IP Library › Granted Patent US 9,255,099

Granted Patent B2

US 9,255,099 · App. 12/303,618 · Granted Feb 9, 2016

Pyrazolo[3,4-D]pyrimidine-4,6(5H,7H)-diones as phosphodiesterase 1 inhibitors

Inventors: Peng Li (New York, NY); Lawrence P. Wennogle (New York, NY)

Assignee: INTRA-CELLULAR THERAPIES, INC.

C07D487/04

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Quick Facts

Patent No.: US 9,255,099
App. No.: 12/303,618
Granted: Feb 9, 2016
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

2-(optionally hetero)arylmethyl-3-(optionally hetero)arylamino-[2H]-pyrazolo[3,4-d]pyrimidine-4,6(5H, 7H)-diones, for example, a compound of Formula I: in free, salt or prodrug form, are useful as pharmaceuticals, particularly as phosphodiesterase 1 inhibitors.

Claims (114)

1. The compound of formula I

wherein:

(i) R 1 is H or alkyl;

(ii) R 2 is H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, or alkoxyarylalkyl;

(iii) R 3 is heteroarylmethyl or formula A

wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen; and R 10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, alkyl sulfonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, or aminocarbonyl;

(iv) R 4 is aryl or heteroaryl; and

(v) R 5 is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl;

provided that when X, Y or Z is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;

wherein “alk” or “alkyl” refers to C 1-6 alkyl and “cycloalkyl” refers to C 3-6 cycloalkyl, in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

2. The compound of Formula II

wherein

R 1 is methyl;

R 2 is H, alkyl, cycloalkyl, heteroaryl, aryl, haloalkyl, alkylaminoalkyl, hydroxyalkyl, arylalkyl, or alkoxyarylalkyl;

R 4 is phenyl;

R 5 is H; and

R 10 is phenyl, pyridyl, pyrimidinyl, pyrazolyl, thiadiazolyl, haloalkyl, alkylsulfonyl, oxadiazolyl, aminocarbonyl, or triazolyl;

wherein “alk” or “alkyl” refers to C 1-6 alkyl and “cycloalkyl” refers to C 3-6 cycloalkyl;

in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

3. The compound selected from a group consisting of:

a. 2-(Biphenyl-4-ylmethyl)-7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

b. 2-(Biphenyl-4-ylmethyl)-7-(4-methoxybenzyl)-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

c. 2-(Biphenyl-4-ylmethyl)-3-((biphenyl-4-ylmethyl)(phenyl)amino)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

d. 7-(4-Methoxybenzyl)-5-methyl-3-(phenylamino)-2-(4-(trifluoromethyl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

e. 7-(4-Methoxybenzyl)-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

f. 5-Methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

g. 7-Cyclopentyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

h. 3-(Cyclopentyl(phenyl)amino)-5-methyl-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

i. 7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

j. 7-Cyclohexyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

k. 5-Methyl-7-neopentyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

l. (S)-5-Methyl-7-(2-methylbutyl)-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

m. 5-Methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-7-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

n. (R)-7-(3-Hydroxy-2-methylpropyl)-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

o. 7-(2-(Dimethylamino)ethyl)-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

p. 2-(4-(1H-pyrazol-1-yl)benzyl)-7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

q. 2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

r. 4-((7-isobutyl-5-methyl-4,6-dioxo-3-(phenylamino)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)benzamide;

s. 7-isobutyl-5-methyl-2-(4-(methylsulfonyl)benzyl)-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

t. 7-isobutyl-5-methyl-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

u. 2-(4-(5-fluoropyrimidin-2-yl)benzyl)-7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

v. 5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-7-((tetrahydrofuran-2-yl)methyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

w. 5-methyl-7-neopentyl-3-(phenylamino)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione; and

x. 3-(4-fluorobenzylamino)-7-isobutyl-5-methyl-2-(4-(trifluoromethyl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;

in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

4. A pharmaceutical composition comprising the compound according to claim 1 , in free, pharmaceutically acceptable salt or physiologically hydrolysable and acceptable ester prodrug form, in admixture with a pharmaceutically acceptable diluent or carrier.

5. A method of making a compound according to claim 1 comprising reacting a pyrazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione having the Formula (IIIc)

wherein R 1 , R 2 , and R 4 are as defined in claim 1 for Formula I, with a compound of formula X—R 3 wherein X is a leaving group and R 3 is heteroarylmethyl or Formula A as defined in claim 1 , and isolating the compound according to claim 1 .

6. The method of claim 5 , wherein the reaction is under basic condition.

7. A method of making a compound according to claim 1 comprising reacting a pyrazolo[3,4-d]pyrimidine-4,6(5H, 7H)-dione of formula (IIh)

wherein R 1 , R 3 , and R 4 are as defined in claim 1 for Formula I, with a compound of formula X—R 2 wherein X is a leaving group and R 2 is as defined in claim 1 for Formula I, and isolating the compound according to claim 1 .

8. The method of claim 7 wherein the reaction is under basic condition.

9. The compound according to claim 1 , wherein R 2 is alkyl in free or salt form, and wherein “alk” or “alkyl” refers to C 1-6 alkyl.

10. The compound according to claim 1 , wherein R 2 is isobutyl in free or salt form.

11. The compound according to claim 1 , wherein R 2 is hydroxyalkyl in free, salt or physiologically hydrolysable and acceptable ester prodrug form, and wherein “alk” or “alkyl” refers to C 1-6 alkyl.

12. The compound according to claim 1 , wherein R 2 is 3-hydroxy-2-methylpropyl in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

13. The compound according to claim 1 , wherein R 3 is substituted benzyl of formula A

in free, salt or physiologically hydrolysable and acceptable ester prodrug form, wherein R 8 , R 9 , R 11 and R 12 are independently H or halogen; and R 10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, or aminocarbonyl, and wherein “alk” or “alkyl” refers to C 1-6 alkyl and “cycloalkyl” refers to C 3-6 cycloalkyl.

14. The compound according to claim 1 , wherein R 10 is pyridyl in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

15. The compound according to claim 1 , wherein R 4 is aryl in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

16. The compound according to claim 1 , wherein R 4 is phenyl in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

17. The compound according to claim 1 , wherein R 5 is H in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

18. The compound according to claim 1 , wherein R 4 is phenyl and R 5 is H, in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

19. The compound according to claim 1 , wherein said compound is (R)-7-(3-Hydroxy-2-methylpropyl)-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, in free, salt or physiologically hydrolysable and acceptable ester prodrug form.

20. The compound according to claim 1 , wherein said compound is 7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, in free or salt form.

21. The pharmaceutical composition according to claim 4 , wherein said compound is a compound of Formula I

(i) R 1 is H or alkyl;

(ii) R 2 is H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl, hydroxyalkyl, arylalkyl, heteroarylalkyl, or alkoxyarylalkyl;

(iii) R 3 is heteroarylmethyl or a substituted benzyl of formula A

wherein X, Y and Z are, C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen; and R 10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, alkyl sulfonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, or aminocarbonyl;

(iv) R 4 is aryl or heteroaryl; and

(v) R 5 is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl;

wherein “alk” or “alkyl” refers to C 1-6 alkyl and “cycloalkyl” refers to C 1-6 cycloalkyl;

in free, pharmaceutically acceptable salt or physiologically hydrolysable and acceptable ester prodrug form.

22. A pharmaceutical composition comprising the compound according to claim 2 , in free, pharmaceutically acceptable salt or physiologically hydrolysable and acceptable ester prodrug form, in admixture with a pharmaceutically acceptable diluent or carrier.

23. A pharmaceutical composition comprising the compound selected from a group consisting of: