Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new substituted heterocyclic compounds, a process for their preparation and the pharmaceutical compositions containing them as active ingredient.
• the present invention relates to a new class of substituted heterocyclic compounds for therapeutic use, in pathological phenomena which involve the tachykinin system such as for example in a nonlimiting and exclusive manner: pain (D. Regoli et al., Life Sciences , 1987, 10 40, 109-1 17), allergy and inflammation (JE Morlay et al, Life Sciences, 1987, ⁇ , 527-544), circulatory failure (J. Losay et al., 1977 , Substance P, Von Euler, IS and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484 ), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50) neurological disorders, neuropsychiatric disorders (CA Maggi et al., J. Autonomie. Pharmacol., 1993, H, 23 -93).
• pain D. Regoli et al., Life Sciences
• Tachykinins are distributed in both the central nervous system and the peripheral nervous system. Tachykinin receptors have been recognized and are classified into three types: NK j , NK-2, NK3.
• Substance P is the endogenous ligand for the NKj receptors, neurokinin A (NK ⁇ ) for the NK2 receptors and neurokinin B (NKg) for the N3 receptors.
• NKj, NK2, NK3 receptors have been demonstrated in different species.
• NKj receptor antagonists the following non-peptide compounds may be mentioned: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993. 250, 403-413).
• SR 48968 a selective non-peptide antagonist, SR 48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).
• a non-peptide selective antagonist (+) - N- [1- [3- [1-benzoyl-3- (3,4-dichlorophenyl) piperid-3-yl] hydrochloride] propyl] -4-phenylpiperid-4-yl] -N-methylacetamide or SR 142801 has been described 35 (Peptides and their antagonists in tissue injury, Montreal, Canada, 1994, July 31- August 3. Canadian J. Physiol. Pharmacol. , 1994, 11 (suppl. 2), 25, Abst. M. 0. 9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterburry, 1995, April 6- 8; Eur. J. Pharmacol., 1995, 22S (1), 17-25; Ist. Eur. Congress Pharmacol., Milan, 1995, June 16-19).
• Patent application EP-A-336230 describes peptide derivative antagonists of substance P and of neurokinin A useful for the treatment and prevention of asthma.
• WO 95/12577, WO 95/16682, WO 95/28389, WO 96/06094, WO 96/05193 also relate to neurokinin receptor antagonists.
• New substituted heterocyclic compounds have now been found which are neurokinin receptor antagonists.
• A represents a bivalent radical chosen from: A 2 ) -CH 2 -O-CO-
• Ar j represents a phen le unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a hydroxy, a (C j -C ⁇ alkoxy, a
• T represents a group chosen from CH2-Z, -CH (CgH5) 2, ; T can also represent the group -CO-BZ when A represents a bivalent radical chosen from • -O-CH2-CH2- or -N (Rj) -CH2-CH2 - or -O-CH2-; - B represents a direct bond or a methylene,
• - Z represents an aromatic or heteroaromatic group mono-, di- or tncyclic optionally substituted
• - Ar2 represents a py ⁇ dyle, a phenyl unsubstituted or substituted one or more times by a substituent chosen from a halogen atom, a hydroxy, a (C [- C4) alkoxy, a (Cj-G ⁇ alkyl, a t ⁇ fluoromethyl, a nitro, a methylenedioxy, said substituents being identical or different, a thienyl; a py ⁇ midyle, an îmidazolyle unsubstituted or substituted by a (C ⁇ -C4) alkyl
• the compounds of formula (I) according to the invention include both the racemates and the optically pure isomers
• the radical Z can be a phenyl group, which can be unsubstituted or optionally contain one or more substituents When Z is a phenyl group, this can be mono substituted or disubstituted in particular in position 2,4 but also for example in position 2,3 or 4,5 or 3,4 or
• radical Z can also represent a bicyc aromatic group such as 1- or 2-naphthyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7- ⁇ ndényle , including one or more links may be hydrogenated, said groups possibly being unsubstituted or optionally containing one or more substituents such as: the alkyl, phenyl, cyano, hydroxyalkyl, hydroxy, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy and trifluoromethyl group, in which the alkyls and the alkoxy are C 1 -C 4 .
