US20050107380A1 - Brain, spinal and nerve injury treatment - Google Patents
Brain, spinal and nerve injury treatment Download PDFInfo
- Publication number
- US20050107380A1 US20050107380A1 US11/017,978 US1797804A US2005107380A1 US 20050107380 A1 US20050107380 A1 US 20050107380A1 US 1797804 A US1797804 A US 1797804A US 2005107380 A1 US2005107380 A1 US 2005107380A1
- Authority
- US
- United States
- Prior art keywords
- methyl
- trifluoromethyl
- bis
- benzyl
- piperazin
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
- 0 *C.*C1=CC=CC=C1C1=CC([4*])=NC=C1CC([3*])([3*])C1=CC=CC=C1.CC.CC Chemical compound *C.*C1=CC=CC=C1C1=CC([4*])=NC=C1CC([3*])([3*])C1=CC=CC=C1.CC.CC 0.000 description 9
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
-
- 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
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- 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
Definitions
- This invention relates to a method to a method of therapy of brain, spinal and nerve injury. There is also provided a formulation which is particularly useful in the method.
- brain magnesium ion concentration is a regulatory factor in a number of biochemical and physiological processes that are activated after brain injury. Indeed, a decrease in the magnesium ion concentration was observed to exacerbate the injury process while an increase in the concentration of magnesium ion was noted to attenuate the injury process and result in an improved outcome. 5
- the treatment of brain injury with magnesium has since been shown to be effective. 1, 6-10 even when administered up to 24 hours after the primary event, and the success of the treatment in experimental animal studies has subsequently led to clinical trials in human brain injury.
- FIGS. 1 and 2 show combination administration of 246 mg/kg N-acetyl-L-tryptophan plus 30 mg/kg magnesium sulphate (intravenously) resulting in a profound attenuation of both motor and cognitive deficits that was significantly greater than obtained with either drug in isolation.
- the formulation in one aspect of the invention comprises a substance P receptor antagonists and a magnesium compound, wherein the combined use of the magnesium compound and the substance P receptor antagonist results in greater protection against injury that either of the magnesium compound of the substance P receptor antagonist used alone.
- the method of the invention includes the step of administering the formulation to a patient suffering from brain injury.
- each of the components of the formulation are administered separately or separated by a time delay that does not affect the effectiveness of the therapy, e.g. 1-30 minutes and up to 24 hours as discussed above.
- Substance P is an excitatory neurotransmitter and has a role in pain transmission and is a peptide having the structure RPKPEEFFGLM-NH 2 . It is from the hypothalamus, CSN and intestine and increases smooth muscle contraction of the GI tract.
- substance P binds to a number of receptors inclusive of the NK1 receptor (i.e. Neurokinin 1 receptor), the NK2 receptor and the NK3 receptor. These receptors are believed to have a role in blood traveling to the brain.
- a substance P antagonist is a substance that inhibits binding of substance P to any one of the receptors referred to above.
- a list of suitable substance P antagonists is referred to in Tables 1, 2, and 3 attached herewith.
- NK1 receptor antagonists as described in U.S. Pat. No. 5,990,125, which is incorporated herein by reference, as constituting substance P antagonists that may be utilized in the formulation of the method of the invention.
- This has specific reference to compounds of structures Ia, Ib, Ic, Id, Ie, X, XVI, XVII, XVIII, XIX, XX, and XXI, as well as other antagonists comprising quinuclidine, piperidine ethylene diamine, pyrrolidine and azabornane derivatives and related compounds that exhibit activity as substance P receptor antagonists as described in column 33 of U.S. Pat. No. 5,990,125.
- receptor antagonists may be employed having regard to the dosages referred to in column 34 of U.S. Pat. No. 4,990,125 and in various forms of administration i.e. alone or with various pharmaceutically acceptable carriers or diluents by oral administration of parenteral administration as referred in column 34 of U.S. Pat. No. 5,990,125.
- the activity of various substances as substance P receptor antagonists for use in the invention may also be determined by the assays referred to in columns 35-36 of U.S. Pat. No. 5,990,125.
- tachykinin antagonists referred to in U.S. Pat. No. 4,981,744 may also be used as substance P antagonists in the invention, and thus this reference is also totally incorporated herein.
- EP-A-1035115 which is totally incorporated herein by reference, which refers to N-benzyl-4-tolylnicotinamides and related compounds as NK1 receptor antagonists for use in the invention.
- EP-A-1035115 discloses compounds of the general formula wherein
- Exemplified compounds in EP-A-1035115 having a morpholine or piperazine group include
- WO 0050398 discloses compounds of general formula wherein
- Exemplified compounds in WO 0050398 having a morpholine or piperazine group include
- WO 0050401 discloses compounds of formula wherein
- Exemplified compounds in WO 0050401 having a morpholine or piperazine group include
- WO 0053572 discloses compounds of formula wherein
- Exemplified compounds in WO 0053572 having a morpholine or piperazine group include
- WO 0073278 discloses compounds of formula wherein
- Exemplified compounds in WO 0073278 having a morpholine or piperazine group include
- WO 0073279 discloses compounds of formula wherein
- Exemplified compounds in WO 0073279 having a morpholine or piperazine group include
- this may comprises any suitable source of magnesium ion such as magnesium chloride, magnesium sulphate, magnesium oxalate, magnesium gluconate or other non toxic magnesium salt.
- the pharmaceutical preparations in accordance with this invention can in addition also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- preservatives solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the term “comprising” used in the specification should be interpreted in this context.
- the dosage can vary within wide limits and can, of course, be fitted to the individual requirements in each particular case. In general, a dosage of 1 to 20000 mg per patient, preferable 10 to 5000 mg and more preferably 50 to 2000 mg of the substance P receptor antagonist should be appropriate.
- substance P may have a similar effect on the cerebral vasculature, where such an effect could lead to increased blood brain barrier permeability and vasogenic cerebral oedema.
- administration of a substance P receptor antagonist may prevent brain swelling and the development of delayed neurologic deficits after injury. This hypothesis was a result of our discovery referred to above, that water accumulated in the brain as a result of vasogenic oedema formation.
- N-acetyl-L-tryptophan A number of commercially synthesized substance P receptor antagonists are currently available from standard scientific chemical suppliers, as is apparent form Tables 1, 2, and 3. We chose to use the compound N-acetyl-L-tryptophan based on its low lipid solubility that limits its ability to naturally cross the blood brain barrier and the fact that it is relatively inexpensive. Administration of N-acetyl-L-tryptophan at an intravenous dose of 246 mg/kg (saline vehicle) given at 30 minutes after brain injury resulted in a significant improvement of cognitive outcome in brain injured animals as assessed by the Barnes Circular Maze. Similarly, there was a significant improvement in motor outcome of animals as assessed by the otarod test. These improvements in outcome were apparent at 24 hours after brain injury and persisted for the 14 day assessment period. Control (vehicle tested) animals had significantly worse neurologic outcome than treated animals at all time points tested.
- N-acetyl-L-tryptophan had a significant reduction in brain water accumulation (i.e. cerebral oedema) at 24 hours after injury as compared to vehicle treated controls. This was consistent with the observation that N-acetyl-L-tryptophan reduced brain penetration of Evans blue at 5 hours after injury: the time associated with maximum blood brain barrier permeability and reduced vasogenic oedema formation. The fact that these effects were noted with a non-permeable formulation of the NK1 antagonist suggests that the effects were largely mediated by vascular receptors and not dependent upon central receptors.
- N-acetyl-L-tryptophan at 24.6 mg/kg also significantly improved cognitive outcome of brain injured animals.
- the drug had less of a beneficial effect on motor outcome.
- the beneficial effects of treatment with the NK1 antagonist were less apparent when injury of mild severity was induced as opposed to injury of a severe nature. This is a major limitation given that mild head injury has the greatest incidence in brain injury patients.
- Each of the compounds in the combination formulation has a number of properties that make it particularly attractive for use in brain injury.
- Substance P(SP) antagonists have been shown to rapidly improve mood by antagonizing substance P induced anxiety. Thus, they are effective in treating post-injury depression. From the word described above, it is apparent that SP antagonists reduce blood brain barrier permeability and inhibit the formation of vasogenic oedema and post-injury brain swelling or cerebral oedema. The antagonists also have been shown to inhibit pain. There are high numbers of substance P receptors in the hippocampus and striatum, those parts of the brain that are known to be associated with learning and memory. Inhibition of binding with SP antagonists may thus prevent substance P induced deficits in learning and memory. Our evidence presented above suggests that this may be the case. This has never been shown previously. Indeed, there has been no literature on the role of substance P, or any neuropeptides, in brain injury.
