyl, heterocyclyl-(C 1 .
  • the present invention concerns the use of a compound comprising the general formula (III) wherein R1 is (CI -C x ) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl or OCH3 and wherein x is an integer of from 1 to 30.
  • R1 is (CI -C x ) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2
  • the present invention concerns the use of a compound comprising the general formula (III) wherein R1 is (C 1 -C x ), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N when R2 is N, O, NH2 optionally substituted with C, CH2OH, CH(CH2)2 (cyclopropane), optionally further substituted one or more times with CH20H, CH2CI and wherein x is an integer of from 1 to 21.
  • the present invention concerns the use of a compound such as an aminoalkylindole or other cannabinoid compound comprising the general formula (IV):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-fd ⁇ -alkyl, heterocyclyl-(C 1 .
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 .
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1 . 4 )-alkyl, heterocyclyl-(C 1 .
  • R2 cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may bond R2 and preferably is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2 and more preferably is (CI-Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or morpholine and any of which may bond R2 and
  • R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1-4 )-alkyl, het- eroaryl-(C 1-4 )-alkyl, heterocyclyl-(C 1 .
  • the present invention concerns the use of a compound comprising the general formula (IV) wherein R1 is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH or phosphate, when R2 is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3, when R3 is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2, when R4 is C, N, O optionally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O, OH, phenyl, diphenyl, morpholino,
  • the present invention concerns the use of a compound comprising the general formula (IV) wherein, wherein R1 is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI-Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or mor- pholine when R4 is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
  • cannabinoid or cannabimimetic compounds specially relevant for the present invention include, but is not limited to classic cannabinoids such as (names in parenthesis are alternative names): delta-9-THC (Tetrahydrocanna-binol), delta-8- THC, delta-8-THC phosphate, Cannabinol (CBN), Cannabidiol (CBD), Cannabidiol- type CBD, Cannabidivarin (CBDV), Cannabichromene-type CBG, Cannabigerol-type CBG, Tetrahydrocanna-bivarin (THCV, THV), Tetrahydrocanna-binol- and cannabinol-type THC or CBN, Iso-Tetrahydro-cannabinol-type iso-THC, Cannabielsion-type CBE, Cannabicyclo l-type CBL, Cannabicitran-type CBT, HU- 308,
  • cannabinoid or cannabimimetic compounds examples include anandamide, delta-9-THC, delta-8-THC, cannabidiol, HU-210, BAY 38-7271 , WIN 55,212 and CP55940 and the phosphate and/or salt derivatives of these.
  • the compounds of the present invention may apart from inducing hypothermia, induce secondary effects or have other characteristics. These may be related to the cannabinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any adverse psychotropic effects.
  • the compound may furthermore have analgesic, anti- convulsive, anti-inflammatory, anti-anxiety, anti-nausea, pulse-lowering and blood- pressure modifying effects. Of these, it is preferable that the compound has analgesic effects.
  • a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
  • a preferred compound of the present invention is a compound capable of binding a cannabinoid receptor, such as CB1 , thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic.
  • cannabinoid or cannabimimetic compounds examples include anandamide, delta-9-THC, delta-8-THC, cannabidiol, HU-210, BAY 38-7271 , WIN 55,212 and CP55940 and the phosphate derivatives of these. Most preferred is HU-210 and the phosphate derivate hereof, HU-210- phosphate, and delta-8-THC and its phosphate derivate, delta-8-THC-phosphate as well as the salt derivate: disodium delta-8-THC- phosphate.
  • These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the cannabinoids or cannabimimetic compounds herein described in binding to their receptors.
  • the purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
  • An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual.
  • antagonists include but are not limited to: Rimonabant (SR141716), Acomplia, SR147778, SR141716A, SR144528, CP-272,871 , NIDA-41020, LY320135, AM251 , AM281 , AM630, WIN56098 and WIN54461.
  • Cannabinoids and cannabimimetic compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the induction of hypothermia in an individual.
  • the induction of hypothermia by any of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising at least one of said compounds.
  • the medicament of the present invention is thus for the induction of hypothermia in an individual for the treatment and/or prophylaxis of ischemia in said individual.
  • the present invention provides a medicament comprising a com- pound wherein at least one compound induces hypothermia slowly.
  • the present invention provides a medicament comprising a compound and a further active ingredient selected from the group of: analgesics, opioids, GABAs and adrenergic antagonists.
  • the present invention further provides a pharma- ceutical formulation, for medicinal application, which comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, as herein defined, and a pharmaceutically acceptable carrier therefore.
  • the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms.
  • the pharmaceutical compositions and dosage forms may comprise the compounds of the invention or its pharmaceutically acceptable salt or a crystal form thereof as the active component.
  • the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid car- rier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
  • the compounds of the present invention may be formulated for parenteral admini- stration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or non-aqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, or syn- thetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulfosuccinates, (c) non-ionic detergents such as, for example, fatty amine oxides, fatty acid alkanola- mides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-.beta.-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more non-ionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds described herein may be solubilized in water, fractionated coconut oil or Tween, such as Tween 80 at any percentage.
  • HU-210 is formulated in fractionated coconut oil and delta-8- THC is formulated in water.
  • the medicament of the present invention comprises a pharmaceutically acceptable carrier.
  • compositions of the instant compounds, where they can be prepared are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating dis- eases.
  • compositions are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.
  • the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
  • a pharmaceutically acceptable salt means any salt of the compounds mentioned. In particular, it means a pharmaceutically acceptable acid addition salt.
  • Pharmaceuti- cally acceptable acid addition salts of the compounds include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydro- bromic, hydriodic, hydrofluoric, phosphorous and the like, as well as the salts derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aro- matic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sul- phate, pyrosulphate, bisulphate, sulphite, bisulphite, nitrate, phosphate, monohydro- genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesul- fonate, and the like.
  • An aspect of the present invention regards the pH of the medicament.
  • the pH of the medicament depends on the administration form, as the pH of the medicament preferably is suitable for the route of administration chosen.
  • An embodiment of the present invention comprises a medicament wherein the pH of the composition is between pH 5 and pH 9, such as between pH 5.5 and 8.5 such as between pH 6 and 8, such as between pH 6.5 and 7.5. Most preferably the pH of the medicament is in accordance with the route of administration and the tissue to which the medicament is administered.
  • the present invention provides a composition comprising a compound, wherein the pH of the composition is between pH 5 and pH 9.
  • the invention provides compounds for the production of a medicament for the treatment of ischemia in an individual. Ischemia may arise due to various circumstances and thus it is an object of the present invention to treat ischemia arising from a plurality of medical indications.
  • cardiovascular diseases such as myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury.
  • cardiovascular diseases such as myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury.
  • Individuals at risk of suffering from ischemia are often individuals who have previ- ously suffered from an event that was capable of or did induce ischemia such as a heart attack, stroke or other. These individuals may benefit from having rapid access to pills, capsules, ampoules, pre-loaded syringes, suppositories or other administration forms of the medicaments of the present invention for self-administration. It is envisioned that these individuals at the onslaught of a new ischemic attack self- administer a dose of the compounds of the present invention prior to receiving medical aid by medical professionals. This is of relevance, as the faster the temperature drops, the better the chances of reducing the detrimental effects of the ischemic attack.
  • compounds of the present invention are used alone or in combi- nation to treat adverse effects of ischemia in the kidney.
  • the present invention provides compounds for treating effects of ischemia, wherein the ischemia is due to cardiovascular diseases such as myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hyper- cholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • cardiovascular diseases such as myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hyper- cholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • Another group of indications are the situations where an individual has an increased body temperature such as fever, hyperpyrexia, hyperthermia or other. It is an aspect of the present invention to provide compounds for the purpose of inducing hypothermia and/or lowering the body temperature of these individuals.
  • This is of relevance, as a severe stroke is known to cause an increase in brain temperature, often subsequently followed by an increase in body temperature.
  • the present invention provides compounds for treating effects of ischemia, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
  • Target temperature and peak effect The target temperature of the medicament is the core body temperature that can be reached upon administering the medicament according to the present invention as prescribed according to potency, dosage and so on.
  • Various ranges and specific hypothermic / reduced core body temperatures that fall within the scope present invention are equal to the temperatures that the compound itself may induce as listed in the section on hypothermia.
  • An embodiment of the present invention is thus a medicament capable of inducing hypothermia below 36 0 C, such as below 35.5 °C, such as below 35 0 C, such as below 34.5 0 C, such as below 34.0 0 C, such as below 33.5 0 C, such as below 33.0 0 C, such as below 32.5 “C, such as such as below 32.0 0 C.
  • the medicament may lower the core body temperature to fall in the range of between 36 and 31 degree Celsius, preferably between 35 and 32 degree Celsius, such as between 34 and 32 degree Celsius.
  • the compounds of this invention will often show a peak in hypothermia inducing effect 30 minutes to 120 minutes after administration, but may potentially peak sooner or later than described by this interval.
  • the hypothermia inducing effect will frequently last from 1 hour to 12 hours, but may potentially last shorter or longer than described by this interval.
  • the compounds / medicaments / treatments herein may be given while the individual receiving the treatment is surrounded by any given temperature.
  • the temperature of the surroundings, especially the room in which the individual resides, is not of relevance to the treatment.
  • the treatment will reduce the temperature of the individual and/or induce hypothermia whether the room temperature is ambient, high or low such as at any temperature between 5 and 45 degree Celsius.
  • the main routes of drug delivery in the treatment method are intravenous, oral, and topical, as will be described below.
  • Other drug-administration methods such as subcutaneous injection or via inhalation, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
  • the mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the individual to which the biologically active substance is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, preferably the mucosa of the nose, mouth or rectum.
  • Compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, intraspinal, subcutaneous, intraarterial, intracardiac, intraosseous, intradermal, intrathecal, transdermal, transmucosal, inhalational, epidural, sublingual, intravitreal, intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the compounds may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the compounds according to the invention may be administered with at least one other compound.
  • the compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
  • a preferred embodiment of the present invention is a medicament for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation. More preferably the administration form is by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
  • the compound of the present invention is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
  • the compound of the present invention is administered by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration. In one embodiment, the compound of the present invention is administered at intervals of 30 minutes to 48 hours.
  • the compound of the present invention is administered at inter- vals of 1 to 6 hours.
  • the individual that may benefit from the administration of a medicament as described herein may be an individual suffering from ischemia or at risk of suffering from ischemia. If the individual is at risk of suffering from ischemia the preferred administration form of the medicament may be suppository, oral administration or inhalation. Preferably, the individual is an individual suffering from ischemia. Also, the individual may have an elevated body temperature and may be in need of a reduction hereof; alternatively the medicaments of the present invention may be given pre-operatively to lower the body temperature of the individual prior to and/or during surgery.
  • the preferred administration form for an individual suffering from ischemia is an injection, such as an intravenous, intramuscular, intraspinal, intraperitoneal or subcutaneous injection. Being in need of treatment thus indicates that the health of the individual is benefitted by the administration of the compound of the present invention.
  • the individual may be any human being, male or female, infant or old.
  • the ischemic condition and/or elevated temperature to be treated or prevented in the individual may relate to the age of the individual, the general health of the individual and whether or not the individual has a prior history of suffering from diseases or disorders that may have or have induced ischemic conditions and/or elevated temperature in the individual.
  • the dosage of the compound according to the invention depends on the compound in question; however, the amount of the compound is also closely related to the pharmaceutical composition of the medicament, any second compound of the medicament or any second active ingredient of the medicament. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques.
  • the optimal course of treatment i.e., the number of doses of a compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the daily dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen will be from about 0.001 to about 80 mg/kg of total body weight.
  • the daily dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen will be from about 0.01 to about 2,400 mg/kg of total body weight, preferably, the dosage of the medicament according to the pre- sent invention is between 10 ⁇ g to 10 mg pr kg total body weight, such as between 100 ⁇ g to 1 mg pr kg total body weight, depending on the compound of choice.
  • the preferred dosage may be between 1 ⁇ g and 1 mg pr kg total body weight, such as between 10 ⁇ g and 100 ⁇ g pr kg total body weight, such as or about 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g or 100 ⁇ g pr kg total body weight, again depending on the compound chosen. It has been found that cannabinoids and vanilloids vary with respect to potency and affinity for the receptor as well as with respect to molecular weight.
  • the dosage of the medicament according to the present invention is be- tween 0.1 ⁇ g to 100 mg pr kg total body weight; such as between 0.1 ⁇ g to 1 ⁇ g pr kg total body weight, for example between 1 ⁇ g to 2 ⁇ g pr kg total body weight, such as 2 ⁇ g to 3 ⁇ g, for example 3 ⁇ g to 4 ⁇ g, such as 4 ⁇ g to 5 ⁇ g, for example 5 ⁇ g to 6 ⁇ g, such as 6 ⁇ g to 7 ⁇ g, for example 7 ⁇ g to 8 ⁇ g, such as 8 ⁇ g to 9 ⁇ g, for example 9 ⁇ g to 10 ⁇ g, such as 10 ⁇ g to 15 ⁇ g, for example 15 ⁇ g to 20 ⁇ g, such as 20 ⁇ g to 25 ⁇ g, for example 25 ⁇ g to 30 ⁇ g, such as 30 ⁇ g to 40 ⁇ g, for example 40 ⁇ g to 50 ⁇ g, such as 50 ⁇ g to 60 ⁇ g, for example 60
  • the dosage of the medicament according to the present invention is between 0.1 ⁇ g to 100 mg pr kg total body weight; such as between 0.1 ⁇ g to 100 mg pr kg total body weight, for example between 1 ⁇ g to 100 mg pr kg total body weight, such as 2 ⁇ g to 100 mg, for example 3 ⁇ g to 100 mg, such as 4 ⁇ g to 100 mg, for example 5 ⁇ g to 100 mg, such as 6 ⁇ g to 100 mg, for example 7 ⁇ g to 100 mg, such as 8 ⁇ g to 100 mg, for example 9 ⁇ g to 100 mg, such as 10 ⁇ g to 100 mg, for example 15 ⁇ g to 100 mg, such as 20 ⁇ g to 100 mg, for example 25 ⁇ g to 100 mg, such as 30 ⁇ g to 100 mg, for example 40 ⁇ g to 100 mg, such as 50 ⁇ g to 100 mg, for example 60 ⁇ g to 100 mg, such as 70 ⁇ g to 100 mg, for example 80 ⁇ g to 100 mg, such as 90 ⁇ g to 100 mg, for example
  • the dosage of the medicament according to the present invention is between 0.1 ⁇ g to 100 mg pr kg total body weight; such as between 0.1 ⁇ g to 1 ⁇ g pr kg total body weight, for example between 0.1 ⁇ g to 2 ⁇ g pr kg total body weight, such as 0.1 ⁇ g to 3 ⁇ g, for example 0.1 ⁇ g to 4 ⁇ g, such as 0.1 ⁇ g to 5 ⁇ g, for example 0.1 ⁇ g to 6 ⁇ g, such as 0.1 ⁇ g to 7 ⁇ g, for example 0.1 ⁇ g to 8 ⁇ g, such as 0.1 ⁇ g to 9 ⁇ g, for example 0.1 ⁇ g to 10 ⁇ g, such as 0.1 ⁇ g to 15 ⁇ g, for example 0.1 ⁇ g to 20 ⁇ g, such as 0.1 ⁇ g to 25 ⁇ g, for example 0.1 ⁇ g to 30 ⁇ g, such as 0.1 ⁇ g to 40 ⁇ g, for example 0.1 ⁇ g to 50 ⁇ g, such as 0.1 ⁇ g to
  • the preferred dosage may be between 0.1 ⁇ g and 100 mg, such as between 1 ⁇ g and 1 mg pr kg total body weight, for example between 10 ⁇ g and 100 ⁇ g pr kg total body weight, such as or about 0.1 ⁇ g, 1 ⁇ g, 5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 150 ⁇ g, 200 ⁇ g, 250 ⁇ g, 300 ⁇ g, 350 ⁇ g, 400 ⁇ g, 450 ⁇ g, 500 ⁇ g, 550 ⁇ g, 600 ⁇ g, 650 ⁇ g, 700 ⁇ g, 750 ⁇ g, 800 ⁇ g, 850 ⁇ g, 900 ⁇ g,
  • the preferred dosage range may be between 10O ⁇ g and 100 mg pr kg total body weight, such as between 200 ⁇ g and 90 mg, between 300 ⁇ g and 80 mg, such as between 400 ⁇ g and 70 mg, such as between 500 ⁇ g and 60 mg, such as be- tween 600 ⁇ g and 50 mg, such as between 700 ⁇ g and 40 mg, such as between
  • the dosage may be found in the range of from 100 ⁇ g to 2000 ⁇ g, such as 200 ⁇ g to 1800 ⁇ g, or 300 ⁇ g to 1600 ⁇ g, 400 ⁇ g to 1400 ⁇ g, 500 ⁇ g to 1200 ⁇ g, 600 ⁇ g to 1000 ⁇ g, 500 ⁇ g to 1000 ⁇ g.
  • the exact dosage may be calculated based on the bovine study model described in Examples 16, 17 and 18.
  • the preferred dosages of a cannabinoid compound such as, but not limited to HU-210 and KN38-7271 (BAY38-7271), is between 1 ⁇ g and 1 mg pr kg total body weight, such as between 10 ⁇ g and 100 ⁇ g pr kg total body weight, such as or about 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g or 100 ⁇ g pr kg total body weight.
  • the dosage may depend on the administration form. For example, it is preferable to administer HU-210 in the range of from 10 ⁇ g and 100 ⁇ g pr kg total body weight intravenously.
  • the dosage regime will be between 2 and 1000 microgram/kg of total body weight, such as between 4 and 900 microgram/kg of total body weight, such as between 6 and 800 microgram/kg of total body weight, such as between 8 and 700 microgram/kg of total body weight, such as between 10 and 600 microgram/kg of total body weight.
  • the dosage regime will be between 15 and 500 microgram/kg of total body weight, more preferably between 20 and 400 microgram/kg of total body weight.
  • At least 40 microgram/kg of total body weight such as at least 50 microgram/kg of total body weight, such as at least 60 microgram/kg of total body weight, such as at least 70 microgram/kg of total body weight, such as at least 80 microgram/kg of total body weight, such as at least 100 microgram/kg of total body weight.
  • the dosages mentioned are the dosages for inducing hypothermia as defined herein.
  • the dosage may be administered as one single bolus or divided into two or more dosages given over a period of time, alternatively it may be administered by continuous iv. Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additionally dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
  • the dosage regime will be between 0.25 and 600 mg/kg of total body weight, such as between 0.5 and 500 mg/kg of total body weight, 1 and 400 mg/kg of total body weight, 2 and 300 mg/kg of total body weight, 3 and 200 mg/kg of total body weight.
  • the dosage regime will be between 4 and 150 mg/kg of total body weight, more preferably between 5 and 100 mg/kg of total body weight.
  • At least 20 mg/kg of total body weight such as at least 30 mg/kg of total body weight, such as at least 40 mg/kg of total body weight, such as at least 50 mg/kg of total body weight, such as at least 60 mg/kg of total body weight, such as at least 100 mg/kg of total body weight.
  • the dosages mentioned are the dosages for inducing hypothermia as defined herein.
  • the dosage may be administered as one single bolus or divided into two or more dosages given over a period of time, alternatively it may be administered by continuous iv.
  • the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later.
  • Such additionally dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a compound, alone or in combination with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
  • the specifications for the unit dosage forms of the present invention depend on the particular compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host.
  • the dose administered should be an "effective amount” or an amount necessary to achieve an "effective level" in the individual patient.
  • the effective level is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharmacokinetics, drug distribution, and metabolism.
  • the "effective level” can be defined, for example, as the blood or tissue level desired in the individual that corresponds to a concentration of one or more compounds according to the invention. Also, the effective level depends on the severity of the ischemic condition, such as total amount of tissue experiencing hyp- or anoxia, the duration of the ischemic condition, whether it is the first or a subsequent ischemic attack of the individual and so forth.
  • the medicament may be administered in any suitable dosage regime, suitable as to the potency of the compound / drug, the target temperature to be reached, the speed of action of the compound, the metabolic stability of the compound, the duration of the treatment and how often the medicament optimally is to be administered.
  • a medicament to be administered at intervals of 30 minutes to 48 hours such as intervals of 1 to 47 hours, 2 to 45 hours, 3 to 43 hours, 4 to 41 hours, 5 to 39 hours, 6 to 37 hours, 7 to 35 hours, 8 to 3 hours, 9 to 31 hours, 10 to 29 hours, 11 to 27 hours, 12 to 25 hours, 13 to 23 hours, 14 to 21 hours, 15 to 19 hours 16 to 18 hours.
  • a medicament to be administered at intervals of 30 minutes to 24 hours such as 1 to 23 hours, 2 to 22 hours, 3 to 20 hours, 4 to 18 hours, 5 to 16 hours, 6 to 14 hours, 7 to 12 hours or 8 to 10 hours.
  • the administration occurs at intervals of 1 to 6 hours, such as 2 to 5 hours, 3 to 4 hours.
  • the optimal administration interval depends on the duration of the hypothermic treatment.
  • the duration of the treatment depends among other things on the severity of the ischemic condition. It is within the scope of the present invention to provide medicaments for the induction of hypothermia wherein the duration of the treatment is from 6 to 72 hours, such as from 7 to 69 hours, such as from 8 to 66 hours, 9 to 63 hours, 10 to 60 hours, 11 to 57 hours, 12 to 54 hours, 13 to 51 hours, 14 to 48 hours, 15 to 45 hours, 16 to 42 hours, 17 to 39 hours, 18 to 36 hours, 1 to 35 hours, 20 to 32 hours, 21 to 29 hours, 22 to 26 hours 23 to 25 hours.
  • the duration of the treatment is between 6 and 48 hours, more preferably between 6 and 24 hours.
  • the duration of the treatment with compounds of the present invention is from 6 to 72 hours.
  • the medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly or alternatively, wherein at least one compound induces hypothermia slowly.
  • rapidly means within few hours, such as within 2 hours, such as within 1 hour, such as within 30 minutes, for example within 15 minutes;
  • slowly means after several hours, such as after 3 hours, for example 4 hours, such as after 5 hours, for example 6 hours, such as after 7 hours, for example 8 hours, such as after 9 hours, for example 10 hours, such as after 11 hours, for example 12 hours, such as after 13 hours, for example 14 hours, such as after 15 hours, for example 16 hours, such as after 17 hours, for example 18 hours, such as after 19 hours, for example 20 hours.
  • a rapidly acting compound or combination of compounds may be administered prior to admission to the hospital such as en route in an ambulance by medically trained personnel.
  • the individual suffering from the ischemic insult will thus already be experiencing a reduction in core body temperature upon arrival at a place of proper facilities enhancing the treatment and reducing the extent of the ischemic insult.
  • An object of the present invention is to provide compounds capable of inducing hypothermia in an individual.
  • the induction of hypothermia depends on the characteristics of the compounds and these characteristics may be to reach different target temperatures or different ranges of target temperatures, reaching the target temperatures and various speeds, the lifetime of the active compound and so on. It is therefore an object of the present invention to provide medicaments comprising more than one compound, such as at least two, at least three or at least four compounds as herein described.
  • the medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly.
  • the medicament may furthermore comprise at least one compound that induces hypothermia over an extended time period, alternatively wherein at least one compound induces hypothermia for a short time period.
  • An embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as herein described and furthermore comprising a second active ingredient.
  • the second active ingredient may increase the hypothermic effect of the compound of the invention, or may have an alternative medical effect such as inducing pain relief or vasodilation.
  • the second active ingredient may thus be selected from the non-limiting group of: capsaicinoids, neurotensins, analgesics, opiods, GABAs and adrenergic antagonists.
  • Capsaicin (8-methyl-N-vanillyl-6- nonenamide) and neurotensin analogues KK13 and KK14.
  • the second active ingredient may also be an antipyretic.
  • Antipyretics are drugs that reduce body temperature in situations such as fever; however, they will not affect the normal body temperature if one does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever. It is an object of the present invention to induce hypothermia in an individual. To prevent a possible overshoot in the body's attempt to regain its normal temperature at the completion of the hypothermia inducing treatment, an antipyretic may be provided in combination with the compounds / medicaments of the present invention.
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • a medicament comprising one or more cannabinoids which may be formulated and /or administered together with an antipyretic drug simultaneously or sequentially.
  • the further active ingredient may also be an analgesic (or painkiller).
  • Analgesics are a diverse group of drugs that relieve pain.
  • Analgesic drugs act in various ways on the peripheral and central nervous systems and include paracetamol (acetaminophen); the non-steroidal anti- inflammatory drugs (NSAIDs) such as the salicylates - aspirin, ibuprofen, naproxen; opioids such as morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine; synthetic drugs with opioid properties such as tramadol and buprenor- phine; and various others.
  • paracetamol acetaminophen
  • NSAIDs non-steroidal anti- inflammatory drugs
  • opioids such as morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine
  • synthetic drugs with opioid properties such as tramadol and buprenor- phine; and various others.
  • Demerol and desflurane both of which are analgesics may also be administered especially for the purpose of reducing shivering as the individual to whom the compounds of the present invention are administered is brought down in temperature. It is especially relevant to use analgesics when inducing actual hypothermia e.g. temperatures below normal.
  • kits may be specifically targeted to persons at risk of suffering from ischemic attacks, such that the kit, apart from instructions, comprises pharmaceutical forms of the medicaments that allow self administration of the medicaments and devices with which to administer the medicaments.
  • An alternative embodiment is an ambulance kit that facilitates the administration of the medicaments of the present invention in a manner most efficient for the rescue personnel.
  • Figure 1 Plot of temperature curves from Day 2 of Example 16.
  • Figure 2 Plot of diastolic blood pressure against time relative to injection for from Day 2 of Example 16.
  • Figure 7 Plot of temperature curves of Example 18; study 5.
  • HU-210 is administered into calves by single intravenous bolus injection at doses of 20, 30 or 40 ⁇ g/kg.
  • a 57-year-old woman is brought into hospital 21 minutes after having collapsed without warning. Staff at the emergency room is alerted in advance. The patient is evaluated in the emergency room where the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
  • An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation).
  • additional intravenous bolus injections may be required (HU-210: Additional injections of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injections of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
  • hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1.
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation).
  • addi- tional bolus injections may be required.
  • concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
  • a 66-year-old man is undergoing elective heart surgery. He suffers from irregular cardiac rhythm during the procedure and goes into cardiac arrest with much impaired circulation for 6 minutes after which the surgical team manages to restore circulation. Subsequent to restoration of circulation, the surgeon in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association rec- ommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association rec- ommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
  • a newborn baby suffers cerebral ischemia during delivery as the umbilical cord gets wrapped around his neck.
  • the APGAR score 10 minutes after delivery is 6.
  • the pediatrician decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
  • An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered. Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation).
  • additional intravenous bolus injections may be required (HU-210: Additional injec- tions of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injections of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
  • Example 6 Asphyxia A 9-year-old boy is in a coma when he is rescued out of a burning house. CRP is commenced on the spot but he is not awake when the ambulance arrives at hospital after a 15 minutes drive. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
  • a 72-year-old is brought to hospital 1 hour and 30 minutes after waking up with the entire right side of his body feeling numb and weak.
  • the patient is evaluated in the neurology department and the physician in charge decides, suspecting a stroke, that the patient shall receive hypothermia therapy immediately to lessen damage to the brain.
  • An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation).
  • additional intravenous bolus injections may be required (HU-210: Additional injections of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injections of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
  • the patient is diagnosed with a stroke.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1.
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • the purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation).
  • addi- tional bolus injections may be required.
  • a 29-year-old man suffers continuous pains in the back of his head for two weeks after which he suddenly collapses and slips into a coma.
  • the patient is diagnosed with a stroke.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1.
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation).
  • addi- tional bolus injections may be required.
  • a 48-year-old man is brought to hospital 35 minutes after experiencing sudden severe chest pain, shortness of breath, and very unpleasant palpitations.
  • Staff at the emergency room is alerted in advance.
  • the patient is evaluated and the cardiologist in charge decides that the patient shall receive hypothermia therapy immediately to lessen damage to the heart and other tissues.
  • An intravenous bolus injection of HU- 210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation).
  • additional intravenous bolus injections may be required (HU-210: Additional injections of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injec- tions of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
  • a 55-year-old man is admitted to hospital 18 minutes after experiencing nausea, shortness of breath, and severe chest pains.
  • the patient who is suffering myocardial infarction is evaluated by the physician in charge who decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the heart and other tissues.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • An intravenous bolus injection of HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. 40 mg/kg body weight
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
  • Example 12 Traumatic brain injury A 41 -year-old man receives a severe blow to the head from a falling brick on a construction site. The patient is still unconscious when he 24 minutes after the trauma is brought to the Emergency Room. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
  • a 60-year-old woman is feeling rather well two days after major surgery when she suddenly slips into a coma. Following acute surgery, brought on by a pulmonary embolism, she is stabilized. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
  • Type of rabbits New Zealand White, Charles River
  • Type of temperature probe PC Based pyrogen testing system, Ellab APT 91
  • Modulation of CB and TRPV1 activities will be assessed in vitro by measuring can- nabinoid and/or cannabimimetic compound and vanilloid receptor agonist induced Ca2+ flux, respectively. This will be done using FLIPR and HEK293 cells stably expressing recombinant human (h) and rat (r) TRPV1 (hTRPV1-HEK293 and rTRPN/1- HEK293, respectively) and recombinant human (h) and rat (r) CB receptors (hCB1- HEK293, hCB2-H293, rCB1 -HEK293 and rCB2-H293) and especially in cells co- expressing human or rat TRPV1 and CB receptors (hTRPV1-hCB1-HEK293 and hTRPVI -hCB2-HEK293).
  • Intracellular Ca2+ levels will be measured in CB, TRPV1 and coCB/TRPVI -expressing cells during exposure to compounds and combinations of compounds. A concentration dependent increase in Ca2+ influx will be observed.
  • the efficacy of vanilloid agonists will be estimated by comparing these to the maximum response induced by capsaicin, likewise the efficacy of cannabinoids will be estimated by comparing these to the maximum response induced by can- nabidiol.
  • a combination of capsaicin and cannabidiol will be used as reference for measuring combinations of drugs.
  • Example 16 - Bovine study model In order to evaluate an effective hypothermic dose of a receptor agonist compound according to the invention, the compound(s) are tested in the bovine study model.
  • the bovine model is used because the body weight of the calves is comparable to the body weight of humans.
  • the efficacy of a compound tested in the bovine model may be correlated with the efficacy of the cannabinoid and/or vanilloid compound tested in the same bovine study model.
  • Calves in the weight target range from 65 to 95 kilo are of primary interest. Calves of higher weight are not be comparable to overweight/obese humans since their weight gain does not arise from increased amount of fatty tissue, but on the contrary from a larger muscle percentage.
  • the calves were kept in the intensive barn for 29 days before the experimental sampling periods were initiated. At an age of app. 50 days (body weight 75 to 85 kg) calves are assigned to the sections of four and injected with test compound. Body temperature, arterial blood pressure, and heart rate are monitored 60 min prior to injection and during 24 h following injection.
  • Calves were surgically implanted with permanent indwelling catheters in the right jugular vein and right carotid artery under total anesthesia prior to the experimental sampling periods. Four of the calves were used to test the sampling procedure, blood pressure probes, equipment and the recording of data without receiving test compound or vehicle.
  • Table 1 (below): Birth weight and age and weights of calves when entering and finishing the pre-trial period. Calf Weight Age when Weight when Age when Weight when at birth entering pre- entering pre- finishing pre- finishing pre-
  • the calves were fed milk-replacer restrictively (4 kg of milk-replacer with 123 g DM/kg supplied once daily) and had ad libitum access to artificially-dried hay and starter concentrate during the trial. During the 29-day pre-trial period, the daily gain was on average 666 gram/day. Calves growing at this level of daily gain will usually be considered as well performing calves.
  • test compound was injected into the left-side jugular vein via a temporary cathe- ter implanted at least one day before injection. Data analyzed within sampling period
  • the recorded data were averaged in 15-min intervals prior to data analysis. Data were sampled from exactly 60 min before injection of test compound and until 23 hours after injection. Data recorded during the 60 min prior to injection were defined as baseline.
  • Variables describing temperature, blood pressure and heart rate were considered as repeated measures and analyzed by using the autoregressive order 1 structure in the mixed model procedure of SAS (SAS Institute, 2001).
  • the model included the effects of block (calves housed in the same room), treatment and time as well as the interaction between treatment and time.
  • Orthogonal polynomial contrasts were used to estimate the linear, quadratic, and cubic effects of treatment.
  • Variables describing number of hours where the body temperature deviated from baseline were constructed within calf and period. Variables were constructed for +0.5, +1.0, +2.0, +2.5, -0.5, -1.0, -2.0, and -2.5 0 C.
  • a variable describing time when body temperature returns to or exceed baseline after injection was calculated as the minimum value for time fulfilling the conditions: time > 0.25 h post injection & (15 min average temperature - baseline temperature) > 0.
  • Variables with only one observation within period and calf were analyzed using a model including the effects of block and treatment.
  • Orthogonal polynomial contrasts were used to estimate the linear, quadratic, and cubic effects of treatment.
  • Means are given as least squares means ⁇ residual standard error of the mean. Allocation of animals
  • Day 1 was designed at dose finding.
  • Day 2 was designed at dose finding.
  • HU-210 is a lipophilic compound and thus may be formulated in several ways, three of which are: Fractionated coconut oil, Tween 80 or in a cyclodextrin complex solution. During the testing phase, our compound precipitated in a cyclodextrin complex solution from the very beginning which ruled that option out. HU-210 was, however, easily dissolved in both coconut oil and Tween 80, and a coconut oil solution was chosen.
  • Day 2 The eight calves received the same doses as tested at Day 1. The results reminded of the results of Day 1. The 6.0 ⁇ g calves both had less pronounced reduction of body temperature (1.8-1.9 0 C) while the 4.0 ⁇ g calf with a proper weight responded as the 4.0 ⁇ g calves of Day 1. The 4.0 ⁇ g calf with a weight above the target range (6086 - weight: 115 kilo) responded less to the test compound. See figures 1 and 2. Day 3: All calves had been used at either Day 1 or Day 2. Seven out of eight had received the active compound while one had received placebo.
  • the doses (5.0+2.5 ⁇ g), 10 and 15 ⁇ g resulted in less behavioral alterations than seen in the 4.0 and 6.0 ⁇ g calves at Day 1 and 2, both in regards to psychotropic behavior as well as the induction of somnolence.
  • Day 3 there was also a tendency to a more pronounced temperature reduction in the calves weighing within the predefined range (65-95 kilo) compared to heavier calves.
  • HU-210 causes hypothermia in calves.
  • the doses tested induced at temporary drop in core body temperature of up to 2.6 0 C in a dose dependent manner.
  • the evaluation is carried out on 80 Holstein bull calves have been purchased for the study that is conducted over 8 study days. At an age of app. 50 days (body weight 75 to 85 kg) calves are assigned to the sections and injected with test compound.
  • Body temperature, arterial blood pressure, and heart rate are monitored 60 min prior to injection and during 24 h following injection. Each calf is receiving experimental injection one time. See the above for further specifications.
  • Each study week consisted of two study days. For each study week 20 calves are purchased. These calves will be at the test facilities for approximately 2 weeks before the operation period. Two calves served as a buffer in case of sickness or unexpected high or low weight gain in the first two weeks after the animals arrive at test facilities. The remaining 18 calves are operated and 16 are ultimately included in the study. The surplus of two operated calves is an extra measure in order to deal with sickness and unexpected high or low weight gain in the two-week period from operation to the study day.
  • the dihydrocapsaicin at day 3 was used to investigate continuous doses.
  • the calves were given the indicated doses until a stable temperature was reached; the reached temperature was then kept stable by administering 0.5 mg to 1.0 mg/kg/h.
  • the calves remained stable at the reached temperature for the duration of the experiment.
  • a reduction in core body temperature of 3.5 degree Celsius was reached for the last calf a reduction of 2.5 degree Celsius was reached.
  • Day 1-5 Each calf received a single intravenous bolus injection of 2 ml administered over 7-8 minutes followed by saline flush of 5 ml.
  • Day 6-7 Each calf will receive an initial intravenous bolus injection of 2 ml administered over 7-8 minutes, followed by one or several similar intravenous injections for up to 12 hours after the initial injection.
  • Blood samples will be taken before and after injection of compounds in order to examine PK/PD.
  • the specifics depend on a meeting with Xendo (www.xendo.dk) where the topic will be a tailor-made pharmacokinetic/pharmacodynamic model for the calf study.
  • Drug administration The compound investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection, alternatively as a continuous administration.
  • Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study.
  • the probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required readouts.
  • Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).
  • the minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose of compound or compound mixture.
  • Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 min- utes subsequently until 24 hours after drug administration.
  • Study 3 Each calf received a single intramuscular injection at variable doses.
  • Study 4-5 Each calf received a single intravenous bolus injection of 2 ml administered over 7-8 minutes followed by saline flush of 5 ml.
  • Blood samples will be taken before and after administration of compounds in order to examine PK/PD.
  • the specifics depend on a meeting with Xendo (www.xendo.dk) where the topic will be a tailor-made pharmacokinetic/pharmacodynamic model for the calf study.
  • Drug administration
  • the compounds investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection, alternatively as a continuous administration.
  • Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study.
  • the probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required readouts.
  • Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).
  • the minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose and administration form of compound.
  • Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration.
  • Fujishima M Hypothermia inhibits ischemia-induced efflux of amino acids and neuronal damage in the hippocampus of aged rats. Brain Res 2000; 884(1 ⁇ 2):23- 30.
  • KiI HY Zhang J, Piantadosi CA: Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab 1996; 16(1):100-106.
  • Pulsinelli W Pathophysiology of acute ischaemic stroke. Lancet 1992; 339(8792):533-536.

