JPS61137871A - 1,4-benzothiazine derivative, production and use thereof - Google Patents

Abstract

NEW MATERIAL:The 1,4-benzothiazine derivative of formula I [R<1> and R<2> are H, halogen, lower alkyl, lower alkoxy, trifluoromethyl, or R<1> and R<2> together form a 5-7-membered ring of formula II (n is 3-5) or 5-6-membered ring of formula III (m is 1 or 2); R<3> and R<4> are H, halogen, lower alkyl, etc.; R<5> is H or lower alkyl; A is alkylene] or its acid addition salt. EXAMPLE:2-{ 3-[ 4-( 4-Fluorophenyl )-1-piperazinyl] propyl }-6,7-dimethyl-2H,1,4- benzothazine-3(4H)-one. USE:It has cspecially intracellular calcium antagonistic activity, and is useful as a remedy for asthma, and preventive and remedy for hypertention and vari ous ischemic diseases of brain, heart, kidney, etc. It has no side effects. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula IV with the compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel 1,4-benzothiazine derivatives that exhibit excellent pharmacological activity. The compounds of the present invention have strong hypotensive and vasodilatory effects, and are useful as medicines.

PRIOR ART As yet, there is no drug that has 3-oxo-1,4-benzothiazine as its main skeleton and has been put to practical use as a drug that acts on the circulatory system. Regarding compounds that have pharmacological effects on the circulatory system, JP-A-59-148771 discloses that a compound having a substituted phenyl group at the 2-position exhibits platelet aggregation inhibiting action and calcium antagonistic action; It is only stated that compounds containing a group represented by - [in the formula, R' and R' may form a heterocyclic ring together with adjacent nitrogen atoms] exhibit diuretic and antihypertensive effects, respectively. do not have.

Problems to be Solved by the Invention There are many unexplored fields in 3-oxo-1,4-benzothiazine derivatives, and substituents, especially 4-phenyl-1- Nothing is known about compounds having a piperazinyl group and their pharmacological effects. The object of the present invention is to provide novel 1,4-benzothiazine derivatives having excellent pharmacological activity.

The present invention is based on the general formula [In the formula, R' and R1 are the same or different and are hydrogen.

Halogen, lower alkyl group, lower alkoxy group, trifluoromethyl group, or each R1 and R2 are the same or different and represent hydrogen, halogen, lower alkyl group, lower alkoxy group, or trifluoromethyl group, R5 is hydrogen or lower The present invention relates to a 1,4-benzothiazine derivative (1) represented by alkyl group and A represents an alkylene group, an acid addition salt thereof, and a pharmaceutical composition containing the derivative as an active ingredient.

The substituents represented by R', R'', R3, and R' in the general formula (0) may be the same or different, and may be substituted at any position on the benzene ring.Such substituents Of these, fluorine is a halogen.

Examples include chlorine, bromine, and iodine, with fluorine or chlorine being particularly preferred. When R' and R' are halogen, particularly fluorine, at least one of them is preferably substituted at the 4-position of the benzene ring. The lower alkyl group preferably has 1 to 4 carbon atoms, such as methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, 5ec
-butyl, L-butyl, etc., and those having 1 to 3 carbon atoms are particularly preferred. It is also acceptable if Rl and R1 are adjacent lower alkyl groups. Examples of the group represented by +CHt% include trimethylene, tetramethylene,
Examples include pentamethylene. The lower alkoxy group preferably has 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, and isopropoxy. Furthermore, when R1 and R1 are adjacent to each other, it can be removed.

The lower alkyl group represented by R5 has the above-mentioned carbon number of 1.
-4 carbon atoms, and those having 1 to 3 carbon atoms are particularly preferred.

The alkylene group represented by A is preferably a linear or branched alkylene group having 1 to 4 carbon atoms, such as methylene,
Methylmethylene, ethylene, propylene, trimethylene, ■-methyltrimethylene, 2-methyltrimethylene,
Examples include tetramethylene. In particular, the number of carbon atoms is 2~
Ethylene and trimethylene of No. 3 are preferred.

The compound of the present invention represented by the general formula (1) is, for example, a compound (II) represented by the general formula [wherein, X is a leaving group and the symbol for pond has the same meaning as above]. All symbols have the same meanings as above] and can be easily produced by reacting with compound (III).

In general formula (II), examples of the leaving group represented by (eg, phenylsulfonyloxy, triylsulfonyloxy 7, etc.).

This reaction is carried out by reacting compound (II) and compound (II[). This reaction can be carried out by heating in a solvent inert to the reaction or by directly heating the mixture of (II) and (III) without a solvent, and in either case the reaction temperature is about 0. ℃～about 200℃
, more preferably about 80'C to about 150C. Examples of such solvents include alcohols such as methanol, ethanol, propatool, 2-propanol, butanol, and 2-methoxoethanol, ethers such as dioxane, tetrahydrofuran, and dimethoxyethane, and aromatic solvents such as benzene, toluene, and xylene. Hydrocarbons 1
Examples include ethyl acetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, and mixed solvents thereof. In addition, since this reaction generates an acid due to the leaving group By adding and using this as a deoxidizing agent, the reaction can proceed smoothly. (III
) is usually used in an amount of 1 to 3 mol per 1 mol of (II),
The amount of the deoxidizing agent to be used is preferably about 1 to 3 moles per month.

Compound (1) in which R's is lower alkyl is R
It can be produced by alkylation of a compound (r) in which 5 is hydrogen. This alkylation reaction is carried out by reacting an alkylating agent in a solvent in the presence of a base. The solvent may vary depending on the type of base used, but examples include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethyl ether, N, N-
Dimethylformamide, dimethyl sulfoxide, etc. can be used as appropriate. Examples of bases include sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, potassium hydride, sodium amide, etc., and examples of alkylating agents include alkyl halides (eg, chloride, bromide).

-iodite, etc.), dialkyl sulfates, and alkyl sulfonates (eg, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.).

In this reaction, it is preferable to first react the compound ((R' is hydrogen) with a base in a solvent to form an anion, and then react with the alkylating agent.

The reaction temperature is usually about -10°C to about 100°C, preferably about θ°C to about 40°C.

The 1.4-benzothiazine derivative (1) can be converted into an acid addition salt if necessary. Examples of such salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, acetates, oxalates, malonates, succinates,
Examples include organic acid salts such as malate, fumarate, maleate, and tartrate, and sulfonate salts such as methanesulfonate, benzenesulfonate, and toluenesulfonate.

The 1,4-benzothiazine derivative (I) and its salts produced as described above are new compounds, and have a strong vasodilatory effect and adrenergic effect in mammals (e.g., rats, rabbits, dogs, cats, humans, etc.). It has effects such as lowering blood pressure and improving cerebral circulation based on receptor blocking effects and intracellular calcium antagonism. In particular, a major feature of the compounds of the present invention is that they exhibit intracellular calcium antagonism.

