Xanthine Derivatives with HM74A Receptor Activity

• US 20090209561A1
• Filed: 04/01/2005
• Published: 08/20/2009
• Est. Priority Date: 10/22/2004
• Status: Abandoned Application

• Current Assignee: Ivan Leo Pinto, Richard Jonathan Daniel Hatley
• Original Assignee: Ivan Leo Pinto, Richard Jonathan Daniel Hatley
• Inventors: Pinto, Ivan Leo, Hatley, Richard Jonathan Daniel
• Application Number:
  US11/577,763
• Publication Number:
  US 20090209561A1
• Time in Patent Office: Days
• US Class Current: 514/263.220
• CPC Class Codes: C07D 473/04 two oxygen atoms
• CPC Class Codes: C07D 473/06 with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Abstract

The present invention relates to therapeutically active xanthine compound derivatives, corresponding pharmaceutical formulations containing, processes for making or manufacture and the use of the aforementioned compounds in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial.

Claims

1-16. -16. (canceled)

17. A compound of formula (I):

and pharmaceutically acceptable derivatives thereof

wherein;

R¹ is a group selected from hydrogen, C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl and -(alk)_m-X-(alk)_n-Y,

wherein X is A, A1, A2 or a direct link;

wherein;

A is selected from cycloalkylene, cycloalkenylene, aryl, heteroaryl, heterocyclyl, —

CH₂—

OC(O)—

;

A1 is selected from —

CH₂—

O—

(CH₂)_qaryl-O—

, —

CH₂—

O—

(CH₂)_wN(R⁵)C(O)O—

, —

CH₂—

N(R⁵)C(O)O—

, —

CH₂—

N(R⁵)C(O)—

, —

CH₂—

(O)_p—

(CH₂)_qC(O)NR⁵—

, —

CH₂—

N(R⁵)C(O)N(R⁵)—

, —

CH₂—

C(O)N((CH₂)_wOH)—

, —

CH₂—

NR⁵—

S(O)₂—

, CH₂—

S(O)₂NR⁵—

, —

CH₂—

C(O)O—

, —

O—

, —

NR⁵—

or —

S—

;

A2 is —

CH(OH)—

;

when X is A, A1 or A2, Y is a group selected from heteroaryl, heterocyclyl, aryl, cycloalkyl, cycloalkenyl, —

O(CH₂)_n-aryl, —

C(O)O-aryl, —

CH(aryl)₂, —

CH(heteroaryl)₂, —

C_1-6 haloalkyl, —

C(O)R^4,, —

NR⁵R⁷, —

C(O)NR⁵R⁷, —

NR⁵C(O)R⁷, —

NR⁵C(O)OR⁷, —

C(O)(CH₂)_qOR⁴, halogen, cyano, —

N(R⁵)C(O)OR⁷, —

OC(O)NR⁵R⁶, —

NR⁵C(O)R⁸, —

OR⁵, or —

OC(O)R⁴;

when X is A1 and Y is selected from —

O(CH₂)_n-aryl, —

O-heteroaryl, —

OR⁵, —

OC(O)R⁵, —

NH-aryl, —

OC(O)NR⁵R⁶ and n is an integer selected from 2, 3, 4 and 5;

when X is A1 and Y is —

CF₃, or when X is A2, n is an integer selected from 1, 2, 3, 4 and 5;

when X is a direct link, Y is selected from —

C(O)(CH₂)_qOR⁵, —

C(O)-aryl, —

C(O)-heteroaryl, —

C(O)-heterocyclyl, -heteroaryl, -heterocyclyl, -aryl, -cycloalkyl, -cycloalkenyl, —

C_1-6 haloalkyl, -halo, -cyano, —

CH(aryl)₂, —

CH(heteroaryl)₂, —

OR⁵, —

NR⁵R⁷, —

NCOOR⁸, —

(O)_pC(O)NR⁵R⁶, —

NR⁵C(O)R⁸, —

OR⁵, —

(O)_pC(O)R⁴ or a 3 or 4 ring fused system;

wherein the 3 or 4 ring fused system is a fused 12-18 membered tricyclic or tetracyclic ring containing 1 to 4 nitrogen atoms and wherein at least one ring is an aromatic ring;

wherein 3 or 4 fused system ring is substituted by one or more of C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halogen, —

