WO2003000643A1 - Nitrate ester derivatives useful for preparing drugs for epilepsy - Google Patents

Nitrate ester derivatives useful for preparing drugs for epilepsy Download PDF

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Publication number
WO2003000643A1
WO2003000643A1 PCT/EP2002/006389 EP0206389W WO03000643A1 WO 2003000643 A1 WO2003000643 A1 WO 2003000643A1 EP 0206389 W EP0206389 W EP 0206389W WO 03000643 A1 WO03000643 A1 WO 03000643A1
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formula
acid
radical
saturated
phenyl
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PCT/EP2002/006389
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French (fr)
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Ennio Ongini
Piero Del Soldato
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Nicox S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C07C327/34—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups with amino groups bound to the same hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
    • C07C335/08—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to drugs for the epilepsy treatment .
  • Epilepsy is defined as a group of cerebral disorders which appear with sudden and transitory episodes (fits or attacks ) of abnormal phenomena having a motor origin (convulsions).
  • the epileptic fits are characterized by patient consciousness loss and often accompanied by convulsions which in the most serious cases are extended to the musculature of the whole body.
  • Epilepsy has a high incidence in the population, only in the United States patients are 2.5 millions and every year about 100,000 new cases are diagnosed.
  • a classification of said disease based on clinical symptoms of the epileptic fits and on the state of the encephalographic trace is the following:
  • Partial fits (simple, complex or partially generalized) which appear with convulsions limited to only one limb or to a group of muscles; generally there is not consciousness loss even though in some cases (complex partial fits) episodes of confused behaviour appear.
  • Epilepsy represents a serious social problem since this disease affects both the patient social relations and the working efficiency; in young people epilepsy influences not only their insertion in the social organization but also the school efficiency.
  • Epilepsy is above all a serious sanitary problem: infact patients must take drugs for long periods (the therapy must be continued at least for two years after the fit disappearance).
  • the drugs at present used such for example phenobarbital , phenytoin, carbamazepine, in some patients are not able to control the convulsive activity and can interact with other drugs and, besides, cause side effects such as headache, nausea, vomit, sedation.
  • An object of the present invention are nitrooxyderivative compounds or salts thereof having the following general formula ( I ) :
  • A R-T t - , wherein R is the radical of a precursor drug, having formula II:
  • W is a carbon atom or a nitrogen atom; is an integer from 0 to 2;
  • R is a linear or branched C 1 -C 10 alkyl, a phenyl or benzyl group; or R 1H has one of the following meanings :
  • P/ Pi P 2 are integers, equal to or different from each other and ar 0 or 1 ; p 3 is an integer from 0 to 10;
  • R 4 is hydrogen, linear or branched C x -C 6 alkyl, free valence
  • R 6 , R 6A , R 7 , R 8 are H, methyl; or free valence ; with the proviso that in the radical of formula (IIA) when one unsaturation of ethylene type is present, between C and C 2 , R caution and R 5 are free valences such as to form the double bond between C x and C 2 ; when the unsaturation is between C 3 and C 4 , R 6 and R 7 are free valences such as to form the double bond between C 3 and C 4 ; when the unsaturation is between C 4 and C 5 , R, and R 8 are free valences such as to form the double bond between C 4 and C 5 ;
  • Q is equal to H, OH, 0R B wherein R B is benzyl, a linear or branched C 1 -C 6 alkyl, optionally substituted with one or more halogen atoms, preferably F, ' phenyl optionally substituted with one halogen atom or with one of the following groups:
  • T B and T BI are equal or different
  • X 2 bivalent radical, is such that the corresponding precursor of B -T B -X 2 -T BI - wherein the free valences of T B and of T BI are saturated each with OZ, with Z or with
  • Z H, C 1 -C 10 , preferably C ⁇ C ⁇ alkyl linear or branched when possible,
  • the precursor compound of B as above defined is preferably selected in the following classes of compounds: aminoacids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicillami- ne, N-acetylpenicillamine, cysteine, N-acetylcysteine, glutathione or esters thereof., preferably ethyl or isopropyl ester; hydroxyacids, sleeted from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid; aromatic and heterocyclic alcohols, selected from the following: nordihydr
  • nIX is an integer from 0 to 5 , preferably 1 ;
  • nllX is an integer from 1 to 5 preferably 1 ;
  • R ⁇ TX , R TIX , , R T[ IX , R T ⁇ ⁇ ' ' - e ual to or different from each other are H or linear or branched C ⁇ C,, alkyl ; preferably
  • Y 3 is a saturated, unsaturated or aromatic heterocyclic ring, having 5 or 6 atoms, containing from one to three heteroatoms, preferably from one to two, said heteroatoms being equal or different and selected among nitrogen, oxygen, sulphur; or Y can be:
  • Y 0 selected from the following: an alkylenoxy group R'O wherein R' is a linear or branched when possible C 1 -C 20 , preferably having from 2 to 6 carbon atoms , or a cycloalkylene having from 5 to 7 carbon atoms , in the cycloalkylene ring one or more carbon atoms can be substituted by heteroatoms, the ring can have side chains of R' type, R' being as above; is selected from one of the following groups:
  • nf ' is an integer from 1 to 6 preferably from 1 to
  • R lf H, CH 3 and nf is an integer from 1 to 6 ; preferably from 2 to 4;
  • Y ⁇ R selected from:
  • n3 is an integer from 0 to 5 and n3 ' is an integer from 1 to 3 ;
  • the precursor drugs of R are synthesized according to the methods reported in "The Merck Index, 12th Ed.” (1996).
  • the precursor drugs of R comprise in the molecule the radical of formula (Ila)
  • they can be synthesized as described in patent application WO 00/79658.
  • the precursor compounds of B of the above groups are prepared according to the methods known in the prior art and are described, for example, in “The Merck Index, 12th Ed.” herein incorporated by reference.
  • Y in the bivalent linking group C is selected between Y p and Y AR as above.
  • Y 3 is selected from the following bivalent radicals:
  • Y 3 is selected from the following bivalent radicals:
  • Y12 (Y13) (Yi4; (Y15) (Y16) (Yi7;
  • the preferred of Y 3 are the following: (Y12), having the two free valences in the ortho position with respect to the nitrogen atom; (Y16) with the two valences linked to the two heteroatoms, Yl (pyrazol) 3 , 5-disubstituted; (Y19), wherein the free valence on the ring is found in para position to the nitrogen atom.
  • the precursors of Y as defined in formula (III), wherein the free valence of the oxygen is saturated with H and the free valence of the end carbon is saturated either with a caraboxylic or a hydroxyl group, are products available on the market or can be obtained by methods known in the prior art.
  • the preferred precursors of B for the synthesis of the nitrooxyderivatives usable in the present invention are the following: ferulic acid, N-acetylcysteine, cysteine, caffeic acid, hydrocaffeic and gentisic acid; the preferred precursor drugs are the following: gabapentin, norvaline, arginine, pregabaline, (S) 3- isobutylGABA, ag atine.
  • the compounds according to the present invention when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in organic solvent such as for example acetonitrile, tetrahydrofuran with an equimolar amount of the corresponding organic or inorganic acid.
  • organic solvent such as for example acetonitrile, tetrahydrofuran with an equimolar amount of the corresponding organic or inorganic acid.
  • organic acids examples include oxalic, tartaric, maleic, succinic , citric acid.
  • inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acid.
  • Salts with nitric acid are preferred.
  • the compounds of the invention have shown to have an improved activity with respect to the precursor drugs in the epilepsy treatment.
  • mice Male Sprague-Dawley rats weighing 280-350 g were used; they were subcutaneously injected with 1 mg/Kg of scopolamine. 15 minutes later, to the groups of animals the tested nitrooxyderivatives and the corresponding precursor drugs, dissolved in sterile saline solution were respectively administered by intraperitoneal injection. After one hour from the scopolamine injection, pilocarpine hydrochloride, dissolved in saline solution, was administered by intraperitoneal injection at the doses of 200 or 350 mg/kg.
  • mice belonging to a lethargic mice stock (Lh/Lh) which, when aged of about 15 days develop an ataxic behaviour (Hosford DA Adv Neurol . 1999; 79: 239-252) .
  • the animals between 11 and 17 weeks old, were anaesthetized with ketamine (7.5 mg/g, i.p.) and medetomidine (0.1 mg/100 g, i.p.).
  • ketamine 7.5 mg/g, i.p.
  • medetomidine 0.1 mg/100 g, i.p.
  • In the frontal cortex and in the parietal cortex (0.8 mm under the dura mater) of each animal two microelectrodes connected to an apparatus for recording the electroencephalographic trace and to a cannula for administering the compounds were inserted. Once a week, counted by the insertion of the electrodes, an electroencephalographic trace of 2 hours was recorded.
  • Absences were quantified on the basis of the duration of the spike discharges on the electroencephalogram as described by Hosford DA et al . Science, 1992 Jul 17; 257(5068): 398-401 (variations of the electroencephalographic trace of amplitudes not lower than 60 ⁇ v and of frequencies in the range 5-6 Hz were recorded, attacks must last not less than 0.6 sec).
  • the electroencephalographic tracing were recorded by amplification of 200-300 ⁇ V/cm and with a paper speed of 3 mm/sec.
  • mice weight 6 to 12 g, 22-26 days old were treated with testing compounds. All compounds were given intraperitoneally ( i .p. ) dissolved in sterile saline solution 60 in prior of exposing mice to auditory stimulation. For each dose of compounds studied against audiogenic seizure 10 mice were used.
  • mice Groups of ICR CD1 mice (weight 16 to 24 g, 42 to 48 days old) were treated with testing compounds to evaluate the pharmacological effects on subconvulsant (40 mg/kg) or convulsant (CD 97 85 mg/kg) dose of pentylenetetrazole was used. All compounds were administered intraperitoneally (i.p.), as above indicated, 60 min before a subcutaneous (s.c.) injection of pentylenetetrazole (0.1 ml/10 g of body weight). All ICR CDl mice were observed for 60 min. Animals were scored as seizure positive if they exhibited continuous limb clonus lasting 3 s or of longer duration. For each dose of compounds studied against pentylenetetrazole seizure 10 mice were used.
  • the compounds of the invention can also be used in combination with NO-donor compounds of the prior art.
  • the NO donor compounds which can be used in combination with the invention compounds must comply with the test in vitro defined hereinafter.
  • the test relates to the generation of nitric oxide from the NO donors, for example nitroglycerin, niocorandil, nitro- prussiate, etc., in the presence of endothelial cells (method a) or platelets (method b) .
  • endothelial cells for example nitroglycerin, niocorandil, nitro- prussiate, etc.
  • chemiluminescence For the analysis by chemiluminescence, an amount equal to 100 ⁇ l was injected in the reaction chamber of a chemiluminescence analyzer containing glacial acetic acid and potassium iodide. The nitrites/nitrates present in the medium, under these conditions, are converted into NO which is then detected after reaction with ozone, which produces light.
  • the produced luminescence is directly proportional to the generated NO levels and can be measured by a suitable photomultiplying unit of a chemiluminescence analyzer. The photomultiplier converts the incident light into electric voltage, which is quantitatively recorded.
  • cGMP determination an aliquot of the incubation medium (equal to 100 ⁇ l ) was centrifuged at 1,000 revolutions for 20 seconds. The surnatant was removed and the sediment treated with iced phosphate buffer (pH 7.4). The produced cGMP levels were tested by specific immunoenzymatic reactants . From said experiments it resulted that, under these experimental conditions, the incubation with one of the various tested NO donors caused a significant increase of cGMP with respect to the values obtained in absence of a NO donor. For example, after incubation with 100 ⁇ M- of sodium nitroprussiate, an increase- of about 20 times the value obtained with the incubation of the carrier alone, without NO donor was recorded, Platelets
  • Washed human platelets prepared substantially in the same way as described by Radomski -et al, (Br. J. Pharmacol. 92, 639-1987), were used. Aliquots of 0.4 ml were incubated for 5 minutes with NO-donor scalar concentrations (1-100 ⁇ g/ml ) . The incubation medium (for ex. Tyrode) was then analyzed to determine the capability of the tested compound to generate NO, by the determination of nitric oxide by chemiluminescence and the determination of cGMP , as described in the previous paragraph for the same analyses carried out on the endothelial cells.
  • the preferred NO-donor compounds are those which in the molecule contain radicals of drugs belonging to the classes of aspirin, ibuprofen, paracetamol, naproxen, diclofenac, flurbiprofen and are described in patent applications WO 95/20641, WO 97/16405, WO 95/09831, WO 01/12584.
  • the compounds of the present invention can be synthesized as follows. Generally when in the drug molecule more reactive groups such as for example COOH and/or HX are present , they must be protected before the reaction according to the methods known in the prior art; for examaple as described in the volume by Th. w. Greene: “Protective groups in organic synthesis", Harward University Press, 1980.
  • acylhalides are prepared according to the methods known in the prior art , for example by thionyl or oxalyl chloride, halides of P or P in solvents inert under the reaction conditions, such as for example toluene, chloroform, DMF, etc.
  • the drug acylhalide is reacted with a compound HO-Y-R 8A , wherein Y is as above, R 3A is OH or halogen in the presence of a base, in an organic solvent inert under the reaction conditions according to the scheme below reported: RCOHal + HO-Y-R 8 ⁇ R-COO-Y-R 8A (ID) l.C)
  • the compounds obtained in the above reactions have formula R-COO-Y-Hal
  • the corresponding nitrooxyderivatives are obtained by reacting the compound R-CO-O-Y-Hal' with AgN0 3 in organic solvent such as acetonitrile, tetrahydrofuran according to the scheme:
  • the drug R-NH 2 is reacted with a compound of formula HX-X 2 -COOH, wherein X and X 2 are as above, in the presence of dicyclohexylcarbodiiird.de as described in l.A, to give the compound R-NH-C0-X 2 -XH, which is reacted with a compound of formula R aA -Y-C0Cl wherein R 8A and Y are as above defined, to give the following compound: R-NH- C0-X 2 -X-C0-Y-R 8A (4.B)
  • the compounds in the present invention have one or more chiral centres , they can be in racemic form or as mixtures of diastereoisomers , enantiomers, as single enantio ers or single diastereoisomers; when the compound shows a geometric asymmetry the compounds in the cis or trans form can be used.
  • the compounds of the present invention are formulated in the corresponding pharmaceutical compositions for parenteral, oral use, etc. , according to the tchniques well known in the field, together with the usual excipients; see for example the volume “Remington's Pharmaceutical Sciences 15th Ed.”
  • the amount on a molar basis of the active principle in said formulations is equal to or lower than the maximum posology indicated for the precursor drugs. Also higher doses can be used, considering their very good tolerability.
  • the administrable daily doses are those of the precursor drugs, or even lower. The daily doses can be found in the publications of the field, such as for example in "Physician's Desk reference".
  • the reaction mixture is left at room temperature, under stirring for 3 hours, filtered and evaporated at reduced pressure.
  • the obtained residue is treated with ethyl acetate and washed with water.
  • the organic phase is dried with sodium sulphate and evaporated at reduced pressure.
  • the residue is purified by chromatography on silica gel eluting with n- hexane/ethyl acetate 9/1. 5 g of the expected compound are obtained as an oil .
  • reaction mixture is left at 0°C under stirring for 30 minutes, and then 1 , 4 -dibromobutane (1.28 ml, 10.8 mmoles) is added.
  • the solution is left under stirring at room temperature overnight, then diluted with ethyl ether and washed with water.
  • the organic phase dried with sodium sulphate is evaporated under vacuum.
  • the obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 8/2. 0.7 g of the expected compound are obtained as an oil .
  • the solvent is evaporated at reduced pressure to give the compound as an yellow oil which is used without further purification.

Abstract

Nitrooxyderivative compounds or salts thereof having the following general formula (I): A-(B)b0-(C)co-NO2 (I) wherein: c0 is an integer and is 0 or 1, b0 is an integer and is 0 or 1, A = R-T1-, wherein R is the radical of formula (II) as defined in the application; B is such that its precursor is selected from aminoacids, hydroxyacids, polyalcohols, compounds containing at least one acid acid function, C is a bivalent radical containing an aliphatic, heterocyclic or aromatic radical.

Description

NITRATE ESTER DERIVATIVES USEFUL FOR PREPARING DRUGS FOR EPILEPSY
* * * * *
The present invention relates to drugs for the epilepsy treatment .
Epilepsy is defined as a group of cerebral disorders which appear with sudden and transitory episodes (fits or attacks ) of abnormal phenomena having a motor origin (convulsions). The epileptic fits are characterized by patient consciousness loss and often accompanied by convulsions which in the most serious cases are extended to the musculature of the whole body.
Epilepsy has a high incidence in the population, only in the United States patients are 2.5 millions and every year about 100,000 new cases are diagnosed.
A classification of said disease based on clinical symptoms of the epileptic fits and on the state of the encephalographic trace is the following:
1) Partial fits (simple, complex or partially generalized) which appear with convulsions limited to only one limb or to a group of muscles; generally there is not consciousness loss even though in some cases (complex partial fits) episodes of confused behaviour appear.
2) Generalized fits which appear with consciousness loss episodes (epileptic absences) which can be accompanied by isolated clonic contractions (myoclonic fits), contractions of all the muscles, (clonic fits), generalized convulsions ( tonic-clonic fits).
Epilepsy represents a serious social problem since this disease affects both the patient social relations and the working efficiency; in young people epilepsy influences not only their insertion in the social organization but also the school efficiency.
Epilepsy is above all a serious sanitary problem: infact patients must take drugs for long periods (the therapy must be continued at least for two years after the fit disappearance). The drugs at present used, such for example phenobarbital , phenytoin, carbamazepine, in some patients are not able to control the convulsive activity and can interact with other drugs and, besides, cause side effects such as headache, nausea, vomit, sedation.
The need was felt to have available drugs for the epilepsy treatment effective in reducing the incidence and/or the seriousness of convulsive fits and having lower side effects .
It has now been surprisingly and unexpectedly found that said technical problem can be solved with the class of drugs which is described hereunder.
An object of the present invention are nitrooxyderivative compounds or salts thereof having the following general formula ( I ) :
A-(B)b0-(C)c0-NO2 (I) wherein: cO is an integer and is 0 or 1, preferably 1; bO is an integer and is 0 or 1, with the proviso that cO and bO cannot be contemporaneously equal to zero; A = R-Tt - , wherein R is the radical of a precursor drug, having formula II:
Figure imgf000004_0001
(II) wherein:
W is a carbon atom or a nitrogen atom; is an integer from 0 to 2;
R0 = H, - (CH2)n-NHR1A, n being an integer from 0 to 2, wherein R1A= H, -C(0)-R1H, -C(0)0-R1H, wherein
R, is a linear or branched C1-C10 alkyl, a phenyl or benzyl group; or R1H has one of the following meanings :
Figure imgf000004_0002
(II-B) (II-C) (II-D) (II-E) wherein Ry is hydrogen, a linear or branched C^C^ alkyl, a phenyl or benzyl group; Rλ - H, when = N, Rx is the electronic doublet on the nitrogen atom (free valence); R2 is chosen between the following groups: phenyl, optionally substituted with an halogen atom or with one of the following groups: -OCH3, -CF3, nitro; mono- or di-hydroxy substituted benzyl, preferably 3-4 di-hydroxy substituted; a idino grou : H2N( C=NH ) - ; the radical of formula (IIA), wherein optionally one unsaturation of ethylene type can be present between the carbon atoms in position 1 and 2 , or 3 and 4 , or 4 and 5:
Figure imgf000005_0001
(IIA) wherein:
P/ Pi P2 are integers, equal to or different from each other and ar 0 or 1 ; p3 is an integer from 0 to 10;
R4 is hydrogen, linear or branched Cx-C6 alkyl, free valence;
R5 can have the following meanings : linear or branched C1-C3 alkyl, C3-C6 cycloalkyl, free valence, ORΛ, wherein RΛ has the following meanings: linear or branched
Figure imgf000005_0002
alkyl optionally substituted with one or more halogen atoms, preferably F, phenyl optionally substituted with one halogen atom or with one of the following groups: -OCH3, -CF3, nitro; R6A = H, methyl;
R6, R6A, R7, R8, equal or different, are H, methyl; or free valence ; with the proviso that in the radical of formula (IIA) when one unsaturation of ethylene type is present, between C and C2, R„ and R5 are free valences such as to form the double bond between Cx and C2; when the unsaturation is between C3 and C4 , R6 and R7 are free valences such as to form the double bond between C3 and C4; when the unsaturation is between C4 and C5, R, and R8 are free valences such as to form the double bond between C4 and C5;
Q is equal to H, OH, 0RB wherein RB is benzyl, a linear or branched C1-C6 alkyl, optionally substituted with one or more halogen atoms, preferably F,' phenyl optionally substituted with one halogen atom or with one of the following groups:
-OCH3, -CF3, nitro; or Q can have one of the following meanings :
C3-C6 cycloalkyl linear or branched
Figure imgf000006_0001
alkyl guanidine (H2NC ( =NH )NH- ) ; thioguanidine (H2NC(=S)NH- ) ; in formula (II) R2 with Rx and with W = C taken together form a
C4-C10, preferably C6 saturated or unsaturated, preferably saturated ring; x = (CO)t or (X)t., wherein X = O, S, NR1C, Rlc is H or a linear or branched alkyl , having from 1 to 5 carbon atoms , t and t ' are integers and equal to zero or 1, with the proviso that t =
1 when t ' = 0; t = 0 when t ' = 1;
B = -TB-X2-TBI- wherein
TB and TBI are equal or different;
TB = (CO) when t = 0, TB = X when t' = 0, X being as above; TBr = (CO)tx or (X)txx, wherein tx and txx have the value of 0 or
1; with the proviso that tx = 1 when txx = 0; and tx = 0 when txx = 1; X is as above;
X2, bivalent radical, is such that the corresponding precursor of B -TB-X2-TBI- wherein the free valences of TB and of TBI are saturated each with OZ, with Z or with
-N(ZX) (Zn) , being:
Z = H, C1-C10, preferably C^C^ alkyl linear or branched when possible,
Z1, ZIX equal or different have the values of Z as above, depending on that TB and/or TBI = CO or X, in function of the values of t , t' , tx and txx; the precursor compound of B as above defined is preferably selected in the following classes of compounds: aminoacids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicillami- ne, N-acetylpenicillamine, cysteine, N-acetylcysteine, glutathione or esters thereof., preferably ethyl or isopropyl ester; hydroxyacids, sleeted from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid; aromatic and heterocyclic alcohols, selected from the following: nordihydroguaiaretic acid, quercetin, catechin, kaempferol, sulphurethyne , ascorbic acid, isoascorbic acid, hydroquinone , gossypol, reductic acid, methoxyhydroquinone , hydroxyhydroquinone , propyl gallate, saccharose, 3 , 5-di- ertbutyl-4-hydroxybenzylthio glycolate, p-cumaric alcohol, -hydroxy-phenylethyl alcohol, coniferyl alcohol, allopurinol; compounds containing at least one free acid function, selected from the following: 3 , 3 ' - thiodipropionic acid, fumaric acid, dihydroxymaleic acid, edetic acid; C = bivalent radical -Tc-Y- wherein: when bO = cO = 1: Tc = (CO) when tx = 0 , Tc = X when txx =
0, X being as above defined, when bO = 0 : Tc = (CO) when t = 0 , Tc = X when t ' = 0 , X being as above defined, when cO = 0 : tx = 0 , TBI = X = -0-; Y has one of the following meanings :
'l'ix TIIX
I I
- [ C]nIX - Y3 - [ C ] nIIX-0- ( III )
I I TIX. κττIx . wherein : nIX is an integer from 0 to 5 , preferably 1 ; nllX is an integer from 1 to 5 preferably 1 ;
RτTX , RTIX, , RT[ IX , RTιιχ' '- e ual to or different from each other are H or linear or branched C^ C,, alkyl ; preferably
Rττx , RTJX, , RTIIχ / rπx' 3-^S rl .
Y3 is a saturated, unsaturated or aromatic heterocyclic ring, having 5 or 6 atoms, containing from one to three heteroatoms, preferably from one to two, said heteroatoms being equal or different and selected among nitrogen, oxygen, sulphur; or Y can be:
Y0, selected from the following: an alkylenoxy group R'O wherein R' is a linear or branched when possible C1-C20, preferably having from 2 to 6 carbon atoms , or a cycloalkylene having from 5 to 7 carbon atoms , in the cycloalkylene ring one or more carbon atoms can be substituted by heteroatoms, the ring can have side chains of R' type, R' being as above; is selected from one of the following groups:
-(CH2- - CH2- O)nf--
Figure imgf000009_0001
wherein nf ' is an integer from 1 to 6 preferably from 1 to
-( O -
Figure imgf000009_0002
wherein Rlf = H, CH3 and nf is an integer from 1 to 6 ; preferably from 2 to 4;
YΛR, selected from:
Figure imgf000009_0003
(V)
wherein n3 is an integer from 0 to 5 and n3 ' is an integer from 1 to 3 ; or
Figure imgf000009_0004
Figure imgf000010_0001
(VI) wherein n3 and n3 ' have the above meaning .
When in formula (II) W = C, m = 1 and R0 = -(CH2)n-NH2 with n = 1, R2 and Rx with W as above form together the cyclohexane ring, in the radical A of formula (I) T1 = CO and the free valence of A is saturated with OH, the precursor drug of R is known as gabapentine; when in formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = 0 , Rx = H, R2 is the radical of formula (IIA) wherein p = px = 1, p2 = p3 = 0, R4 = R5 = R5 = R6A = H, Q = H, in the radical A of formula (I) Tt = CO and the free valence of A is saturated with OH, the precursor drug of R is known as norvaline; when in' formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = 0, ■ R: = H, R2 is the radical of formula (IIA) wherein p = x = 1, p2 = p3 = 0 , R4 = R5 = R6 = R6A = H, Q is the guanidine group, in the radical A of formula (I) x = CO and the free valence of A is saturated with OH, the precursor drug of R is known as arginine ; when in formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = -0, Rx = H, R2 is the radical of formula (IIA) wherein p = i 1 Pa p3 = 0, R4 = R5 e —
Figure imgf000010_0002
H, Q is the thioguanidine group, in the radical A of formula (I) τ1 = CO and the free valence of A is saturated with OH, the precursor drug of R is known as thiocitrulline; when in formula (II) W = C, m = 1 and R0 = -(CH2)n-NH2 with n = 1, R: = H, R2 is the radical of formula (IIA) wherein p = i = P?. ~ 3 = °' i = H' R5 = Q = CH3, in the radical A of formula (I) T1 = CO and the free valence of A is saturated with OH, the precursor drug of R is known as pregabaline; when in formula (II) W = C and has configuration (S), m = 1 and R0 = -(CH2)n-NH2 with n = 1 , R± = H, R2 is the radical of formula (IIA) wherein p = px = p2 = P3 = 0 , R4 = H, R5 = Q = CH3 , in the radical A of formula (I) Tx = CO and the free valence of A is saturatd with OH, the precursor drug of R is known as ( S) 3 - isobutylGAB ; when in formula (II) W = C, m = 1 and R0 = Rx = H, R2 is the radical of formula (IIA) wherein p = px = 1, p2 = p3 = 0, R4 = R5 = R5 = R6A = H, Q is the guanidine group, in the radical A of formula (I) Tt = NH and the free valence of A is saturated with H, the precursor drug of R is known as agmatine; when in formula (II) W = C, m = 2 and R0 = -(CH2)n-NH2 with n = 0, Rt = H, R2 is the radical of formula (IIA) wherein p = px = ρ2 = p3 = 0 , R4 and R5 are free valences and between Cx and C2 there is one ethylene unsaturation, Q = H, in the radical A of formula ( I ) Tt = CO and the free valence of A is saturated with OH, the precursor drug of R is known as vigabatrine; when in formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = 0 , Rx = H, R2 is the radical 3-4 di-hydroxy substituted benzyl, 2 = CO and the free valence of A is saturated with OH, the percursor drug of R is known as 2-amino, (3,4- dihydroxyphenyl)propanoic acid (dopa) .
Generally the precursor drugs of R are synthesized according to the methods reported in "The Merck Index, 12th Ed." (1996). When the precursor drugs of R comprise in the molecule the radical of formula (Ila), they can be synthesized as described in patent application WO 00/79658.
The precursor compounds of B of the above groups are prepared according to the methods known in the prior art and are described, for example, in "The Merck Index, 12th Ed. " herein incorporated by reference.
Preferably when in formula (I) bO = 0, Y in the bivalent linking group C is selected between Yp and YAR as above.
Preferably Y3 is selected from the following bivalent radicals:
Preferably Y3 is selected from the following bivalent radicals:
Figure imgf000012_0001
(Yi; (Y2) (Y3 (Y4) (Y5) (Y6;
(Y19)
Figure imgf000012_0002
(Y7) (Y8 (Y9; (Y10) (γιι : (Y18)
Figure imgf000012_0003
(Y12) (Y13) (Yi4; (Y15) (Y16) (Yi7; The preferred of Y3 are the following: (Y12), having the two free valences in the ortho position with respect to the nitrogen atom; (Y16) with the two valences linked to the two heteroatoms, Yl (pyrazol) 3 , 5-disubstituted; (Y19), wherein the free valence on the ring is found in para position to the nitrogen atom.
