Thiazolidinedione derivatives, their production and use

Thiazolidinedione derivatives of the general formula: ##STR1## [wherein R.sup.1 is hydrogen or a hydrocarbon residue or heterocyclic residue which may each be substituted; R.sup.2 is hydrogen or lower alkyl which may be substituted by hydroxyl group; X is an oxygen or sulfur atom; Z is a hydroxylated methylene or carbonyl; m is 0 or 1; n is an integer of 1 to 3; L and M represent independently a hydrogen atom or L and M combine with each other to cooperate jointly to form a linkage] and their salts, which are novel compounds, possess blood-glucose and blood-lipid lowering actions in mammals, and are of value as a therapeutic agent for diabetes and therapeutic agent for hyperlipemia.

This invention relates to novel thiazolidinedione derivatives which possess 
blood-glucose and blood-lipid lowering actions, to processes for producing 
the same and to pharmaceutical compositions containing the same. 
As a therapeutic agent for diabetes, heretofore, there have been used 
various biguanide and sulfonylurea compounds. However, the biguanide 
compounds are hardly in current use, because they cause lactic acid 
acidosis, while the sulfonylurea compounds exhibit potent hypoglycemic 
action but often bring about severe hypoglycemia, thus requiring careful 
precautions on the occasion of their use. The development of a novel 
therapeutic agent for diabetes which is free from such defects is desired. 
In Japanese Unexamined Patent Publication Nos. 22636/1980 and 64586/1980, 
Chemical & Pharmaceutical Bulletin, 30, 3563 (1982), ibid. 30, 3580 (1982) 
and ibid., 32, 2267 (1984), on the other hand, there is a description that 
various thiazolidinediones exhibit blood-lipid and blood-glucose lowering 
actions, and in Diabetes, 32, 804 (1983), futhermore, there has been 
provided a description of the antidiabetic action demonstrated by 
ciglitazone. Nevertheless, all of these compounds has failed so far to be 
commercialized as a therapeutic agent for diabetes. The present inventors 
conducted repeated research on thiazolidinediones, and as a result, found 
entirely novel derivatives which possess outstandingly potent 
blood-glucose and blood-lipid lowering actions and can be expected to 
provide enhanced therapeutic effect, as compared with the known compounds. 
This invention is concerned with: 
1. A thiazolidinedione derivative of the general formula: 
##STR2## 
[wherein R.sup.1 is hydrogen or a hydrocarbon residue or heterocyclic 
residue which may each be substituted; R.sup.2 is hydrogen or a lower 
alkyl group which may be substituted by hydroxyl group; X is an oxygen or 
sulfur atom; Z is a hydroxylated methylene or carbonyl; m is 0 or 1; n is 
an integer of 1 to 3; L and M represent independently a hydrogen atom or L 
and M combine with each other to cooperate jointly to form a linkage] or 
its pharmacutically acceptable salts, 
2. A pharmaceutical composition which contains a compound of the general 
formula (I) or its pharmacutically acceptable salt, 
3. A process for producing a compound of the general formula: 
##STR3## 
[wherein each of the symbols is as defined hereinbefore] or its salt, 
which comprises reacting a compound of the general formula: 
##STR4## 
[wherein R.sup.1, R.sup.2, X and m are as defined hereinbefore; Y is a 
halogen atom] with a compound of the general formula: 
##STR5## 
[wherein each of the symbols is as defined hereinbefore] or its salt, 
followed by reduction of the reaction product, if desired, 
4. A process for producing a compound of the general formula: 
##STR6## 
[wherein each of the symbols is as defined hereinbefore] or its salt, 
which comprises reducing a compound of the general formula: 
##STR7## 
[wherein each of the symbols is as defined hereinbefore] or its salt, 5. 
A process for producing a compound of the general formula (I-2) or its 
salt, which comprises oxidizing a compound of the general formula (I-3) or 
its salt, 
6. A process for producing a compound of the general formula: 
##STR8## 
[wherein each of the symbols is as defined hereinbefore] or its salt, 
which comprises hydrolyzing a compound of the general formula: 
##STR9## 
[wherein each of the symbols are as defined hereinbefore] or its salt, 7. 
A process for producing a compound of the general formula: 
##STR10## 
[wherein each of the symbols is as defined hereinbefore] or its salt, 
which comprises reacting a compound of the general formula: 
##STR11## 
[wherein each of the symbols is as defined hereinbefore] with a compound 
of the formula: 
##STR12## 
or its salt, 8. A process for producing a compound of the general formula 
(I-4) or its salt, which comprises reducing a compound of the general 
formula (I-5) or its salt, and 
9. A method for the treatment of diabetes or hyperlipemia, which comprises 
administering to a mammal suffering from the disease a compound of the 
formula (I) or its pharmaceutically acceptable salt, in amount of about 
0.001 to 10 mg per kilogram of body weight of the mammal per day. 
In the above general formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (II), 
(III), (IV) and (V), the hydrocarbon residue represented by R.sup.1 is 
that having 1 to 13 carbon atoms and includes aliphatic hydrocarbon 
residues, alicyclic hydrocarbon residues, alicyclic aliphatic hydrocarbon 
residues, aromatic-aliphatic hydrocarbon residues and aromatic hydrocarbon 
residues. The said aliphatic hydrocarbon residue is that having 1 to 8 
carbon atoms and includes saturated aliphatic hydrocarbon residues of 1 to 
8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, 
isohexyl, heptyl and octyl, and unsaturated aliphatic hydrocarbon residues 
of 2 to 8 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 
1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 
2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-2-butenyl, 1-hexenyl, 
3-hexenyl, 2,4-hexadienyl,5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 
2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 
5-hexynyl, 1-heptynyl and 1-octynyl; the said alicyclic hydrocarbon 
residue is that having 1 to 8 carbon atoms and includes saturated 
alicyclic hydrocarbon residues of 3 to 7 carbon atoms, such as 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and 
unsaturated alicyclic hydrocarbon residues of 5 to 7 carbon atoms, such as 
1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 
2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 
3-cycloheptenyl and 2,4-cycloheptadienyl; the alicyclic-aliphatic 
hydrocarbon residue is that consisting of the above-described alicyclic 
hydrocarbon residues bonded to the above-mentioned aliphatic hydrocarbon 
residues but having 4 to 9 carbon atoms, such as cyclopropylmethyl, 
cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 
2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 
2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, 
cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl; and the 
aromatic-aliphatic hydrocarbon residue is that having 7 to 13 carbon atoms 
and includes phenylalkyls of 7 to 9 carbon atoms, such as benzyl, 
phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 
1-phenylpropyl, and naphthylalkyls of 11 to 13 carbon atoms, such as 
.alpha.-naphthylmethyl, .alpha.-naphthylethyl, .beta.-naphthymethyl and 
.beta.-naphthylethyl, while the aromatic hydrocarbon residue includes for 
example, phenyl and naphthyls (.alpha.-naphthyl and .beta.-naphthyl). The 
heterocyclic residue represented by R.sup.1 denotes five-membered or 
six-membered rings containing, in addition to carbon, 1 to 3 atoms 
selected from N, O and S as a ring-forming atom and capable of bonding 
through carbon, and their specific examples include heteroaromatic ring 
groups, such as thienyls (2-thienyl, 3-thienyl), furyls (2-furyl, 
3-furyl), pyridyls (2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyls 
(2-thiazolyl, 4-thiazolyl, 5-thiazolyl) and oxazolyls (2-oxazolyl, 
4-oxazolyl, 5-oxazolyl), and saturated heterocyclic groups, such as 
piperidinyls (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyls 
(2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyls (2-morpholinyl, 
3-morpholinyl) and tetrahydrofuryls (2-tetrahydrofuryl, 
3-tetrahydrofuryl). The hydrocarbon residue and heterocyclic residue 
represented by R.sup.1 may have a substituent or substituents in their 
arbitrary positions. In cases in which R.sup.1 includes an a alicyclic 
group or R.sup.1 is a saturated heterocyclic group, such groups may have 1 
to 3 lower alkyl groups (e.g., methyl, ethyl, propyl, isopropyl) of 1 to 3 
carbon atoms on their rings (inclusive of the N atom). In cases in which 
R.sup.1 includes a aromatic hydrocarbon group or R.sup.1 is a 
hetero-aromatic ring group, such groups may have 1 to 4 of the same or 
different substituents on their rings (exclusive of the hetero atoms), 
whereby the said substituents include, for example, halogens (e.g., 
fluorine, chlorine, iodine), hydroxyl, cyano, trifluoromethyl, lower 
alkoxies (e.g., those having 1 to 4 carbon atoms, such as methoxy, ethoxy, 
propoxy, isopropoxy and butoxy), lower alkyls (e.g., those having 1 to 4 
carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl), lower 
alkoxycarbonyls (e.g. those having 2 to 4 carbon atoms such as 
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) and lower 
alkylthios (e.g., those having 1 to 3 carbon atoms, such as methylthio, 
ethylthio, propylthio and isopropylthio). 
The lower alkyl group represented by R.sup.2 includes those having 1 to 5 
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, t-butyl and pentyl, whereupon those having 1 to 4 carbon atoms 
are preferred and those having 1 to 3 carbon atoms are the most 
preferable. These alkyl groups may have a hydroxyl group or hydroxyl 
groups in their arbitrary positions, with the .alpha. position being 
particularly preferable. 
In the general formulae (I), (I-1), (I-2), (I-3) and (III), when L and M 
combine with each other and cooperate jointly to form a linkage, this is 
understood to mean that the carbon atoms at both ends of this linkage 
combine with each other through the double bond. In cases in which L and M 
combine with each other and cooperate jointly to form a linkage, the 
compound of the general formula (I), for example, is represented by the 
general formula (I-5). In cases in which L and M represent independently a 
hydrogen atom, the compound of the general formula (I) is represented by 
the general formula (I-4). 
The halogen represented by Y in the general formula (II) includes chlorine, 
bromine and iodine. 
The compound of the general formula (I), which has acid nitrogen on its 
thiazolidine ring, forms salts with bases. Such base salts include 
pharmaceutically acceptable salts, such as sodium salt, potassium salt, 
aluminum salt, magnesium salt and calcium salt. 
The compound of the general formula (I) or its salts can be produced by the 
following procedure. 
The compound of the general formula (I) wherein n is 1 or its salts, namely 
the compound represented by the general formula (I-1) or its salts 
[hereinafter referred to collectively as "Compound (I-1)"] can be formed 
by reacting a compound of the general formula (II) with a compound of the 
general formula (III) or its salt [hereinafter referred to collectively as 
"Compound (III)"], followed by reduction of the reaction product, if 
desired. The reaction of Compound (II) with Compound (III) is normally 
carried out in the presence of suitable solvent and base, and this 
reaction can afford the compound (I'), namely the desired compound (I) 
with m=0 and n=1. 
Examples of such a solvent include dimethylformamide, dimethylsulfoxide, 
tetrahydrofuran, dimethoxyethane, etc., while examples of the said base 
include sodium hydride, potassium hydride, sodium amide, sodium alkoxides 
(e.g., sodium methoxide, sodium ethoxide), potassium alkoxides (e.g., 
potassium butoxide). This reaction is preferably carried out by firstly 
reacting 1 mole of Compound (II) with 2 moles of a base to form a dianion 
and subsequently adding 1 mole of Compound (II) to allow the reaction to 
proceed. This condensation reaction is conducted normally at 0.degree. C. 
to 120.degree. C., preferably at 20.degree. C. to 100.degree. C., and the 
reaction time is normally 0.5 to 5 hours. 
In this reaction, the use of the compound of the general formula (II) 
wherein m=1 as a starting compound can produce Compound (I-1) wherein m is 
1 and Z is carbonyl. This compound, when subjected to reduction, if 
desired, can be converted into Compound (I-1) wherein m is 1 and Z is 
##STR13## 
The compound of the general formula (I-2) or its salts [hereinafter 
referred to collectively as "Compound (I-2)"] can be converted through 
reduction into the compound of the general formula (I-3) or its salts 
[hereinafter referred to collectively as "Compound (I-3)"]. This reduction 
reaction can be allowed to proceed readily by utilizing sodium borohydride 
in a solvent such as an alkanol (e.g. methanol, ethanol, 2-propanol, 
2-methoxyethanol), if desired, admixed with N,N-dimethylformamide. The 
amount of sodium borohydride to be used is 0.3 to 2 moles per mole of 
Compound (I-2). The reaction temperature is -10.degree. C. to 100.degree. 
C., while the reaction time is 0.5 to 5 hours. 
Compound (I-3) can be converted through oxidation into Compound (I-2). This 
oxidation reaction can be allowed to proceed readily by means of activated 
DMSO oxidation utilizing dimethylsulfoxide (DMSO) and an electrophilic 
reagent (e.g., acetic anhydride, dicyclohexylcarbodiimide (DCC), 
phosphorus pentaoxide, etc.), by chromic acid oxidation. 
The activated DMSO oxidation can be allowed to proceed by adding an 
electrophilic reagent, such as acetic anhydride, DCC and phosphorus 
pentoxide, in DMSO, if desired, admixed with benzene, pyridine, ether, 
etc. The amount of DMSO to be used is normally in large excess, and the 
reaction temperature ranges from -10.degree. C. to 60.degree. C., 
preferably from 0.degree. to 30.degree. C., varying depending upon the 
type of the electrophilic reagent to be used, while the reaction time is 1 
to 30 hours. The chromic acid oxidation can be allowed to proceed by means 
of the methods of utilizing a Jones reagent (chromium trioxide-sulfuric 
acid-acetone) in chromium trioxide in acetic acid, chromium trioxide in 
pyridine or a previously prepared chromium trioxidepyridine complex in 
dichloromethane used as a solvent. The amount of chromium (VI) to be used 
is normally 0.5 to 2 equivalents against Compound (I-3). The reaction 
temperature is -10.degree. C. to 60.degree. C., preferably 0.degree. to 
30.degree. C., while the reaction time is 0.5 to 50 hours. 
The compound of the general formula (I) wherein L and M both are 
independently a hydrogen atom or its salts, namely the compound of the 
general formula (I-4) or its salts (hereinafter referred to collectively 
as "Compound (I-4)"), can be produced by hydrolyzing a compound of the 
general formula (IV) or its salts (hereinafter referred to collectively as 
"Compound (IV)"). This hydrolysis reaction is carried out normally in a 
suitable solvent in the presence of water and mineral acid. As the 
solvent, there are mentioned normally alkanols (e.g., methanol, ethanol, 
propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol, etc.), 
dimethylsulfoxide, sulfolane, dioxane, dimethoxyethane, etc. The mineral 
acid includes, for example, hydrochloric acid, hydrobromic acid, sulfuric 
acid, etc., and their amount to be used is 0.1 to 10 moles per mole of the 
compound (IV), preferably 0.2 to 3 moles. The amount of water to be added 
is normally in large excess per mole of the compound (IV). This reaction 
is normally conducted under warming or heating, and the reaction 
temperature is ordinarily 60.degree. to 150.degree. C. The reaction time 
is nomally several hours to ten-odd hours. 
The compound of the general formula (I-5) or its salts [hereinafter 
referred to collectively as "Compound (I-5)"] can be produced by reacting 
a compound of general formula (V) with a compound of the formula (VI) or 
its salt [hereinafter referred to collectively as "Compound (VI)"]. This 
reaction is carried out normally in a solvent in the presence of a 
suitable base. As such a solvent-base system, there are used systems being 
suitably selected from solvents, such as alkanols (e.g., methanol, 
ethanol, propanol, 2-propanol, butanol, isobutanol, 2-methoxyethanol, 
etc.), dimethylformamide, dimethylsulfoxide, sulfolane, acetonitrile, 
dioxane, dimethoxyethane and acetic acid, and bases, such as amines (e.g., 
pyrrolidine, piperidine, morpholine, piperazine, diethylamine, 
diisopropylamine, triethylamine, etc.), sodium alkoxides (e.g., sodium 
methoxide, sodium ethoxide), potassium carbonate, sodium carbonate, sodium 
hydride, sodium acetate and potassium acetate. Compound (VI) is used 
normally at a rate of 1 to 5 mole per mole of the compound of the general 
formula (V), preferably 1.5 to 3.0 moles. The amount of the base to be 
used is 0.01 to 3.0 moles per mole of the compound (VI), preferably 0.1 to 
1.0 mole. This condensation reaction is carried out normally at 0.degree. 
C. to 150.degree. C., preferably 20.degree. C. to 100.degree. C., while 
the reaction time is normally 0.5 to 50 hours. 
Compound (I-4) can be produced by reducing Compound (I-5). This reaction is 
carried out normally by catalytic hydrogenation in a solvent in the 
presence of a suitable catalyst. As the solvent, there are mentioned 
normally alkanols (e.g. methanol, ethanol, propanol, etc.), ethers (e.g. 
dioxane, dimethoxyethane, tetrahydrofuran, etc.), ethyl acetate, acetic 
acid, dimethylformamide, etc. The catalyst includes, for example, 
palladium black, palladium carbon, platinum oxide, etc. This reaction can 
proceed at an ordinary temperature and pressure, but may be carried out at 
an elevated temperature (about 40.degree. to 100.degree. C.) and pressure 
in order to accelerate the reaction. 
The compound of the general formula (I) wherein R.sup.2 is an alkyl group 
having a hydroxyl group in the .alpha.-position or its salts can also be 
produced for example by the procedure to be described in the following: 
##STR14## 
[wherein R.sup.3 is hydrogen or a lower alkyl group (e.g., methyl, ethyl, 
propyl, isopropyl, butyl, isobutyl, etc.); each of the other symbols is as 
defined hereinbefore]. 
Namely, the compound (I-6), that is the compound (I) wherein R.sup.2 is 
lower alkyl represented by CH.sub.2 --R.sup.3, or its salts [hereinafter 
referred to collectively as Compound (I-6)"], when halogenated, affords 
the compound of the general formula (VII) or its salts [hereinafter 
referred to collectively as "Compound (VII)]. Compound (VII) is then 
converted into the objective compound (I-7) or its salts [hereinafter 
referred to collectively as "Compound (I-7)] by hydrolysis. The 
halogenation of Compound (VII) can be carried out with N-bromosuccinimide 
or N-chlorosuccinimide, preferably in the presence of a radical initiator, 
such as benzoyl peroxide and .alpha.,.alpha.'-azobisisobutyronitrile. This 
reaction is allowed to proceed readily by refluxing in a solvent, such as 
carbon tetrachloride and chloroform, and the amount of the radical 
initiator to be used is normally 0.01 to 0.2 mole per mole of Compound 
(I-6). The resulting .alpha.-halogenated derivative [Compound (VII)] may 
be hydrolyzed, after being isolated and purified, if necessary, or 
directly without isolation to the .alpha.-hydroxy derivative [Compound 
(I-7)]. This hydrolysis reaction is allowed to proceed advantageously by 
using a mineral acid in a suitable solvent. As the solvent, there are used 
dioxane, tetrahydrofuran, dimethoxyethane, etc., while as the mineral 
acid, there are used hydrochloric acid, sulfuric acid, etc., respectively, 
and the reaction temperature is 20.degree. C. to 100.degree. C., with the 
reaction time ranging from 0.5 to 10 hours. 
The thiazolidinedione derivative (I) and its salts as obtained in this 
manner can be isolated and purified by the known separation and 
purification means, such as concentration, concentration under reduced 
pressure, solvent extraction, crystallization, recrystallization, 
phase-transfer and chromatography. 
The compound (I) of this invention and its salt exhibit excellent 
blood-glucose and blood-lipid lowering actions in mammals (e.g., mouse, 
rat, dog, cat, monkey, horse, and human being), and show a low degree of 
toxicity in terms of both acute and subacute toxicities. Therefore, the 
thiazolidinedione derivative (I) and its salts is of value to human beings 
for the treatment of hyperlipemia, diabetes and their complications. With 
reference to the method of administration, they are normally used orally 
in such dosage forms as tablets, capsules, powders, granules, etc., and 
can also be administered parenterally in dosage forms, such as injectable 
solutions, suppositories and pellets, as the case may be. In the case of 
application as a therapeutic agent for diabetes or hyperlipemia, the 
compounds can be nomally administered to an adult patient orally at a dose 
of 0.003 to 10 mg/kg a day, preferably 0.01 to 10 mg/kg, most preferably 
0.02 to 0.2 mg/kg, or parenterally at a dose of 0.001 to 10 mg/kg a day, 
preferably 0.005 to 10 mg/kg, most preferably 0.01 to 0.1 mg/kg, whereby 
such doses are desirably given once a day or twice to four times a week 
intermittently. 
The starting compound (V) of this invention can be produced, for example, 
by the following procedure. (1a) Preparation of the compound (V-1), i.e. 
compound (V) wherein m=0. 
##STR15## 
[wherein each of the symbols is as defined hereinbefore]. 
The reaction of the compound (VIII) to the compound (X) is carried out by 
allowing the compounds (VIII) and (IX) to undergo condensation for example 
in the presence of sodium hydride. This reaction can be conducted in a 
solvent, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran and 
dimethoxyethane, at -10.degree. C. to 30.degree. C. The subsequent 
reaction of the compound (X) to the compound (V-1) is carried out by 
heating the compound with Raney nickel alloy in an aqueous formic acid 
solution. 
(1b) Production of the compound (V-2) of the general formula (V) wherein 
m=0 and n=1, or m=n=1 and Z=--CO--. 
##STR16## 
[wherein each of the symbols is as defined hereinbefore]. 
The reaction of condensation of the compound (II) with the compound (XI) to 
give (V-2) is normally allowed to proceed in a solvent, such as 
dimethylformamide, tetrahydrofuran, acetone and methyl ethyl ketone, in 
the presence of a base (e.g., sodium carbonate, potassium carbonate, etc.) 
at 0.degree. C. to 150.degree. C. 
(1c) Preparation of the compound (V-3), i.e. compound 
(V) wherein m=n=1 and Z= 
##STR17## 
[wherein each of the symbols is as defined hereinbefore]. 
The reaction of the compound (II-1) with the compound (XII) can be carried 
out in a manner similar to the above-described reaction between the 
compounds (II) and (XI), and the resulting compound (XIII) is reduced in 
accordance with the conventional procedure by use of sodium borohydride in 
a solvent such as methanol, ethanol, and N,N-dimethylformamide, or their 
mixture to give the compound (XIV), which can subsequently be converted to 
(V-3) by a reaction similar to the above-described reaction of converting 
(X) into (V-1). 
(2a) Preparation of the compound (IV-1), i.e. compound (IV) wherein m=0. 
##STR18## 
[wherein R.sup.4 is hydrogen or a lower alkyl group; other symbols are as 
defined hereinbefore]. 
The lower alkyl group represented by R.sup.4 in the above general formulae 
(XVIII) and (XIX) includes alkyl groups of 1 to 4 carbon atoms, such as 
methyl, ethyl, propyl and butyl. 
The reaction of the compound (VIII) to the compound (XVI) is carried out by 
condensation of the compound (VIII) with the compound (XV) for example in 
the presence of sodium hydride. This reaction can be conducted in a 
solvent, such as dimethylformamide and tetrahydrofuran, at -10.degree. C. 
to 30.degree. C. The subsequent reaction of the compound (XVI) to the 
compound (XVII) is readily carried out, for example, by catalytic 
reduction of the compound (XVI) in accordance with the conventional method 
by the use of palladium carbon as a catalyst or by reduction of the 
compound in accordance with the conventional method by the use of zinc or 
iron and acetic acid. The compound (XVII) may be isolated as a pure 
product or can be subjected to the reaction in the subsequent step without 
being isolated and purified. The reaction of the compound (XVII) to the 
compound (XIX) is carried out by means of the so-called Meerwein arylation 
reaction which involves diazotization of the compound (XVII) in the 
presence of a hydrohalogenic acid (HY), followed by reaction with acrylic 
acid or its ester (XVIII) in the presence of a copper catalyst (e.g., 
cuprous oxide, cupric oxide, cuprous chloride, cupric chloride, cuprous 
bromide, cupric bromide, etc.). The compound (XIX) can be purified by 
chromatography, and can also be subjected to the reaction in the 
subsequent step without being isolated and purified. 
The compound (IV-1) can be produced by reacting thereafter the compound 
(XIX) with thiourea. 
This reaction is carried out normally in a solvent, such as alcohols (e.g., 
methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, 
2-methoxyethanol, etc.), dimethylsulfoxide and sulfolane. The reaction 
temperature is normally 20.degree. C. to 180.degree. C., preferably 
60.degree. C. to 150.degree. C. The amount of thiourea to be used is 1 to 
2 moles per mole of the compound (XIX). This reaction proceeds with a 
hydrogen halide being formed as a by-product, and may be carried out in 
the presence of sodium acetate, potassium acetate, etc. for the purpose of 
capturing such a by-product. The amount of these compounds to be used is 
normally 1 to 1.5 moles per mole of the compound (XIX). This reaction can 
yield the compound (IV-1), which can be isolated, if desired, but may be 
subjected to the following hydrolysis step directly without being 
isolated. 
The compound (XVII) having a hydroxy-substituted phenyl group as R.sup.1 
can be synthesized by condensation of the compound (VIII) having a 
benzyloxy-substituted phenyl group as R.sup.1 with the compound (XV) and 
catalytic reduction of the resulting compound (XVI) to perform 
simultaneously reduction of the nitro group and debenzylation. Also, the 
compound (XVII) can be synthesized by the following procedure. 
##STR19## 
[wherein each of the symbols is as defined hereinbefore]. 
The condensation of the compound (II-2) with the compound (XX) to give the 
compound (XXI) can be normally conducted in a solvent, such as 
dimethylformamide, tetrahydrofuran, acetone and methyl ethyl ketone, in 
the presence of a base (e.g., sodium carbonate, potassium carbonate, etc.) 
at 0.degree. C. to 150.degree. C. Subsequently, (XXI) is hydrolyzed to the 
compound (XVII). This hydrolysis reaction can be carried out with a 
mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, 
etc.) or more preferably with an alkali hydroxide (e.g., sodium hydroxide, 
potassium hydroxide, etc.) in a solvent, such as methanol, ethanol, 
propanol, 2-propanol and 2-methoxypropanol, under reflux. 
(2b) Preparation of the compound (IV-2), i.e. compound (IV) wherein m=1. 
##STR20## 
[wherein each of the symbols is as defined hereinbefore]. 
The condensation reaction of the compound (II-3) with the compound (XX) can 
be carried out in a manner similar to that of the above-mentioned reaction 
of the compound (II-2) with the compound (XX). The resulting compound 
(XXII) is reduced, by the conventional method, with sodium borohydride in 
methanol or ethanol to give the compound (XXIII), which then can be 
hydrolyzed, in a manner similar to that of the above hydrolysis of (XXI), 
to afford the compound (XXIV). By the same procedure as that used in 
producing (IV-1) from (XVII), the compound (XXIV) can be converted into 
(IV-2) through (XIX-1). 
The starting materials (II) wherein m=0, can be prepared, for example, by 
the methods described in J. Am. Chem. Soc., 56, 470 (1934) and Japanese 
Unexamined Patent Publication No. 219169 (1983), or by the procedure 
analogous to them. Compounds (II-4), i.e. compound (II) wherein m=1, can 
be produced by the following method: 
##STR21## 
[wherein each of the symbols is as defined hereinbefore]. 
This reaction is performed by halogenating compounds (XXV) which can be 
produced, for example, by the methods described in Chem. Ber., 84, 96 
(1951), Nihon Kagaku Zasshi, 86, 942 (1965), Bull. Soc. Chim. France, 9 
3862 (1968), J. Chem. Soc., C., 1397 (1968) and German Pat. No. 2152557, 
or by the procedure analogous to them. The halogenation is conducted, for 
instance, with a halogen, preferably bromine, in a suitable solvent (e.g. 
chloroform, carbon tetrachloride) at 30.degree.-60.degree. C. 
The starting compounds (VIII) for the preparation of the iminothiazolidine 
compounds (IV-1) are produced by the following methods. 
(4a) Production of (VIII-1), i.e. compound (VIII) wherein n=2. 
##STR22## 
[wherein R.sup.5 is a lower alkyl] 
The reaction of (XXVI) which (XXVII) is easily conducted in a solvent such 
as an alkanol (e.g. methanol, ethanol, propanol, etc.), or without using a 
solvent, by heating at about 40.degree.-150.degree. C. 
The resulting (XXVIII) is reduced by a conventional method, for example, 
using lithium aluminum hydride to yield (VIII-1). The compound (XXVIII) 
wherein x=0 is also prepared by the method described in Japanese 
Unexamined Patent Publication Nos. 201771 (1983) and 219169 (1983)/ or by 
the procedure analogous to them. 
(4b) Compound (VIII) wherein n=1 can be prepared, for example, by the 
method described in Japanese Unexamined Patent Publication No. 219169 
(1983), or by the procedure analogous to it.