WO1998023606A1 - Derives dithio cycliques, remedes contre des maladies renales diabetiques, agents hypoglycemiques, agents hypolipidemiques et agents lenitifs contre les troubles digestifs - Google Patents

Derives dithio cycliques, remedes contre des maladies renales diabetiques, agents hypoglycemiques, agents hypolipidemiques et agents lenitifs contre les troubles digestifs Download PDF

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WO1998023606A1
WO1998023606A1 PCT/JP1997/004281 JP9704281W WO9823606A1 WO 1998023606 A1 WO1998023606 A1 WO 1998023606A1 JP 9704281 W JP9704281 W JP 9704281W WO 9823606 A1 WO9823606 A1 WO 9823606A1
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group
acid
carboxylic acid
compound
integer
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PCT/JP1997/004281
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English (en)
Japanese (ja)
Inventor
Hiroshi Kurobe
Tetsuji Nunozawa
Tomokazu Sugawara
Shinji Kawai
Hironori Kawabata
Yoshihide Matsutani
Jiro Takahashi
Koei Moriguchi
Takeshi Endo
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Fuji Kagaku Kogyo Kabushiki Kaisha
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Publication of WO1998023606A1 publication Critical patent/WO1998023606A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms

Definitions

  • Cyclic dithio derivative therapeutic agent for diabetic renal disease, hypoglycemic agent, lipid lowering agent, gastrointestinal disorder reducing agent
  • the present invention relates to a novel dithiocyclic compound, and more particularly, to a dithiocyclic compound having an inhibitory effect on renal disease progression, a hypoglycemic effect, a hypolipidemic effect, a gastrointestinal disorder-reducing effect, or a medicament thereof.
  • the present invention relates to a medicament useful as an agent or a gastrointestinal disorder reducing agent.
  • lipoic acid which is a cyclic SS-form
  • cholic acid which is a cyclic SS-form
  • one SS-body is expected to be effective for complications of diabetes.
  • the complications of diabetes there are few drugs for diabetic nephropathy, and the development of new drugs is expected.
  • lipoic acid (cholic acid) has not been studied for dysglycemic nephropathy, and the present inventors' studies on renal dysfunction using streptozotocin (STZ) have shown a strong effect. Did not.
  • the present invention relates to a novel dithiocyclic compound, more specifically, a dithiocyclic compound having a renal disease progression-inhibiting action, a hypoglycemic action, a hypolipidemic action, or a gastrointestinal disorder-reducing action, or a pharmaceutically acceptable compound thereof. Salts, intermediate compounds for producing them, and therapeutic agents for diabetic renal diseases, hypoglycemic agents, lipid-lowering agents, or gastrointestinal tract, which contain dithiocyclic compounds and have few side effects such as gastrointestinal disorders.
  • An object of the present invention is to provide a medicament that is useful as a disorder reducing agent.
  • the present inventors have developed a novel compound having less side effects such as gastrointestinal disorders as described above, inhibiting the progress of renal disease, lowering blood glucose, lowering lipids, or reducing gastrointestinal disorders.
  • the following novel dithiopoid compound of the present invention or a pharmaceutically acceptable salt thereof has excellent inhibitory effect on renal disease progression, lowering blood sugar, lowering lipid or reducing gastrointestinal tract disorders. This led to the completion of the present invention.
  • the present invention relates to the following novel dithiocyclic compound or a pharmaceutically acceptable salt, an intermediate compound for producing the compound, and a pharmaceutical composition containing the dithiocyclic compound.
  • the present invention provides a compound represented by the general formula ()
  • m represents an integer of 37
  • RR c is the same or different and is a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, one CONH (CH 9 ), COR.
  • R represents an amino acid residue.
  • R b or R graffiti R which forms a heavy bond or an aromatic ring and exists at any position on the force or ring
  • At least one of ⁇ is —CO— (CH 9 ) j C OR— group
  • n represents an integer of 1 to 7, R d, RJ or the same or different, 7K atom, Al kill group, ⁇ Li - show Le group.
  • the present invention relates to a compound of the general formula (I)
  • R and R c are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, —CONH (CH 0 ), COR.
  • Groups (where 1 is an integer from :! to 10; R- represents a hydroxyl group, an alkoxy group, an amino group, or an alkylamino group); — a COR group (where R represents an amino acid residue).
  • R represents an amino acid residue
  • R b and R which form a double bond or an aromatic ring with each other and are present at an arbitrary position on the ring At least one of the — COR. , — (CH 9 ) COR.
  • m is 3-position one C00H when the 3, - (CH) 4 C00H and single (CH 2) 4 instead C0Nh n
  • m is the 3-position when the 4 - C00H a and 6-position hydrogen atoms Not a child or a CO OH]
  • Preferred compounds are dithiocyclic compounds represented by the general formula (I) in which m is 5 to 7 or an alkyl group in which m is 3 and 4 and —COI ⁇ group (where R is the aforementioned d ⁇ And the dithiocyclic compound according to the general formula (I).
  • alkyl group means an alkyl group having 1 to 20 carbon atoms which may be branched, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl.
  • Preferred are a methyl group, an ethyl group and a propyl group.
  • Alkylamino group means an amino group substituted with the above-mentioned alkyl group. Specific examples include methylamino, dimethylamino, ethylamino, ethylamino, propylamino, isopropylamino, butylamino, and isobutylamino. , Sec-butylamino and tert-butylamino. Preferred are a methylamino group and a dimethylamino group.
  • alkylamino group may be a “heterocyclic group”, and the “heterocyclic group” means one or more selected from a nitrogen atom, an oxygen atom, and a sulfur atom other than a carbon atom as a ring-constituting atom.
  • a 5- or 6-membered aromatic heterocyclic ring containing two hetero atoms, a saturated heterocyclic ring or a condensed heterocyclic ring obtained by condensing a heterocyclic ring with a benzene ring specifically, a pyrrolyl group, imidazolyl Group, pyrazolyl group, thiazolidyl group, isothiazolidyl group, oxazolidyl group, isooxazolidyl group, morpholino group, piperazinyl group, piperidyl group, and indole group.
  • Halogen atom means chlorine atom, bromine atom, fluorine atom and the like.
  • Alkoxy group means an alkoxy group which may be branched, and specifically, They are toxic, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.
  • cycloalkyl group is specifically a cyclopropyl group, a cyclobutyl group
  • a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • Aryl group means, for example, a phenyl group, a naphthyl group, a biphenyl group, etc.
  • the expression “may be substituted” means that the substituent may be substituted with 1 to 6 substituents, and the substituents may be the same or different. Further, the position of the substituent is arbitrary and is not particularly limited. Specifically, methyl, ethyl, propyl, butyl, tert-butyl, etc., hydroxyl, methoxy, ethoxy, propoxy, butoxy and other alkoxy, fluorine, chlorine, bromine, boron Halogen atom such as nitrogen, nitro group, cyano group, formyl group, acetyl group, propylyl group, etc., formyloxy group, acetylyloxy group such as propionyloxy group, etc.
  • mercapto group methylthio group, ethylthio group
  • Alkylthio such as propylthio, isopropylthio, etc.
  • alkylamino such as amino, methylamino, ethylamino, propylamino, butylamino, etc.
  • dialkyl such as dimethylamino, getylamino, dipropylamino, dibutylamino, etc.
  • Amino group, methoxy Carbonyl group, an ethoxycarbonyl group, flop port Po alkoxycarbonyl group is the amino-de group, a cyclopentyl group, a cycloalkyl group such as cyclohexyl group, phenyl group, Ashiruami de group such Puropioniruami de group
  • the “optionally substituted cycloalkyl group” means a cycloalkyl group optionally substituted with the same substituent.
  • the “optionally substituted aryl group” is the aforementioned pyrrolyl group which may be substituted with a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, or the like.
  • the “optionally substituted heterocyclic group” refers to the aforementioned pyrrolyl group which may be substituted with a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, etc. It is.
  • amino acid residue is a residue derived from a natural or synthetic amino acid.
  • natural amino acid residues include glycine, alanine, phosphorus, oral isin, isoleucine, serine, threonine, cystine, cystine, methionine, proline, aspartic acid, glutamic acid, lysine, and ornithine.
  • Examples include tin, arginine, tyrosine, fenylalanine, and tributofan.
  • This amino acid residue may be L-, D- or racemic.
  • “Pharmaceutically acceptable salt” means a salt which forms a salt with the dithiocyclic compound represented by the general formula (I) of the present invention. Salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine And organic bases such as lysine salts, and amino acid salts such as lysine salts and arginine salts.
  • novel dithiocyclic compound represented by the general formula (I) of the present invention the following compounds can be exemplified.
  • the compound of the present invention can be produced by the following methods, but the method of producing the compound of the present invention is not limited thereto.
  • Step 1 A step of reacting 6-bromooctanoic acid (A) with a thionyl halide such as thionyl chloride to obtain an active derivative (B) of a carboxylic acid by an acyl halide reaction.
  • a thionyl halide such as thionyl chloride
  • Step 2 the reaction product (B) and N- Puromosukushiimi halogenating agent such as de (in this example brominating agent) reacted presence of hydrobromic acid as a catalyst if required, halogen ⁇ ones
  • Step 3 a step of subjecting the reaction product (C) to an esterification reaction with an alcohol such as methanol or ethanol to obtain a compound (D),
  • Step 4 a step of reacting the reaction product (D) with potassium thioacetate to obtain a diacetylthio compound (E);
  • Step 5 a step of subjecting the reaction product (E) to a hydrolysis reaction in a base, for example, an aqueous alkali solution such as sodium hydroxide to obtain a compound (F)
  • a base for example, an aqueous alkali solution such as sodium hydroxide
  • the reaction product (F) is represented by the formula (G) by a cyclization reaction step in which the reaction product (F) is oxidized in the presence of, for example, a catalytic amount of ferric chloride or at least an equimolar amount of iodine.
  • Compounds can be prepared.
  • the compound obtained in each of the above steps can be isolated and purified by a conventional method, for example, by silica gel column chromatography (methanol / chloroform), extraction or partitioning operation. Since each step proceeds with high purity and high yield, the above 1 to 5 steps or 1 to 6 steps can be performed in one pot without isolating the reaction product.
  • the benzodichepine derivative is a compound having a benzene skeleton as a starting material, for example, a dithiol compound is synthesized using o-phthalpenzaldehyde, and the same treatment is carried out as in the above reaction. Can be obtained.
  • the reaction process will be described below with reference to the following reaction formula 2.
  • Step 1 Phthalaldehyde and ethoxycarbonylmethyltriphenylphosphorane are reacted in an inert solvent such as benzene by the Wittig reaction under ice-cooling to obtain ethyl 3- (2-formylphenyl) 2-propenoate.
  • an inert solvent such as benzene
  • Step 2 This compound was reacted with methanol in the presence of an acid such as concentrated sulfuric acid to protect the formyl group with acetal to obtain ethyl 3- (2,2 dimethylmethylphenyl) 2-propenoate.
  • Step 3 This compound is reduced with sodium hydrogenborohydride in methanol in the presence of a catalyst such as nickel chloride and the like, to give 3- (2,2-dimethylmethoxyphenyl) propionic acid The ethyl ester was obtained.
  • Step 4 This compound was subjected to a deprotection reaction in THF in the presence of an acid such as 2 N hydrochloric acid to give ethyl 3- (2-formylphenyl) propionate.
  • Step 5 This compound was reduced using sodium borohydride in an alcohol such as ethanol to obtain 3- (2-hydroxymethylphenyl) propionate ethyl ester.
  • Step 6 This compound was hydrolyzed by adding 4NNaOH in methanol to obtain 3- (2-hydroxymethylphenyl) propionic acid.
  • Step 7 This compound is reacted with thionyl chloride, and then reacted with NBS and hydrobromic acid in tetrachloride carbon under heating to give 3- (2-chloromethylphenyl) -2-bromopropione The acid was obtained.
  • Step 8 The reaction product of this compound is reacted with potassium thioacetate in a solvent such as DMF to give 3- (2-acetylthiomethylphenyl) 2-acetylthiopropionate. Acid methyl ester was obtained.
  • Step 9 This compound was heated to reflux in a stream of nitrogen in 2 NNaOH and subjected to a hydrolysis reaction to obtain 3- (2-mercaptomethylphenyl) 2 mercaptopropionic acid.
  • Step 10 By subjecting this compound to a cyclization reaction in the same manner as described above, the desired 4,5-dihydro-1H-2,3-benzodichepine-14-carboxylic acid is obtained.
  • the above reaction can be performed without isolating and purifying the reaction product of each step.
  • the tetrathiacycloalkanedicarboxylic acid derivative can be obtained by the cyclization reaction.
  • the yield of these compounds can be increased by controlling the reaction conditions as needed.
  • the ester derivative is obtained by converting the carboxyl group of the compound into an active derivative of a carboxylic acid by an ordinary method, for example, using an activator such as thionyl halide; And esterification in the presence of an acid such as trimethylsilyl chloride.
  • the alcohols are alcohols having a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl group, heptyl, etc. It may have a substituent.
  • the amide derivative is an active derivative of the above carboxylic acid and an amine compound, for example, ammoniums, alkylamines such as methylamine, dimethylamine, and getyreamine, pyrroline, imidazoline, imidazole, virazoline, thiazoline, isothiazolidine, oxazoline, and morpholine. It can be obtained by subjecting a heterocyclic amine compound such as piperazine, piperidine and indole to an amidation reaction according to a conventional method.
  • a heterocyclic amine compound such as piperazine, piperidine and indole
  • amino acids used in the amidation reaction include glycine, alanine, quinoline, leucine, isoleucine, serine, threonine, cystine, cystine, methionine, proline, aspartic acid, glutamic acid, lysine, and lysine.
  • amino acids used in the amidation reaction include ordinine, arginine, tyrosine, phenylalanine, and tryptophan.
  • the functional groups such as carboxylic acid, hydroxyl group, and thiol of these amino acids are protected with a protecting group used in a conventional manner in peptide synthesis. It is preferable to use it (Basics and experiments of peptide synthesis, Nobuo Izumiya et al., 1985).
  • the compounds that can be used in the therapeutic agent for diabetic renal disease, hypoglycemic agent, lipid-lowering agent, and gastrointestinal disorder reducing agent of the present invention include the novel compounds of the present invention and known compounds.
  • dithiane compounds such as 1,2-dithian-13-carboxylic acid and 1,2-dithian-13,6-dicarboxylic acid
  • cycloalkanones such as cyclohexanone, cycloheptanone, and cyclooctanone to acidification according to a conventional method, for example, by the Bayavillaga reaction, and converting the resulting lactone compound to hydrogen halide, for example, hydrogen bromide.
  • a ring opening reaction is carried out in the presence to synthesize a fatty acid in which the ⁇ -position is halogenated, and then this compound is treated with 7-ethyl-1,2-dicepan-13-carboxylic acid in the same manner as in the above-mentioned production method using rubonic acid.
  • Compounds can be induced.
  • the pharmacologically acceptable salts of the cyclic dithio derivative of the present invention can be prepared by a conventional method.
  • the compound represented by the general formula (I) of the present invention includes stereoisomers. If necessary, these stereoisomers can be isolated and purified by a conventional method, for example, by optical resolution.
  • the compound used in the present invention can be synthesized by a method known in the literature or according to it.
  • the methods for synthesizing the compounds represented by formulas (I) to (VI) of the present invention are described in detail in the following Examples and Reference Examples.
  • the target compound was a mixture of two stereoisomers.
  • a benzene solution of 31.4 g of ethoxycarbonylmethyltriphenylphosphorane (5 Oml) was added dropwise to a benzene solution (10 Oml) of 11 g of o-phthalaldehyde over 30 minutes under ice-cooling. After the dropwise addition, the temperature of the reaction solution was returned to room temperature and stirred. One hour later, the reaction solution was concentrated to dryness, and 50 Oml of petroleum ether was added to the residue, followed by stirring for 30 minutes. The precipitate was removed by filtration, and the precipitate was washed with petroleum ether. The filtrate and the washing were combined and concentrated to dryness. 10 g of 3- (2-formylphenyl) -2-ethyl propenoate was obtained as a yellow liquid (93% yield).
  • This 3- (2-formylphenyl) -1-2-propenoic acid ester 9.78 g was dissolved in 300 ml of methanol, and 3 ml of concentrated sulfuric acid was added. After stirring at room temperature for 3 hours, the reaction solution was concentrated to about half and poured into saturated aqueous sodium hydrogen carbonate for neutralization. After extraction with ethyl acetate and drying over sodium sulfate, the solvent was distilled off. Residues and NiC 12 ⁇ 6H. 1.2 g of 0 was dissolved in 200 ml of methanol, and 3.8 g of sodium borohydride was added little by little while stirring under ice cooling.
  • the solvent was distilled off.
  • the obtained residue was dissolved in 100 ml of THF, 200 ml of 2N-HC1 was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was extracted with ethyl acetate and dried over sodium sulfate, the solvent was distilled off. The obtained residue was dissolved in 100 ml of ethanol, 0.60 g of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated to dryness, the residue was partitioned between dilute hydrochloric acid and chloroform. The dried form layer was dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with black hole form. The corresponding fraction was concentrated to dryness to give 8.13 g of 3- (2-hydroxymethylphenyl) propionic acid ethyl ester as a colorless syrup (yield: 81.5%).
  • reaction product of the corresponding example was isolated and purified by column chromatography.
  • the cis and trans forms of the target compound were obtained from 2,5-dimercaptooctanoic acid.
  • the compound represented by the general formula (I) of the present invention is useful as a therapeutic agent for diabetic renal disease, a blood sugar lowering agent, a lipid lowering agent and a gastrointestinal disorder reducing agent.
  • the compounds (1) used in the present invention (1) a test for inhibiting the progression of renal disease, (2) a test for lowering blood glucose, (3) a test for lowering lipids, and (4) a gastrointestinal disorder-reducing agent are described in more detail in the following test examples. Will be described.
  • the compound used in the present invention was orally administered (po: 402 to 1508 mg / kg), using three Wistar male rats weighing 200 g per group. The death status was observed 7 days after administration, and the MLD (minimum mortality) value was determined.
  • the (1) renal disease progression inhibitory test, (2) hypoglycemic effect test, and (3) lipid lowering effect test are described below.
  • streptozotocin 4 Omg / kg was administered intravenously (day 1), blood was collected on days 35-36, and serum biochemical examination was performed. Blood glucose, CHO, urinary ALB, and body weight were used as indices, and the test drug (1,2-dicepan-13-carboxylic acid, hereinafter referred to as a compound) was neutralized and dissolved in sodium hydrogen carbonate.
  • test compound was neutralized and dissolved with water using sodium bicarbonate to give a 5 ml Zkg aqueous solution.
  • test drug (1,2-dicepan-13-carboxylic acid) was neutralized and dissolved in water using sodium bicarbonate to give a concentration of 0.311111101-1 (administered 5 days a week from 1 & 49. 32 Treated as in Example 1.
  • test was performed in the same manner as in Test Example 1 using metformin (commercially available) as the test drug.
  • Test Examples 1 and 2 and Comparative Example 1 are as shown in Tables 1 to 5.
  • Table 1 shows [BUN (mg / dl)]
  • Table 2 shows [CHO (mg / dl)]
  • Table 3 shows [TG (mg / dl)]
  • Table 4 shows [GLU (mg / dl)]
  • Table 5 Indicates the results of [urine ALB (mg / day)].
  • Urine ALB (mg / day)
  • the hypoglycemic effect of the compound of the present invention is considered to be correlated with the gluconeogenesis inhibitory effect on hepatocytes.
  • the effect of the compound on gluconeogenesis from lactic acid was determined by isolating rat hepatocytes, preparing them at 6 ⁇ 10 6 cells, adding 1 OmM lactic acid, and measuring the amount of glucose released into the ground. Measured and determined. The results are shown in the table below. In the table, each compound is
  • the compound of the present invention showed an improving effect of BUN value, CHO value, TG value, GLU value, urinary ALB value and the like on an STZ-induced renal disorder model, and was used as a therapeutic agent for diabetic nephropathy.
  • the compound of the present invention has an action of lowering the GLU value and is useful as a hypoglycemic agent.
  • the compounds of the present invention lower the CH 0 value and TG value, and are therefore useful as lipid lowering agents.
  • gastrointestinal disorders The effects of the compounds used in the present invention on gastrointestinal disorders are described below. There are no effective measures against gastrointestinal disorders, especially diarrhea, when administering antineoplastic drugs. If the disorder is severe, the drug must be reduced or the administration stopped. Therefore, clinically, it has been desired to develop a compound that reduces gastrointestinal disorders without affecting the antitumor effect when using these drugs.
  • Specific examples of this gastrointestinal tract disorder include, for example, drugs commonly used in the treatment of gastrointestinal cancers, such as 5-fluorouracil (5FU) and its derivatives such as tegafur and 5-deoxyfluorouridine (5DFUR).
  • 5FU 5-fluorouracil
  • DFUR 5-deoxyfluorouridine
  • its use is known to cause major side effects such as gastrointestinal disorders (nausea, vomiting, diarrhea) and bone marrow disorders.
  • An antitumor agent for example, 5FU is dissolved in 5 Wistar male rats (7 weeks old; body weight: 200-230 g) in water and administered orally for 3 days (day 1-3) did.
  • the test drug was dissolved in water or suspended in 3% gum arabic immediately before administration of the antitumor agent and orally administered for 3 days. After the administration of the test drug, changes in body weight and the occurrence of diarrhea were observed. The degree of diarrhea was scored in four steps based on the shape of feces.
  • the compounds of the present invention reduced weight loss and significantly reduced the occurrence of diarrhea.
  • a commercially available fluoropyrimidine-based antitumor agent was used in the above digestive tract disorder reducing action test.
  • fluor-oral pyrimidine antitumor agents include 5-fluorouracil (5FU), tegafur, doxyfluridine, 5-deoxy-5-fluorouridine (FUDR), carmofur, or a combination drug consisting of tegafur and peracil ( UFT) and so on.
  • 5FU 5-fluorouracil
  • FUDR 5-deoxy-5-fluorouridine
  • UFT a combination drug consisting of tegafur and peracil
  • N-1 or N-3 position of the skeleton of these fluoropyrimidine-based antitumor agents may be protected with a protecting group, and when these compounds are administered to a living body, the antitumor effect is reduced.
  • L which is not particularly limited as long as it can demonstrate.
  • the gastrointestinal disorder reducing agent of the present invention is described in more detail in the following Test Examples.
  • 5 FU (8 Omg / kg) was dissolved in 5 Wistar male rats (7 weeks old; weight: 200 to 230 g) per group for 3 days (day 1 to 10). 3) Oral administration.
  • the test drug (butyric acid, hereinafter referred to as compound A) was orally administered for 3 days immediately before administration of 5FU by dissolving 0.5 to 2 IMO1 / kg in water after neutralizing with sodium bicarbonate.
  • the control group received water.
  • changes in body weight and the occurrence of diarrhea were observed, and the degree of diarrhea was scored on a four-point scale based on the shape of feces.
  • fecal status was evaluated on the following four scales. 0: Normal stool (hard fecal mass with low water content), 1: Loose stool (fecal type collapsed, soft with lots of water), 2: Diarrhea stool (fecal type completely collapsed, soft with lots of water), 3: Water soluble Diarrhea stool (watery stool without any fecal type).
  • Test Example 1 The test was carried out in accordance with Test Example 1 using thiotamide (hereinafter referred to as Compound B) as a test drug.
  • Compound B thiotamide
  • Table 7 shows the results.
  • the change in body weight is the mean value of the group from day 1 on day 6 with the largest weight loss after administration of 5 FU, and the fecal status was 0 to 3. Scored into stages and expressed as the mean of the group c Table 7
  • CDF 1 mice (body weight 23 - 2 5 g) and murine leukemia cell L 1 2 1 0 and 1 0 7 implanted intraperitoneally (dayo).
  • 5 FU 3 Omg / kg
  • the test drug was administered orally by dissolving 1-4 mmol Zkg in water immediately before administration of 5FU.
  • Six mice were used per group, and water alone was administered to a control group (control).
  • the antitumor effect was determined by calculating the life extension rate (ILS) by the following formula from the average survival days (C) of the control group and the average survival days (T) of the 5FU administration group.
  • ILS life extension rate
  • the compound of the present invention did not affect the antitumor effect even when 0.5 to 2 mmol / kg was used in combination with 5FU.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is usually a pharmaceutically acceptable carrier, excipient, diluent, bulking agent, disintegrant, It can be used by formulating with stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, flavoring agents, solubilizing agents, and the like.
  • Carrier substances include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol, and serine, and other organic or inorganic inert carriers suitable for intestinal, transdermal, or parenteral administration. Substance.
  • compositions include tablets, dragees, enteric-coated tablets, granules, powders, suppositories and tablets which can be produced in accordance with the usual methods.
  • the compound of the present invention When used as a therapeutic agent for diabetic renal disease, a hypoglycemic agent, a lipid-lowering agent and an agent for reducing gastrointestinal tract disorders, the compound of the present invention may be used alone or in combination of two or more different compounds such as inulin and the like. Can be used in combination.
  • the amount used is about 0.1 force per weight of the pharmaceutical composition, such as 99.5%, preferably 0.5 to 95%.
  • the dosage of the drug of the present invention varies depending on the type of patient, the compound to be administered and the administration route, the age, sex, weight and the like of the patient.
  • a therapeutic agent for diabetic renal disease a blood glucose lowering agent, and a lipid lowering agent
  • it is generally in the range of 20 to 20 mg per person, preferably 60 to 12 O mg.
  • a gastrointestinal disorder reducing agent it may vary depending on the type, dosage, administration method, etc. of the antitumor agent.
  • the timing of administration of the drug is not particularly limited, and it may be before or after administration of the fluoropyrimidine-based antitumor agent or simultaneously, even if administered simultaneously.
  • Tablets are prepared by the usual method using the following composition.
  • a granule is prepared by the usual method using the following composition.
  • a powder is prepared by the usual method with the following composition.
  • the powder obtained in Formulation Example 3 is filled into a forceps container to form a capsule.
  • a dithiocyclic compound or a pharmaceutically acceptable salt thereof having a disease progress-inhibiting action, a blood glucose-lowering action, a lipid-lowering action, or a gastrointestinal disorder-reducing action, an intermediate compound for producing them,
  • a medicament useful as a diabetic renal disease therapeutic agent I which contains these dithiocyclic compounds and has few side effects such as gastrointestinal disorders, a hypoglycemic agent, a lipid lowering agent, and a gastrointestinal disorder relieving agent. was completed.

Abstract

Composés dithio cycliques représentés par la formule générale (I): [dans laquelle A représente (a) ou (b) (dans laquelle les substituants sont tels qu'ils sont définis chacun dans les revendications)]; remèdes contre des maladies rénales diabétiques, agents lénitifs contre les troubles digestifs, agents hypoglycémiques ou agents hypolipidémiques contenant lesdits composés.
PCT/JP1997/004281 1996-11-27 1997-11-25 Derives dithio cycliques, remedes contre des maladies renales diabetiques, agents hypoglycemiques, agents hypolipidemiques et agents lenitifs contre les troubles digestifs WO1998023606A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP8/332941 1996-11-27
JP33294196 1996-11-27
JP27039497 1997-09-16
JP9/270394 1997-09-16

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WO1998023606A1 true WO1998023606A1 (fr) 1998-06-04

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JP2000169443A (ja) * 1998-10-02 2000-06-20 Sankyo Co Ltd ジチオ―ル誘導体
JP2000169371A (ja) * 1998-10-02 2000-06-20 Sankyo Co Ltd ジチオラン誘導体を含有する医薬
CN100436444C (zh) * 2006-07-29 2008-11-26 常熟富士莱医药化工有限公司 硫辛酰胺合成工艺
EP2168567A1 (fr) 2008-09-24 2010-03-31 L'Oréal Utilisations de composés dithiolanes pour la photoprotection de la peau, composés dithiolanes et compositions les contenant
JP2010090123A (ja) * 2008-10-08 2010-04-22 L'oreal Sa ジベンゾイルメタン誘導体およびジチオラン化合物を含む化粧用組成物、ジベンゾイルメタン誘導体を光安定化する方法
EP2191816A1 (fr) 2008-11-28 2010-06-02 L'oreal Procédé de dépigmentation des matières kératiniques à l'aide de composés dithiolanes.
WO2019082962A1 (fr) * 2017-10-26 2019-05-02 四国化成工業株式会社 Composés thiols, procédé de synthèse de ceux-ci, et utilisation desdits composés thiols

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000169371A (ja) * 1998-10-02 2000-06-20 Sankyo Co Ltd ジチオラン誘導体を含有する医薬
JP2000169443A (ja) * 1998-10-02 2000-06-20 Sankyo Co Ltd ジチオ―ル誘導体
CN100436444C (zh) * 2006-07-29 2008-11-26 常熟富士莱医药化工有限公司 硫辛酰胺合成工艺
US20100197759A1 (en) * 2008-09-24 2010-08-05 L'oreal Administration of dithiolane compounds for photoprotecting the skin
EP2168567A1 (fr) 2008-09-24 2010-03-31 L'Oréal Utilisations de composés dithiolanes pour la photoprotection de la peau, composés dithiolanes et compositions les contenant
JP2010077121A (ja) * 2008-09-24 2010-04-08 L'oreal Sa 皮膚を光保護するためのジチオラン化合物の使用、新規ジチオラン化合物、それを含有する組成物
JP2015127348A (ja) * 2008-09-24 2015-07-09 ロレアル 皮膚を光保護するためのジチオラン化合物の使用、新規ジチオラン化合物、それを含有する組成物
US8530511B2 (en) * 2008-09-24 2013-09-10 L'oreal Administration of dithiolane compounds for photoprotecting the skin
JP2010090123A (ja) * 2008-10-08 2010-04-22 L'oreal Sa ジベンゾイルメタン誘導体およびジチオラン化合物を含む化粧用組成物、ジベンゾイルメタン誘導体を光安定化する方法
JP2010132657A (ja) * 2008-11-28 2010-06-17 L'oreal Sa ジチオラン化合物を使用するケラチン物質の脱色方法
KR101198048B1 (ko) 2008-11-28 2012-11-07 로레알 디티올란 화합물을 사용하여 케라틴 물질을 탈색하는 방법
US20100135942A1 (en) * 2008-11-28 2010-06-03 L'oreal Depigmenting keratin materials utilizing dithiolane compounds
US8617524B2 (en) * 2008-11-28 2013-12-31 L'oreal Depigmenting keratin materials utilizing dithiolane compounds
EP2191816A1 (fr) 2008-11-28 2010-06-02 L'oreal Procédé de dépigmentation des matières kératiniques à l'aide de composés dithiolanes.
WO2019082962A1 (fr) * 2017-10-26 2019-05-02 四国化成工業株式会社 Composés thiols, procédé de synthèse de ceux-ci, et utilisation desdits composés thiols
CN111315719A (zh) * 2017-10-26 2020-06-19 四国化成工业株式会社 硫醇化合物、其合成方法和该硫醇化合物的利用
CN114276298A (zh) * 2017-10-26 2022-04-05 四国化成工业株式会社 硫醇化合物、其合成方法和该硫醇化合物的利用
US11807596B2 (en) 2017-10-26 2023-11-07 Shikoku Chemicals Corporation Thiol compounds, synthesis method therefor, and utilization of said thiol compounds

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