QUINAZOLINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

• US 20110071144A1
• Filed: 04/23/2010
• Published: 03/24/2011
• Est. Priority Date: 09/25/1996
• Status: Abandoned Application

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Inventors: Johnstone, Craig, Clayton, Edward, Stokes, Elaine Sophie Elizabeth, Lohmann, Jean-Jacques Marcel, THOMAS, Andrew Peter, Hennequin, Laurent Francois Andre
• Application Number:
  US12/766,106
• Publication Number:
  US 20110071144A1
• Time in Patent Office: Days
• US Class Current: 514/228.2
• 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 (1)

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:

2. A quinazoline derivative as claimed in claim 1 wherein R¹ represents 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 any one of the preceding claims wherein the phenyl group bearing (R³)_m is of the formula II:

5. A quinazoline derivative as claimed in any one of the preceding claims wherein X¹ represents —

O—

, —

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 any one of the preceding claims wherein R⁴ is 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) 1-R⁴⁶prop-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, 1-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-R⁴⁸prop-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_1-3 alkoxycarbonyl);

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_1-3alkylX³R¹⁶;

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 R³³ 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 is 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-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 that X¹ cannot be —

CH₂—

when R⁴ is C_2-3alkylX²C_1-3alkylX³R¹⁶;

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-(isopropoxycarbonylamino)ethyl, 3-(isopropoxycarbonylamino)propyl, 2-(isobutoxycarbonylamino)ethyl, 3-(isobutoxycarbonylamino)propyl, 2-(t-butoxycarbonylamino)ethyl or 3-(t-butoxycarbonylamino)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:

9. A quinazoline derivative as claimed in claim 1 selected from:

—

4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-yn-1-yloxy)quinazoline,

(E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-7-(3-(2,6-dimethylmorpholino)propoxy)-6-methoxyquinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)propoxy)quinazoline,

7-(2-[N-tert-butoxycarbonylamino]ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline,

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)propoxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxoimidazolidin-1-yl)ethoxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline,

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline,

(S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-6-methoxyquinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline,

(S)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline and

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline

and salts thereof.

10. A quinazoline derivative as claimed in claim 1 selected from:

—

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-2-(2-methoxyethoxy)ethoxyquinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline,

4-(4-bromo-2-fluoroanilino)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline,

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropylthio)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([N-methyl-N-methoxyacetyl]amino)ethoxy)quinazoline and

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline

and salts thereof.

11. A quinazoline derivative as claimed in claim 1 selected from:

—

(E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline,

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline,

(S)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline and

(R)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline

and salts thereof.

12. A quinazoline derivative as claimed in claim 1 selected from:

—

4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline and salts thereof.

13. A quinazoline derivative as claimed in any one of the preceding claims in the form of a pharmaceutically acceptable salt.

14. 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;

15. A pharmaceutical composition which comprises as active ingredient a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

16. 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 claim 1.