NH₂, (CH₂)_q—

NR⁵R⁷, (CH₂)_q(O)_p—

(CH₂)_q—

N(R⁵)C(O)OR⁸, —

(CH₂)_q—

N(R⁵)C(O)R⁸, —

(CH₂)_q—

(O)_p—

(CH₂)_q—

C(O)NR⁵R⁶, —

(CH₂)_q—

N(R⁵)C(O)N(R⁵)R⁶, —

(CH₂)_q—

C(O)N((CH₂)_mOH)R⁵, (CH₂)_q—

N(R⁵)—

S(O)₂R³, —

CH₂—

S(O)₂N(R⁵)R⁶, —

C_1-6 haloalkyl, —

OCF₃, —

OCH(F)₂, —

OCH₂F, —

COOR⁵, —

OR⁵, —

(R³)_pCN, —

S(O₂)R⁹, —

(CH₂)_nheteroaryl, —

(CH₂)_nheterocycyl, —

(CH₂)_ncycloalkyl, —

(CH₂)_ncycloalkenyl or —

(CH₂)_naryl;

R² is hydrogen;

or C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally substituted by one or more of;

C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C_1-6 haloalkyl, halogen, —

CN, —

OR⁴, —

(CH₂)_nCOR⁴, —

C(O)OR⁴, —

OCOR⁴, —

(CH₂)_nNR⁵R⁵, —

(NH)_pCONR⁵R⁵, OCONR⁵R⁷, and —

NHC(O)OR⁷;

R³ is fluorinated C_1-6 alkyl;

R⁴ is selected from;

hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, —

(CH₂)_n cycloalkyl, —

(CH₂)_n cycloalkenyl, —

(CH₂)_n heterocyclyl, —

(CH₂)_n aryl, and —

(CH₂)_n heteroaryl;

R⁵ and R⁶ are hydrogen and C_1-4 alkyl;

R⁷ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, —

(CH₂)_t cycloalkyl, —

(CH₂)_n cycloalkenyl, —

(CH₂)_t heterocyclyl, —

(CH₂)_t aryl, and —

(CH₂)_t heteroaryl;

R⁸ is selected from C_1-4 alkyl;

R⁹ is selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, —

(CH₂)_n cycloalkyl, —

(CH₂)_ncycloalkenyl, —

(CH₂)_nheterocyclyl, —

(CH₂)_n aryl, and —

(CH₂)_nheteroaryl, CN;

m represents an integer selected from;

0, 1, 2, 3, 4 and 5;

n represents an integer selected from;

0, 1, 2, 3, 4 and 5;

p represents an integer selected from;

0 and 1;

q represents an integer selected from;

0, 1 and 2;

t represents an integer selected from;

1 and 2;

w represents an integer selected from;

2, 3 and 4; and

provided that when;

(i) R¹ represents hydrogen or C_1-3 alkyl, R² is different to R¹;

(ii) R¹ represents ethyl and R³ represents CF₃, R² is other than CH₂—

CH═

CH₂; and

(iii) R¹ represents methyl and R³ represents CF₃, R² is other than i-butyl.

18. The compound according to claim 17, wherein R¹ is hydrogen C_1-10 alkyl, and -(alk)_m-X-(alk)_n-Y.

19. The compound according to claim 17, wherein X represents A or a direct link.

20. The compound according to claim 17, wherein R¹ is selected from:

hydrogen and C_1-6 alkyl.

21. The compound according to claim 17, wherein R² is selected from:

C_4-6 alkyl.

22. The compound according to claim 17, wherein R³ represents CF₃.

23. A pharmaceutical formulation, which comprises at least one compound of formula (I) according to claim 17 and one or more pharmaceutically acceptable diluents, excipients or carriers.

24. A pharmaceutical combination administered together or separately, sequentially or simultaneously in separate or combined pharmaceutical formulations., wherein the pharmaceutical combination comprises at least one chemical entity according to claim 17 together with another therapeutically active agent.

25. A pharmaceutical formulation comprising:

(i) At least one chemical entity according to claim 17;

(ii) one or more active ingredients selected from statins, fibrates, bile-acid binding resins and nicotinic acid; and

(iii) one or more pharmaceutically acceptable diluents, excipients or carriers.

26. A method for treatment of a disorder of lipid metabolism or diabetes, which comprises administering to a human or an animal subject a therapeutically effective amount of a compound of formula (I) according to claim 17.

27. The method according to claim 26, wherein the disorder of lipid metabolism or diabetes is selected from dyslipidaemia, hyperlipoproteinaemia, didiabetic dyslipidaemia, mixed dyslipidaemia, hypercholesteraemia, type II diabetes mellitus, type I diabetes, obesity, insulin resistance or hyperlipidaemia.

28. A method for treatment of a cardiovascular disease or an inflammatory disease, which comprises administering to a human or an animal subject a therapeutically effective amount of a compound of formula (I) according to claim 17.

29. The method for treatment of cardiovascular disease according to claim 28, wherein the cardiovascular disease is selected from atherosclerosis, arteriosclerosis, hypertriglyceridaemia, coronary artery disease, thrombosis, angina, chronic renal failure, heart failure, peripheral vascular disease or stroke.

30. A method for treatment of anorexia nervosa, which comprises administering to a human or an animal subject a therapeutically effective amount of a compound of formula (I) according to claim 17.