JPH06502145A - Thiazolidinedione derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Thiazolidinedione derivatives The present invention relates to certain novel compounds, methods for producing the compounds, and methods for producing the compounds. The present invention relates to pharmaceutical compositions and pharmaceutical uses of the compounds and compositions.

European patent application, publication number 0OO8203,0139421,0155845,0 177353, 0193256, 0207581 and 0208420 are thiazo Concerning lysine dione derivatives, these have hypoglycemic and hypolipidemic activities (h ypolipidaemic activity).

Chemical and Pharmaceutical Breach:, z (CheIl, P Hart Bull, ), 30(10), 3580-3600 also lowers blood sugar. The present invention relates to thiazolidinedione derivatives having active and hypolipidemic activities.

Surprisingly, certain novel carbamate-substituted thiazolidinedione derivatives have been improved. It exhibits hypoglycemic activity and is therefore useful in the treatment and/or prevention of hyperglycemia. It has been found to be particularly useful in the treatment of type 1 diabetes.

These compounds are linked to hyperlipidemia, hypertension, cardiovascular disease and certain eating disorders. It is also shown to be useful in the treatment and/or prevention of other diseases including.

Therefore, the present invention provides formula (1): In formula c, A1 is an alkyl group, a substituted or unsubstituted aryl group, or an alkylene moiety Aralkyl group whose moiety or aryl moiety may be substituted or unsubstituted represents: A2 represents a benzene ring optionally having up to 3 substituents; R+ represents a hydrogen atom; child, alkyl group, anru group, alkyl moiety or aryl moiety is monosubstituted. an aralkyl group which may be substituted or unsubstituted, or a substituted or unsubstituted aryl group represents: Alternatively, A1 together with R1 represents a substituted or unsubstituted C tocopolymethylene group. and the optional substituents on the polymethylene group are selected from alkyl or aryl. or the adjacent substituents are identical to the polymethylene carbon atom to which they are attached. together form a substituted or non-orthogonal phenylene group: R2 and R3 are each hydrogen or R2 and R3 together represent a bond: X represents 0 or S: n represents an integer in the range of 2 to 6] or its tautomer and/or its pharmaceutically acceptable compound and/or pharmaceutically acceptable solvates thereof.

When AI represents an aryl group, the aryl group is preferably an unsubstituted aryl group. suitable.

When AI represents an aralkyl group, the aralkyl group has the formula niaryl(CHz)- [where m is 1.2.3 or 4, preferably 1 or 2; preferably An aralkyl group in which the ryl moiety is unsubstituted is preferred.

Preferably, AI is an alkyl group, a substituted or unsubstituted aryl group or an alkylene group. Aralkyl moiety or aryl moiety may be substituted or unsubstituted group, R1 is a hydrogen atom, an alkyl group, an acyl group, an alkyl moiety or an ali an aralkyl group in which the ring moiety may be substituted or unsubstituted; or represents an unsubstituted aryl group.

Conveniently, AI together with R1 represents a substituted or unsubstituted C2-3 polymethylene optional substituents on the polymethylene group are alkyl or aryl. or where the adjacent substituents are the methylene carbon atom to which they are attached. Together they form a substituted or unsubstituted phenylene group.

Convenient mono- or unsubstituted C2-3 polymethylene groups include substituted or unsubstituted Examples include ethylene group.

Suitable optional substituents for C2,3 polymethylene groups include C5-6 alkyl and optionally substituted phenyl groups, or adjacent the adjacent substituents together with the carbon atom to which they are attached are optionally substituted; form an optional phenylene group.

Optional substituents on the phenyl group are those described below with respect to the aryl group.

Optional substituents on the phenylene group include halogen, alkyl group, phenyl group, alkyl group, Koxy group, haloalkyl group, hydroxyalkyl group, hydroxy group, amino group, Nitro group, cyano group, carboxy group, alkoxycarbonyl group, alkoxycar Bonylalkyl group, alkylcarbonyloxy group and alkylcarbonyl group selected from.

Preferably, the phenylene group is unsubstituted.

Examples of A1 include phenyl, benzyl and 2-phenylethyl .

Examples of R1 include methyl, phenyl and 2-hydroxy-2-phenylethyl. For example,

Substituted or unsubstituted 02-3 polymethyl represented by AI together with R1 Examples of nitrogen groups include 1,2-phinidine and the formula:%formula%(2 Examples include groups represented by.

Suitable substituents for group A2 include halogen, substituted or unsubstituted alkyl or Examples include alkoxy.

Conveniently, A2 is the formula (a) [In the formula, R4 and R5 are each independently hydrogen, halogen, substituted or unsubstituted atom; represents alkyl or alkoxy] represents a group represented by

Preferably, R4 and R5 are each independently hydrogen, l\logen, alkyl or alkyl. Represents lucoxy.

Preferably R4 and R5 each represent hydrogen.

Preferably R1 is hydrogen, alkyl, aryl, especially phenyl, anru, especially acetate. Represents chill or benzyl.

Preferably R1 represents a methyl group.

Suitably R2 and R3 each represent hydrogen.

In one embodiment, X represents sulfur. Preferably X represents oxygen.

Suitably n represents the integer 2.3 or 4, especially 2 or 3, especially 2.

As mentioned above, the compound represented by formula (I) has one of several tautomers. It may exist in two forms, all of which are encompassed by the present invention. The present invention It includes any stereoisomeric form, whether an isomer or a mixture of isomers. isomeric forms of the compound of formula (I) and its pharmaceutically acceptable salts. It will be understood that all are inclusive.

As used herein, the term "aryl" or e.g. The term "al" as used herein may optionally include halogen, alkyl, fluoride, etc. phenyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, hydroxy group, amino group, nitro group, cyano group, carboxyne group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkylcarbonyloxy group or alkyl substituted with up to 5, preferably up to 3 groups selected from carbonyl groups; phenyl and naphthyl, preferably phenyl.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine. It means urin, preferably chlorine.

As used herein, "alkyl" (alone or others such as aralkyl) in any case used as part of the group of ) or 'alk' (e.g. , when used with "alkoxy") containing up to 12 carbon atoms It means an alkyl group having a straight carbon chain or a branched carbon chain.

Suitable alkyl groups are Cl-12 alkyl groups, especially 01-6 alkyl groups, e.g. , methyl group, ethyl group, n-propyl group, inpropyl group, n-butyl group, iso It is a butyl group or a tert-butyl group.

Suitable optional substituents for any alkyl group include those for aryl. Examples include those mentioned above.

As used herein, the term "acyl" refers to alkylcarbonyl or aryl. carbonyl group.

Suitable pharmaceutically acceptable salts include salts of thiazolidinedione moieties, and In appropriate cases, salts of carboxyne groups may be mentioned.

Suitable pharmaceutically acceptable salts of the thiazolidinedione moiety include metal salts, especially Alkali metal salts such as lithium, sodium and potassium salts, e.g. Examples include thorium salts.

Suitable pharmaceutically acceptable salts of carboxyne groups include, for example, aluminum salts. metal salts, alkali metal salts such as sodium or potassium, calcium or or alkaline earth metal salts such as magnesium and ammonium or substituted ammonium salts, e.g. lower alkyl amines such as triethylamine, Droxyethylamine, bis(2-hydroxyethyl)-amine or tri- Hydroxyalkylamines such as (2-hydroxyethyl)-amine, with nochloroalkylamines, such as lohexylamine, or with prolactin , dibenylpiverine, N-benzyl-b-phenethylamine, dehydroavi Nithylamine, N, N'-bisdehydroabiethylamine, glucamine, N- Pyridine such as methylglucamine or pyridine, collidine or quinoline Examples include those based on type bases.

Suitable pharmaceutically acceptable solvates include hydrates.

Furthermore, the present invention provides the formula (■): [wherein R2, R3 and A2 are the same as defined for formula (I), R" is the formula (b) = A'-0-Co-NR' (CHz), -X (b) (where AI, R 1, X and n are the same as defined for formula (I)) ] The compound represented by is reacted with a suitable reagent capable of converting R'' into group (b). and then optionally (f) Converting the compound represented by formula (1') into another compound represented by formula (I) step = (it) a pharmaceutically acceptable salt of the compound represented by formula (I) and/or or one or more of the steps for producing a pharmaceutically acceptable solvate thereof. a compound of formula (I), or a tautomer thereof, and/or or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydration thereof It also provides methods for manufacturing things.

A1 together with R1 represents a substituted or unsubstituted C2-1 polymethylene group For compounds of formula other than (D), R" is preferably RloHN-(CH2 ), -X-, where X and n are the same as defined for formula (I); Rlo is hydrogen, alkyl, acyl or an alkyl or aryl moiety aralkyl, which may be substituted or unsubstituted, or substituted or unsubstituted aralkyl; Represents a reel.

Preferably, when R' is R"HN-(CHz)-X-, R" is a group (b)14 Suitable reagents that can be used for formula (■): A3-〇-CO-L' (I ff) [In the formula, A3 is alkyl, substituted or unsubstituted aryl, or aryl moiety] vinegar] This is a compound represented by

Suitable leaving groups L+ include halogen atoms, preferably chlorine or bromine atoms or or an alkokyne group.

The reaction between a compound of formula (If) and a suitable reagent is represented by formula (II). can be carried out under conditions appropriate to the particular compound and selected reagent. Thus, For example, a compound represented by formula (II) in which R" represents RloHN-(CH2), -X- The reaction between the compound and the compound represented by formula (ffl) can be carried out using, for example, dimethylform. at an elevated temperature in the range of 0 to 100°C, preferably in any suitable solvent such as Muamide. or 0 to 80°C, for example 80°C; optionally a suitable temperature such as triethylamine It can be carried out in the presence of a suitable base.

Preferably, R" represents a group in which X is the same as defined for formula (I). As a method, Ro can be a leaving group or atom, such as a halogen atom, preferably represents a fluorine atom.

When Ro represents -XH, particularly suitable reagents are those of the formula (■): [where AI, RISX and n are the same as defined for formula (I), and R2 is a Men'l group or a Ton'le group. represents a leaving group such as].

The reaction between the compounds of formulas (II) and (TV) can be carried out using, for example, trimethylform. of the desired product in any suitable non-brotogenic solvent such as an amide. Any temperature that provides a rate of production, conveniently an elevated temperature, preferably between 60°C and 1 00°C, for example 80°C: Preferably, the reaction is in the presence of a base such as sodium hydride in an inert atmosphere such as sodium hydride.

The compound represented by the formula (U) is a compound represented by the formula and Ro represents Ro or its protected form] A compound represented by is reacted with 2,4-thiazolidinedione or its protected form. , then optionally represented by formula (n) in which R2 together with R3 represents a bond. A compound represented by the formula (ff) in which R2 and R3 each represent hydrogen is obtained by reducing the compound represented by and/or remove any protecting groups and/or remove certain groups R° can be prepared by converting R° into another group R°.

The reaction between the compound represented by formula (V) and 2,4-thiazolidinedione is Of course, it will be carried out under conditions suitable to the properties of the compound of formula (V). .

Generally, the reaction is carried out in a solvent such as toluene, preferably at the reflux temperature of the solvent. preferably piperidinium acetate or piperidinium ben It is carried out in the presence of a suitable catalyst such as zoate. Conveniently, as shown in formula (v) In the reaction between the compound and 2,4-thiazolidinedione, the water produced in the reaction is , for example, in the Dean and Stark (Dean and 5tark) device. It is therefore removed from the reaction mixture. piperidinium acetate or piperi Dinium benzoate is prepared in-situ from piperidine and acetic acid or benzoic acid. can be manufactured.

Regarding the compound represented by formula (ff) where Ro is HX-, Rh is a protected form of Ro. It is preferred to represent the group RcX-, for example in which Re is a bennyl group.

The conversion of one group R'' into another may be carried out by any suitable method.

For example, it is represented by the formula (I[) where R" is R"HN-(CH2)-X- The compounds are prepared from the corresponding compounds of formula (If) where Ro is -XH. Thus, a suitable transformation can be carried out in the presence of a suitable binder to convert the formula (I[A): , R2, R3, A2 and X are the same as defined for formula (1), and Ro is hydrogen or a nitrogen protecting group] The compound represented by the formula (■): R"NR"(CHz)--OH(VI) [wherein R1" and n are the same as defined above and R1 is hydrogen or a nitrogen protecting group] and then, if desired, (f) R'' and R3 are A compound represented by formula (II) which together represents a bond, where R2 and Rj are each hydrogen Step of reducing to a compound represented by the formula (]T): (if) Any nitrogen storage This is accomplished by performing one or more of the steps that also remove the protecting group.

Suitable bonds for bonding reactions between compounds of formulas (IIA) and (Vl) The agent is treated by diethyl azodicarboxylate and triphenylphosphine. provided. This coupling reaction can be carried out in any suitable solvent at low to moderate temperatures, e.g. For example, it may be carried out in tetrahydrofuran at temperatures ranging from 0 to 60°C.

The compound represented by the formula (■) has the formula (■): Al-0-Co-N-(CH2), - ):F((VTI) [where AI, RISX and n are the definitions for formula (r) For example, ( When L2 in rV) represents a menthyl or tosol group, a suitable transformation is in an inert solvent such as dichloromethane, a suitable rate of formation of the desired product. at any temperature that brings the by mesylation or tosylation in the presence of a base such as triethylamine Alternatively, the reaction is carried out under similar reaction conditions with a base such as pyridine. It may be carried out in a neutral solvent.

AI is alkyl, substituted or unsubstituted aryl, or an aryl moiety or aryl The alkyl moiety represents a substituted or unsubstituted aralkyl group, and R1 is the The compound represented by the formula (■) representing the same R'' as defined above is the compound represented by the formula (■) in the defined formula (111) above. The compound shown is represented by the formula (■): 1a HN(CH2)! 1st position Leap Reaction with a compound represented by [wherein R11, X and n are the same as defined above] It can be manufactured by

The reaction between the compounds represented by formulas <m> and (■) is carried out under conventional acylation conditions. The reaction can be carried out in a two-phase solvent system such as water/chloroform or in a carbonic acid solution. May be carried out in water alone in the presence of a base such as sodium; alternatively The reaction is carried out in the presence of a base such as pyridine and an inert solvent such as methylene chloride. The reaction may be carried out in a medium: the reaction is carried out at a temperature which results in a favorable rate of formation of the desired product. , preferably at a temperature below room temperature, for example 0°C.

