Pyrazolopyridine compound and processes for preparation thereof

Claim 2

A pyrazolopyridine compound of the formula : wherein R 1 is lower alkyl, aryl which may have one or more suitable substituent(s) or a heterocyclic group, R2 is a group of the formula: (wherein R4 is protected amino or hydroxy and R 5 is hydrogen or lower alkyl); cyano; a group of the formula: -A-R 6 (wherein R 6 is an acyl group, and, A is lower aliphatic hydrocarbon group which may have one or more suitable substituent(s)); amidated carboxy; amino or protected amino; and R 3 is hydrogen, lower alkyl, lower alkoxy or halogen, and a pharmaceutically acceptable salt thereof.

Claim 3

A compound of claim 1, wherein R 1 is lower alkyl; phenyl which may have one or more suitable substituent(s) such as halogen, lower alkoxy, nitro, amino, protected amino; or unsaturated 3 to 8 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), R 2 is a group of the formula: (wherein R4 is acylamino or hydroxy, and R 5 is as defined above); cyano; a group of the formula: -A-R6 (wherein R 6 is as defined above, and A is lower alkyl, lower alkenyl or lower alkynyl, each of which may have halogen); amidated carboxy; amino or acylamino.

Claim 4

A compound of claim 2, wherein R 1 is lower alkyl; phenyl which may have 1 to 3 suitable substituent-(s) selected from a group consisting of halogen, lower alkoxy, nitro, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, lower alkylamino and di(lower)alkylamino; or pyridyl.

Claim 5

A compound of claim 3, wherein R 2 is a group of the formula: (wherein R 4 is ureido; lower alkanoylamino which may have suitable substituent(s) such as di(lower)-alkylamino or cyclic amino group which may have lower alkyl; or hydroxy, and R 5 is as defined above).

Claim 6

A compound of claim 4, wherein R 2 is a group of the formula: (wherein R4 is ureido; di(lower)alkylamino(lower)alkanoylamino; lower alkylpiperidino (lower)alkanoylamino or hydroxy, and R 5 is as defined above).

Claim 7

A compound of claim 3, wherein R 2 is cyano.

Claim 8

A compound of claim 3, wherein R 2 is a group of the formula: -A- R6 (wherein R 6 is lower alkanoyl; carboxy or protected carboxy, and A is lower alkyl; lower alkenyl which may have halogen or lower alkynyl).

Claim 9

A compound of claim 7, wherein R 2 is a group of the formula: -A-R 6 (wherein R 6 is lower alkanoyl; carboxy; esterified carboxy or amidated carboxy, and A is as defined above).

Claim 10

A compound of claim 8, wherein R 2 is a group of the formula: -A- R6 [wherein R 6 is lower alkanoyl; carboxy; lower alkoxycarbonyl which may have N-containing heterocyclic group; N-(lower)alkylcarbamoyl; N-(higher)alkylcarbamoyl; N,N-di(lower)alkylcarbamoyl; N-lower alkyl-N-ar-(lower)alkylcarbamoyl; or a group of the formula: -COR N (wherein R N is N-containing heterocyclic group which may have one or more suitable substituent(s)), and A is as defined above].

Claim 11

A compound of claim 9, wherein R 2 is a group of the formula : -A-R 6 (wherein R 6 is lower alkanoyl; carboxy or lower alkoxycarbonyl, and A is lower alkenyl which may have halogen).

Claim 12

A compound of claim 9, wherein R 2 is a group of the formula: -A- R6 (wherein R 6 is N- (lower)alkylcarbamoyl; N-(higher)alkylcarbamoyl; N,N-di(lower)alkylcarbamoyl or N-lower alkyl-N-ar(lower)alkylcarbamoyl, and A is lower alkenyl).

Claim 13

A compound of claim 9, wherein R 2 is a group of the formula: -A-R6 [wherein R 6 is a group of the formula: -COR N (wherein R N is as defined above) and A is as defined above].

Claim 14

A compound of claim 12, wherein R 2 is a group of the formula: -A- R6 [wherein R 6 is a group of the formula: -COR N (wherein R N is saturated 3 to 8 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s); saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s); or saturated 3 to 8 membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), each of which may have one or more suitable substituent(s) such as lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyloxy(lower)alkyl, carboxy or protected carboxy), and A is a defined above].

Claim 15

A compound of claim 13, wherein R 2 is a group of the formula: -A- R ε [wherein R 6 is a group of the formula: -COR N (wherein R N is piperidino which may have 1 to 4 suitable substituent(s) selected from a group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, lower alkoxycarbonyl and carboxy; pyrrolidin-1-yl which may have lower alkoxy(lower)alkyl; perhydroazepin-1-yl; piperazin-1-yl which may have lower alkyl morpholino; 7-azabicyclo[2.2.1 ]heptan-7-yl; or 3-azabicyclo[3.2.2.]nonan-3-yl), and A is as defined above].

Claim 16

A compound of claim 14, wherein R 1 is isopropyl, phenyl, phenyl having chloro, phenyl having methoxy, phenyl having nitro, phenyl having amino, phenyl having acetylamino, phenyl having methoxycarbonylamino, phenyl having methanesulfonylamino, phenyl having methylamino, phenyl having dimethylamino or pyridyl, R 2 is a group of the formula: -A- R6 [wherein R 6 is a group of the formula: -COR N (wherein R N is piperidino, 2-methylpiperidino, 2-ethylpiperidino, 3-ethylpiperidino, 4-ethyl piperidino, 2-propylpiperidino, 2,2,6,6-tetramethylpiperidino, 2-hydroxymethylpiperidino, 2-(2-hydroxyethyl)piperidino, 4-(2-hydroxyethyl)piperidino, 2-methoxymethylpiperidino, 2-(2-methoxyethyl)piperidino, 2-acetoxymethylpiperidino, 2-(2-acetoxyethyl)piperidino, 2-ethoxycarbonylpiperidino, 2-carboxypiperidino, pyrrolidin-1-yl, 2-methoxymethylpyrrolidin-1-yl, perhydro-1H-azepin-1-yl, 4-methylpiperazin-1-yl, morpholino, 7-azabicyclo-[2.2.1]heptan-7-yl or 3-azabicyclo[3.2.2.]nonan-3-yl), and A is ethyl, vinyl, 1-methylvinyl, 2methylvinyl, 1,3-butadienyl, 1-bromovinyl or ethynyl], and R 3 is hydrogen, methyl, methoxy or chloro.

Claim 17

A compound of claim 15, wherein R' is phenyl, phenyl having chloro or pyridyl, R 2 is a group of the formula: -A-R 6 [wherein R 6 is a group of the formula: -COR N (wherein R N is 2-ethylpiperidino or 2-(2-hydroxyethyl)piperidino), and A is vinyl] and R 3 is hydrogen.

Claim 18

A compound of claim 16, which is selected from a group consisting of: 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine • fumalate (trans isomer), (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine (trans isomer), 1-[3-(2-phenylpyrazolo[1,5-a]-pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine (trans isomer), (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine (trans isomer), 1-[3-{2-(3-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) and 1-[3-{2-(4-pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer).

Claim 19

A compound of claim 17, which is (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine (trans isomer).

Claim 20

A compound of claim 3, wherein R 2 is amidated carboxy.

Claim 21

A compound of claim 19, wherein R 2 is a group of the formula : -COR N (wherein R N is piperidino which may have lower alkyl).

Claim 22

A compound of claim 3, wherein R 2 is amino, lower alkanoylamino or lower alkoxycarbonyl(lower)-alkanoylamino.

Claim 23

A process for preparing the pyrazolopyridine compound of the formula: wherein R' is lower alkyl, aryl which may have one or more suitable substituent(s) or a heterocyclic group, R 2 is a group of the formula: (wherein R 4 is protected amino or hydroxy and R 5 is hydrogen or lower alkyl): cyano; a group of the formula: -A- R6 (wherein R 6 is an acyl group, and. A is lower aliphatic hydrocarbon group which may have one or more suitable substituent(s)); amidated carboxy; amino or protected amino; and R 3 is hydrogen, lower alkyl, lower alkoxy or halogen; or a salt thereof, which comprises 1) reacting a compound of the formula : (wherein R 1 , R 3 and R 5 are each as defined above) or a salt thereof, with a compound of the formula: H 2 N-R 4 (wherein R 4 is as defined above) or a salt thereof, to give a compound of the formula: (wherein R'. R 3 , R 4 and R 5 are each as defined above) or a salt thereof, 2) subjecting a compound of the formula : (wherein R' and R 3 are each as defined above) or a salt thereof, to dehydration reaction, to give a compound of the formula : (wherein R I and R 3 are each as defined above) or a salt thereof, 3) subjecting a compound of the formula : (wherein R' and R 3 are each as defined above, and R 7 is lower alkanoyl) or a salt thereof, to Wittig type reaction, to give a compound of the formula : (wherein R', R 3 and R 6 are each as defined above, and A' is lower alkenyl which may have one or more suitable substituent(s)) or a salt thereof, 4) subjecting a compound of the formula : (wherein R', R 3 and A are each as defined above, and R 6 a is protected carboxy) or a salt thereof, to elimination reaction of carboxy protective group, to give a compound of the formula : (wherein R', R 3 and A are each as defined above) or a salt thereof, 5) reacting a compound of the formula : (wherein R', R 3 and A are each as defined above) or its reactive derivative at the carboxy group or a salt thereof, with N-substituted amine or its reactive derivative at the amino group or a salt thereof, to give a compound of the formula : (wherein R', R 3 and A are each as defined above, and R 6 b is amidated carboxy) or a salt thereof, 6) subjecting a compound of the formula : (wherein R', R 3 and R 6 are each as defined above, and A 1 a is lower alkenyl) or a salt thereof, to halogenation reaction, to give a compound of the formula : (wherein R 1 , R 3 and R 6 are each as defined above, and A 1 b is lower alkenyl having halogen) or a salt thereof, 7) subjecting a compound of the formula : (wherein R 1 , R 3 . R 6 and A 1 b are each as defined above) or a salt thereof, to elimination reaction of hydrogen halide, to give a compound of the formula : (wherein R', R 3 and R 6 are each as defined above, and A 2 is lower alkynyl) or a salt thereof, 8) subjecting a compound of the formula : (wherein R 1 , R 3 , R 6 and A 2 are each as defined above) or a salt thereof, to reduction of triple bond to give a compound of the formula : (wherein R 1 , R 3 , R 6 and A 1 a are each as defined above) or a salt thereof, 9) subjecting a compound of the formula : (wherein R', R 3 and A are each as defined above) or its reactive derivative at the carboxy group or a salt thereof, to esterification reaction to give a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 8 is esterified carboxy) or a salt thereof, 10) subjecting a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 1 N is N-containing heterocyclic group having hydroxy(lower)alkyl) or a salt thereof, to lower alkylation reaction, to give a compound of the formula : (wherein R', R 3 and A are each as defined above, and R 2 N is N-containing heterocyclic group having lower alkoxy(lower)alkyl) or a salt thereof, 11) subjecting a compound of the formula : (wherein R 1 , R 3 , A and R 1 N are each as defined above) or a salt thereof, to acylation reaction, to give a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 3 N is N-containing heterocyclic group having acyloxy(lower)alkyl) or a salt thereof, 12) subjecting a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 4 N is N-containing heterocyclic group having protected carboxy) or a salt thereof, to elimination reaction of carboxy protective group, to give a compound of the formula : (wherein R', R 3 and A are each as defined above, and R5 is N-containing heterocyclic group having carboxy) or a salt thereof, 13) subjecting a compound of the formula : (wherein R 2 and R 3 are each as defined above, and R 1 a is aryl having nitro) or a salt thereof, to reduction of nitro group, to give a compound of the formula : (wherein R 2 and R 3 are each as defined above, and R 1 b is aryl having amino) or a salt thereof, 14) subjecting a compound of the formula : (wherein R 1 b , R 2 and R 3 are each as defined above) a salt thereof, to introduction reaction of amino protective group to give a compound of the formula : (wherein R 2 and R 3 are each as defined above, and R 1 c is aryl having protected amino) or a salt thereof, 15) reacting a compound of the formula : (wherein R 1 and R 3 are each as defined above) or a salt thereof, with a compound of the formula: X-A 1 -R 6 (wherein R 6 and A' are each as defined above, and X is a leaving group) or a salt thereof, to give a compound of the formula : (wherein R 1 , R 3 , R 6 and A' are each as defined above) or a salt thereof, . 16) reacting a compound of the formula : (wherein R 1 and R 3 are each as defined above) or its reactive derivative at the carboxy group or a salt thereof, with N-substituted amine or its reactive derivative at the amino group or a salt thereof, to give a compound of the formula : (wherein R 1 and R 3 are each as defined above, and R 2 a is amidated carboxy) or a salt thereof, 17) subjecting a compound of the formula ; (wherein R 1 and R 3 are each as defined above) or a salt thereof, to reduction of nitroso group, to give a compound of the formula : (wherein R' and R 3 are each as defined above, and R2 is amino or protected amino) or a salt thereof, or 18) subjecting a compound of the formula : (wherein R' and R3 are each as defined above) or a salt thereof, to introduction reaction of amino protective group, to give a compound of the formula : (wherein R 1 and R 3 are each as defined above, and R 2 c is protected amino) or a salt thereof.

