AU700354B2 - Heterocyclic compounds having anti-diabetic activity, their preparation and their use - Google Patents

Description

O

b

L

0

B

AUSTRALIA

PATENTS ACT 1990

ORIGINAL

COMPLETE SPECIFICATION Name of Applicant: Address of Applicant: Sankyo Company Limited 5-1, Nihonbashi Honcho, 3-chome, Chuo-ku, Tokyo 103, Japan Actual Inventor(s): Address for Service: DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

Complete Specification for the invention entitled: Heterocyclic compounds having anti-diabetic activity, their preparation and their use The following statement is a full description of this invention, including the best method of performing it known to us: la- The present invention relates to intermediates useful in the preparation of heterocyclic compounds having hypoglycemic and anti-diabetic activities.

Background to the Invention AU 683348 the entire contents of which are incorporated herein by reference, relates to a series of heterocyclic compounds having hypoglycemic and anti-diabetic activities, and provides processes for their preparation and methods and compositions for their use.

It is known that compounds which, like those of the present invention, contain, inter alia, a thiazolidinedione or oxazolidinedione group attached, via a methylene or methylidene group, to a benzene ring have this type of 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. We have now discovered that the inclusion in such compounds of certain specific bicyclic nitrogen-containing ring systems results in compounds of much improved activity.

Brief Summary of Invention Thus, it is an object of the present invention to provide a series of new chemical compounds which may be regarded as thiazolidine and oxazolidine derivatives or as ring-opened derivatives thereof.

It is a further, and more specific, object of the invention to provide such compounds, at least some of which may be useful for the treatment and/or prophylaxis _I 950 6 71854 2530 95040 2 of a variety of disorders, including one or more of: hyperlipemia, 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.

AU 683348 provides compounds of formula

R

X-(CH2), Y- (I) wherein: X represents an indolyl, indolinyl, 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) -a I 9506 S2530 95040 3 -CH 0 -CH2 0 -CH2 .O S >N-H S N-H (ii) O N-H O 0 0 -CH2 0 0 N-H (iv) -CH21N N NH2 (V)

OH

R represents a hydrogen atom, 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, 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 R a and R 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 substituted by an aryl group having from 6 to ring carbon atoms, an aryl group having from 6 to 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 I 9506 71854 275 0 95040 4 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 substituents a represents an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a trifluoromethyl group, an alkylthio group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a nitro group, an aralkyl group, or a group of formula -NRaR wherein

R

a and R b 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 consisting of substituents 3, defined below; each of said substituents p 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 -NRab, wherein Ra and R are as defined above; and salts thereof.

AU 683348 also provides a pharmaceutical composition for the treatment of prophylaxis or diabetes or hyperlipemia and complications thereof, which composition comprises an effective amount of an active compound in admixture with a pharmaceutically acceptable 9 S 0 6 71 8 54 SS 530 95040 5 carrier or diluent, wherein said active compound is selected from the group consisting of compounds of formula defined above, and salts thereof.

AU 683348 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 selected from the group consisting of compounds of formula defined above, and salts thereof.

AU 683348 also provides processes for the preparation of the compounds of the present invention, which processes are described in more detail hereafter.

The present invention now provides a compound of formula

(XIV):

Q-(C

H

20

Y

7) R Y' NH

(XIV)

wherein: Seach of Y and Y' independently represents an oxygen atom or a Ssulfur atom; ft -22/6/98 R represents a hydrogen atom, 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, an aralkyl group in which an alkyl group having from 1 to carbon atoms is substituted by an aryl group having from 6 to ring carbon atoms, or a group of formula -NRaRb, wherein R a 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 substituted by an aryl group having from 6 to 10 ring 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 it: an integer of from 1 to Q represents a lower alkoxycarbonyl group, a formyl group, a protected formyl group, a carboxyl group or a hydroxy group; and salts thereof.

5B Detailed Description of the Invention In the compounds of AU 683348 where X represents a group derived from an indole ring, it may be, for example, an indol-l-yl, indol-2-yl, indol-3-yl, indol-4-yl, yl, indol-6-yl or indol-7--yl group.

Where X represents a group derived from an indoline ring, it may be, for example, an indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-6-yl or indolin-7-yl group.

Where X represents a group derived from an azaindole ring, it may be, for example, an 4-azaindol-1-ylD 4-azaindol-2-yl, 4-azaindol-3-yl, 4-azaindol-6-yl, 4-azaindol-7-yl, 5-azaindol-2-yl, 5-azaindol-3-yl, S-azaindol-4-yl, 5-azaindol-6-yl, 5-azaindol-7-yl, 6-azaindol-1-yl, *0 6-azaindol-2-yl, 6-azaindol-3-yl, 6-azaindol-4-yl, 9 5 0 6 9506 185 4 6- 6-azaindol-5-y1, 6-azaindol-7-yl, 7-azaindol-l-yl, 7-azaindol-2-yl, 7-azaindol-3-yl, 7-azaindol-4-yl, or 7-azaindol-6-yl group.

Where X represents a group derived from an azaindoline ring, it may be, for example, an 4-azaindolin-l-yl, 4-azaindolin-2 -yl, 4-azaindolin-3 -yl, 4-azaindolin-6-yl, 4-azaindolin- 7-yl, 1-yl, 5-azaindolin-2-yl, 5-azaindolin-3 -yl, 5-azaindolin-4-yl, 5-azaindolin- 6-yl, 5-azaindolin-7-yl, 6-azaindolin-1-yl, 6-azaindolin-2 -yl, 6-azaindolin-3 -yl, 6-azaindolin-4-yl, 6-azaindolin-5-yl, 6-azaindolin- 7-yl, 7-azaindolin-l-yl, 7-azaindolin-2 -yl, 7-azaindolin-3 -yl, 7-azaindolin-4-yl, 7-azaindoliia-5-y1 or 7-azaindolin-6y1 group.

Where X represents a group derived from an imidazopyridine ring, it may be, for example, an 0 a 4 4*ss 4. 6 4* V. .4 V.

C

imidazo 5-b] pyridin-l-yl, imidazo 5-b] pyridin- 7-yl, imidazo 5-b] pyridin- 6-yl, imidazo 5-c] pyridin-2-yl, imidazo[4, 5-clpyridin-6-yl, imidazo 15, 4-b] pyridin-3-yl, imidazo 4-b] pyridin-7-yl, imidazo pyridin- 6-yl, imidazo pyridin-2 -yl, imidazo pyridin-6-y-, imidazo pyridin-2-yl, imidazo pyridin-8-yl, imidazo pyridin- 2-yl, imidazo pyridin- imidazo [4,5 pyridin- 1-yl, imidazo 5-c] pyridin-4-yl, imidazo 5-c] pyridin-7-yl, imidazo pyridin- 2-yl, imidazo pyridin- 5-y1, imidazo [5,4 pyridin- 3-yl, imidazo pyridiri- 4-yl, imidazo pyridin- 7-yl, imidazo pyridin-3-yl, imidazo imidazo[1,2-alpyridin-6-yl or imidazo[l,2-a]pyridin-7yl group.

Where X represents a group derived from an imidazopyrimidine ring, it may be, for example, an imidazo- [4,5-d]pyrimidine-7-yl, imidazo[4,5-dlpyrimidine-8-y1 or 1) 5 0 6 I 4 I *7 imidazo[4,5-d]pyrimidine-9-yl group.

Any of the above groups which may be represented by X may be unsubstituted or it may be substituted by at least one of substituents a, defined above and exemplified below. Where the group is substituted, there is no particular restriction on the number of substituents, except such as may be imposed by the number of substitutable positions, or, occasionally, by steric constraints. In general, however, from 1 to 3 substituents are preferred, 1 or 2 substituents being more preferred. There is also no particular restriction on the position of any such substituent.

Where R, substituent a or substituent 3 represents an alkyl group, this may be a straight or branched chain alkyl group having from 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, of which we prefer the methyl group.

Where R, substituent a or substituent represents an alkoxy group, this may be a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, and examples include the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy groups, of which we prefer the methoxy group.

Where R, substituent a or substituent j represents a halogen atom, it may be, for example, a bromine, chlorine, fluorine or iodine atom, of which we prefer the bromine, chlorine and fluorine atoms, the chlorine atom being most preferred.

Where R represents an aralkyl group, the alkyl part of this group has from 1 to 5 carbon atoms and may be a k 05 b~i 1 1 5 2 5 1 -8straight or branched chain group which is substituted by an aryl group, which itself may be as defined above and exemplified below. In all, the aralkyl group preferably has from 7 to 11 carbon atoms. Examples of the alkyl part of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl and t-pentyl groups (preferably the methyl and ethyl groups. Examples of aryl groups are given hereafter in relation to substituents a.

Specific examples of such aralkyl groups include the benzyl, 2-phenylethyl phenethyl), 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, l-phenylpropyl, 4-phenylbutyl, 1-phenylbutyl, 1-naphthylmethyl and 2-naphthylmethyl groups, of which the phenethyl and benzyl groups are preferred, the '"benzyl group being most preferred.

S.i Alternatively, R, substituent u or substituent 3 may represent an amino group or substituted amino group a b a b of formula -NR Rb, where R and Rb, which may be the same or different are selected from the following: Hydrogen atoms; Alkyl groups having from 1 to 8 carbon atoms, which may be straight or branched chain groups, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1l-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, heptyl, 2-heptyl, 3-heptyl, 4-heptyl, IP~ 0 G I I I 4 o 9 3,3-dimethylpentyl, octyl, 1-methylheptyl, 2-ethylhexyl and 1,1,3,3-tetramethylbutyl groups, of which we prefer those straight and branched chain alkyl groups having from 1 to 6 carbon atoms, and most prefer those straight or branched chain alkyl groups having from 1 to 4 carbon atoms; the.methyl and ethyl groups are most preferred; Aralkyl groups as defined and exemplified above in relation to the group which may be represented by R, and preferably such groups having from 7 to 11 carbon atoms; Aryl groups having from 6 to 10 carbon atoms, for example, the phenyl, l-naphthyl and 2-naphthyl groups; Aliphatic carboxylic acyl groups, which may be straight or branched chain groups heving from 1 to 11 carbon atoms, for example, the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and undecanoyl groups; Aliphatic carboxylic acyl groups which have from 2 to 6 carbon atoms and which are substituted by an aryl group as defined above, and each of which preferably has a total of from 8 to 12 carbon atoms; examples of the aliphatic acyl part of the group are those acyl groups having from 2 to 6 carbon atoms which are included among the aliphatic acyl groups represented by R a and R above (preferably the acetyl and propionyl groups), and examples of the aryl part are included among those aryl groups listed above (preferably the phenyl and naphthyl groups, especially the phenyl group); specific

L-

9506 7185 4 2530 95040 IWAV 10 examples of preferred aromatic-substituted a.liphatic acyl groups include the phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 6-phenylhexanoyl, a-methylphenylacetyl and i,a-dimethylphenylacetyl groups, of which the phenylacetyl group is preferred; Carbocyclic aromatic carboxylic acyl groups, i which the aryl group is as defined and exemplified above (preferably the phenyl and naphthyl groups, especially the phenyl group); preferred groups are those having a total of from 7 to 11 carbon atoms, and examples include the benzoyl, l-naphthoyl and 2-naphthoyl groups, of which the benzoyl group is preferred.

Specific examples of such amino groups which may be represented by R, substituent i or substituent 3 include the following: Substituted amino groups in which one of Ra and Rb represents a hydrogen atom and the other of Ra an b *Ra and R represents an alkyl group, such as the methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, t-butylamino, pentylamino, 2-pentylamino, 3-pentylamino, 2-methylbutylamino, 3-methylbutylamino, 1,1l-dimethylpropylamino, 1,2-dimethylpropylamino, 2,2-dimethylpropylamino, hexylamino, 2-hexylamino, 3-hexylamino, 2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino, 1,1-dimethylbutylamino, 1,2-dim thylbutylamino, 1,3-dimethylbutylamino, 2,2 dimathylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, 1,1,2-trimethylpropylamino, 1,2,2-trimethylpropylamino, heptylamino, 2-heptLamino, 3-heptyl-

I

C 6 71854 '0I 0 amino, 4-heptylamino, 3,3-dimethylpentylamino, octylamino, 1-methylheptylamino, 2-ethylhexylamino and 1,1,3,3-tetramethylbutylamino groups; Substituted amino groups, in which one of Ra and R b represents a hydrogen atom and the other of

R

a and R b represents an aralkyl group, such as the benzylamino, 2-phenylethylamino, 1-phenylethylamino, 3-phenylpropylamino, 2-phenylpropylamino, 1-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 1-naphthylmethylamino and 2-naphthylmethylamino groups; Substituted amino groups, in which one of R a b and R represents a hydrogen atom and the other of Ra b R and R represents an aryl group, such as the phenylamino, 1-naphthylamino and 2-naphthylamino groups; Substituted amino groups, in which one of R a and R represents a hydrogen atom and the other of

R

a and R b represents an aliphatic acyl group, Ssuch as the formamido, acetamido, propionamido, butyramido, isobutyramido, pivaloylamino, pentanoylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino and undecanoylamino groups; Substituted amino groups, in which one of Ra and R represents a hydrogen atom and the other of

R

a and Rb represents aromatic-substituted aliphatic acyl group, such as the phenylacetamido, 3-phenylpropionamido, 4-phenylbutyramido, 6-phenylhexanoylamino, a-methylphenylacetamido and a,a-dimethyl-

YI

1) 5 0 6 S1 5 4 9 I o 1 1i) 4 0 -12 phenylacetamido groups; Substituted amino groups, in which one of Ra and R b represents a hydrogen atom and the other of

R

a and R b represents an aromatic acyl group, such as the benzamido, 1-naphthoylamino and 2 -naphthoylamino; Substituted amino groups, in which R a and

R

b both represent alkyl groups, which may be the same as or different from each other, such as the dimethylamino, diethylamino, N-methyl-N-ethylamino and N-methyl-N-pentylamino groups; Substituted amino groups, in which one of R a Rb and R represents an alkyl group and the other of R.n a b SR and R represents an aralkyl group, such as the N-ethyl-N-benzylamino, N-t-butyl-N-benzylamino and N-hexyl-N-benzylamino groups; Substituted amino groups, in which one of Ra and R repr3ents an alkyl group and the other of

R

a and R b represents an aryl group, such as the N-methyl-N-phenylamino, N-ethyl-N-phenylamino and N-octyl-N-phenylamino groups; i (10) Substituted amino groups, in which one of R a and Rb represents an alkyl group and the other of

R

a and R b represents an aliphatic acyl group, such as the N-propyl-N-acetylamino, N-pentyl-Npropionylamino and N-ethyl-N-hexanoylamino groups; (11) Substituted amino groups, in which one of R a and R represents an alkyl group and the other of

R

a and R b represents an aromatic-oubstituted carboxylic aliphauic acyl group, such as the

'YL

9 0 6 7 1 8 5 4 9:2 515 3 0 9 50 A0 w J13 -N-ethy1--N-phenylacetylamino, N-isopropy1-~-(2phenylpropionyl)amino and N-methyl-N- (6-phenylhexanoyl) amino groups; (12) Substituted amino groups, in which one of Ra and Rbrepresents an alkyl group and the other of R aandR brepresents an aromatic acyl group, such as the N-methyl-N-benzoylamino, N-sec-butyl-Nbenzoylamino and N-hepty1-N-benzoylamino groups; (13) Substituted amino groups, in which R aand R bboth represent aralkyl groups, which may be the same as or different from each other, such as the dibenzylamino, N-benzyl-N- (3-phenylpropyl)amino and N-benzyl-N- (2-naphthylmethyl)amino groups; (14) Substituted amino groups, in which one of Ra and R b represents an aralkyl group and the other of R n represents an aryl. group, such as the N-benzyl-N1-phenylamino and N- (3-phenyipropyl) N-phenyla-mino groups; Substituted amino groups, in which one of Ra and Rb represents an aralkyl group and the other of RaanRb represents an aliphatic acyl group, such as the N-benzyl-N-acetylamino, N-benzyl- N-propionylamino and N-benzy1-N-pentanoylamino groups; (16) Substituted amino groups, in which one of Ra and Rbrepresents an aralkyl group and the other of RaadRbrepresents an aromatic-substituted aliphatic carboxylic acyl group, such as the N-benzy1-N-phenylacetylamino and N-benzyl-N- (4phenylbutyryl) amino groups;

I

9506 7185 4 2530 S 040 w 14 (17) Substituted amino groups, in which one of R a and R b represents an aralkyl group and the other of R a and R b represents an aromatic acyl group, such as the N-benzyl-N-benzoylamino and N-(2-phenylethyl)-_N-benzoylamino groups; (18) Substituted amino groups, in which R a and Rb both represent aryl groups, which may be the same as or different from each other, such as the diphenylatino, N-(l-naphthyl)-N-phenylamino and N-(2-naphthyl)-N-phenylamino groups; (19) Substituted amino groups, in which one of Ra and R represents an aryl group and the other of 'a b Ra and R represents an aliphatic carboxylic acyl group, such as the N-phenyl-N-acetylamino, N-phenyl-N-propionylamino and N-phenyl-N-hexanoylamino groups; (20) Substituted amino groups, in which one of R a S'and Rb represents an aryl group and the other of

R

a and Rb represents an aromatic-substituted aliphatic carboxylic acyl group, such as the N-phenyl-N-phenylacetylamino and N-phenyl-N-(4phenylbutyryl)amino groups; (21) Substituted amino groups, in which one of R a and R b represents an aryl group and the other of

R

a and R b represents an aromatic carboxylic acyl group, such as the N-phenyl-N-benzoylamino and N-phenyl-N-(2-naphthoyl)amino groups; (22) Substituted amino groups, in which R a and Rb both represent aliphatic carboxylic acyl groups, which may be the same as or different from each other, such as the N,N-diacetylamino, N-acetyl- 9 506 7 185 4 2530 95040 Mw 15 N-propionylamino and N-butyryl-N-hexanoylamino groups; (23) Substituted amino groups, in which one of Ra and R b represents an aliphatic carboxylic acyl group and the other of R a and R represents an aromatic-substituted aliphatic carboxylic acyl group, such as the N-acetyl-N-phenylacetylamino, N-acetyl-N-(4-phenylbutyryl)amino and N-butyryl-Nphenylacetylamino groups; (24) Substituted amino groups, in which one of R a and R b represents an aliphatic carboxylic acyl group and the other of R a and Rb represents an aromatic carboxylic acyl group, such as the N-acetyl-N-benzoylamino and N-butyryl-N-(2naphthoyl)amino groups; Substituted amino groups, in which R a and R both represent aromatic-substituted aliphatic carboxylic acyl groups, which may be the same as or different from each other, such as the N,N-diphenylacetylamino, N-phenylacetyl-N-(2-phenylpropionyl)amino and N-phenylacetyl-N-(4-phenylbutyryl)amino groups; (26) Substituted amino groups, in which one of Ra and R b represents an aromatic-substituted aliphatic carboxylic acyl group and the other of Ra and Rb represents an aromatic carboxylic acyl group, such as the N-phenylacetyl-N-benzoylamino and N-phenylacetyl-N-(2-naphthoyl)amino groups; and (27) Substituted amino groups, in which R a and Rb both represent aromatic carboxylic acyl groups, which may be the same as or different from each 9506 7 1 54 2530 95040 other, such as the N,N-dibenzoylamino and N-benzoyl- N-(2-naphthoyl)amino groups.

Where substituent a represents an alkylthio group, this may be a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, for example, the methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio and t-butylthio groups.

Where substituent a represents an aryl group having from 6 to 10 carbon atoms, this group may be unsubstituted or may be substituted by at least one substituent selected from the group consisting of substituents p. Examples of the unsubstituted aryl groups include, for example, the phenyl, l-naphthyl and S. 2-naphthyl groups.

Where substituent 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, nitro, phenyl or trifluoromethyl group or an amino group of formula -NRaRb, the alkyl, alkoxy or amino group and the halogen atom may be as defined and exemplified above in relation to substituents a.

In the case of the substituted aryl groups, there is no particular restriction on the number of substituents p which may be present, the only restrictions being those imposed by the number of substitutable positions and possibly by steric constraints. In general, from 1 to 5 substituents are preferred, from 1 to 3 being more preferred and 1 or 2 being most preferred.

Examples of such substituted aryl groups include the following: -s I 9 5 0 6 7 1 a 5 4 95 6 L~t2 5 3 0 9 0( 4 0 MW 17 1) aryl groups substituted by at leasc one alkyl group having from 1 to 4 carbon atoms, such as the 4-methylphenyl, 4-ethylphenyl, 4-propyiphenyl, 4- isopropylphenyl, 4-butylphenyl, 4-isobutyiphenyl, 4-sec-butylphenyl, 4-t-butylphenyl, 4-methyl-l-naphthyl, naphthyl, B-propyl-l-naphthyl, 4-isopropyl-l-naphthyl, 4-isobutyl-l-naphthyl, 4-sec-butyl- 1-naphthyl, 4-t-butyl-l-naphthyl, 4-fethyl-2-naphthyl, 5-ethyl-2-naphthyl, 8-propyl-2-naphthyl, 4-isopropyl-2naphthyl, 5-butyl-2-naphthyl, 8-isobutyl-2-naphthyl, 4-sec-butyl-2-naphthyl or 5-t-butyl-2-naphthyl groups; 2) aryl groups substituted by at least one alkoxy group having from 1 to 4 carbon atoms, such as the 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4- isopropoxyphenyl, 4-butoxyphenyl, 4-isobutoxyphenyl, 4-sec-butoxyphenyl, 4-t-butoxyphenyl, 4-methoxy-1-naphthyl, 5-ethoxy-l-naphthyl, 8-propoxy-l-naphthyl, 4-isopropoxyl-naphthyl, 5-butoxy-l-naphthyl, 4-isobutoxy-l-naphthyi, 4-sec-butoxy-l-naphthyl, 4-t-butoxy-l-'naphthyl, 4-methoxy-2-naphthyl, S-ethoxy-2-naphthyl, 8-propoxy-2naphthyl, 4-isopropoxy-2-naphthyl, 5-butoxy-2-naphthyl, 8-isobutoxy-2-naphthyl, 4-sec-butoxy-2-naphthyl or 5- t-butoxy- 2- naphthyl groups; 3) aryl groups substituted by a halogen atom, such as the 4-bromophenyl, 4-chlorophenyl, 4- fluorophenyl, 4-iodophenyl, 3-chlorophenyl, 3-f luorophenyl, 3-bromophenyl, 3-iodophenyl, 4-bromo-l-naphth!.. 4-chloro-1naphthyl, 4-f luoro-l-naphthyl, 4-iodo- naphthyl, 5-f luoro-l-naphthyl, naphthyl, 8-chloro-l-naphthyl, 4-f luoro-2-naphthyl, 4-bromo-2-naphthyl, 4-chloro-2-naphtL-hyl, 4-iodo-2naphthyl, 5-bromo-2-naphthyl, 5-chloro-2-naphthyl, luoro-2-naphthyl or 5-iodo-2-naphthyl groups; 9 5 0 6 15 4 7 1 8 5 4 I 11 A W -18 4) aryl groups substituted by a hydroxy group, such as the 2 -hydroxyphenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy- i-naphthyl, 5-hydroxy- 1-naphthyl, 8-hydroxy-l-naphthyl, 4-hydroxy-2-naphthyl, 5-hydroxy-2-naphthyl. or 8-hydroxy-2-naphthyl groups; aryl groups substituted by a nitro group, such as the 2-raitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-nitro-l-naphthyl, 5-nitro-1-naphthyl, 8-nitro- 1naphthyl, 4-nitro-2-naphthyl, 5-nitro-2-naphthyl or 8-nitro-2 -naphthyl groups; 6) aryl groups substituted by a phenyl group, such as the 3-phenylphenyl, 4-phenyiphenyl, 4-phenyl-1-naphthyl, 8-phenyl-l-naphthyl, 4-phenyl-2naphthyl, 5-phenyl-2-naphthyl or 8-phenyl-2-naphthyl groups; 7) aryl groups substituted by a trifluoromethyl group, such as the 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethyl-l-naphthyl, 1-naphthyl, 8-trifluoromethyl-l-naphthyl, 4-trifluoromethyl-2-naphthyl, 5-trifluoromethyl-2-naphthyl or 8- trifluoromethyl.-2 -naphthyl groups; 8) aryl groups substituted by at least one unsubstituted or substituted amino group, such as those substituted by an unsubstituted amino group, for example the 2 -aminophenyl, 3 -aminophenyl, 4 -aminophenyl, 4-amino-l-naphthyl and 8-amino-2-naphthyl groups and those substituted by a substituted amino group, for example: aryl groups substituted by a substituted amino group in which one of R aand R brepresents a hydrogen atom and the other of RPa and Rb 9 1 0 (1 I 0 1 1)4 0 19 represents an alkyl group, such as the 3-methylaminophenyl, 4-ethylaminophenyl, 3-propylaminophenyl, 3-isopropylaminophenyl, 4-butylaminophenyl or 3-isobutylaminophenyl groups; ii) aryl groups substituted by a substituted amino group in which one of R a and R represents a hydrogen atom and the other of Ra and Rb represents an aralkyl group, such as the 4-benzylaminophenyl, 4-(2-phenylethylamino)phenyl, 4-(1-phenylethylamino)phenyl, 4-(4-phenylbutylamino)phenyl or 4-(1-naphthylmethylamino)phenyl groups; *e iii) aryl groups substituted by a substituted amino a b group in which one of R and R represents a a b hydrogen atom and the other of R and R represents an aryl group, such as the 4-phenyl- Saminophenyl or 4-(1-naphthylamino)phenyl groups; *G iv) aryl groups substituted by a substituted amino a b group in which one of R and R represents a a b hydrogen atom and the other of R and R represents an aliphatic acyl group, such as the .4-formamidophenyl, 4-acetamidophenyl, 4-butyramidophenyl, 4-pivaloylaminophenyl, 4-hexanoylaminophenyl, 4-octanoylaminophenyl or 4-undecanoylaminophenyl groups; v) aryl groups substituted by a substituted amino group in which one of R a and R represents a hydrogen atom and the other of Ra and Rb represents an aromatic-substituted aliphatic acyl group, such as the 4-phenylacetylaminophenyl, 4-(4-phenylbutyrylamino)phenyl, 4-(6-phenylhexanoylamino)phenyl, 4-(a-methylphenylacetyl- Is 0 6 718 54 'I 0 4 0 20 amino)phenyl or 4- a-dimethylphenylacetylamino)phen groups; vi) aryl groups substituted by a substituted amino group in which one of R a and R b represents a hydrogen atom d the other of R a and Rb represents an aromatic acyl group, such as the 4-benzoylaminophenyl, 4-(1-naphthoylamino)phenyl or 4-(2-naphthoylamino)phenyl groups; vii) aryl groups substituted by a substituted amino group in which R and R both represent alkyl groups, which may be the same as or different from each other, such as the 4-dimethylaminophenyl, 4-diethylaminophenyl or 4-(N-methyl-N-ethylamino)phenyl groups; .viii) aryl groups substituted by a substituted a b amino group in which one of R and R represents an alkyl group and the other of R a and Rb represents an aralkyl group, such as the 4-(N-ethyl- N-benzylamino)phenyl, 4-(N-t-butyl-N-benzylamino)phenyl or 4-(N-hexyl-N-benzylamino)phenyl groups; ix) aryl groups substituted by a substituted amino group in which one of R a and R b represents an alkyl group and the other of R a and R b represents an aryl group, such as the 4-(N-methyl- N-phenylamino)phenyl or 4-(N-octyl-N-phenylamino)phenyl groups; x) aryl groups substituted by a substituted amino group in which one of R a and R b represents an alkyl group and the other of R a and R b represents an aliphatic acyl group, such as the 4-(N-propyl-N-acetylamino)phenyl or 4-(N-ethyl- 9506 5)U 0 4 W 21 N-hexanoylamino)phenyl groups; xi) aryl groups substituted by a substituted amino group in which one of R a and R represents an alkyl group and the other of R a and R b represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-ethyl-N-phenylacetylamiro)phenyl or 4-[N-methyl-N-(6-phenylhexanoyl)amino]phenyl groups; xii) aryl groups substituted by a substituted amino group in which one of R a and R represents an alkyl group and the other of R a and R b represents an aromatic acyl group, such as the 4-(N-methyl-N-benzoylamino)phenyl or 4-(N-heptyl- N-benzoylamino)phenyl groups; xiii) aryl groups substituted by a substituted amino group in which R a and R both represent aralkyl groups, which may be the same as or different from each other, such as the 4-dibenzylaminophenyl or 4-[N-benzyl-N- (2-naphthylmethyl)amino]phenyl groups; xiv) aryl groups substituted by a substituted amino group in which one of R a and R represents an *aralky" group and the other of R a and Rb represents an aryl group, such as the 4-(N-benzyl- N-phenylamino)phenyl or 4-[N-(3-phenylpropyl)-Nphenylamino] phenyl groups; xv) aryl groups substituted by a substituted amino group in which one of R a and R represents an aralkyl group and the other of R a and R represents an aliphatic acyl group, such as the 4-(N-benzyl-N-acetylamino)phenyl or 4-(N-benzyl-

I

7185 4 2530 95040 rM 22 N-pentanoylamino)phenyl groups; xvi) aryl groups substituted by a substituted amino group in which one of R a and R b represents an aralkyl group and the other of R a and R b represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-benzyl-N-phenylacetylamino)phenyl or 4-[N-benzyl-N-(4-phenylbutyryl)amino]phenyl groups; xvii) aryl groups substituted by a substituted amino group in which one of R a and R represents an aralkyl group and the other of Ra and Rb represents an aromatic acyl group, such as the 4-(N-benzyl-N-benzoylamino)phenyl or 4-[N-(2-phenylethyl)-N-benzoylamino]phenyl groups; xviii) aryl groups substituted by a substituted amino group in which R a and R b both represent aryl groups, which may be the same as or different from each other, such as the 4-diphenylaminophenyl or 4-[N-(2-naphthyl)-N-phenylamino]phenyl groups; xix) aryl groups substituted by a substituted amino a b group in which one of R a and R represents an aryl group and the other of R a and R b represents an aliphatic acyl group, such as the 4- (-phenyl-N-acetylamino)phenyl or 4-(N-phenyl- N-hexanoylamino)phenyl groups; xx) aryl groups substituted by a substituted amino group in which one of R a and R b represents an aryl group and the other of R a and R b represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-phenyl-N-phenylacetylamino)- phenyl or 4-[N-phenyl-N-(4-phenylbutyryl)amino]- phenyl groups; 9506 71854 5)0 1S 4O 23 xxi) aryl groups substituted by a substituted amino group in which one of R a and R represents an aryl group and the other of R a and R b represents an aromatic acyl group, such as the 4-(N-phenyl-N-benzoylamino)phenyl group; xxii) aryl groups substituted by a substituted amino group in which R a and R both represent aliphatic acyl groups, which may be the same as or different from each other, such as the 4-diacetylaminophenyl or 4-(N-butyryl-N-hexanoylamiro)phenyl groups; xxiii) aryl groups substituted by a substituted amino group in which one of R a and R b represents an aliphatic acyl group and the other of R a and

R

b represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-acetyl-N-phenylacetylamino)phenyl or 4-(N-butyryl-N-phenylacetylamino)phenyl groups; xxiv) aryl groups substituted by a substituted amino group in which one of R and R represents an aliphatic acyl group and the other of R and

R

b represents an aromatic acyl group, such as the 4-(N-acetyl-N-benzoylamino)phenyl or 4-[N-butyryl- N-(2-naphthoyl)amino]phenyl groups; xxv) aryl groups substituted by a substituted amino group in which R a and R b both represent aromatic-substituted aliphatic acyl groups, which may be the same as or different from each other, such as the 4-(N,N-diphenylacetylamino)phenyl or 4-[N-phenylacetyl-N-(4-phenylbutyryl)amino]phenyl groups; I----ls 9506 71854 0 5 ?30 )5040 W 24 xxvi) aryl groups substituted by a substituted amino group in which one of R a and R represents an aromatic-substituted aliphatic acyl group and the other of R a and R represents an aromatic acyl group, such as the 4-(N-phenylacetyl-N-benzoylamino)phenyl or 4-[N-phenylacetyl-N-(2-naphthoyl)amino]phenyl groups; xxvii) aryl groups substituted by a substituted amino group in which R a and R both represent aromatic acyl groups, which may be the same as or different from each other, such as the 4-dibenzoylaminophenyl or 4-[N-benzoyl-N-(2-naphthoyl)amino]phenyl grcup.

Where substituent a represents an aralkyl group, this may be unsubstituted or it may be substituted by one or more of substituents 3, defined and exemplified :.above. The group (excluding substituencs, if any) preferably contains a total of from 7 to 11 carbon atoms. The alkyl part of the aralkyl group is an alkyl group having from 1 to 5 carbon atoms. Examples of such aralkyl groups include the benzyl, 2-phenylethyl, l-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, l1-phenylpropyl, 4-phenylbutyl, l-phenylbutyl, l-naphthylmethyl and 2-naphthylmethyl groups.

In the case of the substituted aralkyl groups, there is no particular restriction on the number of substituents p which may be present, the only restrictions being those imposed by the number of substitutable positions and possibly by steric constraints. In general, from 1 to 5 substituents are preferred, from 1 to 3 being more preferred and 1 or 2 being most preferred.

9 5 0 6 ~~507 71 8S4 2 2 5 1 0 Examples of such substituted aralkyl groups include the following: 1) aralkyl gruops substituted by at least one alkyl group having from 1 to 4 carbon atoms, such as the 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 4- isopropylbenzyl, 4 -butylbenzyl, 4- isobutylbenzyl, 4-sec-butylbenzyl, 4-t-butylbenzyl, 4-methyl-l-naphthylmethyl, 5-ethyl-l-naphthylmethyl, 8-propyl-l-naphthylmethyl, 4-isopropyl-l-naphthylmethyl, 5-butyl-1naphthylmethyl, 4- isobutyl- l-naphthylmethyl, 4-sec-butyl-l-naphthylmethyl, 4-t-butyl-l-naphthylmethyl, 4-methyl-2-naphthylmethyl, 5-ethyl-2-naphthylmethyl, 8-propyl-2-naphthylmethyl, 4-isopropyl-2naphthylmethyl, 5-butyl-2-riaphthylmethyl, 8-isobutyl-2napbthylmethyl, 4-sec-butyl-2-naphthylmethyl or t-butyl naphthylmethyl groups; 2) aralkyl groups substituted by at least one alkoxy group having from 1 4 Cabon atoms, such as the *.:4-methoxybenzyl, 4-ethoxybenzyl, 4-propoxybenzyl, 4-isopropoxybenzyl, 4-butoxybenzyl, 4-isobutoxybenzyl, 4-sec-butoxybenzyl, 4-t-butoxybenzyl, 4-methoxy-lnaphthylmethyl, 5-ethoxy-l-naphthylmethyl, 8-propoxy- 1-naphthylmethyl, 4- isopropoxy- l-naphthylmethyl, 4-isobutoxy-l-naphthylmethyl, 4-sec-butoxy-l-naphthylmethyl, 4-t-butoxy-l-naphthylmethyl, 4-methoxy-2-naphthylmethyl, 5-ethoxv-2-naphthylmethyl, S-propoxy-2-naplithylmethyl, 4-isopropoxy-2naphthylmethyl, 5-butoxy-2-naphthylinethyl, 8-isobutoxy- 2-naphthylmethyl, 4-sec-butoxy-2-naphthylmethyl or t -butoxy- 2- naphthylmethyl groups; 3) aralkyl groups substituted by a halogen atom, such as the 4-bromobenzyl, 4-chlorobenzyl, 4-f luorobenzyl, 4- iodobenzyl, 3 -chlorobenzyl, 3 -fluorobenzyl, 9 5 0 6 7 1 6 5 4 952 515 3 0 9 50 w 26 3-bromobenzyl, 3-iodo'oenzyl, 4-bromo-1-raaphthylmethyl, 4-chloro-l-naphthylmethyl, 4-fluoro-1-naphthylmethyl, 4-iodo-1-naphthylmethyl, 5-chloro-1-naphthylmethyl, luoro-i-naphthylmethyl, 5-bromo-1-naphthylmethyl, 8-chloro-i-naphthylmethyl, 4-fluoro-2-naphthylnethyl, 4-bromo-2 -naphthylmethyl, 4- chloro-2 -naphthylmethyl, 4-iodo-2-naphthylmethyl, 5-bromo-2-naphthylmethyl, 5--chloro-2-naphthylmethyl, 5-fluoro-2-naphthylmethyl or iodo naphthylmethyl groups; 4) aralkyl groups substituted by a hydroxy group, such as the 2-hydroxybeizyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-hydroxy-1-naphthylmethyl, 5-hydroxy-1naphthylmethyl, 8-hydroxy- i-raphthylmethyi., 4-hydroxy- 2 -naphthylmethyl, 5 -hydroxy-2 -naphthylmethyl or 8- hydroxy- 2- naphthylmethyl groups; aralkyl groups substituted by a nitro group, such as the 2-nitrob.2nzyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitro-1-naphthylmethyl, *.:8-nitro-1-naphthylmethyl, 4-nitro-2-naphthylmethyl, 5-nitro-2-naphthylmethyl or 8-nitro-2-naphthylmethyl groups; 6) aralkyl groups substituted by a phenyl group, such as the 3-phenylbenzyl, 4-phenylbenzyl, 4-phenyl-lnaphthylmethyl, 5-phenyl-1-naphthylmethyl, 8-phenyl-1naphthylmethyl, 4 -phenyl -2 -naphthylmethy-, 5 -phenyl -2naphthylmethy- or 8 -phenyl -2 -naphthylmethyl groups; 7) aralkyl groups substituted by a trifJluoromethyl group, such as the 3-trifluoromethylbelzyl, 4-trifluoromethylbenzyl, 4-trifluoromethyl~-l-faphthy2lmethyl, 8-trifluoromlethy'l- 1-naphthylmethyl, 4- trifluoromethy--2 -naphthylmethyl, 5-trifluoromethyl-2-naphthylmethyl or 8-trifluoromethyl- 150 6 Sa 1 54 2 1 1 0 27 2-naphthylmethyl groups; 8) aralkyl groups substituted by at least one unsubstituted or substituted amino group, such as those substituted by an unsubstituted amino group, for example the 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 4-amino-l-naphthylmethyl or 8-amino-2-naphthylmethyl groups and those substituted by a substituted amino group, for example: i) aralkyl groups substituted by a substituted amino group in which one of R and R represents a hydrogen atom and the other of R a and Rb represents an alkyl group, such as the 3-methylaminobenzyl, 4-ethylaminobenzyl, 3-propylaminobenzyl, 3-isopropylaminobenzyl, 4-butylaminobenzyl or 3-isobutylaminobenzyl groups; ii) aralkyl groups substituted by a substituted a b amino group in which one of R and R represents a hydrogen atom and the other of Ra and R represents an aralkyl group, such as the 4-benzylaminobenzyl, 4-(2-phenylethylamino)benzyl, 4-(l-phenylethylamino)benzyl, 4-(4-phenylbutylamino)benzyl or 4-(1-naphthylmethylamino)benzyl groups; iii) aralkyl groups substituted by a substituted amino group in which one of R a and R represents a hydrogen atom and the other of Ra and Rb represents an aryl group, such as the 4-phenylaminobenzyl or 4-(l-naphthylamino)benzyl groups; iv) aralkyl groups substituted by a substituted amino group in which one of R a and R represents a hydrogen atom and the other of R a and Rb

-I

9 5 01 6 7 1 8 5 4 '35 0618542 3 0 '3 5 03 4 (3 1W 28 represents an aliphatic acyl group, such as the 4- formamidobenzyl, 4- acetamidobenzy., 4- butyramidobenzyl, 4-pivaloylarninobenzyl, 4-hexanoylaninobenzyl, 4-octanoylaminobenzyl or 4-undecanoylaminobenzy. groups; v) aralkyl groups substituted by a substituted amino group in which one of RPa and RPb represents a hydrogen atom and the other of R a and Rb represents an aromatic-substituted aliphatic acy.

group, such as the 4-phenylacetamidobenzyl, 4- (4-phenylbutyrylamino)benzyl, 4- (6-phenyihexanoylamino)benzyl, 4- (a-methylphenylacetylamido) benzyl or 4- (ai,ai-dimethylphenylacetamido)benzyJ. groups; vi) a.>;ikyl groups substituted by a substituted amino Iroup in which one of R aand RPb represents a b a hydrcgen atom and the other of R and R represents an aromatic acyl group, such as the 4-benzoylaminobenzyl, 4- (i-naphthoylamino) benzyl or 4- naphthoylamino) benzyi groups; vii) aralkyl groups substituted by a substituted amino group in which R a and R b both represent alkyl groups, which may be the same as or different from each other, such as the 4-dimethylaminobenzy-, 4-diethylaminobenzy. or 4- (N-methyJ--N-ethylamino) benzyl groups; viii) aralkyl groups substituted by a substituted amino group in which one of R aand R brepresents an alkyl group and the other of R aand Rb represents an aralkyl group, such as the 4- (LI-ethyl- N-benzylamino)benzyl, 4- (N-t-butyl-N-benzylamino) benzyl or 4- (L-hexyl-N-benzylamino)benzyl groups; 9 5 06 7 1 85 2530 5040 29 ix) aralkyl groups substituted by a substituted amino group in which one of R a and Rb represents an alkyl group and the other of R a and Rb represents an aryl group, such as the 4-(N-methyl- N-phenylamino)benzyl or 4-(N-octyl-N-phenylamino)benzyl groups; x) aralkyl groups substituted by a substituted amino group in which one of R a and R represents an alkyl group and the other of Ra and Rb represents an aliphatic acyl group, such as the 4-(N-propyl-N-acetylamino)benzyl or 4-(N-ethyl- N-hexanoylamino)benzyl groups; xi) aralkyl groups substituted by a substituted amino group in which one of R a and R b represents an alkyl group and the other of Ra and Rb represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-ethyl-N-phenylacetylamino)benzyl or 4-[N-methyl-N-(6-phenylhexanoyl)amino]benzyl groups; xii) aralkyl groups substituted by a substituted amino group in which one of Ra and R represents an alkyl group and the other of R and R represents an aromatic acyl group, such as the 4-(N-methyl-N-benzoylamino)benzyl or 4-(N-heptyl- N-benzoylamino)benzyl groups; xiii) aralkyl groups substituted by a substituted amino group in which R a and R both represent aralkyl groups, which may be the same as or different from each other, such as the 4-dibenzylaminobenzyl or 4-[N-benzyl-N-(2-naphthylmethyl)amino]benzyl groups; 9506 71854 2530 15040 30 xiv) aralkyl groups substituted by a substituted amino group in which one of R a and R b represents an aralkyl group and the other of Ra and Rb represents an aryl group, such as the 4-(N-benzyl- N-phenylamino)benzyl or 4-[N-(3-phenylpropyl)-Nphenylamino]benzyl groups; xv) aralkyl groups substituted by a substituted amino group in which one of R a and R represents an aralkyl group and the other of Ra and Rb represents an aliphatic acyl group, such as the 4-(N-benzyl-N-acetylamino)benzyl or 4-(N-benzyl-Npentanoylamino)benzyl groups; xvi) aralkyl groups substituted by a substituted a b amino group in which one of R and R represents °an aralkyl group and the other of R and R represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-benzyl-N-phenylacetylamino)benzyl or 4-[N-benzyl-N-(4-phenylbutyryl)amino]benzyl groups; xvii) aralkyl groups substituted by a substituted amino group in which one of R a and R represents aralkyl group and the other of R a and Rb represents an aromatic acy- group, such as the 4-(N-benzyl-N-benzoylamino)benzyl or 4-[N-(2-phenylethyl)-N-benzoylamino]benzyl groups; xviii) aralkyl groups substituted by a substituted amino group in which R a and R b both represent aryl groups, which may be the same as or different from each other, such as the 4-diphenylaminobenzyl or 4-[N-(2-naphthyl)-N-phenylamino]benzyl groups; 9 5 0 6 2 2S 0 5040 S- 31 xix) aralkyl groups substituted by a substituted amino group in which one of R a and R b represents an aryl group and the other of R a and Rb represents an aliphatic acyl group, such as the 4-(N-phenyl-N-acetylamino)benzyl or 4-(N-phenyl- N-hexanoylamino)benzyl groups; xx) aralkyl groups substituted by a substituted amino group in which one of R a and R represents an aryl group and the other of Ra and Rb represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-phenyl-N-phenylacetylamino)benzyl or 4-[N-phenyl-N-(4-phenylbutyryl)amino]benzyl groups; xxi) aralkyl groups substituted by a substituted amino group in which one of R and R represents a b an aryl group and the other of R and R represents an aromatic acyl group, such as the 4- (N-phenyl-N-benzoylamino)benzyl groups; xxii) aralkyl groups substituted by a substituted amino group in which R a and R both represent aliphatic acyl groups, which may be the same as or different from each other, such as the 4-diacetylaminobenzyl or 4-(N-butyryl-N-hexanoylamino)benzyl groups; xxiii) aralkyl groups substituted by a substituted amino group in which one of R a and R represents an aliphatic acyl group and the other of R a and R represents an aromatic-substituted aliphatic acyl group, such as the 4-(N-acetyl-N-phenylacetylamino)benzyl or 4-(N-butyryl-N-phenylacetylamino)benzyl groups; 7 1 8 5 4 7 1 0 4 I) MW 32 xxiv) aralkyl groups substituted by a substituted amino group in which one of R a and R b represents an aliphatic acyl group and the other of R a and

R

b represents an aromatic acyl group, such as the 4-(N-acetyl-N-benzoylamino)benzyl or 4-[N-butyryl- N-(2-naphthoyl)amino]benzyl groups; xxv) aralkyl groups substituted by a substituted amino group in which R a and R both represent aromatic-substituted aliphatic acyl groups, which may be the same as or different from each other, such as the 4-(N,N-diphenylacetylamino)benzyl or 4-[N-phenylacetyl-N-(4-phenylbutyryl)amino]benzyl groups; xxvi) aralkyl groups substituted by a substituted amino group in which one of R a and Rb represents an aromatic-substituted aliphatic acyl group and the other of Ra and R represents an aromatic acyl group, such as the 4-(N-phenylacetyl-N-benzoylamino)benzyl or 4-[N-phenylacetyl-N-(2-naphthoyl)amino]benzyl groups; Sxxvii) aralkyl groups substituted by a substituted amino group in which R a and R both represent aromatic acyl groups, which may be the same as or different from each other, such as the 4-dibenzoylaminobenzyl or 4-[N-benzoyl-N-(2-naphthoyl)amino]benzyl groups.

Specific examples of substituted groups derived from the indole, indoline, azaindole, azaindoline, imidazopyridine and imidazopyrimidine rings, each of which is substituted, preferably by from 1 to 3 of substituents a, which may be represented by X, include, for example: 9 5 0 6 1 0 5 4L o A 13 -33 indole ring groups, such as the 3-triphenylrnethylindol-1-yl, l-methylindol-3-yl, l-methylindol-2-yl, 1-ethylindol-2 -yl, 1,2-dimethylindol-3-yl, 3-yl, 1- isopropylindol-3-yl, 2-ethyl- 1-methylindol- 3-yl, 5-methoxy-l-methylindol-3-yl, 5-hydroxy-1,2dimethylindol-3-yl, 5-butoxy-l-methylindol-3-yl, 1,4, 7-trimethylindol-3-yl, 1, 6-dimethylindol-3-yl, 5-bromo-6-chloro-l-methylindol-3 -yl, 3 -yl, 5-hydroxy-l-isobutylindol-3 -yl, 5- fluoro- 1rnethylindol-2-yl, 5-chloro-1-methylindol-2-yl, 5-hydroxy-l-methylindol-2-yl, indol-2-yl, 5-bromo-l-rnethylindol-2-yl, nitroindol-2-yl, 1, 5-dirnethylindol-2-yl, methylindol-2-yl, 5-acetamido-1-methylindol-2-yl, 5-benzamido-l-ethylindol-2-yl, 1-methyl-S-methylaminoindol-2-yl, 5-butylamino-l-methylindol-2-yl, (E-benzoyl-N-methylamino) -1-methylindol-2-yl, 1-methyJ.-5-phenylarninoindol-2-yl, indol-2-yl, 5-benzamido-l-butylindol-2-yl, 4-chloro-l-methylindol-2-yl, 3-methoxy-l-methylindol-2-yl, 6-fluoro-1-methylindol-2-yl, 6-chloro- 1-ethylindol-2-yl, 6-methoxy-l-methylindol-2-yl, 5,6-dimethoxy-l-methylindol-2-yl, 7-methoxyindol- 2-yl, l-methylindol-5-yl, l-methylindol-4-yl, 1-isopropylindol-4-yl and 1-butylindoi-4-yl groups; indoline ring groups, such as the 5-methoxyindolin-1-yl, 1-methylindolin-2-yl, 1-ethylindolin-2-yl, l-propylindolin-2 -yl, 1-butylindolin-2-yl and l-isopropylindolin-2-yl groups; 9 5 0 6 7 1 8 5 4 950 1542 S 3 0 S 0 4 0 34 azaindole ring groups, such as the 1-methyl-7--azaindol-3-yl, 1-isopropyl-7-azaindol- 3-yl, 1-methyl-7-azaindol-2-yl and 1-rnethyl-6azaindol-2-yl groups; azaindoline ring groups, such as the 1-methyl-7-azaindolin-2-yl, I-ethyl-7-azaindolin- 2-yl, 1-isopropyl-7-azaindolin-2-yl and 1-butyl-7azaindol in- 2 -yi groups; imidazopyridine ring groups, such as the 7-methylimidazo[4,5-b]pyridin-2-yl, 1-butylimidazot4,5-b]pyridin-2-yl, 1-methylimidazo[4,5-blpyridin- 2-yl, 1-propylimidazo[4,5-blpyridin-2-yl, 1-methylimidazo[4,5-b]pyridin-2-y., 5-rnethoxy-1methylimidazo[4,5-blpyridin-2-yl, 6,8-dibromoimidazo[1,2-alpyridin-2-yl, 8-hydroxyimidazo- [1,2-alpyridin-2-yl, 6-chloroimidazo[1,2-a]pyridin-2-yl, 2-methylimidazo[1..2-alpyridin-7-yl, 2-ethylimidazo[2.,2-alpyridin-8-yl, 3-methylimidazo- (5,4-bjpyridin-2-yl, 3-ethylimidazo[5,4-blpyridin- 2-yl, 3,7-dirnethyliridazo[5,4-blpyridin-2-yl, 5-chloro-3-methylimidazo[5,4-blpyridin-2-yl, 5-chloro-3-phenylimidazols,4-b]pyridin-2-yl, 5-bromo-2 methylimidazo[5,4-blpyridin-2-yl, 3-methyl-6-trifluoromethylimidazo5,4-blpyridil-2-yl, 3-isopropyl-6-trifluoromethylimidazo[5,4-blpyridil- 2-yl, 3-(3-chlorobenzyl)iuidazo[5,4-b]pyridil-2-yl, 3-benzylimidazo[5,4-blpyridin-2-yl, 3- (4-chiorobenzyl)imidazoll5,4-blpyridin-2-yl, 3-(4-phenylbenzyl)imidazotl5,4-blpyridin-2-yl, 6-bromo-3methylimidazoll5,4-blpyridin-2-yl, 6-bromo-3-ethyliridazo[5,4-blpyridin-2-yl, 6-bromo-3-phenylimidazo- .1 11 0 r.

I I is 1, 4 I) I I 4 I ij j 4 Ii [5,4-bllpyridin-2-y-, 6-chloro-3-methylirnidazo- [5,4-blpyridin-2-yl, 3-butyl-6-chloroimidazo- [5,4-blpyridira-2-yl, 5-methoxy-3-methylirnidazo- [5,4-blpyridin-2-yl, [5,4-blpyridin-2-yl, 5-rethoxy-3-propylimidazo- [5,4-bjpyridin-2-yl, 5-methoxy-3-phenylinidazo- [5,4-bjpyridin-2-yl, [5,4-blpyridin-2-yl, 3-(3-chlorophenyl)-5-methoxyimidazo[5,4-blpyridin-2-yl, 5-hydroxy-3-methylimidazo[5,4-blpyridin-2-yl, imidazo[5,4-blpyridin-2-yl, indazo[5,4-bpyridin-2-yl, 3-phenylimidazo[5,4-b]pyridirl-2-yl, 3- (4-chlorophenyl) imidazo pyridin-2-yl, 3-(3-chloropheayl)irnidazo[5,4-b] pyridin-2-yl, 3- (2-methylphenylj iridazo pyridin-2-yl, 5-chloro-3- (3-chlorophenyl) imidazo- [5,4-b]pyridin-2-yl, 5-rnethoxy-3- (3-methoxyphenyl)imidazo[5,4-blpyridin-2-yl, 5-hydroxy-3,6-dimethylimidazo[5,4-blpyridin-2-yl, 5-methoxy-3,-dinetylimidazo[5,4-b]pyridin-2-yl, 3-methylimidazo[5,4-b] 2,3-dimethylimidazo[5,4-b]pyridia- 5-yl, 3-ethyl-2-methylimidazo[5,4-blpyridin-S-yl, 3-methyl-2-phenylimidazo[5,4-blpyridin-5-yl, 2- 5-di-t-butyl-4-hydroxyphenyl) ethy1] -3-methylimidazo[5,4-b]pyridin-5-y-, 2-(3-chlorophenyl)-3methylimidazo[5,4-blpyridin-5-yl, phenylthioimidazo[5,4-blpyridil-2-yl, 5-butylthio-3methylirnidazo[5,4-blpyridin-2-yl, hydroxyphenylthio) -3-methylimidazo -pyridin- 2-yl, 5-ethoxy-3-methylimidazo[5,4-blpyridil-2-yl, isopropoxy- 3-methylimidazo pyridin- 2-yl, 5-acetoxy-3-metllylimidazo(5,4-blpyridil-2>yl, 3-ethyl-5-phenoxy-6-trifluoromethylimidazo[5,4-b]pyridin-2-yl, 7-chloro-3-methylimidazo[5,4-bI 7 1 a 5 4 iI(1S U 4 0 36 pyridin-2-yl, 7-chloro-3-propylimidazo[5,4-b]pyridin-2-yl, 6-hydroxy-3,j,7-trimethylimidazo- [5,4-blpyridin-2-yl, 3,5,7-trimethyl-6-nitroimidazo- [5,4-blpyridin-2-yl, 6-amino-3,5,7-trimethylimi-dazo- [5,4-b]pyridin-2-%yl, [5.4-b]pyridin-2-yl, 5-dimethylamino-3-methylamino) -3-methylirnidazo(5,4-blpyridin-2-y1, 3-methyl- 5-phenylaininoiLmidazo[5,4-blpyridil-2-yl, amino-3-methylimidazo[5,4-blpyridin-2-yl, (N-ethyl-N-phenylamino) -3-methylimidazo pyridin-2-yl, 5-acetamido-3-methylimidazo pyridin-2-yl, 5-benzoylamino-3-methylimidazo[5,4-b] pyridin-2-yl, 3-methyl-6-nitroimidazo[5,4-blpyridil- 2-yl, 6-amino-3-methylimidazo[5,4-blpyridil-2-yl, 6-benzoylamino-3-methylimidazo[5,4-b]pyridil-2-yl, 6 -valeryl -3 -butylimidazo pyridin- 2-yl, -benzyloxy- 3-methylimidazo pyridin- 2-yl, 2-hydroxy-3-methylimidazo5,4-bpyrdi-5-yl, 2-hydroxy-3H-irnidazo[5,4-blpyridil-5-yl, 2-hydroxy- 3-phenylimidazo[5,4-b]pyridil-5-yl, 2-methyithia- 3H-imidazo[5,4-blpyridin-5-yl, 3-methyl-2-methylthioimidazo[5,4-blpyridil-5-yl, 3-benzyl-2-butylthioimidazo[5,4-blpyridil-5-yl, 5-t-butylanino-3methylimidazo[5,4-blpyridil-2-yl, 5-t.-butylamino-3propylimidaz7o[5,4-blpyridil-2-Yl, 3,5,7-trinethylimidazo[5,4-blroyridin-2-yl, 3-(3-chlorophenyl)-5,7dimethylimidazo[5,4-blpyridil-2-yl, 3-(3,5-di-tbutyL 4-hydroxybenzyl) -5,7-dimethylimidazo pyridin-2-yl, 5-acetoxy-3-methylimidazo[5,4-b]pyridin-2-yl, 5-acetoxy-3-ethylimidazo(b,4-b] pyridin-2-yl, 6-methoxy-3-methylimidazo(5,4-c] pyridin-2-yl, l-methylimidazo[4,5-clpYridil- 2 -y 1 l-butylimidazo[4,5-clpyridil-2-yl groups; IBIIIPII~ IPe~sllllR- O- 95S06 71 85 2530 95040 37 imidazopyrimidine ring groups, such as the 3- methylimidazo[5,4-d]pyrimidin-2-yl, 3-ethylimidazo[5,4-d]pyrimidin-2-yl and 3-(3-methylbenzyl)imidazo[5,4-d]pyrimidin-2-yl groups.

Of the compounds of AU 683348, we prefer those compounds of formula and salts thereof, in which: (Al) X represents an indolyl, indolinyl, azaindolyl, imidazopyridyl or imidazopyrimidinyl group, which is unsubstituted or is substituted by from 1 to 3 of substituents a, defined below; substituent a represents an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, an alkylthio group having from 1 to 4 carbon atoms, a trifluoromethyl group, a nitro Sa b group, an amino group of formula -NR R rua-a b wherein R and R are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, an aralkyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aliphatic acyl group having from 1 to 11 carbon atoms, an aryl-substituted aliphatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to 10 carbon atoms which is unsubstituted or is substituted by at least one substituent selected from the group consisting of -4 9 5 0 6 7 1 8 5 4 S 1 0.1 N0 4 W 38 substituents 3, said substituent P 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 an amino group of formula -NRaRb, wherein R a and Rb are as defined above, provided that, if R a or R b represents an aryl group or represents a group including an aryl group, that aryl group is not itself further substituted by a group of formula -NRaRb; or an aralkyl group having from 7 to 11 carbon atoms which is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents p; and/or (A2) Y represents an oxygen or sulfur atom; and/or (A3) Z represents a 2,4-dioxothiazolidin-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxo- 3,5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group; and/or (A4) R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms or a halogen atom; -bI I is 1 S 1 1 i I) 4 0 39 and/or m is an integer of from 1 to and especially compounds in which X is as defined in Y is as defined in Z is as defined in (A3), R is as defined in (A4) and m is as defined in More preferred compounds of the present invention are those compounds of formula and salts thereof, in which: (Bl) X represents an indolyl, indolinyl, imidazopyridyl or imidazopyrimidinyl group, which is unsubstituted or is substituted by from 1 to 3 of substituents a, defined below; substituent a represents an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, a Sphenylthio group, an alkylthio group having from 1 to 4 carbon atoms, a trifluoromethyl group, a nitro ab group, an amino group of formula -NR aR wherein R a and R b are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, an aralkyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aliphatic acyl group having from 1 to 11 carbon atoms, an aromatic-substituted aliphatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms,

_ME"

9 5 06 7 1 5 4 2rO6 S 1 0 2 O 5 40 an aryl group having from 6 to 10 carbon atoms which is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents 3, substituent ;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 an amino group of formula -NRaR b wherein R a and R are as defined above, or an aralkyl group having from 7 to 11 carbon atoms which is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents p; e and/or (B2) Y represents an oxygen atom; and/or (B3) Z represents a 2,4-dioxothiazolidin-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl or 2,4,-dioxooxazolidin- 5-ylmethyl group; and/or (B4) R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms or a halogen atom; and/or and/or m is an integer of from 1 to 9506 7 1854 2530 95040 MW 41 and especially compounds in which X is as defined in Y is as defined in Z is as defined in (B3), R is as defined in (B4) and m is as defined in Still more preferred compounds of the present invention are those compounds of formula and salts thereof, in which: (Cl) X represents an indolyl, indolinyl or imidazopyridyl group, which is unsubstituted or is substituted by from 1 to 3 of substituents a, defined below; substituent a represents an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, an alkylthio group having from 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, an amino group of formula -NRaR b wherein Ra db wherein R a and R are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, an aralkyl group having from 7 to 11 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aliphatic acyl group having from 1 to 11 carbon atoms, an aromatic-substituted alphatic acyl group having from 8 to 12 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms, an aryl group having from E to 10 carbon atoms which is unsubstituted or is substituted by from 1 to 3 substituents selected from the group consisting of substituents 3, I 9506 71854 2530 95040 42 substituent p 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 an amino group of formula -NRR b wherein R a and R are as defined above, or an aralkyl group having from 7 to 11 carbon atoms which is unsubstituted or is substituted by from 1 to 3 substituents selected from the group consisting of substituents p; and/or (C2) Y represents an oxygen atom; and/or (C3) Z represents a 2,4-dioxothiazolidin-5-ylidenylmethyl or 2,4-dioxothiazolidin-5-ylmethyl group; and/or (C4) R represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom; and/or m is an integer of from 1 to and especially compounds in which X is as defined in Y is as defined in Z is as defined in (C3), R is as defined in (C4) and m is as defined in (CS).

Still more preferred compounds of AU 683348 are those %rur~OBsBsl~s~nrrBRIl~l~ 9 06 71854 S530 95040 43 compounds of formula and salts thereof, in which: (D1) X represents an indolinyl or imidazopyridyl group, which is unsubstituted or is substituted by from 1 to 3 of substituents a, defined below; substituent a represents an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a phenylthio group, an alkylthio group having from 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group; and/or (D2) Y represents an oxygen atom; and/or (D3) Z represents a 2,4-dioxothiazolidin-5-ylmethyl group; and/or (D4) R represents a hydrogen atom or a methoxy group; and/or m is an integer of from 1 to and especially compounds in which X is as defined in Y is as defined in Z is as defined in (D3), R is as defined in (D4) and m is as defined in o r r r s r e The most preferred compounds of AU 683348 ~-Yaa I SS 0 S71 54 2530 95040 44 invention are those compounds of formula and salts thereof, in which: (El) X represents an imidazopyridyl group, which is unsubstituted or is substituted by from 1 to 3 of substituents a, defined below; substituent a represents a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group or a phenyl group; and/or (E2) Y represents an oxygen atom; and/or (E3) Z represents a 2,4-dioxothiazolidin-5-ylmethyl S* group; and/or R represents a hydrogen atom; and/or (E4) R represents a hydrogen atom; and/or m is an integer of from 1 to and especially compounds in which X is as defined in Y is as defined in Z is as defined in (E3), R is as defined in (E4) and m is as defined in The compounds of AU 683348 each contains

I-

9 5 0 71 54 2530 9S040 45 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 unacceptably 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, trifluorometh'anesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids, such as benzenesulfonic acid or g-toluenesulfonic 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 AU 683348 can be converted into a salt with a base by conventional methods. Examples of such salts include: salts with an alkali metal, such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or calcium; and salts with another metal, such as magnesium or aluminum. We prefer the pharmaceutically acceptable Ili~DP~B~a~Ln~aRli~nrr~nap-- 9 06 7 1 5 4 2 530 95040 46 salts.

The compounds of formula can exist in the form of various isomers due to the presence of asymmetric carbon atoms. Thus, where an indoline or azaindoline ring is substituted at the 2- or 3-position, the carbon atoms at these positions are asymmetric and, where Z represents a 2,4-dioxoor 2,4-dioxooxazolidin-5-ylmethyl group, the carbon atom at the 5-position is asymmetric.

Although these isomers are all 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 resolution techniques.

The compounds of formula wherein Z represents a 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxothiazolidin-5ylidenylmethyl, 2,4-dioxooxazolidin-5-ylmethyl or 3,5-dioxooxadiazolidin-2-ylmethyl group can exist in the form of various tautomeric isomers as shown in the following schemes a, p, y and 6, respectively: «b ar 1 ~"lsa 9 9 5 0 6 7 L 8 5 4 950 5L5 30o 9 50 47 Scheme a -CH2 OH ST N

-CH

2 0

OH

-CH2 OH S NH 0 4

-CH

2

OH

OH

Scheme L -wH S N

OH

4l S yNH 0 -CH OH

H\<

S N 9 5 0 6 950571 7 5 4 Sd 1 5 0 4 0 48 Scheme Y -CH 2 OH O -CH2 0

OH

-CH2 OH O NH 0Y Scheme 35 CH, 0 S0 yNH

-CH

2

OH

H

OOH

N

S0 N

N

-CH2 0 O IN

OH

9506 71~0 4 2530 950 0 49 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 Moreover, AU 683348 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.

AU 683348 also embraces all compounds which could be converted in the living mammalian, for example human, body to a compound of formula or a salt thereof by the action of the metabolism, that is so-called "pro-drugs" of the compounds of formula and salts thereof.

e e..

I p I-srl~- Lp 31311s Examples of certain compounds of AUI 683348 are given the following formulae to 0 (1-2) 0 NH 0 up OUI. 1. X-(CH2)--Y

X-(CH

2 )m Y' (1-4)

I

r o o In the above formulae, the substituents are as defined in the following one of Tables I to 5, respectively. That is, Table 1 relates to formula Table 2 relates to formula (Iand so on to Table 5, which relates to formula In the Tables, the following abbreviations are used: r acetyl butyl isobutyl t-butyl benzyl ethyl methyl phenyl propyl isopropyl propionyl FP.9'6 71X4 V ~~nlr ~r l I I A AAQ'; Table I Cpd. x Y m R No. 110 2 H

N

1-2 02 H

ON

H

1-3 CPh 3 0 2 H 1-4 O N0 2 H Me 0 1 H

N

H

1-6 0 1H

N

Me 1-7 02 H Me 1-8 0 1 H Et

S.

FP-95G6 71854 FP90 84ywdodgtss5O6ocscpdIst I 06,04i95 'Fable I (cont.) Cpd. X y No. 1-9 0

N

1-10 eo Mee 111 MHO 0 N M Me 1-12 O

N

1-13 N E S Me FP-9506 71854 FP-50 7134y:\%pdoes~dgt niss56kiocscpdltst 1 06 04,95 4 *4 0 0 Table I Cpd. X V m R No. 1-16 BOCX0 1 H

N

Me 1-17 Me S 4 Cl 4N Me Me 1-18 0 3 OH Me N Me 1-19 Br S 2 Bu Me 1-20 Br/ 0 5 H

N

I

1-21 HO 0 1 H

N

IBu 1-22 F0 1 H

N

Me 4 FP-9306 71854 FP.906 7854vdocWd~t tmss'9SO6'ocswrxlhstl 0~6 04'95 Table I (cont.) o FP-9506 71954 FP.50 154yocs'dgt nmm~95G6\ox3'cpdhst 1 06 04,95 Table I (cont.) Cpd. X Y m R No. 1-30 AcHNJ N 0 1 H Me 1-31 0 0 1 H Et 1-32 H 01H MeN Me 1-33 H 0 1H Bu-N Me 1-34 Me 01H Bz-N Me 1-35 H 01H Ph-N

N

Me S 1:11-9506 71854 FP.906 185 rms9~6'dcsd 06 416 Table 1 (cont.) Cpd. X Y m R 1-36 AcHN S? Me

H

1-37 0 0 4, Meo

N

Me 1-39 SOme 0 1 H

N

Me 1-40 0 1 H Me 1-41 0 2 cI 1-42 01H

I

MeOMN Table 1 (conU} Cpd. xY No. 1-43 MeO 0 MeODO N Me 1-44S MeO H 1-450

N

H

Me 14'70 FP-9506 71854 FP~9SO6 7,V4 y T4powSdgt nw1056docs~cpls-A 0)6041)5 59 Table 1 (cont.)

V

Cpd. __ym No. 1-50 0 1 H

N

I-

1-51 0 1 H

N

Me 1-52 0 2 H

N

Me 1-53 0 2 Me

N

iwr 1-54 S 3 H

N

flu 1-55 01MeO

N

Me FP 9506 71854 PP ~O6 854y pdocsdgt nws.05O6Axs.pIlstt 04,95 Table I (cont.) a FP-9 506 'rable I (cont.) a.

a.

a FP-W6 71RS4 FI.',O 71854Ae nvti6 xi.d t #6 01119 62 Table I (cont.) 9 U 1-70 0 toCI

N

Me 1-71 0 1 H ivr 1-72 0 2 H

NN

1-73 S3H 1-74 0 4 H

NNJ

1-75 Ir0 1 H N N

H

1-76 0 3 H N' N

H

1-77

.OIH

N N Me 63 Table 1 (cont.) No. XJYm 1-78 0 2 H N N Me 1-79 S 3 Me -'4 CN XN Me 1-80 0 2 C N N tPr 1-81 a _0 1 H

N)

N N Me 1-82 0 2 H N N

H

1-84

SIH

N N Me 1-85 02H N

N

Me 171 RU~ I m A- -11-i I flo, III In 64 Table I (cont.) Cpd. X Ym

R

1-86 0 1H CN N 1-87 0 1Me N N 1T-88 S4

H

N N bu 1-89 -N 0 2 H N N2 1-3 ~S 3 H

NJ

1-N H 0 1H N N 1-2Me 0 2

H

NN N

H

NN

N

Me d 140 D It- P bt,~4944 mom Table 1 (cont.) S S *5 a S a Cpd. X Ym R 1-94 N u 0 1 H N N; 1-95 N "me 0 1Me N N N

N

1-96 N Me I H N

N;

1-97 Pr S 5 H N N'- 1-98 NAe 0 3 H N N 1-990 -NMe 0 4 MeI N N 1-100 N 2 14

N'N

1-102

H

NN N Me FP-9506 71854 FP956 184ywpdocadgt nw9506'Zoescpdiist I G604,95 Table I (cont.) Cpd. X x No.

o 5 0

S

1-103 0 2 H

N=N

Me 1-104 0 2 H

N

NJ N~1 1-105 0 4 H

N

NJ Ni 1-106 0 1 H

N

1-107 0 2 H

N

1-108 Br N0 3 H

N

Br 1-109

-N

N

1-110 0 1 H

N

OH

1-111 0 1 H C I N

N

119113 -I I oc, It 4 -I 1 .11 OC 67 Table 1 (cont.1 Cpd. X No.

1-112 c

N

1-113 N

N

1-114 NN N

N

1-115 0~

N

1-116 -s N "Me 1-1180 FP-9506 71854 yP.9506 7154 yds\ 506docsdist 06 04,95 68 Table I (cont.) a a FP-9506 71854 FP-9S0 1854y Vqkx3dgt msas9O6'docsicpdtst 06 0R 4-95 69 Table 1 (cont.) Cpd. x

Y

1-129

N

NN

N N Et 1-130 CF 3 0

NN

N

N)

Me 1131 C F 3 N

NK"

iPr .:1-132 Nr' 1-133N N kT 7W4 tn~4Vlss 9106'kw- II~st (1 049 Table 1. (Cont.) Cpd. x Y in R 1-136 N0 3 H- 1-137 0 1 H Br,,

N,

N Me 1-138 0 3 H Et 1-139 S MeG Br N N N'- Ph :1-140 0 1H N NK" Me *1-141 0i N 1-142 N0 1H MeG N Njt Me FP-9506 7M84 v N~do<sd6,t rnus9506do'cpdtisi2 000495 71 Table I (cont.) Cpd. X Y r R 1-143 0 1H MeG CN N'- 1-144 0 1 H MeG N N Pr 1-145 0 2H MeG N N

I

Me 1-146 N0 3H *MeG N N Me 1-147 N 1 H MeG N Nk Ph 1-148 N 0 1 H MeG N N)- Bz 1-149 N MeG N Nk Me FP-9506 71854 %k-pd~v$sdgt rnvs 9506d'A-dlst2 06 04,95

C

Table I (cont.) Cpd. x Y m R No. 1-150 0 1 Me MeO

N

Me 1-15 1 M e 0 MeO N N 1-152 0 3 H MeO"I"N N' mt-Ct)h 1-153 0 1 H HO N Nk Me 1-154 0 1 H HO N 1-155 0 1 HO N N' 1-156 0 1 H HON N Me 1-157

N

I

'N

L

FP-M6 71854 FP-9~~ 5061154s xjocsdgt rnm9506',docscpoltst2 06 04 Table I (cont.) a 9 0* 5000 S S

S

FP-006 71854 FP-9S06 7834 v wpocsdJgtIiss 9506oScpiIhst 060495 Table 1 (cont.) a. a a.

ta

S.

S S Cpd. X Y rn R No. 1-165 0 1 H N N

N

rn-C IPh 1-166 0 1 H N I N 1-167 0 3 H Cl N Nk m-CIPh 1-168 0 1 H MeO N Nj~ rn-MeOIh 1-169 Me0 1 H

N

HO N~ N- Me 1-7 e0 1 H 1-170 Me NI N I I Me 1-171 0 2H N

NY

Me FP-9506 71854 FP.906 854y pdocdgt ,nwl9506ocs -pdhi~t2 06 04 Table I (cont.) Cpd. X No. 1-172N SN N Me Me 1-173N N NIMe ht 1-174N N N' Ph Me 1-175 tBu

N

N N I tBu Me S* 1-176N

N'N

N N rn-CIPh Me 1-177 PhS" N N FP-9506 7 5 71"4 %kpdNsdgt ntrs9M6,dosA.Whsl2 0(104 9 Table I (cont.) Cpd. X Y m R No. 1-179 0 1 1- Ph J:;N N Me 1-180 03H Ph" N N Me 1-181 0 1 H tBu N

I

Me tBu 1-182 0 1 H EtO' N N3 Me 1-183 0 1 H iPrO" N

N_

Me 84 M eO 01H N N l Me 1-185 0 1 H N

N

AcO N

I

Me H-006 %06 pdlvsdgt Ws90).kip~~2 1'f49'5 Table I (cont.)

N

Pr 1-190 02

I

Me 1-191 Me0

HON

Me N N Me [11-9506 71854 y. wpTdosdniss9506doa~Pdist2 06,04 78 Table I (cont.) Cp.xY m R 1-9 e0 2 H Me N N Me 1-193 Me 0 1 H

N

N

Me~ N N Me 1-194 Me C, 1 H

H

2 N

N

Me N N Me 1-195 0 1 H

N

MeNH N Nk Me 1-196 0 1 H Me 2 N N' Me 1-197 0 1 H Bu

\N

Et' Me 1-198 0 1 H PhH"( N"

I

Me FP-9506 71854 FP.50 7154y:,%pdocs~dg~trnsO506\doc\cpdlist2 06 04.95

I

79 Table I (cont.)

S

S.

FP-9506 71854 FP-50 134ypdocs'dgttns\9506\docs\cpdlist2 06,04195 Table I (cont.) Cpd. x Y m R No. 1 -2 06 BuCONH S2 1 N N Bu 1-207

N

BzO" N N Me 1-208 S 1H BzO' N Nl' Me 1-209 N0 2 H N N, OH Me 1-210 N0 2 H N N OH H 1-211 N0 2 H N N OH Ph 1-212 N0 2 H N N SMe

H

FP-9506714 71854 y, %pdocs~dgtnissO5 061docs\L0d ist 2 0604 81 Table I (cont.) Cpd. x Y i R No. 1-213 N0 2 F ",rNT N N N SMe Me 1-214 N0 2 H N N SBu 1-215 0 1H tBuNH' NNi Me 1-216 0 1H tBuN-~ N N'Y" Pr 1-217 S1 H tBuN-HN'N Me 1-218 Me 0 1H

N

Me NN Me 1-219 Me 0 1H Me N N mCIPh

C

C

C C C. CC C C

C

FP-9506 71854 I0 7184 pdoes'dgtmnss\Sj 06 docs'icpdjitst 2 06 0493 W Table 1 (cont.) Cpd. x No.

1-220 Me

-N

Me N N tBu

OH

tBu 1-221N AcO'- N Nl' Me 1-222N ::AcO 'N N' ht FP-9506 71854 FP.S0 7154y.,%%xiocsdgtrniss'\906\docs,,pdMist2 06 04 83 Table 2 Cpd. X Y m R 2-1 0 2 H 2-2 0 2 H

N

2-4 ~h 0 2 H

N

Me 0 1 H

N

H

2-6 01H

N

Me 2-8 0 1 H

N

ht a.

FP-9506 71854 FP90 784y:\wp dotgtrnss\9506 ,docs\cTpdliSt3 06,04195 84 Table 2 (cont.) Cpd. x

Y

2-90

BZ

2-10 MeO 0 N me Me 2-11 HO 0

N

Me 2-12 s

N)N

tPr 2-13 0 U*N Et Me *2-14 Me o. Me I

N

U*

U FP-9506 71854 FP9 067154y:%% docs~dgtnis\9506dos'Cpdolist3 06104i95 Table 2 (cont.) Cpd. x Y No. 2-16 BuO 0

N

Me 2-17 Me S Me Mve 2-18 0 Me N Me 2-19 Br S a..Cl N Me .:2-20 Br 0

N

H

2-21 HO0 FP-9506 71854 FP.9506 1854 yNpdocs\dgtmss9506docs'codist3 06,04195 86 Table 2 (con t.) Cpd. x Y m R No. 2-23 c, 0 1 H- Me 2-24 HO0 1 H

N

Me 2-25 MeO"a 0 1 H

N

Me 2-26 Br 0 1 H

NJN

Me 2-27 0Na0 1 H

N

t 2-28 Me,_ 0 1 H

N

Me 2-29 H 2 N 0 1 H

N

Me FP-9506 71854 FP-y: I15 wpdocsW gtrniss 9506docs cpLAist3 06,04;95 87 Table 2 (cont.) Cpd. X Y m R No. 2-30 AcHN 0 1 H

N

Me 2-31 0 01H

IN

Et 2-32 Mfe 2 N 1 H

N

Me 2-33 H 0 1H Bu-N Me 2-34 Me 0 1H Bz-N a N Me 2-35 H0 1 H P h- N

N

Me 4 *4 4 FP-9506 71854 FP-906 7854y:\wkpdocs',dgtrnss'9506docs:cpdIist3 06 04.93 88 Table 2 (con t.) Cpd. X Y m R 2-36 AcNH S 2 Me

H

2-37 -o0 4 MeO Hu 2-38 ci 0 1 H

N

Me 2-39 OMe 0 1H

N

tl~u 2-40 0 1 H

FN

Me 2-41 0 2 cI CI N Et 2-42 0 1 H MeOj,- N Me C S FP-9506 71854 FP-95y: 7154doswdgtrnsW5906docs plist 3 06,04,95 Table 2 (cont.) 9* FP-950o 71854 FP95o 184y:wpdoocsldgtniss9S06\do\cspdist3 06x04,93 Table 2 (cont.) FP-9506 71854 FP9 06715y,,%pdo-dgtns\9506dosCNdliSt3 06 04 Table 2 (cont.) 7,1854 y iNTpdocsldgt -"ss\956dcCdist3 06 04'95 92 Table 2 (cont.) Ce

S

FP-9506 71854 FP-906 7854ypdocs\dgt ss95O6dmcpis3 060495 Table 2 (cont.) FP.9506 71854 F P.956 7I:5 'wdoesdgt_ rss\95o6\docs\Ldist3 06 04;95 94 Table 2 (cont.) Cpd. x Y No. 2-78 0 N N Me 2-79

S

NN

Me 2-80 0 N *2-82 0

NI

*N

N

Me 2-83 Me,, 0 FP-9506 7i854 FP.S0 7154y:w%%pdocdgtni\956osL*dhst3 06.04 Trable 2 (cont.) Cpd. X Y m R No. 2-85 0 2 H N

N

Me 2-86 01H N N N

N)

2-88 0 1HM

KN

2-98 S 4 H N N 2-91N I 0 2 H N N 2-92 Me S 3 H 2-91I

HN

N IN F!'-9506 71854 F!'-956 854ydocs\dgt -niss\9506docs\LNpI isQ~ 06 0495 96 Table 2 (cont.)

C

C

Cpd. X Y m R 2-93 Me0 1 H

IN

N N 2-94 Bu 0 1 H N N 2-95 aK N NMe 0 1 Me N N) 2-96 NMe 1 H N N'J 2-97 PrS 5 H 2-98 N Me 0 3 H N N MeG N N; 2-990 N Me 0 4 2-101X 0

N

FP-9506 71854 FP.50 154y kpdocsdgtrnis\9506\docscpdlist3 06.04,95 97 Table 2 (con t.) Cpd. x Y In R No. 2-102 0 1 H

N

Me 2-103 0 2 H

N

Me 2-104 0 2 H-

NN

N

2-105 0 4 H

N

2-106 0 1 H

N

2-107 Me0 2 H

N

2-108 Br" N 0 3 H

N

Br 2-109 a NS I H

N

FP-9506 71854 y ,%vpdocs,,dgtrnss,9506,doc scpist3 06 0495 o *0*s 0o* *0 *0 a a 0 0* S 4

S.

0000 Table 2 (cont.) Cpd. X Y m R No. 2-110 0 1 H

N

OH

2-111 0 1 H

N

2-112 0 2 H

N

2-113 S I H

N

2-114 0 1 H

N

2-115 0 3 H

N

2-116 0 1 H

~N

N Me 2-117 S 2 H N Me 2-118 0 1 H

N

FP-9506 71854 FP9 067154y:X %xjocsdgt rnss\9S06',docs\,cpdlist3 06 04,95 99 Table 2 (con t.) Cpd. X Y Mn R No. 2-119 0 5 Me N' N 2-120 0 1 MeO N' Et V V FP-9506 71854 FP.9506 7184 'wdocsdgtniss\95O6docs\qxdlist3 06.04,95 56tO 90 SI 06d t,58 IL 900-dJ 001 101 Table 3 (con t.) Cpd. x Y m R No. 3-9 O N0 3 MeG

N

Me 3-10 MeG 0 1 H aNlMe Me 3-11 HO 0 5 Me

N

Me 3-12 S I H

N

i~r 3-13 jpro 0 2 MeG N Et Me *3-14 MeG 0 1 H- Me'_ 3-15 HO, I 0 1H N Me Me FP-9506 71854 ,.,"Tdocs\dt _nw0\506\dd is t4 060495 102 Table 3 (con t.) Cpd. x Y No. 3-16 BuO 0

N

Me 3-17 Me S 4N Me Me 3-18 0 Me N Me 3-19 Br S c I N Me Br- 0 N. N

H

3-21 HOy 0 FP-9506 71854 FP- 50 j54y pdocsvdgt rns\9506'docs\cpdlist4 06 04 103 Table 3 (con t.) Cpd. x Y No. 3-23 C .0 c

N

Me 3-24

HO

N

Me 3-25 MeO 0 'N N Me 3-26 BrS

N

3-27 Mee o N a Me FP-9506 71854 FP- 50 7154y: %vpdocs~dgtrnss\9506\docs~cpdIist4 0604,95 104 Table 3 (cont.) Cpd. X Y No. 3-30 AcNHa 0 Me 3-31 0 0

NH

3-32 MeNH 0 Me 3-3H 0 Bu-N Me 3-34 m 0 FP-9506 71854 FP.9506dt~sOS6,dcsc~it 714064i95 "fable 3 (cont.) Cpd. X Y rn R 3-36 AcNH,:X S 2 Me

N

H

3-37 0 0 4 MeG

NHN

Liu 3-38 ci 0 5 H

N

Me 3-39 Me0 1 H

N

Me 3-4001H F' N Me 3-41 02 cI Cl' N Et 3-42 0 1 H

S-

I '1854 I 71S54 y.,%vpdocsdgt, niss95U6dm.ssApdist4 009 060495 106 Table 3 (cont.) Cpd. x Y Mn R 3-3 MeO 0 47 H MeOD oN Me 3-44 S I H MeG H 3-45 0 1 H

N

H

3-46 0 1H

N

Me 3-47 0 2 H iBu 3-48 S1 Me

N

Et 3-49 51 0 4 Me S FP-9506 71854 5P90 7184 ywpocsd-gt nts56,os~it 06 04 107 Table 3 (cont.) Cpd. X Y Mn R No. 3-50 0 1 H

N

H

3-51 0 1 H

N

Me 3-52 0 2 H 6N Me 3-53 02 Me

N

Pr 3-54 S3 H

N

3-55 0 1 MeG

N

Me a 0* a FP-9506 71854 FP-95v 71i y: pdocs~dgt, mssx9kl5tJ6\docscpdlist4 06 04 Table 3 (cont.) Cpd. X Y m R No. 3-56 N6S I H 0 2

N

N

Me 3-57 0 2 H

N

3-8 MeO 0 4 Me 3-59 O N0 1 H

H

3-61 0 2 H

N

H

3-62 M 3 H

N

H

Me S S

S

FP-9506 71854 FP.906 7854y: %%pdos~dgtrni.s\9S6\ocscpdlist4 060O4,95 How 109 Table 3 (cont.) Cpd. X Y m R No. 3-63 O N0 2 H Me__ 3-64 0 3 H Me 3-65

SIH

N

Me 3-66

H

N

ht 3-67 CL0 2 MeG

N

Pr 3-68 01H 3-69 S 5 H Me FP-9506 71854 FP956 184:\%kpdocsdgtTisX906docs~Cqlist4 06,04,:95 110 Table 3 (con t.) Cpd. X Y m R No. 3 -70 e 2 N 0 1C Me 3-71 a _0 1 H

N)

iPr 3-72 0 2 H

NN

3-73 S3H

N

3-74 0 4 H

NN

3-75 0 1 H N N

H

3-76 0 3 if1 N N

H

3-77 0 1 H N N

N

Me So..

0O S 0* 5 5.0.

0* SO S S 5 FP-9506 71854 FP.50 154ydxoc~sdgtA rns0~5061,docs',Ldlist4 (1604

III

Table 3 (cont.) Cpd. x Y m R No. 3-78 0 2 H N N Me 3-79 S 3 Me

CN'N

Me 3-80 0 2 cI iPr 3-81 0 1 H N N Me 3-8 0 2

H

3-82a

N)

Me 3-83C0H N N

H

3-84 Me S1

H

N N Me FP-9506 71854 PP.950y 71854,)dosdgt jms9506'dslL~'dlist4 060(N Table 3_(cont.I Cpd. X y m R 3-85 0 2 H Me 3-86 0 1 H

N

3-87 01Me

CN'N

:.3-88 me S4 H N N 1~3-89 x x02 H 3-90 x NS 3 H 3-91 H1H

N

N N 3-92 Me 02 H

NN

N N rrv.,uuC ocsndnstt nms,95W6docs Lt~list4 060495 rr-,f-,vo 113 Table 3 (cont.) Cpd. X Y m R No. 3-93 Me0 1 H CN 'N 3-9 u 1 N N 3-954M 0 1 Me

NN

N N 3-97 0 1 MeF

IN

396 Me1H N

N

N N

N

3-981 0 3 H

N

FP-9506 71854 FP956 184y:,%%,dcd~tntss 9506\docs\cpdiast4 06,04,95

S

114 Table 3 (con t.) Cpd. x Y rni No. 3-102

N

Me 3-103 0 2 H N4=N

N

3-106 0 2 H N o 3-1075M 0 2 H

N

3-106 a 0 3 H

N

N

FP-9506 71854 FP956 84y pdocs\dgtrnssx95O6docs\cpdist4 06 04:95 115 Table 3 (con t.) *0 4 Cpd. x Y Mn R No. -3-110 0 1 H

N

OH

3-111 0 1 H

N

3-112 0 2 H 3-113 S 1 H

N

3-114 0 1 H 3-115- N

N

3-116 0 3 H a"N 3-118 0 1 H

N

4 a 4 4 FP-9506 71854 FP-50 7154v:'xpdos -gt nss006dcsu.Nh,.st4 0604 Table 3 (con t.) Cpd. X Y Mn R No. 3-119 0 5 Me

SN

N'

3-120 0 1 MeO N Et

I..

S S S C, FP-9506 71854 FP.50 154y docsdgt _nw, 9SO6docpdlist4 06 04,95 Table 4 Cpd. X Y m R No. 4-1 0 2 H 4-2 0 2 H I I

H

4- CPh 3 02H

N

4-4 O N0 2 H

I

Me 0 0 1 H

N

H

4-6 O N0 1 H Me 4-7 0 0 Me 4-8 01H Nt FP-9506 71854 FP-9 50 71854y:-%pdocs~gl =03\906\docs~.cpdis13 06 04 93 Table 4 (cont.) Cpd. x Ym R No.- 4-9 0 3 H 3-PhPr 4-10 mcO 0 1 H Me 4-11 HO 0 5 Me

N

Me 4-12 S I H

N

iPr 4-13 O t 0 2 MeG Me 4-14 MeoGa 0 1 H ~Me 4-15 HO-0 1 H 6 FII-9506 71854 FP950 184y:\wpdxoc\dgtmss\9 506docs~cNI ist5 06.04j'95 11i9 Table 4 (cont.) 1 4 4-16 BUO 0 1H

N

Me 4-7Me S 4 cI

N

Me Me 4-18 0 3 OH Me N 4-19 Br S 2 Bu S I Me 4-20 Br.1 0 5 H

N

H

4-21 HO 0 1H

N

ibu 4-22 F 01H S N Me "Y I R54 'I5 %%Tdcs dgt-tt\9SO6osLpdit5 06 04.95 Table 4 (cont.) FP-9506 71854 FP-9506 T854 y ~dgtn 956docsC4dlist5 06 04 121 Table 4 (cont.) Cpd. x

Y

No. 4-30 AcNH 0 Me 4-31 /E 0

N

4-32 BZH0

N

Me .4-33 H- 0 Bu-N Me 4-34 M 0 Bz-N I FP-9506 71854 FP-9506 71S4 ~docs\dgtmtts\506\dcs Cqdl isI 06 04,95 maw 122 Table 4 (con t.) Cpd. x Y No. 4-36 AcNHS

H

4-37 0 0

-IJ

N

4-39 Cl 0

N

Me L__ S..4-390 0

FN

Me FP-9506 71854 FP.50 7154y:wpdocs 'dgtnis'9506doscpdlist5 06 04,95 123 Table 4 (cont.) FP-9506 71854 FP9 07154y wpdrocsdJgtrnss906docs~cpdlistS 06 04'95 124 Table 4 (cont.) Cpd. X Y M R No. 4-50 0 1 H-

N

H

4-51 0 1 H

N

Me 4-52 0 2 H

N

Me 4-53 0 2 Me

N

i~r 4-54 S3 H

SN

Bu 4-55 0 1 MeO

N

Me FP-9506 71854 PP.906 S54ydocs~gt nt&0\5G6Adocsxcpdhst5 06 04'95 125 Table 4 (cont.) Cpd. X Y m R No. 4-56 S 2 H

N

4-57 0 2 H

N

4-8mo0 4 Me 4-59 0 1 H

KN

H

N0 2 H- 4-610

N

I

H

4-62 O N0 1 H Me FP-9506 71854 FP-9506 7184 pdcdgt twss9506'&cs',qdltst5 06 049q5 Table 4 (con t.)

V

FIV-9506 71854 iP.956 7184 Jt.sdgt nmss,9506'docscpdhsA 06 04 Table 4 (con t.) Cpd. X Y m R No. 4-70 0 1 CI

N

Me 4-71 0 1 H

N

i~r 4-72 5 0 2 H N 4-.73 S 3 H

N'N

*4.-74 0 4 H N N 4-75 01H

II

4-7 CN N

H

4-76 0 3 H

N

N N

I

Me FP-9506 71854 y: N~xlocsdgt nu9506dosv~piist5 06 04 128 Table 4 (cont.) Cpd. X Y m R No. 4-78 0 2

NI

Me 4-79 S 3 Me N N Me 4-80 0 2 Cl CN N T~r 4-81 0 1 H *N NJ" Me 4-20 2 H N

N,

Me 4-30 1 Et

N

H

4-84 S I H N N Me 5*

S

FP-9506 71854 PP.9506 715 pdosdgtnsO5o6docscpdlist5 06 0495 129 Table 4 (con t.) 044* V C 9* 0* 59 9* S S

S

Cpd. x Y m R No. 4-85 0 2 H N N Me 4-86 0 1H N N Et 4-87 0 1 Me N N iPr 4-88 S 4 H N N bu 4-89 0 2 H

-N

4-9 S 3

H

N N 4-91 -NIH 0 1 H N N 4-92 Me 02 H

-IN

NN

N N FP-9506 71854 ri'.906 7854 jVoc-qdgt_ nliss\9506\doic%;sc~ist5 06 04 130 Table 4 (cont.) Cpd. x Y No. 4-930 N N;rl N N) 4-94 eB0 N N; 4-95 ~Me 0

N

N

'N)

4-99 Me FP-9506 71854 FP.9SU. 7154)pdocsdgt rns,9SO61doescpditst5 0004953 131 Trable 4 (con t.) Cpd. X V m R No. 4-102 0 1 H

N

Me 4-103 0 2 H Me 4-104 0 2 Hf

N

4-105 S 4 H 4-106 0 1 H

N

N

.4-107 a0 2 H

N

4-108 Brr-0 3 H

N

Br 4-109 a S I H [P.9506 7183~4 %wpdovs,,dgt rnml506ldtcs,,pdtst5 06 0495 132 Table 4 (cont.) Cpd. X Y i R No. 4-110 -~N0 1 H

N

4-111 0 1 H

N

4-112 0 2 H -N

N

N

4-114 0 1 H

N

4-114 0 1 H a'N-

N

4-1165' 0 3 H

N

N Me 4-118 01H

N

FP-9506 71854 F P950 154ypdocsdgt _nssO9506%dovscpdNst5 06 0495

I

Table 4 (cont.) Cpd. X Y m R 4-119 Me 0 5 Me

N

4-120 01 MeO N Et "1854 IX4yA 1xiou.'sdgt rnUW9506'd(*z\pdltq. 06 0495 134 Table Cpd. X m R No. 5-1 0 2 H

N'

I

H

~30 2 H

N

5-4 0 2 H

ON

Me O N0 1 H

H

5-6 a _0 1 H

NJ

Me 5-7 0 2 H

N

Me 5-8 01H FP-9506 71854 FP956 184y:'%%pdocagtssO 6Mocs\cpdist6 U~ 0495 6 tl() 90 qlsluXL-,-pqo;&-u- jsj)\SVjXlw X tlML t'SiL 90;6di 00INOI 0NI H- O ZI-9

ON

0 H 1 0 09IA t71 H_ 0 I3I olr H 6

S

NO

0 I OH (*Iuo;))S,?31u 1 Table 5 (con t.) Cpd. X Y m R 5-16 BuO01H 'N N Me 5-17 Me S 4 Cl

#N

Me Me 5-18 0 3 OH Me

N

Me 5-19 BrS 2 Bu Cl) N Me 5-20 Br. 0 5 H

N

Me 5-21 HO 0 1H

N.

Me FP.S0 718M&osndit 009 FP-9506 71854 Y

P-

MEOW

Table 5 (cont.) Cpd. x Y No. 5-23 0 xIN Me 5-24 HO0

N

Me 5-25 MeO 0 Me 5-26 B Br" 0 N Me 0 2 N0

N

FP-9506 71854 y..S0 71854 ss906,melW 06 04 Table Cpd. x Y m R No. 5-30 Bz 0 1 H AcN Me 5-31 0 1 H

/-NH

N

Mee 5-3H 0 1 H Bu-N I IN Me 5-4Me 01 H Bz-N 0 1 H

II

Ph-e FP-9506 71854 FP956 84yoxidgts\906d=)cpdiSI6 0604,95 139 Table 5 (cont.) Cpd. X Y No. 5-36 AcNHS

N

H

5-37 o0 iij

OXN

5-389c 0 O~Me0

N

Me 5-400 rP.9506 71854 FP-50 7185 ydomgtni9506dosA.*Ist6 (06 049V5 140 Table 5 (cont.) Cpd. X Y m R 5-3 MeO 0 4 H MeO N Me 5-44 S I H

N

MeO H 5-45 0 1 H-

N

H

5-46 0 1 H Me 5-47 0 2 H

N

Bu 5-48 S1 Me

N

5-49 0 4 M~e

N

Me *9

S

j A.A. A I. 141 Table 5 (cont.) 4* o 0 0

S

5*

S.

40 S ~0 S. 0 a 0* 4 Cpd. x y m R No. 5-50 0 1 H

N

H

5-51 0 1 H

N

Me 5-52 0 2 H

N

Me 5-53 0 2 Me

N

jWr 5-54 S3 H 4N 5-55 0 1 MeO

N

Me R-9M6 71854 FP-5N 7I% ypdocasdgt tm95O6Ao3vcls l6 06 04'95 142 Table 5 (cont.) 5-56

S

N

0 2 N Me 5-57 0 5-58 MeO,.n 0 *5-59 0 5-600

N

FP-9506 71854 FP-y 506 7184 dcdgtmss96.JcszplIist6 v)604'95 143 Table 5 (cont.) Cpd. X Y No. 5-630

N

Me 5-64 a

N

Me -6 Me 5-66 0 Et V 5-670

N

9 Pr PP.9306 7I~S4 wpdoc~dgt nus95O6d~x'L'pdIlS6 Ub 04")5 FP-9506 71854 144 Table 5 (cont.) Cpd. X Y m R No. 5-70 BzNH,,, S I cl

N

Me 5-71 0 1 H 5-72 0 2H N N 5-73 S 3 H S

N)

5-74 0 4 H1 N N3

H

5-76 0 3 H1 N N

H

5-77 01 N N Me F11-9506 71854 vhku~dgj M s9Od~.~dni lvb W4 9S 145 Table 5 (con t.) Cpd. x Y No.

5-78 0 N N Me 5-79

S

N N Me 5-80 0

N

5-82 0~~ NI N' %Me

I

146 Table 5 (con t.) No.mR 5-85 02H N N Me 5-86 0 1H Et 5-87 0 1Me N IN LPr 5-88 S4[

N

bu 5-89 0 2 H

NN

5-91 SN 3I H N- 5-92 Me 0 2 H N~ N- Table 5 (con t.) Cpd. X Y m R No. 5-3N ,me 0 1 H N N' 5-4u 0 1 H N N 59N.Me 0 1 M've N N:' 5-96 NS I H N N"' 5-9 Pr 5 H NI N 5-98 -N ,Me 0 3 H

NN

N N 510N .Me 0 1 H 5-101 0 2 H

N.N

I P 9 06 18 S4 H IXN %k~xkivsdgt m.~s 9i0O~dtxscwIhl16 0604la95 148 Table 5 (cont.) Cpd. x Y m R 5-1020 1H

NN

Me 5-103 0 2 H -a 1

N

Me 5-104 0 2 H

NJ)N

NJ N 5-106 0 1 H1

N

N

N

5-108 0 3 H

N

5-109 Sv 3 H

N

-9 ot 149 TIable 5 (cont.) Cpd. X Y No. 5-110 I0

N

OH

5-111 0 N N 5-112 c N 0

NN

*5-113 C

N

N

5-114 N0

N-

5-115 N

N

5-116 Ni0 rP-9506 71854 PP.50 154y pdTxocdgt mssx9506Jot3scpdltst6 06 0495 150 Table 5 (cont.) x Y 5-119 NI- Me0 5-120 N0 N Et I A-I ~fltflt~J -fl *t COS4U 9 5 06 504 0 12 M&C FOLIO:71854/FP-9506 WANGDOC: 2531H Of the compounds listed above, we particularly prefer the following, that is to say Compounds No. 1-1, 1-2, 1-3, 1-6, 1-57, 1-59, 1-62, 1-72, 1-81, 1-91, 1-93, 1-106, 1-121, 1-122, 1-125, 1-130, 1-134, 1-135, 1-137, 1-140, 1-142, 1-153, 1-156, 1-158, 1-161, 1-177, 1-179, 1-180, 1-182, 1-183, 1-207, 1-218 and 2-100, of which Compounds No. 1-1, 1-57, 1-62, 1-91, 1-93, 1-106, 1-122, 1-125, 1-130, 1-134, 1-137, 1-140, 1-142, 1-153, 1-156, 1-177, 1-179, 1-180, 1-182, 1-183, 1-207, 1-218 and 2-100 are more preferred. Still more preferred compounds are Compounds No. 1-62, 1-93, 1-125, 1-134, 1-140, 1-142, 1-153, 1-177, 1-179, 1-182, 1-183 and 1-207.

The most preferred compounds are Compounds No.: 1-93. 5-{4-(3-methylimidazo(5,4-blpyridin-2-ylmethoxy)benzyl~thiazolidine-2,4-dionie; 1-125. 5-{4-(5-Chloro-3-methylimidazo(5,4-blpyridin- 2-ylmethoxy)benzy1}thiazolidine-2,4-dione; 1-142. 5-{4-(5-Methoxy-3-methylimidazo[5,4-blpyridin- 2-ylmethoxy)benzyllthiazolidine-2,4-dione; 1-153. (5-Hydroxy-3-methylimidazols,4-blpyridin- 2-ylmethoxy)benzyl~thiazolidine-2,4-diole; 1-182. 5-{4-(5-Ethoxy-3-methylimidazot5,4-blpyridin- 2-ylmethoxy)benzyl~thiazolidine-2,4-dionle; 1-183. 5-{4-(5-Isopropoxy-3-methylimidazorL5,4-b)pyridin- 2-ylmethoxy) benzyl }thiazolidine- 2, 4-dione.

A I 9506 7 18 5 4 2 S 3 1 152 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 Schere A This represents a general scheme that may be used to prepare the compounds of the present invention where Z represents a group of formula (iii) or (iv): Reaction Scheme A:

X-(CH

2 )m-I-COOR

(II)

Step Al

X-(CH

2 O I-i

(III)

Step A2 X H2 F -Y -dZ

(IV)

Step A3 X -(CH 2

-Y.

I- -u MMEMMYL ;3Mffi-- 9506 718 54 2S31 ')50 0 152 The compounds of AU 683348 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 AU 683348 where Z represents a group of formula (iii) or (iv): Reaction Scheme A:

X-(CH

2 1

-COOR!

(II)

Step Al X--(CH)nf-O (111) a o rr a o t a rr a r r r Step A2

R

(IV)

Step A3 X-(CH2 (v)

R

X-(CH2) i-Y-

Z

la-MMMW 9506 1, 1 153 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 R and Rb; and Z' represents a group of formula (vii), (viii) or (ix): s r -CH O S N-Tr (v) -C H2 0 O N-Tr 0 (viii) -CH2 0 S N--Tr 0 (vii) -CH2 0

N-H

0 N--Tr 0 (ix) s o where Tr represents a triphenylmethyl group.

In Step Al, a compound of formula (III) is prepared 9 5 0 6 7 1 5 4 1 5 i 4) 154 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 s.uch 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; 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 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, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that tie reaction is I S06 6 7 1 5 4 S I 4 0 155 effected 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 In Step A2, a compound of formula is prepared by 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, 1 (1981)].

The reaction is usually carried out in a solvent in the presence of at least one azo compound and at least 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 tributylphosphine.

5 1 1 'I 4 I i 4 .1 S- 156 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 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 the formula 'I a I 1 i 5 4 I I 1 I I 4 I) 157 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 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 f't" 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 ft f of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlinea 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 hydrogenation of a compound of formula There is no 9 5 0 6 71 8 5 4 040 158 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, ethanol or isopropanol; 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 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 that the reaction is effected under the preferred conditions outlined above, a period of from several

,I

6 7 1 6 4 "4" 159 hours to several days, more preferably from 1 hour to 1 day will usually suffice.

Reaction Scheme B This is a process which may be used to prepare compounds of formula in which Y represents an oxygen atom and Z represents a group of formula or (ii), that is a 2,4-dioxothiazolidin-5-ylidenylmethyl or 2,4-dioxothiazolidin-5-ylmethyl group, i.e. compounds of formulae (VII) and (VIII), respectively.

9 S 0 6 7 1 8 5 4 ~32 5i 5 3.1 5 04 0 160a Reaction Vcheme B: X H2)miO H

(III)

Step B I 1) Base 2) FQ' CHO (VIa)

(VI)

Step S NH (Vila) Step B3 Reduction

(VII)

(Vill) 9506 7 18 54 2531 95040 w 161 Step B1 In Step Bi, 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.

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 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; 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 for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature 9 5 0 6 7 1 8 5 4 2 5 3 1 S 0 4 0 W 162 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 will usually suffice.

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 particular restriction on the nature of the catalyst used, and any catalyst commonly used in this type of 9506 71i854 2 5 3 1 163 reaction may equally be employed here. Examples of such catalysts include sodium acetate, pipe-idinium 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 as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; halogenated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane; nitriles, such as acetonitrile or propionitrile; esters, such as ethyl formate or ethyl acetate; 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 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.

Step B3 In Step B3, a compound of formula (VIII) is prepared 1 9506 71854 253. 5 040 S- 164 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 9- 1 9506 7 1 8 5 2 53 1 W 165 solvent employed. However, provided that the reaction is effected under che 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.

Reaction Scheme C This is a process which may be used to prepare compounds of formula in which Y represents an oxygen atom and Z represents a group of formula (iv) or that is a 3,5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group, i.e. compounds of formulae and respectively.

S

e ea

I

3.910 166 Reaction Sheme C:, Step ClI

(VI)

H

2 NOH. HG! Reduction

(IX)

NH

OH

Step C2 SiNGO S S a..

S*

S S 55 Step C3 GIG NC 0 N NI-I-HI

OH

X-(G H 2 0

N

0506 6 7 1 5 4 I 'i U 4 0 167 In the abcve formulae, X, R and m are as defined above.

Step Cl In Step Cl, a compound of formula (IX) is prepared by reacting a compound of formula (VI) (which may have been prepared as described in Reaction Scheme B) with hydroxylamine (preferably as the hydrochloride), in a first stage, followed, in a second stage, by reducing the product.

The reaction of the compound of formula (VI) with hydroxylamine (hydrochloride) is, in general, 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, dioxane or tetrahydrofuran; alcohols, Ssuch as methanol, ethanol or isopropanol; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; halogenated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane; nitriles, such as acetonitrile or propionitrile; esters, such as ethyl formate or ethyl acetate; amines, such as pyridine, triethylamine or N,N-diisopropyl-N-ethylamine; 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

I

9506 7 1854 2 K I I S- 168 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 hours to several tens of hours will usually suffice.

The subsequent reduction in the second stage of this step may be carried out by hydrogenation in the presence of a reducing agent. There is no particular restriction on the nature of the reducing agent used, and any reducing agent commonly used in this type of reaction may equally be employed here. Examples of such reducing :agents include metal hydrides, such as lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride or sodium cyanoborohydride.

The second stage 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; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; alcohols, such as methanol, ethanol or isopropanol; 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 9506 7 1854 169 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 one day, more preferably from 1 to hours, will usually suffice.

Step C2 In Step C2, a compound of formula is prepared by reacting a compound of formula (IX) with trimethylsilyl "isocyanate.

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 c- suitable solvents include: hydrocarbons, such as benzene, toluene, xylene, hexane or heptane; ethers, such as diethyl ether, dioxane or tetrahydrofuran; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; halogenated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane; 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 9 50 0 6 71854 1 040 170 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 will usually suffice.

The resulting compound of formula is a compound of the present invention.

Step C3 In Step C3, a compound of formula (XI) is prepared by reacting a compound of formula (IX) with N-(chlorocarbonyl) isocyanate.

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 Sor 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; halogenated hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane; nitriles, such as acetonitrile or propionitrile; esters, such as ethyl formate or ethyl acetate; 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 9506 7 1 8 5 4 2 53 1 9 5040 S- 171 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 compounds of formula in which Z represents a group of formula (ii) or (iii), that is a 2,4-dioxothiazolidin- -5-ylmethyl or 2,4-dioxooxazolidin-5-ylmethyl group, i.e.

compounds of formula (XV).

e I II I I 0 0 S- 172 Reaction Scheme D:

Q-(CH

2 )---Halo HY 0 (XII) R I Y lNH (xIII) 0 Step D Q-(CH 2 _Y 0 Base R

NH

(XIV)

,0 Step D2 X(CH2)m yO R NH (xv) In the above formulae: X is as defined above, but preferably represents an imidazopyridyl or imidazopyrimidinyl group; Y, R and m are as defined above; Y' represents an oxygen or sulfur atom; Q represents a lower alkoxycarbonyl group, a formyl group, a protected formyl group, a carboxyl group or a hydroxy group; and 0 I S0 95 173 Halo represents a halogen atom.

Step D1 In Step D1, a ccmpound 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 hydriae) 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, o dimethylacetamide or hexamethylphosphoric criamide; 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 for the reaction may also vary widely, depending on many I 11 I) 174 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 rried 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 (b) 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 preferably has a total of from 2 to 7 carbon atoms the alkoxy part has from 1 to 6 carbon atoms), and may be a straight or branched chain group. Examples of

I

U~I~BQ"--~DI-

950 7 18 54 25 ;03 7 1) 040 A- 175 such groups include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxyc.:- onyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentyloxycarbonyl, l-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, butoxycarbonyl and isobutoxycarbonyl groups, and 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.

Examples of suitable solvents include: hydrocarbons, 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

MMM

11 0 0 }I 1> '1 I 1 4 0 176 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.

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 1 06 7i 54 177 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 So 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 9506 7185 4 25 3 9 5040 178 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 a protected formyl group, the formyl-protecting group may be removed prior to subjecting the compound to the e" o 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, 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 0 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) or (iii), that is a 2,4-dioxothiazolidinor 2,4-dioxooxazolidin-5-ylmethyl group, i.e.

compounds of formula (XV).

'4 D I1 5 o I 1 8 5 A I a 4 1 179 Reaction Schemne E:

Q-(CH

2 )iF--Halo

(XII)

HYP

NO

2

R

Step El

(XVI)

Q-(C2)F--yi NO 2 (XVII)

R

P NH 2 (XVIII)

R

Step E2 Step E3 a (XIX) K Haki Q,-(CH2)Fij-'-Y 0 R(XIV) ,"YN 0 Step E4

H

2 N -C -NH 2 11 Nf, Step

(XVO

9506 S7 18 54 S5 0 4 I) P 180 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.

ease Step E3 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).

i I 9 5 0 6 7 1 5 4 5 5 51 95 I 05 S- 181 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 .nd 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.

9506 7 L 5 4 2 5 3 1 9 0 4 0 182 BIOLOGICAL ACTIVITY The compounds of formula 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 osteoporosis.

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, 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 ary 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 patient, the nature and severity of the disorder to be treated or prevented, the route of administration and 9506 2 5 )1 0 183 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 the present invention is illustrated by the following Experiments.

Experiment 1 Hypoglycemic activity The test animals used were hyperglycemic male mice of the KK strain, each having a body weight of at least 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 BGLt)/BGL s x 100 where: ni 1) i 0 (1 S, I Ii 4 II 184 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 t he present invention is identified by the number of one of the following Examples in which its preparation is illustrated.

Table 6 Cpd. of Dose (mg/kg) Hypoglycemic effect Example No. 1 10 13.2 2 1 27.7 3 10 27.0 10 16.2 6 10 20.9 7 1 24.7 9 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 of the t o

D

r r r -lI 1 1 0 1) S- 185 present invention exhibited excellent activity.

Experiment 2 Inhibition of Aldose reductase Bovine lens \drse 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 the present invention at a concentration of 5 ig/ml, and the measured values were used to calculate the IC 5 0 50 values. The results are shown in the following Table 7.

e a -I R 9 506 S18 4 5 0 4 0 186 Table 7

V.

4ee

V.

Cpd. of Inhibition IC 50 Example No. at 5 ig/ml (ig/ml) 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 61.6 1.8 22 77.2 1.8 23 94.9 1.3 81.6 0.89 27 91.8 0.85 Experiment 3 Toxicity The toxicity of the compounds of the present invention was tested on male F344 rats, divided into groups of 5. The test compound was adminstered orally to each test animal at a dose of 50 mg/kg of body weight I L- I'' t) 5 I) 4 0 187 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 coumpounds. In view of the substantial dose adminstered to each animal, the zero mortality rate indicates that the compounds of the present invention have very low toxicity.

The compounds of the present invention thus have excellent activities combined with a very low toxicity, rendering them ideally suited to therapeutic use.

I- i II I II 9 500 7 1 5 4 0 188 M&C FOLIO:71854/FP-9506 WANGDOC: 2532H The present invention is further illustrated by the following non-limiting Examples. In these Examples, where Compound Nos. are given, they are those numbers assigned in the foregoing Tables 1 to 5. Preparation of certain of the starting materials used in some of these Examples is illustrated by the subsequent Preparations.

EXAMPLE 1 4-(Indolin-2-ylmethoxy)benzvl thiazolidine-2,4-dione (Compound No. 1-59) A mixture of 3.55 g of 5-[4-(1-t-butoxycarbonylindolin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine- 2,4-dione (prepared as described in Preparation 4) and 30 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was poured into water and the aqueous mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography through silica gel, using a 2 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.41 g of the title compound. This product was dissolved in ethanol and precipitated by adding water, to give a powder melting at 55.8 58.2 0

C.

0 5 06 I N u 4 0 -189 EXAMPLE 2 5-r4- (l-Methylindolin-2-vlmethoxv)benzv-l1thiazolidine- 2,4-dione (Compound No. 1-62) 3.1 ml of trifluoroacetic acid were added to a solution of 2.50 g of 5-[4-(1-methylindolin-2-ylmethoxy) benzyll -3-triphenylmethylthiazolidine-2, 4-dione (prepared as described in Preparation 7) in 25 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was worked up following the procedure described in Example 1, to give 1.20 g of the title compound, melting at 46.1 48.9 0

C.

EXAMPLE 3 5-14- f2- (ndolin-l-vl)ethoxylbenzyllthiazolidiC-, :2,4-dione (Compound No. 1-57) A procedure similar to that described in Example 2 was repeated, except that 470 mg of 5-{4-(2-(indolinl-yl) ethoxy] benzyl 1-3- tr-phenylmethylt~hiazolidile -2,4dione (prepared as described in Preparation 10) and 3 ml of trifluoroacetic acid were used, to give 170 mg of the title compound, melting at 132.8 135.6 0

C.

EXAMPLE 4 S-f4- (Indol-3-yl)ethoxvylbenzvllthiazolidile- 2.4-dione (Compound No. 1-2) A procedure similar to that described in Example 2 was repeated, except that 1.77 g of 5-{4-(2-k(indol-3yl) ethoxy] benzyl triphenylmethylthiazol idine 4dione (prepared as described in Preparation 11) 53 ml 9506 7 1 854 2532 15040 190 of methylene chloride and 0.3 ml of trifluoroacetic acid were used, to give 0.67 g of the title compound, melting at 42.6 44.5 0

C.

EXAMPLE 5-{4-[2-(3-Triphenvlmethylindol-l-yl)ethoxy1benzvl}thiazolidine-2,4-dione (Compound No. 1-3) A procedure similar to that described in Example 2 was repeated, except that 2.33 g of 5-{4-(2-(indol-1yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4dione (prepared as described in Preparation 14), 25 ml of methylene chloride and 3.1 ml of trifluoroacetic acid were used, to give 2.20 g of the title compound, melting at 66.6 70.0 0

C.

EXAMPLE 6 [2-(Indol-1-yl)ethoxylbenzyl}thiazolidine- 2,4-dione (Compound No. 1-1) A solution of 2.05 g of 5-{4-[2-(indol-1-yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 14) in 100 ml of dioxane was stirred in an atmosphere of hydrogen and in the presence of 3.1 g of 10% w/w nalladium-on-charcoal, first at room temperature for 30 minutes, then at 60 0

C

for 2 hours and then at 80 0 C for 3 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then purified by column chromatography through silica gel, using a 2 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.06 g of the title compound, melting at 42.3 44.6 0

C.

95~~~6 0 I4~ 0~ EXAMPLE 7 5-f4-(3-Methylimidazor5,4-bl]pvridin-2-ylmethoxy) benzyllthiazolidine-2,4-dione (Compound No. 1-93) A procedure similar to that described in Example 6 was repeated, except that 500 mg of 5-[4-(3-methylimidazoL5,4-blpyridin-2-ylmethoxy)benzyll -3-triphenyl- .methylthiazolidine-2,4-dione (prepared as described in Preparation 16) 1 g of 101; w/w palladium-on-charcoal and 100 ml of methanol were used, to give 77 mg of the title compound, melting at 223 225 0

C.

EXAMPLE 8 5-N4- 2-(7-Azaindol-l-vl)ethoxylbenzyl'lthiazolidine- 2,4-dione (Compound No. 1-72) ;procedure similar to that described in Example 2 was repeated, except that 2.50 g of 5-{4-[2-(7-azaindol-l-yl)ethoxylbenzyl}-3-triphenylmethylthiazolidine- 2,4-dione (prepared as described in Preparation 19), 50 ml of methylene chloride and 3.1 ml of trifluoroacetic acid were used, to give 0.84 g of the title compound, melting at 200.0 202.4 0

C.

EXAMPLE 9 5-14-(Imidazo[1,2-alpvridin-2-vlmethoxv)benzyllz thiazolidine-2,4-dione (Compound No. 1-1061 A procedure similar to that described in Example 1 was repeated, except that 3.0 g of 5-{4-(imidazo- 2-al pyridin- 2- ylmethoxy) benzyl triphenylmethrl thiazolidine-2,4-dione (prepared as described in Preparation 21) were reacted with 30 ml of 9506 7 1 8 5 4 2532 95040 TW 192 trif±uoroacetic acid for 1 hour. At the end of this time, the reaction mixture was freed from trifluoroacetic acid by distillation under reduced pressure. An aqueous solution of potassium carbonate and ethyl acetate were added to the residue, and the resulting precipitated insoluble material was collected by filtration, dried over anhydrous sodium sulfate and recrystallized from ethanol, to give 0.8 g of the title compound, melting at 197 202 0

C.

EXAMPLE 5-[4-(l-Methylindol-2-vlmethoxy)benzyllthiazolidine- 2,4-dione (Compound No. 1-6) A procedure similar to that described in Example 6 was repeated, except that 3.24 g of 5-[4-(l-methylindol- S* 2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4dione (prepared as described in Preparation 24), 4.86 g of 10% w/w palladium-on-charcoal and 100 ml of dioxane were used, to give 1.49 g of the title compound, melting at 174.3 175.5 0

C.

U

EXAMPLE 11 5-[4-f2-(Imidazo[l,2-alpyridin-2-vl)ethoxy}benzyllthiazolidine-2,4-dione (Compound No. 1-107) A procedure similar to that described in Example 2 was repeated, except that 0.94 g of 5-[4-{2-(imidazo- [1,2-a]pyridin-2-yl)ethoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 27), 4 ml of methylene chloride and 1 ml of trifluoroacetic acid were used, to give the title compound as a crude product. This product was purified by column chromatography through silica gel, using a 1; 9506 7 1854 2532 )5040 Wr 193 2 1 by volume mixture of hexane and ethyl acetate and subsequently a 1 2 by volume mixture of ethyl acetate and tetrahydrofuran, as the eluents, to give 287 mg of the title compound, melting at 205.9 207.0 0 C with decomposition).

EXAMPLE 12 5-14-(3-EthylimidazoL5,4-b]pyridin-2-ylmethoxy)benzyllthiazolidine-2,4-dione (Compound No. 1-121) 12 ml of a 3 1 by volume mixture of acetic acid and water were added to 300 mg of 5-{4-(3-ethylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), and the resulting mixture was stirred at 60 0 C f,'r 2 hours. At the end of this time, the reaction mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give mg of the title compound, melting at 210 212 0

C.

EXAMPLE 13 5-14-(1-Methylimidazo[4,5-blpyridin-2-ylmethoxv)benzyl}thiazolidine-2,4-dione (Compound No. 1-122) A procedure similar to that described in Example 12 was repeated, except that 4.1 g of 5-{4-(1-methylimidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in 0 6 7 1 54 2 5 32 15a40 S- 194 Preparation 31) and 160 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.45 g of the title compound, melting at 231 232 0

C.

EXAMPLE 14 4- 3-(3-Methylimidazo 5,4-blpyridin-2-vl)propoxy}benzvllthiazolidine-2,4-dione (Compound No. 1-123) A procedure similar to that described in Example 12 was repeated, except that 240 mg of 5-[4-{3-(3-methylimidazo[5,4-b]pyridin-2-yl)propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 35) and 10 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was Spurified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 3 to 0 1 by volume as the eluent, to give 93 mg of the title compound, melting at 185 186 0

C.

EXAMPLE 4- (H-Imidazo[4,5-b pyridin-2-ylmethoxy)benzyllthiazolidine-2.4-dione (Compound No. 1-91) 1.13 g of 4-(ethoxycarbonylmethoxy)benzylthiazolidine-2,4-dione (prepared as described in Preparation 39) were added to 200 mg of 2,3-diaminopyridine, and the resulting mixture was stirred at 110 0 C for 2 days. At the end of this time, the reaction mixture was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the i 9506 7 18 54 2532 5040 w 195 addition of aqueous ammonia. The aqueous mixture was evaporated to dryness under reduced pressure, and then the residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1 0 to 10 1 by volume as the eluent.

The product was crystallized by trituration with ethyl acetate, to give 400 mg of the title compound, melting at 247 248 0

C.

EXAMPLE 16 5-f4-(3,7-Dimethylimidazof5,4-blpyridin-2-vlmethoxy) benzyllthiazolidine-2,4-dione (Compound No. 1-124) A procedure similar to that described in Example 12 was repeated, except that 1.07 g of dimethylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 41) and 16 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 1 to 1 2 by volume as the eluent. The product was crystallized by trituration with ethyl acetate, to give 0.28 g of the title compound, melting at 205 207 0

C.

9506 7186 4 950 196 EXAMPLE 17 5-f4-(5-Chloro-3-methylimidazo[5,4-blpyridin-2-ylmethoxy)benzyllthiazolidine-2,4-dione (Compound No. 1-125) A procedure similar to theft described in Example 12 was repeated, except that 1.16 g of 5-{4-(5-chloro- 3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 45) and 16 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. The product was crystallized by trituration with ethyl acetate, to give 0.38 g of the title compound, melting at 222 223 0

C.

EXAMPLE 18 5-f4-(3-Methyl-6-trifluoromethylimidazo[5,4-b1]pridin- 2-ylmethoxy)benzvl thiazolidine-2,4-dione (Compound No. 1-130) 4.16 g of 5-(4-(2-oxoethoxy)benzyl)thiazolidine- 2,4-dione (prepared as described in Preparation 47) were added to a solution of 3.00 g of 3-amino-2-methylamino- 5-trifluoromethylpyridine in a mixture of 6 ml of ethanol and 6 ml of acetic acid, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. 50 ml of 1,2-dimethoxyethane and 5.2 g of iodine were added to the residue, and the resulting mixture was stirred at 60 0 C for one day. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The I_ I- 9 06 71854 2 5 2 5 0 0 197 extract was washed with an aqueous solution of sodium chloride and diied over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent. The product was crystallized by trituration with ethyl acetate, to give 520 mg of the title compound, melting at 212 214 0

C.

EXAMPLE 19 5-14-(3-Methylimidazo[5,4-dlpyrimidin-2-ylmethoxy)benzyl thiazolidine-2,4-dione (Compound No. 1-158) a A procedure similar to that described in Example 12 was repeated, except that 0.24 g of 5-{4-(3-methylimidazo[5,4-d]pyrimidin-2-ylmethoxy)benzyl] -3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 51) and 8 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1 0 to 1 by volume as the eluent, to give 30 mg of the i title compound, melting at 244 246 0

C.

EXAMPLE 5-(4-{3-(4-Chlorobenzvl)imidazo 5,4-b1pyridin-2-vlmethoxylbenzyl)thiazolidine-2.4-dione (Compound No. 1-134) A procedure similar to that described in Example 18 was repeated, except that 1.20 g of 3-amino-2-(4-chloro-

I

9 506 7 18 S 2 )2 5 0 4 W 198 benzyl)aminopyridine (prepared as described in Preparation 53), 1.36-g of 5-[4-(2-oxoethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 47), 3 ml of ethanol, 3 ml ot acetic acid, 1.69 g of iodine and 25 ml of 1,2-dimethoxyethane were used, to give the title compound as a crude product.

This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 1 to 1 2 by volume as the eluent, to give 0.40 g of the title compound, melting at 211 213 0

C.

EXAMPLE 21 S 5-(4-{3-(4-Phenylbenzyl)imidazo[5,4-bpyvridin-2-ylmethoxy}benzvl)thiazolidine-2,4-dione (Compound No. 1-135) A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-(4-{3-(4-phenylbenzyl)imidazo[5,4-b]pyridin-2-ylmethoxy}benzyl)-3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 55) and 36 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1 3 by volume mixture of hexane and ethyl acetate as the eluent, to give 450 mg of the title compound, melting at 189 191 0

C.

-I 6 S0 5 4 I 2 I I I) 4 199 EXAMPLE 22 4-(6-Bromo-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyllthiazolidine-2,4-dione (Compound No. 1-137) A procedure similar to that described in Example 12 was repeated, except that 3.00 g of 5-{4-(6-bromo-3methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 60) and 40 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.75 g of the title compound, melting at 204 205 0

C.

EXAMPLE 23 5-{4-(6-Chloro-3-methylimidazo[5,4-blpyridin-2-vlmethoxy)benzyl }thiazolidine-2,4-dione (Compound No. 1-140) A procedure similar to that described in Example 12 was repeated, except that 1.40 g of 5-{4-(6-chloro-3- Smethylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 65) and 20 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 0.75 g of the title compound, melting at 203 205 0

C.

5 0 f, I A 1 I) 4 0 200 EXAMPLE 24 5-f4-(5-Methoxy-3-methylimidazo[5,4-blpyridin-2-ylmethoxy)benzyllthiazolidine-2,4-dione (Compound No. 1-142) and the hydrochloride and fumarate thereof A procedure similar to that described in Example 12 was repeated, except that 680 mg of methoxy-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 70) and 10 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product.

This crude product was crystallized by trituration with ethyl acetate, to give 325 mg of the title compound, melting at 258 260 0

C.

100 mg of 5-{4-(5-methoxy-3-methylimidazo- [5,4-b]pyridin-2-ylmethoxy)benzyl}thiazolidine-2,4dione [prepared as described in step above] were added to 6 ml of a 4 N solution of hydrogen chloride in ethyl acetate, and the mixture was treated with ultrasound for 30 minutes. At the end of this time, the resulting crystals were collected by filtration and dried by evaporation under reduced pressure, to give 87 mg of the hydrochloride of the title compound, melting at 255 262 0

C.

100 mg of 5-{4-(5-methoxy-3-methylimidazo- [5,4-b]pyridin-2-ylmethoxy)benzyl}thiazolidine-2,4dione [prepared as described in step above] were dissolved in 30 ml of methanol, and then 29 mg of fumaric acid were added to the resulting solution. The resulting mixture was treated with ultrasound for minutes. At the end of this time, the solvent was

I

U A85 4 r~ I I U 1, I 8 5 4 201 removed by distillation under reduced pressure. The residue was triturated with ethanol and the resulting crystals were collected by filtration, to give 85 mg of the fumarate ethanol hemi-solvate of the title compound, melting at 245 253 0

C.

EXAMPLE 5-M4-(1-Methylimidazof4,5-clpyridin-2-ylmethoxy)benzvllthiazolidine-2,4-dione (Compound No. 1-156) A procedure similar to that described in Example 12 was repeated, except that 3.40 g of 5-{4-(1-methylimidazo[4,5-c]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 74) and 24 ml of a 3 1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.01 g of the title compound, melting at 264 265 0

C

EXAMPLE 26 5- [4-(l-Methyl-7-azaindol-2-vlmethoxv)benzyl thiazolidine-2,4-dione (Compound No. 1-81) A procedure similar to that described in Example 12 was repeated, except that the reaction was conducted using 270 mg of 5-[4-(1-methyl-7-azaindol-2-ylmethoxy)benzyl] 3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 82) and 3 ml of a 2 1 3 by volume mixture of acetic acid, water and 1,4-dioxane. After the period allowed for the reaction had elapsed, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through 0 6 71 1 5i 4 1 0 0 l 202 silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 157 mg of the title compound, melting at 183 1850C.

EXAMPLE 27 5-f4-(3-Phenylimidazo[5,4-bl]pridin-2-vlmcthoxy)benzvrlthiazolidine-2,4-dione (Compound No. 1-161) A procedure similar to that described in Example 18 was repeated, except that 2.78 g of 3-amino-2-phenylaminopyridine (prepared as described in Preparation 84), 3.98 g of 5-[4-(2-oxoethoxy)benzyl)thiazolidine-2,4dione (prepared as described in Preparation 47), 4.9 g of iodine, 6 ml of ethanol, 6 ml of acetic acid and ml of 1,2-dimethoxyethane were used. After working up the product as described in Example 18, the resulting crude product was purified by column chromatography through silica gel, using a 1 2 by volume mixture of hexane and ethyl acetate as the eluent, to give 400 mg of the title compound, melting at 88 91 0

C.

EXAMPLE 28 5-{4-(3,5,7-Trimethylimidazo[5.4-blyvridin-2-vlmethoxy)benzyl}thiazolidine-2,4-dione (Compound No.

1-218) and its trifluoroacetate A procedure similar to that described in Example 2 was repeated, except that 3.5 g of 5-{4-(3,5,7-trimethylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 87), 100 ml of methylene chloride and 20 ml of trifluoroacetic acid were used.

After the period allowed for the reaction had elapsed, the reaction mixture was freed from the methylene s c 1) 1 0 6 7 I1 4 1I 0) 0 S- 203 chloride and trifluoroacetic acid by distillation under reduced pressure. The crude product thus obtained was recrystallized from a mixture of ethyl acetate and hexane, to give 2.4 g of the trifluoroacetate of the title compound, melting at 226 228 0

C.

The trifluoroacetate (2.3 g) prepared as described above was suspended in a mixture of ethyl acetate ml) and an aqueous solution of sodium hydrogencarbonate (50 ml), and the suspension was stirred at room temperature for 30 minutes. At the end of this time, the crystals which had precipitated were collected by filtration and washed with water, after which they were dried under reduced pressure, to give 1.47 g of the title compound, melting at 229 230 0 c.

EXAMPLE 29 5-{4-(3-Methyl-5-phenylthioimidazo[5,4-blpyridin- 2 -vlmethoxy)benzyl }thiazolidine-2,4-dione (Compound No. 1-177) A procedure similar to that described in Example 12 was repeated, except that 1.58 g of 5-[4-(3-methyl-5phenylthioimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl]-3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 91) were treated with 20 ml of a 3 1 by volume mixture of acetic acid and water.

After working up the producu as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 1.02 g of the title compound, melting at 166 168 0

C.

1) 1 U 0 I I ALI35 4 0 4 1) -204 EXAMPLE 5-14- (5-Benzvloxy-3-methylimidazof5,4-blpvridin-2ylmethoxv)benzvllthiazolidir a-2,4-dione (Compound No. 1-207) A procedure similar to that described in Example 12 was repeated, except that 1.00 g of 5-{4-(5-benzyloxy- 3-methylimidazo[5,4-blpyridin-2-ylmethoxy)benzyl}-3triphenylmethylt"hiazolidine-2, 4-diane (prepared as described in Preparation 95) was treated with 12 ml of a 3 1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 0.63 g of the title compound, melting at 210 211 0

C.

EXAMPLE 31 5-f4- (5-Hvdroxy-3-methxrlimidazoF5,4-blpvridin-2ylmethoxy) benzvl Ithiazolidine dione (Compound No. 1-153) A procedure similar to that described in Example 6 was repeated, except that 1.20 g of 5-{4-(5-benzyloxy- 3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl)-3triphenylmethylthiazolidine-2 ,4-dione (prepared as described in Preparation 95), 1.80 g of 10 16 w/w palladium-on-charcoal and 50 ml of methanol were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1 :0 to 10 :1 by volume as the eluent, to give 0.10 g of the title compound, melting at 240 242 0

C.

sllAannsllls~serr~ rs 5 0 6 I I 1 4 Q506 1 t (1)0 I t 205 EXAMPLE 32 5-4- (5-Ethoxy-3-methylimidazof5,4-b pyridin-2-vlmethoxy)benzyllthiazolidine-2,4-dione (Compound No. 1-182) A procedure similar to that described in Example 12 was repeated, except that 2.75 g of 5-{4-(5-ethoxy-3methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl} -3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 99) were treated with 24 ml of a 3 1 by volume mixture of acetic acid and water.

After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 1.57 g of the title compound, melting at 245 246 0

C.

EXAMPLE 33 5- (5-Isopropoxy-3-methylimidazo[5,4-blopyridin-2ylmethoxy)benzyl}thiazolidine-2,4-dione (Compound No. 1-183) A procedure similar to that described in Example 12 was repeated, except that 0.78 g of 5-{4-(5-isopropoxy- 3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 103) was treated with 12 ml of a 3 1 by volume mixture of acetic acid and water.

After working up the product as described in Example 12, the resulting crude product was crystallized by i: trituration with ethyl acetate, to give 0.40 g of the title compound, melting at 210 212 0

C.

b: m a 6 7 1 6 4 1 I 0 4 206 EXAMPLE 34 5-{4-[2-(3-Methylimidazo[5,4-blpyridin-2-vl)ethoxy benzyl)thiazolidine-2,4-dione (Compound No. 1-190) A procedure similar to that described in Example 18 was repeated, except that 0.94 g of 3-amino-2-methylaminopyridine (prepared as described in Preparation 105), 2.10 g of 5-[4-(3-oxopropoxy)benzyl]thiazolidine- 2,4-dione (prepared as described in Preparation 107), 6 ml of ethanol, 3 ml of acetic acid, 2.32 g of iodine and 30 ml of 1,2-dimethoxyethane were used. After working up the product as described in Example 18, the resulting crude product was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 85 mg of the title compound, melting at 96 100 0

C.

EXAMPLE 5-{4-(3-Methyl-5-phenylimidazo[5,4-b1pyridin-2-ylmethoxy)benzyllthiazolidine-2,4-dione .i (Compound No. 1-179) A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-{4-(3-methyl-5- '..phenylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 111) was treated with 36 ml of ~a 3 1 by volume mixture of acetic acid and water.

After working up the product as described in Example 12, ~the resulting crude product was crystallized by trituration with ethyl acetate, to give 420 mg of the title compound, melting at 211 213 0

C.

LI I I a "O 1 0 4 0I 207 EXAMPLE 36 5-{4-(3-Methylimidazo[5,4-b1]pridin-2-vymethoxy)benzylidenelthiazolidine-2,4-dione (Compound No. 2-100) A mixture of 0.35 g of 2-(4-formylphenoxymethyl)-3methylimidazo[5,4-b]pyridine (prepared as described in Preparation 112), 0.31 g of 2,4-thiazolidinedione, 0.26 ml of piperidine and 10 ml of ethanol was heated under reflux for 4 hours. At the end of this time, the solvent waa removed by distillation under reduced pressure and the residue was crystallized by trituration with water. The crystals were collected by filtration and washed with water and then with ethyl acetate, to give 0.38 g of the title compound, melting at 279 281 0

C.

PREPARATION 1 Ethyl indoline-2-carboxylate A mixture of 25.2 g of indoline-2-carboxylic acid, 50 ml of ethanol and 200 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at room temperature for 3 days. At the end of this time, the reaction mixture was poured into an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation Sunder reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 2 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 28.1 g of the title compound having Rf 0.81 (on silica gel thin layer ~~-IIL =~m i, 0 6 7 1 A S 4 208 chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 2 Indolin-2-ylmethanol A solution of 5.12 g of ethyl indoline-2-carboxylate (prepared as described in Preparation 1) in 20 ml of anhydrous tetrahydrofuran was added dropwise, whilst ice-cooling, to a mixture of 1.20 g of lithium aluminum hydride and 80 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2 hours. After this, an excess of sodium sulfaLe decahydrate was added to the mixture, which was then stirred for 20 minutes. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure.

The concentrate was purified by column chromatography through silica gel, using a 3 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.81 g of the title compound having Rf 0.16 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 3 1- Butoxvcarbonvl -2-hydroxymethylindoline 6.2 ml of di-t-butyl dicarbonate were added dropwise to a solution of 4.0 g of indolin-2-ylmethanol (prepared as described in Preparation 2) and 3.8 ml of triethylamine in 40 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for 10 hours. At the end of this time, the reaction 1 I 4 I I 1 4* j I 11 4 0 -209 mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 5 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.57 g of the title compound having Rf 0.46 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 4 5-[4-(l-t-Butoxvcarbonylindolin-2-vlmethoxy)benzyl 3-triphenvlmethylthiazolidine-2,4-dione A solution of 6.6 g of l,l'-(azodicarbonyl)dipiperidine in 10 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide was added dropwise to a mixture of 6.5 g of l-t-butoxycarbonyl-2-hydroxymethylindoline (prepared as described in Preparation 3), 6.5 ml of tributylphosphine, 12.2 g of 5-(4-hydroxy benzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in European Patent Publication No. 549 365A1] and 100 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for about 20 hours. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced o pressure. The concentrate thus obtained was purified by column chromatography through silica gel, using a 10 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.70 g of the title compound, melting at 85.4 87.2 0

C.

-I mr~nr~l-~ II II 1 I I) I) 210 PREPARATION Methyl l-methylindoline-2-carboxylate 11.7 ml of methyl iodide were added dropwise to a mixture of 10.3 g of (±)-indoline-2-carboxylic acid, 200 ml of dimethylformamide and 25.4 g of anhydrous potassium carbonate, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 7 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 9.12 g of the title compound having Rf 0.77 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

f. PREPARATION 6 l-Methylindolin-2-ylmethanol A procedure similar to that described in Preparation 2 was repeated, except that 8.0 g of methyl 1-methylindoline-2-carboxylate (prepared as described in Preparation 1.91 g of lithium aluminum hydride and 250 ml of tetrahydrofuran were used, to give 6.85 g of the title compound having Rf 0.35 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

*I 1 1 I II 4 I) 211 PREPARATION 7 5-[4-(l-Methylindolin-2-vlmethoxy)benzyll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 2.0 g of l-methylindolin-2ylmethanol (prepared as described in Preparation 6), 4.73 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.53 ml of tributylphosphine, 2.57 g of 1,1'-(azodicarbonyl)dipiperidine and 55 ml of benzene were used, to give 4.39 g of the title compound, melting at 62.5 65.5 0

C.

PREPARATION 8 Methyl indolin-l-ylacetate 0.40 ml of methyl bromoacetate was added dropwise to Sa mixture of 0.25 g of indoline, 2 ml of dimethylformamide and 0.87 g of anhydrous potassium carbonate, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the :'reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and Sdried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 5 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.30 g of the title compound having Rf 0.63 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

-4-Y- 5 0 6 S040 -212 PREPARATION 9 2-(Indolin-l-vl)ethanol A procedure similar to that described in Preparation 2 was repeated, except that 780 mg of methyl indolinl-ylacetate (prepared as described in Preparation 8), 200 mg of lithium aluminum hydride and 12 ml of anhydrous tetrahydrofuran were used, to give 580 mg of the title compound having Rf 0.31 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 5-f4-[2-(Indolin-1-.vl)ethoxy] benzl)}-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 240 mg of 2-(indolin-l-yl)ethanol (prepared as described in Preparation 690 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine- 2,4-dione, 0.37 ml of tributylphosphine, 370 mg of 1,1'-(azodicarbonyl)dipiperidine and 5 ml of anhydrous tetrahydrofuran were used, to give 530 mg of the title compound having Rf 0.88 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 11 5-{4-[2-(Indol-3-vl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2.4-dione A procedure similar to that described in Preparation 4 was repeated, except that 5.0 g of 2-(indol-3-yl)- LPIUa~--PI~-~- I 1) 1 t) I I A 1 I I I 1 4 I)0 -213 ethanol, 14.4 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 7.73 ml of tributylphosphine, 7.83 g of 1,l'-(azodicarbonyl)dipiperidine and 150 ml of anhydrous benzene were used, to give 3.03 g of the title compound, melting at 81.0 82.5 0

C.

PREPARATION 12 Methyl indol-l-vlacetate A solution of 5.0 g of indole in 20 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a mixture of 2.0 g of sodium hydride (as a 55% by weight dispersion in mineral oil, and which had previously been washed with hexane) and 80 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, 4.5 ml of methyl bromoacetate were added dropwise, whilst ice-cooling, to the mixture, which was then stirred at room temperature for 2 hours. After it had been stirred for this time, the reaction mixture was poured into ice-water, and then it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 6.52 g of the title compound having *Rf 0.66 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

e I 1I I II 6t 7 I I1 1 4 1 I) I) 214 PREPARATION 13 2-(Indol-l-yl)ethanol A procedure similar to that described in Preparation 2 was repeated, except that 6.20 g of methyl indol-l-ylacetate (prepared as described in Preparation 12), 1.50 g of lithium aluminum hydride and 220 ml of anhydrous tetrahydrofuran were used, to give 5.25 g of the title compound having Rf 0.33 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 14 5-{4-[2-(Indol-1-vl)ethoxlbenzvll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 2.0 g of 2-(indol-l-yl)ethanol (prepared as described in Preparation 13), 4.81 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.20 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of anhydrous benzene were used, to give 5.69 g of the title compound, melting at 63.5 65.9 0

C.

PREPARATION 3-Methylimidazo[5,4-b] pyridin-2-vlmethanol 3.35 g of imidazo[5,4-b]pyridin-2-ylmethanol were added to a mixture of 0.98 g of sodium hydride (as a by weight dispersion in mineral oil, and which had previously been washed with hexane) and 100 ml of dimethylformamide, and the resulting mixture was stirred I I 1 1) 4 1) 215 at room temperature for 6 hours, after which 3.51 g of methyl iodide were added to the mixture, whilst ice-cooling. The mixture was then stirred at room temperature for 15 hours. At the end of this time, the reaction mixture was freed from dimeth,. ormamide by distillation under reduced pressure. residue thus obtained was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1 0 to 10 1 by volume as the eluent, to give 1.7 g of the title compound, melting at 229 231 0

C.

PREPARATION 16 5-(4-(3-Methylimidazof5,4-blvpridin-2-vlmethoxy)benzvll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 3-methylimidazo- [5,4-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 1.43 g of 5-(4-hydroxybenzyl)-3triphenylmethylthiazolidine-2,4-dione, 0.83 ml of tribucylphosphine, 0.773 g of 1,1'-(azodicarbonyl)dipiperidine and 80 ml of benzene were used, to give 0.3 g of the title compound, melting at 97 102 0

C.

PREPARATION 17 Methyl 7-azaindol-l-acetate A procedure similar to that described in Preparation 12 was repeated, except that 1.90 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.95 g of 7-azaindol, 100 ml of dimethylformamide and 4.2 ml of methyl bromoacetate were used, to give 7.70 g of the title compound having Rf 0.33 (on silica gel thin illll~ 1 506 11854 2 5 3 2 0 4 3 216 layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 18 2-(7-Azaindol-1-vl)ethanol A procedure similar to that described in Preparation 2 was repeated, except that 7.50 g of methyl 7-azaindol- 1-acetate (prepared as described in Preparation 17), 1.80 g of lithium aluminum hydride and 260 ml of anhydrous tetrahydrofuran were used, to give 5.57 g of the title compound, melting at 52.7 53.30C.

PREPARATION 19 5-{4-[2-(7-Azaindol-1-yl)ethoxylbenzyl}-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 1.77 g of 2-(7-azaindol-lyl)ethanol (prepared as described in Preparation 18), 4.40 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.35 ml of tributylphosphine, 2.39 g of l,l'-(azodicarbcnvl)dipiperidine and 45 ml of anhydrous benzene were used, to give 4.58 g of the title compound, melting at 167.5 168.9 0

C.

PREPARATION Imidazo l.2-alpyridin-2-vlmethanol 3.68 g of lithium borohydride were added at room temperature to a solution of 9.17 g of ethyl imidazo[l,2-a]pyridine-2-carboxylate [described in J.

Org. Chem., 30, 2403 2407 (1965)] in 200 ml of q 5 06 1 1 5 S0 4 0 217 tetrahydrofuran, and then 20 ml of methanol were added dropwise to the mixture, which was then allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was diluted with 10 ml of water and then concentrated by evaporation under reduced pressure. The concentrate was mixed with an aqueous solution of sodium chloride, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5 1 by volume mixture of ethyl acetate and ethanol as the eluent. The product was then recrystallized from a mixture of ethyl acetate and hexane, to give 0.56 g of the title compound, melting at 126 128 0

C.

PREPARATION 21 5-{4-(Imidazo[l,2-a]pyridin-2-ylmethoxy)benzyl 3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 920 mg of imidazo[1,2-a]pyridin-2-ylmethanol (prepared as described in Preparation 20), 2.9 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.4 g of tributylphosphine, 1.65 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of benzene were used, to give 3.1 g of the title compound having Rf 0.71 (on silica gel thin layer chromatography using a 10 1 by volume mixture of ~ethyl acetate and ethanol as the developing solvent).

L lc~ -Cd L~ns~PLILPIIIIIY~ 9506 7 8 a 5 4 2 5 32 I 04 a 218 PREPARATION 22 Methyl l-methylindole-2-carboxylate ml of methyl iodide were added dropwise to a mixture of 5.00 g of indole-2-carboxylic acid, 100 ml of dimethylformamide and 13.0 g of anhydrous potassium carbonate, and the resulting mixture was stirred at 100 0 C for 6 hours. At the end of this time, the reaction mixture was worked up following the procedure described in Preparation 5, to give 5.12 g of the title compound, melting at 91.3 92.8 0

C.

PREPARATION 23 1-Methylindol-2-vlmethanol A solution of 5.05 g of methyl l-methylindole-2carboxylate (prepared as described in Preparation 22) in 20 ml of anhydrous tetrahydrofuran was added dropwise to a mixture of 1.85 g of lithium borohydride and 80 ml of anhydrous tetrahydrofuran, and the resulting mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl aceta-e. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 4.30 g of the title compound, melting at 92.8 95.2 0

C.

,-II

s~s~l~rrarrrmr.l l~l~ 0 6 71L 6 4 1 S0 4 219 PREPARATION 24 5-[4-(l-Methylindol-2-vlmethoxy)benzyll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 4.30 g of l-methylindol-2ylmethanol (prepared as described in Preparation 23), 10.3 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 6.65 ml of tributylphosphine, 6.73 g of 1,1'-(azodicarbonyl)dipiperidine and 120 ml of benzene were used, to give 6.28 g of the title compound, melting at 134.3 136.00C.

PREPARATION Ethyl imidazo[l,2-alpyridin-2-vlacetate A solution of 14.6 g of 2-aminopyridine and 25.5 g of ethyl 4-chloroacetoacetate in 200 ml of acetonitrile was heated under reflux for 14.5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue thus obtained was mixed with an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give S2.65 g of the title compound having Rf 0.33 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).

4 I 71 54 1 2 S 2 220 PREPARATION 26 2-(2-Hydroxvethyl)imidazofl,2-alpyridine A procedure similar to that described in Preparation 2 was repeated, except that 2.65 g of ethyl imidazo- [1,2-a]pyridin-2-ylacetate (prepared as described in Preparation 25), 0.5 g of lithium aluminum hydride and 100 ml of tetrahydrofuran were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 20 1 to 4 1 by volume as the eluent, to give 1.32 g of the title compound, melting at 120.3 126.9 0

C.

PREPARATION 27 (Imidazo[l,2-a pyridin-2-vl)ethoxy}benzyl '3-triphenylmethvlthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.80 g of 2-(2-hydroxyethyl)imidazo[1,2-a]pyridine (prepared as described in Preparation 26), 2.79 g of 5-(4-hydroxybenzyl)-3triphenylmethylthiazolidine-2,4-dione, 1.7 ml of tributylphosphine, 1.51 g of 1,1'-(azodicarbonyl)dipiperidine and 30 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 4 to 0 1 by volume as the eluenL, to give 0.97 g of the title compound, melting at 135.5 142.4 0 C (with decomposition).

BtYlli~QIPaolr~rs~isa-~- 1 506 71 54 I '040 221 PREPARATION 28 3-Ethyl-2-hydroxymethylimidazoF5,4-blpyridine 3 g of 2-hydroxymethyl-3H-imidazo[5,4-b]pyridine were added to a suspension of 0.87 g of sodium hydride (as a 55% by weight dispersion in mineral oil, and which had previously been washed with hexane) in 80 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 2 hours. After that, 1.78 ml of ethyl iodide were added dropwise to the mixture while cooling with ice, and the resulting mixture was stirred at room temperature for 2 hours, after which it was allowed to stand overnight. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1 0 to "5 1 by volume as the eluent, to give 570 mg of the title compound, melting at 117 121 0

C.

PREPARATION 29 5--4-(3-Ethvlimidazo[5,4-blyvridin-2-ylmethoxy)benzvl}-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 3-ethyl-2-hydroxymethylimidazo[5,4-b]pyridine (prepared as described in Preparation 28), 1.313 g of 5-(4-hydroxybenzyl)-3triphenylmethylthiazolidine-2,4-dione, 0.77 ml of tributylphosphine, 0.712 g of 1,1'-(azodicarbonyl)dipiperidine and 80 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica

C-I

I~t~ 1 0 6 SI l 5 4 1 I) A 0 A 222 gel, using a 1 3 by volume mixture of hexane and ethyl acetate as the eluent, to give 300 mg of the title compound having Rf 0.55 (on silica gel thin layer chromatography using a 1 3 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 2-Hydroxvmethyl-l-methylimidazo 4,5-b pvridine A procedure similar to that described in Preparation was repeated, except that 45 g of 2-hydroxymethyl-3Himidazo[5,4-b]pyridine, 13.17 g of sodium hydride (as a by weight dispersion in mineral oil), 20.7 ml of methyl iodide and 1.43 liter of dimethylformamide were used, to give the title compound as a crude product.

This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from i 0 to 1 1 by volume as the eluent, to give 3.24 g of the title compound, melting at 130 132 0

C.

PREPARATION 31 5- 4- (l-Methylintidazo[4,5-b pyridin-2-vlmethoxy) benzyl}-3-triphenvlmethvlthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 2.5 g of 2-hydroxymethyl-l- (prepared as described in Preparation 30), 6.5 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.47 ml of tributylphosphine, 3.52 g of 1,1'-(azodicarbonyl)dipiperidine and 250 ml of 1,4-dioxane were used, to give the title compound as a crude product. This crude I, 1I 2 1 )1 040 S- 223 product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 1 to 0 1 by volume and subsequently mixtures of ethyl acetate and methanol in ratios ranging from 1 to 10 1 by volume as the eluent, to give 4.1 g of the title compound.

PREPARATION 32 4-Hydroxybutyric acid A 2 N aqueous solution of sodium hydroxide was added to a solution of 10.0 g of y-butyrolactone in 100 ml of methanol, and the resulting mixture was allowed to stand overnight. At the end of this time, the reaction mixture was neutralized by adding 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 3.70 g of the title compound as an oil.

PREPARATIOL 33 2-(3-Hydroxypropl) -3H-imidazof5,4-b]pvridine o 0.83 g of 4-hydroxybutyric acid (prepared as described in Preparation 32) was added to 0.77 g of 2,3-diaminopyridine, and the resulting mixture was stirred at 150°C for 4 hours. At the end of this time, the reaction mixture was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness under reduced pressure, and then IlyBs~rrrrreaarra~--~~ 9 506 7 1 8 5 4 S2532 95040 224 the resulting residue was purified by column chromatography through silica gel, u-.ing a 5 1 by volume mixture of ethyl acetate and methanol as the eluent. The product was crystallized by trituration with ethyl acetate, to give 0.83 g of the title compound, melting at 151 153 0

C.

PREPARATION 34 2-(3-Hydroxvyropvl)-3-methylimidazo[5,4-bvpyridine A procedure similar to that described in Preparation was repeated, except that 3.40 g of 2-(3-hydroxypropyl)-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 33), 0.81 g of sodium hydride (as a by weight dispersion in mineral oil), 1.2 ml of methyl Siodide and 100 ml of dimethylformamide were used, to "give the title compound as a crude product. This crude product was purified by column chromatograpy through Ssilica gel, using a 10 1 by volume mixture of ethyl S: acetate and methanol as the eluent. The product was crystallized by trituration with ethyl acetate, to give 3.10 g of the title compound, melting at >300 0

C.

PREPARATION 4--3-(3-Methvlimidazor5,4-blpyridin-2-vl)oropoxybenzyll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 750 mg of 2-(3-hydroxypropyl)-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 34), 1.83 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.98 ml of tributylphosphine, 990 mg of 1,1'-(azodicarbonyl)di-

I

i506 1Plilllsti54a-- 1 506 I 854 S- 225 piperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 1 to 0 1 by volume as the eluent, to give 550 mg of the title compound, melting at 76 81 0

C.

PREPARATION 36 Methyl 4-nitrophenoxyacetate A solution of 56 g of 4-nitrophenol, 90 g of methyl bromoacetate and 100 g of potassium carbonate in 500 ml of dimethylformamide was stirred at room temperature for 2 days. At the end of this time, the reaction mixture Swas freed from dimethylformamide by distillation under i reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was crystallized by trituration with hexane, to give 63.3 g of the title compound, melting at 98 99 0

C.

'PREPARATION 37 Methyl 4-aminophenoxyacetate A procedure similar to that described in Example 6 was repeated, except that 30.8 g of methyl 4-nitrophenoxyacetate (prepared as described in Preparation 36), 5.0 g of 10% w/w palladium-on-charcoal and 500 ml of methanol were used, to give 25.8 g of the title compound having Rf 0.79 (on silica gel thin layer IIIII r I- 5 1) 6 .I 1 1 4 1i 1 1~ I 1)U 4 226 chromatography using ethyl acetate as the developing solvent).

PREPARATION 38 Methyl 4-(2-bromo-2-butoxvcarbonvlethyl)phenoxyacetate 98 g of 47% w/v aqueous hydrobromic acid and subsequently 33 ml of an aqueous solution containing 12.8 g of sodium nitrite were added dropwise to a solution of 25.8 g of methyl 4-aminophenoxyacetate (prepared as described in Preparation 37) in 263 ml of a 2 5 by volume mixture of methanol and acetone, whilst cooling with ice, and the resulting mixture was stirred for 30 minutes whilst cooling with ice. 18.2 g of butyl acrylate were then added. The mixture was then stirred for 30 minutes while cooling with ice, after which 3.2 g of copper(I) bromide were added and the resulting mixture was stirred overnight at room temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue was diluted with an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure, to give 51.7 g of a crude product containing the title compound and having Rf 0.46 (on silica gel thin layer chromatography using a 5 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

S506 S5 1 32 0 0 S- 227 PREPARATION 39 5-[4-(Ethoxycarbonvlmethoxy)benzyllthiazolidine-2,4-dione A solution of 100 g of methyl 4-(2-bromo-2-butoxycarbonylethyl)phenoxyacetate (prepared as described in Preparation 38) and 22 g of thiourea in 200 ml of ethanol was heated under reflux for 2.5 hours. After that, 2 N aqueous hydrochloric acid was added to the mixture, and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was diluted with water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromataography Sthrough silica gel, using a 2 E by volume mixture of ethyl acetate and hexane as the eluent, to give 19.4 g of the title compound, melting at 105 106 0

C.

PREPARATION 3,7-Dimethyl-2-hydroxymethylimidazo f5,4-blpyridine A procedure similar to that described in Preparation was repeated, except that 5.00 g of 2-hydroxymethyl- 7-methyl-3H-imidazo[5,4-b]pyridine, 1.34 g of sodium hydride (as a 55% by weight dispersion in mineral oil), ml of methyl iodide and 120 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and I I I g 1) 4 0 228 methanol in ratios ranging from 1 0 to 10 1 by volume as the eluent, to give 4.4 g of the title compound, melting at >300 0

C.

PREPARATION 41 4-(3,7-Dimethylimidazo 5,4-b pyridin-2-ylmethoxy)benzyl -3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 1.50 g of 3,7-dimethyl-2hydroxymethylimidazo[5,4-b]pyridine (prepared as described in Preparation 40), 3.94 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.11 ml of tributylphosphine, 2.14 g of 1,1'-(azodicarbonyl)dipiperidine and 30 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 1 to S1 2 by volume as the eluent, to give 1.11 g of the title compound, melting at 92 105 0 C (softening).

0* PREPARATION 42 6-Chloro-2,3-diaminopyridine A mixture of 12.0 g of 2-amino-6-chloro-3-nitropyridine, 78.0 g of tin(II) chloride dihydrate and 360 ml of a 9 1 by volume mixture of ethyl acetate and 2-methyl-2-propanol was stirred at 60 0 C for 1 hour, after which 1.32 g of sodium borohydride were added at 0 C, and the mixture was stirred for 3 hours at the same temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was diluted I I II 2 5 1 2 1 S 0 4 0 229 with water and neutralized by adding an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 6.50 g of title compound, melting at 120 122 0

C.

PREPARATION 43 5-Chloro-2-hydroxvmethyl-3H-imidazo[5,4-blpyridine 6.60 g of glycolic acid were added to 5.00 g of 6-chloro-2,3-diaminopyridine (prepared as described in Preparation 42), and the resulting mixture was stirred at 150 0 C for 4 hours. At the end of this time, the reaction mixture was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the Saddition of aqueous ammonia. The aqueous mixture was evaporated to dryness, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1 0 to 1 by volume as the eluent. The product was then crystallized by trituration with ethyl acetate, to give 5.33 g of the title compound, melting at 224 226 0

C.

PREPARATION 44 5-Chloro-2-hydroxvmethyl-3-methylimidazor5,4-blpyr-dine A procedure similar to that described in Preparation was repeated, except that 3.00 g of 5-chloro-2hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as

-I'

06 7 18 54 1 040 S- 230 described in Preparation 43), 0.71 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.1 ml of methyl iodide and 70 ml of dimethylformamide were used, to give the title compound as a crude product.

This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1 0 to 10 1 by volume as the eluent, to give 1.60 g of the title compound, melting at 204 210 0

C.

PREPARATION 5-{4-(5-Chloro-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl -3-triphenylmethylthiazolidine-2,4-dione e* A procedure similar to that described in Preparation 4 was repeated, except that 1.20 g of 5-chloro-2hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 44), 2.83 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.51 ml of tributylphosphine, 1.53 g of 1,1'-(azodicarbonyl)dipiperidine and 25 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 2 1 to 1 1 by volume as the eluent, to give 1.29 g of the title compound, melting at 97 99 0 C (softening).

PREPARATION 46 5-4 (2,2-Diethoxvethoxy)benzvllthiazolidine-2,4-dione 530 mg of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione WO6I 7jI-- -54-- 9 06 S18 54 S- 231 were added to a suspension of 260 mg of sodium hydride (as a 55% by weight dispersion in mineral oil, and which had previously been washed with toluene) in 5 ml of dimethylformamide, whilst cooling with ice, and the resulting mixture was stirred at room temperature for minutes. At the end of this time, 0.73 ml of bromoacetaldehyde diethyl acetal was added to the mixture, whilst cooling with ice, and the reselting mixture was stirred at 50 0 C for 3 hours. The reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The resulting residue was diluted with water and the aqueous mixture was adjusted to a pH of from 2 to 3 by the addition of 1 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2 1 by volume mixture of '*hexane and ethyl acetate as the eluent, to give 600 mg of the title compound having Rf 0.46 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 47 45- 4-(2-Oxoethoxy)benzyl thiazolidine-2,4-dione ml of 6 N aqueous hydrochloric acid were added to a solution of 10.07 g of 5-[4-(2,2-diethoxyethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 46) in 80 ml of tetrahydrofuran, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction I I= dld~L_ 9 O 0 4 0) 232 mixture was freed from the solvent by distillation under reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2 3 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.92 g of the title compound having Rf 0.37 (on silica gel thin layer chromatography using a 1 2 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 48 2 -Hydroxymethyl -3H-imidazo [5 4-dl yrimidine 8.58 g of ethyl glycolate were added to 2.27 g of 4,5-diaminopyrimidine, and the resulting mixture was stirred at 140 0 C for 2 hours. At the end of this time, the reaction mixture was freed from et'hyl glycolate by distillation under reduced pressure. The residue thus obtained was decolorized by activated charcoal and crystallized by trituration with ethanol, to give 1.81 g of the title compound having Rf 0.27 (on silica gel i a thin layer chromatography using a 10 1 by volume mixture of ethyl acetate and methanol as the developing solvent).

PREPARATION 49 2-t-Butyldimethylsilyloxymethyl-3H-imidazof5.4-dlpyrimidine A mixture of 1.81 g of 2-hydroxymethyl-3H-imidazo- [5,4-d]pyrimidine (prepared as described in Preparation se 0 0 -233 48), 2.71 g of t-butyldimethylsilyl chloride, 2.45 g of imidazole and 100 ml of dimethylformamide was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.89 g of the title compound, melting at 104 107 0

C.

PREPARATION 2-Hydroxvmethyl-3-methylimidazo[5,4-dlpyrimidine A procedure similar to that described in Preparation was repeated, except that 1.89 g of 2-t-butyldimethylsilyloxymethyl-3H-imidazo[5,4-d]pyrimidine (prepared as described in Preparation 49), 0.37 g of sodium hydride (as a 55% by-weight dispersion in mineral oil), 490 pl of methyl iodide and 30 ml of dimethylformamide were used. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness, and the resulting residue was purified by column chromatography through silica gel, using a 6 1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 0.37 g of the title compound, melting at 122 125 0

C.

~I~LII~P~ IYIPIC-- S I f 7 I 0 4 I S a 4 234 PREPARATION 51 4-(3-Methylimidazof5,4-d]pyrimidin-2-ylmethoxy)benzyl -3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.37 g of 2-hydroxymethyl-3methylimidazo[5,4-d]pyrimidine (prepared as described in Preparation 50), 2.51 g of 5-(4-hydroxybenzyl)-3triphenylmethylthiazolidine-2,4 dione, 1.34 ml of tributylphosphine, 1.36 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of S* hexane and ethyl acetate in a ratio of 2 1 by volume, o*e "and then in ratios ranging from 1 1 to 1 2 by o.-o volume, and subsequently a 6 1 by volume mixture of ethyl acetate a- ethanol as the eluent. The desired Sfractions were collected and concentrated by evaporation under reduced pressure. The concentrate was further purified by preparative reverse-phase high speed liquid chromatography through YMC-Pack ODS-A (a product of YMC Inc.) using a 100 100 1 1 by volume mixture of acetonitrile, water, acetic acid and triethylamine as the eluent, to give 0.24 g of the title compound, melting at 55 65 0 C (softening).

PREPARATION 52 2-(4-Chlorobenzyl)amino-3-nitropyridine A mixture of 10.3 g of 2-hydroxy-3-nitropyridine and 25.5 ml of thionyl chloride was heated under reflux for hours, after which 1.1 ml of dimethylformamide were rapidly added to the mixture, which was then heated .Y I 411LII~- 9 5 06 718 5 4 25 6 5 2 32 I 0 Q4 -235 under reflux for 2.5 hours. At the end of this time, the reaction mixture was freed from the solvent by evaporation under reduced pressure. 80 ml of toluene and 19.1 g of sodium carbonate were added to the residue thus obtained, and then a solution of 12.3 ml of 4-chlorobenzylamine in 20 ml of toluene was added dropwise to the resulting mixture, which was then stirred at 85 0 C for 4 hours. At the end of this time, the insoluble material in the reaction mixture was removed by filtration. The filtrate was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was crystallized by trituration with 2-propanol, to give 12.0 g of the title compound, melting at 95 96 0

C.

PREPARATION 53 3-Amino-2-(4-chlorobenzyl)aminopyridine A procedure similar to that described in Preparation 42 was repeated, except that 5.00 g of 2-(4-chlorobenzyl)amino-3-nitropyridine (prepared as described in Preparation 52), 21.4 g of tin(II) chloride dihydrate, 0.36 g of sodium borohydride and 150 ml of a 9 1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product. This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 3.55 g of the title compound, melting at 123 125 0

C.

~YI~P~6~PIBIYIII 9 5 0 6 7 1 8 5 4 0 4) 236 PREPARATION 54 2-Hydroxvmethyl-3-(4-phenylbenzyl)imidazo 5,4-b pyridine 3.74 g of 2-hydroxymethyl-3H-imidazo[5,4-b]pyridine were added to a suspension of 1.1 g of sodium hydride (as a 55% by weight dispersion in mineral oil, and which had previously been washed with hexane) in 100 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 2 hours. After that, a solution of 5.07 g of 4-(chloromethyl)biphenyl in 20 ml of dimethylformamide was added dropwise to the mixture, whilst cooling with ice, and the resulting mixture was stirred at room temperature for 2 hours. It was then allowed to stand overnight. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1 3 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.8 g of the title compound, melting at 163 165 0

C.

Set°, PREPARATION (4-Phenylbenzvl)imidazo[f5,4-blvpyridin-2-yl methoxvlbenzvll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 2-hydroxymethyl- 3-(4-phenylbenzyl)imidazo[5,4-b]pyridine (prepared as described in Preparation 54), 0.738 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.43 ml of tributylphosphine, 0.4 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of benzene were used, to give the title compound as a crude product. This crude product I i _y 'i Q 4 1' ~6Ba~pr~~ 4 I) 6 I 1 11 237 was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 2 to 1 3 by volume as the eluent, to give 0.95 g of the title compound having Rf 0.44 (on silica gel thin layer chromatography using a 1 3 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 56 2-Amino-5-bromo-3-nitropyridine 100 ml of concentrated sulfuric acid were added to 25.0 g of 2-amino-5-bromopyridine, and 8.9 ml of concentrated nitric acid were then added dropwise to the S mixture at a temperature of 50 to 60 0 C over a period of 1 hour. The mixture was then stirred at 60 0 C for minutes. At the end of this time, the reaction mixture 'was poured into ice-water and neutralized by the addition of an aqueous solution of sodium hydroxide.

The crystals which precipitated were collected by filtration and washed with ethanol, to give 19.1 g of the title c.mpound, melting at 180 1820C.

PREPARATION 57 5-Bromo-2,3-diaminoDyridine A procedure similar to that described in Preparation 42 was repeated, except that 12.0 g of 3-nitropyridine (prepared as described in Preparation 56), 62.1 g of tin(II) chloride dihydrate, 1.04 g of sodium borohydride and 300 ml of a 9 1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product.

This crude product was crystallized by trituration with I 1 8 5 4 SA 2 I 0 4 0 S- 238 a mixture of ethyl acetate and hexane, to give 7.46 g of the title compound, melting at 135 1370C.

PREPARATION 58 6-Bromo-2-hydroxymethyl-3H-imidazo[5,4-bl nyridine A procedure similar to that described in Preparation 43 was repeated, except that 7.00 g of 5-bromo-2,3diaminopyridine (prepared as described in Preparation 57) and 8.50 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.05 g of the title compound, melting at 230 233 0

C.

PREPARATION 59 6-Bromo-2-hydroxymethyl-3-methylimidazo[5,4-blpyridine A procedure similar to that described in Preparation was repeated, except that the reaction was conducted using 3.00 g of 6-bromo-2-hydroxymethyl-3H-imidazo- [5,4-b]pyridine (prepared as described in Preparation 58), 0.58 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 0.92 ml of methyl iodide and ml of dimethylformamide. After completion of the reaction with methyl iodide, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by 9506 7 18 54 5040 A 239 column chromatography through silica gel, using a 50 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.40 g of the title compound, melting at 142 1440C.

PREPARATION E-_4-(6-Bromo-3-methylimidazo[5, 4-blpyridin-2-ylmethoxy)benzyl -3-triphenvlmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of 6-bromo-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 59), 2.60 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.39 ml of tributylphosphine, 1.41 g of 1,1'-(azodicarbonyl)dipiperidine and 35 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.43 g of the title compound, melting at 97 1000C (softening).

.PREPARATION 61 2-Amino-5-chloro-3-nitropyridine A procedure similar to that described in Preparation 56 was repeated, except that 25.0 g of pyridine, 100 ml of concentrated sulfuric acid and 12.5 ml of concentrated nitric acid were used, to give 18.5 g of the title compound, melting at 138 1390C.

1 06 11 A 4I) 240 PREPARATION 62 5-Chloro-2,3-diaminopyridine A procedure similar to that described in Preparation 42 was repeated, except that 12.5 g of 3-nitropyridine (prepared as described in Preparation 61), 82.0 g of tin(II) chloride dihydrate, 1.35 g of sodium borohydride and 300 ml of a 9 1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product.

This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 8.14 g of the title compound, melting at 164 165 0

C.

PREPARATION 63 6-Chloro-2-hydroxymethyl-3H-imidazo 5,4-b pyridine A procedure similar to that described in Preparation 43 was repeated, except that 7.67 g of 5-chloro-2,3diaminopyridine (prepared as described in Preparation 62) and 18.6 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 8.83 g of the title compound, melting at 209 211 0

C.

PREPARATION 64 6-Chloro-2-hvdroxvmethyl -3-methylimidazo l5,4-blpyridine A procedure similar to that described in Preparation 59 was repeated, except that 3.00 g of 6-chloro-2hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as "I I 'I II I I S 4 I 0 4 I 1 241 described in Preparation 63), 0.71 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.03 ml of methyl iodide and 50 ml of dimethylformamide were used, to give the title compound as a crude product.

This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1 0 to 50 1 by volume as the eluent, to give 0.87 g of the title compound, melting at 141 142°C.

PREPARATION 5-14-(6-Chloro-3-mechylimidazo[5,4-bvpyridin-2-ylmethoxy)benzyll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.52 g of 6-chloro-2hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 64), 1.23 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.66 ml of tributylphosphine, 0.67 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.51 g of the title compound, melting at 82 84 0 C (softening).

PREPARATION 66 6-Chloro-2-methylamino-3-nitropyridine 20.0 ml of a 30% ethanolic solution of methylamine were added dropwise to a mixture of 29.0 g of 242 2,6-dichloro-3-nitropyridine, 300 ml of ethanol and 36.6 g of sodium carbonate, whilst cooling with ice, and the resulting mixture was stirred at room temperature for 8 hours. At the end of this time, the reaction mixture was freed from ethanol by distillation. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 22,3 g of the title compound, melting at 114 0

C.

PREPARATION 67 6-Methoxy-2-mnethylamino-3-nitropyridine 19 ml of a 28% methanolic solution of sodium methoxide were added dropwise to a solution of 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66) in 120 ml of methanol at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 5.34 g of the title compound, melting at 152 153 0

C.

-C IBI n ~rOl6 i? c~aqlnu 11854~iinrv 2 5? aO4 9 06 6 71 854 2 5 )7 9 50 4 243 PREPARATION 68 3-Amino-6-methoxy-2-methylaminopvridine A procedure similar to that described in Example 6 was repeated, except that 3.45 g of 6-methoxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 67), 0.70 g of 10% w/w palladium-on-charcoal and 50 ml of dioxane were used, to give 2.66 g of the title compound having Rf 0.12 (on silica gel thin layer chromatography using a 1 1 by volume mixture of hexane and echyl acetate as the developing solvent).

PREPARATION '.9 2-Hydroxymethyl-5-methoxy-3-methyl iidazo 5 4 -bl pyridine A solution of 2.20 g of 3-amino-6-methoxy-2-methylaminopyridine (prepared as described in Preparation 68) and 3.30 g of glycolic acid in 40 ml of toluene was heated under reflux for 4 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 30 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 620 mg of the title compound, melting at 138 140 0

C.

1-- 9506 71854 2532 95040 S- 244 PREPARATION 5-{4-(5-Methoxy-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyll-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.25 g of methoxy-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 69), 0.66 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.35 ml of tributylphosphine, 0.36 g of l,l'-(azodicarbonyl)dipiperidine and 15 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.70 g of the title compound, melting at 80 85 0 C (softening).

PREPARATION 71 2-t-Butyldimethylsilyloxvmethyl-1H-imidazo- A procedure similar to that described in Preparation 49 was repeated, except that 5.00 g of 2-hydroxymethyl- 1H-imidazo[4,5-c]pyridine, 6.85 g of imidazole, 7.58 g of t-butyldimethylsilyl chloride and 100 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.40 g of the title compound, melting at 53 550C.

9506 7 1854 2532 5040 245 PREPARATION 72 2-t-Butyldimethylsilvloxymethyl-1-methylimidazo- A procedure similar to that described in Preparation 59 was repeated, except that 7.4 g of 2-t-butyldimethylsilyloxymethyl-1H-imidazo[4,5-c]pyridine (prepared as described in Preparation 71), 1.23 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.0 ml of methyl iodide and 200 ml of dimethylformamide were used, to give the title compound as a crude product.

This crude product was purified by column chromatography through silica gel, using a 10 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.30 g of the title compound, melting at 93 95 0

C.

PREPARATION 73 S2-Hydroxymethyl-l-methylimidazo A solution of 3.00 g of 2-t-butyldimethylsilyloxy- (prepared as described in Preparation 72) in 60 ml of a 1 1 1 by volume mixture of tetrahydrofuran, acetic acid and water was stirred at room temperature for 1 hour and then at 0 C for 5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 10 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.97 g of the title compound, melting at 285 290 0

C.

inOli*ic~~il~nlSmni~lyn~~~mrrr~vn,~a~7* '.unrrruu rUIIYlnlllWIIYI~.I IY~:~IYLIYI~UUYe~P~yl- -L~-~YYIYU L-I- C 9 5 0 7 1 a 5 j S252 0 4 0 246 PREPARATION 74 4- (1-Methylimidazo[4,5-clpvridin-2-ylmethoxy)benzyll-3-triphenvlmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 1.94 g of 2-hydroxymethyl- (prepared as described in Preparation 73), 5.71 g of 5-(4-hyaroxybenzyl)-3triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.09 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1 0 to 10 1 by volume as the eluent, to give 3.55 g of the title compound having Rf 0.08 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).

PREPARATION 2-Chloro-3-formylpyridine 200 ml of a 1.02 M hexane solution of diisobutylaluminum hydride were added to a solution of 16.7 g of 2-chloro-3-cyanopyridine in 200 ml of tetrahydrofuran at a temperature of -300 to 20 0 C over a period of minutes, after which the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, hydrochloric acid was added to the reaction mixture at 0°C, and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that 9506 71854 2532 95040 247 order, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 6 1 to 5 1 by volume as the eluent, to give 7.0 g of the title compound having Rf 0.50 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 76 Ethyl 2-azido-3-(2-chloropyridin-3-yl)-3-hydroxy- S. propionate A mixture of 2.0 g of 2-chloro-3-formylpyridine (prepared as described in Preparation 75), 7.5 g of ethyl azidoacetate and 87 ml of a 65 mM ethanolic solution of sodium ethoxide was stirred at 0°C for 2 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 3 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.83 g of the title compound having Rf 0.61 (on silica gel thin layer chromatography using a 2 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

FT 1~r~r ~bMian~Mll~YYi 9506 7185 2532 50 248 PREPARATION 77 Ethyl 2-azido-3-t-butyldimethylsilyloxy-3- (2-chloropyridin-3-vyl)ropionate A procedure similar to that described in Preparation 49 was repeated, except that 3.90 g of ethyl 2-azido-3- (2-chloropyridin-3-yl)-3-hydroxypropionate (prepared as described in Preparation 76), 8.6 g of t-butyldimethylsilyl chloride, 10 g of imidazole and 80 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 8 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.6 g of the title compound having .:Rf 0.31 (on silica gel thin layer chromatography using a 3 1 by volume mixture of hexane and ethyl acetate as S. the developing solvent).

6 PREPARATION 78 Ethyl 2-amino-3-t-butvldimethylsilyloxy-3- (2-chlorovpridin-3-vl) propionate A mixture of 5.6 g of ethyl 2-azido-3-t-butyldimethylsilyloxy-3-(2-chloropyridin-3-yl)propionate (prepared as described in Preparation 77), 7.5 g of triphenylphosphine and 18 ml of a 8 1 by volume mixture of tetrahydrofuran and water was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 5 1 by volume mixture of hexane and ethyl acetate and subsequently a 50 1 by volume mixture of methylene chloride and methanol as the eluent, to give 5.9 g of 9506 7 1 854 2532 95040 249 the title compound having Rf 0.59 (on silica gel thin layer chromatography using a 15 1 by volume mixture of methylene chloride and methanol as the developing solvent).

PREPARATION 79 Ethyl 3-t-butvldimethylsilvloxy-3-(2-chloropyridin- 3-vl)-2-methylaminopropionate 182 mg of 35% formalin, 0.1 ml of acetic acid and 121 mg of sodium cyanoborohydride were added to a solution of 0.7 g of ethyl 2-amino-3-t-butyldimethylsilyloxy-3-(2-chloropyridin-3-yl)propionate (prepared as described in Preparation 78) in 4 ml of a 3 2 by *a volume mixture of methylene chloride and water at 0°C, and the resulting mixture was stirred at 0°C for minutes. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 8 1 to 1 1 by volume as the eluent, to give 200 mg of the title compound having Rf 0.38 (on silica gel thin layer chromatography using a 3 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

9506 7 18 5 4 2532 95040 250 PREPARATION Ethyl l-methyl-7-azaindole-2-carboxylate A solution of 994 mg of ethyl 3-t-butyldimethylsilyloxy-3-(2-chloropyridin-3-yl)-2-methylaminopropionate (prepared as described in Preparation 79) and 393 mg of 1,5-diazabicyclo[4.3.0]non-5-ene in 5 ml of dimethylformamide was stirred at 150 0 C for 5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 9 1 to 5 1 by volume as the eluent, to give 150 mg of the title compound having Rf 0.40 (on silica gel thin layer chromatography using a 3 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 81 2-Hydroxvmethyl-1-methyl-7-azaindole A procedure similar to that described in Preparation 2 was repeated, except that 130 mg of ethyl l-methyl-7azaindole-2-carboxylate (prepared as described in Preparation 80), 23 mg of lithium aluminum hydride and 2 ml of tetrahydrofuran were used, to give 110 mg of the title compound having Rf 0.47 (on silica gel thin layer chromatography using a 3 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

m l I 9 5 0 6 7 185 4 2532 95040 0 251 PREPARATION 82 4-(1-Methyl-7-azaindol-2-ylmethoxy)benzyll- 3-triphenylmethylthiazolidine-2,4-dione A solution of 103 mg of 2-hydroxymethyl-l-methyl- 7-azaindole (prepared as described in Preparation 81), 346 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 166 mg of diethyl azodicarboxylate and 250 mg of triphenylphosphine in 3 ml of tetrahydrofuran was stirred at room temperature for hours. At the end of this time, the reaction mixture was freed from the solvent by distillation, The resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 5 1 to 4 1 by volume as the eluent, to give 277 mg of the title compound having Rf 0.41 (on silica gel thin layer chromatography using a 1 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

SPREPARATION 83 3-Nitro-2-phenylaminopyridine A procedure similar to that described in Preparation 66 was repeated, except that 15 g of 2-chloro-3-nitropyridine, 13.22 g of aniline and 25.07 g of sodium carbonate were reacted in 180 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was purified by column chromatography through silica gel, using a 1 5 by volume mixture of ethyl acetate and hexane, to give 6.9 g of the title compound, melting at 66 68 0

C.

7 8 5 4 4 1 4 0 252 PREPARATION 84 3-Amino-2-phenylaminopvridine A procedure similar to that described in Example 6 was repeated, except that 6.9 g of 3-nitro-2-phenylaminopyridine (prepared as described in Preparation 83) was hydrogenated in a mixture of 150 ml of ethanol and ml of dioxane in the presence of 1.38 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.2 g of the title compound, melting at 137 140 0 C, were obtained.

PREPARATION 2 Hydroxymethyl-5,7-dimethyl-3H-imidazo[5,4-blpvridine A mixture of 13.72 g of 2,3-diamino-4,6-dimethylpyridine and 25 g of glycolic acid in 200 ml of toluene was heated under reflux for 3.5 hours, whilst distilling off azeotropically the water formed in the course of the reaction. At the end of this time, the reaction mixture was freed from the toluene by decantation and t'.e oily residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethanol and ethyl acetate in ratios ranging from 2 3 to 1 1 by volume as a eluent, to give 2.7 g of the title compound, melting at 244 246 0

C.

PREPARATION 86 2 Hydroxymethyl-3,5,7-trimethylimidazof5,4-b1pyridine A procedure similar to that described in Preparation was repeated, except that 2.6 g of 2-hydroxymethyl- 5,7-dimethyl-3H-imidazo[5,4-b]pyridine (prepared as 9506 6 7 1 8 5 4 9 4 0 253 described in Preparation 85), 0.64 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.2 g of iodomethane and 80 ml of dimethylformamide were used.

After working up the product as described in Preparation the resulting crude product was purified by column chromatography through silica gel, using a 1 6 by volume mixture of ethanol and ethyl acetate as the eluent, followed by recrystallization from ethyl acetate, to give 1.5 g of the title compound, melting at 178 179 0

C.

PREPARATION 87 5-f4- (3,5,7-Trimethylimidazof5,4-b]pyridin-2-vlmethoxy)benzyvl-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 1.47 g of 2-hydroxymethyl- 3,5,7-trimethylimidazo[5,4-b]pyridine (prepared as described in Preparation 86), 3.58 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.87 g of tributylphosphine, 2.33 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of toluene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.5 g of the title compound, melting at 96 99 0 C (softening).

PREPARATION 88 2-Methvlamino-3-nitro-6-phenylthiovyridine 3.6 ml of thiophenol were added dropwise to a

I~I~I

7 1 a 5 4 I '1 4 .1 U 254 suspension of 1.54 g of sodium hydride (as a 55% by weight dispersion in mineral oil, and which had previously been washed with hexane) in 30 ml of dimethylformamide, and the resulting mixture was stirred for 1 hour at room temperature. The mixture was then added dropwise to a solution of 6.00 g of 6-chloro-2methylamino-3-nitropyridine (prepared as described in Preparation 66) in dimethylformamide, whilst cooling with ice, and then the mixture was stirred at 5 0 C for 2 hours. At the end of this time, the reaction mixture was freed from the dimethylformamide by distillation under reduced pressure. The residue was mixed with water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 3 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.40 g of the title compound having Rf 0.67 (on silica gel thin layer "chromatography using a 3 1 by volume mixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 89 3-Amino-2-methylamino-6-phenylthiopyridine A procedure similar to that described in Example 6, was repeated, except that 5.40 g of 2-methylamino-3nitro-6-phenylthiopyridine (prepared as described in Preparation 88) were hydrogenated in 80 ml of methanol in the presence of 1.10 g of 10 w/w palladium-oncharcoal. After working up the product as described in Example 6, 4.00 g of the title compound having Rf 0.69 (on silica gel thin layer chromatography using ethyl

I

9506 7 18 54 S25 32 55040 255 acetate as the developing solvent) were obtained.

PREPARATION 2-Hydroxymethyl-3-methyl-5-phenylthioimidazof5,4-b pyridine A procedure similar to that described in Preparation 43 was repeated, except that 2.62.g of 3-amino-2-methylamino-6-phenylthiopyridine (prepared as described in Preparation 89) and 2.58 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 50 1 to 10 1 by volume as the eluent, to give 1.80 g of the title compound, melting at 119 120 0

C.

PREPARATION 91

*S

5-{4-(3-Methyl-5-phenylthioimidazo 5,4-bopyridin-2ylmethoxy)benzyl- 3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.70.g of 2-hydroxymethyl-3methyl-5-phenylthioimidazo[5,4-b]pyridine (prepared as described in Preparation 90), 1.20 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.64 ml of tributylphosphine, 0.65 g of 1,1'-(azodicarbonyl)dipiperidine and 25 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.61 g of the title compound, melting at 90 95 0 C (softening).

-~Y

7 1854 2 5 3 253) 5 0 A 256 PREPARATION 92 6-Benzyloxy-2-methylamino-3-nitropyridine A procedure similar to that described in Preparation 88 was repeated, except that 7.00 g of 6-chloro-2methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.79 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.3 ml of benzyl alcohol and 150 ml of dimethylformamide were used.

After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with isopropanol, to give 9.02 g of the title compound, melting at 149 0

C.

PREPARATION 93 3-Amino-6-benzvloxy-2-methylaminopyridine 21.4 g of zinc were added to a solution of 8.50 of 6-benzyloxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 92) in 360 ml of methanol, and then 8.5 ml of acetic acid were added dropwise. The resuluting mixture was then stirred at room temperature for one hour. At the end of this time, the reaction mixture was filtered to remove insoluble material. The filtrate was freed from the solvent by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure, to give 7.50 g of the title compound having Rf 0.63 (on silica gel thin layer chromatography using ethyl acetate as the 9506 7 185 S- 257 developing solvent).

PREPARATION 94 5-Benzyloxy-2-hydroxymetnyl-3-methylimidazo- [5,4-bipyridine A procedure similar to that described in Preparation 43 was repeated, except that 7.50 g of 3-amino-6-benzyloxy-2-methylaminopyridine (prepared as described in Preparation 93) and 7.46 g of glycolic acid were reacted. After working up the product as described in Preparation 43, the resulting crude product was purifying by column chromatography through silica gel, Susing a 10 1 by volume mixture of ethyl acetate and methanol as the eluent, and was then crystallized by Strituration with ethyl acetate, to give 4.10 g of the title compound, melting at 133 135 0

C.

PREPARATION 4-(5-Benzyloxy-3-methylimidazo 5,4-bl pridin-2vlmethoxy)benzyl -3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 3.15 g of 5-benzyloxy-2hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 94), 5.50 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiozolidine-2,4-dione, 2.91 ml of tributylphosphine, 2.95 g of 1,1'-(azodicarbonyl)dipiperidine and 100 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1 1 to 1 2 by volume as the eluent, to give i -LL _1 I II -1 9 5 06 7 1 5 2 1 2 150 4 0 W 258 7.10 g of the title compound, melting at 88 9 0

C

(softening).

PREPARATION 96 6-Ethoxy-2-methylamino-3-nitropyridine A procedure similar to that described in Preparatiol 88 was repeated, except that 6.00 g of 6-chloro-2methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.54 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.1 ml of ethanol and 150 nl of dimethylformamide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with ethanol, to give 5.10 g of the title compound, melting at 101 0

C.

PREPARATION 97 3-Amino-6-ethoxy-2-methylaminopyridine A procedure similar to that described in Example 6 was repeated, except that 4.95 g of 6-ethoxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 96) were hydrogenated in 100 ml of 1,4-dioxane in the presence of 1.00 g of 10 w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.20 g of the title compound having Rf 0.57(on silica gel thin layer chromatography using ethyl acatate as the developing solvent) were obtained.

9 506 7 L8 54 9 6 S I 3 I N 0 4 0 259 PREPARATION 98 5-Ethoxy-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine A procedure similar to that described in Preparation 43 was repeated, except that 4.15 g 3-amino-6-ethoxy- 2-methylaminopyridine (prepared as described in Preparation 97), and 5.66 g of glycolic acid were used, and that the product was purified hy column chromatography through silica gel, using a 10 1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.20 g of the title compound, melting at 161 0

C.

PREPARATION 99 5-f4-(5-Ethoxy-3-methylimidazo[5,4-blpyridin-2-ylmethoxy)benzyl -3-triphenylmethyl S: thiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 1.00 g of 5-ethoxy-2hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 98), 2.25 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiozolidine-2,4-dione, 1.2 ml of tributylphosphine, 1.22 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.81 g of the title compound, melting at 88 100 0 C (softening).

I~

9506 7 1854 2532 W 260 PREPARATION 100 6-Isopropoxy-2-methylamino-3-nitropyridine A procedure similar to that described in Preparation 88 was repeated, except that 6.00 g of 6-chloro-2methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.54 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.7 ml of isopropanol and 150 ml of dimethylformanlide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with isopropanol, to give 6.10 g of the title compound, melting at 75 76 0

C.

PREPARATION 101 3-Amino-6-isopropoxy-2-methylaminopyridine A procedure similar to that described in Example 6 was repeated, except that 2.38 g of 6-isopropoxy-2methylamino-3-nitropyridine (prepared as described in Preparation 100) were hydrogenated in 50 ml of methanol in the presence of 0.50 g of 10 w/w palladium-oncharcoal. After working up the product as described in Example 6, 2.00 g of the title compound having Rf 0.62 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent) were obtained.

PREPARATION 102 5-Isopropoxy-2-hydroxvmethyl-3-methylimidazo- [5,4-b vyridine A procedure similar to that described in Preparation 43 was repeated, except that 1.90 g of 3-amino-6- -I II 9 5 0 6 7 1 8 5 4 j 1 0 4 0 W 261 isopropoxy-2-methylaminopyridine (prepared as described in Preparation 101), and 2.39 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a 10 1 by volume mixture of ethyl acetate and methanol, to give 0.58 g of the title compound, melting at 125 1270C.

PREPARATION 103 (5-Isopropoxy-3-methylimidazo[5,4-blpyridin-2vlmethoxy)benzvl -3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.33 g 5-isopropoxy-2hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 102), 0.69 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.37 ml of tributylphosphine, 0.38 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, and that the product was purified by column chromatography through S" silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.85 g of the title compound, melting at 90 100aC (softening).

PREPARATION 104 2-Methylamino-3-nitropyridine A procedure similar to that described in Preparation 66 was repeated, except that 24.9 g of 2-chloro-3-nitropyridine, 41.7 g of sodium carbonate, 22.7 ml of a 30 ethanolic solution of methylamine were reacted in 250 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was crystallized by trituration with isopropanol, to give c 9 506 7185 4 2532 5040 262 24.0 g of the title compound, melting at 52 53 0

C.

PREPARATION 105 3-Amino-2-methylaminopyridine A procedure similar to that described in Example 6 was repeated, except that 5.00 g of 2-methylamino-3nitropyridine (prepared as described in Preparation 104) were hydrogenated in 80 Lnl of 1,4-dioxane in the presence of 1.00 g of 10 w/w palladium-on-charcoal.

After working up the product as described in Example 6, 3.87 g of the title compound, melting at 90 92 0 C were obtained.

PREPARATION 106 4-[2-(1,3-Dioxolan-2-yl)ethoxy]benzyl thiazolidine-2,4-dione A procedure similar to that described in Preparation 46 was repeated, except that 15.0 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione, 8.80 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 17 ml of 2-(2-bromoethyl)-1,3-dioxolane and 80 ml of dimethylformamide were used, and that the product was purified by column chromatography through silica gel, using a 1 1 by volume mixture cL hexane and ethyl acetate as the eluent, to give 6.67 g of the title compound, melting at 102 104 0

C

PREPARATION 107 5-f4-(3-Oxopropoxy)benzvllthiazolidine-2,4-dione A solution of 6.30 g of 5-{4-[2-(1,3-dioxolan-2-

I

9506 7185 4 2532 95040 263 yl)ethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Preparation 106) in 50 ml of a 4 1 mixture of acetic acid and water was stirred at 60 0 C for 6 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.20 g of the title compound, melting at 48 51 0

C.

PREPARATION 108 2-Methylamino-3-nitro-6-phenvlpyridine e 50 ml of a 2 N aqueous solution of sodium carbonate and 0.34 g of 20% w/w palladium hydroxide on charcoal were added to a solution of 5.0 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66) and 3.9 g of phenyl borate in 80 ml of a 1 1 by volume mixture of ethanol and toluene, and the resulting mixture was stirred at 105 0 C for 4.5 hours.

At the end of this time, the reaction mixture was filtered to remove the palladium hydroxide on charcoal.

The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was diluted with water, after which it was extracted with ethyl acetate.

The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 4.75 g of the title compound, melting at 98 99 0

C.

L 9 5 0 6 I i A S 4 I S 0 4 1 264 PREPARATION 109 3-Amino-2-methylamino-6-phenylpyridine A procedure similar to that described in Example 6 was repeated, except that 5.7 g of 2-methylamino-3nitro-6-phenylpyridine (prepared as described in Preparation 108) were hydrogenated in 200 ml of a 1 1 by volume mixture of ethanol and 1,4-dioxane in the presence of 1.14 g of 10% w/w palladium-on-charcoal.

After working up the product as described in Example 6, 4.9 g of the title compound having Rf 0.08 (on silica gel thin layer chromatography using a 1 5 by volume mixture of ethyl acetate and hexane as the developing solvent) were obtained.

PREPARATION 110 2-Hydroxymethyl-3-methyl-5-phenylimidazo [5,4 -blpyridine

S

A procedure similar to that described in Preparation 43 was repeated, except that 4.9 g of 3-amino-2-methylamino-6-phenylpyridine (prepared as described in Preparation 109) and 5.6 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1 0 to 10 1 by volume as the eluent, to give 0.9 g of the title compound, melting at 174 177 0

C

1 I 9506 265 PREPARATION 111 5-{4-(3-Methyl-5-phenylimidazo[5,4-blpyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 2-hydroxymethyl-3methyl-5-phenylimidazo[5,4-b]pyridine (prepared as described in Preparation 110), 0.97 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.57 ml of tributylphosphine, 0.53 g of l,l'-(azodicarbonyl)dipiperidine and 50 ml of benzene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.9 g of the title compound having Rf 0.26 (on silica gel thin layer chromatography using a 1 1 by volume mixture of ethyl acetate and hexane as *the developing solvent).

PREPARATION 112 2-(4-Formylphenoxymethyl)-3-methylimidazo[5,4-blpyridine A procedure similar to that described in Preparation 4 was repeated, except that 500 mg of 3-methylimidazo- [5,4-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 374 mg of 4-hydroxyben .,aldehyde, 0.76 ml of tributylphosphine, 773 mg of 1,l'-(azodicarbonyl)dipiperidine and 12 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and 9 5 0 6 7 L 8 5 4 95? 715 1 2 1 0 4 0 -266 methanol in ratios ranging from 1 :0 to 50 1by volume as the eluent, to give 0.37 g of the title compound, melting at 124 -125 0

C.

Claims (2)

1. A compound of formula (XIV): Q-(CH2) )0 R y NH (XIV) j wherein: each of Y and Y' independently represents an oxygen atom or a sulfur atom; R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy 15 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 -NRRb, wherein R" and Rb are the same or different and each represents a hydrogen atom, an 20 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 substituted by an aryl group having from 6 to 10 ring 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 ,e ~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 S22/6/98 -268- Q represents a lower alkoxya,-bonyl group, a formyl group, a protected formyl group or a carboyv group; a. salts thereof.

2. A compound according to claim 1 substantially as hereinbefore described with reference to the Examples. DATED this TWENTY SECOND day of JUNE 1998 Sankyo Company Limited By its Patent Attorneys DAVIES COLLISON CAVE Q S 1 I tI\'lill)SANKYO DIV 29.!1/91 ABSTRACT A compound of formula (XIV): Q-(CH2 m -y O R Y' NH wherein: (XIV) each of Y and Y' independently represents an oxygen atom or a sulfur atom; R represents a hydrogen atom, 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, 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 R" 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 20 group having from 1 to 5 carbon atoms is substituted by an aryl group having from 6 to 10 ring 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 25 acyl group in 'ich the aryl part has from 6 to 10 ring carbon atoms, i" m is an integer of from 1 to Q represents a lower alkoxycarbonyl group, a formyl group, a protected formyl group, a carboxyl group or a hydroxy group; and salts thereof.