Substituted or unsubstituted where A1 together with R1 has the same definition as for formula (I) A compound represented by the formula (■) representing a C2-3 polymethylene group is a compound represented by the formula (■): [in the formula , Z is substituted or unsubstituted c2-3 polymethyl as defined for formula (I) The code representing the group A compound represented by formula (X): L3-(CH, -XR' (X) 0, where X and n are the same as defined for formula (r), and L3 is a leaving group, preferably or a bromine atom, and R1 represents hydrogen or a protecting group]. It can be manufactured by reacting.

The reaction between the compounds represented by formulas (IX) and (X) can be carried out using, for example, dimethylpolymers. A suitable solution of the desired product in any suitable aprotic solvent such as Any temperature that results in a growth rate, preferably in the range 06-100°C; e.g. at 80°C, preferably with a base such as potassium carbonate or sodium hydride. can be carried out in the presence of

A formula in which AI together with R1 represents a substituted or unsubstituted C1-, polymethylene group Compounds marked with (■) are listed in the Journal of Heterocyclic Chemist Lee (J, Heterocyclic Chell), 1988.25. It can also be manufactured according to the method disclosed in No. 1601.

The compounds represented by formulas (DI), (V) and (■) are known commercially available compounds. compound or a method used to make a known compound, e.g. Bunst Organic Chemistry (Advanced Organic) Chemistry), Jay March (J, March), McGraw Hi (McGrav Hill) or in particular the formula (Iff) For the compounds shown in ・Edition in English CAngev, Chersie, I ntEd, Eng.), 1987, p. 894. Manufactured using similar methods.

Compounds of formula (I), or tautomers thereof, and/or pharmaceutical compounds thereof Acceptable salts and/or pharmaceutically acceptable solvates thereof have the formula (X[) In formula 0, R1, AI, A2, X and n are the same as defined for formula (1). react the compound shown with 2,4-thiazolidinedione; the law of nature, (i) Converting the compound represented by formula (I) into another compound represented by formula (I) Step; (if) a pharmaceutically acceptable salt of the compound represented by formula (I) and/or or a pharmaceutically acceptable solvate thereof. It may be manufactured by

The reaction between the compound represented by formula (XI) and 2,4-thiazolidinedione is also Of course, the process must be carried out under conditions that depend on the properties of the compound represented by formula (Xr). Dew.

Generally, the reaction is carried out in a solvent such as toluene, preferably at a temperature such as the reflux temperature of the solvent. preferably piperidinium acetate or piperidinium base. It is carried out in the presence of a suitable catalyst such as nizoate. Conveniently, the formula CM) In the reaction between the compound and 2,4-thiazolidinedione, the reaction The diluted water is removed from the reaction mixture, for example by a Dieller and Stark apparatus. leave Piperidinium acetate or piperidinium benzoate is It can be prepared in situ from piperidine and acetic acid or benzoic acid.

In the compound represented by formula (XI), R' can be converted into the group (b) as defined above. A compound represented by formula (v) in which Ro represents R" can be obtained by reaction with a suitable reagent that can or a protected form thereof.

A preferred meaning for Ro in formula (V) is a compound represented by formula CrI) Examples include those defined above regarding things. Suitable reagents may also be used as described above with respect to formula (ff). It is written down.

Suitable reaction conditions for the reaction of the compound of formula (V) and a suitable reagent include For example, those mentioned above regarding the preparation of compound (II) with this suitable reagent may be mentioned. can be lost.

A preferred form of protection for the compound represented by formula (V) is one that protects the aldehyde group. The following can be mentioned. Suitable protecting groups are those conventional in the art. hydroxy It is convenient to protect the aldehyde group by reduction to the methyl group, and deprotection is , has proven convenient to be carried out by oxidation to an aldehyde. suitable A suitable reducing agent is a hydrogenated composite gold R reducing agent such as lithium aluminum hydride. It is a conventional reagent. Suitable oxidizing agents are conventional oxidizing agents such as Mn''02.

In a preferred embodiment regarding the production of the compound represented by formula (XI), in formula (V), R1 may represent a leaving group or a leaving atom, in particular a fluorine atom. Rb is a leaving group or When represents a leaving atom, in particular a fluorine atom, particularly suitable reagents are those of the formula (■ ) is a compound represented by

The reaction between compounds of formulas (V) and (■) can be carried out under any suitable conditions. , in a solvent such as, for example, dimethylformamide or dimethylformamide, At elevated temperatures, such as in the range 60-150°C, preferably sodium hydride, hydroxide in the presence of a base such as sodium chloride or potassium carbonate, preferably hydrogen It can be carried out under an inert atmosphere.

A compound represented by the formula (■) in which Rb is a protected form of Ro is a compound represented by the formula (■) in which Rb is a protected form of Ro. (V).

The compound represented by formula (v) in which R' is hydroxyl or fluorine is a known compound. Manufactured by methods similar to those used to manufacture products or known compounds For example, 4-fluorobenzaldehyde and 4-hydro Xybenzaldehyde is a known commercially available compound. Rb is 18H A compound represented by formula (V) is a compound represented by Beilstein 8 ．． I, 533.

As said conversion of the compound represented by formula (1) to another compound represented by formula (I) The following transformations can be mentioned − (a) A compound of formula CI) in which R'' and R1 together represent a bond, 2 and R3 each represent hydrogen; (b ) converting one group R1 into another group R1: (c) one group A'-0, CO , NR'- to another +7) group A'-0, Co, NR'-11m conversion.

Conversion of a compound represented by formula (1) to another compound represented by formula (I) can be carried out by any of the following methods. It may also be done by using any suitable conventional means.

Suitable reduction methods for transformation (a) include catalytic reduction or metal/solvent reduction. One example is the use of the original system.

A suitable catalyst for catalytic reduction is a palladium on carbon catalyst, preferably a cooked 10% palladium catalyst. the reduction is carried out in a solvent such as dioxane, preferably at room temperature. and, if desired, under high pressure, for example 90 or 900 ps i.

A suitable metal/solvent reducing system includes magnesium in methanol.

R2 and R3 of a compound represented by formula (n) where R2 and R3 together represent a bond. and R3 each represent hydrogen. ) under conditions similar to those cited above in (a). It can be done.

In the conversion (b), preferred conversions of one group R1 to another group R1 include: An example of this is converting the group R1 representing hydrogen into a group R1 representing an alkyl group.

In the compound represented by formula (1) where Ro represents hydrogen, in formula (I) where Ro represents alkyl, Conversion to the compound shown involves converting a suitably protected compound of formula (I) into a halo either by treatment with an alkyl genide, e.g. alkyl iodide. It may also be carried out using any suitable conventional alkylation method.

One example of transformation (C) is alkyl, where AI is the same as defined for formula (I), represents a substituted or unsubstituted aryl or aralkyl, R1 is a hydrogen atom in the alkyl moiety; In the case of a group A'-0, Co, NRI-, which is an aralkyl group having a doxy substituent , the conversion brings A1 together with R1 to form a substituted Cff1-3 polymethylene group. alkyl, aryl or A group of formula A'-0, Co, NR+ selected from aralkyl is obtained.

Thus, if A1 is benzyl and R1 is PhCH(OH)CH2- , the transformation yields 5-phenyl-2-oxazolidinon-3-yl : The conversion is carried out in the presence of an acid such as dilute hydrochloric acid in a solvent such as ethanol, with the formula (1 ) by heating a suitable compound.

In said transformations (a), (b) and (C), if necessary, conventional chemical Depending on the method, any reactive groups in the compound of formula (I) are protected. It is understood that

Suitable protecting groups in any of the above reactions are those commonly used in the art. It is something that can be done. Thus, for example, a suitable nitrogen protecting group is a benzyl group or a penyl group. trimethyl for the thiazolidinedione nitrogen the preferred hydroxyl protecting group is the benzyl group. .

Methods for forming and removing such protecting groups are based on the appropriate routine for the molecule being protected. This is a method for Thus, for example, an N-benzyl group can be added to the bromide of a suitable amine. produced by treatment with benzyl halides such as benzyl and then in situ Conveniently, the benzyl group can be removed using catalytic hydrogenation if desired.

Where appropriate, compounds of formula (I) and pharmaceutically acceptable salts thereof The isomeric forms can be prepared as individual isomers using conventional chemical methods.

Pharmaceutically acceptable salts and/or solvates of the compound represented by formula (r) are: It can be manufactured according to conventional methods.

As noted above, the compounds of the present invention have been shown to have useful therapeutic properties.

Accordingly, the present invention provides compounds of formula (I) useful as effective therapeutic substances. , or its tautomers and/or its pharmaceutically acceptable salts and/or provides pharmaceutically acceptable solvates thereof.

Thus, the present invention provides compounds of formula (r) useful for the treatment and/or prevention of hyperglycemia. the indicated compound, or its tautomer and/or its pharmaceutically acceptable Also provided are salts and/or pharmaceutically acceptable solvates thereof.

The present invention also provides a compound represented by formula (1) that is useful for treating and/or preventing hyperlipidemia. compound, or its tautomers and/or its pharmaceutically acceptable salts. and/or pharmaceutically acceptable solvates thereof.

As mentioned above, the present invention is useful for treating hypertension, cardiovascular disease, and certain eating disorders. Compounds of formula (I) or their tautomers and/or their tautomers useful for therapy and/or pharmaceutically acceptable solvates thereof. There are also things to do.

The compound of formula (I), or its tautomer and/or its pharmaceutical Acceptable salts and/or pharmaceutically acceptable solvates thereof may be administered by themselves. or, preferably, a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. may be administered as a composition.

Therefore, the present invention provides a compound represented by general formula (1) or a tautomer thereof , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable" refers to human and veterinary medicine. Includes compounds, compositions and ingredients useful both in: e.g. The term "salts" includes veterinary acceptable salts.

The composition may optionally be packaged in a package with written or printed instructions for use. It may also be in a dark form.

Generally, the pharmaceutically acceptable compositions of the present invention will be suitable for oral administration, but may also be administered by injection. Compositions for administration by other routes, such as by transdermal absorption, are also contemplated.

Particularly suitable compositions for oral administration are in unit dosage forms such as tablets and capsules. be. Other fixed unit dosage forms may also be used, such as the powders present in Sanae.

According to conventional V-drug practice, the carrier may include diluents, fillers, disintegrants, wetting agents, lubricants. , colorants, flavoring agents or other customary adjuvants.

Typical carriers include, for example, microcrystalline cellulose, starch, and starch. Sodium cholate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, steel Magnesium phosphate, sodium lauryl sulfate and sucrose are included. It will be done.

The most preferred compositions will be formulated in unit dosage form. Such a unit dose usually ranges from 0.1 to 1000, more commonly from 0.1 to 500, especially from 0. ．． It will contain the active ingredient in an amount ranging from 1 to 250 parts.

The present invention also provides compounds represented by general (I), or tautomers and /or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvent thereof administration of a non-toxic, effective amount of the compound to a hyperglycemic human or non-human mammal in need thereof. Treatment of hyperglycemia in humans or non-human animals and/or Or it may provide a preventive method.

The present invention further provides a compound represented by formula (I), or a tautomer and a tautomer thereof. and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solution thereof. A non-toxic effective amount of the vehicle is administered to a hyperlipidemic human or non-human mammal in need thereof. hyperlipidemia, hypertension in humans or non-human mammals, Provides a method of treating cardiovascular disorders or certain eating disorders.

Conveniently, the active ingredient may be administered as a pharmaceutical composition as defined above, which form a particular aspect of the invention.

Treatment and/or prevention of hyperglycemia in humans and/or treatment of hyperlipidemia in humans. In therapy and/or prophylaxis, compounds represented by general formula (I), or their mutual Mutant forms and/or pharmaceutically acceptable salts thereof and/or medicaments thereof The pharmaceutically acceptable solvates, at dosages as indicated above, have a combined effect on 9 out of 70 adults. The daily dose is generally between 1 and 6,000. more generally in the range of about 1 to 1500-9. It may be administered 1 to 6 times a day in such a manner that the

In the treatment and/or prevention of hyperglycemia in non-human mammals, especially dogs, The active ingredient is taken by mouth, usually once or twice a day, from about 0.02519/719 to 25n/kq, for example, an amount in the range of 0, 1*q/J19-20 mq/hq It will be administered at. A similar dosing regimen can be used to treat hyperlipidemia in non-human mammals. Suitable for treatment and/or prevention.

Dosing regimens for the treatment of hypertension, cardiovascular disease, and eating disorders generally include This would be the aforementioned plan regarding the disease.

Furthermore, the present invention provides for the formulation of a drug for the treatment and/or prevention of hyperglycemia. The compound of formula (I), or its tautomer and/or its pharmaceutical Provides for the use of acceptable salts and/or pharmaceutically acceptable solvates thereof The invention also provides treatment for hyperlipidemia, hypertension, cardiovascular disease or certain eating disorders. and/or a compound of formula (I) for the formulation of a prophylactic drug; is its tautomer and/or its pharmaceutically acceptable salt, and/or its tautomer Provided are uses of pharmaceutically acceptable solvates of.

The following methods and examples illustrate, but in no way limit, the invention. -(N-phenoxycarbonyl-N-methylamino)ethanol stirring and water cooling At the same time, 2-(N-methyl acetate dissolved in saturated sodium carbonate solution (200j/) phenyl chloroformate (20 , 4 g; 16.3-j were added. More water (100 l) and chloro Form (150j/) was added and the biphasic mixture was stirred at 0°C for 3 hours. Separate layers Separated and the aqueous layer was extracted with chloroform (300,7). The combined organic layer was diluted with water (3 Wash with X300 and saline solution (300,1), dry and MgSO4 ), evaporated. silica using 15% methanol in dichloromethane as solvent. After chromatography on gel, the title compound was obtained as an oil.

IHNMRδ (CDC7!a) The peaks in this spectrum are complicated by the presence of the inverter of the carbamate group. Ru.

2, 50-3.00 (IH, broad appearance is d above, replace with D20) +3. 15 (3H, br s); 3.50 (2H, distorted t): 3.75 (2H , distorted t) near, 00-7°60 (5H, ?i miscellaneous).

Hotodan 2-(N-phenoquinocarbonyl-N-methylamino)ethanolmethanesulfonate 2-(N-phenoxycarbonyl-N-methinogemino)ethanol (4,89v ) and triethylamine C3,05y: 4.2 ml of dichloromethane (1 2.00 ml) of methanesulfonyl chloride (3,159; 2. 2 m/) was dropped.

The mixture was stirred at 0° C. for 1.5 h and then treated with dichloromethane (Looml). Dilute, wash with water (3 x 200 ml), saline solution (200,7), dry and m g　S　OO1 was evaporated. The title compound (oil) was used without further purification. .

'HNMRδ(CDC/,) The peaks in this spectrum are complicated by the presence of rotamers of the carbamate group. Ru.

3, 05 (3H, s): 3.17 (3H, appearance is above d); 3.75 ( 2H, complex), 445 (2H, D: 7.10-7.70 (5H, complex).

2-(N-methylamino)ethanol (12.0 g; 13-f) was added to sodium carbonate. Mu saturated melt! Benzyl chloroformate in a strongly stirred water-cooled mixture in & (20017). (229; 18.4ml) was added slowly. Warming the mixture to room temperature; It was then stirred for an additional 16.5 hours, then diluted with water (500 tonnage) and dichloromethane. Extracted with methane (3×250×I). Wash the combined organic layers with water and brine. The mixture was dried and evaporated (MgSO4). Further purification of the title compound (oil) It was used without being manufactured.

'HNMRδ(CDC/,) Some peaks in this spectrum are due to the presence of rotamers of the carbamate group. It becomes complicated.

2.00-2.90 (IH, brs, replaced with D20); 3. O0(3H , s): 3.42 (2H1 distorted t); 3.75 (2H, br t): 5. 20(2H,s): and 7.40(52-(N-benzyloxycarbonyl- N-methylamino)ethanolmethane 2-(N-benzyloxycarbonyl- Stirring of N-methylamino)ethanol (1947g) in pyridine (200,7') Methanesulfonyl chloride (12,8Fh; 8.7-1) was dissolved in a stirred water-cooled solution. Added slowly. After stirring the mixture at 0°C for 30 minutes and then at room temperature overnight , diluted with water (11) and extracted with ethyl acetate (3×300.f). combined vinegar Wash the ethyl acid layer with water (3x300m/), brine (300,7), and dry. Mg5O4) was evaporated. The title compound (oil) was used without further purification. .

It gets complicated depending on the situation.

3, 00-3.20 (6H, ?j miscellaneous); 3.60 (2H, complex); 4.30 (2H, distorted t): 5.15 (2H, s): and 7.40 (5H, s) .

-N-methylamino)ethanol methanesulfonyl ester (22,89) and and 4-hydroquinobenzaldehyde (10,129) were reacted together. solvent Purify the crude product on silica gel using 15% methanol in dichloromethane as Chromatography gave the title compound (oil).

3, O0 (3H, s): 3.65 (2H, distorted t) + 4.15 (2H, br t) + 5.05 (2H, s) + 6.85 (2H, br d); 7.2 2 (5H, s); 7.70 (2H, d): and 9.75 (IH, s).

(i): Nitric carbonate in dichloromethane (200,7) at 0°C under nitrogen atmosphere Lolomethyl (109) was dissolved. Pyridine (8,07v: 8.25++l ) was added slowly, and while stirring the resulting solution at 0°C, 2-phenylethane was added. (12.48 g; 12.2 mA') in dichloromethane (total amount 20 y sl) was added carefully. ) The mixture was warmed to room temperature and further heated for 64.5 hours. (tic indicated completion of reaction). Impurity 2-phenychloroformate This reaction mixture containing ruethyl was used directly in step (it).

(if) + 2-(N-methylamine)ethanol (7,67g; 8.2a+ 7) and pyridine (16,19; 16.5++/) in dichloromethane (10 017) Slowly add the chloroformate solution (from (f) above) to the medium stirred water-cooled mixture. The mixture was added over a period of 15 minutes. The resulting mixture was warmed to room temperature over 4 hours, It was then diluted with dilute hydrochloric acid (400,1). Separate the layers and add the organic layer to water (3X4 00 mA') and saline solution (400 mA'), dry, Mg5OJ, and evaporate. I let it emanate. The residue was silicaed using 2% methanol in dichloromethane as the solvent. Chromatography on Kagel gave the title compound as an oil.

YiHNMRδ (CD C4) The peak in this spectrum indicates the presence of rotamers of the carbamate group. It gets more complicated.

2.50 (LH, s exchanged with DzO): 2.95 (5H, *miscellaneous); 3.32 (2H, distorted t); 3.65 (2H, br t); 4.30 (2H, t); and 7.30 (5H, s).

Mutual life 2-(N-(2-phenylethoxy)carbonyl-N-methylamino)ethanol Rumethanesulfonyl ester By a method similar to that described in Method 2, 2-(N-(2-phenylethoxy ) Carbonyl-N-methylamino)ethanol (5,57q) to prepare the title compound. was prepared and used in the next step without further purification.

'HNMRd(CDC13) Some peaks in this spectrum indicate the presence of rotamers of the carbamate group. complicated by

2.80-3.10 (8H, complex) + 3.55 (2H, br t); 4.20 ( 2H, apparent above br s); 4.30 (2H, t): and 7.33 (5H, s).

Method 8 2-(2-Benzoxacylinon-3-yl)ethanolmethanesulfonyl varnish By a method similar to that described in Method 2, 3-(2-hydroxyethyl)ben Zoxazolin-2-one (1,799) to the title compound (melting point 100-102 °C) and used in the next step without further purification.

'HNMRd　(CDCA'3) 3.05 (3H, s); 4.25 (2H, t); 4.62 (2H, D; and 7.10-7, 50 (4H, complex).

Method 9 4-[2-(2-benzoxacylinon-3-yl)ethoxy]benzaldehy Do-2-(2-benzoxacylinon-3-yl)ethanolmethanesulfonyl ether Stell (2,36g), potassium carbonate (1,279), 4-hydroxybenza Mixing of aldehyde (1,129) and dry dimethylformamide (10081) The material was heated with stirring at 80° C. for 17 hours and then left at room temperature for 48 hours.

The solvent was evaporated and the residue was suspended in water (40017) and dissolved in ethyl acetate (3X 25 0 ml'). The combined organic layers were washed with brine and dried with Mg5O4. ), evaporated. Recrystallization from dichloromethane-hexane gave the title compound ( (melting point 124-6°C) was purified.

5 (2H, d), and 9.95 (IH, s).

(i): 4-carboxymethoxybenzaldehyde (20g) in pyridine (6m l) To a stirred water-cooled suspension in dry benzene (200, A') containing thionyl chloride (79 , 39; 48.7d) was added dropwise. The resulting mixture was heated under reflux for 1.5 hours. , then cooled and the solvent was evaporated. Impurity 4-(dichloromethyl)phenoxy The residue containing cyacetyl chloride was used in the next step without further purification.

(ij): Water-cooled stirred solution of acid chloride ((i) above) in dichloromethane (10k) 2-amino-1-phenylethanol (15.2 g) and dichloromethane (10 0g7) solution was added dropwise. Sodium hydroxide solution (10% W/V, 150mA ) was added and the mixture was stirred vigorously at room temperature overnight. Evaporate the mixture and remove the residue , a mixture of dilute hydrochloric acid (2.5M, 2001f) and methanol (50++j) and re-evaporated, then diluted with sodium hydroxide solution (10% w/v, 2 00+wl).

The solution was extracted with ethyl acetate (3X200mA), brine (200,1) and dried. (MgSO,) and evaporated. The residue was dissolved in 2% methanol in dichloromethane. The title compound was obtained by chromatography on silica gel.

'HNMR6 (CDC4:DMSO-da, 1:1)3, OO-3,60 (2H, complex): 4.55 (2H, s): 4.70 (LH, dd) + 5°35 (IH, br　s, exchanged with Dzo) Near, 02 (2H, d); 7.35 (5H, s); 780 (3H, broad d, reduced to 2H, d when shaken with Dzo ); and 9°4-[2-N-(2-hydroxy-2-phenylethyl)amino of lithium aluminum hydride (6.94 g) under a nitrogen atmosphere. 4-[N-( 2-Hydroxy-2-phenylethyl)aminocarbonylmethoxy]benzal Carefully drain the dehyde (10,99) in dry tetrahydrofuran (200 m6). and added. The resulting mixture was heated under reflux for 7 hours, then cooled in water, Water (7 mj’), sodium hydroxide solution (10% W/V, 7 ml) and water ( 14d> was carefully quenched. After refluxing for an additional 30 minutes, the The mixture was filtered through a Soxhlet thimble and the residue was dissolved in refluxing tetrahydrofuran. It was extracted for 3 hours. Evaporation of the solvent gave the title compound as an oil, which was further purified. Used without.

'HNMRδ (CDCIs: DMSOda, 1・1) 3.00 (4I (, complex) ;3.00-4.50 (3H, replaced with broad s, D, o): 4,07 (2H , t) + 4.55 (2H, s) + 4.77 (IH, d d): 6. 90 (2H, d), and 7.35 (7H, complex).

4-[2-(N-benzyloxycarbonyl-N-(2-hydroxy-2-) (2-ethyl)amino)ethoxy]benzyl alcohol 4-[2-N-(2-hydro) Roxy-2-phenylethyl)aminoethoxycobenzyl alcohol (8,09 ), sodium hydroxide solution (10% W/V, 125 blades and dichloromethane ( Benzyl chloroformate (14.3g , 12 ml) was added dropwise. After stirring for 30 minutes, the phases were separated and the aqueous layer was washed with dichloromethane. Extract with water (100 IJ) and combine the organic layers with water (2X 100 ml) and salt. Washed with water (2 x 100 g A'), dried (MgSO4) and evaporated. Residue The distillate was purified on silica gel using dichloromethane 94% methanol as solvent. Chromatography gave the title compound as a rubber.

IHNMRδ (CDCl2) This spectrum is complicated by the presence of rotamers of the carbamate group.

2,00 (LH,s, exchanged with Dzo); 3.20-4.30 (7H, double Miscellaneous; reduced to 6H when shaken with Dzo); 4.61 (2H, s); 5. 05 (IH, broad appearance is one line above); 5.20 (2H, s): and 6.70-7.70 (14H, complicated).

Method 13 4-[2-(N~benzyloxycarbonyl-N-(2-hydroxy-2-phene) Nylethyl)amino)ethoxy]benzaldehyde 4-[2- (N-benzyloxycarbonyl-N-(2-hydroxy-2-phenylethyl )amino)ethoxy]benzyl alcohol (6,39), manganese oxide (rV) (13,09) and dichloromethane (150m6) was stirred. Applicable The mixture was filtered through a Soxhlet thimble and the residue was dissolved in refluxing dichloromethane for 3 hours. Time extracted. The solvent was evaporated and the resulting rubber was dissolved in 3% methanol in dichloromethane. Chromatography on silica gel using Obtained.

'HNMRδ(CD(J3) This spectrum is complicated by the presence of rotamers of the carbamate group.

3.00 (1) (, br　s, exchanged with Dzo): 3.40-4.35 (6H, a Miscellaneous): 5.05 (IH, W miscellaneous); 5.20 (2H, s) + 7. O 0C2H, double M); 7.40 (10H, t! [): 7.85 (2H, d) ; and 10.00 (IH, s).

Method 14 2-(N-phenoxycarbonyl-N-phenylamino)ethanol as described in Method I. Phenyl chloroformate (15,669,12,5 and 2-(N-phenylamino)ethanol (13.72g: 12.6g) The title compound (melting point 124-6°C) was prepared from l) and used without further purification. used.

'HNMRδ　(CD(J3) 2.40 (LH, br　S, replaced with Dzo); 3.63-3.95 (4H, complex ), and 7.00-7.55 (IOH, complex).

Method 15 2-(N-phenoquinecarbonyl-N-phenylamino)ethanol methanesulfate By a method similar to that described in Method 2, 2-(N-phenoquinecarbonyl- The title compound was prepared from N-phenylamino)ethanol (5.14 g), and the solvent Chromatography on silica gel using 1,5% methanol in dichloromethane as Purified by graphy. The obtained oil was used as it was in the next step.

7.65 (IOH, complex).

2-(N-phenoxycarbonyl-N- phenylamino)ethanol methanesulfonyl ester (5,819) and 4 -Hydroxybenzaldehyde (2.08v) was reacted together. crude reaction product The product was purified on silica gel using 15% methanol in dichloromethane as solvent. Chromatography gave the title compound as a dark gum.

H,d) + and 9.95 (IH,s).

(2,4-thiazolidinedione ~50°C).

and 11.55 (LH, br s: replaced with D, O).

In a Dige and Stark apparatus, toluene (400,7 liters) was added under reflux. and 4-C2-(N-benzyloxycarbonyl-N-methylamino)ethquin ] Benzaldehyde (6,579), 2,4-thiazolidinedione (2,95g ), piperidine (10 drops) and acetic acid (5 drops) were heated. 5 under reflux After an hour, the mixture was cooled to room temperature overnight and then evaporated to dryness. Remove the residue Triturate with methyl ether for 24 hours, and collect the resulting solid title compound by filtration. , washed with ether and dried under vacuum. Melting point 160-162°C.

IHNMRδ (CDC13/DMSO-da; 1:1) in this spectrum Some of the peaks in the Ru.

3.00 (3H, br s): 3.65 (2H, t) + 4.20 (2H, br t) +5.15 (2H, s); 7.00 (2H, br d): 7.25-7 ．． 65 (7H, lf miscellaneous) near, 83 (IH, s); and 12.00 (IH, b r　s　; exchanged with D, O).

Example 3 5-(4-[2-(N-benzyloxycarbonyl-N-methylamihaethoxy) ]-benzyl)-2,4-thiazolidinedione dioxane (200 l/)l 5 -(4-[2-(N-penzyloxycarponyl-N-methylamino)ethoxy Suspension of 2,4-thiazolidinedione (cubenzylidene)-2,4-thiazolidinedione (8°849), Hydrogenated over 10% palladium on charcoal (8 g) at 0 ps i overnight. silicon mixture Filter through algae, wash the filter cake thoroughly with dioxane, and remove the combined dioxane. Evaporation of the Sun solution gave the title compound as a low melting foam.

3.10 (3H, s); 3.00-3.80 (4H, complex); 4.15 (2H , distorted t); 4.52 (LH, dd); 5.23 (2H, s); 6.9 0 (2H, br d); 7.25 (2H, cri); 7.50 (5H, s) : and 9.86 (IH, b r s).

Example 4 5-(4-[2-(N-(2-phenylethoquine)carbonyl-N-methylamine -ethquin]benzyl)-2,4-thiazolidinedione Those described in Example 1 2-(N-(2-phenylethoxy)carbonyl-N-methyl Ruamino)ethanol methanesulfonyl ester (7,16g) and 5-(4 -Hydroxybenzitree 2,4-thiazolidinedione (5,59g) -together Made it react. silicage using dichlorone 2291.5% methanol as a solvent. After chromatography on a column, the title compound was obtained as a sticky foam. Ta. This material was used directly for salt formation.

IHNMRδ (CDC/3) Some peaks in this spectrum indicate the presence of rotamers of the carbamate group. complicated by

2, 80-3.10 (6H, complicated); 3.30-3.70 (3H, complicated): 3.95 (2H.

Appearance is above br　s): 4.33 (2H, t): 4.45 (IH, dd); 6 ．． 70-7°40 (9H, complex): and 950 (LH, br　S: Intersect with D20) exchange).

Example 5 5-(4-[2-(N-(2-phenylethoquine)carbonyl-N-methylamine (2) Etquin] benzyl)-2,4-thiazinzinedione sodium salt 5-( 4-[2-(N-(2-phenylethoxy)carbonyl-N-methylamino)eth methanol of benzyl)-2,4-thiazolidinedione (5,009) Sodium hydride (60% dispersion in oil; 0.48 g) was added. The mixture was stirred at 0 °C for 5 min and then evaporated at room temperature under reduced pressure. I set it. The residue was suspended in dry diethyl ether (2001Z) and stirred for 5 minutes at room temperature. After stirring, it was filtered. The solid title compound obtained was thoroughly washed with dry ether. , dried at 70°C under vacuum. The title compound darkens at 235°C, 246-249 Melted at °C.

’HNMRδ (DMSO-dg: 120℃) spectrum shows rotation of carbamate Complicated by the presence of isomers. These become one at 120°C.

2.71 (LH, dd); 2.80-3.00 (5H, complex); 3.36 (I H, dd); 3.52 (2H, t); 4.02 (3H, complex); 4.25 (2 H, t); 6.75 (2H, d) near, 05-7.40 (7H; complex).

in toluene (125 ml) under reflux in a Dige and Stark apparatus. and 4-[2-(2-benzoxacylinon-3-yl)-ethomushroom penzua Rudehyde (1,899), 2,4-thiazolidinedione (0,90g), benzoin A mixture of acid (0,19) and piperidine (0,1,7) was heated. under reflux After 35 hours, the mixture was cooled and crystallized overnight. Title compound (melting point 255-8 ℃) was filtered, washed with cold toluene and dried under vacuum.

'HNMRδCCDCts/DMS○-ds+1:1)4.20-4.60(4 H, complex): 7.00-8.00 (9H, complex): and 12°50 (LH, (replaced with br, D, O).

Example 7 5-(4-[2-(2-benzoxacylinon-3-yl)ethoxy]benzyl )=2.4-thiazolidinedione in the presence of 10% palladium on charcoal (2,79) at room temperature and pressure for 6,75 h. 5-(4-[2-(2-Benzoxazolidinon-3-yl)-ethoxy]ben zylidene)-2,4-thiazolidinedione (2,29 g) in dioxane (200 ml)ll:) The suspension was hydrogenated. Add more catalyst (2,19) and The reaction continued for a total of 23 hours.

The reaction mixture was filtered through diatomaceous earth and the solvent was evaporated. The obtained rubber is dichloromethane. Recrystallization from lomethane-hexane gave the title compound (157-8°C).

IHNMRδ(CD(J,/DMSO-dg+1:1)3.03(LH, dd); 3.41 (IH, dd) + 4.27 (4H, complex) + 4.41 (I H, dd); 6.77 (2H, d); 7.00-7.30 (6H, complex): and 11.61 (exchanged with LH, br, D20).

phenyl-ethyl)amino)-ethquin]benzylidene)-2,4-thiazolidi 4-[2-(N-benzyl) was prepared by a method similar to that described in Example 6. Ki7Carponyl-N-(2-hydroxy-2-phenylethyl)amino)ethoxy The title compound (melting point 157-8°C) is produced from benzaldehyde (5,09) did.

'HNMRδ (CDCh/DMSOds; 1:1) This spectrum Complicated by the presence of rotamers of the bamate group.

3.30-3.70 (4H, complex); 4.10 (2H, complex): 4°75 (I H, appearance is a single broad line above) + 5.05 (2H, appearance is d above); 5 ．． 30 (IH, br　s.

Exchange with DiO) +6.20 (LH, boot F, D to exchange); 6.80 -7.60 (14H1 complex); and 7.68 (1) (,s).

Example 9 5-(4-[2-(N-benzyloxycarbonyl-N-(2-hydroxy-2 -phenyl-ethyl)amino)-ethoxy]benzyl)-2,4-thiazolidine 5-(4-[2-(N-benzyloxycarbonate) rubonyl-N-(2-hydroxy-2-phenyl-ethyl)amino)ethoxyco Dissolve penzylidene)-2,4-thiazolidinedione (5,09) and add 700p Hydrogenated with 10% palladium on charcoal (109) for 6 hours on si. The mixture is Filter through algae, wash the filter cake with dioxane (11) and add the combined dioxane. Evaporate the xane layer to obtain the rubbery title compound, which is used in the next step without purification. did.

'HNMRδ(CDC/,) This spectrum is complicated by the presence of rotamers of the carbamate group.

2, 80-4.30 (9HJI61; D, O Torto 1: Shake ttorto 8H Nilow 4.35 (LH, dd): 4.95 (IH, the appearance is the broad 1 above) Main line); 5.15 (2H, br s) + 6.0O (IH, broad, D20 ): and 6.70-7.40 (14H1 complex).

Example 10 5-(4-[2-(5-phenyl-2-oxazolidinon-3-yl)ethocino cobenzyl)-2,4-thiazolidinedione ethanol (50,1) and dilute salt 5-(4-[2-(N-benzyloxycarbonyl) -N-(2-hydroxy-2-phenylethyl)amino)-ethoxy]benzi )-2,4-thiazolidinedione (5 g) was dissolved and heated under reflux for 4 hours. . The solvent was evaporated and the pH of the residue was adjusted to pH 6.5 with saturated sodium bicarbonate solution. It was knotted. The mixture was extracted with ethyl acetate (3x75m/) and the combined ethyl acetate The layer was dried (MgSO4) and evaporated. 5% in dichloromethane as solvent Foamy marking by chromatography on silica gel using methanol A compound (melting point 72-6°C) was obtained.

