RU2002114809A

RU2002114809A - Quinazoline derivatives as vascular endothelial growth factor (VEGF) inhibitors

Info

Publication number: RU2002114809A
Application number: RU2002114809/04A
Authority: RU
Inventors: Лоран Франсуа Андре ЭННЕКЕН; Элайн Софи Элизабет Стоукс; Эндрю Питер Томас
Original assignee: Астразенека Аб
Priority date: 1999-11-05
Filing date: 2000-11-01
Publication date: 2003-11-27

Claims

1. A quinazoline derivative of formula I

where m = 1 to 3;

R ¹ represents halogen or C _1-3 alkyl;

X ¹ represents —O—;

R ^{2 is} selected from one of the following three groups: 1) C _1-5 -alkyl-R ³ (where R ³ is piperidin-4-yl, which has one or two substituents selected from hydroxy, halogen, C _1-4 -alkyl, C _1-4 hydroxyalkyl and C _1-4 alkoxy); 2) C _2-5 alkenyl-R ³ (where R ³ is as defined herein); 3) C _2-5 -alkynyl-R ³ (where R ³ is as defined herein);

and where any alkyl, alkenyl or alkynyl group may have one or more substituents selected from hydroxy, halogen and amino;

or its salt.

2. The quinazoline derivative of claim 1, wherein the phenyl group having (R ¹ ) _m is selected from 2-fluoro-4-methylphenyl, 4-chloro-2,6-difluorophenyl, 4-bromo-2,6-difluorophenyl, 4-chloro-2-fluorophenyl group and 4-bromo-2-fluorophenyl.

3. The quinazoline derivative according to claim 1 or 2, wherein R ² is C _1-5 -alkyl-R ³ (where R ³ is as defined in claim 1).

4. The quinazoline derivative according to any one of the preceding claims, wherein R ² is piperidin-4-ylmethyl, in which the piperidine ring may have one or two substituents selected from C _1-4 alkyl.

5. The quinazoline derivative according to claim 1 of formula II

where ma = 1 to 3;

R ^1a represents halogen or C _1-3 alkyl;

X ^1a represents —O—;

R ^{2a is} selected from one of the following three groups: 1) C _1-5 -alkyl-R ³ (where R ³ has the meanings indicated in claim 1); 2) C _2-5 alkenyl R ³ (where R ³ has the meanings indicated in claim 1); 3) C _2-5 -alkynyl R ³ (where R ³ has the meanings indicated in claim 1),

or its salt.

6. The quinazoline derivative according to claim 1, selected from:

4- (4-chloro-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline,

4- (2-fluoro-4-methylanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline,

4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline,

4- (4-chloro-2,6-difluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline,

4- (4-bromo-2,6-difluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline,

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

4- (2-fluoro-4-methylanilino) -6-methoxy-7- (piperidin-4-ylmethoxy) quinazoline,

4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (piperidin-4-ylmethoxy-si) quinazoline,

4- (4-chloro-2,6-difluoroanilino) -6-methoxy-7- (piperidin-4-ylmethoxy) quinazoline,

4- (4-bromo-2,6-difluoroanilino) -6-methoxy-7- (piperidin-4-ylmethoxy) quinazoline and their salts.

7. The quinazoline derivative according to claim 1, selected from:

and their salts.

8. The quinazoline derivative according to claim 1, selected from: 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline and its salts.

9. The quinazoline derivative according to any one of the preceding paragraphs as a pharmaceutically acceptable salt.

10. A method of obtaining a quinazoline derivative of the formula I specified in claim 1, or its salt, which includes:

(a) the interaction of the compounds of formula III

where R ² and X ¹ have the meanings indicated in claim 1;

L ¹ represents a substituted group,

with a compound of formula IV

where R ¹ and m have the meanings indicated in claim 1;

(b) the interaction of the compounds of formula V

where m, X ¹ and R ¹ have the meanings indicated in claim 1,

with a compound of formula VI

where R ² has the meanings indicated in claim 1;

L ¹ has the meaning indicated below;

(c) reacting a compound of formula VII

with the compound of formula VIII

where R ¹ , R ² , m and X ¹ have the meanings indicated in claim 1;

L ¹ has the meaning indicated below, or

(d) deprotecting a compound of formula IX

where R ¹ , m and X ¹ have the meanings indicated in claim 1;

R ⁴ represents a protected group R ² where R ² has the meanings specified in claim 1, but additionally contains one or more protective groups R ² ,

and when a pharmaceutically acceptable salt of a quinazoline derivative of formula I is needed, reacting the resulting compound with an acid or base to produce the desired pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising, as an active ingredient, a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier.

12. The use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing anti-angiogenic and / or vascular permeability-reducing effects in a warm-blooded animal such as a human.

13. The use of claim 12, wherein the drug further comprises a vascular “targeted” agent.

14. The use of claim 13, wherein 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline or a pharmaceutically acceptable salt thereof and N-acetylcolquinol-O- are used phosphate.

15. A method of inducing an antiangiogenic and / or vascular permeability-reducing action 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 as defined in claim 1, or a pharmaceutically acceptable salt thereof.

16. The method according to clause 15, where the introduction is carried out before, after or simultaneously with the introduction of an effective amount of "targeted" agent.

17. The method according to clause 16, where the introduction of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt is carried out before, after or simultaneously with effective amount of N-acetylcolquinol-O-phosphate.