IP Library › Granted Patent US 7,718,665
Granted Patent B2
US 7,718,665 · App. 11/659,738 · Granted May 18, 2010

Benzothienopyridines for use as inhibitors of Eg5 kinesin

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 7,718,665
App. No.
11/659,738
Granted
May 18, 2010
Kind
B2
Abstract

Compounds of the formula (1) in which R1, R2, R3, R4 and X have the meanings indicated in the description, are novel effective compounds with Eg5 inhibitory, anti-proliferative and/or apoptosis inducing activity.

Claims (244)

1. A compound of formula (I*)

in which

R1 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, or 2-7C-alkyl substituted by R11,

R11 is —N(R111)R112,

R111 is hydrogen, or 1-4C-alkyl,

R112 is hydrogen, or 1-4C-alkyl,

or R111 and R112 together, and with inclusion of the nitrogen atom to which they are bonded, form a ring Het,

Het is piperidinyl, morpholinyl, thiomorpholinyl, or pyrrolidinyl,

R2 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy, hydroxyl, 1-4C-alkoxy-2-4C-alkoxy, hydroxy-2-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R3 is hydrogen, or 1-4C-alkoxy, and

X is NH, oxygen or sulphur, and

R4 is 1-4C-alkyl,

or

X is sulphur, and

R4 is hydrogen,

or

X is oxygen, and

R4 is hydrogen,

or a salt, stereoisomer or a salt of a stereoisomer thereof.

2. A compound according to claim 1 ,

in which

R1 is 1-2C-alkyl, cyclopropyl, cyclopropylmethyl, or 2-4C-alkyl substituted by R11,

R11 is —N(R111)R112,

R111 is 1-2C-alkyl,

R112 is 1-2C-alkyl,

or R111 and R112 together, and with inclusion of the nitrogen atom to which they are bonded, form a ring Het,

Het is piperidinyl, morpholinyl, thiomorpholinyl, or pyrrolidinyl,

R2 is hydrogen,

R3 is hydrogen, and

X is NH, oxygen or sulphur, and

R4 is methyl,

or

X is sulphur, and

R4 is hydrogen,

or

X is oxygen, and

R4 is hydrogen,

or a salt, stereoisomer or a salt of a stereoisomer thereof.

3. A compound according to claim 1 ,

in which

R1 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, or 2-7C-alkyl substituted by R11,

R11 is —N(R111)R112,

R111 is hydrogen, or 1-4C-alkyl,

R112 is hydrogen, or 1-4C-alkyl,

or R111 and R112 together, and with inclusion of the nitrogen atom to which they are bonded, form a ring Het,

Het is piperidinyl, morpholinyl, thiomorpholinyl, or pyrrolidinyl,

R2 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy, hydroxyl, 1-4C-alkoxy-2-4C-alkoxy, hydroxy-2-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R3 is hydrogen, or 1-4C-alkoxy,

X is NH, oxygen or sulphur, and

R4 is 1-4C-alkyl,

or a salt, stereoisomer or a salt of a stereoisomer thereof.

4. A compound according to claim 1 ,

in which

R1 is 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, or 2-7C-alkyl substituted by R11,

R11 is —N(R111)R112,

R111 is hydrogen, or 1-4C-alkyl,

R112 is hydrogen, or 1-4C-alkyl,

or R111 and R112 together, and with inclusion of the nitrogen atom to which they are bonded, form a ring Het,

Het is piperidinyl, morpholinyl, thiomorpholinyl, or pyrrolidinyl,

R2 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy, hydroxyl, 1-4C-alkoxy-2-4C-alkoxy, hydroxy-2-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R3 is hydrogen, or 1-4C-alkoxy,

X is sulphur, and

R4 is hydrogen,

or a salt, stereoisomer or a salt of a stereoisomer thereof.

5. A compound according to claim 1 ,

in which

R1 is methyl, ethyl, or cyclopropyl,

R2 is hydrogen,

R3 is hydrogen,

X is NH, oxygen or sulphur, and

R4 is methyl,

or a salt, stereoisomer or a salt of a stereoisomer thereof.

6. A compound according to claim 1 ,

in which

R1 is methyl, ethyl, or cyclopropyl,

R2 is hydrogen,

R3 is hydrogen,

X is sulphur, and

R4 is hydrogen,

or a salt, stereoisomer or a salt of a stereoisomer thereof.

7. A compound according to claim 1 ,

in which

R1 is methyl, ethyl, or ethyl substituted by R11,

R11 is —N(R111)R112,

R111 is methyl,

R112 is methyl,

or R111 and R112 together, and with inclusion of the nitrogen atom to which they are bonded, form a ring Het,

Het is morpholinyl,

R2 is hydrogen,

R3 is hydrogen, and

X is NH, oxygen or sulphur, and

R4 is methyl,

or

X is sulphur, and

R4 is hydrogen,

or

X is oxygen, and

R4 is hydrogen,

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 ,

in which

R1 is methyl, or ethyl substituted by R11,

R11 is —N(R111)R112,

R111 is methyl,

R112 is methyl,

R2 is hydrogen,

R3 is hydrogen, and

X is NH, and

R4 is methyl,

or

X is sulphur, and

R4 is methyl,

or

X is oxygen, and

R4 is methyl,

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 ,

in which

R1 is methyl, or ethyl substituted by R11,

R11 is —N(R111)R112,

R111 is methyl,

R112 is methyl,

R2 is hydrogen,

R3 is hydrogen, and

X is sulphur, and

R4 is hydrogen,

or

X is oxygen, and

R4 is hydrogen,

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 ,

in which

R1 is methyl,

R2 is hydrogen,

R3 is hydrogen, and

X is NH, and

R4 is methyl,

or

X is sulphur, and

R4 is methyl,

or

X is oxygen, and

R4 is methyl,

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 ,

in which

R1 is methyl,

R2 is hydrogen,

R3 is hydrogen, and

X is sulphur, and

R4 is hydrogen,

or

X is oxygen, and

R4 is hydrogen,

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 , in which R2 and R3 are both hydrogen, and R1, R4 and X have any one of the meanings 1.1 to 1.6 given in the following table:

R1

R4

X

1.1

—CH 3

—CH 3

NH

1.2

—CH 3

—CH 3

S

1.3

—CH 2 CH 2 —N(CH 3 ) 2

—CH 3

NH

1.4

—CH 2 CH 2 —N(CH 3 ) 2

—CH 3

S

1.5

—CH 3

H

S

1.6

—CH 2 CH 2 —N(CH 3 ) 2

H

S

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to claim 1 , or a salt, stereoisomer or a salt of a stereoisomer thereof, together with a pharmaceutically acceptable excipient and/or vehicle.

14. A compound of according to claim 1 , in which

R4 is 2-4C-alkyl.

15. A compound of according to claim 1 , in which R1 is 3-7C-cycloalkyl.

16. A compound of according to claim 1 , in which R1 is

3-7C-cycloalkyl-1-4C-alkyl.

17. A compound of according to claim 1 , in which R1 is 2-7C-alkyl substituted by R11.

18. A compound according to claim 1 , selected from the group consisting of

(3aS,10R)-10-(3-Hydroxy-phenyl)-2,3a-dimethyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenty[b]fluorene-1,3-dione;

(3aS,10R)-10-(3-Hydroxy-phenyl)-2-methyl-4,10-dihydro-3aH-9-thia-2,10-diaza-cyclopenta[b]fluorene-1,3-dione;

(3aS,10R)-2-Butyl-10-(3-hydroxy-phenyl)-4,10-dihydro-3aH-9-thia-2,10a-diaza-cyclopenta[b]fluorene-1,3-dione;

(3aS,10R)-10-(3-Hydroxy-phenyl)-2,3a-dimethyl-4,10-dihydro-3aH-9-thia-2,10a-diaza-cyclopenta[b]fluorene-1,3-dione;

(3aS,10R)-2-(2-Dimethylamino-ethyl)-10-(3-hydroxy-phenyl)-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenty[b]fluorene-1,3-dione;

(3aS,10R)-2-(2-Dimethylamino-ethyl)-10-(3-hydroxy-phenyl)-4,10-dihydro-3aH-9-thia-2,10-diaza-cyclopenta[b]fluorene-1,3-dione;

(3aS,10R)-2-(2-Dimethylamino-ethyl)-10-(3-hydroxy-phenyl)-3a-methyl-4,10-dihydro-3aH-9-thia-2,10a-diaza-cyclopenta[b]fluorene-1,3-dione.

19. A compound selected from the group consisting of

(±)-(3aSR,10RS)-10-(3-Hydroxy-phenyl)-2,3a-dimethyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenty[b]fluorene-1,3-dione;

(3aSR,10RS)-10-(3-Hydroxy-phenyl)-2,3a-dimethyl-4,10-dihydro-3aH-9-thia-2,10a-diaza-cyclopenta[b]fluorene-1,3-dione;

(3aSR,10RS)-2-(2-Dimethylamino-ethyl)-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenty[b]fluorene-1,3-dione; and

(3aSR,10RS)-2-(2-Dimethylamino-ethyl)-10-(3-hydroxy-phenyl)-3a-methyl-4,10-dihydro-3aH-9-thia-2,10a-diaza-cyclopenta[b]fluorene-1,3-dione.

20. A compound according to claim 2 ,

in which

R1 is 2-4C-alkyl substituted by R11,

R11 is —N(R111)R112,

R111 is 1-2C-alkyl,

R112 is 1-2C-alkyl,

R2 is hydrogen,

R3 is hydrogen,

X is NH,

R4 is methyl,

or a pharmaceutically acceptable salt thereof.

21. A compound according to claim 3 ,

in which

R1 is 2-7C-alkyl substituted by R11,

R11 is —N(R111)R112,

R111 is hydrogen, or 1-4C-alkyl,

R112 is hydrogen, or 1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy, hydroxyl, 1-4C-alkoxy-2-4C-alkoxy, hydroxy-2-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R3 is hydrogen, or 1-4C-alkoxy,

X is NH, and

R4 is 1-4C-alkyl,

or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 21 ,

in which

R112 is hydrogen,

R2 is hydrogen, and

R3 is hydrogen,

or a pharmaceutically acceptable salt thereof.

23. A compound according to claim 1 , in which X is NH, and R4 is methyl.

24. A compound according to claim 23 , in which R2 and R3 are both hydrogen.

25. A compound according to claim 24 , in which R1 is 2-(N,N-dimethylamino)-ethyl.

26. A compound according to claim 24 , in which

R1 is 2-4C-alkyl substituted by R11,

R11 is —N(R111)R112,

R111 is hydrogen, or 1-4C-alkyl,

R112 is hydrogen, or 1-4C-alkyl.

27. A compound according to claim 26 , in which

R111 is hydrogen, and

R112 is 3-4C-alkyl.

28. A method for treating colon cancer comprising administering to a subject in need thereof an effective amount of a compounds of claim 1 .

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 20, 2008
From: NYCOMED GMBH
To: 4SC AG
Reel/Frame 021414/0417 →
CHANGE OF NAME Recorded Sep 4, 2007
From: ALTANA PHARMA AG
To: NYCOMED GMBH
Reel/Frame 019783/0625 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 6, 2007
From: VENNEMANN, MATTHIAS; BAER, THOMAS; GROEGOR, GUDRUN; BRAUNGER, JUERGEN; GIMMNICH, PETRA; MAIER, THOMAS; ROTHFELS, HEIKE
To: ALTANA PHARMA AG
Reel/Frame 018971/0225 →