WO1985004402A1 - Fused 7-membered ring compounds and process for their preparation - Google Patents

Abstract

Novel fused 7-membered ring compounds represented by formula (I) wherein R1 and R2 each represents hydrogen, halogen, tri-fluoromethyl, lower alkyl, alkoxy or, when taken together, they represent tri- or tetra-methylene, R3 represents hydrogen, lower alkyl or aralkyl, R4 represents hydrogen or optionally substituted alkyl, aralkyl or cycloalkyl, X represents S(O)n, where n is an integer of 0 to 2, Y represents optionally esterified or amidated carboxy, and m represents 1 or 2, and salts thereof are effective in inhibiting angiotensin-converting enzyme and are useful for diagnosis, prophylaxis and treatment of hypertension.

Description

 Ming's Condensation 7-membered compound and its production

 The present invention relates to a novel condensed seven-membered ring compound useful as a medicine and a method for producing the same. Background art

 The present inventors have enthusiastically searched for a compound having an inhibitory action on angiotensin-converting enzyme and useful as a therapeutic agent for antihypertensive.As a result, the present inventors have succeeded in producing a fused 7-membered ring compound having an excellent action, completed. Disclosure of the invention

The present invention relates to the formula COOR ³

(Wherein, R ¹ and R ² each represent hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or both are connected to each other to form tri or tetramethylene, and R ³ is hydrogen, lower Alkyl or aralkyl, R ⁴ is hydrogen or optionally substituted alkyl, aralkyl or cycloalkylalkyl, X is S (0) n (where η represents an integer of 0 to 2). Y represents a carboxyl group which may be esterified or amidated, and m represents 1 or 2.] The novel compound represented by the formula: there is provided the above formula relates to (I), as the halogen represented by R ¹ or R ² is for example fluorine group, chlorine, bromine, iodine and the like, lower alkoxycarbonyl represented by R ¹ or R ² Examples of the silyl group include alkoxy groups having about 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. , R ¹ and R ² may be linked together to form an alkylene bridge; Examples include alkylene bridges such as tetramethylene.

Examples of the lower alkyl group represented by R ¹ , R ² or R ³ include alkyl groups having about 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Is raised.

As the alkyl group represented by R ⁴ , a linear or branched alkyl group having about 1 to 16 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, Heptyl, octyl, nonyl, decyl, pendecyl, dodecyl, tridecyl, tetradecyl, pentadecyl), and these groups may be substituted, for example, hydroxy, lower (Ci-14) alkoxy (eg, methyl Xy, ethoxy, propoxy, butoxy), mercapto, lower (Ci-4) alkylthio (eg, methylthio, ethylthio, propylthio, butylthio) amino, mono or di-lower (Ci-14) alkylamino (Eg, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, Butylamino, isobutylamino, dimethylamino, methylethylamino, methylpropylamino, methylethylamino, methylethylamino, ethylpropylamino, ethylethylamino, dipropylamino, propylbutylamino, dibutylamino,), carbon Alkanolamino with a number of 5 or less (eg, formamide, acetate, propylamide, butylamide, zo, 'relamide, piperamide) and acylamino such as benzamide, Cs-8 alkyl amino (E.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclobutylamino, cyclooctylamino), and the like, where R is such a substituted alkyl group. Carbon number 2-6 Those alkyl groups of time is preferred.

Examples of the aralkyl group represented by R ³ or R ⁴ include, for example, benzyl, phenethyl, 3-phenylpropyl group, α-methylbenzyl group, α-ethylbenzyl group, monomethylphenethyl group, / 3-methylphenethyl group, 3- A phenyl lower (C i-*) alkyl group having about 7 to 10 carbon atoms, such as ethyl phenyl group; and the phenyl group in the phenyl lower alkyl group has 1 to 3 halogen atoms (eg, fluorine). , Chlorine, bromine, iodine), Ci-4

_O PI Alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.), C14 alkoxy group (eg, methoxy group, ethoxy group, methoxy group, isopropoxy group, A butoxy group, a methylenedioxy group, etc.), an amino group, a nitro group or a hydroxyl group, etc., and the alkyl group in the phenyl lower alkyl group may also have a peripheral substituent. Examples of such substituted phenyl lower alkyl groups include 2- (4-chlorophenyl) ethyl, 2- (4-hydroxyphenyl) ethyl, and 2- (4-methoxyphenyl) ethyl. , 2- (3.4-dimethyloxyphenyl) ethyl group, 2- (3,4,5-trimethyloxyphenyl) ethyl group, 2- (3,4-methylenedioxyxyphenyl) ethyl group, 2- (P-tolyl) ethyl group, 3,4-dimethyloxybenzyl group, 3,4-methylenedioxybenzyl group, 3,4,5-trimethoxybenzyl group, 4-ethylpentyl group, Examples thereof include a benzyl group, a-aminophenyl group, and a / 3-aminophenyl group.

Examples of the cycloalkylalkyl group represented by R ⁴ include cyclopropylethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, Cs-8 cycloalkyl lower (Ci 14> alkyl group having about 4 to 12 carbon atoms, such as cycloheptylethyl, cyclooctylethyl, etc., such as norpolnyleethyl, bicyclo [2.2.2] octylmethyl) , Bicyclo (3.3.1) nonylpropyl. Bicyclo (3.3.0) bicyclo lower alkyl groups such as octyl butyl, for example, tricyclo lower alkyl groups such as adamantyl ethyl and the like. Are, for example, halogen, Ci-4 alkyl, Ci-14 alkoxy, amino Group, a hydroxy group, or a hydroxy group.

 The group represented by X forms sulfide, sulfoxide, or sulfone depending on its oxidation state.

Examples of the esterified ethoxy group represented by Y include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropoxycarbonyl, sec-propyl. Lower (G i —4) alkoxycarbonyl groups such as xycarbonyl, tert-atoxycarbonyl, etc. Phenyl lower (Ci-14) alkoxycarbonyl groups such as benzyloxycarbonyl, α-phenyloxycarbonyl, & phenyloxycarbonyl, phenylpropyloxycarbonyl, and phenylbutyloxycarbonyl, and amidation is the force Rupokishiru group e.g. heparin, leucine, iso port Issy down, thread old Nin, N ¹ - lysine, Mechisai Nin, phenylene Ruaranin, Ami de reduction in amino groups α- amino acid such as Bok rib Bok fan And the hydrogen atom of the lipoxyl group of these amino acids is a lower (Gi-4) alkyl (eg, methyl, ethyl, propyl, butyl, tert-butyl) or a lower phenyl (Ci

-4) It may be substituted by alkyl (eg, benzyl, phenethyl, phenylpropyl, phenylacetyl).

 Groups represented by ΌτηΗζ include G H2, CHz CH2 and

GH (C H3).

 The compound of the present invention is specifically disclosed below.

 3. (R)-[1-ethoxycarbonyl-2-3-phenylpropyl] amino-4,5-oxo-1,2,3,4,5-tetrahydro b-.1,5, -benzothiazepine-5-acetic acid And its tert-ethyl ester,

'3 (R)-(1-ethoxycarbonyl-1-3-cyclohexylpropyl) amino-4 1-year-old xo 2,3,4,5-tetrahydro-1,

5-benzothiazepine-5-acetic acid and its tert-butyl ester,

3 (R) 1 [1-ethoxycarbonyl 3-(-P-trisole) propyl] amino-4 1-year-old 1,2,4,5-tetratetrahydro-1,5-benzothiazepine-5-acetic acid ^Oyohi; its tert- butyl ester le,

 3 (R)-[1-Isobutoxycarbonyl-2-3-phenylpropyl] amino-4-oxo-1,2,3,4,5-tetrahydro-1,5, -benzothiazepine-5-droxoic acid and its tert- Butyl ester,

 7-chloro-1- (R)-[1-ethoxycarbonyl-3-phenylpropyl] amino-4-oxo-1,2,3,4,5-tetrahydro 1,5-benzothiazepine-5 —Acetic acid and its tert-butyl ester,

3 (R) — [1-ethoxycarbonyl 3-phenylpropyl] 1,7-methoxy-1 41-xoxo 2,3,4,5-tetrahydro-1,5-benzothiazepine-15-acetic acid and its tert-butyl ester,

 3 (R) — [1-ethoxycarbonyl-2- 3-phenylpropyl] amino-7-methyl- 4-isoquinone 2,3,4,5-tetrahydride mouth-1,5-benzothiazepine-5 —Acetic acid and its tert-butyl ester,

 3 (R)-[1-ethoxycarbonyl-3-phenylpropyl] amino-4-year-old oxo-7-trifur-old-methyl-2,3,4,5-tetrahydro-1,5-benzothiazepine- 5-hydroxyacid and its tert-butyl ester,

 3 (R)-(1-ethoxycarponyl-3-phenylpropyl) amino-4-year-old oxo 2,3, 4, 5, 8, 9-hexahydro-7H-indeno (5, 6-b ] (1,5) thiazepine-5-acetic acid and its tert-butyl ester,

 3 (R) -ethoxycarbonylmethylamino-4-isoquinone 2,3,4; 5-tetrahydro-1,5-benzothiazepine-15-acetic acid and its tert-ethyl ester,

 3 (R) 1 (1 benzyl xycarponyl-3-phenylphenyl) amino-4 1 oxo 2,2,3,4,5-tetrahydro-1,1,5-benzothiazepine-5-acetic acid and its tert-butyl ester ,

 3 (R)-(1-ethoxycarbonyl-4-methylbenzyl) 7 Minnow 4 1-year-old oxo-1,2,3,4; 5-tetrahydro-1,5-benzobenzoazepine-5-acetic acid And its tert-butyl ester,

3 (R)-(1 -ethoxycarbonylnonyl) amino-4-1,2,4,5-tetrahydro-1,5 -benzothiazepine 1-5-acetic acid and its tert- Petil S. Ter,

 3 (R)-(1-ethoxycarbonyl 3-phenylpropyl) amino-1-year-old 1,2, 3, 4, 5-tetrahydro Draw 1, 5-benzothiazepine-5-N-N —Acetyl-L-phenylalanine and its tert-butyl ester,

 3 (R) 1 [1-ethoxycarbone 3-phenylpropyl] amino-4-year-old xo 2,3, 4, 5-tetrahydro 1, 5-benzothiazepine-5-benzyl acetate,

ΟΜΡί 3 (R)-(— Ethoxycarbonyl 3-phenylphenyl) amino-4 quinone 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-propionic acid,

 3 (R) — [1-ethoxycarbonyl-2 3-phenylpropyl) amino 4- 4-oxo1, 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 1-year Oxide,

3 (R) — (1-ethoxycarbonyl-1-3-phenylpropyl) amino-4oxo-2,3,4,5-tetrahydro-1,5-pentoziazepine-15-acetic acid 1,1-dioxide

3 (R) 1 (1 ethoxycarbonyl-2'-phenylphenyl) amino-4 1-year-old 2,3,4,5,7,8.9,10-year-old octahydronaphth (2,3 — B] (1, 5) Thiazepine mono-5-acetic acid and its tert-butyl ester,

 3 (R)-[3-Amino-1 (S) -carpoxypropyl] amino 14-year-old xo 2,3.4.5-Tetrahi draw 1,5-benzothiazepine-15-acetic acid,

 3 {R)-[5-amino '-1 (S) lipoxypentyl) Amino 4 1-year-old xo 2, 3, 4, 5-Tetrahi Draw 1, 5-Benzothiazepine-1-acetic acid , '

3 (R)-[7-amino-1 (S) -carpoxyheptyl] amino 4 1-year-old oxo-1,2,3,4,5—Tetrahi draw 1,5—benzothiazebin-1 5—vinegar,

 3 (R)-[1 (S) lipoxy 5-(N-methylamino) pentyl] amino-4-1,2,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid,

 3 (R)-1 C 1 (S)-alkoxy 5-(N-ethylamino) penl] amino-4-1,2-, 45-tetrahydro

1, 5—Benzothiazepine mono-5-acid,

 3 (R)-[1 (S) One-strength lipoxy-5- (N-isopropylamino> pentylamino-4,5-year-old xo 2,3,4,5-tetrahydro-1-, 5-benzothiazepine One ^-,

3 (R) — [1 (S) lipoxy 5-(N, N-dimethylamino) pentyl] amino 1 4, 1-year-old 2,3, 4, 5-tetrahydro 1, 5-benzothi Azepine mono-acetic acid,

3. (R> 1 [1 (S) —Power ropoxy 5— (N, N—Jetilua

ΟΜΡΪ I ^PO Mino) Pentyl] amino-4, 5-year-old xo, 2,3,4,5-tetrahydro-1,5: -benzothiazepine-5-acetic acid,

 3 (R) 1 [1. (S) 1-strength lipoxy 1 5— (N, N-dipropylamino) pentyl〗 amino 1 4 year old xo 2,3,4,5—Tetrahi draw 1,5—benzo Thiazepine mono-acetic acid,

 3 (R) — [1 (S) 1-carboxy-5-(N, N-diptylamino) pentyl] amino-4-oxo-1, 2,3, 4, 5-tetrahydro-1, 5-benzothiazepine-1-5 —Acetic acid,

 3 (R)-[5-Acetylamino--1 (S)-carboxypentyl] amino-4 1-year-old xo 2,3,4 5-tetrahydro-1,5 -benzothiazepine-15- 5acid,

 3 (R) — [5-Benzylamino-1 (S) lipoxypentyl ア ミ ノ amino-4-oxo-1, 2, 3, 5-tetrahydro 15-benzothiazepine-5-drunk acid,

3 (R) 1 [1 (S) 1-Lupoxy 1 5— (N-cyclopentylamino) pentyl] Amino 4 1-year-old 2, 3, 4, 5 -tetrahydro-1,5 benzothiazepine — 5—acetic acid,

3 (R) — [1 (S) one-strength lipoxy 5 — (N-cyclohexylamino) pentyl] amino-4 — 1,2-, 5-, tetrahydro 1, 5- benzothiazepine 1 5 —Acetic acid,

And the like.

 Salts of compound (I) include, for example, hydrochlorides, hydrobromides, sulfates. Inorganic acid salts such as nitrates, phosphates, etc., for example, fossilates, tartrates, citrates, fumaric acid, Organic acid salts such as maleate, toluenesulfonate and methanesulfonate, such as sodium salts, potassium salts, calcium salts and aluminum salts, such as metal salts such as triethylamine salts, guanidine salts, ammonium salts, Pharmacologically acceptable salts such as salts with bases such as hydrazine salt, quinine salt and cinchonine salt.

 The compound (I :) of the present invention is represented by the formula

 (Wherein each symbol is as defined above) and a compound represented by the formula

O PI (I)

[Wherein, R ³ and R * are as defined above. _C can be produced by subjecting the compound represented by the formula to a reduction reaction under the reduction conditions _c. Examples of the conditions for the reduction include, for example, metals such as platinum, palladium, Raney nickel, Reduction using a mixture of benzene and any carrier as catalyst, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, borohydride

 0 C

With metal hydrides such as sodium and sodium borohydride, metal sodium thorium, metal matanesium, etc.

 Four

Reaction conditions such as reduction with metals, metals such as iron and zinc, and acids such as hydrochloric acid and sulfuric acid, electrolytic reduction, and reduction with reductase. The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide). The reaction is carried out, and the reaction temperature is different depending on the remote means, but it is generally preferably about 20 to about 20. This reaction can sufficiently achieve the purpose at normal pressure, but the reaction may be carried out under increased or reduced pressure by convenience.

 Further, the compound (I) of the present invention has, for example, the formula

R ⁴

CHz CHNHCHCOOR ³

COOH (IV)

 G in H 2 τη—

 Wherein each symbol is as defined above. Can also be produced by subjecting the compound represented by the formula to the dehydration ring closure reaction. The dehydration ring closure reaction can be performed, for example, by an amide bond formation reaction in a normal peptide. That is, a peptide-forming reagent such as dicyclohexylcar positimide, Ν, Ν'—capillonyldi, dazole, diphenyl phosphate azide, or cetyl cyanophosphate alone is used alone, or a common inorganic acid (eg, hydrochloric acid, sulfuric acid, Nitric acid, hydrobromic acid) to convert the amino group of compound i: iv〉 into protons, and then, for example, 2,4,5-trichlorophenol, pentachlorophenol, pentaflurophenol, 2-pentachlorophenol. Nitrov

OMPi N-hydroxy compounds such as phenol II or N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxypiperidine, such as phenol or 4-nitrophenol, can be converted to dicyclohexylcarposimid, etc. It can be carried out by condensing in the presence of a medium, converting to an active ester form, and then cyclizing. In any case where the cyclization reaction converts the compound (IV) as it is or the activated ester of the compound (IV), an organic base such as a quaternary ammonium salt or a tertiary amine ( (Eg, triethylamine, N-methylpiperidine). The reaction temperature is usually from −20 to 150, preferably around room humidity, and examples of commonly used solvents include dioxane, tetrahydrofuran, acetonitrile, pyrididine, N 2 N, N-dimethylformamide. N, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, chloroform, methylene chloride and the like, and these may be used alone or as a mixed solvent.

 The compounds of the present invention can also be

(Wherein, Z represents a protecting group which can be eliminated by hydrolysis or catalytic reduction, and other symbols have the same meanings as described above.). As the protecting group which can be eliminated by the hydrolysis represented by Z in (V), any kind of an acyl group or a trityl group can be used, and among them, benzyloxycarbonyl, tert-butoxycarbonyl, trifluryl, It is advantageous when the reaction is carried out under relatively mild reaction conditions such as tert-yl, trityl, etc. Examples of protecting groups that can be removed by catalytic reduction represented by Z include benzyl, diphenylmethyl, and benzyl. The hydrolysis reaction in this method is water or, for example, methanol, ethanol, dioxane, pyridine, or the like. Emissions, acetic acid, acetone, carried out in organic solvent or a mixed solvent thereof and the like methylene chloride, acid (e.g. for reaction rate enhancing, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric o one

 Addition of acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid) or base (eg, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, acetic acid-sodium, triethylamine) You can also. The above reaction is usually carried out in a range of about 120 to about 150. The catalytic reaction in the present method is carried out in water or an organic solvent such as methanol, ethanol, dioxane, tetrahydrofuran or a mixed solvent thereof in the presence of a suitable catalyst such as platinum, palladium-carbon. Done. This reaction is carried out at normal pressure or a pressure of up to about 15 O kgZcnf at normal temperature to +150, but the reaction generally proceeds sufficiently at normal temperature and normal pressure.

 The compound (I) of the present invention may also be, for example, a compound of the formula

 Wherein each symbol is as defined above. In the compound represented by the formula, it can also be produced by solvolysis of a cyano group. The above-mentioned solvolysis reaction is carried out with water or methanol,

The reaction is carried out in an organic solvent such as toluene, dioxane, pyridine, sulfuric acid, acetone, methylene chloride or a mixture thereof, and the acid is used to promote the reaction rate (eg, hydrochloric acid, hydrobromic acid, hydrogen iodide Acid, hydrofluoric acid, sulfuric acid, methanesulfonic acid, Ρ-toluenesulfonic acid, trifluoroacetic acid, or base (eg, sodium hydroxide, potassium hydroxide,

25 Potassium carbonate, sodium bicarbonate, sodium acetate, triethylamine) can also be added. The reaction is usually carried out in the range of about 120 to +150.

 Compound (I) also has the formula (H)

R ⁴ -CHC 0 0 R ³ (VI)

 30 W one

[In the formula, R ³ and have the same meanings as described above, and W represents a halogen or a T¾ group represented by the formula R ⁵ S 0 2 0-(R ^s represents lower alkyl, phenyl or p-tolyl.) . Can be produced by reacting the compound represented by the formula The reaction is appropriate

In a solvent, keep both in a temperature range of about 20 to +150. Therefore, it proceeds. At this time, a base such as potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, pyridine, triethylamine and the like can be coexisted in the reaction system as a deoxidizing agent for the purpose of accelerating the reaction rate.

 The compound of the present invention (I) also has the formula

 (Wherein each symbol is as defined above.)

 W I CITI H2 τη-Υ (IX)

[Wherein, W is a halogen or the formula Rs 'S 02 one 0- group represented by (R ^5' is lower alkyl, phenyl or Ρ- Bok Lil the shown to.), Upsilon are as defined above. Can be also produced by reacting the compound represented by the formula The reaction proceeds in a suitable solvent-keeping both in a temperature range of about 120-150. At this time, it is possible to carry out the reaction in the presence of a base such as charcoal potassium, sodium hydroxide, hydrogenated sodium and the like in the reaction system. '

In compound (I), R ³ is hydrogen or お よ び is carboxyl, and R ³ is lower (Ci-4) alkyl, or Z and Y are lower (Ci-4) alkoxycarbonyl Producing the compound (I) by subjecting the ester compound to hydrolysis or elimination reaction, or by corrosion reduction of a benzyl ester compound in which R ³ is benzyl or Z and Y are benzyl xycarbonyl. Can be.

Further, in the compound (I) R ³ is a lower (Ci one 4) alkyl, or Z and Y is a lower (Ci - if a 4 "alkoxy force Ruponiru is, R ³ is hydrogen, or and Y is a force Rupokishiru The compound can also be produced by subjecting the compound to an esterification reaction.

Further, when Y in compound (I) is esterified or amidated olepoxyl, for example,

 C τη H 2 -m-COOH

 [Wherein each symbol is as defined above. ] To the compound represented by the formula

R ^e -H (XI) (wherein, R ⁶ represents a lower alcohol residue, a phenyl lower alcohol residue, or an α-amino acid residue whose carboxyl group may be protected with lower alkyl or phenyl lower alkyl. Can also be produced by subjecting the compound represented by the formula to a condensation reaction.

Furthermore, the formula R ³ () obtained by the above condensation reaction

Wherein, R ^e is a lower Arupiru or indicates α- amino acid residues force Rupokishiru group is protected by Fuemiru lower Arupiru, and the other symbols are as defined above. ) Is subjected to, for example, a hydrolysis reaction, an elimination reaction, or a catalytic reduction reaction to obtain a compound of the formula 3 (I ")

(Wherein, R ^e ′ represents an α-amino acid residue, and other symbols have the same meanings as described above.).

 When X is a sulfoxide or a sulfone in the compound (I), the compound can also be produced by oxidizing the corresponding sulfide compound. The oxidation reaction is carried out, for example, by the action of an organic peracid (eg, methyl peroxybenzoic acid, peroxide acid) or an inorganic oxidizing agent (eg, hydrogen peroxide, periodic acid). The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, dioxane, dichloromethane), and is usually carried out in a temperature range of 120 to 100.

Ο ΡΪ, When using a compound having a group that may interfere with the reaction,

[Example, reaction of compound (fl) with (H) or (: I;)], a protecting group known per se [eg, benzyloxycarbonyl, tert-butoxycarbonyl, cycloacetyl, phthalimid, The target compound can be obtained by protecting the group with an imido and subjecting the reaction to a reaction, followed by a deprotection reaction known per se.

 For example, the expression „

 To R b

COOR ³

CI a

[Wherein, A represents a linear or branched alkylene having about 1 to 16 carbon atoms, and Ra and Rb each represent hydrogen, lower (C i- ₄ ) alkyl, aryl, or cycloalkyl; The other symbols are as defined above) can be produced, for example, as follows: Compound ((; and formula CHCOOR ³

 Wa

Wherein, Wa is halogen or wherein R e S 0 ₂ - (wherein, R e is a lower alkyl, phenyl or p - shows the Application Benefits Le) groups represented by 0 and one of R c and R d Represents hydrogen and the other represents a protecting group (eg, benzoyl, acetyl), or both represent fluorimidide and succinimide with adjacent nitrogen atoms, and other symbols are as defined above. The compound represented by the formula

 (Wherein each symbol is as defined above), the compound la ′) is subjected to a deprotection reaction, and the amino compound [I] wherein Ra and Rb are hydrogen in the formula la) b) is obtained.

In the formula (la), a compound in which Ra or / and Rb is lower alkyl or cycloalkyl can be prepared, for example, by compounding the corresponding aldehyde or ketone with the compound (lb) usually using water or an organic solvent (eg, alcohol, Reaction under ethereal, tetrahydrofuran, methylformamide, and acetonitrile) or in a mixed solvent thereof under a reducing condition at a temperature range of about 120 to + 100 ° C. It can be manufactured by making it. Examples of the reducing conditions include catalytic reduction using a catalyst such as a metal such as platinum or palladium or a mixture thereof with an optional carrier, for example, lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, hydrogen hydride. Reduction with metal hydrides such as sodium borohydride and sodium borohydride, reduction with alcohols such as sodium and magnesium, reduction with metals such as iron and zinc and acids such as hydrochloric acid and acetic acid Reaction conditions such as electrolytic reduction, reduction with a reductase, etc. can be raised. In the formula (Ia), a compound in which Ra, Z and Rb are acyl is a compound obtained by reacting an activated organic acid derivative such as an acid anhydride or an acid halide with a compound (lb), usually with water or an organic solvent [ Eg, ethyl acetate, methylene chloride, ether. Benzene, toluene, triethylamine, dimethylformamide) or a mixture thereof It can be produced by reacting in a solvent in a temperature range of about 20 to 150 ° C. At this time, an organic base (eg, triethylamine, picolin, pyridine) or an inorganic base (eg, sodium hydrogen carbonate) may be added to promote the reaction rate.

 The target compound (I) of the present invention thus obtained can be separated and purified from the reaction mixture by a conventional means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc. It can be isolated by using it.

The conjugate (IJ may have at least two stereoisomers depending on the type of the substituent represented by R ⁴ , etc.) Each of these isomers and these mixtures is naturally within the scope of the present invention. And, if desired, these isomers can be produced individually. For example, each of the single isomers of the starting compounds .π ^ .IV), CV.CW; and (W) can be used. By carrying out the above reaction, a single optical isomer of compound (I :) can be obtained, and when the product is a mixture of two or more isomers, this can be separated by ordinary separation. Method, for example, an optically active acid (eg, camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc., an optically active base salt (eg, cinchonine, nconidine, quinine, quinidine, monomethylbenzinoleamine, dehydroabiethylamide) And a method for generating a salt with :) such, various chroma Togurafi over, by separation means such as fractional recrystallization, can be separated into its its isomers.

The compound of the present invention, ie, the fused 7-membered ring compound represented by the formula (III) and a salt thereof can be used for angiotensin against animals, particularly mammals (eg, human dog, cat, rabbit, guinea pig, rat) Inhibition of converting enzyme, Bradycun degrading enzyme (kininase, etc.) It is useful as an agent for diagnosing, preventing or treating. Since the compound of the present invention has low toxicity, is well absorbed even when administered orally, and has excellent stability, when it is used as the above-mentioned medicament, it may be used as such or an appropriate pharmaceutically acceptable carrier, excipient, and diluent. mixed with agent, different powders, granules, tablets, capsules, _c dose that can be administered orally or parenterally safely as pharmaceutical compositions such as injections of target disease state, by the route of administration However, when administered to an adult patient for the treatment of hypertension, for example, the oral dose is usually about 0.02 to 20 or about 0.2 to 2;

A dose of about 0.02 to 0.2 / hill is about 0.02 to 0.2 ^ ^, and these doses are about 1 to 5 times a day depending on the symptoms. It is desirable to administer. .

 The starting compounds (ιι), (ιν), [ν), (7Π and · ['..] of the present invention can be easily produced, for example, by a method represented by the following reaction formula.

 w)

OMPI

 .a

 H

CXX) Irichi UISHUIO—

-ΙΛ— 0 / 8Jf / XDJ SO 0 / S8 OA 9S

lO δ

 (MX) OS

-81- J f 0 / S8 OA COOR ³ (W)

In the above reaction, the R ⁷ is halogen or Jiazo two © beam group, Q is C androgenic or formula R ⁸ S 02 groups represented in one 0- (R ³ represents lower alkyl, phenyl or p- Bok Lil.) , And the other symbols are m sd;

 The production method of the compound (H) represented by the above reaction formula will be described in more detail. According to the method of E. Boyland et al. (J. ChemSog., 962, 606), L-cystine (XH ) Is used as a starting compound, compound (V) is induced, and if necessary, the amino group is protected with a suitable protecting group for an amino group (eg, a phthaloyl group) to obtain compound (X). In this reaction, the compound (XV) is converted to a compound (XV) in the presence of N-carboxyphthalimide (XVI) and a base such as sodium carbonate, potassium carbonate, potassium hydrogencarbonate, etc., usually at a temperature of about 0 to +100. The reaction of (XVI) → (XW) is a reduction reaction of a nitro group to an amino group, and any of the known reduction methods can be used. —Catalyst reduction using palladium, sulfide palladium, platinum, etc. as a carrier with carbon or palladium sulfate as a carrier, or reduction reaction with metals such as zinc, tin, stannous chloride, iron, etc. with acid or alkali. The dehydration ring-closure reaction of the compound thus obtained to the compound (XIX) can be advantageously carried out usually in the presence of a known dehydration condensing agent. Examples of such a dehydrating condensing agent include dicyclohexylcarpoimide, carbonyldiimidazole, and getyl cyanophosphate, etc. Examples of the solvent include dioxane, methylene chloride, acetonitrile, N, N-dimethylformamide, tetrahydrofuran, etc. are used, and the reaction is usually carried out in a temperature range of about 110 to 100. At this time, triethylamine, pyridine, etc. The addition of the compound (XXI) by the condensation reaction of the compound (XXI) with the compound (XX) can be carried out usually using a base such as sodium hydride or potassium carbonate. In the presence of N, N-dimethylformamide,

OMPI It can be produced by condensing in a solvent such as methylsulfoxide, acetate and the like in a temperature range of about 110 to about 10100. Next, in the reaction of (XXI) → (1 ′), hydrazine hydrate is treated in a solvent such as methanol, ethanol, dioxane or the like at a temperature of about 10 ° to +100, and the compound (I ′) ) Can be manufactured.

 In the compound (1Γ), when X is a sulfoxide or a sulfone, the compound (IT) can be produced by oxidizing the compound (IT). Acid, peracetic acid) or an inorganic oxidizing agent (eg, 'hydrogen peroxide, periodic acid) The above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol, dioxane). , Dichloromethane) in the presence of the compound (XV), (XVI), (XH), (XIX) or (XXI). ) To convert each sulfide group to sulfoxide or sulfone.

 (n> is subjected to a series of reactions to produce the compound (n>).

 When X in compound (Π) is a sulfide, the compound

 Compound (I) can also be produced by subjecting (I ′) to a reaction for producing compound (I) using compound (n).

 In the process for producing compound (IV), the reaction of (XXII) → (XXffl) can be carried out by a similar reaction to the reaction of (XU) → (XV). The compound (IV ′) can be produced by subjecting the nitro group to a reduction reaction to an amino group and then to an alkylation reaction, and in the case where X in the compound (IV) is sulfoxide or sulfone, (I ′ The compound can be produced by subjecting the reaction to a reaction similar to the reaction of) → (n).

When X is a sulfide in (IV), compound (IV ′) can be subjected to a reaction as compound (IV) to produce compound (I), and the oxidation reaction can be carried out with compound (XX EI ) To convert the sulfido group into sulfoxide or sulfone, and then subject to a reaction for producing compound (IV) to produce compound (IV).

In the production method of compound briquettes (V), compound (XXIV) is compound 勒 It can be produced by subjecting (I) to a per se known amino acid amino group protection reaction. The reaction of (X XIV) → (V) proceeds by keeping both in a suitable solvent at a temperature in the range of about 20 to 150 ° G. At this time, a deoxidizing agent is used to accelerate the reaction rate. For example, bases such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, and triethylamine are coexistent in the reaction system.

 In the production method of compound (VI), compound (VI) can be obtained according to a known Strecker (Strecker) reaction using compounds (I), (XXV) and hydrogen cyanide as starting compounds. In the production of the compound, the reaction of (XIX) → (XXVI) can proceed by the same reaction as the reaction of (XXI) → (II ′). Compound (W) can be produced by condensing compound (XXVI) and compound (M) in the presence of a metal hydride such as sodium cyanoborohydride. When the compound (VI) is X or 'sulfoxide or sulfone, it can be produced by subjecting it to a reaction similar to the reaction of (IT) → (). When X is a sulfide in compound (W), compound (W ') is

 Compound (I) can also be produced by subjecting the reaction to (VI). In the above process for producing compound (I) and intermediates thereof, the compound used in the reaction is selected so as not to interfere with the reaction, for example, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc. For example, organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, and methanesulfonate, for example, sodium, potassium, calcium, and aluminum salts Metal salts such as triethylamine salts, guanidine salts, ammonium salts, hydrazine salts, quinine salts, and salts with bases such as cinchonine salts.

Further, among the Nakazono bodies, the compound <ia ′) has angiotensin converting enzyme inhibitory activity and is useful as a compound for diagnosing, preventing and treating hypertension, like Compound (I). Best form to do

Reference example 1,

S-(o—Nitroguchi phenyl) — L cysteine 2.9 g carbonate Dissolve in 1.4 g of aqueous solution of sodium (200>) and add N-ethoxycarbonylphthalimide 3.59 with stirring, stir at room temperature for 5 hours, filter to remove insolubles, and add concentrated hydrochloric acid. The precipitated crystals were collected and recrystallized from ethanol 30 «6 to give 3-g- (o-nitrophenyl) thio-1 (R) -phthalimide propionic acid (3.6 g) as pale yellow Obtained as needles.

Melting point 220—22 2

Elemental analysis value Cl7 Hl2 N2 Os S

 Calculated: C 54. &4; H 3.25; N 7.53 Found: G 54.46; H 3.26; N 7.46

 twenty four

 (a) -9. (C 0.9, in methanol)

 D Reference example 2.

 3-(o-diphenyl phenyl) 1-2 (R)-phthalimidip 1-g g of methanol-300 8 8 in methanol with 5% palladium on carbon as a catalyst at normal humidity and pressure Reduces erosion. After absorbing the calculated amount of hydrogen, the catalyst is removed and methanol is distilled off under reduced pressure. Ether and petroleum ether were added to the residue, and the mixture was left to stand. The precipitated pale yellow powdery crystals were collected to give 3- (0-aminophenol) -2- (R) -phthalimidopropionic acid 8.49. . Dissolve 8.4 Q in dimethylformamide 50, and add getyl cyanophosphate 5.50! Dropwise while stirring under ice-cooling. Stir for 5 minutes after dropping, then add 2.28 g of triethylamine under water cooling, stir under water cooling for 30 minutes, and stir at room temperature with 1 o'clock. Water 20 is added to the reaction solution and the mixture is left overnight, and the precipitated solid is collected and dried. The product is purified by silica gel column chromatography (dichloromethane: ethyl acetate -2: 1) to give 3 (R) -phthalimidone 2,3-dihydro-1,5 (5H) 1-benzothiazepine-4-one 5. 4 g are obtained as colorless prisms.

Melting point 202-205

Elemental analysis value C 17 H 12 N 2 03 S

 Calculated value: C 62.95; H 3.73: N 8.64 Actual value: C 63.15; H 4.02 Γ 8.49

ΟΜΡΙ twenty one

 ()-1 64. (C-0.9, in methanol)

 D

 Reference example 3.

 Add 0.59 of sodium hydride (oil 6096) to dimethylformamide 5 and stir under ice-cooling. Under ice-cooling, add 4 g of 3 (R) -phthalimid-1,2,3-dihidro 1,5 (5H) 1-benzothiazepine-14-one obtained in Reference Example 2 and stir for 5 minutes. Further, 2 g of tert-butyl chloroacetate is added under ice cooling. After stirring for 15 minutes under water cooling, ice water (200) is added to the reaction solution, and the precipitated crystals are collected by filtration. After drying, the product is purified by silica gel column chromatography (hexane: ethyl acetate-3: 1), yielding 4 1-year-old oxo-13 (R) -phthalimidido 2,3,4,5—tetrahide mouth-1 There are obtained 4 g of tert-butyl ester of 5,5-benzothiazepine-5-drunkate as colorless crystals. When a part is recrystallized from ethyl ether, it becomes colorless prism crystals. Melting point 1 8 1 — 1 84 ° C Elemental analysis: C23 H 22 N 2 Os S

 Calculated value: C 63.01; H 5.06; N 6.39 Actual value: C 62.95; H 5.10; N 6.34

 .20

 () 1 1 56. (C = 0.9, in black mouth form)

 D Reference example 4.

 4 g of 4-oxo-3- (R) -phthalimido-2 ', 3,4,5-tetrahydro-1,5-benzothiazepine-15-acetic acid tert-butyl ester obtained in Reference Example 3 Add 1.4 g of hydrazine hydrate to ethanol 10. The mixture is stirred and allowed to flow forward for 1 hour. The reaction mixture is concentrated under reduced pressure, and the residue is mixed with ethyl acetate 300) ^ and water 1, and shaken well. The ethyl acetate layer is mixed with dilute sodium hydroxide water. After washing with water, the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure.The obtained oil was crystallized from a mixture of ether and petroleum ether. 2,3,4,5-Tetrahydro-1,5-benzothiazepine-15-acetic acid tert-butyl ester 2 g is obtained as colorless prisms.

OMPJ Melting point 86 89 Ό

Elemental analysis value C 15 Η 20 Ν 203 S

 Calculated value: C 58.42; Η6.5 Ν 9 08

 Found: C 58.73; 6.48 48 9 13

 20

 [Α] 238 ° (c = 1, in methanol)

 D Reference example 5.

 Dissolve 4.5 g of sodium in ethanol 1, add 30 g of 3-cyclohexyl || ethyl ethyl ester and 29 g of ethyl oxalate, and ripen in a hot water bath at about 70 for 30 minutes. Subsequently, the mixture was distilled off under reduced pressure at 70 for 30 minutes to remove the low bristles. After cooling, the obtained brown candy was mixed with water 50 ether

Add 1 tel and shake well. Dilute the water, make it slightly acidic with sulfuric acid, and extract with ethyl acetate 200. The extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Obtained oil was added 1096 hydrous dimethyl sulfoxide 1 and brine 10 g, to 2. stirred 5 hours at 140 ^e G. After cooling the reaction solution, add water 1

In addition to the above, extract with ethyl acetate 5 OO, wash the extract with water, dry over anhydrous magnesium sulfate, and evaporate under reduced pressure. The brown oil obtained is distilled under reduced pressure to obtain 18 g of ethyl 4-cyclohexyl-2-year-old ethylene oxide as a pale yellow oil.

Boiling point 105-10 Ό (1.5 m HQ) Reference example 6-10

^ j By performing the same reaction as in the case of synthesizing a non-substituted product (R = H) using an o-ditroaniline derivative having a substituent as a raw material, compounds shown in Table 1 are obtained. table 1.

^ j

参考例 1 1一 14

Reference Example 1 1 1 14

 Table 2 shows the results obtained by reacting the S- (2-dimethoxyphenyl) -l-cysteine derivative obtained in Reference Example 6-9 with N-ethoxycarbonylphthalimid in the same manner as in Reference Example 1. The compound shown is obtained.

 Table 2. H

参考例 1 5— 18

Reference Example 1 5—18

 The compounds shown in Table 3 are obtained by reacting the phthalimid derivative obtained in Reference Examples 11-14 with Reference Example 2 in the same manner. Table 3.

One, Reference example R 3D fusion J53 (a) D Block WS position * 1 (in)!

15 7-CH3 R 222-225 -180. I

 (In methanol)

16 7-0 CH ₃ R 255-258-34. (During black mouth Holm)

17 7.8- (CH2) 3-R 240-243 -136.

 (In methanol)

18 7-C I R 256-258 -169. I

 (In methanol) | Reference Example 1 9— 22

 Reference Example 1 When the phthalimid benzothiazepine derivative obtained in 5.-18 is reacted with Reference Example 3 in a similar manner, the compounds shown in Table 4 are obtained.

 Table 4.

参考例 23— 26

Reference Example 23—26

 Reference Example 19 When the phthalimidobenzothiazepine acetic acid tert-butyl ester derivative obtained in Example 9-22 is reacted with Reference Example 4 in a similar manner, the compound shown in Table 5 is obtained.

O PI

WIPO Table 5

 N H2

C H2 COO C (CH3) 3

参考例 27— 30

Reference example 27-30

When a reaction similar to that of Reference Example 5 is carried out using the ethyl carboxylate shown in Table 6 as a starting compound, the corresponding <<-ketoester is obtained.

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T00 / ^ 8Jf / XDd S0tfO / S8 OA Reference Example 3 1.

 Reference Example 10 S— (2-Nitroguchi-1-4-Trifluoromethylphenyl) -cis-cysteine 5.39 was added to 2.5 N sodium hydroxide solution 6 7 «6 obtained in 10 and stirred at room temperature for 30 minutes. After that, under ice-cooling, benzyl 2-carbonylcarbonyl 2.7 »6 and a 1N aqueous solution of sodium hydroxide are simultaneously added dropwise over 30 minutes. After stirring at room temperature for 2.5 hours, the reaction mixture is extracted with ethyl ether, and the aqueous solution is made weakly acidic with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and ethyl acetate was added to the obtained residue to obtain S- (2-nitro-4-fluorotrifluoromethyl). Enil) — N—Benzil

 5.5 g precipitate as pale yellow crystals.

Melting point 1 50— 1 53

(a) _D + 20. (In methanol)

Elemental analysis Cia His F 3 N ₂ Os S

 Calculated value: C48.65; H3.40; N6.30 Actual value: C48.68; H3.41; N6.27 Reference example 32.

Reference Example 31 S— (2-Nitro 4-trifluoromethylphenyl) —N-benzyl-l-xycarponyl—L-Cysteine obtained in Example 1 43 g and zinc dust 4 g were added to a mixture of acetic acid 5 and water 5. Stir at room temperature for 50 minutes. Add water 1 and ethyl acetate 1 to remove insolubles. The aqueous layer is further extracted twice with ethyl sulphate, combined with the ethyl acetate layer, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethyl ether 5 and hydrogen chloride-ethyl acetate solution (5N) 5 was added to give S- (2-amino-4-1-trifluoromethylphenyl) -1-N-benzyl-one-cysteine. The hydrochloride 3, 4 Q is obtained as a pale yellow powder. Dissolve the product in dimethylformamide 30ff8, stir the mixture under ice-cooling, and add a solution of 0.78 Q triethylamine in dimethylformamide 5 over 10 minutes. 1.83 g of methyl cyanophosphate After dropping 5 irf of dimethylformamide in 5 minutes, add a solution of 0.78 g of triethylamine in dimethylformamide, stir under ice-cooling for 30 minutes, and in room 溫. 2. Stir for 5 hours. 20 Oi? A is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane: ethyl acetate-4: 1 to 2: 1) to give 3 (R) -benzyloxyxicalponylamino-7-triflurylmethyl.

2.3-Dihydro-1.5 (5H) 1-benzothiazepine 1.3 g is obtained as colorless powder crystals.

 With a melting point of 1 20—1 23

 (D-61 '(in methanol)

Elemental analysis value C His Fa N2 03 S '

 Calculated values: C 54.54; H 3.81; 7.07

 Obtained value: C 5.79; H 3.90; N 7.09 Reference example 33.

 1.1 g of 3 (R) -I-benzyloxycarbonylamino obtained in Reference Example 32-7-Trifluoromethyl-2.3-dihydro-1.5 (5H) -benzothiazepine-one-one

 And then add 0.46 g of tert-butyl acetate, 0.42 g of potassium carbonate and 0.1 g of potassium iodide, and stir at room temperature for 4.5 hours. Add water 1 to the reaction mixture and extract with ethyl acetate. The extract was washed with 0.1 N hydrochloric acid, aqueous sodium hydrogen carbonate solution and water in that order, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 3 (R) -benzyloxycarponylamino-4. 1.4 g of 7-trifluoromethyl 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-tert-butylester acetate are obtained as a colorless candy.

 nujol

Γ RV on ' ¹ : 680 680 (amide),

 max

 1 710 (urethane), 1 740 (ester) * 〖R: (Infrared absorption spectrum: like the following) Reference Example 34.

 3 (R) -benzyl-xylcarponylamino-14-oxo-7-triflu-l-methyl-1,2,3,4,5-tetra obtained in Reference Example 33

WIPO Dissolve 1.4 g of lahydro-1,5-benzothiazepine-1-tert-butyl acid ester in acetic acid, add 1% 30% hydrogen bromide monoacetic acid solution 1, and let stand for 4 hours at room temperature. Add petroleum ether to the reaction mixture, shake well, and decant the supernatant. After adding petroleum ether again and performing the same procedure, the residue is dissolved in a mixture of ethyl sulphate and benzene, and evaporated to dryness. When petroleum ether is added to the residue, 3 »α (R) -amino-4 isotope 7-trifluoromethyl-2,3,4,5-tetrahydro-1,5, -benzothiazepine-5-acetic acid-odor 0.75 g of hydrochloride precipitates as crystals. Melting point 1 76— 18 ΟΤ!

Elemental analysis value Ciz Hu F3 Ν203 S, ΗΒ “· Calculated as Η2θ: C34.38; H3.37; Ν6.68 Actual measurement: C34.40; H3.60; Ν6. 66 Reference 35

3 (R) -amino-4,4-isoquinone-1,3,4,5-tetrahydro-1,5-benzothiazepine-5,4-tert-butyl tert-butyl ester obtained in Reference Example 4 And add 1.6 g of benzyl bromide and 1 g of triethylamine, and leave at room temperature for 3 days. The reaction mixture is extracted by adding water 1 and ethyl acetate 200W, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 3 (R) 1-benzylamino-4,4-year-old oxo 2,3,4,5-tetrahydro-1,5 Nzothiazepine 5-tert-butyl tert-butyl ester 29 is obtained as a colorless oil. Dissolve 1.7 g of this product in dimethylformamide 3, add potassium carbonate (1.7 g) and ethyl bromoacetate, heat at 80 for 2 hours, and further add ethyl ethyl bromide and potassium carbonate. Add 39 and ripen at 18:00. Water 300 and ethyl acetate 40 are added to the reaction mixture for extraction, and the extract is dried over anhydrous magnesium sulfate and then distilled off under reduced pressure. The resulting oil was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 3 (R) -1 (Ν-benzyl-Ν-ethoxycarbonylmethylamino). , 4,5-Tetrahydro-1, 5-benzazepine-15-acetic acid tert-butyl ester 1. 6 g are obtained as a colorless oil. Dissolve 1 g of this product in 15 mL of hydrogen chloride / ethyl acetate solution (5N), leave it at room temperature for 4 hours, then add 200 ^ of petroleum ether to add 3 (R) -one (Ν-benzyl-Ν). 0.8 g of colorless powder is obtained as 2,4,5,5-tetrahydro-1,5, -benzothiazepine-1,5-acetic acid / hydrochloride.

Elemental analysis value G22 H24 N 205 S

 Calculated value: C 56.83; H 5.42; N 6.03 Actual value: C 56.61; H 5.59; N 6.07

 [α] D-1 64 ° (in methanol)

Mass spectrum (mZe): 428 ( ⁺ )

Ο ΡΙ Reference Example 36-3 (R) -amino-4, oxo-1,2,3,4,5-tetrahydro obtained in Reference Example 4

— 1,5-zinothazepine mono-5-tert-butyl ester 19

 Dissolves in methanol 20 and has a cyanide potential of 0, 32? , N— (4-Formylbutyl) fudarimide 1.19 and 0.3 acetic acid are added and stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure to give a crude product of 3 (R)-(1-cyano-5-phthalimidopentyl) amino-4-oxo-1,2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-tert-butyl ester acetate is obtained. This product is used as a raw material in Reference Example 37 without purification.

Reference Example 3 7

 3 (R)-(1-Cyan-5-phthalimidopentyl) obtained in Reference Example 36

 Mino 4-oxo-2,3,4,5-tetrahydro 1,5-benzothiazepine-5-acetic acid tert-butyl ester 2 and ethanolic hydrochloric acid (11N)

 Add 20 W, stir for 6 hours under ice cooling, and leave at room temperature overnight. Ethanol was distilled off at reduced pressure, and ethanol was added to the residue at 50 W and a chamber list.

 15 Add ion exchange resin 10 and stir for 7 hours under reflux.

After cooling, treat the resin portion with a 5% solution of pyridine monoethanol, combine the ethanol portions and distill off under reduced pressure. The obtained oil is dissolved in ethyl acetate 300 and washed with 0.1 N hydrochloric acid and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate.

After drying under reduced pressure, the residue was purified by silica gel gel chromatography (hexane: aceton = 2: 1) to give 3 (R) — (1-ethoxy).

Cicarboni-5-phthalimidopentyl) amino-4-oxo-1,2,3,4,5-tetrahydro1,5-benzothiazepine-15-ethyl acetate 0.99 is obtained as a colorless oil.

^--,,, IR _y ^neat cm-i: 1 7 70, 1 7 40, 1 7 2 0, 1 7 1 0 (lid 丄 max

Louis Mide and Ester) 1670 (Amide) Mass Vector (m / e): 567 (M +)

Reference Example 3 8

 3 (R) -Amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-15-acetic acid obtained in Reference Example 4 tert-butyl ester 19 and 2 (S) -base Dissolve benzyloxycarbonylamino-13-phenylpropionaldehyde 1? In methanol 20 and add 0.359 of potassium cyanide and 0.39 of acetic acid, and stir at room temperature overnight. In addition, 2 (3) -benzyloxycarbonylamino-3-furf. Add mouth pionaldehyde, potassium cyanide 0.2 ^ and acetic acid 0.2 ^ and mix for 3 days. The reaction solution was evaporated to dryness under reduced pressure to give a crude product, 3) 1 [2 (S) -benzyloxycarbonylamino-1-cyano 3-phenylpropyl] amino 4-oxo-3,2,3,4,5 — Tetrahydro-1,5— ^ inzothiazepine-5-vinegar tert-butylester is obtained. This product is used as a starting material for Reference Example 39 without purification. Reference Example 3 9

3 (R) — “2 (S) —benzyloxycarbonylamino-1-cyano-3-phenylpropyl” obtained in Reference Example 38 8 amiso-1-oxo-1,2,3,4,5-tetra Add 1,5-benzothiazepine-15-acetic acid tert-butyl ester to 1 IN ethanolic hydrochloric acid 20 and stir overnight at room temperature.The reaction mixture is evaporated to dryness under reduced pressure, and ethanol residue is added to the residue. Add Amberlist 15 ion exchange resin (10) and reflux for 9 hours with stirring.After the eluate, elute the resin portion with ethanol containing ammonia (aqueous ammonia: ethanol = 1: 9 :). After removing the ethanol by distillation, Ethyl acetate 100 Water 50 ml and potassium carbonate 1 are added, and benzyloxycarbonyl chloride 1 'is added dropwise while stirring at room temperature. After stirring for 1.5 hours, the ethyl acetate layer is washed with water and distilled off under reduced pressure. The resulting oil was purified by silica gel column chromatography (hexane: aceton = 3: 1 to 1: 1) to give 3 (E)-[2 (S) -benzyloxycarbonyl. Amino 1—ethoxycarbonyl-13-phenylpropyl] amino 41-oxo-2,3,4,5-tetramethyl 1,5-benzothiazepine-15-ethyl acetate 0.2 2.9 Obtained as an oil.

^{IRV ί η-ί: 3 3} 5 0 (ΝΗ), 1 7 2 0, 1 6 8 0 (C = 0 0 Mass-spectrum Honoré (m / e): 6 1 9 (M +)

 Reference example 4 0

 3 (E) -phthalimido-2,3-dihydro-1,5 (5H) -benzothiazepine-14-one 6.48 S "obtained in Reference Example 2 was added to 25 ml of dimethylformamide. Dissolve, add 2-bromopropionic acid tert-butyl ester, 6.2 79, carbonate carbonate 5.59 and potassium iodide 0.5, and stir overnight at room temperature. And the mixture is extracted with ethyl acetate 300 W. The extract is washed with 0.5 N hydrochloric acid 200 and saturated aqueous sodium bicarbonate 100, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The purified oil was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 2: 1) to give 3 (R) -phthalimid-4-oxo-1,2,3,4,5. —Tetrahydro 1,5-benzobenzoazepine-5-α-methyl acetate tert-butyl ester 7.89 is obtained as a colorless powder.

• I R V: 1770, 1730, 1720, 1680 (C = 0). Elemental analysis: C24H24N205S · As ½Η20

Calculated value: C 6 2.4 6 Η 5.4 6 Ν 6.0 7 Measured value: C 6 2.6 2 H5.1 N 6.1 3

 Reference example 4 1

 Reference Example 40 3 (R) -phthalimidone 4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-5-α-methyldranoic acid tert-butyl ester obtained in 07.6 When 9 was treated with hydrazine hydrate in the same manner as in Reference Example 4, 3 (R) -amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-benzobenzothiazepine 5-a-Methyl acetic acid tert-butyl ester 5.4 is obtained as a pale yellow oil.

^{IR 5 1: 1 7 3 5} , 1 6 7 0 (C = 0).

[A] _D —2 2 3. (C = 0.5, in methanol)

Mass sound (m / e): 3 2 2 (M ⁺ )

 Reference example 4 2.

3 (R) -amino-4,1-oxo-2,3,4,5-tetrahydro-1,3-benzothiazepine-5-group acid tert-butyl ester obtained in Reference Example 4 3.0 8 9 was dissolved dimethylformamidine de 2 0 ίΐ this, Echiru bromo one 6-off Tarui Kisano E to Mi de -. DOO _{7 3} 6 9, iodide force helium 1.6 carbonate Ca Li um 2.7 6 9 Add 6 9 and stir overnight at room temperature. Then add bromoester 3.689 and potassium carbonate 1.38 and stir for 3 days. The reaction solution is extracted by adding water 10 and ethyl acetate 300, and the extract is washed with water and distilled off under reduced pressure. Add 5 parts of oxalic acid and 3 parts of ethyl acetate to the obtained oil, dissolve it, add 120 W of petroleum ether and shake well. After standing, the supernatant was decanted, and the residue was subjected to the same treatment four times.Then, saturated aqueous sodium bicarbonate solution and ethyl acetate (300 W) were added for extraction, followed by extraction. The solution is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting oil was purified by silica gel chromatography (hexane: acetone == 4: 1) to give

O PI l As fractions, 3 (R)-[1 (R) -ethoxycarbonyl-5-phthalimido-pentyl J-amino-14-oxo-1,2,3,4,5-tetrahydro 1,5 —Benzothiazepine-1-5-tert-butylester 1.75 is obtained as an oil.

cw-i: 3 3 3 0 ( NH ) , 1 7 8 0, 1 7 4 0, 1720,IRV

cw-i: 3 3 3 0 (NH), 1 7 8 0, 1 7 4 0, 1720,

1 6 8 0 (C = 0 o

 Mass skip (m / e): 595 (M +)

 As the second fraction, 3 (R)-[1 (S) -ethoxycarbonyl-5-phthalimidopentyl] amino 4-oxo-1,2,3,4,5-tetrahydro-1,5 —Benzothiazepine-15-acetic acid tert-butyl ester 2.59 is obtained as an oil.

^{IR 1 1: 3 3 3 0} (NH), 1 7 7 0. 1 7 4 0, 1720, 1 6 8 0 (C = O) o * Masusu Bae-vector (mZ e): 5 9 5 · (Μ ,)

^{«DD ~ 1 1 9 ° ^} c = 0 - 3 ' in the main Tano Ichiru)

Reference example 4 3

 3 (E)-[1 (S)-{toquinecarbonyl-15-phthalimidintyl] obtained in Reference Example 42:} amino-14-oxo-2,3,4,5-tetrahydro Dissolve 0.29 of 1,5-benzothiazepine mono-tert-butyl ester of 5-acetic acid in a 5 N solution of ethyl acetate in hydrogen chloride and let stand at room temperature for 3 hours. 50 ^ of ethyl ether was added to the reaction mixture, and the precipitate was washed with ethyl ether 10 and the mixture was washed with 3 (E)-[1 (S) -ethoxycarbonyl-15-phthalimidopentyl). 4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-15-acetic acid hydrochloride 0.139 is obtained as a colorless powder.

