AU712294B2 - Heterocyclic compounds having anti-diabetic activity, their preparation and their use - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

S.

Name of Applicant: Actual Inventors: Sankyo Company Limited FUJITA Takashi, FUJIMOTO Koichi, YOSHIOKA Takao, YANAGISAWA Hiroaki, FUJIWARA Toshihiko, HORIKOSHI Hiroyoshi, OGUCHI Minoru AND WADA Kunio.

DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Heterocyclic compounds having anti-diabetic activity, their Address for Service: Invention Title: preparation and their use The following statement is a full description of this invention, including the best method of performing it known to us: QAPER\PDB\32443-97.271 28/9/98 M M M P:\OPER\PDB\87093-98.229 18/8/99 la- Background to the Invention It is known that compounds which, like those of AU 32443/97, contain, inter alia, a thiazolidinedione or oxazolidinedione group attached, via a methylene or methylidne group, to a benzene ring have hypoglycemic and anti-diabetic activity. Compounds of this general type are disclosed in European Patent Publications No. 008 203, 139 421, 441 605, 208 420, 528 734, 177 353, 306 228 and 356 214, and in WO 92/07850, 92/07839, 91/07107, 92/02520 and 92/03425. The inventors have now discovered that the inclusion in such compounds of certain specific bicyclic nitrogen-containing ring systems results in compounds of much improved activity.

15 Brief Summary of Invention Advantageously, the present invention provides a compound, which may be useful for the treatment and/or prophylaxis of a variety of disorders, including one or more of: hyperlipemia, 20 hyperglycemia, obesity, glucose tolerance insufficiency, insulin resistance and diabetic complications.

~Other objects and advantages of the present invention will become apparent as the description proceeds.

*2 S SAU 32443/97 provides compounds of formula

R

X-(CH2)nYA

(I)

wherein: P:\OPER\PDB\87093-98.

2 2 9 18/8/99 -2- X represents an indolyl, idolinyl, azaindolyl, azaindolinyl, imidazopyridyl or imidazopyrimidinyl group which is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents a, defined below; Y represents an oxygen atom or a sulfur atom; Z represents a group of formula (iii), (iv) or o 9* -CH O S N-H (i) 0 -CH2 O S N-H (ii) 0 -CH2 0 O CH N (iii) OyN-H 0 -CH2 0 N 0 0 N-H (iv) -CH2N NH2, 0

OH

25 R represents a hydrogen atom, an alkyl group having from 1 to 4 S carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, an aralkyl group in which an alkyl group having from 1 to 5 carbon atoms is substituted by an aryl group having from 6 to 10 ring carbon atoms, or a group of formula -NRaRb wherein Ra and Rb are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, an aralkyl group in which an alkyl group having from 1 to 5 carbon atoms is k substituted by an aryl group having from 6 to 10 ring P:\OPER\PDB\87093-98.229 2018199 carbon atoms, an aryl group having from 6 to 10 ring carbon atoms, an aliphatic carboxylic acyl group having from 1 to 11 carbon atoms, an aliphatic carboxylic acyl group which has from 2 to 6 carbon atoms and which is substituted by an aryl group having from 6 to 10 ring carbon atoms, or an aromatic carboxylic acyl group in which the aryl part has from 6 to 10 ring carbon atoms, m is an integer of from 1 to each of said subsitutents a represents an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to carbon atoms, a trifluoromethyl group, and alkylthio group t 15 having from 1 to 4 carbon atoms, an alkoxy group having from 1 o to 4 carbon atoms, a benzyloxy group, a halogen group, a hydroxy group, an acetoxy group, a phenylthio group, a nitro group, an aralkyl group, or a group of formula -NRaRb, wherein Ra and i are as defined above; said aryl groups and the aryl parts of said aralkyl groups included in substituents a are carbocyclic aromatic groups having from 6 to 10 ring carbon atoms and are unsubstituted or are substituted at least one substituent selected from the group 25 consisting of substituents 3, defined below; each of said substituents 3 represents an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, or a group of formula -NRaR b wherein Ra and R b are as defined above; and salts thereof.

P:\OPER\PDB\87093-98.229 20/8/99 The present invention now provides 5-{4-[5-(3,5-di-t-butyl- 4-hydroxyphenylthio)-3-methyl-3H-imidazo[4,5-b]pyridin-2ylmethoxy]benzyl}thiazolidine-2,4-dione, or a tautomer, or salts or hydrates thereof.