- magnesium affects over 300 cellular enzymes. It is not surprising; therefore, that magnesium has numerous targets at which it may improve outcome. These include, amongst others, blocking glutamate induced excitotoxicity, improving membrane stability and reducing the production of reactive oxygen species, improving energy status, inhibiting calcium channels, reducing neurotransmitter release, inhibiting mitochondrial transition pore opening, and inhibiting apoptosis. Notably, it also blocks glutamate induced release of substance P. Physiologically, magnesium has been shown (14-17) to improve cerebral blood flow, to reduce cerebral vasospasms, and to reduce vascular ceramide and prostaglandin production.
- magnesium has a beneficial effect in trauma when administered at intravenous doses ranging from 16 to 60 mg/kg.
- the effective dose varies from 45 to 90 mg/kg.
- the target is to increase free magnesium concentration in the blood to approximately 1.0 mM, which is double the normal blood free magnesium concentration. Beneficial results are observed irrespective of the magnesium salt used.
- the formulation When used in combination, the formulation may vary in the range described for the individual components. We have achieved excellent results using the maximum i.v. doses described for the individual components.
- the combination magnesium/SP antagonist is expected to be useful in the following conditions:
Abstract
A treatment for brain, spinal and nerve injury comprising use of a substance P receptor antagonist optionally in combination with a magnesium compound. There is also provided a formulation for use in this treatment comprising a substance P receptor antagonist and a magnesium compound.
Description
- This application is a Division of Ser. No. 10/181,323, filed Oct. 15, 2002, now allowed, which is a § 371 of PCT/AU01/00046, filed Jan. 18, 2001.
- This invention relates to a method to a method of therapy of brain, spinal and nerve injury. There is also provided a formulation which is particularly useful in the method.
- Injury to the brain results in the development of motor and cognitive deficits that contribute to the significant morbidity experienced by survivors of brain injury. Moreover, it is an occurrence that has the highest incidence in younger members of society. Accordingly, injury to the brain is responsible for the greatest loss of productive life as compare to any other disease proves. Despite this, there is no effective therapy to improve outcome after brain injury. We disclose the use of a method of therapy as a robust pharmacologic intervention for the treatment of brain injury. Use of this therapy significantly improves both motor and cognitive outcome in mild to severe experimental brain injury and has also been found to have beneficial effect also for the treatment of spinal cord and nerve injuries.
- It is well known that brain injury results in the development of neurologic deficits through two mechanisms. The first of these is known as primary mechanisms. These occur at the time of the injurious even and include mechanical processes such as laceration, tearing, stretching and compression of verve fibers. Little can be done for this type of injury once it has occurred. The second mechanism is secondary injury, which includes biochemical and physiological processes, initiated by a primary injury but which manifest with time after the injury. It has been demonstrated that much of the morbidity after brain injury is associated with the development of this secondary injury. Give that the secondary injury develops from minutes to days after the primary event, there exists a window of opportunity to pharmacologically prevent this type of injury and significantly improve resultant outcome. However, the factors that make up secondary injury must first be identified and then “antifactors” developed to inhibit the injury process.
- Our studies have concentrated on identifying secondary injury factors after brain injury and developing interventional therapies. One of the factors, that we have previously identified 14 as critical to determining outcome after injury, is brain magnesium ion concentration. This ion is a regulatory factor in a number of biochemical and physiological processes that are activated after brain injury. Indeed, a decrease in the magnesium ion concentration was observed to exacerbate the injury process while an increase in the concentration of magnesium ion was noted to attenuate the injury process and result in an improved outcome.5 The treatment of brain injury with magnesium has since been shown to be effective.1, 6-10 even when administered up to 24 hours after the primary event, and the success of the treatment in experimental animal studies has subsequently led to clinical trials in human brain injury.
- Despite the attenuation of deficits after brain injury with magnesium administration, it was clear that there were still motor and cognitive deficits that persisted after the treatment. Our attention was particularly drawn to the fact that in younger animals, the accumulation of water in the brain (i.e. cerebral oedema or brain swelling) was still present and that this may present a significant risk factor. Indeed, in a recent clinical study,11 delayed brain swelling was responsible for 50% of all deaths recorded in young victims of brain injury.
-
FIGS. 1 and 2 show combination administration of 246 mg/kg N-acetyl-L-tryptophan plus 30 mg/kg magnesium sulphate (intravenously) resulting in a profound attenuation of both motor and cognitive deficits that was significantly greater than obtained with either drug in isolation. - It therefore is an object of the invention to provide a method of therapy in relation to brain injury and a formulation for use in the method.
- The formulation in one aspect of the invention comprises a substance P receptor antagonists and a magnesium compound, wherein the combined use of the magnesium compound and the substance P receptor antagonist results in greater protection against injury that either of the magnesium compound of the substance P receptor antagonist used alone.
- The method of the invention includes the step of administering the formulation to a patient suffering from brain injury. Alternatively, each of the components of the formulation are administered separately or separated by a time delay that does not affect the effectiveness of the therapy, e.g. 1-30 minutes and up to 24 hours as discussed above.
- Substance P is an excitatory neurotransmitter and has a role in pain transmission and is a peptide having the structure RPKPEEFFGLM-NH2. It is from the hypothalamus, CSN and intestine and increases smooth muscle contraction of the GI tract.
- It is known that substance P binds to a number of receptors inclusive of the NK1 receptor (i.e.
Neurokinin 1 receptor), the NK2 receptor and the NK3 receptor. These receptors are believed to have a role in blood traveling to the brain. - Therefore, a substance P antagonist is a substance that inhibits binding of substance P to any one of the receptors referred to above. A list of suitable substance P antagonists is referred to in Tables 1, 2, and 3 attached herewith.
- Reference may also be made to NK1 receptor antagonists as described in U.S. Pat. No. 5,990,125, which is incorporated herein by reference, as constituting substance P antagonists that may be utilized in the formulation of the method of the invention. This has specific reference to compounds of structures Ia, Ib, Ic, Id, Ie, X, XVI, XVII, XVIII, XIX, XX, and XXI, as well as other antagonists comprising quinuclidine, piperidine ethylene diamine, pyrrolidine and azabornane derivatives and related compounds that exhibit activity as substance P receptor antagonists as described in column 33 of U.S. Pat. No. 5,990,125.
- Such receptor antagonists may be employed having regard to the dosages referred to in column 34 of U.S. Pat. No. 4,990,125 and in various forms of administration i.e. alone or with various pharmaceutically acceptable carriers or diluents by oral administration of parenteral administration as referred in column 34 of U.S. Pat. No. 5,990,125.
- The activity of various substances as substance P receptor antagonists for use in the invention may also be determined by the assays referred to in columns 35-36 of U.S. Pat. No. 5,990,125.
- Reference also may be made to substance P receptor antagonists described in U.S. Pat. No. 5,977,104, including the various dosage forms and dosages referred to in this reference which is also totally incorporated by reference.
- Reference also is made to U.S. Pat. No. 4,481,139 that describes various peptide antagonists, which is also totally incorporated herein by reference.
- Reference also is made to U.S. Pat. No. 4,985,896 which refers to various piperidine and morpholine derivatives for use as substance P antagonists for use in the present invention or piperazine derivatives as described in U.S. Pat. No. 5,981,520. Each of these references is totally incorporated herein by reference.
- Reference also is made to piperidinyl compounds as NK1 and NK2 antagonists for use in the invention referred to in U.S. Pat. No. 5,998,444 which is also totally incorporated herein by reference.
- It will also be appreciated that tachykinin antagonists referred to in U.S. Pat. No. 4,981,744 may also be used as substance P antagonists in the invention, and thus this reference is also totally incorporated herein.
- Reference is also made to EP-A-1035115 which is totally incorporated herein by reference, which refers to N-benzyl-4-tolylnicotinamides and related compounds as NK1 receptor antagonists for use in the invention.
-
- R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
- R1 is hydrogen or halogen;
- R and R1 may be together —CH═CH—CH═CH—;
- R2 and R2′ are independently from each other hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; or
- R2 and R2′ may be together —CH═CH═CH═CH—, optionally substituted by one or two substituents selected from lower alkyl or lower alkoxy;
- R3 is hydrogen, lower alkyl or form a cycloalkyl group;
- R4 is hydrogen, —N(R5)2, —N(R5)(CH2)n(OH), —N(R5)S(O)2-lower alkyl, —N(R5)S(O)2-phenyl, —N═CH—N(R5)2, —N(R5)C(O)R5 or a cyclic tertiary amine of the group
- R5 is, independently form each other, hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl;
- R6 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO-lower alkyl, —N(R5)CO-lower alkyl, hydroxy-lower alkyl, cyano, —(CH2)nO(CH2)nOH, —CHO or a 5-or 6 membered heterocyclic group, optionally bonded via an alkylene group,
- X is —C(O)N(R5)—; —(CH2)mO—; —(CH2)mN(R5)—; —N(R5)C(O)—; or —N(R5)(CH2)m—; and
- n is 0-4; and
- m is 1 or 2;
and pharmaceutically acceptable acid addition salts thereof. - Exemplified compounds in EP-A-1035115 having a morpholine or piperazine group include
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
- 2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide,
- (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazin-1-yl)-acetic acid ethyl ester,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,
- N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide and
- [2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine.
