WO1986003200A1 - Derives de 1,4-benzothiazine - Google Patents

Derives de 1,4-benzothiazine Download PDF

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Publication number
WO1986003200A1
WO1986003200A1 PCT/JP1984/000566 JP8400566W WO8603200A1 WO 1986003200 A1 WO1986003200 A1 WO 1986003200A1 JP 8400566 W JP8400566 W JP 8400566W WO 8603200 A1 WO8603200 A1 WO 8603200A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzothiazine
methanol
ethyl acetate
reaction
crystals
Prior art date
Application number
PCT/JP1984/000566
Other languages
English (en)
Japanese (ja)
Inventor
Kanji Meguro
Kohei Nishikawa
Original Assignee
Takeda Chemical Industries, 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
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1984/000566 priority Critical patent/WO1986003200A1/fr
Priority to EP85308509A priority patent/EP0186310A1/fr
Priority to JP60262738A priority patent/JPS61137871A/ja
Priority to KR1019850008870A priority patent/KR860004057A/ko
Priority to HU854537A priority patent/HUT41753A/hu
Priority to US06/803,217 priority patent/US4640916A/en
Priority to CN85108607A priority patent/CN1006382B/zh
Publication of WO1986003200A1 publication Critical patent/WO1986003200A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • 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 novel 1,4-benzothiazine derivatives having excellent pharmacological activity
  • Japanese Patent Laid-Open No. 59-148 771 discloses
  • the present invention relates to novel 1,4-benzothiazine derivatives having excellent pharmacological activity
  • the present invention provides a powerful blood pressure lowering effect and a vasodilating effect.
  • RR 2 , R 3 and R + are the same or different and are hydrogen hydrogen, lower alkyl group, lower alkoxy group or trifluoromethyl group, R 5 is hydrogen or lower alkyl group, A is alkylene
  • R 5 is hydrogen or lower alkyl group
  • A is alkylene
  • the substituents represented by R 1 , R 2 , R 3 and R + may be the same or different, and may be substituted at any position of the benzene ring.
  • examples of the halogen include fluorine, chlorine, bromine, and iodine, and fluorine or chlorine is particularly preferable.
  • R 3 and R 4 are ⁇ -gen, especially fluorene, it is preferable that at least one of them is substituted at the 4-position of the benzene ring.
  • R L and R 2 are adjacent lower alkyl groups, they may be mutually bonded to form a 5- or 6-membered ring such as trimethylene and tetramethylene.
  • the lower alkoxy group those having 1 to 3 carbon atoms are preferable, and examples thereof include methoxy, ethoxy, sigma-oxy, and isopropoxy.
  • R 1 and R 2 when R 1 and R 2 are adjacent to each other, they may be mutually connected to form a 5- or 6-membered ring such as methylenedioxy, ethylenedioxy and the like.
  • the lower alkyl group shown by R 5 or those having 1 to 4 carbon atoms described above Among them, those having 1 to 3 carbon atoms are particularly preferable.
  • alkylene group represented by A a linear or branched alkylene group having 1 to 4 carbon atoms is preferable.
  • trimethylene are preferred.
  • the compound of the present invention represented by the general formula (e) is, for example,
  • examples of the leaving group represented by X include halogen (eg, salt
  • alkylsulfonyloxy group eg, methylsulfonyloxy, ethylsulfonyloxy, etc.
  • arylsulfonyloxy group eg, phenylsulfonyloxy, trisulfonyloxy, etc.
  • This reaction is carried out by reacting compound (III) with compound).
  • This reaction can be carried out by ripening in a solvent inert to the reaction, or by directly heating a mixture of ( ⁇ ) and ( ⁇ ) without a solvent.
  • the temperature is in each case from about 60 ° C to about 200 ° C, more preferably from about 80 ° C to about 150 ° C.
  • a solvent include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, 2-methoxethanol, ethers such as dioxane, tetrahydrofuran, and dimethoxyethane, benzene, toluene, and the like.
  • examples include aromatic hydrocarbons such as xylene, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethylsulfoxide, and the like, and a mixed solvent thereof.
  • reaction an acid originating from the leaving group X is generated, and therefore, the reaction can be carried out in the presence of an appropriate deoxidizing agent, for example, sodium carbonate, carbon dioxide, triethylamine, etc.
  • an appropriate deoxidizing agent for example, sodium carbonate, carbon dioxide, triethylamine, etc.
  • the reaction can be allowed to proceed smoothly by using this as a deoxidizing agent.
  • the amount of (m) used is usually ⁇ ⁇ 3 moles per mole of DO, and the amount of deoxidizer used is
  • This alkylation reaction is carried out by anti-IS reaction of an alkylating agent in an organic solvent in the presence of a base.
  • a solvent although it depends on the type of base used, for example, alcohols such as methanol and ethanol, ethers such as tetrahydro sigma furan, dioxane, dimethoxyethane, and getyl ether, ⁇ , —dimethylformami De.dimethylsulfoxide or the like can be used as appropriate.
  • an alkyl halide eg, chloride, Bromides, chlorides, etc.
  • dialkyl sulfates alkyl sulfonates (clear, methanesulfonate, ethanesulfonate, benzene)
  • O PI Zensulfonate, toluenesulfonate, etc. are used.
  • the compound I R 5 is hydrogen
  • the reaction temperature is usually about 110 to about 100, preferably about 0 to about 40.
  • the benzothiazine derivative (I) can be converted to an acid addition salt if necessary.
  • salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, oxalate, malonate, succinate, malate, fumaric acid. Salts, organic acid salts such as maleate and tartrate, and sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate.
  • 1,4-Benzothiazine derivative (I) and its salt which are produced as described above, are novel compounds that are potent in mammals (eg, rats, rabbits, dogs, cats, humans, etc.). It has a vasodilator action, an adrenaline receptor blocking action, a blood pressure lowering action based on intracellular calcium antagonism, and a cerebral circulation improving action.
  • the compound of the present invention is a major feature to exhibit intracellular calcium antagonism.
  • Calcium ion (C a ++ ) is required for contraction of smooth muscle, but this C a ++ is 1) what has flowed into the cell through the so-called C ++ channel. , 2) those released from intracellular Ca ++ storage sites and 3) those that flowed into cells via receptor-dependent channels.
  • C a ++ channel inhibitors such as diphedipine have little effect on 2) and 3). 2) acts on intracellular
  • the compounds of the invention having significant intracellular C a ++ antagonism 1), 2) and 3 to be suppressed contractile response in the case of any), medicine wider area than C a ++ channel inhibitor It is expected to be applied as a therapeutic agent for asthma, etc., as it exhibits a physiologic effect and suppresses vasoconstriction as well as tracheal muscle contraction.
  • the compound of the present invention is low-toxic and has few side effects such as orthostatic hypotension often seen with ⁇ -receptor blockers represented by brazosin. Therefore, especially hypertension, cerebral circulation disorder (cerebral infarction, It is highly useful for the prevention and treatment of transient cerebral ischemia attacks, etc.).
  • compound (I) or a salt thereof When compound (I) or a salt thereof is used as the above drug, it is mixed with an appropriate pharmaceutically acceptable carrier, excipient, diluent, and then mixed with powders, granules, tablets, capsules, injections, etc. It can be administered orally or parenterally in the form.
  • the dose varies depending on the route of administration, symptoms, age and weight of the patient, but for example, when administered orally to an adult hypertensive patient, 0.0 ⁇ to 10 mgZK g body weight per day, It is preferable to administer 0.1 to 5 mg / Kg body weight / day once to several times a day.
  • the starting compound ( ⁇ ) of the present invention can be produced, for example, as follows.
  • Y is halogen
  • R s , R 7 hydrogen or a lower alkyl group
  • B is a bond or an alkylene group
  • the lower alkyl groups represented by R s and R 7 in the above general formulas (V) and VI) 1) include those having 1 to 4 carbon atoms similar to those represented by R i R 5 .
  • the hagen represented by Y is, for example, chlorine, bromine or iodine.
  • beta is a bond 1, 4 2-position one benzothiazine and the C 00 R 7 are directly connected
  • beta is an alkylene group, such alkylene ⁇ It is limited to the case where the number of carbon atoms is less than 1 and one B—CH 2 — and —A— are equal. The outline of each method is described below.
  • ( ⁇ ) can be obtained at once by reacting compound (17) with compound (V).
  • This reaction is usually carried out in an appropriate solvent at about 0 ° C to about The reaction can be carried out at 100 ° C.
  • a solvent include alkanols such as methanol, ethanol, propanol and 2-propanol, ethers such as tetrahydrofuran, dioxane and dimethoxyethane, and acetonitrile. , ⁇ , ⁇ -dimethylformamide and the like.
  • (VI) is reacted with (VI) to produce (VI), and then this is halogenated or sulfonylated to produce (III).
  • the reaction of R with (“VI) can be carried out in exactly the same manner as the reaction between () and (V).
  • the halogenating agent used for the halogenation of compound (VI) may be thionyl chloride.
  • Examples of the sulfonylating agent used for sulfonylation include methanesulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyl chloride.
  • (VI) halogenation reaction is usually suitable solvent about i 5 3 Celsius to about 1 0 0.
  • (W) is first produced by reducing (II), and this is reacted with a halogenating agent or a sulfonylating agent as in Method B to produce (H).
  • the reduction of compound (II) can be carried out with, for example, sodium borohydride or lithium hydride.
  • a solvent such as ethyl ether and tetrahydrofuran is used. 0 to about 100.
  • GD can be synthesized according to the following reaction, for example.
  • reaction between (iy) and (IX) is carried out in the same manner as the reaction between ( ⁇ ') and (V) to give (1).
  • (VI) can be obtained by reacting (X) with sodium cyanide to form (XI), hydrolyzing it, and, if necessary, further forming it into a stele.
  • the reaction between (X) and sodium cyanide is carried out in an appropriate solvent (eg, methanol, ethanol, X, —dimethylformamide, dimethyl sulfoxide, etc.) at about 0 to 10 ° C. can be done with c.
  • the hydrolysis reaction of (a) uses a mineral acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or an alkaline solvent (eg, sodium hydroxide, potassium hydroxide, etc.) and an appropriate solvent (eg, methanol, Ethanol, 2-methoxyethanol, etc.) at about 60 to about 120 ° C.
  • a mineral acid eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • an alkaline solvent eg, sodium hydroxide, potassium hydroxide, etc.
  • an appropriate solvent eg, methanol, Ethanol, 2-methoxyethanol, etc.
  • the Henseleit solution was suspended under a load of 2 g.
  • the solution 9 7% 0 2 - warmed to 3% C 0 2 mixed gas was saturated with 3 7 ° C.
  • Intracellular C a ++ by shrinkage reaction also, Ca ++ Omm and EGTA [delta] containing ⁇ Krebs- Henseleit off before being added instead of the solution after 5 minutes
  • We two Refuri emissions (1 0 - S M) by Osamu Shrinkage was used as an index. The suppression rate after addition of the compound of the present invention to this shrinkage was determined.
  • Spontaneously hypertensive rats male, 12 to i 3-week old, blood pressure before drug administration, about 200 2Hg
  • mice Male, 12 to i 3-week old, blood pressure before drug administration, about 200 2Hg
  • mice were used as 3 animals per group.
  • the tail artery pressure was measured by the tail-cuff method, and then 10 to 60 gZKg of the compound of the present invention was orally administered as a 2 ml aqueous gum arabic suspension.
  • One hour after the administration the blood pressure was measured again, and the difference from the value before administration (AmmHg) was examined. Table 3 shows the results.
  • the compound (I) of the present invention when used as an antihypertensive, it can be used, for example, according to the following formulation.
  • Min f loaf value C 49.84; H 4.97; X 4.75
  • novel 1,4-benzothiazine derivatives of the present invention have excellent pharmacological activity and are useful as pharmaceuticals and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (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)

Abstract

Dérivés de 1,4-benzothiazine représentés par la formule générale (I), où R1, R2, R3 et R4 peuvent être identiques ou différents et représentent chacun hydrogène, halogène, alkyle inférieur, alkoxy inférieur ou trifluorométhyle, R5 représente hydrogène ou alkyle inférieur et A représente alkylène. Ces composés ainsi que leurs sels d'addition d'acide sont utiles dans la prophylaxie et le traitement de l'hypertension, des troubles circulatoires du cerveau, etc.
PCT/JP1984/000566 1984-11-28 1984-11-28 Derives de 1,4-benzothiazine WO1986003200A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PCT/JP1984/000566 WO1986003200A1 (fr) 1984-11-28 1984-11-28 Derives de 1,4-benzothiazine
EP85308509A EP0186310A1 (fr) 1984-11-28 1985-11-22 Dérivés de 1,4-benzothiazine, leurs préparation et application
JP60262738A JPS61137871A (ja) 1984-11-28 1985-11-22 １，４‐ベンゾチアジン誘導体，その製造法および用途
KR1019850008870A KR860004057A (ko) 1984-11-28 1985-11-27 1,4-벤조티아진 유도체의 제조방법
HU854537A HUT41753A (en) 1984-11-28 1985-11-27 Process for producing 1,4-benzothiazine derivatives and pharmaceutical compositions containing them
US06/803,217 US4640916A (en) 1984-11-28 1985-11-27 1,4-benzothiazine derivatives, compositions containing them and method of use
CN85108607A CN1006382B (zh) 1984-11-28 1985-11-28 1，4-苯并噻嗪衍生物的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1984/000566 WO1986003200A1 (fr) 1984-11-28 1984-11-28 Derives de 1,4-benzothiazine

Publications (1)

Publication Number Publication Date
WO1986003200A1 true WO1986003200A1 (fr) 1986-06-05

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1984/000566 WO1986003200A1 (fr) 1984-11-28 1984-11-28 Derives de 1,4-benzothiazine

Country Status (2)

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JP (1) JPS61137871A (fr)
WO (1) WO1986003200A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2552394Y2 (ja) * 1992-11-30 1997-10-29 株式会社島津製作所 ペプチドフラグメント分取装置

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3471481A (en) * 1966-03-28 1969-10-07 Squibb & Sons Inc Benzothiazines
JPS5093981A (fr) * 1973-12-13 1975-07-26
US4078062A (en) * 1976-10-28 1978-03-07 E. R. Squibb & Sons, Inc. Substituted 2H-1,4-benzothiazin-3(4H)-ones
JPS5651465A (en) * 1979-10-02 1981-05-09 Yoshitomi Pharmaceut Ind Ltd Benzothiazine derivative
JPS5970675A (ja) * 1982-10-15 1984-04-21 Otsuka Pharmaceut Co Ltd ベンゾオキサジン誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3471481A (en) * 1966-03-28 1969-10-07 Squibb & Sons Inc Benzothiazines
JPS5093981A (fr) * 1973-12-13 1975-07-26
US4078062A (en) * 1976-10-28 1978-03-07 E. R. Squibb & Sons, Inc. Substituted 2H-1,4-benzothiazin-3(4H)-ones
JPS5651465A (en) * 1979-10-02 1981-05-09 Yoshitomi Pharmaceut Ind Ltd Benzothiazine derivative
JPS5970675A (ja) * 1982-10-15 1984-04-21 Otsuka Pharmaceut Co Ltd ベンゾオキサジン誘導体

Also Published As

Publication number Publication date
JPS61137871A (ja) 1986-06-25

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