Bicyclic derivatives

Claim 2

A guanidine derivative of the formula I:- in which R 1 and R 2 , which may be the same or different-, are hydrogen atoms or branched or unbranched 1-10C alkyl, 3 - 8C cycloalkyl or 4-14C cycloalkylalkyl radicals, each alkyl, cycloalkyl or cycloalkylalkyl radical being optionally substituted by one or more halogen atoms selected from fluorine, chlorine and bromine atoms, provided that at least one of R 1 and R 2 is a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl radical, and provided that there is no halogen substituent on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl radical which is directly attached to the nitrogen atom or R 2 is a hydrogen atom and -R l is a radical of the formula II:- in which W is an unbranched 2-6C alkylene chain which is optionally substituted by one or two 1-4C alkyl radicals, E is an oxygen or sulphur atom, a sulphinyl or sulphonyl radical, or a radical of the formula NR 4 in which R is a hydrogen atom or a 1-6C alkyl radical, R 3 is a hydrogen atom or an unbranched 1-6C alkyl radical which is optionally substituted by one or two 1-4C alkyl radicals, or R 3 and R 4 are joined to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, or R 2 is a hydrogen atom and R is a hydrogen atom or a 1-10C alkyl, 3-8C cycloalkyl, 4-14C cycloalkylalkyl, 3-6C alkenyl, 3-6C alkynyl, 1-6C alkanoyl, 6-10C aryl, 7-11C arylalkyl or 7-11C aroyl radical, the aryl, arylalkyl and aroyl radicals being optionally substituted on the aryl ring by one or two substituents selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, trifluoromethyl, hydroxy and amino radicals; in ring X the dotted line is a double bond on one side of the nitrogen atom and Z is a carbon or nitrogen atom such that ring X is a 5- or 6-membered aromatic heterocyclic ring which contains at least one nitrogen atom and may optionally contain one or two additional hetero atoms selected from oxygen, nitrogen and sulphur atoms, which heterocyclic ring may, where possible, carry one or two optional substituents, the optional substituents on ring X being selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, trifluoromethyl, hydroxy and amino radicals; A is a 1-8C alkylene chain which is optionally substituted by one or two 1-3C alkyl radicals and into which is optionally inserted, as part of the backbone of the chain, an NH or a 1-6C N-alkyl radical or one or two groups selected from oxygen and sulphur atoms and cis and trans vinylene, ethynylene, phenylene and 5-7C alkylene radicals, provided that no two insertions selected from oxygen and sulphur atoms and NH and N-alkyl radicals are directly attached one to the other, and provided tnat when an optional insertion is made in chain A wnich results in the inserted group being directly attached to ring Y the inserted group is other than an NH or N-alkyl radical, or A is a 5-7C cycloalkylene radical or phenylene radical; in ring Y the dashed line represents an optional double bond, B is an oxygen or sulphur atom or a CH, CH 2 or CO radical and E is a chain of two or three atoms or radicals selected from oxygen, sulphur and nitrogen atoms and CH, CH 2 , SO and SO 2 radicals such that ring Y is a 5- or 6-membered heterocyclic ring, which may be saturated, partially unsaturated or fully unsaturated, and such that to ring Y is optionally fused a benzene ring, ring Y being optionally substituted on a nitrogen atom by a 1-6C alkyl radical or on a carbon atom by a halogen atom or a hydroxy, nitro, amino, 1-6C alkylamilzo, 2-8C dialkylamino, cyano, carboxy, carbamoyl, sulphamoyl, 1-6C alkyl or 1-6C alkanesulphonyl radical and the benzene ring optionally fused to ring Y being optionally substituted by one or two substituents selected from halogen atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, hydroxy and amino radicals: and the pharmaceutically-acceptable acid-addition salts thereof.

