WO1986003200A1

WO1986003200A1 - 1,4-benzothiazine derivatives

Info

Publication number: WO1986003200A1
Application number: PCT/JP1984/000566
Authority: WO
Inventors: Kanji Meguro; Kohei Nishikawa
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1984-11-28
Filing date: 1984-11-28
Publication date: 1986-06-05
Also published as: JPS61137871A

Abstract

1,4-Benzothiazine derivatives represented by the general formula: I (wherein R 1, R2, R3, and R4 may be the same or different and each represents hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl, R5 represents hydrogen or lower alkyl, and A represents alkylene) and acid addition salts thereof are useful for prophylax and treatment of hypertension, brain circulatory troubles, etc.

Description

Specification

1,4 Benzothiazine boast

Technical field

The present invention relates to novel 1,4-benzothiazine derivatives having excellent pharmacological activity

About.

Background art

3-Oxo 1, 4 Benzothiazine as main skeleton, acting on circulatory system

There are no practical drugs yet. As a compound having a pharmacological action on the inserter system, Japanese Patent Laid-Open No. 59-148 771 discloses

It has been shown that a compound having a substituted phenyl group at the 2-position exhibits a platelet aggregation inhibitory action and a calcium antagonistic action, and Japanese Patent Application Laid-Open No. 59-201781 discloses that 1 N < _{2 at the} 2-position. in group [wherein shown, RR ² compounds diuretic with may form a heterocyclic ring together with the adjacent nitrogen atom, mosquitoes to exhibit hypotensive action, have only been described respectively.

However, it has not been revealed yet for 3-oxo 1,4-benzothiazine derivatives.

Many fields of development remain, and nothing is known about compounds having a substituent at the 2-position via an alkylene group, and further having a 4-phenyl-1-piperazinyl group, and their pharmacological actions.

Disclosure of the invention

About. More specifically, the present invention provides a powerful blood pressure lowering effect and a vasodilating effect.

General formulas useful as pharmaceuticals

Ο ΡΙ WIP

[Wherein, 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 Each of the following groups:], a novel 1,4-benzothiazine derivative (I) and an acid addition salt thereof.

In the general formula (I), 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. Among such substituents, examples of the halogen include fluorine, chlorine, bromine, and iodine, and fluorine or chlorine is particularly preferable. When R ³ and R ⁴ are σ-gen, especially fluorene, it is preferable that at least one of them is substituted at the 4-position of the benzene ring. Preferred are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like. When 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. As the lower alkoxy group, those having 1 to 3 carbon atoms are preferable, and examples thereof include methoxy, ethoxy, sigma-oxy, and isopropoxy. Further, 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.

As the alkylene group represented by A, a linear or branched alkylene group having 1 to 4 carbon atoms is preferable. For example, methylene, methylmethylene, ethylene,

Ropylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethyl

Len, tetramethylene and the like. In particular, ethylene with 2-3 carbon atoms

And trimethylene are preferred.

The compound of the present invention represented by the general formula (e) is, for example,

i

R ⁵

[Wherein X is a leaving group, and other symbols': are as defined above] (Π)

And the general formula-

R ³ -to ... (I)

―-_ :. τ

In the two formulas, all symbols can be easily produced by reacting with the compound () represented by the same meaning as above.

In the general formula (Π), examples of the leaving group represented by X include halogen (eg, salt

, Bromine, iodine, etc.), alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy, etc.), arylsulfonyloxy group (eg, phenylsulfonyloxy, trisulfonyloxy, etc.) And so on.

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 (Π) and (ΠΙ) without a solvent.

OMPI The temperature is in each case from about 60 ° C to about 200 ° C, more preferably from about 80 ° C to about 150 ° C. Examples of such 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. In this 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. The reaction can be allowed to proceed smoothly by using this as a deoxidizing agent.

The amount of (m) used is usually ι ~ 3 moles per mole of DO, and the amount of deoxidizer used is

(H) 1 mol 1-3 moles preferably _ΰ

It can also be produced by alkylating a compound (I) in which R ⁵ is lower alkyl: or a compound (I) in which R ⁵ is hydrogen. This alkylation reaction is carried out by anti-IS reaction of an alkylating agent in an organic solvent in the presence of a base. As 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, Χ, —dimethylformami De.dimethylsulfoxide or the like can be used as appropriate. As the base, for example, sodium methoxide, sodium ethoxide, lithium t-butoxide, sodium hydride, lithium hydride, sodium amide, etc., and as the alkylating agent, an alkyl halide (eg, chloride, Bromides, chlorides, etc.), dialkyl sulfates, alkyl sulfonates (clear, methanesulfonate, ethanesulfonate, benzene)

O PI Zensulfonate, toluenesulfonate, etc.) are used. In this reaction, it is preferable to react the compound I (R ⁵ is hydrogen) with a base in a solvent to form an anion, and then to react with an alkylating agent. The reaction temperature is usually about 110 to about 100, preferably about 0 to about 40.

1, The benzothiazine derivative (I) can be converted to an acid addition salt if necessary. Examples of such 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. In particular, 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

Compounds such as trifluoveradine, TMB-8, and W-7 have been known to exhibit C a ⁺⁺ antagonistic activity. Ξ No effect, the former; 'Hypertensive due to side effects such as central action

O PI WIPO It has not been put to practical use as an agent or a cerebral circulation improving agent. 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. In addition, the compound of the present invention is low-toxic and has few side effects such as orthostatic hypotension often seen with α-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.).

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 δ 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 (Π) of the present invention can be produced, for example, as follows.

Method A

ヽ SH

X -A-CHC00R ⁶ (Π)

M

! Y

R ⁵ (V)

(IV)

OMPI Method B

) (W)

Halogenating agent

(Π)

Or sulfonylating agent

Method C (where one A— is represented by B—CH ₂ —)

R ¹ s, B-C00 'Reducing agent Halogenating agent

()-(H)

-,-, Or

, _R

Sulfonylating agent

R ⁵

(VI)

In the above formula, Y is halogen, R ^s , R ⁷ : hydrogen or a lower alkyl group, B is a bond or an alkylene group, and other symbols are as defined above.

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 . In the general formulas (V) and (VI), the hagen represented by Y is, for example, chlorine, bromine or iodine. In the case that if in the general formula (1) beta is a bond 1, 4 2-position one benzothiazine and the C 00 R ⁷ are directly connected, also beta is an alkylene group, such alkylene Α 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.

Method A

According to this method, (Π) 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. Examples of such a solvent include alkanols such as methanol, ethanol, propanol and 2-propanol, ethers such as tetrahydrofuran, dioxane and dimethoxyethane, and acetonitrile. , Ν, Ν-dimethylformamide and the like.

Method Β

First, (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. a (: made in, as such a solvent: or example dichloromethane, black hole ho Lum, benzene, toluene is mentioned The reaction between (W) and the sulfonylating agent can be carried out under the same reaction conditions as for the halogenation, but if necessary, it can be carried out in the presence of a base such as triethylamine or pyridine. If the interest of Raa _c

Method C

In this method, (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. For example, in the case of the former, methanol and ethanol are used, and in the case of the latter, a solvent such as ethyl ether and tetrahydrofuran is used. 0 to about 100. Raw material compounds used in this method

GD can be synthesized according to the following reaction, for example.

O PI R ⁷ 0C0-B-CHC00 ^

Υ

((VI)

(IX)

Small.

Hydrolysis

(X) (XI)

Wherein all symbols are as defined above.

The reaction between (iy) and (IX) is carried out in the same manner as the reaction between (ιν ') and (V) to give (1). Also, (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. The resulting carboxylic acid can be converted to the desired ester by esterification in a manner known per se. Can be converted. Further, when (2) is treated with hydrogen chloride or hydrogen bromide in an appropriate alcohol in the presence of a small amount of water, (1) can be obtained as an ester at once.

The results of pharmacological tests showing the efficacy of the compound (I) of the present invention are shown below. 1. Vasodilator action

ラ A spiral strip (2-3 mm wide, about 3 cm long) of the aorta of a heron was suspended under a 2 g load in a Krebs-Henseleit solution. K rebs- Henseleit solution 9 7% 0 ₂ - warmed to 3 7 ° C was saturated with 3% mixed gas of CO _2. KC 1 (6 0 mM), the present invention for the contractile response of Roh Ruepinefu Li down ^{(NE) (1 0 "e} M) or cell σ Toni emissions (5- ΗΤ) vascular strip caused by (1 0- ⁶ Μ) compound was examined inhibitory effect by pretreatment for 15 minutes of (1 0- ⁵ Micromax). formed續are shown in Table 1 as percent inhibition.

table 1

i 6 33 1 00 70

1 7 1 1 1 0 0

1 8 δ 0 1 0 0

1 9 5 δ 1 0 ο

2 1 3 2 1 0 0 δ 6

22 6 2 1 0 0 1 δ

23 4 0 1 0 ο

24 2 0 1 0 ο 66

2 5 1 0 1 0 0 84

2 6 6 0 6 0

27 2 0 1 0 0 1 00

2 8 1 5 1 0 0 1 00

29 1 0 9 6 73

3 0 4 2 9 0 1 0 0

3 1 4 0; 1 0 0 6 2

3 2 1 0 0 8 8

3 6 '. 1 0 1 0 0 1 0 0

3 8 3 0: .1 0 0

2. Intracellular Ca ⁺⁺ antagonism

を Krebs—Helical strips (2-3 mm wide, about 3 cm long) of the aorta of the heron

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 οιΜ 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.

O PI Was. Table 2 shows the results. Compound concentration suppression rate

(夹 Example o.) (Μ) (%)

1 1 0 ⁶ 6 6

1 i 1 0 - ⁸ 9 7

1 0 " ⁶ 1 0 0

1 1 0 " ⁶ 1 0 0

1 δ 1 0 " ⁶ 3 0

2 2 1 o 1 0 0

TB-8 1 o- ⁺ 5 8

3. Blood pressure lowering effect

Spontaneously hypertensive rats (male, 12 to i 3-week old, blood pressure before drug administration, about 200 2Hg) were used as 3 animals per group. First, 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.

Table 3

Compound; administration amount Blood pressure lowering effect

(Example o.) (Mg / g);-(ΔHg)

1 3 0: 3 δ

2: 3 0 4 3

0 1 0! 4 9

6 1 0: 6 4

9 '6 0 3 5 1 0 3 0 3 3

1 1 3 0 4 9

1 2 6 0 4 9

1 3 6 0 3 6

1 3 0 2 6

1 7 3 0 2 6

2 2 3 0 3 9

2 3 3 0 4 8

2 5 3 0 6 6

2 6 3 0 2 6

2 8 3 0 2 9

2 9 1 0 3 8

3 0 3 0 4 0

3 2 6 0 3 0

3 8 3 0 3 2 Best Mode for Carrying Out the Invention _-In the following examples, all melting points were measured by a thermogravimetric method and are not yet corrected.

Example 1

2- (3-buta-mo-propyl) -1,6,7-dimethyl-2Η, 1,4-benzothiazine-1 3 (4Η) -one 62,8 mg and 1- (4-fluorophenyl) piperazine After dissolving 72 lmg in 1 Oml of ethyl acetate, the residue was stirred at 110 ° C for 1 hour. Water was added to the reaction product, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (concentrated after MgS0J) to give 2- (3- [4- (4-fluorophenyl) 1-1-piperazinyl sigma). Pill) 1-6,7-dimethyl-2 2-1, 1-benzothiazine-1 3 (4Η) -one (6 δ 0 mg, 78.6%) Obtained. Recrystallized from methanol, colorless prisms.

m 16 1-16 2 ° C

I RC ujoDcm " ¹ : 3 1 9 0, 1 6 6 5

NMR δ (ppm) in CD Cl ₃ : 1.4 to 2.1 (4 H, m), 2.19 (6 H, s), 2.28 (2 H, t, J = 6), 2.43-2.6.2 (4 H, m), 3.0 0-3.1 0 (4 H, m), 3.1 (1 H, m), 6.6 3-7.0 3 (6 H, m), 8.87 (1 H, broad)

C ₂₃ H ₂ 8 F sO S

Calculated: C 66.80; H 6.82;? ί 10.16

Split value: C 67.00; Η 6.92; 10.12

Example 2—1 1

The compounds in Table 4 were obtained in the same manner as in Example 1.

Four

R ¹ , Be, / '' ^ .Π

¹ , Κ R ² purchase

Example 1 2

2- (3-bromopropyl) -1-5-methyl-2H-1,4,4-benzothiazine-1 (4H) -3.0 g and 3- (4-fluorophenyl) piperazine 3.6 g After dissolving in ethyl acetate and concentrating, the residue was stirred at 110 ° C for 1 hour. 5 O ml of water and 1Ό O ml of ethyl acetate were added to the reaction and partitioned.ェ Separate the acid ethyl layer, wash with water, dry (MgS 0 ₊ ), and concentrate. The crude product obtained is subjected to column chromatography using silica gel (100 g). 2- (3- [4- (4-fluorophenyl) -1-1-piperazinyl] propyl) -5-methyl-2Η-1,4-1, from the part eluted with ethyl hexane (1: 1, νΖν) Benzothiazin-3 (4Η) -one was obtained (2.6 g, δ δ.

1%). Recrystallized from methanol, colorless prisms.

mp 1 1 6—1 1 7. C

I RC 'iijoDcm- ¹ : 3 2 2 0, 1 6 5 5

NMR δ (ppm) in CDC 1 3:. 1 5~ 2. 1 (4 H, m), 2. 0 3 (3

H, s), 2.3 to 2.59 (6 H, m), 2.99 to 3.11 (4 H, m), 3.0 to 3.49 (1H, HI) , 6. 7 to 7.2 2 (7 H, m)

C ₂₂ H ₂ SFN ₃ 0 S

Calculated: C 66.14; H 6.56; 10.52 '

Min Xin value: C 66.17; H 6.62; 10.49

The crystals obtained above were dissolved in methanol, and a methanol solution of hydrogen chloride was added to obtain crystals of dihydrochloride. Recrystallized from methanol, colorless prism

Say

HBo

m 16 1-16 3 ° C

As _{C 22H26F 3 0 S · 2 H} C1

Calculated: C 55.93; H 5.97; ^ 8.89

Min Xin value: C 55.56; H 5.99; N 8.72

OMPI Example 1 3 — 2 4

Compounds in Table 5 were obtained in the same manner as in Example 12.

OMPI -2111, I one 18 one

Table 5

With HH-(CH ₂ ) ₃ N

H

Four

Application R R R R Melting point CC) Recrystallization solvent Yield c

Example (salt) (%)

H i 5-CH ₃ i 235-236! Metanole

(Decomposition) HCl:

a -CH ₃ [3 '-CI 204-206 methanol 53.2

2HC1 · i / 2H ₂ 0 - ether

129-130 Methanol 55.2! 2HC1

IS H i 5-CH ₃ ; H! -0CH ₃ | 168 -169 ^; methanol i 64.8;

! 2HC1

5 6

-CH: -CH ₃ i 240-242 methanol '59.2 2:

HCl

H: 5-CH ₃ i H 3 '-CH ₃ j 142-144: methanol! 65.0

2HC1 · 1 / 2H ₂ 0

il9 δ-CH H! ! ₃ '-CF 3 132-134 methanol: 42.9;! ! 2HC1

-CH ₃ i 3 '-OCHsi -0CH ₃ | 187-190 Methanol: 54.4

2HC1

CMPI Example 2 5

2.5 g of 2- (3-chloropropyl succinyl) propyl 2- (1,4) -benzothiazine-3 (4 Η) one-one 1.6 g and 2- (2-methoxyphenyl) pirazine The mixture was dissolved in 10 ml of methylformamide, and the mixture was stirred with 100 and 1.5 hours.

The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS 0 ₊ ) and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (15 Og) and eluted with hexane-acetone (2: 1, ν / ν). From the portion eluted with hexane-acetone (2: 1, ν / ν), 2- (3- [4- (2-methoxyphenyl) one 0.7 g of 1-piperazinyl] propyl) -l-l-1,4-l-benzothiazin-l-3 (4l) -one was obtained as an oil. The oxalate of this product was obtained as crystals. The crystals were recrystallized from methanol and dichloromethane to obtain colorless prism crystals. Yield 470 mg (l 3.3%)

mp 2 0 2-2 0 4 ° C

1 RCNujoDcm " ¹ : 3 1 8 0, 2 4 0 0 to 3 0 0 0 (broad), 1 7 2 0, 1 6 6 5

R δ (ppm) in DMS 0-d ₆ : 1.4-2.1 (H, m), 2.9 δ ~ 3.79 (1 1 Hm), 3.80 (3 H's 6 8 7 77.3 3 (8 H, m) 1 0.6 (1 H, broad)

As C ₂₂ H ₂₇ N ₃ 〇 _{_{2 S · 3 / 2C 2 H}} 2 0 4

Calculated: C 58.38; H 5.68; N 7.89

Minute value: C 56.10; H 5.63; S 7.87

Example 26

2— (2—Promoethyl) 1-2H—1,4,1-benzothiazine-3 (4H) —on 36 g and 1.1- (4-fluorophenyl) pyrazine 1.8 g in ethyl acetate 2 ml Then, the mixture was stirred at 110 ° C for 1 hour. The reaction product was extracted with ethyl acetate, washed with water, and dried over MgS 0 ₊ . solvent

O PI After distilling off the crystals, the obtained crystals were recrystallized from methanol to give 2- {2- [4- (4-fluoropropenyl) 1-1-piperazinyl] ethyl} -1H-1, 4-benzene. Thiazin-1- (4H) -one prism crystals were obtained. Yield 0.94 g (5 0.

Five %)

mp 15 8-1 δ 9 ° C

I RCNujoDcm " ¹ : 3 2 1 0, 1 6 6 5

NMR δ (ppm) in CD 2 C 13: 2.5 _{3 to} 26 2 (6 H, m), 3.0 2 to 3.1 1 (4 Hm), 3.6 2 (1 Hd d, J-7 and 8), 6.72

7.34 (8 H, m), 9.46 (1 H .broad)

C ₂₀ H ₂₂ FN ₃₀ S as

Calculated: C 64.67; H 5.97; N 11.31

Min Xin value: C 64.82; H 6.02; N 11.25

Example 2 7—2 9

Compounds in Table 6 were synthesized in the same manner as in Example 26.

Table 6

Example R ¹ R Melting point (T): Recrystallization solvent; Yield (%

27; HH145-146 Methanol: 62.3

28 ¹ H 0CH ₃ 162-163 Methanol: 65.2

29! 0CH ₃ H 157-158 Ethyl acetate: 72.5

Hexane, Example 30

C PI 2- (2-chloroethyl) -1-methyl-2H-1.4-benzothiazine-3 (4H) -one 1.2 lg and 1.1- (4-fluorophenyl) pyrazine 1.08, carbonate 0.69 g of potassium and 0.05 g of sodium iodide were added to 15 ml of dimethylformate and muamide, and the mixture was stirred at 100 ° C for 4 hours. reaction

C

The solution was poured into ice water and extracted with dichloromethane. The dichloromethane layer was washed with water, dried (after MgS Oj, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (13 Og) to give ethyl hexyl monoethyl acetate (1: 1, v / v). )) To give 2- {2- [4- (4-fluorophenyl) -1-piperazinyl] ethyl-4-methyl-2H-1,4,4-benzothiazin-13 (4H) -one as an oil. This product was treated with hydrogen chloride-saturated methanol to obtain hydrochloride crystals, yield 0.99 g (43.2%), and recrystallized from methanol-ether to obtain prism crystals. 0 2-204 ° C

IR (ujol) cma ^l : 2 5 2 0, 24 3 0, 1 6 6 0

MR δ (pm) in D Μ S 0 - d e:... 1 6~2 4 (2 H, m), 3. 5 ~3 64 (1 0 H, m), 3. 7 1~3. 8 7 (1H, m), 3.78 (3H, s), 6.3 (2H.broad), 6.7 8 to 7.47 (8H, m), 11.5 (1H, broad)

C 2i H ₂₊ F ₃ 0 S

Calculated: C 55.02; H 5.72; 9.17

Analyzed values: C 55.21; H 5.84; N 9..21

Example 3 1— 3 3

The compounds in Table 7 were synthesized in the same manner as in Example 30.

Table 7 ヽ, N- (

Various _{ゝゝ 0} R ³

OMTl Example R ₃ R ⁺ Melting point (° C) Recrystallization solvent Yield (%)

(salt)

31 HH

Ethanol 32.3

(HCl)

32 0CH ₃ H 149-151 Methanol 50.4

Ether

33 H ci methanol 32.1

Ether Example 3 4

2- (3-Bromopropyl) -1-methyl-2-H-1,4,4-benzothiazin-1 (4H) -one 1.2 g and 1.44 g of 1— (4-fluorophenyl) piperazine After dissolving in ethyl acetate, the solvent is distilled off and the residue is removed.

Was stirred at 1 L 0 ° C for 1 hour. The reaction product was oiled with ethyl acetate, washed with water, dried (MgS0) and concentrated. The residue was subjected to column chromatography using a silica gel (4 Og). From the part eluted with hexane monoethyl acetate (1: 1 ν / ν ·), '2—ί3—: 4 — (4-Fluorofluorophenyl) — 1 —Piberazinyl di-sigma-pyr) -14-methyl-2 ー -1,4,4-benzothiazine-13 (4Η) -one was obtained as a crystal. Yield 1.00 g (62.5%). The crystals were recrystallized from ethyl ethyl hexane to obtain colorless prism crystals. mp 103-104 ° C

I RCNujoDcm ' ¹ : 1 6 4 5

MR δ (ppm) in CDC 1 3:.. 1 4~2 1 (4 H, m), 2. 3~2.

5 9 (6 H, m), 3.0 1 to 3.0 9 (4 H, m), 3.3 8 to 3.5 2 (1 H, m), 3.43 (3 H, s ), 6.73 to 7.1 (8 H, m)

C ₂₂ H _2S FN ₃₀ S

Calculated: C 66.14; H 6.56; 10.52

CMPI Analytical values: C 66.33; H 6.63; N 10.57

Example 3 5

2- {3-[-(4-fluorophenyl) 1-1-piperazinyl] propyl) ---- 2H-1,4,4-benzothiazine 19% 60% hydrogen in 2 ml dimethylformamide solution 2 Omg of sodium iodide was added, the mixture was stirred at room temperature for 30 minutes, cooled with ice, added with 0.07 ml of methyl iodide, and further stirred for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (MgSC), and concentrated.

1ί3 — [:—( 4-fluorophenyl) —1—piperazinyl] propyl

4-Methyl-13--1,4-benzothiazine-13 (4Η) -one was obtained as crystals. Recrystallization from ethyl acetate and hexane gave prism crystals having a melting point of 103-104 ° C. Yield: 84 mg (42-%) This product was found to be identical with the compound of Example 34 by IR and NMR.

Example 3 6

2— (2— [4- (2-Methoxyphenyl) -1-1-piperazinyl] ethyl]--2H-1, 1-benzothiazine-1 3 (4H) -one 1. Og to dimethylformamide i 0 The mixture was stirred at room temperature, 120% sodium hydride (120 mg) was added under stirring at room temperature, and after stirring for 10 minutes, 48 Omg of iodinated chill was added, and the mixture was stirred for 2 hours. The oily layer was washed with water and dried (MgS0 ₊ ), the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (5 Og) to give hexane. 4-ethyl 2- (2— [4— (2-methoxyphenyl) -1 1-piperazinyl] ethyl-2 Η—1,4—benzothiazine 3 (4 Η) -one was obtained as an oil (0.60 g :) The product was crystallized as the hydrochloride salt Yield 0.50 g (39%) Methanol monoether . To give colorless prism crystals recrystallization Luo mp 1 4 2- 1 4 4 ° (:.

I RCNujoDcm " ¹ : 2450-0—2200.0.1660.

C PI WIP NMR δ (pptn) in DMS O- d e:. Tooth 1 3 (3 H, t, J = 7), 1 7

~ 2.4 (2 H.ra), 2.9 ~ 3.87 (11H, m), 3.79 (3H, s), 4.

0 2 (2 H.q, J = 7), 6.8 4-7.0 (8 H, m)

As _{_{C 23H 29 N 3 0 S ·}} 2 Ita_rei_1 · 1 / 2Η ₂ 0

Calculated: C 55.98; H 6.54; N 8.51

Analyzed values: C 56.18; H 6.47; 8.62

Example 3 7

2-Chloromethyl-2H-1, 4 Benzothiazine-1 3 (4H) -one

After dissolving 720 mg of 427 [1 ^ and 1- (4-fluorofluoro) piperazine in 1 O ml of ethyl acetate, the mixture was ripened, the solvent was distilled off, and the mixture was stirred at 110 ° C for 1 hour. After cooling the reaction mixture and adding water, crystals of 2— “4- (4-fluorophenyl) -11-piperazinyl] methyl-2H—i, 4—benzothiazine-13 (4H) one are precipitated. After filtration, the crystals were washed with water and cold methanol, and recrystallized from methanol dichloromethane to obtain prism crystals Yield 450 mg (62.9%) ₀ mp 192-13 ° C

1 RCXujo cm- ¹ : 3 2 0 0, 1 6 6 5

R 6 (ppm) in DS 0-d ₆ : 2.4 7 to 2.8 (6 H, m), 2.

9 7 to 3.2 4 (4 H.m), 3.86 (lH't, J = 7), 6.78 to 7.3

6 (8 H, m '), 10.5 3 (1 H, broad)

C _t3 H ₂₀ F: \ ' ₃ OS

Calculated: C 63.84; H 5.64; 11.76

Min Xin value: C 63.93; H 5.67; 11.83

Example 3 8

2 — (4 — chlorobutyl) -1 2 H— 1,4 1-benzothiazine-1 3 (4 Η) —one 4 3 5 mg and 1 1 (4-fluorophenyl) piperazine 6 13 mg of ethyl acetate 1 Dissolve in O ml, evaporate the solvent and stir the residue at 110 for 1 hour did. The reaction product was extracted with ethyl acetate, washed with water and dried (MgSC), and the solvent was distilled off.

I left. The residue was subjected to column chromatography using silica gel (40 g). From the portion eluted with hexane monoethyl acetate (1: 1, ν / ν), 2- (4- [4- 1-piperazinyl] butyl} -2 2-1,4 benzothiazin-13 (4Η) -one Yield 293 mg (43.2

%). Recrystallized from methanol to form prism crystals. mp 1 δ 0-15 1 ° C

IR (ujol) cm " ¹ : 3 1 8 0, 1 6 6 5

R δ (ppm) in CD C: 1.3 3 to 2.2 (6 H, m), 2.29

~ 2.67 (6H.m), 3.03 ~ 3.14 (4H, m), 3.1 (1H, d.d, J = 6 and 8), 6.73 -7.34 (8H, m), 9.0 (1H, broad)

As C ₂₂ H ₂₈ FN ₃₀ S

Calculated: C 66.14; H 6.56; N 10.43

Split value: C 66.10; H 6.69; 10.43

Formulation example

When the compound (I) of the present invention is used as an antihypertensive, it can be used, for example, according to the following formulation.

(L) 2— ί 3—: 4- (4-fluorophenyl) 1-1—piverazinyl

sigma pill} — 5—Methyl-2 1— 1, 4 Benzothiazine 1 (4 Η) 1 on 5 g

(2) Lactose 9 5g

(3) Corn starch 2 9g

(4) Magnesium stearate

1 0 0 0 tablets 1 3 0 g

(1), (2) At least 17 g of (3) is mixed and granulated together with a base made from 7 g of (3), and 5 g of (3) and (4) are added thereto. The mixture is compressed on a compression tablet machine to produce 1000 tablets containing 5 mg (1) per tablet.

ΟΜ? Γ Reference example 1

Dissolve 3.06 g of 2-amino-4,5-dimethylthiophenol in 50 mU of dimethylformamide, and stir at room temperature with methyl 2,5-dibromovalerate 5.

48 g was added and the mixture was stirred for 14 hours. The reaction solution was poured into water and extracted with ethyl acetate. After the ethyl acetate layer H was washed with water and dried (MgS 0 ₊ ), the solvent was distilled off. The residue was washed with a mixed solvent of ether and hexane to obtain 2- (3-bromopropyl) 16,7-dimethyl-2H-1,4,4-benzothiazin-13 (4H) -one as crystals. Yield 4.35 g (69.3%). Recrystallized from methanol to form prism crystals. mp 15 2-15 3 ° C

IR (iijoDcm ^-1 : 3 2 0 0, 1 6 6 0

R δ (ppm) in CDC 1 3:. 1 3 7~ 2. 2 7 (4 H .m), 2. 4 2 (6 Hs), 3. 2 3~ 3. 4 (1 H, m), 3.37 (2H, t, J = 6), 6.64 (1H, s), 7.03 (1H, s), 8.9 (1H, broad)

CL ₃ H ₁₆ B r NOS

Calculated: C 49.69; H 5.13; 4.46

Min f loaf value: C 49.84; H 4.97; X 4.75

Reference Example 2—1 0

The compounds shown in Table 8 were obtained in the same manner as in Reference 1.

Table 8

S- ..

CH ₂ ) ₃ Br

0

, WliO Reference Example RR Melting point (° C) Recrystallization solvent; Yield (%)

2 H H j 103-104 Roto acid ethyl 56.9

₃ H 5- 0CH 3! 97- 98 Methanol 40.0

4 H 7-0CH _£ 100-101 Ethyl acetate! 60.3

Hexane

5-CHi 72- 73 Ethyl acetate ―! 45.6

Hexane

!

7-CH _∑ 126-127 Ethyl acetate I 57.7

!

Hexane

6- CI 146 methanol; 7.2

H 7- CI 140-141 Ethyl acetate; 2.1

H 6-CF ₃ 149-150 Ethyl acetate! 17.9

Hexane

10 5-CH3; 7-CH 2 108-109 acetate Echiru ¹ 70.9

Reference example 1 1

4.6 g of 2-aminophenol was dissolved in 50 ml of dimethylformamide, and methyl 2,4-dibromobutyrate (9.55 g) was added thereto while stirring at room temperature. After stirring for 1 hour and pouring into water, crystals of 2- (2-promoethyl) -12H-1, 4,1-benzothiazin-13 (4H) -one were precipitated.锆 Crystals of crystals, water, η-hexane and cold methanol! Washed with. Yield 6. 32 g (63. 3%) = recrystallized from ethyl ethyl pepper to give prism crystals. mp i 5 1— 1 5 2 ° (:.

I RC ujoOcm ' ¹ : 3 2 0 0, 1 6 6 0

XMR δ (ppm) in CDC 1 3: K 9 0 - 2. 6 7 (2 H, m), 3. δ 7 (2 H, t, J = 6), 3. 7 I (1 H, d. d, J = 6 and 8), 6.80 to 7.37 (4 Hm), 9.5 (1 H, broad) C _t0 H ₁₀ B rN 0 S

Calculated: C 44.13; H 3.70; N 5.15

Min Xin value: C 44.03; H 3.54; N 5.13

Reference example 1 2

Dissolve 3.10 g of 2-amino-5-methoxythiophenol and 5.20 g of methyl 2,4-dibutyrate in 3 Omi of dimethylformamide and at room temperature.

After stirring for 2 hours, the resulting crystals were poured into ice water, and the crystals were collected by filtration and washed with water. Methanol

Recrystallized from 2— (2-promoethyl) -1 7—methoxy 2H—1,4

1-benzothiazin-3- (4H) -one was obtained as prism crystals. Yield 3.

9 4g (6 δ .2%) o m 1 2-1 4 3 ° C

I RCNujoDcm " ¹ : 3 1 9 0, 1 6 5 0

XR δ (ppm) in CDC i ₃ : 1-8 7-2.63 (2H, m), 3.6

0 (2 H, t, J = 6), 3.68 (1 H, d.d, J = 6 and 8), 3.76

H.s), 6.6 3 to 6.92 (3H, m), 9.62 (1H, broad)

As C H ₁₂ B r X o ₂ S

Calculated: C 43.72; H 4.00; 4.64

Min li value: C 44.09; H 3.60; 4.52

Reference example 〖3

(1) 2-ethoxycarbonyl 2 H-1, 4-benzothiazine-3 (4

H) -one 3.0 g was suspended in ethanol (50 ml) and hydrogenated

0.95 g of sodium hydrogen was added in small portions. After stirring for 2 hours, dilute with water

After that, it was made acidic with dilute acid and extracted with ether. Wash and dry ether layer

After crushing (MgS 0 ₊ ), the mixture was concentrated under reduced pressure. The residue is washed with hexane and

Kisimetyl 2 H— 1, 4 Benzothiazin-1 3 (4 H) —one

I got it. Yield: 25 g (50.8%). Recrystallized from ethyl acetate

Zum Zheng. mp 1 06 — 1 0 / ⁼ C ws.; I RCNiijoDcm " ¹ : 3500-3300, 3200, 1670

NMR δ (ppm) in DMS 0 - d e:.. 3. 4 1~3 7 4 (3 Hm), δ 0 9 (1 Η, πι), 6. 8 3~ 7, 3 3 (4 H, m), 1 0. 8 3 ( 1 H, broad) as C _₃ H ₃ N 0 ₂

Calculated: C 55.37; H'4.65; 7.17

Min Qi value: C 55.39; H 4.68; 7.29

(2) 2-Hydroxymethyl-1-H, 1,4-benzothiazine-13 (4H) -on, dissolve 0 g in 20 ml of chloroform, add 0.9 ml of thionyl chloride and reflux for 2 hours Ripened. After concentration under reduced pressure, the residue was oiled with ether, washed with water, dried (MgS0) and the solvent was distilled off. The crude product was subjected to column chromatography using silica gel (40 g). 3 (4Η) -one was obtained as crystals. Yield 640 g (58.7%) Recrystallized from _c- ethyl and n-hexane to obtain needles. mp 1 -5 2-1 5 3 ° C

I RCN'ujoDcm- ¹ : 3 1 9 0, 1 6 6 0

XMR δ (ppm) in CDC 1 3: 3. 6 ~ 3. 9 3 (3 H, m), 6. 8 9 - 7. 3 7 (4 H, m), 9. 4 (1 H, broad)

C ₃ H ₈ C 1 λ'—Ο S

Calculated: C 50.59; H 3.77; 6.55

Min Xin value: C 50.44; H 3.53; 6.54

Reference example 1 4

In the same manner as in Reference Example 13-2, 2- (2-hydroxyshethyl) -12H-1, 4-benzothiazin-13 (4H) -one was reacted with thionyl chloride to give 2- (2-alkoxyleutyl). One 2Η-1,4-benzothiazine-1 3 (4Η) -one was obtained. Yield 7 2.7%. Recrystallized from methanol to form prism crystals. mp 1 3 3 -1 3 3.5 ° C

I RCNujoDcm- ¹ : 3 2 0 0, 1 6 6 0

MR δ (ppm) in CDCI ₃ : 1.7 2 to 2.5 7 (2 H, tn), 3.5

9 to 3.87 (3 H, m), 6.8 4 to 7.35 (4 H, fli), 9.6 4 (l H, broad)

C ₁₀ H ₁₀ C1X〇 As S

Calculated: C 52.75; H 4.43; N 6.15

Min Xin value: C 52.62; H 4.27; 6.10

Reference cool 1 5

(1) 6.26 g of 2-aminothiophenol was added to dimethylformamide 5

Dissolve in 0 ml and add 9.85 g of 2-bromo δ-hydroxyvaleric acid. For 2 hours and at 100 ° C. for 1 hour. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS 0 ₊ ) and concentrated under reduced pressure. The residue was subjected to column chromatography using a silica gel (20 Og), and 2- (3-hydroxyproduced) was eluted with hexane-aceton (2: 1, v / v). Pill) 1 2 H— 1, 4 and 1-benzothiazine 13 (4 H) —one were obtained as crystals. Yield 3.7 g (31.6%). Recrystallized from ethyl acetate and hexane to form prism crystals. ip 5 9-60 ° C

IR (jol) cm- ^L : 3500-3100, 3200.0.16600

NMR δ (ppm) in CDC 1 3:. 1 5 3~ 2. 1 (4 H, m), 2. 4 (1 H, broad), 3. 3 7 - 4. 0 2 (3 H, broad) , 6.93 to 7.33 (4 H, ra), 9.57 (1 H, broad)

C 丄 LH ₃ M 0 ₂ S

Calculated: C 59.17; H 5.87; 6.27

Min Qi value: C 58.83; H 5.81; 6.53

(2) 2— (3-hydroxy σ pill) -1 2 H—1,4,1-benzothiazine

-Reaction of 3 (4H) -one with thionyl chloride in the same manner as in Reference Example 13- (2)

O PI This gave 2- (3-chloropropyl) -1 2 H-1,4,4-benzothiazine-13 (4H) -one. Yield 59.1%. Recrystallized from ethyl acetate-hexane, prism crystals. mp 9 8— 9 9 ° C

I RC ujoDcm " ¹ : 3 2 0 0, 1 6 6 5

NR δ (ppm) in CDC 1 3:. 1 6 2~ 2. 2 (4 H.ra), 3. 3 3

~ 3.7 2 (3 H, m), 6.8 6 ~ 7.3 3 (4 H, m) '9.6 4 (l H, broad) .C H ^ ClNO S

Calculated: C 54.66; H 5.00;? ί 5.79

Min Xin value: C 54.51; Η 4.84; Ν 5.74

Reference Example 1 6

Dissolve 2.86 g of (-1) 2- (3-buta-mo-propyl) -2- 2-1,4-benzothiazin-13 (4Η) -one in 10 ml of dimethyl sulfoxide, and add sodium cyanide. 4 g of tritium was added, followed by stirring at room temperature for 3 hours. The crystals obtained by diluting the reaction solution with water were collected by filtration and washed with water. The crystals were recrystallized from methanol to obtain 2- (3-cyano sigma-pill) -12 H-1, 4,1-benzothiazin-13 (4Η) -one as prism crystals. Yield 1.55 g (66.7%). mp 1 0 7-1 0

8. C

I RCNujoDcm- ¹ : 3 1 9 0, 2 2 2 0, 1 6 6 5 (broad)

MR δ (ppm) in CDC 1 3:.. 1 6 2~2 2 2 (4 Hm), 2. 2

3 to 2.45 (2H, m), 3.35 to 3.δ0 (1H, m), 6.85 to 7.35 (4H, m), 9.17 ( 1 H, broad)

C ₁₂ H _{12 20} S

Calculated: C 62.05; H 5.21; 12.06

Analyzed values: C 61.78; H 5.19; 11.79

(2) 2— (3-Cyanob sigma) -1 2 H—1,4—benzothiazine-1 3 (4H) —on and 45 g to 18.8% (w / w) hydrogen chloride ethanol Solution 40 ml

OMPI , And 0.3 ml of water was added, and the mixture was heated under reflux for 24 hours. After cooling, the reaction solution was diluted with water and extracted with ether. The ether layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water in that order, and then dried (MgS0J.) The solvent was distilled off, and the 2- (3-ethoxycarbonylpropyl) 1-2H-1,4 Nzothiazin-3 (4H) -one was obtained as crystals, yielding 60 g (9 i. 4%) o Recrystallized from ethyl acetate, mp 78-79 ° C

I RC ujoDcm ^-1 : 3 2 0 0, 1 7 3 0, 1 6 6 0

R δ (ppm) in CDC 1 3:.. 1 2 1 (3 H, t, J = 7), 1 5~2.

2 (4 H.m), 2.3 l to 2.47 (2 H, m), 3.3 2 to 3.5 1 (1 H, m), 3.

44 (2 H, q, J-7), 6.7 2-7.3 9 (4 H, m) ₍ 8.2 (l H, broad)

As _{_{_{C t + H 17 N 0 3}}} S

Calculated: C 60.19; H 6.13; ¾ 5.01

Analytical values: C 60.33; H 6.03; 5.44

(3) 0.46 g of lithium aluminum hydride was suspended in 50 ml of ether, and 2- (3-ethoxycarbonylpropyl) -12H-1, 4 benzothiazine-1 (4 H) -one 1.6 g of an ether solution (30 ml) was added dropwise. After stirring for 1 hour, water was added dropwise, the white precipitate was filtered off, the filtrate was dried (MgS Oj), the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (70 g). 2- (4-Hydroxybutyl) -12Η- and 4-benzothiazin-13 (4Η) -one were obtained as crystals from the portion eluted with ethyl ethyl xane monoacetate (1: 1, ν / ν ·). Yield 0.75 g (55.6%) _c Recrystallized from ethyl acetate and prism crystals Immediately I 0 1-10 2 ° C

IR (X jol) cm- ¹ : 3400-3150, 3210, 1660

NR δ (ppm) in CDC 1 3:... 1 4 4~ 2. 1 (6 Hm), 1 8 0 (1 H, broad), 3. 3 1~3 7 1 (3 H, m), 6.8 1-7.33 (4 H, m), 9.24 (1 H .broad)

O PI As C ₁₂ H ₁₅ N 0 ₂

Calculated: C 60.73; H 6.37; N 5.90

Split value: C 60.69; H 6.35; 5.82

(4) 2- (4-Hydroxybutyl) -2H-1, 4-benzothiazin 3 (4H) -one was reacted with thionyl chloride in the same manner as in Reference Example 13- (2) to give 2-(-chlorobutyl). 2H-1, 4 Benzothiazine 3 (4H)- Yield 59.0% mp 11 1-11 2 ° C (recrystallized from ethyl hexane).

I RCNLijoDcm ^-1 : 3 1 9 0, 1 6 6 5

XMR δ (ppm) in CDC 1 3:. 1 7 - 2. 0 6 C 6 H, tn), 3. 3 3~3.5 7 (3 H .in), 6.8 6 ~ 7.34 (4 H, m), 9.6 7 (1 H, broad) C _L2 H ₁ C1-N: 0 S

Calculated: C 56.35; H 5.52; 5.48

Analyzed values: C 56.26; H 5.41; N 5.13

Reference 1 7

(1) 2-(2-Hydroxitytyl) 2 H-1, 4

3.18 g of 3 (4H) -one was dissolved in 50 ml of dimethylformamide, and 0.8 g of 60% sodium hydride was added little by little under ice-cooling and stirring. After stirring for 10 minutes, 1.24 mi of methyl iodide was added. After stirring at room temperature for 1 hour, the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgS 0J and concentrated under reduced pressure). The residue was subjected to column chromatography using silica gel (50 g) and eluted with hexane ethyl acetate (2: 1, νΖν). 2- (2-Hyd σ-kisethyl) -1-methyl-2-Η- 14-benzothiazin-3 (4Η) -one was obtained as an oily product Yield 3.90 g (8 7.

Four %

IR (neat) cm " ¹ : 3600-32.5 0, 1660 (broad) NMR δ (ppm) in CD Cl ₃ : 1.6 2 to 2.3 1 (2 H, m), 2.47 (1 H, broad), 3.43 (3 H, s), 3. 6 1 (1 H, t, J-7), 3.77 (2 H, m), 6.90 to 7.41 (4 H, m)

(2) Dissolve 4.90 g of 2- (2-hydroxyxethyl) -1-methyl-2H-1, 4-benzothiazin-13 (4H) -one in 20 mU of dichloromethane and stir at room temperature with stirring. 5 ml of thionyl chloride were added. After stirring for 1 hour, the residue was subjected to force chromatography using silica gel (35 g). From the part eluted with hexane monoethyl acetate (4: 1, ν / ν), 2- (2 —Chloroethyl) -1-methyl-2 2—1,4 一 benzothiazine ジン 3 (4Η) —is obtained as an oil. Yield 5.05 g (95.3%)

1 R (neat) cm ^_1 : 1 6 6 0

MR δ (ppm) in CDC 1 3:.. 1 8 3~ 2. 5 6 (2 H, m), 3. 4 6 (3 H, s), 3. 5 6~3 7 6 (1 H, m), 3.70 (2 H, t, J-6), 6.91 -7. 4 3 (4 H, m)

Ref. 1 8

2.78 g of 2-methylaminophenol and 5.48 g of 2.5-dibu-methyl movalate were dissolved in 100 ml of dimethylformamide, and the mixture was stirred at 50 for 2 hours. The reaction solution was poured into cold water, extracted with ether, washed with water, dried (MgS 0 ₊ ), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (150 g), and 2- (3-bromo) was extracted from the portion eluted with hexane-g ethyl acetate (4: 1, ν / ν '). Propyl) -1-methyl-2 2-1,1benzothiazine-3 (4Η) -one was obtained as an oil. Yield 4.57 g (76.2%).

IR (neat) cra— ¹ : 1 6 6 0

XMR δ (ppm) in CDC 13: 1.5 _{3 to} 2.23 (4 H, m), 3.3 to 3.5 (3 H, m), 3.44 (3 H, s) 6 .9 1 ~ 7.40 (4 H, m) Industrial applicability

The novel 1,4-benzothiazine derivatives of the present invention have excellent pharmacological activity and are useful as pharmaceuticals and the like.

OMPI

Claims

The scope of the claims

1. General formula

R ⁵

[Wherein R ¹ , R ² , R ³ and R ⁺ are the same or different and are hydrogen, halogen, lower alkyl group, lower alkoxy group or trifluoromethyl group; R ⁵ is hydrogen or lower alkyl group; : Each represents an alkylene group], or a 1,4-benzothiazine derivative or an acid addition salt thereof.

2. The monobenzothiazine derivative according to claim i, wherein A is ethylene.

3. The 1,4-benzothiazine derivative according to claim 1, wherein A is trimethylene.

4. The 1,4-benzothiazine derivative according to claim 1, wherein R ⁵ is hydrogen.

5. The i, 4 monobenzothiazine derivative according to claim 1, wherein at least one of R ³ and R ⁺ is fluorine.

6. At least one of R and R ² is a lower alkyl group, and at least one of R ³ and R ⁺ is a substituted or substituted benzene at the 4-position of the benzene ring. The 1,4-benzothiazine derivative described.