• the radical Z can also be a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofurannyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzoxoxylyl, benzoxoxylyl, benzoxoxyl) furyle, pyrannyle, chroményle, isobenzofurannyle, pyrrolyle, pyrazolyle, pyrazinyle, pyrimidinyle, pyridazinyle, indolizinyle, phtalazinyle, quinazolinyle, acridinyle, isothiazolyle, isochroman ⁇ yle, chromannyle, of which one or more double bonds can be hydrogenated, said groups can be hydrogenated, said groups
• the invention relates to compounds of formula (I) in which; - Z is Z 'and represents:
• a phenyl unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C ⁇ ⁇ C4) alk le; a benzylamino; carboxy; a (C ⁇ -Cjo) al ylc; a (C3-Cg) cycioalkyl unsubstituted or substituted one or more times with methyl; a (C ⁇ -C ⁇ o) alco .
• a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted once or twice by a (C ⁇ ⁇ C4) alk le; a benzylamino; carboxy; a (C ⁇ -Cjo) al ylc; a (
• - a naphthyl unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a (C ⁇ -C4) alkyl, a hydroxy, a (C ⁇ -C4) alkoxy; - a pyridyle; thienyl; indolyl; quinolyl; benzothienyl; imidazolyl; a furyle.
• salts of the compounds of formula (I) can be formed.
• These salts include both those with mineral and organic acids which allow suitable separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example a mandelic acid or camphosulfonic, than those which form acceptable pharmaceutical salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, random, fumarate, 2- ⁇ aphthalenesulfonate, benzenesulfonate, gluconate, citrate, isethionate, -toluenesulfonate.
• the a ⁇ ions X ⁇ are those normally used to salify the quaternary ammonium ions, preferably the chloride, bromide, iodide, acetate, hydrogen sulfate, methanesulfonate, paratoluenesulfonate, benzenesulfonate ions.
• the pharmaceutically acceptable anions are used, for example chloride, methanesulfonate or benzenesulfonate.
• alkyl groups or the alkoxy groups are straight or branched;
• halogen atom means a chlorine, bromine, fluorine or iodine atom.
• substituents of group Z phenyl, by (C ⁇ -Cjo) to lkyl e is meant for example a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an isobutyl, a sec-butyl, a terr-butyie, a pentyl or n-pentyl, a hexyl or n-hexyl, a heptyl or a n-heptyl, an octyl or n-octyl, a nonyl or n-nonyl, a decyl or n-decyl; by (C3-Cg) cycloalkyl optionally substituted by a methyl is understood for example to mean a cyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or 3-methylcyclopen
• the radical Z represents a phenyl which is unsubstituted or substituted one or more times with a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (C ⁇ -C4) alkyl, hydroxy, (C ⁇ ⁇ C4) alkoxy; naphthyl unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a (C ⁇ -C4) alkyl, a hydroxy, a (Cj-C4) alkoxy; pyridyl; thienyl; indolyl; quinolyl; benzothienyl; an imidazolyl.
• a halogen atom more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (C ⁇ -C4) alkyl, hydroxy, (C ⁇ ⁇ C4) alkoxy
• a group of preferred compounds according to the present invention are those of formula :, - Aa ⁇
• - Aa represents a bivalent radical chosen from: -O-CO-; -CFH-O-CO-; -O-CH 2 -CO-; -N (R ⁇ ) -CO- or -N ⁇ -CO-CO-; in which R ⁇ represents a hydrogen or a (C ⁇ -C ⁇ alkyl;
• - n is 0 or 1;
• - Ar ⁇ a represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a hydroxy, a (C j -C4) alkoxy, a (C ⁇ -C4) alkyl, trifluoromethyl, said substituents being identical or different;
• Za represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from: a halogen atom, a trifluoromethyl, a (C ⁇ - C ⁇ o) a lk le, a (C ⁇ -C ⁇ o) a l c oy, hydroxy, said substituents being identical or different.
• Ar'ia represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl
• - Z'a represents a 3,5-bis (trifluoromethyl) phenyl, a 3,5-dimethylphé ⁇ yle or a 2,4-bis (trifluoromethyl) phenyl; are particularly preferred.
• - Ab represents the bivalent radical -O-CH2-CH2-; -N (R ⁇ ) -CTb-CH2- or -O-CH2-; in which Rj represents a hydrogen or a (C ⁇ ⁇ C4) alkyl;
• - n is 0 or 1;
• - B represents a direct bond or a methylene
• - X ⁇ represents a pharmaceutically acceptable anion
• - Ar2 is as defined above for a compound of formula (I); - Arj a and Za are as defined above for a compound of formula (la);
• - B represents a direct bond or a methylene
• Z "a represents a phenyl substituted in position 3 by a halogen or a (C ⁇ -C ⁇ o) alkoxy group when B represents a methylene or Z" a represents a 3,5-bis (trifluoromethy) phenyl, a 3,5-dimethylphenyl or 2,4-bis (trifluoromethyl) phenyl when B represents a direct bond; are particularly preferred.