The invention also provides a pharmaceutical composit'ion for the treatment or prophylaxis of diabetes or hyperlipemia and complications thereof, which composition comprises an effective amount of an active compound in admixture with a pharmaceutically acceptable carrier or diluent, wherein said active compound is selected from the group consisting of the compound of the invention and salts thereof.

15 The invention still further provides a method for the treatment or prophylaxis of diabetes or hyperlipemia and complications thereof in a mammal, which may be human, which method comprises administering to said mammal an effective amount of an active compound, wherein said active compound is 20 selected from the compound of the invention and salts thereof.

The invention also provides processes for the preparation of the compound of the present invention, which processes are described in more detail hereafter.

9 9 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

O-

-usS o Pz I':\OPFlR\PDB\8093-98.229 2018,:") 5 The compound of the invention contains a basic group in its molecule, and can thus be converted to salts with acids by conventional methods. There is no particular restriction on the nature of such salts, provided that, where the compounds are to be used medically, the compounds are pharmaceutically acceptable, that is it is not less active, or unacceptably less active, nor more toxic, or 0unacceptably more toxic, than the parent compound.

However, where the compound is to be used for non-medical uses, e.g. as an intermediate in the preparation of other compounds, even this restriction does not apply, and there is then no restriction on the nature of the salts which may be formed. Examples of .such salts include: salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, perchloric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic 25 acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid; and salts with amino acids, such as glutamic acid or aspartic acid. We prefer the pharmaceutically acceptable salts.

Also, the compound of the present invention can be converted into a salt with a base by conventional methods. Examples of such salts include: salts with an S alkali metal, such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or z calcium; and salts with another metal, such as magnesium FF\~ or aluminum. We prefer the pharmaceutically acceptable P:\OPER\PDB\87093-98.229 20/8/99 6 salts.

The compound of the present invention can exist in the form of various isomers due to the presence of asymmetric carbon atoms. Although these isomers are represented herein by a single molecular formula, the present invention includes both the individual, isolated isomers and mixtures, including racemates, thereof and the isomers may be present in such mixtures in any proportions. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional S. resolution techniques.

The compounds of the present invention can exist in the form of various tautomeric isomers as shown in schemes a.

9.

.9 9 9 o* 11 2?2 l/ 1, -7 Scheme a em 9* C U

CC..

9.

0* .9

C

C

C.

9** C 9

U.

U C

U.

U.

S C C U

U.

C C C a

U.

C

99..

C. C

U

CH2 OH -CH2 OH S NH 0 CH2 0

H

-CH2 OH

OH

P:\OPER\PDB\87093-98.229 20/8/99 8 In the above formula all tautomers based thereon and mixtures of equivalent weights or non-equivalent weights of these tautomers are represented by one formula. Thus, all of these isomers and mixtures of these isomers are included in the present invention.

Moreover, the present invention also includes all solvates, for example hydrates, of the compounds of formula and salts thereof, where the relevant compound is capable of forming a solvate.

The invention also embraces all compounds which could be converted in the living mammalian, for example human, body to a S: compound of formula or a salt thereof by the action of the 15 metabolism, that is so-called "pro-drugs" of the compounds of i.

formula and salts thereof.

ea.

a.

a a a *e Pi\OPER\PDB\87093-98.229 20/8199 -9- The compounds of the present invention is depicted by formula (I-1)

X-(CH

2 )m T- (1-1) 9 U a a U 9 a a a a a.

U..

a.

a a U U a.

aa Ua a.

a 9S as a U a a

U.

a. a.

a 9 qaaa *U *C a a a a where 10 The compounds of the present invention may be prepared by a variety of processes well known in the art for the preparation of compounds of this general type.

For example they may be prepared by the following Reaction Schemes A, B, C, D and E: Reaction Scheme-A This represents a general scheme that may be used to prepare the compounds of the present invention.

Reaction.Scheme A: to to.

R

R

E

(IV)(I)

Stp

X~-(C

2

)R-Y-

(V)

11 In the above formulae: X and m are as defined above; R' represents an alkyl group having from 1 to 5 carbon atoms, which may be a straight or branched chain group, for example any of those groups having from 1 to carbon atoms included in the groups which may be represented by Ra and Rb; and Z' represents a group of formula (vii): S. -CH2 0 S N-Tr O

*V

"(vii) where Tr represents a triphenylmethyl group.

Step Al

S

where Tr represents a triphenylmethyl group.

