JPH02289558A - 1,5-benzothiazepine derivative substituted at 8-position - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is aryl or heterocyclic group; R<2> is H or halogen; R<3> is H, acyl or alkoxycarbonyl; R<4> and R<5> are alkyl; A is alkylene) and salts thereof. EXAMPLE:(2S,3S)-8-Benzyl-2,3-dihydro-5-(2-dimethylaminoethyl)-3-hydrox y-2-(4- methoxyphenyl)-1,5-benzothiazepin-4(5H)-one. USE:A remedy for circulatory diseases. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III (R<6> is carboxy-protecting group) according to the reaction formulas to provide a compound expressed by formula IV, which is then hydrolyzed to afford a compound expressed by formula V. The resultant compound expressed by formula V is subsequently heated in xylene, etc., at 100-200 deg.C to provide a compound expressed by formula VI. The obtained compound expressed by formula VI is further reacted with a compound expressed by formula VII in the presence of a base to afford the objective compound expressed by formula I'.

Description

[Detailed Description of the Invention] [Object of the Invention] The present invention provides excellent prevention of heart diseases such as angina, myocardial infarction, and arrhythmia, and circulatory system diseases such as hypertension. , relating to 8-substituted 1,5-penzothiazepine derivatives having therapeutic effects and pharmacologically acceptable salts thereof. Conventional ■Limb■ It is well known that the influx of calcium ions into cells is involved in the contraction of cardiac muscle and vascular smooth muscle, and administration of calcium channel blockers that block this influx can inhibit cardiac contraction. , vasodilator, etc., and is useful as a therapeutic agent for heart diseases such as angina pectoris, myocardial infarction, and arrhythmia, hypertension, and cerebral vascular curvature. Known examples of such calcium channel blockers include dihydropyridine compounds such as nifedipine and nicardipine, verapamils, diltiazem, and flunarizine. Of these, cis-3-acetoxy 2.3
-dihydro-5-(2-(dimethylamino)ethyl)-
2-(4-Methoxyphenyl)-1,5-penzothiazepine-re5H)one (diltiazem) is a medical product that is widely used to improve angina pectoris and treat essential hypertension. 46-43785), cis-3-acetoxy-8-chloro-2,3-dihydro-5-[2-(
(dimethylamino)ethyl)-2-(4-methoxyphenyl)-1,5-penzothiazepine-4(5H)one (8-chlorodiltiazem), etc., have a stronger effect and/or longer duration than diltiazem. are also disclosed (Japanese Patent Application Laid-Open No. 59-225174, JP-A No. 60-20
No. 2871, etc.) are not necessarily sufficient, and there is a particular need for improvement in sustainability. The inventors of the present invention have synthesized a series of 1,5-penzothiazepine derivatives over many years and have investigated the pharmacological effects of these compounds. The present inventors have discovered that a compound having a unique substituent such as a group or a heterocyclic alkyl group not only has a very strong blood pressure lowering effect, but also has excellent sustainability, and has thus completed the present invention. [Structure of the Invention] The present invention relates to an 8-substituted 1,5-penzothiazepine M4 compound having the general formula D2 and a pharmacologically acceptable salt thereof. In the above formula, R1 represents an aryl group or a heterocyclic group;
z represents a hydrogen atom or a halogen atom, -R3 represents a hydrogen atom, an acyl group, or an alkoxy carbonyl group, i
R' and RS are the same or different and represent an alkyl group;
A represents an alkylene group. In the general formula (1), the aryl group represented by R1 can be, for example, a phenyl group or a naphthyl group, preferably a phenyl group, and the heterocyclic group is
For example, it may be a 5- to 6-membered ring group containing 1 to 3 nitrogen, oxygen, or sulfur atoms, and which may be fused with a phenyl group,
Examples include chenyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, thiadiazolyl, biridyl, birimidyl, quinolyl, isoquinolyl, etc., and preferred are chenyl, furyl, isoxazolyl, oxazolyl, thiazolyl, and thiadiazolyl.
More preferred are chenyl and frill. These aryl groups or heterocyclic groups may have 1 to 3 substituents on the ring, and examples of the substituents include CI such as methyl, ethyl, probyl, isopropyl, and butyl.
C4 alkyl group; halogen atom such as fluorine atom, chlorine atom, bromine atom; C4 alkyl group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. -C. Alkoxy group;
Hydroxyl group: C, -C, such as methylthio, ethylthio, propylthio, butylthio, etc. Examples include alkylthio groups, preferably methyl, fluorine, chlorine or methoxy. The halogen atom represented by Rt is, for example, fluorine, chlorine, bromine,
It is an iodine atom, preferably a fluorine or chlorine atom. The acyl group represented by R3 is, for example, an aliphatic acyl group having 2 to 7 carbon atoms (acetyl, probionyl, butyryl, isoptyryl, pentanoyl, hexanoyl, etc.), a cycloalkyl carbonyl group having 4 to 7 carbon atoms (cyclopropane, etc.) carbonyl, cyclobutanecarbonyl, cyclopentanylcarbonyl, cyclohexanecarbonyl, etc.) and/or arylcarbonyl groups having 7 to 11 carbon atoms (benzoyl, P-}luoyl, naphthoyl, etc.), but preferably acetyl , aliphatic acyl such as propionyl, cyclopropane-carbonyl, cyclobutane-carbonyl, benzoyl, and particularly preferred are acetyl and propionyl. The alkoxy carbonyl group represented by R3 has, for example, 2 carbon atoms.
to 5 alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, proboxycarbonyl, isoproboxycarbonyl, ptoxycarbonyl, isobutoxycarbonyl, etc.), or cycloalkoxycarbonyl groups having 4 to 7 carbon atoms (cycloproboxycarbonyl, etc.) Preferred examples include methoxycarbonyl, ethoxycarbonyl, cyclobentoxycarbonyl, cyclopentoxycarbonyl, cyclohexyloxycarbonyl, etc. The alkyl group represented by R4 or R5 is, for example, C. -C
．． It can be an alkyl group, including methyl, ethyl, probyl, isobrobyl, butyl, S-butyl, isobutyl, etc., and is preferably methyl or ethyl. The alkylene group represented by A may be, for example, a Cr C4 alkylene group, and examples thereof include methylene, ethylene, ethylidene, trimethylene, propylene, tetramethylene, etc., but preferably methylene and ethylene,
More preferably, it is methylene. Since the compound represented by the general formula (1) has two asymmetric carbon atoms at the 2- and 3-positions of the benzothiazepine ring, it has two stereoisomers (cis and trans isomers).
and four optical isomers ((2S,3S), (2
R, 3R). (2S, 3R) , (2R, 3S)
isomers) exist. Although the present invention can encompass each of these isomers and mixtures thereof, the preferred isomer is (2S,3S)
It is an isomer. Suitable compounds in the general formula (1) include: 1) R' is a phenyl group, a naphthyl group, or a 5- to 6-membered heterocyclic group having 1 to 3 nitrogen, oxygen, or sulfur atoms (methyl on these rings); , fluorine, chlorine, or methoxy), 2) R3 is a hydrogen atom, C. -C, aliphatic acyl group, C. -C. Cycloalkane carbonyl! Further examples include compounds in which A is a CC4 alkoxy carbonyl group, and 3) compounds in which A is a methylene or ethylene group. More common compounds in the general formula ([) include: 4) R' is phenyl (the ring may have a substituent such as methyl, fluorine, chlorine, or methoxy), naphthyl, chenyl, furyl , oxazolyl, thiazolyl, isoxazolyl or thiadiazolyl group, 5) Compounds where R2 is a hydrogen atom, fluorine atom or chlorine atom, 6) R3 is a hydrogen atom, an acetyl group, a cyclopropane carbonyl group, a methoxycarbonyl group, or 7) Compounds in which R4 and RS are methyl or ethyl groups; 8) R' is phenyl (the ring may have a substituent such as methyl, fluorine, chlorine, or methoxy); ), chenyl, furyl, oxazolyl, thiazolyl, isoxazolyl, or thiadiazolyl group, and R2 is a hydrogen atom, fluorine atom, or chlorine atom, and RMI<acetyl group, cyclopropane carbonyl group, methoxycarbonyl group, or ethoxycarbonyl group Examples include compounds in which R4 and R5 are a methyl group or an ethyl group, and A is a methylene group or an ethylene group. Particularly suitable compounds in the above type (1) include: 9) R1 is a phenyl group, R2 is a hydrogen atom or a fluorine atom, R' is a hydrogen atom or an acetyl group, and R4 is a methyl group; , R5 is a methyl group, and A is a methylene group. Further, specific compounds are illustrated below. Nα Rl R2 R3 R4 RS A CO-ku? O■C}12 m-F H COCI1. m-Cj2 I1 COCHi COCH3 COCHx Nα Rl R2 R3 R4 RS A m-F H COClh Nα R' R2 R3 R4 R5 A CO1jl s 12G COCH3 COCH3 H C. Hs CzHs -Cl2 Nα R1 R2 R3 R4 R5 A Among the compounds represented by the formula (1) of the present invention, the compound (1') in which R3 is a hydrogen atom can be easily produced by the following reaction route. R2 (I') In the above formula, R', R'', R', R' and A have the same meanings as above, and R & represents a protecting group for the carboxy group. Examples of C.-C. alkyl groups commonly used in the field include, but are not limited to, methyl, ethyl, probyl, t-butyl, etc., or optically active menthyl, bornyl, α-methylbenzyl, and the like. Step A is a step for producing a compound having general formula (IV), in which compound (n) and epoxy compound (I) are mixed in a solvent,
at room temperature to 130°C (preferably 70-130″C),
This is carried out by reacting for 4 to 48 hours (preferably 4 to 24 hours). Examples of solvents include hydrocarbons such as hexane, benzene, and toluene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, ethers such as ethyl ether, tetrahydrofuran, and ethyl acetate. Examples include esters such as nitrites such as acetonitrile, hydrocarbons such as benzene and toluene, and nitriles such as acetonitrile.
Examples include halogenated hydrocarbons such as (2),2-dichloroethane, but there are no limitations as long as the solvent does not inhibit this reaction. After completion of the reaction, the target product (IV) of this reaction can be obtained by distilling off the solvent, but if necessary, conventional methods such as
It can be further purified by recrystallization, column chromatography, etc. Furthermore, when R6 is an optically active carboxy protecting group,
The resulting compound (IV) can also be isolated as an optically pure single isomer by fractional recrystallization, column chromatography, or the like. Step B is a step for producing a compound having general formula (V), and is carried out by hydrolyzing compound (IV). When R7 is an alkyl group other than a t-butyl group or an optically active menthyl group, hydrolysis with an alkali such as caustic soda, caustic potash, soda carbonate, or potassium carbonate, t
- In the case of butyl groups, this is achieved by hydrolysis with mineral acids such as hydrochloric acid. The solvent used is water, alcohols (methanol, ethanol, etc.), ether M (dioxane, etc.), the reaction temperature is room temperature to 80'C (preferably room temperature to 50'C), and the reaction time is 30 minutes to 24 minutes. time (preferably 1 to 16 hours). After completion of the reaction, the reaction product is adjusted to a pi of 2.5 to 4 with hydrochloric acid or sodium bicarbonate, and is obtained as a precipitate in water or aqueous alcohol. If necessary, it can be extracted with ethyl acetate or the like. If necessary, it can be further purified by conventional methods such as recrystallization and column chromatography. Step C is a step for producing a compound having the general formula (Vl), in which the amino acid (V) is heated at 100°C to 200°C (preferably 140°C) in a hydrocarbon such as xylene or mesitylene.
It is carried out by heating at 160"C for 6 to 20 hours. The product (Vl) usually precipitates as a precipitate when the reaction solution is cooled, so it can be isolated by collecting it in a furnace. Compound (Vl) can also be produced by a condensation reaction using a condensing agent widely known in chemistry.Generally, N,N'-dicyclohexyllupodiimide, carbonyldiimidazole, diphenylphosphoryl azide,
This is carried out in the presence of a dehydrating agent such as diethyl cyanophosphate or phosphorus pentachloride. When using a carbodiimide dehydrating agent, the reaction can be accelerated by adding a reagent that forms an active ester, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, to the reaction system. The reaction can also be carried out in the presence of a base such as pyridine, pyricone, triethylamine, N-methylmorpholine, sodium carbonate, sodium bicarbonate, and the like. In general, any solvent can be used in the reaction as long as it does not inhibit the reaction, such as amides such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoramide, tetrahydrofuran, dioxane, etc. ethers, nitriles such as acetonitrile, methanol,
Alcohols such as ethanol, ketones such as acetone, halogenated hydrocarbons such as dichloromethane and chloroform, esters such as ethyl acetate, and hydrocarbons such as benzene, toluene, hexane, and cyclohexane. However, preferred are amides such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, hydrocarbons such as toluene, or esters such as ethyl acetate. The reaction conditions vary depending on the dehydrating agent used, but usually the reaction temperature is 0°C to 100°C (preferably 0°C to 5°C).
0° C.) and the reaction time is 3 to 24 hours (preferably 6 to 16 hours). The product may be isolated as crystals from the reaction system, but it can also be obtained by distilling off the solvent and then purifying it by a conventional method, such as column chromatography. Step D is a step for producing general formula (1'), in which compound (V
This reaction is carried out by reacting l) with compound (■) in a solvent that does not inhibit the reaction in the presence of a base. Examples of solvents include hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, N,N
-Dimethylformamide, N,N-dimethylformamide, amides such as N-methyl-2-pyridone, sulfoxides such as dimethyl sulfoxide, etc., but preferably ethers such as tetrahydrofuran, acetone, etc. , ketones such as methyl ethyl ketone, and amides such as dimethylformamide. Bases used include metal carbonates such as sodium carbonate, potassium carbonate, metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, alkali metal hydrides such as sodium hydride, lithium hydride, 1.5 -diazabicyclo (4.3.0
) nonar-5-ene, 1,8-diazabisic (5,4.)
0) Organic bases such as undecar-7-ene can be mentioned, but preferred are metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrides such as sodium hydride. The reaction temperature and reaction time vary depending on the type of base and solvent used, but are usually 0 to 120°C (preferably 0 to 80°C) and 1 hour to 4 days. When using an inorganic base, this reaction may be accelerated by adding a catalytic amount of a pyridine such as 4-dimethylamipyridine or a crown ether such as 18-crown-6 to the reaction system. (B) can be obtained by extracting with an organic solvent such as ethyl acetate, washing with water, drying with anhydrous magnesium sulfate, etc., and distilling off the solvent.
If necessary, it can be further purified by conventional methods such as recrystallization and column chromatography. Among the compounds represented by formula (1) of the present invention, compounds in which R'3 is an acyl group or an alkoxycarbonyl group (■1
) is the step E shown in the lower part, that is, the compound (■')
It can be produced by acylation with compound (■). pg In the above formula, R', R'', R', R' and A have the same meanings as described above, R7 represents an acyl group or an alkoxycarbonyl group in R3, and Y is a halogen atom or a compound of the formula R7- Indicates a group having 0. This reaction is carried out in an inert solvent in the presence of a base. The solvent used is not particularly limited as long as it does not participate in the reaction, and examples include hexane, benzene, toluene, xylene, and cyclohexane. Hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; ethers such as ester, tetrahydrofuran, dioxane; esters such as ethyl acetate ( Preferred examples include halogenated hydrocarbons (v4). Examples of the base used include organic bases such as triethylamine, pyridine, and N-methylmorpholine.The organic base also serves as a solvent and is used in large excess. The reaction temperature is from 0″C to 80°C (preferably from 0″C to 5°C).
0'C), and the time required for the reaction varies depending on the reaction temperature, etc., but is usually 1 to 24 hours (preferably 3 to 20 hours). The target product can be obtained by extracting with an organic solvent such as ethyl acetate, washing with water, drying over anhydrous magnesium sulfate, etc., and then distilling off the solvent. If necessary, it can be further purified by conventional methods such as recrystallization and column chromatography. The novel compound (1) of the present invention can be converted into a pharmacologically acceptable salt by treatment with an acid according to a conventional method. For example, compound (I) is dissolved in an organic solvent such as ethyl acetate or dichloromethane, an equimolar or excess amount of an acid such as hydrogen chloride-dioxane is added thereto, the solvent is distilled off, and diethyl ether or diisopropyl ether is dissolved. It can be obtained by crystallization or solidification in an organic liquid such as Examples of such acid addition salts include salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, and organic acids such as maleic, fumaric, oxalic, citric and tartaric acids. , methanesulfonic acid and benzenesulfonic acid. [Effects of the Invention] As shown below, the compound having the general formula (1) of the present invention exhibits an excellent calcium channel blocking effect and a long-lasting antihypertensive effect on spontaneously hypertensive rats (SHR). It is extremely useful as a preventive and therapeutic drug for circulatory system diseases. 1) Calcium Channel A cecal string removed from a male guinea pig weighing 250-300 g was cut into 6-7 mm lengths, and a calcium ion-free tie was aerated with a mixed gas of 95% oxygen gas and 5% monocarbonate gas. Loading solution (salt 97mM, potassium chloride 40mM, baking soda 11.9mM, disodium hydrogen phosphate 0.4mM, glucose 5.5mM; pH 7.1
) is suspended in the Magnus tank inside. To this, a 30 and 100 mM solution of calcium chloride was added as a contractile agent at 3 minute intervals to a final concentration of 0. Add the solution to a concentration of 4 mM, and measure the contraction height of the cecal string using an isometric transducer. Next, wash the Magnuma bath twice or more with Tyrode's solution that does not contain calcium ions, and after leaving it for 30 minutes, add a physiological saline solution of the test drug that has calcium channel blocking action to the Magnuma bath at a concentration of 10-''g/d. Add so that it becomes 30
Incubate for minutes. Calcium chloride 30
, 100mM solution at 3 minute intervals to a final concentration of 0. 4
Add the solution to a concentration of mM, and measure the contraction height of the cecal string. From the contraction height results thus obtained, the contraction inhibition rate of the test drug is calculated using the following formula. The results are shown in Table I. Compound of Example 2 Compound of Example 4 Compound of Example 6 Compound of Example 8 Diltiazem 20 *) In each case, hydrochloride was used. 2) A 23-30 week old male SHR undergoing SIR was anesthetized with sodium bentobarbital (50 μ/kg intraperitoneally administered), a polyethylene cannula was inserted into the abdominal aorta via the left femoral artery, and the other end of the cannula was inserted into the abdominal aorta. was led out of the body and fixed to the neck. One week after surgery, once the animal has recovered from the surgical insult, connect the other end of the animal's cannula to a blood pressure measuring device;
Blood pressure and heart rate were measured by the direct method without anesthesia and without restraint. The blood pressure measuring device is one manufactured by Laffan et al.
ffan P. J. , Peterson A. ．． Hit
ch S. W. and Jeunelot C. ＋Ca
rdiovascular Res. + 6, 3
19-324 (1972)) was modified and used. After confirming that the blood pressure and heart rate were stable for more than 1 hour, the drug was forcibly administered using a transcutaneous losonde. The test drug was dissolved in 50% dimethyl sulfoxide aqueous solution,
The doses shown in Table ■ were administered. After administration of the sample, blood pressure and heart rate were measured every 15 minutes for 24 hours. The maximum blood pressure lowering value and the half-life of the blood pressure lowering effect thus determined are shown in Table 2. Compound of Example 4 10 -24 8
．． 5 Compound of Example 6 10-32
11.8 Compound of Example 8 10-13
9.0 When compound (1) and its pharmacologically acceptable salts are used as a therapeutic agent for circulatory system diseases, they may be used per se or with appropriate pharmacologically acceptable carriers, excipients,
By mixing with diluents etc., powders, granules, tablets, capsules, etc.
It can be administered orally or parenterally as a pharmaceutical composition such as an injection. The dosage varies depending on the condition of the target disease and the administration method, but when administered orally, it is usually administered once.
000 mg, especially about i-ioo■, but for intra-arterial administration, a single dose of about o. t-100mg, especially about 0.5
The dosage is preferably about 30 mg, and it is desirable to administer these doses once to twice a day depending on the symptoms. EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the scope of the present invention is not limited thereto. Example 1 Zepine H and trans-2,3-epoxy-3-(4-methoxyphenyl)propionic acid! - Menthyl 3 2. 5 g and 2
-Amino-5-benzylbenzenethiol 2 1. 1
g was stirred in 320 d of toluene at 90°C for 16 hours. The reaction solution was cooled, and the precipitated crystals were collected in a furnace and washed sequentially with toluene and hexane to obtain the title compound 1. 9g
I got it. The furnace solution was concentrated, and the residue was subjected to silica gel column chromatography using hexane-1,2-dichloroethane-ethyl acetate (7:12:1) as an iV medium system, and the eluent containing the title compound was concentrated, and the crystals were obtained. was filtered using ethyl ether to further obtain 2.9 g of the title compound. Melting point: 157-159'C, optical rotation [α)''+179° (c = 1
, CHCI 3). NMR spectrum (coj: i 2 +020 (small amount)), δ: 0.6-2.1 (1 8H, m)
．． 3.69 (2H, s), 3.76 (3H, s), 4.34 (IH, d, J=5Hz), 4.48
(IH, d, J=5Hz), 4.80 (IH, m)
, 6.55-7.3 (12H, m). 4-Mexi
Enyl Probion■ (23,3S)-3-(2-amino-5-pendylphenyl)thio 2-hydroxy-3-(4-methoxyphenyl)propionic acid! - Menthyl (Example 1(a)
compound) in a suspension of 17.15 g of ethanol 65d,
Add a solution of 6.2 g of caustic potassium in 20 d of water, and heat at 60°C for 2 hours.
Stir for hours. After ethanol was distilled off under reduced pressure, ethyl ether and water were added, and after stirring, the ether layer was removed. After adding ethyl acetate to the aqueous layer and adjusting the pH to 3 with 3N hydrochloric acid, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The syrupy residue was allowed to stand, and the crystals formed were filtered using ethyl ether to obtain the title compound 7.64.
I got g. Melting point 155-158'C. Optical rotation [α)”-t-304” (c=1, DMF
). NMR spectrum (DMSO db).
δ: 3.60 (2H, s), 3.72 (3H, s), 4. 3 1 (ABQ Δδ= 0.10ppm
, J = 5 Hz) , 6.55-7.3 (1
2H, m). 1(c) S S 2 - Penzinore
-Jihi Mouth -Hi'Roxy 1 1 Scieninore 5-Benzthiazebin-4 5H Oneon 5.05 (IH.d, J=6.5Hz), 6.77
-7.57 (12H, m). 8. 3×(IH, brs). (23,33)-3-(2-amino-5-pendylphenyl)thio 2-hydroxy-3-(4-methoxyphenyl)propion A (6.71 g) was added to 400 g of xylene.
The mixture was refluxed with stirring for 8 hours during d. The mixture was cooled to room temperature, and the precipitated crystals were collected in a furnace and washed with xylene and hexane to obtain 5.8 g of the title compound. Melting point 200-202°C (decomposed). Optical rotation [α)”+1 10@(C=1, DMF)
. NMR spectrum (CDCj2 3 ). δ: 2.5
0 (IH, brs) 3.76 (3H, s), 3.97 (2H, s). 4.4 6 (I H, d, J-6.5fl
z) , (23,3S)-8-benzyl-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)
-1.5-penzothiazebin-4 (5H) one 5.
3g, 2-dimethylaminoethyl chloride hydrochloride 2.
34 g, potassium carbonate 5.6 g and 4-dimethylaminopyridine 0. A mixture of 17 g of acetone 250d was stirred under reflux for 20 hours. Acetone was distilled off, and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in methanol-dichloromethane (1:20
) was purified by silica gel column chromatography using a solvent system to obtain the gum-like title compound 5. 93 g was obtained. Optical rotation (α) ”+ 1 1 0° (c=l, DM
F). NMR spectrum (CDCI!.3), δ:2
．． 24 (6H, S). 2.3-3. 1 (3 H, m). 3.4-4
．． 0 (LH, m), 3.76 (3H, s), 3.95 (2H, s). 4.2-4.7 (2H, m), 4.86 (IH, d, J=6.5Hz), 6.8-7
．． 6 (1 2H, m). Example 2 -Benzothiazebin-4 5H-one (23.3
3) -8-Benzyl-2,3-dihydro-5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-1,5-penzothiazepine-4(5
H) One on 5.92. g, pyridine 12d and acetic anhydride 6
d and left at room temperature for 16 hours. After adding ethanol lod to the reaction solution and leaving it for 20 minutes, the solvent was distilled off, and the remaining pyridine and acetic acid were distilled off by azeotropic distillation with toluene. The residue was dissolved in methanol-dichloromethane (1
:20) was purified by silica gel force column chromatography using a solvent system to obtain the gum-like title compound 6. 0
2 g was obtained. Optical rotation (cr) ”+8 4@(c=1, DMF
). D NMR spectrum (CDC4i). δ: 1.8
7 (3H, s), 2.26 (6H, s), 2.2-3.0 (2H, m). 3.4-4.
7 (2H, m) ,3.80 (3H,
s). 3.98 (2H, s), 4.97 (l H, d, J=6.5H
z) ,5.1 8 (IH, d, J=6.5Hz)
, 6.8-7.6 (1 2 H, m), this gummy description compound 4. 0.5 g to 20 I of ethyl acetate
After dissolving in ethyl ether and adding 6d of 4N hydrochloric acid and ethyl acetate, distilling it off under reduced pressure, powdering it in ethyl ether and taking it in an oven.
After drying, 4.35 g of the hydrochloride of the title compound was obtained. Melting point 115-120℃ (softening) Optical rotation [α)”+8 1' (c=1.0MF
). NMR spectrum (DMSO di), δ
:1.82 (3H,s), 2. 7 7 (3H, brs), 2. 8 2
( 3 H, brs), 3.0 5-3.2 (
IH, m). 3.3-3.5 (L H, m
), 3.77 (3H, s). 4.01 (2H, s), 4.0-4.1 5, (IH, m), 4.3-
4.5 (IH, m) ,4.98 (IH
, d, J=7Hz). 5.14 (IH, d, J=7
Hz), 6.8 5-7.6 5 (1 2 H,
m). Furthermore, monotartrate of the title compound can be obtained by adding the title compound to an equimolar methanol solution of L monotartaric acid, stirring at room temperature, distilling off the solvent, and crystallizing the gummy residue in ethyl acetate. obtained by. Melting point: approximately 95°C (softening) Optical rotation (α) ”+63.2@(c=1.dimethylformamide) NMR spectrum (oMso-d.) . δ: 1.
80 (3H, s). 2.37 (3H, s). 2.3-3.2 (2H, m). 3.5-4.6 (2H, m). 3.16 (3H, s), 3.99 (2H.s), 4.20 (2H, s), 4.9 6 (L H, d, J = 6.5H
z), 5.0 8 (l H, d, J
=6.511z) ,6. 4 0 (4 H,
brs), 6.90 (2H, d, J=9Hz
), 7.3-7.7 (IOH, m). Trans-2.3-Evoxy-3-(4 -methoxyphenyl)propionic acid!
- Menthyl 1 4. 5 g and 2-amino5-(2-
9.65 g of (chenyl)methylbenzenethio-ru were reacted in 150 d of toluene to give the crystalline title compound 1.
84 g was obtained. Melting point 147-148°C. Optical rotation (α)”+1.9° (c = 1, CH
Cj2*). p NMR spectrum (CDC f3), δ:0.
6-2.2 (1 8H, m), 3.75 (3H
,s), 3.86 (2H,s), 3. 90 (3H, brs), 4.36
(LH, d, J=5Hz). 4.52
(IH, d, J=5Hz). 4.75 (I
H, m), 6.5 5-7.3 (10 H, m). Oji d! Characteristics Description Compound 0. 59 g was obtained. Melting point 1 4 9 - 1 5 3. 5°C. Optical rotation (cr) ``+281'' (c=1, dimethylformamide). NMR spectrum (DMSO-d.), δ: 3.
72 (3H, s), 3.79 (2H, s), 4. 30 (2H,'brs), 6.55-7
．． 3 (IOH, m). H In a similar manner to Example lΦ), (23.33)-3-[
2-menthyl 2-amino-5-(2-thenylmethyl)phenyl]thio-2-hydroxy-3-(4-methoxyphenyl)propionate (compound of Example 3(a)) 1
．． 82 g was hydrolyzed to give (2S,3S) -3-[2-amino-5-(2
-thhenylmethyl)phenyl]thio 2-hydroxydi-
3-(4-methoxyphenyl)propionic acid (Example 3
The metal compound (b) 537■ was subjected to ring-closing condensation to obtain the crystalline title compound 411■. Melting point 204-208°C (decomposed). Optical rotation (α) “+103” (c=1.dimethylformamide). NMR spectrum (DMSO di). δ: 3
．． 76 (3H, s), 4.16 (2H, s), 4.30 (IH, t, J='Nlz), 4.
6 1 (IH, d, J=7Hz) ,5.
05 (IH, d, J=7Hz). 6.85-7.6
(IOH, m). 10.29 (IH, brs). 1''D Nico(Z) In the same manner as in Example 1 (d), (23,3S)-2
．． 3-dihydro3-hydroxy-2-(4-methoxyphenyl)-8-(2-thenylmethyl)-1.5-
Penzothiazebin-4 (5H) mono (Example 3 (C)
) Compound 370■ was alkylated with 2-dimethylaminoethyl chloride hydrochloride 161■ to give the title compound 441■ as a foamy solid. Optical rotation (α) ”+113° (c=1, CHCj
! z). NMR spectrum (cocl3). δ:2.27
(68, s), 2.1 5-3.0 (3H, m). 3.79 (
3H, s), 3.4-3.9 (IH, m). 4.14 (2H, s), 4.1-4.7 (2H, m). 4.8 5 (IH, d, J=7Hz)
, 6.75-7.6 (IOH, m). Example 4 One-on In the same manner as in Example 2, (2S,3S) -2. 3
-dihydro5-(2-dimethylaminoethyl)-3-
Hydroxy-2-(4-methoxyphenyl)-8-(2
-thenylmethyl)-1,5-penzothiazepine-4
(5H) one (compound of Example 3) 4 3 6 mg
was acetylated to obtain the candy-like title compound 468■. Optical rotation [α)” + 6 7° (c = 1,
CHCj! sLD NMR spectrum (coclts), δ: 1.86
(3H, s), 2.25 (6}i, S), 2.1-3.1 (2H, m), 3.79
(3H, s), 3.4-4.0 (IH, m), 4.1-4
．． 7 (11{, m) ,4.16 (2H,
s), 4.97 (IH, d, J=7Hz), 5.16
(IH, d, J=7H2). 6.8-7.6 (1
0H, m), this was treated with hydrogen chloride monoethyl acetate in the same manner as in Example 2 to obtain the hydrochloride of amorphous powder cane 492.
Obtain an NMR spectrum (DMSO di). δ
: 1.80 (3H, s), 2.78 (6H, m). 3.76 (3H,'s), 4.22 (2H, s), 4.0-4.5 (2H, m). 4.97 (IH, d, J=7Hz) 5.14 (
IH, d, J=7Hz) 6.8 5-7.6 (l
OH, m). Example 5 Trans-2.3-epoxy-3-(4-methoxyphenyl)probionic acid!
- Menthyl 4 2. 9 g and 2-amino5-(4-
31.2 g of benzenethiol (fluorobenzyl) was reacted in 350 mi of toluene to obtain 21.2.6 g of the crystalline title compound. Melting point 149-150°C. Optical rotation (α) ”+178.0° (c= 1, ';
/ chillformamide). NMR spectrum (CDCl3). δ: 0.
65-1.7 (17H, m), 1.95-2
．． 0 1 (IH, m) ,3.64 (2H
, s). 3.76 (3H, s), 4.1 1 (LH, d, J=7.5Hz), 4.
2 6 ( 3 H, brs), 4.73 (
LH, d, t, J=4.5. 1 1
Hz), 6.60-7.26 (1 1H, m
)． Hydrolyzing 20.65 g of the compound of Example 5 (a),
Crystalline title compound8. 67 g was obtained. Melting point 165.5-167°C. Optical rotation (α) ”+318.6° (c=1, dimethylfomulamide). NMR spectrum (DMSO di). δ: 3
．． 57 (2H, s), 3.70 (3H, s), 4.25 (IH, d, J=5.5Hz), 4.32
(IH, d, J=5.5Hz), 6.56-7.14
(1 1H, m). H In the same manner as in Example 1(b), (23,3S)-3-
[2-amino-5-(4-fluorobenzyl)phenyl]thio-2-hydroxy-3-(4-methoxyphenyl)propionic acid! -menthyl ((2S, 3S)-3-[2-amino-5-(4-fluorobenzyl)phenyl]-2-hydroxy-3-(4-methoxyphenyl) in the same manner as in Example 1 (C) ) Compound 8.37 of propionic acid (Example 5) was subjected to ring-closing condensation to obtain 7.92 g of the crystalline title compound. Melting point 216-218°C Optical rotation [α) ”+93.7° (c=1, dimethylformamide). NMR spectrum (DMSO da) .δ: 3.7
5 (3H, s), 3.93 (2H, s), 4.2 7 (L H, t, J=7Hz),
4.64 (IH, d, J='LHz). 5
．． 02 (IH, d, J=7Hz), 6.86-7.4
5 (IIH, m), 10.23 (IH, s),
21 (Z) In the same manner as in Example 1 (d), (2S, 3dake, 3-
7.62 g of dihydro-8-(4-fluorobenzyl)-3-hydroxy-2-(4-methoxyphenyl)-1,5-penzothiazebin-4(5H)one (compound of Example 5(C)) was -Dimethylaminoethyl chloride hydrochloride 3. Alkylation with 2 2 g gave the title compound 8. as a foamy solid. 44 g was obtained. Optical rotation (α) ”+108.8° (C=1.chloroform) NMR spectrum (CDC f 3) δ: 2.24
(6H, s), 2.2-3.0 (3H, m). 3.4-4.0 (IH, m). 3.77 (
3H,s). 3.93 (2H, s), 4.2-4.7 (2H, m). 4.8 6 (I H, d, J=7.5Hz
), 6.9-7.5 (1 1H, m). Example 6 One-on In the same manner as in Example 2, (2S.3S) -2. 3
-dihydro-5-(2-dimethylaminoethyl)-8
- (4-fluorobenzyl)-3-hydroxy-2-
(4-methoxyphenyl)-1,5-penzothiazepine-4 (5H) one (compound of Example 5) 8.
4.4 g was acetylated to give the crystalline title compound 8.
52 g was obtained. Melting point 154-155.5°C Optical rotation (cr) "+.82.1' (c=1. dimethylformamide). NMR spectrum (CDC I!.3) . δ: 1
．． 89 (3H, s). 2.27 (6H, s). 2.3 9-2.4 9 (lH, m) ,2
．． 6 4-2.7 3 (I H, m). 3.6
3-3.73 (IH, m). 3.82 (3H, s), 3.96 (2H, s), 4.3 3-4.4 4 (lH, m), 4
．． 99 (IH, d, J=7.5Hz), 5. 1 5
(IH, d, J=7.5Hz) ,6.
67-7.48 (1 1H, m). 499 mg of the above compound was treated with hydrogen chloride monoethyl acetate in the same manner as in Example 2 to obtain 466 ml of crystalline hydrochloride. Melting point 190-193°C Optical rotation (α) “+80.9” (c=1.dimethylformamide). NMR spectrum (DMSO d6), δ: 1.8
2 (3H, s), 2.82 (6H, s), 3.08-3.18 (IH, m), 3.3 2-3
．． 4 2 (I H, m) , 3.77 (
3H, s), 4.01 (2H, s), 4.0 1-4.09 (IH, m), 4.3
1-4.37 (LH, m), 4.9 7 (I
H, d, J = 8.0Hz) ,5. 1
4 (IH, d, J=8.0Hz) ,6
．． 89-7.62 (1 1H, m). Furthermore, monotartrate of the title compound was produced in the same manner as in Example 2. Melting point 95-97°C (softening). Optical rotation [α] ”+63.O゜ (c=1.dimethylformamide). NMR spectrum (DMSO di) .δ: 1.8
1 (3H, s), 2.30 (6H, s). 2.4-2.55 (IH, m), 2.68-2.80 (IH, m). 3.7-3.8
3 (IH, m). 3.77 (3H,
s), 3.99 (2H, s), 4.20 (2H, s), 4.20-4.30 (LH, m), 4.96 (
IH, d, J=8Hz) 5.1 1 (IH,
d, J=8Hz) ,6.89-7.62 (1
1H, m). Example 7 CHzCHzN(CH3λ2 7(a) 2S 3S -3 - 2-Aphenyl propion l-menthyl In the same manner as in Example 1 (a), trans-2.3-
Eboxy-3-(4-methoxyphenyl)probionic acid! - Menthyl 5 2. 35 g and 2-amino-5-(5-methyl-2-chenyl)methylbenzenethiol 38. 4.4 g was reacted in 450 g of toluene to give the crystalline title compound 1.2. 75 g was obtained. Melting point 148-150°C. Optical rotation [α) “+150.1” (c = 1, dimethylformamide). 2.31 (3H, s), 3.76 (5H, s), 4.04 (IH, d, J=7.5Hz),
4.2 3 (2 H, brs) ,4.3
6 (IH, d, J=4.5Hz), 4.5 1
(L H, d, d, J=4.5, 7.5
Hz) ,4.7 3 (I H, d, t,
J=4.5. 1 1Hz) ,6.39-7.2
6 (9H, m). Phenyl propion■ (2S, 3S) 3-[2-amino-5-((5-methyl-2-chenyl)methyl]phenyl]thio 2-hydroxy-3-( 4
-methoxyphenyl)propionic acid! - 12.69 g of menthyl (compound of Example 7(a)) was hydrolyzed to give crystalline title compound 5. 36 g was obtained. Melting point 146-147.5'C (decomposed). Optical rotation [α
] ”+280.7 @(c=1.dimethylformamide). NMR spectrum (DMSO-di). δ: 2.3
3 (3H, s), 3.67 (2H, s), 3.70 (3H, s), 4.25 (IH.d, J=5.5Hz). 4.3 2
(IH, d, J=5.5Hz) ,6.3
5-7.1 4 (9H, m). Example 1 (
In a similar manner to C), (23.33)-3-[2-amino-5-((5-methyl-2-chenyl)methyl]phenyl]thio 2-hydroxy-3-(4-methoxyphenyl)propion acid (compound 35.3 of Example 7(b)
By ring-closing condensation of g, the crystalline title compound 2. 7 6 g
I got it. Melting point: Colored from 150℃, 192-199
Decomposed at °C. Optical rotation [α] t+98.9° (c-1. dimethylformamide). NMR spectrum (DMSO-d&), δ:2.
36 (3H, 5), 3.75 (3H.s). 4.05 (2H, s), 4.2 7 (IH, t, J=6.5Hz)
．． 4.67 (IH, d, J=6.5Hz). 5.0
3 (IH, d, J=6.5Hz), 6.6 1-7
．． 4 6 (9 H, m) ,10.24 (
IH, s). In the same manner as in Example 1(d), (23,3S)-2
．． 3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-8-((5-methyl-2-thenyl)methyl)-1,5-penzothiazepine-4(5H) mono(
2.7 g of the compound of Example 7 (C)) was alkylated with 1.13 g of 2-dimethylaminoethyl chloride hydrochloride to give the title compound 3. as a foamy solid. 1g was obtained. NMR spectrum (CDClz), δ:2.
24 (6H, s), 2.40 (3H, s), 2.2-3.0 (3H, m). 3.4-4.
0 (IH, m). 3.77 (3H,
s), 4.05 (2H, s), 4.0-4.7 (2H, m). 4.86
(IH, d, J=7.5Hz). 6.6-7.6 (
9H, m). Example 8 Pin-5H-on In the same manner as in Example 2, (2S,3S) -2.3-
Dihydro-5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-8-((5
-Methyl-2-chenyl)methyl]1,5-penzothiazepine-4(5H) one (compound of Example 7) 3.
Acetylate 1 g to obtain crystalline title compound 3.2
I got g. Melting point 131-134°C Optical rotation (α) 2s+6 3. 5° (c = 1 + chloroform). NMR spectrum (CDClz), δ:t.
86 (3H, s), 2.26 (6H, s), 2.4 1 (3H, s), 2.2-3.1 (2H, m). 3.4-4.0 (IH, m). 3.78 (3H, s), 4.04 (2H, s), 4.0-4.6 (LH, m). 4.95
(IH, d, J=7Hz), 5.14 (IH, d,
J=7}1z), 6.6-7.55 (9H, m
)． 3.0 g of the above compound was treated with hydrogen chloride-ethyl acetate in the same manner as in Example 2, and an amorphous powdery hydrochloride was obtained by NMR analysis.
Spectrum (DMSO-db). δ: 1.83
(3H, s), 2.38 (3H, s), 2.79 (6H, s), 3.04-3.17 (IH, m), 3.3
-3.4 5 (IH, m), 3.77
(3H, s), 4.14 (2H, s), 4.08-4.1 7 (IH, m), 4.3
6-4.45 (IH, m), 4.9 8 (I
H, d, J=7.5Hz) ,5. 1 5
(L H. d, J=7.5Hz) ,6.
6 4-7.6 5 (9 H, m). Reference examples 1-Benzylbenzyl 5. 4 (
2 H, brs), 7. 1-7.5 5 (
8 H, m). Reference example 2 4-penzylaniline 3 9. 7 g and 33 g of ammonium thiocyanate in 400 d of acetic acid solution, add 12 to 18
11.27 d of bromine was added dropwise while maintaining the temperature at °C. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours, and the solvent was distilled off. Add 600 ml of ethyl acetate and 300 r of water to the residue.
nl was added, and potassium carbonate powder was added to neutralize. The ethyl acetate layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to obtain 37.6 g of the title compound. Melting point 173-175°C NMR spectrum (CDC e:+), δ:4
．． 00 (2H, s), 103 g of caustic potash was dissolved in 125 d of water, 6 ethylene glycol 2. After adding 5 d and replacing with nitrogen, 2
25 g of -amino-6-penzylbenzothiazole was added. After stirring for 7 hours on an oil bath at 135° C. while blowing nitrogen, the reaction solution was cooled, 250 ml of toluene was added, and 105 Fnl of acetic acid was added dropwise. The toluene layer was separated and the aqueous layer was extracted again with toluene. The toluene extract was washed successively with aqueous sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 21.0 g of the title compound in the form of a yellow syrup. Although this substance crystallized when left to stand, it was used in the next reaction without purification. Reference Example 3 8.5 g of the title compound in syrup form was obtained from 2-amino-6-2-thenyl methylbenzothiazole g. This compound was used in the next reaction without purification. Reference Example 5 In the same manner as in Reference Example 1, 25 g of the title compound was obtained from 33 g of 4-(2-chenyl)methylaniline. Melting point 188-191″C NMR spectrum (DMSO di) δ: 4.1
2 (2H, s), 6.84-7, 50 (6H, m). Reference Example 4 2-Amino-5-2-chenyl methylbenzenethiol 4-(4-fluorobenzyl)aniline 3 was prepared in the same manner as in Reference Example 1. From 6 g to the listed compound 3 3
．． 8 g was obtained. Melting point 162-164°C NMR spectrum (DMSO d6) δ: 3.31
(2H, s), 7.0 4-7.4 8 (7H, m). Reference Example 6 By the same method as Reference Example 2, 2-amino-6-(2-
chenyl)methylbenzothiazole 9.3 In the same manner as in Reference Example 2, 31.3 g of the title compound in the form of a yellow syrup was obtained from 33.4 g of 2-amino-5-(2-chenyl)methylbenzenethiol. This compound was used in the next reaction without purification. Reference Example 7 Methylbentisol 4-(5-methyl-2-
chenyl) methylaniline 4 5. 41.8 g of the title compound was obtained from 1 g. Melting point 179-181°C NMR spectrum (DMSO di) δ: 2.36
(3H, s), 4.05 (2H, s). 7.0-7.5 (5H, m). Reference Example 8 Tylbenzene All By the same method as in Reference Example 2, 2-amino-6-(5-
Methyl-2-chenyl)methylbenzothiazole41.
3g of title compound 3 in the form of yellow syrup 8. 4 g
I got it. This compound was used in the next reaction without purification.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents an aryl group or a heterocyclic group; R
^2 represents a hydrogen atom or a halogen atom; R^3 represents a hydrogen atom, an acyl group, or an alkoxycarbonyl group; R^4 and R^5 are the same or different and represent an alkyl group; A represents an alkylene group . ) with 8-position substitution 1
, 5-benzothiazepine derivatives and pharmacologically acceptable salts thereof.