Quinazoline derivatives

• US 5,942,514 A
• Filed: 09/26/1997
• Issued: 08/24/1999
• 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): Ford, John M.
• Application Number:
  US08/930,043
• Time in Patent Office: 697 Days
• Field of Search: 544/293, 514/259
• US Class Current: 514/266.4
• 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 quinazoline derivatives of formula wherein n is 1, 2 or 3 and each R² is independently halogeno; and R¹ is 1-4C)alkoxy-(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 quinazoline derivative of the formula I ##STR4## wherein n is 1, 2 or 3 and each R² is independently halogeno;

and R¹ is (1-4C)alkoxy-(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'"'"'-fluoro, 3'"'"'-chloro, 3'"'"'-bromo, 2'"'"',4'"'"'-difluoro, 2'"'"',4'"'"'-dichloro, 3'"'"',4'"'"'-difluoro, 3'"'"',4'"'"'-dichloro, 3'"'"'-fluoro-4'"'"'-chloro or 3'"'"'-chloro-4'"'"'-fluoro;

and

R¹ is 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino or

3-ethoxypropylamino;

or a pharmaceutically-acceptable acid-addition salt thereof.

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

4-(2'"'"',4'"'"'-difluoroanilino)-6-(2-methoxyethylamino)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

8. 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 1-2, 4-7 and 3 which comprises:

(a) the reaction of a quinazoline of the formula II ##STR6## wherein Z is a displaceable group, with an aniline of the formula III ##STR7## (b) the alkylation of a quinazoline derivative of the formula I wherein R¹ is amino;

(c) the reductive amination of an alkoxy-substituted aldehyde with a compound of the formula I wherein R¹ is amino;

(d) the alkylation of a compound of the formula I wherein R¹ is a hydroxy-substituted alkylamino group;

or

(e) the reduction of a compound of the formula I wherein R¹ is an alkoxy-substituted alkanoamido group;

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

9. 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 1-2, 4-7 and 3 in association with a pharmaceutically-acceptable diluent or carrier.

3. A quinazoline derivative of the formula I ##STR5## wherein (R²)_n is 3'"'"',4'"'"'-difluoro or 3'"'"'-chloro-4'"'"'-fluoro;

and R¹ is 2-methoxyethylamino or 3-methoxypropylamino;

or a pharmaceutically-acceptable acid-addition salt thereof.

4. The quinazoline derivative of the formula I as claimed in claim 3 being:

4-(3'"'"'-chloro-4'"'"'-fluoroanilino)-6-(3-methoxypropylamino)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

5. The quinazoline derivative of the formula I as claimed in claim 3 being:

4-(3'"'"',4'"'"'-difluoroanilino)-6-(2-methoxyethylamino)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

6. The quinazoline derivative of the formula I as claimed in claim 3 being:

4-(3'"'"'-chloro-4'"'"'-fluoroanilino)-6-(2-methoxyethylamino)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.