In Step Al, a compound of formula (III) is prepared 12 by reducing a compound of formula (II).

The reaction may be carried out using a reducing agent. The nature of the reducing agent employed in this reaction is not critical, and any such agent commonly used in reactions of this type may equally be used here. Examples of such reducing agents include: metal hydrides, such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or diisopropylaluminum hydride.

The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols, such as methanol, ethanol or isopropanol; adA mixtures of any two or more of these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from that of ice-cooling to heating, e.g. to the reflux temperature of the reaction medium, preferably with ice-cooling or at about room temperature. The time required for the reaction may also vary widely, sT depending on many factors, notably the reaction K- temperature and the nature of the reagents and solvent S employed. However, provided that the reaction is

M

13effected under the preferred conditions outlined above, a period of from 0.5 hour to several days will usually suffice.

The reaction is preferably carried out in an alcohols or in a mixture of one or more alcohols and other organic solvents in the presence of lithium borohydride at a temperature between room temperature and the reflux temperature of the reaction medium for a period of from 1 hour to 1 day; or in a hydrocarbon or an ether in the presence of lithium aluminum hydride or diisobutylaluminum hydride with cooling or heating for a period of from 1 to 10 hours.

Step A2 subjecting a compound of formula (III) and a compound of formula (IV) (in the formula, Y, R and Z' are as defined above) to a Mitsunobu reaction Mitsunobu: Synthesis, o: 1 (1981)] the presence of at least one azo comound and at least

C

one phosphine.

There is no particular restriction on the nature of the azo compounds used, and any azo compounds commonly used in this type of reaction may equally be employed here used. Examples of such azo compounds include diethyl azodicarboxylate and 1,1'-(azodicarbonyl)dipiperidine. There is likewise no particular restriction on the nature of the phosphines used, and examples include triphenylphosphine and tributyl- Sphosphine.

Mill! 14 The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons, such as chloroform, methylene chloride or 1,2-dichloroethane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and mixtures of any two or more of o these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from room temperature to heating, e.g. to the reflux temperature of the reaction mixture, more preferably at a temperature of from room temperature to 60 0 C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from several hours to several days, more preferably from 5 hours to 3 days will usually suffice.

Step A3 In Step A3, a compound of formula is prepared.

This may be any of the compounds of the present invention except those in which Z represents a group of 7 the formula 15 The reaction is effected by reacting a compound of formula with an acid, such as trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, hydrochloric acid or sulfuric acid in the presence or absence of a solvent.

Where a solvent is used, there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons, such as chloroform, methylene chloride or carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; esters, such as ethyl acetate or methyl acetate; water; and mixtures of any two or more .o of these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from ice-cooling to room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from several tens of minutes to several tens of hours, more preferably from 0.5 to 10 hours, will usually suffice.

This step can also be achieved by catalytic V hydrogenation of a compound of formula There is no

I

16 particular restriction on the nature of the catalysts used, and any hydrogenation catalysts commonly used in this type of reaction may equally be employed here.

Examples of such hydrogenation catalysts include palladium-on-charcoal, palladium black, platinum oxide and platinum black, of which we prefer palladium-oncharcoal.

The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons, such as chloroform, methylene chloride or .carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, g* ethanol or isopropanol; amides, such as dimethylo* formamide, dimethylacetamide or hexamethylphosphoric triamide; and mixtures of any two or more of these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from room temperature to heating, e.g. at the reflux temperature of the reaction mixture, preferably at room temperature or with heating. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided Sthat the reaction is effected under the preferred conditions outlined above, a period of from several P:\OPER\PDB\87093-98.229 -20/8/99 -17 hours to several days, more preferably from 1 hour to 1 day will usually suffice.

Reaction Scheme B This is a process which the invention in which Y represents a group of dioxothiazolidin- 5-ylmethyl may be used to prepare compounds of represents an oxygen atom and Z formula that is 2,4group.

a at, a a a.

(I

a..

aa a.

a. Ga a a a a a.

a a e a a a.

a a Ga a.

2 18 Reaction Scheme B: X-(C H 2 )m-OH

(III)

Step B I 1) Base (VIa) H2)E-O

R

Step B2 F--0 S yNH 0 (Vila)

S

as 4* a.

SS

.5.4

S

4 4* 45 a 9 Step B3 Reduction

(VII)

X-(CH

2 (Vill)

M

19 Step B1 In Step Bl, a compound of formula (VI) is prepared by treating a compound of formula (III) with a base (the first stage) and then by reacting the resulting product with a p-fluorobenzaldehyde derivative of formula (VIa), such as 2-methoxy-4-fluorobenzaldehyde or 3-methyl-4fluorobenzaldehyde (the second stage).

There is no particular restriction on the nature of the base used in the first stage, and any base commonly used in this type of reaction may equally be employed here. An example of such a base is sodium hydride.

a a The reaction in the first stage is normally and -preferably effected in the presence of a solvent. There is no particular restriction on the nature of the a solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some :extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric a triamide; and mixtures of any two or more of these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from ice-cooling to heating, e.g. to the reflux temperature of the reaction mixture. The time required s for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature 20 of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from several tens of minutes to one day, more preferably from 1 to hours, will usually suffice.

After completion of the first stage reaction, the second stage can be carried out by adding a p-fluorobenzaldehyde derivative of formula (VIa) to the reaction mixture and then by allowing the mixture to react.

The reaction of the second stage can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction -at a temperature of from room temperature to heating, e.g. to the reflux temperature of the reaction mixture.

The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from several tens of minutes to several days l will usually suffice.

S

Step B2 In Step B2, a compound of formula (VII) is prepared by reacting a compound of formula (VI) with thiazolidine-2,4-dione of formula (VIIa).

The reaction may be carried out in the presence or absence of a catalyst. Where the reaction is carried out in the presence of a catalyst, there is no ST particular restriction on the nature of the catalyst used, and any catalyst commonly used in this type of 21 reaction may equally be employed here. Examples of such catalysts include sodium acetate, piperidinium acetate and piperidinium benzoate.

The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or isopropanol; amides, such a 0 .as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; halogenated hydrocarbons, such as 'methylene chloride, chloroform or 1,2-dichloroethane; b* nitriles, such as acetonitrile or propionitrile; esters, such as ethyl formate or ethyl acetate; and mixtures of any two or more of these solvents.

9. a: The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction with heating, e.g.

to the reflux temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 1 to 50 hours will usually suffice.

SStep B3 In Step B3, a compound of formula (VIII) is prepared -22 by reducing a compound of formula (VII) by means of catalytic hydrogenation. There is no particular restriction on the nature of the catalysts used, and any hydrogenation catalysts commonly used in this type of reaction may equally be employed here. Examples of such hydrogenation catalysts include palladium-on-charcoal and palladium black, preferably palladium-on-charcoal.

The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, dioxane or tetrahydrofuran; alcohols, 'such as methanol, ethanol or isopropanol; organic acids, such as formic acid, acetic acid or propionic acid; amides such dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and mixtures of any two or more of these solvents.

The reaction is normally carried out at atmospheric pressure or under superatmospheric pressure; preferably under superatmospheric pressure.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from room temperature or with heating, e.g. to the reflux temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, notably the reaction pressure /and temperature and the nature of the reagents and 23 solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from several hours to several days, more preferably from 1 hour to 1 day, will usually suffice.

This step can also be effected by treating the compound of formula (VII) with a metal hydride according to the procedure disclosed in WO 93/1309A.

*4

S

P:\OPER\POB\87093-98.229 2018/99 24 not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from ice-cooling to heating, e.g. to the reflux temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

However, provided that the reaction is effected under the preferred conditions outlined above, a period of from several tens of minutes to several tens of hours will usually suffice.

Reaction Scheme D This is a process which may be used to prepare the 15 compounds of the invention in which Z represents a group of formula that is a 2,4-dioxothiazolidin-5-ylmethyl group.

*a* 23 P \OPER\['DB\87093-98.229 20/8/99 25 Reaction Scheme D:

Q-(CH

2 )F--Halo HY 0

((XIII

0' Step DI

Q-(CH

2 )F-y 0 Base R V.NH 9 0 a go Stp 2

-(H

299 R Y, N .9V teabv frule X isa eindaoe Y, R9n r sdfndaoe Y' epeensasufr tm oe loya9bnlgop omlgop prtce fomlgop a9*9x ropo yroygop n -26 Halo represents a halogen atom.

Step D1 In Step Dl, a compound of formula (XIV) is prepared by reacting a compound of formula (XII) with a compound of formula (XIII) in the presence of a..base.

There is no particular restriction on the nature of the base used, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include: inorganic bases, for example hydrides (such as sodium hydride or potassium hydride) and carbonates (such as potassium carbonate or sodium carbonate); and organic bases, such as triethylamine.