The precursors of Y as defined in formula (III), wherein the free valence of the oxygen is saturated with H and the free valence of the end carbon is saturated either with a caraboxylic or a hydroxyl group, are products available on the market or can be obtained by methods known in the prior art.
In formula ( I ) the preferred precursors of B for the synthesis of the nitrooxyderivatives usable in the present invention are the following: ferulic acid, N-acetylcysteine, cysteine, caffeic acid, hydrocaffeic and gentisic acid; the preferred precursor drugs are the following: gabapentin, norvaline, arginine, pregabaline, (S) 3- isobutylGABA, ag atine.
The preferred compounds of formula ( I ) according to the present invention are the following:
1 - ( aminomethyl ) cyclohexan acetic acid 2 - ethoxy- - [ ( IE) - 3- [ 4- (nitrooxy) butoxy] -3 -oxy- 1 -propenyl ]phenyl hydrochloride ester (XV)
Figure imgf000013_0001
(XV) 1- (aminomethyl)cyclohexan acetic acid 3- (nitrooxymethyl; phenyl hydrochloride ester (XVI)
H-C!
Figure imgf000014_0001
(XVI) 2-aminopentanoic acid 3 - (nitrooxymethyl )phenyl hydrochloride ester (XVII)
Figure imgf000014_0002
(XVII) (S) -N-acetylcysteine- , 4- (nitrooxy)butyl ester, 2-amino pentanoate hydrochloride (XVIII)
Figure imgf000014_0003
(XVIII) (S) -N-acetylcysteine- , 4- (nitrooxy)butyl ester, 1- (aminomethyl ) cyclohexanacetate hydrochloride (XIX)
Figure imgf000015_0001
(XIX) 1- (aminomethyl ) cyclohexanacetic acid-, [6- (nitrooxy methyl) -2 -pyridinyl] ethyl hydrochloride ester (XX)
Figure imgf000015_0002
(XX) alpha-amino-delta-thioureidopentanoic acid, 3- (nitrooxy methyl )phenyl hydrochloride ester (XXI)
Figure imgf000015_0003
(XXI) (S) -N-acetylcysteine- , 4- (nitrooxy)butyl ester, alpha- amino-,delta- thioureidopentanoate hydrochloride (XXII)
Figure imgf000015_0004
alpha-amino-delta-thioureidopentanoic acid, 2-methoxy-4- [(1E) -3- [4- (nitrooxy) butoxy] -3 -oxy-l-propenyl]phenyl hydrochloride ester (XXIII)
Figure imgf000016_0001
(XXIII) 2 -amino- 5 -guanidinopentanoic acid , 3- (nitrooxy methyl )phenyl hydrochloride ester (XXIV)
Figure imgf000016_0002
(XXIV)
2 -amino- 5 -guanidinopentanoic acid-, 2-methoxy- 4- [ ( IE) - 3- [4- (nitrooxy)butoxy] - 3 -oxy- 1 -propenyl ]phenyl hydrochloride ester (XXV)
Figure imgf000016_0003
(XXV) (S) -N-acetylcysteine-4- (nitrooxy)butyl ester, 2-amino-5- guanidinopentanoate hydrochloride (XXVI)
Figure imgf000017_0001
( XXVI ) 4- (guanidine)butyl-3-nitrooxymethylbenzamide (XXVII)
Figure imgf000017_0002
(XXVII)
4- ( guanidine )butyl - 3 - [ 4 - ( 4 ' -nitrooxybutyryloxy) - 3■ (methoxy) ]phenyl -2-propenamide chloride (XXVIII)
Figure imgf000017_0003
(XXVIII)
1- (aminomethyl)cyclohexan acetic acid 4- (nitroxy)butyl hydrochloride ester (XXIX)
H-Cl
Figure imgf000017_0004
The preferred above mentioned compounds with the formulas (XV)- (XXIX) can be used as nitrate salts.
The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in organic solvent such as for example acetonitrile, tetrahydrofuran with an equimolar amount of the corresponding organic or inorganic acid.
Examples of organic acids are: oxalic, tartaric, maleic, succinic , citric acid.
Examples of inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acid.
Salts with nitric acid are preferred.
The compounds of the invention have shown to have an improved activity with respect to the precursor drugs in the epilepsy treatment.
To evaluate the efficacy in the epilepsy treatment of the compounds of the present invention, one of the following pharmacological tests were used.
I) imbic convulsions induced by pilocarpine (De Sarro G.B. et al. Eur. J. Pharmacol. 349: 179-185, De Sarro G.B., Brain Res. 591: 209-222, Turski W.A. , Behav. Brain Res., 9: 315-336) .
Male Sprague-Dawley rats weighing 280-350 g were used; they were subcutaneously injected with 1 mg/Kg of scopolamine. 15 minutes later, to the groups of animals the tested nitrooxyderivatives and the corresponding precursor drugs, dissolved in sterile saline solution were respectively administered by intraperitoneal injection. After one hour from the scopolamine injection, pilocarpine hydrochloride, dissolved in saline solution, was administered by intraperitoneal injection at the doses of 200 or 350 mg/kg.
At the end of the treatments the animals were placed in circular Plexiglass cages (40 cm diameter. ) For a time of 180 minutes after the administration of pilocarpine hydrochloride, the onset time and the intensity of the convulsions were checked .
The response of each animal was rated on the basis of a score assigned according to the scheme:
0 no reaction
1 perioral movements and scratching
2 tremors and relaxation of the hind paws
3 head movements and/or animal walking backwards
4 animal rising on the hind paws and tremors of the fore paws
5 falls
6 diffused tremors in the whole body
7 tonic clonic convulsions.
Method by analysis of the electroencephalographic tracing.
In this experiment were used mice belonging to a lethargic mice stock (Lh/Lh) which, when aged of about 15 days develop an ataxic behaviour (Hosford DA Adv Neurol . 1999; 79: 239-252) .
The animals, between 11 and 17 weeks old, were anaesthetized with ketamine (7.5 mg/g, i.p.) and medetomidine (0.1 mg/100 g, i.p.). In the frontal cortex and in the parietal cortex (0.8 mm under the dura mater) of each animal two microelectrodes connected to an apparatus for recording the electroencephalographic trace and to a cannula for administering the compounds were inserted. Once a week, counted by the insertion of the electrodes, an electroencephalographic trace of 2 hours was recorded.
After 15 minutes from the registration of the basic tracing, to the groups of mice solutions of the compounds, the corresponding precursor drugs in sodic phosphate buffer (67 M) and the carrier were respectively administered by intracerebral infusion (2.5 μl/min for a total volume of 10 μl) .
After the pharmacological treatment the electroencephalographic tracing was recorded for 3 hours and the animals were kept under observation for checking behaviour changes .
Absences were quantified on the basis of the duration of the spike discharges on the electroencephalogram as described by Hosford DA et al . Science, 1992 Jul 17; 257(5068): 398-401 (variations of the electroencephalographic trace of amplitudes not lower than 60 μv and of frequencies in the range 5-6 Hz were recorded, attacks must last not less than 0.6 sec).
The electroencephalographic tracing were recorded by amplification of 200-300 μV/cm and with a paper speed of 3 mm/sec.
In order to test the pharmacological effect of the compounds , each electroencephalographic tracing of 3 hours was divided into sections of 30 minutes and for each section the total duration of the spike and wave discharges was calculated; it was then normalized dividing this value by the corresponding value obtained after the administration of the vehicle. II) Evaluation of anticonvulsant activity in DBA/2 mice after auditory stimulation
Groups of DBA/2 mice (weight 6 to 12 g, 22-26 days old) were treated with testing compounds. All compounds were given intraperitoneally ( i .p. ) dissolved in sterile saline solution 60 in prior of exposing mice to auditory stimulation. For each dose of compounds studied against audiogenic seizure 10 mice were used.
Each mouse was placed under a hemispheric perspex dome (diameter 58 cm) and left for 1 min in order to allow habituation and assessment of locomotor activity. Auditory stimulation (12-16 kHz, 109 dB ) was applied for 1 min or until tonic extension occurred. Seizure response was assessed according to De Sarro GB et al . Neuropharmacology, 23(5) : 525-30 , 1984) using the following scale: 0 = no response, 1 = wild running, 2 = clonus, 3 = tonus , 4 = respiratory arrest. The maximum response was recorded for each animal . Rectal temperature was recorded immediately prior to auditory testing using an Elektrolaboratoriet thermometer type T.E.3. Behavioural changes were monitored during period between drug administration and auditory testing.
Ill) Evaluation of anticonvulsant activity by convulsant agent pentylenetetrazole
Groups of ICR CD1 mice (weight 16 to 24 g, 42 to 48 days old) were treated with testing compounds to evaluate the pharmacological effects on subconvulsant (40 mg/kg) or convulsant (CD97 85 mg/kg) dose of pentylenetetrazole was used. All compounds were administered intraperitoneally (i.p.), as above indicated, 60 min before a subcutaneous (s.c.) injection of pentylenetetrazole (0.1 ml/10 g of body weight). All ICR CDl mice were observed for 60 min. Animals were scored as seizure positive if they exhibited continuous limb clonus lasting 3 s or of longer duration. For each dose of compounds studied against pentylenetetrazole seizure 10 mice were used.
The compounds of the invention can also be used in combination with NO-donor compounds of the prior art.
The NO donor compounds which can be used in combination with the invention compounds must comply with the test in vitro defined hereinafter.
The test relates to the generation of nitric oxide from the NO donors, for example nitroglycerin, niocorandil, nitro- prussiate, etc., in the presence of endothelial cells (method a) or platelets (method b) . a) Endothelial cells
Cells of the human umbilical vein, cultured on plates, having a 103 density cells/well were incubated for 5 minutes with scalar concentrations of NO donor (1-100 μg/ml). The incubation medium (physiologic solution, for example Tyrode) was then analyzed to determine the capability to generate NO of the compound under test, by means of :
1) nitric oxide detection by chemiluminescence;
2) cGMP determination (cyclic GMP n° 2715 of the above mentioned Merck) .
