WO1994022845A1 - Benzothiazole compound, process for producing the same, and use thereof - Google Patents

Benzothiazole compound, process for producing the same, and use thereof Download PDF

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Publication number
WO1994022845A1
WO1994022845A1 PCT/JP1994/000490 JP9400490W WO9422845A1 WO 1994022845 A1 WO1994022845 A1 WO 1994022845A1 JP 9400490 W JP9400490 W JP 9400490W WO 9422845 A1 WO9422845 A1 WO 9422845A1
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WIPO (PCT)
Prior art keywords
methyl
compound
succinamic acid
general formula
ethyl
Prior art date
Application number
PCT/JP1994/000490
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English (en)
French (fr)
Japanese (ja)
Inventor
Takema Hase
Takahiro Kumonaka
Chikako Shimizu
Hiroshi Hosono
Tomoji Aotsuka
Yoshiyuki Nakamura
Tetsuo Matsui
Hiromichi Ishikawa
Original Assignee
Senju Pharmaceutical Co., Ltd.
The Green Cross Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Senju Pharmaceutical Co., Ltd., The Green Cross Corporation filed Critical Senju Pharmaceutical Co., Ltd.
Priority to KR1019940704255A priority Critical patent/KR100299558B1/ko
Priority to DE69418961T priority patent/DE69418961T2/de
Priority to US08/343,489 priority patent/US5532257A/en
Priority to AU62914/94A priority patent/AU676894B2/en
Priority to EP94910543A priority patent/EP0647636B1/en
Publication of WO1994022845A1 publication Critical patent/WO1994022845A1/ja

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/25—Aminoacetonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2

Definitions

  • the present invention relates to a novel benzothiabool compound having excellent aldose reductase inhibitory activity and a pharmaceutically acceptable salt thereof (hereinafter, also collectively referred to as "the compound of the present invention"), and a method for producing the compound of the present invention.
  • the present invention relates to intermediates, methods for producing them, and pharmaceutical compositions containing the compound of the present invention.
  • the above-mentioned compound of the present invention is useful as an aldose reductase inhibitor, and as a preventive or therapeutic agent for diabetic complications such as corneal damage fusion defect, diabetic cataract, retinopathy, nephropathy and neurosis. Useful.
  • diabetes treatment drugs such as insulin and synthetic hypoglycemic agents have been widely used as diabetes treatment drugs.
  • Diabetes is a disease accompanied by various complications. It is difficult to prevent this, and new drugs for treating diabetic complications are desired.
  • a compound that inhibits the activity of aldose reductase an enzyme that reduces aldoses such as glucose and galactose to sorbitol and galactitol, may be used in combination with corneal damage fusion defects, cataracts, neuroses, kidney diseases, etc. It is suggested in the literature to be useful for the treatment of diabetic complications such as retinopathy and retinopathy.
  • R represents a halogen atom
  • R 2 and R 3 may be the same or different and each represents a hydrogen atom or a halogen atom
  • R ′ represents a hydrogen atom, a ⁇ -gen atom, a lower alkyl
  • R 5 represents a hydrogen atom or a lower alkyl group
  • a pharmaceutically acceptable salt thereof have been found to achieve the object, and the present invention has been completed by establishing an efficient method for producing the compound.
  • the present invention provides a benzothyl boule compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof, and a compound represented by the general formula (H)
  • R 1 , R 2 , R 3 and R 4 have the same meanings as described above, respectively.
  • X represents a halogen atom
  • R Se represents a lower alkyl group
  • R 1 , R 2 and R 3 have the same meanings as described above, respectively.
  • the present invention provides a method for producing a pharmaceutically acceptable salt, and a pharmaceutical composition containing, as an active ingredient, a benzothiabul compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. is there.
  • halogen atom in the present invention examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the lower alkyl group a straight-chain or branched alkyl group having 1 to 6 carbon atoms is preferable. For example, methyl, ethyl, propyl, isopropyl, butyl, butyl, isobutyl, sec "butyl, teri-butyl, pentyl, isopentyl , Sec to pentyl, ieri-bentil, hexyl, isohexyl, sec- Xyl and iert-hexyl.
  • these lower alkyl groups may be substituted with an aryl group, an amino group, a halogen atom (the same as described above), a cyano group, a water-sulfur group and the like.
  • alkoxy group and the alkyl mercapto group those derived from the lower alkyl groups described above are preferable, and examples include methoxy and methyl mercapto.
  • R 1 , R 2 and R 3 can be in any of the positions 4 to 7 of the benzothiazole group, of which two of the groups are 4, 5 and 5, 7 or S, 7
  • R 1 , R 2, and R 3 are bonded at positions 5, 5, and 7.
  • at least one group, preferably all groups, of R 1 , R 2 and R s be a fluorine atom or a chlorine atom.
  • R 4 can take any position of the 2- to 4-positions of the fuunyl group, but if R 4 is a low-end alkenyl group having 3 or more carbon atoms, an alkoxy group or an alkylmercapto group, it can be in the S or 4-position. It is preferable that R 4 is a branched chain, especially when R 4 is a branched chain.
  • R ⁇ represents a hydrogen atom, methyl, ethyl, propyl propyl, isopropyl, butyl, iert-butyl, an alkoxy group (for example, methoxy) or an alkyl mercapto group (for example, methyl mercapto), a chlorine atom, a halo atom Or a fluorine atom is particularly preferred.
  • RS is particularly preferably a fluorine atom, methyl or ethyl, and R "is particularly preferably methyl, ethyl or propyl.
  • the benzothiabul compound represented by the general formula (I) may be in the form of a pharmaceutically acceptable salt.
  • salts include alkali metal salts such as lithium, sodium, and potassium; alkaline earth metal salts such as calcium, magnesium, and beryllium; aluminum salts; and organic salts such as triethylamine and pyridine.
  • the compound of the present invention represented by the general formula I) can be produced by various methods, and typical production methods are described below.
  • R 1 , R 2 , R 3 and R 4 have the same meanings as described above, respectively.
  • a salt thereof [preferably, the same as the pharmaceutically acceptable salts of the benzothiazole compounds represented by the general formula (I)]. Is the general formula ( ⁇ )
  • X and R 5a have the same meanings as described above, respectively, and X is particularly preferably a chlorine atom or a bromine atom. And, if necessary, in the presence of a base, preferably in an atmosphere of an inert gas such as argon, helium, or nitrogen, and, if necessary, by subjecting it to a hydrolysis reaction. it can.
  • an inert gas such as argon, helium, or nitrogen
  • Examples of the above base include triethylamine, NJ-diisopropyldipyrethylamine, pyridine, 1,8-diazabicyclo [5,4,0] indene 7-ene, 4- (dimethylamino) pyridine and the like.
  • reaction temperature is not particularly limited, it is preferably from 150 to 150 ° C, particularly preferably from 120 to 80 ° C.
  • the hydrolysis reaction is carried out by a usual process in the presence of a base.
  • Suitable bases include, for example, alkaline metal hydroxides such as sodium hydroxide and hydroxylating hydroxide; alkaline metal carbonates such as sodium carbonate and carbonated lithium.
  • This reaction is usually performed in the presence of a solvent, and includes water, acetone, dioxane, dichloromethane, methanol, ethanol, ⁇ -phenol, pyridine, and dimethylphos.
  • the reaction is carried out in a conventional solvent or a mixture thereof which does not have an adverse effect, such as rumamide.
  • the reaction temperature is not particularly limited, and the reaction is performed in a wide range from under cooling to under heating. Manufacturing method 2
  • R 1 , R 2 and R 3 have the same meanings as described above, respectively.
  • the compound represented by the formula (I) or an acid addition salt thereof (hydrochloride or the like) is reacted in the presence of an acid, preferably in an atmosphere of an inert gas such as argon, helium, or nitrogen, and further required. It can be produced by subjecting it to a hydrolysis reaction.
  • This reaction is generally carried out in the presence of a solvent, and suitable solvents to be used include methanol, ethafur, propanol and the like.
  • suitable solvents to be used include methanol, ethafur, propanol and the like.
  • the acid include inorganic acids such as hydrochloric acid, hydrous acid, sulfuric acid, and nitric acid; and organic acids such as formic acid, acetic acid, and propionic acid. Among them, strong acids such as sulfuric acid and hydrochloric acid are preferable.
  • the reaction temperature is preferably from room temperature to 200, particularly preferably from 60 ° C to reflux temperature.
  • the hydrolysis reaction can be carried out under the same reaction conditions as in the above-mentioned production method 1.
  • the compound of the present invention obtained by the above production method 1 or 2 can be isolated and purified by a conventional method such as extraction, precipitation, fractionation chromatography, fractionation, crystallization, and recrystallization. Can be.
  • the compound of the present invention thus produced can be converted into pharmaceutically acceptable salts by a conventional method, if desired.
  • Typical examples of the benzothiabul compound represented by the general formula (I) of the present invention include the following compounds.
  • R 1 , R 2 and R 3 have the same meanings as described above, respectively.
  • a salt thereof [preferably, the same as the pharmaceutically acceptable salts of the benzothiabool derivative represented by the single-injection formula (I)]. Are reacted under the same conditions as in the previous lai method 2.
  • the starting compound represented by the general formula (V) (including a salt thereof) is a known substance or a known method [CJovmal of Medicinal Chemistry] , Vol. 34, pp. 108-122, 1991]].
  • the starting compound represented by the general formula (“VI” (including salts thereof)) is also a known substance or a known method [Helvetica-Himika-Ryuta (He :. Chi. Acta). .). 37, 166-178, 1954].
  • Representative examples of the compound represented by the general formula (H), which is an intermediate of the present invention, include the following compounds.
  • the compound represented by the general formula (W) and a salt thereof used in the above-mentioned production method 2 are also novel substances, and can be produced by the following method. That is, it can be obtained by reacting a compound represented by the general formula (cm) with a compound represented by the general formula (D) or a salt thereof under the same reaction conditions as in the above-mentioned Production Method 1.
  • the starting compound represented by (!) Is a known substance or can be easily produced by a known method.
  • Typical examples of the compound represented by the general formula (IV), which is an intermediate of the present invention include the following compounds.
  • the preparation of the lactose reductase enzyme preparation was performed by the method of S. Hay-man et al. From the Bushu lens [Journal-Bob-Biological-Chemistry, vol. 77-88, 2, 1965). That is, the cryopreserved (-8O'C) lens of bushu was homogenized with distilled water and centrifuged at 10,000 G for 15 minutes. The supernatant was used as a 40 Sulfuric acid ammonium solution, and the supernatant was further centrifuged at 10.000 G for 10 minutes.The supernatant was dialyzed in 0.05 M sodium chloride solution, and the resulting dialysis solution was used as an enzyme preparation. .
  • Test substance Compound of the present invention and epalrestat (described in JP-A-57-40478)
  • aldose reductase was determined by the method of Hyman et al. That is, a 4 OmM phosphate buffer (PH6) prepared to contain a final concentration of 0-4 M lithium sulfate, 0. ImM NADPH (reduced nicotinamide, adenine dinucleotide phosphate) and 3 mM d-triglyceraldehyde as a substrate. -2) To 200, drug solutions 25 ⁇ of various concentrations dissolved in the above enzyme solution 25 and 1% DMSO were added, respectively. Thereafter, the mixture was reacted at 25 ° C for 2 minutes, and the change in absorbance at 330 nm was measured using COB AS FARAI (Roche).
  • the change in absorbance when 1% DMSO was added instead of the drug solution was defined as 100%, and the results are shown in Table 1 as the 50% inhibition aggressiveness (IC s ) of the drug.
  • (M) indicates the concentration of the compound of the present invention that suppresses aldose reductase activity by 50%, and the number of the test drug indicates the number of the example described later.
  • Test drug Compound of the present invention and epalrestat (described in JP-A-57-40478)
  • a Sprague-Dawley rat male, 6 weeks old, 5-6 mice / group was fasted for 18 hours, and streptozotocin (SI GMA) 6 Onig / kg was injected into the tail vein under ether anesthesia.
  • SI GMA streptozotocin
  • test drugs were orally administered at 10 or 30 mZkg as a 0.5% carboxymethylcellulose suspension at 4, 8 and 24 hours after injection of streptozotocin. During this time, the lads were maintained on food and water ad libitum and 3 hours after the last administration, sorbitol content in tissues (red blood cells, sciatic nerve, lens) was determined by the method of HY Bergmeyer et al. 'Methods of Enzymatic Analysis' (Vol. 3, pp. 132-133, 1979)], SDH (sorbitol dehydrogenase) and NAD ( ⁇ -nicotinamide adenine dinucleotide) )). The measurement results are shown as a percentage (%) when the value of the control group to which a 0.5% carboxymethylcellulose solution as a solvent was administered instead of the compound was taken as 100%. Table 2 shows the results.
  • Example 3 7 "1 6.4 ** 1 7.8 ** 55.4"
  • Example 4 8 ' 32.8 ⁇ * 45.7 ** 56.6 *
  • Example 5 2.5 ** 2 1.2
  • Example 6 5 s
  • 6.4 ** 4.0 7 1.8 * example 7 2" 1 9.2 - * 1 0.8 ... 50.0 ** Eparuresu Yu' door b) 66.5 99.9 89. 1
  • mice Male, 7 weeks old, 5 mice per group
  • the compound of the present invention has an excellent aldose reductase inhibitory activity on mammals such as humans, mice, dogs, mice, and rats, and is also excellent in safety. For example, it is effective for the prevention and treatment of diabetic complications such as corneal damage defect, diabetic neuropathy, nephropathy, retinopathy, and cataract.
  • diabetic complications such as corneal damage defect, diabetic neuropathy, nephropathy, retinopathy, and cataract.
  • the compound of the present invention When the compound of the present invention is administered for the purpose of treating and / or preventing the above diseases, it can be administered orally or parenterally.
  • compositions containing the compound of the present invention may be in the form of solid, semi-solid and liquid preparations containing an organic or inorganic carrier suitable for external, internal or topical administration, and a diluent or excipient.
  • suitable dosage forms such as tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and the like.
  • ancillary components include, for example, solids such as water, glucose, lactose, gelatin, mannitol, coconut starch, magnesium tricate, corn starch, keratin, colloidal silica, potatoes, urea, etc.
  • auxiliary substances such as stabilizers, extenders, colorants and fragrances can be included.
  • a preservative may be included to maintain the activity of the compound of the present invention, and may contain a sufficient amount of the compound of the present invention to produce the desired therapeutic effect on the progress or condition of the associated disease. Should be.
  • a compound of the present invention When a compound of the present invention is administered to a human, an amount effective to inhibit aldose reductase or an amount effective to prevent and prevent or treat diabetic complications, desirably, for example, by injection, eye drops Administer non-periodically or orally You.
  • the dose of the compound of the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method, administration period, and the like.In general, in the case of microdose, the administration range is 1 to 2000 mgZ days, preferably 10 to 600 rnZ days It is preferably administered once to three times a day.
  • the pharmaceutical composition of the present invention contains the compound of the present invention, as described above, it may further be used as an aldose reductase inhibitor, as well as keratoderma ulceris deficiency, diabetic dementia, nephropathy, It is effective in preventing and treating diabetic complications such as retinopathy and cataract.
  • the activity of aldose reductase is inhibited, and further, corneal damage healing defect, diabetic neuropathy, nephropathy, It can prevent and / or treat diabetic complications such as retinopathy and cataract.
  • N- (4-chloro ⁇ phenyl) [(4,5,7-trifluorobenzothiazol-12-yl) methyl] amine (30Oiiig) and triethylamine (110 nig) are converted to dichloromethane (5 ⁇ ). Melted and cooled on ice. Methyl succinyl ⁇ -ride (165 g) was added dropwise thereto, and the mixture was stirred for 1.5 hours under an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • Example 18 By substantially the same procedure as in Example 1, the compounds shown in Tables 3 and 4 were obtained. The structural formulas and physical properties of these compounds are also shown in Tables 3 and 4. Example 18
  • Example 1 The title compound (190 iD) of Example 1 was dissolved in a mixture of methanol (0., dioxane (1.6 i) and a 2% (w / v) aqueous sodium hydroxide solution) and stirred at room temperature for 1 hour.
  • reaction solution was diluted with water, diluted with f 3 , acidified with hydrochloric acid, and extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was crystallized by adding toluene to obtain the title compound (10 Omg).
  • Table 7 shows the structural formula and physical properties of this compound.
  • Example 73 By substantially the same procedure as in Example 73, the compounds shown in Tables 11 and 12 were obtained. The structural formulas and physical properties of the compounds obtained according to these examples are also shown in Nos. 11 and 12.
  • the above components were mixed uniformly, and 200% of a 5% aqueous solution of hydroxypropylcellulose was added, and the mixture was extruded into granules using a screen with a diameter of 0 to 5 mm using an extruder, immediately rounded with a marmalizer and dried. .
  • the dried granules were coated with 1.9 kg of a film coating solution having the following composition using a fluidized granulator to give enteric-coated condensates.
  • Soft capsules containing 20 Omg of drug solution per capsule were prepared by the rotary method.
  • the above formulation was used as an eye drop according to a conventional method.
  • the benzothiazole compound which is a novel compound represented by the general formula (I) of the present invention, and a pharmaceutically acceptable salt thereof have an aldose reductase inhibitory activity on human and other mammals, and are safe. Because of its superior properties, it is a drug for the therapeutic treatment of diabetic complications such as corneal injury defect defect, cataract, neuropathy, retinopathy, and renal disorder, especially cataract and dementia.
  • diabetic complications such as corneal injury defect defect defect, cataract, neuropathy, retinopathy, and renal disorder, especially cataract and dementia.
  • novel compounds represented by the general formula (I) and the general formula () are used for producing a benzothiabul derivative of the present invention and a pharmaceutically acceptable salt thereof. It can be suitably used as an intermediate.
  • the compounds of the present invention represented by the general formula (I) and the novel compounds represented by the general formula (I) and the general formula () which have such usefulness And their salts can be efficiently produced.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/JP1994/000490 1993-03-26 1994-03-25 Benzothiazole compound, process for producing the same, and use thereof WO1994022845A1 (en)

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KR1019940704255A KR100299558B1 (ko) 1993-03-26 1994-03-25 벤조티아졸화합물,그의제조방법및용도
DE69418961T DE69418961T2 (de) 1993-03-26 1994-03-25 Benzothiazol-derivate, verfahren zur herstellung sowie anwendungen
US08/343,489 US5532257A (en) 1993-03-26 1994-03-25 Benzothiazole compound, production thereof and use thereof
AU62914/94A AU676894B2 (en) 1993-03-26 1994-03-25 Benzothiazole compound, process for producing the same, and use thereof
EP94910543A EP0647636B1 (en) 1993-03-26 1994-03-25 Benzothiazole compound, process for producing the same, and use thereof

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JP5/90550 1993-03-26
JP05090550A JP3126541B2 (ja) 1993-03-26 1993-03-26 ベンゾチアゾール誘導体、その製法及びその用途

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EP0714893A1 (en) * 1994-11-29 1996-06-05 Grelan Pharmaceutical Co., Ltd. 2-substituted benzothiazole derivatives useful in the treatment of diabetic complications

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JPH05337783A (ja) * 1992-06-08 1993-12-21 Ona Electro Erosion Sa 荷積み荷下ろしパレットのドアの自動開放装置
JPH0782259A (ja) * 1993-09-14 1995-03-28 Senju Pharmaceut Co Ltd スクシンアミド酸誘導体及びそれを含有する糖尿病合併症治療剤
US6121300A (en) * 1998-11-10 2000-09-19 Wagle; Dilip R. Reversing advanced glycosylation cross-links using heterocyclic-substituted thiazolium salts
UA100527C2 (en) * 2007-10-10 2013-01-10 Астразенека Аб Benzothiazoles as ghrelin receptor modulators
KR102833669B1 (ko) 2018-09-25 2025-07-11 앤타바이오 에스에이에스 박테리아 감염의 예방 또는 치료에 사용되는 인단 유도체
CN113795304A (zh) 2019-02-13 2021-12-14 Ptc医疗公司 用于治疗家族性自主神经功能障碍的噻吩并[3,2-b]吡啶-7-胺化合物
US12398140B2 (en) 2019-02-13 2025-08-26 Ptc Therapeutics, Inc. Substituted pyrrolo [2,3-d]pyrimidines for treating familial dysautonomia
WO2024003408A1 (en) * 2022-07-01 2024-01-04 Universität Zürich Small-molecule inhibitors of the frs2-fgfr interaction

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* Cited by examiner, † Cited by third party
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EP0714893A1 (en) * 1994-11-29 1996-06-05 Grelan Pharmaceutical Co., Ltd. 2-substituted benzothiazole derivatives useful in the treatment of diabetic complications
US5700819A (en) * 1994-11-29 1997-12-23 Grelan Pharmaceutical Co., Ltd. 2-substituted benzothiazole derivatives and prophylactic and therapeutic agents for the treatment of diabetic complications

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EP0647636A4 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1995-04-19
TW245717B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1995-04-21
US5532257A (en) 1996-07-02
DE69418961D1 (de) 1999-07-15
ATE181067T1 (de) 1999-06-15
KR950701627A (ko) 1995-04-28
ES2132394T3 (es) 1999-08-16
AU6291494A (en) 1994-10-24
EP0647636B1 (en) 1999-06-09
CA2136743A1 (en) 1994-10-13
JP3126541B2 (ja) 2001-01-22
CN1108456A (zh) 1995-09-13
DE69418961T2 (de) 1999-12-23
JPH06279423A (ja) 1994-10-04
AU676894B2 (en) 1997-03-27
EP0647636A1 (en) 1995-04-12
KR100299558B1 (ko) 2001-11-22

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