• the present invention relates to a process for the preparation of the compounds of formula (I) and their salts, characterized in that:
• Hal-CH 2 -Z (IV) in which Z is as defined above, and Hal represents a halogen, preferably bromine or chlorine, when a compound of formula ( I) where T is -CH2-Z,
• the product thus obtained is isolated in the form of a sulfonate and optionally a sulfonic acid salt or alternatively, the anion and optionally the acid salt thus obtained are exchanged with another anion and optionally another pharmaceutically acceptable mineral or organic acid salt.
• E represents an O-protecting group
• this is chosen from the conventional O-protecting groups well known to those skilled in the art, such as, for example, tetrahydropyran-2-yl, benzoyl or a (C j -C4) aIkylcarbonyle.
• step 1) as the functional derivative of acid (III), the acid itself is used, or else one of the functional derivatives which react with the amines, for example an anhydride, a mixed anhydride, acid chloride, or an activated ester, such as paranitrophenyl ester.
• the functional derivative of acid (III) for example an anhydride, a mixed anhydride, acid chloride, or an activated ester, such as paranitrophenyl ester.
• the acid of formula (III) is used itself, it is carried out in the presence of a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1 hexafluorophosphate -yloxytris (dimethylamino) phosphonium in the presence of a base such as triethylamine or N, N-diisopropylethylamine, in an inert solvent such as dichloromethane or
• N, N-dimethylformamide at a temperature between 0 ° C and room temperature.
• the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine and at a temperature between -60 ° C and room temperature.
• an inert solvent such as dichloromethane or benzene
• a base such as triethylamine or N-methylmorpholine
• reaction is carried out in an inert solvent such as tetrahydrofuran, N, N-dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium terr-butoxide, sodium hydride or lithium diisopropylamide and at a temperature between 0 ° C and 80 ° C.
• inert solvent such as tetrahydrofuran, N, N-dimethylformamide or dimethylsulfoxide
• a base such as potassium terr-butoxide, sodium hydride or lithium diisopropylamide
• step 2 The compound of formula (VII) thus obtained is optionally deprotected in step 2) according to the methods known to those skilled in the art.
• deprotection is carried out by acid hydrolysis using hydrochloric acid in a solvent such as ether, methanol or a mixture of these solvents, or using pyridinium p-toluenesulfonate in a solvent such as methanol or alternatively, using an Amberlyst® resin in a solvent such as methanol.
• the reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent.
• E represents a benzoyl group or a (C j-C4) alkylcarbonyl group
• the deprotection is carried out by hydrolysis in an alkaline medium using for example an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an inert solvent such as water, methanol, ethanol, dioxane or a mixture of these solvents, at a temperature between 0 ° C and the reflux temperature of the solvent.
• an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide
• an inert solvent such as water, methanol, ethanol, dioxane or a mixture of these solvents
• step 3 the reaction of the alcohol of formula (VIII) with a sulfonyl chloride of formula (IX) is carried out in the presence of a base such as triethylamine, pyridine, N, N-diisopropylethylamine or N-methylmorpholine, in an inert solvent such as dichloromethane, benzene or toluene, at a temperature between -20 ° C and the reflux temperature of the solvent.
• a base such as triethylamine, pyridine, N, N-diisopropylethylamine or N-methylmorpholine
• a base is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine or from alkali metal carbonates or bicarbonates such as potassium carbonate, carbonate sodium or sodium bicarbonate.
• reaction is carried out using an excess of the compound of formula (XI) and in the presence of an alkali metal iodide such as potassium iodide or sodium iodide.
• an alkali metal iodide such as potassium iodide or sodium iodide.
• -A- represents the bivalent radical -O-CO- or -CH2-O-CO-, the reaction is carried out at a temperature between room temperature and 80 ° C.
• the sulfonate anion YS ⁇ 3 ⁇ resulting from the reaction between the compound of formula (XI) and the compound of compound of formula (I) according to conventional methods, for example by exchange in solution with a saturated solution of sodium chloride or with a hydrochloric acid solution when X ⁇ represents a chloride anion or by exchange of the anion by elution of the compound (I) on a ion exchange resin, for example Amberlite IRA68® or Duolite A375®.
• the compounds of formula (II) are prepared according to different procedures.
• step a of DIAGRAM 1 a compound of formula (XII) is reacted with a compound of formula (XIII) according to the method described in patent applications EP-A-0428434 and EP-A-0474561.
• step bj The compound (XIV) thus obtained is reacted in step bj . with an aqueous formaldehyde solution, in the presence of a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene, in a solvent such as 1,2-dimethoxyethane, and at a temperature between the ambient temperature and the reflux temperature of the solvent.
• a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene
• solvent such as 1,2-dimethoxyethane
• the nitrile derivative of formula (XV) is reduced in step cj. to obtain the primary amine of formula (XVI).
• This reduction can be carried out using hydrogen, in the presence of a catalyst such as Raney® nickel, platinum oxide or palladium on charcoal, in an inert solvent such as an alcohol, ethanol. for example, alone or as a mixture with ammonia, or by means of a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, borane in THF, in a solvent such as toluene , hexane, petroleum ether, xylene or tetrahydrofuran.
• the reaction is carried out at a temperature between 0 ° C and 70 ° C.
• the compound (XVI) is reacted in step di with a reactive derivative of carbonic acid such as phosgene in solution in toluene, l, l'-carbonyldiimidazole, in the presence of a base such as triethylamine, the
• step a2 of SCHEME 2 the synthesis of a cyanohydrin of formula (XVIII) from an aldehyde of formula (XVII) is carried out according to methods well known to those skilled in the art such as by example that described in Organic Syntheses; Wiley, New York, 1932; Collect. flight. 1, p. 336, or by adaptation of this method using the action of sodium metabisulfite and potassium cyanide in aqueous solution.
• step b2 the hydroxy group of the compound of formula (XVIII) is protected according to the methods known to those skilled in the art.
• step c_2 The compound of formula (XIX) thus obtained is treated in step c_2 with a strong base such as lithium diisopropylamide, potassium / w-butoxide or sodium hydride to provide a carbanion which is reacted with a compound of formula Hal- (CH2) m ⁇ "O-Pr2, in which Hal represents a halogen, preferably bromine or chlorine, to obtain the compound of formula (XX).
• a strong base such as lithium diisopropylamide, potassium / w-butoxide or sodium hydride
• the reaction is carried out in an inert solvent such as '' an ether (tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane for example) or an amide (N, N-dimethylformamide for example) or an aromatic hydrocarbon (toluene, xylene for example) at a temperature between -70 * C and + 60 * C.
• an inert solvent such as '' an ether (tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane for example) or an amide (N, N-dimethylformamide for example) or an aromatic hydrocarbon (toluene, xylene for example) at a temperature between -70 * C and + 60 * C.
• step dj> The nitrile derivative of formula (XX) is reduced in step dj> according to the methods previously described, to obtain the primary amine of formula (XXI).
• step s2 > the compound of formula (XXI) is reacted with a compound of formula Hal-CO-CH2 ⁇ Hal in which Hal represents a halogen, preferably chlorine or bromine, in the presence of a base such as a tertiary amine (triethylamine, N-methylmorpholine, pyridine for example) to obtain a compound of formula (XXII).
• a base such as a tertiary amine (triethylamine, N-methylmorpholine, pyridine for example)
• the reaction is carried out in an inert solvent such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example) or an amide (N, N-dimethylformamide for example) at a temperature comprised between -70 * C and room temperature.
• a chlorinated solvent dichloromethane, dichloroethane, chloroform for example
• an ether tetrahydrofuran, dioxane for example
• an amide N, N-dimethylformamide for example
• step Js2 the O-protective group Prj of the compound of formula (XXI) is eliminated in step j2 by acid hydrolysis, then the compound is reacted, in step Js2,
• the compound of formula (XXIII) thus obtained is cyclized in the presence of a base to obtain the compound of formula (II) expected.
• a base such as an alkali metal carbonate (potassium carbonate for example) or an alkali metal hydride (I ' sodium hydride for example) or potassium ferr-butoxide, in an inert solvent such as an aromatic hydrocarbon (xylene, toluene for example) or an amide (N, N-dimethylformamide for example) or an ether (tetrahydrofuran for example ), at a temperature between -30 ° C and the reflux temperature of the solvent (step).
• a base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide for example) in aqueous solution concentrated in a solvent such as an alkanol (propan-2-ol for example) or an amide (N, N-dimethylformamide for example) or a mixture of these solvents at a temperature between room temperature and the reflux temperature of the solvent (step h2).
