Aryl-substituted indirubin derivatives, their production and use

• US 20020132792A1
• Filed: 11/29/2001
• Published: 09/19/2002
• Est. Priority Date: 11/30/2000
• Status: Abandoned Application

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Siemeister, Gerhard, Jautelat, Rolf, Prien, Olaf, Steinmeyer, Andreas
• Application Number:
  US09/995,862
• Publication Number:
  US 20020132792A1
• Time in Patent Office: Days
• US Class Current: 514/63
• CPC Class Codes: C07D 209/36 in position 3, e.g. adrenochrome
• CPC Class Codes: C07D 209/40 Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Aryl-substituted indirubin derivatives, their production and their intermediate products for production, as well as their use as medications for treating cancer, such as solid tumors and leukemia; auto-immune diseases, such as psoriasis, alopecia and multiple sclerosis, chemotherapy agent-induced alopecia and mucositis; cardiovascular diseases, such as stenoses, arterioscleroses and restenoses; infectious diseases, such as, e.g., those caused by unicellular parasites, such as trypanosoma, toxoplasma or plasmodium, or those caused by fungi; nephrological diseases, such as, e.g., glomerulonephritis; chronic neurodegenerative diseases, such as Huntington'"'"'s disease, amyotrophic lateral sclerosis, Parkinson'"'"'s disease, AIDS dementia and Alzheimer'"'"'s disease; acute neurodegenerative diseases, such as ischemias of the brain and neurotraumas; viral infections, such as, e.g., cytomegalic infections, herpes, hepatitis B and C, and HIV diseases, are described.

Claims

1. Aryl-substituted indirubin derivatives of general formula I,

2. Compounds of general formula I, according to claim 1, in which

R¹ stands for aryl or heteroaryl that is optionally substituted by the same or a different component in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, —

O—

Si(C₁-C₆ alkyl)₃, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy, and R² stands for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, trifluoromethyl, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹, or

R¹ stands for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, trifluoromethyl, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹, and

R² stands for aryl or heteroaryl that is optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R⁴ and R⁵ stand for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, trifluoromethyl, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂ (C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R³ stands for oxygen or the group —

NOR⁹, or

R¹ and R² or

R⁴ and R⁵ optionally form another C₃-C₆-membered ring,

R⁶ stands for hydrogen or C_1-18 alkyl,

R⁷ and R⁸ are the same or different and stand for hydrogen or for C_1-18 alkyl, aryl, heteroaryl or acyl that is optionally substituted in one or more places with hydroxy, halogen and/or amino;

or C_1-18 alkyl, C_3-8 cycloalkyl or C_3-8 cycloalkenyl that is optionally interrupted by one or more oxygen atoms, or

R⁷ or R⁸ together with the nitrogen atom of the amino group forms a C_3-8 cycloalkyl, which can contain one or more other heteroatoms,

R⁹ stands for hydrogen or for C_1-6 alkyl that is optionally substituted in one or more places with hydroxy, halogen, C_1-4 alkoxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂ (C_1-4 alkyl) and/or SO₂-aryl;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, C₁-C₆ alkyl, hydroxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ arylamino and/or C₁-C₆ alkoxy, and

p is 0, 1 or 2, as well as isomers and salts thereof.

3. Compounds of general formula I, according to claims 1 and 2, in which

R¹ stands for phenyl, thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, triazinyl, quinolinyl or isoquinolinyl that is optionally substituted by the same or a different component in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, —

O—

Si(C₁-C₆ alkyl)₃, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy, and

R² stands for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, trifluoromethyl, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹, or

R¹ stands for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, —

CF₃, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂R⁷R⁸, or —

COR⁹, and

R² stands for phenyl, thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, triazinyl, quinolinyl or isoquinolinyl that is optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C_1-6 alkoxy,

R⁴ and R⁵ stand for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, —

CF₃, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R³ stands for oxygen or the group —

NOR⁹, or

R¹ and R² or

R⁴ and R⁵ optionally form another C₃-C₆-membered ring,

R⁶ stands for hydrogen or C_1-18 alkyl,

R⁷ and R⁸ are the same or different and stand for hydrogen or for C_1-18 alkyl, aryl, heteroaryl or acyl that is optionally substituted in one or more places with hydroxy, halogen and/or amino;

or C_1-18 alkyl, C_3-8 cycloalkyl or C_3-8 cycloalkenyl that is optionally interrupted by one or more oxygen atoms, or

R⁷ or R⁸ together with the nitrogen atom of the amino group forms a C_3-8 cycloalkyl, which can contain one or more other heteroatoms,

R⁹ stands for hydrogen or for C_1-6 alkyl that is optionally substituted in one or more places with hydroxy, halogen, C_1-4 alkoxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl) and/or SO₂ aryl;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, C₁-C₆ alkyl, hydroxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ arylamino and/or C₁-C₆ alkoxy, and

p is 0, 1 or 2,

as well as isomers and salts thereof.

