IP Library › Granted Patent US 7,271,163

Granted Patent B2

US 7,271,163 · App. 10/898,029 · Granted Sep 18, 2007

Cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives

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Quick Facts

Patent No.: US 7,271,163
App. No.: 10/898,029
Granted: Sep 18, 2007
Kind: B2

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Abstract

This invention provides compounds of the formulae: wherein: R 1 is hydrogen, —C(O)CH 3 or alkyl of 1-6 carbon atoms; R 2 and R 3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl, alkoxy of 1-6 carbon atoms, —CH 2 OH, fluoroalkyl, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, aryl, or aroyl; R 4 and R 5 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl or cycloalkyl; or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions containing these compounds and methods for their use, including treatment of obsessive-compulsive disorder, panic disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, migraine, sleep disorders, eating disorders, obesity, epilepsy, and spinal cord injury.

Claims (110)

1. A method of treating in a mammal a condition selected from bipolar disorders and psychosis, the method comprising administering to a mammal a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is hydrogen, —C(O)CH 3 or alkyl of 1-6 carbon atoms;

R 2 and R 3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl, alkoxy of 1-6 carbon atoms, —CH 2 OH, fluorinated alkyl of 1-6 carbon atoms, —NH—SO 2 -alkyl of 1-6 carbon atoms, —SO 2 —NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, aryl, or aroyl;

R 4 and R 5 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkyl of 1-6 carbon atoms, —CN, —NH—SO 2 -alkyl of 1-6 carbon atoms, —SO 2 —NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;

R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl of 3 to 7 carbon atoms or —CH 2 —(cycloalkyl of 3 to 7 carbon atoms);

the dashed line indicates an optional double bond.

2. The method of claim 1 wherein the mammal is a human.

3. The method of claim 2 wherein the compound administered is at least one compound selected from

wherein:

R 1 is hydrogen, or alkyl of 1-6 carbon atoms;

R 2 and R 3 are each, independently, hydrogen or alkyl of 1-6 carbon atoms;

R 4 and R 5 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, —CN, amino or fluorinated alkyl of 1 to 6 carbon atoms;

R 6 and R 7 are each independently hydrogen or C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt thereof.

4. The method of claim 2 wherein the compound administered is at least one compound selected from

a) 1,2,3,4,9,10-hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

b) 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

c) 3-acetyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

d) 6-methyl-1,2,3,4,9,10-hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

e) 9-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

f) 9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[1,4]diazepino[6,7,1-hi]indole;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 2 wherein the compound administered is at least one compound selected from:

a) (7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole;

b) (2S)-(rel-7bR,10aR)-2-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

c) (2S)-(rel-7bS,10aS)-2-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

d) (2R)-(rel-7bR,10aR)-2-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

e) (2R)-(rel-7bS,10aS)-2-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

f) (2R,7bS,10aS)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indol-2-ylmethanol;

g) rel-(4S,7bS,10aS)-4-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

h) rel-(4R,7bS,10aS)-4-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

i) (7bR,9R,10aR)-9-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

j) (7b,10aR)-9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

k) (7bS,10aS)-9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

or a pharmaceutically acceptable salt thereof.

6. A method of treating in a mammal a condition selected from drug or alcohol addiction, social phobias, sexual dysfunction, sleep disorders, eating disorders, gastrointestinal disorders, diabetes, and premenstrual tension, the method comprising administering to a mammal a pharmaceutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is hydrogen, —C(O)CH 3 or alkyl of 1-6 carbon atoms;

R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl of 3 to 7 carbon atoms or —CH 2 — (cycloalkyl of 3 to 7 carbon atoms);

the dashed line indicates an optional double bond.

7. The method of claim 6 wherein the mammal is a human.

8. The method of claim 7 wherein the compound administered is at least one compound selected from

wherein:

R 1 is hydrogen, or alkyl of 1-6 carbon atoms;

R 2 and R 3 are each, independently, hydrogen or alkyl of 1-6 carbon atoms;

R 4 and R 5 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, —CN, amino or fluorinated alkyl of 1 to 6 carbon atoms;

R 6 and R 7 are each independently hydrogen or C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt thereof.

9. The method of claim 7 wherein the compound administered is at least one compound selected from

a) 1,2,3,4,9,10-hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

b) 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

c) 3-acetyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

d) 6-methyl-1,2,3,4,9,10-hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

e) 9-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

f) 9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[1,4]diazepino[6,7,1-hi]indole;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 7 wherein the compound administered is at least one compound selected from: