WO1985004657A1 - 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, trifluoromethyl, lower alkyl or lower alkoxy or, when bound to each other, they represent tri- or tetra- methylene, R3 and R5 each represents hydrogen, lower alkyl or aralkyl, R4 represents hydrogen or lower alkyl, R6 represents a fused or non-fused hetero-alicyclic group containing at least one N, O or S as ring atom, A represents an alkylene chain, and n represents 1 or 2) and the salts thereof. These compounds are effective in inhibiting angiotensin converting enzyme, and are useful as agents for diagnosis, prophylaxis and treatment of circulatory organ diseases including hypertension, heart diseases, and apoplexy.

Description

 Akira Glue Condensed 7-membered ring 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 diligently searched for compounds that have angiotensin converting enzyme inhibitory activity and are useful as therapeutic agents for cardiovascular diseases such as hypertension, cardiovascular disease, and stroke. The ring compound was successfully produced, and the present invention was completed.

DISCLOSURE OF THE INVENTION ''

 The present invention uses the formula

[Wherein, R ¹ and R ² each represent hydrogen, halogen, trifluorophenol, lower quinole, or lower oxy, or both are linked to each other to represent tri or tetramethylene, and R ³ and R ⁵ each represent , hydrogen, a lower a Kinore or Aworukiru, R ⁴ is complex No Chijimigoma other non-condensed heteroalicyclic hydrogen or lower a Kinore ¾, R ⁶ is one small ¾ Kutomo of N, 0 or S as a ring-constituting atom And A represents an alkylene chain, and n represents 1 or 2.], a salt thereof, and a method for producing them.

Regarding the above formula (I), halogen represented by R ¹ or R ² is

O PI For example, fluorine, chlorine, bromine, iodine and the like can be mentioned. As the lower alkoxy group represented by R ¹ or R ² , for example, methoxy, ethoxy, broboxy, isopropoxy, butoxy ^, isobutoxy ^, sec-butoxy, tert -An anorecoxy group having about 1 to 4 carbon atoms, such as butoxy. R ¹ and R ² may be linked together to form an alkylene bridge, and examples thereof include trimethylene and tetramethylene, and other alkylene bridges.

R ¹ , R ² , R ³ , R ⁴ is a lower anoalkyl group represented by R ⁵ , for example, methinole, etinole, propi, isobrovinole, butyi, isobuti, sec-butinole, tert-butyl. There are about 4 groups.

Examples of the adenoalkyl group represented by R ³ or R ⁵ include, for example, pendi, phenetinole, 3.1-pheno-nopropyl, a-methinolepene, naechinolependi, namethiphenethyl, β-methinolephenethyl, Examples include phenyl-lower (C _1-4 ) alkyl groups having about 7 to 10 carbon atoms, such as 9-ethylphenylethyl group.

Examples of the fused or non-heteroalicyclic group containing at least one Ν, 0 or S as a ring-constituting atom represented by R ⁶ include a 4- or 8-membered saturated or partially saturated heterocyclic ring. In the case of a heterocyclic ring containing two or more heteroatoms, the same type of atom or two or more types of atoms may coexist as ring constituent atoms, for example, oxetanyl, thio :! : Tar, Azetidyl, Tetrahydrdrofur, Tetrahydroche-Nore, Pyrrolidi-Nore, Oxa-Nore (3,4,5,6-Tetrahidr 2 2—Bi-Α, Chea- ，, ジ, キ,,, /, —, 才,, ヒ, ヒ, ジ, ジ, ジ, ：, ：, ：, ：, ：, ： Raji Nore, Hori, No チ ア 二 /, · ド ロ ジ ロ ジ ロ ジ？？ チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア チ ア—Hydrothiazebi U, キ サ ォ ノ ， ， ノ, ノ? —Hydodiazo = 1 = 1, Jichi Talent-Nore, Zoxo Force-Nore, Chromal, Isochroma2,3,4 Zihi Draw 2H—1 Tianafuti, 3,4 Zihi Draw 1H—2—Thianafuti, 1 1,2,3,4-tetrahydroquinolinole, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydrodropenzofurinole, 1,3 dihydroquinobenzofurino, 2,3-dihydropenzo [b] cheninole, 1 , 3 dihydrobenzo [c] cho =, indore nore, isoindo-nore, 2, 3, 4, 4-5-tetrahydrodraw 1 (1H)-^^ nzoazepi-nore, 2,, 3, 4, 5-Teto draw 3 (1 H)-Penzozepi-, 2, 3, 4, 5-Te. Trahi draw 2 (1 H) Penzoze bunore, 2, 3, 4, 5—Tetrahydro Draw 1—Penzoxepie, 1, 3, 4, 5—Tetrahi Draw 2—Penzox Bi =, 1,2,4,5-tetrahydro-1-31-benzodiene, 2,3,4,5-tetrahidro 1-benzochepi-nore, 1,3,4,5-tetrahidro2-penzochebu, 1, 2, 4, 5 テ Draw 3-Penzodipinole, 2, 3 ヒ ヒ 1 一 4 1 4 1 ゾ ゾ 一 ニ ニ ニ 2 2 2 2 2 2 2 2 2 2 2 2 Tetrahydroquinoxalininole, 3,4-dihydro 2H—: I, 4-Penzoxazir, 3,4-dihydro 2H—1,4,1-Penzothiazyl, 2,3-dihydryl 1,4,1-pen Zoxaxinyl, 3,4-dihydro 2H-1, 5 -Penzodioxepal, 2,3 -dihydro-5H-1, 4Penzodi oxepir, 2,3,4,5 -Tetrahydro 1 1 H—1,5—Penzodiazebi-nore, 2, 3, 4 »5—Tetrahydro

ΟΜΡΙ H-1, 4 -Penzodiazepi =, 3,4 -dihydro-2 Η-1,5 -Penzodichebi, 2,3 -Jihi draw 5 Β-1, 4 -Penzodiazepir, / 1 h Examples include monocyclic or bicyclic heteroalicyclic groups such as droisoindolinyl, phenolic phenol, perhydryl quinolyl, chlorohydrin-l-tianaphthyl w, and propylhd 2-tianaphthynol.

 The fused or non-fused heteroalicyclic group can be substituted at the ¾ position, for example, oxo,

C, ₁₅ akanoi (eg, acetyl, bropio; 1 /), penzoi; >>, low-grade (0χ_) a; U-coxi-box (eg, penoxy-force-), low (C; L- ₄ ) Anolecoxica bonore (eg, tert-butoxyca bonore) ¾ 1 / group, phenyl, naphthyl, etc., penzinole, phenetinole, a-methine fenetinole, β-methine fenethyl It may have a lower () acyl group as a substituent. The phenyl group of the arylene group or the phenyl-lower alkyl group as the substituent is further substituted with a lower (CJL14) such as fluorine * chlorine, bromine or halogen, methoxy, ethoxy-, propoxy or butoxy. It may be substituted by lower (0! _4) aki such as koxy, methyl, ethyl, brovir, and butyl. Examples of such substituted fused or non-fused heteroalicyclic groups include, for example, 11-phenolepiberidi-, 11-pendi-piveridi =, 4-phenyl-p-repi-beridi-, 4-penzino-repi-beridi-, 1-acetyl Bridge =>, 1-Penzoinorepiperigi = ■ Nore, 4-Hue-Bi-Ji-, 4-Achici-Biperazil, 4-I-Penzoi-Pi-, 1-Kisoisoindo ¾ ^, 1,3-Dioxoisoindori, 1,2,3,4-tetrahydro-11oxoisoquinoli, 1,2,3,41-tetrahydro-3-oxoisoquinoli, and which groups are available.

OMPI Examples of the anoalkylene chain represented by A include straight-chain or branched .about.16 alkylene chains, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, and heptamethylene. Octamethylene, nonamethylene, decamethylene, pendecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, pentadecamethylene, hexadecamethylene, provylene, ethenolemethylene, 4-propynolehexamethylene, 3,5-dimethylene, 3,5-dimethylene Examples include divalent groups such as monoethylenoxyhexamethylene and 3,5-dimethylnonamethylene. The alkylene chain may have an unsaturated bond (eg, double bond, triple bond) in the chain.

CwH ₂ is shown. The divalent group depends on the value of n] ?, methylene, dimethylene, : Forms tiliden.

 Specific disclosure of the compound of the present invention includes, for example, compounds shown in Table A.

Table A

CnHgn R ¹ , ^ R3 R4 R5 -A-

C¾ H H H H

CH ₂ H Ξ H ¾) 2 ~

CH ₂ HHHH

OMPI / Aιοο Dimension 8ΐ1: S

Although the compound (I) of the present invention has an asymmetric carbon in the molecule, deviations in the RS configuration and the S configuration are also included in the present invention. However, it is preferable that the compound (* 1) has the absolute configuration of the carbon atom R and the symbol (* 2) has the absolute configuration of the carbon atom S.

Examples of the salt of compound (I) include hydrochloride, specialized hydrochloride, sulfuric acid, nitrate, and acid salt, and inorganic acid boundaries such as acetate, tartrate, citrate, fumarate, and maleic acid.有機 Organic salts such as tonsulfonate and methanesulfone sulphate, such as sodium, potassium and calcium. Metal salts such as shim salt and aluminum salt, for example, triethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchone salt. The compound (I) of the present invention is, for example, a compound of the formula

[Wherein each symbol is as defined above] by subjecting the compound represented by the dehydration ring-closing reaction] to the above. The dehydration ring closure reaction can be carried out, for example, by an ordinary amide bond formation reaction with a peptide. That is, a dibutylide forming reagent such as dicyclohexynoleca bozimid, N, ^ —force is used alone, or a dibutyric acid forming reagent such as diimidazo, azide diphenylate, or jeti cyanophosphate is used alone, or is usually used. Of the compound () by adding an inorganic acid (eg, hydrogen chloride, sulfuric acid, nitric acid, hydrogen bromide) to the amino group of the compound (), and then, for example, 2,4,5-trichloro mouth phenol, pentaque mouth phenol 》, Pentaph Lofno /, 2— = Trophenol or 41-Trofenol ¾ Which phenols or N-Droxysk ^ imide, 1-Hydroxypentz riazor, N-Hydroxyl pyridine It can be carried out by condensing an N-hydroxy compound into an active compound, converting the compound to an active ester, and then cyclizing the compound. In any case where the cyclization reaction converts the compound (Ε) as it is or the activated ester of the compound (¾), it is preferably an organic base such as a quaternary ammonium salt or a tertiary amine. (Eg, Tricheam,

) Can be added by adding The reaction temperature is usually from 120 to + 50 ° C., preferably around room temperature. Examples of commonly used solvents include, for example, dioxane, tetrahydrofuran, acetate-tri, and viridin.

, », N-Dimethyformamide, N, N-Dimethylacetamide, Dimethinolesulfoxide, N-methylidone, Chloride, Chloride, Methylene, etc. May be used. Further, the compound (I) of the present invention is represented by, for example, the formula

 Wherein each symbol is as defined above.

R ⁶ -A- CH-C00R ³

 '(W)

Wherein the halogen or the formula R ^a S0 ₂ - 0- (wherein R ^a is lower alk key, Hue - or p- tri showing a) represents a group represented by the other symbols are as defined above Can be also produced by reacting a compound represented by the formula The reaction is usually carried out in a single or mixed solvent of water or another organic solvent (eg, aceto-trinole, dimethyl / U-pho; muramide, dimethyl sulfoxide, tetrahydrofuran, benzene, tonolene). It is possible to proceed by maintaining the temperature in a temperature range of about 50 degrees. In this case, bases such as lithium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine and triethylamine can be coexistent in the reaction system for the purpose of promoting the reaction rate. Further, the compound (I) of the present invention is represented by, for example, the formula

OMPI

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

W ^¾ -C00R ⁵ (VI)

 o c =

Wherein the - (wherein, ^R-to the lower alk kill, Hue - shows the Honoré or p A- Application Benefits) halogen, or wherein R ^to S0 ₂ -0- represents a group represented by the other

 R

 Symbols are as defined above. "6

 Can be also produced by reacting a compound represented by the formula The reaction is carried out in a single or mixed solvent of water and other organic solvents (eg, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran * benzene, toluene) in a temperature range of about 120 to + 150 ° C. You can make it progress by keeping it. At this time, a base such as, for example, lithium carbonate, sodium hydroxide, or sodium hydride can coexist in the reaction system.

In the formula (I), R ⁴ is hydrogen.

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

[Wherein the symbols are as defined above], by subjecting the compound represented by the above formula to a condensation reaction under reducing conditions.

 The reducing conditions include, for example, catalytic reduction using a metal such as platinum, palladium, rhodium or the like and a mixture thereof with an optional carrier, for example, water.

OMPI Reduction by metal hydride such as lithium aluminum lithium, τΚ lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, by sodium metal, metal magnesium and aryls Reaction conditions such as reduction, reduction with an acid such as hydrochloric acid and acetic acid with metals such as iron and zinc, electrolytic reduction, and reduction with a reductase can be given. The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl; 1 eth, dioxane, methylene chloride, ghom !, benzene, toene, severe acid, dimethylformamide, dimethylacetamide) The reaction temperature varies depending on the means of reduction, but is generally preferably about 120 to +100. This reaction can sufficiently achieve its purpose at normal pressure, but the reaction may be carried out under increased or reduced pressure depending on circumstances.

In the formula (I), a compound in which R ⁴ is hydrogen is, for example, a compound represented by the formula

N-CH- C00R ³

CnH ₂ n-C00R ⁵

[In the formula, Z represents a protecting group which can be removed by hydrolysis or catalytic reduction, and other symbols are as defined above. Can be produced by subjecting the compound represented by the formula [1] to hydrolysis or catalytic reduction. As the protecting group which can be eliminated by hydrolysis represented by Z in (IX), all kinds of acyl groups and triti groups can be used. This is advantageous when the reaction is carried out under relatively mild reaction conditions in which w-tert-butoxycarbo, trifluoroacetyl, and tritidine are relatively mild. Examples of protecting groups which can be eliminated by catalytic reduction represented by Z include, for example, pendyl, Diphenylmethyl and penziloxycarbo. The hydrolysis reaction in the present method is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, severe acid, acetate, methylene dioxide, or a mixed solvent thereof. Acids (eg, hydrogen iodide, hydrogen bromide, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid

, p-toluenesulfonic acid, trifluoroacetic acid) or base (eg, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium acetate, triethylamine) it ₀ above reaction can also is typically carried out in one 2 0 + 1 5 0 range of about. In addition, the catalytic reduction reaction in the present method is carried out in the presence of water, an organic solvent such as methanol, ethanol, dioxane, tetrahydrofuran or a mixed solvent thereof in the presence of an appropriate catalyst such as platinum, .radium ^ "carbon. This reaction is carried out at normal temperature or a pressure of up to about 150 kq / c * ^ at room temperature to + 150 ° C.

In the formula (I), a compound in which R ⁴ is hydrogen is, for example, a compound represented by the formula

(X)

CnH ₂ n C00R ⁵

[Wherein the symbols are as defined above. Can be also produced by solvolysis of a cyano group in the compound represented by the formula Two

The solvolysis reaction is carried out in water or an organic solvent such as methanol, ethanol, dioxane, viridin, diacid, acetate, methylene chloride, or a mixed solvent thereof. acid( Hydrogen hydride, hydrogen bromide, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, triflic acid, acidic resin) or base

(Eg, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium titanate, triethylamine) can be added. The reaction is usually performed in a range of about 120 to +150.

In the compound (I) of the present invention, when the atom in the group R ⁶ bonded to the group A is a nitrogen atom, for example, a compound represented by the formula 0R ³ _r

 )

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

[In the formula, X represents a ring-constituting atomic group, and can also be produced by subjecting a compound represented by the formula 1 (representing a group R ⁶ as ^ ² ) to a condensation reaction under reducing conditions. .

 The reducing conditions include, for example, catalytic reduction using a catalyst such as a metal such as platinum, palladium, and rhodium or a mixture thereof with an optional carrier, such as lithium aluminum hydride, lithium borohydride, cyano hydride. Reduction with metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, reduction with sodium and metal magnesium and alcohols, and metal with iron and zinc and acids such as hydrochloric acid and acetic acid Reduction, electrolytic reduction, reduction by reductase. Various reaction conditions can be used. The above reaction is usually carried out with water or an organic solvent (eg, methanol,

(OMPI, The reaction is carried out in the presence of ethanol, ノ ー, ethi / pate; U, dimethyxane, methylene chloride, black form, benzene, thiocyanate, dimethy U, formamide, dimethylacetamide). Although the temperature varies depending on the reducing means, it is preferably about 120 to +100 to eliminate the temperature. This reaction can sufficiently achieve its purpose at normal pressure, but the reaction may be carried out under increased or reduced pressure depending on circumstances.

In the present compound (I), when the atom in the group ⁶ bonded to the group is a nitrogen atom, for example, the compound () is

W ⁰

 0

Wherein, ff ^c is halogen or wherein R ^c S0 ₂ - 0- (wherein, R ^c is a lower § Noreki, Hue - or p- DOO showing the re) indicates a group represented by, Y is ring members It indicates Dan formula - can be Yotsute produced that reacting a compound represented by a group R ^6] as I.

 The reaction proceeds by keeping both in a suitable solvent or a mixed solvent in a temperature range of about 120 to + 150 ° C. At this time, a base such as, for example, potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine, trimethylamine or the like can be coexisted in the reaction system for the purpose of accelerating the reaction rate.

In the formula (I), a compound in which R ³ is hydrogen or no and R ⁵ is hydrogen can be obtained by hydrolyzing or removing a compound in which R ³ is lower alkyl or Ζ and H ⁵ are lower alkyl. The compound can also be produced by subjecting a compound of the formula (I) in which R ³ is a penge or a compound in which Ζ and R ⁵ are a penge to a catalytic reduction reaction. it can. In this method, the hydrolysis or elimination reaction is water or water. For example, the reaction is carried out in an organic solvent such as methanol, ethanol, ethyl acetate, chloroform 'tetrahydrofuran, dioxane, pyridine, enzymatic acid, acetone, methylene chloride, or a mixture thereof, and the acid (eg, chloride water) Hydrogen, hydrogen bromide, hydrogen fluoride, hydrogen iodide / sulfuric acid, methanesulfonic acid, potassium disulfonic acid, trifluorene or base (eg, sodium hydroxide, potassium hydroxide, liquefied carbonate) , Sodium bicarbonate, sodium carbonate, sodium ferrate) The above reaction is usually performed in the range of about 12 to +150. The catalytic reduction reaction in water or, for example, methanol, ethazole, ethyl diethyl, dioxane, tetrahydrofuran or any organic solvent or a mixed solvent thereof, for example, Beam is carried out 'in the presence of a suitable ¾ catalyst such as one-carbon .. This reaction is carried out at atmospheric pressure or 1 5 0 ^ / «and pressure under normal temperature ¾ to about ² + 1 5 0 Wa temperature.

In the formula (I), a compound in which R ³ is lower anoalkyl or aralkyl or Z and R ⁵ are lower aki or aralkyl is a compound represented by-in the formula (I), R ³ is hydrogen or no and R ⁵ is A compound that is hydrogen is represented by the formula

 R °-OH c)

 Or expression

R ⁵ one QH (XV)

[Wherein R ³ and R ³ represent lower aki or aralkyl]]. The condensation reaction conditions include, for example, reaction conditions using a condensation reagent (eg, dissiglohexoxycarbodiimide, cabonoresimidazo, cyanophosphate jet U, dip-V acidazide), or acid catalyst ( Example: Reaction conditions using hydrogen chloride, hydrogen oxide, p-tonolence; I can do it. The reaction proceeds in a suitable soot or mixed solvent or in the absence of a solvent in a temperature range of about 12 to + 150 ° C.

Wherein (I),. Compounds wherein R ³ is lower § key or § wo kill is Z and R ⁵ is lower alkyl or § wo key during formula (I), R ³ is and hydrogen or Z Compounds wherein R ⁵ is hydrogen are of the formula

 Or expression

R ⁵ *-W ^d (XVI)

[Wherein, R ³ ″ and R ⁵ ″ represent a lower alkyl or an alkyl, W ^d is a halogen or a formula Rd _S o ₂ —0— (where R ^d is a lower alkyl, phenyl or P— Which represents a group represented by tolyl)]. Reaction In the presence of a group (eg, sodium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydrogencarbonate) in a solvent at a temperature in the range of about 120 to + 150 ° C Proceed to

And are in the present invention Compound (I), in the case of an unsubstituted Imino groups in the radical R ^6, catalytic reduction of a compound having a Penjiruimino group or § sheet imino group in the radical R ⁶ in formula (I) It can be produced by elimination reaction or solvolysis reaction.

 In the present method, the reaction reaction is carried out in the presence of water or an organic solvent such as methanol, acetate /, ethanol, dioxane, tetrahydrofuran or a mixed solvent thereof, for example, an appropriate sensitizing agent such as palladium-carbon. Done below. This reaction is carried out under normal pressure or a pressure up to about 150 ° C., at a temperature from normal temperature to + 150 ° C.

In this method, the decomposition or elimination reaction is carried out with water or, for example, The reaction is carried out in any organic solvent or a mixed solvent thereof, such as tanoh, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane pyridine, acetic acid, acetate, methylene chloride, and the like. Hydrogen bromide, hydrogen fluoride, hydrogen iodide, sulfuric acid, methane sulfonic acid, P-toens sulfonic acid, trifnoroleic acid or a base (eg, sodium hydroxide * potassium hydroxide, potassium carbonate, carbonate) It is also possible to add sodium hydrogen, sodium charcoal, and sodium nitrate. The above reaction is usually carried out in a range of about 120 to +150.

Formula (I) in the group R in the ⁶ to lower (one Ci ₄₎ A key, Aworukiru compound Weng also properly will have Imino group substituted with § Shi is unsubstituted Imino the formula (I) middle group R ⁶ Compound having group and formula

R ⁷ one w ^e (xa)

[In the formula, R ⁷ represents lower aki, aryl or acyl, W ^e is halogen or the formula R ^e S0 ₂ — 0— (where, R ^e is lower alkyl, fu-pia and S if, T,

Alternatively, it can be obtained by reacting a compound represented by y representing p-tolyl. The reaction proceeds in a suitable solvent by keeping both in a temperature range of about 120 to +150. At this time, for the purpose of accelerating the reaction rate, an O 氇 group such as lithium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine or triethylamine may be coexisted in the reaction system as a deoxidizing agent.

The compound having the formula lower into the base R ⁶ in (I) (one ₄₎ Imino group substituted with alkyl or § wo key is a compound having an unsubstituted imino group based R ⁶ in the formula (I) the lower (one ₄₎ rather a key aldehyde Domoshi can also be obtained cowpea to the condensation of § La Kirua dehydropeptidase reductive conditions. Such conditions include, for example, platinum, palladium, and rhodium; contact metals catalyzed by any metal or a mixture of any of these and any carrier; for example, lithium aluminum hydride, lithium borohydride, cyano hydride; Lithium borohydride, sodium borohydride, sodium cyanoborohydride Reduction with any metal hydride, reduction with metal sodium, magnesium, etc. and alcohols, iron, zinc Any metal and sulfuric acid, severe acid Reaction conditions such as reduction with an acid, electrolytic reduction, and reduction with a reductase can be given. The above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol 1, dithioate; xanthane, methylene chloride, black honolem, penzenthene, diacid, dimethic water; ^ mamide, dimethylacetamide ), And the reaction temperature varies depending on the likelihood. ~ +100 is preferred. This reaction can be carried out under normal conditions, but the reaction may be carried out under increased or reduced pressure, if necessary.

'In the case of compounds with § shea imino group in the radical R ⁶ of formula (I), compounds having an unsubstituted Imino groups in the radical R ⁶ of the formula (I) and Formula

(R ⁷ ') ₂ 0 (XK)

 [Wherein, 'represents an acyl].

 The reaction proceeds in water or a suitable organic solvent, or a mixed solvent thereof, by keeping the both in a temperature range of about 120 to +150. At this time, for the purpose of accelerating the reaction rate, a base such as lithium carbonate, sodium hydroxide, sodium hydrogencarbonate, viridin, triethylamine or the like is added to the reaction system as a deoxidizing agent. Can also.

In the formula (I), the compound wherein R ⁴ is lower alkyl is a group represented by the formula (I)

OMPI Can also be produced by subjecting a compound in which is is hydrogenation to an oxidation reaction.

The above-mentioned acetylation reaction includes, for example, a reduction alkylation reaction in which a lower alkyl (o1 _→ ) aldehyde is reacted under a reducing condition [as a reducing condition, for example, metals such as platinum, palladium, rhodium and the like, Catalytic reduction using a mixture with a support as a catalyst, for example, lithium hydride aluminum, lithium borohydride »lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, etc. Arrest source, reduction with metal sodium, metal magnesium, etc. and alcohols, reduction of iron, zinc, reduction of metals and sulfuric acid, severe acid, reduction of electrolysis, reduction with reductase, etc. . The reaction is usually in the presence of water or an organic solvent (eg, methanol, ethanol, dimethyl ether, methylene chloride, chlorophonolem, benzene, benzene, severe acid, dimethyl), homamide, dimethyl acetate. The reaction temperature varies depending on the reducing means, but is generally preferably about 120 to + 1%. This reaction can sufficiently achieve its purpose at normal pressure, but may be carried out under increased or reduced pressure depending on circumstances. ] Or expression

R ⁴ one W ^f (XX)

Wherein, Wf is / androgenic or formula R ^f S0 ₂ - 0- (wherein, R ^f is a lower A key shows phenylene or p- tolyl) represents a group represented by, R ⁴ is the same as the Alkylation reaction (reaction conditions include a suitable solvent and a mixed solvent in a mixed solvent) to keep both in a temperature range of about 120-150. During the reaction, for example, sodium carbonate, sodium hydroxide, hydrogen carbonate

O PI Sodium, viridin, _beta can also make coexistence of a base such as preparative Riechi 〃 Amin in the reaction system) ¾ etc. can be mentioned.

 The salt of compound (I) can be obtained by the reaction itself for producing compound (I), but if necessary, an acid, alkali or base can be added to produce a salt of compound (I).

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

Compound (I) may have at least four stereoisomers. The deviations of these individual isomers and mixtures thereof are, of course, included in the scope of the present invention), and if desired, these isomers can be produced individually. For example, when the above reaction is performed using each single isomer of the starting compounds (H), (] ff), (V), (W), (K), (X) and (M), ]), A single optical isomer of compound (I) can be obtained, and when the product is a mixture of two or more isomers, this is separated by a conventional separation method such as optically active 黢 ( For example, a method of forming a salt with camphors fonic acid, tartaric acid, dipentyl tartaric acid, etc., or an optically active base (eg, cinchon-, cinchon-gin, quinine, quinidine, β-methipendinoleamine, dehydroabietamine). When separated into respective isomers by separation means such as chromatography and fractional recrystallization of each S, the condensed 7-membered ring compound represented by formula (I), which is the compound of the present invention, and its salt are And]) mean mammals (eg, birds, cats, cats. Usagi, motor Mocking DOO, Angi O tensin converting enzyme inhibition in the rat), Buwoji Inhibition of kininase (kininase) is indicated, such as hypertension

It is useful as a diagnostic, preventive, or therapeutic agent for heart disease and cerebral circulatory diseases caused by high blood pressure. The compound of the present invention is low-toxic, has good absorption even when orally administered, has excellent kneading properties, and is also excellent in stability. And pharmaceuticals such as powders, granules, tablets, capsules, injections and the like, and can be safely orally or parenterally administered. The dose varies depending on the condition of the target disease and the administration rate.

0.02, these dosages about 1 per day depending on symptoms

New

 The starting compounds (H), (M), (V),. (W), (K), (X) and (XI) of Takaaki Moto can be easily produced by the method shown in the following reaction formula, for example. Can be.

R ⁶ -ACC-0R3 A — R ^S

¾ ¾ 01) R ^: S _S? SCH2CHNH-CH--C00R ³

w _n COOH

R ^{2 N} ° ² ()

O PI R ⁴ A-R ⁶

R'- ^ SCHgCH-N- CH-C00R ³ 1) Reduction

κ ₂ ¾ ο ₂ ^έοΟΗ (XXV) 2) W ^¾ -CnH ₂ n-C00R ⁵ (VI)

Three

O PI

; ^! ΙΈΌ-^ τΐθ ^

O PI ^Λ In the above reaction formula, R ⁸ is halogen or Jiazo - a © beam group, WS halo gen or Formula RgS0 ₂ - represented by 0 (indicating the tri wherein, RS is lower alkyl, Hue - - or p) Represents a group, and other symbols are as defined above.

 The method for producing the compound (H) represented by the above reaction formula will be described in more detail. Stin (XXI) is used as a starting compound to induce cysteine and react with the compound (XXIE) to produce the compound (XI). . Compound

The reaction between (xxm) and (M) can be carried out in the same manner as the reaction between compounds () and (w). The reaction of (ΧΧΠ ■ → (XXV) is a conventional acetylation reaction] ?, for example, by reacting a lower alkyl aldehyde corresponding to group R ⁴ under reducing conditions. The compound (2) can be obtained by subjecting the compound to a usual reduction reaction of an amino group to an amino group followed by an alkylidation reaction.

 In the process for producing the compounds () and (VI), the amino group of the compound (XXVI) is protected with a suitable protecting group for an amino group (eg, a phthalinole group) to obtain a compound (XX). In this reaction, compound (XXVI) is reacted with compound (XXVI) in the presence of a compound (XXVI) and a group (eg, sodium carbonate, carbon dioxide, potassium hydrogen carbonate) at a temperature of about 0 to + 100 ° C. Proceeds easily.

 The reaction of (XMI)-(XXK) is a reduction reaction of the amino group to an amino group), and an ordinary known reduction method can be used. The reduction methods include, for example, catalytic reduction using palladium-carbon, palladium sulfate as a carrier, palladium sulfate, platinum palladium as a catalyst, or zinc, tin, stannous chloride, iron and the like. For example, a reduction reaction with a metal and an acid or an alkali metal is used. The dehydration ring closure reaction of the compound (XXK) thus obtained to the compound (XXX) is usually carried out advantageously in the presence of a known dehydration condensing agent.

O PI Can be. Such dehydrating condensing agents include, for example, dicarboxy carbodimid, carbodimidazo'-1 and cyanophosphate jet. As the solvent, for example, dioxane, methylene chlorinated, acetate, If, N-dimethyl / W "formamide, tetrahydrophenyl, etc. are used, and the temperature range is usually about 110 to + 100 ° C. At this time, for the purpose of promoting the reaction advantageously, a base such as triethiamin / viridine can be added as a catalyst to the reaction mixture Condensation reaction between compound (XXX) and (YE) The production of compound (ΧΧΧΕ) by is usually carried out in the presence of a sodium group such as sodium hydride or potassium carbonate, Ν, ジ -dimethylformamide, dimethyl; In this case, it can be produced by condensing at a temperature range of about 11 o to + i 00. In the following, the reaction of (xxxf) is carried out with hydrazine hydrate in a solvent such as methanol, ethanol, or dioxane. 1 0. Processed in a temperature range of +100 It is possible to produce a compound).

The reaction (w) → () is a normal acetylation reaction, for example, a method in which a lower aldehyde corresponding to the group R ⁴ is reacted under reducing conditions, or the compound (XX) is dissolved in an appropriate solvent. The reaction method can be used.

The compound (V) can be produced by subjecting the compound (XXV) to a usual reduction reaction of a 2-amino group to an amino group, followed by a dehydration ring closure reaction. In the method for producing compound (κ), compound (XXXII> can be produced by subjecting compound (W) to a known amino acid protection reaction of amino acid. (The reaction of XXXH> is carried out in a suitable solvent. The reaction proceeds by keeping the compounds (XXM) and (W) in a temperature range of about 120 + 150 ° C. At this time, the purpose of promoting the reaction rate is, for example, sodium carbonate, sodium hydroxide, Sodium bicarbonate, bilyzine, trietile U ' Amine Any base can coexist in the reaction system.

 In the production method of compound (X), compound (X) can be obtained according to a known Strecker reaction using compounds (I) and (XXXIV) and hydrogen cyanide as starting compounds.

 In the production method of compound (XI), compound (XXXVI) can be obtained by reacting compound W) with (XXXV). Solvents such as acetonitrile, methine;! / Ethylketone, acetone, tetrahydrofuran, shiridani methylene, dimethylsoxide, dimethylethoxide, and dimethy / V formamide are usually used. The reaction takes place in the temperature range 0 ° S¾. At this time, bases such as tritamine, pyridine, potassium carbonate, sodium carbonate and the like, and iodide lime may be added in order to promote the reaction advantageously. The reaction of (XXXVE) → (XXS1) can be carried out in the same manner as the reaction of (ΧΧΠΓ) → (XXV), and the reaction of (XXX I) XI)

The reaction can be carried out in the same manner as in the reaction of (XXXI)-* (VI).

 In the above methods for producing compound (I) and its intermediates, the compounds used in the reaction may not interfere with the reaction], for example, hydrochloride, hydrobromide, sulfate, nitrate, nitric acid, etc. Inorganic acids such as acids, for example, organic acids such as acid, tartrate, citrate, fumarate, maleate, tonesulfonate, methanesulfonic acid, for example, sodium salt; Metals such as potassium salt, calcium salt, aluminum salt, etc., for example, trietinoreamin ア ン, guadin salt, amphibian plant, hydrazine 氇, keyone salt, / conn¾塩 Salt with group よ It may be used in any salt form.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1

S— (0—-Mouth Hue

Dissolve in 1.4 solution (200 ») and add 力 -ethoxycarbbutyrimide a 5». After stirring at room temperature for 5 hours, remove the insoluble matter by passing, and make it weakly acidic with concentrated acid. The precipitated crystals are collected and recrystallized from ethanol 3 to give 3- (o-ditrophen-thio2 (R) -phthalimidobubionic acid 3.6 as pale yellow needle crystals, melting point 2 2 0—2 2 2

Elemental analysis value Ci ₇ Hi ₂ lT206S

 Calculated values: C 54.84; H 3.25; N 7.53

 Measured directly: C 54.46; H 3.26; N 7.46

0] ^4-7 9 ° (in σ = 0. 9 * Metanonore)

Example 2

 3— (ο-. =. Touguchi fu-nore) thio 2 (R) -phthalanoimidrobionic acid 10 is catalytically reduced in methanol 30 at room temperature and normal pressure using 5% palladium carbon as a catalyst. After absorbing the calculated amount of hydrogen, the catalyst is removed and methanol is decompressed and distilled off. After ether and petroleum ether were added to the residue and left to stand, the precipitated pale yellow powdery crystals were collected to give 3-Co-aminophenol) thio2_ (R) -phthalimidobrobionic acid 8.4. This product & 4? Is dissolved in Dimethoformamide 5 and stirred under ice-cooling: Add 5.5 drops of cyanophosphate dichloride. Stir for 5 minutes after dropping, and then drop Triestamine 2.28 under ice-cooling. Stir for 30 minutes under ice-cooling, then stir for 1 hour at room temperature. 200 W of water was added to the reaction solution, and the mixture was allowed to stand overnight, and the precipitated solid was collected and dried. Purification of this product by silica gel column chromatography (dichloromethane: acid anhydride i-2: l>) yields 3 (R) -phthalimid 2,3—dihydro 1,5 (5 5) -pentoziazebin 1 4 1 ON 5

ΟΜΡΙ It is. Melting point 202-205

Elemental analysis value As Ci ₇ Hi ₂ li203S

 Calculated values: C 62.95; H 3.73; N 8.64

 Obtained values: C 63.15; H 4 02; N 8 49

0.9, in methanol)

