JPS6169777A - Xanthinylmethylthiazolidine, manufacture and medicinal composition - Google Patents

Abstract

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

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention has antitussive properties that regulate mucus;
The present invention relates to a pharmaceutical composition containing xanthinelmethylthiazolidine that dilates the bronchial tubes, and a method for producing the same.

[Means to solve the problem]

The present invention relates to the formula (I): (wherein R is 1,3-dimethylxanthine-7-yl or 3,7-dimethylxanthine-1-yl; R2 is an oxygen atom or FiM or esterified carboxyl Group; R3 and R4 are hydrogen atoms or methyl groups; P is ○ or 1: R+ is a hydrogen atom, an alkylsulfonyl group having 1 to 2 carbon atoms, an unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula R5 -C
-(wherein, R5 is a hydrogen atom, -+-CH2→IQ, or an integer of 7; PI and R2 are both a hydrogen atom, or one of them is a hydrogen atom, and the other is a lower alkyl group having 1 to 4 carbon atoms, or Phenyl group, Q is hydrogen atom; carbon number 3
Alkyl group having ~4 branches; cycloalkyl group having 3 to 7 carbon atoms; free or esterified carboxyl group; halogen atom; SH: NH2: mono- or di-substituted amino group, t-butoxycarbonyl Amino group or acrylamino group having 1 to 2 carbon atoms; ether group represented by 〇-T chain, thioether group represented by ST chain (where 1 is unsubstituted, mono- or polysubstituted phenyl Ring or Formula 6-C82 Zuko [■1(
In the formula, ■1 is HlOH, 0CHs, 0C2Hs, HO
CH2-Ct12-1 free or esterified carboxyl group, NH2, acrylamino group having 1 to 2 carbon atoms or mono- or di-substituted amino group) and formula -CH-C
A group selected from the group consisting of O2Re (wherein Re represents a hydrogen atom, a methyl group, or an ethyl group), m is 1 to 3
); unsubstituted or mono- or polysubstituted phenyl, phenoxy or phenylthio ring at the meta, ortho and para positions: formula +CH2C
HCH2+-1i-23 (where m and n are the same as above, P3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted amino and (wherein, TG
, tm may also be a hydrogen atom); Mono-substituted amine groups are linear chains having 1 to 6 carbon atoms. or an alkyl group having a branched chain or -CH2-CH2-0-CH2-CH3, -CH2-C
H2-0-CH2-CH2-OH.

-C)Is-CH2-N)f-C)12-CHI.

-CHz -CH2-NH-CH2-C) The substituent of the di-substituted amine group representing an amino group substituted with a group represented by the formula: is a linear or branched chain having a carbon number of 1 to 6; or they taken together to form morphonyl-1-yl, pyrrolidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, thiomorpholin-1-yl , 4-ethyl-piperazin-1-yl, 4-(2-fluorophenyl)piperazin-1-yl, imidazol-1-yl,
Represents an unsaturated or saturated nitrogen ring such as 3-pyridyl or 4-pyridyl: a mono- or polysubstituted phenyl group substituted in the para position by a fluorine atom and in the meta and/or para position by a chlorine atom. To,
or a phenyl group substituted in the meta position by CF3,
Or formula: (in the formula, Z+ Get H Mataha COC
H3, Z2 H1CH3 or C0CH3 and P4
represents a hydrogen atom, an aminomethyl group, and P4 represents a group selected from the group consisting of an acylaminomethyl group having 1 to 2 carbon atoms or a mono- or di-substituted aminomethyl group as defined above). xanthineylmethylthiazolidine represented by phenyl group).

(Example) Typical examples of saturated or unsaturated heterocycles containing one or more heteroatoms such as 0, S, N are:
Morpholin-1-yl, pyrrolid-1-yl, piperidin-1-yl, 4-methylpiperazin-1-yl, thiomorpholin-1-yl, 4-ethylpiperazin-1-yl, 4-(2'- and Droxyethyl)piperazine-1-
yl, 4-(4-fluorophenyl)piperazine-1-
Ylimidazol-1-yl, 3-pyridyl and 4-
It is pyridyl.

Typical examples of pharmacologically acceptable non-toxic bases are methylamine, dimethylamine, trimethylamine, ethylamine, diisopropylamine, N-methyl-N-hexylamine, thromethamine.
e) , cyclohexy/L/7min, N-methyl-N
-cyclohexylamine, α-phenylethylamine,
Ariso-based materials such as β-phenylethylamine, N,N-dimethylethanolamine, tododiethylethanolamine, ethylenediamine, piperazine, morpholine, piperazine, galactamine, N-methylglucamine, arginine, and alkali and alkaline earth metals. It is an inorganic base such as the hydroxide of No. 2.

Typical examples of pharmacologically acceptable non-toxic acids are acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, malic acid, malonic acid, benzoic acid, salicylic acid, 3,4.5-
)-rimethoxybenzoic acid, methanesulfonic acid, benzenesulfonic acid, camphosulfonic acid, lactic acid, aspartic acid, glutamic acid, and rho-2-thiazolidine-5
- Carboxylic acids, such as cystine and cysteine
m, and non-m acids such as nitric acid, phosphoric acid, sulfuric acid, hydrochloric acid, and hydrobromic acid.

Preferred salts used in the present invention are R2 in formula (1).
is a carboxyl group salted with one of the above bases. More preferred are salts of piperazine and imidazole derivatives.

In the formula of Mizuan IB book, the wavy bond (~V) does not have a defined stereochemical identity of the substituent.

In other words, the 'a substituent can have either the (R) or (S) configuration, and the dashed line (lluI.
・) indicates a substituent with absolute stereochemistry (S), and bold 11 (4) indicates a substituent with absolute structure (R).

In formula (1), R2, R3 and R4 are hydrogen atoms,
Compounds of the invention in which R1 is an acyl group are particularly preferred as mucus modifiers.

In formula (1), R2, R3 and R4 are hydrogen atoms,
A substituted or unsubstituted cinnamoyl group for R1 is particularly preferred as a bronchodilator.

Specific examples of preferred compounds of the invention are as follows.

2-[(1°,3°-dimethylxanthine-7-yl)
2-[(3
”, 7°-dimethylxanthine-1°-yl)methyl]
Thiazolidine-4-carboxylic acid and its methyl, ethyl and tert-butyl esters; 2-[(3°,7-dimethylxanthine-1'-yl)
methyl]-3-[(imidazol-1°-yl)acetyl]thiazolidine: 2-[(1°, 3°)-dimethylxanthine-7′-yl)methyl]-3-[(3′, 4°- hydroxy)cinnamoyl]thiazolidine; 2-[(3°.7′-dimethylxanthine-1-yl)
methyl]-3-[(3°,4′-dihydroxy)cinnamoyl]thiazolidine; 2-[(1°,3°-dimethylxanthine-7-yl)
methyl]-3-[3-methoxy-4°-hydroxy)cinnamoyl]thiazolidine; 2-[(3°,7-dimethylxanthine-1°-yl)
methyl]-3-<3'methoxy-4-hydroxy)cinnamoyl-thiazolidine;2-[(3°.7'-dimethylxanthine-1'-yl)methyl]-3-(3-methoxy-4'-hydroxy )
Cinnamoyl-thiazolidine; 2-[(3°,7°-dimethylxanthine-1°-yl)methyl]-3-[3°-(4″-hydroxyethylpiperazin-1″-yl)propionyl]thiazolidine;
2-[(1′,3°-dimethylxanthine-7°-yl)methyl]-3-(3°-morpholinomethyl-4°-
Hydroxy-3°-methoxy-cinnamoyl)thiazolidine; 2-[(1',3-dimethylxanthine-γ°-yl)
2-[(3°,1°-dimethylxanthine-1-yl)
methyl]-3-(3°-pyrrolidinylmethyl-4°-hydroxy-3°-methoxy-cinnamoyl)thiazolidine; 2-[(1°.3°-dimethylxanthine-1-yl)methy]- 3-[3'-thia-5-carboxy-
5-acetyphreamino-pentanoyl]thiazolidine; 2-H',3-dimethylxanthine-7-yl)methyl]-3-[4°-thia-6°-carboxy-6°-acetyl-amino-hexanoyl]thiazolidine ;2-
[(1°,3°-dimethylxanthine-7°-yl)methyl]-3-[3°-(2“-ethoxyethyloxy)acetyl]thiazolidine; 2-((1°,3°-dimethylxanthine- 7°-yl)methyl]-3-[3'-(imidazol-1-yl)
2-[(1′,3-dimethylxanthine-7-yl)methyl]-3-glycinyl-thiazolidine; 2-[(3°
, 7°-dimethylxanthine-1'-yl)methyl]-
3-Glycinyl-thiazolidine: 2-[(1′,3-dimethylxanthine-7°-yl)methyl]-3-(N-
acetyl)glycinyl-thiazolidine: 2-[(1°,3-dimethylxanthined-yl)methyl]-3-[3'-(2"-hydroxyethylamino)ethylaminobuOvinyl]thiazolidine; 2-[(
3',7-dimethylxanthine-1-yl)methyl]-
3-[3′-(2″-hydroxyethylamino)ethylamino-propionyl]thiazolidine; 2-[(1°,
3-dimethylxanthine-7°-yl)methyl]-3-
[3'-(4''-human O-oxyethylpiperazine-1''-
yl)propionyl]thiazolidine.

The compound of the present invention has the formula (■): (wherein R is the group defined above, Y and Yo are an alkoxy group having 1 to 2 carbon atoms, or - taken together, represent a carbonyl group) A compound represented by the formula I: (wherein R2, R3 and R4 are the same as above) is reacted with an amine alkane alkanethiol represented by the formula (Ia): (representing a group as defined above).

A compound of formula (11) in which R2 is a hydrogen atom may optionally undergo optical resolution.

If R2 is a free or esterified carboxyl group, a single diastereoisomer and/or a racemic mixture of diastereoisomers can optionally be obtained.

