Substituted pyrroles

• US 5,057,614 A
• Filed: 02/06/1989
• Issued: 10/15/1991
• Est. Priority Date: 02/10/1988
• Status: Expired

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Davis, Peter D., Hill, Christopher H., Lawton, Geoffrey
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): Carr, Deborah D.
• Application Number:
  US07/307,104
• Time in Patent Office: 981 Days
• Field of Search: 548/466, 548/468, 514/429, 514/414
• US Class Current: 548/466
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07H 19/044 Pyrrole radicals

Abstract

Compounds of the formula ##STR1## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y have the signficance given in the description, are useful in the control or prevention of inflammatory, immunological, bronchopulmonary or cardiovascular disorders.

Claims

1. A compound of the formula ##STR14## wherein R¹ signifies hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl, isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl or carboxyalkylthioalkyl or a group of the formula ##STR15## in which Het signifies a heterocyclyl group.

W signifies NH, S or a bond,

T signifies NH or S

V signifies O, S, NH. NNO₂, NCN or CHNO₂,

Z signifies alkylthio, amino, monoalkylamino or dialkylamino,

Im signifies 1-imidazolyl,

Ar signifies aryl, and

n stands for 2-6;

R² signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl;

R³ signifies a carbocyclic or heterocyclic aromatic group;

R⁴, R⁵, R⁶ and R⁷ each independently signify hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl;

and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H);

with the proviso that R¹ has a significant different from hydrogen when R² signifies hydrogen, R³ signifies 3-indolyl or 6-hydroxy-3-indolyl, R⁴, R⁵ and R⁷ each signify hydrogen, R⁶ signifies hydrogen or hydroxy and X and Y both signify O and when R² signifies hydrogen, R³ signifies 3-indolyl, R⁴, R⁵, R⁶ and R⁷ each signify hydrogen, X signifies (H,H) and Y signifies O;

or a pharmaceutically acceptable salt of acidic compounds of formula I with bases and of basic compounds of formula I with acids.

2. A compound according to claim 1, wherein R¹ signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, azidoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl or carboxyalkylthioalkyl.

3. A compound according to claim 2, wherein R¹ signifies alkyl or aminoalkyl.

4. A compound according to claim 1, wherein R¹ signifies isothiocyanatoalkyl or a group of formula (b) in which T signifies S, V signifies NH and Z signifies amino or in which T signifies NH, V signifies NH or NNO₂ and Z signifies amino.

5. A compound according to claim 4, wherein R² signifies hydrogen.

6. A compound according to any one of claim 5, wherein R³ signifies phenyl which is monosubstituted by halogen, alkyl, alkoxy, haloalkyl, nitro, amino, alkylthio, alkylsulphinyl or alkylsulphonyl.

7. A compound according to claim 5, wherein R³ signifies a group of the formula ##STR16## wherein R^1'"'"', R^2'"'"', R^4'"'"', R^5'"'"', R^6'"'"' and R^7'"'"' have any of the values accorded to R¹, R², R⁴, R⁵, R⁶ and R⁷ in claim 1.

8. A compound according to claim 7, wherein R⁴, R⁵, R⁶ and R⁷ each signify hydrogen.

9. A compound according to claim 8, wherein R¹ signifies methyl, 3-aminopropyl, 3-isothio-cyanatopropyl or a group of formula (b) in which T signifies S, V signifies NH, Z signifies amino and n stands for 3 or in which T signifies NH, V signifies NH or NNO₂, Z signifies amino and n stands for 3, R² signifies hydrogen, R³ signifies phenyl which is mono-substituted by chlorine, bromine, methyl, methoxy, trifluoromethyl, nitro, amino, methylsulphinyl or methylsulphonyl or a group of formula (i) given in claim 7 in which R^1'"'"' signifies methyl and R^2'"'"', R^4'"'"', R^5'"'"', R^6'"'"' and R^7'"'"' each signify hydrogen, and R⁴, R⁵, R⁶ and R⁷ each signify hydrogen.

10. A compound accordance with claim 1 selected from the group consisting of:

3-(2-Chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-(2-Nitrophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3,4-Bis(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-[1-(3-Aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione

1-[1-[3-(Amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-(1-Methyl-3-indolyl)-4-[1-[3-(2-nitroguanidino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione and

3-[1-(3-Isothiocyanatopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.

11. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR17## wherein R¹ signifies hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl, isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl or carboxyalkylthioalkyl or a group of the formula ##STR18## in which Het signifies a heterocyclyl group,

W signifies NH, S or a bond,

T signifies NH or S,

V signifies O, S, NH, NNO₂, NCN or CHNO₂,

Z signifies alkylthio, amino, monoalkylamino or dialkylamino,

Im signifies 1-imidazolyl,

Ar signifies aryl, and

n stands for 2-6;

R² signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl;

R³ signifies a carbocyclic or heterocyclic aromatic group;

R⁴, R⁵, R⁶ and R⁷ each independently signify hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl;

and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H);

with the proviso that R¹ has a significance different from hydrogen when R² signifies hydrogen, R³ signifies 3-indolyl or 6-hydroxy-3-indolyl, R⁴, R⁵ and R⁷ each signify hydrogen, R⁶ signifies hydrogen or hydroxy and X and Y both signify O and when R² signifies hydrogen, R³ signifies 3-indolyl, R⁴, R⁵, R⁶ and R⁷ each signify hydrogen, X signifies (H,H) and Y signifies O;

or a pharmaceutically acceptable salt of acidic compounds of formula I with bases and of basic compounds of formula I with acids, and an inert carrier material.

12. A pharmaceutical composition in accordance with claim 11, wherein the compound of formula I is selected from the group consisting of:

3-(2-Chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-(2-Nitrophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3,4-Bis(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-[1-(3-Aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione

1-[1-[3-(Amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-(1-Methyl-3-indolyl)-4-[1-[3-(2-nitroguanidino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, and

3-[1-(3-Isothiocyanatopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.