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WO1986006070A1 - Derives de 1,4-benzothiazine - Google Patents

Derives de 1,4-benzothiazine Download PDF

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Publication number
WO1986006070A1
WO1986006070A1 PCT/JP1985/000204 JP8500204W WO8606070A1 WO 1986006070 A1 WO1986006070 A1 WO 1986006070A1 JP 8500204 W JP8500204 W JP 8500204W WO 8606070 A1 WO8606070 A1 WO 8606070A1
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WO
WIPO (PCT)
Prior art keywords
benzothiazine
reaction
methanol
water
crystals
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1985/000204
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English (en)
Japanese (ja)
Inventor
Kanji Meguro
Kohei Nishikawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
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/JP1985/000204 priority Critical patent/WO1986006070A1/fr
Priority to EP85308509A priority patent/EP0186310A1/fr
Priority to HU854537A priority patent/HUT41753A/hu
Priority to US06/803,217 priority patent/US4640916A/en
Priority to KR1019850008870A priority patent/KR860004057A/ko
Priority to CN85108607A priority patent/CN1006382B/zh
Publication of WO1986006070A1 publication Critical patent/WO1986006070A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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 a novel 1.4-benzothiazine derivative having excellent pharmacological activity.
  • Japanese Patent Application Laid-Open No. 59-14871 discloses a compound having a substituted furyl group at the 2-position has a platelet aggregation inhibitory action and a calcium antagonistic action. The ability to show the action. Also, see Japanese Patent Application Laid-Open No. 59-170,081.
  • the present invention relates to novel 1.4-benzothiazine derivatives having excellent pharmacological activity. More specifically, the present invention has a strong blood pressure lowering action, a vasodilator action, etc.
  • 11 1, 1 2, 11 3 Oyobi 11 4 Do or different and each is hydrogen, halogen.
  • R 5 is hydrogen or lower alkyl
  • A represents an alkylene group, respectively]
  • the substituents may be the same or different, and may be substituted at any position on the benzene ring.
  • halogen includes fluorine, chlorine, bromine and iodine, and fluorine or chlorine is particularly preferred.
  • R 3 and R 4 are halogen, particularly fluorine, at least one of them is preferably substituted at the 4-position of the benzene ring.
  • the lower alkyl group is preferably one having 1 to 3 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, t-butyl, etc., particularly preferably 1 to 3 carbon atoms. .
  • the lower alkyl group RR 2 are adjacent, and ⁇ another, for example trimethylene, tetramethylene, may form a 5-7 membered ring such as Pentame styrene.
  • the lower alkoxy group is preferably one having 1 to 3 carbon atoms, such as methoxy, ethoxyquin, propoxy and isopropoxy.
  • R 1 and R 2 when R 1 and R 2 are adjacent to each other, they may be connected to each other to form a 5- to 6-membered ring such as methylenedioxy, ethylenedioxy and the like.
  • the lower alkyl group represented by R 5 are those having 1 to 4 carbon atoms described above Among them, those having 1 to 3 carbon atoms are particularly preferable.
  • the alkylene group represented by A is preferably a linear or branched alkylene group having 1 to 4 carbon atoms.
  • methylene, methylmethylene, ethylene, propylene, / trimethylene, 1-methyltrimethylene, 2-methyltomethylene examples include remethylene, tetra / tin, and styrene.
  • ethylene having 2 to 3 carbon atoms, trimethylene i is preferred.
  • the compound of the present invention represented by the general formula (I) is, for example,
  • examples of the leaving group represented by X include halogen (eg, chlorine, bromine, iodine, etc.), alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy, etc.), a Examples include arylsulfonyloxy groups (eg, phenylsulfonyloxy, tolylsulfonyloxy, etc.).
  • This reaction is carried out by reacting compound ( ⁇ ) with compound (DO.
  • This reaction is carried out by ripening in a solvent inert to the reaction, or directly by using ( ⁇ ) and ( ⁇ ) without a solvent.
  • the reaction temperature is in each case about 60 ° C.
  • a solvent examples include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, 2-methoxethanol, ethers such as dioxane, tetrahydrofuran, and dimethoxyethane, benzene, toluene, and the like.
  • Aromatic hydrocarbons such as xylene, ethyl acetate, acetonitrile, pyridine, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide, etc., or a mixture of these solvents
  • an appropriate deoxidizing agent for example, sodium carbonate, potassium carbonate, triethylamine, etc.
  • the reaction can proceed smoothly by adding an excess amount of ( ⁇ ) and using it as a deoxidizing agent.
  • the amount of ( ⁇ ) used is usually 1 to 3 mol per 1 mol of ( ⁇ ).
  • the amount of the deoxidizing agent used is preferably about 1 to 3 mol per mol of ( ⁇ ).
  • Compound (I) in which R 5 is lower alkyl can also be produced by alkylation of compound (I) in which R 5 is hydrogen.
  • This alkylation reaction is carried out by reacting an alkylating agent in an organic solvent in the presence of a base.
  • the solvent varies depending on the type of base used. Examples of the solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and getyl ether, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide, and dimethyl. Sulfoxide or the like can be used as appropriate.
  • Bases include, for example, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, lithium hydride, sodium amide, and the like.
  • Alkylation agents include, for example, alkyl halide (eg, Chloride, bromide, chloride, etc.), dialkyl sulfate, alkylsulfonate (eg, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.) Used.
  • the reaction temperature is generally about -10 ° C to about 100 ° C, preferably about 0 ° C to about 40 ° C. .
  • the 1,4-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, and fumarate.
  • Organic salts such as oxalate, maleate and tartrate, and sulfonates such as methanesulfonate, benzenesulfonate and toluenesulfonate. .
  • the 1,4-benzothiazine derivative (I) and its salts produced as described above are novel compounds, and have strong vascular effects in mammals (eg, rats, rabbits, dogs, cats, humans, etc.). It has a diastolic action, an adrenaline receptor blocking action, a blood pressure lowering action based on intracellular calcium antagonism, and a cerebral circulation improving action. In particular, the compound of the present invention exhibits an intracellular calcium antagonism.
  • C a ++ calcium ion
  • this C a ++ includes 1) those that have flowed into cells via so-called C ++ channels, 2 ) Those released from the intracellular Ca ++ storage site, and 3) those that flowed into the cell via receptor-dependent channels.
  • Ca ++ channel inhibitors such as difujipine, have little effect on 2) and 3).
  • Compounds such as trifluoperazine, ⁇ MB-8 and W-7 have been known as compounds that act on 2) to exhibit intracellular Ca ++ antagonism.
  • the compounds of the invention having significant intracellular C a ++ antagonism 1), 2) and 3) in order to suppress the contractile response of any case of a wide region than C a ++ channel inhibitor It has pharmacological effects and is expected to be applied as a drug for asthma, etc., because it exhibits a vasoconstriction inhibitory effect as well as a tracheal muscle contraction inhibitory effect.
  • the compounds of the present invention are low-toxic and have few side effects such as orthostatic hypotension, which is often found in ⁇ -receptor blockers represented by brazosin, and are particularly useful for hypertension, cerebral circulation disorders (cerebral infarction, It is highly useful as a prophylactic and therapeutic agent for such as ischemic stroke.
  • 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 powders, granules, coagulants, capsules, injections, etc. It can be administered orally or parenterally in the form of The dose varies depending on the route of administration, symptoms, age and weight of the patient.
  • 0.05 to 1 O mgZK g body weight per day preferably 0.1 ⁇ 50 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the starting compound (H) of the present invention can be produced, for example, as follows.
  • Y represents a halogen
  • R 6 and R 7 represent a hydrogen or a lower alkyl group
  • B represents a bond or an alkylene group
  • other symbols have the same meanings as described above.
  • the lower alkyl groups represented by R S and R 7 include the same ones having 1 to 4 carbon atoms as represented by R i to R 5.
  • Examples of the halogen represented by the general formulas (V) and (VI) include chlorine, bromine and iodine.
  • B in the general formula (VI) is a bond 1
  • the 2-position and the C 0 OR 7 4-Ben Zochiajin are directly connected, also has B is Al Killen group, such alkylene Is limited to those having one less carbon atom than A and one B—CH 2 — and —A— being equal. The outline of each method is described below.
  • the reaction can be performed at 100 ° C.
  • a solvent examples include alkanols such as methanol, ethanol, propanol, and 2-propanol; and ethers such as tetrahydrofuran, dioxane, and dimethoxetane. , Acetonitrile, N, N-dimethylformamide and the like.
  • (VE) is produced by reacting () and (70), and then this is halogenated or sulfonylated to produce ( ⁇ ⁇ ).
  • the reaction between (ff) and (3 ⁇ 4) is carried out by the above (EO)
  • the halogenating agent used for the halogenation of compound (VI) is, for example, thionyl chloride, oxychlorine, or phosphorus tribromide, or sulfonyl.
  • the sulfonylating agent used for the conversion include methanesulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyl chloride, etc.
  • the halogenation reaction of (VII) is usually carried out in an appropriate solvent for about 1 hour.
  • the reaction is carried out at 5 ° C. to about 100 ° C.
  • examples of such a solvent include dichloromethane, chloroform, benzene, toluene, etc.
  • the reaction between (VI) and the sulfonylating agent is also carried out. It can be carried out under the same reaction conditions as halogenated but triethylamine down if necessary, may be advantageous when carried out in the presence of a base such as pyridine.
  • (VI) is first reduced to produce ( ⁇ ), which is then reacted with a halogenating agent or a sulfonylating agent to produce ( ⁇ ) in the same manner as in method ⁇ .
  • Reduction of compound (VI) can be carried out with sodium borohydride or lithium hydride.
  • a solvent such as methanol or ethanol
  • a solvent such as ethyl ether or tetrahydrofuran.
  • ° C which is the substance used in this method () Can be synthesized, for example, according to the following reaction.
  • reaction between (R and (DO) is carried out in the same manner as the reaction between () and (V) to give (3 ⁇ 4).
  • (X) is reacted with sodium cyanide to give (XI)
  • (VI) can be obtained by hydrolyzing the compound and, if necessary, esterifying it.
  • (X) can be reacted with sodium cyanide by a suitable solvent (eg, methanol, ethanol, ⁇ ⁇ ⁇ ⁇ , ⁇ —Can be carried out at about 0 ° C (: up to 100 ° C) in dimethylformamide, dimethyl sulfoxide, etc.
  • the hydrolysis reaction of (a) can be performed with mineral acids (eg, hydrochloric acid, hydrobromic acid, Using sulfuric acid, etc.
  • Spontaneously hypertensive rats and rats (male, 12 to 13 weeks old, blood pressure before drug administration, approximately 200 mmHg) were used as a group of 3 animals.
  • the tail artery pressure was measured by the tail-cuff method, and then 10 to 6011 ⁇ / 1 ⁇ of the compound of the present invention was orally administered as a 21111 aqueous solution of Arabia gum suspension.
  • blood pressure was measured again to examine the difference from the value before administration (hypertensive effect, AmmHg). Table 3 shows the results.
  • Example 1 3-Promopropyl) -1,6,7-dimethyl-2H-1,4, -benzothiazine-1 (4H) -one 62,8 mg and 1- (4-fluorophenyl) pyrazine 7 After dissolving 2 mg in 1 Oml of ethyl sulphate and concentrating, the residue was stirred at 110 ° C for 1 hour. Water was added to the reaction product, which was extracted with ethyl ether.
  • Example 1 2 After dissolving 3.0 g of 2- (3-bromopropyl) -1 5-methyl-2H-1, 4-benzothiazin-3- (4H) -one and 3.6 g of L- (4-fluorophenyl) piperazine in ethyl acetate, the mixture is concentrated. The residue was stirred at 110 ° C for 1 hour. 5 Oml of water and 100 ml of ethyl ethylate were added to the reaction and partitioned. The ethyl shachiol layer was separated, washed with water, dried (MgS C), concentrated, and the crude product obtained was subjected to column chromatography using silica gel (10 Og) to give hexane-ethyl acetate.
  • Benzothiazin-7 (8H) -one was prepared in the same manner as in Example 12; 6- ⁇ 3- [4- (4-fluorophenyl) -1-piperazinyl] propyl ⁇ -1 6H-1, 3-dioxolo [4,5-g], 4] benzothiazine-1 by reacting with 1-fluorophenyl) piperazine (8H) -one 'dihydrochloride was obtained. Yield 64.8%.
  • nip 1 75—1 7 7 ° C (recrystallized from methanol in single-mouthed form)
  • the compound (I) of the present invention when used as an antihypertensive, it can be used, for example, according to the following formulation.
  • (1), (2) and 17 g of (3) are mixed and granulated together with the paste made from 7 g of (3), 5 g of (3) and (4) are added thereto, and the mixture is compressed into tablets.
  • the tablets are compressed to give 100 tablets each containing 5 mg of (1).
  • 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)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

Des dérivés de 1,4-benzothiazine sont représentés par la formule (I), dans laquelle R1, R2, R3 et R4, qui peuvent être identiques ou différents, représentent l'hydrogène, l'halogène, l'alcoyle inférieur, l'alkoxy inférieur ou le trifluorométhyle, R5 représente l'hydrogène ou l'alcoyle inférieur, et A représente l'alcoylidène. Ces dérivés sont utiles comme agents prophylactiques et thérapeutiques de l'hypertension, des troubles de la circulation dans le cerveau, etc.
PCT/JP1985/000204 1984-11-28 1985-04-16 Derives de 1,4-benzothiazine Ceased WO1986006070A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PCT/JP1985/000204 WO1986006070A1 (fr) 1985-04-16 1985-04-16 Derives de 1,4-benzothiazine
EP85308509A EP0186310A1 (fr) 1984-11-28 1985-11-22 Dérivés de 1,4-benzothiazine, leurs préparation et application
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
KR1019850008870A KR860004057A (ko) 1984-11-28 1985-11-27 1,4-벤조티아진 유도체의 제조방법
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/JP1985/000204 WO1986006070A1 (fr) 1985-04-16 1985-04-16 Derives de 1,4-benzothiazine

Publications (1)

Publication Number Publication Date
WO1986006070A1 true WO1986006070A1 (fr) 1986-10-23

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Application Number Title Priority Date Filing Date
PCT/JP1985/000204 Ceased WO1986006070A1 (fr) 1984-11-28 1985-04-16 Derives de 1,4-benzothiazine

Country Status (1)

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WO (1) WO1986006070A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3622572A (en) * 1969-04-01 1971-11-23 Squibb & Sons Inc Process for producing morpholinoalkyl benzothiazinones and related compounds
JPS5651465A (en) * 1979-10-02 1981-05-09 Yoshitomi Pharmaceut Ind Ltd Benzothiazine derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3622572A (en) * 1969-04-01 1971-11-23 Squibb & Sons Inc Process for producing morpholinoalkyl benzothiazinones and related compounds
JPS5651465A (en) * 1979-10-02 1981-05-09 Yoshitomi Pharmaceut Ind Ltd Benzothiazine derivative

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