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Claims for Patent: 4,746,680

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Claims for Patent: 4,746,680

Title: Therapeutic agents
Abstract:Compounds of formula I ##STR1## in which R.sub.1 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, cycloalkylalkyl or optionally substituted phenyl; R.sub.2 is H or C.sub.1-3 alkyl; R.sub.3 and/or R.sub.4 are H, formyl, C.sub.1-3 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, C.sub.3-7 cycloalkyl or R.sub.3 and R.sub.4 together with the nitrogen atom form a heterocyclic ring system; R.sub.5 and/or R.sub.6 are H, halo, CF.sub.3, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio or R.sub.5 and R.sub.6 together with the carbon atoms to which they are attached form a second benzene ring show therapeutic activity in the treatment of depression. Pharmaceutical compositions and processes for preparing compounds of formula I are disclosed.
Inventor(s): Jeffery; James E. (Nottingham, GB), Kozlik; Antonin (Nottingham, GB), Wilmshurst; Eric C. (Nottingham, GB)
Assignee: The Boots Company p.l.c. (GB2)
Application Number:06/725,206
Patent Claims: 1. A compound of the formula I: ##STR33## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms, in which R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; in which R.sub.3 and R.sub.4, which are the same or different, are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; in which R.sub.5 and R.sub.6, which are the same or different, are selected from the group consisting of H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 arbon atoms and phenyl, or R.sub.5 and R.sub.6, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by at least one halo, alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring.

2. A compound according to claim 1 in which R.sub.1 is branched chain alkyl of up to 4 carbon atoms, and R.sub.2 is H or methyl.

3. A compound according to claim 2 in which R.sub.1 is isopropyl, isobutyl or sec-butyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl, and R.sub.5 and R.sub.6 are selected from the group consisting of H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy and phenyl, or R.sub.5 and R.sub.6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by halo.

4. A compound according to claim 1 of the formula III: ##STR34## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different, are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 and R.sub.6, which are the same or different are selected from the group consisting of H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 carbon atoms and phenyl, or R.sub.5 and R.sub.6, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by at least one halo, alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring.

5. A compound according to claim 4 in which R.sub.1 is branched chain alkyl of up to 4 carbon atoms and R.sub.2 is H or methyl.

6. A compound according to claim 4 in which R.sub.1 is isopropyl, isobutyl or sec-butyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl, and R.sub.5 and R.sub.6 are selected from the group consisting of H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy and phenyl, or R.sub.5 and R.sub.6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by halo.

7. A compound according to claim 1 of the formula IV: ##STR35## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different, are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 is H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 carbon atoms or phenyl, and R.sub.6 is fluoro or methyl.

8. A compound according to claim 7 in which R.sub.1 is isopropyl, isobutyl or sec-butyl; R.sub.2 is H or methyl; R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl; R.sub.5 is H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl and R.sub.6 is fluoro or methyl.

9. A compound according to claim 1 of the formula III: ##STR36## or a pharmaceutically acceptable salt thereof in which R.sub.1 is isobutyl; R.sub.2 is H; R.sub.3 is H, methyl or ethyl; R.sub.4 is H, methyl or ethyl; R.sub.5 is chloro; and R.sub.6 is H or chloro.

10. A compound of claim 9 which is N-methyl-1-[1-(4-chlorophenylcyclobutyl]-3-methyl-butylamine or a pharmaceutically acceptable salt thereof.

11. A compound of claim 9 which is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine or a pharmaceutically acceptable salt thereof.

12. A compound of claim 9 which is N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylamine or a pharmaceutically acceptable salt thereof.

13. A compound of claim 9 which is .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition useful for treating depression in humans which comprises an anti-depressantly effective amount of a compound of the formula I: ##STR37## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms,; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different, are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 and R.sub.6, which are the same or different are selected from the group consisting of H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 carbon atoms and phenyl, or R.sub.5 and R.sub.6, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by at least one halo, alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring.

15. A composition according to claim 14 in which R.sub.1 is branched chain alkyl of up to 4 carbon atoms, and R.sub.2 is H or methyl.

16. A composition according to claim 15 in which R.sub.1 is isopropyl, isobutyl or sec-butyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl, and R.sub.5 and R.sub.6 are selected from the group consisting of H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy and phenyl, or R.sub.5 and R.sub.6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by halo.

17. A composition according to claim 14 wherein the compound is of the formula III: ##STR38## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms,; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different, are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 and R.sub.6, which are the same or different are selected from the group consisting of H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 carbon atoms and phenyl, or R.sub.5 and R.sub.6, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by at least one halo, alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring.

