IE881950L - Process for preparing benzothiazepine derivatives - Google Patents
Process for preparing benzothiazepine derivativesInfo
- Publication number
- IE881950L IE881950L IE881950A IE195088A IE881950L IE 881950 L IE881950 L IE 881950L IE 881950 A IE881950 A IE 881950A IE 195088 A IE195088 A IE 195088A IE 881950 L IE881950 L IE 881950L
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- preparing
- group
- benzothiazepine derivatives
- compound
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
PURPOSE:To readily obtain the titled compound useful as a drug, having hypotensive action, vasodilating action on cerebral blood vessel and crown blood vessel, by condensing an N-nonsubstituted 1,5-benzothiqazepine derivative as a raw material with an aminoethanol derivative. CONSTITUTION:An N-nonsubstituted 1,5-benzothiazepine derivative shown by formula I (R<1> is lower alkyl or lower alkoxy; R<2> is H or lower alkanoyl; one of R<3> and R<4> is lower alkyl or halogen atom. and the other H) is used as a raw material and condensed with an aminoethanol derivative shown by formula II (R<5> and R<6> are lower alkyl; Z is H, lower alkylsulfonyl, arylsulfonyl or sulfo). In the reaction, when Z of the compound shown by formula II is preferably H, the reaction is carried out in the presence of a dehydrating agent and when Z is lower alkylsulfonyl, the reaction is done is the presence of an alkali reagent to give a compound shown by formula III.
[JP1050872A]
Description
6 r i 6 9 FP-1679 la - Process for preparing 1,5-benzothiazepine derivatives SUMMARY OF THE INVENTION This invention relates to a process for preparing 1,5-benzothiazepine derivatives and a pharmaceutically accept-5 able salt thereof which is useful as a pharmaceutical compound and represented by the formula: (I) CH2CH2N( wherein R is a lower alkyl group or a lower alkoxy 2 group, R is hydrogen or a lower alkanoyl group, one 3 4 of R and R is a lower alkyl group or halogen atom, 6 and the other is hydrogen, and each of R and R is a lower alkyl group.
The 1,5-benzothiazepine derivatives (I) and a pharmaceutically acceptable acid addition salt thereof are useful pharmaceutical compounds having an excellent hypotensive activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity, and among 2 the compound (I), a compound wherein R is hydrogen atom is also useful of as an intermediate for synthesis of 5 pharmaceuticals.
DESCRIPTION OF THE PREFERRED EMBODIMENTS Examples of the compound (I) of the present invention may 10 include compounds in which R^" is a lower alkyl group, or a 2 lower alkoxy group, R is hydrogen or a lower alkanoyl group, either one of R"^ or R^ is a lower alkyl group or halogen atom, and the other is hydrogen atom, and each of 5 6 R and R is a lower alkyl group.
In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkoxy group, the lower alkyl group and the lower alkanoyl group include an alkoxy group of one to six carbon atoms, an alkyl group of one to six 20 carbon atoms and an alkanoyl group of two to six carbon atoms, respectively. Preferred examples of these group are an alkyl group of one to four carbon atoms and an alkanoyl group of two to five carbon atoms.
According to the present invention, the compound (I) or a pharmaceutically acceptable salt thereof can be prepared by reacting a compound represented by the formula; 12 3 4 wherein R , R , R and R have the same meanings as defined above, with an aminoethanol represented by the formulas n-ch2-ch2-oz (III) 6 wherexn R and R have the same meanings as defined above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, 10 to condensation reaction and, if necessary, convert it to a salt thereof according to a conventional method.
The above condensation reaction, when the starting compound (III) wherein Z is hydrogen is employed, can be practiced 15 suitably in the presence of a dehydrating agent. As the dehydrating agent, for example, a mixture of triphenylphos-phine and diethylazodicarboxylate, a mixture of triphenyl-phosphine and dimethylazodicarboxylate, a mixture of sulfuryldiimidazole and sodium hydride can be suitably 20 used. This condensation reaction may be preferably practiced in a suitable solvent (e.g., chloroform, dichloro-ethane, dichloromethane, acetone, diethyl ketone, methyl ethyl ketone, ethyl acetate, methyl acetate, ethyl propionate, methyl propionate, dimethylformamide, diethylformate, 25 dimethylacetamide, M-formylmorpholine, N-acetylmorpholine, dioxane, tetrahydrofuran, ether, dimethoxyethane, diglyme, toluene, benzene, xylene, etc.) at 0 °C to 150 °C.
On the other hand, when the compound (III) wherein Z is a 30 lower alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group), an arylsulfonyl group (e.g., benzene-sulfonyl group, tosyl group) or sulfo group, the condensation reaction of said compound and the compound (II) can be practiced preferably in the presence of an alkali 35 reagent. Examples of the alkali reagent may include alkali metal hydroxides (e.g., potassium hydroxide, etc.), alkali metal carbonates (e.g., potassium carbonate, etc.), alkali metal hydrogen carbonates (e.g., potassium hydrogen carbonate, etc.), alkali metal hydrides (e.g., sodium hydride, etc.). This condensation reaction should prefer-5 ably be practiced in a suitable solvent (e.g., methyl ethyl ketone, diethyl ketone, acetone, dimethylsulfoxide, dimethylformamide, ethyl acetate, methyl propionate, ethyl propionate, tetrahydrofuran, dioxane, ether, dimethoxy-ethane, diglyme, toluene, benzene, xylene, acetonitrile, 10 dimethylacetamide, diethylformamide, N-formylmorpholine, N-acetylmorpholine, etc.) at 0 °C to 150 °C.
The compound (I) thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt, for 15 example, by treating with an acid, if necessary. Examples of such pharmaceutically acceptable acid addition salts may include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, phosphate, etc.; and organic acid addition salts such as 20 oxalate, maleate, fumarate, tartrate, methanesulfonate, etc.
Since the reaction of the present invention as mentioned above can proceed without accompanying any racemization, by using an optically active compound (II) as the starting 25 material, the compound (I) can be obtained as an optically active compound.
The 1,5-benzothiazapine derivatives (I) or pharmaceutically acceptable acid addition salts thereof of the pre-30 sent invention have excellent hypotensive activity, cerebral or coronary vasodilating activity and/or platelet aggregation-inhibiting activity as mentioned above, and can be used for therapy and prevention of brain diseases such as cerebrovascular contraction, cerebral ischemia, 35 cerebral infarction, etc., or cardiac diseases such as stenocardia, cardiac infarction, etc. Also, among the 2 compound (I), the compound wherein R is hydrogen is also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (I) wherein R is a lower alkanoyl group.
The starting compound (II) to be used in the present invention can be prepared according to the methods as described in Japanese Provisional Patent Publications No. 225174/1984, No. 202871/1985 and No. 122281/1986 (which 10 correspond to U.S. Patents No. 4,567,175, No. 4,590,188 and No. 4,665,068, respectively).
Also, the compound (I) of the present invention and the compound (II) include either two kinds of stereoiso-15 mers (that is, cis and trans-isomers) or four kinds of optical isomers (that is, ( + )-cis, (-)-cis, (4-)-trans and (-)-trans isomers) and mixtures thereof based on asymmetric carbon atoms (two) in the molecule.
Example 1 To 80 ml dichloromethane solution of 3 g of {+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-l,5-benzo-thiazepin-4(5H)-one and 2.3 g of triphenylphosphine were 25 added 15 ml dichloromethane solution of 779 mg of 2-(di-methylamino)ethanol over 20 minutes, then 15 ml dichloromethane solution of 1.52 g of diethylazodicarboxylate at room temperature over 20 minutes. The mixture was stirred for 20 hours at room temperature, followed by condensation 30 under reduced pressure. The residue was dissolved in ethyl acetate and insolubles were removed by filtration. The filtrate was extracted with a 10 % hydrochloric acid, and the aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The extract was 35 washed with water, dried and evaporated under reduced pressure. The residue was converted to maleate and re- crystallization from ethanol gave 3.55 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.maleate. Yield: 79.2 %. mp. 158 to 160 °C.
Example 2 After stirring a mixture of 354 mg of 2-(dimethylamino)-ethanol and 159 mg of a 60 % sodium hydride in 14 ml of dimethylformamide at room temperature for 20 minutes, 787 mg of sulfuryldiimidazole was added at - 40 °C to the mixture and the mixture was stirred at the same tempera- ture for one hour. Subsequently, 5 ml dimethyl sulfoxide solution of 1.0 g of (+)-cis-2-(4-methoxyphenyl)-3-acet-oxy-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one was added at - 40 °C and after gradual warming, the reaction mixture was stirred at room temperature for 20 hours.
After completion of the reaction, methanol and chloroform were added. The mixture was washed with water and dried, followed by removal of the solvent, and the residue was separated by column chromatography. After removal of the starting lactam by elution with chloroform-ethanol (20 : 1), the oily product subsequently eluted was converted to maleate and recrystallized from ethanol to give 777 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino) ethyl]-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.-maleate. mp. 158 to 160 °C.
Example 3 To 30 ml acetone solution of 1.86 g of (-s-) -cis-2- (4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-l,5-benzo- thiazepin-4(5H)-one were added 2.4 g of powdery potassium carbonate and 1.1 g of 2-(dimethylamino)ethyl methane-sulfonate•hydrochloride, and the mixture was refluxed under stirring for 10 hours. After completion of the 5 reaction, inorganic materials were removed by filtration, to the residue were added a 10 % hydrochloric acid and ethyl acetate, and extracted with a 10 % hydrochloric acid. The extract was washed with water, dried and then condensed under reduced pressure. The residue was con-10 verted into hydrochloride and recrystallized from a mixture of acetone-ethanol to give 2.10 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.hydrochloride. Yield: 86.5 %. mp. 127 to 131 °C (decomposed).
Example 4 To 50 ml dimethylsulfoxide solution of 3.36 g of (-!■) -cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one was added 1.35 g of potassium hydroxide under ice-cooling and, after stirring at room temperature, 244 mg of 2-(dimethylamino)ethyl methanesul-25 fonate hydrochloride was added, followed by stirring at room temperature for 16 hours. After completion of the reaction, the mixture was poured into ice-water and the mixture was extracted with a 1 : 1 mixture of chloroform and ethanol. The extract was washed with water, dried and 30 then evaporated under reduced pressure. Recrystallization of 3.48 g of the residue from a mixed solvent of ethyl acetate and hexane gave 3.06 g of (+)-cis-2-(4-methoxyphenyl )-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Yield: 75.2 %. mp. 122 to 124 °C.
Example 5 To 30 ml acetone-0.5 ml water solution of 1.68 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-5 1,5-benzothiazepin-4(5H)-one were added 2.40 g of potassium carbonate and 1.09 g of 2-(dimethylamino)ethyl methanesulfonate•hydrochloride, followed by refluxing for 20 hours. After completion of the reaction, inorganic materials were removed by filtration, to the residue were 10 added a 10 % hydrochloric acid and ethyl acetate and the organic layer was extracted with a 10 % hydrochloric acid. The hydrochloric acid layers were combined and made alkaline with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried, 15 and evaporated under reduced pressure. Recrystallization of the residue from a mixture of ethyl acetate-n-hexane gave 1.40 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-l,5-benzothiaze pin-4(5H)-one. Yield: 68.8 %. mp. 123 to 125 °C.
Example 6 In Example 3, by use of 2-(dimethylamino)ethyl benzene- sulfonate.hydrochloride in place of 2-(dimethylamino)ethyl methanesulfonate, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-l,5-benzo-thiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in Example 3.
Example 7 In Example 3, by use of 2-(dimethylamino)ethyl toluene- sulfonate.hydrochloride in place of 2-(dimethylamino)ethyl methanesulfonate, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-l,5-benzo-thiazepin-4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in Example 3.
Example 8 In Example 3, by use of 2-(dimethylamino)ethyl sulfate in place of 2-(dimethylamino)ethyl methanesulfonate.hydrochloride, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino) ethyl] -8-chloro- 2 ,3-dihydro-l,5-benzothiazepin 15 4(5H)-one.hydrochloride was obtained.
This product had the same physical data as the product in Example 3.
Examples 9 to 14 By treating the corresponding starting materials in the same manner as in Examples 1 to 5, the following compounds were obtained. (9) (-s-) -cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino) ethyl] -9-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H) one.perchlorate ihydrate mp. 190 to 192 °C. (10) (-?-) -cis-2- (4-methoxyphenyl) - 3-acetoxy-5 - [ 2- (dimethyl amino)ethyl]-9-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H) one.hydrochloride monohydrate mp. 140 to 143 °C. (11) (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(dimethylamino) ethyl ]-8-methyl-2,3-dihydro-l,5-benzothiazepin-4(5H) -one mp. 142 to 143 °C (recrystallized from ethyl acetate). (12) (±)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino ) ethyl]-8-methyl-2,3-dihydro-l,5-benzothiazepin-4(5H) -one.hydrochloride mp. 184 to 186 °C (recrystallized from a mixed solvent of isopropanol and ether).
This product, when recrystallized from a mixed solvent of 15 acetone and isopropanol exhibits a melting point of 190 to 192 °c.
Fumarate of this product: mp. 196.5 to 198.5 °C (recrystallized from isopropanol).
Maleate of this product: mp. 173.5 to 175.5 °C (recrystallized from ethanol).
This product, when recrystallized from methanol exhibits a 25 melting point of 172.5 to 174 °C and, when recrystallized from water, gives crystals exhibiting a melting point of 191.9 °C, thus having the properties of crystals polymorphism.
Methanesulfonate of this product: mp. 124 to 128 °C (recrystallized from isopropanol). (13) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino) ethyl] -8-methy 1-2 ,3-dihydro-l,5-benzothiazepin-4(5H)-one.maleate mp. 194 to 197 °C (decomposed) (recrystallized from ethanol). [a]2^ + 83.7° (c=0.362, methanol).
Oxalate of this product: mp. 179 to 180 °C (recrystallized from ethanol). [a]2® + 88.2° (c=0.288, methanol). (14) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethy1-10 amino)ethyl]-8-methyl-2,3-dihydro-l,5-benzothiazepin-4(5H) one.oxalate mp. 179.5 to 181 °C (decomposed) (recrystallized from ethanol). 9f) ~ 83.8° (c=0.333, methanol).
Maleate of this product: mp. 195 to 197.5 °C (decomposed) (recrystallized from ethanol). ~ 83.6° (c=0.50, methanol).
Fumarate of this product: mp. 210.5 to 212.5 °C (decomposed) (recrystallized from ethanol). [^0° " 91°3° (c=0 . 323, methanol).
L-(+)-tartrate of this product: mp. 140 to 143 °C (recrystallized from a mixed solvent of ethanol and ether).
Claims (9)
1. A process for preparing 1,5-benzothiazepine derivatives represented by the formula: (I) CH2CH2\ R wherein R is a lower alkyl group or a lower alkoxy 2 15 group, R is hydrogen or a lower alkanoyl group, one 3 4 of R and R is a lower alkyl group or halogen atom, 5 6 and the other is hydrogen, and each of R and R is a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, 20 which comprises reacting a compound represented by the formula: 25 (II) 12 3 4 wherein R , R , R and R have the same meanings as 30 defined above, with an aminoethanol represented by the formula: 35 R \ /N-CH2"CH2-OZ (III) R 10 - 13 - 5 6 wherein R and R have the same meanings as defined above, and Z is hydrogen, a lower alkylsulfonyl group, an arylsulfonyl group or sulfo group, to condensation reaction and, if necessary, convert it to a pharmaceutacally acceptable acid addition salt thereof.
2. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein the condensation reaction is carried out in a solvent at 0 °C to 150 °C.
3. A process for preparing 1,5-benzothiazepine derivatives according to Claim 2, wherein the condensation reaction is carried out in the presence of a dehydrating agent when Z in the compound of the formula (III) is 15 hydrogen.
4. A process for preparing 1,5-benzothiazepine derivatives according to Claim 3, wherein the dehydrating agent is a mixture of triphenylphosphine and diethylazodicarbo- 20 xylate, a mixture of triphenylphosphine and dimethylazo-dicarboxylate, or a mixture of sulfuryldiimidazole and sodium hydride.
5. A process for preparing 1,5-benzothiazepine deriva-25 tives according to Claim 2, wherein the condensation reaction is carried out in the presence of an alkali reagent when Z in the compound of the formula (III) is a lower alkylsulfonyl group, an arylsulfonyl group or a sulfo group. 30
6. A process for preparing 1,5-benzothiazepine derivatives according to Claim 5, wherein the alkali reagent is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate or an alkali metal hydr- 35 ide. - 14 -
7. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein the compound obtained is treated with an acid to convert it to a pharmaceutically acceptable acid addition salt.
8. A process for preparing 1 s,5-benzothiazepine derivatives of the formula (I) defined in Claim 1» substantially as hereinbefore described by way of Example.
9. 1 .»5-benzothiazepine derivatives of the formula (I) defined in Claim ls substantially as hereinbefore described by way of Example. Dated this the 2/th day of June 1988. BY: (Signed) *§—:*—T 59 Dartmouth Road DUBLIN 6.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62208482A JPS6450872A (en) | 1987-08-21 | 1987-08-21 | Production of 1,5-benzothiazepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE881950L true IE881950L (en) | 1989-02-21 |
| IE61169B1 IE61169B1 (en) | 1994-10-05 |
Family
ID=16556895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE195088A IE61169B1 (en) | 1987-08-21 | 1988-06-27 | Process for preparing 1.5-benzothiazepine derivatives |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS6450872A (en) |
| KR (1) | KR890003723A (en) |
| CN (1) | CN1031374A (en) |
| AT (1) | AT395424B (en) |
| BG (1) | BG49047A3 (en) |
| CA (1) | CA1312077C (en) |
| ES (1) | ES2007993A6 (en) |
| FI (1) | FI93009C (en) |
| GR (1) | GR1000452B (en) |
| IE (1) | IE61169B1 (en) |
| IL (1) | IL87026A (en) |
| NO (1) | NO170541C (en) |
| PT (1) | PT88300B (en) |
| RU (1) | RU1784041C (en) |
| TW (1) | TW207536B (en) |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1236467A (en) * | 1967-10-28 | 1971-06-23 | Tanabe Seiyaku Co | Benzothiazepine derivatives |
| SE449611B (en) * | 1982-07-09 | 1987-05-11 | Tanabe Seiyaku Co | SET TO MAKE 1,5-BENZOTIAZEPINE DERIVATIVES |
| US4564612A (en) * | 1983-04-22 | 1986-01-14 | Takeda Chemical Industries, Ltd. | Condensed, seven-membered ring compounds and their use |
| US4567175A (en) * | 1983-06-03 | 1986-01-28 | Tanabe Seiyaku Co., Ltd. | 8-Chloro-1,5-benzothiazepine derivatives |
| GB8315364D0 (en) * | 1983-06-03 | 1983-07-06 | Tanabe Seiyaku Co | 8-chloro-1 5-benzothiazepine derivatives |
| GB8406318D0 (en) * | 1984-03-10 | 1984-04-11 | Tanabe Seiyaku Co | 1 5-benzothiazepine derivatives |
| JPS61103877A (en) * | 1984-10-24 | 1986-05-22 | Tanabe Seiyaku Co Ltd | Benzothiazepine derivative and its preparation |
| GB2167063A (en) * | 1984-11-17 | 1986-05-21 | Tanabe Seiyaku Co | 6 or 9-chloro-1, 5-benzothiazepine derivatives |
| JPS61225175A (en) * | 1985-03-28 | 1986-10-06 | Sawai Seiyaku Kk | Production of 1,5-benzothiazepine derivative |
| HU195795B (en) * | 1985-11-06 | 1988-07-28 | Richter Gedeon Vegyeszet | Process for preparing (2s,3s)-3-acetoxy-5-(n,n-dimethyl-amino-ethyl)-2-(h-methoxy-phenyl)-2,3-dihydro-1,5-benzothiazepin-h(5h)-one |
-
1987
- 1987-08-21 JP JP62208482A patent/JPS6450872A/en active Pending
-
1988
- 1988-06-27 IE IE195088A patent/IE61169B1/en not_active IP Right Cessation
- 1988-06-29 FI FI883116A patent/FI93009C/en not_active IP Right Cessation
- 1988-07-07 CA CA000571434A patent/CA1312077C/en not_active Expired - Fee Related
- 1988-07-07 IL IL8702688A patent/IL87026A/en not_active IP Right Cessation
- 1988-07-16 CN CN88104429A patent/CN1031374A/en active Pending
- 1988-08-02 BG BG085117A patent/BG49047A3/en unknown
- 1988-08-04 GR GR880100516A patent/GR1000452B/en unknown
- 1988-08-09 NO NO883526A patent/NO170541C/en unknown
- 1988-08-12 ES ES8802539A patent/ES2007993A6/en not_active Expired
- 1988-08-18 PT PT88300A patent/PT88300B/en not_active IP Right Cessation
- 1988-08-19 RU SU884356329A patent/RU1784041C/en active
- 1988-08-19 AT AT0206388A patent/AT395424B/en not_active IP Right Cessation
- 1988-08-20 KR KR1019880010577A patent/KR890003723A/en not_active Application Discontinuation
-
1990
- 1990-05-07 TW TW079103691A patent/TW207536B/zh active
Also Published As
| Publication number | Publication date |
|---|---|
| NO170541B (en) | 1992-07-20 |
| GR1000452B (en) | 1992-07-30 |
| CA1312077C (en) | 1992-12-29 |
| AT395424B (en) | 1992-12-28 |
| NO883526L (en) | 1989-02-22 |
| JPS6450872A (en) | 1989-02-27 |
| FI93009B (en) | 1994-10-31 |
| ATA206388A (en) | 1992-05-15 |
| FI883116A0 (en) | 1988-06-29 |
| RU1784041C (en) | 1992-12-23 |
| PT88300A (en) | 1989-06-30 |
| FI883116A (en) | 1989-02-22 |
| PT88300B (en) | 1995-03-31 |
| IL87026A0 (en) | 1988-12-30 |
| GR880100516A (en) | 1989-05-25 |
| NO170541C (en) | 1992-10-28 |
| BG49047A3 (en) | 1991-07-15 |
| IE61169B1 (en) | 1994-10-05 |
| TW207536B (en) | 1993-06-11 |
| IL87026A (en) | 1995-01-24 |
| KR890003723A (en) | 1989-04-17 |
| CN1031374A (en) | 1989-03-01 |
| FI93009C (en) | 1995-02-10 |
| NO883526D0 (en) | 1988-08-09 |
| ES2007993A6 (en) | 1989-07-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |