US2004002512A1PendingUtilityA1
Alpha-substituted carboxylic acid derivatives
Est. expiryApr 6, 2019(expired)· nominal 20-yr term from priority
A61P 9/10A61P 3/06A61P 43/00A61P 9/12A61P 25/00A61P 35/00A61P 3/10A61P 27/12A61P 29/00C07D 471/04C07D 235/12A61P 11/06C07D 235/06C07H 17/02A61K 31/4184
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Claims
Abstract
The α-substituted carboxylic acid derivatives having the formula (I): wherein R 1 is an alkyl group, etc., R 2 is a hydrogen atom, etc., R 3 is a hydrogen atom, etc., A is ═CH-group, etc., B is an oxygen atom, etc., W 1 is a C 1 -C 8 alkylene group, W 2 is a single bond or a C 1 -C 8 alkylene group, X is a hydrogen atom, etc., Y is an oxygen atom, etc., and Z 1 is an alkoxy group, etc., and pharmacologically acceptable salts, esters and amides thereof are useful for treatment and/or prevention of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, or the like. Some of the derivatives of the formula (I) are novel compounds.
Claims
exact text as granted — not AI-modified1 . An α-substituted carboxylic acid derivative having the general formula (II):
wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents (XI hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents (XI hereafter defined on the aryl moiety thereof), (v) C 1 -C 6 alkylsulfonyl group, (vi) C 1 -C 6 halogenoalkylsulfonyl group, (vii) C 6 -C 10 arylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined) or (viii) C 7 -C 16 aralkylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof);
A is a nitrogen atom or a ═CH-group;
B is an oxygen atom or a sulfur atom;
W 1 is a C 1 -C 8 alkylene group;
W 2 is a single bond or a C 1 -C 8 alkylene group;
X is a (i) hydrogen atom, (ii) C 1 -C 6 alkylene group, (iii) C 1 -C 6 halogenoalkyl group, (iv) C 1 -C 6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C 3 -C 10 cycloalkyl group, (x) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (xi) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof, (xii) C 1 -C 7 aliphatic acyl group, (xiii) C 4 -C 11 cycloalkylcarbonyl group, (xiv) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituents β defined hereafter);
Y is an oxygen atom or an S(O)p group (wherein p is an integer from 0 to 2);
Z 2 is a saturated heterocyclic ring (optionally having 1-5 substituents α 1 hereafter defined) or a C 6 -C 0 aryl group (having 1-5 substituents α 2 hereafter defined), said substituent α 1 is a (i) C 1 -C 6 alkyl group, (ii) C 1 -C 6 halogenoalkyl group, (iii) C 1 -C 6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C 3 -C 10 cycloalkyl group, (ix) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (x) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xi) C 1 -C 7 aliphatic acyl group, (xii) C 4 -C 11 cycloalkylcarbonyl group, (xiii) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xiv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvi) carbamoyl group, (xvii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituents β hereafter defined) or (xix) carboxyl group;
said substituent α 2 is a (i) C 3 -C 10 cycloalkyl group, (ii) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (iii) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (iv) C 1 -C 7 aliphatic acyl group, (v) C 4 -C 11 cycloalkylcarbonyl group, (vi) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (vii) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (viii) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), or (ix) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof);
said substituent β is a (i) C 1 -C 10 alkyl group, (ii) halogen atom, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents γ hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (v) C 1 -C 7 aliphatic acyl group, (vi) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents γ hereafter defined), (vii) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (viii) C 4 -C 11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents γ hereafter defined), (x) carbamoyl group or (xi) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof); and
said substituent γ is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenoalkyl group, a halogen atom or a hydroxy group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
2 . An α-substituted carboxylic acid derivative according to claim 1 , wherein Z 2 is a tetrahydropyranyl group (optionally having 1-5 substituents α 1 ), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
3 . An α-substituted carboxylic acid derivative according to claim 1 , wherein Z 2 is a phenyl group (having one substituent α 2 ), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
4 . An α-substituted carboxylic acid derivative according to any one of claims 1 to 3 , wherein α 2 is a (i) C 6 -C 10 cycloalkyl group, (ii) phenyl group (optionally having 1-3 substituents β), (iii) phenylcarbonyl group (optionally having 1-3 substituents β) or (iv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-3 substituents β), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
5 . An α-substituted carboxylic acid derivative according to any one of claims 1 to 3 , wherein α 2 is a C 6 -C 10 cycloalkyl group, or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
6 . An α-substituted carboxylic acid derivative according to claim 1 , wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 4 alkyl group or (iii) benzyl group (optionally having one substituent (XI on the phenyl moiety thereof);
A is a ═CH-group;
B is an oxygen atom;
