Quinazoline derivatives as angiogenesis inhibitors

• US 20060004017A1
• Filed: 06/29/2005
• Published: 01/05/2006
• Est. Priority Date: 02/10/1999
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: McKerrecher, Darren, Ple, Patrick, Stokes, Elaine SE, Hennequin, Laurent FA
• Application Number:
  US11/169,122
• Publication Number:
  US 20060004017A1
• Time in Patent Office: Days
• US Class Current: 514/252.170
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 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 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 239/88 : Oxygen atoms
• CPC Class Codes: C07D 239/94 : Nitrogen atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• 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 403/12 : 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 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The invention relates to the use of compounds of formula (I), wherein ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which optionally may contain 1-3 heteroatoms selected independently from O, N and S; Z is —O—, —NH—, —S—, —CH₂— or a direct bond; n is 0-5; m is 0-3; R² represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylsulphanyl, —NR³R⁴ (wherein R³ and R⁴, which may be the same or different, each represents hydrogen or C_1-3alkyl), or R⁵X^t— (wherein X¹ and R⁵ are as defined herein; R¹ represents hydrogen, oxo, halogeno, hydroxy, C_1-4alkoxy, C_1-4alkyl, C_1-4alkoxymethyl, C_1-4alkanoyl, C_1-4haloalkyl, cyano, amino, C_2-5alkenyl, C_2-5alkynyl, C_1-3alkanoyloxy, nitro, C_1-4alkanoylamino, C_1-4alkoxycarbonyl, C_1-4alkylsulphanyl, C_1-4alkylsulphinyl, C_1-4alkylsulphonyl, carbamoyl, N—C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, aminosulphonyl, N—C_1-4alkylaminosulphonyl, N,N-di(C_1-4alkyl)aminosulphonyl, N-(C_1-4alkylsulphonyl)amino, N—(C_1-4alkylsulphonyl)—N—(C_1-4alkyl)amino, N,N-di(C_1-4alkylsulphonyl)amino, a C_3-7alkylene chain joined to two ring C carbon atoms, C_1-4alkanoylaminoC_1-4alkyl, carboxy or a group R⁵⁶X¹⁰ (wherein X¹⁰ and R⁵⁶ are as defined herein); and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula (I). The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Claims

1-30. -30. (canceled)

31. A process for the preparation of a compound of formula I:

32. The compound 4-fluoro-5-hydroxy-2-methylindole or a salt thereof.

36. A process for the preparation the compound of claim 32 comprising the steps of:

(i) reacting 2-fluoro-4-nitroanisole with 4-chlorophenoxyacetonitrile to give a mixture of 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole;

(ii) reacting 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole with di-tert-butyl dicarbonate to give a mixture of 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole;

(iii) reacting 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole with tert-butyllithium followed by deprotection to give 6-fluoro-5-methoxy-2-methylindole and 4-fluoro-5-methoxy-2-methylindole; and

(iv) de-alkylating 4-fluoro-5-methoxy-2-methylindole to give 4-fluoro-5-hydroxy-2-methylindole.

37. A process for the preparation of the compound of claim 32 comprising the steps:

(i) reacting alkyl or aryl acetoacetate and 1,2,3-trifluoro-4-nitrobenzene to give 3-acetylmethyl-1,2-difluoro-4-nitrobenzene;

(ii) reacting 3-acetymethyl-1,2-difluoro-4-nitrobenzene with an orthoformate to give 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene;

(iii) reacting benzyl alcohol or substituted benzyl alcohol or ethanol or propanol with sodium hydride and 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene to give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene; and

(iv) hydrogenating 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene to give 4-fluoro-5-hydroxy-2-methylindole.

38. A process for the preparation of the compound of claim 32 comprising the steps:

(i) reacting alkyl or aryl acetoacetate and 1,2,3-trifluoro-4-nitrobenzene to give 3-acetymethyl-1,2-difluoro-4-nitrobenzene;

(ii) reacting 3-acetymethyl-1,2-difluoro-4-nitrobenzene with an orthoformate to give 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene;

(iii) reacting sodium methoxide with 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene to give 3-acetylmethyl-2-fluoro-methoxy-4-nitrobenzene;

(iv) reacting 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene with titanium trichloride to give 4-fluoro-5-methoxy-2-methylindole; and

(v) dealkylating 4-fluoro-5-methoxy-2-methylindole to give 4-fluoro-5-hydroxy-2-methylindole.

33. The compound 4-fluoro-5-hydroxyindole or a salt thereof.

39. A process for the preparation of a compound of claim 33 or claim 35, comprising the steps:

(i) reacting 2-fluoro-4-nitrophenol and benzyl bromide to give 2-fluoro-4-nitrobenzyloxybenzene;

(ii) reacting 2-fluoro-4-nitro-benzyloxybenzene with 4-chlorophenoxyacetonitrile to give a mixture of 3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and 5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene; and

(iii) hydrogenating a mixture of 3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and 5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene to give 4-fluoro-5-hydroxyindole and 6-fluoro-5-hydroxyindole.

34. The compound 6-fluoro-5-hydroxy-2-methylindole or a salt thereof.

40. A process for the preparation of a compound of claim 34 comprising the steps:

(i) reacting 2-fluoro-4-nitroanisole with 4-chlorophenoxyacetonitrile to give a mixture of 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole;

(ii) reacting 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole with di-tert-butyl dicarbonate to give a mixture of 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole;

(iii) reacting 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole with tert-butyllithium followed by deprotection to give 6-fluoro-5-methoxy-2-methylindole and 4-fluoro-5-methoxy-2-methylindole; and

(iv) de-alkylating 6-fluoro-5-methoxy-2-methylindole to give 6-fluoro-5-hydroxy-2-methylindole.

35. The compound 6-fluoro-5-hydroxyindole or a salt thereof.