US 7,547,680 B2 · Benzimidazole derivatives and medical uses thereof

Abstract

The present invention provides benzimidazole derivatives represented by the following formula (I) or pharmaceutically acceptable salts thereof, or prodrugs thereof, which exert an inhibitory activity on sodium-dependent nucleoside transporter 2 and are useful for a disease associated with an abnormality of plasma uric acid level. The compounds of the present invention are useful for the prevention or treatment of gout, hyperuricemia, urinary lithiasis, hyperuricemic nephropathy or the like. In the formula, n is 1 or 2; R1 and R2 are H, a halogen atom, cyano group, optionally substituted alkyl group, optionally substituted aryl group or the like; R3 is H, a halogen atom, optionally substituted alkyl group or the like; R4 and R5 are H, a halogen atom, OH or the like; and R6 and RX are H or OH: RY is F or OH.

A benzimidazole derivative represented by the general formula:

wherein
n represents 1 or 2;
R1 and R2 independently represents a hydrogen atom, a halogen atom, a cyano group, any of the following substituents (A) to (C) which may have the same or different 1 to 3 groups selected from a substituent group α, any of the following substituents (D) to (G) which may have the same or different 1 to 3 groups selected from a substituent groups α and β, or any of the following substituents (H) to (M);
R3 represents a hydrogen atom, a halogen atom, any of the following substituents (A) to (C) which may have the same or different 1 to 3 groups selected from a substituent group α, or any of the following substituents (H) to (M);
(A) a C1-6 alkyl group;
(B) a C2-6 alkenyl group;
(C) a C2-6 alkynyl group;
(D) a C3-8 cycloalkyl group;
(E) a 3 to 10-membered cyclic heterocycloalkyl group;
(F) a C6-10 aryl group;
(G) a 5 to 10-membered cyclic heteroaryl group;
(H)OR7;
(I) SR8;
(J)NR9R10;
(K) COOR11;
(L)CONR12R13;
(M) NHCOR14
in which R7 to R14 independently represents a hydrogen atom, or any of the following substituents (N) to (P) which may have the same or different 1 to 3 groups selected from a substituent group α, or any of the following substituents (Q) to (V) which may have the same or different 1 to 3 groups selected from substituent groups α and β
(N) a C1-6 alkyl group;
(O) a C2-6 alkenyl group;
(P) a C2-6 alkynyl group;
(Q) a C3-8 cycloalkyl group;
(R) a 3 to 10-membered cyclic heterocycloalkyl group;
(S) a quaternary salt of a 3 to 10-membered cyclic nitrogen-containing heterocycloalkyl group;
(T) a C6-10 aryl group;
(U) a 5 to 10-membered cyclic heteroaryl group;
(V) a quaternary salt of a 5 to 10-membered cyclic nitrogen-containing heteroaryl group;
R4 and R5 independently represent a hydrogen atom, a hydroxy group, a C1-6 alkyl group or C1-6 alkoxy group;
R6 and Rx independently represent a hydrogen atom or a hydroxy group;
RY represents a fluorine atom or a hydroxy group,
and with the proviso that at least one of R1, R2 and R3 does not represent a group selected from a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkoxy group, NH2 and COOH
wherein Substituent group α is:
wherein Substituent group α is:
(a) a halogen atom;
(b) a cyano group;
any of the following substituents (c) to (h) which may have the same or different 1 to 3 groups selected from a substituent group γ, or any of the following substituents (i) to (v):
(c) a C3-8 cycloalkyl group;
(d) a 3 to 10-membered cyclic heterocycloalkyl group;
(e) a quaternary salt of a 3 to 10-membered cyclic nitrogen-containing heterocycloalkyl group;
(f) a C6-10 aryl group;
(g) a 5 to 10-membered cyclic heteroaryl group;
(h) a quaternary salt of a 5 to 10-membered cyclic nitrogen-containing heteroaryl group;
(i) OR15;
(j) SR16;
(k) NR17R18;
(l) N+RDRERF;
(m) COOR19;
(o) NHCOR20;
(p) NHC(═NH)—NH2;
(q) C(═NH)—NH2 (which is bound to a nitrogen atom of a nitrogen-containing heterocycloalkyl group);
(r) NR21CONR22R23;
(s)NRGSO2RH;
(t) SO2R1(R1 represents a C1-6 alkyl group, a C2-6 alkenylene group or a hydroxyl (C1-6 alkyl) group);
(u) CONR24R25;
(v) SO2NR26R27
in which RD-F independently represent any of the following substituents (y1) to (y11) which may have the same or different 1 to 3 groups selected from a substituent group γ;
R15,R16, R19-21 and RG-H independently represent a hydrogen atom,
or any of the following substituents (y1) to (y11) which may have the same or different 1 to 3 groups selected from a substituent group γ;
R17, R18 and R22 to R27 independently represent a hydrogen atom, or any of the following substituents (y1) to (y11) which may have the same or different 1 to 3 groups selected from a substituent group γ;
or R17 and R18, R22 and R23, R24 and R25, and R26 and R27 independently may bind together with the neighboring nitrogen atom to form a 3 to 8-membered aliphatic cyclic amino group
(y1) a C1-6 alkyl group;
(y2) a C2-6 alkenyl group;
(y3) a C2-6 alkynyl group;
(y4) a C3-8 cycloalkyl group;
(y5) a 3 to 10-membered cyclic heterocycloalkyl group;
(y6) a C6-10aryl group;
(y7) a 5 to 10-membered cyclic heteroaryl group;
(y8) a C3-8 cycloalkyl-C1-6 alkyl group;
(y9) a 3 to 10-membered cyclic heterocycloalkyl-C1-6 alkyl group;
(y10) a C6-10 aryl-C1-6 alkyl group;
(y11) a 5 to 10-membered cyclic heteroaryl-C1-6 alkyl group
wherein Substituent group β is:
any of the following substituents (z1) to (z3) which may have the same or different 1 to 3 groups selected from a substituent group γ;
substituent group γ:
(z1) a C1-6 alkyl group;
(z2) a C2-6 alkenyl group;
(z3) a C2-6 alkynyl group
wherein Substituent group γ is:
(1) a halogen atom;
(2) a nitro group;
(3) a cyano group;
(4)OR28;
(5)SR29;
(6) NR30RJ wherein R30 and RJ independently represent a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a hydroxy(C1-6 alkyl) group, a C6-10 aryl-C1-6 alkyl group or a C6-10 aryl group;
(7) N+RKRLRM wherein RK-M independently represent a C1-6 alkyl group, a C2-6 alkenyl group, a hydroxy(C1-6 alkyl) group, a C6-10 aryl-C1-6 alkyl group or a C6-10 aryl group);
(8) COR31;
(9) COOR32;
(10) OCOR33;
(11) NHCOR34;
(12) NHC(═NH)—NH2;
(13) C(═NH)—NH2 which is bound to a nitrogen atom of a heterocycloalkyl group
(14)NR35CONR36R37;
(15)NRNCOORO;
(16)CONR38R39;
(17)SO2NR40R41;
(18) a hydroxy(C2-6 alkyl) group;
(19) a 5 to 10-membered cyclic nitrogen-containing heteroaryl group wherein R28, R29, R31-35, RN and RO independently represent a hydrogen atom, a C1-6 alkyl group or a C6-10 aryl-C1-6 alkyl group;
R36 to R41 independently represent a hydrogen atom, or a C1-6 alkyl group, or R36 and R37, R38 and R39, and R40 and R41 independently may bind together with the neighboring nitrogen atom to form a 3 to 8-membered aliphatic cyclic amino group, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

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Benzimidazole derivatives and medical uses thereof

Life of this patent

Benzimidazole derivatives and medical uses thereof

Life of this patent

Abstract

Claims14