Thiazolidines of formula (Ia) and enantiomers or diastereoisomers thereof are cyclic anhydrides such as succinic anhydride, glutaric anhydride, etc.; active species of carboxylic acids of formulas (IVa) and (IVb) (aCtiV
ated species) and sulfonyl halides of formula (IVC): Q-fCH2ycOZ (IVa
)Ps-802-Hal
(IVc) (in each formula, Q, PI, R2 and n
is defined above, R5 is an alkyl group having 1 to 2 carbon atoms or an unsubstituted or mono- or polysubstituted phenyl ring, Hal is a chlorine atom, a bromine atom and an iodine atom; l is a chlorine atom Atom, bromine atom, azide, formula 0-CO-D (wherein O is a lower alkoxy group having 1 to 5 carbon atoms or a benzyloxy group, a lower alkyl group having 1 to 5 carbon atoms (mixed anhydride and anhydride) Optionally, subsequent acylation is effected by reaction with an acylating agent selected from the group consisting of activated esters and activated esters.

The resulting acylated thiazolidine has the formula %): R'1 (wherein R1R3, R4 and R2 have the above meanings and R'1 has the formula SO2-ps or CO-R5 ( During the ceremony,
R5 and R5 are as defined above).

When carposide is used as the active molecular species of the carboxyl group in the acylation reaction, the acylation reaction converts the thiazolidine of formula (I) into compounds of formulas (IVa) and (IVb) in which 1 is a hydroxyl group.
can optionally be made by reacting with an acid.

The compound of formula (Ib) is optionally oxidized with a suitable reagent to form a compound of formula (Ic): Compounds that can be obtained are obtained.

General formula (Id): Co(Id) " ■ Q.

(In the formula, R, R2, R3, R4, P are as defined above, at least one of Pl and R2 is a hydrogen atom, the other is a hydrogen atom, a methyl group or a phenyl group, and Qo is a halogen atoms, n is preferably 0)
is the formula: % formula % (wherein R3 is a group as defined above; aase represents a group selected from the group consisting of sodium, potassium, magnesium, calcium, lower trialkylammonium, phenyl dialkylammonium) It may be optionally reacted with a thiocarboxylic acid salt, and Q
The compound of the formula (Idl) where o is R3-+C2-+-1-CO8 (wherein R3 and 0 are the same as above) can be changed.

These latter compounds optionally react with ammonia to provide Q
Compounds of formula (Id) in which o is a free thiol group are obtained and optionally reacted with an alkyl halide in the presence of a base to obtain compounds of formula (Id) in which Qo is an alkylthioether group.

Finally, compounds in which n is 0, Pl and R2 are hydrogen atoms, and Qo is chlorine, bromine, or iodine atoms in formula 1) can be prepared using triphenyl Reaction with phosphine T formula (Id)
(CaHs) 3 Optionally, the compound of formula (Ie) is converted into a stabilized ylide compound of the formula (V): T -CHO(V), where ■ is Formula (H) is optionally reacted with an aldehyde of the group defined above to remove the protecting group.
: CO \. In the 3-thiazolidine acrylamide of H-C□-1 (in the formula, R, R2, R3, R4, T and P are the same as above), ■ is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or In the case of triyl group, amine, i.e., 82 N−+C) 12 I
T+ (in the formula, ■ and R1 are the same as above), mono- or di-substituted amines or thiols (i.e. HS (C82 edition)-T + (in the formula, m and T1 are the same as above), substituted Q.

(wherein R, R2, R3, R4, T and P are the groups defined above, 0° is HN%CH, →-tube-T+ (in the formula, I and R1 are the same as above), mono and di Substituted amine I, S+CH2→n T+ (wherein,
1, n and R1 are as defined above), representing an unsubstituted or polysubstituted phenylthio group).
obtain the adduct).

Cyclization of a compound of formula [1[1] to form a 2-substituted thiazolidine ring with an aminoalkanethiol of formula l is carried out using a stoichiometric amount or a small excess of the aminoalkanethiol and acetic acid a in an aqueous solvent. The reaction may be carried out in the presence or absence of a catalytic amount of its ammonium salt, such as salt, f-acid, camphosulfonate, hydrochloride.

Suitable solvents include, for example, water, methanol, ethanol,
Acetic acid and mixtures thereof.

The reaction is preferably carried out at about -20°C to the reflux temperature of the solvent, more preferably at air temperature.

Reaction times range from 1.2 minutes to several days, but
Usually the reaction time does not exceed 2 hours, and often a few minutes is sufficient to bring the reaction to completion.

The optical resolution of compounds of formula (Ia) is e.g.
Forms salts with optically active enzymes such as -7-zinecarboxy-bicyclo[2,2,1]heptane -3-one-3,3-ethylenedioxy, etc., and subsequently provides a certain degree of light exposure. This may optionally be carried out by crystallizing up to 50% and recovering the optically active 2-dissolved thiazolidine.

Suitable solvents include, for example, methanol, ethanol, 1
- Alcohols such as propatool, 2-propyl ether, ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, esters such as ethyl formate, ethyl acetate, carbonization such as benzene, toluene, cyclohexane, hexane. hydrogen and mixtures thereof.

Optical resolution is preferably carried out at air temperature, and 1.2 crystallizations are generally required to achieve a constant light absorption.

Acylation of a compound of formula (Ia) with an acylating agent of formula (IV) is carried out in the presence of a stoichiometric or small excess of a base in an insoluble solvent. This is done by reacting with a curing agent.

Suitable solvents are, for example, CH2CIJ, CHCl
3, CI CM 2CR2 (halogenated hydrocarbons such as J, ketones such as acetone and butan-2one,
Hydrocarbons such as hexane, cyclohexane, benzene, toluene, pyridine and mixtures thereof.

Near stoichiometric amounts of base are useful for any species of acylating agent. Such bases include, for example, CaO1CaCO3, 2C03, Na2COx, N
alkali metal or alkaline earth metal oxides such as HCOs, carbonates or bicarbonates, etc.
lI bases; organic bases such as tertiary amines such as trimethylamine, tributylamine, etc. or aromatic bases such as pyridine, alkyl-substituted pyridines, N,N-dialkylanilines, or anionic ion exchange Resin can be given.

The acylation reaction is preferably carried out at a temperature ranging from about -40°C to about the temperature of the solvent.

More preferably the reaction is carried out at room temperature.

In the acylation reaction, formula (IVa) and formula (IVb
) (in which 2 represents an OH group), the reaction is carried out in an inert solvent at room temperature, optionally in the presence of 4-dimethylaminopyridine as a catalyst, with a carbodiimide, preferably is carried out in the presence of an excess of a condensing agent such as dicyclohexylcarbodiimide.

The reaction of oxidizing the compound of formula (Ib) to obtain the thiazolidine sulfoxide of formula (IC) involves the use of organic peroxides such as monoperphthalic acid, perbenzoic acid, peracetic acid, performic acid, and perbenzoic acid. It is obtained by reaction with a stoichiometric amount or a small excess in an inert solvent in the presence or absence of a base.

The preferred oxidizing agent is a stoichiometric amount of monoperphthalic acid;
The preferred solvent is ethyl acetate and the reaction is carried out with excess Ha
Preferably, this is carried out in the presence of HCO.

Preferably, the oxidation reaction is carried out at a temperature ranging from about -25°C to room temperature. Most preferably the reaction is carried out at 0°C.

In formula (Id), the compound in which Q'' is a halogen atom can be thiolated using, for example, sodium, potassium and/or trimethylamine,
The stoichiometry or excess of thiocarboxylic acid salts, such as salts formed in situ with organic bases such as triethylamine, tributylamine, etc. This is done by processing in I1M.

Preferred solvents include, for example, halogenated hydrocarbons, ketones,
Esters, ethers, alcohols and mixtures thereof.

The reaction is preferably carried out at room temperature, and the reaction time is 1,2
The time period ranges from minutes to several hours, but usually does not exceed 2 hours at room temperature.

Free thiol groups are obtained by reacting the thioacyl compound with an excess of aqueous ammonia in an inert gas atmosphere.

The reaction is carried out at room temperature, and suitable solvents are alcohols such as metal, ethanol, glycols; ethers miscible with aqueous ammonia such as dimethoxyethane, dioxane, tetrahydrofuran, and mixtures thereof.

Acrylation of free thiols may be accomplished as described above.

Alkylation of free thiol groups may be carried out by treating potassium and/or sodium salts of thiol compounds with alkyl halides.

Although the reaction of the stabilized ylide of formula (Ie) and the aldehyde of formula (v) is the well-known Witsch reaction, this experimental procedure is also well-known to those in the art. There is. Generally, the reaction is carried out using halogenated solvents, ether solvents (THE, dimethoxyethane),
, acetonitrile, cyclohexane, benzene, toluene, hexane, dimethylsulfoxide, or mixtures thereof, preferably by mixing the reagents in equimolar ratios at room temperature.

The Michael addition of the nucleophile formula (■'') defined above to acryl 7mide is also a well-known reaction. The preferred solvent is an alcohol and the reaction is carried out by mixing the solvents and heating at reflux temperature. It is done by heating.

The compound of formula (Il) is a known compound and can be prepared by a known method (
De Martiis et al.
Fal? :] (jl Farmaco) J, Ed,
Sc, 1.526 (1956)).

In particular, compounds in formula (1) in which Y and Yo are methoxy or ethoxy groups can be prepared by dissolving a suitable α-halogenated acetaldehyde-acetal in a suitable solvent such as dimethylformamide, dimethylsulfoxide or water, and mixtures thereof. Among them, lithium of 1,3-dimethylxanthine or 3,7-dimethylxanthine,
Produced by reaction with an alkali salt such as sodium or potassium.

The compounds according to the invention are therapeutically active substances, without acute, subacute or chronic toxic effects, and are suitable for use as antitussives, mucus regulators or bronchodilators.

In fact, for example, the compounds according to the invention do not exhibit acute toxic effects in mice and rats.

After oral and intraperitoneal administration of the compounds according to the invention, 19/
LD5° values greater than Kg are determined with systemic administration.

The compound 2-[(1',3'-dimethylxanthined-yl)methyl]chacilidine according to the invention shows that it has an LD5oIi of 0.69/double (oral) and 0.489/Kg (intraperitoneal). It differs from other compounds of the invention because it has been shown in mice.

Charlier et al.
Archives Internationala
les de Pharmacodynawie),
134, p. 306, 1961) and Stefko et al., Journal of Pharmaceutical Experimental Therapy (J, Pharm, Exp.

108, p. 217, 1953) has demonstrated, with little modification, the antitussive action of the compounds according to the invention.
Used to heal. Phosphocodine was the positive control compound ylJ (positive rererencecom
Pound).

According to Charlier's method, guinea pigs are exposed to an aerosol of citric acid (75%) and coughs are recorded for 60 minutes after being treated with an antitussive via the intraperitoneal route. Male animals weighing 300-400 g are used in all experiments.

The guinea pigs were placed in a transparent box (20 x 30 x 30 cm) connected to an aerosol spray device and treated with compounds according to the invention (0, IM and 0.3 M solutions, l#Ii!
60 minutes after intraperitoneal administration of /1(j), animals are exposed to a citric acid saturated atmosphere.

Total number of cough attacks and first cough delay time for the first 5
Record in minutes.

Five guinea pigs are used for each dose level and the results are compared to the control (vehicle treatment) and 0.07M solution of codine phosphate (standard treatment).

The EDso and the corresponding delay time of the first cough attack are counted.

Data obtained with intraperitoneal administration are confirmed with oral administration.

In the Stefko method, unanesthetized Mongrel dogs (body weight 15±3 Ky) are used. Compounds according to the invention are tested for their ability to inhibit cough induced by electrical stimulation.

Under general anesthesia, two insulated nichrome wires (0.4 m+ diameter) are surgically implanted into the epimucosa of the trachea.

Approximately 2 days later, the dog was suspended from a sling.
The externally exposed electrodes are connected to an electrical stimulation device such as a Grass 1348 Moto (Nod, ).

Delay time 0.01ms, duration 1ms and annoyance level 30
Stimulation parameters such as H2 are used.

To determine the minimum voltage required to elicit a reproducible cough response, 10 1 second electrical impulses are applied at 5 second intervals.

Next, the cough response to electrical stimulation was determined by oral administration of the compound according to the present invention at 15, 30, and 60 minutes.

90 minutes, 120 minutes, 150 minutes, 180 minutes, 24
Recorded after 0, 300 and 360 minutes.

The cough response is scored as follows:

1: no response 2: sigh or loud exhalation 3: pronounced cough 4: 1 pronounced cough and 1 loud exhalation 5: 2 pronounced coughs Six dogs were used for each determination; Calculate the average activity.

Compare percent inhibition of cough response and duration of action with Codin.

In the guinea pig cough test, codin phosphate exhibits an ED5o value of 1,=23m9/K9 and a delay of 170%.

In the dog cough test, codine phosphate did not exhibit a 52% inhibition of cough irritation for an extended period of time (approximately 2-4 hours) when tested at 8 lbs/Kg.

The mucus-modulating properties of the compounds according to the invention are investigated "in vivo" by experiments carried out on male New Sealant white rabbits. vJ product is 5% by aerosol)
, 303 aqueous solution (3 hours a day, every other day for 3 days), induces chronic bronchitis, the disease producing pathological sputum in the bronchi.

The purpose of the experiment was to determine the sputum dry weight, viscosity, and protein, phospholipid, galactose, sialic acid, and fucose-like effects induced by pharmacological treatment of the compounds of the present invention in this pathological sputum. The goal is to evaluate changes in selected parameters.

For this purpose, one of the compounds of the invention is administered twice a day (
9:OOa, n+, and 4:OOp, m,) rT inserted into the trachea before and after oral treatment.
Sputum produced within the bronchi is collected daily using a J-shaped glass cannula.

The schedule of the processing procedure is shown in Fig. 1 below.

Figure 1 MHHH In Figure 1, O represents the day the tracheal cannula was captured, -7, -5 and -3 represent the date of H2SO3 treatment (old), 1.2.3 and 4 represent the day the tracheal cannula was captured. Day of oral administration of the compound of the present invention Time of collection of fTl and mucus (
H).

Mucus collected in the morning of day 1 is considered a blank, and 7 indicates the day the animal is sacrificed after mucus collection.

Sputum samples are stored in a freezer (-20°C) until biological and rheological parameter studies are performed.

The sample was a 1.565° cone plate.
Brookfield Viscometer (Model L) equipped with
The relative viscosity was measured at 37° C. using a TVD) and then divided and subjected to the goldstone biological analysis of proteins, phospholipids, galactose, sialic acid and fucose, respectively. The mucus dryness ff is also determined. For each parameter, the cumulative data are for 7 days after the start of the treatment and they are removed using the At1C (area of the curve) method calculated by the trapezoidal rule.

Finally, data are shown for control (vehicle treated), non-bronchitis rabbits (vehicle treated) and 0,1538 S
- data obtained from a positive control rabbit with bronchitis treated with carboxymethylcystine.

Table 1 shows the AUG determined for various parameters in rabbits with bronchitis treated with S-ruboxymethylcysteine in % compared to controls with tracheitis. i.

As is clear from Table 1, all parameters are S
- It varied depending on the treatment with hydroxymethylcysteine.

The ideal mucus modifier should reduce the viscosity and protein content of mucus.

In pathological conditions, the protein content of mucus increases, which may be associated with abnormal production of mucus large molecules and abnormal hexagonal passive transport of serum proteins from capillaries.

At the same time, the mucoprotein content should decrease with a decrease in the content of galactose and sialic acid in the sputum, indicating a decrease in the production of mucins that contribute to mucus viscosity.

Fucose content is involved in the production of neutral mucin.

The increase in mucus volume is involved in local repair processes that cause mucus dissolution and liquefaction. This process is particularly desirable when the patient's mucus is sticky and highly viscous, such as in certain pathological conditions, resulting in respiratory tract obstruction.

Table 2 shows the results obtained by orally administering equimolar amounts of the two compounds of the tree invention compared to the standard S-ruboxymethylcysteine, with AUC values compared with the bronchitis control as 100%. show.

[Margin below]

2-[(1,3-dimethylxanthine-7'-yl)methyl]thiazolidine-4-carboxylic acid is a typical compound of the present invention and has good antitussive and mucus regulating properties. In fact, in the guinea pig cough test this compound showed an EDso value of 62119/KW, 213%
), showing a better duration of action compared to Codin. At a dose of 20q/II, this compound shows a 32% inhibition of cough irritation in dogs and compares favorably with Codin in its duration of action. 4-carboxyxanthine-methylthiazolidine with free or esterified carboxyl groups is also effective as an antitussive, with a 50%
It shows an EDs- of ~65a+y/Ny and can induce 38% to 50% inhibition in the dog cough stimulation test.

This action as an antitussive is also combined with mucus-regulating action, which is at least as potent as S-carboxymethylcysteine.

The guinea pig cough test and the dog cough test are valid and reliable methods for screening substances useful in treating coughs of different origins and in alleviating the pain caused by cough attacks.

Therefore, the compounds of the invention may be useful in treating patients to prevent and reduce cough attacks.

Therefore, the compounds of the invention are also useful for inhibiting cough attacks that can lead to syncope.

Prevention and control of severe coughs is also very helpful, as coughs may cause emphysematous bleb rupture and rib fractures.

Although rib fractures caused by coughing may occur in otherwise normal patients, their occurrence raises the possibility of pathological fractures seen in multiple myeloma, osteoporosis, and osteolytic metastases. At least it will increase.

Particularly preferred compounds according to the invention as antitussive agents are:

2-[(1°,3°-dimethylxanthine-7°-yl)methyl]thiazolidine-4-carboxylic acid, and C!
- Its ester with C5 alcohol, 2-[(3°,7-dimethylxanthine-1゛-yl)
methyl]thiazolidine-4-carboxylic acid, and C1~
Its ester with Cs alcohol, 2-[fl“, 3-dimethylxanthine-7°-yl)
methyl]-3-[3'-(2''-hydroxyethyl-aminoethylamino)propionyl 1thiazolidine, 2-
[(1°,3-dimethylxanthine-2-7°-yl)methyl]-3-[3′-(4″-hydroxyethyl-piperazin-1″-yl)propionyl]thiazolidine.

In certain pathological conditions, such as chronic bronchitis, suppressing a cough that produces large amounts of sputum is not necessarily desirable, and a moderate antitussive action with very strong mucus-regulating action is highly desirable. . In some cases, suppressing a cough too early can cause mucus to build up in the bronchi, blocking alveolar ventilation and inhibiting the lungs' ability to fight infections.

As a result, the changes caused to the mucus by treating the selective viscosity modifier reduce the number of cough attacks.

Particularly useful and preferred compounds exhibiting reduced antitussive action and high mucus regulating action for this purpose are as follows.

2-((1°, 3-dimethylxanthine-7-yl)methyl]thiazolidine, 2-[(3', 7-dimethylxanthine-7-yl)methyl]thiazolidine and its 3-7 cetylthioacetyl derivative, 2-[(1′,3-dimethylxanthine-7-yl)methyl]-3-[3-thia-5′-carboxy-acetylamino-hexanoyl]thiazolidine, 2-[(1′,3°-dimethylxanthine) -7°-yl)methyl]-3-[3'-(imidazol-1''-yl)propionyl]thiazolidine.

Particularly preferred mucus modifiers are 2-[(1',3-dimethylxanthine-7-yl)methyl]-thiazolidine and imida-zol
-1-yl-alkanoic), caffeic acid, ferulic acid, (3-phorphorinylmethyl-4-hydroxy-3
-methoxy)cinnamic acid and (3-pyrrolidinylmethyl-4-hydroxy-3-methoxy)cinnamic acid.

The above compounds change the numerically calculated rheological parameters (proteins, phospholipids, fucose, sialic acid and viscosity) similar to those obtained with the starting thiazolidines, but at lower doses ω.

In particular, these superior compounds according to the invention are also characterized by a pronounced effect on causing relaxation of tracheal and bronchial smooth muscle. For example, the compound 2-[(1',3-dimethylxanthine-7°- yl) methyl]-3-[3°
-morpholinylmethyl-4-hydroxy-5-methoxycinnamoyl]thiazolidine relaxes methacholine-contracted guinea pig tracheal smooth muscle strips with an EDso value of 1.9 x 10-48. sell. The lI spasmodic effect of this new substance is that of dihydroxypropyltheophylline (E05o value is 0.76 x 1G-4M)
compared favorably with that of

After intrajugular administration, the compound has been shown to resolve bronchospasm induced by intravenous administration of histamine in anesthetized guinea pigs (Hunzetto-Resler).
It appears to have at least four times more activity than aminophylline in the Onzett-Ressler study).

