Therapy

• US 20030225111A1
• Filed: 08/28/2002
• Published: 12/04/2003
• Est. Priority Date: 03/06/2000
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre, McKerrecher, Darren, Poyser, Jeffrey Philip, Ple, Patrick, Lambert, Christine Marie Paul, Crawley, Graham Charles
• Granted Patent: US 7,498,335 B2
• Time in Patent Office: Days
• US Class Current: 514/260.1
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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 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

Abstract

The invention concerns the use of a quinazoline derivative of Formula (I) wherein Q¹ includes a quinazoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q³—X¹— wherein X¹ includes a direct bond and O and Q³includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R² and R³ is hydrogen or (1-6C)alkyl; Z includes O, S and NH; and Q² includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human.

Claims

1. Use of a compound of the formula I:

2. Use of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for producing a VEGF receptor tyrosine kinase inhibitory effect in a warm-blooded animal such as a human.

3. Use according to claim 1 or claim 2 wherein the compound of formula I is a compound of formual II:

4. Use according to claim 1 or claim 2 wherein the compound of formula I is a compound of formula III:

5. Use according to claim 1 or claim 2 wherein the compound of formula I is a compound of formula IV:

6. Use according to claim 3 of a compound of formula II, as defined in claim 3, or a pharmaceutically acceptable acid addition salt thereof, wherein

m is 1 and the R¹ group is located at the 6- or 7-position and is selected from methoxy, benzyloxy, cyclopropylmethoxy, 2-aminoethylamino, 3-methoxypropylamino, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid4-ylpropoxy, N-[3-(imidazol-1-yl)propyl]carbamoyl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-pyrrolidin-1-ylpropyl-1,3-(pyrrolidin-1-yl)-1-propenyl, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, N-methylpyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 2-(N-methylpyrrolidin-2-yl)ethoxy, 3-pyrrolidin-2-ylpropoxy, 3-(N-methylpyrrolidin-2-yl)propoxy, 4-(pyrrolidin-1-yl)but-2-en-1-yloxy, 2-(2-oxoimidazolidin-1-yl)ethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidinyl)ethoxy, 3-(4-aminomethylpiperidin-1-yl)propoxy, 3-(4tert-butoxycarbonylaminopiperidin-1-yl)propoxy, 3-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy, 4-tert-butoxycarbonylpiperazin-1-yl, 3-(4-carbamoylpiperidin-1-yl)propoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, N-[3-(4-methylpiperazin-1-yl)propyl]carbamoyl, 4-morpholinobut-2-en-1-yloxy, 4-morpholinobut-2-yn-1-yloxy, 2-(2-morpholinoethoxy)ethoxy, 3-morpholinopropylcarbamoyl, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, N-(2-diethylaminoethyl)-N-methylamino, 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy, 3-[N2-methoxyethyl)-N-methylamino]propoxy, 2-(2-methoxyethoxy)ethoxy, 3-methylamino-1-propynyl, 3-dimethylamino-1-propynyl, 3-diethylamino-1-propynyl, 6-methylamino-1-hexynyl, 6-dimethylamino-1-hexynyl, 3-(pyrrolidin-1-yl)-1-propynyl, 3-(piperidino)-1-propynyl, 3-(morpholino)-1-propynyl, 3-(4-methylpiperazin-1-yl)-1-propynyl, 6-(2-methylimidazol-1-yl)-1-hexynyl, 6-(pyrrolidin-1-yl)-1-hexynyl, 6-(piperidino)-1-hexynyl, 6-(morpholino)-1-hexynyl, 6-(4-methylpiperazin-1-yl)-1-hexynyl, piperazin-1-yl, 4-methylpiperazin-1-yl, 3-imidazol-1-ylpropylamino, 3-pyrrolidin-1-ylpropylamino, 3-morpholinopropylamino, 3-piperidinopropylamino and 3-piperazin-1-ylpropylamino, 6-(4-methylpiperazin-1-yl)hexyl,

or m is 2 and the R¹ groups are located at the 6- and 7-positions, one R¹ group is located at the 6- or 7-position and is selected from the groups defined immediately hereinbefore and the other R¹ group is a methoxy group;

R² is hydrogen or methyl;

R³is hydrogen;

Z is O, S, NH or N(Et); and

Q² is phenyl, benzyl or phenethyl which optionally bears 1, 2or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, nitro, methyl, ethyl and methoxy provided that at least one substituent is located at an ortho position.

