IP Library › Granted Patent US 8,367,655

Granted Patent B2

US 8,367,655 · App. 12/803,701 · Granted Feb 5, 2013

Pyridoindolobenzox—and thiazepine derivatives and uses thereof

Inventor: Parthasarathi Rajagopalan (St. Peters, MO)

Assignee: Daya Drug Discoveries, Inc.

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Quick Facts

Patent No.: US 8,367,655
App. No.: 12/803,701
Granted: Feb 5, 2013
Kind: B2

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Abstract

The present invention discloses pyridoindolobenzox- and thiazepine compositions of Formula 1, wherein A is —CH(R 9 )—X—, —XCH(R 9 )—; —CO—X— or —X—CO—; X is —O—, —S—, —SO—, or —SO 2 —. Y is a single bond or a double bond. D and E are independently —(CH 2 ) n —; and ‘n’ varies from 0 to 2. R 1 to R 9 are various electron donating, electron withdrawing, hydrophilic, or lipophilic groups selected to optimize the physicochemical and biological properties of compounds of Formula I.

Claims (156)

1. A compound of Formula I, wherein

A is —CH(R 9 )X—, —XCH(R 9 )—, —COX—, or —XCO—;

X is —O—, —S—, —SO—, or —SO 2 —;

Y is a single bond or a double bond;

D and E are independently —(CH 2 ) n —, and ‘n’ varies from 0 to 2;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 2 , R 3 ,R 4 , R 5 ,R 6 , R 7 , R 8 , and R 9 is independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, hydroxyl, C 1 -C 10 alkoxyl, —NR 10 R 11 , C 1 -C 10 hydroxyalkyl, halogen, trihaloalkyl, cyano, carboxyl, C 1 -C 10 acyl, C 1 -C 10 alkxoyalkyl, C 1 -C 10 alkxoycarbonyl, C 5 -C 10 aryl, and C 6 -C 10 arylalkyl; and

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

2. The compound of claim 1 , wherein

A is —CH(R 9 )X—;

X is —O—, or —S—;

Y is a single bond or a double bond;

D and E are —(CH 2 ) n —, and ‘n’ is 1;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkxoycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

3. The compound of claim 2 , wherein

X is —O—, or —S—;

Y is a double bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

4. The compound of claim 2 , wherein

X is —O—, or —S—;

Y is a single bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

5. The compound of claim 3 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

6. The compound of claim 4 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

7. The compound of claim 1 , wherein

A is —XCH(R 9 )—;

X is —O—, or —S—;

Y is a single bond or a double bond;

D and E are —(CH 2 ) n —, and ‘n’ is 1;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkxoycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

8. The compound of claim 7 , wherein

X is —O—, or —S—;

Y is a double bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

9. The compound of claim 7 , wherein

X is —O—, or —S—;

Y is a single bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

10. The compound of claim 8 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

11. The compound of claim 9 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

12. A pharmaceutically acceptable drug product comprising compound of Formula I,

wherein A is —CH(R 9 )X—, —XCH(R 9 )—, —COX—, or —XCO—;

X is —O—, —S—, —SO—, or —SO 2 —;

Y is a single bond or a double bond;

D and E are independently —(CH 2 )—, and ‘n’ varies from 0 to 2;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

13. The composition of claim 12 , wherein

A is —CH(R 9 )X—;

X is —O—, or —S—;

Y is a single bond or a double bond;

D and E are —(CH 2 ) n —, and ‘n’ is 1;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkxoycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

14. The drug product of claim 13 , wherein

X is —O—, or —S—;

Y is a double bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

15. The composition of claim 13 , wherein

X is —O—, or —S—;

Y is a single bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

16. The composition of claim 14 , wherein

X is —S—;

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

17. The composition of claim 15 , wherein

X is —S—;

R 1 is hydrogen, methyl, or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

18. A method of treating CNS disorders comprising administering an effective amount of pharmaceutically acceptable composition of Formula I, wherein

A is —CH(R 9 )X—, —XCH(R 9 )—, —COX—, or —XCO—;

X is —O—, —S—, —SO—, or —SO 2 —;

Y is a single bond or a double bond;

D and E are independently —(CH 2 ) n —, and ‘n’ varies from 0 to 2;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

19. The method of claim 18 , wherein

A is —CH(R 9 )X—;

X is —O—, or —S—;

Y is a single bond or a double bond;

D and E are —(CH 2 ) n —, and ‘n’ is 1;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkxoycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

20. The method of claim 19 , wherein

X is —O—, or —S—;

Y is a double bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

21. The method of claim 19 , wherein

X is —O—, or —S—;

Y is a single bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

22. The method of claim 20 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

23. The method of claim 21 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

24. The method of claim 18 , wherein

A is —XCH(R 9 )—;

X is —O—, or —S—;

Y is a single bond or a double bond;

D and E are —(CH 2 ) n —, and ‘n’ is 1;

R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkxoycarbonylalkyl, C 5 -C 10 aryl, C 6 -C 10 arylalkyl, and C 6 -C 15 aroylalkyl;

each of R 10 and R 11 is independently hydrogen or C 1 -C 10 alkyl.

25. The method of claim 24 , wherein

X is —O—, or —S—;

Y is a double bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

26. The method of claim 24 , wherein

X is —O—, or —S—;

Y is a single bond;

R 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 arylalkyl, or C 6 -C 15 aroylalkyl;

each of R 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is hydrogen; and

each of R 4 and R 7 is independently hydrogen, C 1 -C 10 alkyl, or halogen.

27. The method of claim 25 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

28. The method of claim 26 , wherein

R 1 is hydrogen, methyl or 3-(4-fluorobenzoyl)propyl; and

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

Continuity (2)

Provisional Application 61270093 · Jul 3, 2009

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