W 1 is a C 1 -C 2 alkylene group;
W 2 is a C 1 -C 2 alkylene group;
X is a hydrogen atom;
Y is an oxygen atom or an S(O)p group (in which p is an integer of 0-2);
Z 2 is a tetrahydropyranyl group (optionally having 1-5 substituents α 1 ); and said substituent α 1 is a hydroxy group or a carboxyl group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
7 . An α-substituted carboxylic acid derivative according to claim 1 , wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 4 alkyl group or (iii) benzyl group (optionally having one substituent (XI on the phenyl moiety thereof);
A is a ═CH-group;
B is an oxygen atom;
W 1 is a C 1 -C 2 alkylene group;
W 2 is a C 1 -C 2 alkylene group;
X is a hydrogen atom;
Y is an oxygen atom or an S(O)p group (in which p is an integer of 0-2);
Z 2 is a phenyl group having one substituent (X 2 ;
said substituent α 1 is a halogen atom or an adamantyl group, and said substituent α 2 is an adamantyl group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
8 . An α-substituted carboxylic acid derivative having the general formula (III):
wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 6 -C 10 aryl group (optionally having 1-5,substituents α 1 hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (v) C 1 -C 6 alkylsulfonyl group, (vi) C 1 -C 6 halogenoalkylsulfonyl group, (vii) C 6 -C 10 arylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined) or (viii) C 7 -C 16 aralkylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof);
A is a nitrogen atom or a ═CH-group;
B is an oxygen atom or a sulfur atom;
W 1 is a C 1 -C 8 alkylene group;
W 2 is a single bond or a C 1 -C 8 alkylene group;
X is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 1 -C 6 halogenoalkyl group, (iv) C 1 -C 6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C 3 -C 10 cycloalkyl group, (x) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (xi) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xii) C 1 -C 7 aliphatic acyl group, (xiii) C 4 -C 11 cycloalkylcarbonyl group, (xiv) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituent β hereafter defined on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituents β defined hereafter);
Y is an oxygen atom or an S(O)p group (wherein p is an integer from 0 to 2);
Z 3 is a (i) C 1 -C 6 alkyl group, (ii) C 6 -C 10 aryl group (optionally containing 1-5 substituents α 1 hereafter defined), (iii) C 7 -C 16 aralkyl group (optionally containing 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (iv) C 3 -C 10 cycloalkyl group or (v) saturated heterocyclic ring group (optionally containing 1-5 substituents α 1 hereafter defined);
said substituent α 1 is a (i) C 1 -C 6 alkyl group, (ii) C 1 -C 6 halogenoalkyl group, (iii) C 1 -C 6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C 3 -C 10 cycloalkyl group, (ix) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (x) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xi) C 1 -C 7 aliphatic acyl group, (xii) C 4 -C 11 cycloalkylcarbonyl group, (xiii) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xiv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvi) carbamoyl group, (xvii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituents β defined hereafter) or (xix) carboxyl group;
said substituent β is a (i) C 1 -C 10 alkyl group, (ii) halogen atom, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents γ hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (v) C 1 -C 7 aliphatic acyl group, (vi) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents γ hereafter defined), (vii) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (viii) C 4 -C 11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents γ hereafter defined), (x) carbamoyl group or (xi) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof); and
said substituent γ is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenoalkyl group, a halogen atom or a hydroxy group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
9 . An α-substituted carboxylic acid derivative according to claim 8 , wherein Z 3 is a (i) C 1 -C 4 alkyl group, (ii) C 6 -C 10 aryl group (optionally having 1-3 substituents α 1 ) or (iii) C 3 -C 10 cycloalkyl group), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
10 . An α-substituted carboxylic acid derivative according to claim 8 , wherein Z 3 is a phenyl group (optionally having 1-3 substituents α 1 ), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
11 . An α-substituted carboxylic acid derivative according to claim 8 , wherein:
R 1 , R 2 or R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 4 alkyl group or (iii) benzyl group (optionally having one substituent α 1 on the phenyl moiety thereof);
A is a ═CH-group;
B is an oxygen atom;
W 1 is a C 1 -C 2 alkylene group;
W 2 is a C 1 -C 2 alkylene group;
X is a hydrogen atom;
Y is an oxygen atom or an S(O)p group (in which p is an integer of 0-2);
Z 3 is a (i) C 1 -C 4 alkyl group, (ii) C 6 -C 10 aryl group (optionally having 1-3 substituents α 1 ) or (iii) C 3 -C 10 cycloalkyl group; and
said substituent α 1 is a (i) C 1 -C 4 alkyl group, (ii) halogen atom, (iii) hydroxy group or (iv) adamantyl group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
12 . An α-substituted carboxylic acid derivative according to claim 8 , wherein:
R 1 is a C 1 -C 2 alkyl group;
R 2 is a hydrogen atom;
R 3 is a C 1 -C 4 alkyl group or a phenyl-C 1 -C 4 alkyl group (optionally having one substituent α 1 on the phenyl moiety thereof);
A is a ═CH-group;
B is an oxygen atom;
W 1 is a methylene group;
W 2 is a methylene group;
X is a hydrogen atom;
Y is an oxygen atom or an S(O)p group (in which p is an integer of 0-2);
Z 3 is a phenyl group (optionally having 1-3 substituents α 1 ); and
said substituent α 1 is a C 1 -C 4 alkyl group or a hydroxy group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
13 . An α-substituted carboxylic acid derivative having the general formula (IV):
wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents α 1 hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (v) C 1 -C 6 alkylsulfonyl group, (vi) C 1 -C 6 halogenoalkylsulfonyl group, (vii) C 6 -C 10 arylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined) or (viii) C 7 -C 16 aralkylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof);
R 4 is a (i) C 1 -C 6 alkyl group, (ii) C 6 -C 10 aryl group (optionally having 1-5 substituents α 1 hereafter defined) or (iii) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof);
A is a nitrogen atom or a ═CH-group;
B is an oxygen atom or a sulfur atom;
W 1 is a C 1 -C 8 alkylene group;
W 2 is a single bond or a C 1 -Cg alkylene group;
X is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 1 -C 6 halogenoalkyl group, (iv) C 1 -C 6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C 3 -C 10 cycloalkyl group, (x) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (xi) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xii) C 1 -C 7 aliphatic acyl group, (xiii) C 4 -C 11 cycloalkylcarbonyl group, (xiv) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituents β defined hereafter);
Y is an oxygen atom or an S(O)p group (wherein p is an integer from 0 to 2);
Z 4 is a (i) C 1 -C 6 alkoxy group, (ii) C 1 -C 6 alkylthio group, (iii) halogen atom, (iv) C 6 -C 10 aryl group (optionally having 1-5 substituents α 1 hereafter defined), (v) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (vi) C 6 -C 10 aryloxy group (optionally having 1-5 substituents α 1 hereafter defined), (vii) C 7 -C 16 aralkyloxy group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof, (viii) C 3 -C 10 Cycloalkyloxy group, (ix) C 3 -C 10 cycloalkylthio group, (x) saturated heterocyclic ring-oxy group (optionally having 1-5 substituents α 1 hereafter defined), (xi) monocyclic type heteroaromatic ring-oxy group (optionally having 1-5 substituents α 1 hereafter defined), (xii) C 6 -C 10 arylthio group (optionally having 1-5 substituents α 1 hereafter defined), (xiii) C 7 -C 16 aralkylthio group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (xiv) saturated heterocyclic ring-thio group (optionally having 1-5 substituents α 1 hereafter defined), (xv) monocyclic type heteroaromatic ring-thio group (optionally having 1-5 substituents α 1 hereafter defined), (xvi) amino group (optionally having 1-2 substituents α 1 hereafter defined) or (xvii) hydroxy group;
said substituent α 1 is a (i) C 1 -C 6 alkyl group, (ii) C 1 -C 6 halogenoalkyl group, (iii) C 1 -C 6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C 3 -C 10 cycloalkyl group, (ix) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (x) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xi) C 1 -C 7 aliphatic acyl group, (xii) C 4 -C 11 cycloalkylcarbonyl group, (xiii) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xiv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvi) carbamoyl group, (xvii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituents β defined hereafter) or (xix) carboxyl group;
said substituent β is a (i) C 1 -C 10 alkyl group, (ii) halogen atom, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents γ hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (v) C 1 -C 7 aliphatic acyl group, (vi) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents γ hereafter defined), (vii) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (viii) C 4 -C 11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents γ hereafter defined), (x) carbamoyl group or (xi) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof); and
said substituent γ is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenoalkyl group, a halogen atom or a hydroxy group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
14 . An α-substituted carboxylic acid derivative according to claim 13 , wherein R 4 is a C 1 -C 4 alkyl group or a phenyl group (optionally having 1-3 substituents α 1 ), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
15 . An α-substituted carboxylic acid derivative according to claim 13 , wherein R 4 is a phenyl group (optionally having one substituent α 1 ), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
16 . An α-substituted carboxylic acid derivative according to any one of claims 13 to 15 , wherein Z 4 is a (i) C 1 -C 4 alkoxy group, (ii) C 1 -C 2 alkylthio group, (iii) phenoxy group (optionally having 1-3 substituents α 1 ) or (iv) phenylthio group (optionally having 1-3 substituents α 1 ), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
17 . An α-substituted carboxylic acid derivative according to any one of claims 13 to 15 , wherein Z 4 is a C 1 -C 2 alkoxy group, or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
18 . An α-substituted carboxylic acid derivative according to any one of claims 13 to 15 , wherein Z 4 is a phenoxy group (optionally having 1-3 substituents α 1 ), or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
19 . An α-substituted carboxylic acid derivative according to claim 13 , wherein:
R 1 is a C 1 -C 2 alkyl group;
R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a phenyl group (optionally having one substituent α 1 );
A is a ═CH-group;
B is an oxygen atom;
W 1 is a methylene group;
W 2 is a methylene group;
X is a hydrogen atom;
Z 4 is a C 1 -C 2 alkoxy group; and
said substituent α 1 is a benzoyl group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
20 . An α-substituted carboxylic acid derivative according to claim 13 , wherein:
R 1 is a C 1 -C 2 alkyl group;
R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a phenyl group (optionally having one substituent α 1 );
A is a ═CH-group;
B is an oxygen atom;
W 1 is a methylene group;
W 2 is a methylene group;
X is a hydrogen atom;
Z 4 is a phenoxy group (optionally having 1-3 substituents α 1 );
said substituent α 1 is a C 1 -C 4 alkyl group, a benzoyl group or an amino group (optionally having one substituent β);
said substituent β is a phenylaminocarbonyl group (optionally having one substituent γ on the phenyl moiety thereof); and
said substituent γ is a trifluoromethyl group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
21 . An α-substituted carboxylic acid derivative selected from the group consisting of:
3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-phenyl]-2-(4-fluorobenzyloxy)propionic acid,
3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]-phenyllactic acid,
4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-phenyllactic acid,
4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid,
2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]-propionic acid,
N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)-phenylalanine,
4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
4-[6-[4-(4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,
3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic acid,
3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid,
3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,
3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylthiopropionic acid,
3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid, and
3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
22 . An α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to claim 21 selected from the group consisting of:
3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-phenyl]-2-(4-fluorobenzyloxy)propionic acid,
3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid,
2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]-propionic acid,
N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)-phenylalanine,
4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,
3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic acid, and
3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid.
23 . An α-substituted carboxylic acid derivative according to claim 22 which is
3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-phenyl]-2-(4-fluorobenzyloxy)propionic acid.
24 . An α-substituted carboxylic acid derivative according to claim 22 which is
3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionic acid.
25 . An α-substituted carboxylic acid derivative according to claim 22 which is
2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]-propionic acid.
26 . An α-substituted carboxylic acid derivative according to claim 22 which is
N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)-phenylalanine.
27 . An α-substituted carboxylic acid derivative according to claim 22 which is 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine.
28 . An α-substituted carboxylic acid derivative according to claim 22 which is
3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic acid.
29 . An α-substituted carboxylic acid derivative according to claim 22 which is
3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid.
30 . A pharmaceutical composition comprising an effective amount of a pharmacologically active compound together with a carrier therefor, wherein said pharmacologically active compound is a compound according to any one of claims 1 - 3 , 6 - 15 and 19 - 22 or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
31 . A pharmaceutical composition comprising an effective amount of a pharmacologically active compound together with a carrier therefor, wherein said pharmacologically active compound is a compound according to claim 4 or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
32 . A pharmaceutical composition comprising an effective amount of a pharmacologically active compound together with a carrier therefor, wherein said pharmacologically active compound is a compound according to claim 16 or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
33 . A pharmaceutical composition comprising an effective amount of a pharmacologically active compound together with a carrier therefor, wherein said pharmacologically active compound is a compound according to any one of claims 23 to 29 .
34 . A method of treating a human in need of treatment with an active agent selected from the group consisting of insulin resistance improving agents, hypoglycemic agents, immunoregulatory agents, aldose reductase inhibitors, 5-lipoxygenase inhibitors, peroxidized lipid production suppressors, PPAR activators, leukotriene antagonists, adipose cell formation promotors and calcium antagonists comprising administering an effective amount of said active agent to said human, wherein said active agent is an α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to any one of claims 1 - 3 , 6 - 15 and 19 - 29 .
35 . A method of treating a human in need of treatment with an active agent selected from the group consisting of insulin resistance improving agents, hypoglycemic agents, immunoregulatory agents, aldose reductase inhibitors, 5-lipoxygenase inhibitors, peroxidized lipid production suppressors, PPAR activators, leukotriene antagonists, adipose cell formation promoters and calcium antagonists comprising administering an effective amount of said active agent to said human, wherein said active agent is an α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to claim 5 .
36 . A method of treating a human in need of treatment with an active agent selected from the group consisting of insulin resistance improving agents, hypoglycemic agents, immunoregulatory agents, aldose reductase inhibitors, 5-lipoxygenase inhibitors, peroxidized lipid production suppressors, PPAR activators, leukotriene antagonists, adipose cell formation promotors and calcium antagonists comprising administering an effective amount of said active agent to said human, wherein said active agent is an α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to claim 17 .
37 . A method of treating a human in need thereof according to claim 34 wherein said active agent is a hypoglycemic agent.
38 . A method of treatment or prophylaxis of a disease selected from the group consisting of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, neurosis, cataract and coronary artery diseases comprising administering to a human in need thereof, an effective amount of an active agent, wherein said active agent is an α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to any one of claims 1 - 3 , 6 - 15 and 19 - 22 .
39 . A method of treatment or prophylaxis of a disease selected from the group consisting of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, neurosis, cataract and coronary artery diseases comprising administering to a human in need thereof, an effective amount of an active agent, wherein said active agent is an α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to claim 4 .
40 . A method of treatment or prophylaxis of a disease selected from the group consisting of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, neurosis, cataract and coronary artery diseases comprising administering to a human in need thereof an effective amount of an active agent, wherein said active agent is an α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to claim 18 .
41 . A method of treatment or prophylaxis of a disease selected from the group consisting of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, neurosis, cataract and coronary artery diseases comprising administering to a human in need thereof, an effective amount of an active agent, wherein said active agent is an α-substituted carboxylic acid derivative or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof according to any one of claims 23 - 29 .
42 . A method according to claim 38 wherein said disease is diabetes mellitus.
43 . A method according to claim 39 wherein said disease is diabetes mellitus.
44 . A method according to claim 40 wherein said disease is diabetes mellitus.
45 . A method according to claim 41 wherein said disease is diabetes mellitus.
46 . A method of treatment or prophylaxis of a disease selected from the group consisting of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, neurosis, cataract and coronary artery diseases comprising administering to an animal in need thereof, an effective amount of an active agent, wherein said active agent is an α-substituted carboxylic acid derivative of the general formula (I):
wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents α 1 hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (v) C 1 -C 6 alkylsulfonyl group, (vi) C 1 -C 6 halogenoalkylsulfonyl group, (vii) C 6 -C 10 arylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined) or (viii) C 7 -C 16 aralkylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof);
A is a nitrogen atom or a ═CH-group;
B is an oxygen atom or a sulfur atom;
W 1 is a C 1 -C 8 alkylene group;
W 2 is a single bond or a C 1 -C 8 alkylene group;
X is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 1 -C 6 halogenoalkyl group, (iv) C 1 -C 6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C 3 -C 10 cycloalkyl group, (x) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (xi) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xii) C 1 -C 7 aliphatic acyl group, (xiii) C 4 -C 11 cycloalkylcarbonyl group, (xiv) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituents β defined hereafter);
Y is an oxygen atom or an S(O)p group (wherein p is an integer from 0 to 2);