7. Use according to claim 3 of a compound of formula II, as defined in claim 3, or a pharmaceutically acceptable acid addition salt thereof, wherein

m is 1 and the R¹ group is located at the 6- or 7-position and is selected from methoxy, cyclopropylmethoxy, 2-aminoethylamino, 2-dimethylaminoethoxy, 3-(1,2,3-triazol-1-yl)propoxy, 2-pyridylethoxy, N-[3-(imidazol-1-yl)propyl]carbamoyl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-pyrrolidin-1-ylpropyl, 3-(pyrrolidin-1-yl)-1-propenyl, 4-(pyrrolidin-1-yl)but-2-en-1-yloxy, 2-(2-oxoimidazolidin-1-yl)ethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 3-(1,1-dioxotetrahydro4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, N-methylpiperidin-3-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 3-(4-aminomethylpiperidin-1-yl)propoxy, 3-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy, 4-tert-butoxycarbonylpiperazin-1-yl, 3-(4-carbamoylpiperidin-1-yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, N-[3-(4-methylpiperazin-1-yl)propyl]carbamoyl, 4-morpholinobut-2-en-1-yloxy, 4-morpholinobut-2-yn-1-yloxy, 3-methylsulphonylpropoxy, N-(2-diethylaminoethyl)-N-methylamino, 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy, 2-(2-methoxyethoxy)ethoxy, 6-methylamino-1-hexynyl, 3-(pyrrolidin-1-yl)l-propynyl, 6-(2-methylimidazol-1-yl)-1-hexynyl, 6-(morpholino)-1-hexynyl, 4methylpiperazin-1-yl, 3-imidazol-1-ylpropylamino, 3-morpholinopropylamino, and 6-(4methylpiperazin-1-yl)hexyl,

or m is 2 and the R¹ groups are located at the 6- and 7-positions, one R¹ group is located at the 6- or 7-position and is selected from the groups defined immediately hereinbefore and the other R¹ group is a methoxy group;

R² is hydrogen;

R³ is hydrogen;

Z is O, S, NH or N(t); and

Q² is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, methyl and ethyl provided that at least one substituent is located at an ortho position.

8. Use according to claim 4 of a compound of formula III, as defined in claim 4, or a pharmaceutically acceptable acid addition salt thereof, wherein the fusion of ring Y¹ to the adjacent pyrimidine ring forms a thieno[3,2-d]pyrimidin-4-yl group;

m is 0, or m is 1 and the R¹ group is a methyl, ethyl, vinyl or ethynyl group which is located at the 6-position and bears a substituent selected from carboxy, carbamoyl, N-(2-methylaminoethyl)carbamoyl, N-(2-dimethylaminoethyl)carbamoyl, N-(3-methylaminopropyl)carbamoyl or N-(3-dimethylaminopropyl)carbamoyl, or from a group of the formula;

Q⁴—

X²—

 

wherein X² is NHCO or N(Me)CO and Q⁴ is 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyrid-2-ylethyl, 2-pyrrolidin-1-ylethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 3-pyrrolidin-1-ylpropyl, 3-(2-oxopyrrolidin-1-yl)propyl, pyrrolidin-2-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 2-(1-methylpyrrolidin-2-yl)ethyl, 3-pyrrolidin-2-ylpropyl, 3-(1-methylpyrrolidin-2-yl)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 1-methylpiperidin-3-ylmethyl, 2-piperidin-3-ylethyl, 2-(1-methylpiperidin-3-yl)ethyl, piperidin-4-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-(1-methylpiperidin-4-yl)ethyl, 2-piperazin-1-ylethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-piperazin-1-ylpropyl or 3-(4-methylpiperazin-1-yl)propyl,

R² is hydrogen or methyl;

R³ is hydrogen;

Z is O; and

Q² is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl and methyl.

9. A method of producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to the animal an effective amount of a compound of the formula (I) as defined in claim 1 or a pharmaceutically-acceptable salt thereof