Tricyclic inhibitors of poly(ADP-ribose) polymerases

• US 20060009517A1
• Filed: 09/06/2005
• Published: 01/12/2006
• Est. Priority Date: 01/11/1999
• Status: Active Grant

• Current Assignee: Agouron Pharmaceuticals LLC (Pfizer Inc.)
• Original Assignee: Cancer Research Campaign Technology Ltd (Cancer Research UK), Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Tikhe, Jayashree, Webber, Stephen Evan, Canan-Koch, Stacie S., Thoresen, Lars Henrik
• Granted Patent: US 7,429,578 B2
• Time in Patent Office: Days
• US Class Current: 514/520
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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: 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 471/06 Peri-condensed systems
• CPC Class Codes: C07D 487/06 Peri-condensed systems

Abstract

Compounds of the formula below are poly(ADP-ribosyl)transferase (PARP) inhibitors, and are useful as therapeutics in treatment of cancers and the amelioration of the effects of stroke, head trauma, and neurodegenerative disease. As cancer therapeutics, the compounds of the invention may be used, e.g., in combination with cytotoxic agents and/or radiation.

Claims

1. A method of inhibiting activity of a PARP enzyme, comprising contacting the PARP enzyme with an effective amount of a compound of formula (I):

2. The method of claim 1 wherein in the compound of formula (I)

Y is (CR⁵R⁶)(CR⁷R⁸)_n, where:

n is 1;

R⁵, R⁶, R⁷ and R⁸ are H.

3. The method of claim 2 wherein in the compound of formula (I)

R¹ is 4-methylaminomethyl-phenyl;

R² is H;

R³ is H;

R⁴ is 8-fluoro;

X is O.

4. The method of claim 1 wherein a PARP-inhibiting activity corresponds to a K_i of 100 μ

M or less in a PARP enzyme inhibition assay.

5. A method of inhibiting PARP enzyme activity in mammalian tissue by administering to a mammal a therapeutically effective amount of a compound of formula (I):

6. The method of claim 5 wherein in the compound of formula (I)

Y is (CR⁵R⁶)(CR⁷R⁸)_n, where:

n is 1;

R⁵, R₆, R⁷ and R₈ are H.

7. The method of claim 6 wherein in the compound of formula (1)

R¹ is 4-methylaminomethyl-phenyl;

R² is H;

R³ is H;

R⁴ is 8-fluoro;

X is 0.

8. A method of potentiating cytotoxicity of a cytotoxic drug or ionizing radiation, comprising contacting cells with an effective amount of a compound of formula (I):

9. The method of claim 8 wherein in the compound of formula (1)

Y is (CR⁵R⁶)(CR⁷R⁸)_n, where:

n is 1;

R⁵, R⁶, R⁷ and R⁸ are H.

10. The method of claim 9 wherein in the compound of formula (I)

R¹ is 4-methylaminomethyl-phenyl;

R² is H;

R³ is H;

R⁴ is 8-fluoro;

X is 0.

11. The method of claim 8 wherein the compound of formula (I) has a cytotoxicity potentiation activity corresponding to a PF₅₀ of at least 1.1 in a cytotoxicity potentiation assay.

12. The method of claim 8 wherein the compound of formula (I) has a cytotoxicity potentiation activity corresponding to a PF₅₀ of from about 1.1 to about 3 in a cytotoxicity potentiation assay.