IE61168B1

IE61168B1 - Process for preparing 1.5-benzothiazepine derivatives

Info

Publication number: IE61168B1
Application number: IE194988A
Authority: IE
Inventors: Hirozumi Inoue; Tsunehiro Harada; Masaaki Nagasawa
Original assignee: Tanabe Seiyaku Co
Priority date: 1987-08-12
Filing date: 1988-06-27
Publication date: 1994-10-05
Also published as: AT395010B; CN1030570C; NO883525L; NO883525D0; KR890003722A; BG50501A3; ES2007990A6; JPS6445376A; NO170017B; PT88250B; ATA202388A; CN1031229A; IE881949L; FI883115A0; GR1000385B; CA1337346C; NO170017C; IL86978A0; FI883115A; GR880100515A

Abstract

PURPOSE:To readily obtain the titled compound useful as a medicinal compound having excellent hypotensive, cerebral coronary vasodilator and/or blood platelet agglutination inhibitory action, by reacting a specific compound with amines as raw materials. CONSTITUTION:An compound expressed by formula I (R<1> is lower alkyl or lower alkoxy; R<2> is H or lower alkanoyl; either of R<3> and R<4> is lower alkyl or halogen and the other is H; X' is reactive residue) is reacted with an amine expressed by formula II (R<5> and R<6> are lower alkyl) or salt thereof in a suitable solvent in the presence or absence of a deacidifying agent, preferably at ambient temperature - while being heated to afford the aimed compound, expressed by formula III and useful for treating.preventing cerebropathy, such as cerebral vasospasm, cerebral ischemia or cerebral infraction, and cardiopathy, such as angina pectoris. The above-mentioned compound is treated with an acid to provide an acid addition salt. Furthermore, since the aforementioned reaction proceeds without accompanying racemization, the aimed compound can also be obtained as an optically active substance by using the optically active compound expressed by formula I. [JP1045376A]

Description

Process for preparing 1,5-benzothiazepine derivatives SUMMARY OF THE INVENTION This invention relates to a process for preparing 1,5benzothiazepine derivatives and a pharmaceutically acceptable salt thereof which is useful as a pharmaceutical compound and represented by the formula: 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 pharmaceuticals.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Examples of the compound (I) of the present invention may include compounds in which R1 is a lower alkyl group, or a 2 lower alkoxy group, R is hydrogen or a lower alkanoyl 3 4 group, either one of R or R is a lower alkyl group or halogen atom, and the other is hydrogen atom, and each of R3 and R° is a lower alkyl group.

In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkyl group, the lower alkoxy group, and the lower alkanoyl group include an alkyl group of one to six carbon atoms, an alkoxy group of one to six carbon atoms and an alkanoyl group of two to six carbon atoms, respectively.

Preferred examples of these groups are an alkyl group of one to four carbon atoms, an alkoxy 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: <} R Ο ch2ch2x (II) 12 3 wherein X is a reactive residue and R , R , R and R have the same meanings as defined above, with an amine represented by the formulas (III) rwherein R*5 and R° have the same meanings as defined above, or a salt thereof, and if necessary convert it to a salt thereof.

The reaction of the compound (II) and the amine (III) or a salt thereof may be carried out in a suitable solvent in the presence or absence of base. In the compound (II), examples of the reactive residue represented by X^ may include halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom, an alkylsulfonyloxy group such as methylsulfonyloxy group, and a substituted or unsubstituted phenylsulfonyloxy group such as tosyloxy group. Also, the amine (III) can be used in the state of free or as a salt thereof to the above reaction. Examples of such a salt may include conventional acid addition salt such as hydrochloride, hydrobromide, sulfate, nitrate, etc. As the base, there may be suitably mentioned alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, tertiary amine, etc., and also the amine (III) may be used to this purpose. The present reaction is preferably carried out in a suitable solvent (for example, dimethylformamide, diethylformamide, dimethylacetamide, N-formylmorpholine, N-acetylmorpholine, dimethylsulfoxide, diglyme, diethylether, tetrahydrofuran, dimethoxyethane, dioxane, pyridine, alkanol, acetonitrile, acetone, methyl ethyl ketone, ethylacetate, methylacetate, methylpropionate, ethylpropionate, benzene, xylene, toluene, etc.) at the temperature between 0 °C and 150 °C.

The compound (I) thus obtained can be easily converted into a pharmaceutically acceptable acid addition salt, for 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 oxalate, maleate, tartrate, methanesulfonate, etc.

Since the reaction of the present invention as mentioned above proceeds without accompanying any racemization, by using an optically active compound (II) as the starting 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 present 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, 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 compound (II) of the present invention can be produced by reacting the compound represented by the formula: same meanings as (IV) defined above, which can be obtained in accordance with the method as described, for example, in Japanese Provisional Patent Publication No. 225174/1984 (which corresponds to U.S. Patent No. 4,567,175) with the compound represented by the formula: x1-ch2ch2-x2 (V) 1 wherein X is a reactive residue and X has the same meaning as defined above, in a suitable solvent (for example, dimethylsulfoxide) in the presence of base (for example, alkali metal hydroxide, alkali metal hydride), and further the product is carried out condensation reaction with a reactive derivative (for example, acid anhydride, acid halide) of a lower aliphatic acid, if required.

Also, the compound (I) of the present invention and the compound (II) include either two kinds of stereoisomers (that is, cis and trans-isomers) or four kinds of optical isomers (that is, ( + )-cis, (-)-cis, (-i-)-trans and (-)-trans isomers) and mixtures thereof based on asymmetric carbon atoms (two) in the molecule.

Example 1 (1) In 50 ml of dimethylsulfoxide containing 590 mg of potassium hydroxide was dissolved 3.36 g of (+)-cis-2-(4methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one, and the solution was stirred at room temperature for 30 minutes. Then, 1.75 g of l-chloro-2methanesulfonyloxyethane was added to the solution and the mixture was stirred at room temperature. After completion of the reaction, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried and then the solvent was distilled off. After the residue was dissolved in ether and allowed to stand, insoluble starting materials were removed by filtration.

The filtrate was condensed to remove the solvent. Oily products obtained were purified by silica gel column chromatography (eluent: chloroform : ethyl acetate = 20 : 1), and recrystallized from ethanol to give 1.05 g of a mixture (9 : 1) of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy5-(2-chloroethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin4(5H)-one and (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2(methanesulfonyloxy)ethyl]-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one. mp. 125 to 128 °C.

MS (m/e); 365, 363 (M+ - CH3SO2) (2) This product (1.03 g) was dissolved in 10 ml of dimethylformamide, and 90 mg of a 51 % dimethylaminetoluene solution was added to the solution and the mixture was stirred at room temperature for 62 hours. Further, 180 mg of a 51 % dimethylamine-toluene solution was added to the mixture and the mixture was stirred at room temperature. After completion of the reaction, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform : ethanol = 95 : 5) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 687 mg of (+)-cis-2~(4~methoxvphenyl)-3-hydroxy-5~[2-(dime thylamino) ethyl ]-8-chloro-2,3-dihydro-l,5-benzothiazepin4(5H)-one. mp. 122 to 124 °C (decomposed).

Example 2 (1) In 150 ml of dimethylsulfoxide containing 1.77 g of potassium hydroxide was dissolved 10. 08 g of (+)~cis~2~(4~ methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-l L, 5-benzothiazepin-4(5H,-one and the solution was stirred at room temperature for 30 minutes. Subsequently, 4.70 g of l-bromor2-chloroethane was added to the solution and the mixture was stirred at room temperature. After completion of the reaction, the mixture was poured into ice-water and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. After the residue was dissolved in ether and allowed to stand, precipitated starting material was removed by filtration. The filtrate was condensed to distill off most of the solvent. The residue was allowed to stand and precipitated crystals were collected by filtration to obtain crude product (594 mg). The filtrate was applied to a silica gel column chromatography (eluent: chloroform : ethyl acetate - 20 : 1) and the crude product obtained was combined with the crude product obtained above, and they were recrystallized from ethanol to give 7.94 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-S-(2-chloroethyl)8 8-chlorο-2,3-dihydro-l,5-benzothiazepin-4(5Η)-one. mp. 128 to 131 °C.

IRvNujol (c -1). 3460 1660 1590> max ' ' MS (m/e): 399, 397 (M ) . (2) This product, a 51 % dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis 2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one. mp. 122 to 124 °C (decomposed).

Example 3 (1) To a mixture of 3 ml of acetic anhydride and 2 ml of acetic acid was added 484 mg of (-r)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro1,5-benzothiazepin-4(5H)-one and the mixture was stirred at 110 °C. After completion of the reaction, the mixture was condensed under reduced pressure to distill off the solvent. After the residue was dissolved in toluene, it was condensed to dryness under reduced pressure to give 535 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2chloroethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin4(5H)-one as oily product.

IRvliq- (cm-1): 1740, 1680, 1600, 1580. max + MS (m/e): 439, 441 (M ). (2) This product, a 51 % dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis 2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.

Maleate of this products mp. 158 to 160 °C (recrystallized from ethanol).

Examples 4 to 9 By treating corresponding starting materials in the same manner as in Examples 1 to 3, the following compounds can be obtained. (4) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino) ethyl ]-9-chloro-2,3-dihydro-l,5-benzothiazepin4(5H)-one.perchlorate.Ihydrate mp. 190 to 192 °C. (5) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino) ethyl ]-9-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)one.hydrochlor ide. monohydrate mp. 140 to 143 °C. (6) (±)-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). (7) (±)-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 acetone and isopropyl ether, exhibits a melting point of 190 to 192 °C, thus having the properties of crystals polymorphism.

Fumarate of this products mp. 196.5 to 198.5 °C (decomposed) (recrystallized from isopropanol).

Maleate of this products mp. 173.5 to 175.5 °C (decomposed) (recrystallized from ethanol).

This product, when recrystallized from methanol, exhibits a 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 products mp. 124 to 128 °C (recrystallized from isopropanol). (8) (+)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino ) ethyl ] -8-methy 1-2 ,3-dihydro-1,5-benzothiazepin-4(5H)one.maleate mp. 194 to 197 °C (decomposed) (recrystallized from ethanol). on [a]p + 83.7° (c=0.362, methanol).

Oxalate of this product: mp. 179 to 180 °C (recrystallized from ethanol) . [α]2θ + 88.2° (c=0.288, methanol). (9) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino) ethyl ]-8-methy1-2,3-dihydro-l,5-benzothiazepin-4(5H)one.oxalate -limp. 179.5 to 181 °C (decomposed) (recrystallized from ethanol). [α]^θ - 83.8° (c=0.333, methanol).

Maleate of this product: mp. 195 to 197.5 °C (decomposed) (recrystallized from ethanol) [α]2θ - 83.6° (c=0.50, methanol) Fumarate of this product: mp. 210.5 to 212.5 °C (decomposed) (recrystallized from ethanol). [α]2θ - 91.30 (c=0.323, methanol).

L-(+)-tartrate of this product: mp. 140 to 143 °C (recrystallized from a mixed solvent of ethanol and ether).

Claims

Claims:

1. A process for preparing 1,5-benzothiazepine derivatives represented by the formula: (I) 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: defined above, and X is a reactive residue, with an amine represented by the formula: R' HN (III) c 6 wherein R and R have the same meanings as defined above, or a salt thereof, and if necessary convert it to a pharmaceutically acceptable acid addition salt thereof.

2. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein the reaction is carried out in a solvent in the presence or absence of base at the temperature between 0 °C and 150 °C.

3. A process for preparing 1,5-benzothiazepine derivatives according to Claim 2, wherein said base is alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate or tertiary amine.

4. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein the reactive residue represented by X^ is halogen atom, an alkylsulfonyloxy group, or a substituted or unsubstituted phenylsulfonyloxy group.

5. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein said salt of the amine is hydrochloride, hydrobromide, sulfate or nitrate of the amine.

6. A process for preparing 1,5-benzothiazepine derivatives according to Claim 1, wherein said compound represented by the formula (II) is prepared by reacting the compound represented by the formula: defined in Claim 1, with the compound represented by the formulas x 1 -ch 2 ch 2 -x 2 (V) 2 1 wherein X is a reactive residue and X has the same meaning as defined in Claim 1, in a solvent in the presence of base, and further the product is carried out condensation reaction with a reactive derivative of a lower aliphatic acid, if required.

7. A process for preparing 1,5-benzothiazepine derivatives according to Claim 6, wherein said reactive derivative of a lower aliphatic acid is acid anhydride or acid halide.

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 9 5-benzothiazepine derivatives of the formula (I) defined in Claim 1, substantially as hereinbefore described by way of Example.