18. A composition according to claim 17 in which R.sub.1 is branched chain alkyl of up to 4 carbon atoms, and R.sub.2 is H or methyl.

19. A composition according to claim 17 in which R.sub.1 is isopropyl, isobutyl or sec-butyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl, and R.sub.5 and R.sub.6 are selected from the group consisting of H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy and phenyl, or R.sub.5 and R.sub.6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by halo.

20. A composition according to claim 14 of the formula IV: ##STR39## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different, are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alknynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 is H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 carbon atoms or phenyl, and R.sub.6 is fluoro or methyl.

21. A composition according to claim 14 in which R.sub.1 is isopropyl, isobutyl or sec-butyl,; R.sub.2 is H or methyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl,, R.sub.5 is H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl and R.sub.6 is fluoro or methyl.

22. A composition according to claim 14 wherein the compound is of the formula III: ##STR40## or a pharmaceutically acceptable salt thereof in which R.sub.1 is isobutyl; R.sub.2 is H; R.sub.3 is H, methyl or ethyl; R.sub.4 is H, methyl or ethyl; R.sub.5 is chloro; and R.sub.6 is H or chloro.

23. A composition according to claim 22 wherein the compound is N-methyl-1-[1-(4-chlorophenylcyclobutyl]-3-methylbutylamine or a pharmaceutically acceptable salt thereof.

24. A composition according to claim 22 wherein the compound is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine or a pharmaceutically acceptable salt thereof.

25. A composition according to claim 22 wherein the compound is N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylamine or a pharmaceutically acceptable salt thereof.

26. A method of treating depression in humans which comprises administering to a human in need thereof an anti-depressantly effective amount of a compound of the formula I: ##STR41## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms,; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 and R.sub.6, which are the same or different, are selected from the group consisting of H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 carbon atoms and phenyl, or R.sub.5 and R.sub.6, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by at least one halo, alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring, in combination with a pharmaceutically acceptable carrier.

27. A method according to claim 26 in which R.sub.1 is branched chain alkyl of up to 4 carbon atoms, and R.sub.2 is H or methyl.

28. A method according to claim 27 in which R.sub.1 is isopropyl, isobutyl or sec-butyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl, and R.sub.5 and R.sub.6 are selected from the group consisting of H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy and phenyl or R.sub.5 and R.sub.6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by halo.

29. A method according to claim 26 wherein the compound is of the formula III: ##STR42## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different, are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 and R.sub.6, which are the same or different, are selected from the group consisting of H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkythio groups containing 1 to 3 carbon atoms and phenyl, or R.sub.5 and R.sub.6, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by at least one halo, alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring.

30. A method according to claim 29 in which R.sub.1 is branched chain alkyl of up to 4 carbon atoms and R.sub.2 is H or methyl.

31. A method according to claim 29 in which R.sub.1 is isopropyl, isobutyl or sec-butyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl, and R.sub.5 and R.sub.6 are selected from the group consisting of H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy and phenyl, or R.sub.5 and R.sub.6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by halo.

32. A method according to claim 29 of the formula IV: ##STR43## or a pharmaceutically acceptable salt thereof in which R.sub.1 is branched chain alkyl of up to 6 carbon atoms,; R.sub.2 is selected from the group consisting of H and alkyl groups containing 1 to 3 carbon atoms; R.sub.3 and R.sub.4, which are the same or different are selected from the group consisting of H, straight or branched chain alkyl groups containing 1 to 4 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, alkynyl groups having 3 to 6 carbon atoms, cycloalkyl groups in which the ring contains 3 to 7 carbon atoms, and a group of formula CHO; R.sub.5 and R.sub.6, which are the same or different are selected from the group consisting of H, halo, trifluoromethyl, alkyl groups containing 1 to 3 carbon atoms, alkoxy groups containing 1 to 3 carbon atoms, alkylthio groups containing 1 to 3 carbon atoms and phenyl, or R.sub.5 and R.sub.6, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by at least one halo, alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring and R.sub.6 is fluoro or methyl.

33. A method according to claim 32 in which R.sub.1 is isopropyl, isobutyl or sec-butyl, R.sub.2 is H or methyl, R.sub.3 and R.sub.4 are selected from the group consisting of H, methyl, ethyl and formyl, R.sub.5 is H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl and R.sub.6 is fluoro or methyl.

34. A method according to claim 29 wherein the compound is of the formula III: ##STR44## or a pharmaceutically acceptable salt thereof in which R.sub.1 is isobutyl; R.sub.2 is H; R.sub.3 is H, methyl or ethyl; R.sub.4 is H, methyl or ethyl; R.sub.5 is chloro; and R.sub.6 is H or chloro.
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