For the analysis by chemiluminescence, an amount equal to 100 μl was injected in the reaction chamber of a chemiluminescence analyzer containing glacial acetic acid and potassium iodide. The nitrites/nitrates present in the medium, under these conditions, are converted into NO which is then detected after reaction with ozone, which produces light. In the equipments measuring the chemiluminescence, the produced luminescence is directly proportional to the generated NO levels and can be measured by a suitable photomultiplying unit of a chemiluminescence analyzer. The photomultiplier converts the incident light into electric voltage, which is quantitatively recorded. On the basis of a calibration curve, prepared with scalar nitrite concentrations, it can be quantitatively determined the generated NO concentration. For example, from the incubation of 100 μM of nicorandil, an amount equal to about 10 μM of NO was generated.
For cGMP determination, an aliquot of the incubation medium (equal to 100 μl ) was centrifuged at 1,000 revolutions for 20 seconds. The surnatant was removed and the sediment treated with iced phosphate buffer (pH 7.4). The produced cGMP levels were tested by specific immunoenzymatic reactants . From said experiments it resulted that, under these experimental conditions, the incubation with one of the various tested NO donors caused a significant increase of cGMP with respect to the values obtained in absence of a NO donor. For example, after incubation with 100 μM- of sodium nitroprussiate, an increase- of about 20 times the value obtained with the incubation of the carrier alone, without NO donor was recorded, Platelets
Washed human platelets, prepared substantially in the same way as described by Radomski -et al, (Br. J. Pharmacol. 92, 639-1987), were used. Aliquots of 0.4 ml were incubated for 5 minutes with NO-donor scalar concentrations (1-100 μg/ml ) . The incubation medium (for ex. Tyrode) was then analyzed to determine the capability of the tested compound to generate NO, by the determination of nitric oxide by chemiluminescence and the determination of cGMP , as described in the previous paragraph for the same analyses carried out on the endothelial cells. For the determination by chemiluminescence, also in this case, on the basis of a calibration curve prepared with scalar concentrations of nitrite, it was possible to quantitatively determine the produced NO amount. For example, after incubation of 100 μM of nicorandil, an amount equal to 35 μM of NO was generated.
For cGMP determination, it resulted that also under these experimental conditions the incubation with one of the tested NO donors gave a significant increase of cGMP with respect to the values obtained in absence of a NO donor. For example, after incubation with 100 uM of sodium nitroprussiate, an increase of about 30 times the value obtaind with the incubation of the only carrier without NO donor took place.
The preferred NO-donor compounds are those which in the molecule contain radicals of drugs belonging to the classes of aspirin, ibuprofen, paracetamol, naproxen, diclofenac, flurbiprofen and are described in patent applications WO 95/20641, WO 97/16405, WO 95/09831, WO 01/12584.
The compounds of the present invention can be synthesized as follows. Generally when in the drug molecule more reactive groups such as for example COOH and/or HX are present , they must be protected before the reaction according to the methods known in the prior art; for examaple as described in the volume by Th. w. Greene: "Protective groups in organic synthesis", Harward University Press, 1980.
The acylhalides are prepared according to the methods known in the prior art , for example by thionyl or oxalyl chloride, halides of P or P in solvents inert under the reaction conditions, such as for example toluene, chloroform, DMF, etc.
1) When in formula (I) bO = 0 and the free valence of the radical R of the drug is saturated with a carboxylic group, the synthesis methods to obtain the corresponding nitrooxyderivatives are the following: l.A) The drug of formula RCOOH is treated with an agent activating the carboxyl group selected from N,N'carbonyldiimidazol (CDl), N-hydroxybenzotriazol and dicyclohexylcarbodiimide (DCC) in solvent such as for example DMF, THF , chloroform, etc., at a temperature in the range from -5°C to 50°C and reacted in situ with a compound HO-Y-Hal, wherein Y and Hal are as above defined.
DCC, HO-Y-Hal
RCOOH > R-C0-0-Y-Hal (1C) l.B) Alternatively, the drug acylhalide is reacted with a compound HO-Y-R8A, wherein Y is as above, R3A is OH or halogen in the presence of a base, in an organic solvent inert under the reaction conditions according to the scheme below reported: RCOHal + HO-Y-R8Λ R-COO-Y-R8A (ID) l.C) When the compounds obtained in the above reactions have formula R-COO-Y-Hal the corresponding nitrooxyderivatives are obtained by reacting the compound R-CO-O-Y-Hal' with AgN03 in organic solvent such as acetonitrile, tetrahydrofuran according to the scheme:
R-COO-Y-Hal + AgN03 > R-C00-Y-0N02 l.D) When the compounds obtained in the above reactions have formula R-COO-Y-OH the hydroxyl group is subjected to halogenation, for example with PBr3, PC15, S0C12, PPh3 +
I2, and then reacted with AgN03 in organic solvent such as acetonitrile, tetrahydrofuran. 2) When in formula (I) bO = 0, and the reactive function of the drug is the group NH2, the synthesis methods to obtain the corresponding nitrooxyderivatives are the following: 2. a) By reaction of the drug R-NH2 with an acyl halide of formula Hal-Y-COHal, wherein Y and Hal are as above, according to the scheme:
R-NH2 + Hal-Y-COHal -» R- NHCO-Y-Hal (2A)
2.b) By reaction of the drug R-NH2 with an acyl halide of formula OH-Y-COHal, wherein Y and Hal are as above, according to the scheme:
R-NH2 + Hal-Y-COCl - R-NHCO-Y-OH (2B)
2.c) When the compounds obtained in the above reactions have formula R-NHCO-Y-Hal or R-NHCO-Y-OH the corresponding nitrooxyderivatives are obtained as above described in l.C and l.D respectively. 3. When in formula (I) bO = cO = 1, and the free valence of the radical R of the drug is saturated with a carboxylic group, the synthesis methods to obtain the corresponding nitrooxyderivatives are the following:
3. a) Alternatively the acyl halide of the drug and the compound of formula HX-X2-COOH, wherein X and X2 are as above , are reacted according to the methods known in the prior art, to give the compound R-CO-X-X2-COOH which is transformed into the corresponding sodic salt and reacted with a compound of formula Hal-Y-Ra wherein Hal and Y are as above and R8 is Cl , Br, Iodine, OH:
R-COHal + HX-X2-COOH -> R-CO-X-X2-COOH (3.A)
R-CO-X-X2-COONa + Hal-Y-R8A > R-CO-X-X2-CO-Y-R8A (3.A')
When R8A = OH the compound of formula (3.A') is subjected to halogenation as above described in l.D, when R8A = Hal the compound of formula (3. ') is reacted with AgN03 in organic solvent such as acetonitrile, tetrahydrofuran.
3.b) When Yτ is a C4 linear alkylene, the precursor of B of formula H0-X2-C00H is reacted with triphenylphosphine in the presence of a halogenating agent such as CBr4 or N- bromosucciniimide in tetrahydrofuran to give the compound of formula HO-X2-COO( CH2 ) 4Br which is reacted with the molecule of the drug RCOOH as described in l.A and l.C.
4) When in formula (I) p = l 0 = c0 = l, and the reactive function of the drug is the group NH2, the synthesis methods to obtain the corresponding nitrooxyderivatives are the following:
4. a) Reaction of the drug R-NH2 with an acyl halide of formula HX-X2-C0Hal, wherein X and X2 are as above, according to the methods known in the prior art , to give the compound R-NH-C0-X2-XH which is reacted with a compound of formula R8A-Y-C0Hal wherein R8A and Y are as above. R-NH2 + HX-X2-C0C1 > R-NH-C0-X2-XH ( 4 . A)
R-NH-C0-X2-XH + R8A-YCO-Hal > R-NH-C0-X2-X-C0-Y-R8A ( 4A' )
4.b) Alternatively, the drug R-NH2 is reacted with a compound of formula HX-X2-COOH, wherein X and X2 are as above, in the presence of dicyclohexylcarbodiiird.de as described in l.A, to give the compound R-NH-C0-X2-XH, which is reacted with a compound of formula RaA-Y-C0Cl wherein R8A and Y are as above defined, to give the following compound: R-NH- C0-X2-X-C0-Y-R8A (4.B)
When R8A = OH the compound of formula (4.B) or of formula (4a') is subjected to halogenation as above described in l.D; when R8A = Hal the compound of formula (4.B) is reacted with AgN03 in organic solvent such as acetonitrile, tetrahydrofuran.
When the compounds in the present invention have one or more chiral centres , they can be in racemic form or as mixtures of diastereoisomers , enantiomers, as single enantio ers or single diastereoisomers; when the compound shows a geometric asymmetry the compounds in the cis or trans form can be used.
The compounds of the present invention are formulated in the corresponding pharmaceutical compositions for parenteral, oral use, etc. , according to the tchniques well known in the field, together with the usual excipients; see for example the volume "Remington's Pharmaceutical Sciences 15th Ed."
The amount on a molar basis of the active principle in said formulations is equal to or lower than the maximum posology indicated for the precursor drugs. Also higher doses can be used, considering their very good tolerability. The administrable daily doses are those of the precursor drugs, or even lower. The daily doses can be found in the publications of the field, such as for example in "Physician's Desk reference".
The following Examples illustrate the invention without limiting the scope thereof. EXAMPLE 1
Synthesis of the 1- (aminomethyl )cyclohexan acetic acid 2- methoxy- 4 - [ ( IE) - 3 - [ 4 - (nitrooxy) butoxy] - 3 -oxy- 1-propenyl ] phenyl hydrochloride ester (XV)
Figure imgf000029_0001
A) Synthesis of the 1- (N-tert-butoxycarbonylaminomethyl) cyclohexan acetic acid
To a solution of 1- (aminomethyl )cyclohexanacetic acid (10 g, 58.4 mmoles) in a mixture of dioxane (100 ml) and water (150 ml), triethyla ine (16.27 ml, 116.8 mmoles) and di- tert-butyldicarbonate (15.3 g, 70 mmoles) are added. The reaction mixture is left at room temperature, under stirring for 4 hours. After having cooled the solution to 0°C it is brought to pH 2 with HC1 5%. The precipitate is filtered and dried under vacuum. 15 g of the expected compound are obtained as a white solid having m.p. = 125°-127°C.
