JPS61130278A - 1,5-benzothiazepin-4(5h)-one derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:The 1,5-benzothiazepin-4(5H)-one derivative of formula I (R1 is H, halogen, lower alkyl or lower alkoxy; R2 is benzoyl, substituted benzoyl, or halogen- or lower alkoxy-substituted phenylsulfonyl; R3 is lower alkylaminoalkyl) or its acid addition salt. EXAMPLE:2-(4-Methoxyphenyl)- 3-(2,5-dichlorobenzenesulfonyloxy)-5-(2-dimethyl aminoethyl)-1,5-benzothiazepin-4(5H)-one. USE:A medicinal drug having pharmacological activities such as calcium antagonistic, central nervous controlling, coronary vasodilating, antiarrhythmic, local anesthetic, analgesic, antiinflammatory, and diuretic activities. It has low toxicity. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II or its acid addition salt with a halogen reagent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel benzothiazepine derivatives of the formula (I) (I)C, where R is a hydrogen atom, a halogen atom, or a lower 1μ
R3 represents a lower acylaminooxy group, R21t, a benzyi μ group, a substituted bency p group, a halogen- or lower alkoxy-substituted phenylene/V-sulfonyl μ group, and R3 represents a lower acylaminooxy group. The present invention relates to a 1,5-benzothiazepin-4(5H)-one derivative represented by () or an acid addition salt thereof, and a method for producing the same.

The novel compound (I) of the present invention has low toxicity and has pharmacological effects such as calcium antagonism, central nervous system regulating effect, coronary vasodilatory effect, antiarrhythmic effect, local anesthetic effect, analgesic effect, anti-inflammatory effect, and diuretic effect. and is useful as a medicine. These can be administered orally or parenterally in the form of tablets, capsules, granules, syrups, injections or similar products, and if necessary, in the form of physiologically acceptable salts, usually 18111
Used at doses of P~2f.

Next, one example of a typical method for producing the novel compound (I) of the present invention will be shown.

(1) (I) (in the formula or represents a halogen atom, R, R2 and R5 have the same meanings as above), that is, 2-pheny/L/l or 2-(substituted phenyl
v) -2,a-dihydro-5-substituted-1,5-benzothiazepine-8,4(55)-dione or its acid addition m
When (II) is reacted with a halogen reagent in the presence or absence of a dehydrochlorination agent, the desired new compound (I) is obtained in high yield. The reaction is usually carried out in the cold or at room temperature for several hours (
It will be finished in ten hours.

Pyridine and triamine are often used as dehydrochlorination agents. Further, examples of the halogen reagent include penceyl μ hafide, halogen-substituted) phenyl phenyl hafide, lower alkoxy-substituted phenyl phenyl hafide, and lower aμ kyl group.

Examples include benzyi μ halide substituted with a lower acoky group, a nitro group, a halogen atom, and the like.

Post-reaction post-treatment and purification are carried out by conventional methods such as extraction, recrystallization, column chromatography, and activated carbon treatment.

The raw material (It) used in the present invention is 2-phenimethylidene (or 2-substituted Fediμmethylidane)-4-substituted-2
H-1,4-benzothiazin-3(4H)-one (II
It can be easily obtained by reacting I) with trimethylhalogenone, hydrogen peroxide, and water (Japanese Patent Application Laid-open No. 1983-1993).
No. 180476).

(III) (II) (wherein R and R3 are as defined above) The novel compound of the formula (1) thus obtained can be converted into various inorganic or organic salts by known methods, if desired.

Next, the present invention will be explained in detail with reference to Examples.

Example 1 2-(4-methoxyphenylene/I/)-2,:3-dihydro-5-(2-dimethyaminoethyl/L/)-1,5
-Benzothiazepine-a, 4(5H)-dione hydrochloride 2
．． 0.3F was dissolved in 8gt of dry pyridine, cooled to an internal temperature of 5°C, and added dropwise to 5ft of 2.5-dichlorobenzene chloride dissolved in 2ml of dry pyridine with stirring. After dropping, stir at room temperature for 80 minutes, leave to cool in the refrigerator overnight,
The reaction solution was poured into 50 g of ice water, made weakly alkaline by adding 10% aqueous sodium hydroxide solution, and the precipitated oil was extracted with ethyl acetate μ ester. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-(4-methquinpheniμ)-a-(2°5
2.4 f of a pale brown oil of -dichlorobenzenesulfonyloxy)-5-(2-dimethipaminoethyl I'v)-4,5-benzothiazepin-4(5H)-one are obtained.

1, R, (neat, ax)8070. 2940
．． 281G.

2460. 1650. 1600. 16B0. 1
500°1480, 1440. ta95゜This product is prepared by the usual method, when dissolved in isoglobin alcohol/L/, concentrated hydrochloric acid is added, and the precipitated crystals are purified with isoglobin alcohol.The melting point is 199-202℃. It becomes a hydrochloride showing (a).

Engineering. R, (Nujol, i”) 2550 (br
oad), 2400 (broad), 1646.16
00.16B0.1500゜IJ90.1250,11
95,1185°N, M, R, (DMso-a6.
pptll) 2.78 (a, 6H), 8.77
(s, In), 6.58-7.81 (m, 11M).

Elemental analysis 1m1 (%) C26-4N,! 0. C1□Insult・
Theoretical value as HCI C, 50,69: H, 4,06
;N, 4.54 actual value C, 5G, 5as E[, 4
, 11; N, 4.62 Example 2 2-(4-methoxyphenylene/l/)-2,a-dihydro-5-(2-dimethyρaminoethyl/L') -1,5-
Benzothiazepine-3,4(5H)-dione hydrochloride4.
061 was dissolved in dry pyridine 16g, and at room temperature, 2.4.5-)lichlorobenzene chloride/I'8.8
A solution of 6F dissolved in 76 ml of dry viridi was added dropwise while stirring. After the dropwise addition, the reaction is completed by stirring at room temperature for 20 minutes. After the reaction was completed, the mixture was poured into 70gt of ice water, made weakly alkaline by adding a 10% aqueous sodium hydroxide solution, and the precipitate was recrystallized from isopropylene. (4-methoxyphenylene/
I/) -3-(2,4,5-)riku probenzenes μ
Honioki V)-5-(2-dimethylaminoethyl/l/
)-1,5-benzothiazepin-4(5H)-one colorless crystals 1.6F are obtained.

■, R, (Nujol, 3) 1650.1600.
1500°14&0,1890.1100.1255,
1195° 1187° Elemental analysis value (%) C, 61123N20. C138
2 as theory [C, 50, '85: Ilf, a, 74
; N, 4.56* Measurement 11 G, 51.07 ±
III, 3.48; L4.49 When this product is dissolved in acetone, concentrated hydrochloric acid is added and left to cool, the melting point is 211-21.
A colorless hydrochloride salt having a temperature of 4°C (d) is obtained.

X, R, (Nujol, OX) 2650 (b
r, ), 2400(br,), 1645.1600.
1500.18g7゜1300.1.260,1190
, 1170°N, M, R, (DMSO-d6.p
pm ) 2.79 (s, 6H), 8.79 (s, aH
), 6.60-7.84 (m, 10H).

Example 3 2-(4-methoxyphenylene/L')-2,3-dihydro-5-(2-dimethoxyphenylene/L')-1,5-benzothiazepine-8,4(5H)- Dione 1 (1) was dissolved in 25 g JK of dry pyridine, cooled to an internal temperature of 5°C, and 4-chlorobenzenesulfony chloride N6.af dissolved in 15 Ill dry pyridine was added dropwise to the vessel while stirring. After the dropwise addition, it was left to cool in the refrigerator overnight. The reaction solution was poured into 200 ml of ice water and made weakly alkaline by adding 10% hydroxide to thorium aqueous solution.The precipitate was washed with water and dried to give 2-(2-() with a melting point of 148-145°C. 4-methoxyphenyl/l/)-3-(4-chlorobenzenesulfonyloxy)-5-(2-dimethy~aminoethyl/l/)-1,5
-Benzothiazepine-4(5H)-one pale yellow powder 1
Get 8f.

■, R, (Nujol, oII) 1640, 1600
．． 1580°1500.1475°1a00.1260
゜Elemental analysis value C%) C26H2S "Theoretical value as 205CIS2 C, 57, aoi H, 4, 59i N,
5.14 Actual measurement value C, 57,564H, 4,61; N
, 5.08 Dissolve this product in acetone, add concentrated hydrochloric acid, distill off the solvent under reduced pressure, and add 1μ of isopropyl alcohol to the residue to obtain the hydrochloride having a melting point of 178-180°C.

Engineering, R, (Nujol, cll) 2580.2450
,1640°1600.1570,1500.1295
．． 126 (1°N, M, R, (CDC13, ppm
) 2.96 (s, 6H), 3.80 (a, aH
), 6.48 7.72 (m, 12H).

Example 4 2-(4-methoxyphenylated)-2,3-dihydro-5
-(2-dimethylaminoethyl/L')-1,5-benzothiazepine-3,4(5H)-dione hydrochloride group 2. Oaf
was dissolved in 8 ml of dry pyridine, and bency chloride/L10.84f was added dropwise under stirring at room temperature.

After the dropwise addition, the mixture was stirred at room temperature for 2 hours and then heated and stirred at an internal temperature of 50° C. for 5 minutes to complete the reaction. From now on, when 50ml of ice water is added and the precipitate is recrystallized from acetone, the melting point is 19.
2-(4-methoxypheni/I/)-3-bency-oxy-5-(2-dimethylaminoethyl 1L/)-1,5-benzothiazepine-4(
1.5 f of colorless needle crystals of 5H)-one are obtained.

r, R, (Mujo'J-, OR) 1725.1640
,1600°1580.1500.1480,1a90
,1a20゜1a00,1270,1250゜N, M, R, (CDCl2.ppm)2.23(s
, 6H), 2.50-2.70 (m, 2H), 3.
77 (s, an), 3.82-8.90 (m, LH),
4゜4B-4,70 (m, IH).

6°80-7.96 (m, IIH).

Elemental analysis ff1 (%) Theoretical value as C2W H26N204S C, 68, 29 Electric I1.5.48; N, 5.9
0 actual measurement it C, 68, soaked in al, 5.50; H,
6,87 After dissolving this product in acetone and adding concentrated hydrochloric acid, the solvent was distilled off under reduced pressure and the residue was mixed with Inpropyl alcohol.
When added, colorless crystals of hydrochloride having a melting point of 168-171°C (d) are obtained.

F R0 (Nujol, all) 2580 (br,),
2400 (br,).

1720.1620,1600,1575.1500゜Example 5 2-(4-methoxyphenylene/L/)-2,a-dihydro-5-(2-dimethyaminoethyl/L/)-1,5-benzothiazepine -a,4(5H)-dione hydrochloride 4.0
61 was dissolved in 20xlK of dry pyridine, cooled to an internal temperature of 10°C, and 2.10f of 4-chlorobenzoyl chlorophyte dissolved in LOwl of dry pyridine was added dropwise with stirring. After dropping, the mixture was stirred at room temperature for 1 hour, and then left at room temperature overnight.
2-(4-methoxypheni/L/)-8-(4-
Chlorobenzy p-oxine)-5-(2-dimethylaminoethyl/l')-1,5-benzothiazepine-4 (5K)
Colorless powder of -one hydrochloride4. Get Of.

Engineering, R, (Nujol, QI) 2a00.1740
．． 1640°1600, 1500. 1485. 1
a20. 1a00°1260, 12aO.

N, M, R, (CDCl2.ppm) 2.86 (b
r, s, 6Fi).

3.90 (s, 3H), 6.82-7.85 (m, 1
2H).

Elemental analysis it (%) C2ヮEr2. N204S C'
Theoretical value as 1-HCI C,59,4o: L4.7
6-M, 5.1a actual measurement value C, 59,54±H, 4,7
7; N, 5.08 Example 6 A reaction is carried out according to Example 4t or Example 5 to obtain a compound for the surface treatment.

As mentioned above, the force/L/V antagonism of the compounds described in the Examples was tested using isolated rat aorta specimens, and the results were 10 to 5. KCI contraction was suppressed at 0x10 M.

Claims (1)

[Claims] 1 Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, and R_2 is a benzoyl group, a substituted 1,5-benzothiazepin-4(5H)-one derivative or its acid addition salt represented by a benzoyl group, a halogen- or lower alkoxy-substituted phenylsulfonyl group, R_3 represents a lower alkylaminoalkyl group, or an acid addition salt thereof 2 ) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) 2-phenyl or 2-(substituted phenyl)-2,3- (in the formula, R_1 and R_3 have the same meanings as above)
dihydro-5-substituted-1,5-benzothiazepine-3,
A method for producing a compound represented by formula (I) according to claim 1, which comprises reacting 4(5H)-dione or an acid addition salt thereof with a halogen reagent.