WO1995013269A1 - Derive de 1,4-benzothiazine - Google Patents

Derive de 1,4-benzothiazine Download PDF

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Publication number
WO1995013269A1
WO1995013269A1 PCT/JP1994/001907 JP9401907W WO9513269A1 WO 1995013269 A1 WO1995013269 A1 WO 1995013269A1 JP 9401907 W JP9401907 W JP 9401907W WO 9513269 A1 WO9513269 A1 WO 9513269A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
hydroxy
lower alkyl
butyl
Prior art date
Application number
PCT/JP1994/001907
Other languages
English (en)
Japanese (ja)
Inventor
Yoichi Kawashima
Atsutoshi Ota
Hiroyuki Mibu
Kenichiro Matsubayashi
Original Assignee
Santen Pharmaceutical Co., Ltd.
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
Priority claimed from JP5283684A external-priority patent/JP2840807B2/ja
Priority claimed from JP5283685A external-priority patent/JP2840808B2/ja
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO1995013269A1 publication Critical patent/WO1995013269A1/fr

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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

Definitions

  • the present invention relates to a novel 1,4-benzothiazine derivative having a protein stabilizing action and an action of suppressing lipid peroxide production and useful as a drug such as a therapeutic agent for cataract, and a synthetic intermediate thereof.
  • Cataract is an intractable eye disease in which the lens becomes cloudy and loses vision. Although various factors have been studied for a long time for the onset factor, mechanism, and treatment of cataracts, there are very few effective drugs at present.
  • Compounds having a benzylidene group at the 2-position of the 1,4-benzothiazine derivative, which is the basic skeleton of the compound of the present invention include a herbicide (Amerili Patent No. 3923379), a tranquilizer (specifically) It has been reported that it can be used as an intermediate for synthesizing a benzothiazepine derivative (Japanese Patent Application Laid-Open No. 60-72875). However, the compounds disclosed in these known documents have an oxo group at the 3-position of the benzothiazine ring, and have a different skeleton chemical structure from the compound of the present invention. Further, no information has been reported on the protein stabilizing action or the lipid peroxide production inhibiting action, which are the characteristics of the effect of the compound of the present invention.
  • Japanese Patent Application Laid-Open No. 1-28707 discloses a 2-benzylidene-3-oxo-1,4-benzothiazine derivative having an active oxygen scavenging action and a lipid peroxide production inhibitory action.
  • the compounds disclosed in this publication and the compound of the present invention have different skeleton chemical structures, and there is no description of a protein stabilizing effect in this publication. .
  • an aldose reductase inhibitor has recently attracted attention as a cataract therapeutic agent, but the compound of the present invention also has an aldose reductase inhibitory effect, and its usefulness as a cataract therapeutic agent is extremely high. Is expensive. Disclosure of the invention
  • the present inventors have conducted intensive studies to find a compound having both a lipid peroxide production inhibitory action and a protein stabilizing action.
  • a benzylidene group wherein the 2-position is substituted with a benzylidene group and the 4-position is substituted with a carboxyalkyl group, respectively, and the 3-position is a thioxo or unsubstituted 3,4-dihydro-1,4-benzothiazine compound; It has been found that a compound in which the phenyl ring 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 present invention relates to a compound represented by the following general formula [ ⁇ or a salt thereof (hereinafter, referred to as the present compound [1]) and a synthetic intermediate of the present compound [I] represented by the following general formula [ ⁇ ] or a salt thereof: (Hereinafter referred to as the intermediate [II] of the present invention).
  • R 1 represents a hydroxy group which may be protected by a protecting group.
  • 2 represents a lower alkyl group.
  • ⁇ 3 ⁇ represents a hydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group which may be protected with a protecting group, and the lower alkyl group is a hydroxy group or an amino group which may be protected with a protecting group. Or a lower alkylamino group.
  • R 4 represents a carboxyl group which may be converted to an ester or an amide.
  • A represents an alkylene group.
  • lower alkyl groups are defined as 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl and (dimethyl) ethyl.
  • the lower alkoxy group means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, tert.-butoxy and the like.
  • An alkylene group is a linear or branched alkylene group having 1 to 10 carbon atoms, such as methylene, ethylene, propylene, tetramethylene, heptamethylene, decamethylene, (dimethyl) methylene, and (getyl) methylene.
  • the protecting group for the hydroxy group includes lower alkylsulfonyl such as methanesulfonyl, phenylsulfonyl, lower alkanol such as arylsulfonyl such as P-toluenesulfonyl, acetyl, propionyl, and vivaloyl, and methoxy.
  • Examples include those commonly used as protecting groups for hydroxy groups, such as lower alkoxymethyl such as methyl, benzoyl, benzyloxymethyl, tetrahydrobiranyl, and trimethylsilyl.
  • Esters are those commonly used as esters of carboxylic acids such as lower alkyl esters such as methyl ester, ethyl ester, isopropyl ester, butyl ester and hexyl ester, and aryl lower alkyl esters such as benzyl ester.
  • Amides are amides with ammonia, amides with lower alkylamines such as methylamine, dimethylamineethylamine, and aryl lower alkylamines such as benzylamine.
  • the compound [I] of the present invention and the intermediate [II] of the present invention may be in the form of a pharmaceutically acceptable salt.
  • examples of such salts include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium, etc., ammonium salts, getylamine, triethanolamine.
  • Salts with organic amines such as salts and salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid and the like can be mentioned.
  • X represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group. same as below. ]
  • the intermediate [II] of the present invention represented by the formula [IV] can be obtained by treating the compound represented by the formula [IH] with a reducing agent. Next, the intermediate [H] of the present invention and a compound represented by the formula [V] Is reacted in the presence of a base to obtain a compound [I] of the present invention represented by the formula [I].
  • the present invention intermediate [H] represented by the formula [VI] can be obtained by treating the compound represented by the formula [III] with a mouth reagent or phosphorus pentasulfide or the like. Then, the intermediate [[] of the present invention is reacted with the compound represented by the formula [VII] in the presence of a base to obtain the compound [1] of the present invention represented by the formula ⁇ ].
  • the compound represented by the formula [111] can be synthesized by the method described in Japanese Patent Application Laid-Open No. 1-28707, and a typical synthesis method is shown below.
  • the hydroxy group substituted on the phenyl ring of the benzylidene group may be protected by the above-mentioned protecting group according to a commonly used method before or after the reaction, and the protecting group may be removed by a commonly used method. Can be.
  • the carboxyl group substituted at the 4-position of benzothiazine can be converted into an ester or 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 [1] of the present invention and the intermediate [11] of the present invention also include stereoisomers and optically active forms, all of which are included in the present invention.
  • the compound [I] of the present invention and the intermediate ⁇ of the present invention have a benzylidene group and thus have a Z-form and an E-form.
  • the present invention includes all of them.
  • the present inventors have reported that a 1,4-monobenzothiazine derivative having a benzylidene group introduced at the 2-position and an oxo group introduced at the 3-position has a lipid peroxide production-suppressing action (Japanese Patent Application Laid-Open No. Hei 12-287007). Based on 7), a study was conducted to solve the above-mentioned problems by using 1,4-benzothiazine as the skeleton.
  • a benzylidene group is substituted by a benzylidene group, and the phenyl ring of the benzylidene group has at least one hydroxy group and one lower alkyl group.
  • compounds used as pharmaceuticals include carbohydrates for the purpose of prodrugation for the purpose of promoting absorption in the living body and improving sustainability, and stabilizing the formulation. Techniques such as esterification of acids and protection of hydroxy groups with appropriate protecting groups are widely used, and techniques for using these derivatives as production means, that is, synthetic intermediates are also commonly used. Have been.
  • the hydroxy group may be protected with a protecting group that is widely used as a protecting group for the hydroxy group, and the carboxyl group of the carboxyalkyl group is a general-purpose derivative of carboxylic acid. It may be converted to a certain ester or amide form. .
  • the structural features of the compound of the present invention [1] are as described above. Among them, preferred examples of the substituent of the benzyl ring of the benzylidene group are described, and the hydroxy group is preferably located at the 4-position.
  • a lower alkyl group is substituted at a position adjacent to the hydroxy group. That is, the lower alkyl group Compounds substituted at both the 3- and 5-positions are preferred.
  • a tert.-butyl group is a more preferable example.
  • the intermediate [II] of the present invention which is a stage before the introduction of the carboxyalkyl group into the compound [1] of the present invention, is a novel substance particularly useful as an intermediate for the synthesis of the compound [I] of the present invention.
  • the compound of the present invention was found to have an inhibitory activity on aldose reductase as a result of an experiment conducted according to the literature by Kato et al. (Chem. Pharm. Bui I., 11 (1) 74-83 (1985)). I'm sorry. This finding further supports that 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 [I] of the present invention can be administered orally or parenterally.
  • the dosage form include tablets, capsules, granules, powders, injections, eye drops and the like, and can be formulated using widely used techniques.
  • bulking agents such as lactose, crystalline cellulose, starch, etc.
  • lubricants such as magnesium stearate, talc, hydroxypropyl pilsenolerose, polyvinylpyrrole Binders such as lidon, carboxymethylcellulose calcium
  • a disintegrating agent such as low-substituted hydroxypropylmethylcellulose and a coating agent such as hydroxypropylmethylcellulose, macrogol, and silicon resin may be added as needed.
  • isotonic agents such as sodium chloride, chlorinated potassium and concentrated glycerin, and buffering agents such as sodium phosphate, boric acid, and monoamine amide.
  • Stabilizers such as edetate sodium, preservatives such as benzalkonium chloride and paraoxybenzoate, polysorbate 80, surfactants such as polyoxyethylene hydrogenated castor oil, diluted hydrochloric acid, and hydroxylated A pH adjuster such as sodium may be added as needed.
  • the dose of the compound [I] of the present invention can be appropriately selected depending on the symptom, age, dosage form, and the like.
  • it is usually 0.1 to 500 mg / day, preferably 1 to 100 mg / day. mg may be administered once or in several divided doses.
  • a concentration of 0.001% to 10%, preferably a concentration of 0.1% to 3% may be instilled once or several times a day.
  • Compound [I] of the present invention 0 1 g Concentrated glycerin 20 g Polyoxyethylene hydrogenated castor oil 08 g Benzalkonidum chloride 0.055 g Sodium edetate 0.01 g Dilute hydrochloric acid.
  • bovine serum alpinin (Sigma) was dissolved in 0.2 M phosphate buffer (pH 5.3) to a concentration of 0.75%. .
  • 0.2 M phosphate buffer pH 5.3
  • To this albumin solution add 0.3 ml of a dimethyl sulfoxide solution in which the test compound is dissolved in 2.7 ml. After the addition and stirring, the mixture was 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 heat aggregation was measured at a wavelength of 660 nm, and the protein stabilizing effect of the test compound was determined using the following equation. .
  • compound 3-1 and compound 9-1 clearly inhibited the thermal aggregation of protein, and showed an excellent protein stabilizing effect of 98 % or more at a concentration of 10-4 M. .
  • 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 was analyzed by TBA method (Biochem. Med. , J_ 5, 212 (1976)). . (Result)
  • Compound 3-1 and Compound 9-1 showed an excellent lipid peroxide production inhibitory effect with an inhibition rate of 9.9 % or more at a concentration of 10 _DM .
  • compound [I] of the present invention has a protein stabilizing effect and an inhibitory effect on lipid peroxide production, and is expected to be an excellent therapeutic agent for cataract. .
  • Industrial applicability
  • the compound [I] of the present invention has a protein stabilizing effect and a lipid peroxide production suppressing effect, and is expected to be an excellent therapeutic agent for cataract.

Abstract

L'invention concerne un composé représenté par la formule générale (I) ou un sel de ce dernier, et un intermédiaire pour le synthétiser, formule dans laquelle R1 représente de l'hydroxy éventuellement protégé; R2 représente de l'alkyle inférieur; R3 représente de l'hydrogène, de l'alkyle inférieur, de l'hydroxy éventuellement protégé ou de l'alcoxy inférieur, le groupe alkyle inférieur peut être substitué par un hydroxy, un amino ou un alkylamino éventuellement protégés; R4 représente du carboxyle qui peut avoir la forme d'un ester ou d'um amide; A représente de l'alkylène; et B représente du -CH¿2?- ou >C=S. Ce composé a pour activité de stabiliser les protéines et d'inhiber la formation du peroxyde lipidique, et est très prometteur pour soigner la cataracte.
PCT/JP1994/001907 1993-11-12 1994-11-10 Derive de 1,4-benzothiazine WO1995013269A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP5/283684 1993-11-12
JP5283684A JP2840807B2 (ja) 1993-11-12 1993-11-12 ３，４−ジヒドロ−１，４−ベンゾチアジン誘導体
JP5283685A JP2840808B2 (ja) 1993-11-12 1993-11-12 ３−チオキソ−１，４−ベンゾチアジン誘導体
JP5/283685 1993-11-12

Publications (1)

Publication Number Publication Date
WO1995013269A1 true WO1995013269A1 (fr) 1995-05-18

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PCT/JP1994/001907 WO1995013269A1 (fr) 1993-11-12 1994-11-10 Derive de 1,4-benzothiazine

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WO (1) WO1995013269A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075139A2 (fr) * 1999-06-03 2000-12-14 Basf Aktiengesellschaft Composes de benzothiazinone et de benzoxazinone

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
JPH01287077A (ja) * 1988-05-14 1989-11-17 Santen Pharmaceut Co Ltd ３−オキソ−１，４−ベンゾチアジン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
JPH01287077A (ja) * 1988-05-14 1989-11-17 Santen Pharmaceut Co Ltd ３−オキソ−１，４−ベンゾチアジン誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CURRENT EYE RESEARCH, Vol. 5, No. 1, 1986, N. NISHIGORI et al., pages 37-40. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075139A2 (fr) * 1999-06-03 2000-12-14 Basf Aktiengesellschaft Composes de benzothiazinone et de benzoxazinone
WO2000075139A3 (fr) * 1999-06-03 2001-03-29 Basf Ag Composes de benzothiazinone et de benzoxazinone
US7049312B1 (en) 1999-06-03 2006-05-23 Abbott Gmbh & Co. Kg Benzothiazinone and benzoxazinone compounds

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