B) Synthesis of 2-methoxy-4- [ (IE) -3 - [4- (bromo)butoxy] -3-oxy-l- propenyl ]phenol
To a solution of ferulic acid (11.6 g, 59.7 mmoles) in tetrahydrofuran (400 ml), tetrabromomethane (39.62 g, 119.47 mmoles) and triphenylphosphine (31.34 g, 119.47 mmoles) are added. The obtained mixture is kept under stirring at room temperature for 5 hours, filtered and evaporated at reduced pressure. The residual crude compound is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 8 g of the expected compound are obtained as a yellow solid having m.p. = 86°-89°C.
C) Syntheis of 2-methoxy- - [ (IE) -3 - [4 - (nitrooxy)butoxy] -3-oxy- 1 -pr openyl ] phenol
To a solution of 2-methoxy-4- [ ( IE) -3- [ - (bromo) butoxy] - 3 -oxy- 1- ropenyl]phenol (8 g, 24.3 mmoles) in acetonitrile (500 ml) silver nitrate (12.25 g, 72.9 mmoles) is added. The reaction mixture is heated at 40°C for 12 hours sheltered from light. The formed salt is removed by filtration and the solution is evaporated at reduced pressure. The residue is purified by chromatography on silica gel eluting with n- hexane/ethyl acetate 75/25. 4 g of the expected compound are obtained as a yellow solid having m.p. = 65°-68°C.
D) Synthesis of the 1- (N-tert-butoxycarbonylaminomethyl ) cyclohexan acetic acid 2-m thoxy-4- [ (IE) -3- [4- (nitrooxy)butoxy] -3 -oxy-1 - ropenyl ]phenyl ester
To a solution of 1 - (N- tert -butoxyca bony1 aminomethyl) cyclohexan acetic acid (2.5 g, 9.2 mmoles) in chloroform (200 ml) and N,N-dimethylfor amide (3 ml), 2-methoxy-4- [ (IE) -3- [ - (nitrooxy)butoxy] -3 -oxy- 1-propenyl] phenol (3.15 g, 10.1 mmoles), dicyclohexylcarbodiimide (5.7 g, 27.6 mmoles) and N,N-dimethylaminopyridine (33 mg, 0.27 mmoles) are added.
The reaction mixture is left at room temperature, under stirring for 3 hours, filtered and evaporated at reduced pressure. The obtained residue is treated with ethyl acetate and washed with water. The organic phase is dried with sodium sulphate and evaporated at reduced pressure. The residue is purified by chromatography on silica gel eluting with n- hexane/ethyl acetate 9/1. 5 g of the expected compound are obtained as an oil .
E) Synthesis of the 1- (aminomethyl ) cyclohexan acetic acid 2- methoxy-4- [ (IE) -3- [4- (nitrooxy)butoxy] -3 -oxy-1-propenyl ] phenyl hydrochloride ester
To a solution of 1- (N- tert-butoxycarbonylamino methyl) cyclohexan acetic acid 2-methoxy-4- [ ( IE) -3- [ 4- (nitrooxy) butoxy] -3-oxy-l- ropenyl]phenyl ester (5 g, 8.8 mmoles) in ethyl acetate (100 ml), a solution of HC1 IN in ethyl acetate (50 ml) is added. The reaction mixture is left overnight at room temperature, then concentrated under vacuum to a volume of 40 ml. The obtained residue is treated with ethyl ether. The precipitate is filtered and dried under vacuum. 1.8 g of the expected compound are obtained as a white solid having m.p. = 103°-105°C.
JH-NMR (CDC13) ppm: 8.43 (2H, m) ; 7.55 (1H, d) ; 7.10 (3H, m) ; ■6. 34 (1H, d); 4.51 (2H, t), 4.26 (2H, t); 3.89 (3H, s); 3.12 (2H, s); 2.81 (2H, s); 1.82 (4H, m) ; 1.54 (10H, ) . EXAMPLE 2
Synthesis of the 1- (aminomethyl ) cyclohexan acetic acid 4- ( itrooxy) butyl hydrochloride ester
H-Cl
Figure imgf000031_0001
A) Synthesis of the 1- (N- tert-butoxycarbonylaminomethyl ) cyclohexan acetic acid 4 - (bro o )butyl ester
To a solution of 1- (N- tert-butoxycarbonyl aminomethyl ) cyclohexan acetic acid (1 g, 3.6 mmoles) in N,N- dimethyl formamide (50 ml) cooled at 0°C, sodium ethylate (246 mg, 3.6 mmoles) is added.
The reaction mixture is left at 0°C under stirring for 30 minutes, and then 1 , 4 -dibromobutane (1.28 ml, 10.8 mmoles) is added. The solution is left under stirring at room temperature overnight, then diluted with ethyl ether and washed with water. The organic phase dried with sodium sulphate is evaporated under vacuum. The obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 8/2. 0.7 g of the expected compound are obtained as an oil .
B) Synthesis of the 1- (N- tert-butoxycarbonylaminomethyl ) cyclohexan acetic acid 4- (nitrooxy) utyl ester
To a solution of 1- (N-tert-butoxycarbonylamino methyl) cyclohexan acetic acid 4 -( bromo)butyl ester (1 g, 2.5 mmoles) in acetonitrile (200 ml) silver nitrate (1.3 g, 7.5 mmoles) is added. The reaction mixture is heated at 80°C for 6 hours sheltered from light. The formed salt is removed by filtration and the solution is evaporated at reduced pressure. The residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 8/2. 0.8 g of the expected compound are obtained as an oil .
C) Synthesis of the 1- (aminomethyl ) cyclohexan acetic acid 4- (nitrooxy)butyl hydrochloride ester
To a solution of 1- (N-tert-butoxycarbonylamino methyl) cyclohexan acetic acid 4- (nitrooxy) butyl .ester (0.8 g, 2.06 mmoles) in ethyl acetate (5 ml) a solution of HCl IN in ethyl acetate (20 ml) is added. The reaction mixture is left for 3 hours at room temperature then it is treated with n-hexane. The precipitate is filtered and dried under vacuum. 0.45 g of the expected compound are obtained as a white solid having m.p. = 80.3°-81.3°C.
XH-NMR (DMSO) ppm: 8.23 (2H, s); 4.58 (2H, t), 4.09 (2H, t); 2.92 (2H, s); 2.56 (2H, s); 1.74 (4H, m) ; 1.44 (10H, m) . EXAMPLE 3
Synthesis of the 1-(aminomethyl ) cyclohexan acetic acid 3- (nitrooxymethyl)phenyl hydrochloride ester (XVI)
H-Cl
Figure imgf000033_0001
A) Synthesis of 3 - (bromomethyl ) henol
To a solution of 3 -hydroxybenzyl alcohol (4 g, 32.2 mmoles) in methylene chloride (250 ml), cooled at 0 °C , tetrabromomethane (12.82 g, 38.6 mmoles) and triphenylphosphine (12.67 g, 48.3 mmoles) are added. The mixture is kept under stirring at 0° for 10 minutes, then evaporated at reduced pressure. The crude product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 8/2. 3.5 g of the expected product are obtained.
B) Synthesis of the 1- (N- tert-butoxycarbonylaminomethyl ) cyclohexan acetic acid 3- (bromomethyl )phenyl ester
To a solution of 1- (N-tert-butoxycarbonylamino methyl) cyclohexan acetic acid (2.6 g, 9.7 mmoles) in chloroform (200 ml) and N,N- imethylformamide (2 ml), 4 - (bromomethyl )phenol (2g, 10.7 mmoles), dicyclohexylcarbodiimide (4 g, 19.7 mmoles) and N,N-dimethylaminopyridine. (24 g, 0.20 mmoles) are added. The reaction mixture is left at room temperature for 4 hours under stirring, filtered and evaporated at reduced pressure. The obtained residue is treated with ethyl acetate and washed with water. The organic phase is dried with sodium sulphate and evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 9/1. 1.4 g of the compound are. obtained as an oil .
C) Synthesis of the 1- (N-tert-butoxycarbonylamino methyl ) cyclohexan acetic acid 3 - (nitrooxymethyl )phenyl ester
To a solution of 1- (N-tert-butoxycarbonylamino methyl ) cyclohexan acetic acid 3 - (bromomethyl) phenyl ester (1.4 g, 3.18 mmoles) in acetonitrile (300 ml) silver nitrate (1 g, 6.36 mmoles) is added. The reaction mixture is heated at 50°C for 4 hours sheltered from light. The formed salt is removed by filtration and the solution is evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 8/2. 0.75 g of the expected compound are obtained as an oil.
D) Synthesis of the 1- (aminomethyl )cyclohexan acetic acid 3- (nitrooxymethyl)phenyl hydrochloride ester
To a solution of 1- (N-tert-butoxycarbonylamino methyl) cyclohexan acetic acid 3- (nitrooxymethyl )phenyl ester (0.75 g, 1.8 mmoles) in ethyl acetate ( 5 ml ) , a solution of HCl IN in ethyl acetate (18 ml) is added. The reaction mixture is left for 1'5 minutes at room temperature, then it is treated with n-hexane. The precipitate is filtered and dried under vacuum. 0.45 g of the expected compound are obtained as a white solid having m.p. = 106°-108°C.
*H-NMR (DMSO) ppm: 8.16 (3H, m) ; 7.52 (1H, t ) ; 7.44 (lH,d);
7.34 (1H, s), 7.28 (1H, d) ; 5.65 (2H, s), 3.03 (2H, m) ; 2.86
(2H, s) ; 1.55 (10H, m) .
EXAMPLE 4
Synthesis of the 2 -aminopentanoic acid 2-methoxy-4- [ (IE) -3 -
[4- (nitrooxy) butoxy] -3 -oxy- 1-propenyl ]phenyl hydrochloride ester
Figure imgf000035_0001
A) Synthesis of the 1- (N-tert-butoxycarbonylamino) pentanoic acid.
To a solution of 2 -aminopentanoic acid (4 g, 34.14 mmoles) in dioxane (40ml) and water (75ml), triethylamine (9.5 ml, 68.29 mmoles) and di- tert-butyldicarbonate (8.94 g, 49.97 mmoles) are added. The reaction mixture is left at room temperature ,. under stirring for 17 hours. Afte having cooled the solution at 0°C it is brought to pH = 2 with HCl at 5%. One extracts with ethyl acetate, the joined organic phases are washed with water and dried with sodium sulphate.
The solvent is evaporated at reduced pressure to give the compound as an yellow oil which is used without further purification.
B) Synthesis of 2-methoxy-4- [ (IE) - 3 - [ 4- (bromo)butoxy] -3-oxy-l- propenyl ]phenol To a solution of ferulic acid (11.6 g, 59.7 mmoles)' in tetrahydrofuran (400 ml), tetrabromomethane '(39.62 g, 119.47 mmoles) and triphenylphosphine (31.34 g, 119.47 mmoles) are added. The obtained mixture is kept under stirring at room temperature for 5 hours, filtered and evaporated at reduced pressure. The obtained crude compound is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 8 g of the expected compound are obtained as a yellow solid having m.p. = 86°-89°C.
C) Synthesis of 2 -methoxy-4- [ ( IE) -3- [ 4- (nitrooxy)butoxy] -3 - oxy- 1 - ropenyl ] henol
To a solution of 2 -methoxy-4- [ ( IE) -3 - [ 4- (bromo) butoxy] - 3 - oxy- 1-propenyl ]phenolo (8 g, 24.3 mmoles) in acetonitrile (500 ml) silver nitrate (12.25 g, 72.9 mmoles) is added. The reaction mixture, is heated at 40°C for 12 hours sheltered from light. The formed salt is removed by filtration and the solution is evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 75/25. 4 g of the expected compound are obtained as a yellow solid having m.p. = 65°-68°C.
C) Synthesis of the 2- (N-tert-butoxycarbonylamino) pentanoic acid 2 -methoxy-4- [ (IE) -3- [4- (nitrooxy)butoxy] - 3-oxy-l- propenyl ]phenyl ester
To a solution of 2 - (N-tert-butoxycarbonylamino) pentanoic acid (0.5 g, 2.3 mmoles) in chloroform (12 ml), 2- methoxy-4- [ (IE) -3- [4- (nitrooxy)butoxy] -3 -oxy-1-propenyl ]phenol (0.86 g, 2.76 mmoles), dicyclohexylcarbodiimide (0.52 g, 2.53 mmoles) and N,N-dimethylaminopyridine (0.03 g, 0.23 mmoles) are added. The reaction mixture is left at room temperature for 1 hour under stirring, filtered and evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with n- hexane/ethyl acetate 75/25. 0.5 g of the expected compound are obtained as an oil. Yield 43%.
D) Synthesis of the 2 -aminopentanoic acid 2 -methoxy-4- [( IE) -3 - [4- (nitrooxy)butoxy] -3 -oxy- 1-propenyl ] henyl hydrochloride ester
To a solution of 2- (N-tert-butoxycarbonylamino) pentanoic acid 2 -methoxy-4- [ (IE) -3- [ 4- (nitrooxy)butoxy] -3 - oxy- 1 -propenyl ]phenyl ester (0.28 g, 0.548 mmoles) in ethyl acetate (7 ml), a solution of HCl in ethyl acetate (6.8 N, 0.700 ml) is added. The reaction mixture is left 3 hours at room temperature. The precipitate is filtered and dried under vacuum. 0.1 g of the expected compound are obtained as a white solid.
XH-NMR (DMSO) ppm: 8.75 (3H, m) ; 7.62 (1H, d) ; 7.58 (1H, s); 7.3 (1H, d); 7.2 (1H, d) ; 6.72 (1H, d) ; 4.57 (2H, t), 4.26 (1H, t); 4.18 (2H, t); 3.82 (3H, s); 1.95 (2H, m) ; 1.75 (4H, m); 1.45 (2H, m) 0.98 (3H, m) .

Claims

Nitrooxyderivative compounds or salts thereof having the general formula ( I ) :
A-(B)b0-(C)c0-NO2 (I)
wherein: cO is an integer and is 0 or 1, preferably 1; bO is an integer and is 0 or 1 , with the proviso that cO and bO cannot be contemporaneously equal to zero;
A = R-Tt- , wherein
R is the radical of a precursor drug of formula II:
Figure imgf000038_0001
(II)
wherein:
W is a carbon atom or a nitrogen atom; is an integer from 0 to 2;
Rn H, - (CH2)n-NHR1Λ, n being an integer from 0 to 2 wherein
R1A = H, -C(0)-Rlf[, -C(0)0-R1H, wherein
R. 1H is a linear or branched C^ ^ alkyl, a phenyl or benzyl group; or R has one of the following meanings :
Figure imgf000039_0001
(II-B) (II-C) (II-D) (II-E) wherein Ry is hydrogen, a linear or branched C - C10 alkyl , a phenyl or benzyl group; Rx = H, when W = N, Rx is the electronic doublet on the nitrogen atom (free valence); R2 is chosen between the following groups: phenyl, optionally substituted with an halogen atom or with one of the following groups: -0CH3, -CF3, nitro; mono- or di-hydroxy substituted benzyl, preferably
3-4 di-hydroxy substituted; amidino group: H2N( C=NH) - ; the radical of formula (IIA), wherein optionally one unsaturation of ethylene type can be present between the carbon atoms in position 1 and 2 , or 3 and 4, or
4 and 5 :
Figure imgf000039_0002
(IIA) wherein: p, pl t p2 are integers, equal to or different from each other and are 0 or 1 ; p3 is an integer from 0 to 10;
R„ is hydrogen, linear or branched C^Cg alkyl, free valence;
R5 can have the following meanings: linear or branched C^Cg alkyl, C3-C6 cycloalkyl, free valence , 0RΛ, wherein RΛ has the following meanings: linear or branched C^Cg alkyl optionally substituted with one or more halogen atoms, preferably F, phenyl optionally substituted with one halogen atom or with one of the following groups : -0CH3 , -CF3 , nitro ; R6, R6Λ, R7, R8, equal or different, are H, methyl; or free valence; with the proviso that in the radical of formula (IIA) when one unsaturation of ethylene type is present, between Cx and C2, R4 and R5 are free valences such as to form the double bond between Cx and C2; when the unsaturation is between C3 and C4, R6 and R7 are free valences such as to form the double bond between C3 and C4; when the unsaturation is between C4 and C5, R7 and R8 are free valences such as to form the double bond between C4 and C5; Q is equal to H, OH, ORB wherein RB is benzyl, a linear or branched Cx-C6 alkyl, optionally substituted with one or more halogen atoms, preferably F, phenyl optionally substituted with one halogen atom or with one of the following groups : -OCH3, -CF3, nitro; or Q can have one of the following meanings:
C3-C6 cycloalkyl; iinear or branched C^Cg alkyl; guanidine (H2NC ( =NH )NH- ) ; thioguanidine (H2NC(=S)NH- ) ; in formula (II) R2 with Rx and with W = C taken together form a C4-C10, preferably C6, saturated or unsaturated, preferably saturated ring;
Tx = (C0)t or (X)t., wherein X = 0, S, NR1C, Rlc is H or a linear or branched alkyl, having from 1 to 5 carbon atoms , t and t ' are integers and equal to zero or 1 , with the proviso that t = 1 when t' = 0; t = 0 when t' = 1; B = -TB-X2-TBI- wherein TB and TBI are equal or different;
TB= ( CO) when t = 0 , TB = X when t ' = 0 , X being as above ; TBI= (C0)tx or (X)txx, wherein tx and txx have the value of 0 or 1; with the proviso that tx = 1 when txx = 0; and tx = 0 when txx = 1; X is as above;
X2, bivalent radical, is such that the corresponding precursor of B -TB-X2-TBI- wherein the free valences of TB and of TBI are saturated each with OZ, with Z or with -N(ZI) (Z11) , being:
Z = H, Cx-C10, preferably C1-C5 alkyl linear or branched when possible,
Z1, ZIr equal or different have the values of Z as above, depending on that TB and/or TBI = CO or X, in function of the values of t, t', tx and txx; the precursor compound of B as above defined is selected from the following classes of compounds: aminoacids, selected from the following: L- carnosine, anserine, selenocysteine , selenomethionine, penicillamine, N-acetyl- penicillamine, cysteine , N-acetylcysteine, glutathione or esters thereof, preferably ethyl or isopropyl es er; hydroxyacids, selected from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid; aromatic and heterocyclic polyalcohols, selectd from the following: nordihydroguaiare ic acid, quercetin, catechin, kaempferol, sulphurethyne , ascorbic acid, isoascorbic acid, hydroquinone , gossypol, reductic acid, methoxyhydroquinone , hydroxyhydroquinone , propyl gallate, saccharose, 3 ,5-di-tertbutyl-4- hydroxybenzylthio glycolate, p-cumaric alcohol, 4- hydroxy-phenylethylalcohol, coniferyl alcohol, allopurinol ; compounds containing at least one free acid function, . selected from the following: 3,3'- thiodipropionic acid, fumaric acid, dihydroxymaleic acid, edetic acid;
C = bivalent radical -Tc-Y- wherein when bO = cO = 1: Tc = (CO) when tx = 0, Tc = X when txx =
0, X being as above defined, when bO = 0 : Tc = (CO) when t = 0, Tc = X when t' = 0, X being as above defined, when cO = 0 : tx '= 0, TBI = X = -0-; Tc = (CO) when tx = 0, Tc - X when txx = 0, X being as above ;
Y has one of the following meanings :
Y.
