Quinazoline derivatives as VEGF inhibitors

• US 6,184,225 B1
• Filed: 08/13/1998
• Issued: 02/06/2001
• Est. Priority Date: 02/13/1996
• 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
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): SCHROEDER, THOMAS B
• Application Number:
  US09/125,271
• Time in Patent Office: 908 Days
• Field of Search: 544/245, 544/287, 544/293, 514/259
• US Class Current: 514/234.5
• 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 37/02 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 239/88 Oxygen atoms
• CPC Class Codes: C07D 239/93 Sulfur atoms
• CPC Class Codes: C07D 239/94 Nitrogen atoms

Abstract

The invention relates to quinazoline derivatives of formula (I)

wherein: Z represents —O—, —NH— or —S—; m is an integer from 1 to 5; R¹ represents hydrogen, hydroxy, halogeno, nitro, trifluorometlyl, 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—, —NR⁶—, NR⁸CO—, —CONR⁹—SO₂NR¹⁰— or —NR¹¹SO₂—, (wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ each represents C_1-3alkyl, C_1-3alkoxyC_2-3alkyl); R⁴ represents 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 5 or 6 membered saturated carbocylic 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 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 compound of the formula I:

wherein;

Z represents —

O—

, —

NH—

or —

S—

;

m is an integer from 1 to 5 with the proviso that where Z is —

NH—

m is an integer from 3 to 5;

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—

, —

S—

, —

SO—

, —

SO₂—

, —

NR⁷—

, —

NR⁸CO—

, —

CONR⁹—

, —

SO₂NR¹⁰—

or —

NR¹¹SO₂—

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

R⁴ is selected from one of the following seven groups;

1) hydrogen, C_1-5hydroxyalkyl, C_1-5fluoroalkyl, C_1-5 aminoalkyl;

2) C_1-5alkylX²COR¹² (wherein X² represents —

O—

or —

NR¹³—

(in which R¹³ represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R¹² represents C_1-3alkyl, —

NR¹⁴R¹⁵ or —

OR¹⁶ (wherein R¹⁴, R¹⁵ and R¹⁶ which may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));

3) C_1-5alkylX³R¹⁷ (wherein X³ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR¹⁸CO—

, —

CONR¹⁹—

, —

SO₂NR²⁰, —

NR²¹SO₂—

or —

NR²²—

(wherein R¹⁸, R¹⁹, R²⁰, R²¹ and R²² each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R¹⁷ represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy);

4) C_1-5alkylR²³ (wherein R²³ 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 and C_1-4alkoxy);

5) C_2-5alkenylR²³ (wherein R²³ is as defined hereinbefore);

6) C_2-5alkynylR²³ (wherein R²³ is as defined hereinbefore); and

7) C_1-5alkylX⁴C_1-5alkylX⁵R²⁴ (wherein X⁴ and X⁵ which may be the same or different are each —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR²⁵CO—

, —

CONR²⁶—

, —

SO₂NR²⁷—

, —

NR²⁸SO₂—

or —

NR²⁹—

(wherein R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁴ represents hydrogen or C_1-3alkyl);

and salts thereof.

2. The compound as claimed in claim 1 wherein R¹ is hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy, or ethoxy.

3. The compound as claimed in claim 1 wherein R² is hydrogen.

4. The compound as claimed in claim 1 wherein the phenyl group bearing (R³)_m is of the formula II:

wherein;

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

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

R^c represents hydrogen or hydroxy; and

R^d represents hydrogen, fluoro or chloro.

5. The compound as claimed in claim 1 wherein Z is NH.

6. The compound as claimed in claim 1 wherein Z is —

O—

.

7. The compound as claimed in claim 1 wherein X¹ represents —

O—

, —

S—

, —

NR⁸CO—

, —

NR¹¹SO₂—

(wherein R⁸ and R¹¹ each independently represents hydrogen or C_1-2alkyl) or NH.

8. The compound as claimed in claim 1 wherein R⁴ is selected from one of the following nine groups:

1) C_2-5hydroxyalkyl, C_1-5fluoroalkyl;

2) C_2-3alkylX²COR¹² (wherein X² is as defined in claim 1 and R¹² represents C_1-3alkyl, —

NR¹⁴R¹⁵ or —

OR¹⁶ (wherein R¹⁴, R¹⁵ and R¹⁶ which may be the same or different are each C_1-2alkyl or C_1-2alkoxyethyl));

3) C_2-4alkylX³R¹⁷ (wherein X³ is as defined in claim 1 and R¹⁷ is a group selected from C_1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X³ through a carbon atom and which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);

4) C_1-4alkylR³⁰ (wherein R³⁰ is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C-₄alkyl through a carbon atom and which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy) or C_2-4alkylR³¹ (wherein R³¹ is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);

5) C_3-4alkenylR³⁰ (wherein R³⁰ is as defined herein);

6) C_3-4alkynyl³⁰ (wherein R³⁰ is as defined herein);

7) C_3-4alkenyl³¹ (wherein R³¹ is as defined herein);

8) C_3-4alkynylR³¹ (wherein R³¹ is as defined herein); and

9) C_2-3alkylX⁴C₂₃alkylX⁵R²⁴ (wherein X⁴ and X⁵ are as defined in claim 1 and R²⁴ represents hydrogen or C_1-3alkyl).

9. The compound as claimed in claim 1 wherein R⁴ is selected from one of the following five groups:

1) C_2-3hydroxyalkyl, C_1-3fluoroalkyl;

2) 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;

3) C_2-3alkylX³R¹⁷ (wherein X³ is as defined in claim 1 and R¹⁷ is a group selected from C_1-2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X³ through a carbon atom and which C_1-2alkyl group may bear one or two substituents selected from hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);

4) C_1-2alkylR³⁰ (wherein R³⁰ is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-2alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy) or. C_2-3alkylR³¹ (wherein R³¹ is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and-C_1-2alkoxy); and

5) C_2-3alkylX⁴C_2-3alkylX⁵R²⁴ (wherein X⁴ and X⁵ are as defined in claim 1 and R²⁴ represents hydrogen or C_1-2alkyl).

10. The compound as claimed in claim 1 wherein R⁴ represents trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl or 2-(2-methoxyethoxy)ethyl.

11. The compound as claimed in claim 1 wherein R⁴ represents 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl or 2-(2-methoxyethoxy)ethyl.

15. The compound as claimed in any one of claims 1, 12, 13 and 14 in the form of a pharmaceutically acceptable salt.

16. A process for the preparation of a compound 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 Z, 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, R⁴ and Z 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 —

O—

, —

S—

or —

NR⁷—

, (wherein R⁷ is as defined in claim 1), the reaction of a compound of the formula VI;

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

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

18. 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.

12. A compound selected from the group consisting of:

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline;

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyacetamidoquinazoline;

4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline;

and salts thereof.

13. A compound selected from the group consisting of:

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline;

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthioethoxy)quinazoline;

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline;

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline;

7-(2-acetoxyethoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline;

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-morpholinoethoxy)quinazoline;

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-piperidinoethoxy)quinazoline;

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethylamino)quinazoline;

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-cyclopentyloxyethoxy)quinazoline;

4-(2,4-difluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline;

and salts thereof.

14. A compound selected from the group consisting of:

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline;

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline;

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-hydroxyethoxy)-6-dimethoxyquinazoline;

4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline;

4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinazoline;

4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-(methylsulphinyl)ethoxy)quinazoline;

and salts thereof.