The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and mixtures of any two or more of these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from ice-cooling to heating, e.g. to the reflux Stemperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many -27 factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 0.5 hour to several days will usually suffice.

The reaction is most preferably carried out with cooling or heating or at room temperature in an amides or a mixture of at least one amide with at least one other organic solvent, in the presence of sodium hydride for a period of from 1 to 10 hours.

The compounds of formula (XIV), which are prepared by this method, are new compounds and are important intermediates for the preparation of the compounds of formula of the present invention. These compounds of formula (XIV) thus also form part of the present invention.

Step D2 In Step D2, a compound of formula (XV) is prepared by one of the following two methods and Step D2(a) The compound of formula (XV) can be produced by reacting a compound of formula (XIV), in which Q represents a lower alkoxycarbonyl group, with a 2,3-diaminopyridine derivative or a pyrimidine derivative.

Where Q represents a lower alkoxycarbonyl group, this preterably has a total of from 2 to 7 carbon atoms the alkoxy part has from 1 to 6 carbon atoms), and \U's may be a straight or branched chain group. Examples of 28 such groups include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl, 2-ethylbutoxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups. Of these, we prefer those alkoxycarbonyl groups having from ~1 to 4 carbon atoms, preferably the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, d butoxycarbonyl and isobutoxycarbonyl groups, an most preferably the methoxycarbonyl and ethoxycarbonyl groups.

The reaction is normally and preferably effected in the presence or the absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.

.p Examples of suitable solvents include: hydrocarbons, p. *p r preferably aromatic hydrocarbons, such as benzene, toluene or xylene; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols, such as methanol, ethanol or butanol; acids, such as acetic acid or propionic acid; and mixtures of any two or more of these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it 29 convenient to carry out the reaction with heating, e.g.

to the reflux temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 3 hours to several days will usually suffice.

The reaction is most preferably carried out in the absence of a solvent with heating at a temperature of from 50 0 C to 150 0 C for a period of from 5 hours to 2 days.

9* Step D2(b) As an alternative, the compound of formula (XV) can be produced by reacting a compound of formula (XIV), in which Q represents a formyl group, in a first stage, with a 2,3-diaminopyridine derivative or a pyrimidine derivative, and then, in a second stage, treating the product with an oxidizing agent.

The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols, such as methanol, ethanol 30 or isopropanol; acids, such as acetic acid or propionic acid; sulfoxides, such as dimethyl sulfoxide; and mixtures of any two or more of these solvents.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at about room temperature or with heating, e.g. to the reflux temperature of the reaction mixture. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 1 hour to several days will usually suffice.

The product is then treated, in the second stage, with an oxidizing agent. There is no particular restriction on the nature of the oxidizing agent used, and any oxidizing agent commonly used in this type of reaction may equally be employed here. Examples of such oxidizing agents include iodine, silver oxide and lead tetraacetate, of which we prefer iodine.

The treatment with the oxidizing agent is normally and preferably effected in the presence of a solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include the solvents cited above for use in the first stage, preferably the ethers.

The reaction can take place over a wide range of i -I 31 temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction with heating. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction-is effected under the preferred conditions outlined above, a period of from 1 hour to several days will usually suffice.

In the compound of formula (XIV), where Q represents 0 a protected formyl group, the formyl-protecting group may be removed prior to subjecting the compound to the reaction of Step D2. Examples of such protected formyl groups include: for example, the dimethoxymethyl, diethoxymethyl, 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl, o 1,3-dithian-2-yl and 1,3-dithiolan-2-yl groups. The formyl-protecting group can be removed by conventional -methods well known in the art, for example by contacting the compound of formula (XIV) with a conventional deprotecting agent under the conditions conventionally used for deprotection. These conditions are described in T. W. Green: Protective Groups in Organic Synthesis (John Wiley Sons Ed.) or J. F. W. McOmie: Protective Groups in Organic Chemistry (Plenum Press Ed.).

Reaction Scheme E This is a process which may be used to prepare compounds of formula in which Z represents a group of formula (ii) that is a 2 ,4-dioxothiazolidin-5-ylmethyl group: 32 )?eaction Scheme E:

Q-(CH

2 jj--alo (X-11) HfY

NO

2

R

Step ElI (Xvi)

PNO

2 (XVII)

R

Step E2 3* *3 3 3

S

339.

33 3* *393 3 4, 9 3*93 .3 3 3..

