Patent EA-005117-B1 (EA)
Title: 3-azabicyclo (3.1.0)hexane derivatives having opioid 3-receptor affinity
Inventor: BANKS BERNARD JOSEPH
IPC: A61K31/506
Filed: 2001-06-07
Abstract: 1. A compound of formula I, wherein the "Ar" ring represents a phenyl ring; R<1> is NH2, or NHSO2Y<1>, Y<1> is C1-10 alkyl, R<3> is C1-6 alkyl (wherein the alkyl group is optionally substituted by phenyl), R<4> is C1-10 alkyl linked to the N atom via a sp3 carbon, and substituted by one or more substituents selected from: aryl<2>, cycloalkyl<1>, aryl<2>oxy, heterocyclyl substituted by one or more substituents selected from CO2(C1-6 alkyl) and aryl, aryl<2> is phenyl substituted by one or more substituents selected from CO(C1-6 alkyl), heterocyclyl, aryl (CH2)oxy, CN and C3-7 cycloalkyl, cycloalkyl<1> is C3-10 carbocyclic system with one or two rings and substituted by aryl, with the proviso that there are no N-R<4> groups wherein there is a hetero-atom linked to another heteroatom via one SP3 carbon, "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 acceptable salts thereof. 2. The compound according to claim 1, wherein R<3> is C1-6 alkyl. 3. The compound according to claim 1, wherein R<3> is H, CH3, C2 H5, iso-C3H7, n- C3H7 or CH2OCH3. 4. The compound according to any one of claims 1-3, wherein R<4> is C1-6 alkyl substituted by cycloalkyl<1>. 5. The compound according to any one of claims 1-4, wherein R<3> is CH3 or C2 H5. 6. The compound according to any one of claims 1-5, wherein R<1> is NHSO2CH3, NHSO2C2H5, NHSO2(n-C3H7), NHSO2(iso-C3H7), NHSO2(n-C4H7). 7. The compound according to claim 6, wherein R<1> is NHSO2CH3 or NHSO2C2H5. 8. The compound according to any one of claims 1-7, wherein R<4> is C2-4 alkyl substituted by cycloalkyl<1>. 9. The compound according to claim 8, wherein R<4> is propyl substituted by cycloalkyl<1>. 10. The compound according to claim 1 selected from the group of: N-(3-{3-[3-(4-acetylphenyl) propyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide, N-[3-(3-{2-[4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]ethyl}-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide, N-(3-{6-ethyl-3-[2-(4-phenoxyphenoxy)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl]methanesulfonamide, N-{3-[3-(4-cyanobenzyl)-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide, N-(3-{3-[2-(4-cyclopropylphenoxy) ethyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide, N-{3-[6-ethyl-3-(oktahydro-1H-inden -2-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl}phenyl]methanesulfonamide, N-(3-{3-[3-(4-acetylphenyl) propyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide, N-(3-{3-[2-(benzyloxy) benzyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)]methanesulfonamide, N-{3-[3-(4-cyanobenzyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-ylphenyl}methanesulfonamide, N-(3-{3-[2-(4-cyclopropylphenoxy)ethyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide, N-(3-{6-ethyl-3-[2-phenylcyclopropyl)methyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide or pharmaceutically acceptable salts thereof. 11. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier. 12. A compound according to any of claims 1 to 10 for use in medicine. 13. A compound according to any of claims 1 to 10 for use as a medicament useful for the treatment of an opiate-mediated disease or condition. 14. The use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of a disease or condition mediated by opiate receptors. 15. A method of treatment of a condition mediated by an opiate receptor or receptors comprising administration of a therapeutically active amount of a compound according to any one of claims 1 to 10. 16. A process for the preparation of a compound of formula I according to claim 1 wherein R<1> is NHSO2Y<1> which comprises reacting a compound of formula II: with a compound of formula III: Z<1>-SO2Y<1>		III wherein Z<1> is a suitable leaving group, such as halogen or Y<1>SO2O-; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable derivative or vice versa. 17. A process for the preparation of a compound of formula I according to claim 1 which comprises reduction of a compound of formula IV: using a suitable reducing agent; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable derivative or vice versa. 18. A process for the preparation of a compound of formula I according to claim 1 which comprises reacting a compound of formula VIII: with a compound of formula IX: R<4>-Lg			IX wherein Lg is a leaving group; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable derivative or vice versa. 19. A process for the preparation of a compound of formula I according to claim 1 which comprises reduction of a compound of formula X: with a suitable reducing agent; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable derivative or vice versa. 20. A process for the preparation of a compound of formula I according to claim 1 by reduction of a corresponding compound of formula XXXI: where R<4A>CH2 takes the same meaning as R<4> as defined above, and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable derivative or vice versa. 21. A process for the preparation of a compound of formula I according to claim 1 which comprises reductive amination reaction of the amine of formula VIII above with an aldehyde of formula R<4A>-CHO wherein R<4A>CH2 takes the same meaning as R<4> as defined above, and where desired or necessary converting the resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa. 22. A compound of formula II: wherein R<3> and R<4> as defined in claim 1 or a salt thereof. 23. A compound of formula IV: wherein R<1>, R<3> and R<4> as defined in claim 1 or a salt thereof. 24. A compound of formula X: wherein R<1>, R<3> and R<4> as defined in claim 1 or a salt thereof. 25. A compound of formula XII: wherein R<3> and R<4> as defined in claim 1 or a salt thereof. 26. A compound of formula XXX: wherein R<3> and R<4> as defined in claim 1 or a salt thereof. 27. A compound of formula XXXI: wherein R<4A> as defined above and R<1> and R<3> as defined in claim 1 or a salt thereof.