Back to results
US 8,273,750 B2Granted
Organic compounds
AssigneeTakeda Pharmaceutical Company Limited
InventorsPeng Li, Haiyan Wu
Life of this patent
Estimating the term…
Abstract
The invention provides novel 7,8-dihydro-imidazo[1,2-α]pyrazolo[4,3-e]pyrimidin-4-one compounds and 7,8,9-trihydro-[1H or 2/f]-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one compounds, substituted at the 1 or 2 position with C2-g allcyl, C3-9 cycloalkyl, heteroarylalkyl, or substituted arylalkyl, in free, salt or prodrug form, processes for their production, their use as pharmaceuticals, particularly as PDE1 inhibitors, and pharmaceutical compositions comprising them.
Claims21
A compound of Formula III:
- wherein
- R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge;
- R6 is phenylamino or benzylamino;
- R10 is haloalkyl, phenyl, pyridyl, or thiadiazolyl;
- wherein
- phenyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy, C1-4carboxy or an additional aryl or heteroaryl;
- or
- pyridyl or thiadiazolyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy or C1-4carboxy;
- in free, salt or physiologically hydrolysable and acceptable ester prodrug form.
6 more elements
A compound of Formula IV
- wherein
- R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge;
- R6 is phenylamino or benzylamino;
- R10 is phenyl, pyridyl, or thiadiazolyl,
- wherein
- phenyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy, C1-4carboxy or an additional aryl or heteroaryl;
- or
- pyridyl or thiadiazolyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy or C1-4carboxy;
- in free, salt or physiologically hydrolysable and acceptable ester prodrug form.
6 more elements
A compound selected from the following:
- Cis-(6aR*,10aS*)-1-(4-Benzoylbenzyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-3-(phenylamino)cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(1H-one;
- Cis-(6aR*,10aS*)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-3-(phenylamino)-1-(4-(pyridin-2-yl)benzyl)benzyl)-cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(1H)-one;
- Cis-(6aR*,10aS*)-2-(4-(Pyridin-2-yl)benzyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-3-(phenylamino)cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- Cis-(6aR*,10aS*)-3-(Benzyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-2-(4-(1,2,3-thiadiazol-4-yl)benzyl)-cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- Cis-(6aR*,10aS*)-3-(Benzyl)-2-(4-Biphenyl-4-ylmethyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-(4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-1-(4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(1H)-one;
- (6aR,9aS)-3-(benzylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(biphenyl-4-ylmethyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(trifluoromethyl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-((6-trifluoromethyl)-pyridin-3-yl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(3-fluoro-4-(trifluoromethyl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- and
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-methylsulfonyl-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- in free or salt form, or in pure enantiomeric form.
12 more elements
A pharmaceutical composition comprising a compound of Formula III:
- wherein
- R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge;
- R6 is phenylamino or benzylamino;
- R10 is haloalkyl, phenyl, pyridyl, or thiadiazol,
- wherein
- phenyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy, C1-4carboxy or an additional aryl or heteroaryl;
- or
- pyridyl or thiadiazolyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy or C1-4-carboxy;
- in free or pharmaceutically acceptable salt or physiological hydrolysable and acceptable ester prodrug form, in admixture with a pharmaceutically acceptable diluent or carrier.
6 more elements
A pharmaceutical composition comprising a compound of Formula IV
- wherein
- R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge;
- R6 is phenylamino or benzylamino;
- R10 is phenyl, pyridyl, or thiadiazolyl;
- wherein
- phenyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy, C1-4carboxy or an additional aryl or heteroaryl;
- or
- pyridyl or thiadiazolyl is optionally substituted with C1-4alkyl, halogen, haloC1-4alkyl, hydroxy or C1-4carboxy;
- in free or pharmaceutically acceptable salt or physiological hydrolysable and acceptable ester prodrug form, in admixture with a pharmaceutically acceptable diluent or carrier.
6 more elements
A pharmaceutical composition comprising a compound selected from the group consisting of:
- Cis-(6aR*,10aS*)-1-(4-Benzoylbenzyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-3-(phenylamino)cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(1H-one;
- Cis-(6aR*,10aS*)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-3-(phenylamino)-1-(4-(pyridin-2yl)benzyl)benzyl)-cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(1H)-one;
- Cis-(6aR*,10aS*)-2-(4-(Pyridin-2-yl)benzyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-3-(phenylamino)cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- Cis-(6aR*,10aS*)-3-(Benzyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-2-(4-(1,2,3-thiadiazol-4-yl)benzyl)-cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- Cis-(6aR*,10aS*)-3-(Benzyl)-2-(4-Biphenyl-4-ylmethyl)-5,6a,7,8,9,10,10a-heptahydro-5-methyl-cyclohex[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-(4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-1-(4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(1H)-one;
- (6aR,9aS)-3-(benzylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(biphenyl-4-ylmethyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(trifluoromethyl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-((6-trifluoromethyl)-pyridin-3-yl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(3-fluoro-4-(trifluoromethyl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- and
- (6aR,9aS)-3-(phenylamino)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-methylsulfonyl-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one;
- in free or pharmaceutically acceptable salt form, or in pure enantiomeric form, in admixture with a pharmaceutically acceptable diluent or carrier.
12 more elements
Dependencies are inferred from the claim text.