In other words, calcium ions (Ca+
+), but this Ca"+ requires 1) Ca"+ that flows into the cell through the so-called Ca"+ channel; 2)
) released from intracellular Ca"+ storage sites, and 3) those that flow into cells via receptor-dependent channels.Ca such as nifedipine
"+ channel inhibitors have almost no effect on 2) and 3). So far, trifluoberazine, TMB
Compounds such as -8 and W-7 are known, but the latter two have weak effects and do not show antihypertensive effects in living organisms, while the former has side effects such as central action, so they are used as antihypertensive agents and cerebral circulation improving agents. It has not yet been put into practical use. The compound of the present invention, which has a marked intracellular Ca"+ antagonistic effect, exerts pharmacological action over a wider range than Ca++ channel inhibitors in order to suppress the contractile response in all of cases 1), 2), and 3). In addition to inhibiting blood and ductal contraction, the compound of the present invention is also expected to be used as a treatment for asthma, as it exhibits an inhibitory effect on tracheal muscle contraction.The compound of the present invention also has a protective effect on the ischemic heart, brain, and kidneys. It has low toxicity and has few side effects such as orthostatic hypotension, which is often seen with α-receptor blockers such as prazosin. It is highly useful as a prophylactic and therapeutic drug for cerebral infarction, transient ischemic attack, myocardial infarction, acute renal failure (0. nephritis, etc.).

When compound (1) and its salts are used as the above-mentioned pharmaceuticals, they are mixed with appropriate pharmaceutically acceptable carriers, excipients, and diluents and prepared in the form of powders, granules, 11 tablets, capsules, injections, etc. It can be administered orally or parenterally. The dosage varies depending on the route of administration, symptoms, condition, age or weight of the patient, etc., but for example, when orally administered to adult hypertensive patients, it is 0.05 to 10 mg/Kg body weight/day, preferably O11 to 51 g. /Kg body weight/day is preferably administered in one to several divided doses per day.

The raw material compound (■) of the present invention can be produced, for example, as follows.

Method A Method B Method C (when -A- is represented by -B -CHt-) [In the above formula, Y represents halogen, RI, R? represents hydrogen or a lower alkyl group, B represents a bond or an alkylene group,
Other symbols have the same meanings as above].

Examples of lower alkyl groups represented by R' and R' in the above general formulas (V), (■), and (■) include those having 1 to 4 carbon atoms similar to those represented by R1 and R5. The halogen represented by general formulas (V) and (Vl) is chlorine.

Examples include bromine or iodine. In addition, when B in the general formula (■) represents a bond, it means that the 2-position of 1,4-benzothiazino and C0OR' are directly connected, and when B is an alkylene group, such alkylene is more important than A. It is limited to cases where the number of carbon atoms is one less and -B-CR2- and -A- are equal. An outline of each method is described below.

Method A According to this method, (rl) can be obtained by reacting compound (IV) and compound (■). This reaction can usually be carried out at a suitable solvent range of about 0°C to about 100°C, and such solvents include, for example, methanol,
Alkanols such as ethanol, propatool, 2-propanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, acetonitrile, N,
Examples include N-dimethylformamide.

Method B First, (ff) and (VI) are reacted to produce (■), and then this is halogenated or sulfonylated to produce (II). The reaction between (■) and (V[) can be carried out in exactly the same manner as the reaction between (ff) and (V) described above. Examples of the halogenating agent used for halogenating compound (■) include thionyl chloride.

Examples of the sulfonylating agent used for sulfonylation include phosphorus oxychloride and phosphorus tribromide, and methanesulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyl chloride. (
The halogenation reaction (ii) is usually carried out at a temperature of about 15°C to about 100°C using a suitable solvent, such as dicumylmethane.

Examples include chloroform, benzene, and toluene.

The reaction between (■) and a sulfonylating agent can be carried out under the same reaction conditions as for halogenation, but it may be advantageous to carry out the reaction in the presence of a base such as triethylamine or pyridine, if necessary.

Method C In nature, (■) is first reduced to produce (■), and this is reacted with a halogenating agent or a sulfonylating agent in the same manner as in Method B to produce (n). The reduction of compound (■) can be carried out using, for example, sodium borohydride or lithium aluminum hydride, for example, in the case of the former, methanol, ethanol, etc., in the case of the latter, ethyl ether, tetrahydrofuran, etc., in a solvent width of about 0'C to about 100°C. ℃
It will be held in

The starting compound (■) used in this method can be synthesized, for example, according to the reaction of the following formula.

R'0CO-13-CHCOOR' c All symbols in the formula have the same meanings as above] The reaction between (IV) and (IX) is the reaction between the above (1'/) and (V)
The reaction is carried out in exactly the same way as the reaction with (■).

Also, by reacting (X) with sodium cyanide, (XI)
(■) can be obtained by hydrolyzing this and further esterifying it if necessary. The reaction between (X) and sodium cyanide can be carried out in an appropriate solvent (eg, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, etc.) at a temperature of about 0°C to 100°C. The hydrolysis reaction of (X[) uses a mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or an alkali (e.g., sodium hydroxide, kaium hydroxide, etc.) and an appropriate solvent (e.g.,
Meta! The reaction can be carried out at a temperature of about 60° C. to about 120° C., and the produced carboxylic acid can be converted into a desired ester by esterification by a method known per se. In addition, when (X[) is treated with hydrogen chloride or hydrogen bromide in the presence of a small amount of water in an appropriate alcohol, the ester form (■
) can also be obtained.

The results of pharmacological tests showing the effectiveness of the compound (1) of the present invention are shown below.

1. Vasodilatory effect A spiral strip of rabbit aorta (medium 2-3 mg+, length about 3 C-) was suspended in Krebs-Hen5eleit solution with a load of 2 g. Krebs-He
n5eleit solution is 97% 0. The mixture was saturated with a mixed gas of -3% CO1 and heated to 37°C. KCI (80-M),
Compounds of the present invention wJ (to□4 M
) was investigated for the inhibitory effect of 15 minutes of pretreatment. The results are shown in Table 1 as inhibition rates.

Table 1 2. Intracellular Ca” + antagonism 4 Rabbit aorta spiral strip (width 2-3111I11
．． Krebs-Hen5eleit (about 3 CI in length)
Suspended with 2g load in solution = solution is 97% 0
．． It was saturated with a mixed gas of -3% CO9 and heated to 37°C.

° Contractile response due to intracellular Ca"+ is caused by K rebs -Hen5el containing Ca"OmM and EGTA5sM.
Contraction due to phenylephrine (10-'M) added 5 minutes after changing to the eit solution was used as an index. Table 2 shows the results of determining the inhibition rate after adding the compound of the present invention to this shrinkage.
Shown below.

Table 2 3. Blood pressure lowering effect Spontaneously hypertensive rats (male, 12-13 weeks old).

The blood pressure before drug administration was approximately 200 miHg), and each group of 3 animals was used. First, the tail artery pressure was measured by the tail-cuff method, and then 3 to 60 mg/Kg of the compound of the present invention was administered to a 2 m
It was orally administered as an aqueous suspension of gum arabic.

One hour after administration, blood pressure was measured again and the difference from the pre-administration value (hypertensive effect, 6 mmHg) was examined. The results are shown in Table 3.

