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

Patent metadata

Field	Value
Publication number	US-9255099-B2
Application number	US-30361807-A
Country	US
Kind code	B2
Filing date	Jun 6, 2007
Priority date	Jun 6, 2006
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

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.

First claim

What is claimed is:

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 compou

Assignees

• Li Peng
• Wennogle Lawrence P
• Intra Cellular Therapies Inc

Inventors

• Li Peng
• Wennogle Lawrence P

Classifications

• A61P5/32

  Antioestrogens · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P39/02

  Antidotes · CPC title