JPH0466585A - Thienotriazolothiazepine derivative and intermediate - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is H, lower alkyl or halogen; R<2> is H or lower alkyl; R<3> is H or halogen). EXAMPLE:5-(2-Chlorophenyl)-1,2,3,5-tetrahydrothieno[2,3-e][1,4]-t-hiaz epin-2-one. USE:Having antagonism on platelet activating factor and useful as an antiasthmatic, etc. PREPARATION:A compound shown formula II is reacted with hydrazine hydrate to give a compound shown by formula III. The compound is reacted with a compound shown by the formula R<2>C(OR<5>)3 (R<5> is lower alkyl) or a carboxylic acid shown by formula R<2>COOH or a reactive derivative thereof in an inert solvent such as benzene in the presence of an inorganic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to pharmaceuticals, particularly platelet activating factor (PAF).
The present invention relates to chenotriazolothiazepine derivatives and conductors that have antagonistic effects and are useful as anti-asthmatic agents, as well as novel intermediates of the compounds.

(Prior Art) PAF is a chemical substance released from human and animal cells, and is acetylglyceryl ether of phosphorylcholine represented by the following formula.

CH20(CH2)/CH3 CH3COO-CH0 CH20-P'-0(CH2)2 N"(CH3)3
(In the formula, l means 15 or 17.) PAF is
airway smooth muscle contraction, increased vascular permeability, platelet aggregation,
It has physiological activity that lowers blood pressure and is thought to be a factor that causes various symptoms such as asthma, inflammation, thrombosis, nephritis, and shock. Therefore, research into substances that antagonize the physiological activity of PAF is underway, and several anti-PAF drugs have been reported (e.g., JP-A-59-134798, JP-A-61-93191, JP-A-61-93191; JP-A-60-116679, JP-A-60-142932, JP-A-59-134798
No., JP-A-61-87684, JP-A-61-3772
No. 6, JP-A-63-22588, JP-A-63-225
No. 89. ) The present inventor completed the present invention by recognizing the excellent anti-PAF activity of a novel chenotriazolothiazepine derivative and its salt, which have a different chemical structure from conventional anti-PAF drugs.

(Means for Solving the Problems) That is, the present invention provides a chenotriazolothiazepine derivative represented by the following general formula (I), and a chenotriazolotiazepine derivative represented by the following general formula (II) useful as a synthetic intermediate for the compound. It is a chenothiazepine derivative.

(In the formula, R1 is a hydrogen atom, a lower alkyl group, or a halogen atom, and R2 is a hydrogen atom or a lower alkyl group.
3 means a hydrogen atom or a halogen atom, and X means an oxygen atom or a sulfur atom. The same applies below) The compound of the present invention will be described in more detail as follows.

In the definition of the general formula herein, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, specific examples of lower alkyl groups include methyl group, ethyl group, globyl group, improhil group, butyl group,
Isobutyl group, sec -f # group, ter
t-butyl group, pentyl (amine) group.

isohentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1
, 2-dimethylglobil group, hexyl group.

Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-#tylpentyl group-1゜1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1.2-trimethylpropyl group.

1.2,2-trimethylglobyl group, 1-ethyl 1-methylglobyl M, I-ethyl-2-methylbutyl group, and the like.

Furthermore, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The compound of the present invention has various optical isomers based on asymmetric carbon atoms. The present invention includes separated versions of these isomers as well as mixtures of each isomer.

(Manufacturing method) The method for synthesizing the compound (I) of the present invention will be explained below.

That is, the compound represented by general formula (I) is.

General formula (H&) React the compound shown with hydrazine hydrate.

A compound represented by the general formula (TV) is obtained (first step), and this compound is combined with the general formula (V) R2C(OR')! (v) (in the formula R
5 means a lower alkyl group. The same applies hereinafter) or a carboxylic acid represented by the general formula (VD R2COOH(Vl)) or a reactive derivative thereof (second step).

In the first step, the reaction between the compound represented by the general formula (IIa) and hydrazine hydrate involves alcohols such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane,
The reaction can be carried out in a solvent inert to the reaction, such as acetonitrile, under cooling or heating. The reaction time is from several minutes to several hours.

Second step: Reaction of the compound represented by the general formula (rV) with the compound represented by the general formula (V) or the carboxylic acid represented by the general formula (VD) or a reactive derivative thereof.

Benzene, toluene, xylene, tetrahydrofuran,
In a reaction-inert solvent such as dioxane.

If necessary, the reaction can be carried out in the presence of an organic acid such as acetic acid or propionic acid or an inorganic acid such as hydrochloric acid or sulfuric acid at room temperature or under heating under reflux. What is the reaction time?

It takes several tens of minutes to several hours.

The compound (IV) obtained in the first step of the one-step production method is
- can be subjected to the second step with or without isolation.

Next, the compound represented by general formula (II) is also a novel product that has not been described in any literature, and a typical method for producing this compound will be described below.

(■) (■) (IX) (X) (IIa) (Ilb) (■c) (In the formula, R'a is a hydrogen atom or a lower alkyl group.

R4 means a nitrogen atom protecting group, and R5 means a lower alkyl group. (The same applies hereinafter) Step a General formula (Compounds shown in ``City'' are converted into compounds by reduction with potassium borohydride, sodium borohydride, lithium aluminum hydride, etc., or catalytic reduction using a catalyst such as palladium on carbon, Raney nickel, rhodium on carbon, etc.) (V
ll).

The protecting group for the nitrogen atom in the compound (VID) is a protecting group that is generally well known in organic synthetic chemistry, such as trimethylsilylethoxycarbonyl,
tert-butoxycarbonyl.

Allyloxycarbonyl, penzyloxysulfonyl,
These include alkoxycarbonyl groups such as p-methoxypendyloxycarbonyl, and acyl groups such as formyl, acetyl, and benzoyl.

Step b Compound represented by general formula (IX): 'i, general formula (hair l
It can be obtained by reacting the compound represented by 1l) with thioglycolic acid lower alkyl ester in the presence of 7, for example, triphenylphosphine or diethyl azodicarboxylate.

C process The carboxylic acid derivative represented by general formula (X) is.

It can be obtained by hydrolyzing Nisdel represented by the general formula ([).

Hydrolysis is carried out using thorium hydroxide using a conventional method.

This can be carried out using an aqueous solution of potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, or the like.

Step d The compound represented by the general formula (IIa) can be produced by cyclizing the carboxylic acid derivative represented by the general formula (X) with 9, for example, oxalyl chloride.

Examples of the reaction solvent include dichloromethane and chloroform.

Further, the reaction temperature is between cooling and room temperature.

Step e: The compound represented by the general formula (rIb) has the general formula (Il,
) is phosphorus pentasulfide, Lawesso
n reagent (2,4-bis(4-methquinphenyl)-13
It can be obtained by reacting Kujithia-2,4-diphosphethane-2,4-sulfide and the like. Pyridine, dimethylaniline, benzene,
Toluene, xylene, tetrahydrofuran, chloroform, geocan.

, 2-dimethoxyethane, etc., and the reaction temperature is from room temperature to elevated temperature.

Step f The compound represented by general formula (■c) is represented by general formula (IIb)
It can be obtained by introducing a halogen atom into the compound represented by. This halogenation.

This is carried out by applying a halogen such as chlorine or bromine at room temperature or under heating. Examples of the reaction solvent include dichloromethane, chloroform, dioxane, and the like.

The resulting reaction product is isolated and purified in its free form or as a salt. Salts can be produced by subjecting them to commonly used salt-forming reactions.

Isolation and purification includes extraction, concentration, crystallization, 'f1 filtration, recrystallization,
It is carried out by applying ordinary chemical operations such as various types of chromatography.

(Effects of the Invention) Compound (I) of the present invention and its salts have PAF antagonistic activity and are useful for treating and preventing various diseases caused by PAF. Especially anti-asthmatic drugs.

Anti-inflammatory agent, anti-tumor agent, and shock symptom reliever.