Abstract

The present invention relates to the use of a cannabinoid receptor agonist for use in induction of hypothermia in a human being for the prophylaxis and treatment of ischemia.

Description

Use of hypothermia inducing drugs
Field of invention
The present invention relates to the use of compounds for the induction of hypothermia for the prophylaxis and treatment of ischemia. Ischemia is the lack of oxygenated blood flow to various body parts and may result from apoplexia, cardiac arrest and asphyxia.
Background of invention Ischemia is the lack of oxygenated blood flow to various body parts and organs.
Cerebral ischemia is an ischemic condition where the brain or parts of the brain do not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various serious diseases such as stroke and cardiac arrest, or the result of arterial obstruction such as strangulation. Severe or prolonged cerebral ischemia will result in unconsciousness, brain damage or death.
The neuroprotective efficacy of induced hypothermia following or during ischemia of the brain is evident in experimental animal models of stroke [1-11]. In humans, two trials conducted in cardiac arrest patients have shown improved neurological out- come of inducing hypothermia [12;13]. The therapeutic hypothermia did not increase the complication rate in these two trials and the use of induced hypothermia in comatose survivors of cardiac arrest is now recommended internationally [14].
Hypothermia counteracts ischemic brain damage by several mechanisms: 1. Ischemia induces opening of the blood-brain barrier, a process that seems to be very sensitive to brain temperature [15]. This is evident from studies of tracers and their migration across the blood-brain barrier, in which hypothermia attenuates extravasation several hours after ischemia [16] and prevents vasogenic oedema [17]. 2. Reperfusion after brain ischemia results in the production of free radicals, which causes peroxidation and destruction of membrane lipids [18]. Hypothermia prevents the production of free radicals such as hydroxyl and nitric oxide during reperfusion after brain ischemia [19;20]. 3. Amino acids, such as glutamate, aspartate, and glycine, act as excitotoxic neurotransmitters by over stimulation of neurons in the vicinity of ischemic damage, which causes further injury. Hypothermia lowers the release and may even cause a more rapid reuptake of these transmitters [21-24]. Re- lease of excitotoxic neurotransmitters might also cause progressive neuronal death in the penumbra in stroke patients [22], and hypothermia after cerebral ischemia could attenuate this process.
4. During ischemia, cellular metabolism in the penumbra undergoes significant changes. As the neurons continue to fire, potassium ions flood into the extra- cellular space, calcium ions flow into the neurons leading to cytoskeletal degradation, and ATP concentrations fall as energy depletion continues [25]. Hypothermia reduces calcium influx and the subsequent breakdown of intracellular structures [26], improves potassium ion homoeostasis [27], and helps metabolic functions such as calcium or calmodulin-dependent protein kinase activity to recover [28;29].
5. By lowering of neutrophil and microglial activation after ischemia, hypothermia also has an anti-inflammatory effect [30;31].
6. Apoptosis and DNA changes are crucial stages in delayed neuronal death after transient cerebral ischemia [32]. Hypothermia directly inhibits apoptosis [33] and may also increase endogenous production of the anti-apoptotic protein Bcl-2 [34]. Hypothermia may even have effects at the DNA level: A slight lowering of brain temperature results in less DNA fragmentation [35] and less apoptosis [36].
Induction of hypothermia by lowering of the core temperature of the body has been attempted by mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel. However, these mechanical inducers of hypothermia have been shown to have considerable unwanted side effects. These side effects include shivering, serious infections and lung puncture. Shivering causes an increased exertion of the heart of the patient, and this will in some cases result in ischemia of the heart and thereby increased morbidity and mortality.
The regulation of the core temperature of the body by a pharmaceutical composition comprising a compound capable of inducing hypothermia would not only solve the problem of preventing the effects of ischemia, but also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.
Leker et al. [37] described that the cannabinoid HU-210 did provide hypothermia and protection against ischemic damages in Sprague-Dawley rats. However, Leker et al. observed hemodynamic and behavioural side effects due to the treatment in the rats, such side effects precluding the drug used in humans.
The results found by Leker et al. cannot be translated into treatment of humans due to a variety of reasons. Leker et al. themselves do state that the cannabinoid of their choice provides too serious side effects to be used for human treatment. Furthermore, according to Howlett et al. [42] with respect to cannabinoid receptors choice it is not possible to translate rat or monkey results to human results, since cannabinoid receptors are expressed differently in the different species accounting for the different effects seen when administering the same cannabinoid to various species. Herkenham et al. [43] also demonstrate that cannabinoid effects in humans and dogs differ.
Another reason for the variation observed may be the less than 100 % homology in cannabinoid receptors of the various species.
Furthermore, medical induction of hypothermia in animals having a body weight of 300 g differs significantly from induction of hypothermia in humans having an average body weight of 70-75 kg, i.e. a 250-fold difference in body weight and thus volume that has to be reduced in temperature when inducing hypothermia.
Cannabinoid-containing drugs have been administered to humans for the treatment of pain, however no reports of significant hypothermia observed in humans during such treatment has been described.
Summary of invention
The present inventors have found that it is possible to medically induce hypothermia in human beings by administration of a cannabinoid. Thus, the present invention relates to the induction of hypothermia in humans in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising a compound capa- ble of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue ischemia and anoxia. The inventors have found that such hypothermic effects can be obtained in humans as a result of compounds such as cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors.
Thus the present invention discloses the use of a compound for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof.
It is also an aspect of the present invention to provide a medicament comprising a compound capable of inducing hypothermia in an individual.
A kit of parts comprising the medicament as herein disclosed is yet an aspect of the present invention.
Furthermore, the use of a compound according for the preparation of a medicament for obviating the induction of hypothermia in an individual, is an aspect of the present invention.
Brief description of figures
Figure 1 : Plot of temperature curves
Figure 2: Plot of diastolic blood pressure.
Figure 3: Plot of temperature curves (Example 18; study 1) Dihydrocapsaicin.
Figure 4: Plot of temperature curves (Example 18; study 2) Dihydrocapsaicin. Figure 5:. Plot of temperature curves (Example 18; study 3) Dihydrocapsaicin.
Figure 6: Plot of temperature curves (Example 18; study 4) Delta-8-THC phosphate
Figure 7: Plot of temperatur.e curves (Example 18; study 5) HU-210.
Detailed description of the invention Definitions
Agonist: A cannabinoid receptor agonist is a cannabinoid or a cannabimimetic compound. Antagonist: A cannabinoid receptor antagonist is a substance capable of inhibiting the effect of a cannabinoid receptor agonist.
Alcohol: A class of organic compounds containing one or more hydroxyl groups (OH). In this context a saturated or unsaturated, branched or unbranched hydrocar- bon group sitting as a substituent on a larger molecule.
Alicyclic group: the term "alicyclic group" means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
Aliphatic group: in the context of the present invention, the term "aliphatic group" means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.
Alkyl group: the term "alkyl group" means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like.
Alkenyl group: the term "alkenyl group" means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as a vinyl group.
Alkvnyl group: the term "alkynyl group" means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds.
Amphiphil: substance containing both polar, water-soluble and nonpolar, water- insoluble groups.
Aromatic group: the term "aromatic group" or "aryl group" means a mono- or poly- cyclic aromatic hydrocarbon group.
Cannabinoid: Compound capable of binding to a cannabinoid receptor and isolated from or identical to a compound isolated from an organism such a plant or animal. In the present context any compound capable of binding a cannabinoid receptor.
Cannabimimetic: Compound capable of binding to a cannabinoid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a cannabinoid receptor.
Cyclic group: the term "cyclic group" means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group. Cycloalkenyl: means a monovalent unsaturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkenyl, lower alkoxy, lower haloalkoxy, alkenylthio, halo, haloalkenyl, hydroxyalkenyl, nitro, alkoxycarbonenyl, amino, alkenylamino, alkenylsulfonyl, arylsulfonyl, alkenylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkenylaminocarbonyl, arylaminocarbonyl, alkenylcarbonylamino and arylcarbonylamino.
Cycloalkyl: means a monovalent saturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylamino- sulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino.
Cationic group: A chemical group capable of functioning as a proton donor when a compound comprising the chemical group is dissolved in a solvent, preferably when dissolved in water.
Form a ring: means that the atoms mentioned are connected through a bond when the ring structure is formed.
Group: (Moiety / substitution) as is well understood in this technical area, a large degree of substitution is not only tolerated, but is often advisable. Substitution is anticipated on the materials of the present invention. As a means of simplifying the discussion and recitation of certain terminology used throughout this application, the terms "group" and "moiety" are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not allow or may not be so substituted. Thus, when the term "group" is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with O, N, or S atoms, for example, in the chain as well as carbonyl groups or other conventional substitution. Where the term "moiety" is used to describe a chemical compound or substituent, only an unsubstituted chemical material is intended to be included. For example, the phrase "alkyl group" is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc. Thus, "alkyl group" includes ether groups, haloal- kyls, nitroalkyls, carboxyalkyls, hydroxyalkyls, sulfoalkyls, etc. On the other hand, the phrase "alkyl moiety" is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like. The same definitions apply to "alkenyl group" and "alkenyl moiety"; to "alkynyl group" and "alkynyl moiety"; to "cyclic group" and "cyclic moiety; to "alicyclic group" and "alicyclic moiety"; to "aromatic group" or "aryl group" and to "aromatic moiety" or "aryl moiety"; as well as to "heterocyclic group" and "heterocyclic moiety". Heterocyclic group: the term "heterocyclic group" means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulphur, etc.).
Heterocyclyl means a monovalent saturated cyclic radical, consisting of one to two rings, of three to eight atoms per ring, incorporating one or two ring heteroatoms (chosen from N, O or S(O)0-2, and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino, or arylcarbonylamino.
Heteroaryl means a monovalent aromatic cyclic radical having one to three rings, of four to eight atoms per ring, incorporating one or two heteroatoms (chosen from nitrogen, oxygen, or sulphur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, aryl- aminocarbonyl, alkylcarbonlamino and arylcarbonylamino.
Hypothermia: Lowering of the body temperature below normal level. Ischemia: Restriction in blood supply with resultant dysfunction or damage of tissue. Ischemic tissue damage: Tissue damage due to ischemia.
Moieties of a particular compound cover group(s) or part(s) of said particular compound. Pharmaceutical composition: or drug, medicament or agent refers to any chemical or biological material, compound, or composition capable of inducing a desired therapeutic effect when properly administered to a patient. Some drugs are sold in an inactive form that is converted in vivo into a metabolite with pharmaceutical activ- ity. For purposes of the present invention, the terms "pharmaceutical composition" and "medicament" encompass both the inactive drug and the active metabolite.
Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.
The principle of the present invention is the use of cannabinoids and/or cannabimimetic compounds for induction of hypothermia, such as for alleviating the effects of ischemia, such as but not limited to tissue damaging effects of ischemia.
Ischemia
Ischemia is the reduction or abolition of blood supply to a tissue. The associated deficiency of oxygen and nutrients may lead to cell death (necrosis) in areas of the affected tissue. The damage induced by the lack of oxygenated blood in the brain occurs in two stages. First cellular metabolism is arrested due to lack of oxygen and some cells and tissue will die within minutes as a consequence hereof. Secondly a cascade of processes such as apoptosis is initiated and continues up to 12 hours after the event that initially induced the ischemic state has been abolished. The tissue damaged by the second cascade can be crucial and cause greater harm to the individual than the primary damage happening within the first minutes of ischemia.
In one embodiment, the current invention is aimed at correcting ischemia of the brain thereby minimizing the damage to the central nervous system. The invention does so by administering a drug to induce hypothermia in patients. The hypothermic effect is presumed to counteract ischemic damage by several mechanisms in the brain: Prevention of the blood-brain-barrier disruption that happens soon after ischemic onset that allows oedema formation from extravasation; Diminishing of the oxygen-based free-radical production that results from activation of microglia and other cell types; Reduction of the excitotoxic-neurotransmitter release that over- stimulates neighbouring neurons; Lowering of the metabolic rate and subsequent energy depletion; and anti-inflammatory action.
It is an object of the present invention to provide a compound capable of inducing hypothermia in an individual and further to provide the use of said compound for the production of a medicament for the treatment of ischemia in an individual.
Ischemia may occur under various circumstances; of special relevance to the present invention are the circumstances relating to cardiovascular diseases, asphyxia and traumatic brain injuries.
It is thus within the scope of the present invention to provide means for reducing the risk of ischemia as well as treating ischemia in an individual, under circumstances where ischemia is brought about by for example: cardiovascular diseases, asphyxia and traumatic brain injuries.
In a highly preferred embodiment, the compound of the present invention is administered to prevent or treat or treat and prevent tissue damaging effects subsequent or in conjunction with ischemia.
Cardiovascular diseases
Cardiovascular disease is the most common cause of death and of physical as well as mental impairment in the developed world. A similar development is seen in the rest of the world as it emulates the lifestyle of the Western hemisphere with its fatty diets, lack of exercise and increasing average lifespan.
The main causes of death and disability among cardiovascular diseases are myocardial infarction, acute coronary syndrome, cardiac arrest and stroke, but many less common cardiovascular diseases may be equally detrimental to the individual affected. These less common diseases include among others arterial aneurism, subarachnoid haemorrhage, arteriosclerosis or atherosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis. Each of the abovementioned diseases follow a course of events leading to ischemia, and are thus all of interest in relation to the present invention. Myocardial infarction (heart attack) is a result of an atherosclerotic plaque slowly building up in the inner lining of a coronary artery which then suddenly ruptures, partially or totally occluding the artery and preventing blood flow. Cardiac arrest is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively. Brain damage is likely to occur after 3-4 minutes without medical intervention, except in cases of hypothermia. Stroke is an acute neurological injury, lasting more than 24 hours, in which the blood supply to a part of the brain is interrupted, either by a clot in the artery or if the artery bursts. Arterial aneurism is a localized ballooning of an artery by more than 50% of the diameter of the vessel. Aneurysms most commonly occur in the arteries at the base of the brain and in the aorta. This bulge in an artery carries the risk of bursting and leading to internal hemorrhage. The larger an aneurysm becomes, the more likely it is to burst. Subarachnoid haemorrhage (SAH) is bleeding into the subarachnoid space surrounding the brain, i.e., the area between the arachnoid and the pia mater. It may arise due to trauma or spontaneously, and is a medical emergency, which can lead to death or severe disability even if recognized and treated in an early stage. Arteriosclerosis is a disease in which arterial walls harden over years or decades as a result of the formation of collagen and cal- cium deposits. Atherosclerosis is the most common subgroup of arterioscleosis, and is characterised by a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells ('foam cells') and promoted by low density lipoproteins (LDL; plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macro- phages by functional high density lipoproteins (HDL). Hypertension or high blood pressure is a medical condition wherein the blood pressure is chronically elevated. Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is a derangement that can contribute to many forms of disease, most notably cardiovascular disease. Arrhythmia is a group of conditions in which the muscle con- traction of the heart is irregular or is faster or slower than normal. Some arrhythmias are life threatening medical emergencies that can cause cardiac arrest and sudden death. Cardiomegaly is a medical condition wherein the heart is enlarged. It can often be associated with other serious medical conditions. Cardiomyopathy is the deterioration of the function of the myocardium (i.e., the actual heart muscle). Peo- pie with cardiomyopathy are at risk of arrhythmia and/or sudden cardiac death. Heart valve regurgitation, also known as heart valve insufficiency, is the abnormal leaking of blood through heart valves. Heart valve stenosis is a heart condition caused by the incomplete opening of a heart valve, typically the aortic valve or the mitral valve, impairing blood flow through the heart.
Each of the cardiovascular diseases mentioned, as well as others not mentioned, may cause ischemia of organs. This ischemia, whether of the brain, heart or other organs, may lead to death or impairment if not treated rapidly.
It is an object of the present invention to provide a compound for the production of a medicament for the treatment or prophylaxis of an individual suffering from or at risk of suffering from of ischemia due to cardiovascular diseases such as, but not limited to: myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hyperten- sion, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
Preferably, the medicament is for the treatment or prophylaxis of ischemia due to cardiac arrest, myocardial infarction, acute coronary syndrome, stroke, arterial aneu- risms, sub-arachnoid haemorrhage or angina pectoris.
All of the above-mentioned cardiovascular diseases require specific diagnostic tests and treatments. These tests and treatments, as specified for sudden cardiac arrest, stroke and heart attack in the below, may be carried out in conjunction with the ad- ministration of medicaments defined in this patent.
Sudden cardiac arrest victims may be subjected to early CPR, early defibrillation and early advanced care. Further tests and treatments may include cardiac catheterization, electrophysiologic tests, coronary artery bypass surgery, balloon angio- plasty or PTCA, antiarrhythmic medicine, implantable cardioverter / defibrillator, implantable pacemaker and heart transplant.
Depending on whether patients suffer an ischemic or hemorrhagic stroke, acute treatment may include clot-busters (e.g. tPA) or surgical intervention (e.g. aneurysm clipping, and endovascular procedures such as insertion of "coils"). Preventive treatment includes the administration of anticoagulants/anti-platelet. It may furthermore include carotid endarterectomy and angioplasty and/or stents.
Patients suffering a heart attack (myocardial infarction) may have one or several treatments and procedures done to survive and diagnose the condition: These include resuscitation (early CPR, early defibrillation, early advanced care), thrombolysis, coronary angioplasty (also known as Percutaneous Transluminal Coronary Angioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation), and coronary artery bypass graft surgery (CABG).
Asphyxia
Asphyxia (suffocation) is a common cause of death and of physical as well as mental impairment in perinatals, neonatals or newborns, children and adults of all ages. According to WHO (World Health Organization), the perinatal period commences at 22 completed weeks (154 days) of gestation (the time when birth weight is normally 500 g), and ends seven completed days after birth or delivery. The neonatal period is most often and herein defined as four weeks after birth; regardless of whether or not birth occurs prematurely. A premature infant is born after a gestation period of less than the normal time (about 266 days in the human).
Asphyxia can be divided into perinatal asphyxia and non-perinatal asphyxia. Perinatal asphyxia is the medical condition resulting from deprivation of oxygen to a newborn infant long enough to cause apparent harm. It results most commonly from a drop in maternal blood pressure or interference during delivery with blood flow to the infant's brain, but may also stem from umbilical cord entanglement. This can occur due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation. Extreme degrees of asphyxia can cause cardiac arrest and death. Hypoxic damage can occur to most of the infant's organs, but brain damage is of most concern and perhaps the least likely to quickly and completely heal. In severe cases, an infant may survive, but with damage to the brain manifested as developmental delay and spasticity. In one embodiment of the present invention, the compound is administered to the infant while it resides within the uterus and/or birth canal, i.e. as soon as asphyxia is determined. Asphyxia may be determined for ex- ample by measuring the pH of the blood of the infant. Non-perinatal asphyxia is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. Common causes hereof include drowning, strangulation and exposure to toxic gasses. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs most sensitive to hypoxia first, such as the brain, hence resulting in cerebral hypoxia. The absence of effective remedial action will very rapidly lead to unconsciousness, brain damage and death.
Each kind of asphyxia mentioned, as well as others not mentioned, may cause ischemia of organs and is thus an object of the present invention.
It is an aspect of the present invention to provide a compound for the treatment of an individual suffering from ischemia due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
Treatment by administration of the cannabinoid receptor agonists defined in this patent may be carried out in conjunction with test and treatments of diseases and accidents including asphyxia (perinatal asphyxia, and non-perinatal asphyxia includ- ing, but not limited to, drowning, strangulation and exposure to toxic gasses). Such diseases and injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
Traumatic brain injury Traumatic brain injury (TBI) is a common cause of death and of physical as well as mental impairment throughout the world. TBI may result from accidents, be due to violence or be self-inflicted.
Traumatic brain injury, also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage. TBI can result from a closed head injury or a penetrating head injury. Parts of the brain that can be damaged include the cerebral hemispheres, cerebellum, and brain stem. Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain. Outcome can be anything from complete recovery to permanent disability or death. Ischemia is a significant factor contributing to the neurological damage frequently seen in patients suffering from TBI.
