Patent EA-005185-B1 (EA)
Title: New 1,1- and 1,2-disubstituted cyclopropane compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: GOLDSTEIN SOLO
IPC: A61P25/16
Filed: 2001-06-27
Abstract: 1. A compound selected from those of formula (I): wherein: p represents an integer of from 0 to 6 inclusive, n represents an integer of from 0 to 6 inclusive, R1 and R2, which may be identical or different, each independently of the other represent a group selected from hydrogen, linear or branched (C1-C6)alkyl, aryl, and aryl-(C1-C6)alkyl, which contain linear or branched alkyl moiety, or R1+R2 form together with nitrogen carrying them saturated, 5- to 6-membered, monocyclic system, X represents a group selected from oxygen, sulphur, -CH(CH-, methylene, a group of formula -HC(N-O- and a group of formula -O-CH2-CH(CH-, in which groups oxygen is linked to Y moiety, Y represents a group selected from aryl, heteroaryl, aryl-(C1-C6)alkyl in which alkyl moiety is linear or branched, heteroaryl-(C1-C6)alkyl in which alkyl moiety is linear or branched, -C(O)-A, and -C(S)-A, A represents a group selected from linear or branched (C1-C6)alkyl, heteroaryl and NR3R4 wherein R3, and R4, which may be identical or different, each represent a group selected from hydrogen, linear or branched (C1-C6)alkyl, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base, with the proviso that: in the case of 1,1-disubstituted compounds of formula (I), p is other than zero, when X represents methylene, n has the value zero, Y represents aryl, or heteroaryl, and R1 and R2, which may be identical or different, represent hydrogen, linear or branched (C1-C4)alkyl, benzyl, phenylethyl, or form together with nitrogen carrying them 5- to 7-membered saturated carbocyclic system, p is other than zero, when X represents methylene, n has the value zero, Y represents acetyl, and R1 and R2, which may be identical or different, represent hydrogen, linear or branched (C1-C4)alkyl, phenyl, benzyl, R1 and R2 do not simultaneously represent methyl: either when p, and n each have the value 1, X represents oxygen, and Y represents selected from p-nitrobenzoyl, p-aminobenzoyl, p-chlorophenylaminocarbonyl, and acetyl, or, when p has the value zero, n has the value 1, X represents oxygen, or sulphur, and Y represents 2-quinolyl substituted in the 3-position by linear or branched (C3-C4)alkyl, or phenyl, Y does not represent 1,2-benzisoxazol-3-yl when n has the value 1, p has the value zero, and X represents oxygen, in the case of 1,2-disubstituted compounds of formula (I), R1 and R2 do not simultaneously represent hydrogen when p, and n each have the value zero, and X-Y together represent phenoxy (optionally substituted by one or two, identical or different, groups selected from methoxy, dimethylamino, halogen, methyl, trifluoromethyl, nitro, and amino), phenylsulphanyl, benzyloxy, benzyl group, or 2-phenylethyl, R1 and R2 do not simultaneously represent methyl when p, and n each have the value zero and X-Y together represent phenoxy (optionally substituted by a group selected from chlorine, and trifluoromethyl), phenylsulphanyl, or benzyl, and also with the proviso that the compounds of formula (I) are other than the following compounds: (1-benzylcyclopropyl)methanamine, (1-benzylcyclopropyl)-N,N-dimethylmethanamine, 2-(phenoxycyclopropyl)methanamine, 2-(phenoxymethyl)-cyclopropanamine, (N,N-dimethyl)-2-(acetoxymethyl)-cyclopropanemethanamine, N-{2-[2-(benzyloxy)ethyl]cyclopropyl}-N,N-dimethylamine, it also being understood that: aryl denotes phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, or indenyl, each of those groups being optionally substituted by one or more, identical or different, groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, cyano, nitro, linear or branched (C1-C6)alkoxy, linear or branched (C2-C7)acyl, linear or Kilo branched (C1-C6)alkoxycarbonyl, linear or branched (C1-C6)trihaloalkyl, linear or branched (C1-C6)trihaloalkoxy, and amino optionally substituted by one or two linear or branched (C1-C6)alkyl, heteroaryl denotes 5- to 12-membered, monocyclic aromatic or bicyclic system containing from one to three, identical or different, hetero atoms selected from oxygen, is nitrogen and sulphur, one of the rings of which, in the case of bicyclic system, is aromatic in character, and the other ring of which may be aromatic, or partially hydrogenated, each of those groups being optionally substituted by one or more, identical or different, groups selected from substituents defined hereinbefore for aryl. 2. A compound of formula (I) according to claim 1, characterised in that n is an integer of from 0 to 2 inclusive, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 3. A compound of formula (I) according to claim 1, characterised in that R1 and R2, which may be identical or different, each represent hydrogen, or linear or branched (C1-C6)alkyl, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 4. A compound of formula (I) according to claim 1, characterised in that X represents oxygen, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 5. A compound of formula (I) according to claim 1, characterised in that Y represents a group selected from -C(O)NR3R4 wherein R3 and R4, are as defined for formula (I), acetyl, -C(O)-heteroaryl, aryl-(C1-C6)alkyl in which alkyl is linear or branched, and heteroaryl, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 6. A compound formula (I) according to claim 1, characterised in that Y represents pyridyl, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 7. A compound of formula (I) according to claim 1, characterised in that it represents a compound of formula (IA): wherein n, p, X, Y, R1 and R2 are as defined for formula (I), its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 8. A compound of formula (I) according to claim 1, characterised in that it represents a compound of formula (IB): wherein n, p, X, Y, R1 and R2 are as defined for formula (I), its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 9. A compound of formula (I) according to claim 1, characterised in that p is an integer having the value 0 or 1, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 10. A compound of formula (IB) according to claim 8, characterised in that p represents 0, or 1, n represents 0, or 1, R1 and R2, which may be identical or different, represent hydrogen, or linear or branched (C1-C6)alkyl, X represents oxygen, and Y represents a group selected from phenyl-(C1-C6)alkyl in which alkyl is linear or branched, pyridyl, and -C(O)-A wherein A represents linear or branched (C1-C6)alkyl, mono(C1-C6)alkylamino, or di(C1-C6)alkylamino, alkyl moiety being linear or branched, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 11. A compound of formula (IA) according to claim 7, characterised in that p represents 0, or 1, n is an integer of from 0 to 3 inclusive, R1 and R2, which may be identical or different, represent hydrogen, linear or branched (C1-C6)alkyl or form together with nitrogen carrying them, pyrrolidinyl group, X represents oxygen, sulphur or -CH(CH-, and Y represents a group selected from phenyl (optionally substituted by hydroxy, linear or branched (C1-C6)alkyl or halogen), pyridyl, pyridyl-(C1-C6)alkyl in which alkyl moiety is linear or branched (pyridyl in each of those groups being optionally substituted by a group selected from halogen, and linear or branched (C1-C6)alkyl), and -C(O)-A wherein A represents a group selected from linear or branched (C1-C6)alkyl, linear or branched mono(C1-C6)alkylamino, linear or branched di(C1-C6)alkylamino, and pyridyl, its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base. 12. A compound of formula (I) according to claim 1, which is: 2-[1-(dimethylamino)cyclopropyl]ethyl methylcarbamate, 2-[1-(dimethylamino)cyclopropyl]ethyl dimethylcarbamate, [1-(dimethylamino)cyclopropyl]methyl dimethylcarbamate, [1-(dimethylamino)cyclopropyl]methyl acetate, 2-[1-(dimethylamino)cyclopropyl]ethyl acetate, 1-[(dimethylamino)methyl]cyclopropyl acetate, [1-(dimethylamino)cyclopropyl]methyl nicotinate, N,N-dimethyl-1-[(3-pyridyloxy)methyl]cyclopropanamine, N-methyl-1-[(3-pyridyloxy)methyl]cyclopropanamine, N,N-dimethyl-1-[(3-pyridylmethoxy)methyl]cyclopropanamine, N,N-dimethyl-1-[2-(3-pyridyloxy)ethyl]cyclopropanamine, 4-({2-[1-dimethylamino)cyclopropyl]ethyl}sulphanyl)phenol, (+-)-cis-2-(dimethylamino)cyclopropyl methylcarbamate, (+-)-trans-2-(dimethylamino)cyclopropyl methylcarbamate, (+-)-cis-2-(dimethylamino)cyclopropyl acetate, (+-)-trans-2-(dimethylamino)cyclopropyl acetate, (+-)-cis-2-(dimethylamino)cyclopropyl]methyl acetate, (+-)-trans-2-(dimethylamino)cyclopropyl]methyl acetate, (+-)-cis-2-[(benzyloxy)methyl]-N,N-dimethylcyclopropanamine, (+-)-trans-2-[(benzyloxy)methyl]-N,N-dimethylcyclopropanamine, (+-)-trans-2-[(dimethylamino)methyl]cyclopropyl acetate, 1-[(3-pyridyloxy)methyl]cyclopropanamine dihydrochloride, N-methyl-1-{[(6-methyl-3-pyridyl)oxy]methyl}cyclopropanamine hydrochloride, N-methyl-1-{[(6-chloro-3-pyridyl)oxy]methyl}cyclopropanamine hydrochloride, N-{1-[(3-fluorophenoxy)methyl]cyclopropyl}-N-methylamine hydrochloride, 3-[1-(dimethylamino)cyclopropyl]propyl dimethylcarbamate fumarate, 3-[1-(dimethylamino)cyclopropyl]propyl methylcarbamate fumarate, N-methyl-1-[(2-pyridylsulphanyl)methyl]cyclopropanamine dihydrochloride, N-methyl-1-[3-(3-pyridyloxy)propyl]cyclopropanamine dihydrochloride, N-methyl-1-[2-(3-pyridyl)ethyl]cyclopropanamine dihydrochloride, N-methyl-1-[(Z)-2-(3-pyridyl)ethenyl]cyclopropanamine fumarate, [1-(1-pyrrolidinyl)cyclopropyl]methyl dimethylcarbamate fumarate, N,N-dimethyl-1-[2-(3-pyridyl)ethyl]cyclopropanamine hydrochloride, 3-{[1-(1-pyrrolidinyl)cyclopropyl]methoxy}pyridine fumarate, N-methyl-1-[2-(3-pyridyloxy)ethyl]