Quinazoline derivatives as VEGF inhibitors

• US 10,457,664 B2
• Filed: 12/28/2017
• Issued: 10/29/2019
• Est. Priority Date: 11/05/1999
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Thomas, Andrew Peter, Stokes, Elaine Sophie Elizabeth, Hennequin, Laurent Francois Andre
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US15/856,235
• Publication Number:
  US 20190002433A1
• Time in Patent Office: 670 Days
• 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; R′ represents halogeno or C_1-3alkyl; X¹ represents —O—; R² is selected from one of the following three groups: 1) C_1-5alkylR³ (wherein R³ is piperidin-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 process for the preparation of a quinazoline derivative of formula I

2. The process according to claim 1, wherein m is 2.

3. The process according to claim 1, wherein R¹ is selected from fluoro and bromo.

4. The process according to claim 1, wherein R² is CH₂R³.

5. The process according to claim 1, wherein R³ is piperidin-4-yl where the nitrogen atom of the piperidine ring may bear a CH₃ substituent.

6. The process according to claim 1, wherein the compound of formula I is 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline or a salt thereof.

7. The process according to claim 1, wherein the compound of formula III is 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.

8. The process according to claim 1, wherein the compound of formula IV is 4-bromo-2-fluoroaniline, 4-chloro-2-fluoroaniline, 4-bromo-2,6-difluoroaniline or 4-chloro-2,6-difluoroaniline.

9. The process according to claim 1, wherein the compound of formula V is 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline, 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline or 4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline.

10. The process according to claim 1, wherein the compound of formula VI is 1-(tert-butoxycarbonyl)-4-(hydroxymethylpiperidine.

11. The process according to claim 1, wherein the compound of formula IX is 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline or 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline.

12. The process according to claim 1, wherein trifluoroacetic acid is used to deprotect the compound of formula IX in step c.

13. The process according to claim 9, wherein 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline is the compound of formula V and is prepared by deprotection of 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline or 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline.

14. The process according to claim 9, wherein 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline is the compound of formula V and is prepared by deprotection of 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline.