Pyrazole derivatives, preparation method thereof, and composition for prevention and treatment of osteoporosis containing same

A method for preparing a compound of formula I-2, comprising reacting a compound of formula I-1 with one compound selected from acetyl chloride, tris(C1-C4) alkylsilyl chloride and di-tert-butyl dicarbonate (BOC2O), in the presence of a base:

• wherein X represents —CH— or nitrogen;
• R1 represents an acetyl group, a tri(C1-C4) alkylsilanyl group or a (t-butoxy)carbonyl group;
• and
• R2, R3 and R4 each independently represent a hydrogen atom, a halogen atom, a halo(C1-C3) alkyl group or a (C2-C6) alkoxy group, provided that all of R2, R3 and R4 are not a hydrogen atom at the same time.

A method for preparing a compound of formula I-3, comprising reacting a compound of formula I-2 with a compound of formula IV in the presence of a palladium metal catalyst and a base:

• wherein X represents —CH— or nitrogen;
• R1 represents hydrogen, an acetyl group, a tri(C1-C4) alkylsilanyl group or a (t-butoxy)carbonyl group;
• and
• R2, R3 and R4 each independently represent a hydrogen atom or a halogen atom, provided that all of R2, R3 and R4 are not a hydrogen atom at the same time;
• wherein R5, R6 and R7 each independently represent a hydrogen atom, a halogen atom, a (C1-C4) alkylamine group, a halo(C1-C3) alkyl group, a (C1-C6) alkoxy group, a phenoxy group, a benzyloxy group, a formyl group, a phenyl group or a halogen-substituted phenyl group, or alternatively R5 and R6 or R6 and R7 represent —OCH2O— or —CH═CH—CH═CH—, provided that all of R5, R6 and R7 are not a hydrogen atom at the same time;
• wherein X represents —CH— or nitrogen;
• R1 represents hydrogen, an acetyl group, a tri(C1-C4) alkylsilanyl group, a diphenylboranyl group or a (t-butoxy)carbonyl group;
• and
• R5, R6 and R7 each independently represent a hydrogen atom, a halogen atom, a (C1-C4) alkylamine group, a halo(C1-C3) alkyl group, a (C1-C6) alkoxy group, a phenoxy group, a benzyloxy group, a formyl group, a phenyl group or a halogen-substituted phenyl group, or alternatively R5 and R6 or R6 and R7 represent —OCH2O— or —CH═CH—CH═CH—, provided that all of R5, R6 and R7 are not a hydrogen atom at the same time.

A pharmaceutical composition for the treatment of osteoporosis, comprising a compound of formula I:

• wherein X represents —CH— or nitrogen;
• R1 represents a hydrogen atom, an acetyl group, a tri(C1-C4) alkylsilanyl group, a diphenylboranyl group or a (t-butoxy)carbonyl group;
• and
• R2, R3 and R4 each independently represent a hydrogen atom, a halogen atom, a halo(C1-C3) alkyl group, a (C1-C6) alkoxy group, a benzo[d][1,3]dioxole group, an unsubstituted or substituted biphenyl group or an unsubstituted or substituted (C6-C10) aryl group, wherein the substituent is a halogen atom, a (C1-C4) alkylamine group, a halo(C1-C3) alkyl group, a (C1-C6) alkoxy group, a phenoxy group, a benzyloxy group, a formyl group or a halogen-substituted phenyl group, provided that all of R2, R3 and R4 are not a hydrogen atom at the same time;
• or a pharmaceutically acceptable salt thereof.

A composition for the treatment of osteoporosis, comprising a compound or a pharmaceutically acceptable salt thereof selected from:

• 1-(pyridin-2-yl)-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-ol,
• 1-(pyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-ol,
• 3-(3-nitrophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-nitrophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3,4-dimethoxyphenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 1-(pyridin-2-yl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-ol,
• 3-(2-fluorophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3-fluorophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-fluorophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(2-chlorophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3-chlorophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-chlorophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3-bromophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-bromophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(2-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-iodophenyl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-ol,
• 2-(3-(4-iodophenyl)-5-(triisopropylsilyloxy)-1H-pyrazol-1-yl)pyridine,
• 3-(4-bromophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• tert-butyl 3-(2-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• tert-butyl 3-(3-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• tert-butyl 3-(4-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• tert-butyl 3-(4-iodophenyl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl carbonate,
• 3-(4-bromophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl acetate,
• 3-(biphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(3′-phenylbiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• tert-butyl 3-(4-(naphthalene)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• tert-butyl 3-(3′-(dimethylamino)biphenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• 3-(2-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(3′-phenylbiphenyl-2-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(biphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(4′-(benzyloxy)biphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(4′-bromobiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• tert-butyl 3-(3′-formylbiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• tert-butyl 3-(2′-phenoxybiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• 3-(3-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(3′-phenylbiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• tert-butyl 3-(3-(naphthalen-1-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• tert-butyl 3-(3′-(dimethylamino)biphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• tert-butyl 3-(4′-methoxybiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• 3-(4′-(benzyloxy)biphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(4′-bromobiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(3′-formylbiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• tert-butyl 3-(2′-phenoxybiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl carbonate,
• 3-(biphenyl-4-yl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 3-(3′-phenylbiphenyl-4-yl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate,
• 2-(3-(4′-bromobiphenyl-4-yl)-5-(triisopropylsilyloxy)-1H-pyrazol-1-yl)pyridine,
• 2-(3-(biphenyl-4-yl)-5-(diphenylboryloxy)-1H-pyrazol-1-yl)pyridine,
• 3-(biphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-phenylbiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-(naphthalen-1-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-(dimethylamino)biphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(2-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-phenylbiphenyl-2-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(biphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4′-(benzyloxy)biphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4′-bromobiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-formylbiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(2′-phenoxybiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-phenylbiphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3-(naphthalen-1-yl)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-(dimethylamino)biphenyl-3-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4′-methoxybiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4′-(benzyloxy)biphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(4′-bromobiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-formylbiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(2′-phenoxybiphenyl-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol,
• 3-(biphenyl-4-yl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-ol,
• 3-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-ol,
• 3-(3′-phenylbiphenyl-4-yl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-ol, and
• 4-benzyl-3-phenyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol.

A method for treating osteoporosis, comprising administering a composition containing a compound represented by formula I or a pharmaceutically acceptable salt thereof to a subject.

• wherein X represents —CH— or nitrogen;
• R1 represents a hydrogen atom, an acetyl group, a tri(C1-C4) alkylsilanyl group, a diphenylboranyl group or a (t-butoxy)carbonyl group;
• and
• R2, R3 and R4 each independently represent a hydrogen atom, a halogen atom, a halo(C1-C3) alkyl group, a (C1-C6) alkoxy group, a benzo[d][1,3]dioxole group, an unsubstituted or substituted biphenyl group or an unsubstituted or substituted (C6-C10) aryl group, wherein the substituent is a halogen atom, a (C1-C4) alkylamine group, a halo(C1-C3) alkyl group, a (C1-C6) alkoxy group, a phenoxy group, a benzyloxy group, a formyl group or a halogen-substituted phenyl group, provided that all of R2, R3 and R4 are not a hydrogen atom at the same time.