*9 33 3 4, 9 9.

9333 33 33 3.

3333 33 3 33 3 3 3 3.

3333 3 3 *333 93 33 3 Q-(CH)i P -NH 2 (XVIII) R Step E3

(CH

2 )m jY-

(XIX)

Step E4

H

2 N -C -NH 2 11

Y,

Step (XI V) 0

(X-V)

1 :33 In the above formulae, Q, Y, R' and m are as defined above; Step El In Step El, a compound of formula (XVII) is prepared by reacting a compound of formula (XII) with a compound of formula (XVI) with a base. This reaction is essentially the same as that described in Step D1 of Reaction Scheme D, and may be carried out using the same reagents and reaction conditions.

Step E2 In Step E2, a compound of formula (XVIII) is _prepared by reducing a compound of formula (XVII).

The reaction may be carried out by a conventional catalytic hydrogenation or by using any reducing agent capable of reducing a nitro group, such as zinc-acetic acid or tin-hydrochloric acid.

Step E3 S, In Step E3, a compound of formula (XIX) is prepared by subjecting a compound of formula (XVIII) to a Meerwein arylation reaction.

The conditions employed for the reaction are well known and are generally similar to those disclosed in Japanese Patent Kokai Application No. Sho 55-22657 or reported by S. Oae et al.: Bull. Chem. Soc. Japan, 53, 1065 (1980).

34 Step E4 In Step E4, a compound of formula (XIV) is prepared by reacting a compound of formula (XIX) with urea or thiourea and then subjecting the product to hydrolysis.

The conditions employed for this reaction are well known and are generally similar to those disclosed in Japanese Patent Kokai Application No. Sho 55-22657.

Step :In Step E5, a compound of formula (XV) is prepared from the compound (XIV), by one of Steps D(a) and D(b).

The reaction is exactly the same as that shown in those Steps and may be carried out using the same reagents and reaction conditions.

'In the steps described above, the products of each step can, if desired, be recovered from the reaction mixture by conventional means at the end of each reaction and, if necessary, the compounds obtained can be further purified by conventional means, for example, by column chromatography, recrystallization, reprecipitation or similar well known procedures. An example of one such technique comprises: adding a solvent to the reaction mixture; extracting the desired compound; and finally distilling off the solvent from the extract. The residue obtained may be purified by column chromatography through silica gel or like adsorbent to afford the desired compound as a pure specimen.

i 35 BIOLOGICAL ACTIVITY The compound of the present invention and salts thereof possess the ability to lower blood glucose levels, to relieve obesity, to alleviate impaired glucose tolerance, to inhibit hepatic glucose neogenesis, to lower blood lipid levels and to inhibit aldose reductase. They are thus useful for the prevention and/or therapy of hyperglycemia, obesity, hyperlipidemia, diabetic complications (including retinopathy, nephropathy, neuropathy, cataracts, coronary artery disease and arteriosclerosis) and furthermore for obesity-related hypertension and 060 osteoporosis.

0 The compounds of the present invention can be administered in various forms, depending on the disorder to be treated and the age, condition and body weight of the patient, as is well known in the art. For example, S:9. where the compounds are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, they may be formulated as eyedrops or eye ointments. These formulations can be prepared by conventional means, and, if desired, the active ingredient may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent. Although the dosage will vary depending on the symptoms, age and body weight of the STrf, patient, the nature and severity of the disorder to be -n Z^ treated or prevented, the route of administration and 36 the form of the drug, in general, a daily dosage of from 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose or in divided doses.

The activity of the compounds of AU 32443/97 which are closely related to the compound of the invention is illustrated by the following Experiments.

Experiment 1 Hypoqlycemic activity The test animals used were hyperglycemic male mice :.of the KK strain, each having a body weight of at least 40 g. The compounds under test were mixed with a 1 1 -by volume mixture of polyethylene glycol 400 and water.

Each animal was orally administered a test compound in the amount shown in the following Table 6 and then allowed to feed freely for 18 hours. At the end of this 'time, blood was collected from the tail veins without anesthesia. The blood glucose level (BGL) was determined by means of a glucose analyzer (GL-101, manufactured by Mitsubishi Kasei Co. or a Glucoroder-F manufactured by Shino Test Co.).

The hypoglycemic effect was calculated by the following equation: Hypoglycemic effect

[(BGL

s BGL )/BGL s x 100 5 t. 6 where: 37 BGL is the blood glucose level in the group s administered a solvent only, but no active compound; and

BGL

t is the blood glucose level in the group administered a test compound.