• an alkali metal hydroxide sodium hydroxide, potassium hydroxide for example
• a solvent such as an alkanol (propan-2-ol for example) or an amide (N, N-dimethylformamide for example) or a mixture of these solvents at a temperature between room temperature and the reflux temperature of the solvent (step h2).
• step j2 a compound of formula (II) is prepared in which E represents an O-protecting group Prj according to the methods known to those skilled in the art.
• a compound of formula (II) is reduced in which -A- represents the bivalent radical -O-CH2-CO- and E represents hydrogen or an O-protective group, obtained according to DIAGRAM 2.
• the reduction is carried out using a reducing agent such as aluminum and lithium hydride, diisobutylaluminium hydride, sodium borohydride, borane in THF, in an inert solvent such as tetrahydrofuran , diethyl ether, 1,2-dimethoxyethane or toluene at a temperature between room temperature and the reflux temperature of the solvent.
• step a4 of SCHEME 4 the O-protective group Pr j is removed from the compound of formula (XXI), obtained in step d2 of SCHEME 2, by acid hydrolysis according to the methods previously described.
• the compound of formula (XXIV) thus obtained is reacted in step b4 with a reactive carbonic acid derivative such as U'-carbonyldiimidazole, phosgene in toluene, p-nitrophenyl chloroformate, and presence of a base such as triethylamine, NN-diisopropylethylamine, N-methylmorpholine, to obtain a compound of the expected formula (II) in which E represents an O-protecting group.
• a reactive carbonic acid derivative such as U'-carbonyldiimidazole, phosgene in toluene, p-nitrophenyl chloroformate, and presence of a base such as triethylamine, NN-diisopropylethylamine, N-methylmorpholine
• the reaction is carried out in an inert solvent such as a chlorinated solvent (1.2-dichloroethane, dichloromethane for example) or a ether such as tetrahydrofuran or an amide such as N, N-dimethylformamide or an aromatic solvent such as toluene at a temperature between -60 ° C and room temperature.
• an inert solvent such as a chlorinated solvent (1.2-dichloroethane, dichloromethane for example) or a ether such as tetrahydrofuran or an amide such as N, N-dimethylformamide or an aromatic solvent such as toluene at a temperature between -60 ° C and room temperature.
• step ç4 the O-protective group Pr2 is removed (step ç4) to obtain the compound of formula (II) in which E represents hydrogen.
• step a5 of SCHEME 5 the preparation of an ⁇ -ammonitrile compound of formula (XXV) is carried out from an aldehyde of formula (XVII) according to the method described in Tetrahedron Letters, 1984, 21 (41), 4583-4586 and using an an ine of formula H2N-R.
• N-protecting group such as ferr-butoxycarbonyl (Boc), benzyloxycarbonyl for example according to methods known to those skilled in the art.
• Boc ferr-butoxycarbonyl
• benzyloxycarbonyl for example according to methods known to those skilled in the art.
• the ferf-butoxycarbonyl group is illustrated in SCHEME 5 above.
• step ç The compound of formula (XXVI) thus obtained is treated in step ç with a strong base to form a carbanion which is reacted with a compound of formula Hal- (CH2) m -O-Pr ⁇ to obtain a compound of formula (XXVII).
• the reaction is carried out according to the method described in step & of SCHEME 2.
• nitria derivative of formula (XXVII) is reduced in step c according to the methods previously described to obtain the primary amine of formula (XXVIII).
• the O-protective group and the N-protective group of the compound of formula (XXVIII) are eliminated in step ç5 by acid hydrolysis using hydrochloric acid or trifluoroacetic acid, for example in a solvent such as an alcohol ( methanol for example) or an ether (diethyl ether, dioxane, tetrahydrofuran for example) or a chlorinated solvent (dichloromethane for example) at a temperature between O'C and the reflux temperature of the reaction mixture.
• a solvent such as an alcohol ( methanol for example) or an ether (diethyl ether, dioxane, tetrahydrofuran for example) or a chlorinated solvent (dichloromethane for example) at a temperature between O'C and the reflux temperature of the reaction mixture.
• step f £ the preparation of the expected compound of formula (II) is carried out by application or adaptation of the method described by R. Granger, H. Orzalesi and
• step g a compound of formula (II) is prepared in which E represents an O-protective group P ⁇ ⁇ according to the methods known to those skilled in the art.
