WO1995005369A1 - Derive de thiazoline-2-thione et remede contre les maladies de foie - Google Patents

Derive de thiazoline-2-thione et remede contre les maladies de foie Download PDF

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Publication number
WO1995005369A1
WO1995005369A1 PCT/JP1994/001306 JP9401306W WO9505369A1 WO 1995005369 A1 WO1995005369 A1 WO 1995005369A1 JP 9401306 W JP9401306 W JP 9401306W WO 9505369 A1 WO9505369 A1 WO 9505369A1
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Prior art keywords
group
carbon atoms
thione
thiazoline
general formula
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PCT/JP1994/001306
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English (en)
Japanese (ja)
Inventor
Mitsuo Masaki
Tomio Yamakawa
Chiharu Inoue
Shinichi Yoshida
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Nippon Chemiphar Co., Ltd.
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Priority claimed from JP22646793A external-priority patent/JPH0753374A/ja
Priority claimed from JP22646693A external-priority patent/JPH0753532A/ja
Application filed by Nippon Chemiphar Co., Ltd. filed Critical Nippon Chemiphar Co., Ltd.
Priority to AU72762/94A priority Critical patent/AU7276294A/en
Publication of WO1995005369A1 publication Critical patent/WO1995005369A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms

Definitions

  • the present invention relates to a novel thiazoline-2-thione derivative, and a therapeutic agent for liver disease containing the novel thiazoline-2-thione derivative or a similar thiazoline-2-thione derivative as an active ingredient.
  • Liver in the body detoxification, carbohydrate metabolism, lipid metabolism, protein metabolism, production and secretion of bile, production of blood clotting factors, hormonal regulation, storage of various biological components such as fat, glycogen, protein, and vitamins Perform various functions such as viruses, drugs, poisons, alcohol, malnutrition, hepatic circulatory system disorders, bile duct obstruction, etc. Hepatitis, toxic hepatitis of drugs, alcoholic hepatitis, depressive hepatitis, liver damage due to the biliary depression, fatty liver, jaundice, or eventually cirrhosis.
  • An object of the present invention is to provide a novel thiazoline-12-thione derivative useful as an active ingredient of a therapeutic agent for liver disease, and a novel thiazoline-12-thione derivative or a similar thiazoline-2-thione derivative as an active ingredient.
  • the present invention provides the following general formula (1):
  • R 1 may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms.
  • R 2 represents a halogen atom; a hydroxyl group; a halogen atom, a hydroxyl group and a substituent selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms.
  • n represents 0 or 1)
  • the thiazoline-2-thione derivative of the present invention can be used in vivo in a carbon tetrachloride acute liver injury model and a galactosamine acute liver injury model, using GOT (glutamine one-year quisaloacetic acid transaminase) and GPT (glutamine-pyruvate transaminase). It has an excellent inhibitory effect on departure and prolongation of prothrombin time, has an alleviating or treating liver injury, or has an excellent protective effect on liver injury, and is particularly useful as a therapeutic or preventive agent for liver diseases.
  • GOT glucose one-year quisaloacetic acid transaminase
  • GPT glutamine-pyruvate transaminase
  • the thiazoline-2-thione derivative of the general formula (1) is represented by the following general formula (2):
  • R 1 may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms.
  • R 1 may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms.
  • An alkoxyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an amino group;
  • R 1 may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms.
  • an alkoxyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; An alkylamino group having 1 to 6 carbon atoms; a dialkylamino group having 1 to 6 carbon atoms
  • each R 2 may be the same or different, and two R 2 forces s—in connection with the number of carbon atoms of 1 to 6 May represent an alkylenedioxy group, and t represents an integer from 0 to 4)
  • the salt of the thiazoline-2-thione derivative represented by the formula (1) exhibits a therapeutic effect on liver disease and is effective as a therapeutic agent for liver disease.
  • the thiazoline-2-thione derivative represented by the general formula (3) and the salt of the thiazoline-2-thione derivative represented by the general formula (4) are used in the acute liver injury model as described above in G0T, G ⁇ It has an excellent inhibitory effect on departure and prolongation of prothrombin time, and exhibits an excellent protective effect against liver damage or liver damage, and is useful as an agent for treating and preventing liver diseases.
  • the thiazoline-2-thione derivatives represented by the general formula (3) some compounds not included in the thiazoline-2-thione derivative of the general formula (1) are known. For example, 3-benzyl-4-methylthiazoline-2-thione is described as effective as a bactericide in Arch. Pharm., 296, 310-324 (1963).
  • alkyl group having 1 to 6 carbon atoms represented by R 1 include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group and an isobutyl group.
  • Specific examples of the cycloalkyl group having 3 to 6 carbon atoms include cyclopropyl, cyclopentyl, cyclohexyl, etc.
  • alkenyl group examples include, but are not limited to, an ethyl group, a 2-propenyl group, a 2-methyl-2-propenyl group, a 3-butenyl group, and a 3-methyl-2-butenyl group.
  • 2 to 6 alkynyl groups include an ethur group, a 2-propynyl group, a 2-butynyl group, a 3-buturyl group and the like.
  • alkyl group, alkenyl group and alkynyl group include a halogen atom (preferably, a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, It may have one to three substituents selected from the group consisting of a propoxy group and a butoxy group.
  • alkyl group, alkenyl group and alkynyl group having such a substituent include monofluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, hydroxymethyl, And 3-fluoropropynyl group.
  • alkoxyl group having 1 to 6 carbon atoms represented by R 2 include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and an n-butoxy group. , Isobutoxy, sec-butoxy, t-butoxy, etc. It is.
  • the alkoxy group includes a halogen atom (preferably, a fluorine atom, a chlorine atom, and a bromine atom), a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms (eg, a methoxy group, an ethoxy group, a propoxy group, a butoxy group). May have from 1 to 3 substituents selected from the group consisting of
  • examples of the alkylamino group having 1 to 6 carbon atoms represented by R 2 include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, an n-butylamino group, and an isobutyl group. Amino group, sec-butylamino group, t-butylamino group and the like.
  • the dialkylamino group represented by R 2 wherein each alkyl group is independently an alkyl group having 1 to 6 carbon atoms, a dialkylamino group having two alkyl groups of the above alkylamino group (an alkyl group) May be the same or different).
  • alkylthio group having 1 to 6 carbon atoms represented by R 2 include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, an n-butylthio group, and an isobutylthio group. , Sec-butylthio group, t-butylthio group and the like. '
  • alkoxycarbonyl group having 2 to 7 carbon atoms represented by R 2 include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, and an isopropoxycarbonyl group.
  • R 2 specific examples of the alkoxycarbonyl group having 2 to 7 carbon atoms represented by R 2 include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, and an isopropoxycarbonyl group.
  • R 2 when m is 2 or more, R 2 may be the same or different.
  • two R 2 preferably, R 2 bonded to a carbon atom adjacent to the benzene ring
  • R 1 is an unsubstituted alkyl group having 1 to 6 carbon atoms (particularly, 1 to 4 carbon atoms), or a halogen atom, a hydroxyl group and 1 to 6 carbon atoms (particularly, It is preferably an alkyl group having 1 to 6 carbon atoms (particularly, 1 to 4 carbon atoms) having 1 to 3 substituents selected from the group consisting of alkoxyl groups having 1 to 4 carbon atoms.
  • R 2 is an unsubstituted alkoxyl group having 1 to 6 carbon atoms (particularly, 1 to 4 carbon atoms), or a halogen atom, a hydroxyl group and 1 to 6 carbon atoms (particularly, 1 to 6 carbon atoms).
  • the alkoxyl group having 1 to 3 carbon atoms (particularly, 1 to 4 carbon atoms) having 1 to 3 substituents selected from the group consisting of the alkoxyl group of 4) is preferable.
  • m is preferably an integer of 1 to 3
  • n is preferably 1.
  • iso-C 3 H 7 represents a isopropyl group
  • eye- C 3 H 7 represents a cyclopropyl group.
  • Representative compounds of the thiazoline-2-thione derivative represented by the general formula (1) include the following.
  • the thiazoline-2-thione derivative represented by the general formula (1) can be produced, for example, by the following synthesis route synthesis method.
  • R 1 , R 2 , m and n have the same meaning as defined in the general formula (1), and R 3 has 1 to 6 carbon atoms.
  • M represents an alkyl group;
  • Z represents a leaving group;
  • Each unit reaction in the above synthesis method is a generally known reaction, and is described in, for example, Chem. Pharm. Bull., 30 (10), 3548-3554 (1982). Based on the above, a person skilled in the art can easily synthesize a thiazoline-2-thione derivative represented by the general formula (1).
  • the amine compound represented by the general formula (5) in the above self-reaction formula can be obtained as a commercial product, or can be synthesized by Gabriel reaction from halide via phthalimide.
  • the general formula (5) Amin compound represented by the formula R 3 0M (where, R 3 represents an alkyl group of 1 to 6 carbon atoms, M represents an alkali metal) compound and carbon disulfide and the normal solvent By reacting in the reaction, the glutamine rubamine represented by the general formula (6) Synthesize the acid salt.
  • R 3 is preferably a methyl group, an ethyl group, a propyl group, a t-butyl group or the like, and M is preferably sodium, potassium, lithium or the like.
  • R 3 OM triethylamine, 1,8-diazabicyclo
  • Bases such as 7-indene (DBU) can also be used.
  • a solvent for this reaction an alcohol such as ethanol or methanol is usually used.
  • a polar solvent such as tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or the like which does not adversely affect the reaction can be used.
  • Carbon disulfide itself can be used as the solvent.
  • This reaction usually proceeds sufficiently at room temperature for a reaction time of 10 minutes to 1 hour. Even at low temperatures, the reaction proceeds sufficiently by increasing the reaction time.
  • Jichio force Rubamin acid salt represented by the general formula (6) can be used in the next reaction without force s isolated it is relatively unstable.
  • R 1 has the same meaning as defined in the general formula (1), and Z represents a leaving group
  • Z represents a leaving group
  • the leaving group represented by Z is generally a halogen atom such as a chlorine atom or a bromine atom, but a group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group can also be used.
  • the solvent used for this reaction may be another solvent as long as it does not adversely affect the reaction, which is usually an alcohol such as ethanol, methanol or the like. This reaction can be carried out usually under ice cooling for a reaction time of several minutes to several hours. The reaction proceeds without any problem even at room temperature.
  • Thiazolidine-12-thione derivatives represented by the general formula (2) are classified into stable and unstable.
  • the stable thiazolidine-12-thione derivative represented by the general formula (2) is isolated and purified, and then subjected to a dehydration reaction with an acid to obtain a thiazoline-2-thione derivative represented by the general formula (1).
  • the acid used in this reaction is preferably an inorganic strong acid such as hydrochloric acid, sulfuric acid, or nitric acid, but may be an organic acid such as methanesulfonic acid or p-toluenesulfonic acid. This reaction usually proceeds sufficiently at room temperature for several minutes. The reaction can be performed at a temperature lower or higher than room temperature.
  • a thiazolidine represented by the general formula (2) is used as a product of a reaction for synthesizing a thiazolidine-2-thione derivative represented by the general formula (2) from the dithiol rubbamate represented by the general formula (6).
  • a mixture S of the 2-thione derivative and the thiazoline-2-thione derivative represented by the general formula (1) may form.
  • an acid is added to the reaction system to convert any remaining thiazolidine-2-thione derivative represented by the general formula (2) into a thiazoline-2-thione derivative represented by the general formula (1). it can.
  • a thiazoline-2-thione derivative represented by the general formula (1) is converted to a compound represented by the formula R 4 -X (where R 4 is a phenylalkyl containing an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 3 carbon atoms)
  • X represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group), and is reacted with a compound represented by the general formula (7):
  • R 1 , R 2 , R 4 , m, n, and X are as defined above
  • the formula R 4 - methyl group as in R 4 in X, Echiru group, t one-butyl group, a benzyl group, Fuwenechiru group are preferable, especially a chlorine atom as a halogen atom, a bromine atom and an iodine atom.
  • This reaction can be carried out by stirring a thiazoline-12-thione derivative represented by the general formula (1) in a compound represented by the formula R 4 —X at room temperature to reflux temperature for several hours.
  • the salt of the thiazoline-2-thione derivative represented by (7) can be obtained in high yield.
  • Particularly preferred as the compound represented by the formula R 4 -X are methyl bromide, methyl iodide and petit bromide. Butyl iodide, butyl iodide, benzyl chloride, benzyl bromide, etc.
  • the salt of the thiazoline-2-thione derivative represented by the general formula (7) is characterized by having a higher solubility in an aqueous medium than the thiazoline-2-thione derivative represented by the general formula (1).
  • Representative compounds of the salt of the thiazoline-2-thione derivative represented by the general formula (7) include, for example, 4-methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-l-thione and methyl iodide And 4-methyl-2-methylthio-3- (2,3,4-trimethoxybenzyl) -11,3-thiazol-1-dimethoxide.
  • the thiazolidine-12-thione derivative represented by the general formula (2) of the present invention is a novel compound, and is shown in the synthesis route for the thiazoline-2-thione derivative represented by the general formula (1).
  • the compound is useful as an intermediate for synthesizing the thiazoline-2-thione derivative represented by the general formula (1).
  • R 1 , R 2 , m and n are the same as those described for the general formula (1).
  • -Representative compounds of the thiazolidine-2-thione derivative represented by the general formula (2) include the following.
  • the therapeutic agent for liver disease of the present invention contains, as an active ingredient, a thiazoline-1-thione derivative represented by the general formula (3) or a salt of a thiazoline-2-thione derivative represented by the general formula (4).
  • R 1 and R 2 in the general formula (3) are the same as those described for R 1 and R 2 in the general formula (1), respectively.
  • s is preferably an integer of 1 to 3
  • t is preferably 1.
  • Representative compounds of the thiazoline-2-thione derivative represented by the general formula (3) include the following compounds in addition to the representative compounds of the thiazoline-2-thione derivative represented by the general formula (1). be able to.
  • the thiazoline-2-thione derivative represented by the general formula (3) can be produced by the same synthetic route as described for the synthesis of the thiazoline-2-thione derivative represented by the general formula (1). .
  • R 1 and R 2 are the same as those respectively described in the general formula (1) at Keru R 1 and R 2, also, specific examples of R 4 and X And are the same as those described for R 4 and X in the general formula (7).
  • s is preferably an integer of 1-3, and t is preferably 1.
  • the salt of the thiazoline-2-thione derivative represented by the general formula (4) can be produced in the same manner as described for the production of the salt of the thiazoline-2-thione derivative represented by the general formula (7).
  • the salt of the thiazoline-2-thione derivative represented by the general formula (4) is characterized by having a higher solubility in an aqueous medium than the thiazoline-2-thione derivative represented by the general formula (3).
  • the representative compound of the salt of the thiazoline-2-thione derivative represented by the general formula (4) is the same as the representative compound of the salt of the thiazoline-2-thione derivative represented by the general formula (7).
  • thiazoline-2-thione derivative including the novel thiazoline-2-thione derivative of the present invention
  • its salt which are the active ingredients of the therapeutic agent for liver disease of the present invention.
  • the pharmacological experiments showed that the inhibitory effect on lipid peroxidation, the inhibitory effect of G0T and GPT departure and the prolongation of prothrombin time (PT) in the acute liver injury model of carbon tetrachloride, and the acute liver injury model of D-galactosamine GOT and GPT were examined in vivo for their ability to inhibit the escape and prothrombin time (PT) prolongation.
  • Prothrombin time (PT) is a test method to evaluate the blood coagulation system. Blood coagulation factors are mainly produced in hepatocytes, and hepatic dysfunction prolongs PT. Therefore, the effect of suppressing PT elongation means suppressing liver function decline.
  • Test solution (dissolved in dimethylsulfoxide) in microsomal (0.5 mg, protein) 250 prepared from rat liver 2.5 u 1,0.5 M Tris-HCl buffer (PH7.4 147.51 Add 50 wl of 1,2 Omg / ml ADP and 5 mgZml ⁇ -NADPH501, mix and incubate at 37 ° C for 60 minutes.
  • the reaction was stopped by adding 5 mg Zml butylhydroxytoluene 501, and further 250 ml of 8.1% sodium dodecyl sulfate, 1.75 ml of 20% acetic acid (pH 3.5) and 0.8% thiobarbituric acid (pH 3.5) After adding 1.5 ml, the mixture was heated in a boiling water bath for 60 minutes. After cooling in ice water, the mixture was centrifuged at 1,500 X g for 10 minutes, and the absorbance at 535 nm of the supernatant was measured. The amount of lipid peroxide was determined from a calibration curve prepared using tetraethoxypropane as a standard substance. The lipid peroxidation inhibitory action was represented by the inhibition rate obtained from the following equation. Lipid peroxide in the presence of test compound
  • Serum transaminases include GOT (glutamic acid-glutamic acid acetate transaminase) and GPT (glutamic acid-pyruvate transaminase). It was measured as an indicator of liver damage.
  • GOT glutamic acid-glutamic acid acetate transaminase
  • GPT glutamic acid-pyruvate transaminase
  • a test substance (10 Omg / kg) is orally administered to a Wistar male rat of 160 to 180; The test substance is suspended in 1% methylcellulose and administered at a dose of 1 Omi / kg. The control group receives 1% methylcellulose.
  • olive oil is orally administered at a dose of 1 ml / Zkg to cause acute liver injury.
  • the normal group receives oral oil instead of carbon tetrachloride. Feed water 4 hours after the administration of carbon tetrachloride.
  • PT uses protron as a plasma sample collected from the abdominal vena cava as described above.
  • the thromboplastin reagent for bottle time measurement (Simplastin; Organon Techni Riki Co., Ltd.) was added, and the time required for fibrin formation (seconds) was measured.
  • the PT elongation inhibition rate (%) was determined by the following equation. Test substance group value-Normal group value
  • Table 2 shows the measured values of the compounds obtained in each Example.
  • test substance 100 mgZkg is orally administered to a Wistar male rat of 180 to 200 g that has been fasted for 24 hours, and glycyrrhizin (40 mg ml) is intraperitoneally administered at a dose of 5 mlZkg.
  • the test substance is suspended in 1% methylcellulose and administered at a dose of 1 Om1 / kg.
  • the control group receives 1% methylcellulose.
  • D-galactosamine solution (dissolve D-galactosamine in physiological saline, adjust the pH to about 7 with a small amount of aqueous sodium hydroxide solution, and adjust to a concentration of 160 mg / ml) Is adjusted subcutaneously at a dose of 5 ml 1 g to cause acute liver injury.
  • the normal group receives subcutaneous saline instead of D-galactosamine.
  • the rats were laparotomized under ether anesthesia, blood was collected from the aorta and abdominal vena cava, and the probed blood was processed in the same manner as in Experiment 2. Addition suppression rate (%) and PT extension suppression rate
  • Table 2 shows the measured values of the compounds obtained in each Example.
  • Example 7 43 48 61 Note: (300) indicates that the dose of the test compound is 300 mgZkg.
  • the dose of the test compound is 30 mg / kg.
  • the dose of the test compound is 1 OmgZkg.
  • the dose of the test compound is 100 mg / kg.
  • the thiazoline-2-thione derivative which is the active ingredient of the present invention, has excellent G0T and GPT departure suppression effects and PT elongation suppression effects in an in vivo acute liver injury model. Having glue.
  • stomach acid converts it to 4-methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione and acts.
  • the thiazoline-2-thione derivative represented by the general formula (3) showed no remarkable change even in SOOmgZkg in rat 2-week repeated oral dose toxicity screening.
  • the thiazoline-2-thione derivative represented by the general formula (1) is a therapeutic agent for liver diseases, an anti-inflammatory agent, an anti-rheumatic agent, a therapeutic agent for gastrointestinal diseases, particularly, as is clear from the results of the above pharmacological experiments. It is a useful substance as an active ingredient of a therapeutic agent for liver disease.
  • the therapeutic agent for liver disease of the present invention can be administered either orally or parenterally, and is usually in the form of a pharmaceutical composition together with a pharmaceutical carrier.
  • diluents or excipients such as extenders, binders, disintegrants, lubricants and the like which are usually used for preparing a drug according to the use form are used.
  • the preparation may be in any form such as injections, powders, capsules, granules and tablets.
  • the dose varies depending on the degree of the patient's symptoms, but usually, the thiazoline-2-thione derivative of the present invention may be administered to the patient at a dose of about 10 mg to lg per day.
  • 3400 3090, 3070, 2970, 2950, 2910, 2810, 1590, 1580, 1490, 1460, 1435, 1420, 1400, 1370, 1355, 131 5, 1290, 1260, 1250, 1220, 12 10, 1 190, 1 140, 1080, 1020, 1000, 980,
  • 2,3,4-Trimethoxybenzylamine (0.986 g, 5.00 mmol) was dissolved in ethanol (10 ml), and carbon disulfide (0.3 ml, 5 mmol) was added to this solution. Was added and stirred at room temperature for 15 minutes.
  • a 28% sodium methoxide Z methanol solution (0.965 g, 5.00 mmol) was added, and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in ethanol (10 ml), and this solution was dissolved in 1-bromo-1-methyl-12-butanone (0.825 g, 5.00 mmol) in ethanol (1 Oml).
  • the extract was washed once with a saturated saline solution (1 Oml) and dried over anhydrous sodium sulfate.
  • the solvent was distilled off from this solution under reduced pressure, and the residue was crystallized from ethanol (1 ml) and Zn-hexane (1.5 ml).
  • the precipitated crystals were collected by filtration, washed with n-hexane, and dried under reduced pressure (40 ° C) to give 0.535 g (yield: 89.8%) of the title compound as white crystals.
  • 2,3,4 Trimethoxybenzylamine (1.g, 5.07 mmol) was dissolved in ethanol (1 Om 1), and carbon disulfide (0.31 m (1 mmol) and stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methoxide / methanol solution (1.0 g, 5.2 mmol), and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was added to a solution of 1-promo-2-butanone (0.789 g, 5.07 mmol) in ethanol (1 Oml) under ice-cooling for 5 minutes. Was added.
  • 3,4,5-Trimethoxybenzylamine (1.24 g, 6.29 mmol) is dissolved in ethanol (5 ml), and carbon disulfide (0.38 ml, 6.29 mmol) is added to this solution. And stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methoxide Z methanol solution (1.22 g, 6.32 mmol), and the mixture was further stirred at room temperature for 15 minutes. This solution was added to a solution of acetone (0.64 g, 6.92 mmol) in ethanol (2 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
  • 2,3,4-Trimethoxybenzylamine (1.18 g, 6.0 mmol) was dissolved in ethanol (10 ml), and to this solution was added carbon disulfide (0.36 ml, 6.0 mmol). The mixture was stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methoxide Z methanol solution (1.16 g, 6.00 mmol), and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was ethanol
  • the above-mentioned substances were uniformly mixed to obtain powder or fine granules to obtain a powder.
  • the above substance was heated and mixed and then sterilized to give an injection.
  • Example 10 The powder obtained in Example 10 was filled in a commercially available capsule container to prepare a capsule.
  • the thiazoline-2-thione derivative represented by the general formula (1) of the present invention has an excellent G0T, G ⁇ ⁇ ⁇ departure inhibitory effect and prolonged prolongation time in an acute liver injury model. It has an inhibitory effect, reduces or treats liver damage, or has an excellent protective effect against liver damage.It is particularly useful as a treatment and prevention agent for liver diseases, and is also an anti-inflammatory, anti-rheumatic, and digestive agent.
  • thiazolidine-2-thione derivative represented by the general formula (2) is useful as an intermediate for producing the thiazoline-2-thione derivative represented by the general formula (1)
  • a therapeutic agent for liver disease containing as an active ingredient a thiazoline-2-thione derivative represented by the general formula (3) or a salt of a thiazoline-2-thione derivative represented by the general formula (4) It has excellent efficacy for liver disease.

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Abstract

L'invention concerne : un nouveau dérivé de thiazoline-2-thione représenté par la formule générale (1), constituant le principe actif d'un remède contre les maladies de foie; un autre dérivé de thiazoline-2-thione utilisé comme intermédiaire dans la synthèse du dérivé susmentionné; et un remède contre les maladies de foie, contenant le susdit dérivé. Dans ladite formule (1), R1 représente alkyle, cycloakyle, alcényle ou alkynyle; R2 représente halogéno, hydroxy, alcoxy, alkyle, amino, alkylamino, dialkylamino, alkylthio, nitro, carboxy ou alcoxycarbonyle; m représente un nombre entier compris entre 1 et 5, à condition que lorsque m vaut au moins 2, deux R2 puissent être combinés pour représenter alkylènedioxy; et n représente 0 ou 1.
PCT/JP1994/001306 1993-08-19 1994-08-09 Derive de thiazoline-2-thione et remede contre les maladies de foie WO1995005369A1 (fr)

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Application Number Priority Date Filing Date Title
AU72762/94A AU7276294A (en) 1993-08-19 1994-08-09 Thiazoline-2-thione derivative and remedy for liver diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP22646793A JPH0753374A (ja) 1993-08-19 1993-08-19 チアゾリン−２−チオン誘導体を含有する肝疾患治療剤
JP5/226466 1993-08-19
JP22646693A JPH0753532A (ja) 1993-08-19 1993-08-19 チアゾリン−２−チオン誘導体
JP5/226467 1993-08-19

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WO1995005369A1 true WO1995005369A1 (fr) 1995-02-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002070456A1 (fr) * 2001-03-01 2002-09-12 Technological Resources Pty Limited Bases de mannich de benzene-1 2-diol, ligands, polymeres, et methode d'elimination selective d'ions metalliques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4834169B1 (fr) * 1969-09-05 1973-10-19
JPS5215703A (en) * 1975-07-29 1977-02-05 Fuji Photo Film Co Ltd Treatmenttfree lithographic press plate material
EP0286089A1 (fr) * 1987-04-07 1988-10-12 Kanebo, Ltd. Dérivés de l'acide quinolinocarboxylique, composition les contenant, procédé pour les préparer et utilisation dans la préparation de médicaments
JPH04120081A (ja) * 1990-09-11 1992-04-21 Kanebo Ltd 新規キノリンカルボン酸誘導体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4834169B1 (fr) * 1969-09-05 1973-10-19
JPS5215703A (en) * 1975-07-29 1977-02-05 Fuji Photo Film Co Ltd Treatmenttfree lithographic press plate material
EP0286089A1 (fr) * 1987-04-07 1988-10-12 Kanebo, Ltd. Dérivés de l'acide quinolinocarboxylique, composition les contenant, procédé pour les préparer et utilisation dans la préparation de médicaments
JPH04120081A (ja) * 1990-09-11 1992-04-21 Kanebo Ltd 新規キノリンカルボン酸誘導体

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 107, 1986, Abstract No. 58266. *
CHEMICAL ABSTRACTS, Vol. 71, 1969, Abstract No. 3306. *
INDIAN CHEM. SOC., Vol. 50, No. 6, 1973, pages 417-419. *
INDIAN J. CHEM., Sect. B, Vol. 19B, No. 10, 1980, pages 918-920. *
J. CHROMATOGR., No. 462, 1989, pages 95-103. *
J. HETEROCYCL. CHEM., Vol. 4, No. 4, 1967, pages 605-609. *
J. INDIAN CHEM. SOC., Vol. 61, No. 11-12, 1984, pages 973-974. *
J. ORG. CHEM., Vol. 53, No. 21, 1988, pages 5076-5080. *
NEW J. CHEM., Vol. 12, No. 11-12, 1988, pages 947-952. *
ORG. MAGN. RESON., Vol. 14, No. 3, 1980, pages 166-170. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002070456A1 (fr) * 2001-03-01 2002-09-12 Technological Resources Pty Limited Bases de mannich de benzene-1 2-diol, ligands, polymeres, et methode d'elimination selective d'ions metalliques

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