RTIX R-ΓIIX
I I
[C]πIX - Y3 - [C]nIIX-0- (III)
Figure imgf000043_0001
wherein: nIX is an integer from 0 to 5 , preferably 1; nllX is an integer from 1 to 5 preferably 1;
RTIX, RTIX. , RTn / R ιιx- ' equal to or different from each other are H or linear or branched Cx-C4 alkyl; preferably RTIX, RT]:x., RTIιX RTnx' a^e H.
Y3 is a saturated, unsaturated or aromatic heterocyclic ring, having 5 or 6 atoms, containing from 1 to three heteroatoms , preferably from one to two, said heteroatoms being equal or different and selected from nitrogen, oxygen, sulphur; or Y can be:
Y0, selected from the following: an alkylenoxy group R'O wherein R' is a linear or branched when possible C1-C20, preferably having from 2 to 6 carbon atoms , or a cycloalkylene having from 5 to 7 carbon atoms , in the cycloalkylene ring one or more carbon atoms can be substituted by heteroatoms, the ring can have side chains of R' type, R' being as above; or Y is selected from one of the following groups: (CH2- CH2- O)'nf
Figure imgf000044_0001
wherein nf ' is an integer from 1 to 6 preferably from 1 to 4;
- -(CH-CH2-0)nf- -(CH2-CH-0)nf-
wherein Rlf = H, CH3 and nf is an integer from 1 to 6; preferably from 2 to 4; YAR, selected from:
Y
Figure imgf000044_0002
(V) wherein n3 is an integer from 0 to 5 and n3 is an integer from 1 to 3 ; or
Figure imgf000044_0003
(VI) wherein n3 and n3 ' have the above mentioned meaning. Compounds according to claim 1, wherein: when in formula (II) W = C, m = 1 and R0 = -(CH2)n-NH2 with n = 1, R2 and Rx with W as above form together the cyclohexane ring, in the radical A of formula (I) Tx = CO and the free valence of A is saturated with OH, the precursor drug of R is known as gabape tine ; when in formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = 0 , Rx = H, R2 is the radical of formula (IIA) wherein p = px = 1 , p2 = p3 = 0 , R4 = R5 = R6 = R6A = H, Q = H, in the radical A of formula (I) Tx = CO and the free valence of A is saturated with OH, the precursor drug of R is known as norvaline; when in formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = 0, R] = H, R2 is the radical of formula (IIA) wherein p = px = 1 , p2 = p3 = 0 , R4 = R5 = R6 = R6Λ = H, Q is the guanidine group, in the radical A of formula (I) Tx = CO and the free valence of A is saturated with OH, the precursor drug of R is known as arginine; when in formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = 0 , Rx = H, R2 is the radical of formula (IIA) wherein p = px = 1, p2 = p3 = 0 , R4 = R5 = R6 = R6Λ - H, Q is the thioguanidine group, in the radical A of formula (I) Tx = CO and the free valence of A is saturated with OH, the precursor drug of R is known as thiocitrulline; hen in formula (II) W = C, = 1 and R0 = -(CH2)n-NH2 with n = 1, Rx = H, R2 is the radical of formula (IIA) wherein p = ρx = p2 = p3 = 0 , R4 = H, R5 = Q = CH3, in the radical A of formula (I) Tx = CO and the free valence of A is saturated with OH, the precursor drug of R is known as pregabaline; when in formula (II) W = C and it has configuration (S), = 1 and R0 = -(CH?)n-NH2 with n = 1, Rx = H, R2 is the radical of formula (IIA) wherein p = ρx - p2 = p3 = 0, R4 = H, R5 = Q = CH3, in the radical A of formula (I) Tx = CO and the free valence of A is saturated with OH, the precursor drug of R is known as (S)3-isobutylGABA; when in formula (II) W = C, m = 1 and R0 = Rx = H, R2 is the radical of formula (IIA) wherein p = px = 1 , p2 = p3 = 0 , R4 = R5 = R6 = R5A = H, Q is the guanidine group, in the radical A of formula (I) Tx = NH and the free valence of A is saturated with H, the precursor drug of R is known as agmatine; when in formula (II) W = C, m = 2 and R0 = -(CH2)n-NH2 with n = 0, Rx = H, R2 is the radical of formula (IIA) wherein p = px = p2 = p3 = 0 , R4 and R5 are free valences and between Cx and C2 there is one ethylene unsaturation, Q = H, in the radical A of formula (I) Tx = CO and the free valence of A is saturated with OH, the precursor drug of R is known as vigabatrine; when in formula (II) W = C, m = 0 and R0 = -(CH2)n-NH2 with n = 0, Rx = H, R2 is the radical 3-4 di-hydroxy substituted benzyl, Tx = CO and the free valence of A is saturated with OH, the percursor drug of R is known as 2-amino ,(3,4-dihydroxyphenyl )propanoic acid ( dopa) . Compounds according to claims 1-2, wherein when in formula (I) bO = 0, Y in the bivalent linking group C is selected between Yp and YΛR as above defined.
4. Compounds according to claim 3 , wherein Y3 is selected from the following bivalent radicals:
Figure imgf000047_0001
(YD (Y2) (Y3 (Y4) (Y5) :Y6:
(Y19)
Figure imgf000047_0002
(Y7) ;Y8) (Y9) (Y10) • (Yll) (Y18)
Figure imgf000047_0003
(Y12) (Y13) (Y14) (Y15) (Y16) (Y17) Compounds according to claim 4 , wherein Y3 is selected from (Y12), having the two free valences in the ortho position with respect to the nitrogen atom; (Y16) with the two valences linked to the two heteroatoms, Yl (pyrazol) 3 , 5-disubstituted; ; (Y19), wherein the free valence on the ring is found in para position to the nitrogen atom.
Compounds according to claims 1-5, wherein in formula (I) the precursors of B are the following: ferulic acid, N- acetylcysteine, cysteine, caffeic acid, hydrocaffeic and gentisic acid.
Compounds according to claims 1-6, wherein the precursor drugs are selected from gabapentine, norvaline, arginine, pregabaline, (S) 3 -isobutylGABA, ag atine. Compounds according to claims 1-7, selected from the following: 1- (aminomethyl ) cyclohexan acetic acid 2- methoxy-4- [ (IE) -3- [4- (nitrooxy) butoxy] - 3 -oxy-1-prope- nyl]phenyl hydrochloride ester (XV)
Figure imgf000048_0001
(XV) 1- (aminomethyl ) cyclohexan acetic acid 3- ;nitrooxymethyl ) phenyl hydrochloride ester (XVI)
H-Cl
Figure imgf000048_0002
(XVI) 2 -aminopentanoic acid 3- (nitrooxymethyl)phenyl hydrochloride ester (XVII)
Figure imgf000048_0003
(XVII) (S) -N-acetylcysteine- , 4- (nitrooxy)butyl ester, 2- amino pentanoate hydrochloride (XVIII)
Figure imgf000049_0001
(XVIII) (S) -N-acetylcysteine- , 4- (nitrooxy)butyl ester, 1- ; minomethyl ) cyclohexanacetate hydrochloride (XIX)
Figure imgf000049_0002
(XIX) 1 - ( aminomethyl ) cyclohexanacetic acid- , [ 6 - (nitrooxy methyl) -2-pyridinyl]methyl hydrochloride ester (XX)
Figure imgf000049_0003
(XX) alpha-amino-delta-thioureidopentanoic aci , 3- (nitrooxy methyl )phenyl hydrochloride ester (XXI)
Figure imgf000049_0004
(S) -N-acetylcysteine- , 4- (nitrooxy)butyl ester, alpha-amino- elta-thioureidopentanoate hydrochloride (XXII)
Figure imgf000050_0001
(XXII) alpha-a ino-delta-thioureidopentanoic acid, 2- methoxy-4- [ (IE) -3- [4- (nitrooxy)butoxy] -3 -oxy-1 -propenyl]phenyl hydrochloride ester (XXIII)
Figure imgf000050_0002
(XXIII) 2 -amino- 5 -guanidinopentanoic acid, 3- (nitrooxy methyl )phenyl hydrochloride ester (XXIV)
Figure imgf000050_0003
(XXIV) 2-amino-5-guanidinopentanoic acid-, 2-methoxy-4- [ ( IE) - 3 - [ 4 - (nitrooxy)butoxy] - 3 -oxy-1 - ropenyl ]phenyl hydrochloride ester (XXV)
Figure imgf000051_0001
(XXV) ( S ) -N-acetylcysteine- 4 - (nitrooxy)butyl ester, 2- amino-5-guanidinopentanoate hydrochloride (XXVI)
Figure imgf000051_0002
(XXVI ) 4 - (guanidine )butyl - 3 -nitrooxymethylbenzamide ( XVII )
Figure imgf000051_0003
(XXVII) 4- (guanidine)butyl-3- [4- (4 ' -nitrooxybutyryloxy) -3- ( ethoxy) ] phenyl - 2 -propenamide chloride (XXVIII )
Figure imgf000051_0004
(XXVIII) 1- (aminomethyl ) cyclohexan acetic acid 4-(nitroxy) butyl hydrochloride ester (XXIX) H-Cl
Figure imgf000052_0001
( XXIX )
9. Compounds according to claims 1-8, as nitrate . salts .
10 Compounds according to claims 1-9, in combination with NO donor compounds .
11 Compounds according to claim 10, wherein the NO donor compounds contain in the molecule radicals of drugs belonging to the classes of aspirin, ibuprofen, paracetamol, naproxen, diclofenac, flurbiprofen.
12, Pharmaceutical compositions for parenteral , oral and topical use comprising the compounds according to claims
1-11. 3 Compounds according to claims 1-12, for use as medicament . 4 Use of the compounds according to claims 1-13, for preparing drugs for epilepsy.
PCT/EP2002/006389 2001-06-21 2002-06-11 Nitrate ester derivatives useful for preparing drugs for epilepsy WO2003000643A1 (en)

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