• step a6 of SCHEME 6 a compound of formula (II) is reduced in which -A- represents the bivalent radical -N (Rj) -CO-CO- and E represents an O-protective group, obtained with STEP 5 of SCHEME 5.
• the reduction is carried out using a reducing agent such as lithium aluminum hydride, in an inert solvent such as an ether (tetrahydrofuran, 1,2-dimethoxyethane or ether diethyl, for example) or an aromatic solvent such as toluene at a temperature between room temperature and the reflux temperature of the solvent.
• the O-protecting group is removed in step b6 by acid hydrolysis according to the methods described above, to obtain the compound of formula (II) in which E represents hydrogen.
• step a1 the hydroxyl of the compound of formula (XXIX), obtained in step e> of SCHEME 5, is protected according to the methods known to those skilled in the art.
• step ⁇ 7 the compound of formula (XXX) thus obtained is reacted with a reactive derivative of carbonic acid such as 1, l'-carbonyldiimidazole, phosgene in toluene, chloroformate of? - nitrophenyl, in the presence of a base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, to obtain a compound of formula (II) expected in which E represents an O-protecting group.
• a reactive derivative of carbonic acid such as 1, l'-carbonyldiimidazole, phosgene in toluene, chloroformate of? - nitrophenyl
• a base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine
• the reaction is carried out in an inert solvent such as a chlorinated solvent (1,2-dichloroethane, dichloromethane for example) or an ether (tetrahydrofuran for example) or an amide (N, N-dimethylformamide for example) or an aromatic solvent (toluene for example) at a temperature between -60 ° C and 60 ° C.
• an inert solvent such as a chlorinated solvent (1,2-dichloroethane, dichloromethane for example) or an ether (tetrahydrofuran for example) or an amide (N, N-dimethylformamide for example) or an aromatic solvent (toluene for example) at a temperature between -60 ° C and 60 ° C.
• a compound of formula (II) in which E represents hydrogen is prepared in step ç7 according to methods known to those skilled in the art.
• step a8 of SCHEME 8 a compound of formula (XXIV) is reacted with an aqueous solution of formaldehyde in an inert solvent such as tetrahydrofuran and at a temperature between room temperature and the reflux temperature of the solvent to obtaining a compound of the expected formula (II) in which E represents an O-protecting group.
• an inert solvent such as tetrahydrofuran
• step a £ of DIAGRAM 9 the nitrogen atom of the piperidine of formula (XXXI) is protected by a benzyl group according to the methods known to those skilled in the art.
• the carboxy group in position 4 of the piperidine of formula (XXXII) thus obtained is reduced in step & £ to obtain the compound of formula (XXXIII) substituted in position 4 by a hydroxymethyl group.
• the reduction is carried out by means of a reducing agent such as borane in THF or the borane-dimethylsuifure complex, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyetha ⁇ e or dichloromethane to a temperature between room temperature and the reflux temperature of the solvent.
• the compound of formula (XXXIII) can also be obtained from the compound of formula (XXXI) by reduction of the carboxy group (step c9), then protection of the nitrogen from the piperidine of formula (XXXIV) obtained (step d9) according to the methods mentioned above.
• step e9 the compound (XXXIII) is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine to obtain the compound of formula (XXXV) cyclized in the form of quaternary ammonium.
• a base such as triethylamine
• the reaction is carried out in an inert solvent such as dichloromethane or toluene, at a temperature between -20 ° C. and the reflux temperature of the solvent.
• 4-Cyanopiperidine is obtained by reaction of isonipecotamide with phosphorus oxychioride.
• the compounds of formula (I) above also include those in which one or more atoms of hydrogen, carbon or iodine have been replaced by their radioactive isotope for example tritium, carbon-14 or iodine 125.
• radioactive isotope for example tritium, carbon-14 or iodine 125.
• the tests were carried out according to X. Emonds-Alt et al. (Eur. J. Pharmacol., 1993, 250. 403-413).
• the compounds according to the invention generally have an affinity for the tachykinin receptors mentioned above, with an inhibition constant Ki preferably less than 10 ° -M.
• the compounds of the present invention are in particular active principles of pharmaceutical compositions, the toxicity of which is compatible with their use as medicaments.
• the compounds of the present invention are generally administered in dosage units.
• Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
• the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I) or one of its pharmaceutically acceptable salts.
• the compounds of formula (I) above and their pharmaceutically acceptable salts can be used in daily doses of 0.01. at 100 mg per kilogram of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 50 mg / kg.