- Reference is also made to International Publication WO 0050398 which is totally incorporated herein by reference, which refers to various phenyl and pyridinyl derivatives as NK1 receptor antagonists for use in the invention.
-
- R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
- R1 is hydrogen or halogen; or
- R and R1 may be together —CH═CH—CH═CH—;
- R2 is hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
- R3 is independently from each other hydrogen, lower alkyl or form a cycloalkyl group;
- R4 is hydrogen, halogen, lower alkyl, lower alkoxy, —N(R5)2, —N(R5)S(O)2-lower alkyl, —N(R5)C(O)R5 or a cyclic tertiary amine of the group
- R5 is, independently from each other, hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl;
- R6 is hydrogen, hydroxy, lower alkyl, —N(R5)CO-lower alkyl, hydroxy-lower alkyl, cyano, —CHO or a 5-or 6 membered heterocyclic group, optionally bonded via an alkylene group,
- X is —C(O)N(R5)—, —(CH2)mO—, —(CH2)mN(R5)—, —N(R5)C(O)—, —C(O)O— or —N(R5)(CH2)m—;
- Y is —(CH2)n—, —O—, —S—, —SO2—, —C(O)— or —N(R5)—;
- Z is ═N—, —CH═ or —C(Cl)═;
- n is 0-4; and
- m is 1 or 2;
and pharmaceutically acceptable acid addition salts thereof. - Exemplified compounds in WO 0050398 having a morpholine or piperazine group include
- N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,
- 4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide and
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide.
- Reference is also made to International Publications WO 0050401, WO 0053572, WO 0073278 and WO 0073279, which refer to 3-phenyl pyridines, biphenyl derivatives, 5-phenyl-pyrimidine derivatives and 4-phenyl pyrimidine derivatives respectively which specifications are also totally incorporated herein by reference. These specifications refer to NK1 receptor antagonists for use in the present invention.
-
- R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
- R1 is hydrogen or halogen; or
- R and R1 may be together —CH═CH—CH═CH—;
- R2 is hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
- R3 is hydrogen, lower alkyl or form a cycloalkyl group;
- R4 is hydrogen, —N(R5)2, —N(R5)S(O)2-lower alkyl, —N(R5)C(O)R5 or a cyclic tertiary amine of the group
- R5 is, independently from each other, hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl;
- R6 is hydrogen, hydroxy, lower alkyl, —N(R5)CO-lower alkyl, hydroxy-lower alkyl, cyano, —CHO or a 5-or 6 membered heterocyclic group, optionally bonded via an alkylene group,
- X is —C(O)N(R5)—, —(C H2)mO—, —(CH2)mN(R5)—, —N(R5)C(O)— or —N(R5)(CH2)m—;
- n is 0-4; and
- m is 1 or 2;
and pharmaceutically acceptable acid addition salts thereof. - Exemplified compounds in WO 0050401 having a morpholine or piperazine group include
- N-(3,5-Bis-trifluoromethyl-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,
- N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-5-phenyl-isonicotinamide, and
- N-(3,5-Dichloro-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide.
-
- R is hydrogen, lower alkyl, lower alkoxy, halogen, amino, —N(R6)2 or trifluoromethyl;
- R1 is hydrogen, lower alkoxy or halogen;
- R and R1 may be together —CH═CH—CH═CH—;
- R2 is halogen, lower alkyl or trifluoromethyl;
- R3 is hydrogen or lower alkyl;
- R4 is hydrogen or a cyclic tertiary amine, optionally substituted by lower alkyl;
- R5 is hydrogen, nitro, amino or —N(R6)2;
- R6 is hydrogen or lower alkyl;
- X is —C(O)N(R6)—, —(CH2)nO—, —(CH2)nN(R6)—, —N(R6)C(O)— or —N(R6)(CH2)n—; and
- n is 1 or 2;
and pharmaceutically acceptable acid addition salts thereof. - Exemplified compounds in WO 0053572 having a morpholine or piperazine group include
- 2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide and
- 2′-chloro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
-
- R1 is hydrogen or halogen;
- R2 is hydrogen, halogen, lower alkyl or lower alkoxy;
- R3 is halogen, trifluoromethyl, lower alkoxy or lower alkyl;
- R4/R4 are independently from each other hydrogen or lower alkyl;
- R5 is lower alkyl, lower alkoxy, amino, hydroxy, hydroxy-lower alkyl, —(CH2)n-piperazinyl, optionally substituted by lower alkyl, —(CH2)n-morpholinyl, —(CH2)n+1-imidazolyl, —O—(CH2)n+1-morpholinyl, —O—(CH2)n+1-piperidinyl, lower alkyl-sulfanyl, lower alkyl-sulfonyl, benzylamino, —NH—(CH2)n+1N(R4″)2, —(CH2)n—NH—(CH2)n+1N(R4″)2, —(CH2)n+1N(R4′″)2, or —O—(CH2)n+1N(R4″)2, wherein R4″ is hydrogen or lower alkyl;
- R6 is hydrogen;
- R2 and R6 or R1 and R6 may be together with the two carbon ring atoms —CH═CH—CH═CH—, with the proviso that n for R1 is 1;
- n is independently 0-2; and
- X is —C(O)N(R4″)— or —N(R4″)C(O)—;
or pharmaceutically acceptable acid addition salts thereof. - Exemplified compounds in WO 0073278 having a morpholine or piperazine group include
- 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidin-4-yl]-isobutyramide,
- 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,
- 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide, and
- 2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-N-methyl-isobutyramide.
-
- R1 is hydrogen or halogen;
- R2 is hydrogen, halogen, lower alkyl or lower alkoxy;
- R1 and R2 may be together with the two carbon ring atoms —CH═CH—CH═CH—;
- R3 is halogen, trifluoromethyl, lower alkyl or lower alkoxy;
- R4/R4′ are independently from each other hydrogen or lower alkyl;
- R5 is lower alkyl, lower alkoxy, amino, phenyl, hydroxy-lower alkyl, cyano-lower alkyl, carbamoyl-lower alkyl, pyridyl, pyrimidyl, —(CH2)n-piperazinyl, Ih is optionally substituted by one or two lower alkyl groups or by hydroxy-lower alkyl, —(CH2)n-morpholinyl, —(CH2)n-piperidinyl, —(CH2)n+1-imidazolyl, lower alkyl-sulfanyl, lower alkyl-sulfonyl, benzylamino, —NH—(CH2)n+1N(R4″)2, —(CH2)n+1N(R4″)2, —O—(CH2)n+1-morpholinyl, —O—(CH2)n+1-piperidinyl or —O—(CH2)n+1N(R4″)2, wherein R4″, is hydrogen or lower alkyl; and
- n is 0-2;
- X is —C(O)N(R4″)- or —N(R4″)C(O)—;
and pharmaceutically acceptable acid addition salts thereof. - Exemplified compounds in WO 0073279 having a morpholine or piperazine group include
- 4-(2-bromo-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid
- (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, (3R,5S)-4-(2-bromo-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-bromo-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- (3R,5S)-4-(2-chloro-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-chloro-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 2-piperazin-1-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-methoxy-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-methoxy-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(4-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(4-fluor-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(4-fluor-2-methyl-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 2-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-naphthalen-1-yl-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-bromo-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-chloro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 2-morpholin-4-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(2-methoxy-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 4-(4-fluoro-2-methyl-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 2-morpholin-4-yl-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
- 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidin-5-yl]-isobutyramide and
- 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyl-pyrimidin-5-yl)-isobutyramide.
- Reference also may be made to the reference the 1998 Sigma Catalogue and more particularly to pages 1194-1997 which describe modifications of substance P or substance P fragments, which may be used as substance P antagonists, for use in the invention. This publication is also totally incorporated herein by reference.
- In relation to the magnesium compound, this may comprises any suitable source of magnesium ion such as magnesium chloride, magnesium sulphate, magnesium oxalate, magnesium gluconate or other non toxic magnesium salt.
- The pharmaceutical preparations in accordance with this invention can in addition also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Thus the term “comprising” used in the specification should be interpreted in this context. The dosage can vary within wide limits and can, of course, be fitted to the individual requirements in each particular case. In general, a dosage of 1 to 20000 mg per patient, preferable 10 to 5000 mg and more preferably 50 to 2000 mg of the substance P receptor antagonist should be appropriate.
- In relation to the development of the inventive concept, it was established by the present inventors that one reasons for acute water accumulation in the brain after injury was the result of vasogenic oedema formation. This is caused by an increased permeability of the blood brain barrier thus permitting vascular proteins and water to enter the extracellular space in the brain and cause swelling. Few studies have examined how this increased blood brain barrier permeability contributes to the development of neurological deficits after injury, and no studies have investigated whether inhibition of brain swelling improves outcome. Studies of migraine12, 13 have suggested that the vasculature of the dura matter (outer meningeal lawyer) becomes more permeable to vascular components as a result of substance P release. We therefore hypothesized that substance P may have a similar effect on the cerebral vasculature, where such an effect could lead to increased blood brain barrier permeability and vasogenic cerebral oedema. We further hypothesized that administration of a substance P receptor antagonist may prevent brain swelling and the development of delayed neurologic deficits after injury. This hypothesis was a result of our discovery referred to above, that water accumulated in the brain as a result of vasogenic oedema formation.
- This, in another aspect of the invention there is provided the use of a substance P receptor antagonist for reducing brain barrier permeability and/or vasogenic cerebral oedema.
- A number of commercially synthesized substance P receptor antagonists are currently available from standard scientific chemical suppliers, as is apparent form Tables 1, 2, and 3. We chose to use the compound N-acetyl-L-tryptophan based on its low lipid solubility that limits its ability to naturally cross the blood brain barrier and the fact that it is relatively inexpensive. Administration of N-acetyl-L-tryptophan at an intravenous dose of 246 mg/kg (saline vehicle) given at 30 minutes after brain injury resulted in a significant improvement of cognitive outcome in brain injured animals as assessed by the Barnes Circular Maze. Similarly, there was a significant improvement in motor outcome of animals as assessed by the otarod test. These improvements in outcome were apparent at 24 hours after brain injury and persisted for the 14 day assessment period. Control (vehicle tested) animals had significantly worse neurologic outcome than treated animals at all time points tested.
- Animals treated with N-acetyl-L-tryptophan had a significant reduction in brain water accumulation (i.e. cerebral oedema) at 24 hours after injury as compared to vehicle treated controls. This was consistent with the observation that N-acetyl-L-tryptophan reduced brain penetration of Evans blue at 5 hours after injury: the time associated with maximum blood brain barrier permeability and reduced vasogenic oedema formation. The fact that these effects were noted with a non-permeable formulation of the NK1 antagonist suggests that the effects were largely mediated by vascular receptors and not dependent upon central receptors.
- Administration of N-acetyl-L-tryptophan at 24.6 mg/kg also significantly improved cognitive outcome of brain injured animals. However, the drug had less of a beneficial effect on motor outcome. Moreover, because there was also some residual cognitive and motor deficits noted in all treated animals, the beneficial effects of treatment with the NK1 antagonist were less apparent when injury of mild severity was induced as opposed to injury of a severe nature. This is a major limitation given that mild head injury has the greatest incidence in brain injury patients.
- Combination Magnesium and N-acetyl-L-tryptophan
- The most common form of brain injury is mild head injury. Guidelines to be introduced next year (2000) by the World Federation of Neurological Surgeons will recommend that all cases of minor head injury with any complications such as vomiting, nausea, loss of consciousness or amnesia MUST present to a hospital. This will place considerable pressure on the health system to adequately treat these individuals such that secondary injury does not develop any further. Currently, there is no such therapy.
- Our results with N-acetyl-L-tryptophan suggest that this compound closes the blood brain barrier after head injury and reduces brain swelling or cerebral oedema. This is extremely important in young victims of head injury who are particularly vulnerable to delayed brain swelling. Furthermore, our results with magnesium therapy suggest that magnesium treatment is effective at reducing neurologic deficits not necessarily associated with increased blood brain permeability. We therefore propose that a combination of a substance P antagonist with a magnesium compound or salt will be a particularly effective therapy for the treatment of brain injury irrespective of severity.
- Combination administration of 246 mg/kg N-acetyl-L-tryptophan plus 30 mg/kg magnesium sulphate (intravenously) resulted in a profound attenuation of both motor and cognitive deficits that was significantly greater than obtained with either drug in isolation. (
FIG. 1 andFIG. 2 ). - Each of the compounds in the combination formulation has a number of properties that make it particularly attractive for use in brain injury.
- Substance P(SP) antagonists have been shown to rapidly improve mood by antagonizing substance P induced anxiety. Thus, they are effective in treating post-injury depression. From the word described above, it is apparent that SP antagonists reduce blood brain barrier permeability and inhibit the formation of vasogenic oedema and post-injury brain swelling or cerebral oedema. The antagonists also have been shown to inhibit pain. There are high numbers of substance P receptors in the hippocampus and striatum, those parts of the brain that are known to be associated with learning and memory. Inhibition of binding with SP antagonists may thus prevent substance P induced deficits in learning and memory. Our evidence presented above suggests that this may be the case. This has never been shown previously. Indeed, there has been no literature on the role of substance P, or any neuropeptides, in brain injury.
- Magnesium affects over 300 cellular enzymes. It is not surprising; therefore, that magnesium has numerous targets at which it may improve outcome. These include, amongst others, blocking glutamate induced excitotoxicity, improving membrane stability and reducing the production of reactive oxygen species, improving energy status, inhibiting calcium channels, reducing neurotransmitter release, inhibiting mitochondrial transition pore opening, and inhibiting apoptosis. Notably, it also blocks glutamate induced release of substance P. Physiologically, magnesium has been shown (14-17) to improve cerebral blood flow, to reduce cerebral vasospasms, and to reduce vascular ceramide and prostaglandin production.
- The combined use of magnesium and the substance P antagonist results in greater protection against neural injury than either drug used alone.
- We have previously shown that magnesium has a beneficial effect in trauma when administered at intravenous doses ranging from 16 to 60 mg/kg. When administered as an intramuscular injection, the effective dose varies from 45 to 90 mg/kg. The target is to increase free magnesium concentration in the blood to approximately 1.0 mM, which is double the normal blood free magnesium concentration. Beneficial results are observed irrespective of the magnesium salt used.
- Our studies with the substance P antagonist have demonstrated that the effective i.v. dose varies from 24.6 mg/kg to 240.6 mg/kg or higher, with the higher doses having a greater beneficial effect on motor outcome. Moreover, these doses pertain to antagonists that have low lipid solubility and thus limited blood brain barrier permeability. A highly lipid soluble formulation should exact the same beneficial actions; however, there may be centrally mediated side-effects that may be inappropriate.
- When used in combination, the formulation may vary in the range described for the individual components. We have achieved excellent results using the maximum i.v. doses described for the individual components.
- The combination magnesium/SP antagonist is expected to be useful in the following conditions:
-
- As a “first-aid” prophylactic treatment following traumatic brain injury
- As a “first aid” prophylactic treatment following minor head injuries, including concussion
- As a therapy following non-traumatic brain injuries, including stroke, hypoxia and any form of brain injury where oedema is implicated
- As a maintenance therapy following brain injury
-
- 1. Vink R, Mcintosh T K, Demediuk P, Weiner M W, Faden A I: Decline in intracellular free magnesium concentration is associated with irreversible tissue injury following brain trauma. J Biol Chem 263: 757-761, 1998
- 2. Vink R, Heath D L, McIntosh T K: Acute and prolonged alterations in brain free magnesium following fluid percussion induced brain trauma in rats. J Neurochem 66:2477-2483,1996
- 3. Heath D L, Vink R: Brain intracellular free magnesium concentration declines following impact-acceleration induced brain injury in rats. Neurosci Res Commun 18:163-168,1996
- 4. Heath D L, Vink R: Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration. Brain Research 738:15-153,
- 5. McIntosh T K, Faden A I, Yamakami I, Vink R: Magnesium deficiency exacerbates and pretreatment improves outcome following traumatic brain injury in rats: 31P magnetic resonance spectroscopy and behavioral studies. J Neurotrauma 5:17-31, 1988
- 6. Vink R, Mcintosh T K: Pharmacological and physiological effects of magnesium on experimental traumatic brain injury. Magnesium Res 3:163-169, 1990
- 7. Heath D L, Vink R: Magnesium sulphate improves neurologic outcome following severe closed head injury in rats. Neuroscience Letters 228:175-178,1997
- 8. Heath, D L, Vink R: Neuroprotective effects of MgSO4 and MgCl2 in closed head injury: a comparative phosphorus NMR study. J Neurotrauma 15:183-189,1998
- 9. Heath D L, Vink R: Delayed therapy with magnesium up to 24 hours following traumatic brain injury improves motor outcome. J Neurosurg 90:504-409,
- 10. Heath D L, Vink R: Optimisation of magnesium therapy following severe diffuse axonal brain injury in rats. J Pharmacol Exp Ther 288:1311-1316,
- 11. Feickert H G, Drommer S, Heyer R: Severe head injury in children: impact of risk factors. J Trauma 47:33-38,1999
- 12. Moskkowitz M A: The neurobiology of vascular head pain. Ann Neurol 16: 157-168, 1984
- 13. Ferrari M D: Migraine. Lancet 351:1043-1052, 1998
- 14. Aktura B T, Altura B M: The role of magnesium in etiology of strokes and cerebrovasospasm. Magnesium 1: 277-291,1982
- 15. Ferago M, Szabo C, Dora E, Horvath I, Kovach A G B: Contractile and endothelium-dependent dilatory responses of cerebral arteries at various extracellular magnesium concentration. J Cereb Blood Flow Metab 11:161-164,1991
- 16. Kemp, P A, Gardiner S M, March J E, Rubin P C, Bennett T: Assessment of the effects of endothelin-1 and magnesium sulphate on regional blood flows in conscious rats, by the colour microsphere reference technique. Br J Pharmacol 126:621-626, 1999
- 17. Morril M A, Gupta R K, Kostellow A B, Gy M, Zhang, A, Altura B T, Altura B M: Mg2+ modulates membrane sphingolipid and lipid second messenger levels in vascular smooth muscle cells. FEBS Lett 167-171, 1998
TABLE 1 NK1 RECEPTOR ANTAGONISTS Chemical Code Chemical Name CGP49823 (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl]-4-piperineamine) dihydrochloride CP-96,345 (2S,3S)-cis-(2(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl-piperidine)dihydrochloride CP-122,721 (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine FK 888 N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl\-N-methyl-N-phenylmethyl-L-3-(2- naphthyl)-alaninamide GR203040 (2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)amine GR-205171 3-Piperidinamine,N-[[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]phenyl]methyl]-2-phenyl-, (2S-cis) GR 82334 [D-Pro9]spiro-gamma-lactam]Leu10, Trp1]physalaemin-(1-11) GR 94800 PhCO-Ala-Ala-DTrp-Phe-DPro-Pro-Nle-NH2 HSP-117 3-Piperidinamine,N-[[2,3-dihydro-5-(1-methylethyl)-7-benzofuranyl]methyl]2-phenyl-, dihydrochloride, (2S-cis)- L 703,606 1-Azabicyclo[2.2]octan-3-amine,2-(diphenylmethyl)-N-[(2-idophenyl)methyl]-, (2S-cis)-, oxalate L 732,138 N-acetyl-L-tryptophan L 733,060 ((2S,S)-3((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine L 742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(s)-phenyl-4-(5-(3-oxo-1,2,4-triazolo)methylmorpholine L 754,030 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5- yl)methylmorpholine L 668,169 L-Phenylalanine, N-[2-[3-[[N-[2-(3-amino-2-oxo-1-pyrrolidinyl)-4-methyl-1-oxopentyl]-L-methionyl-L- glutaminyl-D-tryptophyl-N-methyl-L-phenylalanyl]amino]-2-oxo-1-pyrrolidinyl]-4-methyl-1-oxopentyl]-L- methionyl-L-glutaminyl-D-tryptophyl-N-methyl-, cyclic (*->1)-peptide, [3R-[1[S*[R*(S*)]],3R*]]- LY 303241 1-Piperazineacetamide, N-[2-[acetyl[2-methoxyphenyl]methyl]amino]-1-(1H-indol-3-ylmethyl)(ethyl)-4- phenyl-, (R)- LY 303870 (R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-Indol-3-yl)-2-[N-(2-(4-(pi peridinyl)piperidin-1- yl)acetyl)amino]propane LY 306740 1-Piperazineacetamide, N-[2′-acetyl[(2-methoxyphenyl)methyl]amino]-1-(1H-indol-3-ylmethyl)ethyl]-4- cyclohexyl-, (R)- MEN 11149 2-(2-naphthyl)-1-N-[(1R,2S)-2-N-[1(H)indol-3-ylcarbonyl]aminocyclohexanecarbonyl]-1-[N′-ethyl-N′-(4- methylphenylacetyl)]diaminoethane MK-869 3H-1,2,4-Triazol-3-one, 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4- morpholinyl]methyl]-1,2-dihydro-, [2R-[2α(R*), 3α]]- PD 154075 (2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)Ph R-544 Ac-Thr-D-Trp(FOR)-PHe-N-MeBzl RP-67580 (3aR, &aR)-7,7-diphenyl-2[1-imino-2(2-methoxyphenyl)-ethyl+++perhydroisoindol-4-one hydrochloride RPR 100893 (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2- methoxyphenyl)proprionyl]perhydroisoindol-4-ol Spendide Tyr-D-Phe-Phe-D-His-Leu-Met-NH2 Spantide II D-NicLys1, 3-Pal3, D-Cl2Phe5, Asn6, D-Trp7.0, Nle11-substance P Spantide III L-Norleucinamide, N6-(3-pyridinylcarbonyl)-D-lysyl-L-prolyl-3-(3-pyridinyl)-L-alanyl-L-prolyl-3,4-dichloro- D-phenylalanyl-L-asparaginyl-D-tryptophyl-L-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-leucyl- SR140333 (S)-1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)-piperidin-3-yl]ethyl]-4-phenyl-1- azabicyclo[2.2.2]octane WIN-41,708 (17beta-hydroxy-17alpha-ethynyl-5alpha-androxtano[3,2-b]pyrimido[1,2-a]benzimidazole WIN-62,577 1H-Benzimidazo[2,1-b]cyclopenta[5,6]naphtha[1,2-g]quinazolin-1-ol, 1-ethynyl- 2,3,3a,3b,4,5,15,15a,15b,16,17,17a-dodecahydro-15a,17a-dimethyl-, (1R,3aS, 3bR, 15aR, 15bS, 17aS)- -
TABLE 2 NK2 RECEPTOR ANTAGONISTS Chemical Code Chemical Name SR-48,968 (S)-N-methyl-N[4-(4-acetylamino-4- [phenylpiperidino]-2- (3,4-dichlorophenyl)-butyl)benzamide L-659,877 Cyclo[Gln,Trp,Phe,Gly,Leu,Met] MEN 10627 Cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2beta05beta) SR 144190 (R)-3-(1-[2-(4-benzoyl-2- (3,4-difluorophenyl)-morpholin-2-yl)-ethyl] -4-phenylpiperidin-4-yl)-1-dimethylurea GR 94800 PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 -
TABLE 3 NK3 RECEPTOR ANTAGONISTS Chemical Code Chemical Name SR-142,801 (S)-(N)-(1-(3-(1-benzoyl-3- (3,4-dichlorophenyl)piperidin-3-yl)propyl)- 4-phenylpiperidin-4-yl)-N-methyl acetamide R820 3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl R486 H-Asp-Ser-Phe-Trp-beta-Ala-Leu-Met-NH2 SB222200 (S)-(−)-N-(a-ethylbenzyl)- 3-methyl-2-phenylquinoline-4-carboximide L 758,298 Phosphonic acid, [3-[[2-[1-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]- 2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-, [2R-[2α(R*), 3α]]- NK-608 (2R,4S)-N-[1-{3,5-bis(trifluoromethyl)-benzoyl}-2- (4-chloro-benzyl)-4-piperidinyl]-quinoline-4-carboxamide
Claims (11)
1. A method of treating a mechanical traumatic brain, spinal cord or nerve tissue injury by substantially reducing a secondary injury caused by a vasogenic oedema in the brain comprising administering to a patient in need of such treatment, a therapeutically effective amount of pharmaceutical preparation comprising a therapeutically effective amount of a substance P receptor antagonist selected from
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide,
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazin-1-yl)-acetic acid ethyl ester,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,
N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]4-o-tolyl-pyridin-3-yl}-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide,
[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine,
N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,
4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-5-phenyl-isonicotinamide,
N-(3,5-Dichloro-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,
2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2′-chloro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidin-4-yl]-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-N-methyl-isobutyramide,
4-(2-bromo-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-4-(2-bromo-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-bromo-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-4-(2-chloro-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-piperazin-1-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-methoxy-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-methoxy-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluor-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluor-2-methyl-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-naphthalen-1-yl-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-bromo-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-morpholin-4-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-methoxy-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluoro-2-methyl-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-morpholin-4-yl-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidin-5-yl]-isobutyramide, and
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyl-pyrimidin-5-yl)-isobutyramide; a non-toxic magnesium compound; and a pharmaceutically acceptable vehicle.
2. The method of claim 1 wherein the substance P receptor antagonist is selected from
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide,
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]4-o-tolyl-pyridin-2-yl}-piperazin-1-yl)-acetic acid ethyl ester,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, and
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide.
3. The method of claim 1 wherein the substance P receptor antagonist is selected from
N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,
N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide, and
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide.
4. The method of claim 1 wherein the substance P receptor antagonist is selected from
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, and
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.
5. The method of claim 1 wherein the substance P receptor antagonist is selected from
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide,
[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine,
N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,
4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide, and
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide.
