Quinazoline derivatives and pharmaceutical compositions containing them

• US 6,673,803 B2
• Filed: 02/25/2002
• Issued: 01/06/2004
• Est. Priority Date: 09/25/1996
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre, Johnstone, Craig, Thomas, Andrew Peter, Stokes, Elaine Sophie Elizabeth, Lohmann, Jean-Jacques Marcel
• Primary Examiner(s): Ford; John M.
• Assistant Examiner(s): Patel; Sudhaker B.
• Application Number:
  US10/080,716
• Publication Number:
  US 20020173646A1
• Time in Patent Office: 680 Days
• Field of Search: 514/266,266.4,231.5,228.2 544/28,284,293,106,56,59,62
• US Class Current: 514/263.4
• CPC Class Codes: A61F 13/02 Adhesive bandages or dressings
• CPC Class Codes: A61F 13/023 wound covering film layers without a fluid retention layer
• CPC Class Codes: A61F 2013/00221 biodegradable, non-irritating
• CPC Class Codes: A61F 2013/8408 with odour control
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 405/12 : 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 formula (I)

wherein m is an integer from 1 to 2; R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, or —NR⁵R⁶ (wherein R⁵ and R⁶, which may be the same or different, each represents hydrogen or C_1-3alkyl); R² represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R³ represents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X¹ represents —O—, CH₂—, —S—, —SO—, —SO₂—, —NR⁷CO—, —CONR⁸—, —SO₂NR⁹—, —NR¹⁰SO₂— or —NR¹¹— (wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);R⁴ represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and 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 I:

wherein;

m is an integer from 1 to 2;

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

NR⁵R⁶ (wherein R⁵ and R⁶, which may be the same or different, each represents hydrogen or C_1-3alkyl);

R² represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;

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

X¹ represents —

CH₂—

, —

S—

, —

SO—

, —

SO₂—

, —

NR⁷CO—

, —

CONR⁸—

, —

SO₂NR⁹—

, —

NR¹⁰SO₂—

or —

NR¹¹—

(wherein R⁷, R⁸, R⁹, R¹⁰, and R¹¹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

R⁴ is selected from one of the following twelve groups;

1) C_1-5alkylR¹² (wherein R¹² is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C_1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl) or C_1-5alkylR¹³ (wherein R¹³ is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl);

2) C_2-5alkenylR¹⁴ (wherein R¹⁴ is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl);

3) C_2-5alkynylR¹⁵ (wherein R¹⁵ is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl);

4) C_1-5alkylX²C_1-5alkylX³R¹⁶ (wherein X² and X³ which may be the same or different are each —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹⁷CO—

, —

CONR¹⁸—

, —

SO₂NR¹⁹—

, —

NR²⁰SO₂—

or —

NR²¹—

(wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R¹⁶ represents hydrogen or C_1-3alkyl) with the proviso that X¹ cannot be —

CH₂—

when R⁴ is C_1-5alkylX²C_1-5alkylX³R¹⁶;

5) C_1-5alkylX⁴COR²² (wherein X⁴ represents —

O—

or —

NR—

(wherein R represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²² represents —

NR²⁴R²⁵ or —

OR²⁶ (wherein R²⁴, R²⁵ and R²⁶ which may be the same or different each represents hydrogen, C_1-4alkyl or C_1-3alkoxyC_2-3alkyl));

6) C_{1-5 alkylX}⁵R²⁷ (wherein X⁵ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR²⁸CO—

, —

CONR²⁹—

, —

SO₂NR³⁰—

, —

NR³¹SO₂—

or —

NR³² —

(wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) or X⁵ is carbonyl, and R²⁷ represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, carbamoyl, C_1-4 alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl or R²⁷ is C_1-3alkyl with the proviso that when R²⁷ is C_1-3alkyl, X⁵ is —

S—

, —

SO—

, —

SO₂—

, —

SO₂NR³⁰—

or —

NR³¹SO₂— and

X¹ is not —

CH₂—

);

7) C_1-3alkoxyC_2-4alkyl provided that X¹ is —

S—

, —

SO—

or —

SO₂—

;

8) C_1-5alkylX⁶C_1-5alkylR³³ (wherein X⁶ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR³⁴CO—

, —

CONR³⁵—

, —

SO₂NR³⁶—

, —

NR³⁷SO₂—

or —

NR³⁸—

(wherein R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R³³ represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl);

9) R³⁹ (wherein R³⁹ is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl);

10) C_1-5alkylR₄₀ (wherein R₄₀ is piperazin-1-yl which bears at least one substituent selected from C_1-4alkanoyl, C_1-4alkoxycarbonyl, C_1-4hydroxyalkyl and —

CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each independently represents hydrogen or C_1-4alkyl);

11) C_1-5alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or two substituents selected from oxo, C_1-4alkyl, C_1-4hydroxyalkyl, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl) with the proviso that when R⁴ is C_1-5alkylR⁴³, X¹ is —

S—

, —

SO—

, —

SO₂—

, —

SO₂NR⁹—

or —

NR¹⁰SO₂—

; and

12) C_1-5alkylR⁴⁴ (wherein R⁴⁴ is morpholino which bears at least one and optionally two substituents selected from oxo, C_1-4alkyl, C_1-4hydroxyalkyl, carbamoyl, C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, C_1-4alkanoyl and C_1-4alkoxycarbonyl); and

salts thereof.

2. A quinazoline derivative as claimed in claim 1 wherein R¹ hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.

3. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R² is hydrogen.

4. A quinazoline derivative as claimed in claim 1 or claim 2 wherein the phenyl group bearing (R³)m is of the formula II:

wherein;

R^a represents hydrogen, methyl, fluoro or chioro;

R^b represents hydrogen, methyl, methoxy, bromo, fluoro or chloro;

R^c represents hydrogen or hydroxy;

R^d represents hydrogen, fluoro or chloro.

5. A quinazoline derivative as claimed in claim 1 or claim 2 wherein X¹ represents —

S—

, —

NR⁷CO—

, —

NR¹⁰SO₂—

or —

NR¹¹—

(wherein R⁷, R¹⁰ and R¹¹ each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl).

6. A quinazoline derivative as claimed in claim 1 or claim 2 wherein R⁴ selected from one of the following eleven groups:

1) C_1-4alkylR¹² (wherein R¹² is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl) or C_2-4alkylR⁴⁵ (wherein R45 is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl);

2) 1R⁴⁶prop-1-en-3-yl, 1-R⁴⁶but-2-en-4-yl, 1-R⁴⁶but-1-en-3-yl, 1-R⁴⁶pent-2-en-4-yl or 2-R⁴⁶pent-3-en-5-yl (wherein R⁴⁶ is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl) or 1-R₄₇but-2-en-4-yl, l-R⁴⁷pent-2-en-4-yl or 2-R⁴⁷pent-3-en-5-yl (wherein R⁴⁷ is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl);

3) 1-R⁴⁸ prop-1-yn-3-yl, 1-R⁴⁸but-2-yn-4-yl, 1-R⁴⁸but-1-yn-3-yl, 1-R⁴⁸pent-2-yn-4-yl or 2-R⁴⁸pent-3-yn-5-yl (wherein R⁴⁸ is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl) or 1-R⁴⁹but-2-yn-4-yl, 1-R⁴⁹pent-2-yn-4-yl or 2-R⁴⁹pent-3-yn-5-yl (wherein R⁴⁹ is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl);

4) C_2-3alkylX²C_1-3alkylX³R¹⁶ (wherein X² and X³ are as defined in claim 1 and R¹⁶ represents hydrogen or C_1-3alkyl) with the proviso that X¹ cannot be —

CH₂—

when R⁴ is C_2-3alkylX²C_1-3alkylX³R^16;

5) C_2-3alkylX⁴COR²² (wherein X⁴ is as defined in claim 1 and R²² represents —

NR²⁴R²⁵ or —

OR²⁶ (wherein R²⁴, R²⁵ and R²⁶ which may be the same or different each represents hydrogen, C_1-4alkyl or C_1-2alkoxyethyl));

6) C_2-3alkylX⁵R²⁷ (wherein X⁵ is as defined in claim 1 and R²⁷ represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X⁵ through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl or R²⁷ is C_1-3alkyl with the proviso that when R²⁷ is C_1-3alkyl, X⁵ is —

S—

, —

SO—

, —

SO₂—

, —

SO₂NR³⁰—

or —

NR³¹SO₂— and

X¹ is not —

CH₂—

);

7) C_1-2alkoxyC_2-3alkyl provided that X¹ is —

S—

, —

SO—

or —

SO₂—

;

8) C_2-3alkylX⁶C_2-3alkylR³³ (wherein X⁶ is as defined in claim 1 and R represents a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl, and C_1-3alkoxycarbonyl);

9) C_2-3alkylR⁴⁰ (wherein R⁴⁰ is piperazin-1-yl which bears at least one substituent selected from acetyl, C_1-2alkoxycarbonyl, C_1-2hydroxyalkyl and CONR⁴¹R⁴² (wherein R⁴¹ and R⁴² each independently represents hydrogen or C_1-2alkyl);

10) C_2-3alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or two substituents selected from oxo, C_1-2alkyl, C_1-2hydroxyalkyl, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl) with the proviso that when R⁴ is C_2-3alkylR⁴³, X¹ is —

S—

, —

SO—

, —

SO₂—

, —

SO₂NR⁹—

or —

NR¹⁰SO₂—

; and

11) C_2-3alkylR⁴⁴ (wherein R⁴⁴ is morpholino which bears at least one and optionally two substituents selected from oxo, C_1-2alkyl, C_1-2hydroxyalkyl, carbamoyl, C_1-2alkylcarbamoyl N N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl).

7. A quinazoline derivative as claimed in claim 6 wherein R⁴ selected from one of the following nine groups:

1) C_1-3alkylR¹² (wherein R¹² is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl) or C_2-3alkylR⁴⁵ (wherein R⁴⁵ is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl);

2) 1-R⁵⁰but-2-en-4-yl (wherein R⁵⁰ is a group selected from imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino and piperidino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl);

3) 1-R⁵¹but-2-yn-4-yl (wherein R⁵¹ is a group selected from imidazolidin-1-yl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazin-1-yl, morpholino, thiomorpholino and piperidino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl);

4) C_2-3alkylX²C_1-3alkylX³R¹⁶ (wherein X² and X³ are as defined in claim 1 and R¹⁶ represents hydrogen or C_1-3alkyl) with the proviso thatX¹ cannot be —

CH₂—

when R⁴ is C_2-3alkylX²C_{1-3 alkylX}³R¹⁶;

5) C_1-2alkoxyC_2-3alkyl provided that X¹ is —

S—

, —

SO—

or —

SO₂—

;

6) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2(N,N-dimethylcarbamoyloxy)ethyl, 3-(N,N-dimethylcarbamoyloxy)propyl, 2(N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl, 2-(1,3,3-trimethylureido)ethyl, 3-(1,3,3-trimethylureido)propyl, 2- (isopropoxycarboylamino)ethyl, 3 (isopropoxycarbonylamino)propyl, 2-(isobutoxycarbonylamino)ethyl, 3 (isobutoxycarbonylamiflo)propyl, 2-(t-butoxycarbonylamino)ethyl or 3(t-butoxycarbonylamiflo)propyl;

7) C_2-3alkylX⁵R²⁷ (wherein R²⁷ is C_1-2alkyl and X⁵ is —

S—

, —

SO—

, —

SO₂—

, —

SO₂NR³⁰—

or —

NR³¹SO₂— and

with the proviso that X¹ is not —

CH₂—

);

8) C_2-3alkylX⁶C_2-3alkylR³³ (wherein X⁶ is as defined in claim 1 and R³³ represents a group selected from morpholino, 2-oxopyrrolidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl) and

9) C_2-3alkylR⁴³ (wherein R⁴³ is morpholino which may bear one or two substituents selected from oxo, C_1-2alkyl, C_1-2hydroxyalkyl, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl) with the proviso that when R⁴ is C_2-3alkylR⁴³, X¹ is —

S—

, —

SO—

, —

SO₂—

, —

SO₂NR⁹—

or —

NR¹⁰SO₂—

.

8. A compound as claimed in claim 1 of the formula Ia:

wherein;

R^1a is hydrogen or methoxy;

R^2a is hydrogen;

the phenyl group bearing (R^3a)_ma is the 4-chloro-2-fluoropheiiyl group or the 4-bromo-2-fluoropheiiyl group;

X^1a is —

S—

, —

NR^5aCO—

or —

NR^6aSO₂—

(wherein R^5a and R^6a each independently represents hydrogen or C_1-2alkyl);

R^4a is selected from one of the following eleven groups;

1) C_1-4alkylR^7a (wherein R^7a is a group selected from 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, 1,3-dithian-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl and piperazin-2-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamOyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl) or C_2-4alkylR^8a (wherein R^8a is a group selected from imidazolidin-1-yl, pyrrolidin-1-yl and thiomorpholino which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl)

2) 1-R^9aprop-1-en-3-yl, 1-R^9abut-2-en-4-yl, 1-R^9abut-1-en-3-yl,1-R^9apent-2-en-4-yl or 2-R^9apent-3-en-5-yl (wherein R^9a is embered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl) or 1-R^10abut-2-en-4-yl, 1-R^10apent-2-en-4-yl or 2-R^10apent-3-en-5-yl(wherein R^10a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkenyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl);

