Pyridinone and Pyridazinone Derivatives as Inhibitors of Poly (Adp-Ribose) Polymerase (Parp)

• US 20090176765A1
• Filed: 05/25/2007
• Published: 07/09/2009
• Est. Priority Date: 05/31/2006
• Status: Active Grant

• Current Assignee: Msd Italia Srl (Merck & Co., Inc.)
• Original Assignee: Istituto Di Ricerche Di Biologia Molecolare P Angeletti SPA (Merck & Co., Inc.)
• Inventors: Pescatore, Giovanna, Llauger Bufi, Laura, Jones, Philip, Ferrigno, Federica, Kinzel, Olaf, Schultz-Fademrecht, Carsten
• Granted Patent: US 8,188,084 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 17/18 Antioxidants, e.g. antiradicals preparations for protection against sunlight A61Q17/00
• 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 27/02 Ophthalmic agents
• 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 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 237/14 Oxygen atoms
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems

Abstract

The present invention relates to compounds of formula I:

and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of poly(ADP-ribose)polymerase (PARP) and thus useful for the treatment of cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitizers for cancer treatment.

Claims

1-15. -15. (canceled)

16. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I:

wherein;

the sum of a and j is 1 or 2;

b is 0, 1, 2 or 3;

c is 0, 1, 2, 3, 4, 5 or 6;

d is 0 or 1;

e is 0 or 1;

f is 0 or 1;

g is 0 or 1;

h is 0, 1, 2, 3, 4, 5 or 6;

i is 0 or 1;

X is N or CH;

Z is C or SO;

each R¹ is independently C_1-6alkyl, haloC_1-6alkyl, halogen or cyano;

each R² is independently hydroxy, halogen, cyano, nitro, C_1-6alkyl, haloC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy or NR^aR^b;

R³ is hydrogen or C_1-6alkyl;

R⁴ is hydrogen or C_1-6alkyl;

R⁵ is hydrogen, hydroxy, cyano, oxo, halogen, C_1-6alkyl, C_2-10alkenyl, haloC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkoxycarbonyl, carboxy, nitro or a ring which is;

C_6-10aryl;

C_6-10arylcarbonyl;

C_3-10cycloalkyl;

a 4 membered saturated heterocyclic ring containing one N atom;

a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three N atoms and zero or one O atom;

a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S;

a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;

or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

any of which rings being optionally substituted by one or more groups independently selected from A-(CR⁹R¹⁰)_qR⁶;

each A is independently a direct bond, O, C═

O, (C═

O)NR⁷, NR⁷(C═

O), (C═

O)O, O(C═

O), (C═

S)NR⁷, NR⁷ or S(O)_r;

each q is independently 0, 1, 2, 3, or 4;

r is 0, 1 or 2;

each R⁶ is independently hydroxy, oxo, cyano, halogen, nitro, C_1-6alkyl, C_2-10alkenyl, haloC_1-6alkyl, NR^aR^b or a ring which is;

C_3-10cycloalkyl;

C_6-10aryl;

C_6-10aryloxy;

4 membered saturated heterocyclic ring containing one N atom;

a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing one, two or three atoms independently selected from N, O and S;

a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S;

a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;

or a 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

any of which rings being optionally substituted by one or more groups independently selected from R⁸;

R⁷ is hydrogen or R⁶;

each R⁸ is independently hydroxy, oxo, cyano, halogen, nitro, C_1-6alkyl, C_1-6alkoxy, C_2-10alkenyl, haloC_1-6alkyl, haloC_1-6alkoxy, —

O(CO)C_1-6alkyl, —

(C═

O)OC_1-6alkyl, NR^aR^b or a ring which is;

C_3-10cycloalkyl, C_6-10arylC_1-6alkyl, C_6-10arylC_1-6alkoxycarbonyl, C_6-10aryl, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;

any of which rings being optionally substituted by one or more groups independently selected from halogen, C_1-7alkyl or haloC_1-6alkyl;

each of R⁹ and R¹⁰ is independently hydrogen, halogen, C_1-6alkyl or haloC_1-6alkyl;

each of R^a and R^b is independently selected from hydrogen, C_1-6alkyl, C_3-10cycloalkyl, C_3-10cycloalkyl, C_3-10cycloalkylC_1-6alkyl, C_1-6aryl or C_6-10arylC_1-6alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