It can be used as a therapeutic agent for ischemic heart disease, liver disease, facet syndrome, and nephritis, and as a rejection inhibitor for organ transplantation.

The anti-PAF effect of the compound of the present invention was confirmed by the following method.

Inhibition test against platelet aggregation caused by PAF Test method: Nine volumes of blood were collected from the ear artery of a male Japanese white rabbit weighing 3 kg/cm into a plastic syringe containing 1 volume of 38% sodium citrate aqueous solution.

Platelet rich plasma (PRP) is obtained by centrifuging the blood at 270Xg for 10 minutes.
plasma), and the remaining blood was further diluted with 11 (lo
Centrifuge at xg for 15 minutes to collect platelet poor plasma (P P P :
platelet poor plasma) was obtained.

Dilute PRP with P P P and increase the platelet count to 500,000/
After preparing µl, platelet aggregation by PAF was inhibited by bone and cross [Journal of Physiology] Vol. 68, 1.
78-195 (1963).

That is, the change in light transmittance of PRP due to PAF (10-'M) was measured using an NBS hematotracer (Binogen Biosciences). In addition, the compound is PAF-added 2
The IC50 value (50% inhibitory concentration) is determined from the inhibition rate of the maximum light transmittance by PAF in the control.

The compound of the present invention contains ADP (3 μM), arachidonic acid (1 μM),
P.0011M) and collagen (10 μg/ml) showed no inhibition on platelet aggregation.
It seems to be an antagonist with different AFK%.

One or two compounds represented by general formula (I) or salts thereof
Preparations containing these as active ingredients include 5 commonly used carriers and excipients for preparations.

2 tablets, powders, fine granules with other additives.

It is prepared into granules, capsules, pills, liquids, injections, tablets, ointments, patches, etc., and is administered either baldly (including tongue administration) or parenterally.

The clinical dosage of the compound of the present invention is appropriately determined taking into consideration the symptoms, weight, age, gender, etc. of the patient to whom it is applied, but is usually 0.1 to 100 [11 g] per day for adults, and this is administered once. (Example) The present invention will be explained in more detail with reference to Examples below.

Reference example 1 2-amino-3-(2-chlorobenzoyl)thiophene (3.1 g), di-tert-butyl dicarbonate
) (8,3 g), 10% aqueous sodium hydroxide solution (5
A mixture of 0mZ) and tetrahydrofuran (50mZ) was stirred at 80°C for 4 days. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate-100:1) to obtain 2-(t
ert-butoxycarbonylamino)3-(2-10 lobensoyl)thiophore (2.8 g) was obtained.

Physical and chemical properties Mass spectrometry value m / z 337 (M”) Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard) δ:
1.54' (s, 9H), 6.55 (d, IH), 6
．． 67(d, IH).

7.28-7.49 (m, 4H), 11.1 (
br, IH) Reference example 2 Sodium hydride (54■) dimethylformamide (2
2-amino-3-(2chlorobenzoyl)-5-ethylthiophene (500 mg) (
7) Add dimethylformamide (5mt) solution dropwise.

The mixture was heated to room temperature and stirred for 20 minutes. Add tert to the reaction solution.
A solution of -butyl dicarbonate (6 oomg) in dimethylformamide (5 ml) was added, and the mixture was stirred at room temperature for 1 hour, and then at 70°C for 1 hour. Add water to the reaction mixture,
It was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate 10:1) to give 2-(tert-butoxycarbonylamino)-3-(2-chlorobenzoyl)5- Ethylthiophene (440rl1g) was obtained.

Physical and chemical properties Melting point 118°C Elemental analysis value (as C, 8H2oNCINO3S) C (
h) Hf coefficient + N (@S (ch) C1 (ch) Theoretical value 59,095.51 3,838,769.69 Experimental value 58,925,513,738,789.61 Reference example 3 2-(tert -butoxycarbonylamino)-3(2
Sodium borohydride (2.0 g) was added to a solution of -1'lolobensoyl)thiophene (7.2 g) in dimethylformamide (20 ml), and the mixture was stirred at room temperature for 36 hours. The reaction solution was diluted with water and ethyl acetate, several ml of acetic acid was added under water cooling, and the mixture was stirred for 2 hours. Extract with ethyl acetate, and wash the extract sequentially with water and saturated brine.

