IP Library › Granted Patent US 9,481,676

Granted Patent B2

US 9,481,676 · App. 14/048,656 · Granted Nov 1, 2016

Azepino[4,5-B]indoles and methods of use

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Quick Facts

Patent No.: US 9,481,676
App. No.: 14/048,656
Granted: Nov 1, 2016
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

This disclosure relates to new azepino[4,5-b]indole compounds that may be used to modulate a histamine receptor in an individual. Novel compounds are described, including new 1,2,3,4,5,6-tetrahydroazepino[4,5-b]indoles. Pharmaceutical compositions are also provided.

Claims (763)

1. A method of modulating a histamine receptor in an individual comprising administering to an individual in need thereof a compound of formula (I):

wherein:

R 1 is 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, alkylsulfonylamino, or carbonylalkylenealkoxy;

each R 2a , R 2b ,R 3a and R 3b is independently 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, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R 2 or R 3 to form a cycloalkyl moiety or a carbonyl moiety;

each R 10a , R 10b , R 11a and R 11b is independently 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 amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R 10 or R 11 to form a cycloalkyl moiety or a carbonyl 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;

each m and q is independently 0 or 1;

each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, alkoxy, halo, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 8 alkenyl, or is taken together with a geminal R 8 to form a moiety of the formula —OCH 2 CH 2 O—, 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, is taken together with a geminal R 8 to form a methylene or a substituted methylene, is taken together with a vicinal R 8 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 to form a bond, provided when an R 8 is taken together with a vicinal R 8 to form a bond, the geminal R 8 is other than hydroxyl; and

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

or a salt thereof.

2. The method of claim 1 , wherein X 7 , X 8 , X 9 and X 10 are CR 4 .

3. The method of claim 1 , wherein at least one of X 7 , X 8 , X 9 and X 10 is N.

4. The method of claim 1 , wherein each R 4 is independently H, halo, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 perhaloalkyl or a substituted or unsubstituted aryl.

5. The method of claim 1 , wherein R 1 is substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aralkyl.

6. The method of claim 1 , wherein R 1 is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

7. The method of claim 1 , wherein:

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

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

8. The method of claim 7 , wherein each of R 2a , R 2b , R 3a and R 3b is H.

9. The method of claim 1 , wherein each R 10a , R 10b , R 11a and R 11b is independently H, bromo, methyl, or hydroxyl, or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl, or R 11a and R 11b are taken together with the carbon to which they are attached to form a carbonyl.

10. The method of claim 1 , wherein each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, or unsubstituted C 1 -C 4 alkyl, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety.

11. The method of claim 1 , wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is taken together with a geminal R 8 to form a methylene or a substituted methylene.

12. The method of claim 1 , wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is taken together with a vicinal R 8 to form a bond.

13. The method of claim 1 , wherein q is 0 and m is 0 or 1.

14. The method of claim 1 , wherein:

R 1 is a substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl;

each R 2a and R 2b is independently H, methyl, or fluoro, or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety;

each R 3a and R 3b is independently H or fluoro;

each R 10a and R 10b is independently H, fluoro or methyl, or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl; and

each R 11a and R 11b is independently H, fluoro or methyl, or R 11a and R 11b are taken together with the carbon to which they are attached to form a carbonyl.

15. The method of claim 1 , wherein Q is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

16. The method of claim 1 , wherein Q is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group.

17. The method of claim 1 , wherein Q is substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

18. The method of claim 1 , wherein:

R 1 is a substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl;

each R 2a and R 2b is independently H, unsubstituted C 1 -C 8 alkyl or halo;

each R 3a and R 3b is independently H or halo;

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

each R 10a , R 10b , R 11a and R 11b is independently H or methyl; and

Q is a substituted or unsubstituted aryl.

19. The method of claim 1 , wherein the compound is of formula (C-3a) or (C-3b):

wherein:

R 1 is CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH;

R 4a is H or F;

R 4c is H, CH 3 , CF 3 , Cl, F, or —NHCH 3 ;

R 9b is H or F; and

R 9c is F, CF 3 , OCH 3 , —CONH(CH 3 ), or —CON(CH 3 ) 2;

or a salt thereof.

20. The method of claim 19 , wherein R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F or —NHCH 3 ; R 9b is H or F, and R 9c is F, OCH 3 , —CONH(CH 3 ) or —CON(CH 3 ) 2 .

21. The method of claim 19 , wherein R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F or —NHCH 3 ; R 9b is H, and R 9c is F or OCH 3 .

22. The method of claim 1 , wherein the compound is of formula (C-4a) or (C-4b):

wherein:

R 1 is CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH;

R 4a is H or F; and

R 4c is H, CH 3 , CF 3 , Cl, F, or —NHCH 3 ;

or a salt thereof.

23. The method of claim 22 , wherein R 1 is CH 3 ; R 4a is H; and R 4c is CH 3 , Cl, F or —NHCH 3 .

24. The method of claim 22 , wherein R 1 is CH 3 ; R 4a is H; and R 4c is CH 3 , Cl, F.

25. The method of claim 1 , wherein the compound is of formula (C-5a) or (C-5b):

wherein:

R 1 is CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH;

R 4a is H or F;

R 4c is H, CH 3 , CF 3 , Cl, F, or —NHCH 3 ; and

R 9c is H, F, CH 3 , CF 3 , OCH 3 , —CONH(CH 3 ), or —CON(CH 3 ) 2 ;

or a salt thereof.

26. The method of claim 25 , wherein R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F or —NHCH 3 ; and R 9c is H, F, or CH 3 .

27. The method of claim 25 , wherein R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F; and R 9c is H or CH 3 .

28. The method of claim 1 , wherein the compound is of formula (C-6a) or (C-6b):

wherein:

R 1 is CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH;

R 4a is H or F; and

R 4c is H, CH 3 , CF 3 , Cl, F, or —NHCH 3 ;

or a salt thereof.

29. The method of claim 28 , wherein R 1 is CH 3 ; R 4a is H; and R 4c is CH 3 , Cl, F or —NHCH 3 .

30. The method of claim 28 , wherein R 1 is CH 3 ; R 4a is H; and R 4c is CH 3 , Cl, or F.

31. The method of claim 1 , wherein the compound is selected from the group consisting of Compounds 1-286, J-1 to J-30, K-1 to K-59, and L-1 to L-61:

No.

Structure

100

101

102

103

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271

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274

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276

277

278

279

280

281

282

283

284

285

286

J-1

J-2

J-3

J-4

J-5

J-6

J-7

J-8

J-9

J-10

J-11

J-12

J-13

J-14

J-15

J-16

J-17

J-18

J-19

J-20

J-21

J-22

J-23

J-24

J-25

J-26

J-27

J-28

J-29

J-30

K-1

K-2

K-3

K-4

K-5

K-6

K-7

K-8

K-9

K-10

K-11

K-12

K-13

K-14

K-15

K-16

K-17

K-18

K-19

K-20

K-21

K-22

K-23

K-24

K-25

K-26

K-27

K-28

K-29

K-30

K-31

K-32

K-33

K-34

K-35

K-36

K-37

K-38

K-39

K-40

K-41

K-42

K-43

K-44

K-45

K-46

K-47

K-48

K-49

K-50

K-51

K-52

K-53

K-54

K-55

K-56

K-57

K-58

K-59

L-1

L-2

L-3

L-4

L-5

L-6

L-7

L-8

L-9

L-10

L-11

L-12

L-13

L-14

L-15

L-16

L-17

L-18

L-19

L-20

L-21

L-22

L-23

L-24

L-25

L-26

L-27

L-28

L-29

L-30

L-31

L-32

L-33

L-34

L-35

L-36

L-37

L-38

L-39

L-40

L-41

L-42

L-43

L-44

L-45

L-46

L-47

L-48

L-49

L-50

L-51

L-52

L-53

L-54

L-55

L-56

L-57

L-58

L-59

L-60

L-61

or a salt thereof.

32. The method of claim 1 , wherein the compound is of formula (Ic):

wherein:

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

each R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 8 alkenyl, or is taken together with a geminal R 8 to form a moiety of the formula —OCH 2 CH 2 O—, 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, is taken together with a geminal R 8 to form a methylene or a substituted methylene, is taken together with a vicinal R 8 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 to form a bond, provided when an R 8 is taken together with a vicinal R 8 to form a bond, the geminal R 8 is other than hydroxyl; and

or a salt thereof.

33. The method of claim 32 , wherein at least one of R 8c , R 8d , R 8e and R 8f is hydroxyl.

34. The method of claim 1 , wherein the compound is selected from the group consisting of Compounds 1-231:

No.

Structure

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

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118

119

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128

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231

or a salt thereof.

35. The method of claim 1 , wherein the individual exhibits one or more symptoms associated with schizophrenia or Parkinson's disease.

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 7, 2016

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

To: MEDIVATION TECHNOLOGIES, INC.

Reel/Frame 037913/0888 →

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 →