Claim 3

A guanidine derivative of the formula I given in claim 1 in which R 1 and R 2 are selected from the group consisting of hydrogen atoms and 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2-bromo-2,2-difluoroethyl, 2,2-dibromo-2-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2-chloro-2-fluoroethyl, 2-bromo-2-fluoroethyl, 2,2,3,3-tetra- fluoropropyl, 2,2,3,3,3-pentafluoropropyl, 1,1,1,3,3,3-hexafluoroisopropyl, 1,3-dichloro-1,1,3,3-tetrafluoro- isopropyl, 1-chloro-1,1,3,3,3-pentafluoroisopropyl, 1,3-difluoroisopropyl, 2,2,3,3,4,4,4-heptafluorobutyl, 2,2,3,3-tetrafluorocyclopropyl, 2-chloro-2,3,3-trifluoro- cyclopropyl, 2,2-difluorocyclopropyl, 2-chloro-3,3-difluorocyclopropyl, 2,2,3,3,4,4-hexafluorocyclobutyl, 2-chloro-2,3,3,4,4-pentafluorocyclobutyl, (1,2,2,3,3-pentafluorocyclopropyl)methyl, (2-chloro-l,2,3,3-tetrafluorocyclopropyl)methyl, (1,2,2,3,3,4,4-heptafluoro- cyclobutyl)methyl, (2-chloro-1,2,3,3,4,4-hexafluorocyclobutyl)methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl. radicals provided that at least one of R 1 and R 2 is a halogen-substituted radical, or R 2 is a hydrogen atom and -R 1 is a radical of the formula II given in claim 1 in which W is a 2-6C alkylene chain which is optionally substituted by one or two methyl radicals, E is an oxygen or sulphur atom, a sulphinyl or sulphonyl radical or a radical of the formula NR 4 in which R 6 is a hydrogen atom or a methyl radical, R 3 is a hydrogen atom or a methyl radical, or R and R are joined to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, or R 2 is a hydrogen atom and R l is a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, cyclohexylmethyl, allyl, propargyl, acetyl, phenyl, benzyl or benzoyl radical, the phenyl, benzyl and benzoyl radicals being optionally substituted on the phenyl ring by one or two substituents selected from fluorine, chlorine and bromine atoms and methyl, methoxy, methylthio, trifluoromethyl, hydroxy and amino radicals; ring X is an oxazole, thiazole, imidazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyrazine, pyridine, pyrimidine or 1,3,5-triazine ring, ring X being optionally substituted, where possible, by one or two substituents selected from fluorine, chlorine and bromine atoms and methyl, methoxy, methylthio, trifluoromethyl, hydroxy and amino radicals; -A- is a phenylene, cyclopentylene, cyclohexylene, trimethylene, tetramethylene, pentamethylene, thioethylene, thiotrimethylene, thiotetramethylene, thiopentamethylene, oxyethylene, oxytrimethylene, oxytetramethylene, methylenethiomethylene, methylenethioethylene, methylenethiopropylene, methyleneoxymethylene, methyleneoxyethylene, ethyleneoxyethylene, oxy-2-methylethylene, thiopropylenethiomethylene, oxypropyleneoxy, oxyethyleneoxymethylene, oxyethylenethio, oxypropylenethio, iminoethylene, iminopropylene, vinylenepropylene, oxymethylenevinylene, 1,3-phenylene, 1,3-cyclopentylene, methylene-l,4-phenylene, ethyleneoxymethylene-l,4-phenylene, oxy-l,3-phenylenemethylene, thiomethylene-ethynylenemethylene or tetramethyleneoxy radical: ring Y is of the formula IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV or XVII:- in which R 5 is a hydrogen atom or a radical of the formula NHR 7 , R 6 is a hydrogen atom or a cyano, nitro, methoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl radical, R 7 is a hydrogen atom or a methyl radical, R 8 is a hydrogen, chlorine or bromine atom and p is 1 or 2: and the pharmaceutically-acceptable acid-addition salts thereof.

Claim 4

A guanidine derivative as claimed in claim 1 or 2 in which ring Y is of the formula IV, V, VI, VII, VIII, IX, X, XI, XII or XIII given in claim 2 in which R 5 is a hydrogen atom or a radical of the formula NHR 7 , R 6 is a hydrogen atom or a cyano, nitro, methoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl radical, R is a hydrogen atom or a methyl radical and p is 1 or 2.

Claim 5

A guanidine derivative as claimed in any of claims 1 to 3 in which R 2 is a hydrogen atom, R 1 is a 2,2,2-trifluoroethyl radical and ring X carries no optional substituent.

Claim 6

A guanidine derivative as claimed in any of claims 1 to 4 in which ring X is a pyrazole ring, or a pyrimidine ring in which A is linked at the 2-position.

Claim 7

A guanidine derivative as claimed in any of claims 1 to 5 in which ring Y is of the formula IV given in claim 2 in which R 5 is a hydrogen atom or an amino or methylamino radical.

Claim 8

A guanidine derivative as claimed in any of claims 1 to 6 in which ring X is a pyrimidine in which A is linked at the 2-position and A is a tetramethylene or thiotrimethylene radical or ring X is a pyrazole and A is a tetramethylene radical.

Claim 9

A guanidine derivative selected from the group consisting of 4-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]-pyrimid-2-yl)butyl]imidazole, 4-[3-(4-[2-(2,2,2-trifluoroethyl) guanidino]pyrimid-2-ylthio)propyl]imidazole, 4-[4-(3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazol-1-yl)butyl]imidazole and the pharmaceutically-acceptable acid-addition salts thereof.

Claim 10

A guanidine derivative selected from the group consisting of 4-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]-pyrimid-2-yl)butyl]imidazole, 4-[3-(4-[2-(2,2,2-trifluoroethyl) guanidino]pyrimid-2-ylthio)propyl]imidazole, 4-[4-(3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazol-1-yl)butyl]imidazole and the pharmaceutically-acceptable acid-addition salts thereof.

Claim 11

A process for the manufacture of a guanidine derivative as claimed in claim 1, characterised by:- (a) construction of the guanidine radical attached to ring X by reaction of the appropriate thiourea, or a 1-6C S-alkyl or S-benzyl derivative thereof, or a salt of such a derivative, with the appropriate amine; (b) for those compounds in which the group inserted into A is an oxygen or sulphur atom or an NH radical, reaction of a compound of the formula V or VI:- with a compound of the formula VII or VIII respectively:- in which G is an oxygen or sulphur atom or an NH or N-alkyl radical, R 9 is a displaceable radical and A 1 and A 2 are fragments of -A-, including direct bonds, and are such that A 1 -G-A 2 falls within the definition of A given above; (c) construction of ring Y by reaction of a suitably functionalised carbon atom attached to the end of chain A in a standard heterocyclic ring synthesis; (d) for those compounds in which Z is a nitrogen atom, reaction of a compound of the formula X:- with a compound of the formula XI:- in which R 9 is a displaceable radical; (e) construction of the guanidine radical attached to ring X by reaction of the appropriate cyanamide with the appropriate amine; (f) for those compounds in which ring X is a thiazole ring, reaction of a compound of the formula XII:- with a compound of the formula XIII:- in which Hal is a chlorine or bromine atom and R 10 is a hydrogen atom or the optional substituent on the thiazole ring: Whereafter, when the process manufactures the compound in the form of the free base and an acid-addition salt is required, the compound of the formula I in the free base form is reacted with an acid which affords a pharmaceutically-acceptable anion.

Claim 12

A pharmaceutical composition comprising a guanidine derivative as claimed in claim 1 in association with a pharmaceutically-acceptable diluent or carrier. Claim for Austria

Claim 13

A process for tne manufacture of a guanidine derivative of the formula I:- in which R and R 2 , which may be the same or different, are hydrogen atoms or branched or unbranched 1-10C alkyl, 3-bC cycloalkyl or 4-14C cycloalkylalkyl radicals, each alkyl, cycloalkyl or cycloalkylalkyl radical being optionally substituted by one or more halogen atoms selected from fluorine, chlorine and bromine atoms, provided that at least one of R 1 and R 2 is a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl radical and provided that there is no halogen substituent on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl radical which is directly attached to the nitrogen atom or R2 is a hydrogen atom and -R 1 is a radical of the formula II:- in which W is an unbranched 2-6C alkylene chain which is optionally substituted by one or two 1-4C alkyl radicals, E is an oxygen or sulphur atom, a sulphinyl or sulphonyl radical, or a radical of the formula N R 4 in which R 4 is a hydrogen atom or a 1- 6C alkyl radical, R 3 is a hydrogen atom or an unbranched 1-6C alkyl radical which is optionally substituted by one or two 1-4C alkyl radicals, or R 3 and R 4 are joined to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, or R 2 is a hydrogen atom and R 1 is a hydrogen atom or a 1-10C alkyl, 3-8 C cycloalkyl, 4-14C cycloalkylalkyl, 3 - 6C alkenyl, 3-6C alkynyl, 1-6C alkanoyl, 6-10C aryl, 7 - IIC arylalkyl or 7-11C aroyl radical, the aryl, arylalkyl and aroyl radicals being optionally substituted on the aryl ring by one or two substituents selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, trifluoromethyl, hydroxy and amino radicals; in ring X the dotted line is a double bond on one side of the nitrogen atom and Z is a carbon or nitrogen atom such that ring X is a 5- or 6-membered aromatic heterocyclic ring which contains at least one nitrogen atom and may optionally contain one or two additional hetero atoms selected from oxygen, nitrogen and sulphur atoms, which heterocyclic ring may, where possible, carry one or two optional substituents, the optional substituents on ring X being selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, trifluoromethyl, hydroxy and amino radicals; A is a 1-8C alkylene chain which is optionally substituted by one or two 1-3C alkyl radicals and into which is optionally inserted, as part of the backbone of the chain, an NH or a 1-6C N-alkyl radical or one or two groups selected from oxygen and sulphur atoms and cis and trans vinylene, ethynylene, phenylene and 5-7C alkylene radicals, provided that no two insertions selected from oxygen and sulphur atoms and NH and N-alkyl radicals are directly attached one to the other, and provided tnat when an optional insertion is made in chain A which results.in the inserted group being directly attached to ring Y the inserted group is' other than an NH or N- alkyl radical, or A is a 5-7C cycloalkylene radical or phenylene radical; in ring Y the dashed line represents an optional double bond, B is an oxygen or sulphur atom or a CH, CH 2 or CO radical and E is a chain of two or three atoms or radicals selected from oxygen, sulphur and nitrogen atoms and CH, CH 2 , SO and S0 2 radicals such that ring Y is a 5- or 6-membered heterocyclic ring, which may be saturated, partially unsaturated or fully unsaturated, and such that to ring Y is optionally fused a benzene ring, ring Y being optionally substituted on a nitrogen atom by a 1-6C alkyl radical or on a canbon atom by a halogen atom or a hydroxy, nitro, amino, 1-6C alkylamino, 2-8C dialkylamino, cyano, ca rboxy, carbamoyl, sulphamoyl, 1-6C alkyl or 1-6 C alkanesulphonyl radical and the benzene ring optionally fused to ring Y being optionally substituted by one or two substituents selected from halogen atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, hydroxy and amino radicals: and the pharmaceutically-acceptable acid-addition salts thereof, characterised by:- (a) construction of the guanidine radical attached to ring X by reaction of the appropriate thiourea, or a 1-6C S-alkyl or S-benzyl derivative thereof, or a salt of such a derivative, with the appropriate amine; ( b ) for those compounds in which the group inserted into A is an oxygen or sulphur atom or an NH radical, reaction of a compound of the formula V or VI: - with a compound of the formula VII or VIII respectively:-. in which G is an oxygen or sulphur atom or an NH or N-alkyl radical, R 9 is a displaceable radical and A 1 and A 2 are fragments of -A-, including direct bonds, and are such that Al-G-A2 falls within the definition of A given above; ( c ) construction of ring Y by reaction of a suitably functionalised carbon atom attached to the end of chain A in a standard heterocyclic ring synthesis; ( d ) for those compounds in which Z is a nitrogen atom, reaction of a compound of the formula X:- with a compound of the formula XI:- in which R 9 is a displaceable radical; ( e ) construction of the guanidine radical attached to ring X by reaction of the appropriate cyanamide with the appropriate amine; ( f ) for those compounds in which ring X is a thiazole ring, reaction of a compound of the formula XII: - with a compound of the formula XIII:- in which Hal is a chlorine or bromine atom and R 10 is a hydrogen atom or the optional substituent on the thiazole ring: Whereafter, when the process manufactures the compound in the form of the free base and an acid-addition salt is required, the compound of the formula I in the free base form is reacted with an acid which affords a pharmaceutically-acceptable anion.

