Quinazoline derivatives as VEGF inhibitors

• US 8,642,608 B2
• Filed: 04/15/2010
• Issued: 02/04/2014
• Est. Priority Date: 11/05/1999
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Thomas, Andrew Peter, Stokes, Elaine Sophie Elizabeth, Hennequin, Laurent Francois Andre
• Primary Examiner(s): Ward, Paul V.
• Application Number:
  US12/761,105
• Publication Number:
  US 20110065736A1
• Time in Patent Office: 1,391 Days
• Field of Search: 514/266.1, 544/283, 544/284
• US Class Current: 514/266.1
• 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 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 3/00 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 37/00 Drugs for immunological or allergic disorders
• 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 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to quinazoline derivatives of formula (I), wherein m is an integer from 1 to 3; R¹ represents halogeno or C_1-3alkyl; X¹ represents —O—; R² is selected from one of the following three groups: 1) C₁-5alkylR³ (wherein R³ is piperidinyl-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy; 2) C_2-5alkenylR³ (wherein R³ is as defined hereinbefore); 3) C_2-5alkynylR³ (wherein R³ is as defined hereinbefore); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. 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. A method of inhibiting vascular endothelial growth factor (VEGF) receptor tyrosine kinase activity or endothelial growth factor (EGF) receptor tyrosine kinase activity in a warm-blooded animal suffering from a cancer associated with VEGF or EGF, comprising administering to said animal an effective amount of 4-(4-bromo-2-fluoroanilino)-6- methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline or a pharmaceutically acceptable salt thereof, wherein the cancer is a primary or recurrent solid tumor.

2. The method as claimed in claim 1, wherein the warm-blooded animal is a human.

3. The method as claimed in claim 1, wherein the solid tumor is significantly dependent on VEGF for its growth and/or spread.

4. The method as claimed in claim 1, wherein the solid tumor is significantly dependent on EGF for its growth and/or spread.

5. The method as claimed in claim 1, wherein the solid tumor is significantly dependent on VEGF and EGF for its growth and/or spread.

6. The method as claimed in claim 3, wherein the solid tumor which is significantly dependent on VEGF for its growth and spread is a tumor of the colon.

7. The method as claimed in claim 1, wherein the administering of the 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidine-4-ylmethoxy)quinazoline or a pharmaceutically acceptable salt thereof results in inhibition or slowing of the growth of the primary or recurrent solid tumor.

8. The method as claimed in claim 3, wherein the solid tumor which is significantly dependent on VEGF for its growth and spread is a tumor of the breast.

9. The method as claimed in claim 3, wherein the solid tumor which is significantly dependent on VEGF for its growth and spread is a tumor of the lung.

10. The method as claimed in claim 3, wherein the solid tumor which is significantly dependent on VEGF for its growth and spread is a tumor of the vulva.

11. The method as claimed in claim 3, wherein the solid tumor which is significantly dependent on VEGF for its growth and spread is a tumor of the skin.