WO2008065444B1 - Substituted quinazolines - Google Patents

Abstract

This invention relates to the discovery of 3-and 5-substituted analogues of the selective platelet lowering agent anagrelide with reduced potential for cardiovascular side-effects which should lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting megakaryocytopoeisis and hence the formation of blood platelets.

Claims

AMENDED CLAIMS received by the International Bureau on 1st August 2008 (01.08.08)

A compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof

wherein;

R¹ and R² independently represent a blocking group which functions to prevent metabolic reaction at the position of substitution;

R³ and R⁴ independently represent hydrogen or a blocking group which functions to prevent metabolic reaction at the position of substitution;

or wherein R¹ and R² together with the carbon to which they are attached form a blocking group which functions to prevent metabolic reaction at the 3-position and R³ and R⁴ are hydrogen;

or wherein R¹ and R², and R³ and R⁴, together with the carbons to which they are attached each form a blocking group which functions to directly or indirectly prevent metabolic reaction at the 3-position;

R⁵ is selected from the group comprising: fluoro, chloro, bromo and iodo;

R⁶ is selected from the group comprising: fluoro, chloro, bromo and iodo; R⁷ and R⁸ are independently selected from the group comprising: H; halo; cyano; C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, and C_1-6 haloalkoxy; and

R⁹ is H, C_1-6 alkyl, or a Group I metal ion;

provided always that R¹ , R², R³ and R⁴ are not all hydrogen.

2. A compound according to claim 1, wherein R¹ and R² are both independently selected from the group comprising: cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, in which the alkyl, alkenyl, and alkynyl groups may be optionally substituted;

or wherein R¹ and R² together with the carbon to which they are attached form an optionally substituted C_3-8 carbocyclic ring

or wherein R¹ and R² together with the carbon to which they are attached represent an optionally substituted C_2-6 alkenyl or C_2-6 alkynyl group.

3. A compound according to claim 1 or 2, wherein R³ and R⁴ are independently selected from the group comprising: H; cyano; C_1-6 alkyl, SC_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-8 cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C_1-4 alkylsulphonyl and COOH; C_1-6 hydroxyalkyl; C_1-6 carboxyalkyl; and sulphide;

or R³ and R⁴ together with the carbon to which they are attached form a C_3-8 carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C_1-4 haloalkyl, C_1-4 alkylsulphonyl and COOH;

or R³ and R⁴ together represent a C_2-6 alkenyl or C_2-6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C_1-4 haloalkyl and COOH.

4. A compound as claimed in claim 1, 2 or 3, wherein R³ is H or C_1-6 alkyl.

5. A compound as claimed in claim 1, 2, 3 or 4, wherein R⁴ is H or C_1-6 alkyl.

6. A compound as claimed in any preceding claim, wherein R⁵ is chloro.

7. A compound as claimed in any preceding claim, wherein R⁶ is chloro.

8. A compound as claimed in any preceding claim, wherein R⁷ is H.

9. A compound as claimed in any preceding claim, wherein R⁸ is H.

10. A compound as claimed in any preceding claim, wherein R⁹ is H.

11. A compound as claimed in any of claims 1 to 9, wherein R⁹ is methyl.

12. A compound as claimed in any of claims 1 to 9, wherein R⁹ is sodium.

13. A compound as claimed in any preceding claim, wherein R¹ is an optionally substituted C_1-4 alkyl or C_3-8 cycloalkyl group.

14. A compound as claimed in any preceding claim, wherein R² is an optionally substituted C_1-4 alkyl or C_3-8 cycloalkyl group.

15. A compound as claimed in any preceding claims wherein R¹ is methyl, cyclopropyl, CF₃ or CHF₂.

16. A compound as claimed in any preceding claim, wherein R² is methyl, cyclopropyl, CF₃ Or CHF₂.

17. A compound as claimed in any of claims 1 to 12, wherein R¹ and R² together form an optionally substituted C_3-8 cycloalkyl group,

18. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable diluent or carrier, which may be adapted for oral, parenteral or topical administration.

19. A compound of formula (I) as defined in any of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing any of the foregoing, for use as a medicament

20. The use of a compound of formula (I) as defined in any of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease selected from: myeloprolific diseases and generalised thrombotic diseases.

21. A method of treating a disease selected from: myeloprolifϊc diseases and generalised thrombotic diseases in a human, which comprises treating said human with an effective amount of a compound of formula (I) as defined in any of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, or with a pharmaceutical composition containing any of the foregoing.

22. Use of a compound of formula (I) as defined in any of claims 1 to 17 for the reduction of platelet count.