US 7,888,487 B2 · Pyrazole derivative, medicinal composition containing the same, medicinal use thereof and intermediate in producing the same

Abstract

Pyrazole derivatives represented by the general formula: wherein R1 represents H, an optionally substituted C1-6 alkyl group etc.; one of Q and T represents a group selected from the following groups: and the other represents —(CH2)n—Ar wherein Ar represents a substituted C6-10 aryl group, etc., and n represents 0 to 2, R represents an optionally substituted C3-8 cycloalkyl group, etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human 1,5-anhydroglucitol/fructose/mannose transporter and are useful as agents for the prevention, inhibition of progression or treatment of a disease associated with the excess uptake of at least a kind of carbohydrates from glucose, fructose and mannose or a disease associated with hyperglycemia and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.

A method for preparing a compound represented by the general formula (I)

wherein
R1 represents a hydrogen atom, a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), a C2-6 alkenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), a C2-6 alkynyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B);
one of Q and T represents a group selected from
and the other represents a group represented by the formula:
—(CH2)n—Ar wherein Ar represents a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B) or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B);
and n represents an integral number from 0 to 2, a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), a C1-6 alkoxy group which may have the same or different 1 to 3 groups selected from the following substituent group (A), an optionally mono or di(C1-6 alkyl)-substituted amino group wherein the C1-6 alkyl groups may have the same or different 1 to 3 groups selected from the following substituent group (A), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), or a heterocycle-fused phenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (B);
R represents a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B);
[substituent group (A)]:
a halogen atom, a nitro group, a cyano group, an oxo group, -G1, —OG2, —SG2, —N(G2)2, —C(═O)G2, —C(═O)OG2, —C(═O)N(G2)2, —S(═O)2G2, —S(═O)2OG2, —S(═O)2N(G2)2, —S(═O)G1, —OC(═O)G1, —OC(═O)N(G2)2, —NHC(═O)G2, —OS(═O)2G1, —NHS(═O)2G1 or —C(═O)NHS(═O)2G1;
[substituent group (B)]:
a halogen atom, a nitro group, a cyano group, -G1, —OG2, —SG2, —N(G2)2, -G3OG4, -G3N(G4)2, —C(═O)G2, —C(═O)OG2, —C(═O)N(G2)2, —S(═O)2G2, —S(═O)2OG2, —S(═O)2N(G2)2, —S(═O)G1, —OC(═O)G1, —OC(═O)N(G2)2, —NHC(═O)G2, —OS(═O)2G1, —NHS(═O)2G1 or —C(═O)NHS(═O)2G1;
in the above substituent group (A) and/or (B),
G1 represents a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C2-6 alkenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C2-6 alkynyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D);
G2 represents a hydrogen atom, a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C2-6 alkenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C2-6 alkynyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D), and with the proviso that G2 may be the same or different when there are 2 or more G2 in the substituents;
G3 represents a C1-6 alkyl group;
G4 represents a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C), and with the proviso that G4 may be the same or different when there are 2 or more G4 in the substituents;
[substituent group (C)]:
a halogen atom, a nitro group, a cyano group, an oxo group, -G5, —OG6, —SG6, —N(G6)2, —C(═O)G6, —C(═O)OG6, —C(═O)N(G6)2, —S(═O)2G6, —S(═O)2OG6, —S(═O)2N(G6)2, —S(═O)G5, —OC(═O)G5, —OC(═O)N(G6)2, —NHC(═O)G6, —OS(═O)2G5, —NHS(═O)2G5 or —C(═O)NHS(═O)2G5;
and
[substituent group (D)]:
a halogen atom, a nitro group, a cyano group, -G5, —OG6, —SG6, —N(G6)2, —C(═O)G6, —C(═O)OG6, —C(═O)N(G6)2, —S(═O)2G6, —S(═O)2OG6, —S(═O)2N(G6)2, —S(═O)G5, —OC(═O)G5, —OC(═O)N(G6)2, —NHC(═O)G6, —OS(═O)2G5, —NHS(═O)2G5 or —C(═O)NHS(═O)2G5;
in the substituent group (C) and/or (D),
G5 represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl, a C3-8 cycloalkyl group, a C6-10 aryl group, a C2-9 heterocycloalkyl group or a C1-9 heteroaryl group;
and
G6 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl, a C3-8 cycloalkyl group, a C6-19 aryl group, a C2-9 heterocycloalkyl group or a C1-9 heteroaryl group, and with the proviso that G6 may be the same or different when there are 2 or more G6 in the substituents,
characterized by subjecting a pyrazole compound represented by the general formula (III)
wherein
R1A represents a hydrogen atom, a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C2-6 alkenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C2-6 alkynyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B1), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B1);
one of QB and TB represents a hydroxy group, and the other represents a group represented by the formula:
—(CH2)n—ArA wherein ArA represents a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B1) or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B1);
and n represents an integral number from 0 to 2, a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C1-6 alkoxy group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), an optionally mono or di(C1-6 alkyl)-substituted amino group wherein the C1-6 alkyl groups may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), or a heterocycle-fused phenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (B1);
RA represents a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B1), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (A1), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (B1);
[substituent group (A1)]:
a halogen atom, a nitro group, a cyano group, an oxo group, -G1A, —OG2B, —SG2B, —N(G2B)2, —C(═O)G2A, —C(═O)OG2B, —C(═O)N(G2B)2, —S(═O)2G2A, —S(═O)2OG2A, —S(═O)2N(G2B)2, —S(═O)G1A, —OC(═O)G1A, —OC(═O)N(G2B)2, —NHC(═O)G2A, —OS(═O)2G1A, —NHS(═O)2G1A or —C(═O)NHS(═O)2G1A;
[substituent group (B1)]:
a halogen atom, a nitro group, a cyano group, -G1A, —OG2B, —SG2B, —N(G2B)2, -G3OG4A, -G3N(G4A)2, —C(═O)G2A, —C(═O)OG2B, —C(═O)N(G2B)2, —S(═O)2G2A, —S(═O)2OG2A, —S(═O)2N(G2B)2, —S(═O)G1A, —OC(═O)G1A, —OC(═O)N(G2B)2, —NHC(═O)G2A, —OS(═O)2G1A, —NHS(═O)2G1A or —C(═O)NHS(═O)2G1A;
in the above substituent group (A1) and/or (B1),
G1A represents a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C2-6 alkenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C2-6 alkynyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D1), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D1);
G2A represents a hydrogen atom, a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C2-6 alkenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C2-6 alkynyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D1), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D1);
G2B represents a protective group, a hydrogen atom, a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C2-6 alkenyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C2-6 alkynyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C3-8 cycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), a C6-10 aryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D1), a C2-9 heterocycloalkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), or a C1-9 heteroaryl group which may have the same or different 1 to 3 groups selected from the following substituent group (D1), and with the proviso that G2B may be the same or different when there are 2 or more G2B in the substituents;
G3 has the same meaning as defined above;
G4A represents a C1-6 alkyl group which may have the same or different 1 to 3 groups selected from the following substituent group (C1), and with the proviso that G4A may be the same or different when there are 2 or more G4A in the substituents;
[substituent group (C1)]:
a halogen atom, a nitro group, a cyano group, an oxo group, -G5, —OG6A, —SG6A, —N(G6A)2, —C(═O)G6, —C(═O)OG6A, —C(═O)N(G6A)2, —S(═O)2G6, —S(═O)2OG6, —S(═O)2N(G6A)2, —S(═O)G5, —OC(═O)G5, —OC(═O)N(G6A)2, —NHC(═O)G6, —OS(═O)2G5, —NHS(═O)2G5 or —C(═O)NHS(═O)2G5;
and
[substituent group (D1)]:
a halogen atom, a nitro group, a cyano group, -G5, —OG6A, —SG6A, —N(G6A)2, —C(═O)G6, —C(═O)OG6A, —C(═O)N(G6A)2, —S(═O)2G6, —S(═O)2OG6, —S(═O)2N(G6A)2, —S(═O)G5, —OC(═O)G5, —OC(═O)N(G6A)2, —NHC(═O)G6, —OS(═O)2G5, —NHS(═O)2G5 or —C(═O)NHS(═O)2G5;
in the substituent group (C1) and/or (D1),
G5 has the same meaning as defined above;
G6 has the same meaning as defined above;
and
G6A represents a protective group, a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl, a C3-8 cycloalkyl group, a C6-10 aryl group, a C2-9 heterocycloalkyl group or a C1-9 heteroaryl group, and with the proviso that G6A may be the same or different when there are 2 or more G6A in the substituents,
to glycosidation using a sugar donor represented by the general formula (IV)
G-X (IV)
wherein
G represents a group selected from a β-D-glucopyranosyl group, a β-D-mannopyranosyl group, an α-D-glucopyranosyl, an α-D-mannopyranosyl group, β-D-2-deoxyglucopyranosyl group or an α-D-2-deoxyglucopyranosyl group, which has one to four hydroxy-protective groups at the hydroxy groups;
and
X represents a leaving group,
and removing the protective groups.

56 more elements

Pyrazole derivative, medicinal composition containing the same, medicinal use thereof and intermediate in producing the same

Life of this patent

Pyrazole derivative, medicinal composition containing the same, medicinal use thereof and intermediate in producing the same

Life of this patent

Abstract

Claims3