3) 1-R^11aprop-1-yn-3-yl, 1-R^11abut-2-yn-4-yl, 1-R^11abut-1-yn-3-yl, 1-R^11apent-2-yn-4yl or 2-R^11apent-3-yn-5-yl(wherein R^11a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl) or 1-R^12abut-2-yn-4-yl, R^12apent-2yn-5-yl(wherein R^12a is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to the alkynyl group through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl and C_1-3alkoxycarbonyl)

4) C_2-3alkylX^2aC_1-3alkylX^3aR^13a(wherein X^2a and X^3a which may be the same or different each represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^14aCO—

, or —

NR^15a—

(wherein R^14a and R^15a each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl) and R^13a represents hydrogen or C_1-3alkyl);

5) C_2-3alkylX^4aCOR^16a (wherein R^17arepresents hydrogen, C_1-3alkyl or C_1-2alkoxyethyl) and R^16a represents —

NR^18aR^19aor —

OR^20a (wherein R^18a, R^19a and R^20a which maybe the same or different each represents hydrogen, C_1-4alkyl or C_1-2alkoxyethyl));

6) C_2-3alkylX^5aR^21a (wherein X^5a represents carbonyl, —

O—

, —

S—

, —

SO—

, —

SO₂—

, NR^22aCO—

, —

NR^23aSO₂—

or —

NR^24a—

(wherein R^22a, R^23a and R^24a each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl) and R^21a represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X^5a through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl, C_1-2alkoxy, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl or R^21a is C_1-3alkyl with the proviso that when R^21a is C_1-3alkyl, X^5a is —

S—

, —

SO—

, —

SO₂—

or —

NR^23aSO₂—

);

7) C_1-2alkoxy C_2-3alkyl provided that X^1a is —

S—

;

8) C_2-3alkyX^6aC_{2-3 alkylR}^25a (wherein X^6a represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^26aCO—

, —

NR^27aSO₂—

or —

NR^28a—

(wherein R^26aR^27a and R^28a each independently represents hydrogen, C_1-2alkyl or C_1-2alkoxyethyl) and R^25a represents a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, carbamoyl, C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, C_2-3alkanoyl, and C_1-3alkoxycarbonyl);

9) C_2-3 alkylR^29a (wherein R^29a is piperazin-1-yl which bears at least one sub stituent selected from acetyl, C_1-2alkoxycarbonyl, C_1-2hydroxyalkyl and CONR^30a R^31a (wherein R^30a and R^31a each independently represents hydrogen or C_1-2alkyl);

10) C_2-3alkylR^32a (wherein R^32ais morpholino which may bear one or two substituents selected from oxo, C_1-2alkyl, C_1-2hydroxyalkyl, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl) with the proviso that when R^4a is C_2-3alkylR^32a, X^1a is —

S—

or —

NR^6aSO₂—

(wherein R^6a is as defined herein); and

11) C_2-3alkylR^33a (wherein R^33a is morpholino which bears at least one and optionally two substituents selected from oxo, C_1-2alkyl, C_1-2hydroxyalkyl, carbamoyl, C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, acetyl and C_1-2alkoxycarbonyl); and

salts thereof.

9. A quinazoline derivative as claimed in claim 1 selected from 4-(4-chloro-2-fluroanilino)-6-methoxy-7(3-morpholionopropylthio)quinazoline and salts thereof.

10. A quinazoline derivative as claimed in any one of claims 1, 2, 8 and 9 in the form of a pharmaceutically acceptable salt.

11. A process for the preparation of a quinazoline derivative of formula I or salt thereof (as defined in claim 1) which comprises:

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

(wherein R¹, R², X¹ and R⁴ are as defined in claim 1 and L¹ is a displaceable moiety), with a compound of the formula IV;

(wherein R³ and m are as defined in claim 1) 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 IIa;

(wherein R³ and m are as defined in claim 1) represents a phenyl group carrying one or more hydroxy groups, the deprotection of a compound of formula V;

(wherein X¹, m, R¹, R², R³ and R⁴ are as defined in claim 1, 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 X¹ is —

S—

, —

NR¹¹—

, —

SO₂NR⁹—

, the reaction of a compound of the formula VI;

(wherein m, X¹, R¹, R² and R³ are as defined in claim 1) with a compound of formula VII;

(wherein R⁴ is as defined in claim 1 and L¹ is as defined herein);

(d) the reaction of a compound of the formula VIII;

with a compound of the formula IX;

12. A pharmaceutical composition which comprises as active ingredient a compound of formula I as defined in any one of claims 1, 2, 8, and 9 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

13. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1, 2, 8, and 9.