4-›3-indolyl!-1H-pyrrolone

• US 5,721,245 A
• Filed: 01/17/1995
• Issued: 02/24/1998
• Est. Priority Date: 02/23/1989
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Davis, Peter David, Hill, Christopher Huw, Lawton, Geoffrey
• Primary Examiner(s): Rotman, Alan L.
• Application Number:
  US08/373,681
• Time in Patent Office: 1,134 Days
• Field of Search: 546/94, 514/294, 514/411, 514/414, 514/418, 548/428, 548/455, 548/456
• US Class Current: 514/294
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/06 Peri-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

A compound of the formula ##STR1## wherein R is hydrogen or hydroxy, R¹ and R² taken together are a group of the formula --(CH₂)_m -- and R⁷ is hydrogen or R¹ and R⁷ taken together are a group of the formula --(CH₂)_n -- and R² is hydrogen; R³ is an aryl or aromatic heterocyclic group; R⁴, R⁵ and R⁶ each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl; R⁸ is a group of the formula --(CH₂)_p --R⁹ or --(CH₂)_q --R¹⁰ ; R⁹ is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl; R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, a 5- or 6-membered saturated nitrogen-containing heterocycle; X and Y are oxygen; Z is CH; m, p and q are, independently, an integer from 0 to 5, and n an integer from 1 to 5,

as well as pharmaceutically acceptable salts thereof which are useful in the control of inflammatory, immunological, oncological, bronchopulmonary or cardiovascular disorders.

Claims

1. A compound of the formula ##STR7## wherein R is hydrogen or hydroxy, R¹ and R² taken together are --CH₂ -- and R⁷ is hydrogen;

R³ is unsubstituted phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl or phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl substituted with one substituent selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl;

R⁴, R⁵ and R⁶ each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl;

R⁸ is a group of the formula --(CH₂)_p --R⁹ or --(CH₂)_q --R¹⁰ ;

R⁹ is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl;

R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, amino-carbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, or a group of the formula --U--C(V)--W;

U is S or NH;

V is NH, NNO₂, NCN, CHNO₂ ;

W is amino, monoalkylamino or dialkylamino;

one of X and Y is O and the other is O or (H,H);

Z is CH;

m is 1 or 2 and p and q are, independently, an integer from 0 to 5;

or a pharmaceutically acceptable salt of an acidic compound of formula I with a base or of a basic compound of formula I with an acid.

2. A compound according to claim 1, wherein R is hydrogen, and R⁹ is hydrogen, alkylcarbonyl, cyano, amidino, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl and R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy or a group of the formula --U--C(V)--W.

3. A compound according to claim 1, wherein R³ is 1-methyl-3-indolyl.

4. A compound according to claim 3, wherein R⁴, R⁵ and R⁶ are hydrogen.

5. A compound according to claim 4, wherein R⁸ is a group of the formula --(CH₂)_q --R¹⁰.

6. A compound according to claim 5, wherein q stands for 1 or 2.

7. A compound according to claim 6, wherein R¹⁰ is hydroxy, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylcarbonyloxy or alkylsulfonyloxy or a group of the formula --U--C(V)--W.

8. A compound according to claim 7, wherein U is S, V is NH and W is amino.

9. A compound according to claim 8, wherein X and Y and O.

10. A compound according to claim 1, selected from the group consisting of8-(aminomethyl)-6,7,8,9-tetrahydropyrido 1,2-a!indol-10-yl!-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,7-(amidinothiomethyl)-6,7,8,9-tetrahydropyrido 1,2-a!indol-10-yl!-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,6,7,8,9-tetrahydro-8- (dimethylamino)methyl!pyrido 1,2-a!indol-10-yl!-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, or a pharmaceutically acceptable acid addition salt thereof.

12. The compound of claim 1, 3- 6,7,8,9-tetrahydropyrido- 1,2-a!indol-10-yl!-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.

11. A compound of the formula ##STR8## wherein R¹ and R² taken together are --CH₂ -- and R⁷ is hydrogen;

R³ is unsubstituted phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl or phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl substituted with one substituent selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl;

R⁴, R⁵ and R⁶ each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl;

R⁸ is a group of the formula --(CH₂)_p --R⁹ or --(CH₂)_q --R¹⁰ ;

R⁹ is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl;

R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, amino-carbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, or a group of the formula --U--C(V)--W;

U is S or NH;

V is NH, NNO₂, NCN, CHNO₂ ;

W is amino, monoalkylamino or dialkylamino;

Z is CH;

m is 1 or 2 and p and q are, independently, an integer from 0 to 5.

13. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR9## wherein R is hydrogen or hydroxy, R¹ and R² taken together are --CH₂ -- and R⁷ is hydrogen;

R³ is unsubstituted phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl or phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl substituted with one substituent selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl;

R⁴, R⁵ and R⁶ each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl;

R⁸ is a group of the formula --(CH₂)_p --R⁹ or --(CH₂)_q --R¹⁰ ;

R⁹ is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl;

R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, amino-carbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, or a group of the formula --U--C(V)--W;

U is S or NH;

V is NH, NNO₂, NCN, CHNO₂ ;

W is amino, monoalkylamino or dialkylamino;

one of X and Y is O and the other is O or (H,H);

Z is CH;

m is 1 or 2 and p and q are, independently, an integer from 0 to 5;

or a pharmaceutically acceptable salt of an acidic compound of formula I with a base or of a basic compound of formula I with an acid, and an inert carrier material.

14. A pharmaceutical composition according to claim 13, wherein R is hydrogen, and R⁹ is hydrogen, alkylcarbonyl, cyano, amidino, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl and R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy or a group of the formula --U--C(V)--W.

17. A pharmaceutical composition of claim 13, wherein the compound of formula I is 3- 6,7,8,9-tetrahydro-pyrido- 1,2-a!indol-10-yl!-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.

15. A method of inhibiting protein kinase which comprises administering an effective amount of a compound of the formula ##STR10## wherein R is hydrogen or hydroxy, R¹ and R² taken together are --CH₂ -- and R⁷ is hydrogen;

R³ is unsubstituted phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl or phenyl, naphthyl, 3-benzothienyl, 3-benzofuranyl or 3-indolyl substituted with one substituent selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl;

R⁴, R⁵ and R⁶ each independently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl;

R⁸ is a group of the formula --(CH₂)_p --R⁹ or --(CH₂)_q --R¹⁰ ;

R⁹ is hydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl;

R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, amino-carbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy, or a group of the formula --U--C(V)--W;

U is S or NH;

V is NH, NNO₂, NCN, CHNO₂ ;

W is amino, monoalkylamino or dialkylamino;

one of X and Y is O and the other is O or (H,H);

Z is CH;

m is 1 or 2 and p and q are, independently, an integer from 0 to 5;

or a pharmaceutically acceptable salt of an acidic compound of formula I with a base or of a basic compound of formula I with an acid.

16. A method according to claim 15, wherein R is hydrogen, and R⁹ is hydrogen, alkylcarbonyl, cyano, amidino, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl or aminothiocarbonyl and R¹⁰ is hydroxy, alkoxy, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, azido, acylamino, alkylsulfonylamino, arylsulfonylamino, alkylthio, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy, alkylsulfonyloxy or arylsulfonyloxy or a group of the formula --U--C(V)--W.

18. A method according to claim 15, wherein the compound of formula I is 3- 6,7,8,9-tetrahydro-pyrido- 1,2-a!indol-10-yl!-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.