Chemical compounds

• US 6,258,951 B1
• Filed: 02/09/2000
• Issued: 07/10/2001
• Est. Priority Date: 12/18/1995
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC), Zeneca Pharma S.A. (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre, Thomas, Andrew Peter, Lohmann, Jean-Jacques Marcel
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US09/500,470
• Time in Patent Office: 517 Days
• Field of Search: 514/259, 544/283, 544/284, 544/287, 544/288, 544/293
• US Class Current: 544/283
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 239/88 Oxygen atoms
• 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 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 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 relates to quinazoline derivatives of the formula:

and salts thereof; processes for their preparation and pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient.

The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Claims

1. A quinazoline derivative of the formula Ia:

wherein;

Y¹ represents —

O—

, —

NH—

, —

S—

or —

CH₂—

;

n is an integer from 0 to 5;

X¹ represents a phenyl group or a 5- or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl or heterocyclic group may carry up to 5 substituents selected from halogeno, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4hydroxyalkoxy, carboxy, cyano, —

CONR⁴¹R⁴² and —

NR⁴³COR⁴⁴,

wherein R⁴¹, R⁴², R⁴³ and R⁴⁴, which may be the same or different, each represents hydrogen or C_1-4alkyl;

R¹ represents hydrogen, hydroxy, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or NR⁴⁵R⁴⁶,

wherein R⁴⁵ and R⁴⁶, which may be the same or different, each represents hydrogen or C_1-3alkyl;

R² represents hydrogen, hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, trifluoromethyl, cyano, amino or nitro;

m is an integer from 1 to 5;

R³ represents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

Z represents —

NH—

; and

Y⁶ represents a direct bond; and

salts thereof.