Claim 14

A process for tne manufacture of a guanidine derivative of the formula I:- in which R and R 2 , which may be the same or different, are hydrogen atoms or branched or unbranched 1-10C alkyl, 3-bC cycloalkyl or 4-14C cycloalkylalkyl radicals, each alkyl, cycloalkyl or cycloalkylalkyl radical being optionally substituted by one or more halogen atoms selected from fluorine, chlorine and bromine atoms, provided that at least one of R 1 and R 2 is a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl radical and provided that there is no halogen substituent on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl radical which is directly attached to the nitrogen atom or R2 is a hydrogen atom and -R 1 is a radical of the formula II:- in which W is an unbranched 2-6C alkylene chain which is optionally substituted by one or two 1-4C alkyl radicals, E is an oxygen or sulphur atom, a sulphinyl or sulphonyl radical, or a radical of the formula N R 4 in which R 4 is a hydrogen atom or a 1- 6C alkyl radical, R 3 is a hydrogen atom or an unbranched 1-6C alkyl radical which is optionally substituted by one or two 1-4C alkyl radicals, or R 3 and R 4 are joined to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, or R 2 is a hydrogen atom and R 1 is a hydrogen atom or a 1-10C alkyl, 3-8 C cycloalkyl, 4-14C cycloalkylalkyl, 3 - 6C alkenyl, 3-6C alkynyl, 1-6C alkanoyl, 6-10C aryl, 7 - IIC arylalkyl or 7-11C aroyl radical, the aryl, arylalkyl and aroyl radicals being optionally substituted on the aryl ring by one or two substituents selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, trifluoromethyl, hydroxy and amino radicals; in ring X the dotted line is a double bond on one side of the nitrogen atom and Z is a carbon or nitrogen atom such that ring X is a 5- or 6-membered aromatic heterocyclic ring which contains at least one nitrogen atom and may optionally contain one or two additional hetero atoms selected from oxygen, nitrogen and sulphur atoms, which heterocyclic ring may, where possible, carry one or two optional substituents, the optional substituents on ring X being selected from fluorine, chlorine and bromine atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, trifluoromethyl, hydroxy and amino radicals; A is a 1-8C alkylene chain which is optionally substituted by one or two 1-3C alkyl radicals and into which is optionally inserted, as part of the backbone of the chain, an NH or a 1-6C N-alkyl radical or one or two groups selected from oxygen and sulphur atoms and cis and trans vinylene, ethynylene, phenylene and 5-7C alkylene radicals, provided that no two insertions selected from oxygen and sulphur atoms and NH and N-alkyl radicals are directly attached one to the other, and provided tnat when an optional insertion is made in chain A which results.in the inserted group being directly attached to ring Y the inserted group is' other than an NH or N- alkyl radical, or A is a 5-7C cycloalkylene radical or phenylene radical; in ring Y the dashed line represents an optional double bond, B is an oxygen or sulphur atom or a CH, CH 2 or CO radical and E is a chain of two or three atoms or radicals selected from oxygen, sulphur and nitrogen atoms and CH, CH 2 , SO and S0 2 radicals such that ring Y is a 5- or 6-membered heterocyclic ring, which may be saturated, partially unsaturated or fully unsaturated, and such that to ring Y is optionally fused a benzene ring, ring Y being optionally substituted on a nitrogen atom by a 1-6C alkyl radical or on a canbon atom by a halogen atom or a hydroxy, nitro, amino, 1-6C alkylamino, 2-8C dialkylamino, cyano, ca rboxy, carbamoyl, sulphamoyl, 1-6C alkyl or 1-6 C alkanesulphonyl radical and the benzene ring optionally fused to ring Y being optionally substituted by one or two substituents selected from halogen atoms and 1-6C alkyl, 1-6C alkoxy, 1-6C alkylthio, hydroxy and amino radicals: and the pharmaceutically-acceptable acid-addition salts thereof, characterised by:- (a) construction of the guanidine radical attached to ring X by reaction of the appropriate thiourea, or a 1-6C S-alkyl or S-benzyl derivative thereof, or a salt of such a derivative, with the appropriate amine; ( b ) for those compounds in which the group inserted into A is an oxygen or sulphur atom or an NH radical, reaction of a compound of the formula V or VI: - with a compound of the formula VII or VIII respectively:-. in which G is an oxygen or sulphur atom or an NH or N-alkyl radical, R 9 is a displaceable radical and A 1 and A 2 are fragments of -A-, including direct bonds, and are such that Al-G-A2 falls within the definition of A given above; ( c ) construction of ring Y by reaction of a suitably functionalised carbon atom attached to the end of chain A in a standard heterocyclic ring synthesis; ( d ) for those compounds in which Z is a nitrogen atom, reaction of a compound of the formula X:- with a compound of the formula XI:- in which R 9 is a displaceable radical; ( e ) construction of the guanidine radical attached to ring X by reaction of the appropriate cyanamide with the appropriate amine; ( f ) for those compounds in which ring X is a thiazole ring, reaction of a compound of the formula XII: - with a compound of the formula XIII:- in which Hal is a chlorine or bromine atom and R 10 is a hydrogen atom or the optional substituent on the thiazole ring: Whereafter, when the process manufactures the compound in the form of the free base and an acid-addition salt is required, the compound of the formula I in the free base form is reacted with an acid which affords a pharmaceutically-acceptable anion.