It is an aspect of the present invention to provide a compound for the treatment of an individual suffering from ischemia due to traumatic brain injury.
Treatment by administration of the cannabinoid receptor agonists defined in this patent may also be carried out in conjunction with test and treatments in relation to traumatic head injury (closed head injury or penetrating head injury). Such injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
Elevated body temperature
Individuals suffering from elevated body temperatures due to an infection, ischemic damage, heat- or sunstroke or the like will also benefit from the administration of the compound of the present invention.
Fever (also known as pyrexia, or a febrile response) is a frequent medical symptom that describes an increase in especially internal body temperature to levels above normal. Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, meaning that the temperature is raised by the body in a controlled manner. Fever is a symptom of many different diseases such as infectious diseases, immunological diseases, cancers, metabolic disorders and more.
Hyperpyrexia is an extreme degree of fever, where the set body temperature is elevated greater than or equal to 41 degree Celsius. Such a high temperature is considered a medical emergency and requires immediate medical attention.
Fever and hyperpyrexia differ from hyperthermia. Hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production or insufficient thermoregulation, or both. Hyperthermia may be caused by heat- or sunstroke, exposure, dehydration and more. A special variant of hyperthermia is malignant hyperthermia which may arise due to administration of general anesthesia. It is an object of the present invention to provide a compound for the induction of hypothermia and/or lowering of body temperature in an individual with an elevated body temperature, such as an individual suffering from fever, hyperpyrexia and/or hyperthermia.
Furthermore it is an object of the present invention to induce hypothermia in an individual in whom the initial temperature prior to treatment is above the normal temperature for said individual. Such an individual may be an individual suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other. It is common that individuals suffering from a heart attack or stroke e.g. suffering from ischemia develop a fever and it is an object of the present invention to reduce the fever and induce hypothermia in such an individual. An Individual otherwise suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other may benefit by administration of the compound of the present invention to reduce the elevated temperature to normal; that is to within 35 to 39 degree Celsius, such as to within 35.5 to 38.5 degree Celsius, such as to within 36 to 38 degree Celsius, such as to within 37 degree Celsius +/- 0.6 degree Celsius, or to reduce their body temperature further to hypothermic levels as described above.
An individual with elevated body temperatures may have any temperature considered to be above normal, which is any temperature above 36 degree Celsius. The temperature of the individual in need of treatment according to the present invention may thus be a temperature of above 36 degree Celsius, such as above 36.5 degree Celsius, such as above 37 degree Celsius, such as above 37.5 degree Celsius, such as above 38 degree Celsius, such as above 38.5 degree Celsius, such as above 39 degree Celsius, such as above 39.5 degree Celsius, such as above 40 degree Celsius, such as above 40.5 degree Celsius, such as above 41 degree Celsius such as above 41.5 degree Celsius such as above 42 degree Celsius, such as above 42.5 degree Celsius, such as above 43 degree Celsius, such as above 43.5 degree Celsius and higher.
Pre-operative administration
The outcome of several types of surgery is improved if the individual undergoing the surgery is placed under hyperthermia prior to or during the surgery. Examples of such operations are neurosurgeries, thorax surgeries and especially cardiac surger- ies. The lowering of the body temperature slows down the metabolic rate and thus reduces the need for e.g. oxygen during the surgery thus giving more time to the surgeon to perform complicated procedures.
It is an object of the present invention to provide a compound for the induction of hypothermia in an individual prior to surgery. The compound of the present invention is preferably administered pre-operatively. It is also an aspect of the invention to provide a compound for the induction of hypothermia in an individual in need of surgery prior to and/or during transportation of said individual.
A specific procedure in which it is of interest to lower the body temperature is in the case of organ transplants, where it is beneficial that the organs to be transplanted are cooled prior to removal and especially prior to and during transport before transplantation into the recipient. It is furthermore of interest for the preservation of or- gans, tissues, and cells that hypothermia may be induced in these by induction of hypothermia in the individual from which these are taken. Either prior to or after removal, stasis (very low or no detectable metabolic rate) may be induced by further administration of the compounds of the present invention. Therefore it is an object of the present invention to administer a compound herein disclosed for the induction of hypothermia in an individual and in the organs, tissues and cells of said individual, prior to the excision of the organs, tissues and cells for the purpose of transplantation, implantation, cryopreservation or other.
Hypothermia Hypothermia is the lowering of the core temperature of the body below normal level. Normal body temperature in an adult human measured rectally over 24 hours is 37 degree Celsius +/- 0.6 degree Celsius and is thus variable between individuals, and over time within the individual. Hypothermia as a medical condition is usually defined as the effects seen on the body once the core temperature drops below 35 degree Celsius. It may become critical, if the body temperature falls below 32 0C. In the present application hypothermia is defined as the lowering of the core body temperature below normal levels. This implies that any temperature below the normal core body temperature of the specific individual with its natural variations at the given point in time of the day, or period, herein is defined as being hypothermic. In particular, hypothermia is a temperature below 35.5 0C, such as below 35 0C, such as below 34.5 0C, such as below 34.0 0C.
Body temperature may be measured by a variety of means; by mercury, electronic or plastic strip thermometers on different areas of the body such as the forehead, mouth, armpit, ear or rectum. It is presently understood, that the temperature referred to in the present application is the core body temperature, and that some of the above methods of measurement will indicate a different temperature than the core temperature.
It is of importance, that induction of hypothermia in an individual can follow a predictable course and be responsive to the dose in which the compound capable of inducing hypothermia is administered. The induction of the hypothermic condition may be rapid or slow depending on the situation of the individual in need of treatment. Also depending on the severity of the ischemic condition, it is of interest to provide a medicament for retaining the individual in the hypothermic state for variable durations of time. A single compound may be used depending on dosage within a range of temperatures or for the induction of hypothermia to a specific temperature. A combination of compounds may furthermore be used for an initial rapid decrease in core body temperature, and the subsequent maintenance of the reached temperature over a prolonged period. It is furthermore beneficial if the hypothermic state can be reversed in a rapid and controlled fashion either slowly or rapidly depending on the status of the individual.
It is thus an object of the present invention to provide a compound for the production of a medicament for the induction of hypothermia in an individual suffering from ischemia, wherein the compound is capable of inducing hypothermia to any range of temperatures between 37 and 31 degree Celsius, such as between 36.5 and 31.5 degree Celsius, such as between 36 and 32 degree Celsius, such as between 35.5 and 32.5 degree Celsius, such as between 35 and 33 degree Celsius, such as between 34.5 and 33.5 degree Celsius. The ranges may furthermore be between 37 and 34 degree Celsius, such as between 36.5 and 34.5 degrees, such as 36 and 35 degrees, alternatively between 34 and 31 degree, such as between 33.5 and 31.5 degree, such as 33 and 32 degree Celsius, alternatively between 36 and 33 degree or 35 and 32 degree Celsius. Preferably, the compound of the present invention is capable of inducing hypothermia in the range of between 36 to 32 degree Celsius, more preferably between 35 and 33 degree Celsius.
It is also an object of the present invention to provide a compound capable of inducing hypothermia to a specific temperature such as 37 degree Celsius, 36.5 degree Celsius, 36 degree Celsius, 35.5 degree Celsius, 35 degree Celsius, 34.5 degree Celsius, 34 degree Celsius, 33.5 degree Celsius, 33 degree Celsius, 32.5 degree Celsius, 32 degree Celsius, 31.5 degree Celsius or 31 degree Celsius or most preferably, the compound of the present invention is capable of inducing hypothermia to any of the above specific temperatures within a range of +/- 0.5 degree Celsius, such as the range thus being between +/- 0.4 degree Celsius, such as between +/-0.3 degree Celsius, such as between +/- 0.2 degree Celsius, or such as between +/- 0.1 degree Celsius. The temperature range or specific temperature a given compound is capable of inducing is herein also referred to as the target temperature of the combination of compounds and/or the medicament comprising the combination of compounds.
Thus it is an object of the present invention to lower the core body temperature of an individual with about 10 degree Celsius or less such as 9 degree Celsius, 8 degree, 7 degree, 6 degree, 5 degree, 4 degree, 3 degree, 2 degree or 1 degree Celsius. By "about 10 degree" is meant 10 +/- 0.5 degree Celsius and likewise for 9 degree and so on. Preferably, the temperature is lowered with 5 degree Celsius or less, such as 4 degree, 3 degree, 2 degree or 1 degree Celsius.
When inducing hypothermia in individuals suffering from ischemia the target temperature may be of greater interest than the specific amount of degrees of reduction in core body temperature a given compound or combination of compounds may induce. Depending on the severity of the ischemic insult, the core body temperature of the individual may already be decreased prior to treatment due to reduced blood flow. Typically, the temperature of the individual may be between 35 and 36 degree Celsius. Therefore the compound of the present invention may not only induce hypothermia in regards to lowering the core body temperature a certain amount of degrees, the compound or combination of compounds of the present invention are furthermore capable of reaching a predetermined target temperature. The target temperature of the compounds or combination of compounds of the present invention is: 32 to 34 degree Celsius
Preferably, the person in need of the hypothermic treatment e.g. the administration of a compound of the present invention suffers from ischemia, or is in need of surgery such as neurosurgery or cardiac surgery, e.g. the compound is administered pre-operatively.
It is also an object of the present invention to provide a compound capable of inducing hypothermia / reducing body temperature to a specific temperature such as 39 degree Celsius, 38.5 degree Celsius, 38 degree Celsius, 37.5 degree Celsius, 37 degree Celsius, 36.5 degree Celsius, 36 degree Celsius, 35.5 degree Celsius, 35 degree Celsius, or most preferably, the compound of the present invention is capable of inducing hypothermia to any of the above specific temperatures within a range of +/- 0.5 degree Celsius, the range thus being between +/- 0.4 degree
Celsius, such as between +/-0.3 degree Celsius, such as between +/- 0.2 degree Celsius, or such as between +/- 0.1 degree Celsius.
An aspect of the present invention regards the treatment of an individual in need thereof by the use of a compound of the present invention for the induction of hypothermia. The individual in need of the treatment is an individual suffering from conditions that are benefitted by the induction of hypothermia and/or reduction in body and/or brain temperature. Such an individual include but are not limited to: an individual suffering from or at risk of suffering from ischemia, elevated body temperatures due to fever, hyperthermia, hyperpyrexia, malign hyperpyrexia or are in need of treatment, such as but not limited to surgery, wherein the outcome of the procedure or the procedure itself is benefitted by a reduction in temperature of the individual undergoing the treatment and/or surgery.
Cannabinoids
Cannabinoids and cannabimimetic compounds are a group of chemicals which activate the body's cannabinoid receptors, CB1 and CB2. Before other types were discovered, the term referred to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological ef- fects. Cannabinoids are generally grouped into five classes based mainly on chemical composition and in part on origin:
1. The eicosanoids, also referred to as endocannabinoids are produced in the bodies of humans and other animals 2. Classical cannabinoids, a group which includes natural cannabinoids found in larger or smaller amounts in the hemp plant Cannabis sativa.
3. Non-classical cannabinoids
4. Aminoalkylindoles
5. Other compounds that are capable of binding cannabinoid receptors, but fall out of the four previous categories.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence. Cannabinoids and cannabimimetic compounds (CB1/CB2 agonists) have furthermore received interest as putatively neuroprotective substances.
Several mechanisms have been proposed to account for the neuroprotective effects of various cannabinoids and cannabimimetic substances such as prevention of excitotoxicity by cannabinoid CB1 -mediated inhibition of glutamatergic transmission, reduction of calcium influx, anti-oxidant activity, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, induction of phosphorylation of extracellular regulated kinases and the expression of transcription factors and neutrophins, lowering of the cerbrovasoconstriction and induction of hypothermia.
Any compound which can be defined as a cannabinoid or cannabimimetic compound falls within the scope of the present invention. The two terms cannabinoids and cannabimimetic are used interchangeably herein. Cannabinoids are generally termed such due to their ability to bind one or more of the cannabinoid receptors CB1 and CB2.
Receptors
There are currently two known types of cannabinoid receptors, CB1 and CB2, which are common in animals, and have been found in mammals, birds, fish, and reptiles.
CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the antiinflammatory and possible other therapeutic effects of cannabis.
Researchers have noted that the behavioural effects, including hypothermia, seen when introducing animals to cannabinoids seems to be due to other factors besides CB1 receptor stimulation [37;40]. Inducing hypothermia by cannabinoids is therefore not solely equivalent to stimulating the CB1 receptor. Furthermore, there is evidence in the literature for other receptors than CB1 and CB2 as recipients of the cannabinoid ligands.
The receptors to which the cannabinoids and cannabimimetic compounds of the present invention may bind includes, apart from CB1 and CB2: a third CB receptor, herein termed CB3, GABA (gamma-aminobutyric acid) receptors, the NMDA (N- methyl-D-aspartate) receptor, the 5-HT(1 A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR) and TRPV1 (transient receptor potential vanilloid 1). It is furthermore within the scope of the invention that the compounds of the invention may bind CB1 , CB2 or CB3 co-receptors. Compounds capable of bind- ing any of the above-mentioned receptors thus fall within the scope of the present invention.
Structure The cannabinoids of this application are, based on their structure, categorized as follows: classic cannabinoids, non-classic cannabinoids, aminoalkylindoles, eicosanoids (endogenous cannabinoids) and other compounds that fall out of the classification. Compounds belonging to any of these categories fall within the scope of the present invention.
It is within the scope of the invention that the compounds of the invention are capable of inducing hypothermia in an individual.
It is furthermore within the scope of the invention that the compounds of the invention are capable of binding a cannabinoid receptor.
Accordingly, in the broadest aspect the present invention concerns the use of a compound comprising a structure of one of the general formulas illustrated in the below. In these illustrations R is a chemical bond or a chemical moiety as defined in the above. R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1-4)-alkyl, heterocyclyl-(C1. 4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, phenyl, amine (NH), halogen, substituted lower alkyl or alkyl such as (C1-Cx) any of which may be further substituted one or more times with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, sulphate, phosphate, halogen or further substituted by fluoride, sulphate, phosphate, methyl, dimethyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryHC^)- alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, dicycloalkyl, tricycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, nitro, halogen or alcohol, and wherein x is an integer of from 1 to 30, and of which any of the mentioned substituents capable thereof may form a ring with another R. R may furthermore be a chemical bond, or a pharmaceutically acceptable addition salt or hydrate thereof. Phosphate resides have been implicated in the reduction of toxicity of certain cannabinoids without altering their hypothermic effect. It is therefore an object of the present invention that any of the compounds may carry one or more phosphate groups bound as phosphate esters.
For each general formula, a more specific choice of substituent for a given R is listed along with along with a preferred and a more preferred list of substituent groups.
The present invention concerns the use of a compound such as a classic or non- classic cannabinoid comprising the general formula (I):
Figure imgf000024_0001
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate and more preferably is C, optionally substituted with H, OH, OCH3 or phosphate and
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C1-Cx), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, fluoride, phenyl, phosphate, and more preferably is C substituted with C, O, OSO2, alkyl such as (C3- C11) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1- Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl and wherein x is an integer of from 1 to 20 and
- wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halo- gen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, methyl, phenyl, diheterocycle, amine (NH), halogen, substituted lower alkyl, aryl, lower alcohol, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, preferably is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or more times with methyl, diheterocycle, lower alcohol, alkyl or phosphate more preferably is C which may be substituted with C, O, N, OH, phosphate, any of which may be substi- tuted one or more times with C, ethyl, methyl, phosphate, diheterocycle, lower alcohol, alkyl such as (C1-C2) wherein C2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate and
- wherein R4 is selected from the group of: C, H, S, N, O, optionally substituted with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl- (C1.4)-alkyl, heteroaryl-(C1-4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, substituted lower alkyl, alkyl such as (C1- Cx) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1- Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1-4)-alkyl, hetero- cyclyl-(C1.4)-alkyl, cycloalkylalkyl, dicycloalkyl, tricycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, (alcohol) and preferably is C, H, N, O optionally substituted with alkyl, alkenyl, alkynyl, alcohol, phenyl, di- phenyl, dicycloalkyl, tricycloalkyl, cycloalkenyl any of which may bond with R1 or R3 forming a ring, optionally further substituted with one or more alkyl, alkenyl, alkynyl, OH, and more preferably is C, H, (C1-Cy), dicycloalkyl, or tricycloalkyl, cycloalkenyl any C of which may bond with R1 or R3 forming a ring, and optionally is substituted with methyl, dimethyl, phenyl, diphenyl, optionally further substituted with alkyl and/or OH and wherein x is an integer of from 1 to 15 and y is an integer of from 1 to 8.
Preferably, the present invention concerns the use of a compound comprising the general formula (I) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C 1-CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or more times with methyl, diheterocycle, lower alcohol, alkyl or phosphate, when R4 is C, H, N, O optionally substituted with alkyl, alkenyl, alkynyl, alcohol, phenyl, diphenyl, dicycloalkyl, tricycloalkyl, cycloalkenyl any of which may bond with R1 or R3 forming a ring, optionally further substituted with one or more alkyl, alkenyl, alkynyl or OH.
Most preferably, the present invention concerns the use of a compound comprising the general formula (I) wherein R1 is C, optionally substituted with H, OH, OCH3 or phosphate, when R2 is C substituted with C, O, OSO2, alkyl such as (C3-C11) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted with C, ethyl, phosphate, alkyl such as (C1-C2) wherein C2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate when R4 as defined in claim 8 is C, (C1 -C8) any C of which may bond with R3 and optionally is substituted with methyl, dimethyl, phenyl, diphenyl optionally further substituted with an alcohol and wherein x is an integer of from 1 to 15.
The present invention also concerns the use of a compound such as a classic or non-classic cannabinoid comprising the general formula (II):
Figure imgf000027_0001
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alky!, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with the C in the ring next to R5, optionally further substituted one or more times with C, S, N, O, OH, phenyl, phosphate, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-4)- alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate and more prefera- bly is C, optionally substituted one or more times with H, O, OH, OCH3 or phosphate and
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phos- phate, heterocycloalkyl, cycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C1-Cx), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl, phosphate, and more preferably is C substituted with C, O, OSO2, alkyl such as (C3-C11) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl and wherein x is an integer of from 1 to 15, and
- wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may connect with R4 and preferably is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 and more preferably is O, OH, NH, optionally connecting with R4 thus forming a ring and
- wherein R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halo- gen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylal- kyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may connect with R3 and preferably is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, phenyl, optionally substituted with OH, methyl, dimethyl any of which may connect with R3 and more preferably is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn and - wherein R5 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with R1 , optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1-4)-alkyl, heterocy- clyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, phosphate or nitro, and preferably is C, N, O, option- ally substituted with C, O, CH2OH, methyl, dimethyl, alkyl, alkenyl, alkynyl, phenyl, phosphate and more preferably is C, CO, optionally substituted with C, methyl, rπe- thyn (CH2), optionally substituted with CH20H.
Preferably, the present invention concerns the use of a compound comprising the general formula (II) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C1-CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 thus forming a ring, when R4 is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, phenyl, optionally substituted one or more times with OH, methyl and/or dimethyl any of which may connect with R3, when R5 is C, N, O, optionally substituted with C, O, CH20H, methyl, dimethyl, al- kyl, alkenyl, alkynyl, phenyl or phosphate.
Most preferably, the present invention concerns the use of a compound comprising the general formula (II) wherein R1 is C, optionally substituted with H, OH, OCH3 or phosphate when R2 is C substituted with C, O, OSO2, alkyl such as (C3-C8) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is O, OH, NH, optionally connecting with R4, when R4 is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn, when R5 is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH2OH and wherein x is an integer of from 1 to 15. In relation to the classic and non-classic cannabinoids and cannabimimetic compounds illustrated here by the general formulas (I) and (II), the presence of a phenolic hydroxyl group seems to play an essential role for ensuring high affinity binding of the compounds to the cannabinoid receptors.