17. A compound of formula I:

wherein;

a, b, c, d, e, f, g, h, i, j, X, Z, R¹, R², R³, R⁴ and R⁵ are as defined in claim 16;

provided that;

(a) when (CH₂)_c(CO)_d(NR³)_e(Z-0)_f(O)_g(CH₂)_h(NR⁴)_i represents an O linker, R² is fluoro and X is N then R⁵ is not an optionally substituted ring selected from C_6-10aryl, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring or a 7-15 membered unsaturated or partially saturated heterocyclic ring;

(b) when X is N then R⁵ is not C_1-6alkyl, haloC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkylcarbonyl or an optionally substituted C_3-10cycloalkyl, phenyl, napthyl, pyridinyl, pyridine N-oxide, indole, indole N-oxide, quinoline, quinoline N-oxide, pyrimidinyl, pyrazinyl or pyrrolyl; and

(c) when (CH₂)_c(CO)_d(NR³)_e(Z=O)_f(O)_g(CH₂)_h(NR⁴)_i represents a CO linker and X is N then R⁵ is not an optionally substituted phenyl, pyridinyl, thienyl or furyl;

or a pharmaceutically acceptable salt or tautomer thereof.

18. A compound of claim 17 of formula II:

wherein;

a, b, j, q, A, X, R¹, R², R⁶, R⁹ and R¹⁰ are as defined in claim 16;

t is 0, 1, 2 or 3;

when t is 0 then B is CH₂;

when t is 1, 2 or 3 then B is CH₂, NH or O;

w is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt or tautomer thereof.

19. A compound of claim 17 of formula IV:

wherein;

a, b, c, d, e, f, h, i, j, X, Z, R¹, R², R³ and R⁴ are as defined in claim 16;

R⁵ is a 4 membered saturated heterocyclic ring containing one N atom, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three N atoms and zero or one O atom or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

any of which rings being optionally substituted by one or more groups independently selected from A-(CR⁹R¹⁰)_qR⁶;

or a pharmaceutically acceptable salt or tautomer thereof.

20. A compound of claim 17 of formula V:

wherein;

a, b, d, i, j, X, R¹, R², R⁴ and R⁵ are as defined in claim 16;

provided that;

(a) when X is N then R⁵ is not C_1-6alkyl, haloC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, C_1-6alkylcarbonyl or an optionally substituted C_3-10cycloalkyl, phenyl, napthyl, pyridinyl, pyridine N-oxide, indole, indole N-oxide, quinoline, quinoline N-oxide, pyrimidinyl, pyrazinyl or pyrrolyl; and

(b) when d is 1, i is 0 and X is N then R⁵ is not an optionally substituted phenyl, pyridinyl, thienyl or furyl;

or a pharmaceutically acceptable salt or tautomer thereof.

21. A compound of claim 17 of formula VII:

wherein;

a, b, j, i, X, R¹, R², and R⁴ are as defined in claim 16;

R⁵ is a 4 membered saturated heterocyclic ring containing one N atom, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three N atoms and zero or one O atom or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

any of which rings being optionally substituted by one or more groups independently selected from A-(CR⁹R¹⁰)_qR⁶;

or a pharmaceutically acceptable salt or tautomer thereof.

22. A compound of claim 17 of formula VIII:

wherein;

a, b, d, j, q, A, R¹, R², R⁶, R⁹ and R¹⁰ are as defined in claim 16;

C is a 4 membered saturated heterocyclic ring containing one N atom, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three N atoms and zero or one O atom or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

or a pharmaceutically acceptable salt or tautomer thereof.

23. A compound of claim 17 of formula IX:

wherein;

a, b, d, q, j, A, R¹, R², R⁶, R⁹, R¹⁰ are as defined in claim 16;

C is a 4 membered saturated heterocyclic ring containing one N atom, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three N atoms and zero or one O atom or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

or a pharmaceutically acceptable salt or tautomer thereof.

24. A compound of claim 17 wherein X is N.

25. A compound of claim 17 wherein R² is fluorine.

26. A pharmaceutical composition comprising a compound of claim 17 or a pharmaceutically acceptable salt or tautomer thereof in association with a pharmaceutically acceptable carrier.

27. A method of treating or preventing cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence or UV-induced skin damage, which method comprises administration to a patient in need thereof of an effective amount of a compound of claim 17 or a composition comprising a compound of claim 17.