Elemental analysis value C27H29N307S · HC1 · Η2θ Calculated value: C 5 5.4 2 H 5.3 4 N 7.1 8

 Measured value: C55.09H5.12N7.15

[N] _D — 1 1 4. (C = 0.5 in methanol)

Reference example 4 4

 Reference Example 4 3 (E)-[1 © -ethoxycarbonyl1.5-phthalimidopentylamino-4-oxo-1 2,3,4,5-. 5—Benzothiazepine 5-tert-Butylester 1.6? Is dissolved in ethanol, and 85% hydrazine hydrate (0.89) is added. The mixture is allowed to stand at room temperature overnight. The reaction mixture was extracted by adding ethyl acetate 200 and water 200, and the ethyl persulfate portion was washed with a 0.1 N aqueous sodium hydroxide solution and then with water to give 3 (E) — [5-amino 1 1 (S) -hydroxycarbylpentyl: 1 amino-14-oxo2,3,4,5 nitehtrahydro-1,5-benzothiazepine-5 monoethyl acetate tert-butyl ester. A solution is obtained. Baking soda 1.6 in this solution? And 50 W of water are added, and while stirring at room temperature, a solution of g-tert-butyl di-carbonate 0.99 in ethyl acetate 5 is added dropwise. After stirring for 30 minutes, separate the ethyl ethyl phosphate layer and dry with anhydrous magnesium sulfate. The oily substance obtained after evaporation under reduced pressure was purified by silica gel gel chromatography (hexane: aceton = 4: 1) to give 3 (E)-[5-tert-butoxycarbonylamino i ( ) -Ethoxycarbonylpentyl] amino 4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1,49 as a colorless oil can get. I R V t cm →: 3 350 (NH), 1 7 4 0, 1 7 1 0,

1 6 8 0 (C = 0) ₀

Mass skip (me): 5 6 5 (M +)

Reference example 4 5 Reference Example 4 3 (R) -1 (S) -ethoxycarbone 5- (phthalimidopentyl) obtained in 2) Amino 4-oxo-1,2,3,4,5-tetrahydrodraw 1,5 — Benzothiazepine-5-acetic acid ヽ 61 ^ —butylester 2.6 9 Reference example

4 4 and similarly hydrazine treated, and purified by silica gel column chromatography one was reacted with di-one tert- butyl dicarbonate ³⁾ Single [

5-tert-Butoxycarbonylamino-1 (S) -ethoxycarbonylpentyl] amino 4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid The tert-butyl ester 1.879 is obtained as a colorless oil.

 I R V J ^ l ^ C5 »-1: 3 350 (NH), 1 7 4 0, 1 7 1 0,

1 6 7 0 (C = 0) ₀

Mass Spectacle (mZe): 5 6 5 (MT)

[N] _D — 13 c = 0.8 in methanol

Reference Example 4 6

 Reference Example 4 3 (R)-[5-tert tert-butoxycarbonylamino obtained in 5

1 (S) -ethoxycarbonylpentyl] amino 1-year-old oxo-1,2,3,4,5-tetrahydro-1,5-benzothine 1-pin-5-tert-butyl acetate Dissolve 0.69 in a mixture of 40 W of methanol and 25 W of 1N sodium hydroxide water, add water 10 and stir at room temperature for 2 hours. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 3 (E)-[5-tert-butoxycarbonylamino 1 (S). —Carboxypentyl J-amino-4-oxo-1,2,3,4,5-Tetrahydro-1,5-benzothiazepine-15-acetic acid tert-butyl ester 0.37 is obtained as a colorless candy. This product becomes colorless powder when treated with ethyl acetate. 1 3 5 ° C

Elemental analysis value As C26H39N3O7S

 Calculated value: C58.08H7.31N7.82.

 Measured value: C 5 8.1 1 H 7.2 2 N 7.73

IRV ^ 1 ° ¹ cm-i: 3350 (NH), 173 0, 170 0,

1 6 8 0 (C = 0) o

Reference Example 7

 3 (R) -amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-15-acetic acid tert-butyl ester 59 obtained in Reference Example 4 Dissolve 17.99 of ethyl 2-bromo-16-phthanoleidohexanoate in 200 of acetone-linoleate, add 2.469 of triethylamine and reflux for 45 hours. Acetonitrile is distilled off under reduced pressure, and water 200 W and ethyl acetate 300 are added to the residue and extracted. The extract is washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained oil was separated and purified by silica gel column chromatography (hexane: aceton == 4: 1), and the same product as that obtained in Reference Example 42 was obtained. [1 (10-ethoxycarbon-5-phthalimidopentyl)] amino 4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-tert-butyl acetate 3.9 9 and 3 (¾— [1 (S) -ethoxycarbonyl-5-phthalimidopentyl] amino-1 4-oxo-1,2,3,4,5—tetrahydro-1,5 —Benzothazepine-15-acetic acid tert-butyl ester 4.19 is obtained as a colorless oil.

Reference example 4 8—5 0

3 (E) -Amino-4-oxo-1,2,3,4,5-tetrahydro 1,5-benzothiazepine 5-tert-butyl tert-butyl ester as in Reference Example 47 Then, when reacted with a monobromoester shown in Table 7, the following benzothiazepine derivative is obtained.

 table

 0

 Coming Digestion-Mixture

 O PI

 Λ

' Reference example 5 1— 5 3

REFERENCE EXAMPLE 4 When the besozoti-ratio zepin derivative obtained in 8-50 is treated with an ethyl acetate hydrogen chloride solution in the same manner as in Reference Example 43, the compounds shown in Table 8 are obtained. table

 Next Diastereoma Mixture Reference Example 5 4— 5 6 '

 Reference Example 48—The benzothiazepine derivative obtained in 50 was treated with hydrazine in the same manner as in Reference Example 4, and then reacted with di-tert-butyl di-dicarbonate to obtain the compound shown in Table 9. can get. Table NH OO-R-

(CH ₂ ) _n HCOOC (CH ₃ ) 3

 Come diastereo mixture

OMPf Example 1.

 3 (R) -amino-4 obtained from Reference Example 4

 Dissolve 1.5 g of 5-tert-hydro-1,5-benzothiazepine-5-hydroxy acid tert-butyl ester in ethanol 5 and add acetic acid

 0.3 g, technician 2-year old Kiso 4-phenyl petitate 4.2 g, molecular sieve 4 A8 g is added. At room temperature

After stirring for 30 minutes, add a solution of sodium cyanoborohydride 0.69 in ethanol 4 over 2 hours while stirring at room temperature. After stirring overnight at room temperature, add 2.1 g of ethyl 2-chlorobutyryl 4-butyrate, and add dropwise a solution of 1.3 g of sodium cyanoborohydride in ethanol at 2 hours. The reaction solution is distilled off under reduced pressure, and water and ethyl ether 200 are added to the residue and shaken. The mixture is filtered to remove insoluble matter, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Ethyl ether 5 in residue

 Add 2 g of oxalic acid, shake well, add 300 parts of petroleum ether and leave overnight. Decant the solution, add water 5 and ethyl acetate 3 to the precipitate, and neutralize by adding excess sodium bicarbonate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give an oil. When this product is separated and purified by silica gel column chromatography (hexane: ethyl acetate = 51-10: 3), 3 (R) — (1 (R) — ethoxycarbonyl 3-phenylpropyl) 0.55 g of amino-4,5,5-oxotetra 2,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained as an oily oil.

I R

 neat

 -i

 D cm 3320 (NH), 1 730 (ester)

 max

 1 670 (amide)

OMPI

v / o "-_'0 Elemental analysis value C 27 H 34 N 2 O's S

 Calculated values: G 65.04; H 6.87; N 5.62

 Found: C 65.36; H 6.91; 5.61. From the subsequent fractions, the above 3 (R) —C1 (R) -ethoxycarbonyl 3-phenylphenyl] amino-4-oxo—2,3 , 4,5-Tetrahydro-1, 5-benzothiazepine-5-acetic acid tert-butyl ester and the following 3 (R) -C (S) -ethoxy-ponyl-3--3-phenylpropyl] amino-4 A mixture of 2,3,4,5-tetrahydro-1,5-benzothiazepine-15-butyl tert-butyl ester, that is, 0.4 g of the unseparable fraction of the astereomer was obtained as an oil. Can be The mixture ratio is almost * 1 :: 1.

 Pure 3 (R) — C (S) — ethoxypropyl 3-phenylpropyl] amino-4-oxo-1 2,3,4,5-tetratetrahydro-1, 0.75-g of 5-benzothiazepine-5-acetic acid tert-butyl ester is obtained as a colorless oil. · '. ·

 neat

IR Re ^{cm '1: 3320 (NH)} , 1 740 ( ester), max

 1 670 (amide).

Elemental analysis: C27 H3 N2 05 S

 Calculated value: C 65.04: H 6.87; N 5.62

 Found: C 64.90; H 6.63; N 5.66 Example 2.

 In the same manner as in Example 1, 1.5 g of 3 (R) -amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-15-acetic acid tert-ethyl ester was obtained as a reference example. The reaction was carried out using 5 g of the ethyl 4-cyclohexyl-2-oxobutylate obtained in step 5. Purification by silica gel column chromatography (hexane: ethyl acetate = 4: 1) gave 3 fractions as the first fraction. (R) 1 (1 (R) 1-Edoxycarboxyl 3-cyclohexylpropyl) 7 Minnow 4 1-year-old xo 2,3,4,5-tetrahydro-1,5-benzothiazepine-15-tert-butyl acetate 0.3 g of ester

ΟΜΡΪ

\ YIPO Obtained as a colored oil.

Sour boil 3 neat

IRV cm ' ¹ : 3320 (NH), 1 730 (ester), max

 1 670 (amide). Then, as the second fraction, 3 (R) 1 (1 (S) —ethoxyl 3-3-cyclohexylpropyl) amino-4 Torahi Draw 1,5-benzothiazepine-5-drunk tert-butyl ester 0.45 g was obtained as a colorless oil and neat

IRV cm " ¹ : 3320 (NH), 1 730 (ester) max

 1 670 (amide) Example 3.

Ethanol in 3 (R) -amino-4 1-year-old oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-5-carboxylic acid tert-butyl ester 1 g, acetic acid 0.4 g, ethyl 41 (P-Methylphenyl) 12-year-old sorbet 3.6 g, Molexura 1Sia 4 A 5 g are added in a row and stirred at room temperature for 1 hour. To the mixture is added 0.5 g of 5% palladium on carbon, and the mixture is subjected to catalytic reduction at room temperature and pressure. After reacting for 7 hours, the catalyst was removed, and the catalyst was distilled off under reduced pressure, and oxalic acid treatment was performed in the same manner as in Example 1. The resulting oil was purified by silica gel column chromatography to give 3 (R)-[1—ethoxycarbonyl-2- 3- (P-tolyl) pulpyl] amino-4,3-oxo-1,2,4 , 5-Tetrahedro, 5-benzothiazepine-5-acetic acid tert-acetyl ester 0.3 Q is obtained as a colorless oil This product is a mixture of two diastereomers (ratio 1: 1). . neat

 I R v -1

 cm: 3320 (NH), 1730 (ester), max

 1 670 (amide). Example 4.

 3 (R) -Amino-4-oxo-1,2,3,4,5-tetrahydro 1,5-benzothiazepine-5-tert-butyl ester 19 and isobutyl 2-oxo-3-phenylbutyrate Using 4 g, the reaction was carried out in the same manner as in Example 3 to obtain '3 (R)-[1-isobutoxycarporinyl 3-phenylpropyl] amino-4-oxo 2,3,4,5 0.45 g of —titrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained as a colorless oil.

 neat

IRV c-m ' ¹ : 3330 (NH), Ί; 30 (ester), max

 1 670 (amide). Example 5.

 3 (R) 1-1 (1 (R) -ethoxycarbonyl-2-3-phenylpropyl) amino-4,1-oxo-2,3,4,5-tetrahydro-1,5-benzothi obtained in Example 1 Dissolve 0.5 g of azepine-5-acetic acid tert-butyl ester in 5 N ethyl chloride hydrochloride solution 5 and leave it overnight at room temperature Add ether 20) ^ and petroleum ether 1 to the reaction mixture to precipitate To obtain the colorless powder that was obtained, 3 (R) 1 [1 (R) 1 -ethoxycarbone 3-phenylpropyl) amino 4-oxo 1 2, 3, 4, 5-tetrahydro 1 "], 5-42-benzothiazepine-5-acetic acid 漦 salt g0.42 g is obtained.

Elemental analysis value C23 H 2s N 2 0s S * As HCI

 Calculated: C 57.68; H 5.68; N 5.85 Actual: C 57.53; H 5.76; N 5.70 22

 ί α 173 ° (c = 1, in methanol)

 0

O PI

iPO Example 6-1.

 When the 1,5-benzothiazepine-5-acetic acid tert-butyl ester derivative obtained in Examples 1-4 is treated with hydrogen chloride in the same manner as in Example 5, the compounds shown in Table 10 are obtained.

 Table 10.

HCI

 * Mixture of diastereomers Example 1 2.

3 (R) -1- (1- (R) -ethoxycarbonyl-3-3-phenylpropyl) amino-4 obtained in Example 5 2,3-, 4,5-tetrahydro-1,5- Benzothiazepine 1.5-acetic acid / hydrochloride 0.1 Q is dissolved in a mixture of ethanol and aqueous sodium hydroxide solution, left in a room for 10 minutes, and then left in a refrigerator for 30 minutes. After arresting the colorless scaly crystals, 3 (R) — (1 (R) —capilloxy—3-phenylpropyl) amino—4—1,2,3,4,5—tetrahydro— 1,5-benzothiazepine-5-acetic acid ♦ 0.05 g of disodium salt is obtained. Melting point 2 I 5 — at 220

 neat

IR Ri cm " ¹ 1 660 (amide)

 max

 1 600 (carboxylate)

Elemental analysis ill C a H 20 N 2 Na ₂ Os S · 52 H 20 Calculated value: C 50.10; H 5.00; N 5.56 Actual value: C 50.28; H 5. 29; N 5.91 Example 1 3.

 3 (R) -1C1 (S) ethoxycarbonyl-1-3-phenylpypyl obtained in Example 7] amino-4oxo-1,2,3,4,5-tetrahydro'D-1 Dissolve 0.2 g of 5-Penzothiapine-5-acetic acid in ethanol 2 and 1 N 'sodium hydroxide solution; After leaving at room temperature for 30 minutes, distill off under reduced pressure at room temperature to make the volume almost 1 ^. The solution was neutralized with acetic acid to make it weakly acidic, and the precipitated colorless prism crystals were taken. It was found that 3 (R) -— (1 (S> Ichiru-l-poxy-1-3-phenylpropyl) amino-4. 0.134 g of 4,5-tetrahydro-1,5-monobenzothia tf-pin-5-acetic acid monosodium salt is obtained, mp 166—169 C

 neat

 I R V -1

 cm: 1 720 (carponic acid), 1 670 (amide) max

 1 640 (force box)

 twenty two

 [Α] 22 ° (c = 0.2 (methanol: water = Ί: 1))

0 Example 1 4 1 1 7

 When the aminoaminobenzothiazepine acetic acid tert-butyl ester derivative obtained in Reference Examples 23 to 26 was reacted with Example 1 in the same manner as in Example 1 to give 2-ethyl-1-oxo-4-phenylbutyrate, the compounds in Table 11 were converted to oily substances. Is obtained as

7 Table 11

 s

実施例 1 8— 2 4

Example 1 8—2 4

Example 14 The methoxycarbonyl-3-phenylpropylaminobenzothiazepine derivative obtained in 41-17 was treated with hydrogen chloride as in Example 5 to give the compounds shown in Table 12 as colorless powders. . Table 12 2s HC

 * Diastereomeric mixture Examples 25-29

 3 (R) -Amino-4-butyriso-2,3,4,5-tetratetra-1,5-benzothiazepine-15-acetic acid tert-butyl ester obtained in Reference Example 4 and Reference Example 27-30 When the peak ester or ethyl pyruvate obtained in the above was reacted with Example 1 in the same manner as in Example 1, the compounds shown in Table 13 were obtained as oily substances.

Table 13 Hs

OMH

 Approval diastereomer mixture Example 30-35

 1,5-benzothiazepine mono-5-acid obtained in Examples 25-29

 When the tert-butyl ester derivative is treated with hydrogen chloride as in Example 5, the compounds shown in Table 14 are obtained as a colorless powder.

 Table 14

OMPI WIPO ^

❖ diastereo 7—mixture Example 36

3 (R) -Amino-4-oxo-1 7-trimethyl obtained from Reference Example 34-methyl-2,3,4,5-tritrahydro-1,5-benzothiazepine-5- 齚 acid / odor Dissolve 0.659 hydride in 50 ethanol and add 0.2 g of sodium acetate, 0.19 g of acetic acid, 1.67 g of ethyl 2-oxo-4-phenylbutyrate, and 1.67 g of molecular shear 4A. Add and stir at room temperature for 1 hour. An ethanol solution of sodium cyanoborohydride 0.5-69 is added dropwise to the mixture at 2 o'clock. The solvent was distilled off under reduced pressure, water 50 »δ and ethyl acetate 1 50 ^ were added, and the insoluble matter was arrested. The ethyl layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in a mixture of ether and petroleum ether, and a solution of hydrogen chloride-ethyl acetate was added to give 3 (R) — (1-ethoxygalponyl-3-phenylpropyl) amino-4—sixol. Lifluoromethyl-1,2,3,4,5-tetrahydrochloride 1,1,5-benzothiazepine-15-hydroxy acid, 0.7 g of hydrochloride precipitates as a colorless powder (a) _D -95. In methanol) Mass spectrum: m Ze 5 10 (M ⁺ )

OMPI Example 3 7 *

 3 (R) -I (1 (S) -ethoxycarbonyl-2-3-phenylpropyl) amino-4 obtained from Example 7 2,3,4,5-Tetrahi draw 1,5 Benzothiazepine—5—Drossic acid / hydrochloride (0.3 g) is dissolved in dimethylformamide (1), and sodium hydrogen carbonate (1 g) and benzene (0.15 g) are added. The mixture is stirred overnight at room temperature. Water is added to the reaction mixture, oil is extracted with 200 mL of ethyl acetate, washed with water, aqueous sodium hydrogen carbonate, water, 0.1 N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The oily substance obtained was dissolved in ether 3 and a solution of hydrogen chloride monoacetate (5N) 0. was added dropwise to give 3 (R) -1 (1 (S) -ethoxycarbonyl-3 —Phenylpropyl] amino-4 1-year-old xo 2,3,4,5—tetrahydro-1,5—benzothiazepine—5-benzylamine Steal ♦ 0.25 g of hydrochloride precipitates as a colorless powder.

Elemental analysis value C 30 H 32 N 2 Os S As H C I

 Calculated value: C63.311: H5, 84; N492 Actual value: C63.02; H5.82; N519 Mass spectrum (mze): 532 (M +)

[] _D — 90 ° (in methanol) Example 38

 3 (R)-((S)-ethoxycarbonyl 2-3-phenylphenol pill) amino-4-year-old oxo-1, 2, 3, 4, 5-tetrahydro 1, 5-benzothiazepine-5-acetic acid · Benzyl ester ♦ 0.1 g of hydrochloric acid salt is dissolved in 1 C 'of ethanol, and catalytic reduction is carried out at room temperature and pressure using 10% palladium carbon (containing 50% water) 0.29 as a catalyst. After removing the catalyst, the solvent was distilled off under reduced pressure, and a mixture of ether and petroleum ether was added to the solvent. The mixture obtained in Example 7 was similar to that obtained in Example 7 with 3 (R)-(1 (S) -ether. Xycarbonyl-3-phenylpropyl] amino-4-amino-1,2,3,4,5-tetrahydro-1,

0.05 g of 5-benzothiazepine-5-drunkic acid · hydrochloride is obtained as a colorless powder. Example 39

 3 (R) -C1 (S) ethoxycarbonyl 2-3-phenylpropyl obtained in Example 7 Amino-1- 4-oxo1,2,3,4,5-tetrahydro-1,5 Dissolve 0.5 g of benzothiazepine monohydroquinate hydrochloride in 50 ^ methylene chloride, stir at room temperature, and add 0.559 of m-chloroperbenzoic acid in small portions in 2.5 hours. . After stirring at room temperature for 1 hour, water 200 and methylene chloride 50 are added and extracted. The methylene chloride layer is washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethyl ether 10 and an ethyl hydrogen chloride monoacetate solution (5N) 0.5 was added to give 3 (R) — C (S) — ethoxycarbone 3-phenylphenyl) amino-4 1,3,4,5-Tetrahydro-1,5-benzothiazepine-15-acetic acid S-oxide * hydrochloride 0.3 g is precipitated as a colorless powder.

As elemental analysis value G23 H 2s N 2 0s S * HCI · Η 2 0

 Calculated value: Ρ 53.85; Η 5.70 Ν .5

マススペク トル （mZe ) : 458 ) Observed value: C 54. 29; Η 5.70 Ν 5

Mass spectrum (mZe): 458)

C α) 0 -80. (In methanol) Example 40 67. 3 (R) 1-1 (1 (S) -1-ethoxycarpo; Ru-3-phenylpropyl) amino obtained in Example 7-amino-1,4-year-old 2,3,4,5 -0.5 g of tetrahydro-1,5-benzothiazepine-5-acetic acid.hydrochloride -0.3 g of phenylalanine.tert-butyl ester dissolved in 10 ^ of dimethylformamide Add dropwise 0.23 g of dimethylformamide in 2 W solution After stirring for 10 minutes, add 0.23 g of triethylamine in dimethylformamide solution, and then stir for 30 minutes under water cooling The reaction mixture was extracted with 200 ml of ethyl acetate and water 1 and extracted. The ethyl acetate layer was washed with 0.02N hydrochloric acid, 0.05N aqueous sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. The residue was dissolved in petroleum ether, and hydrogen chloride-ethyl acetate was added. Addition of solution (5N) 1 gives 3 (R) 1 [1 (S) ethoxy carbonyl- 3- phenylpropyl] amino 4- oxo- 2,3 4,5-tetra-hydro-1,5-pentoziazepine-5-ylu

 0.63 g of N-acetyl-L-I-I-alanalanine tert-butyl ester hydrochloride precipitates as a colorless powder.

 Elemental analysis value Css H43 Ns Os S · HCI · 12H2O

 Calculated value: G 62.55; Η6.56; Ν6.08

 Measured value: C 62.61 Η 6.77; Ν 5.89

Mass spectrum (mZe): 645 (M ⁺ )

 (H) D-79. <in methanol> Example 41

 3 (R)-(1 (S) —ethoxycarbo 2-ru 3-furinylpropyl) amino obtained in Example 40 4-amino-1,2,3,4

 5-Tetrahydro-1,5-benzothiazepine-1-yl N-acetyl-L-phenylalanine tert-butyl ester ♦ 0.45 g of hydrochloric acid salt was dissolved in hydrogen chloride / ethyl acetate solution (5N) 5. After leaving at room temperature for 3 hours, evaporate under reduced pressure. A mixture of ethyl acetate and ethyl ether was added to the residue to obtain 3 (R)-[1 (S) -i

Xicarboneru 3 : Nilp pill] Amino 4

 2,3,4,5-tetrahydro-1,5-benzothiazepine-1-yl N-acetyl-L-phenylalanine ♦ 0.26 g of hydrochloride is obtained as colorless crystals.

Melting point 1 53— 1 57

Elemental analysis value C32 H 35 N 3 06 S ♦ As H C I

 Calculated values: G 61.38; H 5.79; N 67

 Found: C 61.21; H 5.78; N 666

Mass spectrum (mZe): 58 9 (M +)

 (Hi) 0-96. Example 42 (in methanol)

 3 (R) 1 (1 (S) —ethoxycarbonyl obtained in Example 1

3-phenylpropyl) amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-tert-butyl-acetic ester 1 g is dissolved in methylene chloride 100, Add 0.51 g of chloroperbenzoic acid and stir for 30 minutes. Further m

After adding 0.159 of monochloroperbenzoic acid and stirring for 30 minutes,

O — ■ P

ΤίΟ ^ A 1 N aqueous solution of sodium hydroxide is added, the methylene chloride layer is separated, washed with water and evaporated under reduced pressure. Product 3 (R) -C1 (S) -ethoxycarbone 3-phenylpropyl] amiso 4 1-year-old xo 2,3,4,5-tetrahydro- 1,5-benzothiazepine-5- S-acid tert-butyl ester 1 One-year-old oxide is a mixture of two stereoisomers. When separated by silica gel column chromatography, 0.3 g as the pre-effluent and 0.5 g as the post-effluent Was obtained as a colorless oil, and both showed a molecular ion peak of 5 14 in the mass spectrum. Example 43

 3 (R) -1 ((S) -ethoxycarbonyl-2-3-phenylpropyl) amino obtained in Example 1 4-amino-1,2,3,4,5 -tetrahydro-1,5 Dissolve 0.8N QNzothiazepine-5-sulfuric acid tert-butyl ester in ethanol 6, add 1 I aqueous sodium hydroxide solution 3 »8, stir at room temperature for 2 hours, add water 2'00 to the reaction solution, Extraction with ethyl ether 1 and making the aqueous layer weakly acidic with 1N hydrochloric acid yielded 3 (R)-[1 (S) -l-oxyl-3-phenylpropyl] amino-4-year-old 1,2,3,4, 0.5 g of 5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-acetyl ester are obtained as colorless crystals, mp 165-167 1

(H) _D — 101. (in methanol)

Elemental analysis G25 H30 N2 Os S

 Calculated values: C 63.81; H6.43; N5.95.

 Found: C 63.69; H 6.38; N 5.87 Example 44

 3 (R) — [1 (S) —potassium 3-phenylphenyl] amino obtained in Example 43 4-amino-1,2,3,4,5-tetrahydro-1,5- Dissolve 0.3 g of benzothiazepine-5-tert-butyl ester in dimethylformamide 1, add 0.59 g of sodium hydrogen carbonate and 0.15 g of benzyl bromide and stir overnight at room temperature. . Water (1Ο Οι ^) and ethyl acetate (20

 The extract is washed with 0.1 Ν hydrochloric acid and water,

ΟΜΡί Dry over magnesium sulfate and evaporate under reduced pressure 'and 3 (R)-(1 (S) -benzyl-l-xylcarpine-l-3-phenylpropyl] amino-1 4-oxo-1 2,3,4,5- Tetrahydro-1,5-benzothiazepine-5-acetic acid tert-acetyl ester 0.359 is obtained as a colorless oil.

 neat

IRV ctn " ¹ : 3330 (NH),

 max

1 740 (ester), 1680 (amide) Mass spectrum (mZe): 560 ( ⁴ ·) Example 45

 3 (R)-((S) -benzyloxyxylbonyl-3-phenylphenyl) amino-4 obtained in Example 44 2,3,4,5-tetratetrahydro-1,5-benzothiazepine Treating 0.35 g of 1-acetic acid trt-butyl ester with hydrogen chloride in the same manner as in Example 5 yielded 3 (R) 1- (1 (S) -benzyl 3-hydroxypropyl 3-aminopropyl) amino- 0.25 g of 2,3,4,5-tetrahydro-1,5-monobenzothiazepine-5- 齚 -acid / hydrochloride is obtained as a colorless powder.

Elemental analysis: as C 28 H 28 N 2 Os S · H C I

 Calculated value: C 62.16; Η 5.40; Ν 5.18 Actual value: C 61.777; Η 5.44; Ν 4.96

(a) D-8 2 ^β (in methanol)

Mass vector (m / e): 504 (tenth) Example 46

2 g of 3 (R) -amino-4 1-year-old xo 2,3,4,5-tetrahydro-1,5-benzothiazepine-15-acetic acid tert-butyl ester obtained in Reference Example 4 was dissolved in ethanol 2 and bromo Add 1.6 g of ethyl acetate and 1 g of triethylamine, and leave overnight at room leak. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1). 3 (R) -ethoxycarbonylmethylamino-4 4,5—Tetrahydro-1,5—Benzothiazepine 1—Drunken Tert-Butyl ester 1.8 g is obtained as a colorless oil neat

IRV en ¹ : 3330 (NH) ',

 max

1 740 (ester), 1670 (amide) Mass spectrum (me): 394 (M ⁺ ) Example 47

 3 (R) -Ethoxycarbonylmethylamino obtained in Example 46-4 years old xo 2,3,4,5-tetrahydro-1,5-benzothiazepine-15-monoacetic acid tert-butyl ester 1. Dissolve 89 in ethyl chloride monoethyl acetate solution (5N) 15 and leave at room temperature for 3 hours. When ethyl ester 5 is added to the reaction mixture, 3 (R) -ethoxycarbonyldimethylamino-4-tetraquinone 2,3,4,5--tetrahydro-1,5-benzobenzoazepine-5-acetic acid-hydrochloric acid salt

1.6 Q is obtained as colorless prisms.

Melting ^ 2 ― 225Ό (decomposition)

Elemental analysis value c is H is I 20 s S · H C i

 Measured value: C 48.06; H5.1; N7.47 Actual value: G47.99; H5.11; N7.25 (α) D-193 ° (in methanol)

Mass spectrum (m / e): 338 (M +)

3 (R) obtained in Reference Example 35 — (N-benzyl-N-ethoxyproponylmethylamino) — 4 1-year-old xo 2,3,4,5-tetrahydro-1,5 benzothiazepine-1 —Dissolve 0.5 g of succinic acid / hydrochloride in ethanol 2 and perform catalytic reduction at room temperature and pressure using 0.5 g of 1090 radium monocarbon (containing 5096 water) as a catalyst. When the absorption of hydrogen stops, the catalyst is removed by filtration, and the base solution is distilled off under reduced pressure to precipitate crystals. After adding ethyl acetate, 3 (R) -ethoxycarbonylmethylamino-4 isotoxol 2,3,4,5-tetrahydro-1,5 dibenzothiazepine-1-5-acetic acid 0.3 Q Obtained as colorless prism crystals. [A] D-171 with a melting point of 223-226. (In methanol) Mass storage vehicle (mZe): 338 (M ⁺ ) Example 49

 3 (R) -ethoxycarbonylmethylamino obtained in Example 47 14-year-old xo 2,3,4,5-tetrahydro-1,5-benzobenzothiazepine-5-acetic acid.hydrochloride 0 Dissolve 5 g in 1 N aqueous sodium hydroxide solution and leave for 3 hours at room leak. After neutralization with 1 N hydrochloric acid, adsorb to Amberlite IR-45.

 19 Drain the target substance with aqueous ammonia, evaporate to dryness under reduced pressure, add a mixture of ethanol and ether, and remove the precipitated powder.

 (R) 1-Rupoxymethyl-1,4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-5- 齚 acid 0,25 Q is obtained.

Elemental analysis value Cl3 H! 4 N2 〇5 S * 2H2 0

 Calculated values: C 45.09; H 5.24; N 8.09

 Found: C 45. 9; H 4.94; N 8.03

 [Na] D-1 96. (Underwater) '' Project 50

 3 (R)-[1 {S> -ethoxycarpinyl-3-cyclodoxylpropyl] amino-4-amino-1,2,3,45-tetrahydro-1,5-benzozazepine obtained in Example 9 Dissolve 0.15-acetic acid / hydrochloride in methanol, add 1 1aqueous sodium hydroxide solution and leave at room temperature for 2 hours. The reaction solution is reduced to a volume of approximately 40 by reducing the reaction solution under reduced pressure to less than 40. When the solution is made weakly acidic with 1Ι hydrochloric acid, 3 (R)-(1 (S) -caproloxy-3-cyclohexylpropyl) amino-4 2,3,4,5-Tetrahydro-, 5-benzothiazepine-5-acetic acid 0.0679 is obtained as colorless prisms.

With a melting point of 207-210

Elemental analysis value Ca Ha N 205 S ♦ As H20

 Calculated values: C 57.52; H 6.89; N 6.39

 Found: C 57.20; H6.9; 6.42

 (α) D-37 ° (C =. in methanol)

OMPI Example 5 1

 3 (R) — (1-ethoxycarbonyl-15-phthalimidopentinole) amino-4, oxo-1,2,3,4,5—tetrahydro-1,5—benzothiazepine obtained in Reference Example 37 —Dissolve 0.7 ethyl acetate in 20π ^ ethanol and add 0.3 ^ 85% hydrazine hydrate. Add 5% hydrazine hydrate 0: 3 ^ after 1 hour and 2 hours, then leave it overnight. Ethanol is distilled off under reduced pressure. To the residue is added 5 5π ^ of water, saturated with sodium chloride, and extracted three times with ethyl acetate or ^. The extract is washed with 0.1 N aqueous sodium hydroxide solution (5ΟπΟ) and then with water (10), and dried over anhydrous magnesium sulfate. To the resulting ethyl acetate solution, 5N hydrogen chloride in ethyl acetate 0.5π ^ was added, and the mixture was evaporated under reduced pressure. Ethyl ether was added to the residue to give 3 (¾)-(5-amino-1-ethoxy-carbonyl). Amino. — 4-oxo-1,2,3,4,5—tetrahydro-1,1,5-benzothiazepine-5-ethyl acetate.2 · hydrochloride 0.13 ^ is obtained as a colorless powder .

Elementary analysis: as _{C 2 i H 31 3 0 5} S · 2HC1-H 2 0

 Calculated value: C 47.73 H 6.6 7 N 7.95 'Actual value: C 47.8 1 H 6.5 3 N 7.8 3

Mass vector (: m / e: 437 M)

Example 5 2

 1; 3 (R) — (: 5—aminol 1-ethoxyquinponyl pentyl) obtained in Example 51 1—amino-4-oxo-1,2,3,4,5—tetrahydrodraw 1,

5 Benzothiazepine mono 5-ethyl acetate · dihydrochloride 50 ^ is dissolved in a mixture of ethyl acetate 3Οι ^ and water 1 Om ^, and benzyloxycarbonyl chloride 0.15m £ and sodium bicarbonate! 2.5 hours at room temperature after adding 0.3 ^ Mix. After washing the ethyl acetate layer with water, use anhydrous magnesium sulfate! ^ Then evaporate under reduced pressure. The obtained oil was dissolved in a mixture of ethyl ether 20π ^ and petroleum ether 20 and 5N hydrogen chloride in ethyl acetate 0.2 was added to give 3 (R)-(5-benzyloxycarbonylamino 1 Ethoxycarbonyl pentyl) Amino-1-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-ethyl acetate 'Hydrochloride 5 5 ^ is a colorless powder Is obtained as .

 Mass vector (m / 'e): 57 1 (M;

 2) Example 5 2-3-(5-benzyloquincarbonyl 'amino 1-ethoxyquinone porponylpentyl) amino-4 -oxo 1 2 obtained in (1),

3,4,5-tetrahydro-1,5-benzothiazepine-15-ethyl acetate.Hydrochloride 55 ^ into a mixture of 3m of ethanol and 1N7_K sodium hydroxide aqueous solution 2: ^ Dissolve and leave at room temperature for 1 hour. After adding 5 ml of water to the reaction solution and extracting with ²⁰ ml of ethyl ether, the aqueous layer is adjusted to pH ⁴ with 1N hydrochloric acid. After adding ammonium chloride until a saturated solution is obtained, the aqueous layer is extracted 10 times with ethyl acetate 20: ^. The extract is washed with a small amount of water, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure to give 3-((5-benzyloxycarbonylamino-1) ruboxypentyl) amino 4-oxo. 1,2,3,4,5-Tetrahydro-11,5-benzothiazepine-15-acetic acid 40 '/ ^^ Obtained as a colorless powder.

Mass spectrum (m / e: 5 15 C

3) Example 5 3— (5-benzyloxycarnylamino-11-carboquinpentyl :) obtained in 2— (2): amino-4, oxo-1,2,3,4,5— Dissolve tetrahydro-1,5 -benzothiazepine-15-acetic acid 40 ^ in acetic acid 1, add 30% hydrogen bromide acetic acid solution 1 and release at room temperature for 1 hour. Place. After adding ⁸ Om of ethyl ether and 2 Or ^ of petroleum ether to the reaction mixture and shaking, stir, remove the supernatant by decanting, collect the precipitate, and dry it to obtain 3 R.)-C 5-Amino-11-carboxypentylamino-4-oxo-1,2,3,4,5-Tetrahi draw 1.5-Benzothiazepine-5-monoacetic acid dihydrobromide 33 3 ^ is obtained as a colorless powder. Can be

S IMS spectrum (/ e): 382 (MH ⁺ );

 Κ Ι®Π 42 0

Example 5 3

3 (R)-[2 (S-benzyloxycarbonylamino-1-ethoxyquincarbonyl-3-phenylpropyl) amino-4-oxo2,3,4 obtained in Reference Example 39 , 5—Tetrahydro 1, 5—Benzothiazepine-monoethyl ethyl acetate 0.22 ^ was treated with hydrogen bromide in the same manner as in Example 52- to give ³ (R) -C 2 (S) Amino-1-ethoxycarbonyl-13-phenylp sigma] amino 4-oxo-1,2,3,4,5-tetrahydrodraw 1,5-benzothiazepine-5-ethyl acetate '2 hydrobromide 0.18 ^ Is obtained as a colorless powder.

Elemental analysis: C ₂₅ H ₃₁ N ₃ 0 ₅ S · 2HBr · Ή ₂₀

 Calculated value: C 4 5.1 2 Η5.3 0 6.3 6.3 1

 Measured value: C 4 5.1 1 Η 5.2 8 Ν 6.2 7

Mass spectrum (/ e): 485 CM

Example 5 4. 3— [2 (S) -amino 1-ethoxycarbonyl-13-phenylphenyl σ pill obtained in Example 5 3 [amino 4-oxo 1-2,3,4 , 5-Tetrahydro 1, 5-benzothiazepine-2-ethyl acetate / dihydrobromide 0.15 ^ to methanol 5 and 1-sodium hydroxide aqueous solution 5 Dissolve in the mixture, and leave at room temperature for 1 hour. Evaporate methanol under reduced pressure, add 10m of water, and purify by Amberlite XAD-2 column chromatography (methanol: water = 1: 1). The effluent is concentrated under reduced pressure and freeze-dried to give 3-[2 (S) -amino-1-carboxy-3-phenylpropyl] amino-14-oxo-1,2,3,4,5-te. TrahydroDraw 1,5-benzothiazepine-15-dinatriacetic acid salt 37 ^ is obtained as a colorless powder. .

Elemental analysis: C _2l H ₂₁ N _{3 Na 2} 0 ₅ S ' ³ Z ₂ H ₂₀

 Calculated value: C 5 0.40 H4.8 3 N 8.4 0

 Measured value: C 5 0.42 H 5.0 8 N 8.5 3

 S IMS spectrum (m / e: 474 (MH), 452, 4330.

 I addition: 506, 4'68, 430.

Example 55

 Reference Example 41 3 (R) -amino-4,1-oxo-2,3,4,5-tetrahydro-1-1,5-benzothiazepine-15--1-methylacetate obtained in 1 The butyl ester 2.5 ^ was reacted with ethyl 4-cyclohexyl 2-oxobutylate in the same manner as in Example 2 and purified with silica gel column chromatography (hexane: ethyl acetate = 4: 1). As the first fraction, 3CH) -Γ1 (R) -ethoxycarbonyl-3—cyclohexylpropylamino-4oxo-1,2,3,4,5—tetrahydro-1,5— Benzothiazepine tert-butyl ester 5-^-methylacetate ^ Obtained as an oil.

Mass vector (/ e): 518 C M;

Subsequently, as the second fraction, 3 (R)-[1 (S) -ethoxycarbonyl 3-chlorohexylpropyl] amino 41-oxo-2,3,4,5-tetra- Rahydro-1,5-benzothiazepine-5-α-methylacetic acid tert-butyl ester 0.28 is obtained as a colorless oil.

IR ^^ c £ ^l : 1740, 1670C = 0)

[Α] ² _υ ³ — 2 2 2. (C = 0.4 in methanol

(Mass vector m / ;: 5 18 CM) Example 56, 57 Example of using 1,5-benzothiazepine 5-na-methyl monoacetic acid tert-butyl ester derivative obtained in Example 55 Treatment with hydrogen hydride as in 5 gives the compounds shown in Table 15. Table 15

HC1

Stand arrangement

Example No. C «3 _D [in main Tano Lumpur)

 1 2

5 6 R R -1 55 ° C c = 0.4)

5 7 R S -13 2 ° (c = 0.4

Examples 58, 59 When the benzothiazepine derivatives obtained in Reference Examples 44, 45 are treated with hydrogen chloride in the same manner as in Example 5, the compounds in Table 16 are obtained as colorless crystals.

OMPI Table 16

Stand arrangement

 Example No. (B) u (in methanol)

 * 1 * 2

5 8-1.61 ° C c = 0.7

5 9 R S -128 ° (c = 0.5

Example 6 0

3 (— [5—Amino 1 (S) —ethoxycarbonyl pentyl) amino-1-4-oxo-12,3,4,5—Tetrahi draw 1,5 obtained in Example 5 9 —Benzothiazepine—5—Acetic acid · dihydrochloride 0,2 is added to 4m of 1N aqueous sodium hydroxide solution and stirred for 1.5 hours at room temperature. XAD—Purification with 2-column chromatograph (methanol: water = 3: 7) After concentrating the effluent under reduced pressure, freeze-drying yields 3 (R) — [5-amino-1 (S ) —Carboxypentyl] Amino 4-oxo-1,2,3,4,5-tetrahydro-1,5—benzothiazepine-5—acetic acid 0.1 is obtained as a colorless powder Elemental analysis: C ₁₇ as _{H 23 N 3 0 5 S ·} H 2 0

 Calculated value: C 5 1.1 2 H 6.3 1 N 1 0.5 2 Actual value: C 5 0.8 7 H 5.8 3 N 1 0.3 4

[] _D -14 9 ° (c = 0.3 IN in hydrochloric acid S IMS spectrum (mZe): 382 C MH ⁺ ), *

 (KI added 4 20 C M + K)

Example 6 1

 Reference Example 46 3C¾- [5-tert-butoxycarbonylamino-ICS) -carboxypentinole] amino 4-oxo-1,2,3,4,5—tetrahdroh 1,5-benzo obtained in Reference Example 6 When thiazepine-5-tert-butyl ester 0.329-acetate was treated with hydrogen chloride in the same manner as in Example 5, 3 (-[5-amino-1 (SJ-potoxyl-poxyntyl) amino-4) -Oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride 0.26 is obtained as colorless powdery crystals.

Elemental analysis: CH ₂₃ N ₃ 0 ₅ S. SHC C¾COOC ₂ H ₅

 Calculated value: C 4 6.4 9 H 6.1 3 N 7.7 5

 Measured value: .6 4 6.1 2 H 6.1 6 N 7.5 2

Dissolve 0.15 of this product in 2π ^ water, add 0.5π ^ sodium hydroxide aqueous solution followed by 0.5π ^ acetic acid, and purify with Amberley XAD- ² in the same manner as in Example 60. 0.096 of the same educt as obtained in Example 60 are obtained.

Example 6 2— 6 4 ′

 When the benzothiazepine derivative obtained in Reference Examples 54 to 56 is treated with a hydrogen chloride acetate solution in the same manner as in Example 5, the compounds shown in Table 17 are obtained.

Table 17

 Diastereomeric mixture.

Example 6 5.. Reference Example 4 3 (H) — [1 (S) ethoxycarbonyl-15-phthalimidopentyl] amino obtained from 2 or 47—amino-4,1-oxo-2,3 , - 4, 5-te us arsenide draw 1, 5-Benzochiaze etc. down one 5 - after hydrazine processed similarly ί second and acid t Ert- Buchirue ester 0.5 9 reference example ⁴ 4, benzoyl torque When reacted with the mouth lid, 3 (KJ— [5—benzoylamino-1 (S) ethoxycarbonylcarbonyl) tylamino-4-oxo-12,3,4,5—tetrahydro Draw 1,5-benzothiazepine-15-acetic acid tert-butyl ester 0.14 is obtained as a colorless oil IR ^record : 335 (NH

 Example 1 6 7 4 1 (ester), 1 660 (amide)

3 (R;-[1 (S) -ethoxyquinone-5-phthalimidincinole]] amino 4-oxo-1,2,3,4,5—tetrahydrodraw 1,5—benzothiazepine-15 —Acetic acid tert-butyl ester 0.5 ^ was treated with hydrazine in the same manner as in Reference Example 4 4 and reacted with acetyl chloride to give 3 — [5-Acetylamino 1 (S) -ethoxycarbylpentyl] amino—4-oxo-1,2,3, · 4,5-tetrahydro-11, '5-benzothiazepine-5-tert-acetate Butyl ester 0.25 ^ was obtained as a colorless oil.

IR di _{^{^ e a m 1: 3 3}} 2 0 NH,

 1 Τ 30 (ester), 1660 (amide)

Example 6 7, 6 8

When the benzothiazepine derivatives obtained in Examples 65 and 66 are treated with a hydrogen chloride ethyl acetate solution in the same manner as in Example 5, the compounds shown in Table 18 are obtained. Table 18

Example 6 9

Example 5 9 3 (¾) —C 5 —Amino 1 (S) —Ethoxycanolepone Lpentinole] amino 1 4-oxo 1 2,3,4,5—Tetrahydrodraw 1 , 5-benzothiazepine mono 5-acetic acid dihydrochloride 0.2 ^ ethanol 1 Οπ ^ And add cyclohexanone ² ^ and sodium cyanoborohydride 0.3 ^, and leave at room temperature overnight. After distilling off ethanol under reduced pressure, add 1N aqueous sodium hydroxide solution 4 to the residue and stir at room temperature for 1 hour. Water ² is added to the reaction mixture, and the mixture is extracted ^three times with 20 ml of ethyl acetate. And acetic acid 1 was added to the aqueous layer, after the weakly acidic, Anpa one line Bok XAD- ² force Ramuku Roma Bok chromatography (methanol: water = 1: 1) to give the effluent freeze dried after concentration, ³ [10— [1 (S—Carboquin—5—1 mouth hexylaminopentyl J amino—4—oxo-1,2,3,4,5—Tetrahi draw 1,5—Benzothiazebine-5—acetic acid 0.1 2 ^ is obtained as a colorless powder.

Elementary analysis: as _{C 23 H 33 N 3 0 5} S H 2 0.

 Calculated value: C 5 7.3 6 H 7.3 2 .. N 8.7 2

 Measured value: C 5 6.8 6 H 7.4 8 8.3 4

«J _D — 1 1 7. (C = 0.5 'in methanol)

 S I MS Sect No. (m / e): 4 6 4 (H)

 KI addition 502 (M "fKJ, 464

Example 7 0, 7 1

3 (R) — [5—Amino-1 (S-ethoxycarbonyl) pentyl] obtained in Example 59 9Amino-1-4-oxo-1,2,3,4,5—Tetrahydro Draw 1 , 5-Benzothiazepine-5-acetic acid 'dihydrochloride was reacted with the carbonyl compounds shown in Table 19 in the same manner as in Example 69, followed by hydrolysis to give the following: can get. Table 19

OMPI

'' WIPO Experimental example 1.

 Angiotensin I-converting enzyme of the compound of the present invention <ACE)

 Suppression experiment

 (experimental method〕

The experiments were performed by a modified method of Cushman et al. (Biochemical Ph.a., maco Iogy, 20, 637, 197 "!). That is, the inhibitory effect on ACE was determined from the rate of inhibition of hippuric acid production when the compound of the present invention was added to the amount of hippuric acid produced by ACE using hypol-L-histidyl-l-leucine (（) as a substrate. ACE 100 (Protein concentration 20mgZ), 1.25mHHL 100 / to 0.02 to 0.596 dimethyl sulfoxide 1 OOmM boric acid-hydrochloric acid buffer (PH8. '3, containing 300mM salt) A solution of the invention compound was added. As a control, a boric acid monohydrochloric acid buffer solution containing dimethyl sulfoxide having the same degree as that of the sample solution was used. After heating this solution at 37 ° C for 1 hour, the reaction was stopped by adding 1N hydrochloric acid 150 ^, centrifugation was performed at 5000 rpm for 2 minutes after adding ethyl acetate (0.1). The ethyl ethyl drunk layer was removed, dried under nitrogen gas at 4 CTC or less, and distilled water was added to the residue (4), mixed well, and colorimetrically determined at a wavelength of 228 nm.

(Experimental result) '

 The experimental results for the compound of the present invention are shown in Table 20.

実験例 2.

Experimental example 2.

 Effect of the compound of the present invention on the pressor action of angiotensin I (Experimental method)

 Male rats (Sp “ague-Daw I ey”) weighing 250-350 g and bred under free access to food and water were used.The day before the experiment, pentoparbital sodium (50 mgZkg) was used. After injection into the abdominal cavity, the rat was crushed, and a polyethylene tractor was inserted and fixed in the hip artery for blood pressure measurement and in the hip vein for injection of angiotensin I and I, respectively.

The average blood pressure of the control period on the day of the experiment was measured using an electric sphygmomanometer (Nihon Kohden, MP-4T or NEC-San-ei, MPU-0.5-290-0-) After recording, 300 ngZkg of angiotensin I and then 100 ngZkg of angiotensin E were injected into the crotch vein to examine the blood pressure effect. Next, 3 and ΊOmg Zkg of the compound of the present invention were orally administered as an aqueous solution or a gum arabic suspension, and angiotensin I and II were repeatedly injected at 20.60 and 120 minutes after the administration, and the pressor response was monitored. . In calculating the suppression rate of the pressure-boosting action of Anji Taishin I, Anji Taishin! [The suppression rate was corrected based on the time variation of the pressure increase reaction.

(Experimental results)

 The experimental results for the compound of the present invention are shown in Table 21. Table 21

調 剤 例

Preparation example

 When the compound (I) of the present invention is used, for example, as a therapeutic agent for hypertension, it can be used, for example, according to the following formulation. 1.1) Tablets

 (1) 3 (R) — (1 (S) — ethoxycarpineol 3-phenylpropyl) amino-4 1-year-old xo-2,3,4,5-tetrahydro—1,5-benzothiazepine I-5—Hydrosalt

 00 (2) Lactose 90 g

(3) Starch sorghum starch 29 Q

(4) Magnesium stearate 1 g

1000 tablets 130 g Ingredients (I), (2) and 17 g of (3) are mixed and granulated together with a paste made from 7 g of ingredient (3). And ingredients (4) And the mixture is compressed with a compression tablet machine to produce 1,000 tablets of 7 ira in diameter containing 10 mg of ingredient (1) per tablet.

 2> tablets

 As component (1), 3 (R)-1 [S (S) -cyclohexylaminopentyl] amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothi A tablet is produced using azepine-15-acetic acid (10 g) in the same manner as in Preparation Example 1- (1).

2. Capsules

 (1) 3 (R) 1 (1 (S) —ethoxycarbonyl 2—cyclo

 Hexylpropyl) amino-4 1 year old xo 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-phosphate 0 g

 (2) Lactose 1 35 Q

 (3) Cellulose fine powder 70 g

 (4) Magnesium stearate 5 g

 ^ κ) Revised Pharmacopoeia, 1000 capsules, 220 g.

 Combine all ingredients and fill in 1 000 gelatin capsules No. 3 to manufacture capsules containing 1 Omg of ingredient (1) per capsule.

3.1 1) Injection.

 (I) 3 (R)-(1 (S) —Holepoxy— 3-phenylphenyl

 Amino-4oxo-2,3,4,5-Tetrahydro-1,5-benzobenzoazepine-5-Mononatriacetic acid salt

 0 Q

 G) 9 g sodium chloride

 (3) Chlorobutanol 5 g

 Dissolve all components in 1,000 liters of distilled water, dispense into 1,000 brown ampules, replace with nitrogen gas, and seal. All steps are performed under aseptic conditions.

OMFI 2) Injection

 (1) 3 (R)-[5-amino-(S) carboxypentyl] amino-4-oxo-1, 2, 3 4, 5-tetrahydro 1, 5-benzothiazepine 5-succinic acid

 10 Q

(2) Dissolve the sodium chloride 9Q components (1) and (2) in 1000 parts of distilled water, add 1000 brown samples each, replace with nitrogen gas, and seal.

 All steps are performed under aseptic conditions. Industrial applicability

 The condensed 7-membered ring compound (I) provided by the present invention has excellent pharmacological action and is useful as a pharmaceutical.

Claims

Range of request 1. Formula COOR ³

(Wherein, R ¹ and R ² each represent hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or both of them represent tri or tetramethylene, and R ³ represents hydrogen or lower R ⁴ represents hydrogen or an optionally substituted alkyl, aralkyl or cycloalkylalkyl, X represents S (0) n (where n represents an integer of 0 to 2). Y represents a carboxyl group which may be esterified or amidated, and m represents 1 or 2.) A compound represented by the formula: or a salt thereof. 2. R ¹ and R ² are each hydrogen, halogen, trifluromethyl, lower alkyl or lower alkoxy or a combination of both, trimethylene; m is 1, n is 0 or 1; Item. 3. R ¹ and R ² are both hydrogen, R ³ is hydrogen or lower alkyl, R ⁴ is optionally substituted aralkyl or cycloalkylalkyl, Y is an optionally esterified propyloxyl group, m is 2. The compound according to claim 1, wherein 1, n is 1. 4. The compound according to claim 3, wherein R ⁴ is cycloalkylalkyl. ― 5. The compound according to claim 1, wherein R ^{4 is} aminoalkyl. O PI Vi ,, vi 6 Equation ()

 [In the formula, each symbol has the same meaning as in the first claim. ] And a compound represented by the formula R ³ 0-CCR ⁴  6 & (Wherein, and R ⁴ are the same as in claim 1) by subjecting the compound represented by the formula to a condensation reaction under reducing conditions, or  () Expression R ⁴ C H.COO R ³

(Wherein each symbol has the same meaning as in claim 1). The compound represented by the formula is subjected to a dehydration-closing reaction, or  Equation (c)

 [In the formula, Ζ represents a protecting group which can be eliminated by hydrolysis or catalytic reduction, and other symbols have the same meanings as in claim 1. ) By subjecting the compound represented by the formula to hydrolysis or catalytic reduction, or  Equation (d) R ⁴ N HCHCN

m one Y --78- (Wherein each symbol is as defined in claim 1), by subjecting the compound represented by  (e) Compound (I) has the formula R ⁴ -CHC 00 R ³  W Wherein R ³ and R ⁴ are as defined in claim 1, W is a halogen or a group represented by the formula R ^s S 02-10 (RS is lower alkyl, phenyl or p- Lil is shown. ] 10 by reacting the compound  (f) expression R ⁴ NHCHC00R ³

 (Wherein each symbol is as defined in claim 1 and in the surroundings.) Compound represented and formula- W-Cm H 2 m-Y 20 [wherein, W represents a halogen or a group represented by the formula R ^s 'SOz-0- (R ⁵ ' represents lower alkyl, phenyl or P-tolyl,); Terms and Zhou significance. ) By reacting the compound represented by (Q) A contract in which R ³ is hydrogen or R and Y are 25 In order to obtain the compound described in claim 1, the ester compound of the compound described in claim 1 wherein R ³ is lower alkyl or Z and Y are lower alkoxycarbonyl, By subjecting it to a refuge reaction, or (h) R ³ is hydrogen or Z and Y are lipoxyl 30 In order to obtain the compound described in claim 1, a benzyl ester compound of the compound described in claim 1 is catalytically reduced, wherein R ³ is benzyl, or Z and Y are benzyloxycarbonyl. By or (i) Claims wherein R ³ is lower alkyl, or Y is lower alkoxycarbonyl, wherein R ³ is hydrogen or Z and Y are lipoxyl to obtain the compound of claim 1. By subjecting the compound of paragraph 1 to an esterification reaction, or  (j) In order to obtain the compound according to claim 1, wherein Y is esterified or amidated propyloxyl, the compound according to claim 1 wherein Y is propyloxyl and a compound represented by the formula R ⁸ one H (In the formula, R ⁸ represents a lower alcohol residue, a phenyl lower alcohol residue, or an α-amino acid residue whose carboxyl group may be protected with lower alkyl or phenyl lower alkyl.) By condensation reaction or  (k)

(Wherein, R ^e 'represents a α- amino acid residue, for the other symbols to obtain a compound represented by the range囲第1 wherein the circumferential significance.] According the formula R ³

[In the formula, R ⁶ represents a 0-amino acid residue in which the carboxy group is protected by lower alkyl or phenyl lower alkyl, and the other symbols have the same meanings as in claim 1. By subjecting the compound represented by the above to a hydrolysis reaction, an elimination reaction or a catalytic reduction reaction, and  (i) A method for producing the compound according to claim 1 or a salt thereof by converting the obtained compound according to claim 1 into a salt, if desired.