An additional element of importance for especially CB1 receptor recognition is the side chain of R2. It is preferably a lipophilic carbon chain comprising from 1 to 15 carbon atoms, preferably from 3 to 1 1 carbon atoms. It may have any number and type of substituents, especially methyl and/or dimethyl groups. The methyl groups are preferably close to the phenol group, as this appears to induce the greatest effect of the drug. Interestingly, it appears that shorter side chains increase the intensity and decrease the duration of the activity of the compounds.
The present invention concerns the use of a compound such as an eicosanoids or other cannabinoid compound comprising the general formula (III):
R1 s R2
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryl-(Ci.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is (CI-Cx) is saturated or unsaturated and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N and wherein x is an integer of from 1 to 30, more preferably is (C1-CY), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N and wherein Y is an integer of from 15 to 21 and
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halo- gen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1^)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, OCH3, substituted lower alkyl, aryl, heterocy- clyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl, OCH3, and more preferably is N, O, NH2 optionally substituted with C, CH20H, CH(CH2)2, C2H4, C3H6, optionally further substituted one or more times with NH2, OH, CH2OH, CH2CI, phenyl, CH3 and/or OCH3.
Preferably, the present invention concerns the use of a compound comprising the general formula (III) wherein R1 is (CI -Cx) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl or OCH3 and wherein x is an integer of from 1 to 30.
Most preferably, the present invention concerns the use of a compound comprising the general formula (III) wherein R1 is (C1-Cx), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N when R2 is N, O, NH2 optionally substituted with C, CH2OH, CH(CH2)2 (cyclopropane), optionally further substituted one or more times with CH20H, CH2CI and wherein x is an integer of from 1 to 21.
The present invention concerns the use of a compound such as an aminoalkylindole or other cannabinoid compound comprising the general formula (IV):
Figure imgf000031_0001
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-fd^-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(CiJt)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH, phosphate and more preferably is C, substituted with O, further substituted with methyl and
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, het- eroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may bond with R3, and preferably is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3 and more preferably is C, substituted with O, further substituted with C optionally bond forming with R3 and
- wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci.4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may bond R2 and preferably is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2 and more preferably is (CI-Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or morpholine and any of which may bond R2 and
- wherein R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1-4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, N, O optionally substituted with C, N, O, OH, lower al- kyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O, OH, phenyl, diphenyl, morpholino, and halogen, and more preferably is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
Preferably, the present invention concerns the use of a compound comprising the general formula (IV) wherein R1 is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH or phosphate, when R2 is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3, when R3 is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2, when R4 is C, N, O optionally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O, OH, phenyl, diphenyl, morpholino, and/or halogen.
Most preferably, the present invention concerns the use of a compound comprising the general formula (IV) wherein, wherein R1 is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI-Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or mor- pholine when R4 is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
Examples of compounds Examples of cannabinoid or cannabimimetic compounds specially relevant for the present invention include, but is not limited to classic cannabinoids such as (names in parenthesis are alternative names): delta-9-THC (Tetrahydrocanna-binol), delta-8- THC, delta-8-THC phosphate, Cannabinol (CBN), Cannabidiol (CBD), Cannabidiol- type CBD, Cannabidivarin (CBDV), Cannabichromene-type CBG, Cannabigerol-type CBG, Tetrahydrocanna-bivarin (THCV, THV), Tetrahydrocanna-binol- and cannabinol-type THC or CBN, Iso-Tetrahydro-cannabinol-type iso-THC, Cannabielsion-type CBE, Cannabicyclo l-type CBL, Cannabicitran-type CBT, HU- 308, JWH-133, JWH-139, JWH-051 , L-759633, L-759656, HU-210 ((-)-H-OH-delta- 8-tetrahydrocannabinol-dimethylheptyl), HU-211 (Dexanabinol, 7-hydroxy-D6- tetrahydrocannabinol 1 ,1-dimethylheptyl), Desacetyl-L-nandrolol, Nabilone and Levonantradol, non-classic cannabinoids such as: CP-55940, CP55244 and CP47497, aminoalkylindoles such as: R(+)WIN55212, S(-)WIN-55213, JWH-015 and L-768242, eicosanoids / endogenous cannabinoids such as: Anandamide (arachidonyl ethanolamine), 2-Arachidonyl-glycerol (2-AG, Noladin ether), Palmitoylethanol-amine, Virodhamine (O-arachidonoyl-ethanolamine), Palmitoyl ethanolamide, Oleamide, other cannabinoid compounds such as: Arvanil, Metanandamide, ACEA, ACPA, BAY 38-7271 (also known as KN38-7271) and O- 1812. Phosphate and/or salt derivatives of these compounds are especially relevant for the present invention.
Examples of especially relevant cannabinoid or cannabimimetic compounds are anandamide, delta-9-THC, delta-8-THC, cannabidiol, HU-210, BAY 38-7271 , WIN 55,212 and CP55940 and the phosphate and/or salt derivatives of these.
Preferred cannabinoid and/or cannabimimetic compounds
The compounds of the present invention may apart from inducing hypothermia, induce secondary effects or have other characteristics. These may be related to the cannabinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any adverse psychotropic effects. The compound may furthermore have analgesic, anti- convulsive, anti-inflammatory, anti-anxiety, anti-nausea, pulse-lowering and blood- pressure modifying effects. Of these, it is preferable that the compound has analgesic effects. Furthermore, a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
A preferred compound of the present invention is a compound capable of binding a cannabinoid receptor, such as CB1 , thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic.
Examples of preferred cannabinoid or cannabimimetic compounds are anandamide, delta-9-THC, delta-8-THC, cannabidiol, HU-210, BAY 38-7271 , WIN 55,212 and CP55940 and the phosphate derivatives of these. Most preferred is HU-210 and the phosphate derivate hereof, HU-210- phosphate, and delta-8-THC and its phosphate derivate, delta-8-THC-phosphate as well as the salt derivate: disodium delta-8-THC- phosphate.
Antagonists to cannabinoid and cannabimimetic compound function
It is an object of the present invention to provide compounds that are capable of obviating the effect of the compounds that induce hypothermia. These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the cannabinoids or cannabimimetic compounds herein described in binding to their receptors. The purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual. Examples of antagonists include but are not limited to: Rimonabant (SR141716), Acomplia, SR147778, SR141716A, SR144528, CP-272,871 , NIDA-41020, LY320135, AM251 , AM281 , AM630, WIN56098 and WIN54461.
Novel use of compounds
Cannabinoids and cannabimimetic compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the induction of hypothermia in an individual.
Medicament
The induction of hypothermia by any of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising at least one of said compounds. The medicament of the present invention is thus for the induction of hypothermia in an individual for the treatment and/or prophylaxis of ischemia in said individual.
It is an aspect of the present invention to provide a medicament comprising a compound capable of inducing hypothermia in an individual in need thereof.
It is also an aspect of the present invention to provide a medicament comprising a compound for prophylactic and/or therapeutic applications.
It is further an aspect of the present invention to provide a medicament comprising a compound for therapeutic applications.
It is an aspect of the present invention to provide a medicament comprising a compound capable of inducing hypothermia in an individual in need thereof of between 32 and 36 degree Celsius.
It is also an aspect of the present invention to provide a medicament comprising a compound wherein at least one compound induces hypothermia rapidly.
In another aspect the present invention provides a medicament comprising a com- pound wherein at least one compound induces hypothermia slowly. In a further embodiment the present invention provides a medicament comprising a compound and a further active ingredient selected from the group of: analgesics, opioids, GABAs and adrenergic antagonists.
Pharmaceutical composition
Whilst it is possible for the compounds or salts of the present invention to be administered as the raw chemical, it is preferred to present them in the form of a pharmaceutical formulation. Accordingly, the present invention further provides a pharma- ceutical formulation, for medicinal application, which comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, as herein defined, and a pharmaceutically acceptable carrier therefore.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise the compounds of the invention or its pharmaceutically acceptable salt or a crystal form thereof as the active component. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid car- rier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
The compounds of the present invention may be formulated for parenteral admini- stration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
Oils useful in parenteral formulations include petroleum, animal, vegetable, or syn- thetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulfosuccinates, (c) non-ionic detergents such as, for example, fatty amine oxides, fatty acid alkanola- mides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-.beta.-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more non-ionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. It is an object of the present invention that the compounds described herein may be solubilized in water, fractionated coconut oil or Tween, such as Tween 80 at any percentage. Preferably, HU-210 is formulated in fractionated coconut oil and delta-8- THC is formulated in water.
Thus, in one embodiment the medicament of the present invention comprises a pharmaceutically acceptable carrier.
Pharmaceutically acceptable salts Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating dis- eases.
Pharmaceutically acceptable salts are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.
The compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
A pharmaceutically acceptable salt means any salt of the compounds mentioned. In particular, it means a pharmaceutically acceptable acid addition salt. Pharmaceuti- cally acceptable acid addition salts of the compounds include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydro- bromic, hydriodic, hydrofluoric, phosphorous and the like, as well as the salts derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aro- matic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sul- phate, pyrosulphate, bisulphate, sulphite, bisulphite, nitrate, phosphate, monohydro- genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesul- fonate, and the like.
βH An aspect of the present invention regards the pH of the medicament. The pH of the medicament depends on the administration form, as the pH of the medicament preferably is suitable for the route of administration chosen. An embodiment of the present invention comprises a medicament wherein the pH of the composition is between pH 5 and pH 9, such as between pH 5.5 and 8.5 such as between pH 6 and 8, such as between pH 6.5 and 7.5. Most preferably the pH of the medicament is in accordance with the route of administration and the tissue to which the medicament is administered.
Thus, in an embodiment the present invention provides a composition comprising a compound, wherein the pH of the composition is between pH 5 and pH 9.
Indications
The invention provides compounds for the production of a medicament for the treatment of ischemia in an individual. Ischemia may arise due to various circumstances and thus it is an object of the present invention to treat ischemia arising from a plurality of medical indications.
These indications include, but are not limited to, cardiovascular diseases such as myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury. Thus, it is an aspect of the present invention to provide compounds for the induction of hypothermia in an individual suffering from or at risk of suffering from ischemia.
Individuals at risk of suffering from ischemia are often individuals who have previ- ously suffered from an event that was capable of or did induce ischemia such as a heart attack, stroke or other. These individuals may benefit from having rapid access to pills, capsules, ampoules, pre-loaded syringes, suppositories or other administration forms of the medicaments of the present invention for self-administration. It is envisioned that these individuals at the onslaught of a new ischemic attack self- administer a dose of the compounds of the present invention prior to receiving medical aid by medical professionals. This is of relevance, as the faster the temperature drops, the better the chances of reducing the detrimental effects of the ischemic attack.
It is also an aspect of the present invention to provide compounds for the prophylaxis and/or treatment of ischemia in connection with cardiovascular diseases, asphyxia and/or traumatic brain injuries.
In one embodiment compounds of the present invention are used alone or in combi- nation to treat adverse effects of ischemia in the kidney.
It is also an aspect of the present invention to provide prophylaxis and/or treatment of ischemia or tissue damaging effects occurring during or after ischemia in the kidney or nephroischemia.
In one embodiment, the present invention provides compounds for treating effects of ischemia, wherein the ischemia is due to cardiovascular diseases such as myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hyper- cholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
Another group of indications are the situations where an individual has an increased body temperature such as fever, hyperpyrexia, hyperthermia or other. It is an aspect of the present invention to provide compounds for the purpose of inducing hypothermia and/or lowering the body temperature of these individuals.
It is furthermore an aspect of the present invention to provide means for selectively inducing hypothermia in either the brain or the body or both simultaneously. This is of relevance, as a severe stroke is known to cause an increase in brain temperature, often subsequently followed by an increase in body temperature. Thus it is an aspect of the present invention to induce hypothermia in the brain without, as far as it is physically possible, inducing hypothermia in the body, just as it is an aspect of the present invention to induce hypothermia in the body without, as far as it is physically possible, inducing hypothermia in the brain. Likewise it is as often stated herein an aspect of the present invention to induce hypothermia and/or lower the body temperature of an individual in need thereof.
In a further embodiment, the present invention provides compounds for treating effects of ischemia, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
Target temperature and peak effect The target temperature of the medicament is the core body temperature that can be reached upon administering the medicament according to the present invention as prescribed according to potency, dosage and so on. Various ranges and specific hypothermic / reduced core body temperatures that fall within the scope present invention are equal to the temperatures that the compound itself may induce as listed in the section on hypothermia.
An embodiment of the present invention is thus a medicament capable of inducing hypothermia below 36 0C, such as below 35.5 °C, such as below 35 0C, such as below 34.5 0C, such as below 34.0 0C, such as below 33.5 0C, such as below 33.0 0C, such as below 32.5 "C, such as such as below 32.0 0C. The medicament may lower the core body temperature to fall in the range of between 36 and 31 degree Celsius, preferably between 35 and 32 degree Celsius, such as between 34 and 32 degree Celsius. The compounds of this invention will often show a peak in hypothermia inducing effect 30 minutes to 120 minutes after administration, but may potentially peak sooner or later than described by this interval. The hypothermia inducing effect will frequently last from 1 hour to 12 hours, but may potentially last shorter or longer than described by this interval.
It is an object of the present invention to provide medicaments suitable for a quick induction of hypothermia which may be of long or short duration and medicaments suitable for a slow reduction in core body temperature which may be of long or short duration.
It is an aspect of the present invention that the compounds / medicaments / treatments herein may be given while the individual receiving the treatment is surrounded by any given temperature. In other words, the temperature of the surroundings, especially the room in which the individual resides, is not of relevance to the treatment. The treatment will reduce the temperature of the individual and/or induce hypothermia whether the room temperature is ambient, high or low such as at any temperature between 5 and 45 degree Celsius.
Administration
The main routes of drug delivery in the treatment method are intravenous, oral, and topical, as will be described below. Other drug-administration methods, such as subcutaneous injection or via inhalation, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
The mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the individual to which the biologically active substance is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, preferably the mucosa of the nose, mouth or rectum.
Compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, intraspinal, subcutaneous, intraarterial, intracardiac, intraosseous, intradermal, intrathecal, transdermal, transmucosal, inhalational, epidural, sublingual, intravitreal, intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. The compounds may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
The compounds according to the invention may be administered with at least one other compound. The compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
A preferred embodiment of the present invention is a medicament for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation. More preferably the administration form is by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
It has previously been demonstrated that administration of cannabinoids by the intravenous route produced a greater hypothermic response than that produced by the intraperitoneal route, [41]. Therefore the most preferable mode of administration of a medicament comprising a compound according to the present invention for the induction of hypothermia in an individual suffering from ischemia is by intravenous injection.
In one embodiment, the compound of the present invention is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
In another embodiment, the compound of the present invention is administered by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration. In one embodiment, the compound of the present invention is administered at intervals of 30 minutes to 48 hours.
In one embodiment, the compound of the present invention is administered at inter- vals of 1 to 6 hours.
Individual
The individual that may benefit from the administration of a medicament as described herein may be an individual suffering from ischemia or at risk of suffering from ischemia. If the individual is at risk of suffering from ischemia the preferred administration form of the medicament may be suppository, oral administration or inhalation. Preferably, the individual is an individual suffering from ischemia. Also, the individual may have an elevated body temperature and may be in need of a reduction hereof; alternatively the medicaments of the present invention may be given pre-operatively to lower the body temperature of the individual prior to and/or during surgery. The preferred administration form for an individual suffering from ischemia is an injection, such as an intravenous, intramuscular, intraspinal, intraperitoneal or subcutaneous injection. Being in need of treatment thus indicates that the health of the individual is benefitted by the administration of the compound of the present invention.
The individual may be any human being, male or female, infant or old. The ischemic condition and/or elevated temperature to be treated or prevented in the individual may relate to the age of the individual, the general health of the individual and whether or not the individual has a prior history of suffering from diseases or disorders that may have or have induced ischemic conditions and/or elevated temperature in the individual.
Dosage The dosage of the compound according to the invention depends on the compound in question; however, the amount of the compound is also closely related to the pharmaceutical composition of the medicament, any second compound of the medicament or any second active ingredient of the medicament. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
For all methods of use disclosed herein for the compounds, the daily dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen will be from about 0.001 to about 80 mg/kg of total body weight.
For all methods of use disclosed herein for the compounds, the daily dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen will be from about 0.01 to about 2,400 mg/kg of total body weight, preferably, the dosage of the medicament according to the pre- sent invention is between 10 μg to 10 mg pr kg total body weight, such as between 100 μg to 1 mg pr kg total body weight, depending on the compound of choice. It follows, that the preferred dosage may be between 1 μg and 1 mg pr kg total body weight, such as between 10 μg and 100 μg pr kg total body weight, such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg or 100 μg pr kg total body weight, again depending on the compound chosen. It has been found that cannabinoids and vanilloids vary with respect to potency and affinity for the receptor as well as with respect to molecular weight.
Preferably, the dosage of the medicament according to the present invention is be- tween 0.1 μg to 100 mg pr kg total body weight; such as between 0.1 μg to 1 μg pr kg total body weight, for example between 1 μg to 2 μg pr kg total body weight, such as 2 μg to 3 μg, for example 3 μg to 4 μg, such as 4 μg to 5 μg, for example 5 μg to 6 μg, such as 6 μg to 7 μg, for example 7 μg to 8 μg, such as 8 μg to 9 μg, for example 9 μg to 10 μg, such as 10 μg to 15 μg, for example 15 μg to 20 μg, such as 20 μg to 25 μg, for example 25 μg to 30 μg, such as 30 μg to 40 μg, for example 40 μg to 50 μg, such as 50 μg to 60 μg, for example 60 μg to 70 μg, such as 70 μg to 80 μg, for example 80 μg to 90 μg, such as 90 μg to 100 μg, for example 100 μg to 125 μg, such as 125 μg to 150 μg, for example 150 μg to 175 μg, such as 175 μg to 200 μg, for example 200 μg to 250 μg, such as 250 μg to 300 μg, for example 300 μg to 350 μg, such as 350 μg to 400 μg, for example 400 μg to 450 μg, such as 450 μg to 500 μg, for example 500 μg to 600 μg, such as 600 μg to 700 μg, for example 700 μg to 800 μg, such as 800 μg to 900 μg, for example 900 μg to 1000 μg, such as 1 mg to 1.5 mg, for example 1.5 mg to 2 mg, such as 2 mg to 2.5 mg, for example 2.5 mg to 3 mg, such as 3 mg to 3.5 mg, for example 3.5 mg to 4 mg, such as 4 mg to 4.5 mg, for example 4.5 mg to 5 mg, such as 5 mg to 5.5 mg, for example 5.5 mg to 6 mg, such as 6 mg to 6.5 mg, for example 6.5 mg to 7 mg, such as 7 mg to 7.5 mg, for example 7.5 mg to 8 mg, such as 8 mg to 8.5 mg, for example 8.5 mg to 9 mg, such as 9 mg to 9.5 mg, for example 9.5 mg to 10 mg, such as 10 mg to 11 mg, for example 1 1 mg to 12 mg, such as 12 mg to 13 mg, for example 13 mg to 14 mg, such as 14 mg to 15 mg, for example 15 mg to 16 mg, such as 16 mg to 17 mg, for example 17 mg to 18 mg, such as 18 mg to 19 mg, for example 19 mg to 20 mg, such as 20 mg to 21 mg, for example 21 mg to 22 mg, such as 22 mg to 23 mg, for example 23 mg to 24 mg, such as 24 mg to 25 mg, for example 25 mg to 26 mg, such as 26 mg to 27 mg, for example 27 mg to 28 mg, such as 28 mg to 29 mg, for example 29 mg to 30 mg, such as 30 mg to 35 mg, for example 35 mg to 40 mg, such as 40 mg to 45 mg, for example 45 mg to 50 mg, such as 50 mg to 55 mg, for example 55 mg to 60 mg, such as 60 mg to 65 mg, for example 65 mg to 70 mg, such as 70 mg to 75 mg, for example 75 mg to 80 mg, such as 80 mg to 85 mg, for example 85 mg to 90 mg, such as 90 mg to 95 mg, for example 95 mg to 100 mg pr kg total body weight, depending on the compound of choice.