 Example 3

 To a mixture of dimethiformamide 5 and sodium hydrogenated (0.5% oil 60%), the mixture is stirred under permanent cooling. Under ice cooling, the 3 (R) -phthalimide 2,3— obtained in Example 2 is obtained. Add Jihi Draw 1 »5 (5H) -Penzothiazebine 4-one-one 4 and stir for 5 minutes, and then add ice-cooled ter-butyl-ester 2-, and stir under ice-cooled for 15 minutes. Thereafter, ice water (20 o *) is added to the reaction mixture, and the precipitated crystals are collected by filtration. After drying, the crystals are purified by silica gel chromatography (hexane: ethyl acetate; 3: 1), and then purified. Oxo-3 (R) -phthalimide-2 * 3,4,5-tetrahydro-1,5-pentoziazevin-15-tert-butylester 4 enzymatic acid is obtained as colorless crystals, part of which is recovered from thioate. When crystallized, it forms a colorless bristol crystal, melting point 18 1— 1 8 4

As Elemental analysis _{C 23 H 2 2N 2 0 5} S

 Calculated values: C 63.01; H 5.06; N 6.39

 Found: C 62.95; H 5.10 N 6.34

[Β] ⁰ — 1 56. (C = (X 9, black mouth home)

Example 4

The 4-oxo-13 (R) -phthalimido-2,3,4,5-tetrahydro-1,5-pentazothiazebine-5-drunkic acid tert-butyl ester 49 obtained in Example 3 and the hydrazine hydrate L 4 were converted to ethanol. Add to 1 0. The mixture is heated to reflux for 1 hour with stirring. The reaction mixture is lysed under reduced pressure, and the residue is mixed with potassium acetate (30) and water (10), and shaken well. The ethyl acetate layer is washed successively with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting oil was crystallized from a mixture of ether and petroleum ether to give 3 (R) -amino- ⁴ -oxo-1,2,3,4,5-tetrahydro-1,5, -pentoziazebine-15-sulfonic acid tert- 'Buchi estenole 2 is obtained as a colorless bryth crystal.

Melting point 8 6-8 9

Elemental analysis value Ci ₅ H2 ₀ N20 ₃ S

 Calculated value: C 58.42; Η6.54; Ν9.08

 Measured value: C 58. 73; Η 6.48 ϊ Ν 9.13

[A] ² _D ⁰ — 23 38 ° Metazo Medium)

Example 5-9

 When a reaction similar to the case of synthesizing an unsubstituted product (R = H) is performed using an o-trojan-phosphorus derivative having a substituent as a raw material, the compounds shown in Table 1 are obtained.

table 1·

OMPI_ Examples 10-13

 Table 2 shows the results obtained by reacting the 7 tS- (2-trophenyl) -L-stain derivative obtained in Examples 5-8 with N-ethoxycarbophthalimide in the same manner as in Example 1. A compound is obtained.

 Table 2.

Example 14-1 17

 When the phthalimide derivatives obtained in Examples 10 to 13 were reacted in the same manner as in Example 2, the compounds shown in Table 3 were obtained.

 Table a

 ΟΪ, ίΡΙ

Ί ' Example 1 8-21

 When the phthalimidopenzothiazevin derivative obtained in Examples 14 to 17 was reacted in the same manner as in Example 3, the compounds shown in Table 4 were obtained.

 Table 4

Example 2 2-25

 Example 18 When the phthalimidobenzothiazepine acetic acid tert "ester derivative obtained in Example 8-21 is reacted in the same manner as in Example 4, the compounds shown in Table 5 are obtained.

 Table 5

 ΟΜΡΙ

' Example 26

 TtS— (2-trough 4-trifluoromethane 7e) obtained in Example 9 1-L-cysteine 5.3 was added to 2.5 Ν sodium hydroxide water 67, stirred at room temperature for 30 minutes, and then iced. Penzoxykale chloride under cooling

 7 wl and 1 N aqueous sodium hydroxide solution 19 are simultaneously added dropwise for 30 minutes. After stirring at room temperature for 2.5 hours, the reaction solution is extracted with diethyl ether, and the aqueous solution is made weak with 1 N hydrochloric acid. After extraction with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, distilled off under reduced pressure, and ethyl acetate was added to the obtained residue to obtain S— (2-—Tro 4-tetrafluoromethyi). Le) One N-Penzi / Woxyka B-One L-Cistine 5.5 9 Force i Precipitates as pale yellow crystals. Melting point 1 5 0— 1 5 3

 [A] D + -20. (In methanol)

As Elemental analysis _{C 18 H 15 F 3 Ii 2} 0 6 S

 Calculated value: C 48.65; H3 · 40; N 6.30

 Found: C 48.68; H 3.41 Ν Ν 6, 27

Example 27

 7tS— (2-tro-4 4-trif-mouth methinolephenyl) -1 N-penti woxyca-bo-lu L-cysteine obtained in Example 26 4.3 9 and sub powder 4? Is added to a mixture of severe acid 5 and water 50, and the mixture is stirred at room temperature for 50 minutes. Add water 15 and acid acid 15 to remove insolubles. The aqueous layer is extracted twice more with ethyl acetate, and the aqueous layer is combined, washed with water, dried over anhydrous magnesium nitrate and distilled under reduced pressure. Dissolve the residue in 50% water and add a solution of hydrogen chloride in ethyl acetate (5N) to give S- (2-amino-4-phosphate reflourmetif); -1 L 1 cysteine hydrochloride 3 «4 is a pale yellow powder

OMPI Obtained. Dissolve the product in Dimethoformamide 30 and stir under ice-cooling. Add a solution of Trimethamine (X78 fi> in Dimethiformamide over 10 minutes). 1.83 dimethylformamide 5 After dropwise addition for 5 minutes, add triethylamine 0.78 dimethylformamide 5 ι ^ solution, stir under ice-cooling for 30 minutes, and mix at room temperature for 2.5 minutes. Water 20 was added to the reaction mixture, extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and distilled under reduced pressure, and the resulting oil was purified by silica gel column chromatography (hexane: hexane). Purification by acid ratio = 4: 1 to 2: 1), 3 (R) -Penorrexicabo-amino, 7-Trifluoromethyl-1,2,3-Dihydro 1,5 (5H) -Penzothiazebin 4 One-on-1.3 is obtained as colorless powder crystals Melting point 1 2 0— one two Three

 0] ϊ) 1 1 6 1 ° (Methanol)

As elemental analysis Cl 8H l ₅ F3½0 ₃ S

 Calculated value: C 54.54; H 3.81 »N 7.07

 Found: C 5.79; H 3.9; N 7.09

Example 28

Example 2 3 (R) -Penzoxyka-baminomin 7-Trifluorometh-1,2,3-dihydro-1,5 (5H) -Venzothia zebin-1 41 obtained in 7.Dimethyl 1/19 Dissolve in Formamide 2, add tert-butyl acetate; v (469, potassium carbonate 0.42?), Potassium iodide 0.19 and stir at room temperature for 4.5 hours Water is added to the reaction mixture, and the mixture is extracted with 100 ml of ethyl acetate.The extract is washed with 0.1 N hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water in that order, and then washed with anhydrous magnesium sulfate. After drying, decompression distillation removes 3 (R) -pentyloxycarbamide. No 4 1 year old kiso 7 1 tri 7 olomethy 2,3,4,5-tetrahydro 1, 5 benzothiazebine 1-5-hydroxy tert-butyester; ^ 1.4 ^ is obtained as a colorless candy.

IR ν ^ ⁰¹ * »" ¹ : 1680 (amide), 1710 (urethane), 1740 (esthetic)

 * IR: (Infrared absorption spectrum: same as below)

 Example 29

 3 (R) -Penzoxyka-baminomin obtained in Example 28 41-year-old 7-trimethylamine 2,3,4,5, -Tetrahi draw 1,5, -Penzothiazebine-5-Acetate tert-acetate Dissolve butyl ester 1.4 in sulfuric acid 5 », add 30% hydrogen bromide monoacetic acid solution 10 *, and leave at room temperature for 4 hours. Add petroleum ^ -tel 100 »to the reaction mixture, mix well, and remove the supernatant by decanting. After adding petroleum ether again and performing the same operation, the residue is dissolved in a mixture of ethyl acetate and benzene, and dried under reduced pressure. When petroleum ether is added to the residue, 3 (R) -amino-4,7-oxo7-trif-methyl 2.3,4,5, -tetrahydro 1,5, -benzothiazebine-5-strong acid odor Hydrofluoric acid 氇 0.75? Precipitates as crystals. Melting point 176-1 80

Elemental analysis value As Cx2HnP3N2O3S.HBr.H2O

 Calculated values: C 34.38; H 3.37; N 6.68

 Found: C 34.40 40 H 3.60; N 6.66

Example 30.

 3 (R) -Aminnow 4-oxo-1,2,3,4,5-tetrahi draw 1,5-Penzothiazebine-5 obtained in Example 4 5 tert-butyl ester 1f dissolved in methanol 20 » , And ^ ^ anionizing power (32, N

OMPI Add 1.1- (1.1) phthalimide 1.1 and 0.3 f

 Stir at room temperature overnight. The reaction mixture was evaporated to dryness, and as a crude product, 3 (R)-{1-cyano 5-phthalimide pentamine) amino 4-oxo-2,3,4,5—tetrahedral 1,1,5-1 Penzothiazebine 1 5 1 Severe acid tea ^ —butyesute is obtained. This product should not be purified.

 Used as raw material for 31.

Example 31

3 (H)-(1-cyano-5-phthalimidopent) amino-4oxo-2,3,4,5, -tetrahidro 1,5-benzothiazebine-5-acetate 5- (acetate) obtained in Example 30 Add ethanolic hydrochloric acid (11N) 2 to Este 2, stir under ice cooling for 6 hours, and leave at room temperature overnight. Ethanol is distilled off under reduced pressure, and the residue is mixed with 50% of ethanol and 15% of ion exchange resin, and stirred for 7 hours and refluxed. After cooling, the resin part is treated with a 5% pyridine-ethanol solution, and the ethanol part is combined and distilled off under reduced pressure. The obtained 7 t oily product is dissolved in ethyl acetate 30 and washed with (XI) hydrochloric acid and water. The ethyl acetate layer is dried over anhydrous magnesium sulfate, decompressed and distilled, and the residue is silica gel solvent. Purification by chromatography (hexane: aceton-2-1) yields 3 (R)-(1 -ethoxycarbo- 1 -5-phthalimidopentyl) amino 4 -oki, no 2,3, 4, 5 Tetorahi draw 1, 5-Penzochia Zebin one ₅ Ichikokusan Echiruesuteru 0.9 ⁹ are obtained as a colorless oil _c

IR ^v mlx ^{ta l:} 1770, 1740, 1720, 1710 (lid

 Imido and Esthetics, 1 670 (amide)

Spect (mZe): 567 (M ⁺ )

Example 32

-", 0, Dissolve 6.48 of 3 (R) -phthalimido-2,3-dihydro-1'5 (5H) -pentoziazevin-14one obtained in Example 2 in dimethylformamide 25 »^, and give 2-bromobrobion Add 6.27 tert-butyl ester, 5.5 lium carbonate and 0.5 f potassium iodide and stir at room temperature overnight. Add water 20 to the reaction solution and extract with water acid 30. The extract is washed with 0.5N hydrochloric acid (200%) and saturated aqueous sodium hydrogen carbonate solution (10), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting oil is purified by silica gel column chromatography (hexane: ethyl acetate-). Purification by 3: 1 to 2: 1) yields 3 (R) -phthalimidone 4-oxo-1,2,3,4,5-tetrahydro-1,5-pentazothiazebine-5-a-tert-butyl methyl sulfate Ester 7.8 is obtained as a colorless powder.

n _u neat--: 1 770, 1 730 .1 720 .1 680 (00)

As Elemental analysis _{C 24 H 2 4N 2 0 5} S '½H 2 0

 Calculated: C 62.46; H 5.46; N 6.07

 Found: C 62.62; H 5.14; N 6.13

 Example 33

 The tert-butyl ester 7.6 of 3 (R) -phthalimidido-4-oxo-1,2,3,4,5-tetrahydro-1,5-pentazothiazevin-5-methyl-methylene acid obtained in Example 32 was prepared in the same manner as in Example 4 Similarly, when treated with hydrazine hydrate, 3 (R) -amino-4-oxo-1,2,3,4,5-tetra-dro 1,5-pentazothiazebine 5-a-methylacetic acid tert, butylacete 5.4 Obtained as a pale yellow oil.

 I R vjfatce-l: 1735.1670 (0 = 0) a-223. 5, in Methaneau)

O PI Mass spectrum (rn / e): 32 2 (M *)

Example 34

 The tert-butylester 3.08 obtained in Example 4 was converted to dimethylformamide 2 by adding 3 (R) -amino-4oxo-1,2,3,4,5-tetrahydro1,5,5-benzothiazebine-5-monoacetic acid obtained in Example 4. Dissolve and etch 2-butane oxalic phthalocyanide hexanoate 7.3 6? Then, add potassium carbonate 2.76 and potassium iodide 1.66 and stir overnight at room temperature. In addition, broester 3 · 682 and charcoal potassium! · 38? And stir for 3 days. The reaction mixture is extracted by adding 100 ml of water and 300 ethyl acetate, and the extract is washed with water and distilled off under reduced pressure. Add oxalic acid 59 and acetic acid salt 3 to the obtained oil and dissolve it. Add petroleum ether 12 Oa and mix well. After standing, the supernatant was removed by slanting, and the residue was again subjected to the same treatment.Then, saturated aqueous sodium bicarbonate solution (10) and sodium acetate (30) were added for extraction, and the extract was dried over anhydrous magnesium sulfate. After drying under reduced pressure. The obtained oily substance was purified by silica / U-Liquid Mouth Gravity (Hexane: acetone-4: 1) to give 3 (R) -1 (R) -1-ethoxycarbonyl as the first fraction. Phthalimidopenchi] amino-4oxo-1,2,3,4,5—tetrahydro draw 1,5—pentoziazevin-5—drungic acid tert-butyl; ester! · 75 is obtained as an oil.

IR

3 3 30 (NH), 1 78 0. 1 740,

 1 720 »168 G (C = 0)

Mass start (m / β): 5 95 (M +)

 As the second fraction, 3 (R)-[1 (S) ethoxycarbo-5-phthalimid-pench] amino 4-oxo-1,2,3,4,5-tetradraw 1,5 benzothiazin-1 5 蘼Acid tert-butyl ester

OMPI 2.5 9 is obtained as an oil.

IR

cm ' ¹ : 3 3 3 0 (NH), 1770, 1740.

 1 7 20, 1 6 8 0 (0 = 0)

Mass spectrum (rn e) 5 9 5 (M ⁺ )

[<X] _D — 1 19 ° (c-0.3, medium methanol)

 Example 35

 Example 3 3 (R) -C 1 (S) -ethoxyca-boru 51 obtained in 4-phthalimidopenti A-amino-4-oxo-2,3,4,5, tetrahydro 1, 5-pentazothiazebin Dissolve 0.2 g of 5-tert-butyric acid in 5 W of a 5 N hydrogen chloride-purse solution and leave at room temperature for 3 hours. The PET 5 OWf was added to the reaction solution, and the precipitated precipitate was washed with PD 10 to give 3 (R)-[1 (S) -ethoxycarbonyl 5-phthalimidopenp] amino-4oxo-oxo 2 , 3,4,5-Tetrahydro 1,5, -benzothiazebine-15-acetic acid'hydrochloride 0.139 is obtained as a colorless powder.

As Elemental analysis _{C 27 H 29 N 3 0 7} S .HC1. ½H 2 0

 Calculated: C 55.42; H 5.34; 7.18

 Found: C 55.09; H 5.12; N 7.15

[A] _D -114 "(c == 0,5 in methano)

Example 36

 3 (R)-[1 (R) -ethoxycarbonyl-boru 51-phthalimidopench obtained in Example 34;! /] Amino-4, oxo-1,2,3,4,5-tetradraw 1,5- Dissolve pentozhiazepine-1.5 tert-butyl ester in monobasic acid in ethanol 2, add 85% hydrazine hydrate 0.8 and leave it at room temperature overnight. Add drench acid 20 and water 200 a to the reaction solution.

O PI In addition, extraction was performed, and the sodium sulphate moiety was washed with 0.1 I aqueous sodium hydroxide solution and then with water to give 3 (R)-[5-amino-1 (R) -ethoxycarbo- _J «/ pentyl]. A solution of acetic acid tert-butyester in the form of aminow 4-oxo-2,3,4,5-tetrahydro-1,5-pentazothiazebine-5-carboxylic acid is obtained. Add 1.6% sodium bicarbonate and 50 * water to this solution, stir at room temperature, and add dropwise a 5W solution of di-tert-butyl dicarbonate 0.9 * in ethyl acetate. ₀ Stir for 30 minutes, then separate the ethyl acetate layer. , Dry with anhydrous magnesium sulfate. The oil obtained after decompression distillation was purified by silica gel 1 column chromatography (hexane: aceton-4.1) to obtain 3 (R)-[5-tert-butoxylity; -AMINO 1 (R)-ethoxyca-pent) MINOH 4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazebine-5-acetic acid tert-butylester 1.4 is obtained as a colorless oily extract. Can be

IR vS x ^tc * ^1: 335 0 (NH), 1 740, 1710,

 168 0 (C = O)

Mass spectrum (m / β): 565 (M +)

Example 37

3 (R) -Cl (S) -ethoxy power obtained in Example 34 5- (phthalimidopentyl) amino-4,3-oxo-4,2,3,4,5-tetrahydro-1,5-pentazothiazebin 5-Tertiary tert-butyl ester 26- was treated with hydrazine in the same manner as in Example 36 to give G-tert-petit! After reacting with dicarbonate and purifying by Rigel gel chromatography, 3 (R) — [5-tert-butoxyca; ubonylamine ι (3) — ヱ toxicabonii / ύpench A amino-4oxo-1,3,3, 4,5—tetrad ^ "1,5-pentazothiazebine 5-tert-butyl tert-butyl Te 1.87 is obtained as a colorless oil.

IR vgH * em- ¹ : 3350 (NH), 1740 »1710,

 1 6 7 0 (C = O)

 Mass spectrum (m / e): 5 6 5 (M +)

[Β] _D -136. (C-0.8, in Methanow)

 Example 38

 3 (R) — [5-tert-butoxycabo namino-1 1 (S) —ethoxybobo =: pliers; i] amino-4-1, oxo-1,2,3,4,5-tetrahydro-1 obtained in Example 37 Dissolve 0.69 tert-butyl ester, 5-pentoziazebine-5-pate, in a mixture of 4 Qml of methanol and 25 of 1N aqueous sodium hydroxide, add water 10 »and stir at room temperature for 2 hours. . Remove methanol under reduced pressure, weakly acidify with citric acid, and extract with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. , 3,4 »5-Tetrahydro 1, 5-pentazothiazebine 5-pentanoic acid ter —butyric ester (X 37? Is obtained as a colorless age substance. Melting point 1 3 4— 1 3 5

Elemental analysis 傢 As C ₂₆ H ₃₉ N ₃ 0 ₇ S

 Calculated: C 58.08; H 7.31; 7.82

 Found: C, 58.11; H, 7.22; N, 7.73.

IR yj¾ ⁰¹ one ^{1:. 3 3 5 0 (} WH), 1 7 3 0 1 7 0 0,

 1 68 0 (C = 0)

Example 39

3 (R) -amino-4 obtained in Example 4 1,3,4,5-te Toro Draw 1,5-Penzothiazebin-5-Heronic acid tert-butyl ester 5 and eth 2-bromo-6-phthalimid hexanoate

1 7.99 was dissolved in deacetonitrile 200 dew, triethylamine 2.46 was added, _β- acetitol refluxed for 45 hours was distilled off under reduced pressure, and water 20 and drench acid solution were added to the residue. Add and extract. 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: acetone = 4: 1) to give the same product 3 (R) — [ 1 (R) -ethoxycarbonyl-1—5-phthalimidopenti] amino-4oxo-1,2,3,4,5-tetrahydro-1,5, -benzothiazebine-5-hydroacid tert-butylester 3.9 f 3 (R) — [1 (S) — ヱ Toxicabo-51-butyl-imidobench] amino-4-oxo-2,3,4,5-tetohydro-1,5— ^ t-n-zothiazebine-5-acetic acid tert-acetate Buty Este 4.19 is obtained as a colorless oil.

Example 40-42

 3 (R) -Amino-4oxo-1,2,3,4,5-tetrahydro-1,5, -benzothiazebine-5-acetic acid ter-butyester was prepared in the same manner as in Example 39, and the «-bromoester shown in Table 6 was used. The following benzothiazebine derivative is obtained by reacting

 Table β

ΟΜΡΪ

 * Diastereomer mixture Example 4 3-4 4 5,

 The compounds shown in Table 7 are obtained by treating the benzothiazebine conductor obtained in Examples 40-42 with an ethyl hydrogen chloride acetate solution in the same manner as in Example 35.

Table 7

 * Diastereomer mixture

, G.-' Example 46-48

 After treating the benzo'thiazebine derivative obtained in Examples 40-42 with hydrazine in the same manner as in Example 36, and reacting with tert-butyl dicarbonate, the compounds shown in Table 8 are obtained.

Table 8

 Diastereomer mixture Example 49

 3 (R)-(1-Ethoxycanolepo-Lu-5-phthalimidopenti A amino-1 41-oxo-1,2,34,5-tetrahydro-1, 5-pentazothiazevin-15-acetic acid obtained in Example 31 Dissolve 1 Este 0.79 in ethanol 20 * and add 85% hydrazine hydrate 0.3-Add 85% pickling hydrazine 0.3 after 1 hour and 2 hours, then leave overnight Ethanol was distilled off under reduced pressure, water was added to the residue, and food was added to saturate, and the mixture was extracted three times with acid salt.

 Wash with 0.1 W 50% aqueous sodium hydroxide followed by water 100 and dry over anhydrous magnesium sulfate. To the resulting acid solution was added a 5% aqueous hydrogen chloride solution, and the mixture was distilled under reduced pressure.

 ΟΜΡΙ

¹ Addition of 3 (R)-(5-amino-11-ethoxycarbopent) aminow 4-oxo-2,3,4,5-titrahydro-1,5-pentazothiazebine-5-acetic acid monoester '2HCl 0.13 salt is obtained as a colorless powder.

Elemental analysis value C ₂₁ H ₃₁ N ₃ 0 _{5 As} S.2HC1'H ₂₀

 Calculated values: C 7.73; H 6.67; N 7.95

 Found: C 47.81; H 6 · 53; N 7.83

 Mass spectrum (m / e): 437 (M +)

Example 50

3 (R)-(5-Amino-11-ethoxycanolevone pentyne) amine obtained in Example 49 4-oxo-1,2,3,4,5-tetrahydro-1,5-benzozoazepine-5. Dissolve 50 W of Thieste dihydrochloride in a mixture of 30 30 of ethyl acetate and 10 »of water, add 0.1 g of pentacarboxychloride and 0.3 δ ¹ of sodium bicarbonate, and stir for 2.5 hours at room temperature. After washing the drunk acid layer with water, it is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained oily substance was dissolved in a mixture of ethyl ether 20 »and petroleum ether 20 and 0.2 W of ethyl pentoxide solution was added to give 3 (R) — (5-pentoxyca-boramine). Ethoxy carboxy-amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-pentazothiazebine-5-ethyl ethinolestearate 55-W is obtained as a colorless powder.

Mass spectrum (mZe): 571 ( ^τ ;

Example 51

3 (R) — (5-Penzoxyca-Voramino-Ethoxyka-Io-Penchi) obtained in Example 50; 1) Amino-4-oxo-2,3,4 , 5-Tetrahydrido 1,5-Penzothiazebine-5-Enzyme acid and hydrochloric acid 55 ^ are dissolved in a mixture of ethanol 3 and 1 3 aqueous sodium hydroxide solution 2 W and left at room temperature for 1 hour I do. After adding 503 ^ to the reaction mixture and extracting with ethyl ether 20 », the aqueous layer is adjusted to ρΗ4 with monocarboxylic acid. After adding ammonia chloride to a saturated solution, the aqueous layer is acidified.

 Extract 10 times at 20 W. The extract was washed with a small amount of water, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure to obtain 3 (R)-(5-pentoxycarbonylaminol 1-canoleboxixintyl) amino-4-isoxo-2, 40 W of 3,4,5-tetrahydro 1,5-benzothiazebine-5-acid is obtained as a colorless powder. ·

Mass vector (me): 5 15 (M ⁺ )

Example 52

 Example 51 3 (R)-(5-Penzinoleoxycarbamino-1-l-carboxypentene) amino-4oxo-1,2,3,4,5-tetrahydro-1,5-pentozothiazepine obtained in 1 Dissolve 5-acetic acid 4 in acetic acid, add 1% of 30% hydrogen bromide acetic acid solution, and leave it at room temperature for 1 hour. <Add reaction mixture 8 and petroleum ether 2> The solution is allowed to stand, the supernatant is decanted, the precipitate is collected and dried, and 3 (R)-(5-amino-1-carboxypentyl) amino-4oxo-1,2,3,4,5- Tetrahydro draw 1,5-bendathiazevin-15-hydroacid-2 hydrobromide 33 is obtained as a colorless powder.

SIMS spectrum (m / e): 382 (H ⁺ );

 K I addition 420 (M + K) +

Examples 53 and 54

The benzothiazebin derivatives obtained in Examples 36 and 37 were the same as in Example 35. When treated with hydrogen chloride, the compounds in Table 9 are obtained as colorless crystals.

Table 9 HCHC00C ₂ H ₅ • 2HC1

j 0 CH ₂ CH ₂ CH ₂ CH ₂ NH ₂

 HOOC ^ configuration

 Example number * 1 * z [a] D (methanol)

5 3 R R -161 ° (c-0.7)

54 R S one 128. (c = 0.5) Example 55

 3 (R)-[5-Amino-1 (3) -ethoxycarbonyl-pentyl] amino-4oxo-1,2,3,4,5-tetradihydro-1,5 — ^: nzothiazevin obtained in Example 54 —Drossic acid 'dihydrochloride 0.2 is added to 4N aqueous 1N sodium hydroxide solution and stirred for 1.5 hours at room temperature. Severe acid in reaction solution

Then, the mixture is made weakly humid and purified with Amberite X AD-2 Cam Chromatography (Methanol: Water-3: 7). After the effluent was compressed and lyophilized, it was freeze-dried to give 3 (R)-[5-amino-1 (S) -carboxypentyl] amine 4-oxo-1,2,3,4,5-tetrahydro-1,5-pentoziazevin. One 5-acetic acid 0.1 is obtained as a colorless powder. As Elemental analysis _{C 17 H 23 N 3 0 5} SH 2 0

 Calculated: C 51.12; H 6.31 5 N 10.52

 Found: C 50.87 ί H 5.83; N 10.34

 a D-149 ° (c = 0.3, in 11ί hydrochloric acid)

SIMS spectrum (me): 382 (MH +); KI added 420 (M +) ⁺

C recitation MPI r: Example 56

 Example 38 it 3 (R) — [5-tert-butoxycarbo-l-amino-1 (S) —force; V-boxy] aminol 4-oxo-1,2,3,4,5-tetra-t-Draw 1,5-pentazothiazebin Treating 0.35 of tsrt-butynoleeste 5-acetic acid with hydrogen chloride in the same manner as in Example 35, gave 3 (R)-[5-amino-1 (S) -carboxy-pinch] amino 4 4-oxo1-2,3 , 4,5-Tetrahydro-1,5, -benzothiazebine-1-5- · hydrochloride ¾α 26 is obtained as colorless powder crystals.

Elemental analysis: C ₁₇ H ₂ 3 ₃ 05S-2HC1.CH ₃ C 00 C ₂ H ₅ Calculated: C 46.49; H 6.13; N 7.75

 Found: C 46.12; H 6.16; N 7.52

 Dissolve 0.15 of this product in water, add 0.5 ml of 1N aqueous sodium hydroxide solution, add acetic acid (X5W), and purify with ampalite XAD-2 in the same manner as in Example ^ ". The same educt 0.096 as obtained is obtained.

Examples 57 to 59 When the benzothiazebine derivative obtained in Examples 46 to 48 is treated with a hydrogen chloride solution in the same manner as in Example 35, the compounds shown in Table 10 are obtained.

Table 10 2HC1

O PI

¹

 * Diastereomer mixture

 Example 60

 Sodium 0.4 3? Dissolve in ethanol 10 0, add ethyl 3- (1-pentoxyca-boru-4-piperidyl) brobionet 5 and getyl oxalate 2.75, and then add 60-70 in a hot water bath. 4 Evaporate under reduced pressure while heating for 5 minutes. After cooling, 20 Qnt of water is added to the obtained brown candy, and the mixture is made weakly acidic with hydrochloric acid. Extract with ethyl acetate 30Ο, dry the extract over anhydrous magnesium sulfate and evaporate under reduced pressure. To the obtained yellow oil was added 50% water-containing dimethyl sulfoxide (50%) and lithium chloride (0.73), and the mixture was heated at 100 ° C for 30 minutes, at 120 ° C for 30 minutes, and then at 140 ° C for 45 minutes. Stir. After cooling the reaction solution, water 3.00 »was added thereto, and the mixture was extracted with ethyl acetate 300 0«. The extract was washed with water, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to give ethyl 4--as a pale brown oil. (1 pen zipper box: 1 4-1 bi-peripheral) 1 2-oxo butyl plate 4.5

Can be

Mass Spect; << (me): 347 (M ⁺ )

Examples 61 and 62

 Using the ethyl propenoate derivative shown in Table 11 as a starting compound

Ο ΡΙ By carrying out the same reaction as in Example 60, each corresponding a-keto ester is obtained.

Obtained ketoester compound Example No. Starting compound bp isaHg)

CQ ~ CB ₂ CH ₂ COCOOC ₂ H ₅

61 0) -CHoC¾C00C ₂ H5!

 115-125 (2)

S G C¾CH ₂ C0C00C ₂ H ₅

 62

 i 148—151 (3)

 Example 63

 3 (R) -amino-4,4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazebine-5-drungic acid tert-butylester 2 obtained in Example 4 was dissolved in ethanol 5 Then, acetic acid 0.439, ethyl 4- (4-carboxylic acid 4-vinyl) obtained in Example 60, 2-oxobutyrate 45, molecular sieve 3A10? Is added. After stirring this mixture at room temperature for 1 hour, a solution of sodium cyanoborohydride 0.4 in ethanol 3 is added dropwise over 2.5 hours while stirring at room temperature. Further, a solution of sodium cyanoborohydride 0.5 in 20 W of ethanol is added dropwise for 3 hours and left overnight. The reaction solution is evaporated under reduced pressure, and water 30 and ethyl acetate 30 are added to the residue, followed by shaking. After filtering to remove insolubles, the ethyl acetate layer is dried over anhydrous magnesium sulfate and distilled under reduced pressure. Add residue 5 to the residue and add a solution of oxalic acid 19 in residue 50 »^. Add petroleum ether 0, shake, stir, allow the supernatant to dislodge, remove the precipitate, add petroleum ether 10 again, and shake. After removing the petroleum layer with a slant,

/ Two I Add 50 50 of water and 20 ml of 酔 tyl persulfate to the precipitate, and neutralize by adding excess baking soda while stirring. The acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give an oil. This product is separated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 4: 3). First, 3 (R) — [3- (1-benzyloxycarbol-141) Peridi-nore) -l (R) -ethoxycanolepol-rubrobi] amino 4-oxo-1,2,3,4,5-tetrahydro-1,5-pentozia zebin-5-tert-butyl acetate (X 6 is Obtained as a colorless oil.

IR vgH * ca ¹ : 3 320 (NH), 1 740, 1 700,

 1 6 80 (0 = 0.)

Mass skipping (mZe): 639 (. ⁺ )

 Subsequent fraction: ^ 3 (R) — [3— (1—1 pentyl) —1— (1) (S) —ethoxyxabo: Provir] amino—4—oxo 2,3,4 , 5-Tetohydro-1,5-pentazothiazepine 5-tert-Butylester 1.3? Is obtained as a colorless oil.

IR

: 3320 (NH), 1 740, 1 70 0,

 1 690, 1 6 70 (0 = 0)

Mass skipping (mZe): 639 ( ⁺ )

Examples 64, 65

Example 6 Using the β-ketoester obtained in 1, 62 in the same manner as in Example 63, 3 (R) -amino-4oxo-1,2,3,4,5-tetrahydro-1,5, -benzothiazebine-5-acetic acid tert-acetate When reacted with butyl ester, the compounds shown in Table 12 are obtained as oils. Table 1 2

Example 66

 3 (R) — [3— (1-Penoxy 'force! / Bo -—— Biperidini) -1 1 (S) —Ethoxy power! Bo-Brobi] obtained in the practical example 63 Dissolve 2,3,4,5-tetradihydro-1,5-pentoziazevin-15-tert-butynoleeste 5-acetate in 5K hydrogen chloride-acetate solution 2 and leave at room temperature for 3 hours. When petroleum ether 20 is added to the reaction solution, 3 (R) — [3— (11-pentoxycabo-^-one-biperidur) -1-1 (S)-ヱ toxica / 1 / bo-brovir] aminnow 4-oxo-one-2 , 3,4,5-Tetrahydro-1,5-pentazotazebine-15-enzyme 'hydrochloride precipitates. After decanting and removing the supernatant, drying yields 0.229 of a colorless powder.

C ₃₀ H ₃₇ N ₃ 0 ₇ S.HC1.H ₂₀

 Calculated: C 56.46; H 6.32; N 6.58

Found: C 56, 29; H 6.31; 6.57 [A] _D — 91 ° (c = 0.6 in methanol)

 Examples 67-70

 When the benzothiazebine derivatives obtained in Examples 64 and 65 are treated with hydrogen chloride in the same manner as in Example 66, the compounds shown in Table 13 are obtained.

Table 13

 Hooc Example No.R 'Configuration s

 * 1 * 2 La) D in methanol

 6 7 R R-15 1 °

 O

 6 8 R S-1 1 9

6 9 .R R-1 4 4

7 0 R S-1 0 8

Example 71

 Example 6 3 (R)-[3-((1-Penzyloxycarbo-141-biphenyl-)-1 (R) -ethoxy power obtained in 3; 1-Bolbrobi] amino 4 Dissolve 0.6-oxo-1,2,3,4,5-tetrahydro-1,5-pentazothia zevin-1-butanoic acid tert-butyrate 0.6 in acetic acid 2} and add 30% hydrogen bromide acid solution 2 And leave at room temperature for 1 hour. After adding 15 ether to the reaction mixture and allowing it to stand, the supernatant is removed in an inclined manner. After washing the sediment with ethyl ether, and drying, 3 (R)-[1 (R) -ethoxyxa / bo zj- 3-((4-biphenyl-)) brovi t /

Amino-4oxo-1,2,3,4 »5-tetrahydro 1,5,1-pentazothiazebine-5- 5acid 'dihydrobromide 0.5 is obtained as a colorless powder. _Β

Elemental analysis value C ₂₂ H ₃₁ li ₃ 0 _{5 As} S-2HBr.H ₂₀

 Calculated value: C 41.98 ϊ H 5.60 J N 6.68

 Found: C 41.3; H 5.39; N 6.30

[<<] ² 106. (C-0.6, medium methanol)

Example 72

 Example 6 3 (R) — [3— (1 pen oxy force bo—4 bibellige =) 1 (S) ethoxyca bo—bu π bi] obtained in 3) amino 4 oxo 2,3,4,5 —Tetrahydrido 1,5 benzothia zevin pentabutyl acetate 0.49 treated with hydrogen bromide in the same manner as in Example 71 gives 3 (R) — [1 (S) -toxicabo-norre 3 -— (4biveridi- [Noreb mouth vinore] amino-4 oxo 2,3,4,5 tetrahydro 1,5 benzothiazebine acetic acid, dihydrobromide 0.35? Is obtained as a colorless powder.

