JPH1072371A - Inhibitor of ileum type bile acid transporter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an inhibitor of an ileum type bile acid transporter, hardly causing adverse effects, excellent in effectiveness and safety and useful as a preventing and therapeutic agent, etc., for hyperlipemia by including an insulin- resistant improving substance as an active ingredient therein. SOLUTION: This inhibitor of an ileum type bile acid transporter comprises an insulin-resistant improving substance such as a thiazolidonedione derivative represented by formula I [R<1> and R<2> are each H, a lower alkyl, a (substituted) aryl or a heterocyclic ring; R<4> is H, hydroxyl group, a lower alkyl, etc.; R<5> is a lower alkyl; (m) and (n) are each 0-2] or formula II [R<1> is a (substituted) aryl; A is an alkylene; B is a lower alkylene; R<2> and R<3> are each H or a halogen; Y is O or imino], e.g. 5-((4-(2-(methyl-2-(pyridin-2-yl)amino)ethoxy)phenyl) methyl)-2,4-thiazolidinedione as an active ingredient. Furthermore, the daily dose of the active ingredient for an adult is preferably within the range of 10-2,000mg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an ileal bile acid transporter inhibitor comprising an insulin resistance improving substance as an active ingredient.

[0002]

2. Description of the Related Art Hyperlipidemia is one of the three major risk factors for ischemic heart disease such as arteriosclerosis. It recognized. HMG-C currently on the market
An oA reductase inhibitor is a potent therapeutic agent for hyperlipidemia and not only inhibits cholesterol synthesis but also LDL (l
It is thought to have the effect of increasing ow density (lipoprotein) receptor, taking up blood cholesterol, and promoting excretion into bile. The efficacy and safety of these drugs are widely recognized and used by many patients.

On the other hand, as a conventionally known treatment method for hyperlipidemia, an anion exchange resin is orally administered to adsorb bile acids, thereby preventing reabsorption and promoting conversion of cholesterol to bile acids in the liver. As a result, there are methods for lowering blood cholesterol levels. For example, a method using cholestyramine has already been put to practical use, and since it is not absorbed into the body, it is regarded as a first-line drug in the treatment of hyperlipidemia in children who require more safety. However, cholestyramine has drawbacks such as a very large dose per dose when taken and a rough feeling of resin remaining in the mouth, making it extremely difficult for patients to take. In addition, certain types of vitamins and drugs are also adsorbed by the resin and are discharged, so that it is necessary to consider replenishment of vitamins and changes in the administration method of concomitant drugs, and thus there are many problems.

[0004] In recent years, a protein that functions in bile acid reabsorption in the ileum, ie, an ileal bile acid transporter, has been cloned (Wong MH et al., "Journal of Biologica").
l Chemistry ", Volume 269, pp. 1340-1347 (1994). The ileal bile acid transporter is considered to be a protein that acts as the first step in bile acid reabsorption in the ileum. Therefore, it physically adsorbs bile acids. It is expected that the ileal bile acid transporter will exert the same pharmacological action as cholestyramine if it inhibits the action of the ileal bile acid transporter as well as inhibits the absorption of the ileal bile acid transporter. It is clear that the ileal bile acid transporter is different from the transporter, and the ileal bile acid transporter and hepatic bile acid transporter also have different reactivity to drugs. It may be possible to develop a therapeutic agent for hyperlipidemia that exhibits the same pharmacological action as cholestyramine and overcomes the disadvantages of cholestyramine. You.

[0005] From such an idea, it was attempted to find an inhibitor from a bile acid derivative (Wess G. et al., "Jo
urnal of Medicinal Chemistry ", 37, 873-875 (1
994)), but no truly potent inhibitors have been obtained. The ileal bile acid transporter inhibitory activity has also been reported for cyclosporin A, which is known as an immunosuppressant (Sauer P. et al., "European Journal of Clin
ical Investigation ", Volume 25, pp. 677-682 (1995)
), Cyclosporin A is also known to inhibit liver-type bile acid transporters (Stacey NH and
kotecka B., "Gastroenterology", Volume 95, pp. 780-786
(1988)), but not a specific inhibitor.

Have found 2164U90 as a compound that acts strongly on the ileal bile acid transporter (Lewis MC et al., "Journal of Lipid Resea
rch ", 36, 1098-1105 (1995) and Root C.,
et al., "Journal of LipidResearch", 36, 1106-111
5 (1995)). 2164U90 is a brush border membrane vesicle prepared from rat, monkey and human ileum.
rane vesicles), as well as inhibiting the activity of bile acid transporters,
-2 also inhibits the activity of bile acid transporters in cells.
However, it does not inhibit the transporter activity of glucose, indicating specificity for the transport molecule. Furthermore, the experimental system using the inverted intestinal tract of the rat ileum also inhibits bile acid transporter activity, inhibits reabsorption of bile acids in rats and mice in vivo, and consequently lowers blood cholesterol levels. Admitted. 21
The effect of 64U90 in vivo was 30 mg / kg equivalent to cholestyramine 500 mg / kg.
It is presumed that the cholestyramine overcame the disadvantages of cholestyramine. However, 2164
U90 has problems such as poor solubility, and its safety has not been sufficiently confirmed. Thus, there is a need for the development of more potent, specific and safe ileal bile acid transporter inhibitors from more candidate compounds. From such a viewpoint, a physiologically active substance showing specific inhibition to the ileal bile acid transporter is desired.

[0007] Meanwhile, thiazolidine derivatives such as troglitazone have been developed as antidiabetic drugs, are effective for insulin-resistant diabetes, have a hypoglycemic action in vivo, and increase glycogen synthase activity in vitro. It is reported to enhance insulin action (Fujiwara T. et al., "Di
abetes ", 37, 1549-1558 (1998) and Ciar
aldi TP et al., "Metabolism", 39, 1056-1062 (1
990)). Furthermore, in addition to its glucose lowering effect, it suppresses the effects of inflammatory cytokines such as TNF,
It is mainly known to promote the differentiation of 3T3 cells into adipocytes (Ohsumi J. et al., "Endocrinology", 135
Volume 2279-2282 (1994) and Szalkowski D., et.
al., "Endocrinology", 136, 1474-1481 (1995
)), But no effect on bile acid transporters is known. The mechanism of action of the thiazolidine derivative is PPAR which is a cell nuclear receptor protein.
Although it has been suggested to be via gamma (Forman
BM et al., "Cell", 83, 803-812 (1995)
), The relationship between PPAR gamma and bile acid transporters is not known at all.

[0008]

SUMMARY OF THE INVENTION The present inventors have conducted studies on an ileal bile acid transporter inhibitor, and as a result, have found that certain ileal bile acid transporters have an effect of significantly inhibiting insulin bile acid transporter. The substance was found and the present invention was completed. The inhibitor is expected as a therapeutic and / or prophylactic agent for hyperlipidemia.

[0009]

Means for Solving the Problems The present invention relates to [1] an ileal bile acid transporter inhibitor comprising an insulin resistance improving substance as an active ingredient.

The insulin resistance ameliorating substance which is the active ingredient compound of the present invention is originally used for the prevention and / or treatment of diabetes and encompasses a very wide range of compounds. Representative examples thereof include thiazolidinedione compounds, oxazolidinedione compounds and oxathiadiazole compounds, which are described, for example, in (I) WO 94/01433 (= JP-A-6-8066).
No. 7), (II) JP-A-4-69383, (III) WO 92/02520 (= Tokuhyo Hei 6-50)
0538), (IV) WO 91/07107 (= JP-A-3-170)
No. 478 = Japanese Patent Publication No. 7-8862), (V) US Pat.
No. 1), (VI) U.S. Pat. No. 4,897,405 (= JP-A-2-29)
No. 2272), (VII) WO 89/08651 (= JP-A 1-27)
No. 2574), (VIII) US Pat.
No. 4,522,522 (= JP-A-1-272573), (IX) U.S. Pat.
5232925, 5260445 (= JP-A-1-131
No. 169), (X) U.S. Pat. No. 4,180,091 (= JP-A-64-13)
076), (XI) U.S. Pat. Nos. 4,897,393 and 4,948,900.
(= JP-A-64-56675 = Japanese Patent Publication No. 5-5832)
(XII), U.S. Pat.
No. 38090), (XIII) U.S. Pat.
-271287 = Japanese Patent Publication 5-86953), (XIV) U.S. Pat.
(XV) U.S. Pat. No. 4,725,610 (= JP-A-61-8)
No. 5372 = Japanese Patent Publication No. 5-66956), (XVI) U.S. Pat.
No. 51189 = Japanese Patent Publication No. 2-31079), (XVII) U.S. Pat.
-118577 = Japanese Patent Publication No. 2-57546), (XVIII) U.S. Pat.
05, 4438141, 444479 (= Japanese Patent Laid-Open No. 55-55)
No. 22636 = JP-B-62-42903), (XIX) EP 0708098A, (XX) EP 0676398A (= JP-A-7-330)
728), and the like.

For example, (I) WO 94/01433 (= JP-A-6-8066)
No. 7) includes (1) general formula

[0012]

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(Wherein R ¹ and R ² are each independently substituted with a hydrogen atom, a lower alkyl group or a lower alkyl group, an acyl group, a lower alkoxy group, a cyano group, a nitro group, a lower alkoxycarbonyl group, and a sulfonyl group. R ⁴ represents a hydrogen atom, a hydroxyl group, a lower alkyl group, an acyl group, a lower alkoxy group, a cyano group, a nitro group, a lower alkoxycarbonyl group or a sulfonyl group; ⁵ represents a lower alkyl group; m represents 0 or an integer of 1 to 2; n represents 0 or 1 to 2;
A thiazolidinedione derivative represented by the formula: or a pharmaceutically acceptable salt thereof, (2) In particular, R ¹ and R
² is a hydrogen atom, a lower alkyl group or an aryl group, R ⁴ is a hydrogen atom, R ⁵ is a methyl group, m is 0, and n is 0. A thiazolidinedione derivative or a pharmaceutically acceptable salt thereof,
(3) In particular, the general formula

[0014]

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Wherein R ¹ , R ² , m and n are as described in (1), (4)
A compound according to (3), wherein R ¹ , R ² , m and n are as described in (2), (5) a compound of the general formula

[0016]

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Wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n are as described in (1), and R ³ is a hydrogen atom or a lower alkyl group; (6) In particular, the compound according to (5), wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n are as described in (2), and R ³ is as described above, (7) General formula

[0018]

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Wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n are as described in (1),
(8) In particular, the compound according to (7), wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n are as described in (2), (9)
In particular, the general formula

[0020]

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Wherein R ¹ , R ² , R ⁴ , R ⁵ , m and n are as described in (1), and X is a leaving group, (10) , R ¹ , R ² , R ⁴ ,
The compound according to (9), wherein R ⁵ , m and n are as described in (2), and X is as described above.

(II) JP-A-4-69383 discloses that
(1) General formula

[0023]

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(Wherein, R ¹ represents a substituted or unsubstituted aryl group, A represents an alkylene group, B represents a lower alkylene group, R ² and R ³ represent a hydrogen atom or a halogen atom, Represents an oxygen atom or an imino group.) Or a salt thereof.

(III) WO 92/02520 (= Japanese Translation of PCT Application No. 6-500538) has the formula (1)

[0026]

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Wherein A ¹ is a substituted or unsubstituted aromatic heterocyclyl group: R ¹ is a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl group is substituted or substituted Or a substituted or unsubstituted aryl group: A ² is a benzene ring having up to a total of 5 substituents: and n represents an integer in the range of 2 to 6]. Or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, (2)
In particular, the compound according to (1), wherein A ¹ is a substituted or unsubstituted mono- or condensed aromatic heterocyclyl group containing up to 4 heteroatoms selected from oxygen, sulfur or nitrogen in each ring. (3) In particular, the compound according to (1), wherein A ¹ is thiazolyl, oxazolyl, pyridyl or pyrimidinyl, (4) In particular, A ¹ is of the formula (a), (b) or (c):

[0028]

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Wherein R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group, or R ⁴ and R ⁵ are each bonded to an adjacent carbon atom R ⁴ and R ⁵ together with the carbon atom to which they are attached, together form a benzene ring (where
The carbon atom represented by R ⁴ and R ^{5 taken} together may be substituted or unsubstituted, respectively, wherein X in the group of formula (a) is oxygen or (5) In particular, the compound according to (1), wherein A ¹ is a group of the formula (a), (6) In particular, R ⁴ And R ⁵ together form formula (d):

[0030]

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Wherein R ⁶ and R ⁷ are each independently
Hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy], the compound according to (1), wherein A ² is a group represented by formula (e):

[0032]

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Wherein R ⁸ and R ⁹ are each independently
Hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy], (8) a compound represented by the formula (II):

[0034]

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Wherein A ¹ , R ¹ and n are the same as those described for formula (I), and R ⁸ and R ⁹ are the same as those described for formula (e), or a tautomeric form thereof. And / or a pharmaceutically acceptable solvate thereof, (9)
In particular, the compound according to (1), wherein n is an integer of 2, 3 or 4, (10) especially 5- (4- [2- (N-methyl-N- (2-benzoxazolyl) amino) ethoxy). ]
Benzyl) -2,4-oxazolidinedione: or the tautomeric form thereof and / or the pharmaceutically acceptable salt thereof and / or the compound according to (1), which is a pharmaceutically acceptable solvate thereof. ing.