Table 3 4. Protective effect on the ischemic heart, brain, and kidneys 4-1. Effect of ischemia-reperfusion on ventricular arrhythmia development in rats Sprague-Davley rats (male, 9-1
At 0 weeks of age, the drug or water was orally administered at a dose of 5 d/kg, and 1 hour later bendoparbital (50 mg/kg,
The animals were anesthetized by intraperitoneal injection. The chest was opened under artificial respiration, and the left anterior descending coronary artery was ligated for 5 minutes, and the frequency of ventricular tachycardia, ventricular fibrillation, and cardiac arrest occurring within 10 minutes after reperfusion was measured.

The results are shown in Table 4. Compound of Example 48 at 1°3 and 10 mg/kg and compound of Example 46 at 0.3
Oral administration of , 1.3 and 10 mg/kg suppressed the incidence of ventricular tachycardia, ventricular fibrillation and cardiac arrest in a dose-dependent manner.

(Left below) Table 4 Experimental group Dose Ventricular Ventricular cardiac arrest mg/kg,
p, o, tachycardia fibrillation control group -20/20 Note 20/20 12/20 Example 1 7/1 (1"'5/10"
3/1048 3 ・ 4/9"3/9"
l/9"101/6" l/6° G/6"
'Control group -12/12 12/12 9/12
0.3 12/19 9/19" 9/19 Example 1 7/12"5/12" 0/
12'46 3 5/12° 2/12"
O/12'10 1/4" l/4°
074''・Note: The denominator is the number of rats used. The numerator represents the number of rats that developed abnormal cardiac function.

・Significant difference test, Xt-test, "P<0.05゜*"P<
0.01 4-2 Effect on cerebral ischemic attack in spontaneously hypertensive rats Drugs or water were initially administered to spontaneously hypertensive rats (male, 20-22 weeks old) at a dose of 5 d/kg, and 1 hour later they were given a bend. The animals were anesthetized with Parvicool.

Immediately after bilateral marginal carotid arteries were ligated, the time until seizures (convulsions, jumping, etc.) occurred was measured.

The results are shown in Table 5. Compound of Example 48 at 1.3 and 10 mg/kg and compound of Example 46 at o, 3°1
Oral administration of 3 mg/kg also prolonged the time to onset of cerebral ischemic attack in a dose-dependent manner.

(Left below) Table 5 Experimental group Dose Rat cerebral ischemic attack nag/kg
, p, o, number Example 48 1
10 167±87 Example 483 5214
±22°Example 48 10 5 275±
22#l Example 46 0.1 5 167
±13 Example 46 0.3 11 190±
11 Example 46 1 5 217±tt
"""p<o,ot 4-3 Effect on acute renal failure in rats Spragu
e-Dawley rats (male, 6 weeks old) were orally administered drugs or water at a dose of 5 d/kg, and anesthetized with bendoparbital 1 hour later. The abdomen was opened and the left renal artery was completely ligated for 1 hour. -Then, the ligature was removed, the abdomen was opened, and 20 hours later, the drug or water was orally administered again. Four hours later, the animal was anesthetized again, blood was collected from the abdominal aorta, plasma was separated, and urea nitrogen (BUN) was placed. □・ The results are shown in Table 6. Example: Compound '48 is 10na
g/kg, and the compound of Example 46 at 1 and 3 mg/kg.
When administered orally, the increase in BUN was suppressed.

(Margins below) Table 6 Experimental group Dose Rat BUN mg/kg, p, o, number s+g/d12 Control group
10 20.3±0.6 Example 483
Compound control group of 918.9±0.6 23 22.8±1.0 Example 48 10 22 16.9±0.7
1 compound control group = -520°4±0.4 Example 461
518.0±0.7” compound control group -1825,1±0.8 Example 46
3 17 19.6±0.8" Compound Significance Difference Test: 5student's t-test, '
P<0,05.

I''”p<o,ot Example Next, the present invention will be explained in more detail with reference to Examples.

In the examples, all melting points were measured using a hot plate φ and are uncorrected.

Example 1 2-(3-bromopropyl)-6゜7-dimethyl-2H
-1,4-benzothiazin-3(4H)-one 628m
g and 1-(4-fluorophenyl>piperazine 721m
g was dissolved in 10 ml of ethyl acetate and concentrated, and the residue was stirred at 110°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (M
gSO4) and then concentrated to yield 2-(3-[4-(4-fluorophenyl)-1-piperazinyljpropyl)-6,7-
Cymethyl-2H-1,4-benzothiazine-3(4H)
-one (650 mg, 78.6%) was obtained. Recrystallized from methanol, colorless prismatic crystals.

mp 161-162°C IR (Nujol) cm-': 3190. 1
665NMRδ (ppm) in CD CLa: 1.
4-2.1 (4fi, I+1).

2.19(61(,s), 2.28(2H,tj=6
), 2.43-2.62 (4H, II+).

3.00-3.10 (4H, m), 3.41 (IH,
m), 6.63-7.03 (6H.

s), 8117(lIl, broad)Ct3Hts
Calculated value as F N, OS: C66,8Q, H6,82,N 10.1
6 analysis value: C67.00, H6.92, N 10.1
2 Example 2-11 The compounds shown in Table 7 were obtained in the same manner as inversion.

(Margin below) Table 7 Example I2 2-(3-bromopropyl)-5-methyl-2H-1,
3.0 g of 4-benzothiazin-3(4H)-one and 1-
After 3.6 g of (4-fluorophenyl)piperazine was dissolved in 30 ae of ethyl acetate and concentrated, the residue was stirred at 110°C for 1 hour. 50+1 liters of water and 1 ooiL of ethyl acetate were added to the reaction and partitioned. The ethyl acetate layer was separated, washed with water, dried (MgSO,), and concentrated. The crude product obtained was subjected to column chromatography using silica gel (100 g), and hexane-ethyl acetate (I2l: ,v/
2-(3-[4-(4-fluorophenyl)-1-piperazinyl]propyl)-5-methyl-28-1°4-benzothiazin-3(4H)-one was obtained from the part eluted in v). (2.6g, 55.1%). Recrystallized from methanol, colorless prism product.

ap 116-117℃ IR(Nujol)co+-': 3220.165
5NMRδ (ppm) in CD Cla: 1.5~
2.1 (4H, m).

2.03 (38, s), 2.3-2.59 (6H, m)
, 2.99-3.11 (4H,i).

3.01-3.49 (18, m), 6.7-7.22
(7H,i)C! Calculated value as tHtsF N30 S: C66,14,H6,56,N 1G,52
Analysis value: C66, 17, H6, 62, N 1G, 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 prismatic crystals.

6 161-163℃ C, H1mFNSOS Calculated value as -28C1: C
55,93: H5,97,N 8.89 Analysis value: C
55,56; 115.99. N 8.72 Example 1
3-24 The compounds shown in Table 8 were obtained in the same manner as in Example 12.

Table 8 Example 25 1.6 g of 2-(3-chloropropyl)-28-1,4-benzothiazin-3(4)()-one and 55 g of 1-(2-methoxyphenyl)piperazine 2 were mixed in 10 il of dimethylformamide. The mixture was stirred at 100°C for 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 (MgSO,), and concentrated under reduced pressure.