4. Compounds of general formula I, according to claims 1 to 3, in which

R¹ stands for phenyl or pyridyl that is optionally substituted by the same or a different component in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, —

O—

Si(C₁-C₆ alkyl)₃, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy, and

R² stands for hydrogen, hydroxy, C_1-6 alkyloxy, aryloxy, trifluoromethyl, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹, or

R¹ stands for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, trifluoromethyl, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹, and

R² stands for phenyl or pyridyl that is optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R⁴ and R⁵ stand for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, —

CF₃, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸ or —

COR⁹;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R³ stands for oxygen or the group —

NOR⁹, or

R¹ and R2 or

R⁴ and R⁵ optionally form another C₃-C₆-membered ring,

R⁶ stands for hydrogen or C_1-18 alkyl,

R⁷ and R⁸ are the same or different and stand for hydrogen or for C_1-18 alkyl, aryl, heteroaryl or acyl that is optionally substituted in one or more places with hydroxy, halogen and/or amino;

or C_1-18 alkyl, C_3-8 cycloalkyl or C_3-8 cycloalkenyl that is optionally interrupted by one or more oxygen atoms, or

R⁷ or R8 together with the nitrogen atom of the amino group forms a C_3-8 cycloalkyl, which can contain one or more other heteroatoms,

R⁹ stands for hydrogen or for C_1-6 alkyl that is optionally substituted in one or more places with hydroxy, halogen, C_1-4 alkoxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl) and/or SO₂-aryl;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, C₁-C₆ alkyl, hydroxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ arylamino and/or C₁-C₆ alkoxy, and

p is 0, 1 or 2,

as well as isomers and salts thereof.

5. Compounds of general formula I, according to claims 1 to 4, in which

R¹ stands for phenyl or pyridyl that is optionally substituted by the same or a different component in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, —

O—

Si(C₁-C₆ alkyl)₃, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(CO_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R² stands for hydrogen,

R⁴ and R⁵ stand for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, —

CF₃, nitro, halogen, cyano, or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹;

or for aryl or heteroaryl that are optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, C_1-6 alkoxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R³ stands for oxygen or the group —

NOR⁹, or

R⁴ and R⁵ optionally form another C₃-C₆-membered ring,

R⁶ stands for hydrogen or C_1-18 alkyl,

R⁷ and R⁸ are the same or different and stand for hydrogen or for C_1-18 alkyl, aryl, heteroaryl or acyl that is optionally substituted in one or more places with hydroxy, halogen and/or amino;

or C_1-18 alkyl, C_3-8 cycloalkyl or C_3-8 cycloalkenyl that is optionally interrupted by one or more oxygen atoms, or

R⁷ or R⁸ together with the nitrogen atom of the amino group forms a C_3-8 cycloalkyl, which can contain one or more other heteroatoms,

R⁹ stands for hydrogen or for C_1-6 alkyl that is optionally substituted in one or more places with hydroxy, halogen, C_1-4 alkoxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl) and/or SO₂-aryl;

or for aryl or heteroaryl that is substituted in one or more places with halogen, C₁-C₆ alkyl, hydroxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ arylamino and/or C₁-C₆ alkoxy, and

p is 0, 1 or 2,

as well as isomers and salts thereof.