The results are shown in the following Table 6, in which each compound of AU 32443/97 is identified by the number of one of the Examples described therein in which its preparation is illustrated.

Table 6 Example No.

ea 2 1 27.7 3 10 27.0 5 10 16.2 *6 0 20.9 7 1 24.7 3 10 27.6 1 11.6 13 1 34.0 1 13.8 17 1 37.1 1 24.5 22 1 10.2 23 1 21.7 As is apparent from Table 6, the compounds P:\OPER\PDB\87093-98.229 20/8/99 38 exhibited excellent activity.

Experiment 2 Inhibition of Aldose reductase Bovine lens aldose reductase was separated and partially purified by the method of S. Hyman and J. H. Kinoshita Biol.

Chem., 240, 877 (1965)] and K. Inagaki, I. Miwa and J. Okuda [Arch. Biochem. Biophys., 316, 337 (1982)], and its activity was determined photometrically by the method of Varma et al.

[Biochem. Pharmac., 25, 2505 (1976)]. Inhibition of enzyme activity was measured for the compounds of AU 32443/97 at a 0 15 concentration of 5 ug/ml, and the measured values were used to calculate the IC 50 values. The results are shown in the fllowing Table 7.

S '39 Table 7 p

S

S

S S S S

S.

*5S* p *5S

S.

9 9. 9

S.

*9 *5S*

S

a S

S*

B S *9 *55S

S

*5 9 5

S

S

Cpd. of Inhibition (Wi) IC 50 Example No. at 5 ig/m1 (4g/m1) 1 54.5 2 58.1 3.2 3 -3.7 4 -2.3 6 47 7 9 53.3 12 -1.7 13 -2.6 14 53.9 -2.4 16 59.1 3.7 17 -1.8 18 76.3 0.88 20 61.6 1.8 22 77.2 1.8 23 94.9 1.3 25 81.6 0.89 27 91.8 0.85 Experiment 3 Toxicity The toxicity of the compounds of AU 32443/97 was tested on male F344 rats, divided into groups of 5. The test compound was administered orally to each test animal at a dose of 50 mg/kg of \\body weight P:\OPER\PDB\87093-98.229 2018/99 per day for 2 weeks. The test compounds used were those of Examples 7 and 17. The animals were observed for 2 successive weeks, and, during that period, they showed no abnormalities which could be attributed to the test compounds. In view of the substantial dose administered to each animal, the zero mortality rate indicates that the compounds of AU 32443/97 have very low toxicity.

The compounds of AU 32443/97 thus have excellent activities combined with a very low toxicity, rendering them ideally suited to therapeutic use.

A preparation of 5-{4-[5-(3,5-di-t-butyl-4hydroxyphenylthio) -3-methyl-3H-imidazo [4,5-b]pyridin-2- 15 ylmethoxy]benzyl}thiazolidine-2,4-dione, or a tautomer, or salts or hydrates thereof is described in the following Example.

*9 9 S 03 -41-

II

MIR-Tr Example 5-(4-[5-(3,5-Di-t-butyl-4-hdroxyphenylthio)-3-ttethyl-3Himidazo(4, 5-b pyridin-2-ylmethoxylbenzyl)thiazolidine-2, 4dione (Exemplified Compound No. 1-181) A mixture of 5-(4-[5-(3,5-di-t-butyl-4hydroxyphenylthio)-3-methyl-3-imida o 4,5-b)pyridin-2ylmethoxyjbenzyl)-3-triphenylmethylthiazolidine-2,4-dione acetic acid (24 ml) and water (8 ml) was stirred at 70'C for hours. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate.

The extract was washed with saturated NaC. and dried over anhydrous sodium sulfate. The solvent was then removed by disi.llation under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 1/1 to give the title compound (0.64 g).