It was dried with anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the resulting residue was filtered through a silica gel column Chromadog 7F (
Hegisan:ethyl acetate = 10:1 to 2:1) to purify + 2- (t, ert-bu[xycarbonylamino)-:3-1(2-chlorotanyl)hydroxymethylcothiophene ( 6.4g) wo(Lri.

Physical and chemical properties Melting point 115-117'C Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard) δ: 1.52 (s, 9H), 3.07 (
d, IH), 6.27 (d, IH).

6.40 (d, IH), 6.75 (d, IH), 7.1
6-757 (m, 4H), 8.05 (br, IH) Reference Example 1 )
2-(tert-butoxycarbonylamino L-3-[(2-chlorophenyl)hydroxymethylio5-ethylthiophene) was synthesized from 5-dimethylthiophene.

Physical and chemical properties Melting point 119-120°C Elemental analysis value (as Cl8H2□ClN0.S) C (chi) H (chi) N (%l S (%) CI (%) Theoretical value 58,776,033.81 8,729.64 Experimental value 58,636,103,798,839.87 Diameter example 5 2-(tert-)゛toxycarbonylamino)-3
A mixture of 1(2-1'rollophenyl)hydroxymethyl]5-ethylthiophene (6.8 g), rlinoenylphesphine (5.8 g), and benzene (100 ml) was stirred at room temperature for 10 minutes. A solution of deutyl azodicarbokinra) (3.9 g) in benzene (20 m, ') was added to the anti-riT solution under water cooling, and after stirring at the same temperature for 5 minutes,
Ch/S force gel column chromatography (hexafulbol-5-ylmethylthio) -:? -ri DO phenylmethyl:)
-5-ethylthio-7ene (5.9 g) was obtained.

Physical and chemical properties Mass spectrometry values m,・z 470 (M+) Nuclear magnetic resonance subekle (CDCl2. TMS internal standard) δ
: 11:2-1.39 (m, 6H), 1.55 (q,
9H).

2.65 (dq, 2H), 3.11 (a, 2
H), 4.24 (q.

2H), 5.82 (s, IH), 6.26
(br, IH i).

7.12~7.43 (m, 3H), 7.76~7
．． 88 (m, IH) Reference Example 6 In the same manner as in Reference Example 5, 2-(tert-butoxycarbonylamino)-3-[(2-chlorophenyl)hydroxymethylcothiophene to +2 (tert-butoxycarpogylamino)-13- Combine [(ethoxycarbonylmethylthio)2-chlorophgonylmethyl]thiophene and bM L f=.

Physical and chemical properties Mass spectrometry value m7”z 4 = 11 (M+) Nuclear magnetic resonance spectrum (CDCl2. TMS internal standard) δ
: 1.34(t, 3H), 1.58(s, 9
HL 3.12 (s, 2H).

4. 26 (q, 2H), 5.87 (s, IH)
, 6.51 (d, IH).

6.74 (d, IH), 7°16~76M (m, 3
H).

7.8:? -7.94 (m, IH) Reference example 7 2- (tert-butogine carbonyl amine 7)) [(
A 10% aqueous solution of sodium hydroxide (sn+l) was added to a solution of giacarbonylmethylthio) dilorophenylmethyl]thiophene (6601 ng) in methanol (5 ml) under water cooling, and the mixture was stirred at room temperature for 12 hours.

The reaction solution was diluted with water, concentrated hydrochloric acid was added to adjust the pH of the solution to 1, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2-(tert-butoxycarbonylamino)-3-[(carboxymethylthio)-2-chlorophenylmethylcothiophene (510 mg).

Physical and chemical properties Mass spectrometry value m/z 413 (M”) Nuclear magnetic resonance spectrum (CDCI5.TMS internal standard) δ:
1.54 (s, 9H), 3.20 (s, 2H), 5.8
2(s, IH).