6. The method of claim 1 wherein the substance P receptor antagonist is selected from
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-5-phenyl-isonicotinamide,
N-(3,5-Dichloro-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,
2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2′-chloro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and
5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
7. The method of claim 1 wherein the substance P receptor antagonist is selected from
5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidin-4-yl]-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-N-methyl-isobutyramide,
4-(2-bromo-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and
(3R,5S)-4-(2-bromo-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
8. The method of claim 1 wherein the substance P receptor antagonist is selected from
4-(2-bromo-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-4-(2-chloro-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-piperazin-1-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and
4-(2-methoxy-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
9. The method of claim 1 wherein the substance P receptor antagonist is selected from
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-methoxy-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluor-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
10. The method of claim 1 wherein the substance P receptor antagonist is selected from
4-(4-fluor-2-methyl-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(4-methyl-piperazin-1-yl)4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
(3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-naphthalen-1-yl-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-bromo-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and
2-morpholin-4-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
11. The method of claim 1 wherein the substance P receptor antagonist is selected from
4-(2-methoxy-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(4-fluoro-2-methyl-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-morpholin-4-yl-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidin-5-yl]-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyl-pyrimidin-5-yl)-isobutyramide.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/475,627 US9186404B2 (en) | 2000-01-18 | 2009-06-01 | Brain, spinal and nerve injury treatment |
US14/882,084 US20160030474A1 (en) | 2000-01-18 | 2015-10-13 | Brain, Spinal and Nerve Injury Treatment |
US15/714,819 US10201568B2 (en) | 2000-01-18 | 2017-09-25 | Brain, spinal, and nerve injury treatment |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPQ5146 | 2000-01-18 | ||
AUPQ5146A AUPQ514600A0 (en) | 2000-01-18 | 2000-01-18 | Brain injury treatment |
WOPCT/AU01/00046 | 2001-01-18 | ||
PCT/AU2001/000046 WO2001052844A1 (en) | 2000-01-18 | 2001-01-18 | Brain, spinal and nerve injury treatment |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10181323 Division | 2001-01-18 | ||
US10/181,323 Division US6841551B2 (en) | 2000-01-18 | 2001-01-18 | Brain, spinal, and nerve injury treatment |
PCT/AU2001/000046 Division WO2001052844A1 (en) | 2000-01-18 | 2001-01-18 | Brain, spinal and nerve injury treatment |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/475,627 Continuation US9186404B2 (en) | 2000-01-18 | 2009-06-01 | Brain, spinal and nerve injury treatment |
Publications (1)
Publication Number | Publication Date |
---|---|
US20050107380A1 true US20050107380A1 (en) | 2005-05-19 |
Family
ID=3819274
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/181,323 Expired - Fee Related US6841551B2 (en) | 2000-01-18 | 2001-01-18 | Brain, spinal, and nerve injury treatment |
US11/017,978 Abandoned US20050107380A1 (en) | 2000-01-18 | 2004-12-21 | Brain, spinal and nerve injury treatment |
US12/475,627 Expired - Lifetime US9186404B2 (en) | 2000-01-18 | 2009-06-01 | Brain, spinal and nerve injury treatment |
US14/882,084 Abandoned US20160030474A1 (en) | 2000-01-18 | 2015-10-13 | Brain, Spinal and Nerve Injury Treatment |
US15/714,819 Expired - Lifetime US10201568B2 (en) | 2000-01-18 | 2017-09-25 | Brain, spinal, and nerve injury treatment |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/181,323 Expired - Fee Related US6841551B2 (en) | 2000-01-18 | 2001-01-18 | Brain, spinal, and nerve injury treatment |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/475,627 Expired - Lifetime US9186404B2 (en) | 2000-01-18 | 2009-06-01 | Brain, spinal and nerve injury treatment |
US14/882,084 Abandoned US20160030474A1 (en) | 2000-01-18 | 2015-10-13 | Brain, Spinal and Nerve Injury Treatment |
US15/714,819 Expired - Lifetime US10201568B2 (en) | 2000-01-18 | 2017-09-25 | Brain, spinal, and nerve injury treatment |
Country Status (21)
Country | Link |
---|---|
US (5) | US6841551B2 (en) |
EP (1) | EP1261335B1 (en) |
JP (1) | JP4794794B2 (en) |
KR (1) | KR100780119B1 (en) |
CN (1) | CN1261095C (en) |
AU (2) | AUPQ514600A0 (en) |
BR (1) | BR0107695A (en) |
CA (1) | CA2397723C (en) |
CZ (1) | CZ20022804A3 (en) |
DE (1) | DE60139244D1 (en) |
HK (1) | HK1054872A1 (en) |
HR (1) | HRP20020593B1 (en) |
HU (1) | HUP0301920A3 (en) |
IL (2) | IL150548A0 (en) |
MX (1) | MXPA02007004A (en) |
NO (1) | NO329320B1 (en) |
NZ (2) | NZ519990A (en) |
RU (1) | RU2276996C2 (en) |
WO (1) | WO2001052844A1 (en) |
YU (1) | YU54702A (en) |
ZA (1) | ZA200205715B (en) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060239921A1 (en) * | 2005-04-26 | 2006-10-26 | Novadaq Technologies Inc. | Real time vascular imaging during solid organ transplant |
US20070122345A1 (en) * | 2005-09-02 | 2007-05-31 | University Of Rochester Medical Center | Intraoperative determination of nerve location |
US20080161744A1 (en) * | 2006-09-07 | 2008-07-03 | University Of Rochester Medical Center | Pre-And Intra-Operative Localization of Penile Sentinel Nodes |
WO2009009829A1 (en) * | 2007-07-19 | 2009-01-22 | Adelaide Research & Innovation Pty Ltd | Method for reducing intracranial pressure |
US20100222673A1 (en) * | 2005-08-10 | 2010-09-02 | Novadaq Technologies Inc. | Intra-operative head and neck nerve mapping |
US20110053954A1 (en) * | 2001-07-10 | 2011-03-03 | Torsten Hoffmann | Method of treatment and/or prevention of brain, spinal or nerve injury |
US8185176B2 (en) | 2005-04-26 | 2012-05-22 | Novadaq Technologies, Inc. | Method and apparatus for vasculature visualization with applications in neurosurgery and neurology |
US9610021B2 (en) | 2008-01-25 | 2017-04-04 | Novadaq Technologies Inc. | Method for evaluating blush in myocardial tissue |
US9816930B2 (en) | 2014-09-29 | 2017-11-14 | Novadaq Technologies Inc. | Imaging a target fluorophore in a biological material in the presence of autofluorescence |
US10041042B2 (en) | 2008-05-02 | 2018-08-07 | Novadaq Technologies ULC | Methods for production and use of substance-loaded erythrocytes (S-IEs) for observation and treatment of microvascular hemodynamics |
US10201568B2 (en) | 2000-01-18 | 2019-02-12 | Eustralis Pharmaceuticals Limited | Brain, spinal, and nerve injury treatment |
US10219742B2 (en) | 2008-04-14 | 2019-03-05 | Novadaq Technologies ULC | Locating and analyzing perforator flaps for plastic and reconstructive surgery |
US10278585B2 (en) | 2012-06-21 | 2019-05-07 | Novadaq Technologies ULC | Quantification and analysis of angiography and perfusion |
US10492671B2 (en) | 2009-05-08 | 2019-12-03 | Novadaq Technologies ULC | Near infra red fluorescence imaging for visualization of blood vessels during endoscopic harvest |
US10631746B2 (en) | 2014-10-09 | 2020-04-28 | Novadaq Technologies ULC | Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography |
US10992848B2 (en) | 2017-02-10 | 2021-04-27 | Novadaq Technologies ULC | Open-field handheld fluorescence imaging systems and methods |
Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ541595A (en) | 2003-01-28 | 2008-08-29 | Microbia Inc | Methods and compositions for the treatment of gastrointestinal disorders |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
GB0410215D0 (en) * | 2004-05-07 | 2004-06-09 | Lescroart Pol | Nerve damage |
US20080045610A1 (en) * | 2004-09-23 | 2008-02-21 | Alexander Michalow | Methods for regulating neurotransmitter systems by inducing counteradaptations |