6. Compounds of general formula I, according to claims 1 to 5, in which

R¹ stands for phenyl or pyridyl that is optionally substituted by the same or a different component in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, —

O—

Si(C₁-C₆ alkyl)₃, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R² stands for hydrogen,

R⁴ and R⁵ stand for hydrogen, hydroxy, C_1-6 alkoxy, aryloxy, trifluoromethyl, nitro, halogen, cyano or the group —

SO_pR⁶, —

SO₂NR⁷R⁸, or —

COR⁹;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R³ stands for oxygen or the group —

NOR⁹, or

R⁴ and R⁵ optionally form another C₃-C₆-membered ring,

R⁶ stands for hydrogen or C_1-18 alkyl,

R⁷ and R⁸ are the same or different and stand for hydrogen or for C_1-8 alkyl, aryl, heteroaryl or acyl that is optionally substituted in one or more places with hydroxy, halogen and/or amino;

or C_1-18 alkyl, C_3-8 cycloalkyl or C_3-8 cycloalkenyl that is optionally interrupted by one or more oxygen atoms, or

R⁷ or R⁸ together with the nitrogen atom of the amino group forms a C_3-8 cycloalkyl, which can contain one or more other heteroatoms,

R⁹ stands for hydrogen or for C_1-6 alkyl that is optionally substituted in one or more places with hydroxy, halogen, C_1-4 alkoxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl) and/or SO₂ aryl;

or for aryl or heteroaryl that is optionally substituted in one or more places with halogen, C₁-C₆ alkyl, hydroxy, amino, nitro, trifluoromethyl, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂-arylamino and/or C₁-C₆ alkoxy, and

p is 0, 1 or 2,

as well as isomers and salts thereof.

7. Compounds of general formula I, according to claims 1 to 6, in which

R¹ stands for phenyl that is optionally substituted by the same or a different component in one or more places with halogen, hydroxy, C₁-C₆ alkyl, amino, nitro, trifluoromethyl, —

O—

Si(C₁-C₆ alkyl)₃, cyano, COOC_1-4 alkyl, CO_1-4 alkyl, CO_1-4 aryl, SO₂(C_1-4 alkyl), SO₂ aryl and/or C₁-C₆ alkoxy,

R² stands for hydrogen,

R⁴ and R⁵ stand for hydrogen,

R³ stands for oxygen,

as well as isomers and salts thereof.

8. Compounds of general formula I, according to claims 1 to 7, in which

R¹ stands for phenyl that is optionally substituted by the same or a different component in one or more places with halogen, hydroxy, C₁-C₄ alkyl, amino, nitro, trifluoromethyl, cyano, —

O—

Si(C₁-C₆ alkyl)₃, or C₁-C₄ alkoxy,

R² stands for hydrogen,

R⁴ and R⁵ stand for hydrogen,

R³ stands for oxygen,

as well as isomers and salts thereof.

9. Use of the compounds of general formula I, according to claims 1 to 8, for the production of a pharmaceutical agent for treating cancer, auto-immune diseases, chemotherapy agent-induced alopecia and mucositis, cardiovascular diseases, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections.

10. Use according to claim 9, characterized in that cancer is defined as solid tumors and leukemia;

auto-immune diseases are defined as psoriasis, alopecia and multiple sclerosis;

cardiovascular diseases are defined as stenoses, arterioscleroses and restenoses;

infectious diseases are defined as diseases that are caused by unicellular parasites;

nephrological diseases are defined as glomerulonephritis;

chronic neurodegenerative diseases are defined as Huntington'"'"'s disease, amyotrophic lateral sclerosis, Parkinson'"'"'s disease, AIDS dementia and Alzheimer'"'"'s disease;

acute neurodegenerative diseases are defined as ischemias of the brain and neurotraumas; and

viral infections are defined as cytomegalic infections, herpes, hepatitis B and C, and HIV diseases.

11. Pharmaceutical agents that contain at least one compound according to claims 1 to 8.

12. Pharmaceutical agents according to claim 11 for treating cancer, auto-immune diseases, cardiovascular diseases, infectious diseases, nephrological diseases, neurodegenerative diseases and viral infections.

13. Compounds according to claims 1 to 8 and pharmaceutical agents according to claims 11 to 12 with suitable formulation substances and vehicles.

14. Use of the compounds of general formula I, according to claims 1 to 8, as inhibitors of cyclin-dependent kinases.

15. Use according to claim 14, wherein the kinase is CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9.

16. Use of the compounds of general formula I, according to claims 1 to 8, as inhibitors of the glycogen-synthase-kinase (GSK-3β

).

17. Use of the compounds of general formula I, according to claims 1 to 8, in the form of a pharmaceutical preparation for enteral, parenteral and oral administration.