Elemental analysis value C ₂₂ H ₃ iN ₃ 0 _{5 As} S'2HBr'H ₂₀

 Calculated values: C 40.81; H 5.76; N 6.49

 Found: C 40.47; H 5.32; N 6.28

 [A] 86. (C = 0.6, medium

Example 73

 Example 7 3 (R)-[1 (S) -ethoxycarboxy-3 obtained in 2

(4, Bidyl) * σbi] amino-4 oxo 2,3,4,5-tetrahydro-15 benzothiazevin 5 acetic acid'2 hydrogen bromide 0.15 dissolved in 1 1 aqueous sodium hydroxide solution 4 and room temperature And leave for 3 hours. Add weak acid 1 to make it weakly acidic, and then purify it by amparite X AD-2 column chromatography (methanol: 汆 -1: 1).

Οί, ίΡΙ After decompression and freeze-drying, 3 (R)-[1 (S) -carboxy-3- (4-vinylidyl) propyl:) amino-4-oxo-1,2,3,4,5-tetrahydro 1,5-Penzothiazebine-5-drunk acid 0.06 It is obtained as colorless powder.

Elemental analysis value C ₂₀ H ₂₇ N ₃ 0 ₅ S 'H ₂₀

 Calculated value: C 54.65 ϊ H 6.65; N 9.56

 Actual measurement: C 54.05 J H 6.17; N 9.21

Mass spectrum (mZe): 4 2 2 (MH ⁺ );

 I addition, 460 (M + K) +

0] _D — 1 2 8 (o-0.1, methanol + water)

Examples 74 and 75

 Example 6 The benzothiazebine derivative obtained in 88 and 70 was hydrolyzed with a 1% aqueous sodium hydroxide solution in the same manner as in Example 73, and purified by Amberite XAD-2 column chromatography to obtain the compounds shown in Table 14. Is obtained as a colorless powder.

 Table 14

Example 76

 3 (R) — [1 (S) —ethoxyxin-1- (4-biperidi-) butyl] amine obtained in Example 72 4-amino-1,2,3,4,5-tetrahydro draw 1,5— Penzothiazebine 5-acetic acid · dihydrobromic acid 氇 0.25? Dissolve in ethanol 10 dew, and add sodium acetate 6 and penzaldehyde 52 «9. Stir the mixture and add a solution of sodium cyanoborohydride 3 in ethanol 1 for 30 minutes. Ethanol is distilled off under reduced pressure, water is added to the residue, the mixture is made weakly acidic with hydrochloric acid, and extracted three times with dichloromethane. The extract is washed with a small amount of water, distilled off under reduced pressure, dissolved in the obtained oil (dichloromethane 1), and added with 0.5 W of a 5Ν aqueous solution of hydrogen chloride and a strong acid. The precipitated colorless powder is washed with ethyl acetate and dried to obtain 3 (R) -C3- (1 ^ 5-diene-4-biperidi = Λ—1 (S) -ethoxycarbolbrovir) amino-4oxo-oxo. 2,3,4,5-Tetohydro-1,5-benzothiazebin-15-severe acid 'dihydrochloride 157 is obtained.

Elemental analysis 攛 C2 ₉ H ₃₇ H ₃ 0 _{5 As} S'2HC1'H ₂₀

 Values: C 55.23; H 6.55; N 6, 66

 Found: C 54.92; H 6.74? N 6.14

 [N] D —76 ° (c = 0.4, in Methanow)

Example 77

 3 (R) -Cl (S) -ethoxy-113-(-biphenyl-). Bumin] amine obtained in Example 72 4-amino-1 2,3,4,5-tetra-t Draw 1,5—benzothiazevin-5-acetic acid'hydrobromide salt 0.1? Is dissolved in 5 W of acid acid, and triethylamine 6 is added, and the mixture is stirred with eternal cooling, and a solution of benzoyl chloride 23 in acid acid 2 »

OMPI In 2 minutes. Stir at room temperature for 50 minutes, add petroleum ether 20 and extract 6 times with saturated aqueous sodium hydrogen carbonate. The aqueous layer is made weakly acidic with hydrochloric acid, and extracted three times with dichloromethane. The extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting oil was dissolved in acetic acid Echiru 1, 5 N hydrochloric Kokusan Echiru solution 0.3 * added, washed the precipitate obtained by _e precipitated dilution with We Chi ether E Ji ether and dried 3 (R) - [3- (I-Penzoxy 4-biperidi-)-1 1 (S) -ethoxycarbo-blovinole] amino-4-1, oxo-1,2,3,4,5, tetrahydro 1, 5-benzothiazebine-1-5-acid Hydrochloride 28 is obtained as a colorless powder.

As Elemental analysis _{C 29 H 35 N 3 0 6} S'HC1'H 2 0

 Calculated value: C 57.27; H 6.30 ί N 6.91

 Measured value: C 56.98; Η5.99; Ν7.01

Example 78

 Example 7 3 (R) — [1 (S) — ヱ Toxicarbol-31 obtained in 2

(4-biveridyl) brovir] amino-4-oxo-2,3,4,5-tetradihydro-1,5-pentazothiazebine-5-acetic acid dihydrobromide 0.12 was prepared in the same manner as in Example 77 to obtain acetyl chloride. Reacts with 3 (R) — [3- (1-acetyl-41-bis-A-1 (S) — ヱ toxiccarborub-σ-bill] amino-4 4-year-old kiso 2,3,4,5 —Tetrahydro 1,5,1-Penzothiazebine-5-Acetic acid / HCl 77 is obtained as a colorless powder.

[A] _D -97. (C-0.3, in Methanow)

Example 79

3 (R) to (5-Amino-11-hydroxycarbonyl) obtained in Example 43 Pliers Amino-4-oxo-1,2,3,4,5, -tetrahydro-1,5, -pentozazebine-15-acetate / »ester · 2HCl 壎 60 is dissolved in ethanol5 _| ^, and a 25% aqueous solution of galaldehyde 0.5 And sodium borohydride 0.3? And stir at room temperature for 2 hours. After adding 50 W of water to the reaction solution and further adding sodium chloride to saturate the mixture,

 Extract twice with 3. After the extract is washed with water, it is dried and distilled under anhydrous magnesium sulfate. The obtained oily substance is dissolved in a small amount of ethyl acetate, and 0.2 N of 5 N hydrogen chloride solution is added to give 3 (R)-(1-ethoxycarbonyl 2-nitro-5-biperidinopent) amino-4-oxo-one. 2,3,4,5-Tetrahydro 1,5-pentazothiazevin-15-hydroxyethyl dihydrochloride 5.0 ^ is obtained as a colorless powder.

Mass spectrum (m / e): 505 ( ⁺ )

Example 80

 3 (R) — (110-Toxicarbo-norre-51-Bili-dino-penti!) Obtained in Example 79 Amino-4,1-year-old xo 2,3,4,5—Tetohidro 1,5,5-benzothiazebine—5- Ethyl ester; Dissolve 30% dihydrochloric acid in 30% of 1W of methanol and 1N of 1N aqueous sodium hydroxide solution 1 and leave at room temperature for 1 hour. After methanol was distilled off under reduced pressure, water 2 * and acid 0.5! ^ Were added, and the mixture was purified by amphibit XAD-2 column chromatography (acetone: water-2: 1), and the eluate was concentrated under reduced pressure. When freeze-dried, 3 (R)-(1-carboxyl 5-biperidi pliers) minnow 4-oxo-1,2,3,4,5—tetrahydro draw 1,5-pentozhiazebine-15-hydroacid 17 ^ Is obtained as a colorless powder.

SI 14 S spectrum (mZe): 450 (MH ⁺ );

KI addition: 488 (M + K) + Example 81

 3 (R)-[5-amino-1 (S)-{toxicabo-pentyl] amino] obtained in Example 58 4-oxo-1,2,3,4,5-tetrahydro-1,5-^: nzothiazebine-1 5 —Dissolve 0.4 t of acetic acid · dihydrochloride in 1 of ethanol, add 1.2 aqueous solution of guata aldehyde (25%) and sodium cyanoborohydride α4 », and stir at room temperature for 1 hour. water

Add 50 », acidify with 1 Ν hydrochloric acid, and extract twice with ethyl acetate 30) ^. The aqueous layer is neutralized with sodium hydrogencarbonate and extracted twice with ethyl acetate. The aqueous layer is purified by Amberlite XAD-2 column chromatography (acetone: water = 2: 1). After concentration under reduced pressure the effluent and lyophilized, 3 (R) - [1 (S) - Wetokishikarubo two Lou 5- piperidines Rijinopen chill] ami _f / one 4 one Okiso one 2, 3, 4, 5 Tetowohi Draw 1,5—Penzodazebine-5-acetic acid 0.3 is obtained as a colorless powder.

0] _D -139. (<5 = 0.4, medium

 S IMS spectrum (m / e): 478 (MH "")

Elemental analysis value C ₂₄ H ₃₅ N ₃ 0 ₅ SH ₂₀

 Calculated value: C 58. 16? H 7.53 5 N 8.49

 Found: C 58.47; H 7.55; N 8.52

Example 82

 3 (R) -1 (S) -1-ethoxycarbonyl-5-biperidino pentyl] amino-4oxo-1,2,3,4,5-tetradodo-1,5-^: nzothiazebi y-5 obtained in Example 81 Dissolve 0.23 ^ monoacetic acid in water, add 4N 1N aqueous sodium hydroxide, and leave at room temperature for 1.5 hours. After addition of severe acid 1 », Amberite X AD-2 column chromatography purification yields a colorless powder. Dissolve the product in methanol and concentrate under reduced pressure

.: Then, agar-like substances precipitate. After adding 5 W of ethanol, 3 (R)-[1 (S) -force boxy 5-biphenyl dizopentyl] amino-4-oxo-2,3,4,5-tetrahydro 1, 5-benzothiazebin One-half severe acid 0.09 is obtained as a colorless powder.

[<∑] _D— 117. (C = 0.2, medium methanol)

S I M S spec (m / e): 450

Implementation 钶 83

3 obtained in Example 44 (R) - 1 one Etokishika ball - Lou 3- phthalic I Mi Doburobi] amino-4 one Okiso one 2 _r 3, 4, 5 Tetorahi mud one 1, 5-Penzochiazepin one 5- Kokusan tert-butyl ester! << 89 was separated and purified by silica gel column chromatography (hexane: ethyl acetate; 2: 1), and 3 (R)-[1 (R)-ヱ -Toxicanolepol-Lu3 was obtained from the first fraction. Imidobropi] aminou 4-oxo-1,2,3,4,5—tetrahydro-1,5— ^? N-zothiazebine 5-tert-butyl acetate 0.8-? Is obtained as a colorless oil.

IR 2a ^tc * ¹ : 3 320 (Ν Η), 1770, 1740,

 1 71 0, 1 6 7 0 (C = 0)

0] _Pichi 142. (Ο-(Χ4, in Methanow)

 Then, from the second fraction, 3 (R)-[1 (S)-ヱ ethoxycarbo-;-3-phthalimidbrovir] amine 4-oxo-1,2,3,4,5, -tetrahi draw 1,5-pentazothiazepine-15 —Severe acid terfc—butyl ester (99 is obtained as a colorless oil.

IR vS x ^{t <5} * ¹ : 3 330 CNH). 1 770, 1 740,

 1 7 20, 1 68 0 (C = 0)

[< _D -134. (O-O.4, in Methanow)

One Example 84

 3 (R)-1 (S)-ethoxy force; volu- l 3-peptidomidobro] amino-4 oxo-1,2,3,4,5, tetrahidro 1,5, benzothiazebine-5-penoic acid Dissolve 0.2 g of tert-butyl ester in a solution of hydrogen chloride (5,5 «) and leave at room temperature for 4 hours. Petroleum ether 10 was added to the reaction solution, and the precipitated precipitate was taken out of the furnace and treated with 3 (R) -Cl (S) -1-toxica-bolu-3-phthalimidobro] amino 4-oxo-1,2,3 , 4,5-Tetrahi draw 1,5-Penzothiazebine-15-acetic acid.HCl 0.18 is obtained as a colorless powder. [A] n-102 ° (c-0.3, in Methanol)

Example 85

 In the same manner as in Example 39, 3 (R) -amino-4, one-year-old kiso 2,3,4,5-tetrahydro 1.5-pentoziazebine-15-drunk tert-butyl ester 29 and industrial 2- React with broth 1 1 1 1 The obtained product was separated and purified by silica gel column chromatography (hexane: severe acid-3: 1), and as a first fraction, 3 (R)-[1 (R) -ethoxycarb-1-1 0-phthalimiddecyl] amino 4 1-year-old xo 2,3,4,5-tetrahydro-11,5-benzothiazebin-5-terttert-butylester 1.2 is obtained as a colorless oil.

IR

: 3 320 (NH), 1770, 1740,

 1 7 1 0, 1 68 0 (C = O)

[A] _D — 104 ° (c-0.5, medium methanol)

 As the second fraction, 3 (H)-[1 (S)-{toxica-bo- 10-phthalimidodecinole] amine 4-1-oxo-1,2,3,4,5-tetraz

/ OMPI Draw 1,5-Penzothiazebine 5-tert-butyrate / ^ 1.29 is obtained as a colorless oil.

1 R

^: 3320 (Ν Η), 1 770, 1 740,

 171 0, 1670 (0 = 0)

[A] _D —113 ° (o = 0.5 in methanol)

Example 86

 3 (R) -1 (S) -1-ethoxyca-1-10-phthalimidido) obtained in Example 85] amino-4-oxo-1,2,3,4,5-tetrahydro 1,5,5-pentazothiazebin 5-1 When tert-butynoleic acid 0.259 was treated in the same manner as in the Example with a hydrogen chloride-hydroxyacid solution (5N), 3 (H)-[1 (S) -ethoxycarbo-norate 10-phthalimidate was obtained. Dodecy] amino-4,3-oxo-2,3,4,5-tetrahydro-1,5-pentazothiazevin-15-acetic acid'hydrochloride 0.23 is obtained as a colorless powder.

[A] _D — 101 ° (o = 04, in methano)

Experiment example

 Experiment on inhibition of angiotensin I converting enzyme (ACE) by the compound of the present invention

 Experiments were carried out by a method modified from Cushman et al.'S method II (Biochemical Pharmacology, 20 vol., 1637Κ, 1971). That is, using Hybri 1 L-1 Histid t / L 1 mouthful (HHL) as a substrate, and using ACE! [The suppression rate of hippuric acid production when the compound of the present invention is added to the amount of hippuric acid generated]], and the ACE inhibitory effect was determined. A C E 100

2 Q / nl), 1.25 HH L 100 in 0.02-0.5% dimethyl / uoxide 100 mM boric acid-ponic acid buffer (pH & 3, 300 mil

CMPI A solution of the compound of the present invention dissolved in a solution containing sodium chloride) was added. As a control, a boric acid monohydrochloric acid buffer solution containing dimethyl snorreoxide at the same level as the sample solution was used. After heating this solution for 1 hour at 37 ° C, the reaction was stopped by adding 150 μ $ of 1N hydrochloric acid, and 0.8 W of severe acid was added, followed by centrifugation at 11,500 rpm for 2 minutes. . (0.5 ethyl acetate layer was removed!), Dried under nitrogen gas at 40 ° C or less, added with distilled water of 4.5 to the residue, mixed well, and colorimetrically determined at a wavelength of 228 nm. did.

 〔Experimental result〕

 The experimental results for the compound of the present invention are shown in Table 15].

 Table 15

Preparation example

 When the compound (I) of the present invention is used, for example, as a therapeutic agent for blood pressure, it can be used, for example, by the following prescription.

 1. Tablet

 (1) 3 (R) -Cl (S) one-strength; 1-boxy-3- (4-bipyridine) σ-bi / u] amino-4-oxo-2,3,4,5-tetrahydro 1, 5—Penzothiazebin-5-acetic acid 10 0?

(2) Lactose 9 0 #

(3) Tow sorghum starch 2?

(4) Magnesium stearate 19 130 9 Ingredients (1), (2) and 1 79 (3) are mixed and granulated together with the base made from 7% ingredient (3). Ingredient (4) is added and mixed, and the mixture is compressed with a compression tablet machine to produce 100 tablets of female female having a diameter of 7 containing 10 tablets (1 tablet).

2 Injection-

(1) 3 (R)-Cl (S) one strength! / Boxy 3-(4 -biperidi-) broviaminnow 4-1-2, 3, 4, 5-tetrahydro 1 1, 5-benzothiazebine 5—Severe acid 1 0?

(2) Sodium iodide 99 Components (1) and (2) are dissolved in distilled water (100 OWi), dispensed into 100 pieces of brown amber, and replaced with nitrogen gas. All processes are performed under aseptic conditions.

Industrial applicability

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

V-IfO

Claims

The scope of the claims

 1 set

Wherein R ¹ and R ² represents hydrogen, halogen, Application Benefits full old Lome chill, or a lower alkyl or lower killing alkoxy, both linked Application Benefits or tetramethylene, R ³ and R ⁵ is hydrogen, lower alkyl or aralkyl, R is hydrogen or lower alkyl, and R ⁶ is a condensed or non-condensed heteroalicyclic having at least one Ν, 0 or S. as a ring atom. Represents an alkylene chain; n represents 1 or 2

Or a salt thereof.

2. The compound according to claim 1, wherein R ¹ and R ² are hydrogen.

3. The compound according to claim 1, wherein R ⁴ is hydrogen.

4. The method according to claim 1, wherein R ⁶ is a fused or non-fused heteroalicyclic group containing at least one M, 0 or S which may be substituted with 0 or 1 substituent as a ring-constituting atom. 1 The compound according to 3 above.

4. The compound according to claim 1, wherein R ⁶ is optionally substituted quinazol, thiol, piberidyl or 1,3-dioxoisoindolinyl.

6. The compound according to claim 1, wherein R ⁶ is an optionally substituted oxal, thiol, or biperidyl.

 7. The compound according to claim 1, wherein n is 1.

OMPI

Ί ⁰ .

2. Equation (a)

R

 6

A

 W c I

 a H

 Wherein each symbol is as defined in claim 1.

 C

 o

 By subjecting it to a water ring closure reaction o] ?, or

 R

 Three

 Equation (b)

 Wherein each symbol is as defined in claim 1.

[Wherein W ^a represents a halogen or a group represented by the formula R ^a S0 ₂ — 0— (where R ^a represents lower alkyl, phenol or p-tolyl), and other symbols are Having the same meaning as defined in claim 1), or

 Equation (c)

 Wherein each symbol is as defined in claim 1) and a compound represented by the formula

W ^D — Cn n-one C00R ⁵ [In the formula, W ^b represents a halogen or a group represented by the formula R ^b S0 ₂ —0— (wherein R ^¾ represents lower alkyl, phenol or p-tolyl), and the other symbols are With the same meaning as defined in paragraph (1)]))), or

 Equation (d)

 Wherein each symbol is as defined in claim 1) and a compound represented by the formula

H ³ — 0— C-C— A— R ⁶

 II II

 0 0

[Wherein each symbol is as defined in claim 1], a compound represented by the formula (I) wherein R ⁴ is hydrogen by condensation reaction under reducing conditions; Or

(e) Equation 00R ³

[Wherein Z represents a protecting group which can be eliminated by hydrolysis or catalytic reduction, and the other symbols have the same meanings as in claim 1]. To obtain a compound of formula (I) wherein R ⁴ is hydrogen, or

OMPI

,, ヾ, Equation (f)

[Wherein each symbol is as defined in claim 1], is subjected to a solvolysis reaction to obtain a compound in which R ⁴ is hydrogen in the formula (I), or

 (g) expression

Wherein each symbol is as defined in claim 1) and a compound represented by the formula

[In the formula, a group R ⁶ is represented as

The other symbols have the same meanings as in claim 1.] The compound represented by the formula (I) is subjected to a condensation reaction under reducing conditions, and in the formula (I), the atom in the group R ⁶ bonded to the group A is a nitrogen atom. Obtains a compound that is

 Equation (H)

CnH ₂ n-C00R ⁵ Wherein each symbol is as defined in claim 1) and a compound represented by the formula

Wherein, W ^c is halogen or wherein R ⁰ S0 ₂ - 0- (wherein, R ^c is lower alk kill, illustrating the phenyl or p- Torinore) represents a group represented by, Y is a ring-constituting atom group And the compound represented by formula (1) represents a group represented by NY], to obtain a compound in which the atom in the group R ⁶ bonded to the group A in the formula (I) is a nitrogen atom, or

in (i) formula (I), the by the subjecting the R ³ is a lower alkyl or / and R ⁵ are lower § Ruki compound to a hydrolysis reaction or an elimination reaction] in ?, formula (I), R ³ Is hydrogen or a compound wherein Z and R ⁵ are hydrogen, or

(j) In the formula (I), a compound in which R ³ is a pen or and / or is a benzene is subjected to a catalytic reduction reaction, whereby in the formula (I :), R ³ is hydrogen and / or H ⁵ is hydrogen. Obtaining a compound that is

(k) In the formula (I), a compound wherein R ³ is hydrogen or Z and R ⁵ are hydrogen

R ³ - 0H

Or expression

R ⁵ one 0H

Wherein, R ³ preliminary R? Represents a lower alkyl or Aworukiru] by the be subjected to a condensation reaction a compound I Table in, in formula (I), R ³ is lower alkyl or § la kill or / and Obtaining a compound wherein R ⁵ is lower alkyl or aralkyl, or

(1) In the formula (I), a compound in which R ³ is hydrogen or Z and R ⁵ are hydrogen

O PI WIPO Things and formulas

R ³ — W ^d

Or expression

R ⁵ one W ^d

[Wherein, R ³ ″ and R ⁵ ″ represent lower alkyl or aralkyl, W ^d represents halogen or a formula Rd _S 02—0— (where R ^d represents lower alkyl, phenol or P -Representing a group represented by -tolyl)], wherein in formula (I), is a lower alkyl or aralkyl and / or R ⁵ is a lower alkyl or aralkyl. Get the compound, or

(m) In the formula (I), a compound having benzoimino or ashimino in the group R ⁶ is subjected to a catalytic reduction reaction, an elimination reaction or a solvolysis reaction, whereby the group R in the formula (I) Obtaining a compound having an unsubstituted imino in ⁶ , or

 (n) In the formula (I), a compound having an unsubstituted imino in the group is represented by the formula

R ⁷ One W®

Wherein, R ⁷ represents a lower Arukinore _t Aworukiru or Ashiru, ¾Ganma ^theta is halogen or the formula Rss0 ₂ - represented by - 0- (indicating Le or P- tolyl wherein, R ^e is a lower alkyl, Hue) A compound having a lower alkyl, aralkyl or imyl substituted in the group R ⁶ in the formula (I). Or

 (o) In the formula (I), a compound having an unsubstituted imino and a lower alkyl aldehyde or an aralkyl aldehyde are subjected to a condensation reaction under a reducing condition to obtain a compound represented by the formula RS Low-grade archi or ara

(OMPI Obtaining a compound having imino substituted with alkyl, or

(p) a compound having an unsubstituted imino in the group R ⁶ in the formula (I)

(R ⁷ ') ₂ 0

[Wherein R ⁷ 'represents acyl]. ), In the formula (I), a compound having an acylimino in the group R ⁶ is obtained, or

(q) subjecting a compound in which R ⁴ is hydrogen in the formula (I) to an alkylation reaction], to obtain a compound in which R ⁴ is a lower alkyl in the formula (I), and By

 (r) The method for producing a compound or a salt thereof according to claim 1, wherein the obtained compound represented by ^ (I) is converted into a salt.

OMPI

WIFO