IP Library › Granted Patent US 9,085,580

Granted Patent B2

US 9,085,580 · App. 13/791,559 · Granted Jul 21, 2015

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

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Quick Facts

Patent No.: US 9,085,580
App. No.: 13/791,559
Granted: Jul 21, 2015
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. Pyrido[3,4-b]indoles 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 (140)

1. A compound of the formula (I):

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, or R 1 and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a cycloalkyl moiety, or R 2a and R 1 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, or R 2a and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, or R 3a and R 10a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) 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 a cycloalkyl moiety, or R 10a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 10a and R 2a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 10a and R 3a are taken together to form an ethylene (-CH 2 CH 2 -) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

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

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;

m and q are independently 0 or 1;

n is 1;

each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R 8(a-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH 2 CH 2 O—, or is taken together with a geminal R 8(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or 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 when an R 8(a-f) is taken together with a vicinal R 8(a-f) to form a bond, the geminal R 8(a-f) is other than hydroxyl;

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;

provided that the compound conforms to one of provisions (i)-(vi): (i) R 1 and R 2a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety; (ii) R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; (iii) R 1 and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; (iv) R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety; (v) R 2a and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; and (vi) R 3a and R 10a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

and provided that:

(A) when R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety, provisions (a)-(d) apply: (a) when each X 7 , X 8 and X 10 is CH, X 9 is CR 4 where R 4 is H or methoxy, each q and m is 0, n is 1 and each R 8e and R 8f is H, Q is other than phenyl, (b) when each X 7 -X 10 is CH, each q, m and n is 1 and each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is H, Q is other than dimethylamino, (c) when each X 7 -X 10 is CH, q is 0, each m and n is 1 and each R 8c , R 8d , R 8e and R 8f is H, Q is other than pyrrolidin-1-yl, and (d) when each X 7 -X 10 is CH, each q and m is 0, n is 1 and R 8e and R 8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;

(B) when R 1 and R 3a are taken together to form a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety and each X 7 -X 10 is CR 4 where R 4 is H, provisions (f)-(k) apply: (f) when each q, m and n is 1 and each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, unsubstituted heterocyclyl, substituted heterocyclyl other than a substituted azetidinyl, alkoxy, carbonylalkoxy, or aminocarbonylalkoxy, (g) when each q, m and n is 1, each R 8a , R 8b , R 8c and R 8d is H and R 8e and R 8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than a substituted amino group having the formula —NHR where R is a substituted alkyl, (h) when q is 0, each m and n is 1 and each R 8c , R 8d , R 8e and R 8f is H, Q is other than carboxyl and an acylamino group having the formula —C(O)NHR where R is a substituted alkyl, (i) q is 0, each m and n is 1, each R 8c and R 8d is H and R 8e and R 8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than methoxy and cyclopentylamino, (j) when each q and m is 0, n is 1 and each R 8e and R 8f is H, Q is other than phenyl, methoxy, carboxyl, carbonylmethoxy and acylamino substituted with a cyclopentyl group [—C(O)NH-cyclopentyl], and (k) when each q and m is 0, n is 1 and R 8e and R 8f are taken together with the carbon to which they are attached to form a carbonyl moiety, Q is other than alkoxy;

(C) when R 1 and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety and each X 7 -X 10 is CH, R 8(a-f) , m, n, q and Q are not taken together to form a tert-butoxycarbonyl group;

(D) when R 3a and R 10a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, X 7 -X 10 is CR 4 , each R 2a , R 2b , R 3b and R 10b are H, then (i) at least one of R 8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl;

(E) when R 1 and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, X 7 -X 10 is CR 4 , each R 2a , R 2b , R 3b , R 10a and R 10b are H, then (i) at least one of R 8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl;

(F) when R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, X 7 -X 10 is CR 4 , each R 2b , R 3b , R 10a and R 10b are H, then (i) at least one of R 8(a-f) is hydroxyl, alkyl or alkoxy, and/or (ii) Q is other than substituted heteroaryl; and

(G) when R 1 and R 3a are taken together to form a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety and when q is 0, each m and n is 1 and each R 8c , R 8d , R 8e and R 8f is H, Q is other than cyano;

or a pharmaceutically acceptable salt thereof.

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

3. The compound of claim 2 , wherein X 7 , X 8 and X 10 are CR 4 where R 4 is H, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein X 8 and X 10 are CR 4 where R 4 is H; X 9 is CR 4 ; q is 0; m is 1 and R 8c and R 8d are both H, or a pharmaceutically acceptable salt thereof.

5. A compound of the formula (A):

wherein:

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 2a and R 1 are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, or R 2a and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) 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 10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 10a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 10a and R 2a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 10a and R 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;

each X 7 , 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, halo, alkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R 8(a-d) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH 2 CH 2 O—, or is taken together with a geminal R 8(a-d) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;

each R 11 and R 12 is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, carboxy, carbonylalkoxy or C 1 -C 8 perhaloalkyl and the bond indicates the presence of either an E or Z double bond configuration, or R 11 and R 12 are taken together to form a bond or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 3-8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is of the formula (II):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 , wherein the compound is of the formula (B):

or a pharmaceutically acceptable salt thereof.

8. A compound selected from compounds 1-7,

Comp.#

Structure

or a pharmaceutically acceptable salt thereof.

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

10. A kit comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is of the formula (III):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is of the formula (IV):

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is of the formula (V):

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is of the formula (VI):

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is of the formula (VII):

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is selected from the group consisting of compounds 8-73,

Comp.#

Structure

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising (a) a compound of claim 16 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.

18. A kit comprising a compound of claim 16 or a pharmaceutically acceptable salt thereof.

19. The compound of claim 6 , wherein each X 7 , X 8 , X 9 and X 10 is independently CR 4 ; or a pharmaceutically acceptable salt thereof.

20. The compound of claim 6 , wherein p is 1; q is 0 and m is 1; or a pharmaceutically acceptable salt thereof.

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 →

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 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 30, 2015

From: JAIN, RAJENDRA PARASMAL; CHAKRAVARTY, SARVAJIT

To: MEDIVATION TECHNOLOGIES, INC.

Reel/Frame 034858/0598 →