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  • 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
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  • 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.

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Citations (17)

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• 2002
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