Chemical compounds

• US 6,362,336 B1
• Filed: 06/11/2001
• Issued: 03/26/2002
• 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.
• Inventors: Hennequin, Laurent Francois Andre, Thomas, Andrew Peter, Lohmann, Jean-Jacques Marcel
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US09/877,005
• Publication Number:
  US 20020032208A1
• Time in Patent Office: 288 Days
• Field of Search: 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:

[wherein:

Y¹ represents —O—, —S—, —CH₂—, —SO—, —SO₂—, —NR⁵CO—, —CONR⁶—, —SO₂NR⁷—, —NR⁸SO₂— or —NR⁹— (wherein R⁵, R⁶, R⁸ and R⁹ each independently represents hydrogen, alkyl or alkoxyalkyl);

R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, alkyl, alkoxy, alkylthio, amino or alkylamino.

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

m is an integer from 1 to 5;

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

R⁴ represents a group which is or which contains an optionally substituted pyridone, phenyl or aromatic heterocyclic group] 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 process for the preparation of a quinazoline derivative of formula I, or a salt thereof:

wherein;

Y¹ represents —

O—

, —

S—

, —

CH₂—

, —

SO—

, —

SO₂—

, —

NR⁵CO—

,—

CONR⁶—

, —

SO₂NR⁷—

, —

NR⁸SO₂—

or —

NR⁹—

,

wherein R⁵, R⁶, R⁷, R⁸ and R⁹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl;

R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or NR¹⁰R¹¹,

wherein R¹⁰ and R¹¹, 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;

R⁴ is selected from one of the following eight groups;

1) X¹, wherein X¹ represents a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from 0, N and S, which pyridone, phenyl or heterocyclic group may carry up to 5 substituents selected from halogeno, amino, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4aminoalkyl, C_1-4alkylamino, C_1-4hydroxyalkoxy, carboxy, cyano, —

CONR¹²R¹³ and —

NR¹⁴COR¹⁵,

wherein R¹², R¹³, R¹⁴ and R¹⁵, which may be the same or different, each represents hydrogen, C_1-4alkyl or C_1-3alkoxyC_2-3alkyl;

2) C_1-5alkylX¹, wherein X¹ is as defined hereinbefore;

3) C_2-5alkenylX¹, wherein X¹ is as defined hereinbefore;

4) C_2-5alkynylX¹, wherein X¹ is as defined hereinbefore;

5) C_1-5alkylY²X¹, wherein Y² represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR¹⁶CO—

, CONR¹⁷—

, —

SO₂NR¹⁸—

, —

NR¹⁹SO₂—

or —

NR²⁰—

,

wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl, and X¹ is as defined hereinbefore;

6) C_2-5alkenylY³X¹, wherein Y³ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR²¹CO—

, —

CONR²²—

, —

SO₂NR²³—

, —

NR²⁴SO₂—

or —

NR²⁵—

,

wherein R²¹, R²², R²³, R²⁴, and R²⁵ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and X¹ is as defined hereinbefore;

7) C_2-5alkynylY⁴X¹, wherein Y⁴ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR²⁶CO—

, —

CONR²⁷—

, —

SO₂NR²⁸—

, —

NR²⁹SO₂—

or —

NR₃₀—

,

wherein R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl, and X¹ is as defined hereinbefore; and

8) C_1-3alkylY⁵C_1-3alkylX¹, wherein Y⁵ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR³¹CO—

, —

CONR³²—

, —

SO₂NR³³—

, —

NR³⁴SO₂—

or —

NR³⁵—

,

wherein R³¹, R³², R³³, R³⁴ R³⁵ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl, and X¹ is as defined hereinbefore;

Z represents —

NH—

, —

O—

, —

S—

, or —

CH₂—

;

with the proviso that where R⁴ is selected from one of the groups

     1),

     2), and

     5) above and X¹ is unsubstituted phenyl or substituted phenyl with 1 to 2 substituents selected from halogeno, C_1-4alkyl and C_1-4alkoxy, then m is an integer from 3 to 5 and/or Z is —

O—

, S—

, or —

CH₂—

;

which process comprises;

(a) the reaction of a compound of the formula III;

 

wherein R¹, R², R⁴ and Y¹ are as defined above and L¹ is a displaceable group, with a compound of the formula IV;

 

wherein Z, R³ and m are as defined above, whereby to obtain compounds of the formula I and salts thereof;

(b) for the preparation of compounds of formula I and salts thereof in which the group of formula IIb;

 

represents a phenyl group carrying one or more hydroxy groups, the deprotection of a compound of formula V;

 

wherein Y¹, m, R¹, R², R³, R⁴ and Z are as defined above, P represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that m−

p¹ is equal to the number of R³ substituents which are not protected hydroxy;

(c) for the preparation of those compounds of formula I and salts thereof wherein the substituent Y¹ is —

O—

, —

S—

or —

NR⁹—

, the reaction, of a compound of the formula VI;

 

wherein m, Y¹, R¹, R², R³ and Z are as defined above, with a compound of formula VII;