Melting point: 217.8 to 218.0*C OX A) NO2 cQ ~NH jUr \t Me tlt Referential Exapple 1 6-(3,5-Di-t-butyl-4-hydroxyphenylthio)-2-methylamino-3nitropyridine To a suspension of sodium hydride (1.63 g D55% by weight, washed with tolure) in anhydrous N,1-dimethylformazuide (DMF,3O ml), a solution of 3 .5-di-t-butyl-4-hydroxybenzenethio1 (5.36 g) in anhydrous DMF (60 ml) was added dropwise under ice cooling, followed by stirring at room tempecature for one hour. To the -I~p tnmixture, 6 -chloro-2-methvaamino-3-nitropyridine (2.81g) 42 was added. The resulting mixture was stirred at room~ temperature for 2 hours. To the reaction mixture, sodium hydride 33 g) and 3, 5-di-t-butyl-4-hydroxybenzelethiol (1.79 9) were added further, followed by stirring at rcoom temperature for 1.5 hours. The reaction mixture was allowed to stand overflight at the same temperature.- The solvent was evaporated under reduced pressure.

water was added to the residue and the resulting mixture was neutralized with 2N, HCI, followed by extraction with ethyl acetate.

After the insoluble matter was filtered off, the filtrate was washed with a saturated aqueous solution of sodium chloride and dried over anihydrous sodium sulfate. The solvent was then removed by distliatioft under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane -0 n hexcane/ethyl acetate 97/3 95/5) to afford the title compound (2.35 gj) Silica gel thin-layer chromatography; Rf value 0.32 (solvent: n-hexanelethyl acetate 95/5).

tax0 *pHe Referential Example 2 5-D±-t-butyl-4-hydroxyphenylthio) -2-hydroxytuethyl-3methyl-3H-irnidazo[415-bjpyridine A mixture of 6- 5-di-t-butyl-4-hydroxyphenylthio) -2methylamino-3-nitropyridine (2.25 10% palladium carbon (2.25 methanol (50 ml) and 1.4-dioxane (30 ml) was stirred at room temperature for 2 hours under a hydrogen atmosphere. At stirring was continued for further 3. 5 hours. The catalyst in the reaction mixture Wa3 f iltered of f and the filtrate was concentrated, To the residue, glycolic acid (1.32 q) was added, followed by st irring at 14 0C f or 2 hours.- To the reaction mixture, 2N Hcl (2 0 mlj) was added and the resulting mixture was stirred at 140*C for 2 hours. After the reaction mixture was cooled to room temperature, Z/ uas added. The resulting mixture was neutralized with 1 0 43 saturated sodium bicarbonate. After the extraction of the mixture with ethyl acetate, the extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate ethyl acetate/ethanol 9/1) to give the title compound (1.47 g).

Melting point: 134 to 150'C 0 Referential Example 3 5-(4-5-(3,5-Di-t-butyl-4-hydroxyphenylt hi)3mty-H imidazo 5-b pyridin-Z-ylmethoxy benzyl)-3triphenylmethylthiazolidine-2,4-dione To a mixture of 5-(3,5-di-t-butyl-4-hydroxyphenylthio)-2h3edroxymethy1-3-methyl-3H-imidazo(4,5-bJpyridine 61.32 :4-hydroxybenzyl) -3-triphenylmethylthiazo.idine-2, 4-dione (1.54 g) and azodicarbcnylcipiperidine (1.67 q) in toluene (30 ml), tributyiphosphine (I 6 ml) was added dropwise at room teaperature.

The mixture was ultrasonicated for 1 hour and stirred for 5 hours at room temperature. The reaction mixture was allowed to stand overnight at the same temperature. The solvent of the mixture was removed by distillation under reduced presurt The residue was purified by column chromatography on silica gel (eluent: nhexane/ehyl acetate 7/3 to afford the title compound (2.13 g).

Silica gel thin-layer chromatography; Rf value 0.48 (solvent: n-hexane/ethyl acetate 1/1)

Claims (4)

1. 5-{4-[5-(3,5-di-t-butyl-4-hydroxyphenylthio)-3-methyl- 3 H-imidazo[4,5-b]pyridin-2-ylmethoxy]benzyl}thiazolidine-2,4- dione, or tautomers, or salts-or hydrates thereof.

2. A pharmaceutical composition containing the compound of claim 1 or a tautomer, or salt or hydrate thereof, together with a pharmaceutically acceptable carrier or diluent.

3. A method for the treatment or prophylaxis of diabetes or hyperlipemia and complications thereof in a mammal comprising administering to said mammal an effective amount of the compound of claim 1 or a tautomer or salt or hydrate thereof. S 4

4. Use of the compound of claim 1 or a tautomer, or salt or hydrate thereof, in the manufacture of a medicament for the treatment or prophylaxis of diabetes or hyperlipemia and complications thereof in a mammal. S DATED this 18th day of August 1999 Sankyo Company Limited. By its Patent Attorneys DAVIES COLLISON CAVE