(IV) WO 91/07107 (= JP-A-3-170478 = Japanese Patent Publication No. 7-8862)
(1) Expression

[0037]

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(Where the dotted line represents a bond or a non-bond,
R is cycloalkyl having 3 to 7 carbon atoms, naphthyl, thienyl, furyl, phenyl or a group having 1 to 3 carbon atoms.
Alkyl, -C 1-3 alkoxy, trifluoromethyl, chloro, a substituted phenyl, fluoro or bis (trifluoromethyl); R ₁ is alkyl of 1-3 carbon atoms; X is O Or C = O; A is O or S; R is N or CH)
Or a pharmaceutically acceptable salt thereof, (2)
In particular, in formula I, the compound according to (1), wherein the dotted line represents non-bonding, (3) the compound according to (2), wherein R ₁ is methyl, X is O, and A is O, (4)
In particular, the compound according to (3), wherein R is phenyl, (5)
In particular, the compound according to (3), wherein R is 2-naphthyl,
(6) In particular, the compound according to (3), wherein R is 3,5-bis (trifluoromethyl) phenyl; (7) the compound according to (1), particularly, in Formula II, wherein the dotted line represents non-bonding; 8) In particular, R ₁ is methyl and A is O
(9) In particular, the compound according to (8), wherein R is phenyl and B is CH.
(10) In particular, R is p-tolyl and B is C
A compound according to (8), wherein H is H, (11) especially a compound according to (8), wherein R is cyclohexyl and B is CH, (12) especially a compound wherein R is m-tolyl and B is (8) The compound according to (8), which is CH, (13) especially the compound according to (8), wherein R is phenyl and B is N, (14) especially the compound wherein R is β-naphthyl, and B is The compound according to (8), which is CH, is described.

(V) US Pat. No. 5,132,317 (= JP-A-3-90071) discloses that (1) the formula (I):

[0040]

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In the compound or a tautomeric form thereof, and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, A ¹ represents a substituted or unsubstituted aryl group, A ² represents a benzene ring having a total of up to 5 substituents, X is O, S or NR ¹ [R ¹ is a halogen atom, an alkyl group, an acyl group, an aralkyl group (the aryl group portion is substituted or unsubstituted) Or a substituted or unsubstituted aryl group, Y represents O or S, R ² represents hydrogen,
R ³ represents hydrogen or an alkyl, aralkyl or aryl group, or R ² together with R ³ represents a bond, and n represents an integer in the range of 2 to 6, Or a tautomeric form thereof, and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, (2) In particular, A ¹ is halogen, alkyl, phenyl, alkoxy, haloalkyl,
(1) The compound according to (1), which represents phenyl or naphthyl optionally substituted with up to 5 groups selected from hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl. 3) In particular,
(1) The compound according to (1) or (2), wherein A ¹ represents a phenyl group, (4) In particular, any one of the above items (1) to (3), wherein R ² represents hydrogen and R ³ represents an alkyl group. (5) In particular, the compound according to any one of (1) to (3), wherein R ² and R ³ each independently represent hydrogen, (6) In particular, A ¹ is a group represented by the formula (a) ):

[0042]

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Wherein R ⁴ and R ⁵ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy, and any one of the above items (1) to (5) (7) In particular, the compound according to (6), wherein R ⁴ and R ⁵ each independently represent hydrogen, halogen, alkyl, or alkoxy, (8) In particular, X is O, and Y is O The compound according to any one of (1) to (7), (9) especially the compound of the formula (II):

[0044]

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(Where A ¹ , X, Y, R ² , R ³ , and n are as defined for formula (I) in (1), and R ⁴ and R ⁵ are each independently hydrogen or halogen. , Represents a substituted or unsubstituted alkyl or alkoxy) (1) or a tautomeric form thereof, and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, Is described.

(VI) US Pat. No. 4,897,405 (= Japanese Patent Laid-Open No. 2-292272) discloses that (1) the formula (I):

[0047]

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Wherein R ¹ and R ² are independently hydrogen,
Lower alkyl containing 1 to 6 carbon atoms, 1
Lower alkoxy, halogen, ethynyl, nitrile, methylthio, trifluoromethyl, vinyl, nitro or halogen-substituted benzyloxy containing from 6 to 6 carbon atoms: n represents 0 to 4] or a medicament thereof. (2) In particular, salts of the formula (I)
I):

[0049]

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Wherein R ¹ and R ² are independently hydrogen,
Lower alkyl containing 1 to 6 carbon atoms, 1
Lower alkoxy, halogen, ethynyl, nitrile, trifluoromethyl, vinyl or nitro containing from 1 to 6 carbon atoms: n represents 1 or 2] or a pharmaceutically acceptable salt thereof. (1)
The compounds described are described.

(VII) WO 89/08651 (= Japanese Patent Application Laid-Open No. 1-272574) has a formula (1)

[0052]

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(Wherein the dotted line indicates a bond or no bond, and V is -CH = CH-, -N = CH-, -CH = N-
Or S, and W is CH ₂ , CHOH, CO, C =
NOR or CH = CH, and X is S, O, NR
¹ , -CH = N- or -N = CH-, and Y is C
H or N, Z is hydrogen, C ₁ -C ₇ alkyl,
C ₃ -C ₇ cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl or identical or different C ₁
-C ₃ alkyl, trifluoromethyl, C ₁ -C ₃ alkoxy, fluoro, chloro or bromo, phenyl mono- or disubstituted by a group which is bromo, wherein Z ¹ is hydrogen or C ₁ -C ₃ alkyl; R and R ¹ are each independently hydrogen or methyl, and n is 1, 2 or 3), a pharmaceutically acceptable cation salt thereof, or, when the compound has a basic nitrogen, Pharmaceutically acceptable acid addition salts, (2) in particular, the dotted line indicates no bond and W is CO or CH
(3) The compound according to (1), wherein V is-
CH = CH-, -CH = N- or S, and n
(2) wherein X is O
Wherein Y is N which forms an oxazol-4-yl group, Z is 2-thienyl, 2-furyl, phenyl, substituted phenyl or naphthyl, and Z ¹ is 5-methyl. (5) In particular, when V is -C
The compound according to (4), wherein H = N- or S and Z is 2-phenyl, (6) In particular, V is -CH = C
The compound according to (3), wherein H is H, W is CO, and Z is 2- (2-furyl), 2-phenyl, 2- (4-methylphenyl) or 2- (2-naphthyl). ,
(7) In particular, the compound according to (3), wherein X is O or S, and Y is N which forms an oxazol-5-yl group, a thiazol-4-yl group or a thiazol-5-yl group. In particular, X is -CH = N- and Y is CH forming a pyrid-2-yl group, or CH is X is O and Y is a full-2-yl group. (3) is described.

(VIII) US Pat.
5120754, 5223522 (= Japanese Patent Laid-Open No. 1-272)
No. 573) includes the formula (1):

[0055]

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Wherein the dashed lines indicate a bond or no bond; A and B are each independently CH or N;
Provided that when A or B is N, the other is CH; and X is S, SO, SO ₂ , CH ₂ , CHOH or CO.
N is 0 or 1; Y is CHR ¹ or NR
^2, where, X is when n is at 1 Y is NR ² is S
O ₂ or CO; R, R ¹ , R ² and R ³ are each independently hydrogen or methyl; and X ¹ and X ² are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, Benzyloxy, bromo, chloro or fluoro], or a pharmaceutically acceptable cation salt thereof; or a pharmaceutically acceptable acid addition salt when A or B is N. (2) Each of A and B is CH,
X is CO, n is 0, and R is hydrogen (1)
(3) In particular, the compound according to (2), wherein Z is CH ₂ CH ₂ , X ² is hydrogen, and X ¹ is hydrogen, 4-benzyloxy or 4-phenyl, (4)
In particular, X ² is hydrogen, Z is CH = CH having a geometry trans about the double bond, X ¹ is hydrogen, 2-methoxy, 4-benzyloxy or 4-methoxy (2), wherein In particular, the dotted line represents no bond, and each of A and B is CH;
Is S, n is 0, Z is CH ₂ CH ₂ ,
(1) The compound according to (1), wherein X ¹ and X ² are each hydrogen and R is methyl or hydrogen. (6) In particular, A and B are each CH, X is SO ₂ , and n is 0. Yes, Z
Is CH ₂ CH ₂ , wherein R, X ¹ and X ² are each hydrogen, (7) In particular, the dotted line represents no bond, A and B are each CH, X is S
O ₂ , n is 0, Z is CH ₂ CH ₂ ,
The compound according to (1), wherein R and X ² are each hydrogen and X ¹ is 4-chloro.

(IX) US Patent 5002953,51
94443, 5232925, 5260445 (= JP-A-1-131169), (1) Formula (I)

[0058]

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[In the formula, A ¹ represents a substituted or unsubstituted aromatic heterocyclic group; R ¹ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (wherein the aryl moiety is represents even or it may be unsubstituted) or substituted or unsubstituted aryl group; R ² and R ³ or R ² and R ³ each represent hydrogen represents a bond together; a ² is a total of 5 And n represents an integer ranging from 2 to 6] or a tautomeric form thereof, and / or a pharmaceutically acceptable salt thereof, and / or
Or a pharmaceutically acceptable solvate thereof, (2) in particular, A ¹ is a substituted or unsubstituted monocyclic or condensed ring aromatic containing up to 4 heteroatoms selected from oxygen, sulfur or nitrogen in the ring The compound according to (1), which represents a heterocyclic group, (3)
In particular, A ¹ has the formula (a), (b) or (c)

[0060]

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[In the formula, R ⁴ and R ⁵ each independently represent a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group, or when R ⁴ and R ⁵ are each bonded to a carbon atom, ⁴ and R ⁵ together with the carbon atom to which they are attached form a benzene ring, and together each carbon atom represented by R ⁴ and R ⁵ may be substituted or unsubstituted. And a compound according to (1) or (2), wherein X represents oxygen or sulfur in the moiety of formula (a), (4) in particular, R ⁴ and R ⁵ are each independently hydrogen, The compound according to (3), which represents an alkyl or a substituted or unsubstituted phenyl group, (5)
In particular, R ⁴ and R ⁵ together form formula (d)

[0062]

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Wherein R ⁶ and R ⁷ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy, and the compound according to (3),
In particular, R ⁶ and R ⁷ both represent hydrogen (5) The compound according (7) in particular, A ² has the formula (e)

[0064]

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(Wherein R ⁸ and R ⁹ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy), and any one of (1) to (6). (8) In particular, the compound according to (7), wherein R ⁸ and R ⁹ each represent hydrogen, (9)
Formula (II)

[0066]

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Wherein A ¹ , R ¹ , R ² , R ³ and n are as defined for formula (I) in (1), and R ⁸ and R ⁹ are in formula (e) of (7) (1) The compound according to (1) or a tautomer thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, (10) In particular, n is The compound according to any one of (1) to (9), which represents an integer of 2 or 3,
(11) In particular, R ¹ represents a methyl group (1) to (1)
0) The compound according to any one of the above items, (12)
5-((4- (2-methyl-2- (pyridin-2-yl) amino) ethoxy) phenyl) methyl) -2,4-
Thiazolidinedione (BRL-49653): or the compound according to (1), which is a tautomer thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. .

(X) US Pat. No. 4,180,091 (= Japanese Patent Laid-Open No. 64-13076) discloses that

[0069]

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Wherein R is hydrogen or alkyl;
¹ represents an alkyl group or a substituted or unsubstituted aryl group, R ² and R ³ each represent hydrogen, or R ² and R ³
A represents a bond together, A represents a benzene ring having a total of 5 or less substituents, X represents oxygen, sulfur or a partial NR ⁴
Wherein R ⁴ represents hydrogen or alkyl, and n represents an integer in the range of 2 to 6] or a tautomer thereof, or a pharmaceutically suitable salt thereof;
(2) In particular, R ¹ is of the formula (a)

[0071]

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[Wherein R ⁵ , R ⁶ and R ⁷ each independently represent hydrogen, halogen, or substituted or unsubstituted alkyl or alkoxy].
(3) In particular, A is a compound of formula (b)

[0073]

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Wherein R ⁸ and R ⁹ each independently represent hydrogen, halogen, or substituted or unsubstituted alkyl or alkoxy, and the compound according to (1) or (2), In particular, the compound according to (2) or (3), wherein R ⁵ , R ⁶ and R ⁷ each independently represent hydrogen.
(5) In particular, R ⁸ and R ⁹ each independently represent hydrogen. (3) or (4), and (6) In particular, X represents oxygen. The compound described,
(7) In particular, the compound according to any one of (1) to (5), wherein n represents 2 is described.

(XI) US Pat. No. 4,897,393, 49
48900 (= JP-A-64-56675 = Japanese Patent Publication 5-)
No. 5832): (1) General formula

[0076]

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Wherein R is a phenyl group, naphthyl group, cycloalkyl group or heterocyclic group which may have a substituent, and Alk is a single bond, a lower alkenylene group, a lower alkynylene group or a substituent. A lower alkylene group and a dotted line indicate that the bond at the site may be a double bond. A) a benzoxazole derivative or a salt thereof, wherein R is a lower alkoxy group, a lower alkyl group, a trihalogeno lower alkyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a phenyl group, or a halogen atom. A phenyl group which may be substituted with 1 to 3 groups selected from a nitro group, a pyrrolidino group, a piperidino group, a morpholino group, a pyrrolyl group and a di (lower alkyl) amino group; a lower alkoxy group, a lower alkyl group, A naphthyl group optionally substituted with a halogen atom or a nitro group; one or two naphthyl groups selected from a pyridyl group or a lower alkyl group optionally substituted with a lower alkyl group, a lower alkylthio group, a cycloalkyl group and a phenyl group; A 1,3-thiazol-4-yl group or 1 3-oxazole -4
A benzoxazole derivative or a salt thereof according to (1), wherein R is a lower alkoxy-substituted phenyl group;
The benzoxazole derivative or salt thereof according to (2), wherein the benzoxazole derivative is a di (lower alkyl) amino group-substituted phenyl group or a naphthyl group, Alk is a linear lower alkylene group, and the group shown by a dotted line is a methylene group. 4) In particular, the benzo according to (1), (2) or (3), wherein a 2,4-dioxothiazolidin-5-yl (or ylidene) methyl group is bonded to the 5- or 6-position of the benzoxazole ring. An oxazole derivative or a salt thereof,
Is described.

(XII) US Pat. No. 4,873,255 (=
JP-A-64-38090) includes (1) a general formula

[0079]

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[Wherein, R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² , R ⁴ and R ⁵ is the same or different, a hydrogen atom, an aralkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a halogen atom, A hydroxyl group which may be protected, a formyl group, an alkanoyl group which may have a substituent,
An arylalkanoyl group which may have a substituent, a cycloalkylcarbonyl group which may have a substituent,
Optionally substituted arylcarbonyl group, carboxy group, alkoxycarbonyl group, optionally substituted aryloxycarbonyl group, nitro group, formula-
An N (R ⁷ ) (R ⁸ ) group wherein R ⁷ and R ⁸ are the same or different and are each a hydrogen atom, a lower alkyl group, an aralkyl group,
A cycloalkyl group, an aryl group optionally having a substituent, a formyl group, an alkanoyl group optionally having a substituent, an arylalkanoyl group optionally having a substituent, And an arylcarbonyl group or an alkoxycarbonyl group, which may be combined with a nitrogen atom in the formula to form a 5- to 7-membered cyclic amino group. ) Or the formula —CON (R ^{7 ′} ) (R ^{8 ′} ) wherein R ^{7 ′}
And R ^{8 ′} are the same as those shown for R ⁷ and R ⁸ except for the acyl substituent. And R ³ is the same as R ² , R ⁴ and R ⁵ except for the hydroxyl group which may be protected, but when R ³ is a hydroxyl group which may be protected Has at least one of R ² , R ⁴ and R ⁵ having an alkyl group having a substituent, a halogen atom, a hydroxyl group, an alkoxy group having a substituent, a formyloxy group, and a substituent. Optionally substituted alkanoyloxy group, optionally substituted arylcarbonyloxy group, sulfoxy group, formyl group, optionally substituted alkanoyl group, optionally substituted aryl Alkanoyl group, cycloalkylcarbonyl group which may have a substituent, arylcarbonyl group which may have a substituent, carboxy group, alkoxycarbonyl group, which may have a substituent Aryloxy carbonyl group, a nitro group, the formula -N (R ⁷⁾ (R
⁸ ) wherein R ⁷ and R ⁸ have the same meanings as described above; and -CON (R ^{7 ′} ) (R ^{8 ′} )
(Wherein R ^{7 ′} and R ^{8 ′} have the same meanings as described above).

R ⁶ represents a hydrogen atom or an alkyl group which may have a substituent, and Ar may have a divalent aromatic ring group which may have a substituent or a substituent. Represents a divalent heteroaromatic ring group, W is a methylene group, a carbonyl group,
A formula = CH-OY group (wherein Y represents a hydrogen atom or an acyl group) or a formula = C = N-OV (where V represents a hydrogen atom or a hydroxyl-protecting group), Alternatively, a double bond may be formed with U described later, U represents a single bond or a methylene group, or forms a double bond with W, W is a carbonyl group or a formula = C = N-OV group ( Wherein V is as defined above, may form a double bond with R ¹ , and n represents 1 to 1
Indicates an integer of 0. And a salt thereof.

(XIII) US Pat. No. 4,703,052
(= Japanese Patent Laid-Open No. 61-271287 = Japanese Patent Publication 5-8695)
No. 3), Formula (1)

[0083]

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Or a pharmaceutically suitable cation salt thereof, wherein the dashed line represents a single bond or a non-bond, n is 0, 1 or 2, and X is O, S, S = O, S ( = O) (=
In O), R is H, CH ₃ or C ₂ H _5, R ₁ is in a separate H, C ₅ -C ₇ cycloalkyl, C ₆ -C ₈ methyl substituted cycloalkyl, pyridyl, thienyl, furyl, Naphthyl, p-biphenylyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, C
₆ H ₄ W ₂ [W ₂ is H, OH, F, Cl, Br, C _1-
C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ thioalkyl] or alk-W ₁ [alk is C ₁
-C ₆ alkylene, ethylidene or isopropylidene, W ₁ is H, OH, C ₁ ~C ₄ alkoxy, C ₁ ~
C ₄ thioalkyl, pyridyl, furyl, thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, C
₅ -C ₇ cycloalkyl or C ₆ H is ₄ W _2] in R
₂ is H or CH ₃ , R ₃ is H, C ₁ -C ₆ alkyl,
C ₆ H ₄ W ₂ or benzyl, R ₄ is H, and when R ₁ and R ₂ are taken together, they are C ₄ -C ₆
Forming an alkylene, wherein R ₃ and R ₄ are each H;
If R ₃ and R ₄ are taken together they are C ₄
-C ₆ alkylene to form, R ₁ and R ₂ are each H, when R ₂ and R ₃ are taken together, they form a C ₃ -C ₄ alkylene, R ₁ and R ₄ is each H], (2) the compound according to (1), wherein R is H, the broken line is non-bonded, and n is 0 or 1, (3)
In particular, R ₂ , R _{3 and} R ₄ are each H, and R ₁ is H, cyclohexyl, C ₆ H ₄ W ₂ (W ₂ is H, F, Cl, B
r, CH ₃ is CH ₃ O) or alk-W ₁ [a
lk is C ₁ -C ₄ alkylene, ethylidene or isopropylidene; W ₁ is H, OH, C ₁ -C ₄ alkoxy,
Cyclohexyl or C ₆ H ₄ W ₂ ] (2)
(4) In particular, X is O, and R ₁ is cyclohexyl, cyclohexylmethyl, benzyl, fluorobenzyl, C ₁ -C ₄ alkyl, hydroxymethyl,
The compound according to (3), which is methoxymethyl or ethoxyethyl, (5) especially the compound according to (4), wherein R ₁ is benzyl, (6) especially 5-((3,4-dihydro-2- ( Phenylmethyl) -2H-benzopyran-6-
Yl) Methyl-2,4-thiazolidinedione (engritazone) or a sodium salt thereof according to (5), (7) In particular, R ₂ and R ₃ together form (CH ₂ ) ₄ , The compound according to (2), wherein ₁ and R ₄ are each H and X is O, (8) In particular, (a) R ₁ and R ₂
Together form (CH ₂ ) ₅ , R ₃ and R ₄ are each H and X is O, or (b) R ₃ and R ₄ together form (CH ₂ ) ₅ ; R ₁ and R ₂ are each H and X
Is a compound according to (2), wherein (n) is 0
Wherein R ₁ is H, CH ₃ or benzyl and X is S or S
(= O) (= O), the compound according to (3).

(XIV) US Pat. No. 4,687,777 (=
JP-A-61-267580 = Japanese Patent Publication No. 5-31079
No.) has the formula (1)

[0086]

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Or a pharmacologically acceptable salt thereof.

(XV) US Pat. No. 4,725,610 (= Japanese Patent Application Laid-Open No. 61-85372 = Japanese Patent Publication No. 5-66956) has the following general formula:

[0089]

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[In the formula, R ¹ represents hydrogen or a hydrocarbon residue or a heterocyclic residue which may be substituted,
² is hydrogen or a lower alkyl group optionally substituted by a hydroxyl group, X is an oxygen atom or a sulfur atom, Z is methylene hydroxide or carbonyl, m is 0 or 1, and n is an integer of 1 to 3. Show. L and M are each a hydrogen atom, or L and M are combined to form one bond. A thiazolidinedione derivative or a salt thereof represented by the formula:

(XVI) US Pat. No. 4,572,912 (=
JP-A-60-51189 = Japanese Patent Publication No. 2-31079)
Has the general formula (1)

[0092]

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[In the formula (I), R ¹ and R ² are the same or different and each represent a hydrogen atom or a lower alkyl group, and R ³ has a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group or a substituent. An aromatic acyl group, a heterocyclic acyl group, an optionally substituted araliphatic acyl group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ⁴ and R ⁵ may be the same or different A hydrogen atom, a lower alkyl group or a lower alkoxy group, and n is 1 to 3
Y represents an oxygen atom or an imino group, and Z represents an oxygen atom, a sulfur atom or an imino group. A thiazolidine derivative represented by the formula (I):
In particular, 5- (4-((6-hydroxy-2,5,7,8
-Tetramethylchroman-2-yl) methoxy) benzyl) -2,4-thiazolidinedione (troglitazone).

(XVII) US Pat. No. 4,461,902
(= JP-A-58-118577 = Japanese Patent Publication No. 2-5754)
No. 6) includes (1) general formula

[0095]

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[Where:

[0097]

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Represents a cyclohexane ring having an oxo group or a hydroxyl group as a substituent on any methylene constituting the ring, and R represents hydrogen or a lower alkyl group. A thiazolidine derivative represented by the formula:

(XVIII) US Pat. No. 4,287,720
0, 4340605, 4438141, 4444779
(= JP-A-55-22636 = JP-B-62-4290)
No. 3) includes (1) general formula

[0100]

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[Wherein R ¹ is an alkyl group, a cycloalkyl group, a phenylalkyl group, a phenyl group, a nitrogen atom,
A 5- or 6-membered heterocyclic group having one or two hetero atoms selected from an oxygen atom and a sulfur atom, or -N (R
³ ) (R ⁴ ) (where R ³ and R ⁴ are the same or different and each represents a lower alkyl group, or R ³ and R ⁴ are directly or a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. And may form a 5- or 6-membered ring together with the nitrogen atom adjacent to R ³ and R ⁴ ). R ² represents a bond or a lower alkylene group. When R ¹ is an alkyl group, L ¹ and L ² may be the same or different and represent a lower alkyl group, or L ¹ and L ²
May combine to form an alkylene group. Also R
^{When 1} is not an alkyl group, L ¹ and L ² may be hydrogen atoms in addition to the above definition.] (2) In particular, 5-((4- (2- (5- Ethyl-pyridin-2-yl) ethoxy) phenyl) methyl)
2,4-thiazolidinedione (pioglitazone) or 5-((4-((1-methylcyclohexyl) methoxy) phenyl) methyl) -2,4-thiazolidinedione (ciglitazone) is described.

(XIX) EP 0708098A includes: (1) a general formula

[0103]

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[In the formula, R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.

R ² represents a linear or branched alkylene group having 2 to 6 carbon atoms.

R ³ is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A linear or branched alkylthio group having 1 to 4 carbon atoms, a halogen atom, a nitro group, an amino group, a linear or branched monoalkylamino group having 1 to 4 carbon atoms, The same or different, each alkyl is a linear or branched dialkylamino group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. Show.

X represents an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents or a heteroaromatic ring group which may have 1 to 3 substituents. Show.

The substituents include 1) a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and 2) a straight-chain or branched alkyl group having 1 to 4 carbon atoms. 3) a hydroxy group, 4) a linear or branched acyloxy group having 1 to 4 carbon atoms, 5) a linear or branched chain having 1 to 4 carbon atoms Alkoxy group,
6) a linear or branched alkylenedioxy group having 1 to 4 carbon atoms; 7) a 7 to 12 carbon atoms.
Aralkyloxy group having 1 to 4 carbon atoms, 8) linear or branched alkylthio group having 1 to 4 carbon atoms, 9) linear or branched alkylsulfonyl having 1 to 4 carbon atoms Group) 10) halogen atom, 11) nitro group, 12) amino group, 13) linear or branched monoalkylamino group having 1 to 4 carbon atoms, 14) same or different alkyl groups A linear or branched dialkylamino group having 1 to 4 carbon atoms, 15) an aralkyl group having 7 to 12 carbon atoms, 16) an aryl group having 6 to 10 carbon atoms (the aryl group) Is a linear or branched alkyl having 1 to 6 carbons,
Straight or branched alkyl halide having 1 to 4 carbon atoms, straight or branched alkoxy having 1 to 4 carbon atoms, halogen or having 1 to 4 carbon atoms Linear or branched alkylenedioxy, which may be substituted) 17) aryloxy group having 6 to 10 carbon atoms (the aryl group is a straight-chain having 1 to 6 carbon atoms) Or a branched-chain alkyl, a straight-chain or branched-chain alkyl halide having 1 to 4 carbon atoms, a straight-chain or branched-chain alkoxy having 1 to 4 carbon atoms,
Halogen or a linear or branched alkylenedioxy having 1 to 4 carbon atoms, which may be substituted) 18) an arylthio group having 6 to 10 carbon atoms (the aryl group is Linear or branched alkyl having 1 to 6 carbon atoms, 1 to 4 carbon atoms
Linear or branched alkyl halide having 1 to 4 carbon atoms, linear or branched alkoxy having 1 to 4 carbon atoms, halogen or linear or branched alkyl having 1 to 4 carbon atoms. It may be substituted by a branched alkylenedioxy), 19) C6-C10.
Arylsulfonyl group having 1 to 6 carbon atoms (linear or branched alkyl having 1 to 6 carbons, linear or branched alkyl having 1 to 4 carbons) May be substituted by a straight-chain or branched alkoxy having 1 to 4 carbon atoms, halogen, or a straight-chain or branched alkylenedioxy having 1 to 4 carbon atoms) , 2
0) an arylsulfonylamino group having 6 to 10 carbon atoms (the aryl group is a linear or branched alkyl having 1 to 6 carbon atoms, and 1 to 4 carbon atoms)
Linear or branched alkyl halide having 1 to 4 carbon atoms, linear or branched alkoxy having 1 to 4 carbon atoms, halogen or linear or branched alkyl having 1 to 4 carbon atoms. It may be substituted with a branched alkylenedioxy. The nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms), 21) heteroaromatic group, 22) heteroaromatic oxy group, 23) heteroaromatic ring A thio group, 24) a heteroaromatic sulfonyl group, and 25) a heteroaromatic sulfonylamino group (the nitrogen atom may be substituted by a straight-chain or branched alkyl having 1 to 6 carbon atoms) Is shown.

Y is an oxygen atom, a sulfur atom or a group> N-
R ⁴ is shown.

(Wherein R ⁴ is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a linear or branched alkyl group having 1 to 8 carbon atoms) Z represents a group.

[0111]

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Is shown. Or a salt thereof, (2) wherein R ¹ is a hydrogen atom or a group having 1 to 4 carbon atoms.
A straight-chain or branched alkyl radical having pieces; R ² is a straight-chain or branched alkylene group having 2 to 5 carbon atoms; R ³ is a hydrogen atom, the number of carbon atoms X is 1 to 3; a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 2 carbon atoms, an alkylthio group having 1 to 2 carbon atoms, and a halogen atom; An aryl group having 6 to 10 carbon atoms which may have a substituent, or 1
A 5- to 10-membered (single or bicyclic) heteroaromatic ring group having 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms which may have 3 to 3 substituents; These groups are represented by the following substituents: 1) straight-chain or branched alkyl having 1 to 6 carbons, 2) straight-chain or branched alkyl having 1 to 4 carbons Alkyl halide of 3) hydroxy,
4) linear or branched acyloxy having 1 to 4 carbon atoms; 5) linear or branched alkoxy having 1 to 4 carbon atoms; 6) 1 to 4 carbon atoms. A) straight-chain or branched alkylthio having 7 to 12 carbon atoms; 8) straight-chain or branched alkylthio having 1 to 4 carbon atoms; ) Carbon number 1
Linear or branched alkylsulfonyl having from 4 to 4, 10) halogen atoms, 11) carbon atoms of 7
Aralkyl having from 12 to 12) phenyl (where phenyl is straight-chain or branched alkyl having 1 to 6 carbons, straight-chain or branched having 1 to 4 carbons) Alkyl halide, straight-chain or branched alkoxy having 1 to 4 carbon atoms, halogen or straight-chain or branched alkylenedioxy having 1 to 4 carbon atoms, 13) phenoxy (the phenyl is a linear or branched alkyl having 1 to 6 carbons, a linear or branched alkyl halide having 1 to 4 carbons) Linear or branched alkoxy having 1 to 4 carbon atoms, halogen or linear or branched alkylenedioxy having 1 to 4 carbon atoms May be substituted), 1
4) phenylthio (the phenyl is a linear or branched alkyl having 1 to 6 carbons, a linear or branched alkyl halide having 1 to 4 carbons, 1 carbon Linear or branched alkoxy having 4 to 4 carbon atoms, halogen or linear or branched alkylenedioxy having 1 to 4 carbon atoms), 15) phenyl Sulfonyl (the phenyl is a linear or branched alkyl having 1 to 6 carbons, a linear or branched alkyl halide having 1 to 4 carbons,
Straight-chain or branched alkoxy having 1 to 4 carbon atoms, which may be substituted by halogen or straight-chain or branched alkylenedioxy having 1 to 4 carbon atoms), 16) phenylsulfonylamino (the phenyl is a linear or branched alkyl having 1 to 6 carbons, a linear or branched alkyl halide having 1 to 4 carbons, carbon It may be substituted by a linear or branched alkoxy having 1 to 4 carbon atoms, halogen, or a linear or branched alkylenedioxy having 1 to 4 carbon atoms. May be substituted by linear or branched alkyl having 1 to 6 carbons), 17) furyl, thienyl, oxazolyl, isoxazolyl, thi Zolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, 18) imidazolyl (the nitrogen atom may be substituted by straight-chain or branched-chain alkyl having 1 to 6 carbon atoms), and / or 19 ) Pyridylsulfonylamino (where the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms); Y is an oxygen atom, a sulfur atom or Group>
NR ⁴ (R ⁴ is a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms or a linear or branched alkanoyl group having 2 to 5 carbon atoms) Z is a 2,4-dioxothiazolidine-5-ylmethyl group, a 2,4-dioxooxazolidine-5-ylmethyl group or a 3,5-dioxooxadiazolidine-2-ylmethyl group. ; an oxime derivative or a salt thereof (1) compounds described, (3) in particular, to R ¹ is 1 -C hydrogen or C 4
R ² is a linear or branched alkylene group having 2 to 5 carbon atoms; R ³ is a hydrogen atom; X is an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents, or a nitrogen atom, an oxygen atom and / or 1 to 3 substituents which may have 1 to 3 substituents. A 5- to 10-membered (single or bicyclic) heteroaromatic ring group having 1 to 3 sulfur atoms, and these groups are, as said substituents, 1) having 1 to 6 carbon atoms Linear or branched alkyl,
2) linear or branched alkyl halides having 1 to 4 carbon atoms, 3) hydroxy, 4)
Linear or branched alkanoyloxy having 1 to 4 carbon atoms; 5) linear or branched alkoxy having 1 to 4 carbon atoms; 6) 1 to 4 carbon atoms. Linear or branched alkylenedioxy, 7) aralkyloxy having 7 to 12 carbon atoms, 8) linear or branched alkylthio having 1 to 4 carbon atoms, 9) Carbon number 1
Linear or branched alkylsulfonyl having from 4 to 4, 10) fluorine, chlorine, bromine,
11) aralkyl having 7 to 12 carbon atoms;
12) phenyl (the phenyl is a linear or branched alkyl having 1 to 6 carbons, a linear or branched alkyl halide having 1 to 4 carbons, 1 carbon Straight or branched alkoxy having 1 to 4 carbon atoms, halogen or 1 to 4 carbon atoms
13) phenoxy, wherein the phenyl is a linear or branched alkyl having 1 to 6 carbons, Straight or branched alkyl halide having 1 to 4 carbon atoms, straight or branched alkoxy having 1 to 4 carbon atoms, halogen or having 1 to 4 carbon atoms Linear or branched alkylenedioxy, which may be substituted), 14) phenylthio (the phenyl is a linear or branched alkyl having 1 to 6 carbons, 1 carbon Linear or branched alkyl halide having 1 to 4 carbon atoms, linear or branched alkoxy having 1 to 4 carbon atoms, halogen or 1 to 4 carbon atoms May be substituted by straight-chain or branched alkylenedioxy having), 1
5) phenylsulfonyl (the phenyl is a linear or branched alkyl having 1 to 6 carbons, a linear or branched alkyl halide having 1 to 4 carbons, Linear or branched alkoxy having 1 to 4 carbon atoms, halogen or 1 carbon atom
16) phenylsulfonylamino (where phenyl is a linear or branched chain having 1 to 6 carbon atoms) Alkyl, 1 carbon
Straight-chain or branched alkyl halide having 1 to 4 carbon atoms, straight-chain or branched alkoxy having 1 to 4 carbon atoms, halogen or straight-chain having 1 to 4 carbon atoms Alternatively, it may be substituted with a branched alkylenedioxy. The nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbons), 17) furyl, thienyl,
Oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, 18) imidazolyl (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms), And / or 19) pyridylsulfonylamino (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms); Is;
Z is a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxooxazolidin-5-ylmethyl group; an oxime derivative or a salt thereof (1)
(4) In particular, R ¹ is a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms;
R ² is a linear or branched alkylene group having 2 to 3 carbon atoms; R ³ is a hydrogen atom;
Is a phenyl group, a naphthyl group, an imidazolyl group, an oxazolyl group, a pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group which may have 1 to 3 substituents. A) straight-chain or branched alkyl having 1 to 6 carbons,
2) linear or branched alkyl halides having 1 to 4 carbon atoms, 3) hydroxy, 4)
Linear or branched alkanoyloxy having 1 to 4 carbon atoms, 5) linear or branched alkoxy having 1 to 4 carbon atoms, 6) methylenedioxy, 7) carbon Aralkyloxy having 7 to 12 carbon atoms; 8) linear or branched alkylthio having 1 to 4 carbon atoms; 9) linear or branched alkylthio having 1 to 4 carbon atoms. Alkylsulfonyl, 10) fluorine, chlorine, bromine,
11) aralkyl having 7 to 12 carbon atoms;
12) phenyl, which may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy; 13) phenoxy, wherein phenyl is methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy. May be substituted),
14) phenylthio (the phenyl may be substituted with methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), 15) phenylsulfonyl (the phenyl is methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy 16) phenylsulfonylamino (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy. The nitrogen atom has 1 to 6 carbon atoms.) Linear or branched alkyl), 17)
Furyl, thienyl, oxazolyl, isoxazolyl,
Thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, 18) imidazolyl (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms), and / or 19 ) Pyridylsulfonylamino (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbons);
Y is an oxygen atom; Z is a 2,4-dioxothiazolidine-5-ylmethyl group; the compound according to (1), which is an oxime derivative or a salt thereof; (5) In particular, R ¹ is a hydrogen atom or a methyl group R ² is an ethylene group, a trimethylene group or a methylethylene group; R ³ is a hydrogen atom; X is a phenyl group or a naphthyl group optionally having 1 to 3 substituents , An imidazolyl group, an oxazolyl group, a pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group.
Linear or branched alkyl having 2
Linear or branched alkyl halide having 1 to 4 carbon atoms, 3) hydroxy, 4) linear or branched alkanoyloxy having 1 to 4 carbon atoms, 5) carbon Linear or branched alkoxy having 1 to 4 carbon atoms, 6) methylenedioxy, benzyloxy, phenethyloxy, naphthylmethoxy, 7) linear or branched chain having 1 to 4 carbon atoms Alkylthio, 8) having 1 to 4 carbon atoms
Linear or branched alkylsulfonyl having 9 carbon atoms, 9) fluorine atom, chlorine atom, bromine atom, 10)
Benzyl, 11) phenyl (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy), 12) phenoxy (the phenyl is methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy) Phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonyl Amino, N-methylpyridylsulfonylamino,
And / or 14) imidazolyl (the nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbons);
Y is oxygen atom; Z is 2,4 is dioxothiazolidin-5-ylmethyl group; an oxime derivative or a salt thereof (1) The compound according (6), especially R ¹ is a hydrogen atom, a methyl group R ² is an ethylene group, a trimethylene group or a methylethylene group; R ³ is a hydrogen atom; X is a phenyl group or a naphthyl group optionally having 1 to 3 substituents A pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group;
Linear or branched alkyl having 1 to 3 carbons, 2) trifluoromethyl, difluoromethyl, fluoromethyl, hydroxy, formyloxy, acetoxy, 3) linear having 1 to 3 carbons Or branched alkoxy, 4) methylenedioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, 5) fluorine, chlorine, bromine, 6) benzyl, phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-
Methoxyphenyl, 4-fluorophenyl, 3,4-methylenedioxyphenyl, phenoxy, phenylthio,
Phenylsulfonyl, phenylsulfonylamino, N-
Methylphenylsulfonylamino, furyl, thienyl,
Oxazolyl, thiazolyl, imidazolyl, N-methylimidazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino and / or N-methylpyridylsulfonylamino; and Y is an oxygen atom; A compound according to (1), which is an oxime derivative or a salt thereof; (7) especially R ¹ is a hydrogen atom, a methyl group or an ethyl group; R ² is a 2,4-dioxothiazolidine-5-ylmethyl group X is an ethylene group; R ³ is a hydrogen atom; X is a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group or an isoquinolyl group optionally having 1 to 3 substituents; Methyl,
Ethyl, isopropyl, trifluoromethyl, hydroxy, acetoxy, methoxy, ethoxy, isopropoxy, methylenedioxy, benzyloxy, methylthio,
Ethylthio, methylsulfonyl, ethylsulfonyl, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino,
May have N-methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino and / or N-methylpyridylsulfonylamino; Y is an oxygen atom; Z is 2,4- A dioxothiazolidine-5-ylmethyl group; the compound according to (1), which is an oxime derivative or a salt thereof; (8) particularly, R ¹ is a methyl group or an ethyl group;
X is 1; ² is an ethylene group; R ³ is a hydrogen atom;
A phenyl group which may have 3 to 3 substituents, wherein the group includes, as a substituent, methyl, hydroxy, acetoxy, chlorine atom, benzyl, phenyl, phenoxy,
May have phenylthio, phenylsulfonyl, phenylsulfonylamino, N-methylphenylsulfonylamino, pyridyl, pyridyloxy, pyridylthio and / or pyridylsulfonyl; Y is an oxygen atom; Z is 2,4-dioxo A compound according to (1), which is an oxime derivative or a salt thereof; (9) especially R ¹ is a methyl group or an ethyl group;
X is 1; ² is an ethylene group; R ³ is a hydrogen atom;
A pyridyl group which may have from 3 to 3 substituents, wherein the group is methoxy, ethoxy, isopropoxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, benzyl,
Y may have phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino and / or N-methylphenylsulfonylamino; Y
Is an oxygen atom; Z is a 2,4-dioxothiazolidine-5-ylmethyl group; the compound according to (1), which is an oxime derivative or a salt thereof, (10) In particular, 1) 5- [4- [ 2-[[[1- (4-biphenylyl)
[Ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, 2) 5- [4- [2-[[[1- (4-phenylsulfonylphenyl) ethylidene] amino] oxy] ethoxy] benzyl] Thiazolidine-2,4-dione, 3) 5- [4- [2-[[[1- [4- (2-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione (Less than,
4) 5- [4- [2-[[[1- [4- (3-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione 5) 5- [4- [2-[[[1- [4- (4-pyridyl) phenyl] ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione; 6) 5- [4 -[2-[[[1- (2-phenyl-5-
Pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione 7) 5- [4- [2-[[[1- (2-methoxy-5-
Pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione 8) 5- [4- [2-[[[1- (2-ethoxy-5-
Pyridyl) ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione 9) 5- [4- [2-[[[1- (2-isopropoxy-5-pyridyl) ethylidene] amino] oxy ] Ethoxy] benzyl] thiazolidine-2,4-dione or 10) 5- [4- [2-[[[1- (2-benzyl-5)
-Pyridyl) ethylidene] amino] oxy] ethoxy]
Benzyl] thiazolidine-2,4-dione; a compound according to (1), which is an oxime derivative or a salt thereof, (XX) EP 0676398A (= JP-A-7-330)
No. 728) includes 5- (4- (5-methoxy-3-methylimidazo [5,4-b] pyridin-2-ylmethoxy) benzyl) thiazolidine-2,4-dione thiazolidine derivative or a thiazolidine derivative thereof. Salts are described.

(XXI) Further, 1) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 2) 5- [4- (1 -Methylbenzimidazole-2-
Ylmethoxy) benzyl] thiazolidine-2,4-dione, or 3) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2, Benzimidazole derivatives selected from 4-dione or salts thereof are also useful.

Among them, preferred are troglitazone,
Pioglitazone, ciglitazone, englitazone and BRL-49653. Troglitazone is described in JP-B-2-31079, and its chemical name (planar structural formula) is 5- (4-((6-hydroxy-2,5,7,
8-tetramethylchroman-2-yl) methoxy) benzyl) -2,4-thiazolidinedione. Pioglitazone is disclosed in JP-B-62-42903 and JP-B-5
-66956, its chemical name (planar structural formula)
Is 5-((4- (2- (5-ethyl-pyridine-2-
Yl) ethoxy) phenyl) methyl) -2,4-thiazolidinedione. Ciglitazone is available in
No. 42903, its chemical name (planar structural formula)
Is 5-((4-((1-methylcyclohexyl) methoxy) phenyl) methyl) -2,4-thiazolidinedione. Englitazone is available from Tokuhei 5-86995
And its chemical name (planar structural formula) is 5-
((3,4-dihydro-2- (phenylmethyl) -2H
-Benzopyran-6-yl) methyl-2,4-thiazolidinedione. BRL-49653 is disclosed in
The chemical name (planar structural formula) is 5-((4- (2-methyl-2- (pyridine-
2-yl) amino) ethoxy) phenyl) methyl)-
2,4-thiazolidinedione.

In the present invention, [2] the insulin resistance improving substance is preferably a thiazolidinedione compound,
Oxazolidinedione compound and oxathiadiazo-
And a compound selected from the group consisting of:

Preferably, [3] the inhibitor according to [1], wherein the insulin sensitizer is selected from troglitazone, pioglitazone, ciglitazone, englitazone and BRL-49653.

[0117]

BEST MODE FOR CARRYING OUT THE INVENTION The ileal bile acid transporter activity was determined by the method of Wong et al. (Wong MH et al., "Journal of
Biological Chemistry ", Volume 269, pp. 1340-1347 (1994
Year)) can be measured by the following method.

Namely, Caco-2 cells (Chandler C.E. et al., "Amer
ican Journal of Physiology ", Volume 264, G1118-G1125
(1993)) and culture for 14 days or more. After addition of the sample to the culture system, radioactive taurocholic acid ^([3 H]
-taurocholic acid) and add 5% C at 37 ℃ for 1 hour
Incubation with O ₂ allows Caco-2 cells to incorporate radioactive taurocholic acid by the ileal bile acid transporter. Thereafter, the Caco-2 cells are washed several times with PBS (phosphate buffered serine) containing bovine serum albumin and taurocholate (cold). Next, the radioactive taurocholate incorporated into the cells is measured with a liquid scintillation counter.

The activity of the ileal bile acid transporter was measured by a method other than the above, as described in Ileal brush border membrane vesicles (Ileal
brush border membrane vesicles) (Root
C. et al., "Journal of Lipid Research", 36, 1106
-1115 (1995)), rat everted intestinal sac (rat everted)
ileal sacs) (Root C. et al., "Journal
of Lipid Research ", 36, 1106-1115 (1995)
), A method of culturing and using Caco-2 cells in a transwell (Root C. et al., "Journal of Lipid Researc
h ", 36, 1106-1115 (1995)), a method using rat everted ileal rings (Stew
art BHet al., "Pharmaceutical Research", Volume 12, 6
93-699 (1995)), a method for measuring the uptake of radioactive taurocholic acid from the ileum in vivo (Le
wis MC and Root C., "American Journal of Physiol
ogy ", Volume 259, G233-G238 (1990)).

In the present invention, one or more of the insulin resistance improving substances are used. The administration form of the insulin sensitizer used in the present invention is generally an oral route. Such dosage forms can be, for example, tablets, powders, granules, capsules, syrups and the like. Or parenteral administration by intravenous, intramuscular or subcutaneous injections, drops, suppositories and the like. These various preparations can be prepared by usual preparation techniques.

These various preparations are prepared by adding an excipient, a binder, a disintegrant, a lubricant, a dissolving agent, a flavor,
It can be formulated using known auxiliaries usually used in the field of known pharmaceutical preparations such as coating agents.

For example, in the case of molding into tablets, widely known carriers in this field can be used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and the like. Excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution,
Carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone sugar binder, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearin Disintegrating agents such as acid monoglyceride, starch and lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil; quaternary ammonium bases; absorption promoters such as sodium lauryl sulfate; humectants such as glycerin and starch; Examples thereof include adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

In molding into pills, carriers conventionally known in the art can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and the like. Examples thereof include rubber powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be added as necessary.

The amount of the active ingredient compound contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected in a wide range. Is appropriate.

The dose of the insulin resistance improving substance used in the present invention can vary greatly depending on various conditions such as the activity of each substance, the condition of the patient, age, weight, administration method and the like. For example, troglitazone and BRL-49
653, the in vivo activity using a diabetic model animal is about 100 times stronger in the latter than in the former, so that the dosage of these two compounds is theoretically two orders of magnitude, practically one order or more. It can be different. Usually about 10 per day for adults
-2000 mg.

Hereinafter, the present invention will be described more specifically with reference to Examples, Test Examples, Formulation Examples and Reference Examples.

[0127]

【Example】

Embodiment 1 FIG. Ileum type bile acid tiger using Caco-2 cells
Measurement of Transporter Inhibitory Activity In this example, the ileal bile acid transporter inhibitory activity was measured by the method of Wong et al. (Wong MH et al., "Journ
al of Biological Chemistry ", Volume 269, pp. 1340-1347 (1
994)).

That is, Caco-2 cells (Chandler C.E. et al., "Amer
ican Journal of Physiology ", Volume 264, G1118-G1125
(1993)). Caco-2 cells were added to each well of a collagen-coated 96-well culture plate (trade name: View plate, manufactured by Packard) at 4 × 10 ⁴ / ml.
, And the medium was replaced at appropriate times for at least 15 days and cultured. After adding the specimen to the main culture system, radioactive taurocholic acid ([ ³ H] -taurocholic) was added.
acid: NEN) 0.1 μCi was added and incubated for 1 hour at 37 ° C. with 5% CO ₂ , so that Caco- by the ileal bile acid transporter.
Radioactive taurocholate was incorporated into the two cells. Thereafter, Caco-2 cells were ice-cooled in 0.2% bovine serum albumin, 1 mM taurocholic acid (c
old) containing PBS (phosphate buffered serine) five times. Further, after washing the cells with ice-cold PBS, the cells were allowed to stand overnight and dried. 250 μl per well of a 96-well culture plate (trade name: View plate, manufactured by Packard)
Liquid scintillation cocktail (trade name: Micros
cint 20, manufactured by Packard) was added, and the radioactivity was measured by a top count (top count: a type of liquid scintillation counter manufactured by Packard).

The troglitazone, ciglitazone, pioglitazone, englitazone and BRL-49653 concentrations required to inhibit the ileal bile acid transporter activity measured by this method by 50% were 1.7 and 1.7, respectively.
1.8, 4.6, 4.6 and 2.1 μg / ml
Met.

Embodiment 2 FIG. Rat inverted intestinal ring (rat eve
ileal bile acid transport using rted ileal rings)
Measurement of Iter Inhibitory Activity In this example , the measurement of ileal bile acid transporter inhibitory activity was performed by the method of Stewart et al. (Stewart BHet a).
l., "Pharmaceutical Research", Volume 12, pages 693-699 (1
995)).

That is, as a material for the bile acid transporter, rat everted ileal rings
Was used. Wistar Imamichi male rats (6-10
Under anaesthesia with ether, the ileum was excised about 20 cm from the blind end, inverted, cut in ice-cold Ringer's buffer, and cut 5 mm at a time from the blind end in order. Got a ring. In order to correct the difference in the expression level of the bile acid transporter depending on the site of the ileum, rings were appropriately selected from the upper and lower portions of the ileum, and four rings were grouped into six groups in total. The ileal bile acid transporter incorporated the rings with radiotaurocholic acid while shaking each ring in 1 ml of radioactive taurocholic acid solution at 37 ° C. for 3 minutes at a speed of 90 rpm. The composition of the radioactive taurocholic acid solution consists of 1.0 μCi radioactive taurocholic acid, 0.037 mM taurocholic acid (cold), appropriate concentrations of various analytes and Ringer's buffer. After the ring was washed three times with Ringer's buffer, the wet weight was measured, placed in a vial, and the tissue lysing agent NCS-II (trade name:
0.5 ml (AMERSHAM) was added and left at 50 ° C. overnight to completely dissolve. Thereafter, 2.5 ml of liquid scintillation cocktail was added, and the radioactivity was measured with a liquid scintillation counter.

For the ileal bile acid transporter activity, each radioactivity was corrected by wet weight and expressed as dpm / mg (radioactivity per mg), and the average value of each group was defined as the activity.

The concentration of troglitazone required to inhibit ileal bile acid transporter activity measured by this method by 50% was 30 to 100 μg / ml.

[0134]

[Test Example] Next, the acute toxicity of the insulin sensitizer of the present invention was measured by a conventional method.

That is, three ddy mice (male) were used.
Troglitazone was orally administered at a dose of 300 mg / kg to these animals and observed for 5 days, and all survived.

[0136]

[Formulation Examples] Next, the formulations of the present invention will be described below.

Formulation Example 1 Capsule troglitazone 100 mg lactose 168.3 mg corn starch 70 mg magnesium stearate 1.7 mg ──────────────────────────── ──── Total amount: 340.0 mg Powder of the above formulation was mixed and passed through a 20-mesh sieve, and 340 mg of this powder was placed in a No. 2 gelatin capsule to make a capsule.

[0138]

Reference Example Next, the novel insulin resistance improving substance used in the present invention will be described below.

Reference Example 1 5- [4- (1-methylbenz)
Zimidazol-2-ylmethoxy) benzyl] thiazo
Lysine-2,4-dione (a) methyl 4-nitrophenoxyacetate 4-nitrophenol 56 g, methyl bromoacetate 9
A mixture of 0 g, 100 g of potassium carbonate and 500 ml of dimethylformamide was stirred at room temperature for 2 days. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, crystallization was performed using hexane to obtain 63.3 g of the desired compound having a melting point of 98 ° C. to 99 ° C.

(B) Methyl 4 -aminophenoxyacetate 30.8 g of methyl 4-nitrophenoxyacetate, 10%
5.0 g of palladium-carbon and 500 of methanol
Hydrogen gas was introduced into the ml mixture for 6 hours. After the completion of the reaction, insolubles were filtered off from the reaction mixture, and the filtrate was distilled off under reduced pressure to obtain 25.8 g of the desired compound having an Rf value of 0.79 (silica gel thin layer chromatography; ethyl acetate).
was gotten.

(C) 4- (2-bromo-2-butoxy)
Methyl carbonylethyl-1-yl) phenoxyacetate To a solution of 263 ml of methanol-acetone (2: 5) containing 25.8 g of methyl 4-aminophenoxyacetate, 98 g of 47% hydrobromic acid was added dropwise under ice-cooling. 33 ml of an aqueous solution containing 12.8 g of sodium nitrite was added dropwise. After stirring for 30 minutes under ice-cooling, 18.2 g of butyl acrylate was added to the reaction mixture, followed by stirring for 30 minutes under ice-cooling, 3.2 g of copper (I) bromide, and stirring at room temperature overnight. After the completion of the reaction, the solvent was distilled off from the reaction mixture, brine was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saline and then dried over anhydrous sodium sulfate. When the solvent was distilled off from the extract, the Rf value was 0.4.
51.7 g of a crude product containing the desired compound having a molecular weight of 6 (silica gel thin layer chromatography; hexane: ethyl acetate = 5: 1) were obtained.

(D) 5- [4- (ethoxycarbonyl )
Methoxy) benzyl] thiazolidine-2,4-dione 4- (2-bromo-2-butoxycarbonylethyl-1
-Yl) methyl phenoxyacetate 100 g, thiourea
2.5 g of a mixture of 22 g and 200 ml of ethanol
Heated to reflux for an hour. Next, 2N hydrochloric acid was added to the reaction mixture, and the mixture was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, water was added to the obtained residue, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate.
The solvent was distilled off from the extract and purified by silica gel column chromatography (ethyl acetate: hexane = 2: 5) to obtain 19.4 g of the desired compound having a melting point of 105 ° C. to 106 ° C.

(E) 5- [4- (1-methylbenzi)
Midazol-2-ylmethoxy) benzyl] thiazolidi
2,4-dione N-methyl-1,2-phenylenediamine 1.0 g,
5- [4- (ethoxycarbonylmethoxy) benzyl]
3.8 g of thiazolidine-2,4-dione, concentrated hydrochloric acid 2
0 ml, 1,4-dioxane 10 ml and water 1
0 ml of the mixture was heated at reflux for 5 hours. The insolubles precipitated from the reaction mixture were collected by filtration, dissolved in tetrahydrofuran, added with water, and neutralized with sodium hydrogen carbonate. Ethyl acetate was added to the resulting solution for extraction. The extract was washed with saline and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent from the extract was subjected to silica gel column chromatography (ethyl acetate → ethanol), and the obtained product was further recrystallized twice using tetrahydrofuran and ethyl acetate. Melting point 2
1.3 g of the title compound having a temperature between 30 ° C. and 231 ° C. are obtained.

Reference Example 2 5- [4- (6-methoxy-
1-methylbenzimidazol-2-ylmethoxy) be
Ndyl] thiazolidine-2,4-dione (a) 5-methoxy-2-nitroaniline 5-chloro-2-nitroaniline 25 g of 1,4-dioxane solution 500 ml of sodium methoxide 2
70 ml of an 8% methanol solution was added at room temperature, and the mixture was heated under reflux for 4 hours. The solvent was distilled off from the reaction mixture, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 → 1: 2)
The product was purified by purification to give 16.3 g of the desired compound having a melting point of 124 ° C to 128 ° C.

(B) N-tert-butoxycarboni
To a solution of 16 g of 5-methoxy-2-nitroaniline in 500 ml of anhydrous tetrahydrofuran was added 25 g of di-tert-butyl dicarbonate, 15 ml of pyridine and 0.6 g of 4-dimethylaminopyridine at room temperature. Stirred for hours. The solvent was distilled off from the reaction mixture, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain 12.5 g of the desired compound having a melting point of 112 ° C. to 114 ° C.

(C) N-tert-butoxycarboni
12.0 g of sodium ru-N-methyl-5-methoxy-2-nitroaniline hydride (containing 55% or more) was suspended in 300 ml of anhydrous N, N-dimethylformamide,
Under ice-cooling, a solution of 49.6 g of N-tert-butoxycarbonyl-5-methoxy-2-nitroaniline in 300 ml of anhydrous N, N-dimethylformamide was added to the suspension, followed by stirring at room temperature for 30 minutes. 17.2 ml of methyl iodide was added to this mixture at room temperature, and the mixture was stirred for 1 hour.
Left at room temperature overnight. After the reaction mixture was concentrated to about 1/5 volume, it was added to ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. When the solvent was distilled off from the extract, the melting point was 12
52.1 g of the title compound having a temperature between 2 ° C. and 124 ° C. are obtained.

(D) N-methyl-5-methoxy-2-
Nitroaniline N-tert-butoxycarbonyl-N-methyl-5
To 52 g of methoxy-2-nitroaniline was added 750 ml of a 4N hydrogen chloride-1,4-dioxane solution at room temperature, followed by stirring for 2 hours. After evaporating the solvent from the reaction mixture, water and ethyl acetate were added, and the mixture was neutralized with sodium hydrogen carbonate. Ethyl acetate was further added to the mixture for extraction, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to give a melting point of 10
35.3 g of the title compound having a temperature of 7 ° C. to 110 ° C. are obtained.

(E) 5-methoxy-N-methyl-1,
2-phenylenediamine N-methyl-5-methoxy-2-nitroaniline 35
g of tert-butanol solution in a mixture of 900 ml of ethyl acetate and 100 ml of ethyl acetate in tin (II) chloride dihydrate
346 g was added at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. 11 g of sodium borohydride was added to this mixture little by little,
The mixture was added at 60 ° C. over about 1 hour, stirred at 60 ° C. for 3 hours, and then left at room temperature for 2 days. After the reaction mixture was added to ice water, it was neutralized with sodium hydrogen carbonate. Ethyl acetate was added to the mixture for extraction, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 2).
21.9 g of the target compound having an Rf value = 0.18 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1) were obtained.

(F) 5- (4-methoxycarbonylmethyl )
Toxibenzyl) -3-triphenylmethylthiazolidi
To a 2.5 liter acetone solution of 120 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione was added 126 g of cesium carbonate, and 36 ml of methyl bromoacetate was added at room temperature. Add 1
Stirred for hours. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract, and diethyl ether was added to the oily residue.
One liter was added, and ultrasonic vibration was applied for 10 minutes. The precipitated solid was collected by filtration to give a melting point of 158 ° C to 162 ° C.
126.3 g of the target compound having a temperature of 12 ° C. are obtained.

(G) 5- (4-methoxycarbonylmethyl )
Toxylbenzyl) thiazolidine-2,4-dione 5- (4-methoxycarbonylmethoxybenzyl) -3
-Triphenylmethylthiazolidine-2,4-dione
To a suspension of 344 g in 400 ml of 1,4-dioxane, 1700 ml of acetic acid and then 400 ml of water
Was added at room temperature, followed by stirring at 80 ° C. for 5 hours. The solvent was distilled off from the reaction mixture, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 → 2: 1 →
Purification by ethyl acetate only) provided 161.7 g of the desired compound having a melting point of 100 ° C. to 106 ° C.

(H) 5- [4- (6-methoxy-1-)
Methylbenzimidazol-2-ylmethoxy) benzene
Ru] thiazolidine-2,4-dione 5-methoxy-N-methyl-1,2-phenylenediamine 21.8 g, 5- (4-methoxycarbonylmethoxybenzyl) thiazolidine-2,4-dione 63.4
g, 1,4-dioxane 250 mg and concentrated hydrochloric acid 7
50 ml of the mixture was heated to reflux for 60 hours. After the reaction mixture was ice-cooled, the precipitate was collected by filtration. 5%
800 ml of aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 2 hours. The insolubles were collected by filtration, and 1000 ml of N, N-dimethylformamide and 200 ml of methanol were added.
The resulting mixture was dissolved in a mixed solution (ml), and activated carbon was further added to remove the color.
After filtering off the activated carbon, the solvent was concentrated to about 50 ml.
To this was added 750 ml of diethyl ether, and the mixture was left at room temperature for 2 days. The precipitate was collected by filtration. ) Was obtained 20.1 g.

Reference Example 3 5- [4- (5-hydroxy)
C-1,4,6,7-tetramethylbenzimidazole
-2-ylmethoxy) benzyl] thiazolidine-2,4
-Dione [a] trimethylbenzoquinone trimethylhydroquinone 20 g acetone 150
25.6 g of iron (III) chloride in 50 ml of water.
ml was added at room temperature and stirred for 1 hour,
Left for 2 days. After concentrating the solvent to about half, water was added and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the extract was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 6) to obtain Rf = 0.48 (silica gel thin layer chromatography; ethyl acetate: n). 1-hexane (1: 6) was obtained.

[B] 2,3,6-trimethylbenzoxy
To 150 ml of a methanol solution of 16.9 g of non-4 -oximetrimethylbenzoquinone was added hydroxylamine hydrochloride (7.04).
30 g of an aqueous solution of g) was added at room temperature and stirred for 2 hours.
Left for 2 days. After 1000 ml of water was added to the reaction mixture, the precipitate was collected by filtration. This precipitate is treated with ethyl acetate-n
When purified by recrystallization from a hexane mixture, the melting point was 188.
11.2 g of the target compound having a temperature of from 190 ° to 190 ° C. are obtained.

[C] 4-hydroxy-2,3,5-to
Trimethyl aniline 2,3,6-trimethyl-benzoquinone-4-oxime
36.15 g and 1N aqueous sodium hydroxide solution 880
sodium hydrosulfite in 15 ml of the mixture
After adding 2 g under ice-cooling, the mixture was stirred at room temperature for 1 hour and left overnight. The reaction mixture was added to ice, the pH was adjusted to 4 to 5 with a 5N aqueous hydrochloric acid solution, and the mixture was neutralized with sodium hydrogen carbonate. This was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. Isopropyl ether was added to the crystals obtained by evaporating the solvent from the extract, and the crystals were collected by filtration and washed with isopropyl ether.
30.1 g were obtained.

[D] N-tert-butoxycarboni
4-hydroxy-2,3,5-trimethylaniline 4-hydroxy-2,3,5-trimethylaniline 2
To a solution of 0 g of tetrahydrofuran in 500 ml was added 22.0 ml of triethylamine at room temperature.
34.6 g of rt-butyl dicarbonate was added, stirred for 6 hours, and left overnight. After evaporating the solvent from the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, n-hexane was added to the crystals obtained, and the crystals were collected by filtration and washed with n-hexane to give the desired compound 3 having a melting point of 158 ° C to 161 ° C.
1.9 g were obtained.

[E] N-methyl-4-hydroxy-
Nt was added to a suspension of 6.8 g of lithium aluminum hydride in 300 ml of 2,3,5-trimethylaniline anhydrous tetrahydrofuran.
tert-butoxycarbonyl-4-hydroxy-2,
A solution of 15 g of 3,5-trimethylaniline (15 g) in anhydrous tetrahydrofuran (200 ml) was added under ice-cooling, and
After stirring for 2 hours, the mixture was heated under reflux for 2 hours. Water 1 in the reaction mixture
A mixture of 0 ml and 30 ml of tetrahydrofuran was added dropwise under ice cooling to decompose excess lithium aluminum hydride. After the reaction mixture was stirred at room temperature for 1.5 hours, insolubles were removed by filtration using Celite. The insolubles were washed with ethyl acetate, and the combined washings and filtrate were dried over anhydrous sodium sulfate. After evaporating the solvent from the solution, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain 5.1 g of the desired compound having a melting point of 120 ° C. to 122 ° C. .

[F] N-tert-butoxycarboni
Ru-N-methyl-4-hydroxy-2,3,5-trime
Tylaniline N-methyl-4-hydroxy-2,3,5-trimethylaniline 5.0 g tetrahydrofuran solution 70 m
5.0 ml of triethylamine and di-tert
30 ml of a tetrahydrofuran solution of 7.92 g of -butyl dicarbonate was added at room temperature, and the mixture was stirred for 1 hour.
Left at night. After evaporating the solvent from the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract, n-hexane was added to the crystals obtained, and the crystals were collected by filtration and washed with n-hexane.
7.35 g of the target compound having a temperature of 63 ° C. to 166 ° C.
was gotten.

[G] N-tert-butoxycarboni
Ru-N-methyl-4-acetoxy-2,3,5-trime
Tylaniline N-tert-butoxycarbonyl-N-methyl-4-
Hydroxy-2,3,5-trimethylaniline 7.2
g of anhydrous tetrahydrofuran in 100 ml of anhydrous triethylamine and 5.64 ml of acetyl chloride.
2.9 ml was added at room temperature, and the mixture was stirred for 1 hour and left overnight. Water was added to the reaction mixture, and extracted with ethyl acetate.
The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off from the extract, the residue was crystallized by adding ice-cooled n-hexane. Ice-cooled n-hexane was added, and the crystals were collected by filtration and washed with ice-cooled n-hexane to obtain 6.25 g of the desired compound having a melting point of 103 ° C to 104 ° C.

[H] N-methyl-4-acetoxy-
2,3,5-trimethylaniline hydrochloride N-tert-butoxycarbonyl-N-methyl-4-
Acetoxy-2,3,5-trimethylaniline 5.4
To 5 g, 4N hydrogen chloride-1,4-dioxane solution 1
00 ml was added at room temperature and stirred for 3 hours. The solvent was distilled off from the reaction mixture, and isopropyl ether was added to the resulting crystals. The crystals were collected by filtration and washed with isopropyl ether to obtain 4.36 g of the desired compound having a melting point of 172 ° C to 176 ° C.

[I] N-methyl-4-acetoxy-
4.3 g of 2,3,5-trimethyl-6-nitroaniline N-methyl-4-acetoxy-2,3,5-trimethylaniline hydrochloride was added to ice-cooled concentrated nitric acid, and the mixture was stirred under ice-cooling for 10 minutes. Thereafter, the mixture was further stirred at room temperature for 10 minutes. The reaction mixture was added to ice water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, 50 ml of isopropyl ether and 50 ml of n-hexane were added to the residue,
Ultrasonic vibration was applied for 5 minutes. A mixed solution of isopropyl ether: n-hexane (= 1: 1) was added to the insoluble crystals, and the crystals were collected by filtration and washed with a mixed solution of isopropyl ether: n-hexane (= 1: 1). 2.76 g of the target compound having a temperature of 2.degree. C. are obtained.

[J] 4-acetoxy-N-methyl-
2.65 g of 3,5,6-trimethyl-1,2-phenylenediamine N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline ethanol 20 m
20 ml of ethyl acetate and 0.1 ml of platinum oxide in a 1 l solution.
2 g was added, and hydrogen gas was introduced into the mixture at room temperature for 3.5 hours, and further at 40 ° C. for 3 hours. Next, platinum oxide was filtered off from the reaction mixture, and the solvent was distilled off from the filtrate.
The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give 1.3 g of the desired compound having a melting point of 113 ° C. to 116 ° C.
was gotten.

[K] 5- (4-methoxycarbonylmethyl)
Toxibenzyl) -3-triphenylmethylthiazolidi
To a 2.5 liter acetone solution of 120 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione was added 126 g of cesium carbonate, and 36 ml of methyl bromoacetate was added at room temperature. Add 1
Stirred for hours. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract, and diethyl ether was added to the oily residue.
One liter was added, and ultrasonic vibration was applied for 10 minutes. The precipitated solid was collected by filtration to give a melting point of 158 ° C to 162 ° C.
126.3 g of the target compound having a temperature of 12 ° C. are obtained.

[L] 5- (4-methoxycarbonylmethyl)
Toxylbenzyl) thiazolidine-2,4-dione 5- (4-methoxycarbonylmethoxybenzyl) -3
-Triphenylmethylthiazolidine-2,4-dione
To a suspension of 344 g in 400 ml of 1,4-dioxane, 1700 ml of acetic acid and then 400 ml of water
Was added at room temperature, followed by stirring at 80 ° C. for 5 hours. The solvent was distilled off from the reaction mixture, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 → 2: 1 →
Purification by ethyl acetate only) provided 161.7 g of the desired compound having a melting point of 100 ° C. to 106 ° C.

[M] 5- [4- (5-hydroxy-
1,4,6,7-tetramethylbenzimidazole-2
-Ylmethoxy) benzyl] thiazolidine-2,4-di
On 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine 1.0 g, 5- (4-
Methoxycarbonylmethoxybenzyl) thiazolidine-
2.7 g of 2,4-dione, 5 m of 1,4-dioxane
and a mixture of 25 ml of concentrated hydrochloric acid was heated to reflux for 2 days. The reaction mixture was added to ice water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off from the extract, the residue was purified by silica gel column chromatography (ethyl acetate), and the fraction containing the target compound was collected. The solvent was distilled off from this fraction to obtain a red oily substance. 150 ml of diethyl ether was added to the oil, and ultrasonic vibration was applied for 5 minutes, and the precipitate was collected by filtration. This precipitate is dissolved in 300 ml of tetrahydrofuran, and the solvent is
It was concentrated to 0 ml. When 200 ml of ethyl acetate was added thereto and ultrasonic vibration was applied for 20 minutes, a precipitate was formed. The precipitate was collected by filtration to give a melting point of 240 ° C to 24 ° C.
0.52 g of the target compound having an Rf value of 0.44 (silica gel thin layer chromatography; ethyl acetate) at 4 ° C.
was gotten.

[0165]

Industrial Applicability The insulin resistance improving substance of the present invention is useful as an ileal bile acid transporter inhibitor and can be expected as a therapeutic and / or prophylactic agent for hyperlipidemia.

Continued on the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication // C07D 263/32 C07D 263/32 263/44 263/44 271/06 271/06 277/34 277/34 277/38 277/38 291/04 291/04 413/02 413/02 417/06 207 417/06 207 213 213 263 263 333 333 333 417/1213 213 417/12 213 263 263 311 311

Claims (29)

