US 2007/0185197 A1 · Phenol derivative, medicinal composition containing the same, and medicinal use thereof

Abstract

The present invention provides phenol derivatives represented by the following general formula or pharmaceutically acceptable salts thereof, or prodrugs thereof, which exhibit an inhibitory activity in human SGLT and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic complications, obesity or the like, and pharmaceutical compositions comprising the same, and pharmaceutical uses thereof. In the chemical structure, R1 and R2 represent H, OH, NH2, etc.; R3and R4represent H, OH, a halogen atom, an optionally substituted alkyl group, etc.; ring A represents an aryl group or a heteroaryl group; G represents a group represented by the following general formula (G); E1 represents H or F; and E2 represents H, F, or a methyl group, etc.

A phenol derivative represented by the following general formula (I):

wherein
R1 or R2 independently represents a hydrogen atom, a hydroxy group, an amino group, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a cyano group, a carboxy group, a C2-7 alkoxycarbonyl group, a carbamoyl group, a mono or di(C1-6 alkyl)amino group, a halo(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, a cyano(C1-6 alkyl) group, a carboxy(C1-6 alkyl) group, a C2-7 alkoxycarbonyl(C1-6 alkyl) group, a carbamoyl(C1-6 alkyl) group, an amino(C1-6 alkyl) group, a mono or di(C1-6 alkyl)amino(C1-6 alkyl) group, a halo(C1-6 alkoxy) group, a hydroxy(C1-6 alkoxy) group, a carboxy(C1-6 alkoxy) group, a C2-7 alkoxycarbonyl(C1-6 alkoxy) group, a carbamoyl(C1-6 alkoxy) group, an amino(C1-6 alkoxy) group, a mono or di(C1-6 alkyl)amino(C1-6 alkoxy) group, a C3-7 cycloalkyl group, C3-7 cycloalkyl-O—, a C3-7 cycloalkyl(C1-6 alkyl) group, or C3-7 cycloalkyl(C1-6 alkoxy) group;
R3 and R4 independently represent a hydrogen atom, a hydroxy group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C1-6 alkylthio group, a C2-6 alkenylthio group, a halo(C1-6 alkyl) group, a halo(C1-6 alkoxy) group, a halo(C1-6 alkylthio) group, a hydroxy(C1-6 alkyl) group, a hydroxy(C2-6 alkenyl) group, a hydroxy(C1-6 alkoxy) group, a hydroxy(C1-6 alkylthio) group, a carboxy group, a carboxy(C1-6 alkyl) group, a carboxy(C2-6 alkenyl) group, a carboxy(C1-6 alkoxy) group, a carboxy(C1-6 alkylthio) group, a C2-7 alkoxycarbonyl group, a C2-7 alkoxycarbonyl(C1-6 alkyl) group, a C2-7 alkoxycarbonyl(C2-6 alkenyl) group, a C2-7 alkoxycarbonyl(C1-6 alkoxy) group, a C2-7 alkoxycarbonyl(C1-6 alkylthio) group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, —U—V—W—N(R5)-Z, or any of the following substituents (i) to (xxviii) which may have any 1 to 3 substituents selected from the later identified substituent group a on the ring;
(i) a C6-10 aryl group, (ii) C6-10 aryl-O—, (iii) C6-10 aryl-S—, (iv) a C6-10 aryl(C1-6 alkyl) group, (v) a C6-10 aryl(C1-6 alkoxy) group, (vi) a C6-10 aryl(C1-6 alkylthio) group, (vii) a heteroaryl group, (viii) heteroaryl-O—, (ix) heteroaryl-S—, (x) a heteroaryl(C1-6 alkyl) group, (xi) a heteroaryl(C1-6 alkoxy) group, (xii) a heteroaryl(C1-6 alkylthio) group, (xiii) a C3-7 cycloalkyl group, (xiv) C3-7 cycloalkyl-O—, (XV) C3-7 cycloalkyl-S—, (xvi) a C3-7 cycloalkyl(C1-6 alkyl) group, (xvii) a C3-7 cycloalkyl(C1-6 alkoxy) group, (xviii) a C3-7 cycloalkyl(C1-6 alkylthio) group, (xix) a heterocycloalkyl group, (xx) heterocycloalkyl-O—, (xxi) heterocycloalkyl-S—, (xxii) a heterocycloalkyl(C1-6 alkyl) group, (xxiii) a heterocycloalkyl(C1-6 alkoxy) group, (xxiv) a heterocycloalkyl(C1-6 alkylthio) group, (xxv) an aromatic cyclic amino group, (xxvi) an aromatic cyclic amino(C1-6 alkyl) group, (xxvii) an aromatic cyclic amino(C1-6 alkoxy) group or (xxviii) an aromatic cyclic amino(C1-6 alkylthio) group,
U represents —O—, —S— or a single bond and with the proviso that at least one of V and W is not a single bond when U is —O— or —S—);
V represents a C1-6 alkylene group which may have a hydroxy group, a C2-6 alkenylene group or a single bond;
W represents —CO—, —SO2—, —C(═NH)— or a single bond;
Z represents a hydrogen atom, a C2-7 alkoxycarbonyl group, a C6-10 aryl(C2-7 alkoxycarbonyl) group, a formyl group, —RA, —CORB, —SO2RB, —CON(RC)RD, —CSN(RC)RD, —SO2NHRA or —C(═NRE)N(RF)RG;
R5, RA, RC and RD independently represent a hydrogen atom, a C1-6 alkyl group which may have any 1 to 5 substituents selected from the later identified substituent group β, or any of the following substituents (xxix) to (xxxii) which may have any 1 to 3 substituents selected from the later identified substituent group α;
(xxix) a C6-10 aryl group, (xxx) a heteroaryl group, (xxxi) a C3-7 cycloalkyl group or (xxxii) a heterocycloalkyl group
or Z and R5 bind together with the neighboring nitrogen atom to form an aliphatic cyclic amino group which may have any 1 to 3 substituents selected from the later identified substituent group α;
or RC and RD bind together with the neighboring nitrogen atom to form an aliphatic cyclic amino group which may have any 1 to 3 substituents selected from the later identified substituent group α;
RB represents a C2-7 alkoxycarbonyl group, a C1-6 alkylsulfonylamino group, a C6-10 arylsulfonylamino group, a C1-6 alkyl group which may have any 1 to 5 substituents selected from the later identified substituent group β, or any of the following substituents (xxxiii) to (xxxvi) which may have any 1 to 3 substituents selected from the later identified substituent group α;
(xxxiii) a C6-10 aryl group, (xxxiv) a heteroaryl group, (xxxv) a C3-7 cycloalkyl group or (xxxvi) a heterocycloalkyl group,
RE, RF and RG independently represent a hydrogen atom, a cyano group, a carbamoyl group, a C2-7 acyl group, a C2-7 alkoxycarbonyl group, a C6-10 aryl(C2-7 alkoxycarbonyl) group, a nitro group, a C1-6 alkylsulfonyl group, a sulfamoyl group, a carbamimidoyl group, or a C1-6 alkyl group which may have any 1 to 5 substituents selected from the later identified substituent group β;
or RE and RF bind together to form an ethylene group;
or RF and RG bind together with the neighboring nitrogen atom to form an aliphatic cyclic amino group which may have any substituent selected from the later identified substituent group α;
ring A represents a C6-10 aryl group or a heteroaryl group;
G represents a group represented by a formula:
E1 represents a hydrogen atom or a fluorine atom;
E2 represents a hydrogen atom, a fluorine atom or a methyl group;
[substituent group α]
a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group, a C1-6 alkoxy group, a halo(C1-6 alkyl) group, a halo(C1-6 alkoxy) group, a hydroxy(C1-6 alkyl) group, a C2-7 alkoxycarbonyl(C1-6 alkyl) group, a hydroxy(C1-6 alkoxy) group, an amino(C1-6 alkyl) group, an amino(C1-6 alkoxy) group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, a C1-6 alkylsulfonyl group, a C1-6 alkylsulfonylamino group, a C1-6 alkylsulfonylamino(C1-6 alkyl) group, a carboxy group, a C2-7 alkoxycarbonyl group, a sulfamoyl group and —CON(RH)RI
[substituent group β]
a halogen atom, a hydroxy group, an amino group, a C1-6 alkoxy group, a C1-6 alkylthio group, a halo(C1-6 alkoxy) group, a halo(C1-6 alkylthio) group, a hydroxy(C1-6 alkoxy) group, a hydroxy(C1-6 alkylthio) group, an amino(C1-6 alkoxy) group, an amino(C1-6 alkylthio) group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6 alkyl)ureido group, a mono or di[hydroxy(C1-6 alkyl)]ureido group, a mono or di(C1-6 alkyl)sulfamide group, a mono or di[hydroxy(C1-6 alkyl)]-sulfamide group, a C2-7 acylamino group, an amino(C2-7 acylamino) group, a C1-6 alkylsulfonyl group, a C1-6 alkylsulfonylamino group, a carbamoyl(C1-6 alkylsulfonylamino) group, a carboxy group, a C2-7 alkoxycarbonyl group, —CON(RH)RI, and any of the following substituents (xxxvii) to (xxxxviii) which may have any 1 to 3 substituents selected from the above substituent group α on the ring;
(xxxvii) a C6-10 aryl group, (xxxviii) C6-10 aryl-O—, (xxxix) a C6-10 aryl(C1-6 alkoxy) group, (xxxx) a C6-10 aryl(C1-6 alkylthio) group, (xxxxi) a heteroaryl group, (xxxxii) heteroaryl-O—, (xxxxiii) a C3-7 cycloalkyl group, (xxxxiv) C3-7 cycloalkyl-O—, (xxxxv) a heterocycloalkyl group, (xxxxvi) heterocycloalkyl-O—, (xxxxvii) an aliphatic cyclic amino group or (xxxxviii) an aromatic cyclic amino group,
RH and RI independently represent a hydrogen atom or a C1-6 alkyl group which may have any 1 to 3 substituents selected from the following substituent group γ;
or both of RH and RI bind together with the neighboring nitrogen atom to form an aliphatic cyclic amino group which may have any 1 to 3 substituents selected from the following substituent group δ
[substituent group γ]
a halogen atom, a hydroxy group, an amino group, a C1-6 alkoxy group, a halo(C1-6 alkoxy) group, a hydroxy(C1-6 alkoxy) group, an amino(C1-6 alkoxy) group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6 alkyl)ureido group, a mono or di[hydroxy(C1-6 alkyl)]ureido group, a mono or di(C1-6 alkyl)sulfamide group, a mono or di[hydroxy(C1-6 alkyl)]sulfamide group, a C2-7 acylamino group, an amino(C2-7 acylamino) group, a C1-6 alkylsulfonyl group, a C1-6 alkylsulfonylamino group, a carbamoyl(C1-6 alkylsulfonylamino) group, a carboxy group, a C2-7 alkoxycarbonyl group and —CON(RJ)RK
[substituent group δ]
a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group, a C1-6 alkoxy group, a halo(C1-6 alkyl) group, a halo(C1-6 alkoxy) group, hydroxy(C1-6 alkoxy) group, a C2-7 alkoxycarbonyl(C1-6 alkyl) group, a hydroxy(C1-6 alkoxy) group, an amino(C1-6 alkyl) group, an amino(C1-6 alkoxy) group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, a C1-6 alkylsulfonyl group, a C1-6 alkylsulfonylamino group, a C1-6 alkylsulfonylamino(C1-6 alkyl) group, a carboxy group, a C2-7 alkoxycarbonyl group, a sulfamoyl group and —CON(RJ)RK,
RJ and RK independently represent a hydrogen atom or a C1-6 alkyl group which may have any 1 to 3 substituents selected from a hydroxy group, an amino group, a mono or di(C1-6 alkyl)amino group, a C2-7 alkoxycarbonyl group and a carbamoyl group;
or both of RJ and RK bind together with the neighboring nitrogen atom to form an aliphatic cyclic amino group which may have any 1 to 3 substituents selected from a hydroxy group, an amino group, a mono or di(C1-6 alkyl)amino group, a C1-6 alkyl group, a hydroxy(C1-6 alkyl) group, a C2-7 alkoxycarbonyl group, a C2-7 alkoxycarbonyl(C1-6 alkyl) group and a carbamoyl group, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

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Phenol derivative, medicinal composition containing the same, and medicinal use thereof

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Phenol derivative, medicinal composition containing the same, and medicinal use thereof

Life of this patent

Abstract

Claims25