Z 1 is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 1 -C 6 alkoxy group, (iv) C 1 -C 6 alkylthio group, (v) halogen atom, (vi) C 6 -C 10 aryl group (optionally having 1-5 substituents α 1 hereafter defined), (vii) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (viii) C 6 -C 10 aryloxy group (optionally having 1-5 substituents α 1 hereafter defined), (ix) C 7 -C 16 aralkyloxy group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (x) C 3 -C 10 cycloalkyloxy group, (xi) C 3 -C 10 cycloalkylthio group, (xii) saturated heterocyclic ring-oxy group (optionally having 1-5 substituents α 1 hereafter defined), (xiii) monocyclic type heteroaromatic ring-oxy group (optionally having 1-5 substituents α 1 hereafter defined), (xiv) C 6 -C 10 arylthio group (optionally having 1-5 substituents α 1 hereafter defined), (xv) C 7 -C 16 aralkylthio group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (xvi) saturated heterocyclic ring-thio group (optionally having 1-5 substituents α 1 hereafter defined), (xvii) monocyclic type heteroaromatic ring-thio group (optionally having 1-5 substituents α 1 hereafter defined), (xviii) amino group (optionally having 1-2 substituents α 1 hereafter defined) or (xix) hydroxy group;
said substituent α 1 is a (i) C 1 -C 6 alkyl group, (ii) C 1 -C 6 halogenoalkyl group, (iii) C 1 -C 6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C 3 -C 10 cycloalkyl group, (ix) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (x) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xi) C 1 -C 7 aliphatic acyl group, (xii) C 4 -C 11 cycloalkylcarbonyl group, (xiii) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xiv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvi) carbamoyl group, (xvii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituents β defined hereafter) or (xix) carboxyl group;
said substituent β is a (i) C 1 -C 10 alkyl group, (ii) halogen atom, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents γ hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (v) C 1 -C 7 aliphatic acyl group, (vi) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents γ hereafter defined), (vii) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (viii) C 4 -C 11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents γ hereafter defined), (x) carbamoyl group or (xi) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof); and
said substituent γ is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenoalkyl group, a halogen atom or a hydroxy group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
47 . A method according to claim 46 wherein R 1 , R 2 and R 3 are the same or different and each is a (i) hydrogen atom, (ii) C 1 -C 4 alkyl group, (iii) phenyl group (optionally having one substituent α 1 ), (iv) phenyl-C 1 -C 2 alkyl group (optionally having 1-3 substituents α 1 on the phenyl moiety thereof) or (v) C 1 -C 2 alkylsulfonyl group.
48 . A method according to claim 46 wherein R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 4 alkyl group or (iii) benzyl group (optionally having one substituent α 1 on the phenyl moiety thereof).
49 . A method according to claim 46 wherein R 1 is a C 1 -C 2 alkyl group, R 2 is a hydrogen atom and R 3 is a C 1 -C 4 alkyl group or a phenyl-C 1 -C 4 alkyl group (optionally having one substituent α 1 on the phenyl moiety thereof).
50 . A method according to claim 46 wherein R 1 is a C 1 -C 2 alkyl group, R 2 is a hydrogen atom and R 3 is a hydrogen atom.
51 . A method according to claim 46 wherein A is a ═CH-group.
52 . A method according to claim 46 wherein B is an oxygen atom.
53 . A method according to claim 46 wherein W 1 is a C 1 -C 4 alkylene group.
54 . A method according to claim 46 wherein W 1 is a C 1 -C 2 alkylene group.
55 . A method according to claim 46 wherein W 2 is a C 1 -C 4 alkylene group.
56 . A method according to claim 46 wherein W 2 is a methylene group.
57 . A method according to claim 46 wherein X is a (i) hydrogen atom, (ii) C 1 -C 2 alkyl group, (iii) halogen atom, (iv) hydroxy group, (v) C 1 -C 2 aliphatic acyl group or (vi) amino group.
58 . A method according to claim 46 wherein X is a hydrogen atom.
59 . A method according to claim 46 wherein Z 1 is a (i) C 1 -C 2 alkoxy group, (ii) C 1 -C 2 alkylthio group, (iii) halogen atom, (iv) phenoxy group (optionally having 1-5 substituents α 1 ), (v) saturated heterocyclic ring-oxy group (optionally having 1-5 substituents α 1 ), (vi) phenylthio group (optionally having 1-5 substituents α 1 ), (vii) saturated heterocyclic ring-thio group (optionally having 1-5 substituents α 1 ), (viii) amino group or (ix) hydroxy group.
60 . A method according to claim 46 wherein Z 1 is a (i) C 1 -C 2 alkoxy group, (ii) C 1 -C 2 alkylthio group, (iii) phenoxy group (optionally having 1-5 substituents α 1 ), (iv) saturated heterocyclic ring-oxy group (optionally having 1-5 substituents α 1 ), (v) phenylthio group (optionally having 1-5 substituents α 1 ) or (vi) hydroxy group.
61 . A method according to claim 46 wherein the substituent α 1 is a (i) C 1 -C 4 alkyl group, (ii) C 1 -C 2 halogenoalkyl group, (iii) C 1 -C 2 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantyl group, (ix) benzoyl group (optionally having one substituent α 1 , (x) amino group (optionally having one substituent β) or (xi) carboxyl group.
62 . A method according to claim 46 wherein the substituent α 1 is a (i) C 1 -C 4 alkyl group, (ii) halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoyl group, (vi) amino group (optionally having one substituent β) or (vii) carboxyl group.
63 . A method according to claim 46 wherein the substituent α 1 is C 1 -C 4 alkyl group or hydroxy group.
64 . A method according to claim 46 wherein the substituent α 1 is a halogen atom or an adamantyl group.
65 . A method according to claim 46 wherein the substituent α 1 is a C 1 -C 4 alkyl group, a benzoyl group or an amino group (optionally having one substituent β).
66 . A method according to claim 46 wherein the substituent β is a (i) C 1 -C 4 alkyl group, (ii) halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3 substituents γ on the phenyl moiety thereof).
67 . A method according to claim 46 wherein the substituent β is a phenylaminocarbonyl group (optionally having one substituent γ on the phenyl moiety thereof).
68 . A method according to claim 46 wherein the substituent γ is a trifluoromethyl group or a halogen atom.
69 . A method according to claim 46 wherein the substituent γ is a trifluoromethyl group.
70 . A method according to claim 46 wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 4 alkyl group, (iii) phenyl group (optionally having one substituent α 1 ), (iv) phenyl-C 1 -C 2 alkyl group (optionally having 1-3 substituents α 1 on the phenyl moiety thereof) or
(v) C 1 -C 2 alkylsulfonyl group;
A is a ═CH-group;
B is an oxygen atom;
W 1 is a C 1 -C 2 alkylene group;
W 2 is a C 1 -C 2 alkylene group;
X is a (i) hydrogen atom, (ii) C 1 -C 2 alkyl group, (iii) halogen atom, (iv) hydroxy group, (v) C 1 -C 2 aliphatic acyl group or (vi) amino group;
Y is an oxygen atom or an S(O)p group (in which p is an integer of 0-2);
Z 1 is a (i) C 1 -C 2 alkoxy group, (ii) C 1 -C 2 alkylthio group, (iii) halogen atom, (iv) phenoxy group (optionally having 1-5 substituents α 1 ), (v) saturated heterocyclic ring-oxy group (optionally having 1-5 substituents α 1 ), (vi) phenylthio group (optionally having 1-5 substituents α), (vii) saturated heterocyclic ring-thio group (optionally having 1-5 substituents α 1 ), (viii) amino group or (ix) hydroxy group;
said substituent α 1 is a (i) C 1 -C 4 alkyl group (ii) C 1 -C 2 halogenoalkyl group, (iii) C 1 -C 2 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantyl group, (ix) benzoyl group (optionally having one substituent β) (x) amino group (optionally having one substituent β), or (xi) carboxyl group;
said substituent β is a (i) C 1 -C 4 alkyl group, (ii) halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3 substituents γ on the phenyl moiety thereof); and
said substituent γ is a trifluoromethyl group or a halogen atom.
71 . A method according to claim 46 wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 4 alkyl group or (iii) benzyl group (optionally having one substituent α on the phenyl moiety thereof);
A is a ═CH-group;
B is an oxygen atom;
W 1 is a C 1 -C 2 alkylene group;
W 2 is a methylene group;
X is a hydrogen atom;
Y is an oxygen atom or an S(O)p group (in which p is an integer from 0-2);
Z 1 is a (i) C 1 -C 2 alkoxy group, (ii) C 1 -C 2 alkylthio group, (iii) phenoxy group (optionally having 1-5 substituents α 1 ), (iv) saturated heterocyclic ring-oxy group (optionally having 1-5 substituents α 1 ), (v) phenylthio group (optionally having 1-5 substituents α 1 ) or (vi) hydroxy group;
said substituent α 1 is a (i) C 1 -C 4 alkyl group (ii) halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoyl group (vi) amino group (optionally having one substituent β or (vii) carboxyl group;
said substituent β is a phenylaminocarbonyl group (optionally having one substituent γ on the phenyl moiety thereof); and
said substituent γ is a trifluoromethyl group.
72 . A method according to any one of claims 46 - 71 wherein said disease is diabetes mellitus.
