RU98117074A

RU98117074A - Quinazoline derivatives and their use as vascular endothelial growth factor inhibitors

Info

Publication number: RU98117074A
Application number: RU98117074/04A
Authority: RU
Inventors: Петер Томас Эндрю; Джонстоун Крэйг; Франсуа Андре Эннекэн Лоран
Original assignee: Зенека Лимитед; Зенека Фарма С.А.
Priority date: 1996-02-13
Filing date: 1997-02-10
Publication date: 2000-07-20

Claims

1. Derivatives of quinazoline of the formula I:

in which Z is —O—, —NH— or —S—;
m is an integer of 1 to 5, provided that when Z is —NH—, m is an integer of 3 to 5;
R ¹ is hydrogen, hydroxy, halogen, nitro, trifluoromethyl, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio or -NR ⁵ R ⁶ (where each of R ⁵ and R ⁶ which may have the same or different meanings, denotes hydrogen or C _1-3 alkyl);
R ² is hydrogen, hydroxy, halogen, methoxy, amino or nitro;
R ³ is hydroxy, halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
X ¹ is —O—, —CH ₂ -, -S-, -SO-, -SO ₂ -, -NR ⁷ -, -NR ⁸ CO-, -CONR ⁹ -, -SO ₂ NR ¹⁰ - or -NR ¹¹ SO ₂ - (where each of R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl;
R ^{4 is} selected in one of the following seven groups which contain: 1) hydrogen, C _1-5 alkyl, C _1-5 hydroxyalkyl (preferably C _2-5 hydroxyalkyl), C _1-5 fluoroalkyl, C _1-5 aminoalkyl; 2) C _1-5 alkyl X ² COR ¹² (where X ² is —O— or —NR ¹³ - (where R ¹³ is hydrogen, C _1-3 alkyl or C _1-3 alkoxy C _2-3 alkyl) and R ¹² is C _1-3 alkyl, —NR ¹⁴ R ¹⁵ or —OR ₁₆ (where each of R ¹⁴ , R ¹⁵ and R ₁₆ , which may have the same or different meanings, is hydrogen, C _1-3 alkyl or C _1-3 alkoxy C _2-3 alkyl); 3) C _1-5 alkylX ³ R ¹⁷ (where X ³ is —O—, —S—, —SO—, —SO ₂ -, -OCO-, -NR ¹⁸ CO-, -CONR ¹⁹ -, -SO ₂ NR ²⁰ -, -NR ²¹ SO ₂ - or -NR ²² - (where R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen, C _1-3 alkyl or C _1-3 alkoxy C _2-3 alkyl) and R ¹⁷ is hydrogen, C _1-3 alkyl, cyclopentyl, cyclohexyl or the 5- or 6-member a saturated heterocyclic group with one or two heteroatoms independently selected from O, S and N, while the C _1-3 alkyl group may have one or two substituents selected from oxo, hydroxy, halogen and C _1-4 alkoxy and the cyclic group may have one or two substituents selected from oxo, hydroxy, halogen, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy); 4) C _1-5 alkyl R ²³ (where R ²³ represents a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms independently selected from O, S and N, which may have one or two substituents selected from oxo, hydroxy, halogen, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy); 5) C _2-5 lkenyl R ²³ (where R ²³ has the above meanings); 6) C _2-5 alkynyl R ²³ (where R ²³ has the above meanings); and 7) C _1-5 alkyl X ⁴ C _1-5 alkyl X ⁵ R ²⁴ (where each of X ⁴ and X ⁵ , which may have the same or different values, means —O—, —S—, —SO—, —SO ₂ -, -NR ²⁵ CO-, -CONR ²⁶ -, -SO ₂ NR ²⁷ -, -NR ²⁸ SO ₂ - or -NR ²⁹ - (where R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ^{29 are} independently from each other are hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl) and R ²⁴ is hydrogen or C _1-3 alkyl)]; or their salts.

