Quinazoline compounds

• US 7,160,889 B2
• Filed: 04/03/2001
• Issued: 01/09/2007
• Est. Priority Date: 04/07/2000
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre, Stokes, Elaine Sophie Elizabeth
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): Ward; Paul V.
• Application Number:
  US10/240,658
• Publication Number:
  US 20030191308A1
• Time in Patent Office: 2,107 Days
• Field of Search: 544/242, 544/253, 514/258, 514/258.1
• US Class Current: 514/258.1
• 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 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 3/10 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• 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 239/94 Nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention concerns quinazoline derivatives of Formula (I)

wherein ring A is phenyl or a 5-or 6-membered heterocyclic ring which may be saturated, partially saturated or unsaturated and may be aromatic or non-aromatic and which contains 1, 2 or 3 ring heteroatoms selected from O, N and S; Z is —O—, —NH— or —S—; and X¹, R¹, R², R³, m and R⁴ have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in producing an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals, and in the treatment of disease states such as cancer, rheumatoid arthritis and psorlasis.

Claims

1. A compound of the formula (I):

2. A compound according to claim 1 wherein R² is hydrogen.

3. A compound according to claim 1 or claim 2 wherein R¹ is hydrogen or methoxy.

4. A compound according to claim 1 wherein R³ is hydroxy, halogeno, C_1-2alkyl, C_1-2alkoxy, trifluoromethyl, cyano, amino or nitro.

5. A compound according to claim 1 wherein m is 2 or 3.

6. A compound according to claim 1 wherein ring A bearing bearing (R³)_m is 2-fluoro-4-chloro-5-hydroxyphenyl, 2-fluoro-4-bromo-5-hydroxyphenyl, 2-fluoro-4-chlorophenyl or 2-fluoro-4-bromophenyl.

7. A compound according to claim 1 wherein X¹ is —

O—

, —

S—

, —

NR⁷CO—

or —

NR⁷SO₂—

(wherein R⁷ is hydrogen, methyl or ethyl).

8. A compound according to claim 1 wherein R⁴ is of the formula —

Y²—

R¹⁶, —

Y²—

NR¹⁷R¹⁸ or —

Y³—

R^a, wherein Y², Y³, R^a, R¹⁶, R¹⁷ and R¹⁸ are as defined in claim 1.

9. A compound according to claim 1 wherein the alkylene, alkenylene or alkynylene chain in Y¹ or Y² in R⁴ is substitued by hydroxy or acetoxy, wherein Y¹, Y² and R⁴ are as defined in claim 1.

11. A compound according to claim 1 in the form of a pharmaceutically acceptable salt.

12. A process for the preparation of a compound of the formula (I) as defined in claim 1 or a salt thereof which comprises:

(a) the reaction of a compound of the formula III;

13. A pharmaceutical composition which comprises a compound of the formula (I) as defined in claims 1–

3 and 4–

10 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

14. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) as defined in claims 1–

3 and 4–

10 or a pharmaceutically acceptable salt.

10. A compound selected from

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy)quinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxy) quinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy)quinazoline

4-(4-chloro-2-fluorophenylamino)-7-(2-hydroxy-3-(morpholino)propoxy)-6-methoxy) quinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(thiazolidin-3-yl)propoxy]-6-methoxy) quinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(3-pyrrolin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-(2-morpholinoethyl)piperazin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-(3-hydroxypropyl)piperazin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(1,2,3,6-tetrahydropyridin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(N-tertbutyl-N-methylamino)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isopropyl-N-methylamino)propoxy]-6-methoxyquinazoline hydrochloride

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isobutyl-N-methylamino)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(N-(2-hydroxyethyl)-N-methylamino) propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(morpholino)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-(2-hydroxy-3-(N,N-dimethylamino)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(piperidin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N,N,-dimethylamino)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(piperidin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(homopiperidin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-(2-hydroxyethyl)-N-methylamino) propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(3-pyrrolin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(thiomorpholin-4-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(3-hydroxypyrrolidin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-{2-hydroxy-3-[4-(2-morpholinoethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-{2-hydroxy-3-[4-(2-hydroxyethyl)]piperazin-1-yl]propoxy}-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(2,5-dimethyl-3-pyrrolin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(4-methylpiperidin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(2-methylpyrrolidin-1-yl)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-(2-cyanoethyl)-N-methylamino) propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isopropyl-N-methylamino)propoxy]-6-methoxyquinazoline

4-(4-chloro-2-fluorophenylamino)-7-[2-hydroxy-3-(N-isobutyl-N-methylamino)propoxy]-6-methoxyquinazoline

4-chloro-2-fluoro-5-hydroxyphenylamino-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline

4-chloro-2-fluoro-5-hydroxyphenylamino-7-(2-acetoxy-3-piperidinopropoxy)-6-methoxyquinazoline

4-bromo-2-fluoro-5-hydroxyphenylamino-7-[2-acetoxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline

4-bromo-2-fluoro-5-hydroxyphenylamino-7-[2-hydroxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline;

or a salt thereof.