US 8,134,015 B2 · Compound inhibiting in vivo phosphorous transport and medicine containing the same

Abstract

An objective of the present invention is to provide compounds that can effectively suppress the concentration of phosphorus in serum to effectively prevent or treat diseases induced by an increase in concentration of phosphate in serum. The compounds according to the present invention are compounds represented by formula (I) and pharmaceutically acceptable salts and solvates thereof: wherein A represents an optionally substituted five- to nine-membered unsaturated carbocyclic moiety or a five- to nine-membered unsaturated heterocyclic moiety, and represents a single bond or a double bond, R5 represents optionally substituted aryl or the like, Z represents —N═CHR6R7 or the like, R6 and R7 represent H, optionally substituted alkyl, optionally substituted aryl or the like, R101 and R102 together form ═O, and R103 and R104 represent H, or R101 and R104 together from a bond, and R102 and R103 together form a bond.

A compound represented by formula (I-1), or a pharmaceutically acceptable salt thereof:

wherein
A represents a five- to nine-membered unsaturated heterocyclic moiety, and selected from the group consisting of formula (IIb), formula (IIc), and formula (IId):
wherein in formula (IIb)
R31 and R32, which may be the same or different, represent a hydrogen atom;
a halogen atom;
or C1-6 alkyl in which the alkyl group is optionally substituted by (1) hydroxyl, (2) thiol, (3) amino, (4) C1-6 alkoxy, (5) C1-6 alkylthio, (6) C1-6 alkylsulfonyl, (7) mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino may form cyclic amino optionally containing 1 to 3 heteroatoms, (8) aryloxy, (9) arylthio, (10) arylsulfonyl, (11) aryl, (12) a heterocyclic group, (13) a halogen atom, or (14) arylamino in which the amino group is optionally substituted by C1-6 alkyl, and the aryl group is optionally substituted by a halogen, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino;
or C2-6 alkenyl,
when R31 and R32 represent C1-6 alkyl or C2-6 alkenyl, the alkyl or the alkenyl groups together with the carbon atoms to which they are respectively attached may form an unsaturated five- to seven-membered carbocyclic ring,
wherein in formula (IIc)
R33 and R34, which may be the same or different, represent a hydrogen atom;
a halogen atom;
or C1-6 alkyl in which the alkyl group is optionally substituted by (1) hydroxyl, (2) thiol, (3) amino, (4) C1-6 alkoxy, (5) C1-6 alkylthio, (6) C1-6 alkylsulfonyl, (7) mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino may form cyclic amino optionally containing 1 to 3 heteroatoms, (9) arylthio, (10) arylsulfonyl, (11) aryl, (12) a heterocyclic group, (13) a halogen atom, or (14) arylamino in which the amino group is optionally substituted by C1-6 alkyl, and the aryl group is optionally substituted by a halogen, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino;
or C2-6 alkenyl,
when R33 and R34 represent C1-6 alkyl or C2-6 alkenyl, alkyl or the alkenyl groups together with the carbon atoms to which they are respectively attached may form an unsaturated five- to seven-membered carbocyclic ring,
wherein in formula (IId)
R35 and R36, which may be the same or different, represent a hydrogen atom;
a halogen atom;
or C1-6 alkyl in which the alkyl group is optionally substituted by (1) hydroxyl, (2) thiol, (3) amino, (4) C1-6 alkoxy, (5) C1-6 alkylthio, (6) C1-6 alkylsulfonyl, (7) mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino may form cyclic amino optionally containing 1 to 3 heteroatoms, (9) arylthio, (10) arylsulfonyl, (11) aryl, (12) a heterocyclic group, (13) a halogen atom, or (14) arylamino in which the amino group is optionally substituted by C1-6 alkyl, and the aryl group is optionally substituted by a halogen, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino;
or C2-6 alkenyl, and
wherein in formula (IIb), formula (IIc), and formula (IId) * represents a bond to —C(═O)—NH(—Z)
represents a single bond or a double bond,
R5 represents C1-6 alkyl, aryl, C1-6 alkoxy, aryloxy, C1-6 alkylamino, arylamino, C1-6 alkylthio, arylthio, C3-7 cycloalkyl, or a heterocyclic group, and the C1-6 alkyl, the aryl, the C1-6 alkoxy, the aryloxy C1-6 the alkylamino, the arylamino, the C1-6 alkylthio, the arylthio, the C3-7 cycloalkyl, or the heterocyclic group represented by R5 is optionally substituted by
(I) a halogen atom;
(II) C1-6 alkyl optionally containing a substituent selected from the group consisting of (1) hydroxyl, (2) thiol, (3) amino, (4) C1-6 alkoxy, (5) C1-6 alkylthio, (6) C1-6 alkylsulfinyl, (7) C1-6 alkylsulfonyl, (8) mono- or di C1-6 alkylamino, (8′) amino substituted by a heterocyclic group optionally substituted by C1-6 alkyl, (9) C1-6 alkylcarbonyloxy, (10) C1-6 alkylcarbonylthio, (11) C1-6 alkylcarbonylamino, (12) aryloxy, (13) arylthio, (14) arylsulfinyl, (15) arylsulfonyl, (16) arylamino, (17) C1-6 alkyl- or aryl-sulfonylamino, (18) C1-6 alkyl- or aryl-ureido, (19) C1-6 alkoxy- or aryloxy-carbonylamino, (20) C1-5 alkylamino- or arylaminocarbonyloxy, (21) carboxyl, (22) nitro, (23) a heterocyclic group, (23′) Het-S(═O)j wherein the Het represents a heterocyclic group, j is 0, 1, or 2, and the Het is optionally substituted by alkyl optionally substituted by mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms and one or two alkyl groups on the amino group and the cyclic amino moiety are optionally substituted by hydroxyl, (24) cyano, and (25) a halogen atom, wherein the alkyl moiety in (4) the C1-6 alkoxy group, (5) the C1-6 alkylthio group, (6) the C1-6 alkylsulfinyl group, and (7) the C1-6 alkylsulfonyl group is optionally substituted by a halogen atom;
C1-6 alkyl;
C1-6 alkoxy;
C1-6 alkylthio;
mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms;
aryloxy;
arylthio;
hydroxyl;
carboxyl;
—S(═O)2(—OH);
C1-6 alkoxy- or aryloxy-carbonyl;
C1-6 alkylcarbonyl;
aryl;
or a heterocyclic group optionally substituted by alkyl optionally substituted by mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms, and one or two alkyl groups on the amino group and the cyclic amino moiety are optionally substituted by hydroxy, and
in (8) the mono- or di-C1-6 alkylamino group, the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms, and one or two alkyl groups on the amino group and the cyclic amino moiety are optionally substituted by a halogen atom;
C1-6 alkyl optionally substituted by hydroxyl, a halogen atom, aryl optionally substituted by a halogen atom, C1-6 alkyl, or C1-6 alkyloxy, or a heterocyclic group optionally substituted by a halogen atom, C1-6 alkyl, or C1-6 alkyloxy, and, when one or two alkyl groups on the amino group and the cyclic amino moiety are substituted by two C1-6 alkyl groups, they together may form C3-7 cycloalkyl;
C1-6 alkoxy;
C1-6 alkylthio;
mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino may form cyclic amino optionally containing 1 to 3 heteroatoms, and one or two alkyl groups on the amino group and the cyclic amino moiety are optionally substituted by hydroxyl;
arylamino in which the amino group is optionally substituted by C1-6 alkyl;
mono- or di-C1-6 alkylcarbamoylmethyl in which the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms, and one or two alkyl groups on the amino group and the cyclic amino moiety are optionally substituted by hydroxyl;
aryloxy;
arylthio;
an oxygen atom (═O);
hydroxyl;
carboxyl;
C1-6 alkoxy- or aryloxy-carbonyl;
C1-6 alkylcarbonyl;
aryl optionally substituted by a halogen atom or hydroxyl;
or a heterocyclic group, and, when one carbon atom in the cyclic amino moiety is substituted by two C1-6 alkoxy groups which may be the same or different, the two alkoxy groups together may form group —O—(CH2)p—O— wherein p is an integer of 2 to 4, and the cyclic amino group may condense with a monocyclic or bicyclic aromatic carbocyclic ring or a monocyclic or bicyclic aromatic heterocyclic ring to represent a bicyclic or tricyclic heterocyclic group;
(III) C1-6 alkoxy optionally substituted by a halogen atom;
(IV) C1-6 alkylthio optionally substituted by a halogen atom;
(V) C3-7 cycloalkyl;
(VI) aryl;
(VII) aryloxy;
(VIII) C1-6 alkylcarbonylamino;
(VIX) C1-6 alkylcarbonyloxy;
(X) hydroxyl;
(XI) nitro;
(XII) cyano;
(XIII) amino;
(XIV) mono or di-C1-6 alkylamino in which the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms;
(XV) arylamino;
(XVI) C1-6 alkyl- or aryl-sulfonylamino;
(XVII) C1-6 alkyl- or aryl-ureido;
(XVIII) C1-6 alkoxy- or aryloxy-carbonylamino;
(XIX) C1-6 alkylamino- or arylamino-carbonyloxy;
(XX) C1-6 alkoxy- or aryloxy-carbonyl;
(XXI) acyl;
(XXII) carboxyl;
(XXIII) carbamoyl;
(XXIV) mono- or di-alkylcarbamoyl;
(XXV) a heterocyclic group;
(XXVI) alkyl- or aryl-sulfonyl;
(XXVII) C2-6 alkenyloxy group;
or
(XXVIII) C2-6 alkenyloxy,
Z represents group (A):
wherein
R6 and R7, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, aryl, aryl C1-6 alkyl, aryl C2-6 alkenyl, or a heterocyclic group, and the C1-6 alkyl, the aryl, the aryl C1-6 alkyl, the aryl C2-6 alkenyl, and the heterocyclic groups, which may be the same or different, are optionally substituted by;
(I) a halogen atom;
(II) C1-6 alkyl optionally having one or more substituents selected from a group consisting of(1) hydroxyl, (2) thiol, (3) amino, (4) C1-6 alkoxy, (5) C1-6 alkylthio optionally substituted by hydroxyl, (6) C1-6 alkylsulfinyl, (7) C1-6 alkylsulfonyl, (8) mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms, (9) C1-6 alkylcarbonyloxy, (10) C1-6 alkylcarbonylthio, (11) C1-6 alkylcarbonylamino, (12) aryloxy, (13) arylthio, (14) arylsulfinyl, (15) arylsulfonyl, (16) arylamino, (17) C1-8 alkyl- or aryl-sulfonylamino, (18) C1-6 alkyl- or aryl-ureido, (19) C1-6 alkoxy- or aryloxy-carbonylamino, (20) C1-6 alkylamino- or arylamino-carbonyloxy, (21) carboxyl, (22) nitro, (23) a heterocyclic group, (23′) Het-S— wherein the Het represents a heterocyclic group, (24) cyano, (25) a halogen atom, and (26) C1-6 alkyl- or aryl-oxycarbonyl;
(III) C1-6 alkoxy optionally having one or more substituents selected from the group consisting of (1) hydroxyl, (2) thiol, (3) amino, (4) C1-6 alkoxy, (5) C1-6 alkylthio optionally substituted by hydroxyl, (6) C1-6 alkylsulfinyl, (7) C1-6 alkylsulfonyl, (8) mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino group may form cyclic amino optionally containing 1 to 3 heteroatoms, (9) C1-6 alkylcarbonyloxy, (10) C1-6 alkylcarbonylthio, (11) C1-6 alkylcarbonylamino, (12) aryloxy, (13) arylthio, (14) arylsulfinyl, (15) arylsulfonyl, (16) arylamino, (17) C1-6 alkyl- or aryl-sulfonylamino, (18) C1-8 alkyl- or aryl-ureido, (19) C1-6 alkoxy- or aryloxy-carbonylamino, (20) C1-6 alkylamino- or arylamino-carbonyloxy, (21) carboxyl, (22) nitro, (23) a heterocyclic group, (23′) Het-S— wherein the Het represents a heterocyclic group, (24) cyano, (25) a halogen atom, and (26) C1-6 alkyl- or aryl-oxycarbonyl;
(IV) C1-6 alkylthio optionally substituted by a halogen atom;
(V) C3-7 cycloalkyl;
(VI) aryl;
(VII) aryloxy;
(VIII) C1-6 alkylcarbonylamino;
(VIX) C1-6 alkylcarbonyloxy;
(X) hydroxyl;
(XI) nitro;
(XII) cyano;
(XIII) amino;
(XIV) mono- or di-C1-6 alkylamino in which the di-C1-6 alkylamino may form cyclic amino optionally containing 1 to 3 heteroatoms;
(XV) arylamino;
(XVI) C1-6 alkyl- or aryl-sulfonylamino;
(XVII) C1-6 alkyl- or aryl-ureido;
(XVIII) C1-6 alkoxy- or aryloxy-carbonylamino;
(XIX) C1-6 alkylamino- or arylamino-carbonyloxy;
(XX) C1-6 alkoxy- or aryloxy-carbonyl;
(XXI) aryl;
(XXII) carboxyl;
(XXIII) carbamoyl;
(XXIV) mono- or di-alkylcarbamoyl;
(XXV) a heterocyclic group;
(XXVI) alkyl- or aryl-sulfonyl;
(XXVII) C2-6 alkenyloxy;
or
(XXVIII) C2-6 alkynyloxy.

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Compound inhibiting in vivo phosphorous transport and medicine containing the same

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Compound inhibiting in vivo phosphorous transport and medicine containing the same

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Abstract

Claims12