IP Library › Granted Patent US 9,469,641

Granted Patent B2

US 9,469,641 · App. 13/679,883 · Granted Oct 18, 2016

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

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Quick Facts

Patent No.: US 9,469,641
App. No.: 13/679,883
Granted: Oct 18, 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 of formula (F) 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 (166)

1. A compound of the formula (F):

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 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, 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;

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

m and q are each 0;

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 10 and R 12 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, 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 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;

or a pharmaceutically acceptable salt thereof.

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

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein Q is phenyl or substituted phenyl.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(x) apply, provided that provisions (iii) and (iv) are not combined, provisions (i) and (x) are not combined and (ii) and (x) are not combined:

(i) R 11 is H;

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

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

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

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

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

(vii) X 7 , X 8 and X 10 are each CR 4 where R 4 is H;

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

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

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

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

wherein:

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;

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

q is 0;

each R 8d and R 8f is independently H, C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, or R 8d is taken together with R 8f and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety, or R 8d is taken together with R 8f to form a bond;

R 8c and R 8e are taken together to form a bond;

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,

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(vi) apply, provided that if any of provisions (i) or (ii) applies, only one of (i) and (ii) applies:

(i) R 8d is taken together with R 8f to form a bond;

(ii) R 8d is H and R 8f is H or methyl;

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

(iv) X 7 , X 8 and X 10 are each CR 4 where R 4 is H;

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

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

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

wherein:

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

m is 1;

q is 0;

R 8c and R 8e are taken together to form a bond;

T is an integer from 0 to 4,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(iv) apply:

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

(ii) X 7 , X 8 and X 10 are each CR 4 where R 4 is H;

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

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

9. A compound of the formula (E-4):

wherein:

R 3a is H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino, cycloalkyl, acylamino or acyloxy;

X 9 is CR 4 ;

q is 0;

R 4 is 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;

R 8c and R 8e are taken together to form a bond;

each R 10a and R 10b 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; and

or a pharmaceutically acceptable salt thereof.

10. A compound of the formula (E-5):

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, acylamino, phenyl 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 9 is CR 4 where R 4 is a substituted or unsubstituted C 1 -C 8 alkyl or halo;

q is 0;

R 8c and R 8e are taken together to form a bond;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(v) apply:

(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 or unsubstituted C 1 -C 8 alkyl;

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

(iv) R 8d is H and R 8f is substituted or unsubstituted C 1 -C 8 alkyl; and

(v) Q is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

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

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;

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

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

m is 1;

q is 0;

R 8c and R 8e are taken together to form a bond;

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

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(vii) apply, provided that if any of provisions (iv) or (v) apply, only one of provisions (iv) and (v) applies:

(i) X 9 is CR 4a where R 4a 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) R 8d is H and R 8f is substituted or unsubstituted C 1 -C 8 alkyl or H;

(v) R 8d is taken together with R 8f to form a bond;

(vi) X 7 , X 8 and X 10 are each CR 4 where R 4 is H;

(vii) Q is substituted or unsubstituted phenyl or pyridyl.

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

wherein:

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

q is 0;

R 8c and R 8e are taken together to form a bond;

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

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein any one or more of (i)-(v) applies:

(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) X 7 , X 8 and X 10 are each CR 4 where R 4 is H; and

(v) Q is substituted or unsubstituted cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

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

wherein:

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

m and n are each 1;

each R 8d and R 8f is independently H, C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, or are taken together to form a bond;

R 8c and R 8e are taken together to form a bond;

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

or a pharmaceutically acceptable salt thereof.

17. A compound of the formula (G):

wherein:

R 3 is H, methyl, ethyl or phenyl;

R 4 is methyl or chloro;

Y is CH or N;

R 9 is fluoro, chloro or methoxy;

T is 0, 1 or 2;

R 8a and R 8d are independently H or methyl, or are taken together to form a bond;

R 8b and R 8c are taken together to form a bond,

or a pharmaceutically acceptable salt thereof.

18. A compound selected from the group consisting of compounds 90-124, 126-157, 160-162, 164-170, 172, 174-178, and 180-184:

or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of compounds 90-124 and 126-157:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 18 , wherein the compound is selected from the group consisting of compounds 160-162, 164-170, 172, 174-178, and 180-184:

or a pharmaceutically acceptable salt thereof.

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

22. A kit comprising a compound according to claim 17 or a pharmaceutically acceptable salt thereof and instructions.

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

24. A kit comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and instructions.

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 Mar 9, 2016

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

To: MEDIVATION TECHNOLOGIES, INC.

Reel/Frame 037936/0804 →

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 →