EP1809104A4 (en) * | 2004-09-23 | 2009-04-29 | Alexander Michalow | Methods for regulating neurotransmitter systems by inducing counteradaptations |
BRPI0606187A2 (en) | 2005-02-25 | 2009-06-09 | Hoffmann La Roche | tablets with improved drug substance dispersibility |
WO2006110118A1 (en) * | 2005-04-15 | 2006-10-19 | Victor Pavlovich Kutnyak | Cytoprotection preparation |
US20070154448A1 (en) * | 2005-11-22 | 2007-07-05 | Ted Reid | Methods and compositions using Substance P to promote wound healing |
US8945623B2 (en) * | 2006-05-03 | 2015-02-03 | Warsaw Orthopedic, Inc. | Compositions comprising biomembrane sealing agent for treatment of neuronal injury, and methods of use |
US20100086543A1 (en) * | 2007-04-02 | 2010-04-08 | Saint Louis University | Compositions and methods for treating conditions associated with ceramide biosynthesis |
US20080241121A1 (en) * | 2007-04-02 | 2008-10-02 | Daniela Salvemini | Inhibitors of the ceramide metabolic pathway as adjuncts to opiates for pain |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
CA3089569C (en) | 2007-06-04 | 2023-12-05 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US20090263507A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Biological markers and response to treatment for pain, inflammation, neuronal or vascular injury and methods of use |
JP2011522828A (en) | 2008-06-04 | 2011-08-04 | シナジー ファーマシューティカルズ インコーポレイテッド | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer, and other disorders |
EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
WO2018129556A1 (en) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
KR20200111230A (en) | 2008-12-31 | 2020-09-28 | 알데릭스, 인코포레이티드 | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
US8852566B2 (en) * | 2009-03-26 | 2014-10-07 | Warsaw Orthopedic, Inc. | Compositions and methods for preferential distribution of active agents to injury sites |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
JP6154135B2 (en) * | 2010-12-03 | 2017-06-28 | 国立大学法人 岡山大学 | Traumatic neuropathy treatment |
WO2012125020A1 (en) * | 2011-03-14 | 2012-09-20 | N.V. Nutricia | Method for treating neurotrauma |
WO2014029983A1 (en) | 2012-08-21 | 2014-02-27 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
US10376481B2 (en) | 2012-08-21 | 2019-08-13 | Ardelyx, Inc. | Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
MX2015014351A (en) | 2013-04-12 | 2016-04-20 | Ardelyx Inc | Nhe3-binding compounds and methods for inhibiting phosphate transport. |
JP6606491B2 (en) | 2013-06-05 | 2019-11-13 | シナジー ファーマシューティカルズ インコーポレイテッド | Ultra high purity agonist of guanylate cyclase C, method for producing and using the same |
WO2015000035A1 (en) * | 2013-07-02 | 2015-01-08 | Eustralis Pharmaceuticals Limited (Trading As Pressura Neuro) | Method for preventing and/or treating chronic traumatic encephalopathy-iv |
RU2016103099A (en) * | 2013-07-02 | 2017-08-07 | Юстрэлиз Фармасьютикалз Лимитед (Трейдинг Эз Пресшура Нейро) | METHOD FOR PREVENTING AND / OR TREATMENT OF CHRONIC INJURY ENCEPHALOPATHY - I |
RU2674653C2 (en) * | 2013-07-02 | 2018-12-12 | Юстрэлиз Фармасьютикалз Лимитед (Трейдинг Эз Пресшура Нейро) | Method for preventing and/or treating chronic traumatic encephalopathy-ii |
WO2015000034A1 (en) * | 2013-07-02 | 2015-01-08 | Eustralis Pharmaceuticals Limited (Trading As Pressura Neuro) | Method for preventing and/or treating chronic traumatic encephalopathy-iii |
CN110291082A (en) | 2017-01-09 | 2019-09-27 | 阿德利克斯股份有限公司 | The inhibitor for the antiport that NHE is mediated |
AU2018205400B2 (en) | 2017-01-09 | 2022-07-14 | Ardelyx, Inc. | Compounds useful for treating gastrointestinal tract disorders |
AU2020337177A1 (en) * | 2019-08-23 | 2022-04-07 | Eustralis Pharmaceuticals Limited (Trading As Pressura Neuro) | Therapeutic methods and uses thereof |
WO2021202286A1 (en) * | 2020-03-30 | 2021-10-07 | Dignify Therapeutics, Llc | Compositions and methods for treating autonomic dysreflexia |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4481139A (en) * | 1983-04-13 | 1984-11-06 | Board Of Regents, The University Of Texas System | Peptide antagonists of substance P |
US4981744A (en) * | 1990-04-24 | 1991-01-01 | Swank Michael W | Non-planar expandable honeycomb structure |
US4985896A (en) * | 1985-03-29 | 1991-01-15 | Canon Kabushiki Kaisha | Laser driving device |
US5610165A (en) * | 1994-02-17 | 1997-03-11 | Merck & Co., Inc. | N-acylpiperidine tachykinin antagonists |
US5716979A (en) * | 1992-08-13 | 1998-02-10 | Warner-Lambert Company | Tachykinin antagonists |
US5744482A (en) * | 1994-10-05 | 1998-04-28 | Eli Lilly And Company | Serotonin agonist in combination with a tachykinin receptor antagonist in the treatment or prevention of migraine |
US5977104A (en) * | 1996-12-02 | 1999-11-02 | Merck Sharp & Dohme Ltd. | Use of NK-1 receptor antagonists for treating bipolar disorders |
US5981520A (en) * | 1995-05-02 | 1999-11-09 | Schering Corporation | Piperazino derivatives as neurokinin antagonists |
US5990125A (en) * | 1996-01-19 | 1999-11-23 | Pfizer Inc. | NK-1 receptor antagonists for the treatment of cancer |
US5998444A (en) * | 1995-10-24 | 1999-12-07 | Zeneca Ltd. | Piperidinyl compounds as NK1 or NK2 antagonists |
US6376507B1 (en) * | 1994-12-12 | 2002-04-23 | Pfizer Inc. | NK-1 receptor antagonists for the treatment of neuronal injury and stroke |
US6479483B2 (en) * | 1999-02-24 | 2002-11-12 | Hoffmann-La Roche Inc. | 4-phenyl-pyridine derivatives |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU4918796A (en) * | 1995-02-10 | 1996-08-27 | Eli Lilly And Company | Methods of treating or preventing psychiatric disorders |
WO1997038701A1 (en) * | 1996-04-12 | 1997-10-23 | Neotech Medical Innovations In | Composition and method for the treatment of premenstrual syndrome |
WO1999009987A1 (en) * | 1997-08-28 | 1999-03-04 | Merck & Co., Inc. | Method for treating premenstrual or late luteal phase syndrome |
GB9812662D0 (en) * | 1998-06-11 | 1998-08-12 | Merck Sharp & Dohme | Therapeutic use |
EP1157006B1 (en) | 1999-02-24 | 2006-10-25 | F. Hoffmann-La Roche Ag | Phenyl- and pyridinyl derivatives as neurokinin 1 antagonists |
SI1157005T1 (en) | 1999-02-24 | 2005-02-28 | F. Hoffmann-La Roche Ag | 3-phenylpyridine derivatives and their use as nk-1 receptor antagonists |
US6291465B1 (en) | 1999-03-09 | 2001-09-18 | Hoffmann-La Roche Inc. | Biphenyl derivatives |
JO2308B1 (en) | 1999-05-31 | 2005-09-12 | اف. هوفمان- لاروش أيه جي | 5-phenyl purinidine derivatives |
US6274588B1 (en) | 1999-05-31 | 2001-08-14 | Hoffmann-La Roche Inc. | 4-phenyl-pyrimidine derivatives |
GB9923748D0 (en) * | 1999-10-07 | 1999-12-08 | Glaxo Group Ltd | Chemical compounds |
AUPQ514600A0 (en) | 2000-01-18 | 2000-02-10 | James Cook University | Brain injury treatment |
US6479433B1 (en) | 2000-10-02 | 2002-11-12 | Smithers-Oasis Company | Polyurethane foam composites for grower applications and related methods |
-
2000
- 2000-01-18 AU AUPQ5146A patent/AUPQ514600A0/en not_active Abandoned
-
2001
- 2001-01-18 RU RU2002121640/15A patent/RU2276996C2/en not_active IP Right Cessation
- 2001-01-18 CA CA2397723A patent/CA2397723C/en not_active Expired - Fee Related
- 2001-01-18 NZ NZ519990A patent/NZ519990A/en not_active IP Right Cessation
- 2001-01-18 WO PCT/AU2001/000046 patent/WO2001052844A1/en active IP Right Grant
- 2001-01-18 US US10/181,323 patent/US6841551B2/en not_active Expired - Fee Related
- 2001-01-18 EP EP01901048A patent/EP1261335B1/en not_active Expired - Lifetime
- 2001-01-18 NZ NZ534278A patent/NZ534278A/en not_active IP Right Cessation
- 2001-01-18 JP JP2001552892A patent/JP4794794B2/en not_active Expired - Fee Related
- 2001-01-18 KR KR1020027009218A patent/KR100780119B1/en not_active IP Right Cessation
- 2001-01-18 HU HU0301920A patent/HUP0301920A3/en unknown
- 2001-01-18 DE DE60139244T patent/DE60139244D1/en not_active Expired - Fee Related
- 2001-01-18 AU AU26560/01A patent/AU782799B2/en not_active Expired
- 2001-01-18 MX MXPA02007004A patent/MXPA02007004A/en active IP Right Grant
- 2001-01-18 YU YU54702A patent/YU54702A/en unknown
- 2001-01-18 CZ CZ20022804A patent/CZ20022804A3/en unknown
- 2001-01-18 CN CNB018037208A patent/CN1261095C/en not_active Expired - Fee Related
- 2001-01-18 IL IL15054801A patent/IL150548A0/en unknown
- 2001-01-18 BR BR0107695-7A patent/BR0107695A/en not_active IP Right Cessation
-
2002
- 2002-07-02 IL IL150548A patent/IL150548A/en not_active IP Right Cessation
- 2002-07-16 HR HR20020593A patent/HRP20020593B1/en not_active IP Right Cessation
- 2002-07-17 ZA ZA200205715A patent/ZA200205715B/en unknown
- 2002-07-17 NO NO20023423A patent/NO329320B1/en not_active IP Right Cessation
-
2003
- 2003-10-14 HK HK03107353A patent/HK1054872A1/en not_active IP Right Cessation
-
2004
- 2004-12-21 US US11/017,978 patent/US20050107380A1/en not_active Abandoned
-
2009
- 2009-06-01 US US12/475,627 patent/US9186404B2/en not_active Expired - Lifetime
-
2015
- 2015-10-13 US US14/882,084 patent/US20160030474A1/en not_active Abandoned
-
2017
- 2017-09-25 US US15/714,819 patent/US10201568B2/en not_active Expired - Lifetime
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4481139A (en) * | 1983-04-13 | 1984-11-06 | Board Of Regents, The University Of Texas System | Peptide antagonists of substance P |
US4985896A (en) * | 1985-03-29 | 1991-01-15 | Canon Kabushiki Kaisha | Laser driving device |
US4981744A (en) * | 1990-04-24 | 1991-01-01 | Swank Michael W | Non-planar expandable honeycomb structure |
US5716979A (en) * | 1992-08-13 | 1998-02-10 | Warner-Lambert Company | Tachykinin antagonists |
US5610165A (en) * | 1994-02-17 | 1997-03-11 | Merck & Co., Inc. | N-acylpiperidine tachykinin antagonists |
US5744482A (en) * | 1994-10-05 | 1998-04-28 | Eli Lilly And Company | Serotonin agonist in combination with a tachykinin receptor antagonist in the treatment or prevention of migraine |
US6376507B1 (en) * | 1994-12-12 | 2002-04-23 | Pfizer Inc. | NK-1 receptor antagonists for the treatment of neuronal injury and stroke |
US5981520A (en) * | 1995-05-02 | 1999-11-09 | Schering Corporation | Piperazino derivatives as neurokinin antagonists |
US5998444A (en) * | 1995-10-24 | 1999-12-07 | Zeneca Ltd. | Piperidinyl compounds as NK1 or NK2 antagonists |
US5990125A (en) * | 1996-01-19 | 1999-11-23 | Pfizer Inc. | NK-1 receptor antagonists for the treatment of cancer |
US5977104A (en) * | 1996-12-02 | 1999-11-02 | Merck Sharp & Dohme Ltd. | Use of NK-1 receptor antagonists for treating bipolar disorders |
US6479483B2 (en) * | 1999-02-24 | 2002-11-12 | Hoffmann-La Roche Inc. | 4-phenyl-pyridine derivatives |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10201568B2 (en) | 2000-01-18 | 2019-02-12 | Eustralis Pharmaceuticals Limited | Brain, spinal, and nerve injury treatment |
US20110053954A1 (en) * | 2001-07-10 | 2011-03-03 | Torsten Hoffmann | Method of treatment and/or prevention of brain, spinal or nerve injury |
US8185176B2 (en) | 2005-04-26 | 2012-05-22 | Novadaq Technologies, Inc. | Method and apparatus for vasculature visualization with applications in neurosurgery and neurology |
US20090203993A1 (en) * | 2005-04-26 | 2009-08-13 | Novadaq Technologies Inc. | Real time imagining during solid organ transplant |
US9421280B2 (en) | 2005-04-26 | 2016-08-23 | Novadaq Technologies Inc. | Real time imaging during solid organ transplant |
US8647605B2 (en) | 2005-04-26 | 2014-02-11 | Novadaq Technologies, Inc. | Real time imaging during solid organ transplant |
US20060239921A1 (en) * | 2005-04-26 | 2006-10-26 | Novadaq Technologies Inc. | Real time vascular imaging during solid organ transplant |
US20100222673A1 (en) * | 2005-08-10 | 2010-09-02 | Novadaq Technologies Inc. | Intra-operative head and neck nerve mapping |
US10231624B2 (en) | 2005-08-10 | 2019-03-19 | Nov Adaq Technologies Ulc | Intra-operative head and neck nerve mapping |
US10265419B2 (en) | 2005-09-02 | 2019-04-23 | Novadaq Technologies ULC | Intraoperative determination of nerve location |
US20070122345A1 (en) * | 2005-09-02 | 2007-05-31 | University Of Rochester Medical Center | Intraoperative determination of nerve location |
US10434190B2 (en) | 2006-09-07 | 2019-10-08 | Novadaq Technologies ULC | Pre-and-intra-operative localization of penile sentinel nodes |
US20080161744A1 (en) * | 2006-09-07 | 2008-07-03 | University Of Rochester Medical Center | Pre-And Intra-Operative Localization of Penile Sentinel Nodes |
WO2009009829A1 (en) * | 2007-07-19 | 2009-01-22 | Adelaide Research & Innovation Pty Ltd | Method for reducing intracranial pressure |
US9936887B2 (en) | 2008-01-25 | 2018-04-10 | Novadaq Technologies ULC | Method for evaluating blush in myocardial tissue |
US10835138B2 (en) | 2008-01-25 | 2020-11-17 | Stryker European Operations Limited | Method for evaluating blush in myocardial tissue |
US11564583B2 (en) | 2008-01-25 | 2023-01-31 | Stryker European Operations Limited | Method for evaluating blush in myocardial tissue |
US9610021B2 (en) | 2008-01-25 | 2017-04-04 | Novadaq Technologies Inc. | Method for evaluating blush in myocardial tissue |
US10219742B2 (en) | 2008-04-14 | 2019-03-05 | Novadaq Technologies ULC | Locating and analyzing perforator flaps for plastic and reconstructive surgery |
US10041042B2 (en) | 2008-05-02 | 2018-08-07 | Novadaq Technologies ULC | Methods for production and use of substance-loaded erythrocytes (S-IEs) for observation and treatment of microvascular hemodynamics |
US10492671B2 (en) | 2009-05-08 | 2019-12-03 | Novadaq Technologies ULC | Near infra red fluorescence imaging for visualization of blood vessels during endoscopic harvest |
US10278585B2 (en) | 2012-06-21 | 2019-05-07 | Novadaq Technologies ULC | Quantification and analysis of angiography and perfusion |
US11284801B2 (en) | 2012-06-21 | 2022-03-29 | Stryker European Operations Limited | Quantification and analysis of angiography and perfusion |
US10488340B2 (en) | 2014-09-29 | 2019-11-26 | Novadaq Technologies ULC | Imaging a target fluorophore in a biological material in the presence of autofluorescence |
US9816930B2 (en) | 2014-09-29 | 2017-11-14 | Novadaq Technologies Inc. | Imaging a target fluorophore in a biological material in the presence of autofluorescence |
US10631746B2 (en) | 2014-10-09 | 2020-04-28 | Novadaq Technologies ULC | Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography |
US10992848B2 (en) | 2017-02-10 | 2021-04-27 | Novadaq Technologies ULC | Open-field handheld fluorescence imaging systems and methods |
US11140305B2 (en) | 2017-02-10 | 2021-10-05 | Stryker European Operations Limited | Open-field handheld fluorescence imaging systems and methods |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10201568B2 (en) | Brain, spinal, and nerve injury treatment | |
US8377936B2 (en) | Nicotinic receptor agonists for the treatment of inflammatory diseases | |
PT1897546E (en) | Combined compositions comprising (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid | |
AU2002249023A1 (en) | Nicotinic receptor agonists for the treatment of inflammatory diseases | |
Diz et al. | Acute depressor actions of angiotensin II in the nucleus of the solitary tract are mediated by substance P | |
US5981526A (en) | Use of tachykinin antagonist and rizatriptan | |
ES2206762T3 (en) | NEW THERAPEUTIC APPLICATION OF A DERIVATIVE OF TIENILCICLOHEXILAMINA. | |
US20050031608A1 (en) | Modified alpha-neurotoxins as painkillers | |
EP1631282A1 (en) | Use of the hydrochloride of the active ingredient base 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-piperazine combined with sumatriptan for the treatment of migraines | |
PL203468B1 (en) | Preparation for venous or intramammary treatment of brain, spinal cord and nerve damage | |
JP2002515461A (en) | Use of COX-2 inhibitors and NK-1 receptor antagonists for the treatment of inflammation | |
JP2004262814A (en) | Medicine composition for alleviating pain or spasticity in spinal cord injury patient | |
CA2441096C (en) | Nicotinic receptor agonists for the treatment of inflammatory diseases | |
EP1011678A1 (en) | Nicotine antagonists for nicotine-responsive neuropsychiatric disorders | |
Kaplan et al. | Transient Blindness during Pralidoxime Administration for Organophosphate Toxicity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: EUSTRALIS PHARMACEUTICALS LIMITED, AUSTRALIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HOFFMANN-LA ROCHE INC.;REEL/FRAME:023044/0720 Effective date: 20090730 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |