Patent EA-004672-B1 (EA)
Title: 3-azabicyclo[3.1.0] hexane derivatives as opiate receptors ligands
Inventor: BANKS BERNARD JOSEPH
IPC: C07D409/10
Filed: 1999-11-19
Abstract: 1. A substance which is a compound of formula I, wherein the "Ar" ring represents a phenyl or 6-membered heteroaryl ring; R<1> when taken alone is H, halogen, NH2, NY<2>WY<1>, Het<1> or OE, Y<2> is H, W is SO2 or C(O)O, Y<1> is C1-10 alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, C1-4alkoxy, CONH2, C1-6alkoxycarbonyl, NH2, aryl or phthalimidyl), Het<1>, aryl (optionally substituted by one or more substituents independently selected from C1-4 alkyl and halogen), NH2, N(C1-6alkyl)2 or NH(C1-6alkyl), Het<1> is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more C1-6alkyl substituents, and if a S atom is present in a ring, it can be present as part of a -S-, S(O) or -S(O2)-group, and carbon atoms in the ring can be present as a part of a carbonyl moiety, E represents H, R<2> when taken alone is H, halogen, or R<1> and R<2> when attached to adjacent carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Het<1A>; Het<1A> is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (and is preferably an optionally benzo-fused 5 to 7-membered heterocyclic ring) and which group is optionally substituted by C1-4halogenalkyl, and if a S atom is present in a ring, it can be present as part of a -S-, S(O) or -S(O2)-group, R<3> is CN or C1-6alkyl (optionally substituted by one or more halogen, OH, C1-6alkoxy, C1-6alkanoyloxy and/or NY<2>WY<1>), R<4> is C1-10alkyl, C3-10alkenyl or C3-10alkynyl, each of which groups is linked to the N atom via a sp<3> carbon, and which is optionally substituted by one or more OH, CN, halogen, C1-6alkoxy (optionally substituted by aryl), aryloxy (optionally substituted by one or more halogen, C1-6alkyl (optionally substituted by one or more halogen), and/or C1-4alkoxy), C1-6alkoxycarbonyl, C2-6alkanyloxy, C3-8cycloalkyl, C3-8cycloalkyloxy,C4-9cycloalkanoyl, aryl (optionally substituted by one or more halogen, C1-6alkyl (optionally substituted by one or more CN and/or halogen), C1-4 alkoxy, OH and/or NY<2>WY<1>), heterocycle (optionally benzo-fused and optionally substituted by one or more halogen, C1-6alkyl, C1-4alkoxy and/or =O, heterocyclyloxy (optionally substituted by one or more C1-6alkyl or =O), adamantyl or ZBNR<14>R<15>, Z is a CO group, B is (CH<2>)p, R<14> and R<15>each independently represent H, C1-10alkyl, C3-8cycloalkyl or heteroaryl, R<5> and R<8> are H, R<6>, R<7>, R<9> and R<10> are H, X is halogen, n is 0, 1 or 2; p is 0; q is 0; "heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if a S atom is present in the ring, it can be present as part of a-S-, S (O)- or -S(O)2- group, and which may be joined to the remainder of the compound via any available atom (s); "heterocycle" is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms; "aryl", including in the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom (s) (examples of such groups include naphthyl, indanyl, etc.); "alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbon atoms allows; "cycloalkyl" groups can be polycyclic if the number of carbon atoms allows; or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof. 2. A substance according to claim 1 wherein the "Ar " ring represents phenyl or pyridyl. 3. A substance according to any preceding claim wherein R<1> when taken alone is OH, halogen, NH2, NY<2>WY<1> or Het<1>. 4. A substance according to any preceding claim wherein R<2> when taken alone is H. 5. A substance according to claim 1 or 2 wherein R<1> and R<2> are taken together with the carbon atoms to which they are attached and represent an optionally benzo-fused 5- to 7-membered heteroaryl ring optionally substituted by C1-4haloalkyl. 6. A substance according to any preceding claim wherein X is Cl. 7. A substance according to any preceding claim wherein n is 0 and q is 0. 8. A substance according to any preceding claim wherein R<3> is H, CN, or C1-6alkyl (optionally substituted by one or more halogen, OH, C1-6alkoxy, C2-6alkanoyloxy and/or NY<2>WY<1>). 9. A substance according to any preceding claim wherein R<4> is C1-10alkyl, C3-10alkenyl or C3-10alkynyl each of which groups is linked to the N atom via a sp<3> carbon, each of which is optionally substituted byC3-8cycloalkyl, aryl (optionally substituted by one or more methyl, ethyl, halogen, CH2CN, CF3, NHSO2CH3, OH, methoxy), optionally benzo-fused heteroaryl (optionally substituted by one or more methyl, halogen, methoxy, =O), OH, aryloxy (optionally substituted by one or more methyl, halogen, CF3, methoxy), CN, C1-6alkoxy,C3-8cycloalkyloxy, CONH(C3-8cycloalkyl), adamantyl or (optionally benzo-fused) heteroaryloxy (optionally substituted by one or more methyl, =O). 10. A substance according to any preceding claim wherein the "Ar" ring represents a group of formula: 11. A substance according to any preceding claim wherein R<3> is H, CH3, C2H5, iso-C3H7, n-C3H7 or CH2OCH3. 12. A substance according to any preceding claim except claim 5 wherein R<1> is OH, CN, I, NO2, optionally benzo-fused heteroaryl, NHSO2Y<1> or NHCO2Y<1>. 13. A substance according to any preceding claim wherein R<4> is n-hexyl, 3-phenylpropyl, 3-phenyloxypropyl, 3-cyclohexylpropyl, 5-methylhexyl, 2-phenyloxyethyl, (4-cyanomethyl) benzyl, 2-cyclohexyloxyethyl, 2-benzyloxyethyl, 3-cyclohexylprop-2-en-1-yl, 2-(cyclohexylcarbonyl) ethyl, 3-(2-methylphenyl) propyl, phenylprop-2-en-1-yl, 2-(indol-3-yl) ethyl, 3-cyclohexyl-3-hydroxypropyl, (indan-2yl) methyl, 3-(4-fluorophenyl) propyl, 3-(thien-2-yl) propyl, 3-(thien-3-yl) propyl, 3-(pyrid-2-yl) propyl, 3-(3-methylthien-2-yl) propyl, 3-(thien-2-yl) prop-2-en-1-yl, 3-(thien-3-yl) prop-2-en-1-yl, 3-(pyrid-2-yl) prop-2-en-1-yl, 3-(3-methylthien-2-yl) prop-2-en-1-yl, 3-(3-methylpyrid-2-yl) prop-2-en-1-yl or 3-(2-methoxyphenyl) propyl. 14. A substance according to any preceding claim except claims 3,4 and 13, wherein R<1> and R<2> are taken together with the carbon atoms to which they are attached are a 5membered heteroaryl moiety optionally substituted by C1-4haloalkyl. 15. A substance according to any preceding claim wherein R<3> is CH3 or C2H5. 16. A substance according to any preceding claim except claims 5 and 15 wherein R<1> when taken alone is OH, CN, I, Cl, NH2, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazol- 2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO2(C1-6alkyl), NHSO2(C1-6alkyl substituted by methoxy, CONH2, OH, CO2(C2-6alkyl), phthalimido, NH2 or halogen), NHSO2NH2, NHSO2NH(C1-6alklyl), NHSO2N(C1-6alkyl)2, NHCO(C1-6alkyl) or NHCO2(C1-6alkyl). 17. A substance according to claim 16 wherein R<1> is OH, NHSO2CH3, NHSO2C2H5, NHSO2(n-C3H7), NHSO2(iso-C3H7), NHSO2(n-C4H7), NHSO2NH (iso-C3H7), NHSO2(N-methylimidazol-4-yl), NHSO2(CH2)2OCH3, NHSO2(CH2)2OH, 1,2,4-triazolyl or imidazol-2-yl. 18. A substance according to claim 17 wherein R<1> is OH, NHSO2CH3, NHSO2C2H5 or imidazol-2-yl. 19. A substance according to claim 14 wherein R<1> and R<2> when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2substituted by CF3. 20. A substance according to any preceding claim wherein R<4> is n-hexyl, 3-phenylpropyl, (4-cyanomethyl) benzyl, 2-benzyloxyethyl, 3-cyclohexylprop-2-en-1-yl, 2-(indol-3-yl) ethyl, 3-(2-methylphenyl) propyl, 3-(4-fluorophenyl) propyl, 3-(pyrid-2-yl) propyl, 3-phenylprop-2-en-1-yl, 3-cyclohexyl-3-hydroxypropyl, 3-(thien-2yl) propyl, 3-(thien-3-yl) propyl, 3-(3-methylthien-2-yl) propyl, 3-(thien-2-yl) prop-2-en1-yl, 3-(thien-3-yl) prop-2-en-1-yl, 3-(pyrid-2-yl) prop-2-en-1-yl, 3-(3-methylthien-2-yl) prop-2-en-1-yl, 3-(6-methylpyrid-2-yl) prop-2-en-1-yl or 3-(2methoxyphenyl) propyl. 21. A substance according to claim 1 which has the following relative stereochemistry: 22. A compound according to claim 1 which is selected from: (1) N-{3-[6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl} methanesulfonamide; (2) N-{3-[6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl} methanesulfonamide acetate salt; (3) N-{3-[6-methyl-3-(phenylpropyl)-3 azabicyclo[3.1.0]hex-6-yl]phenyl}-1-ethanesulfonamide; (4) N-{3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide; (5) N-{3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-1-ethanesulfonamide; (6) N-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide; (7) N-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]-1-ethanesulfonamide; (8) N-[3-[2 hexyl-6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl]-1-propanesulfonamide; (9) N-[3-[2 hexyl-6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl]-3-pyridinesulfonamide; (10) N-{3-[6-ethyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide acetate salt; (11) N-{3-[6-ethyl-3-(phenylpropyl)-3 azabicyclo[3.1.0]hex-6-yl]phenyl}-1-ethanesulfonamide acetate salt; (12) N-[3-(6-Ethyl-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide; (13) N-[3-(6-Ethyl-3-hexyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]-1-ethanesulfonamide; (14) N-[3-(3-{3-phenylpropyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide; (15) 3-Hexyl-6-phenyl-3-azabicyclo[3.1.0]hexane; (16) N-{3-[6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-benzolsulfonamide acetate salt; (17) N,N-dimethyl-N'-{3-[6-Methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}sulfonam