'HNMRδ (CDCj73) 3.11 (LH, dd) + 3.43 (IH, dd); 3.55-3.80 and 4.15 (combined 6H, complex): 4.48 (LH, dd); 5°50 (IH , d d); 6.81 (2H.

d) + 7.14 (2H, d): and 7.36C6H, complex + together with D20 When shaken, it decreases to 5H).

Example 11 ]-2,4-Thiazolinonedione A method similar to that described in Example 6 4-[2-(N-phenoxycarbonyl-N-phenylamino)eth The title compound (melting point 187-9°C) was obtained from benzaldehyde (3.67g). Obtained.

IHNMR6 (CD (J'3/DMSO-da, 1:1) 4.20 (4H, complex): 6.95-7.60 (14H, complex); 7.70 (LH, s); and and 12.22 (IH, brs, replaced with D20).

benzyl]-2,4-thiazolidinedione in a manner similar to that described in Example 7. , at room temperature and pressure for a total of 98 hours. -N-phenylamino)ethomushroom benzylidene]-2,4-thiazolidine di (3,939) was hydrogenated. 1,5% meth in dichloromethane as solvent After chromatography of the crude product on silica gel using The following compound (foam, melting point 55-60°C) was obtained.

t); 4.75 (IH, dd): 6.81 (2H, d); 7.05-7.45 ( 12H, complex) and 11.53 (IH, br　s, replaced with D20).

Demonstration of compound effectiveness Expressed below as percent reduction in area under the curve. 7 animals for each treatment A mouse was used.

There wasn't.

m near investigation report ,--1-1,□+,,,w,, PCT/Leap 91101834 International Search Report Pcr/GO91101834 Continuation of front page (72) Inventor Bell, Dipid Essex CM 19.5A.D., Barlow, The Pinnacle, United Kingdom SmithKline Beecher, Coldharbour Road (no address displayed) Inside Mu Pharmaceuticals

Claims (11)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A1 is an alkyl group, or unsubstituted aryl group or alkylene moiety or aryl moiety is substituted. represents an aralkyl group which may be substituted or unsubstituted; A2 represents a benzene ring having up to three substituents in total if desired; R1 is a hydrogen atom child, alkyl group, acyl group, alkyl moiety or aryl moiety is substituted. an aralkyl group which may be substituted or unsubstituted, or a substituted or unsubstituted aryl group Does it represent; Alternatively, A1 together with R1 represents a substituted or unsubstituted C2-3 polymethylene group. and the optional substituents on the polymethylene group are selected from alkyl or aryl. selected or adjacent substituents to the polymethylene carbon atom to which they are attached. together form a substituted or unsubstituted phenylene group; R2 and R3 each represent water; represents an element, or R2 and R3 together represent a bond; X represents O or S; n represents an integer in the range of 2 to 6] or its tautomer and/or its pharmaceutically acceptable compound and/or pharmaceutically acceptable solvates thereof. 2. A1 together with R1 represents a substituted or unsubstituted C2-3 polymethylene group; , the optional substituents on the polymethylene group are selected from alkyl or aryl. or adjacent substituents together with the methylene carbon atom to which they are attached 2. A compound according to claim 1, which forms a substituted or unsubstituted phenylene group. 3. Substituted or unsubstituted C2-3 polymethylene group substituted or unsubstituted ethylene group 4. A compound according to claim 3, comprising: 4. substituted or unsubstituted C2-3 polymer represented by A1 together with R1 The tyrene group is 1,2-phenylene and formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 4. The compound according to claim 1, which contains a group represented by: 5.5-(4-[2-(N-phenoxycarbonyl-N-methylamino)ethoxy 5-(4-[2-(N-benzyl)-2,4-thiazolidinedione; carbonyl-N-methylamino)ethoxy]-benzylidene)-2,4 -thiazolidinedione; 5-(4-[2-(N-benzyloxycarbonyl-N -methylamino)ethoxy]-benzyl)-2,4-thiazolidinedione; 5- (4-[2-(N-(2-phenylethoxy)carbonyl-N-methylamino) -ethoxy]benzyl)-2,4-thiazolidinedione; 5-(4-[2-(N -(2-phenylethoxy)carbonyl-N-methylamino)ethoxy]benzi 5-(4-[2-(2-beta)-2,4-thiazolidinedione sodium salt; nzoxazolinon-3-yl)ethoxy]benzylidene)-2,4-thiazoli Jinjion; 5-(4-[2-(2-benzoxazolinon-3-yl)ethoxy]benzyl) -2,4-thiazolidinedione; 5-(4-[2-(N-benzyloxycarbonyl-N-(2-hydroxy-2 -phenyl-ethyl)amino)-ethoxy]benzylidene)-2,4-thiazoli Jinjion; 5-(4-[2-(N-benzyloxycarbonyl-N-(2-hydroxy-2 -phenyl-ethyl)amino)ethoxy]benzyl)-2,4-thiazolidine di 5-(4-[2-(5-phenyl-2-oxazolidinon-3-yl)ethyl) 5-[4-[2-(N-benzyl)-2,4-thiazolidinedione; phenoxycarbonyl-N-phenylamino)ethoxy]benzylidene]-2,4 -thiazolidinedione; and 5-[4-[2-(N-phenoxycarbonyl- N-phenylamino)ethoxy]benzyl]-2,4-thiazolidinedione; or its tautomer and/or its pharmaceutically acceptable salt, and/or A compound according to claim 1 selected from the group consisting of pharmaceutically acceptable solvates thereof. thing. 6. a) Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R2, R3 and A2 are the formula The definition for (I) is the same, and Ra is the formula (b): A1-O-CO-NR1- (CH2)n-X- (b) (wherein A1, R1, X and n are related to formula (I) is a group that can be converted into a group shown in A compound represented by is reacted with a suitable reagent capable of converting Ra into group (b). respond, b) Formula (XI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XI) [In the formula, R1, A1, A2, and n are the same as defined for formula (I)]. react with lysine dione; then, optionally, (i) A process for converting a compound represented by formula (I) into another compound represented by formula (I) (ii) a pharmaceutically acceptable salt of the compound represented by formula (I) and/or carrying out one or more of the steps for producing the pharmaceutically acceptable solvate; a compound of formula (I), or a tautomer thereof, and/or Preparation of pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable hydrates thereof Construction method. 7. The compound represented by formula (I), or its tautomer, or its pharmaceutically acceptable pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof; A pharmaceutical composition comprising a carrier. 8. Compounds of formula (I), or tautomers thereof, useful as effective therapeutic substances and/or pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable salts thereof. solvate. 9. Treatment of hyperglycemia, hypertension, cardiovascular disease and certain eating disorders and/or or a compound of formula (I), its tautomer and/or useful for prophylaxis. is a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof. 10. Administer a compound of formula (I) to a human or non-human mammal in need thereof. or its tautomer and/or its pharmaceutically acceptable salt and/or its tautomer administration of a non-toxic effective amount of a pharmaceutically acceptable solvate of hyperglycemia, hyperlipidemia, hypertension, cardiovascular disease and methods of treating and/or preventing certain types of eating disorders. 11. hyperglycemia, hyperlipidemia, hypertension, cardiovascular disease and some eating disorders. Compounds of formula (I) for the formulation of therapeutic and/or prophylactic drugs, or its tautomers and/or its pharmaceutically acceptable salts and/or Use of pharmaceutically acceptable solvates thereof.