2. The quinazoline derivatives of claim 1, wherein R ¹ is hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.

3. Derivatives of quinazoline according to claim 1 or 2, in which R ² denotes hydrogen.

4. Derivatives of quinazoline according to any one of the preceding paragraphs, in which the phenyl group containing (R ³ ) _m has the formula II:

in which R ^a represents hydrogen, methyl, fluorine or chlorine;
R ^b is hydrogen, methyl, methoxy, bromo, fluoro or chloro;
R ^c is hydrogen or hydroxy;
R ^d is hydrogen, fluorine or chlorine.

5. Derivatives of quinazoline according to any one of the preceding claims, wherein Z is NH.

6. Quinazoline derivatives according to any one of the preceding claims, wherein X ¹ is —O—, —S—, —NR ⁸ CO—, —NR ¹¹ SO ₂ -, (where R ⁸ and R ^{11 are} independently hydrogen or C _1-2 alkyl) or NH.

7. Quinazoline derivatives according to any one of the preceding claims, wherein R ^{4 is} selected in one of the following nine groups, comprising: 1) C _1-5 alkyl, C _2-5 hydroxyalkyl, C _1-5 fluoroalkyl, C _2-4 aminoalkyl; 2) C _2-3 alkyl X ² COR ¹² (where X ² has the meanings specified in paragraph 1, and R ¹² is C _1-3 alkyl, —NR ¹⁴ R ¹⁵ or —OR ¹⁶ (where each is R ¹⁴ , R ¹⁵ and R ¹⁶ , which may have the same or different meanings, is C _1-2 alkyl or C _1-2 alkoxyethyl); 3) C _2-4 alkyl X ³ R ¹⁷ (where X ³ has the meanings specified in paragraph 1, and R ¹⁷ is a group selected from C _1-3 alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl, which is attached to X ³ via a carbon atom, while the C _1-3 alkyl group may have one or two substituents selected from oxo, hydroxy, halogen and C _1-2 alkoxy, and the cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may have one substituent selected from oxo, hydroxy, halogen, C _1-2 alkyl, C _1-2 hydroxyalkyl and C _1-2 alkoxy); 4) C _1-4 alkyl R ³⁰ (where R ³⁰ represents 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 is attached to C _1-4 alkyl via a carbon atom and may have one or two substituents selected from oxo, hydroxy, halogen, C _1-2 alkyl, C _{1- 2} hydroxyalkyl and C _1-2 alkoxy) or C _2-4 alkyl R ³¹ (where R ³¹ is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino, which may have one or two substituents selected from oxo, hydroxy , halogen, C _1-2 alkyl, C _1-2 hydroxyalkyl and C _1-2 alkoxy); 5) C _3-4 alkenyl R ³⁰ (where R ³⁰ has the indicated meanings); 6) C _3-4 alkynyl R ³⁰ (where R ³⁰ has the indicated meanings); 7) C _3-4 alkenyl R ³¹ (where R ³¹ has the indicated meanings); 8) C _3-4 alkynyl R ³¹ (where R ³¹ has the indicated meanings); and 9) C _2-3 alkylX ⁴ C _2-3 alkylX ⁵ R ²⁴ (where X ⁴ and X ⁵ are as defined in claim 1, and R ²⁴ is hydrogen or C _1-3 alkyl).

8. Quinazoline derivatives according to any one of the preceding claims, wherein R ^{4 is} selected in one of the following five groups, comprising: 1) C _1-3 alkyl, C _2-3 hydroxyalkyl, C _1-3 fluoroalkyl, C _2-3 aminoalkyl; 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 _2-3 alkyl X ³ R ¹⁷ (where X ³ has the meanings specified in paragraph 1, and R ¹⁷ denotes a group selected from C _1-2 alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl, which is attached to X ³ using a carbon atom, wherein the C _1-2 alkyl group may have one or two substituents selected from hydroxy, halogen and C _1-2 alkoxy, and the cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may have one substituent selected from oxo, hydroxy, halogen, C _1-2 alkyl, C _1-2 hydroxyalkyl and C _1-2 alkoxy); 4) C _1-2 alkyl R ³⁰ (where R ³⁰ represents 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 is attached to C _1-2 alkyl via a carbon atom and may have one substituent selected from oxo, hydroxy, halogen, C _1-2 alkyl, C _1-2 hydroxyalkyl and C _1-2 alkoxy) or C _2-3 alkyl R ³¹ (where R ³¹ is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl, which may have one substituent selected from oxo , hydroxy, halogen, C _1-2 a alkyl, C _1-2 hydroxyalkyl and C _1-2 alkoxy); and 5) C _2-3 alkylX ⁴ C _2-3 alkylX ⁵ R ²⁵ (where X ⁴ and X ⁵ are as defined in claim 1, and R ²⁴ is hydrogen or C _1-2 alkyl).

9. Quinazoline derivatives according to any one of the preceding claims, wherein R ⁴ is methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, 2- (N, N-dimethylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl, 2-sulfamoylethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N -dimethylamino) propyl, 2-morpholinoethyl, 3-morpho-3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (piperazin-1-yl) ethyl, 3- (piperaeen-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.

10. Derivatives of quinazoline according to any one of the preceding paragraphs, wherein R ⁴ is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) 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-hydroxy syethylamino) propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2- (4-methylpiperazin-1-yl) ethyl, 3- (4-methylpiperazin-1-yl) propyl or 2- (2-methoxyethoxy) ethyl.

11. Derivatives of quinazoline according to claim 1, which are selected from the group consisting of:
4- (2-fluoro-5-hydroxy-4-methylanilino) -6,7-dimethoxyquinazoline;
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 their salts.

12. Derivatives of quinazoline according to claim 1, which are 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- (4-chloro-2-fluoro-5-hydroxyanilino) -6,7-dimethoxyquinazoline;
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) chinzaolin;
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) -6,7-dimethoxyquinazoline;
4- (2,4-difluoro-5-hydroxyanilino) -6-methoxy-7- (2-methoxyethoxy) quinazoline
and their salts.

13. Derivatives of quinazoline according to claim 1, which are selected from the group consisting of:
4- (4-bromo-2,6-difluoroanilino) -6,7-dimethoxyquinazoline;
4- (4-bromo-2-fluoro-5-hydroxyanilino) -6,7-dimethoxyquinazoline;
4- (4-chloro-2-fluoro-5-hydroxyanilino) -6-methoxy-7- (2-thiomorpholinoethoxy) quinazoline;
6,7-dimethoxy-4- (3-hydroxy-4-methylphenoxy) 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-methoxyquinazoline;
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- (methylsulfinyl) ethoki) quinazoline
and their salts.

14. Derivatives of quinazoline according to any one of the preceding paragraphs in the form of a pharmaceutically acceptable salt.

15. A method of obtaining derivatives of quinazoline of the formula I or their salts (p. 1), which consists in the fact that:
(a) a compound of formula III:

in which R ¹ , R ² , X ¹ and R ⁴ have the meanings specified in paragraph 1, and L ¹ is the replaced part, is reacted with a compound of formula IV:

in which Z, R ³ and m have the meanings indicated in paragraph 1, which gives the compounds of formula I and their salts;
(b) for the preparation of compounds of formula I and their salts in which group IIa:

in which R ³ and m have the meanings indicated in paragraph 1, is a phenyl group having one or more hydroxyl groups, deprotect the compound of formula V:

in which X ¹ , m, R ¹ , R ² , R ³ , R ⁴ and Z have the meanings indicated in paragraph 1, P denotes a phenolic hydroxy protecting group and p ¹ is an integer from 1 to 5 equal to the number of protected hydroxyl groups wherein mp ¹ is equal to the number of R ³ substituents that are not protected hydroxyl groups;
(c) for the preparation of compounds of formula I and their salts in which the substituent X ¹ is —O—, —S— or —NR ⁷ - (wherein R ⁷ is as defined in claim 1, the compound of formula VI:

in which m, X ¹ , R ¹ , R ² , R ³ and Z have the meanings indicated in paragraph 1, are reacted with a compound of formula VII:
R ⁴ -L ¹
in which R ⁴ has the meanings specified in paragraph 1, and L ¹ has the above meanings;
(d) a compound of formula VIII:

in which, R ¹ , R ² , R ³ , Z and m have the meanings specified in paragraph 1, and L ¹ has the above meanings, is reacted with a compound of formula IX:
R ⁴ -X ¹ -H
in which R ⁴ and X ¹ have the meanings indicated in paragraph 1;
(e) for the preparation of compounds of formula 1 and their salts in which R ⁴ is C _1-5 alkyl R ³² [where R ^{32 is} selected in one of the following four groups which contain: 1) X ⁶ C _1-3 alkyl (where X ⁶ is —O—, —S—, —SO ₂ -, —NR ³³ CO— or —NR ³⁴ SO ₂ - (where R ³³ and R ^{34 are} independently hydrogen, C _1-3 alkyl or C _{1- 3} alkoxyC _2-3 alkyl); 2) NR ³⁵ R ³⁶ (where each of R ³⁵ and R ³⁶ , which may have the same or different meanings, is hydrogen, C _1-3 alkyl or C _1-3 alkoxyC _2-3 alkyl ); 3) X ⁷ C _1-3 alkyl X ⁵ R ²⁴ (where X ⁷ is —O—, —S—, —SO ₂ -, —NR ³⁷ CO—, —NR ³⁸ SO ₂ -, or —NR ³⁹ (where R ³⁷ , R ³⁸ and R ^{39 are} independently hydrogen, C _1-3 alkyl or C _1-3 alkoxy C _2-3 alkyl) and X ⁵ and R ²⁴ are as defined in 1; and 4) R ³¹ (where R ³¹ represents a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms, one of which is N, and the second is independently selected from O, S and N, while the heterocyclic group is attached to C _2-5 alkyl with nitrogen atom and has one or two substituents selected from oxo, hydroxy, halogen, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy);]
compound of formula X:

in which X ¹ , R ¹ , R ² , R ³ , Z and m have the meanings specified in paragraph 1, L ¹ has the above meanings and R ⁴⁰ is C _1-5 alkyl, is reacted with a compound of formula XI:
R ³² -H
in which R ³² has the above meanings;
(f) for the preparation of compounds of formula I and their salts in which R ¹ is NR ⁵ R ⁶ , where one or both R ⁵ and R ⁶ are C _1-3 alkyl, and / or the substituent R ⁴ -X ¹ is alkylamino or a dialkylamino group, a compound of formula I in which the substituent R ¹ and / or the substituent R ⁴ -X ¹ is an amino group, is reacted with an alkylating agent;
(g) to obtain compounds of formula I and their salts in which one or more substituents R ¹ , R ² or R ³ are an amino group or R ⁴ -X ¹ is an amino group, the corresponding compound of formula 1 in which one or more substituents are the corresponding positions of the quinazoline and / or phenyl ring are nitro groups;
and when it is necessary to obtain a salt of a quinazoline derivative of the formula 1, the resulting compound is reacted with an acid or a base to give the desired salt.

16. A pharmaceutical composition which contains, as an active ingredient, a quinazoline derivative of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient or carrier.

17. A method of inhibiting angiogenesis and / or reducing vascular permeability in warm-blooded animals in need of such treatment, which consists in the fact that the specified animal is administered an effective amount of a compound of formula 1 or its pharmaceutically acceptable salt according to claim 1.

18. Derivatives of quinazoline according to any one of paragraphs. 1-14, which are intended for use as medicines.