Therefore, the compounds represented by general formula [1] are effective as antitussives, bronchodilators and mucus regulators.

The compounds may be administered orally, sublingually, intravenously, subcutaneously, intramuscularly, rectally, or by the inhalation route.

The inhalation route is particularly preferred when a mucus-regulating effect is required.

The preferred dosage of the compounds of the present invention is from 0.05 to about 5.
It varies between q/*/days.

The preferred dose for the inhalation route is O,OS to 1η, /
K9 ,,'It's during the day.

As mentioned above, the compounds of the invention can be administered to both humans and animals in various dosage forms: orally as a tablet, capsule or solution; rectally as a lozenge; parenterally as subcutaneously. or intramuscularly, preferably intravenously in emergency cases; by inhalation in the form of an aerosol or in the form of a solution for a nebulizer; for long-term action it can be administered in sterile implantable form. . Pharmaceutical compositions containing compounds of the invention may be manufactured by conventional methods and may contain conventional carriers and/or diluents.

For example, for intravenous administration or infusion, sterile isotonic aqueous solutions are preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous or non-aqueous media may be used, and for tissue implantation, sterile tablets or silicone containing or impregnated with the compound. Rubber capsules are used.

Common carriers or diluents include, for example, water, gelatin, lactose, dextrose, sucrose, mannitol,
These include sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycol, starch, gum arabic, gum tragacanth, alginic acid or algin W1 salt, lecithin, polysorbate and vegetable oil.

For administration by nebulizer, suspensions or solutions of the compounds of the invention, preferably in salt form, such as the sodium salt (and/or nitrate) in water may be used. Alternatively, the formulation may be in the form of a solution or suspension of a compound of the invention in one of the common liquefied propellants, such as dichlorodifluoromethane or dichlorotetrafluoroethane, such as in an aerosol bomb. Can be administered from a pressurized container. If the compound is not soluble in the propellant, co-solvents such as ethanol, dipropylene glycol and/or surfactants may be used.
ent) may need to be added to the formulation.

The present invention will be described below with reference to Examples, but the present invention is not limited to the Examples.

Example 1 Cystamine hydrochloride 1.65g and potassium acetate 1.47g
Add 10 Irl of a 70% aqueous acid solution containing 2.413 liters of theophylline acetaldehyde dimethyl acetal,
The mixture was heated at reflux temperature for 3 hours. The resulting suspension was diluted with water, the precipitate was filtered and washed with water, and 2-[(
1°, 3-dimethylxandin-7-yl)methyl]
2.4 g of thiazolidine was obtained. Melting point 141-143℃,
(Crystallized from ethanol) Example 2 70 d of an ethanol solution containing 2.4 g of theopromine acetaldehyde was added to 10 portions of an aqueous solution containing 2.12 g of cysteine hydrochloride (1) and 1.4 g of potassium acetate. The suspension was stirred overnight at room temperature, diluted with water and filtered. 2-[
(3°,7')-dimethylxanthine-1°-yl)methyl]thiazolidine-4-carboxylic fermentation was obtained.

Example 3 Cystine ethyl ester hydrochloride, Cystine J7!, was prepared in the same manner as in Examples 1 and 2. iH salt, d-7
3 and g-penicillamine were reacted with theophylline acetaldehyde, theobromine acetaldehyde, and the corresponding dialkyl acetals to produce the compounds listed below.

2-[(3',7°)-dimethylxanthine-1-yl)methyl]thiazolidine: Melting point: 16G-167''C
2-[(1',3-dimethylxanthine-7-yl)methyl]thiazolidine-4-carboxylic acid; Melting point: 147~
150℃ 2-trio, 3-dimethylxanthine-7'-yl)
Methyl]-4-carboethoxythiazolidine; Melting point: 1
11-113℃ 2-[(3",7'-dimethylxanthine-1-yl)
Methyl 1-4-carboethoxythiazolidine; Melting point: 1
29-130℃ 2-[(3°, 1°-dimethyl-based 1-yl)
methyl]-5,5-dimethylthiazolidine-4-carboxylic acid: point a: 132-135°C 2-[(1',3'-dimethylxanthine-7°-yl)methyl]-5,5-dimethylthiazolidine- 4-Carboxylic acid; melting point = 125-130°C Example 4 Pyridine 3 containing 0.25 g of methanesulfonyl chloride 2-[(1°,3′-dimethylxanthine-7′-yl)methyl]thiazoline
．． 5d and cooled at 0°C. After 30 minutes, the mixture was heated to air temperature, diluted with aqueous sulfuric acid solution for 1 hour, and extracted with chloroform.

After the usual treatment, the residue was crystallized from ethanol to yield 0.24 l of 2-((1°,3-dimethylxanthinedyl)methyl)-3-methanesulfonyl-thiazolidine with a melting point of 206°C. .

Example 5 The following compound was obtained using methanesulfonyl chloride, benzenesulfonyl chloride, and p-toluenesulfonyl chloride in the same manner as in Example MW44.

2-((1°.3-dimethylxanthine-1'-yl)
Methyl 1-3-ethanesulfonylthiazolidine: Melting point:
208°C 2-[(1″,3-dimethylxanthine-7-yl>methyl]-3-phenylsulfonylthiazolidine; Melting point:
215-220°C 2-[(1°.3′-dimethylxanthine-7′-yl)methyl]-3-p-toluenesulfonylthiazolidine; Melting point = 215-218°C 2-[(3°, 1°- Dimethylxanthine-1°-yrunmethyl]-3-methanesulfonylthiazolidine; Melting point: 210-213°C 2-((3',7-dimethylxanthine-1-yl)methyl]-3-ethanesulfonylthiazolidine; Melting point: 2
10-215℃ 2-((3',γ'-dimethylxanthine-1-yl)
Methyl]-3-methanesulfonylthiazolidine; Melting point:
220-222°C 2-[(3°,7-dimethylxanthine-1-yl)methyl]-3-p-1-luenesulfonylthiazolidine; Melting point: 220-222°C Example 6 α- Cooled to 0°C Chloracetyl chloride 0.31
A solution of dichloroethane 2d containing m is being stirred 2
-[(1°13゛-dimethylxanthine-7'-yl)
1 g of methyl]thiazolidine and 0.54 g of triethylamine
Dichloroethane lGm1 containing m! was added dropwise to the suspension.

After being kept at 0° C. for 30 minutes and at room temperature for 2 hours, the mixture was partitioned between 50 Id of water and 50 Id of dichloroethane, and the organic phase was washed with a 5% aqueous sodium bicarbonate solution and water.
Dry over sodium sulfate and evaporate the solvent under vacuum.

The residue was crystallized from ethanol, melting point 205-207°C.
1 g of 2-[(1',3'-dimethylxanthine-7'-yl)methyl 1-3-chloroacetylthiazolidine was obtained.

Example 7 In the same manner as in Example 6, 2-[(3°17-cymethylxanthine-1-yl)methyl]thiazolidine, 2-[
(1',3-dimethylxanthined-yl)methyl]
The following compounds were obtained using thiazolidine, α-chloroacetyl chloride, α-buO mobropionyl chloride, cyclopropylcarbonyl chloride, cyclohexylpropionyl chloride, cyclopentylpropionyl chloride and ethyloxalyl chloride.

2-[(3',7-dimethylxanthine-1-yl)methyl]-3-chloroacetylthiazolidine; Melting point: 20
8-210℃ 2-[(3',7-dimethylxanthine-1'-yl)
Methyl 1-3-cyclopropylcarbonyl-thiazolidine: 2-[(3°,7'-dimethylxanthine-1-yl)
methyl]-3-(2'-bromo)-propionyl-thiazolidine; melting point: 215-218°C 2-[(3',7''-dimethylxanthine-1'-yl)methyl]-3-(3-cyclohexyl) Propionyl-thiazolidine; Melting point: 170-172℃24(3',
7°-dimethylxanthine-1-yl)methyl]-3-
(3-cyclopentyl)propionyl-thiazolidine:
Melting point: 175-177°C 2-[(3°,7°-dimethylxanthine-1°-yl)methyl 1-3-ethyloxalylthiazolidine; Melting point: 142-144°C 2-[(+',3' -dimethylxanthine-7-yl)
Methyl 1-3-cyclopropylcarbonyl-thiazolidine; Melting point: 210-212°C 2-1°,3-dimethylxanthine-7°-yl)methyl]-3-(2°-bromo)buOpionyruthiazolidine; Melting point : 220-222°C 2-[(+',3-dimethylxanthine-7-yl)methyl]-3-(3-cyclohexyl)propionyl-thiazolidine; Melting point: 165-166°C 2-[(1',
3-dimethylxanthine-7-yl)methyl]-3-(
3-cyclopentyl)propionyl-thiazolidine; melting point: 168-170°C 2-[(1"13-dimethylxanthine-7-yl)methyl 1-3-ethyloxalyl-
Thiazolidine; melting point: 150-152°C Example 8 5 gi of anhydrous sym-dichloroethane containing 1.14 d of ethyl chlorocarbonate under a nitrogen atmosphere! acetylthioic acid 9, cooled to -20°C while stirring.
Anhydrous sy containing (] and triethylamine 1, 7d
It was added dropwise to a solution of n+-dichloroethane.

After 1 hour, the mixture was diluted with 2-[(1'.3'-dimethylxanthine-1°-yl)methyl 1thiazolidine
9 in 1 od of anhydrous syn+-dichloroethane and heated to room temperature. After 3 hours, water and ice were added. Wash the organic phase with 5% sodium bicarbonate and water until neutral, lil! [Dried over sodium chloride and evaporated under vacuum. Crystallization from ethanol gave 2-((1°13°-dimethylxanthine-1-yl)methyl)-3-acetylthioacetyl-thiazolidine with a melting point of 202-204°C.

Example 9 2-[(3'
,7'-dimethylxanthine-1'-yl)methyl 1-
It was added to a suspension of 3.5 g of 3-chloroacetyl-thiazolidine in 100 ml of anhydrous acetone.

After 3 hours, the solvent was evaporated and the residue was dissolved in 100 d of water and 150 sl of chloroform! It was divided using The organic phase was washed with a 5% aqueous sodium bicarbonate solution and water until neutral;
Evaporated to dryness. The residue was crystallized from ethanol, melting point 1
3.2 g of 2-[(3°,7'-dimethylxanthine-1'-yl)methyl]-3-7cetylthioacetylthiazolidine was obtained at 16-120°C.

Example 10 Dichloroethane 501d containing 0.911 of 2-[(2°,4°-dimethylxanthine-7°-yl)methyl]-3-α-lyoacetylthiazolidine under nitrogen atmosphere
.

was treated with 0.551 l of thiobenzoic acid and 0.15 g of tetrabutylammonium bromide and with 25 d of an aqueous solution containing 0.539 g of potassium carbonate.

The mixture was stirred overnight. The organic phase was washed twice with 25 d of water, dried over sodium sulfate, the solvent was evaporated under vacuum, and the 2-[(1',3-dimethylxanthine-7'-yl)methyl, m.p. 210-213 °C 0.85 g of -3-benzoylthioacetyl-thiazolidine was obtained (precipitation solvent: ethanol).

Example 11 In the same manner as in Example 10, benzoyl ester, cyclohexylpropionyl ester, cyclopentylpropionyl ester and 3.4-
Diacetoxy-cinnamoyl ester was converted into 2-[(1°,
Reaction with 3°-dimethylxanthine-7'-yl)methyl]thiazolidine and 2-[(3°,7-dimethylxanthine-1-ylcomethyl]thiazolidine gave the following compound.

2-[(3°, 7-dimethylxanthine-1-ylcomethyl 1-3-benzoyl-thioacetyl-thiazolidine; melting point = 220-223°C 2-[(3″, 7°-dimethylxanthine-1゛-ylcomethyl]) -3-(3°-cyclopentylpropionyl-thio)acetyl-thiazolidine: melting point 210-213
°C 2-[(3°,7-dimethylxanthine-1'-ylcomethyl]-3-(3'-cyclopentylpropionyl-
thio>acetyl-thiazolidine; melting point 215-217°C 2-H',3-dimethylxanthine-7-yl)methyl]-3-(3-cyclohexylpropionyl-thio)acetyl-thiazolidine; melting point = 200-203°C 2- [(1°, 3′-dimethylxanthine-7°-yl)methyl]-3-(3,4-diacetoxy-cinnamoyl-thio)acetyl-thiazolidine: Melting point: 2GG~2
05°C Example 12 2-[(1°13°-dimethylxanthine-7′-yl)methyl]-3-α-chloroacetylthiazolidine 3.
A suspension of 50 ml of methyl ethyl ketone containing 5 g of sodium iodide and 2.1 g of sodium iodide was refluxed for 12 hours with stirring.

After removing the solvent, the residue was partitioned between chloroform and water. The organic phase was washed with aqueous sodium bicarbonate and sodium thiosulfate and once again with water. The solvent was evaporated and the resulting residue was crystallized from ethanol to give 2-[(1°, 3′-
3.4 q of dimethylxanthine-7-yl)methyl]-3-α-iodoacetylthiazolidine were obtained.

Example 13 2-[(1′,3°-dimethylxanthine-7°-yl)methyl]-3-acetylthioacetyl- while stirring 1.5 m of 30% ammonium hydroxide aqueous solution under an inert gas atmosphere. Added to a solution of thiazolidine o,sg in dimethoxyethane. After 2 hours, the mixture was diluted with water, excess ammonia was removed under vacuum, and the resulting solid was filtered. After washing with ethanol, melting point: 276-27
2-[(1'.

3°-dimethylxanthine-7°-yl)methyl]-3
-α-Mercaptoacetyl-thiazolidine 025g was changed. Similarly, 2-[(3
°, 7゛-dimethylxanthine-1-yl)methyl 1-
3-α-mercaptoacetyl-thiazolidine was produced.

Example 14 Methylene chloride 6#11 containing 1.44 m of isobutyl chlorocarbonate! A solution of methylene chloride containing 1.7313 d of (4-methyl-piperazin-1-yl)acetic acid and 1.52 d of triethylamine was cooled to 20°C.
It was added dropwise to the 0- solution. The mixture was kept at -20°C for 45 minutes, then 2-[(1',3-dimethylxanthine-
A solution of methylene chloride containing 4.6 g of 7-yl)methyl]-3-mercaptoacetyl-thiazolidine was added. The mixture was kept at -20°C for 45 minutes and it was heated to room temperature. After normal processing, melting point 212-214
2-[(1°, 3′-dimethylxanthine-7°-
yl)methyl]-3-(4'-methylpiperazin-1'-yl)acetyl-thioacetyl-thiazolidine was obtained.

2-[(3°,7-dimethylxanthine-7°-yl)methyl]-3-(4°
-methylpiperazin-1-yl)acetyl-thioacetyl-thiazolidine was obtained.

Example 15 2-[(1′,3°-dimethylxanthine-1-yl)
A solution of 10 Itl of DH8O containing 1 g of methyl]-3-chloroacetyl-thiazolidine was treated with 0.5 g of sodium imidazole. - Stirred overnight at room temperature, the mixture was diluted with water and extracted with chloroform.

2-[(1',3-dimethylxanthine-7'-yl)methyl]-3-(imidazol-1-yl)acetyl, having a melting point of 235-238°C, is crystallized from ethyl ether after the usual treatment. -0.6 g of thiazolidine was obtained.

In a similar manner, 2-[(3°) with a melting point of 231-234°C was prepared.

7-dimethylxanthine-1°-yl)methyl]-3-
(imidazol-1-yl)acetyl-thiazolidine was produced.

Example 16 0.48 g of succinic anhydride was added to 2-[(3′,7′-dimethylxanthine-7°-yl)methylcorchizolidine 1
．． 9 g of dimethylaminopyridine 63-Q. - After leaving for the night. The solution was diluted with water and acidified with 2N acid.

The aqueous phase was extracted with chloroform and the collected organic phases were washed with water. After evaporation of the solvent, the residue was crystallized from methanol/ethyl ether to give 2-[(
3',7°-dimethylxanthine-1-yl)methyl]
0.4 g of -3-(3°-carboxypropionyl)thiazolidine was obtained.

Similarly, 2-((1°, 3-dimethylxanthine-7-yl)methyl)-3-(3-carboxypropionyl)thiazolidine having a melting point of 208-210°C was obtained.

Example 17 In a similar manner to Example 15, using potassium thioacetate instead of sodium imidazole, melting point 116-1
2-[(3', γ°-dimethylxanthine-1) at 20°C
°-yl)methyl 1-3-acetylthioacetyl-thiazolidine was obtained.

Example 18 Using potassium thiobenzoate instead of sodium imidazole, a method similar to Example 15 was carried out to obtain a melting point of 210 to
2-[(1',3°-dimethylxanthine-
1-yl)methyl]-3-benzoylthioacetyl-
I received thiazolidine.

Example 19 1.38 g of potassium carbonate and 1.275-N-methylpiperazine were dissolved in 2-[(1°13-dimethylxanthine-
anhydrous acetonitrile containing 3.571;l of methyl 1-3-α-chloroacetyl-thiazolidine
Added to the solution of d. The suspension was centrifuged for 1 hour under stirring. After removing the solvent, the residue was partitioned between water and chloroform, the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum.

The residue was crystallized from ethyl ether, mp 222-2
25″C 2-[(1°, 3-dimethylxanthine-
7-yl)methyl]-3-(4°-methylpiperazine-
2.85 g of 1-yl)acetyl-thiazolidine were obtained.

Example 20 2-[(3',7-dimethylxanthine-1) as a raw material
-yl)methyl]-3-α-chloroacetyl-thiazolidine with a melting point of 115 to 115 in the same manner as in Example 1.
2-[(3°, 1-dimethylxanthine-1) at 180°C
-yl)methyl 1-3-α-(4-methylpiperazine-
1-yl)acetyl-thiazolidine was produced.

Example 21 1, 23 (l of triphenylphosphine was converted into 2-[(1
'.

3-dimethylxanthine-7°-yl)methyl]-3-
It was added to a solution of anhydrous acetate 1-nitrile 15d containing 1.3 g of α-chloroacetyl-thiazolidine.

The mixture was heated to reflux for 4 hours, cooled and diluted with 15 ml of ethyl ether. The crystalline precipitate was filtered, washed with ethyl ether, and 2-[(1°, 3
-dimethylxanthine-7°-yl)methyl 1-3-α
-2 g of trinoenylphosphonium-acetylthiazoline chloride was obtained. 30 d of methylene chloride and a few drops of phenolphthalein alcohol solution were added to 30 ml of the aqueous solution containing this product. Then add 0.1N aqueous sodium hydroxide solution until the pink color persists. Separate the aiso phase, wash with water, evaporate to dryness,
1.6 g of 2-[(1',3-dimethylxanthine-7-yl)methyl 1-3-triphenylphosphylidenemethylcarbonyl-thiazolidine having a melting point of 122-126 DEG C. was obtained. Dimethyl sulfoxide 6#ti containing 0.9g of this compound! The solution was treated with 0.3 g of 4-acetoxy-3-methoxybenzaldehyde.

After being kept at room temperature for 2 hours, the solution was diluted with 100 d of water and extracted with methylene chloride. After removing the solvent,
The residue was crystallized from ethyl acetate, melting point 208-210.
0.7 g of 2-[(1°, 3-dimethylxanthine-1-yl)methyl]-3-(4′-acetoxy-3°-methoxy)cinnamoyl-thiazolidine was obtained.

Example 22 Under an inert gas atmosphere, 2 parts of methylene chloride containing 0.44 m of ethyl chlorocarbonate was added to a solution of 15 m of methylene chloride containing 1 g of 3,4-diacetoxycinnamic acid and 0.55 m of triethylamine with stirring. added. The mixture was stirred at -20°C for 1 hour. 2-[(1°13-dimethylxanthine-7'-yl)methyl]thiazolidine?
A solution of methylene chloride 10-containing 0.2 g was added dropwise and the resulting mixture was stirred at room temperature overnight. After the usual processing, the residue is crystallized from ethyl ether,
0.9 g of 2-[(1°, 3-dimethylxanthine-7-yl)methyl]-3-(3°, 4-diacetoxy)cinnamoyl-thiazolidine having a melting point of 190-195°C was obtained.

Example 23 0.32 g of fine powdered potassium carbonate was added to 2-[(1°
.

3-dimethylxanthine-1-yl)methyl]-3-(
Ethanol containing 05g of 3',4-diacetoxy)cinnamoyl-thiazolidine! Added to the solution of IM and the suspension was stirred for 2 hours. The solvent was removed under vacuum, and the residue was separated between an aqueous sodium hydrogen phosphate solution and chloroform.

Washed with water until neutral, the precipitate phase was dried over sodium sulfate and evaporated to dryness under vacuum. The resulting residue was crystallized from ethyl ether to give 2-[
0.20 of (1°, 3-dimethylxanthine-7'-yl)methyl]-3-(3°, 4-dihydroxy)cinnamoyl-thiazolidine was obtained.

Example 24 From 2-[(3′,7°-dimethylxanthine-1-yl)methyl]thiazolidine, 2-[f3°, 7
-Simethylxanthine-1-yl)methyl]-3-(3
°.

4-dihydroxy)cinnamoyl-thiazolidine was obtained.

Example 25 DHF containing dicyclohexylcarboimide 226Q
A suspension of 25 d of DHF containing 281 g of 2-[(1°, 3-dimethylxanthined-yl)methyl]thiazolidine, 1.28!11 g of N-acetylcystine and 4-dimethylamino-pyridine was added to a solution of 10 d of DHF. The mixture was added under stirring while cooling at 0°C. After 12 hours, the dicyclohexylurea was filtered off and the solvent was concentrated under vacuum. After the usual work-up, the residue is crystallized with isopropanol to give 2-[f1',3-dimethylxanthined-yl)methyl]-318-acetylglycinyl)thiazolidine, melting point 204-205°C. I got 59.

In a similar manner, using 2-[(3', 7-dimethylxanthine-1'-yl)methyl]thiazolidine, 2
- [(3',7-dimethylxanthine-1-yl)methyl]-3-(N-acetylglycinyl)thiazolidine was obtained.

Example 26 In the same manner as in Example 25, N-formylglycine 25
The following products were obtained by reacting g with the appropriate thiazolidine.

2- [(1°, 3-dimethylxanthine-7-yl)
methyl]-3-(N-formylglycinyl)thiazolidine 2-[(3',7-dimethylxanthine-1-yl)
Methyl]-3-(N-formylglycinyl)thiazolidine A solution of the first toformylglycinyl derivative in methanol is added to an 8N solution of hydrochloric acid in methanol.
Treated with a solution of isopropanol containing hydrochloric acid for 8 hours at room temperature and concentrated the mixture to its original volume of 173 to 2-(
(1°,3-dimethylxanthine-1'-yl)methyl]-3-(glycinyl)thiazolidine hydrochloride was obtained.

Example 27 3.5-dibromo-salicylaldehyde 279o,2-
A solution of 250 ml of methanol containing 3.6 g of [(1°, 3-dimethylxanthine-7-yl)methyl]-3-(glycinyl)thiazolidine and 1.38-triethylamine was heated at reflux temperature for 3 hours with stirring. , then cooled to room temperature. 2-[(1'.

3-dimethylxanthine-1-yl)methyl 1-3-[
Stirring was continued for 8 hours to precipitate 2°-(3″,5″-dibromo-2″-hydroxy-benzylidene-amino)acetyl-thiazolidine. 8 g of alumina.
10% sodium borohydride supported by 10% sodium borohydride was added to a solution of 5.3 g of this compound in 250 d of dichloroethane with stirring. After 6 hours, the organic phase was filtered, washed with water and dried over sodium sulfate.

Next, isopropanol containing 8N-hydrochloric acid 4.8#I! !
2- [(1', 3
-dimethylxanthine-7-yl)methyl]-3-[(
3°.

4.7 g of 5-dibromo-6'-hydroxyphenyl)methyl-aminoacetyl 1-thiazolidine was obtained.

Example 28 0.88 td of acryloyl chloride was added to 2.8 td of 2-[(1',3-dimethylxanthine-7-yl)methyl]thiazolidine cooled to 0°C, 1.52 d of triethylamine and anhydrous methylene. It was added dropwise under stirring to a mixture of 50 m of chloride. The mixture was warmed to room temperature and heated to reflux for 1 hour. The organic phase was washed successively with water, 5% sodium hydroxide, and then water. I!iI After drying over sodium chloride, the solvent was evaporated to dryness under vacuum and the crude product was crystallized from isopropyl alcohol to give 2-[(1',3-dimethylxanthine-7) with a melting point of 190-192°C. 2.7 g of -yl)methyl]-3-(propenoyl)thiazolidine were obtained.

Example 29 2-(2-aminoethylamino)ethanol 0.21
d to 2-((1°, 3-dimethylxanthined-yl)methyl]-3-(propenoyl)thiazolidine 0.f
37() in 10 mQ of ethanol, and the solution was refluxed for 2 hours. The solvent was evaporated to dryness under vacuum, and the solution was refluxed for 2 hours.
The crude product was dissolved in 20 Idt of methylene chloride, the resulting solution was washed twice with 10 Idt of water, dried over sodium sulfate and the solvent was evaporated to dryness under vacuum.

The crude product solid was crystallized from ethanol, melting point 14
2-[(1°,3-dimethylxanthine-7-yl)methyl]-3-[3'-(2''-hydroxyethyl-aminoethyl-amino)propionyl]thiazolidine at 0-142°C was obtained.

In the same way as this, N-(2-hydroxyethyl)
2-[(1'
, 3'-dimethylxanthine-7'-yl,)methyl]
-3-(3°-[2”-hydroxyethylpiperazine-
1″-yl)propionyl]thiazolidine and 2-[
(1',3-dimethylxanthine-7-yl)methyl]
-3-[3'-(imidazol-1''-yl)propionyl-1-thiazolidine were produced, respectively.

Example 30 N,N-dicyclohexylcarbodiimide 2.26! I
2-[(3',7'-dimethylxanthine-1-yl)methyl]thiazolidine 2,81(
J, 219 g of 3-(2-morpholinoethyl)thioacetic acid
and 4-dimethylaminopyridine 0. 12! Added to a solution of 30 IIi of DHF containing II. 12 hours later,
The dicyclohexyl urea was removed by filtration, the organic phase was concentrated under vacuum and the residue dissolved in 150 ml of 0,0 form was washed with a 5% aqueous sodium bicarbonate solution and then with water and dried over sodium sulfate. The solvent was removed under vacuum and the oily residue was crystallized from ethanol and 2-[
3.5 g of (1'.3'-dimethylxanthine-7°-yl)methyl]-3-[3°-(2#-morpholinoethyl)thioacetyl 1-thiazolidine was obtained.

In a similar manner, 2-[(1",3'-dimethylxanthine-7-yl)methyl]-3-[2'-(4"-methyl-piperazinoethyl)thioacetyl 1-thiazolidine was produced.

Example 31 A solution of anhydrous 08306m containing 0.9 g of 2-[(1′,3°-dimethylxanthine-7-yl)methyl]-3-(triphenylphosphylidene-methyl-carbonyl)thialicin was converted into 3-morph orinylmethyl-4
- 1 nitroxy-5-methoxy-benzaldehyde 0
．． 38 (l) at room temperature under stirring. After 24 hours,
The mixture was diluted with 50% of 00-form and washed with water.

The organic phase was dried over sodium sulfate and concentrated under vacuum. Crystallization several times from ethyl acetate and then from ethanol gives pure 2-[(1
',3°-dimethylxanthine-7°-yl)methyl]
-3-[(3-morphorinylmethyl-4°-humanOxy5°-methoxy)cinnamoyl]thiazolidine 0.
Gained 7Q.

The following compounds were produced in a similar manner.

2-[(1°,3-dimethylxanthine-7'-yl)methyl]-3-[(3'-pyrrolidinylmethyl-4
°-humanOxy5°-methoxy)cinnamoyl]thiazolidine 2-[(1°,3゛-dimethylxanthine-7-yl)
methyl]-3-[(3-dimethylamino-methyl-4
-Hydroxy-5-methoxy)cinnamoyl]thiazolidine Example 32 Example 1) [2-(
4-methylpiperazin-1-yl)ethanal, 2-(
The following compound was obtained using morpholin-1-yl)ethanal and p-fluorobenzaldehyde.

2-1°,3-dimethylxanthine-7°-yl)methyl]-3-(5-morpholinyl)-2-butenoyl-
Thiazolidine 2-[(1°.3′-dimethylxanthine-7°-yl)methyl]-3-[(4°-methylpiperazine-1°-
yl)-2-butenoylchothiazolidine 2-[(1',3-dimethylxanthine-7°-yl)methyl]-3-(4°-fluoro)cinnamoyl-
Thiazolidine Example 33 The following compound was produced in a similar manner to Examples 25 and 26 using phenoxyacetic acid, (2-ethoxy-ethyloxy)acetic acid, and (2°-diethylamino-ethyloxy)acetic acid as acids.

2- [ (1',3°-dimethylxanthine-7°-
yl)methyl]-3-phenoxyacetyl-thiazolidine 2-[(1°,3°-dimethylxanthine-7-yl)methyl]-3-[(2°-11-xy)-ethyloxyacetyl]thiazolidine 2-[ (1°13-dimethylxanthinedyl)methyl]-3-[(2-diethylamino)ethyloxyacetyl]thiazolidine Example 34 Under an inert gas atmosphere, 1.13 g of cystamine hydrochloride was mixed with 2
- [(1°,3°-dimethylxanthine-7-yl>methyl]-3-benoylthiazolidine 2,69
The mixture was treated with 100 d of methanol containing 100 ml of alcohol at reflux temperature for 8 hours.

The reaction mixture was cooled and after 2 days the crystalline precipitate was filtered and 2
- [ (1°.3-dimethylxanthine-7-yl)
3.5 g of methyl]-3-[3°-(2''-ethyl-amino-thio)propionyl]thiazolidine hydrochloride were obtained.

In a similar manner, N-acetylcysteine was used in the presence of a catalytic amount of sodium methylate, melting point 240-24.
2-[(1°13-dimethylxanthine-7-
yl)methyl]-3-[(4-thia-5'-carboxy-5-acetylamino)hexanoyl]thiazolidine was obtained.

Example 35 A solution in 20 ml of methanol containing 2.5 g of N-acetylcysteine disodium salt was mixed with a solution containing 3 g of 2-[(1°, 3′-dimethylxanthine-7°-yl)methyl 1-3-chloroacetyl-thiazolidine. 083010 m solution. After 3 hours at room temperature, the mixture was evaporated and the residue was partitioned between chloroform and 20% aqueous sodium hydrogen phosphate. 2-[(1',3-dimethylxanthine-
1°-yl)methyl]-3-(3°-thia-5′-carboxy-5-7cetylaminopentanoyl)thiazolidine was obtained.

Claims (1)

[Scope of Claims] 1 Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is 1,3-dimethylxanthine-7-yl or 3,7-dimethylxanthine-1 -yl; R_2 is an oxygen atom or a free or esterified carboxyl group; R_3 and R_4 are hydrogen atoms or methyl groups; P is 0 or 1; R_1 is a hydrogen atom, having 1 to 2 carbon atoms
Alkylsulfonyl group, unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_5 is a hydrogen atom, ▲ There are mathematical formulas, chemical formulas, tables, etc.) or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, (In the formula, n is 0 or an integer from 1 to 7; P_1 and P_
2 are both hydrogen atoms or one of them is a hydrogen atom, the other is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group, Q is a hydrogen atom; an alkyl group having a branched chain having 3 to 4 carbon atoms; 3-7 cycloalkyl group; free or esterified carboxyl group; halogen atom; S
H; NH_2; mono- or di-substituted amino group, t-
Butoxycarbonylamino group or acrylamino group having 1 to 2 carbon atoms; ether group represented by an O-T chain, S
-thioether group represented by a T chain (where T is an unsubstituted or mono- or polysubstituted phenyl ring or a formula (CH_2) -_m-T_1 (wherein T_1 is H, OH
, OCH_3, OC_2H_5, HOCH_2-CH_
2-, free or esterified carboxyl group, N
H_2, an acrylamino group or a mono- or di-substituted amino group having 1 to 2 carbon atoms) and the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (in the formula, Re represents a hydrogen atom, methyl group, or ethyl group) (m represents an integer from 1 to 3); unsubstituted or mono- or polysubstituted phenyl, phenoxy or phenylthio rings in the meta, ortho and para positions; formula -(CH_2)- _mSCO-(CH_2)-_nP_
3 (where m and n are the same as above, P_3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, 3 carbon atoms
~6 cycloalkyl group, substituted amino group, optionally mono- or polysubstituted phenyl group or phenoxy ring at ortho, meta and para positions); and formula: ▲ Numerical formula, chemical formula, table Represents a group selected from the group consisting of alkenyl chains represented by ▼ (wherein T may be a hydrogen atom in addition to the above definition); a mono-substituted amino group is is 1~
6 or -CH_2-CH_2-O-CH_2-CH_3, -C
H_2-CH_2-O-CH_2-CH_2-OH, -
CH_2-CH_2-NH-CH_2-CH_3, -C
Represents an amino group substituted by a group represented by H_2-CH_2-NH-CH_2-CH_2-OH or ▲There are mathematical formulas, chemical formulas, tables, etc.▼;
The substituent of the di-substituted amino group is a linear or branched alkyl group having 1 to 6 carbon atoms;
yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, thiomorpholin-1-yl, 4-ethyl-
Piperazin-1-yl, 4-(2'-fluorophenyl)piperazin-1-yl, imidazol-1-yl, 3-
represents an unsaturated or saturated nitrogen ring such as pyridyl or 4-pyridyl; a mono- or polysubstituted phenyl group is substituted in the para position by a fluorine atom, in the meta and/or para position by a chlorine atom; or a phenyl group substituted at the meta position by CF_3, or the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Z_1 is H or COCH_3, Z_2 is H,
CH_3 or COCH_3 and P_4 are hydrogen atoms,
The aminomethyl group, P_4, represents a group selected from the group consisting of an acylaminomethyl group having 1 to 2 carbon atoms or a mono- or di-substituted aminomethyl group as defined above); xanthinelmethylthiazolidine represented by 2. The xane according to claim 1, wherein in formula (I), R_2, R_3 and R_4 are hydrogen atoms, and R_1 is an acyl group represented by the formula R_5CO (wherein R_5 is as defined above). Thinylmethylthiazolidine. 3 In formula (I), R_2, R_3 and R_4
The xanthinenylmethylthiazolidine according to claim 1, wherein R_1 is a hydrogen atom and R_1 is a substituted or unsubstituted cinnamoyl group. 4 The compound of formula (I) is 2-[(1',3'-dimethylxanthine-7'-yl)methyl]thiazolidine-4-carboxylic acid and its methyl and tert-butyl esters; 2-[(3' ，
7'-dimethylxanthine-1'-yl)methyl]thiazolidine-4-carboxylic acid and its methyl, ethyl and tert-butyl esters; 2-[(1',3'-dimethylxanthine-7'-yl)methyl] Thiazolidine; 2-[(3',7'-dimethylxanthine-1'-yl)methyl]thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-(imidazole-1′-yl)acetyl]thiazolidine;2-[(3′,7′-dimethylxanthine-1′-yl)methyl]-3-(imidazol-1-yl)acetyl]thiazolidine; 2-[(1′, 3'-dimethylxanthine-7'-yl)methyl]-3-[(3',4'-hydroxy)cinnamoyl]thiazolidine;2-[(3',7'-dimethylxanthine-1'-yl)methyl]-3[(3',4'-dihydroxy)cinnamoyl]thiazolidine;2-[(1',3'-dimethylxanthine-T-yl)
methyl]-3-(3'-methoxy-4-hydroxy)cinnamoyl-thiazolidine;2-[(3',7'-dimethylxanthine-1'-yl)methyl]-3-(3'-methoxy-4'-hydroxy)cinnamoyl-thiazolidine;2-[(3′,7′-dimethylxanthine-1′-yl)methyl]-3-[3-(4″-hydroxyethylpiperazin-1″-yl)propynyl]thiazolidine;2-[1',3'-dimethylxanthine-7'-yl)
methyl]-3-(3-morpholinomethyl-4'-hydroxy-3-methoxy-cinnamoyl)thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-(3'-pyrrolidyl-methyl-4'-
Hydroxy-3-methoxy-cinnamoyl)thiazolidine;2-[(3',7'-dimethylxanthine-1'-yl)methyl]-3-[3-pyrrolidinylmethyl-4'-hydroxy-3-methoxy-cinnamoyl)thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-[3'-thia-5'-carboxy-5
'-acetylamino-pentanoyl]thiazolidine; 2
-[(1',3'-dimethylxanthine-7'-yl)
methyl]-3-[4'-thia-6'-carboxy-6'
-acetyl-amino-hexanoyl]thiazolidine; 2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-[3'-(2''-ethoxyethyloxy)acetyl]thiazolidine; 2- [(1',3'-dimethylxanthine-7'-yl)methyl]-3-[3-(imidazol-1'-yl)
2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-glycinyl-thiazolidine; 2-[(
3',7'-dimethylxanthine-1'-yl)methyl]-3-glycinyl-thiazolidine;2-[(1',3
'-dimethylxanthine-7'-yl)methyl]-3-
(N-acetyl)glycinyl-thiazolidine;2-[(1',3'-dimethylxanthine-7'-yl)methyl]-3-[3'-(2''-hydroxyethylamino)ethylamino-propionyl]thiazolidine2-[(3′,7′-dimethylxanthine-1′-yl)methyl]-3-[3′-(2″-hydroxyethylamino)ethylamino-propionyl]thiazolidine; and 2-[(1′ , 3'-dimethylxanthine-7'-yl)methyl]-3-[3-(4''-hydroxyethylpiperazin-1''-yl)propionyl]thiazolidine. The xanthinenylmethylthiazolidine according to item 1. 5 Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R is 1,3-dimethylxanthine-7-yl or 3,7-dimethylxanthine-1-yl, Y and Y ' together represent an alkoxy group having 1 to 2 carbon atoms, or together represent a carboxyl group) is formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R_2 is an oxygen atom or a free or esterified carboxyl group; R_3 and R_4 represent a hydrogen atom or a methyl group) to obtain the formula (I a): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(I a) (wherein R, R_2, R_3, R_4 represent the groups defined above), then optionally succinic anhydride, glutaric anhydride or formulas (IVa), (IVb), (IVc) Q-(CH_2)-_nCOZ(IVa) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IVb) P_5-SO_2-Hal(IVc) (In the formula, n is 0 or an integer from 1 to 7; P_1 and P_
2 are both hydrogen atoms or one of them is a hydrogen atom, the other is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group, Q is a hydrogen atom; an alkyl group having a branched chain having 3 to 4 carbon atoms; 3-7 cycloalkyl group; free or esterified carboxyl group; halogen atom; S
H; NH_2; mono- or di-substituted amino group; t-
Butoxycarbonylamino group or acrylamino group having 1 to 2 carbon atoms; ether group represented by an O-T chain, S
-Thioether group represented by a T chain, where T is an unsubstituted or mono- or polysubstituted phenyl ring or a formula (CH_2) -_m-T_1 (wherein T_1 is H, OH, OCH_3, OC_2H_5, HOCH_2
-CH_2-, free or esterified carboxyl group, NH_2, acrylamino group having 1 to 2 carbon atoms or mono- or di-substituted amino group) and formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (in the formula, Re represents a hydrogen atom, a methyl group or an ethyl group); m represents an integer of 1 to 3); unsubstituted or mono- or polysubstituted at the meta, ortho and para positions; phenyl, phenoxy or phenylthio ring; formula -(CH_2)-_mSCO-(CH_2
)-_nP_3 (where m and n are the same as above, P_
3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted amino group, and optionally mono- or polysubstituted at the ortho, meta, and para positions. (representing a phenyl group or phenoxy ring); and alkenyl represented by the formula: ▲ Numerical formula, chemical formula, table, etc.▼ (wherein, T may be a hydrogen atom in addition to the above definition) a group selected from the group consisting of chains, P_5 is an alkyl group having 1 to 2 carbon atoms or an unsubstituted, mono- or polysubstituted phenyl ring, Hal is a halogen atom, Z is a halogen atom, azide, active Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is 1,3-dimethylxanthine-7- yl or 3,7-dimethylxanthine-1-yl; R_2 is an oxygen atom or a free or esterified carboxyl group; R_3 and R_4 are a hydrogen atom or a methyl group; P is 0 or 1; R_1 is a hydrogen atom, carbon number 1~2
alkylsulfonyl group, unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R_5 is a hydrogen atom, -(CH_2)-_nQ or ▲ mathematical formula, There are chemical formulas, tables, etc. ▼, (In the formula, n is 0 or an integer from 1 to 7; P_
1 and P_2 are both hydrogen atoms, or one of them is a hydrogen atom, the other is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group, Q is a hydrogen atom; a branched alkyl group having 3 to 4 carbon atoms ; Cycloalkyl group having 3 to 7 carbon atoms; Free or esterified carboxyl group; Halogen atom; SH; NH_2; Mono- or di-substituted amino group, t-butoxycarbonylamino group or 1 to 2 carbon atoms acrylamino group; ether group represented by an O-T chain, thioether group represented by an S-T chain (where T is an unsubstituted or mono- or polysubstituted phenyl ring or a formula (CH_2)-_mT_1( In the formula, Ti is H, OH, OCH_3, OC_2H_5, H
OCH_2-CH_2-, free or esterified carboxyl group, NH_2, acrylamino group having 1 to 2 carbon atoms or mono- or di-substituted amino group) and formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (in the formula, Re represents a hydrogen atom, a methyl group or an ethyl group),
m represents an integer of 1 to 3); unsubstituted or mono- or polysubstituted phenyl, phenoxy or phenylthio ring at meta, ortho and para positions; formula -(CH_2)-_m-SCO-(CH_2) -_nP
_3 (where m and n are the same as above, P_3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted amino group, ortho, A compound represented by a phenyl group or a phenoxy ring optionally mono- or polysubstituted at the meta- and para-positions; and formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, T is in addition to the above definition represents a group selected from the group consisting of alkenyl chains represented by
6 or -CH_2-CH_2-O-CH_2-CH_3, -C
H_2-CH_2-O-CH_2-CH_2-OH, -
CH_2-CH_2-NH-CH_2-CH_3, -C
Represents an amino group substituted by a group represented by H_2-CH_2-NH-CH_2-CH_2-OH or ▲There are mathematical formulas, chemical formulas, tables, etc.▼;
The substituent of the di-substituted amino group is a linear or branched alkyl group having 1 to 6 carbon atoms, or a combination of these groups to form morphonyl-1-yl, pyrrolidine-1-
yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, thiomorpholin-1-yl, 4-ethyl-
Piperazin-1-yl, 4-(2'-fluorophenyl)piperazin-1-yl, imidazol-1-yl, 3-
represents an unsaturated or saturated nitrogen ring such as pyridyl or 4-pyridyl; a mono- or polysubstituted phenyl group is substituted in the para position by a fluorine atom, in the meta and/or para position by a chlorine atom; or a phenyl group substituted at the meta position by CF_3, or the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Z_1 is H or COCH_3, Z_2 is H,
CH_3 or COCH_3 and P_4 are hydrogen atoms,
The aminomethyl group, P_4, represents a group selected from the group consisting of an acylaminomethyl group having 1 to 2 carbon atoms or a mono- or di-substituted aminomethyl group as defined above); A method for producing xanthinelmethylthiazolidine represented by 6 Formula (Ie): ▲Mathematical formulas, chemical formulas, tables, etc.▼(Ie) (In the formula, R is 1,3-dimethylxanthine-7-yl or 3,7-dimethylxanthine-1-yl; R_2 is an oxygen atom or a free or esterified carboxyl group; R_3 and R_4 are a hydrogen atom or a methyl group; P represents 0 or 1);
V): T-CHO(V) (wherein T is an unsubstituted mono- or polysubstituted phenyl ring or formula (CH_2)-_m-T_1 (wherein T_1 is H, OH
, OCH_3, OC_2H_5, HOCH_2-CH_
2-, free or esterified carboxyl group, N
H_2, acrylamino group or mono- or di-substituted amino group having 1 to 2 carbon atoms) and the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, Re represents a hydrogen atom, methyl group or ethyl group) The resulting compound has the formula; H_2N-(CH_2)-_mT_1 (where m is 1 to
3 integer, T_1 is H, OH, OCH_3, OC_2H
_5, HOCH_2-CH_2-, free or esterified carboxyl group, NH_2, acrylamino group having 1 to 2 carbon atoms or mono- or di-substituted amino group) and formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (in the formula , Re represents a hydrogen atom, a methyl group or an ethyl group), mono- or di-substituted amines or mono- or di-substituted amines of the formula HS-(CH_2)-_nT_1 (where n is an integer of 0 or 1 to 7, T_1 is the same as above), optionally subjected to a Michael reaction with a nucleophilic compound selected from the group consisting of a mono- or di-substituted thiophenol. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is -CH=CH-T; R_2, R_3,
R_4, R and P are the same as above). 7 Formula ( I d) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ ( I d) (In the formula, R is 1,3-dimethylxanthine-7-yl or 3,7-dimethylxanthine-1-yl; R_2 is an oxygen atom or a free or esterified carboxyl group; R_3 and R_4 are hydrogen atoms or methyl groups; P is O or 1; at least one of P_1 and P_2 is a hydrogen atom, the other is a hydrogen atom, a methyl group or a phenyl group, Q' is a halogen atom, and n preferably represents O).
where P_3 and n are defined above, Bas
e represents an alkali or alkaline earth metal, lower trialkylammonium or phenyl dialkylammonium);
The resulting compound is reacted with ammonia to yield a compound of the formula: Q=SH, where Q is the same as above, which can be optionally alkylated with an alkyl halide in the presence of a base. General formula (I) characterized by
: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, R, R_2, R_3, R_4, S are the same as above; R_1 is a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n is 0 or an integer from 1 to 7, P_1 and P_
2 are both hydrogen atoms, or one of them is a hydrogen atom, and the other is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group; Q' is SH, an alkylthioether group, or the formula: P_3-(CH_2)-_nCOS( In the formula, P_3 is a linear or branched alkyl chain having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted amino group,
A method for producing a compound represented by a phenyl group or a phenoxy ring optionally mono- or polysubstituted at the ortho, meta and para positions, n and S are the same as above. 8 Therapeutically effective amount formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) (wherein R is 1,3-dimethylxanthine-7-yl or 3,7-dimethylxanthine -1-yl; R_2 is an oxygen atom or a free or esterified carboxyl group; R_3 and R_4 are hydrogen atoms or methyl groups; P is O or 1; R_1 is a hydrogen atom, having 1 to 2 carbon atoms
alkylsulfonyl group, unsubstituted or mono- or polysubstituted phenylsulfonyl group, formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R_5 is a hydrogen atom, -(CH_2)-_nQ or ▲ mathematical formula, There are chemical formulas, tables, etc. ▼ (In the formula, n is 0 or an integer from 1 to 7; P_1 and P_2 are both hydrogen atoms or one of them is a hydrogen atom,
The other is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group; Q is a hydrogen atom; a branched alkyl group having 3 to 4 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms; free or esterified Carboxyl group; halogen atom; SH;
NH_2; mono- or di-substituted amino group, t-butoxycarbonylamino group or acrylamino group having 1 to 2 carbon atoms; ether group represented by an OT chain, thioether group represented by an S-T chain (here in which T is an unsubstituted or mono- or polysubstituted phenyl ring or a compound of the formula (CH_
2) −_mT_1 (where T_1 is H, OH, OCH_
3, OC_2H_5, HOCH_2-CH_2-, free or esterified carboxyl group, NH_2, acrylamino group with 1 to 2 carbon atoms or mono- or di-substituted amino group) and formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ ( a group selected from the group consisting of (wherein Re represents a hydrogen atom, a methyl group or an ethyl group),
m represents an integer of 1 to 3); unsubstituted or mono- or polysubstituted phenyl, phenoxy or phenylthio ring at meta, ortho and para positions; formula (CH_2)-_mSCO-(CH_2)-_nP_3
(In the formula, m and n are the same as above, P_3 has 1 carbon number
~7 linear or branched alkyl chains, 3 to 7 carbon atoms
6 cycloalkyl group, substituted amino group, ortho,
A compound represented by a phenyl group or a phenoxy ring optionally mono- or polysubstituted at the meta- and para-positions; and formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, T is in addition to the above definition represents a group selected from the group consisting of alkenyl chains represented by
6 or -CH_2-CH_2-O-CH_2-CH_3, -C
H_2-CH_2-O-CH_2-CH_2-OH, -
CH_2-CH_2-NH-CH_2-CH_3, -C
Represents an amino group substituted by a group represented by H_2-CH_2-NH-CH_2-CH_2-OH or ▲There are mathematical formulas, chemical formulas, tables, etc.▼;
The substituent of the di-substituted amino group is a linear or branched alkyl group having 1 to 6 carbon atoms, or a combination of these groups to form morphonyl-1-yl, pyrrolidine-1-
yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, thiomorpholin-1-yl, 4-ethyl-
Piperazin-1-yl, 4-(2'-fluorophenyl)piperazin-1-yl, imidazol-1-yl, 3-
represents an unsaturated or saturated nitrogen ring such as pyridyl or 4-pyridyl; a mono- or polysubstituted phenyl group is substituted in the para position by a fluorine atom, in the meta and/or para position by a chlorine atom; or a phenyl group substituted at the meta position by CF_3, or the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Z_1 is H or COCH_3, Z_2 is H,
CH_3 or COCH_3 and P_4 are hydrogen atoms,
The aminomethyl group, P_4, represents a group selected from the group consisting of an acylaminomethyl group having 1 to 2 carbon atoms or a mono- or di-substituted aminomethyl group as defined above); A pharmaceutical composition having mucus-regulating, bronchodilatory and/or antitussive effects, which contains a compound represented by the following formula (representing the formula: ) together with a non-toxic carrier or excipient.