IP Library › Granted Patent US 8,338,408

Granted Patent B2

US 8,338,408 · App. 12/259,234 · Granted Dec 25, 2012

Tetracyclic compounds

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Quick Facts

Patent No.: US 8,338,408
App. No.: 12/259,234
Granted: Dec 25, 2012
Kind: B2

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Abstract

This disclosure relates to new tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic [4,3-b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

Claims (117)

1. A compound of the Formula (E):

or a salt thereof,

wherein:

R 1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 and wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring;

wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 - substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic;

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or R 2a and R 2b are taken together with the carbon to which they are attached to form a cycloalkyl moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or R 3a and R 3b are taken together with the carbon to which they are attached to form a cycloalkyl moiety;

each X 7 , X 8 , X 9 and X 10 is independently N or CR 4 ;

m is 1;

q is 0;

each R 4 is independently H, hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, carboxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring;

wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic;

each R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety;

each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl moiety or R 10a and R 10b are taken together with the carbon to which they are attached to form a cycloalkyl moiety; and

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;

provided that when each of X 7 , X 8 , X 9 and X 10 is CR 4 , then one of R 8e and R 8f is hydroxyl.

2. The compound of claim 1 , or a salt thereof, wherein X 7 , X 8 and X 10 are each CR 4 where R 4 is H and X 9 is CR 4 where R 4 is substituted or unsubstituted C 1 -C 8 alkyl or halo.

3. The compound of claim 2 , or a salt thereof, wherein X 9 is CR 4 where R 4 is methyl, chloro or fluoro.

4. The compound of claim 1 , or a salt thereof, wherein at least one of X 7 , X 8 , X 9 and X 10 is N.

5. The compound of claim 1 , or a salt thereof, wherein one of R 8c -R 8f is hydroxyl and its geminal R 8c -R 8f is C 1 -C 8 alkyl or C 1 -C 8 perhaloalkyl.

6. The compound of claim 1 , or a salt thereof, wherein one of R 8c , R 8d , R 8e and R 8f is hydroxyl and its geminal R 8c , R 8d , R 8e and R 8f is C 1 -C 8 alkyl or C 1 -C 8 perhaloalkyl; X 7 , X 8 and X 10 are each CR 4 where R 4 is H; X 9 is CR 4 where R 4 is substituted or unsubstituted C 1 -C 8 alkyl or halo and R 1 is substituted or unsubstituted C 1 -C 8 alkyl.

7. The compound of claim 1 , or a salt thereof, wherein-one of R 8c , R 8d , R 8e and R 8f is hydroxyl and its geminal R 8c , R 8d , R 8e and R 8f is methyl, ethyl, cyclopropyl or trifluoroalkyl; X 7 , X 8 and X 10 are each CR 4 where R 4 is H; X 9 is CR 4 where R 4 is methyl, chloro or fluoro and R 1 is methyl or cyclopropyl.

8. The compound of claim 1 , or a salt thereof, wherein R 8e is hydroxyl and R 8f is methyl.

9. The compound of claim 8 , or a salt thereof, wherein the compound has one or more of the following structural features:

R 1 is methyl;

Q is a substituted or unsubstituted pyridyl; and

X 9 is CR 4 where R 4 is halo or a substituted or unsubstituted C 1 -C 8 alkyl.

10. The compound of claim 9 , or a salt thereof, wherein:

Q is 3-pyridyl, 4-pyridyl or 6-methyl-3-pyridyl; and

X 9 is CR 4 where R 4 is chloro or methyl.

11. The compound of claim 8 , or a salt thereof, wherein the compound has two or more of the following structural features:

R 1 is methyl;

Q is a substituted or unsubstituted pyridyl; and

X 9 is CR 4 where R 4 is halo or a substituted or unsubstituted C 1 -C 8 alkyl.

12. The compound of claim 8 , or a salt thereof, wherein the compound has all three of the following structural features:

R 1 is methyl;

Q is a substituted or unsubstituted pyridyl; and

X 9 is CR 4 where R 4 is halo or a substituted or unsubstituted C 1 -C 8 alkyl.

13. The compound of claim 1 , or a salt thereof, wherein

at least one of R 8c , R 8d , R 8e and R 8f is other than H;

Q is an unsubstituted 3-pyridyl;

X 9 is CR 4 where R 4 is methyl; and

R 1 is methyl.

14. The compound of claim 1 , or a salt thereof, wherein:

R 1 is methyl or ethyl;

R 8c and R 8d are both H;

R 8e and R 8f are independently H, hydroxyl or methyl;

X 7 is CR 4 where R 4 is H;

X 8 and X 10 are independently CR 4 where R 4 is H or halo;

X 9 is CR 4 where R 4 is halo, methyl, trifluoromethyl or ethyl; and

Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.

15. The compound of claim 1 , or a salt thereof, wherein —R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH 2 —C(H)(OH)—, and —CH 2 —C(OH)(CH 3 )—.

16. The compound of claim 1 wherein the compound is selected from the group consisting of compounds:

or a salt thereof.

17. A compound according to claim 1 , selected from the group consisting of compounds:

or a salt thereof.

18. The compound of claim 1 or a salt thereof, wherein the compound modulates at least one of the following receptors: adrenergic receptor, serotonin receptor, dopamine receptor and histamine receptor.

19. A compound of the Formula (Vf), or a salt thereof,

wherein:

R 4 is independently H, hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, aryloxy, carboxyl, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring;

wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic;

m is 1;

q is 0;

—R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH 2 —C(H)(OH)—, and —CH 2 —C(OH)(CH 3 )—; and

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl.

20. The compound of claim 19 , or a salt thereof, wherein R 4 is H, halo, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted aryl.

21. The compound of claim 20 , or a salt thereof, wherein R 4 is H, halo, methyl, perfluoromethyl or cyclopropyl.

22. The compound of claim 21 , or a salt thereof, wherein Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.

23. The compound of claim 20 , or a salt thereof, wherein Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.

24. The compound of claim 19 , or a salt thereof, wherein Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.

25. The compound of claim 24 , or a salt thereof, wherein Q is an unsubstituted phenyl or an unsubstituted pyridyl.

26. The compound of claim 19 , or a salt thereof, wherein R 1 is methyl or ethyl.

27. A compound of the formula (B):

or a salt thereof,

wherein:

wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano or nitro or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety;

each X 7 , X 8 , X 9 and X 10 is independently N or CR 4 provided that at least one of X 7 , X 8 , X 9 and X 10 is other than CR 4 where R 4 is H;

each R 4 is independently H, hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring;

wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic;

each R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, C 1 -C 8 alkyl or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety;

each R 10a and R 10b is independently H, halo, a substituted or unsubstituted C 1 -C 8 alkyl, hydroxyl, alkoxyl or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl; and

Q is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

wherein at least one of (i) and (ii) applies: (i) at least one of X 7 , X 8 , X 9 and X 10 is N; and (ii) at least one of R 8c , R 8d , R 8e and R 8f is other than H; and

provided that when each of X 7 , X 8 , X 9 and X 10 is CR 4 , then one of R 8e and R 8f is hydroxyl.

28. The compound of claim 27 or a salt thereof, wherein at least one of X 7 , X 8 , X 9 and X 10 is N.

29. The compound of claim 27 or a salt thereof, wherein each of X 7 , X 8 , X 9 and X 10 is CR 4 .

30. The compound of claim 27 or a salt thereof, wherein —R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH 2 —C(H)(OH)—, and —CH 2 —C(OH)(CH 3 )—.

31. The compound of claim 27 or a salt thereof, wherein Q is a substituted or unsubstituted heteroaryl.

32. The compound of claim 31 or a salt thereof, wherein Q is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which may be substituted with one, two or three moieties selected from a C 1 -C 4 alkyl, halo, perhaloalkyl, and perhaloalkoxy.

33. The compound claim 27 or a salt thereof, wherein Q is a substituted or unsubstituted aryl.

34. The compound of claim 33 or a salt thereof, wherein Q is phenyl which may be substituted with one, two or three moieties selected from halo, C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, perhaloalkyl, and perhaloalkoxy.

35. The compound of claim 34 or a salt thereof, wherein Q is fluoro-substituted phenyl.

36. The compound of claim 35 or a salt thereof, wherein Q is para-fluoro phenyl.

37. The compound of claim 27 or a salt thereof, wherein R 1 is methyl.

38. The compound of claim 27 , or a salt thereof, wherein:

R 1 is methyl or ethyl;

R 8c and R 8d are both H;

R 8e and R 8f are independently H, OH or CH 3 ;

X 7 is CH; X 8 is CH or C-halo; X 10 is CH or C-halo;

X 9 is CR 4 where R 4 is halo, CH 3 , CF 3 or ethyl; and

Q is a substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl.

39. The compound of claim 27 or a salt thereof, wherein the compound is selected from the group consisting of compounds:

40. A pharmaceutical composition comprising a compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable carrier.

41. A pharmaceutical composition comprising a compound according to claim 19 or 27 or a salt thereof and a pharmaceutically acceptable carrier.

42. A kit comprising a compound according to claim 1 or a salt thereof, and instructions.

43. A kit comprising a compound according to claim 19 or 27 , or a salt thereof, and instructions.

Assignments (7)

RELEASE OF SECURITY INTEREST Recorded Sep 28, 2016

From: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT

To: MEDIVATION PROSTATE THERAPEUTICS, INC.; MEDIVATION TECHNOLOGIES, INC.

Reel/Frame 040181/0177 →

CONFIRMATORY GRANT OF SECURITY INTEREST IN UNITED STATES PATENTS Recorded Sep 4, 2015

From: MEDIVATION TECHNOLOGIES, INC.

To: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT

Reel/Frame 036553/0925 →