• the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
• the active ingredients can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, animals and humans.
• Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, implants, forms subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.
• a solid composition is prepared in the form of tablets, the main active principle is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or analogues.
• the tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
• a preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
• a preparation in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably calorie-free, methyiparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
• a sweetener preferably calorie-free, methyiparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
• the water-dispersible powders or granules may contain the active principle in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or taste.
• Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
• binders that melt at rectal temperature
• for parenteral, intranasal or intraocular administration aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
• an aerosol containing, for example, sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant is used; one can also use a system containing the active ingredient alone or associated with an excipient, in the form of powder.
• the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
• each dosage unit the active principle of formula (I) is present in the quantities adapted to the daily doses envisaged.
• each dosage unit is suitably adjusted according to the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 0.5 to 1000 mg of active ingredient, preferably 2.5 to 250 mg to be administered one to four times a day.
• the aforementioned compositions can also contain other active products such as, for example, bronchodilators, cough suppressants, antihistamines, anti-inflammatories, antiemetics, chemotherapy agents.
• the present invention relates to the use of the products of formula (I) for the preparation of medicaments intended to treat physiological disorders associated with an excess of tachykinins and all the neurokinin-dependent pathologies of the respiratory system, gastro -intestinal, urinary, immune, cardiovascular and central nervous system as well as pain and migraine.
• the products of formula (I) for the preparation of medicaments intended to treat physiological disorders associated with an excess of tachykinins and all the neurokinin-dependent pathologies of the respiratory system, gastro -intestinal, urinary, immune, cardiovascular and central nervous system as well as pain and migraine.
• inflammations such as neurogenic inflammations, chronic inflammatory diseases, for example, chronic obstructive respiratory diseases, asthma, allergies, rhinitis, coughs, bronchitis, hypersensitivity for example to pollens and mites, rheumatoid arthritis, fibrositis, osteoarthritis, psoriasis, ulcerative colitis, Crohn's disease, inflammation of the intestines (irritable colon), prostatitis, neurological bladder, incontinence, cystitis, urethritis, nephritis, ophthalmic diseases such as conjunctivitis, vitreoretinopathy, skin diseases such as contact dermatitis, atopic dermatitis, urticaria, eczema, pruritus, burns, especially sunburn,
• chronic inflammatory diseases for example, chronic obstructive respiratory diseases, asthma, allergies, rhinitis, coughs, bronchitis, hypersensitivity for example to pollens and mites,
• rheumatoid arthritis for example rheumatoid arthritis, psoriasis, Crohn's disease, diabetes, lupus, rejection reactions after transplantation,
• demyelinating diseases such as multiple sclerosis or amyotrophic lateral sclerosis
• demyelinating diseases such as multiple sclerosis or amyotrophic lateral sclerosis
• - diseases of the central nervous system of the neuropsychiatric or neurological type such as anxiety, impaired alertness, , depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drug dependence, alcoholism, Do n syndrome and chorea Huntingto ⁇ as well as neurodegenerative diseases, somatic disorders linked to stress
• - diseases of the gastrointestinal system such as nausea, vomiting of all origins, colon i itable, gastric and duodenal ulcers, esophageal ulcers, diarrhea, hypersecretions,
• - diseases of the cardiovascular system such as hypertension, vascular aspects of migraine, edema, thrombosis, angina pectoris, vascular spasms, circulatory diseases due to vasodilation, Reynauld's diseases, fibrosis , collagen diseases,
• the present invention also includes a method for treating said conditions at the doses indicated above.
• Na2C ⁇ 3 sodium carbonate
• NaHC ⁇ 3 sodium hydrogen carbonate
• Na2SO4 sodium sulfate
• MgSO4 magnesium sulfate
• TFA trifluoroacetic acid hydrochloric ether: saturated solution of hydrochloric acid in ether
• Na2S2 ⁇ 5 sodium metabisulfite
• DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
• NMR nuclear magnetic resonance
• ⁇ chemical shift
• s singlet se: widened singlet
• d doublet t: triplet
• qd quadruplet
• mt multiplet
• a suspension of 17.75 g of sodium hydride is cooled in an ice bath.
• reaction mixture is poured onto a solution of 31 g of ammonium chloride in 1.4 liters of water, extracted with ether, the combined organic phases are washed with saturated NaCl solution, dried over MgS ⁇ 4 and evaporated under vacuum solvents.