The residue was subjected to force column chromatography using silica gel (150 g) and hequinane-acetone (2:1
, v/v) 2-(3-[4-(2
-methoxyphenyl)-1-piperazinyl]propyl)
0.7 g of -28-1,4-benzothiazin-3(4H)-one was obtained as an oil. Oxalate from the main island was obtained as crystals. Recrystallized from methanol and dichloromethane,
Colorless prismatic crystals were obtained. Yield 470 mg (13,3%
) tap 202-204℃ IR (Nujol) cm-': 31g0.2400
~3000 (broad).

1720, 1665'N M Rδ
(ppm) in DMSO-ds: 1.4-2.1 (
4H, *), 2.95-3.79 (I IH, s)
, 3.80 (3H, s), 6.87-7.33 (
81,a), 10.6(In, broad)C*t
Calculated value as HttNsOtS・3/2C,HtO,:
C5B, 38; H5,68, N 7.89 Analysis value: C58,10: H5,63; N 7.87 Example 26 2-(2-bromoethyl)-28-1,4,-benzothiazine-3(4H )-one and 1.8 g of 1-(4-fluorophenyl)piperazine in 20 m of ethyl acetate.
After the solvent was distilled off, the mixture was stirred at 110° C. for 1 hour. After extracting the reaction product with ethyl acetate and washing with water, Mg5O
, dried. After evaporating the solvent, the obtained crystals were recrystallized from methanol to give 2-(2-[4-(4-fluorophenyl)-t-piperazinyl]ethyl)-28-1,4-benzothiazine-3(4H)- I got a prismatic product that was on. Yield 0.94g (50.5%) sp 158-159℃ ER (Nujol)ca+-': 3210.166
5NMRδ(Jj9rtr)in CD C1,:2
．． 53-2.62 (6H.

m), 3.02-3.11 (4H, m), 3.62 (
lH, d, dj-i=? and 8).

6.72-7.34 (8[+, m), 9.46 (Il
l, broad) Calculated value as C2oHztFN30S C64,67: H5,97,N 11.31
Analysis value C64,82, H602, N 11.25 Examples 27-29 The compounds in Table 9 were synthesized in the same manner as in Example 26.

Table 9 Example 30 2-(2-chloroethyl)-4-methyl-28-1,4
-Benzothiazin-3(4H)-one 1.21g and 1-
(4-fluorophenyl)piperazine 1.08g.

Potassium carbonate 0.69g and sodium iodide 0.0
Add 5g to 15Illl of dimethylformamide and add 100
The mixture was stirred at ℃ for 4 hours. The reaction solution was poured into ice water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried (M
After gS Oa), the solvent was distilled off. The residue was subjected to column chromatography using solica gel (130 g), and the portion eluted with hexane-ethyl acetate (1:1, v/v) gave 2-(2-[4-(4-fluorophenyl)- 1-piperazinyl]ethyl-4-methyl-2H-1
, 4-benzothiazin-3(4H)-one was obtained as an oil. The main island was treated with hydrogen chloride saturated methanol to obtain hydrochloride crystals. Yield 0.99g (43.2%). A prism product was obtained by recrystallization from methanol-ether. mp
202-204℃IR(Nujol)co+-'
: 2520.2430.166ONMRδ(pI)I
) in DMSO-da: 1.6-2.4 (2H,
m) J, 5-3.64 (101, m), 3.71-3.
87 (18, m), 3.78 (3H, s), 6
．． 3 (2H, broad), 6.7-7.47 (88
0m), 11.5 (IH, broad) C21H24F N 30 Calculated value as S・2HC1 C55,02; [15,72; N 9.17 Analysis value: C55,21: H5,84, N 9.21
Examples 31 and -33 The compounds shown in Table 10 were synthesized in the same manner as in Example 30.

(Margin below) Table 1O Hs Example 34 2-(3-bromopropyl)-4-methyl-2H-1.
After dissolving 1.20 g of 4-benzothiazine-3(4H)-,one and 1.44 g of 1-(4-fluorophenyl)piperazine in 20 ml of ethyl acetate, the solvent was distilled off, and the residue was stirred at 110°C for 1 hour. did. The reaction mixture was extracted with ethyl acetate, washed with water, dried (MgSO), and concentrated. The residue was subjected to column chromatography using silica gel (40 g), and hexane-ethyl acetate (1: l, v/
2-(3-[4-(4-fluorophenyl)-■-piperazinyl 1-p-a-pyr)-4-methyl-2H-1,4-benzothiazin-3(4H)-one was extracted from the part eluted with v). Obtained as crystals.

Yield 1.00 g (62.5%). Recrystallization from ethyl acetate-hexane yielded a bright yellow prism product. mp103-1
04℃ IR (Nujol) cm-': 1645NMRδ(
ppm) in CD C13:1.4-2.1(4H
, a+).

2.3-2.59 (6H, a), 3.01-3.09
(4H, s+), 3.38-3.52 (IH, i),
3.43(3H,s), 6.73~7.41(,8H
, m) Calculated value as Cz*HtJ'Na0S: C66,14; H6,56,N 1G,
52 analysis value・C66,33; II 6.63; N
1G, 57 Example 35 2-(3-K4-(4-fluorophenylpiperazinyl]propyl)-2H-1,4-benzothiazine 193a
2" Omg of 60% sodium hydride was added to 2ml of dimethylformamide solution of +g, stirred at room temperature for 30 minutes, cooled with water, added 0.07n+1 methyl iodide and stirred for an additional hour. The reaction mixture was poured into water and diluted with ethyl acetate. Extracted with water, washed with water, dried (Mgso) and concentrated to give 2-(3-[4-(
4-fluorophenyl)=1-piperazinyl]propyl)-4-methyl-2 8-1,4-benzothiazine-3
(4H)-one was obtained as crystals. Recrystallization from ethyl acetate and hexane gave prismatic crystals with a melting point of 103-104°C. Yield: 84++g (42%) The IR and NMR of this product matched those of the compound of Example 34.

Example 36 2-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-2H-1.4-benzothiazine-
3(4H)-ON! ．． Og to dimethylformamide IO
60% sodium hydride under stirring at room temperature.
Added 20a+g. After stirring for 10 minutes, ethyl iodide 48
Add 0tsg and 2 o'clock nj! Ia continued stirring. The reaction mixture was poured into ice water and extracted with ethyl acetate. Wash the ethyl acetate layer with water. After drying (MgSO.), the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (5.Og), and hexane-ethyl acetate (2: l, v/
4-ethyl-2-(2-
[4-(2-methoxyphenyl)-l-piperazinyl]
ethyl)-2H-1,4-benzothiazine-3(4H)
-one was obtained as an oil (0.60 g). This product crystallized as hydrochloride. Yield 0.50g (39%). Recrystallization from methanol-ether gave colorless prism crystals. s
p 142-144℃IR (Nujol)a
Ill-den: 2450-2200. 16
6ONMR δ (ppm) in DMSO -da
: 1.13 (3H.t.

J=7), 1.7-2.4 (2H, Ill), 2.9
~3.87 (IIH, a), 3.79 (3H.s),
4.02 (211.q, J'=7), 6.84~7
．． 0 (8H.m)Ct3HtsN-OS・2 HCI・
l/2H. Calculated value as O: C 55.98; I
! 6.54; N 8.51 Analysis value: C 56.
18. fl 6.47. N 8.82 Example 37 2-Chloamethyl-2H-1,4-benzothiazine-3
(4H)-one 427B and 720 mg of 1-(4-fluorophenyl)piperazine were dissolved in ethyl acetate 10-1 and heated to distill off the solvent, followed by stirring at 110°C for 1 hour. After cooling the reaction mixture and adding water, 2-[4-(4
-fluorophenyl)-1-piperazinylcomethyl-2
Crystals of H-1,4-benzothiazin-3(4H)-one precipitated. Handle the crystals by filtration and wash with water and cold methanol. A prism product was obtained by recrystallization from methanol-dichloromethane.

Yield 450 o+g (62.9%). mp 19
2-193°C [R(Nujol)cm-': 320
0. 1665NMR δ(pPIi)in DM
S O ds: 2.47-2.8 (6H, a),
2.97 ~ 3.24 (4H, m), 3.86 (IH
, t, J=7).

6, 78-7.36 (88, a), 10.53 (LH
．． Broad) Calculated value as C +sH 1oF' N so S: C 63.84: H 5.64:
N 11.76 Analysis value: C 63.9:1. H
5.67, N 11.83 Example 38 2-(4-chlorobutyl)-2H-1,4-benzothiazin-3(4H)-one 435. o+g and 613n+g of 1-(4-fluorophenyl)piperazine were dissolved in ethyl acetate lo+++l, the solvent was distilled off, and the residue was heated at 100°C.
The mixture was stirred for 1 hour. The reaction product was extracted with ethyl acetate, washed with water, dried (MgSO,), and then the solvent was distilled off.

The residue was subjected to column chromatography using silica gel (40 g), and hexane-ethyl acetate (1; 1, v/
2-(4-[4-(4-fluorophenyl-1-piperazinylcobutyl)-28-1,
4-benzothiazin-3(4H)-one was obtained. Yield 2
93 mg (43,2%). Prism product recrystallized from methanol. mp 150-151'c[R(Nujo
l) cm-': 3180.1665NMRδ(ppI
Il) in CDCl3: 1.33-2.2 (6)
1°111), 2.29-2.67 (6H, m), 3
．． 03-3.14 (4B, a), 3.41 (1) 1.
d, d, J=6 and 8), 6.73-7.34
(8H, +++), 9.0 (1°broad) C□HtsF N30 Calculated value as S: C66,14:II 6.56; N 1
0.43 analysis value・C66,10,l(6,69,N
10.43 Examples 39-44 The compounds shown in Table 11 were obtained in the same manner as in Example 12.

Table 11 Example 45 6-(3-bromopropyl)-6H-1,3-dioxo[4,5-gco[1,4]benzothiazine-7(8H
)-one with 1-(4-fluorophenyl)piperazine in the same manner as in Example 12 to produce 6-(3
-[4-(4-fluorophenyl)-1-piperazinyl]propyl)-68-1,3-dioxo[4,5-g
][t,4]Benzothiazin-7(8H)-one dihydrochloride was obtained. Yield 64.8%.

mp 175-177°C (recrystallized from methanol-chloroform) C! ! Calculated value as Ht, FN303S-28C1:
C52,59,H5,22,N 8.36 Analysis value:
C52,68,H5,30,N 8.34 Example 4
6 2-(3-bromopropyl)-6,7-fuclopenteno-2H-1,4-benzothiazin-3(4H)-one was converted to 1-(4-fluorophenyl) in the same manner as in Example 2.
6,7-Cyclobenteno-2-(3-[4-(4-fluorophenyl)-5-piverazinylcopropyl)-28-1,4-benzothiazine-3(4)1 by reacting with piperazine. )-one hydrochloride was obtained. Yield 35
,1%. IIIp 135-137°C (recrystallized from ethanol-water).

Calculated value as C*hHtsFNsOS-HCl-1/2HtO: C61,19,H6,42,N 8.92
Analysis value: Cat, as: H6, 27: N 8.
Example 12 Similarly, 1
3-13-[4-(4-fluorophenyl)- by reacting with -(4-fluorophenyl)piperazine
1-Biveranyl]propyl)-7°8.9.10-tetrahydro-IH-naphtho[2,1-b][1,4]thiazin-2(3H)-one hydrochloride was obtained. Yield 60.
6%. mp l 45-147°C (recrystallized from methanol-dichloromethane).

CzsHi. Calculated value as F N 3 OS/2HCI: C5g, 59. H6, 29, N 8.20 analysis value/C58, 54; He, ao: N 8.03,
Example 48 2-(3-[4-(4-fluorophenyl)-1-piperazinyl]propyl)-5-methyl- obtained in Example 12
2H-1,4-benzothiazin-3(4H)-one 2
The hydrochloride salt was obtained by recrystallizing it from ethanol-water. ap189-191'C C*tHy. Calculated value as F NaOS-HCl:
C60,51, H6,53, N 9.57 Analysis value:
C60,61,HL24: N 9.64 Example 49 2-(3-bromopropyl)-5-methyl-2H-1,
4-benzothiazin-3(4H)-one was reacted with 1-(2-fluorophenyl)piperazine in the same manner as in Example 12 to produce 2-(3-[4-(2-fluorophenyl)-1-piperazinyl ] Propyl)-5-methyl-28-1,4-benzothiazin-3(4H)-one dihydrochloride was obtained.

Yield 24.2%. a+p 121-12.3℃C□H
Calculated value as tsFNaOS・2 HCl・I/2H,O: C54.8g, H6.07, N 8.73 Analysis value: C55.12, H5.76, N 8.44 Example 5
0 2-(3-bromopropyl)-5-methyl-2H-1,
By reacting 4-benzothiazin-3(4H)-one with 1-(3-fluorophenyl)piperazine in the same manner as in Example 12, 2-(3-[4-(3-fluorophenyl)-1-piperazinyl) ] Propyl)-5-methyl-28-1,4-benzothiazin-3(4H)-one dihydrochloride was obtained.

Yield 37.2%. mp132-134°C□H7°F
N30 S・2 Calculated value as HC1-1/2H*O: C54,88, H, 6,07, N 8.73 Analytical value: C55,05; H5,82, N 8.72 Formulation example of the present invention When compound (1) is used as an antihypertensive agent, it can be used, for example, in the following formulation.

(1) 2-(3-[4-(4-fluorophenyl)
-l-piperazinyl]provyl)-5-methyl-
2H-1,4-benzothiazin-3(4H)-one
5g (2) Lactose
95g (3) Corn starch ・2
9g (4) Magnesium stearate lo・
1000 tablets 130g (1), (2) and 17g of (3) are mixed together, granulated with a paste made from 7g of (3), and 5
g of (3) and (4) are added and the mixture is compressed in a compression tablet machine to give 1000 tablets containing (1)5+g per tablet.
Manufacture pieces.

Reference example 1 2-amino-4,5-dimethylthiophenol 3.06
Dissolve g in dimethylformamide 501 and stir at room temperature 2
．． 5.48 g of methyl 5-dibromovalerate was added and stirred for 14 hours. The reaction solution was poured into water and extracted with ethyl acetate.

After washing the ethyl acetate layer with water and drying (MgSo), the solvent was distilled off. The residue was washed with a mixed solvent of ether and hexane to give 2-(3-bromopropyl)-6,7-dimethyl-2.
8-1,4-benzothiazin-3(4H)-one was obtained as crystals.

Yield 4.35g (69.3%). Prism crystals recrystallized from methanol. -p 152-153℃ IR (Nujol) cm-': 320G, 166
GNMRδ (ppm) in CD C13: 1.3
7-2.27 (4■.

s), 2.42 (6H', s), 3.23-3.4 (
111, i), 3. :(7(2H,t,J=6),
6.64 (lH, s), 7.03 (LH, s), 8
．． 9(11,broad)C+sH+*B rN OS
Calculated value as: C49,69; H5,H; N 4.4
6 analysis value: C49.84, H4.97, N 4.7
5 Reference Example 2-10 The compounds shown in Table 12 were obtained in the same manner as in Reference Example 1.

(Margin below) Table 12 Reference Example II 4.6 g of 2-aminothiophenol was dissolved in 50 ml of dimethylformamide, and methyl 2.4-dibromobutyrate (9.55 g) was added while stirring at room temperature. After stirring for 1 hour and pouring into water, 2-(2-bromoethyl)-2H-1,
Crystals of 4-benzothiazin-3(4H)-one were precipitated. Filter the crystals and add water and n-hexane.

Washed with cold methanol. Yield 6.32g (63,3
%).

Prism product recrystallized from ethyl acetate. mp151-15
2℃.

l R(Nujol)am-': 3200.166O
NMRδ(1)PI)in CDCl5: 1.90
~2.67 (28゜m), 3.57 (2H, t, J=
6), 3.71 (ill, d, d, J=6 and
8).

6.80-7.37 (4H, m), 9.5 (IH, b
load) Calculated as CloH+oB rN OS: C44,13; H3,7G, M 5.
15 Analysis value: C44,0:I; H3,54,N
5.13 Reference Example 12 3.10 g of 2-amino-5-methoxythiophenol and 5.20 g of methyl 2.4-dibromobutyrate were dissolved in trimethylformamide 30+1, stirred at room temperature for 2 hours, and then poured into ice water to obtain the crystals. The water intake was filtered. Recrystallized from methanol to give 2-(2-bromoethyl)-7-medoxy 2H.
-1,4-benzothiazin-3(4H)-one was obtained as prismatic crystals. Yield 3.94g (65.2%), mp
I 42-143℃I R(Nujol)Cm-'
: 3190.165ONMRδ(pI)m)in
CDC1,: 1.87-2.63 (21(.

m), 3.60 (2H, t, J=6), 3.68 (IH
, d, d, J=6 and 8).

3.76 (3H, s), 6.83-6.92 (3H,
m), 9.62 (IH.

broad) Calculated value as C++H+tBrNOtS; C43°72; Fl 4.00. N4.
64 analysis value: C44, 09, H3, 6G, N 4
．． 52 Reference Example 13 (1) 3.0 g of 2-ethoxycarbonyl-2H-1,4-benzothiazin-3(4H)-one was dissolved in ethanol (
0.95 g of sodium borohydride was added little by little to 50 ml of the solution under stirring at room temperature. After stirring for 2 hours, the mixture was diluted with water, acidified with dilute acetic acid, and extracted with ether. The ether layer was washed with water, dried (MgS O), and concentrated under reduced pressure.

The residue was washed with hexane to give 2-hydroxymethyl-2
H-1,4-benzothiazin-3(4)1)-one was obtained as crystals. Yield ff 11.25g (50.8%). Prism crystals recrystallized from ethyl acetate.

mp156-157℃ IR (Nujol) cm-': 3500-3300
．． 3200.167ONMRδ(99m)tut D
MS Ods: 3.41-3.74 (3H, m),
5.09 (18, m), 6.83-7.33 (41 (
, m), 10.83 (IH.

Broad) Calculated value as CeH*NO2: C55°37; l(4,65,N 7.1?
Analysis value: C55,39; H4,68: II 7
．． 29(2) 2-hydroxymethyl-2H-1,4-
Benzothiazin-3(4H)-one 1. Og was dissolved in 20 ml of chloroform, 0.9 ml of thionyl chloride was added, and the mixture was heated under reflux for 2 hours. After concentration under reduced pressure, the residue was extracted with ether, washed with water, dried (MgSO,), and the solvent was distilled off. The crude product was subjected to column chromatography using Norica gel (40 g) and hexane-ethyl acetate (40 g).
・1. 2-chloromethyl-
28-1,4-benzothiazin-3(4H)-one was obtained as crystals. Yield: 640 mg (58.7%) Recrystallized from ethyl acetate and n-hexane to give needle-shaped crystals. mp 152
-153°C [R(Nujol)cm-': 3190
．． 166ON M Rδ (ppm) in CDCl3
: 3.6-3.93 (3fl.

m), 6.89-7.37 (411, m), 9.4 (
III, broad) Calculated as ceHsclNOs: C50,59, H3,77, N 6.55
Analysis value: C50,44: l(3,53,N 6.
54 Reference Example 14 2-(2-hydroxyethyl) in the same manner as Reference Example 13
-2H-1,4-benzothiazin-3(4H)-one is reacted with thionyl chloride and 2-(2-chloroethyl)-
2H-1,'4-benzothiazin-3 (4H)-one was obtained. Yield 72.7%. Prism crystals recrystallized from methanol. mp133-133.5℃ IR(Nujol)cIll-': 3200.16
6ONMRδ(1)Ill)in CDCl3:
1.72-2.57 (21+.

m), 3.59-3.87 (311, i+), '6.8
4-7.35 (411, m), 9.64 (IH, br
oad) Calculated value as C1oH1o01NO8: C52,75: H4,43,N 6.1
5 analysis value: C52, 62; H4, 27; N 6
．． 1G Reference Example 15 (1) Dissolve 6.26 g of 2-aminothiophenol in 50 nl of dimethylformamide, add 9.85 g of 2-bromo-5-hydroxyvaleric acid, and stir at room temperature for 2 hours.

The mixture was stirred at 100°C for 1 hour. After cooling the reaction solution, it was poured into water and extracted with ethyl acetate. Wash the ethyl acetate layer with water.

After drying (MgSO,), it was concentrated under reduced pressure. The residue was subjected to column chromatography using a sorbent gel (200 g), and the portion eluted with hexane-acetone (2: L, v/v) contained 2-(3-hydroxypropyl) = 2H-.
1,4-Benzothiazin-3 (4H)-one was obtained as crystals. Yield 3.7 g (31.6%). Recrystallized from ethyl acetate and hexane to give prismatic crystals. mp59-60℃ IR(Nujol)co+""l: 3500-3
100.3200.166ONMRδ(pI)l)in
CDCl5: 1.53-2.1 (4H.

m), 2.4 (IH, broad), 3.37~
4.02 (3H, broad).

