Quinazoline derivative

• US 6,015,814 A
• Filed: 09/26/1997
• Issued: 01/18/2000
• Est. Priority Date: 04/27/1995
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Barker, Andrew John
• Primary Examiner(s): Jones, Dwayne C.
• Application Number:
  US08/930,042
• Time in Patent Office: 844 Days
• Field of Search: 544/291, 514/259
• US Class Current: 514/266.2
• 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: C07D 239/94 Nitrogen atoms

Abstract

The invention concerns derivatives of the formula wherein n is 1, 2 or 3 and each R² is independently halogeno; and R¹ is amino-(2-4C)alkylamino, (1-4C)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, or 4-(1-4C) alkylpiperazin-1-yl-(2-4C)alkylamino, or pharmaceutically acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them, and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of proliferative disease such as cancer.

Claims

1. A quinazole derivative of the formula I ##STR7## wherein n is 1, 2 or 3 and each R² is independently halogeno;

and R¹ is 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 or 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino;

or a pharmaceutically-acceptable salt thereof.

2. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R²)_n is 3'"'"'-chloro,3'"'"'-bromo,3'"'"',4'"'"'-difluoro or 3'"'"'-chloro-4'"'"'-fluoro;

and R¹ is 2-methylaminoethylamino,3-methylaminopropylamino,2-dimethylaminoethylamino, 3-dimethylaminopropylamino,2-(pyrrolidin-1-yl)ethylamino,3-(pyrrolidin-1-yl)propylamino, 2-piperidinoethylamino,3-piperidinopropylamino,2-morpholinoethylamino or 3-morpholinopropylamino;

or a pharmaceutically-acceptable acid-addition salt thereof.

3. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R²)_n is 3'"'"',4'"'"'-difluoro or 3'"'"'-chloro-4'"'"'-fluoro;

and R¹ is 3-dimethylaminopropylamino, 3-(pyrrolidin-1-yl)propylamino, 3-piperidinopropylamino or 3-morpholinopropylamino;

or a pharmaceutically-acceptable acid-addition salt thereof.

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

4-(3'"'"'-chloro-4'"'"'-fluoroanilino)-6-[3-(pyrrolidin-1-yl)propylamino]quinazoline;

or a pharmaceutically-acceptable salt thereof.

5. A process for the preparation of a quinazoline derivative 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 II ##STR8## wherein Z is a displaceable group, with an aniline of the formula III ##STR9## (b) for the production of those compounds of the formula I wherein R¹ is an amino-substituted (2-4C)alkylamino group, the alkylation of a quinazoline derivative of the formula I wherein R¹ is an amino group;

and when a pharmaceutically-acceptable salt of a quinazoline derivative of the invention is required it may be obtained by reaction of said compound with a suitable acid using a conventional procedure.

6. A pharmaceutical composition which comprises a quinazoline derivative 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 in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4.

8. A pharmaceutical product comprising a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4 and an additional anti-tumour substance for the conjoint treatment of cancer.

9. A method for producing a Class I receptor tyrosine kinase inhibitory effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4.