Substituted indoles which are PARP inhibitors

• US 7,087,637 B2
• Filed: 05/09/2001
• Issued: 08/08/2006
• Est. Priority Date: 05/11/2000
• Status: Expired due to Term

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: BASF AG (BASF SE)
• Inventors: Hoger, Thomas, Muller, Reinhold, Lubisch, Wilfried, Grandel, Roland, Holzenkamp, Uta, Kock, Michael, Schult, Sabine
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US10/275,574
• Publication Number:
  US 20040067949A1
• Time in Patent Office: 1,917 Days
• Field of Search: 514/414, 514/419, 548/492, 548/495
• US Class Current: 514/414
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Abstract

The present invention relates to novel indole derivatives, to their preparation and to their use, as inhibitors of the enzyme poly(ADP-ribose)polymerase or PARP (EC 2.4.2.30), for producing drugs.

Claims

1. A compound of the formula I or II

2. A compound of the formula I or II as claimed in claim 1, wherein

X is O, and

R′

is hydrogen, and

all the other variables have the above-mentioned meanings.

3. A compound of the formula I or II as claimed in claim 1, wherein,

X is O, and

R¹ is hydrogen, and

A is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine or pyrazine, which compounds can be additionally substituted by one R⁴ or at most 2 R⁵, and

all the other variables have the meanings as given in claim 1.

4. A compound of the formula I or II as claimed in claim 1, wherein

X is O, and

R′

is hydrogen, and

A is phenyl, cyclohexyl, piperidine, pyridine, pyrimidine or pyrazine, which compounds can be additionally substituted by one R⁴ or at most 2 R⁵, and

R⁴ is -Dp-F_0.1-G²-G³ with G³ equal hydrogen, wherein, when A is phenyl and p is 1, D is not NR⁴³ and R⁵ is not NR¹¹R¹², and when A is phenyl and p is 0, G² is a bond

and R⁵ is not NR¹¹R¹²,

D is O or NR⁴³, where R⁴³ is hydrogen or C₁–

C₃-alkyl, and

F is C₂–

C₄-alkyl, and

G² has the same meaning as given above, and

R⁵ has the same meaning as given above.

5. The compounds of the general formulae I and II for producing drugs for treating neurodegenerative diseases and neuronal damage as in claim 1, with R¹, R², R³ and X having the same meanings as given above and with it being possible for B to be hydrogen or a C₁–

C₆ alkyl chain.

6. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating neurodegenerative diseases and neuronal damage.

7. The compounds as claimed in claim 6 for treating such neurodegenerative diseases and neuronal damage which are induced by ischemia, trauma or hemorrhages.

8. The compounds as claimed in claim 6 for treating stroke and craniocerebral trauma.

9. The compounds as claimed in claim 6 for treating Alzheimer'"'"'s disease, Parkinson'"'"'s disease and Huntington'"'"'s disease.

10. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for the treatment or prophylaxis of damage due to ischemias.

11. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating epilepsies, in particular generalized epileptic attacks, such as petit mal and tonic/clonic attacks and partial epileptic attacks, such as temporal lobe, and complex partial attacks.

12. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for the treatment of damage to the kidneys following renal ischemias and for treatment during and after kidney transplants.

13. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating damage to the heart following cardiac ischemias.

14. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating microinfractions as, for example, during and after heart valve replacement, aneurysm resections and heart transplants.

15. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating coronary arteries which are critically stenosed in association with a revascularization, as, for example, in association with PTCA and bypass operations, or critically stenosed peripheral arteries, in particular arteries of the leg.

16. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating acute myocardial infraction and damage during and after its medicinal or mechanical lysis.

17. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating tumors and their metastasization.

18. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating sepsis and septic shock.

19. The compounds of the formulae I–

II as claimed in claim 1 for producing drugs for treating immunological diseases such as inflammations and rheumatic disorders, for example rheumatoid arthritis.

20. The compounds of the formula I–

II as claimed in claim 1 for producing drugs for treating diabetes mellitus.

21. A compound of the formula I or II