IP Library › Granted Patent US 9,260,429

Granted Patent B2

US 9,260,429 · App. 13/725,937 · Granted Feb 16, 2016

Pyrido[3,4-B]indoles and methods of use

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Quick Facts

Patent No.: US 9,260,429
App. No.: 13/725,937
Granted: Feb 16, 2016
Kind: B2

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Abstract

This disclosure relates to new heterocyclic compounds that may be used to modulate a histamine receptor in an individual. Compounds having the structures are described, as are pharmaceutical-compositions comprising the compounds and 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 (176)

1. A compound of the formula (E-2):

or a pharmaceutically acceptable salt thereof, wherein:

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

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

X 7 is N;

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

q is independently 0 or 1;

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, thiol, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R 8a , R 8b , 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, is taken together with the carbon to which it is attached and a geminal R 8(a-f) to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R 8(a-f) to form a methylene or a substituted methylene, is taken together with a vicinal R 8(a-f) and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(a-f) to form a bond, provided that when an R 8(a-f) is taken together with a vicinal R 8 to form a bond, the geminal R 8(a-f) is other than hydroxyl;

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

J is halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino; and

T is an integer from 0 to 5,

provided that when X 8 , and X 9 are each CR 4 , then X 10 is CR 4 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

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

X 9 is N; and each X 8 and X 10 is independently CR 4 .

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

each X 8 , X 9 and X 10 is independently CR 4 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein q is 0.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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 8c , R 8d , R 8e or R 8f to form a cycloalkyl moiety or a carbonyl moiety, provided that at least one of R 8c , R 8d , R 8e and R 8f is other than H.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(vii) apply, provided that if any of provisions (ii), (iii) or (iv) applies, only one of (ii), (iii) and (iv) applies:

(i) q is 0;

(ii) R 8c and R 8d are both H and R 8e and R 8f are independently H, hydroxyl or methyl;

(iii) R 8c is taken together with R 8e to form a bond and R 8d is taken together with R 8f to form a bond;

(iv) one of R 8c and R 8d is taken together with one of R 8e and R 8f to form a bond and the R 8c or R 8d that is not taken to form a bond is H and the R 8e or R 8f that is not taken to form a bond is H or methyl;

(v) X 9 is CR 4 where R 4 is halo or substituted or unsubstituted C 1 -C 8 alkyl;

(vi) R 2a and R 2b are both H; and

(vii) R 10a and R 10b are both H.

9. A compound of the formula (E-3):

or a pharmaceutically acceptable salt thereof, wherein:

X 7 is N;

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

m and q are independently 0 or 1;

T is an integer from 0 to 4,

provided that when X 8 and X 9 are each CR 4 , then X 10 is CR 4 .

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

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

X 9 is N; and each X 8 and X 10 is independently CR 4 .

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

each X 8 , X 9 and X 10 is independently CR 4 .

12. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of

13. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of

14. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein m is 1; and q is 0.

15. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein 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 8c , R 8d , R 8e or R 8f to form a cycloalkyl moiety or a carbonyl moiety, provided that at least one of R 8c , R 8d , R 8e and R 8f is other than H.

16. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(v) apply, provided that provisions (i) and (ii) are not combined:

(i) q is 0;

(ii) m and q are each 1 and R 8c , R 8d , R 8e and R 8f are each H;

(iii) X 9 is CR 4 where R 4 is halo or substituted or unsubstituted C 1 -C 8 alkyl;

(iv) R 2a and R 2b are both H; and

(v) R 10a and R 10b are both H.

17. A compound of the formula (E-6):

or a pharmaceutically acceptable salt thereof, wherein:

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

X 7 is N;

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

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

m and q are independently 0 or 1;

Q is a substituted phenyl, unsubstituted phenyl, substituted pyridyl or unsubstituted pyridyl moiety,

provided that when X 8 and X 9 are each CR 4 , then X 10 is CR 4 .

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein:

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

X 9 is N; and each X 8 and X 10 is independently CR 4 .

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:

each X 8 , X 9 and X 10 is independently CR 4 .

20. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of

21. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of

22. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein q is 0.

23. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein 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 8c , R 8d , R 8e or R 8f to form a cycloalkyl moiety or a carbonyl moiety, provided that at least one of R 8c , R 8d , R 8e and R 8f is other than H.

24. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(viii) apply, provided that if any of provisions (iv), (v) or (vi) apply, only one of provisions (iv), (v) and (vi) applies:

(i) X 9 is CR 4 where R 4 is an unsubstituted C 1 -C 8 alkyl or halo;

(ii) R 3a and R 3b are independently H, phenyl or unsubstituted C 1 -C 8 alkyl;

(iii) R 2a , R 2b , R 10a and R 10b are each H;

(iv) m is 1 and R 8c and R 8d are taken together to form a carbonyl;

(v) m is 1 and one of R 8c and R 8d is taken together with one of R 8e and R 8f to form a bond and the R 8c or R 8d that is not taken to form a bond is H and the R 8e or R 8f that is not taken to form a bond is substituted or unsubstituted C 1 -C 8 alkyl or H;

(vi) m is 1 and R 8 is taken together with R 8e to form a bond and R 8d is taken together with R 8f to form a bond;

(vii) q is 0; and

(viii) Q is a substituted or unsubstituted phenyl or pyridyl moiety.

25. A compound of the formula (E-7):

or a pharmaceutically acceptable salt thereof, wherein:

X 7 is N;

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

q is 0 or 1;

Q is an unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocyclyl or substituted heterocyclyl moiety,

provided that when X 8 and X 9 are each CR 4 , then X 10 is CR 4 .

26. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein:

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

X 9 is N; and each X 8 and X 10 is independently CR 4 .

27. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein q is 0.

28. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein 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 8c , R 8d , R 8e or R 8f to form a cycloalkyl moiety or a carbonyl moiety, provided that at least one of R 8c , R 8d , R 8e and R 8f is other than H.

29. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(vii) applies, provided that provisions (iv) and (v) are not combined:

(i) X 9 is CR 4 where R 4 is H, an unsubstituted C 1 -C 8 alkyl or halo;

(ii) R 3a and R 3b are each H;

(iii) R 2a , R 2b , R 10a and R 10b are each H;

(iv) R 8e and R 8f are taken together to form a carbonyl;

(v) R 8c , R 8d , R 8e and R 8f are each H;

(vi) q is 0; and

(vii) Q is a substituted or unsubstituted cyclopentyl, cyclohexyl, piperidinyl or piperazinyl moiety.

30. A compound of the formula (E-8):

or a pharmaceutically acceptable salt thereof, wherein:

X 7 is N;

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

m is 0 or 1;

n is 1 or 0, provided that n is 0 only when Q is a substituted heterocycle wherein the heterocycle is a lactam;

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, is taken together with the carbon to which it is attached and a geminal R 8(c-f) to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R 8(c-f) to form a methylene or a substituted methylene, is taken together with a vicinal R 8(c-f) and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(c-f) to form a bond, provided that when an R 8(c-f) is taken together with a vicinal R 8 to form a bond, the geminal R 8(c-f) is other than hydroxyl;

Q is unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl,

provided that when X 8 X 9 are each CR 4 ; then X 10 is CR 4 .

31. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein:

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

X 9 is N; and each X 8 and X 10 is independently CR 4 .

32. The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein 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 8c , R 8d , R 8e or R 8f to form a cycloalkyl moiety or a carbonyl moiety, provided that at least one of R 8c , R 8d , R 8e and R 8f is other than H.

33. A compound of the formula (F):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, hydroxyl, 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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

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

X 7 is N;

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

m and q are independently 0 or 1;

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

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

R 11 and R 12 are independently H or C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or are taken together to form a bond, thereby providing an acetylenyl moiety;

indicates the presence of either an E or Z double bond configuration when R 11 and R 12 are independently H, C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy or carbonylalkoxy; and

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl;

provided that when X 8 and X 9 are CR 4 , then X 10 is CR 4 .

34. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein:

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

X 9 is N; and each X 8 and X 10 is independently CR 4 .

35. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein q is 0.

36. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted C 1 -C 8 alkyl.

37. The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein Q is phenyl or substituted phenyl.

38. The compound according to claim 33 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(x) apply, provided that provisions (iv) and (v) are not combined, provisions (ii) and (x) are not combined and (iii) and (x) are not combined:

(i) q and m are both 0;

(ii) R 11 is H;

(iii) R 12 is an unsubstituted C 1 -C 8 alkyl;

(iv) one of R 3a and R 3b is methyl, ethyl or phenyl and the other is H;

(v) R 3a and R 3b are both H;

(vi) R 1 is an unsubstituted C 1 -C 8 alkyl;

(vii) X 9 is CR 4 where R 4 is unsubstituted C 1 -C 8 alkyl or halo;

(viii) R 2a and R 2b are both H;

(ix) R a and R 10b are both H; and

(x) R 11 and R 12 are taken together to form a bond.

39. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising (a) a compound of claim 1 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.

41. A kit comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

42. A pharmaceutical composition comprising (a) a compound of claim 9 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.

43. A kit comprising a compound according to claim 9 or a pharmaceutically acceptable salt thereof and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

44. A pharmaceutical composition comprising (a) a compound of claim 17 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.

45. A kit comprising a compound according to claim 17 or a pharmaceutically acceptable salt thereof and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

46. A pharmaceutical composition comprising (a) a compound of claim 25 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.

47. A kit comprising a compound according to claim 25 or a pharmaceutically acceptable salt thereof and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

48. A pharmaceutical composition comprising (a) a compound of claim 30 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.

49. A kit comprising a compound according to claim 30 or a pharmaceutically acceptable salt thereof and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

50. A pharmaceutical composition comprising (a) a compound of claim 33 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.

51. A kit comprising a compound according to claim 33 or a pharmaceutically acceptable salt thereof and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

Assignments (3)

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 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 11, 2015

From: HUNG, DAVID T.; PROTTER, ANDREW ASHER; CHAKRAVARTY, SARVAJIT; JAIN, RAJENDRA PARASMAL; DUGAR, SUNDEEP

To: MEDIVATION TECHNOLOGIES, INC.

Reel/Frame 037276/0795 →

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 →