[Claims] An ileal bile acid transporter inhibitor comprising an insulin resistance improving substance as an active ingredient. 2. The method of claim 1, wherein the substance for improving insulin resistance has the general formula: (Wherein R ¹ and R ² are each independently substituted with a hydrogen atom, a lower alkyl group or a lower alkyl group, an acyl group, a lower alkoxy group, a cyano group, a nitro group, a lower alkoxycarbonyl group, and a sulfonyl group. R ⁴ represents a hydrogen atom, a hydroxyl group,
A lower alkyl group, an acyl group, a lower alkoxy group, a cyano group, a nitro group, a lower alkoxycarbonyl group or a sulfonyl group, R ⁵ represents a lower alkyl group, m represents an integer of 0 or 1-2, and n represents The inhibitor according to claim 1, which is a thiazolidinedione derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: (Wherein, R ¹ represents a substituted or unsubstituted aryl group, A represents an alkylene group, B represents a lower alkylene group, R ² and R ³ represent a hydrogen atom or a halogen atom, and Y represents an oxygen atom. Or an imino group.) The inhibitor according to claim 1, which is a substituted thiazolidine derivative represented by the formula: 4. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [Wherein A ¹ is a substituted or unsubstituted aromatic heterocyclyl group: R ¹ is a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl group is substituted or unsubstituted; Or a substituted or unsubstituted aryl group: A ² is a benzene ring having up to 5 substituents in total: and n represents an integer in the range of 2 to 6] or a compound represented by the formula: The inhibitor according to claim 1, which is a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. 5. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: (Wherein the dotted line represents a bond or a non-bond, and R has 3 carbon atoms)
-7 cycloalkyl, naphthyl, thienyl, furyl,
Phenyl or an alkyl having 1 to 3 carbon atoms as a substituent,
C 1-3 alkoxy, trifluoromethyl,
A substituted phenyl which is chloro, fluoro or bis (trifluoromethyl); R ₁ is alkyl of 1-3 carbon atoms; X is O or C ＝ O; A is O or S; Is N or CH) or a pharmaceutically acceptable salt thereof [claim 1]. 6. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: In the compounds, or their tautomeric forms, and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, A ¹ represents a substituted or unsubstituted aryl group, A ² is X represents O, S or NR ¹ [R ¹ represents a halogen atom, an alkyl group, an acyl group, an aralkyl group (this aryl group portion may be substituted or unsubstituted) )], Or a substituted or unsubstituted aryl group, Y represents O or S, R ² represents hydrogen, R ³ represents hydrogen, or an alkyl, aralkyl, or aryl group, or R ² represents R ³ and represents a bond together, n represents a compound characterized by an integer in the range of 2-6, or its tautomeric forms, and / or pharmaceutically acceptable salts thereof and, Or inhibitors of [claim 1], wherein the pharmaceutically acceptable solvate. 7. The method according to claim 1, wherein the insulin resistance improving substance is represented by the general formula (I): Wherein R ¹ and R ² are independently hydrogen, 1 to 6
Alkyl containing 1 to 6 carbon atoms, lower alkoxy containing 1 to 6 carbon atoms, halogen, ethynyl, nitrile, methylthio, trifluoromethyl, vinyl, nitro or halogen-substituted benzyloxy: n is 0 to 4 Or a pharmaceutically acceptable salt thereof [claim 1]. 8. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: (Wherein the dotted line indicates no bond or bond, V is -CH = CH -, - N = CH -, - CH = an N- or S, W is _{CH 2, CHOH, CO, C} = NOR or CH
X is S, O, NR ¹ , -CH = N- or -N = CH
Y is CH or N; Z is hydrogen, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl or the same or different C ₁ -C ₃ alkyl , trifluoromethyl, a C ₁ -C ₃ alkoxy, fluoro, phenyl monosubstituted or disubstituted by a group which is chloro or bromo, Z ¹ is hydrogen or C ₁ -C ₃ alkyl, R and R ¹ Are each independently hydrogen or methyl and n is 1, 2 or 3), a pharmaceutically acceptable cation salt thereof, or a pharmaceutically acceptable salt thereof when the compound has a basic nitrogen. The inhibitor according to claim 1, which is an obtained acid addition salt. 9. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: Wherein the dotted lines indicate a bond or no bond; A and B are each independently CH or N, provided that when A or B is N, the other is CH; and X is S,
SO, SO _2, CH _2, a CHOH or CO-; n
Is 0 or 1; Y is CHR ¹ or NR ² provided that when n is 1 and Y is NR ² , X is SO ₂ or CO 2
Is; R, R ¹ , R ² and R ³ are each independently hydrogen or methyl; and X ¹ and X ² are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, Benzyloxy, bromo, chloro or fluoro], a pharmaceutically acceptable cation salt thereof, or a pharmaceutically acceptable acid addition salt when A or B is N [claim 1]. Agent. 10. The method according to claim 1, wherein the insulin resistance improving substance is represented by the general formula (I): [In the formula, A ¹ represents a substituted or unsubstituted aromatic heterocyclic group; R ¹ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl moiety is substituted or unsubstituted) R ² and R ³ each represent hydrogen or R ² and R ³ together represent a bond; and A ² represents a total of up to 5 Represents a substituted benzene ring; and n is 2-6
Or a tautomeric form thereof,
The inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof. 11. The method according to claim 1, wherein the insulin resistance improving substance is 5-((4-
(2-methyl-2- (pyridin-2-yl) amino) ethoxy) phenyl) methyl) -2,4-thiazolidinedione (BRL-49653) [Inhibition according to [1] or [10]. Agent. 12. The method according to claim 1, wherein the insulin resistance improving substance is represented by the general formula (I): Wherein R is hydrogen or alkyl, R ¹ represents an alkyl group or a substituted or unsubstituted aryl group, R ² and R ³ each represent hydrogen, or R ² and R ³ together represent a bond , A represents a benzene ring having a total of 5 or less substituents, X represents oxygen, sulfur or a partial NR ⁴ (wherein R ⁴
Represents hydrogen or alkyl), and n is 2-6
And a tautomer thereof, or a pharmaceutically suitable salt thereof [Claim 1]. 13. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [Where R is a phenyl group, a naphthyl group, a cycloalkyl group or a heterocyclic group which may have a substituent, and Alk is a single bond, a lower alkenylene group, a lower alkynylene group or a lower alkylene which may have a substituent. The group and dotted line indicate that the bond at the site may be a double bond. The inhibitor according to claim 1, which is a benzoxazole derivative represented by the formula or a salt thereof. 14. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [Wherein, R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² , R ⁴ and R ⁵ are the same. Or differently, a hydrogen atom, an aralkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a halogen atom, A hydroxyl group, a formyl group, an alkanoyl group which may have a substituent, an arylalkanoyl group which may have a substituent, a cycloalkylcarbonyl group which may have a substituent, An arylcarbonyl group, a carboxy group, an alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, a nitro group, a formula —N (R ⁷ )
(R ⁸ ) groups (wherein R ⁷ and R ⁸ are the same or different and are a hydrogen atom, a lower alkyl group, an aralkyl group, a cycloalkyl group, an aryl group which may have a substituent, a formyl group, a substituent An alkanoyl group which may have a substituent, an arylalkanoyl group which may have a substituent, an arylcarbonyl group or an alkoxycarbonyl group which may have a substituent, May form a 5- to 7-membered cyclic amino group together) or a compound of the formula -CON (R7 ^' ) (R8 ^' ), wherein R7 ^' and R8 ^'
Has the same meaning as that shown for R ⁷ and R ⁸ except for the acyl substituent. And R ³ is the same as R ² , R ⁴ and R ⁵ except for the hydroxyl group which may be protected, but when R ³ is a hydroxyl group which may be protected Has at least one of R ² , R ⁴ and R ⁵ having an alkyl group having a substituent, a halogen atom, a hydroxyl group, an alkoxy group having a substituent, a formyloxy group, and a substituent. Optionally substituted alkanoyloxy group, optionally substituted arylcarbonyloxy group, sulfoxy group, formyl group, optionally substituted alkanoyl group, optionally substituted aryl Alkanoyl group, cycloalkylcarbonyl group which may have a substituent, arylcarbonyl group which may have a substituent, carboxy group, alkoxycarbonyl group, which may have a substituent Group (wherein, R ⁷ and R ⁸ have the same meanings as defined above.) Represented by the aryloxy carbonyl group, a nitro group, the formula -N (R ⁷⁾ (R ^8), formula -CON (R ^{7 '} ) (R ^8' ) (wherein R ^{7 '} and R ^8' have the same meanings as described above). R ⁶ represents a hydrogen atom or an alkyl group which may have a substituent, and Ar represents a divalent aromatic ring group which may have a substituent or a divalent group which may have a substituent. A heteroaromatic group; W represents a methylene group, a carbonyl group, a formula = CH-OY group (wherein Y represents a hydrogen atom or an acyl group) or a formula = C = N-OV (where V is A protecting group for a hydrogen atom or a hydroxyl group.) Or a double bond may be formed with U described later, and U represents a single bond or a methylene group, or forms a double bond with W. , W represents a carbonyl group or a group of the formula = C = N-OV (wherein V has the same meaning as described above), and may form a double bond with R ¹ , and n represents 1 to Indicates an integer of 10. [3] The inhibitor according to [1], which is a thiazolidine compound represented by the formula: 15. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: Or a cation salt suitable as a pharmaceutically acceptable salt thereof, wherein the dashed line represents a single bond or a non-bond, n is 0, 1 or 2, and X is O, S, S = O, S (= O) (= O)
R is H, CH ₃ or C ₂ H _5, R ₁ is independently the H, C ₅ -C ₇ cycloalkyl, C ₆ -C ₈ methyl substituted cycloalkyl, pyridyl, thienyl, furyl, naphthyl, p- Biphenylyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, C ₆ H ₄ W ₂
[W ₂ is H, OH, F, Cl, Br, C 1 ~C 4 alkyl, C ₁ -C a ₄ alkoxy or C ₁ -C ₄ thioalkyl] or alk-W ₁ [alk is C ₁ -C ₆ Alkylene, ethylidene or isopropylidene; W ₁ is H, OH, C ₁ -C ₄ alkoxy, C ₁ -C ₄ thioalkyl, pyridyl, furyl, thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, C ₅ -C ₇ cyclo Alkyl or C ₆ H ₄ W ₂ ] wherein R ₂ is H or C
H _{3 wherein} R ₃ is H, C ₁ -C ₆ alkyl, C ₆ H ₄ W ₂
Or benzyl, wherein R ₄ is H and R ₁ and R ₂ are taken together to form a C ₄ -C ₆ alkylene; R ₃ and R ₄ are each H; _{When 3} and R ₄ are taken together they form a C ₄ -C ₆ alkylene, R ₁ and R ₂ are each H, and when R ₂ and R ₃ are taken together Means that they are C ₃ -C ₄
Forming an alkylene, and R ₁ and R ₄ are each H.
The inhibitor according to claim 1, which is: 16. The method according to claim 1, wherein the insulin resistance improving substance is 5-((3,4,
The inhibitor according to claim 1 or claim 15, which is -dihydro-2- (phenylmethyl) -2H-benzopyran-6-yl) methyl-2,4-thiazolidinedione (englitazone). 17. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: Or a pharmacologically acceptable salt thereof. 18. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [Wherein, R ¹ represents hydrogen or a hydrocarbon residue or a heterocyclic residue which may each be substituted, R ² represents a hydrogen or a lower alkyl group which may be substituted with a hydroxyl group, X
Represents an oxygen atom or a sulfur atom, Z represents methylene hydroxide or carbonyl, m represents 0 or 1, and n represents an integer of 1 to 3. L and M are each a hydrogen atom, or L and M are combined to form one bond. [3] The inhibitor according to [1], which is a thiazolidinedione derivative represented by the formula: or a salt thereof. 19. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [In the formula (I), R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ has a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group, or a substituent. R ⁴ and R ⁵ may be the same or different hydrogen atoms, such as an aromatic acyl group, a heterocyclic acyl group, an araliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group. A lower alkyl group or a lower alkoxy group; n is an integer of 1 to 3;
Represents an oxygen atom or an imino group, and Z represents an oxygen atom, a sulfur atom or an imino group. [3] The inhibitor according to [1], which is a thiazolidine derivative represented by the formula: or a pharmacologically acceptable salt thereof. 20. The method according to claim 1, wherein the insulin resistance improving substance is 5- (4-
((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) methoxy) benzyl) -2,4-thiazolidinedione (troglitazone) [Claim 1] or [Claim 19]. Inhibitors. 21. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [Wherein, Represents a cyclohexane ring having an oxo group or a hydroxyl group as a substituent on any methylene constituting the ring, and R represents hydrogen or a lower alkyl group. The inhibitor according to claim 1, which is a thiazolidine derivative represented by the following formula: 22. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [Wherein, R ¹ is a 5- or 6-membered heterocyclic ring having one or two hetero atoms selected from an alkyl group, a cycloalkyl group, a phenylalkyl group, a phenyl group, a nitrogen atom, an oxygen atom, and a sulfur atom] Group or —N (R ³ ) (R ⁴ )
(Provided that R ³ and R ⁴ are the same or different and represent a lower alkyl group, or R ³ and R ⁴ are bonded directly or via a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom; ³ , or a nitrogen atom adjacent to R ⁴ which may form a 5- or 6-membered ring). R ² represents a bond or a lower alkylene group. R ¹
Is an alkyl group, L ¹ and L ² may be the same or different and represent a lower alkyl group, or L ¹ and L ² may combine to form an alkylene group. In addition, when R ¹ is not an alkyl group, L ¹ and L ² may be hydrogen atoms in addition to the above definition]. 23. The method according to claim 1, wherein the insulin resistance improving substance is 5-((4-
(2- (5-ethyl-pyridin-2-yl) ethoxy)
Phenyl) methyl) -2,4-thiazolidinedione (pioglitazone) or 5-((4-((1-methylcyclohexyl) methoxy) phenyl) methyl) -2,4-
The inhibitor according to claim 1 or 22, which is thiazolidinedione (ciglitazone). 24. The method according to claim 1, wherein the insulin resistance improving substance has a general formula: [In the formula, R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. R ² represents a linear or branched alkylene group having 2 to 6 carbon atoms. R ³ is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms,
Linear or branched alkoxy group having 1 to 4 carbon atoms, linear or branched alkylthio group having 1 to 4 carbon atoms, halogen atom, nitro group, amino group, 1 to 4 carbon atoms A straight-chain or branched-chain monoalkylamino group having 4 carbon atoms, a straight-chain or branched-chain dialkylamino group having the same or different alkyl groups each having 1 to 4 carbon atoms, An aryl group having 10 or an aralkyl group having 7 to 12 carbon atoms is shown. X represents an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents or a heteroaromatic group which may have 1 to 3 substituents. Examples of the substituent include: 1) a linear or branched alkyl group having 1 to 6 carbon atoms; 2) a linear or branched halogen group having 1 to 4 carbon atoms. Alkyl group, 3) hydroxy group, 4) linear or branched acyloxy group having 1 to 4 carbon atoms, 5) 1 to 4 carbon atoms
Linear or branched alkoxy groups having
6) a linear or branched alkylenedioxy group having 1 to 4 carbon atoms; 7) a 7 to 12 carbon atoms.
Aralkyloxy group having 1 to 4 carbon atoms, 8) linear or branched alkylthio group having 1 to 4 carbon atoms, 9) linear or branched alkylsulfonyl having 1 to 4 carbon atoms Group) 10) halogen atom, 11) nitro group, 12) amino group, 13) linear or branched monoalkylamino group having 1 to 4 carbon atoms, 14) same or different alkyl groups A linear or branched dialkylamino group having 1 to 4 carbon atoms, 15) an aralkyl group having 7 to 12 carbon atoms, 16) an aryl group having 6 to 10 carbon atoms (the aryl group) Is a linear or branched alkyl having 1 to 6 carbons,
Straight or branched alkyl halide having 1 to 4 carbon atoms, straight or branched alkoxy having 1 to 4 carbon atoms, halogen or having 1 to 4 carbon atoms Linear or branched alkylenedioxy, which may be substituted) 17) aryloxy group having 6 to 10 carbon atoms (the aryl group is a straight-chain having 1 to 6 carbon atoms) Or a branched-chain alkyl, a straight-chain or branched-chain alkyl halide having 1 to 4 carbon atoms, a straight-chain or branched-chain alkoxy having 1 to 4 carbon atoms,
Halogen or a linear or branched alkylenedioxy having 1 to 4 carbon atoms, which may be substituted) 18) an arylthio group having 6 to 10 carbon atoms (the aryl group is Linear or branched alkyl having 1 to 6 carbon atoms, 1 to 4 carbon atoms
Linear or branched alkyl halide having 1 to 4 carbon atoms, linear or branched alkoxy having 1 to 4 carbon atoms, halogen or linear or branched alkyl having 1 to 4 carbon atoms. It may be substituted by a branched alkylenedioxy), 19) C6-C10.
Arylsulfonyl group having 1 to 6 carbon atoms (linear or branched alkyl having 1 to 6 carbons, linear or branched alkyl having 1 to 4 carbons) May be substituted by a straight-chain or branched alkoxy having 1 to 4 carbon atoms, halogen, or a straight-chain or branched alkylenedioxy having 1 to 4 carbon atoms) , 2
0) an arylsulfonylamino group having 6 to 10 carbon atoms (the aryl group is a linear or branched alkyl having 1 to 6 carbon atoms, and 1 to 4 carbon atoms)
Linear or branched alkyl halide having 1 to 4 carbon atoms, linear or branched alkoxy having 1 to 4 carbon atoms, halogen or linear or branched alkyl having 1 to 4 carbon atoms. It may be substituted with a branched alkylenedioxy. The nitrogen atom may be substituted by linear or branched alkyl having 1 to 6 carbon atoms), 21) heteroaromatic group, 22) heteroaromatic oxy group, 23) heteroaromatic ring A thio group, 24) a heteroaromatic sulfonyl group, and 25) a heteroaromatic sulfonylamino group (the nitrogen atom may be substituted by a straight-chain or branched alkyl having 1 to 6 carbon atoms) Is shown. Y is an oxygen atom, a sulfur atom or a group>
NR ⁴ is shown. (Wherein R ⁴ represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a linear or branched acyl group having 1 to 8 carbon atoms) Shown) Z is a group Is shown. The inhibitor according to claim 1, which is an oxime derivative having the formula: or a salt thereof. 25. The method according to claim 1 or 24, wherein the insulin resistance improving substance is 1) 5- [4- [2-[[[1- (4-biphenylyl)].
[Ethylidene] amino] oxy] ethoxy] benzyl] thiazolidine-2,4-dione, or 2) 5- [4- [2-[[1- [4- (2-pyridyl) phenyl] ethylidene] amino] oxy] The inhibitor according to claim 1 or 24, which is an oxime derivative selected from ethoxy] benzyl] thiazolidine-2,4-dione (compound A) or a salt thereof. 26. The method according to claim 1, wherein the insulin resistance improving substance is 5- (4- (5-methoxy-3-methylimidazo [5,
4-b] The inhibitor according to claim 1, which is a thiazolidine derivative which is pyridin-2-ylmethoxy) benzyl) thiazolidine-2,4-dione or a salt thereof. 27. The method according to claim 1, wherein the insulin resistance improving substance is: 1) 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione. 2) 5- [4- (1-methylbenzimidazole-2-
Ylmethoxy) benzyl] thiazolidine-2,4-dione, or 3) 5- [4- (5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2, The inhibitor according to claim 1, which is a benzimidazole derivative selected from 4-dione or a salt thereof. 28. The inhibitor according to claim 1, wherein the insulin resistance improving substance is selected from a thiazolidinedione compound, an oxazolidinedione compound and an oxathiadiazole compound. 29. The inhibitor according to claim 1, wherein the insulin sensitizer is selected from troglitazone, pioglitazone, ciglitazone, englitazone and BRL-49653.