WO1994005647A1 - 3-oxo-1,4-benzothiazine derivative - Google Patents
3-oxo-1,4-benzothiazine derivative Download PDFInfo
- Publication number
- WO1994005647A1 WO1994005647A1 PCT/JP1993/001190 JP9301190W WO9405647A1 WO 1994005647 A1 WO1994005647 A1 WO 1994005647A1 JP 9301190 W JP9301190 W JP 9301190W WO 9405647 A1 WO9405647 A1 WO 9405647A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- oxo
- hydroxy
- benzothiazine
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel 3-oxo-1,4-benzothiazine derivative which has a protein stabilizing action and an action of suppressing lipid peroxide production, and is useful as a drug such as a therapeutic agent for cataract.
- Cataract is an intractable eye disease in which the lens becomes opaque and the eyesight is lost.
- the causes, mechanism, and treatment of cataract have been studied for a long time, but there are very few effective drugs. is the current situation.
- the present inventors have studied the effect of inhibiting lipid peroxide production and the effect of protein stability.
- a 3-oxo-11,4-benzothiazine compound in which the 2-position is substituted with a benzylidene group and the 4-position is substituted with a carboxyalkyl group As a result of intensive studies to find a compound that also has a stabilizing effect, a 3-oxo-11,4-benzothiazine compound in which the 2-position is substituted with a benzylidene group and the 4-position is substituted with a carboxyalkyl group.
- a compound in which the phenyl ring of the benzylidene group is further substituted with a hydroxy group and a lower alkyl group has both effects of inhibiting lipid peroxide production and stabilizing a protein.
- the compound having a benzylidene group at the 2-position of the 3-oxo-1,4-benzothiazine derivative, which is the basic skeleton of the compound of the present invention, is a herbicide (American Patent No. 3,923,709), It has been reported that it can be used as an intermediate for the synthesis of lanquilizers (Japanese Patent Publication No. 49-10671) and benzothiazepine derivatives (Japanese Patent Application Laid-Open No. 60-72875). It goes without saying that the chemical structures of the compound disclosed in the literature and the compound of the present invention are different, and these known documents do not disclose any protein stabilizing action or lipid peroxide production inhibitory action.
- Japanese Patent Application Laid-Open No. Hei 1-287770 discloses a 2-benzylidene 3-year-old 1,4-benzothiazine derivative having an active oxygen scavenging action and an action of inhibiting the production of lipid peroxides. Only lower alkyl groups are disclosed as substituents at the position, and there is no description of protein stabilizing action.
- Aldose reductase inhibitors have recently attracted attention as cataract treatment agents, but the compounds of the present invention also have an aldose reductase inhibitory effect, and their usefulness as cataract treatment agents is Very expensive. Disclosure of the invention
- the present invention relates to a compound represented by the following general formula [I] or a salt thereof.
- R 1 represents a hydroxy group which may be protected by a protecting group.
- R 2 represents a lower alkyl group.
- R 3 represents a hydrogen atom, a lower alkyl group, a hydroxy group which may be protected with a protecting group or a lower alkoxy group, and the lower alkyl group is a hydroxy group which may be protected with a protecting group; It may be substituted with a amino group or a lower alkylamino group.
- R represents a carboxyl group which may be converted to an ester or an amide.
- A represents an alkylene group. same as below. ]
- the lower alkyl group is defined as a group such as methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl, (dimethyl) ethyl and the like.
- a lower alkoxy group is a group of 1 to 4 such as methoxy, ethoxy, propoxy, hexyloxy, isopropoxy, tert.-butoxy. Indicates a straight-chain or branched alkoxy group having 6 carbon atoms.
- An alkylene group is a carbon atom of 1 to 10 carbon atoms, such as methylene, ethylene, propylene, tetramethylene, heptamethylene, decamethylene, (dimethyl) methylene, and (getyl) methylene.
- the hydroxy-protecting group is defined as lower alkylsulfonyl such as methanesulfonyl, phenylsulfonyl ⁇ p-arylsulfonyl such as toluenesulfonyl, lower alkanol such as acetyl, propionyl, and vivaloyl, and methoxime.
- lower alkylsulfonyl such as methanesulfonyl, phenylsulfonyl ⁇ p-arylsulfonyl such as toluenesulfonyl, lower alkanol such as acetyl, propionyl, and vivaloyl, and methoxime.
- Examples are those commonly used as a protecting group for a hydroxy group, such as lower alkoxymethyl such as tyl, benzoyl, benzyloxymethyl, tetrahydrobiranyl or trimethylsilyl
- Esters are esters of carboxylic acids such as lower alkyl esters such as methyl ester, ethyl ester, isopyl pill ester, butyl ester, and hexyl ester, and aryl lower alkyl esters such as benzyl ester. It shows what is commonly used.
- Amide refers to amide with ammonia, amide with lower alkylamine such as methylamine, methylamine, and aryl lower amine such as benzylamine. It shows those commonly used as amides of carboxylic acids, such as amides with ruquilamine.
- the compound of the present invention can also form a salt with a base.
- pharmaceutically acceptable salts include salts with alkali metals such as sodium, potassium, calcium and the like, and salts with alkali earth metals. Salts with organic amines such as monium salt, getylamine, triethanolamine salt and the like can be mentioned.
- Representative methods for synthesizing the compound of the present invention include the following 1) and 2).
- X represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group.
- the compound of the present invention represented by the formula [I] can be obtained by reacting the compound represented by the formula [IV] with the compound represented by the formula [V] in the presence of a base.
- the compound represented by the formula [IV] can also be synthesized according to the method described in JP-A-1-287077.
- the above formula [VI] and the compound represented by the formula [111] are By reacting in the presence, a compound represented by the formula [VI I] is obtained.
- the compound of the present invention represented by the general formula [I] can be obtained by dehydrating the compound.
- the compound represented by the formula [VI] can be obtained by the method of Raj N andan Prasad et al. (Can.) Cheni., U, 12H (1966)).
- the hydroxy group substituted on the phenyl ring of the benzylidene group may be protected by the above-mentioned protecting group before or after the reaction according to a commonly used method, and the protecting group is removed by a commonly used method. Can be separated.
- the carboxyl group substituted at the 4-position of benzothiazine can be converted to an ester amide before or after the reaction using a commonly used method.
- esters and amides can be hydrolyzed to carboxylic acids using commonly used methods.
- the compound obtained by the above method may be converted into a salt as described above by a conventional method.
- the compound of the present invention also has a stereoisomer or an optically active form. All of them are included in the present invention.
- the compound of the present invention has a benzylidene group, there are a Z-form and an E-form, and the present invention includes all of them.
- a toluene derivative having a hydroxy group and a tert.-butyl group as substituents has an antioxidant effect. Since antioxidants have the effect of suppressing the formation of lipid peroxides, various substituents such as alkyl and hydroxy groups are introduced into the phenyl ring of the benzylidene group to reduce the effect of lipid peroxide formation. The role of the substituent was discussed. As a result, it was found that by introducing a hydroxy group and a lower alkyl group to the phenyl ring of the benzylidene group, a compound having an excellent lipid peroxide production inhibitory action was obtained.
- the basic constitutional requirement of the compound of the present invention is that the 4-position of 3-oxo-1,4-benzothiazine is substituted with a carboxyalkyl group, the 2-position is substituted with a benzylidene group, and the benzylidene group is substituted with a benzylidene group.
- the phenyl ring of the den group has at least one hydroxy group and one lower alkyl group.
- compounds used as pharmaceuticals are intended to be used as prodrugs for the purpose of promoting absorption in the living body and improving sustainability, and for stabilizing the formulation.
- the hydroxy group may be protected by a protecting group commonly used as a protecting group for the hydroxy group
- the carboxyl group of the carboxyalkyl group may be protected by a general-purpose derivative of carboxylic acid.
- C The structural characteristics of the compound of the present invention which may be converted into an ester or amide form are as described above, and among them, preferred are substituents on the benzylidene group in the unityl ring.
- the hydroxy group is located at the 4-position, and that at least one of the hydroxy groups is substituted with a lower alkyl group. That is, a compound in which the lower alkyl group is substituted at the 3-position or both 3- and 5-positions is preferred. Further, as the lower alkyl group, a methyl group or a tert-butyl group is a more preferable example.
- the compound of the present invention has both a lipid peroxide production inhibitory action and a protein stabilizing action, and is useful as an anti-cataract agent.
- the compound of the present invention is excellent as a therapeutic agent for cataract, and indicates that it is expected to be a therapeutic agent for diabetic complications.
- the compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, eye drops, and the like, and can be formulated using commonly used techniques.
- oral preparations such as tablets, capsules, capsules, and granules may be used, if necessary, as fillers such as lactose, starch, crystalline cellulose, vegetable oil, etc., and lubricants such as magnesium stearate, talc, etc. It can be formulated using a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as calcium carboxymethylcellulose, a coating agent such as hydroxypropylmethylcellulose, and the like.
- isotonic agents such as sodium chloride, buffering agents such as sodium phosphate, solubilizing agents such as polysorbate 80, benzalkonium chloride, etc. It can be formulated using a preservative or the like.
- the dose can be appropriately selected depending on the symptoms, age, dosage form, and the like.
- 1 to 500 Omg per day can be administered once or divided into several times.
- 0.001% to 5% may be instilled once or several times a day.
- reaction mixture was added with 3-tert-butyl-5- (1,1-dimethyl-2-hydroxyshetyl) -tetrahydroxybenzaldehyde (1.71 g) of tetrahydrohydran (1.71 g). 15 ml) Add the solution and stir for 1.5 hours. After adding an aqueous solution of ammonium chloride to the reaction solution, extract with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- reaction solution is placed in a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. Organic layer is anhydrous sodium sulfate And then concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 0.36 g (58.1%) of the title compound.
- the reaction mixture is acidified with 6N hydrochloric acid (6.5 ml), concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 0.19 g (65.2%). Get.
- Protein stabilization and lipids The effect of inhibiting peroxide formation was studied.
- bovine serum alpmin manufactured by Sigma
- bovine serum alpmin manufactured by Sigma
- 0.2 M potassium phosphate buffer pH 5.3
- a dimethyl sulfoxide solution in which the test compound was dissolved was added, and the mixture was stirred and left for about 15 minutes to return to room temperature. After reacting the solution in a water bath at 67 ° C for 2 minutes while shaking, the reaction was stopped by ice cooling.
- the absorbance caused by the cloudiness of the water-soluble protein due to thermal aggregation was measured at a wavelength of 660 nm, and the protein stabilization of the compound of the present invention was performed using the following formula 1. The effect was sought.
- a 0 Absorbance when test compound is not added
- a j Absorbance when test compound is added
- Table 1 shows the obtained results.
- the compound of the present invention clearly inhibits the thermal aggregation of the protein, and shows an excellent protein stabilizing effect, whereas the comparative compound does not show the protein stabilizing effect, but rather tends to promote the thermal aggregation of the protein.
- the compound of the present invention clearly inhibits the thermal aggregation of the protein, and shows an excellent protein stabilizing effect, whereas the comparative compound does not show the protein stabilizing effect, but rather tends to promote the thermal aggregation of the protein.
- Rat liver microsomes were purified from ADP (13 M) in 0.04 M Tris buffer (0.09 M potassium chloride, pH 7.4) containing the test compound. 2 mM), Fe 2+ (0.9 mM) and ascorbic acid (0.5 mM) at 37 ° C for 15 minutes, and the resulting lipid peroxide is analyzed by TBA method (Yagi et al. Biochem. .
- each of the compounds of the present invention had an excellent effect of suppressing the production of lipid peroxide.
- the compound of the present invention has a protein stabilizing action and a lipid peroxide production inhibitory action, and is expected to be an excellent therapeutic agent for cataract.
- the present invention provides a novel 3-oxo-1, 4-benzothiazine derivative which has a protein stabilizing action and a lipid peroxide production inhibiting action, and is useful as a drug such as a therapeutic agent for cataract.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT93919568T ATE197297T1 (de) | 1992-08-31 | 1993-08-25 | 3-oxo-1,4-benzothiazin-derivate |
US08/211,940 US5496817A (en) | 1992-08-31 | 1993-08-25 | 3-oxo-1,4-benzothiazine derivatives |
DE69329618T DE69329618T2 (de) | 1992-08-31 | 1993-08-25 | 3-oxo-1,4-benzothiazin-derivate |
EP93919568A EP0627425B1 (en) | 1992-08-31 | 1993-08-25 | 3-oxo-1,4-benzothiazine derivative |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4/231669 | 1992-08-31 | ||
JP23166992 | 1992-08-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994005647A1 true WO1994005647A1 (en) | 1994-03-17 |
Family
ID=16927129
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1993/001190 WO1994005647A1 (en) | 1992-08-31 | 1993-08-25 | 3-oxo-1,4-benzothiazine derivative |
Country Status (6)
Country | Link |
---|---|
US (1) | US5496817A (ja) |
EP (1) | EP0627425B1 (ja) |
AT (1) | ATE197297T1 (ja) |
CA (1) | CA2122370A1 (ja) |
DE (1) | DE69329618T2 (ja) |
WO (1) | WO1994005647A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0657444A1 (en) * | 1993-12-09 | 1995-06-14 | Santen Pharmaceutical Co., Ltd. | Novel 3-oxo-1, 4-benzothiazine derivatives |
WO2000075139A2 (en) * | 1999-06-03 | 2000-12-14 | Basf Aktiengesellschaft | Benzothiazinone and benzoxazinone compounds |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5556841A (en) * | 1994-02-04 | 1996-09-17 | Santen Pharmaceutical Co., Ltd. | Thiazine or thiomorpholine derivatives |
US6713477B1 (en) | 2000-04-19 | 2004-03-30 | Sumitomo Pharmaceuticals Company, Limited | Hydroxamic acid derivatives |
EP1726587B1 (en) * | 2004-03-02 | 2010-09-01 | Dainippon Sumitomo Pharma Co., Ltd. | Benzothiazin-3-one compound and intermediate therefor |
KR20140048891A (ko) | 2011-05-27 | 2014-04-24 | 템플 유니버시티-오브 더 커먼웰쓰 시스템 오브 하이어 에듀케이션 | 치환된 2-벤질리덴-2H-벤조[b][1,4]티아진-3(4H)-온, 이의 유도체, 및 이의 치료적 용도 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3923709A (en) * | 1974-08-30 | 1975-12-02 | Monsanto Co | 3,4-Dihydro-3-oxo-2H-1,4-benzothiazines and benzoxazines |
US4490292A (en) * | 1983-10-07 | 1984-12-25 | Hamari Chemicals, Ltd. | 1,5-Benzothiazepine derivatives and production thereof |
JPS6140264A (ja) * | 1984-05-18 | 1986-02-26 | ラボラトワース ユーペーエスア | 新規複素環誘導体、その製法およびこれらを含有し、アルド−ス還元酵素抑制剤として特に有用な医薬の製法 |
JPS63107970A (ja) * | 1986-04-17 | 1988-05-12 | Takeda Chem Ind Ltd | チオラクタム−n−酢酸誘導体 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE914455A1 (en) * | 1990-12-27 | 1992-07-01 | Green Cross Corp | 1,4-benzothiazine-2-acetic acid derivatives, processes for production thereof |
-
1993
- 1993-08-25 EP EP93919568A patent/EP0627425B1/en not_active Expired - Lifetime
- 1993-08-25 CA CA002122370A patent/CA2122370A1/en not_active Abandoned
- 1993-08-25 WO PCT/JP1993/001190 patent/WO1994005647A1/ja active IP Right Grant
- 1993-08-25 DE DE69329618T patent/DE69329618T2/de not_active Expired - Fee Related
- 1993-08-25 US US08/211,940 patent/US5496817A/en not_active Expired - Fee Related
- 1993-08-25 AT AT93919568T patent/ATE197297T1/de not_active IP Right Cessation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3923709A (en) * | 1974-08-30 | 1975-12-02 | Monsanto Co | 3,4-Dihydro-3-oxo-2H-1,4-benzothiazines and benzoxazines |
US4490292A (en) * | 1983-10-07 | 1984-12-25 | Hamari Chemicals, Ltd. | 1,5-Benzothiazepine derivatives and production thereof |
JPS6140264A (ja) * | 1984-05-18 | 1986-02-26 | ラボラトワース ユーペーエスア | 新規複素環誘導体、その製法およびこれらを含有し、アルド−ス還元酵素抑制剤として特に有用な医薬の製法 |
JPS63107970A (ja) * | 1986-04-17 | 1988-05-12 | Takeda Chem Ind Ltd | チオラクタム−n−酢酸誘導体 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0657444A1 (en) * | 1993-12-09 | 1995-06-14 | Santen Pharmaceutical Co., Ltd. | Novel 3-oxo-1, 4-benzothiazine derivatives |
US5547952A (en) * | 1993-12-09 | 1996-08-20 | Santen Pharmaceutical Co., Ltd. | 3-oxo-1,4-benzothiazine derivatives |
WO2000075139A2 (en) * | 1999-06-03 | 2000-12-14 | Basf Aktiengesellschaft | Benzothiazinone and benzoxazinone compounds |
WO2000075139A3 (en) * | 1999-06-03 | 2001-03-29 | Basf Ag | Benzothiazinone and benzoxazinone compounds |
US7049312B1 (en) | 1999-06-03 | 2006-05-23 | Abbott Gmbh & Co. Kg | Benzothiazinone and benzoxazinone compounds |
Also Published As
Publication number | Publication date |
---|---|
CA2122370A1 (en) | 1994-03-17 |
EP0627425B1 (en) | 2000-11-02 |
DE69329618T2 (de) | 2001-05-17 |
EP0627425A4 (ja) | 1994-12-21 |
ATE197297T1 (de) | 2000-11-15 |
DE69329618D1 (de) | 2000-12-07 |
EP0627425A1 (en) | 1994-12-07 |
US5496817A (en) | 1996-03-05 |
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