In another embodiment, the dosage of the medicament according to the present invention is between 0.1 μg to 100 mg pr kg total body weight; such as between 0.1 μg to 100 mg pr kg total body weight, for example between 1 μg to 100 mg pr kg total body weight, such as 2 μg to 100 mg, for example 3 μg to 100 mg, such as 4 μg to 100 mg, for example 5 μg to 100 mg, such as 6 μg to 100 mg, for example 7 μg to 100 mg, such as 8 μg to 100 mg, for example 9 μg to 100 mg, such as 10 μg to 100 mg, for example 15 μg to 100 mg, such as 20 μg to 100 mg, for example 25 μg to 100 mg, such as 30 μg to 100 mg, for example 40 μg to 100 mg, such as 50 μg to 100 mg, for example 60 μg to 100 mg, such as 70 μg to 100 mg, for example 80 μg to 100 mg, such as 90 μg to 100 mg, for example 100 μg to 100 mg, such as 125 μg to 100 mg, for example 150 μg to 100 mg, such as 175 μg to 100 mg, for example 200 μg to 100 mg, such as 250 μg to 100 mg, for example 300 μg to 100 mg, such as 350 μg to 100 mg, for example 400 μg to 100 mg, such as 450 μg to 100 mg, for example 500 μg to 100 mg, such as 600 μg to 100 mg, for example 700 μg to 100 mg, such as 800 μg to 100 mg, for example 900 μg to 100 mg, such as 1 mg to 100'mg, for example 1.5 mg to 100 mg, such as 2 mg to 100 mg, for example 2.5 mg to 100 mg, such as 3 mg to 100 mg, for example 3.5 mg to 100 mg, such as 4 mg to 100 mg, for example 4.5 mg to 100 mg, such as 5 mg to 100 mg, for exam- pie 5.5 mg to 100 mg, such as 6 mg to 100 mg, for example 6.5 mg to 100 mg, such as 7 mg to 100 mg, for example 7.5 mg to 100 mg, such as 8 mg to 100 mg, for example 8.5 mg to 100 mg, such as 9 mg to 100 mg, for example 9.5 mg to 100 mg, such as 10 mg to 100 mg, for example 11 mg to 100 mg, such as 12 mg to 100 mg, for example 13 mg to 100 mg, such as 14 mg to 100 mg, for example 15 mg to 100 mg, such as 16 mg to 100 mg, for example 17 mg to 100 mg, such as 18 mg to 100 mg, for example 19 mg to 100 mg, such as 20 mg to 100 mg, for example 21 mg to 100 mg, such as 22 mg to 100 mg, for example 23 mg to 100 mg, such as 24 mg to 100 mg, for example 25 mg to 100 mg, such as 26 mg to 100 mg, for example 27 mg to 100 mg, such as 28 mg to 100 mg, for example 29 mg to 100 mg, such as 30 mg to 100 mg, for example 35 mg to 100 mg, such as 40 mg to 100 mg, for example 45 mg to 100 mg, such as 50 mg to 100 mg, for example 55 mg to 100 mg, such as 6600 mmgg ttoo 110000 mmgg,, ffoorr eexxaammppllee 6655 mmgg ttoo 110000 mmgg,, ssuucchh aass 7700 mmgg ttoo 110000 mmgg,, ffoorr eexaammppllee 7755 mmgg ttoo 110000 mmgg,, ssuucchh aass 8800 mmgg ttoo 110000 mmgg,, ffoorr eexxaammppllee 8855 mmgg ttoo 110000 mmgi , s suucchh a ass 9900 m mπg t tno 11 Ω 0Ω0 m mng, f fnorr e exvaammnpllee P 9R5 m mπg t tno 11 Ω 0Ω0 m mng n prr k kπg t tnottaall h boordlvy w weeiinghhtt, depending on the compound of choice.
In yet another embodiment, the dosage of the medicament according to the present invention is between 0.1 μg to 100 mg pr kg total body weight; such as between 0.1 μg to 1 μg pr kg total body weight, for example between 0.1 μg to 2 μg pr kg total body weight, such as 0.1 μg to 3 μg, for example 0.1 μg to 4 μg, such as 0.1 μg to 5 μg, for example 0.1 μg to 6 μg, such as 0.1 μg to 7 μg, for example 0.1 μg to 8 μg, such as 0.1 μg to 9 μg, for example 0.1 μg to 10 μg, such as 0.1 μg to 15 μg, for example 0.1 μg to 20 μg, such as 0.1 μg to 25 μg, for example 0.1 μg to 30 μg, such as 0.1 μg to 40 μg, for example 0.1 μg to 50 μg, such as 0.1 μg to 60 μg, for exam- pie 0.1 μg to 70 μg, such as 0.1 μg to 80 μg, for example 0.1 μg to 90 μg, such as 0.1 μg to 100 μg, for example 0.1 μg to 125 μg, such as 0.1 μg to 150 μg, for example 0.1 μg to 175 μg, such as 0.1 μg to 200 μg, for example 0.1 μg to 250 μg, such as 0.1 μg to 300 μg, for example 0.1 μg to 350 μg, such as 0.1 μg to 400 μg, for example 0.1 μg to 450 μg, such as 0.1 μg to 500 μg, for example 0.1 μg to 600 μg, such as 0.1 μg to 700 μg, for example 0.1 μg to 800 μg, such as 0.1 μg to 900 μg, for example 0.1 μg to 1000 μg, such as 0.1 μg to 1.5 mg, for example 0.1 μg to 2 mg, such as 0.1 μg to 2.5 mg, for example 0.1 μg to 3 mg, such as 0.1 μg to 3.5 mg, for example 0.1 μg to 4 mg, such as 0.1 μg to 4.5 mg, for example 0.1 μg to 5 mg, such as 0.1 μg to 5.5 mg, for example 0.1 μg to 6 mg, such as 0.1 μg to 6.5 mg, for example 0.1 μg to 7 mg, such as 0.1 μg to 7.5 mg, for example 0.1 μg to 8 mg, such as 0.1 μg to 8.5 mg, for example 0.1 μg to 9 mg, such as 0.1 μg to 9.5 mg, for example 0.1 μg to 10 mg, such as 0.1 μg to 1 1 mg, for example 0.1 μg to 12 mg, such as 0.1 μg to 13 mg, for example 0.1 μg to 14 mg, such as 0.1 μg to 15 mg, for example 0.1 μg to 16 mg, such as 0.1 μg to 17 mg, for example 0.1 μg to 18 mg, such as 0.1 μg to 19 mg, for example 0.1 μg to 20 mg, such as 0.1 μg to 21 mg, for example 0.1 μg to 22 mg, such as 0.1 μg to 23 mg, for example 0.1 μg to 24 mg, such as 0.1 μg to 25 mg, for example 0.1 μg to 26 mg, such as 0.1 μg to 27 mg, for example 0.1 μg to 28 mg, such as 0.1 μg to 29 mg, for example 0.1 μg to 30 mg, such as 0.1 μg to 35 mg, for example 0.1 μg to 40 mg, such as 0.1 μg to 45 mg, for ex- ample 0.1 μg to 50 mg, such as 0.1 μg to 55 mg, for example 0.1 μg to 60 mg, such as 0.1 μg to 65 mg, for example 0.1 μg to 70 mg, such as 0.1 μg to 75 mg, for example 0.1 μg to 80 mg, such as 0.1 μg to 85 mg, for example 0.1 μg to 90 mg, such as 0.1 μg to 95 mg, for example 0.1 μg to 100 mg pr kg total body weight, depending on the compound of choice.
It follows, that the preferred dosage may be between 0.1 μg and 100 mg, such as between 1 μg and 1 mg pr kg total body weight, for example between 10 μg and 100 μg pr kg total body weight, such as or about 0.1 μg, 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 150 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg pr kg total body weight, again depending on the compound chosen. Also, the preferred dosage range may be between 10O μg and 100 mg pr kg total body weight, such as between 200 μg and 90 mg, between 300 μg and 80 mg, such as between 400 μg and 70 mg, such as between 500 μg and 60 mg, such as be- tween 600 μg and 50 mg, such as between 700 μg and 40 mg, such as between
800 μg and 30 mg, such as between 900 μg and 20 mg, such as between 1 mg and 10 mg pr kg total body weight. Alternatively, the dosage may be found in the range of from 100 μg to 2000 μg, such as 200 μg to 1800 μg, or 300 μg to 1600 μg, 400 μg to 1400 μg, 500 μg to 1200 μg, 600 μg to 1000 μg, 500 μg to 1000 μg.
For any other receptor agonist compound according to the invention the exact dosage may be calculated based on the bovine study model described in Examples 16, 17 and 18.
Based hereon, the preferred dosages of a cannabinoid compound such as, but not limited to HU-210 and KN38-7271 (BAY38-7271), is between 1 μg and 1 mg pr kg total body weight, such as between 10 μg and 100 μg pr kg total body weight, such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg or 100 μg pr kg total body weight. The dosage may depend on the administration form. For example, it is preferable to administer HU-210 in the range of from 10 μg and 100 μg pr kg total body weight intravenously.
For one of the compounds in this invention, HU-210, the dosage regime will be between 2 and 1000 microgram/kg of total body weight, such as between 4 and 900 microgram/kg of total body weight, such as between 6 and 800 microgram/kg of total body weight, such as between 8 and 700 microgram/kg of total body weight, such as between 10 and 600 microgram/kg of total body weight. Preferably, the dosage regime will be between 15 and 500 microgram/kg of total body weight, more preferably between 20 and 400 microgram/kg of total body weight. More preferably at least 40 microgram/kg of total body weight, such as at least 50 microgram/kg of total body weight, such as at least 60 microgram/kg of total body weight, such as at least 70 microgram/kg of total body weight, such as at least 80 microgram/kg of total body weight, such as at least 100 microgram/kg of total body weight. The dosages mentioned are the dosages for inducing hypothermia as defined herein. The dosage may be administered as one single bolus or divided into two or more dosages given over a period of time, alternatively it may be administered by continuous iv. Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additionally dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
For another compound in this invention, delta-8-THC phosphate, the dosage regime will be between 0.25 and 600 mg/kg of total body weight, such as between 0.5 and 500 mg/kg of total body weight, 1 and 400 mg/kg of total body weight, 2 and 300 mg/kg of total body weight, 3 and 200 mg/kg of total body weight. Preferably, the dosage regime will be between 4 and 150 mg/kg of total body weight, more preferably between 5 and 100 mg/kg of total body weight. More preferably at least 20 mg/kg of total body weight, such as at least 30 mg/kg of total body weight, such as at least 40 mg/kg of total body weight, such as at least 50 mg/kg of total body weight, such as at least 60 mg/kg of total body weight, such as at least 100 mg/kg of total body weight. The dosages mentioned are the dosages for inducing hypothermia as defined herein. The dosage may be administered as one single bolus or divided into two or more dosages given over a period of time, alternatively it may be administered by continuous iv. Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additionally dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a compound, alone or in combination with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage forms of the present invention depend on the particular compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host. The dose administered should be an "effective amount" or an amount necessary to achieve an "effective level" in the individual patient. Since the "effective level" is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharmacokinetics, drug distribution, and metabolism. The "effective level" can be defined, for example, as the blood or tissue level desired in the individual that corresponds to a concentration of one or more compounds according to the invention. Also, the effective level depends on the severity of the ischemic condition, such as total amount of tissue experiencing hyp- or anoxia, the duration of the ischemic condition, whether it is the first or a subsequent ischemic attack of the individual and so forth.
Dosage regime and duration of treatment
The medicament may be administered in any suitable dosage regime, suitable as to the potency of the compound / drug, the target temperature to be reached, the speed of action of the compound, the metabolic stability of the compound, the duration of the treatment and how often the medicament optimally is to be administered.
It is within the scope of the invention to provide a medicament to be administered at intervals of 30 minutes to 48 hours, such as intervals of 1 to 47 hours, 2 to 45 hours, 3 to 43 hours, 4 to 41 hours, 5 to 39 hours, 6 to 37 hours, 7 to 35 hours, 8 to 3 hours, 9 to 31 hours, 10 to 29 hours, 11 to 27 hours, 12 to 25 hours, 13 to 23 hours, 14 to 21 hours, 15 to 19 hours 16 to 18 hours. It is also within the scope of the present invention to provide a medicament to be administered at intervals of 30 minutes to 24 hours, such as 1 to 23 hours, 2 to 22 hours, 3 to 20 hours, 4 to 18 hours, 5 to 16 hours, 6 to 14 hours, 7 to 12 hours or 8 to 10 hours. Preferably, the administration occurs at intervals of 1 to 6 hours, such as 2 to 5 hours, 3 to 4 hours.
The optimal administration interval depends on the duration of the hypothermic treatment. The duration of the treatment depends among other things on the severity of the ischemic condition. It is within the scope of the present invention to provide medicaments for the induction of hypothermia wherein the duration of the treatment is from 6 to 72 hours, such as from 7 to 69 hours, such as from 8 to 66 hours, 9 to 63 hours, 10 to 60 hours, 11 to 57 hours, 12 to 54 hours, 13 to 51 hours, 14 to 48 hours, 15 to 45 hours, 16 to 42 hours, 17 to 39 hours, 18 to 36 hours, 1 to 35 hours, 20 to 32 hours, 21 to 29 hours, 22 to 26 hours 23 to 25 hours. Preferably, the duration of the treatment is between 6 and 48 hours, more preferably between 6 and 24 hours.
In one embodiment, the duration of the treatment with compounds of the present invention is from 6 to 72 hours.
The medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly or alternatively, wherein at least one compound induces hypothermia slowly. In the present context rapidly means within few hours, such as within 2 hours, such as within 1 hour, such as within 30 minutes, for example within 15 minutes; whereas slowly means after several hours, such as after 3 hours, for example 4 hours, such as after 5 hours, for example 6 hours, such as after 7 hours, for example 8 hours, such as after 9 hours, for example 10 hours, such as after 11 hours, for example 12 hours, such as after 13 hours, for example 14 hours, such as after 15 hours, for example 16 hours, such as after 17 hours, for example 18 hours, such as after 19 hours, for example 20 hours. A rapidly acting compound or combination of compounds may be administered prior to admission to the hospital such as en route in an ambulance by medically trained personnel. The individual suffering from the ischemic insult will thus already be experiencing a reduction in core body temperature upon arrival at a place of proper facilities enhancing the treatment and reducing the extent of the ischemic insult.
Multiple compound medicaments
An object of the present invention is to provide compounds capable of inducing hypothermia in an individual. The induction of hypothermia depends on the characteristics of the compounds and these characteristics may be to reach different target temperatures or different ranges of target temperatures, reaching the target temperatures and various speeds, the lifetime of the active compound and so on. It is therefore an object of the present invention to provide medicaments comprising more than one compound, such as at least two, at least three or at least four compounds as herein described.
The medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly. The medicament may furthermore comprise at least one compound that induces hypothermia over an extended time period, alternatively wherein at least one compound induces hypothermia for a short time period.
Second active ingredient
An embodiment of the present invention is a pharmaceutical composition comprising a compound as herein described and furthermore comprising a second active ingredient. The second active ingredient may increase the hypothermic effect of the compound of the invention, or may have an alternative medical effect such as inducing pain relief or vasodilation.
The second active ingredient may thus be selected from the non-limiting group of: capsaicinoids, neurotensins, analgesics, opiods, GABAs and adrenergic antagonists.
Examples of these include, but are not limited to: Capsaicin (8-methyl-N-vanillyl-6- nonenamide) and neurotensin analogues KK13 and KK14.
The second active ingredient may also be an antipyretic. Antipyretics are drugs that reduce body temperature in situations such as fever; however, they will not affect the normal body temperature if one does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever. It is an object of the present invention to induce hypothermia in an individual. To prevent a possible overshoot in the body's attempt to regain its normal temperature at the completion of the hypothermia inducing treatment, an antipyretic may be provided in combination with the compounds / medicaments of the present invention.
There are at least 3 classes of antipyretic medications all of which are of relevance to the present invention, that include, but are not limited to: 1 ) Salicylates - aspirin (acetylsalicylic acid), choline salicylate (Arthropan), magnesium salicylate (Ar- thriten), and sodium salicylate (Scot-Tussin Original); 2) Acetaminophen / Paracetamol (Panodil / Tylenol); and 3) Nonsteroidal anti-inflammatory drugs (NSAIDs) ~ ibuprofen (Advil), naproxen (Naprosyn, Aleve), and ketoprofen. It is an aspect of the present invention to provide a medicament comprising one or more cannabinoids which may be formulated and /or administered together with an antipyretic drug simultaneously or sequentially.
The further active ingredient may also be an analgesic (or painkiller). Some drugs that are antipyretics will also have an analgesic effect, and thus there will be an overlap between these two groups. Analgesics are a diverse group of drugs that relieve pain. Analgesic drugs act in various ways on the peripheral and central nervous systems and include paracetamol (acetaminophen); the non-steroidal anti- inflammatory drugs (NSAIDs) such as the salicylates - aspirin, ibuprofen, naproxen; opioids such as morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine; synthetic drugs with opioid properties such as tramadol and buprenor- phine; and various others. Demerol and desflurane both of which are analgesics may also be administered especially for the purpose of reducing shivering as the individual to whom the compounds of the present invention are administered is brought down in temperature. It is especially relevant to use analgesics when inducing actual hypothermia e.g. temperatures below normal.
Kit of parts Another embodiment of the present invention comprises a kit of parts, wherein the kit includes at least one compound according to any of the above, a means for administering said compound and the instruction(s) on how to do so. It is within the scope of the present invention to include multiple dosages of the same composition or several different compositions. In a preferred embodiment the kit of parts further comprises a second active ingredient.
One kit may be specifically targeted to persons at risk of suffering from ischemic attacks, such that the kit, apart from instructions, comprises pharmaceutical forms of the medicaments that allow self administration of the medicaments and devices with which to administer the medicaments.
An alternative embodiment is an ambulance kit that facilitates the administration of the medicaments of the present invention in a manner most efficient for the rescue personnel. Detailed description of figures
Figure 1 : Plot of temperature curves from Day 2 of Example 16.
Figure 2: Plot of diastolic blood pressure against time relative to injection for from Day 2 of Example 16. Figure 3: Plot of temperature curves of Example 18; study 1. Dihydrocapsaicin is administered into calves by intravenous infusion at a dosis of 1 mg/kg/h for 12 hours. The resulting temperature difference from baseline is measured at t = -1 until t = 24h.
Figure 4: Plot of temperature curves of Example 18; study 2. Dihydrocapsaicin is administered into calves by intravenous infusion at a dosis of 0.6 mg/kg/h for 4 hours. The resulting temperature difference from baseline is measured at t = -1 until t = 24h.
Figure 5: Plot of temperature curves of Example 18; study 3. Dihydrocapsaicin is administered into calves by single intramuscular bolus injection at doses of 0.5, 1.0 or 2.0 mg/kg. The resulting temperature difference from baseline is measured at t = -1 until t = 24h.
Figure 6: Plot of temperature curves of Example 18; study 4. Delta-8-THC phosphate is administered into calves by single intravenous bolus injection at a dosis of 20 mg/kg. The resulting temperature difference from baseline is measured at t = -1 until t = 24h.
Figure 7: Plot of temperature curves of Example 18; study 5. HU-210 is administered into calves by single intravenous bolus injection at doses of 20, 30 or 40 μg/kg. The resulting temperature difference from baseline is measured at t = -1 until t = 24h.
Examples
Example 1 - Cardiac arrest
A 57-year-old woman is brought into hospital 21 minutes after having collapsed without warning. Staff at the emergency room is alerted in advance. The patient is evaluated in the emergency room where the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-4 additional intravenous bolus injections may be required (HU-210: Additional injections of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injections of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such treatments and examinations proceed uninterrupted.
Example 2 - Cardiac arrest
A 22-year-old male athlete collapses when doing sports. Medical staff finds ventricular fibrillation/ventricular tachycardia approximately 6 minutes after collapse. He is successfully defibrillated and the patient is rushed to the hospital. In the ambulance, the physician present in the ambulance team decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered: 1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 addi- tional bolus injections may be required. At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 3 - Cardiac arrest
A 66-year-old man is undergoing elective heart surgery. He suffers from irregular cardiac rhythm during the procedure and goes into cardiac arrest with much impaired circulation for 6 minutes after which the surgical team manages to restore circulation. Subsequent to restoration of circulation, the surgeon in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as de- scribed in this invention. The dose will likely be in the interval 0.01 mg/kg to
80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association rec- ommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and exami- nations proceed uninterrupted.
Example 4 - Cardiac arrest
An electrician accidentally receives a high-voltage jolt and immediately slips into a coma. The company physician manages to resuscitate the cardiac arrest patient after just 7 minutes. The patient is rushed to hospital where the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as de- scribed in this invention. The dose will likely be in the interval 0.01 mg/kg to
80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association rec- ommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and exami- nations proceed uninterrupted.
Example 5 - Perinatal asphyxia
A newborn baby suffers cerebral ischemia during delivery as the umbilical cord gets wrapped around his neck. The APGAR score 10 minutes after delivery is 6. The pediatrician decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered. Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-4 additional intravenous bolus injections may be required (HU-210: Additional injec- tions of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injections of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such treatments and examinations proceed uninterrupted.
Example 6 - Asphyxia A 9-year-old boy is in a coma when he is rescued out of a burning house. CRP is commenced on the spot but he is not awake when the ambulance arrives at hospital after a 15 minutes drive. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted. Example 7 - Stroke
A 72-year-old is brought to hospital 1 hour and 30 minutes after waking up with the entire right side of his body feeling numb and weak. The patient is evaluated in the neurology department and the physician in charge decides, suspecting a stroke, that the patient shall receive hypothermia therapy immediately to lessen damage to the brain. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-4 additional intravenous bolus injections may be required (HU-210: Additional injections of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injections of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such treatments and examinations proceed uninterrupted.
Example 8 - Stroke
A 78-year-old woman is admitted to hospital 50 minutes after experiencing sudden onset lack of mobility of the left arm and leg and as well and difficulties speaking.
The patient is diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered: 1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg. The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 addi- tional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 9 - Stroke
A 29-year-old man suffers continuous pains in the back of his head for two weeks after which he suddenly collapses and slips into a coma. The patient is diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered: 1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 addi- tional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted. Example 10 - Myocardial infarction
A 48-year-old man is brought to hospital 35 minutes after experiencing sudden severe chest pain, shortness of breath, and very unpleasant palpitations. Staff at the emergency room is alerted in advance. The patient is evaluated and the cardiologist in charge decides that the patient shall receive hypothermia therapy immediately to lessen damage to the heart and other tissues. An intravenous bolus injection of HU- 210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) is administered.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12 to 24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-4 additional intravenous bolus injections may be required (HU-210: Additional injections of 20-100 microgram/kg body weight; delta-8-THC phosphate: Additional injec- tions of 8-40 mg/kg body weight). Additional bolus injection may be administered after 6-12 hours from the first bolus injection.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such treatments and examinations proceed uninterrupted.
Example 11 - Myocardial infarction
A 55-year-old man is admitted to hospital 18 minutes after experiencing nausea, shortness of breath, and severe chest pains. The patient who is suffering myocardial infarction is evaluated by the physician in charge who decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the heart and other tissues.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and 2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 12 - Traumatic brain injury A 41 -year-old man receives a severe blow to the head from a falling brick on a construction site. The patient is still unconscious when he 24 minutes after the trauma is brought to the Emergency Room. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required. At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 13 - Pulmonary embolism
A 60-year-old woman is feeling rather well two days after major surgery when she suddenly slips into a coma. Following acute surgery, brought on by a pulmonary embolism, she is stabilized. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1-8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 14 - Modified pyrogenicity test on rabbits
Each combination of compounds in a low, medium and high dose will be screened initially on 3 rabbits. Temperature, blood pressure, pulse will be measured for 72 hours following administration of active substances. These parameters will be recorded as follows: Continuous recording (time=0-3h), every 30 minutes (time=3-6h), every 1 hour (time=6-12h), every 2 hours (time=12-24h), every 6 hours (time=24-48h), every 12 hours (time=48-72h) These are the specifics of the initial screening:
Type of rabbits: New Zealand White, Charles River
Weight: >1.5 kg
Gender: Female
Room temperature: 210C (+/- 1 °C) Relative humidity: 55% (+/- 5%)
Type of temperature probe: PC Based pyrogen testing system, Ellab APT 91
Cage type: Pro Plast Noryl, 2475 cm2
Number of rabbits in a cage: 1
Water and food access: Ad lib in cage. 12-hour light period: Yes
Example 15 - Receptor studies
Modulation of CB and TRPV1 activities will be assessed in vitro by measuring can- nabinoid and/or cannabimimetic compound and vanilloid receptor agonist induced Ca2+ flux, respectively. This will be done using FLIPR and HEK293 cells stably expressing recombinant human (h) and rat (r) TRPV1 (hTRPV1-HEK293 and rTRPN/1- HEK293, respectively) and recombinant human (h) and rat (r) CB receptors (hCB1- HEK293, hCB2-H293, rCB1 -HEK293 and rCB2-H293) and especially in cells co- expressing human or rat TRPV1 and CB receptors (hTRPV1-hCB1-HEK293 and hTRPVI -hCB2-HEK293). Intracellular Ca2+ levels will be measured in CB, TRPV1 and coCB/TRPVI -expressing cells during exposure to compounds and combinations of compounds. A concentration dependent increase in Ca2+ influx will be observed. The efficacy of vanilloid agonists will be estimated by comparing these to the maximum response induced by capsaicin, likewise the efficacy of cannabinoids will be estimated by comparing these to the maximum response induced by can- nabidiol. A combination of capsaicin and cannabidiol will be used as reference for measuring combinations of drugs.
Example 16 - Bovine study model In order to evaluate an effective hypothermic dose of a receptor agonist compound according to the invention, the compound(s) are tested in the bovine study model. The bovine model is used because the body weight of the calves is comparable to the body weight of humans. The efficacy of a compound tested in the bovine model may be correlated with the efficacy of the cannabinoid and/or vanilloid compound tested in the same bovine study model. Calves in the weight target range from 65 to 95 kilo are of primary interest. Calves of higher weight are not be comparable to overweight/obese humans since their weight gain does not arise from increased amount of fatty tissue, but on the contrary from a larger muscle percentage.
Study subjects
Fifteen male Danish Holstein calves were moved to an intensive research barn. The calves were kept separated form other cattle throughout the trial. The insulated barn had 4 separate rooms (sections) each with 4 pens and no windows. A 16 hour light and 8 hour dark program was imposed. Each pen was equipped with a rubber mat- tress and further bedded with sawdust. Pens were cleaned daily and new sawdust added. Calves were loose housed, but each day around milk-feeding calves were tied for 1 hour to get accustomed to the experimental sampling situation, where calves had to be tied due to the fitted cords from the probes and catheters (see below). Rooms were automatically heated and ventilated and temperatures were set at 2O0C. Real time recordings of room temperature and humidity were performed. The calves were kept in the intensive barn for 29 days before the experimental sampling periods were initiated. At an age of app. 50 days (body weight 75 to 85 kg) calves are assigned to the sections of four and injected with test compound. Body temperature, arterial blood pressure, and heart rate are monitored 60 min prior to injection and during 24 h following injection.
During the pre-trial period all calves received surgery. Calves were surgically implanted with permanent indwelling catheters in the right jugular vein and right carotid artery under total anesthesia prior to the experimental sampling periods. Four of the calves were used to test the sampling procedure, blood pressure probes, equipment and the recording of data without receiving test compound or vehicle.
Table 1 (below): Birth weight and age and weights of calves when entering and finishing the pre-trial period. Calf Weight Age when Weight when Age when Weight when at birth entering pre- entering pre- finishing pre- finishing pre-
(kg) trial period trial period trial period trial period
(days) (kq) (days) (kq)
6086 41 45 81.8 74 109.5
6089 31 40 73.5 69 99.0
6090 41 35 75.0 64 96.8
6092 42 33 74.5 62 104.0
6093 40 33 67.5 62 86.0
6094 45 32 77.3 61 104.5
6096 41 27 73.8 56 91.5
6097 48 27 72.0 56 95.0
6101 42 23 61.5 52 83.8
6102 40 19 59.3 48 70.3
6104 46 18 61.5 47 71.8
6105 36 18 53.0 47 66.5
6106 41 17 56.8 46 71.3
6108 47 15 64.5 44 78.8
6110 41 13 51.3 42 64.3
All calves stayed healthy during the trial and none of the calves received veterinary treatments during the trial except for the preplanned treatments with antibiotics and analgesics connected with surgical procedures.
The calves were fed milk-replacer restrictively (4 kg of milk-replacer with 123 g DM/kg supplied once daily) and had ad libitum access to artificially-dried hay and starter concentrate during the trial. During the 29-day pre-trial period, the daily gain was on average 666 gram/day. Calves growing at this level of daily gain will usually be considered as well performing calves.
On the sampling days, 8 calves were fitted with at temperature probe (MLT 1401 ; ADInstruments) inserted into the jugular vein via the permanent catheter. The arterial catheter was connected to a pressure transducer and filled with saline containing 100 IU sodium heparin. Data were recorded using Powerlab (Chart 5 version 5.5.4, ADInstruments) at 100 Hz. All pressure probes were individually tested and calibrated against a 2-m water column.
The test compound was injected into the left-side jugular vein via a temporary cathe- ter implanted at least one day before injection. Data analyzed within sampling period
All calves completed the planned injections and recordings with no loss of data apart from shorter periods of time (minutes) where temperature probes accidentally were disconnected or repositioned. Pressure transducers were flushed when needed and pressure data are only missing or invalid for shorter periods before these flushings and during the flushing procedure.
The recorded data were averaged in 15-min intervals prior to data analysis. Data were sampled from exactly 60 min before injection of test compound and until 23 hours after injection. Data recorded during the 60 min prior to injection were defined as baseline.
Variables describing temperature, blood pressure and heart rate were considered as repeated measures and analyzed by using the autoregressive order 1 structure in the mixed model procedure of SAS (SAS Institute, 2001). The model included the effects of block (calves housed in the same room), treatment and time as well as the interaction between treatment and time. Orthogonal polynomial contrasts were used to estimate the linear, quadratic, and cubic effects of treatment.
Variables describing number of hours where the body temperature deviated from baseline were constructed within calf and period. Variables were constructed for +0.5, +1.0, +2.0, +2.5, -0.5, -1.0, -2.0, and -2.50C.
A variable describing time when body temperature returns to or exceed baseline after injection was calculated as the minimum value for time fulfilling the conditions: time > 0.25 h post injection & (15 min average temperature - baseline temperature) > 0.
Variables with only one observation within period and calf were analyzed using a model including the effects of block and treatment. Orthogonal polynomial contrasts were used to estimate the linear, quadratic, and cubic effects of treatment.
Means are given as least squares means ± residual standard error of the mean. Allocation of animals
Three test days (October 4, 8 and 12) were planned involving testing on 16 calves. Eight calves were tested each day. The calves used at the first two days had not been used previously in the study, while all the calves used at day 3 had been used either 4 or 8 days earlier. At Day 3, seven out of eight calves had received the test compound and one out of eight had gotten placebo at either Day 1 or 2.
Test days:
Day 1 was designed at dose finding. Day 2 was designed at dose finding.
Day 3 was designed to test the effect of repetitive doses.
Drug formulation:
HU-210 is a lipophilic compound and thus may be formulated in several ways, three of which are: Fractionated coconut oil, Tween 80 or in a cyclodextrin complex solution. During the testing phase, our compound precipitated in a cyclodextrin complex solution from the very beginning which ruled that option out. HU-210 was, however, easily dissolved in both coconut oil and Tween 80, and a coconut oil solution was chosen.
Day 1 : Five calves received 2.0, 4.0, 4.0, 6.0 and 6.0 μg HU-210 respectively. As seen in table 5 there was a dose response relationship both in terms of body temperature reduction and the duration of hypothermia. 2.0, 4.0 and 6.0 μg resulted in an average reduction of body temperature of approx 1.0, 2.0 and 2.5 0C respec- tively. In 3 out of 4 calves a reduction of body temperature of 2.0 0C was achieved within 2-3 hours. One of the 4.0 μg and one of the 6.0 μg calves were above and at the upper edge of the target weight range respectively. Both responded less to HU- 210 than their lighter counterparts.
Day 2: The eight calves received the same doses as tested at Day 1. The results reminded of the results of Day 1. The 6.0 μg calves both had less pronounced reduction of body temperature (1.8-1.9 0C) while the 4.0 μg calf with a proper weight responded as the 4.0 μg calves of Day 1. The 4.0 μg calf with a weight above the target range (6086 - weight: 115 kilo) responded less to the test compound. See figures 1 and 2. Day 3: All calves had been used at either Day 1 or Day 2. Seven out of eight had received the active compound while one had received placebo. The doses (5.0+2.5 μg), 10 and 15 μg resulted in less behavioral alterations than seen in the 4.0 and 6.0 μg calves at Day 1 and 2, both in regards to psychotropic behavior as well as the induction of somnolence. At Day 3 there was also a tendency to a more pronounced temperature reduction in the calves weighing within the predefined range (65-95 kilo) compared to heavier calves.
Conclusion
The studies clearly demonstrated that HU-210 causes hypothermia in calves. The doses tested induced at temporary drop in core body temperature of up to 2.6 0C in a dose dependent manner.
The following effects of HU-210 were observed in calves: 1. Decreased body temperature for 6 to 15 h after injection
2. Overshoot in body temperature starting 6 to 15 h after injection
3. Decreasing heart rate following injection
4. No clear effects on systolic and diastolic blood pressure
Example 17 - Extended Bovine study Study subjects
The evaluation is carried out on 80 Holstein bull calves have been purchased for the study that is conducted over 8 study days. At an age of app. 50 days (body weight 75 to 85 kg) calves are assigned to the sections and injected with test compound.
Body temperature, arterial blood pressure, and heart rate are monitored 60 min prior to injection and during 24 h following injection. Each calf is receiving experimental injection one time. See the above for further specifications.
Each study week consisted of two study days. For each study week 20 calves are purchased. These calves will be at the test facilities for approximately 2 weeks before the operation period. Two calves served as a buffer in case of sickness or unexpected high or low weight gain in the first two weeks after the animals arrive at test facilities. The remaining 18 calves are operated and 16 are ultimately included in the study. The surplus of two operated calves is an extra measure in order to deal with sickness and unexpected high or low weight gain in the two-week period from operation to the study day.
Calf study outline
The study days are allocated to the examination of the following compounds and purposes:
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000072_0003
The dihydrocapsaicin at day 3 was used to investigate continuous doses. The calves were given the indicated doses until a stable temperature was reached; the reached temperature was then kept stable by administering 0.5 mg to 1.0 mg/kg/h. The calves remained stable at the reached temperature for the duration of the experiment. For three calves, a reduction in core body temperature of 3.5 degree Celsius was reached for the last calf a reduction of 2.5 degree Celsius was reached.
Figure imgf000072_0004
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000073_0003
Administration
Day 1-5: Each calf received a single intravenous bolus injection of 2 ml administered over 7-8 minutes followed by saline flush of 5 ml. Day 6-7: Each calf will receive an initial intravenous bolus injection of 2 ml administered over 7-8 minutes, followed by one or several similar intravenous injections for up to 12 hours after the initial injection.
Pharmacokinetics / Pharmacodynamics (PK/PD)
Blood samples will be taken before and after injection of compounds in order to examine PK/PD. The specifics depend on a meeting with Xendo (www.xendo.dk) where the topic will be a tailor-made pharmacokinetic/pharmacodynamic model for the calf study.
Drug administration The compound investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection, alternatively as a continuous administration.
Generally 4 different doses plus vehicle are tested producing varying degrees of hypothermic responses.
Hypothermic effect
The primary effect evaluated is hypothermia. Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study. The probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required readouts.
Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).
The minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose of compound or compound mixture.
Other effects
Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 min- utes subsequently until 24 hours after drug administration.
Example 18 - Extended Bovine study #2
Study subjects
The evaluation is carried out on Holstein bull calves purchased for the study. At an age of app. 50 days (body weight 75 to 85 kg) calves are assigned to the test compound and administration mode under examination. Body temperature, arterial blood pressure, and heart rate are monitored 60 min prior to administration and during 24 h following injection. See Example 16 above for further specifications.
Calf study outline
The studies are allocated to the examination of the following compounds and administrations:
Figure imgf000075_0001
Administration Study 1-2: Each calf received an intravenous infusion over 12 or 4 hours, respectively.
Study 3: Each calf received a single intramuscular injection at variable doses. Study 4-5: Each calf received a single intravenous bolus injection of 2 ml administered over 7-8 minutes followed by saline flush of 5 ml.
Pharmacokinetics / Pharmacodynamics (PK/PD)
Blood samples will be taken before and after administration of compounds in order to examine PK/PD. The specifics depend on a meeting with Xendo (www.xendo.dk) where the topic will be a tailor-made pharmacokinetic/pharmacodynamic model for the calf study. Drug administration
The compounds investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection, alternatively as a continuous administration.
Hypothermic effect
The primary effect evaluated is hypothermia. Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study. The probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required readouts.
Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).
The minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose and administration form of compound.
Other effects
Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration.
References
[1] Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD: Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987; 7(6):729-738.
[2] Barone FC, Feuerstein GZ, White RF: Brain cooling during transient focal ischemia provides complete neuroprotection. Neurosci Biobehav Rev 1997; 21 (1):31-44. [3] Onesti ST, Baker CJ, Sun PP, Solomon RA: Transient hypothermia reduces focal ischemic brain injury in the rat. Neurosurgery 1991 ; 29(3):369-373.
[4] Coimbra C, Wieloch T: Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol (Berl) 1994; 87(4):325-331.
[5] Zhang Y, Wong KC, Zhang Z: The effect of intraischemic mild hypothermia on focal cerebral ischemia/reperfusion injury. Acta Anaesthesiol Sin 2001 ; 39(2):65-69.
[6] Yamashita K, Eguchi Y, Kajiwara K, lto H: Mild hypothermia ameliorates ubiquitin synthesis and prevents delayed neuronal death in the gerbil hippocampus. Stroke 1991 ; 22(12):1574-1581.
[7] Ooboshi H, lbayashi S, Takano K, Sadoshima S, Kondo A, Uchimura H,
Fujishima M: Hypothermia inhibits ischemia-induced efflux of amino acids and neuronal damage in the hippocampus of aged rats. Brain Res 2000; 884(1 ~2):23- 30.
[8] Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM: Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab 2000; 20(12):1702-1708.
[9] Kawai N, Okauchi M, Morisaki K, Nagao S: Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats. Stroke 2000; 31 (8):1982-1989.
[10] Maier CM, Sun GH, Kunis D, Yenari MA, Steinberg GK: Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J Neurosurg 2001 ; 94(1):90-96.
[11] Maier CM, Ahern K, Cheng ML, Lee JE, Yenari MA, Steinberg GK: Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke 1998; 29(10):2171-2180. [12] Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest: N Engl J Med 2002; 346(8):549-556.
[13] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346(8) :557-563.
[14] Bernard S: Therapeutic hypothermia after cardiac arrest: now a standard of care. Crit Care Med 2006; 34(3) :923-924.
[15] Dietrich WD, Halley M, Valdes I, Busto R: Interrelationships between increased vascular permeability and acute neuronal damage following temperature-controlled brain ischemia in rats. Acta Neuropathol (Berl) 1991 ; 81 (6):615-625.
[16] Karibe H, Zarow GJ, Graham SH, Weinstein PR: Mild intraischemic hypothermia reduces postischemic hyperperfusion, delayed postischemic hypoperfusion, blood-brain barrier disruption, brain edema, and neuronal damage volume after temporary focal cerebral ischemia in rats. J Cereb Blood Flow Metab 1994; 14(4):620-627.
[17] Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM: Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can J Neurol Sci 1999; 26(4):298-304.
[18] Bagenholm R, Nilsson UA, Kjellmer I: Formation of free radicals in hypoxic ischemic brain damage in the neonatal rat, assessed by an endogenous spin trap and lipid peroxidation. Brain Res 1997; 773(1 -2):132-138.
[19] KiI HY, Zhang J, Piantadosi CA: Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab 1996; 16(1):100-106. [20] Kumura E, Yoshimine T, Takaoka M, Hayakawa T, Shiga T, Kosaka H: Hypothermia suppresses nitric oxide elevation during reperfusion after focal cerebral ischemia in rats. Neurosci Lett 1996; 220(1 ):45-48.
[21] Baker AJ, Zornow MH, Grafe MR, Scheller MS, Skilling SR, Smullin DH, Larson AA: Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits. Stroke 1991 ; 22(5):666-673.
[22] Takagi K, Ginsberg MD, Globus MY, Dietrich WD, Martinez E, Kraydieh S, Busto R: Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat: correlation with histopathology. J Cereb Blood Flow Metab 1993; 13(4):575-585.
[23] Nakashima K, Todd MM: Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke 1996; 27(5):913-918.
[24] Maier CM, Sun GH, Cheng D, Yenari MA, Chan PH, Steinberg GK: Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. Neurobiol Dis 2002; 11 (1 ):28-42.
[25] Pulsinelli W: Pathophysiology of acute ischaemic stroke. Lancet 1992; 339(8792):533-536.
[26] Eguchi Y, Yamashita K, Iwamoto T, lto H: Effects of brain temperature on calmodulin and microtubule-associated protein 2 immunoreactivity in the gerbil hippocampus following transient forebrain ischemia. J Neurotrauma 1997; 14(2):109-1 18.
[27] Sick TJ, Tang R, Perez-Pinzon MA: Cerebral blood flow does not mediate the effect of brain temperature on recovery of extracellular potassium ion activity after transient focal ischemia in the rat. Brain Res 1999; 821 (2):400-406. [28] Hu BR, Kamme F, Wieloch T: Alterations of Ca2+/calmodulin-dependent protein kinase Il and its messenger RNA in the rat hippocampus following normo- and hypothermic ischemia. Neuroscience 1995; 68(4):1003-1016.
[29] Busto R, Globus MY, Neary JT, Ginsberg MD: Regional alterations of protein kinase C activity following transient cerebral ischemia: effects of intraischemic brain temperature modulation. J Neurochem 1994; 63(3):1095-1 103.
[30] Ishikawa M, Sekizuka E, Sato S, Yamaguchi N, lnamasu J, Bertalanffy H, Kawase T, ladecola C: Effects of moderate hypothermia on leukocyte- endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke 1999; 30(8):1679-1686.
[31] lnamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, Kawase T: Post- ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol 2000; 109(2):66-74.
[32] Hara A, Niwa M, Iwai T1 Yano H, Bunai Y, Uematsu T, Yoshimi N, Mori H: Increase of fragmented DNA transport in apical dendrites of gerbil CA1 pyramidal neurons following transient forebrain ischemia by mild hypothermia. Neurosci Lett 2000; 280(1 ):73-77.
[33] Xu L, Yenari MA, Steinberg GK, Giffard RG: Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb Blood Flow Metab 2002; 22(1 ):21 -28.
[34] Zhang Z, Sobel RA, Cheng D, Steinberg GK, Yenari MA: Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia. Brain Res MoI Brain Res 2001 ; 95(1-2)75-85.
[35] Niwa M, Hara A, Iwai T, Nakashima M, Yano H, Yoshimi N, Mori H, Uematsu T: Relationship between magnitude of hypothermia during ischemia and preventive effect against post-ischemic DNA fragmentation in the gerbil hippocampus. Brain Res 1998; 794(2):338-342. [36] lnamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, Kawase T: Postischemic hypothermia attenuates apoptotic cell death in transient focal ischemia in rats. Acta Neurochir Suppl 2000; 76:525-527.
[37] Leker R. R, Gai N, Mechoulam R, Ovadia H: Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210. Stroke 2003; 34(8):2000- 2006.
[38] Ovadia H, Wohlman A, Mechoulam R, Weidenfeld J: Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens. Neuropharmacology 1995; 34(2):175-180.
[39] Maas Al, Murray G, Henney H, III, Kassem N, Legrand V, Mangelus M, Muizelaar JP, Stocchetti N, Knoller N: Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol 2006; 5(1):38-45.
[40] Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA: Blockade of effects of smoked marijuana by the CB1 -selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 2001 ; 58(4):322- 328.
[41] Hosko MJ, Schmeling WT, Hardman HF: Evidence for a Caudal Brainstem Site of Action for Cannabinoid Induced Hypothermia. Brain Research Bulletin. 1981 , Vol. 6, p. 253.
[42] Howlett AC, Barth, F, Bonner, Tl, Cabral, G, Casellas, P, Devane; WA, Felder; CC, Herkenham, M, Mackie, K, Martin, BR, Mechoulam, R, and Pertwee, EG: International Union of Pharmacology, XXVII. Classification of Cannabinoid Receptors, Pharmacological Reviews, 2002, Vol. 54, No. 2, 161-202.
[43] Herkenham, M, Lynn, AB, Johnson, MR, Melvin, LS, de Costa, BR, and Rice, KC: Cannabinoid Receptor Localization in Brain, PNAS 1990; 87; 1932-1936.