6.93~? , (3(4H,m), 9.57(l[(
, broad) C, , H, , NO, S Calculated values: C59,17, H5,87; N 6.2
7: Analysis value: C5g, 83; H5,81: N
6.53(2) 2-(3-hydroxypropyl)-
28-1゜4-Benzothiazin-3(4H)-one was reacted with thionyl chloride in the same manner as in Reference Example □13-(2) to form 2-(3-chloropropyl)-2H-1,4-benzothiazine- 3(4H)-one was obtained. Yield 59
．． 1%.

Recrystallized from ethylhexane sieve, prism product.

g+p98-99℃'-IR(Nujol)cm-': 32G0.166
5NMRδ (ppm) in cDC13: 1.62
~2.2 (4H.

l11), 3.33-3.72 (3H, m), 6.8
6-7.33 (4H, a+), 9.64 (1[, br
oad) CII Hlt CI S OS Calculated value 2 C5
4,66, II 5.00. N 5.79 analysis value:
C54,51; 114.84. N 5.74 Reference Example 16 (1) 2-(3-Bromop-d-Pyr)-28-1,4
-Penzothiadiy-3(4H)-72.86g was dissolved in dimethyl sulfoxide Ihl, 0.54g of sodium cyanide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water, and the resulting crystals were collected by filtration and washed with water.

Recrystallized from methanol to give 2-(3-cyanopropyl)-
28-1,4-benzothiazin-3(4H)-one was obtained as a prismatic product. Yield 1.55g (66.7%).

tap l 07-108℃IR(Nujol)c
m-' 3190.2220, [6σ5(broad)
NMRδ (ppm) in CDCl3: 1.62~
2.22 (4H.

m), 2.23-2.45 (211, Il), 3.35
~3.50 (ill, m), 6.85~? J5 (4H
,・i), 9.17(lH,broad)CI t
H1! Calculated value as N20S: C62,05
, H5, 21; N 12.06 analysis value: ” C61
,78;■5.1(+, g 11.79(2) 2
-(3-cyanopropyl)-28-1,4-penzothiazin-3(4H)-one i, 4sg at 18.8% (W/
W) Dissolve in hydrogen chloride ethanol solution 40s+l, water 0
．． 3 ml was added and heated under reflux for 24 hours. After cooling the reaction solution, it was diluted with water and extracted with ether. The ether layer was washed with water, a saturated aqueous sodium bicarbonate solution, and water in this order, and then dried (MgSO4). The solvent was distilled off to obtain 2-(3-ethoxycarbonylpropyl)-2H-1,4-benzothiazin-3(4H)-one as crystals. Yield 1.
60g (91,4%). Prism crystals recrystallized from ethyl acetate. 6 78-79℃IR(Nujol)cm-'
: 320G, 1730.166ONMRδ(ppa
) in CDC1a: 1.21 (3H, t, J=7
), 1.5-2.2 (4H, m), 2.31-2.
47 (2H, a), 3.32-3.51 (IH, m)
, 3.44 (2H, q, J=7), 6.72-7.
39 (4H.

1), 8.2 (IH, broad) Calculated value as C14H17N Os S: C80,19,H6,13; N 5.0
1 Analysis value 2 C60,33,H6,03,N 5.44
(3) 0.46 g of lithium aluminum hydride was suspended in 50 ml of ether, and under stirring under water cooling, 2-(3-ethoxycarbonylpropyl)-28-1,4-benzothiazine-
A solution of 1.6 g of 3(41-1)-one in ether (30 m
l) was added dropwise. After stirring for 1 hour, water was added dropwise, white starch was filtered off, and the filtrate was dried (MgSO,).

After evaporating the solvent, the residue was subjected to column chromatography using silica gel (70 g), and 2-(4-
hydroxybutyl)-28-1,4-benzothiazine-
3(4H)-one was obtained as crystals.

Yield 0.75 g (55.6%). Prism crystals recrystallized from ethyl acetate. ip l 01-102℃ IR (Nujol) cm-': 3400-3150
．． 3210.166ONMRδ(1)l)l)in
CDCb: 1.44-2.1 (6H.

m), 1.80 (IH broad), 3.
31-3.71 (3H, n+), 6.81-7.3
3 (4H, m), 9.24 (IH, broad) C1
Calculated value as x Hls N Ot: C60,73; H6,37,N 5.9
0 analysis value: C60, 69, H6, 35: N 5.
82(4) 2-(4-hydroxybutyl)-2H-
1゜4-Benzothiazin-3(4H)-one in Reference Example 1
2-(4-
Chlorbutyl)-21-1-1,4-benzothiasif
-3(4H)-one was obtained. Yield 59.0%. ll1p
Ill-112°C (recrystallized from ethyl acetate-hexane)
.

I R (Nujol) cm-'+ 3190.1665
NMRδ(pl)l)in CD CIs: 1.4
7-2.06 (6H.

n+), 3.3(~3.57(3H,*), 6.86~
7.34 (4H, s), 9.67 (IH, broad
) C,, H,, Calculated value as CIN OS: C56,35;■5.52. N5.4
g analysis value: C56,26; H5,41,N 5.
13 reference examples! 7 (1) Dissolve 4.18 g of 2-(2-hydroxyethyl)-28-1°4-benzothiazin-3(4H)-one in 50 ml of dimethylformamide, and stir under water cooling for 60 minutes.
% sodium hydride was added little by little, and after stirring for 10 minutes, 1.24 ml of methyl iodide was added.

The mixture was stirred for 1 hour at room temperature, diluted with water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO,), and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (50 g), and hexane-ethyl acetate (2
:l, v/v) 2-(2-hydroxyethyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one was obtained as an oil. Yield 3.9
0g (87,4%).

IR (Nujol) cm-': 3600-3250.
1660 (broad) NMRδ (ppm) in
CD CI3: 1.62-2.31 (2H.

m), 2.47 (11, broad), 3.43 (3
B, s), 3.61 (18, t, J=7), 3.7
7 (2H, s), 6.90-7.41 (4H, m) (
2) 2-(2-hydroxyethyl)-4-methyl-
28-1,4-benzothiazin-3(4H)-one4.
90 g was dissolved in 20+ nl of dichloromethane, and 5 ml of thionyl chloride was added while stirring at room temperature. After stirring for 1 hour,
The residue was subjected to column chromatography using silica gel (35 g), and hexane-ethyl acetate (4:I
, v/v), 2-(2-chloroethyl)-4-methyl-2H-1,4-benzothiazine-3(
4H)-one was obtained as an oil. Yield 5.05g (9
5.3%).

I R(r+eat)cm-'+ 1660NMRδ(
1)I)l)in CD Cls: 1.83-2.5
5 (2H.

m), 3.46 (3H, s), 3.56-3.
76 (lit, amount), 3.70 (28, t.

J=6), 6.91-7.43 (4H, l) Reference Example 1
8 2.78g of 2-methylaminothiophenol and 2.5-
5.48 g of methyl dibromovalerate was dissolved in 1 Ohl of dimethylformamide and stirred at 50° C. for 2 hours. Pour the reaction solution into cold water, extract with ether, and wash with water.

After drying (MgSO,) the solvent was distilled off. The residue was subjected to column chromatography using silica gel (150 g) and hexane-ethyl acetate (4: l, v/v).
2-(3-bromopropyl)-4-
Methyl-28-1,4-benzothiazine-3(4H)-
On was obtained as an oil. Yield 4.57g (76.2%
).

I R(neat)am″″’: 166ONMRδ(
ppa+)in c D Cts:t, sa ~2.
23 (4H, a).

3.31-3.5 (3B, a), 3.44 (31, s
), 6.91-7.40(4H)+) Reference Examples 19-23 The following compound was obtained in the same manner as in Reference Example 1.

Table 13 Reference Example 24 2-Amino-4,5-methylenedioxythiophenol was reacted with methyl 2,5-dibromovalerate in the same manner as in Reference Example 1 to produce 6-(3-bromopropyl)-
6H-1,3-dioxo[4°5-g][1,4]benzothiazin-7(8H)-one was obtained. Yield 45.0
%. ap 168-169°C (recrystallized from methanol-dichloromethane).

Reference example 25.

By reacting 2-amino 4,5-cyclopentenothiophenol with methyl 2,5-dibromovalerate in the same manner as in Reference Example 1, 2-(3-bromopropyl)-6,
7-cyclopenteno-2H-1,4-benzothiazine-
3(4H)-one was obtained.

Yield 44.3%. B 178-179°C (recrystallized from methanol-dichloromethane).

Reference Example 26 1-Amino-5,6,7,8-tetrahydro-2-thionaphthol was reacted with methyl 2,5-dibromovalerate in the same manner as in Reference Example 1 to produce 3-(3-bromopropyl). -7,8,9,10-tetrahydro-IH-naphtho[2,lb][1,4]thiazine-2(3H)-
Got it on. Yield 38.2%.

mp 122-123°C (recrystallized from methanol). -Effects of the Invention The 1,4-benzothiazine derivative (1) and its salts of the present invention have strong vasodilatory effects, adrenaline receptor blocking effects, hypotensive effects based on intracellular calcium antagonism, and cerebral circulation improving effects. has. In particular, a major feature of the compound of the present invention is that it exhibits intracellular calcium antagonism, and exhibits pharmacological effects in a wider range than conventional Ca"+ channel inhibitors. In addition to inhibiting vasoconstriction, it also inhibits tracheal muscle contraction In order to show its effectiveness, it is used as an anti-asthma drug.
.

It is also expected that it will be applied as In addition, the compound of the present invention has a protective effect on the ischemic heart, brain, and kidneys, has low toxicity, and has few side effects such as orthostatic hypotension that is often seen with α-receptor blockers such as prazosin. Especially hypertension, brain,
It is highly useful as a prophylactic and therapeutic drug for ischemic diseases of the heart, kidneys, etc. (cerebral infarction, hyperischemic attack, myocardial infarction, acute renal failure, nephritis, etc.).

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent hydrogen, halogen, lower alkyl group, lower alkoxy group, trifluoro The methyl group, or R^1 and R^2, are bonded to each other and have the formula ▲ mathematical formula, chemical formula, table, etc. ▼ [in the formula,
n represents an integer of 3 to 5] or form a 5- to 7-membered ring represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
5 to 6 represented by [in the formula, m is 1 or 2]
R^3 and R^4 are the same or different and represent hydrogen, halogen, lower alkyl group, lower alkoxy group, or trifluoromethyl group, R^5 represents hydrogen or lower alkyl group, A each represents an alkylene group] or an acid addition salt thereof. 2. In the general formula, R^1 and R^2 are combined with each other to form the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n is 3 to 5
The 1,4-benzothiazine derivative according to claim 1, which forms a 5- to 7-membered ring represented by the following integer. 3. In the general formula, R^1 and R^2 are bonded to each other to form a 5- to 6-membered ring represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, m is 1 or 2] The 1,4-benzothiazine derivative according to claim 1, which is formed by: 4. The 1,4-benzothiazine derivative according to claim 1, wherein in the general formula, at least one of R^3 and R^4 is fluorine. 5. Claim 1 in which R^5 is hydrogen in the general formula
The 1,4-benzothiazine derivative described in 1. 6. Claim 1 in which A is ethylene in the general formula
The 1,4-benzothiazine derivative described in 1. 7. The 1,4-benzothiazine derivative according to claim 1, wherein A is trimethylene. 8. In the general formula, at least one of R^1 and R^2 is a lower alkyl group, and at least one of R^3 and R^4 is fluorine substituted at the 4-position of the benzene ring. 1,4-benzothiazine derivative according to item 1. 9. In the general formula, R^1 and R^2 are combined with each other to form the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n is 3 to 5
[indicates an integer] to form a 5- to 7-membered ring, R^
The 1,4-benzothiazine derivative according to claim 1, wherein at least one of 3 and R^4 is fluorine. 10,6,7-cyclopenteno-2-{3-[4-(4
-fluorophenyl)-1-piperazinyl]propyl)
The 1,4-benzothiazine derivative according to claim 1, which is -2H-1,4-benzothiazin-3(4H)-one. 11,2-{3-[4-(4-fluorophenyl)-1
-piperazinyl]propyl}-5-methyl-2H-1,
The 1,4-benzothiazine derivative according to claim 1, which is 4-benzothiazin-3(4H)-one. 12. As active ingredients, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. Or, R^1 and R^2 are combined with each other to form a formula ▲ a mathematical formula, a chemical formula, a table, etc. ▼ [in the formula,
n represents an integer of 3 to 5] or form a 5- to 7-membered ring represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
[In the formula, m is 1 or 2] forming a 5- to 6-membered ring, R^3R^4 are the same or different and hydrogen, halogen, lower alkyl group, lower alkoxy group, or trifluoromethyl group, R^5 represents hydrogen or a lower alkyl group, and A represents an alkylene group, respectively] and a pharmacologically acceptable carrier or diluent of a 1,4-benzothiazine derivative or an acid addition salt thereof. A pharmaceutical composition containing the agent. 13. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different and are hydrogen, halogen, lower alkyl group, lower alkoxy group, trifluoromethyl group, or R^ 1 and R^2 are mutually combined to form a formula ▲ mathematical formula, chemical formula, table, etc. ▼ [in the formula,
n represents an integer of 3 to 5] or form a 5- to 7-membered ring represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
5 to 6 represented by [in the formula, m is 1 or 2]
Compounds that form a membered ring, R^5 represents hydrogen or a lower alkyl group, and A represents an alkylene group] and the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^ 3 and R^4 are the same or different and represent hydrogen, halogen, lower alkyl group, lower alkoxy group or trifluoromethyl group] General formula ▲ Numerical formula, chemical formula, table etc. ▼ [In the formula, R^1, R^2, R^3, R^
4, R^5 and A have the same meanings as defined above] or an acid addition salt thereof.