Claim 24

A process for preparing the pyrazolopyridine compound of the formula: wherein R' is lower alkyl, aryl which may have one or more suitable substituent(s) or a heterocyclic group, R 2 is a group of the formula: (wherein R 4 is protected amino or hydroxy and R 5 is hydrogen or lower alkyl): cyano; a group of the formula: -A- R6 (wherein R 6 is an acyl group, and. A is lower aliphatic hydrocarbon group which may have one or more suitable substituent(s)); amidated carboxy; amino or protected amino; and R 3 is hydrogen, lower alkyl, lower alkoxy or halogen; or a salt thereof, which comprises 1) reacting a compound of the formula : (wherein R 1 , R 3 and R 5 are each as defined above) or a salt thereof, with a compound of the formula: H 2 N-R 4 (wherein R 4 is as defined above) or a salt thereof, to give a compound of the formula: (wherein R'. R 3 , R 4 and R 5 are each as defined above) or a salt thereof, 2) subjecting a compound of the formula : (wherein R' and R 3 are each as defined above) or a salt thereof, to dehydration reaction, to give a compound of the formula : (wherein R I and R 3 are each as defined above) or a salt thereof, 3) subjecting a compound of the formula : (wherein R' and R 3 are each as defined above, and R 7 is lower alkanoyl) or a salt thereof, to Wittig type reaction, to give a compound of the formula : (wherein R', R 3 and R 6 are each as defined above, and A' is lower alkenyl which may have one or more suitable substituent(s)) or a salt thereof, 4) subjecting a compound of the formula : (wherein R', R 3 and A are each as defined above, and R 6 a is protected carboxy) or a salt thereof, to elimination reaction of carboxy protective group, to give a compound of the formula : (wherein R', R 3 and A are each as defined above) or a salt thereof, 5) reacting a compound of the formula : (wherein R', R 3 and A are each as defined above) or its reactive derivative at the carboxy group or a salt thereof, with N-substituted amine or its reactive derivative at the amino group or a salt thereof, to give a compound of the formula : (wherein R', R 3 and A are each as defined above, and R 6 b is amidated carboxy) or a salt thereof, 6) subjecting a compound of the formula : (wherein R', R 3 and R 6 are each as defined above, and A 1 a is lower alkenyl) or a salt thereof, to halogenation reaction, to give a compound of the formula : (wherein R 1 , R 3 and R 6 are each as defined above, and A 1 b is lower alkenyl having halogen) or a salt thereof, 7) subjecting a compound of the formula : (wherein R 1 , R 3 . R 6 and A 1 b are each as defined above) or a salt thereof, to elimination reaction of hydrogen halide, to give a compound of the formula : (wherein R', R 3 and R 6 are each as defined above, and A 2 is lower alkynyl) or a salt thereof, 8) subjecting a compound of the formula : (wherein R 1 , R 3 , R 6 and A 2 are each as defined above) or a salt thereof, to reduction of triple bond to give a compound of the formula : (wherein R 1 , R 3 , R 6 and A 1 a are each as defined above) or a salt thereof, 9) subjecting a compound of the formula : (wherein R', R 3 and A are each as defined above) or its reactive derivative at the carboxy group or a salt thereof, to esterification reaction to give a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 8 is esterified carboxy) or a salt thereof, 10) subjecting a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 1 N is N-containing heterocyclic group having hydroxy(lower)alkyl) or a salt thereof, to lower alkylation reaction, to give a compound of the formula : (wherein R', R 3 and A are each as defined above, and R 2 N is N-containing heterocyclic group having lower alkoxy(lower)alkyl) or a salt thereof, 11) subjecting a compound of the formula : (wherein R 1 , R 3 , A and R 1 N are each as defined above) or a salt thereof, to acylation reaction, to give a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 3 N is N-containing heterocyclic group having acyloxy(lower)alkyl) or a salt thereof, 12) subjecting a compound of the formula : (wherein R 1 , R 3 and A are each as defined above, and R 4 N is N-containing heterocyclic group having protected carboxy) or a salt thereof, to elimination reaction of carboxy protective group, to give a compound of the formula : (wherein R', R 3 and A are each as defined above, and R5 is N-containing heterocyclic group having carboxy) or a salt thereof, 13) subjecting a compound of the formula : (wherein R 2 and R 3 are each as defined above, and R 1 a is aryl having nitro) or a salt thereof, to reduction of nitro group, to give a compound of the formula : (wherein R 2 and R 3 are each as defined above, and R 1 b is aryl having amino) or a salt thereof, 14) subjecting a compound of the formula : (wherein R 1 b , R 2 and R 3 are each as defined above) a salt thereof, to introduction reaction of amino protective group to give a compound of the formula : (wherein R 2 and R 3 are each as defined above, and R 1 c is aryl having protected amino) or a salt thereof, 15) reacting a compound of the formula : (wherein R 1 and R 3 are each as defined above) or a salt thereof, with a compound of the formula: X-A 1 -R 6 (wherein R 6 and A' are each as defined above, and X is a leaving group) or a salt thereof, to give a compound of the formula : (wherein R 1 , R 3 , R 6 and A' are each as defined above) or a salt thereof, . 16) reacting a compound of the formula : (wherein R 1 and R 3 are each as defined above) or its reactive derivative at the carboxy group or a salt thereof, with N-substituted amine or its reactive derivative at the amino group or a salt thereof, to give a compound of the formula : (wherein R 1 and R 3 are each as defined above, and R 2 a is amidated carboxy) or a salt thereof, 17) subjecting a compound of the formula ; (wherein R 1 and R 3 are each as defined above) or a salt thereof, to reduction of nitroso group, to give a compound of the formula : (wherein R' and R 3 are each as defined above, and R2 is amino or protected amino) or a salt thereof, or 18) subjecting a compound of the formula : (wherein R' and R3 are each as defined above) or a salt thereof, to introduction reaction of amino protective group, to give a compound of the formula : (wherein R 1 and R 3 are each as defined above, and R 2 c is protected amino) or a salt thereof.

Claim 25

A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.

Claim 26

A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

Claim 27

A compound of claim 1 or a pharmaceutically acceptble salt thereof for use as diuretic,antihypertensive agent, remedy for renal insufficiency, remedy for thrombosis or cardiotonic agent.