73 . A method of treating an animal in need of treatment with an active agent selected from the group consisting of insulin resistance improving agents, hypoglycemic agents, immunoregulatory agents, aldose reductase inhibitors, 5-lipoxygenase inhibitors, peroxidized lipid production suppressors, PPAR activators, leukotriene antagonists, adipose cell formation promoters and calcium antagonists comprising administering an effective amount of said active agent to said animal, wherein said active agent is an α-substituted carboxylic acid derivative of the general formula (I):
wherein:
R 1 , R 2 and R 3 are the same or different, and each is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents α 1 hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (v) C 1 -C 6 alkylsulfonyl group, (vi) C 1 -C 6 halogenoalkylsulfonyl group, (vii) C 6 -C 10 arylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined) or (viii) C 7 -C 16 aralkylsulfonyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof);
A is a nitrogen atom or a ═CH-group;
B is an oxygen atom or a sulfur atom;
W 1 is a C 1 -Cg alkylene group;
W 2 is a single bond or a C 1 -C 8 alkylene group;
X is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 1 -C 6 halogenoalkyl group, (iv) C 1 -C 6 alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C 3 -C 10 cycloalkyl group, (x) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (xi) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xii) C 1 -C 7 aliphatic acyl group, (xiii) C 4 -C 11 cycloalkylcarbonyl group, (xiv) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xv) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof) or (xix) amino group (optionally having 1 to 2 substituents β defined hereafter);
Y is an oxygen atom or an S(O)p group (wherein p is an integer from 0 to 2);
Z 1 is a (i) hydrogen atom, (ii) C 1 -C 6 alkyl group, (iii) C 1 -C 6 alkoxy group, (iv) C 1 -C 6 alkylthio group, (v) halogen atom, (vi) C 6 -C 10 aryl group (optionally having 1-5 substituents α 1 hereafter defined), (vii) C 7 -C 16 aralkyl group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (viii) C 6 -C 10 aryloxy group (optionally having 1-5 substituents α 1 hereafter defined), (ix) C 7 -C 16 aralkyloxy group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (x) C 3 -C 10 cycloalkyloxy group, (xi) C 3 -C 10 cycloalkylthio group, (xii) saturated heterocyclic ring-oxy group (optionally having 1-5 substituents α 1 hereafter defined), (xiii) monocyclic type heteroaromatic ring-oxy group (optionally having 1-5 substituents α 1 hereafter defined), (xiv) C 6 -C 10 arylthio group (optionally having 1-5 substituents α 1 hereafter defined), (xv) C 7 -C 16 aralkylthio group (optionally having 1-5 substituents α 1 hereafter defined on the aryl moiety thereof), (xvi) saturated heterocyclic ring-thio group (optionally having 1-5 substituents α 1 hereafter defined), (xvii) monocyclic type heteroaromatic ring-thio group (optionally having 1-5 substituents α 1 hereafter defined), (xviii) amino group (optionally having 1-2 substituents α 1 hereafter defined) or (xix) hydroxy group;
said substituent α 1 is a (i) C 1 -C 6 alkyl group, (ii) C 1 -C 6 halogenoalkyl group, (iii) C 1 -C 6 alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C 3 -C 10 cycloalkyl group, (ix) C 6 -C 10 aryl group (optionally having 1-5 substituents β hereafter defined), (x) C 7 -C 16 aralkyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xi) C 1 -C 7 aliphatic acyl group, (xii) C 4 -C 11 cycloalkylcarbonyl group, (xiii) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents β hereafter defined), (xiv) C 9 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xv) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents β hereafter defined), (xvi) carbamoyl group, (xvii) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents β hereafter defined on the aryl moiety thereof), (xviii) amino group (optionally having 1 to 2 substituents β defined hereafter) or (xix) carboxyl group;
said substituent β is a (i) C 1 -C 10 alkyl group, (ii) halogen atom, (iii) C 6 -C 10 aryl group (optionally having 1-5 substituents γ hereafter defined), (iv) C 7 -C 16 aralkyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (v) C 1 -C 7 aliphatic acyl group, (vi) C 7 -C 11 arylcarbonyl group (optionally having 1-5 substituents γ hereafter defined), (vii) C 8 -C 17 aralkylcarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof), (viii) C 4 -C 11 cycloalkylcarbonyl group, (ix) monocyclic type heteroaromatic ring-carbonyl group (optionally having 1-5 substituents γ hereafter defined), (x) carbamoyl group or (xi) C 7 -C 11 arylaminocarbonyl group (optionally having 1-5 substituents γ hereafter defined on the aryl moiety thereof); and
said substituent γ is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenoalkyl group, a halogen atom or a hydroxy group;
or a pharmacologically acceptable ester thereof, a pharmacologically acceptable amide thereof or a pharmacologically acceptable salt thereof.
74 . A method according to claim 73 wherein said active agent is an insulin resistance improving agent.
75 . A method according to claim 73 wherein said active agent is a hypoglycemic agent.Join the waitlist — get patent alerts
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