• Hydrogenation is carried out for 5 hours at 30 ° C. and at atmospheric pressure a mixture of 15.5 g of the compound obtained in the preceding step, 5 g of Raney® nickel in 200 ml of EtOH and 40 ml of a solution 20% ammonia in the water.
• the catalyst is filtered and the filtrate is concentrated under vacuum.
• the residue is taken up in DCM, the organic phase is washed with water, with a saturated NaCl solution, dried over MgS ⁇ 4 and the solvent is evaporated under vacuum. 14.9 g of the expected product are obtained in the form of an oil and which is used as it is.
• a mixture of 34 g of the compound obtained in the preceding step, 10 g of Raney® nickel in 400 ml of EtOH and 40 ml of a concentrated ammonia solution is hydrogenated at RT and at atmospheric pressure.
• the catalyst is filtered and the filtrate is concentrated under vacuum.
• the residue is taken up in water, extracted with ether, the organic phase is washed with a saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum.
• the residue is chromatographed on silica H, eluting with a gradient of the DCM / MeOH mixture from (100/1; v / v) to (100/3; v / v). 16 g of the expected product are obtained, which product is used as it is.
• a suspension of 1.6 g of aluminum and lithium hydride in 25 ml of THF is heated to 60 ° C., a solution of 4 g of the compound obtained in step F of Preparation 1.3 is added dropwise 20 ml of THF and leaves for 30 minutes with stirring at reflux. After cooling, 1.5 ml of water, 1.5 ml of 4N NaOH are added, then 4.5 ml of water.
• the mineral salts are filtered on Celite®, the filtrate is decanted, and evaporated under vacuum the organic phase. The residue is taken up in ether, dried over Na2S ⁇ 4 and the solvent evaporated under vacuum. 3.6 g of the expected product are obtained.
• Hydrogenation is carried out at RT and at atmospheric pressure a mixture of 20 g of the compound obtained in the preceding step, 7 g of Raney® nickel in 300 ml of MeOH.
• the catalyst is filtered and the filtrate is concentrated under vacuum.
• the residue is taken up in water, extracted with ether, the organic phase is washed with water, dried over Na2S ⁇ 4 and the solvent evaporated under vacuum. 20 g of the expected product are obtained, which product is used as it is.
• a suspension of 0.82 g of aluminum hydride and lithium in 10 ml of THF is heated to 60 ° C., a solution of 2 g of the compound obtained in the preceding step is added dropwise in 20 ml of THF and leaves for 30 minutes with stirring at reflux. After cooling, 1 ml of water, 1 ml of 4N NaOH and then 3 ml of water are added.
• the mineral salts are filtered through Celite®, the filtrate is decanted, and the organic phase is evaporated under vacuum. The residue is taken up in ether, dried over Na2S ⁇ 4 and the solvent evaporated under vacuum. 2 g of the expected product are obtained.
• the organic phase is washed with water, dried over MgS ⁇ 4 and the solvent is evaporated under vacuum.
• the residue is taken up in 400 ml of propan-2-ol, 15 g of fumaric acid are added, the mixture is left stirring for 30 minutes and the precipitate formed is drained.
• the precipitate is taken up in 400 ml of a 10% Na2C23 solution, extracted with ether, the organic phase is dried over MgS ⁇ 4 and the solvent is evaporated under vacuum. 22 g of the expected product are obtained in the form of an oil.
• a suspension of 70 g of the compound obtained in the preceding step in 150 ml of THF is cooled to 5 ° C., 237 ml of a 1M solution of borane in THF are rapidly added, then the mixture is heated at reflux for 1 hour. 474 ml of an IM solution of borane in THF are then added and the reflux is continued for 3 hours.

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Citations (2)

• 1996
  • 1996-07-26 FR FR9609439A patent/FR2751654B1/fr not_active Expired - Fee Related
• 1997
  • 1997-07-25 WO PCT/FR1997/001393 patent/WO1998004561A1/fr not_active Application Discontinuation
  • 1997-07-25 EP EP97935628A patent/EP0915882A1/fr not_active Withdrawn
  • 1997-07-25 JP JP10508555A patent/JP2000515878A/ja active Pending
  • 1997-07-25 AU AU38545/97A patent/AU3854597A/en not_active Abandoned
  • 1997-07-25 CA CA002261808A patent/CA2261808A1/en not_active Abandoned
  • 1997-07-25 BR BR9710517A patent/BR9710517A/pt not_active IP Right Cessation
• 1999
  • 1999-01-22 NO NO19990278A patent/NO312244B1/no unknown

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