Quinazoline compounds

• US 5,814,630 A
• Filed: 02/13/1997
• Issued: 09/29/1998
• Est. Priority Date: 02/14/1996
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Johnstone, Craig, Barker, Andrew John
• Primary Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/800,830
• Time in Patent Office: 593 Days
• Field of Search: 544/284, 544/293, 544/122, 514/234.5, 514/253, 514/254, 514/259
• US Class Current: 514/234.5
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 35/00 Antineoplastic agents
• 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: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond

Abstract

The invention concerns quinazoline compounds of the formula I ##STR1## wherein Q¹ is a 5- or 6-membered heteroaryl moiety and Q¹ optionally bears up to 3 substituents;

wherein m is 1 or 2 and each R¹ may be a group such as hydrogen, halogeno and trifluoromethyl;

and wherein Q² is phenyl which optionally bears up to 3 substituents; or a pharmaceutically-acceptable salt thereof;

processes for their preparation, pharmaceutical compositions containing them and the use of their receptor tyrosine kinase inhibitory properties in the treatment of proliferative disease such as cancer.

Claims

1. A quinazoline compound of the formula I ##STR6## wherein Q¹ is a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heterocyclic moiety is a single ring or is fused to a benzo ring, and Q¹ optionally bears up to 3 substituents selected from halogeno, hydroxy, amino, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1yl, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl, N,N-di- (1-4C)alkyl!carbamoyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di- (1-4C)alkyl!amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di- (1-4C)alkyl!amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di- (1-4C)alkyl!amino-(2-4C)alkylamino, pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino, morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino, N-(1-4C)alkyl-halogeno-(2-4C)alkylamino, N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino, N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino, (3-4C)alkynoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino, di- (1-4C)alkyl!amino-(2-4C)alkanoylamino, pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino, morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of the above-mentioned substituents comprising a CH₂ (methylene) group which is not attached to a halogeno, SO or SO₂ group or to a N, O or S atom optionally bears on said CH₂ group a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di- (1-4C)alkyl!amino;

wherein m is 1 or 2 and each R¹ is independently hydrogen, halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl or N,N-di- (1-4C)alkyl!carbamoyl;

and wherein Q² is phenyl which optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di- (1-4C)alkyl!amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;

or a pharmaceutically-acceptable salt thereof.

2. A quinazoline compound of the formula I as claimed in claim 1 wherein Q¹ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-oxazolyl, 4-oxazolyl, 5-isoxazolyl, 3-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-isothiazolyl or 1,2,3-triazol-4-yl which optionally bears a substituent selected from methyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl, 2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1, 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

3. A quinazoline compound of the formula I as claimed in claim 1 wherein Q¹ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-oxazolyl, 4-thiazolyl or 1-imidazolyl which optionally bears a substituent selected from aminomethyl, morpholinomethyl and 2-morpholinoethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

4. The quinazoline derivative of the formula I as claimed in claim 1 selected from:

4-(3-chloro-4-fluoroanilino)-7-(3-furyl)quinazoline,

4-(3-chloro-4-fluoroanilino)-7-(3-thienyl)quinazoline and

4-(3-chloro-4-fluoroanilino)-7-(5-morpholinomethylthien-3-yl)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

5. A process for the preparation of a quinazoline compound of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4 which comprises:

(a) the reaction of a quinazoline of the formula III ##STR7## wherein Z is a displaceable group, with an aniline of the formula Q² --NH₂ ;

(b) the reaction of a quinazoline of the formula IV ##STR8## wherein Z is a displaceable group, with an organoboron reagent of the formula Q¹ --B(L¹)(L²) wherein each L¹ and L², which may be the same or different, is a suitable ligand;

(c) the reaction of a quinazoline of the formula V ##STR9## wherein each of L¹ and L², which may be the same or different, is a suitable ligand, with a compound of the formula Q¹ --Z wherein Z is a displaceable group;

(d) for the production of those compounds of the formula I which possess an aminomethyl substituent, the reduction of a compound of the formula I which possesses a cyano substituent;

or

(e) for the production of those compounds of the formula I which possess an amino substituent, the reduction of a compound of the formula I which possesses a nitro substituent;

and when a pharmaceutically-acceptable salt of a quinazoline compound of the formula I is required it may be obtained by reaction of said compound using a conventional procedure.

6. A pharmaceutical composition which comprises a quinazoline compound of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4 in association with a pharmaceutically-acceptable diluent or carrier.

7. A method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline compound of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4.