Claims

Claims
1. A cannabinoid receptor agonist compound for use in induction of hypothermia in a human being.
2. The cannabinoid receptor agonist compound according to claim 1 , wherein the compound is a cannabinoid of the general formula:
Figure imgf000082_0001
wherein R1 , R2, R3 and R4 individually is a chemical moiety or a chemical bond.
3. The cannabinoid receptor agonist compound as defined in claim 2, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloal- kenyl or phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyKC^)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate and more preferably is C, optionally sub- stituted with H, OH, OCH3 or phosphate.
4. The cannabinoid receptor agonist compound as defined in claim 2, wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, hetero- cycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H,
OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (Ci-Cx), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, cycloalkyl, hetereo- cycloalkyl, cycloalkenyl, fluoride, phenyl, phosphate, and more preferably is C substituted with C, O, OSO2, alkyl such as (C3-C11) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl and wherein x is an integer of from 1 to 20.
5. The cannabinoid receptor agonist compound as defined in claim 2, wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O,
P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, ' substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1^)-alkyl, het- eroaryl-(C1^)-alkyl, heterocyclyl^C^-alkyl, cycloalkylalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, methyl, phenyl, diheterocycle, amine (NH), halogen, substituted lower alkyl, aryl, lower alcohol, heterocyclyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1-4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, preferably is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally fur- ther substituted one or more times with methyl, diheterocycle, lower alcohol, alkyl or phosphate more preferably is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted one or more times with C, ethyl, methyl, phosphate, diheterocycle, lower alcohol, alkyl such as (C1-C2) wherein C2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate.
6. The cannabinoid receptor agonist compound as defined in claim 2, wherein R4 is selected from the group of: C, H, S, N, O, optionally substituted with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1- 4)-alkyl, heteroaryl-(C1-4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloal- kyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, substituted lower alkyl, alkyl such as (C1-Cx) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci.4)-alkyl, het- eroaryl-(C1^)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, dicycloalkyl, tricy- cloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, (alcohol) and preferably is C, H, N, O optionally substituted with alkyl, al- kenyl, alkynyl, alcohol, phenyl, diphenyl, dicycloalkyl, tricycloalkyl, cycloalkenyl any of which may bond with R1 or R3 forming a ring, optionally further substituted with one or more alkyl, alkenyl, alkynyl, OH, and more preferably is C, H, (CI-Cy), dicycloalkyl, or tricycloalkyl, cycloalkenyl any C of which may bond with R1 or R3 forming a ring, and optionally is substituted with methyl, dimethyl, phenyl, diphenyl, optionally further substituted with alkyl and/or OH and wherein x is an integer of from 1 to 15 and y is an integer of from 1 to 8.
7. The cannabinoid receptor agonist compound as defined in claim 2, wherein R1 as defined in claim 5 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate, when R2 as defined in claim 6 is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C1-CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, hetereocycloalkyl, fluoride, phenyl or phosphate, when R3 as defined in claim 7 is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or more times with methyl, diheterocycle, lower alcohol, alkyl or phosphate, when R4 as defined in claim 8 is C, H, N, O optionally substituted with alkyl, alkenyl, alkynyl, alcohol, phenyl, diphenyl, dicycloalkyl, tricycloalkyl, cycloalkenyl any of which may bond with R1 or R3 forming a ring, optionally fur- ther substituted with one or more alkyl, alkenyl, alkynyl or OH.
8. The cannabinoid receptor agonist compound as defined in claim 2, wherein R1 as defined in claim 5 is C, optionally substituted with H, OH, OCH3 or phosphate, when R2 as defined in claim 6 is C substituted with C, O, OSO2, alkyl such as (C3-C11) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 as defined in claim 7 is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted with C, ethyl, phosphate, alkyl such as (C1-C2) wherein C2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate when R4 as defined in claim 8 is C, (C1-C8) any C of which may bond with R3 and optionally is substituted with methyl, dimethyl, phenyl, diphenyl optionally further substituted with an alcohol and wherein x is an integer of from 1 to 15.
9. The cannabinoid receptor agonist compound according to claim 1 , wherein the compound is a cannabinoid of the general formula:
Figure imgf000085_0001
wherein R1 , R2, R3, R4 and R5 individually is a chemical moiety or a chemical bond.
10. The cannabinoid receptor agonist compound as defined in claim 9, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1.4)-alkyl, het- eroaryl-(C1^)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloal- kenyl, phosphate, optionally bonding with the C in the ring next to R5, optionally further substituted one or more times with C, S, N, O, OH, phenyl, phosphate, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, het- eroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate and more preferably is C, optionally substituted one or more times with H, O, OH, OCH3 or phosphate.
11. The cannabinoid receptor agonist compound as defined in claim 9, wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O,
P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (C1-Cx), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, hetereocycloalkyl, fluoride, phenyl, phosphate, and more preferably is C substituted with C, O, OSO2, alkyl such as (C3-Cn) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl and wherein x is an integer of from 1 to 15.
12. The cannabinoid receptor agonist compound as defined in claim 9, wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1.4)-alkyl, het- eroaryl-(C1^l)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloal- kenyl, phosphate, optionally further substituted one or more times with C, S, N,
O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may connect with R4 and preferably is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 and more preferably is O, OH, NH, optionally connecting with R4 thus forming a ring.
13. The cannabinoid receptor agonist compound as defined in claim 9, wherein R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(CiJl)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloal- kenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may connect with R3 and preferably is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, phenyl, op- tionally substituted with OH, methyl, dimethyl any of which may connect with R3 and more preferably is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn.
14. The cannabinoid receptor agonist compound as defined in claim 9, wherein R5 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O,
P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with R1 , optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1-4)- alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, phosphate or nitro, and preferably is C, N, O, optionally substituted with C, O, CH2OH, methyl, dimethyl, al- kyl, alkenyl, alkynyl, phenyl, phosphate and more preferably is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH2OH.
15. The cannabinoid receptor agonist compound as defined in claim 9, wherein R1 as defined in claim 12 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate, when R2 as defined in claim 13 is C substituted with C, O, P, H, OH, 0S02, phosphate, alkyl, alkenyl, alkynyl such as (C1-CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, hetereocycloalkyl, fluoride, phenyl or phosphate, when R3 as defined in claim 14 is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may con- nect with R4 thus forming a ring, when R4 as defined in claim 15 is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, phenyl, optionally substituted one or more times with OH, methyl and/or dimethyl any of which may connect with R3, when R5 as defined in claim 16 is C, N, O, optionally substituted with C, O, CH2OH, methyl, dimethyl, alkyl, alkenyl, alkynyl, phenyl or phosphate.
16. The cannabinoid receptor agonist compound according to claim 9, wherein R1 as defined in claim 11 preferably is C, optionally substituted with H, OH, OCH3 or phosphate when R2 as defined in claim 12 preferably is C substituted with C, O, OSO2, alkyl such as (C3-C8) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1-Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 as defined in claim 13 preferably is O, OH, NH, optionally connecting with R4, when R4 as defined in claim 14 preferably is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn, when R5 preferably is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH2OH and wherein x is an integer of from 1 to 15.
17. The cannabinoid receptor agonist compound as defined in claim 1 , wherein the compound has the general formula:
R1 R2
Wherein, R1 is (CI-Cx) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl or 0CH3 and wherein x is an integer of from 1 to 30.
18. The cannabinoid receptor agonist compound as defined in claim 1 , wherein the compound has the general formula:
R1 R2 wherein R1 preferably is (C1-Cx), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N when R2 is N, O, NH2 optionally substi- tuted with C, CH2OH, CH(CH2)2 (cyclopropane), optionally further substituted one or more times with CH2OH, CH2CI and wherein x is an integer of from 1 to 21
19. The cannabinoid receptor agonist compound according to any of claims 1 to 3, wherein the compound is an aminoalkylindole of the general formula:
Figure imgf000089_0001
wherein R1 , R2, R3 and R4 individually is a chemical moiety or a chemical bond.
20. The cannabinoid receptor agonist compound as defined in claim 19, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(C1-4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloal- kenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH, phosphate and more preferably is C, substituted with O, further substituted with methyl.
21. The cannabinoid receptor agonist compound as defined in claim 19, wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-fC^-alkyl, het- eroaryl-(CM)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloal- kenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may bond with R3, and preferably is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3 and more preferably is C, substituted with O, further substituted with C optionally bond forming with R3.
22. The cannabinoid receptor agonist compound as defined in claim 19, wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1.4)-alkyl, het- eroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may bond R2 and preferably is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2 and more preferably is (CI-Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or morpholine and any of which may bond R2.
23. The cannabinoid receptor agonist compound as defined in claim 19, wherein R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1-4)-alkyl, het- eroaryl-(CiJt)-alkyl, heterocyclyl-(C1.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, het- erocyclyl, heteroaryl, aryl-(C1-4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1.4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, N, O optionally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O, OH, phenyl, diphenyl, morpholino, and halogen, and more preferably is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
24. The cannabinoid receptor agonist compound as defined in claim 19, wherein R1 is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, op- tionally further substituted with lower alkyl, OH or phosphate, when R2 is C, N,
O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3, when R3 is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2, when R4 is C, N, O option- ally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O, OH, phenyl, diphenyl, morpholino, and/or halogen.
25. The cannabinoid receptor agonist compound as defined in claim 19, wherein R1 preferably is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI-Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or morpholine when R4 is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
26. The cannabinoid receptor agonist compound according to claim 1 , wherein the cannabinoid receptor is CB1 and/or CB2.
27. The cannabinoid receptor agonist compound according to claim 1 , wherein the cannabinoid receptor is CB1.
28. The cannabinoid receptor agonist compound according to any of claims 1 to 27, which is hydrophilic.
29. The cannabinoid receptor agonist compound according to any of the preceding claims, wherein the medicament induces hypothermia of between 32 and 36 degree Celsius.
30. The cannabinoid receptor agonist compound according to any of the preceding claims, wherein the treatment comprises administration of at least two compounds according to any of claims 1 to 29.
31. The cannabinoid receptor agonist compound according to claim 30, wherein at least one compound induces hypothermia rapidly.
32. The cannabinoid receptor agonist compound according to any of claims 30 and 31 , wherein at least one compound induces hypothermia slowly.
33. The cannabinoid receptor agonist compound according to any of the preceding claims, wherein the treatment comprises administration of a second active ingredient.
34. The cannabinoid receptor agonist compound according to claim 33, wherein the second active ingredient is selected from the group of: capsaicinoids, neurotensins, analgesics, opiods, GABAs and adrenergic antagonists.
35. The cannabinoid receptor agonist compound according to any of claims 1 to 34, for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
36. The cannabinoid receptor agonist compound according to claim 35, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
37. The cannabinoid receptor agonist compound according to any of claims 38 to 50, wherein administration occurs at intervals of 30 minutes to 24 hours.
38. The cannabinoid receptor agonist compound according to any of claims 1 to 37, wherein administration occurs at intervals of 1 to 6 hours.
39. The cannabinoid receptor agonist compound according to any of claims 1 to 38, wherein the duration of the treatment is from 6 to 72 hours.
40. The cannabinoid receptor agonist compound according to any of claims 1 to 39, wherein the dosage of the medicament is between 10 μg to 10mg pr kg body mass.
41. The cannabinoid receptor agonist compound according to any of claims 1 to 40, wherein the cannabinoid or cannabimimetic compound is administered in a dosage of 10 μg and 100 μg pr kg total body weight.
42. Cannabinoid receptor agonist compound for use in induction of hypothermia in a human being for treatment of ischemia, wherein the cannabinoid receptor ago- nist compound is as defined in any of claims 1 to 40.
43. Cannabinoid receptor agonist compound for use in induction of hypothermia in a human being for suffering from or at risk of suffering from ischemia, wherein the cannabinoid receptor agonist compound is as defined in any of claims 1 to 40.
44. The cannabinoid receptor agonist compound according to claim 41 or 42, for prophylaxis and/or treatment of ischemia in connection with cardiovascular diseases, asphyxia and/or traumatic brain injuries.
45. The cannabinoid receptor agonist compound according to claim 43, wherein the ischemia is due to cardiovascular diseases such as: myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regur- gitation and heart valve stenosis.
46. The cannabinoid receptor agonist compound according to claim 43, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
47. A pharmaceutical composition comprising at least one cannabinoid receptor agonist compound according to any of the preceding claims 1-40 or a salt or an ester thereof, and optionally a pharmaceutically acceptable carrier.
48. The pharmaceutical composition according to claim 46, comprising a second active ingredient.
49. The pharmaceutical composition according to claim 47, wherein the second active ingredient is selected from the group of: capsaicinoids, neurotensins, analgesics, opiods, GABAs, adrenergic antagonists and antipyretics.
50. The pharmaceutical composition according to any of claims 46 to 48, wherein the pH of the composition is between pH 5 and pH 9.
51. The pharmaceutical composition according to any of claims 46 to 49, formulated for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
52. The pharmaceutical composition according to any of claims 46 to 50, formulated for injection, wherein the injection is intravenous, intramuscular, intraspinal, in- traperitoneal, subcutaneous, a bolus or a continuous administration.
53. A kit of parts comprising at least two cannabinoid receptor agonist compounds as defined in any of claims 1 to 40.
54. A kit of parts comprising at least one cannabinoid receptor agonist compound as defined in any of claims 1 to 40, and a second second active ingredient.
55. The kit of parts according to claim 53, wherein the second active ingredient is selected from the group of: capsaicinoids, neurotensins, analgesics, opiods, GABAs, adrenergic antagonists and antipyretics.
56. A cannabinoid receptor antagonist for use in reverting hypothermia in a human being.
PCT/DK2009/000092 2008-04-09 2009-04-08 Use of hypothermia inducing drugs WO2009124553A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DKPA200800515 2008-04-09
DKPA200800515 2008-04-09
DKPA200801141 2008-08-21
DKPA200801141 2008-08-21

Publications (2)

Publication Number Publication Date
WO2009124553A2 true WO2009124553A2 (en) 2009-10-15
WO2009124553A3 WO2009124553A3 (en) 2009-12-03

Family

ID=41130582

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2009/000092 WO2009124553A2 (en) 2008-04-09 2009-04-08 Use of hypothermia inducing drugs

Country Status (1)

Country Link
WO (1) WO2009124553A2 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8608696B1 (en) 2009-02-24 2013-12-17 North Carolina State University Rapid fluid cooling devices and methods for cooling fluids
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4837228A (en) * 1979-05-31 1989-06-06 The University Of Mississippi Antiinflammatory and antimicrobial compounds and compositions
WO2001024645A1 (en) * 1999-10-07 2001-04-12 Societe Des Produits Nestle S.A. Nutritional composition
WO2004004702A2 (en) * 2002-07-09 2004-01-15 The Scripps Research Institute Method to inhibit ischemia and reperfusion injury
US20040229850A1 (en) * 2003-05-12 2004-11-18 Moore Bob M. Method and kit for regulation of microvascular tone
WO2004105699A2 (en) * 2003-05-28 2004-12-09 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a cannabinoid agent for the treatment of central nervous system damage
US20070203209A1 (en) * 2005-08-18 2007-08-30 Wilmin Bartolini Useful indole compounds
WO2007140786A1 (en) * 2006-06-08 2007-12-13 Neurokey A/S Use of cannabinoid receptor agonists as hypothermia inducing drugs for the treatment of ischemia
WO2008040360A2 (en) * 2006-10-04 2008-04-10 Neurokey A/S Use of hypothermia inducing drugs to treat ischemia
WO2008116816A1 (en) * 2007-03-26 2008-10-02 Glaxo Group Limited Combination of cb2 ligand and paracetamol
WO2009071095A2 (en) * 2007-12-05 2009-06-11 Neurokey A/S Prevention of hyperthermia subsequent to hypothermia treatment of ischemia

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4837228A (en) * 1979-05-31 1989-06-06 The University Of Mississippi Antiinflammatory and antimicrobial compounds and compositions
WO2001024645A1 (en) * 1999-10-07 2001-04-12 Societe Des Produits Nestle S.A. Nutritional composition
WO2004004702A2 (en) * 2002-07-09 2004-01-15 The Scripps Research Institute Method to inhibit ischemia and reperfusion injury
US20040229850A1 (en) * 2003-05-12 2004-11-18 Moore Bob M. Method and kit for regulation of microvascular tone
WO2004105699A2 (en) * 2003-05-28 2004-12-09 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a cannabinoid agent for the treatment of central nervous system damage
US20070203209A1 (en) * 2005-08-18 2007-08-30 Wilmin Bartolini Useful indole compounds
WO2007140786A1 (en) * 2006-06-08 2007-12-13 Neurokey A/S Use of cannabinoid receptor agonists as hypothermia inducing drugs for the treatment of ischemia
WO2008040360A2 (en) * 2006-10-04 2008-04-10 Neurokey A/S Use of hypothermia inducing drugs to treat ischemia
WO2008116816A1 (en) * 2007-03-26 2008-10-02 Glaxo Group Limited Combination of cb2 ligand and paracetamol
WO2009071095A2 (en) * 2007-12-05 2009-06-11 Neurokey A/S Prevention of hyperthermia subsequent to hypothermia treatment of ischemia

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AHN ET AL: "Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid-induced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception" PAIN, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 132, no. 1-2, 3 October 2007 (2007-10-03), pages 23-32, XP022283606 ISSN: 0304-3959 *
GUINDON J ET AL: "Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?" EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER BV, NL, vol. 550, no. 1-3, 21 November 2006 (2006-11-21), pages 68-77, XP025170094 ISSN: 0014-2999 [retrieved on 2006-11-21] *
LEKER RONEN R ET AL: "Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210" STROKE, LIPPINCOTT WILLIAMS & WILKINS, US, vol. 34, no. 8, 1 August 2003 (2003-08-01), pages 2000-2006, XP002451424 ISSN: 0039-2499 *
SLIVA JIRI ET AL: "Analgesic efficacy of CP 55940 in combination with diclofenac in rodents" ACTA PHARMACOLOGICA SINICA, vol. 27, no. Suppl. 1, July 2006 (2006-07), page 113, XP009123932 & 15TH WORLD CONGRESS OF PHARMACOLOGY; BEIJING, PEOPLES R CHINA; JULY 02 07, 2006 ISSN: 1671-4083 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US8608696B1 (en) 2009-02-24 2013-12-17 North Carolina State University Rapid fluid cooling devices and methods for cooling fluids
US8808241B2 (en) 2009-02-24 2014-08-19 North Carolina State University Rapid fluid cooling devices and methods for cooling fluids
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones

Also Published As

Publication number Publication date
WO2009124553A3 (en) 2009-12-03

Similar Documents

Publication Publication Date Title
US20100029739A1 (en) Use of a combination of hypothermia inducing drugs
US20090318526A1 (en) Use of cannabinoid receptor agonists as hypothermia inducing drugs for the treatment of ischemia
US20090197966A1 (en) Use of Hypothermia Inducing Drugs
WO2009124552A2 (en) Use of a combination of hypothermia inducing drugs
WO2009124553A2 (en) Use of hypothermia inducing drugs
Yin et al. Dexmedetomidine attenuated early brain injury in rats with subarachnoid haemorrhage by suppressing the inflammatory response: The TLR4/NF-κB pathway and the NLRP3 inflammasome may be involved in the mechanism
WO2010015260A2 (en) Administration by infusion for the treatment of ischemic effects
KR101918669B1 (en) New compositions for treating neurological disorders
ES2935605T3 (en) Combinations of cannabinoids and N-acylethanolamines
US20150313867A1 (en) Anti-tumoural effects of cannabinoid combinations
WO2009071095A2 (en) Prevention of hyperthermia subsequent to hypothermia treatment of ischemia
WO2009071094A2 (en) Combination treatment of ischemic effects
WO2009071096A2 (en) Combination of medical and physical cooling treatment of ischemic effects
JP2020075931A (en) Nervous system disease therapeutic agent
WO2009071097A1 (en) Use of hypothermia inducing drugs
JP2020045359A (en) Salvinorin compositions and uses thereof
CA3101878A1 (en) Acyl sulfonamides that are bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer
WO2009124551A2 (en) Use of hypothermia inducing drugs
JP2020504721A (en) Method for treating glioblastoma multiforme using ibudilast
WO2010056710A1 (en) Compositions and methods for treating eye diseases
ES2902838T3 (en) Glycolic acid protects against heart attacks
WO2005018541A2 (en) Cox-2 inhibitor and serotonin modulator for treating cns damage
JP2016509046A (en) Inhibitors of NA (V) 1.9 channel activity and their use for the treatment of pain
US20050054646A1 (en) Compositions of a cyclooxygenase-2 selective inhibitor and an antioxidant agent for the treatment of central nervous system disorders
WO2020023755A1 (en) Treatment for ischemic stroke

Legal Events

Date Code Title Description
NENP Non-entry into the national phase in:

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205 DATED 07/02/2011)

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09730274

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 09730274

Country of ref document: EP

Kind code of ref document: A2