6.58 (d, IH), 6.78 (d, IH), 7.2
1-744 (m, 3H), 7.78-7.90 (m, I
H) Reference Example 8 2-(tert-butoxycarbonylamino)-3-[(carboxymethylthio)-
2-chlorophenylmeth]-5-r-thiophene was synthesized.

Raw material compound: 2-(tert-butoxycarbonylamino)-3-[(ethoxycarbonylmethylthio)-
2-chlorophenylmethyl]-5ethylthiophene Physical and chemical properties Mass spectrometry value m/z 441 (M+) Nuclear magnetic resonance spectrum (CDCI, TMS internal progression) δ 1.20
(t, 3H), 1.51 (s, 9H), 2.
66(q, 2H).

3.19 (s, 2H), 5.79 (s, IH),
6.34 (s, IH).

7.12-7.43 (m, 3H), 7.76-7.
86(m, IH) Example 1゜2-(tert-butoxycarbonylamino)-3-
[(carboxymethylthio)-2-chlorophenylmethylcothiophene (310ff1g) in dichloromethane (
A solution of N,N-dimethylformamide (1 drop) and oxalyl chloride (110 ml) in dichloromethane (1 mt) was added to the 5 mt) solution at -78°C.

The temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate 4:1) to give 5-(2-chlorophenyl)-1,2,3,5-tetrahydrocheno[2 ,3-e][1,4]]thiazepin-2-one (32111 g) was obtained.

Physical and chemical properties Melting point 186-188°C Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)
δ 3.16 (d, IH), 3.44 (d, IH), 6
．． 05 (s, IH).

6.40 (d, IH), 6.92 (d, IH), 7.2
2-2.88 (m.

5H) Example 2゜2 (tert-butoxycarbonylamino)-3-
To a solution of [(carboxymethylthio)-2-chlorophenylmethyl]-5-ethylthiophene (110 IT] g) in dichloromethane (2 ml) was added N,N-dimethylformamide (1 drop), oxalyl chloride (7 ml) at 78°C.
0 mg) in dichloromethane.

The temperature was gradually raised to room temperature and stirred for 1 hour. Trifluoroacetic acid (1 ml) was added under water cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure, .N, was purified using silica gel column chromatography (-\xane:ethyl acetate 2=]) and 5-(2-chlorophenyl)7-nityl 1.2 ,3,5-tetrahydrochenoC2,3-e]CI,4]]'? '-azepin-2-one 53ITIg) was obtained.

Physical and chemical properties Melting point 181-183°C Nuclear magnetic resonance spectrum (CDC1, TMS internal standard)
δ 1.21 (t, 3H), 2.65 (q, 2H
), 3.15(d, H().

3.42 (d, LH), 5.99 (s, IH),
6.08 (s, IH).

7.21-7.68 (m, 5H) Example 3 ■) and toluene (3m+:) at 100°C.
Stir for hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate-10:I) to obtain 5-(2-10lophenyl)-1,2,3,5-tetrahydrochene. No[2,3-
eco[1,,4]thiazepine-2-thione (11Tl)
g) was obtained.

Physical and chemical properties Melting point 178~]79°C Nuclear magnetic resonance spectrum (CDC1, TMS internal standard)
δ 3.74 (d, LH), 3.82 (d, IH
), 6.03(s, IH).

6.46 (s, IH), 7.00 (s, IH)
7.18-7.61 (m.

4H) Example 4 5-(2--chlorotunyl-],2.3.5-tetrahyto'1-]cheno[2,3-e J C1,4 cothiazehin 2-one (IOVng), Rawenoson's reagent (17 In the same manner as in Example 3, 5-(2-di-DD-fer)-7-nithyl]235-te[・Lahydroti,
) [2,3-e ] [1,4]]thiazepine-2-thio was synthesized.

Original + compound: 5-(2-chlorophenyl)-7-]dical-1,2,3,5-tetrahydrocheno[2,3-
c ] CI, 4-cothiazehino-2-one Physical and chemical properties Mass spectrometry value m/z 339 (M) Nuclear magnetic resonance spectrum (CDCIs + DMSO-do.

TMS internal standard) δ 1.23 (t, 3H), 2.68 (q, 2H), 3
．． 70(d, IH).

3.78 (d, IH), 5.93 (s, IH), 6.1
1 (s, IH).

7.18-7.60 (m, 4H), 11.5 (br, I
H) Example 5 To a mixture of lysine (2 drops) and dichloromethane (2 ml) was added bromine (4.8 ml) and dichloromethane (0.4 ml) at room temperature.
l) The solution was added and stirred at room temperature for 15 minutes.

Water was added to the reaction solution, extracted with dichloromethane, and the extract was washed successively with IN hydrochloric acid, water, and saturated brine.

It was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.
3.5-tetrahydrocheno[2,3-e:][]1.
4] Thiazepine-2-thione il [11 g) was obtained.

Physical and chemical properties Mass spectrometry value m/z 389.391 (M″-) Nuclear magnetic resonance spectrum (CDCI, TMS internal standard)
δ 3.38(d, ], IH, 3,75(d, IH
), 5.80 (s, ], IH.

6.54 (d, IH), 6.82-7.50 (
m, 4. H) Example 6 Alcon WfM-T, 5-(2-chlorophenyl)1,2,3.5-del=lahydrocheno[2,3-e
] [11,4'l diazebin-2-thio 7 (9,3rl
1g), Pi-5-(2-chlorophenyl)-1235
-tetrahydrocheno[2,3-e ] [1,4]]
A few drops of hydrazine monohydrate were added to a solution of thiazepine 2-thione (7.5 ml) in tetrahydrofuran (1 ml), and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methyl orthoacetate (5 ml).

The mixture was stirred at 80°C for 3 hours. Remove the solvent under reduced pressure.

4-(2-chlorophenyl)-9-methyl-4,6-dihydrothieno[2,3-e][L4cotrianthro[
3+4c][1+4]thiazepine (3mg
) was obtained.

Physical and chemical properties Melting point 212°C Nuclear magnetic resonance spectrum (CDCIs, TMS internal standard) δ 2.43 (s, 3H), 3.83 (d+I
H), 395 (d, I H).

5.73 (s, IH), 6.35 (d, IH),
6.76(d, IH).

7.17-7.42 (m, 3H), 7.55-7.
67 (m, IH) Example 7゜ 2-ethyl-4-(2-chlorophenyl)-9-methyl-4,6->hydrocheno[2
,3-e] [1,2,4]) Riazolo[3,4c
][1+4]thiazepine was synthesized.

Raw material compound = 7-nia-5-(2-chlorophenyl)
-1,2,3,5-tetrahydrocheno[2,3-e
] [1,4]] Thiazepine-2-thione Physical and chemical properties 159-161°C Elemental analysis value (as Cl7H16N3CI 82) C (
%)H(%)N(%J S(%)C1(%) Theoretical value
56,424.4611.61 17.72 9.80
Experimental value 56,214.3511.5717.84 1
0.02 Example 8° Same as Example 6 2-7'Romo4-.(2chlorophenyl)-9-)f-4.6-Shihi)''.

Cheno[2,3-e][1,2,4]to1noiso[3,4-c][1,4]thiazepine was synthesized.

Raw material compound near-fromo-5-(2-chlorophenyl)
-1,2,3,5-tetrahydrocheno[2+ 3
e] [1,4]]thiazepine-2-thione physicochemical properties

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a hydrogen atom, a lower alkyl group, or a halogen atom, R^2 is a hydrogen atom or a lower alkyl group, and R^3 is a A thienotriazolothiazepine derivative represented by (meaning a hydrogen atom or a halogen atom). (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a hydrogen atom, a lower alkyl group, or a halogen atom, R^3 is a hydrogen atom or a halogen atom,
X means an oxygen atom or a sulfur atom. ) Thienothiazepine derivatives.