WO1986000618A1 - Condensed 7-membered ring compounds and process for their preparation - Google Patents

Abstract

Novel condensed 7-membered ring compounds represented by formula (I), (wherein R1 and R2 each represents hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy or, when taken together, they represent tri- or tetramethylene, R3 and R5 each represents hydrogen, lower alkyl or arakyl, R4 represents hydrogen or lower alkyl, R6 represents a condensed or non-condensed hetero-alicyclic group containing at least one N, O or S as a ring atom, A represents an alkylene chain, and n represents 1 or 2) and salts thereof. These compounds and their salts are effective in inhibiting angiotensin-converting enzyme, and are useful for diagnosis, prophylaxis, and treatment of circulatory system diseases, e.g., hypertension, heart disease or apoplexy.

Description

 Mysterious book

 Condensed 7-shell coral compound: ^ and its manufacturing method

Technical field

 The present invention is useful as a medicament. Although various compounds having angiotensin-converting enzyme inhibitory activity are known, a compound having a condensed 7-membered 基本 as a basic skeleton is a 3-port pupa Patent Publication No. 723552 * C Only what was done *

 We have angiotensin!素 醇 ¾ 高 作用 »卒 卒» 卒 卒 卒 卒 卒 卒 卒. As a result of diligent search for a compound useful as a compound, a 7-condensed compound having excellent action was successfully produced, and the present invention was completed.

 Ming disclosure

 The present invention uses the formula

[Wherein, R ¹ and R ² each represent hydrogen, halogen, trifluoromethyl, lower aki or lower oxy, or rain or swiftly form tri or tetramethylene, and ^ "tit, hydrogen, lower aki or araki, R ⁴ is hydrogen or lower aki, S ⁶ is a condensed or non-fused complex containing at least 1, 0 or S as a ring atom A represents an acetylene chain, _n represents 1 or 2) and its method of producing K and K.

ΟΜΡΙ ₀

According to the above formula (I) tC, the halogen represented by H ¹ or E ² includes, for example, fluorine, nitrogen, bromine, and tertiary oxygen, and lower alkoxy represented by R ¹ or ttR ^2. Examples of the group include methoxy, ethoxy, buta-poxy, y-broxy, butoxy, isobutoxy, << — butoxy, ter-butoxy * Akoxy group having about 1 to 4 carbon atoms. In addition, R ¹ spare S ² is, rather it may also form a A Killen Lou and the rain's, trimethylene, A Killen Bridge, and the like, such as ^{tetramethylene, H 1, R 2, R} 3, there is R ⁴ methyl example is a lower a key group represented by R ^5, Chi, Burobi, isopropoxy bi, Petit, I, knobs Ji, «- butyl, ter - the a kill group Buchi * which number 1 to 4 § of carbon can give.

The § la key group represented by R ³ or Y ^[delta] for example benzylidene, Fuenechi, three to Fuenirubu building group, «over Ji Penji group, - E Ji Penjiru radical, a one Mechirufuenechi group ₃ beta one methylcarbamoyl u phenethyl, beta -Ethene group A lower (_ aki group) of which has about 7 to 10 carbon atoms.

As a condensed or non-fused heterocyclic group represented by R ⁶ and containing at least * 1 at least one W, 0 or S as a ring-constituting atom, a saturated or «min ft In the case of a heterocyclic ring containing a heterozygote on 2β (C may be the same kind of atom or two or more kinds of atoms may coexist as a ring-constituting atom, for example, oxeta -, Thieta, azetzi, tethydrov 9, tetrat droche, biloli zini, oxa-(3, 4, 5, 6-tedrhidraw 2 H-villa-), cheat, bilidil, and kissiba -, Ceva, Perhi droazebiru, O Small Kisoriki, Chiokaji, Perhydroazo ^-/ w, Dioxur, Zixa, Biperazini, Hori-, Bahidrothiajel, Kissiati, Perhydrodiazebu, Kisachepa / 1, Zixa Kisepa, Dicepael, Perhid Mikisazebu, Perhidrothiazebi, Pert droxazosini, Perhidrothiazo ^, Taikisachi, Perhydrodiazo- / V, Zhiocani, Dioxocani, Kusomah, Doroshoji 2 Η— 1-thianaphthia, 3,4 dihydro-1H—2-thianaphthium, 1,2,3,4-tetra ¾: drokinori, 1,2,3,4-tetrahydroisoquinoli, 2,3-dihydropenzafuri , 1,3-Dihydroisobenzofuri, 2,3-Dihydrobenzo ["b] ch-, 1,3-Dihydrobenzo [c] chal, indrier, isoi Drill, 2,3,4,5—tetrahydro 1 (1H) —Penazebul, 2,3,4,5—tetrahydro 3 (1H) —Benazebul, 2 ^ 3 ^ 4,5 -Tetrahydro-2C1H) 1-Penzozeby, 2,3,4,5-tetradose 1-Penzoxebul, 1,3,4,5—Tet-dro draw 2-Penzoxe w, 1,2,4,5-tetrad Draw 3—Penzo-Kisepi = 2,3,4,5-Tetrahi Draw 1 Benzochebul, 1,3,4,5—Tetrat Draw 2—Venzochebul, 1,2,4,5—Tetrahi Draw 3—Penzocheby, 2,3—Jihi draw 1,4,1—Pizodzoquish, 2,3—Jihi draw 1,4,1-Dithianafti, 1,2,3,3,4-Hydroquinoxali-, 3,4—Jihi draw 2H — 1,4,1 Penzo-aged Kisaziru, 3,4, Zihi-Draw 2H—1,1-Penzothiazyl 2, 3 dihydric draw 1, 4 one base Nzookisachu, 3, 4 Jihi Draw 2 H- 1, 5-base Nzodzu old Kisepa -, 2, 3 dihydric draw -1, 1-Benzodioxeby, 2,3, 4, 5-Tetrahydro-1 H-1, 5-Penzodiazeb, 2, 3, 4, 5-Tetrahydro 1 H-1, 1-Penzodiazeb ^, 3, 4-Zhihi Draw 2 H-1, 51-Penzodichebi, 2,3-dihydro-5 H-1, 1-penzodiche-beil, Part-t-Drawin 9, Part-Droisoindolyl, Part-de-Mouth Kinori, Parth-Droisokinori, Part-Draw 11 Chianafti

, Perhidraw 2-thianaphthyl, and any herbal or bicyclic alicyclic group.

該纖case or Hichijimikai heterocycloaliphatic璣基the killing low for example置裏friendly tlg ¾ position (Ci one ₄₎ alkyl group (methyl, E Ji, blanking bi, butyl) old Kiso,

C l-5 akanoy (, acechi, brobi), benzoy, fu 一 袋 (¾1 -4) コ 力 力 例 例 (eg, 、 低 ジ ル,), low-grade C Ci-4) Alkoxy carbole (eg, ter-butoxy) ガ ァ 基 フ ナ ナ ¾ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァ ァIt may have a (Cl_4) group as a substituent. An aryl group or a lower ethyl group as the substituent;

7 E group further fluorine, ¾ arsenide, bromine any halogen, methoxy, E butoxy, Puroboki ^, butoxy how low毂(C _{1 - 4)} A Kokishi, methylcarbamoyl, Echiru, blanking bi, butyrate which lower (one ₄₎ A It may be replaced by g. Examples of such interspersed condensed or non-condensed heteroalicyclic groups include, for example, 1-ferviperidi, 1-pendiviperidi, 1-furbiperidyl, 1-pendibiperidi, 1-acetibiperidyl, 1 One Penzo Biradil, One Ferni Bildaj; V, 4-Ace Biperaziru, One Penzo Biperaj, One Chile Dorinyl, 1,3 dioxoisoindori-, 1,2,3,4-tetratetra-dose 1-year-old xoisoquinolyl, 1,2,3,4-tetrahidroxy 3-oxoisoquinolyl 4 groups Is raised.

The A Quillen chain represented by A for example linear or branched A Killen chain of 1 to 1 about 6 carbon atoms can be mentioned, Kisamechi such as methylene, E styrene, preparative Rimechiren, tetramethylene _s pentamethylene, to Ren, hebutamethylene, octamethylene, nonamethylene, decamethylene, pendecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, pentadecamethylene, hexadecamethylene, provylene, ethylmethylene, 4-butyhexamethylene, 3,3-dimethyl Hexamethylene, 5,5—diethylhexamethylene, 3,5-dimethylnonadiethylene and other two superior groups. The alkylene chain may have an uncomplexed bond (eg, a double bond or a triple bond) in the chain.

 The two dominant groups denoted by Cn 镓 n are methylene, ethylene or ethylidene, depending on the 镓 of n.

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

Table A

Replacement OMPI one

Replacement.

8 οl] d df / ε9δο /-

00

One S—

Replacement 89Ϊ9 / 8-one l: cif /> 0t * d C9c0 /

df / l: s o / one

00

— U—

 The present invention, ^ * (I), has an asymmetric carbon in the molecule, but the present invention includes the deviation of the R configuration and the S configuration. * However, it is preferable that the absolute position of the carbon in the £ (* 1) is R and the absolute position of the carbon in the £ (* 2) is S ^.

 Examples of itMs (I) include: * Mongolia, hydrobromic acid,

 珀, 酒 ェ, ェ 蒙 ど の た と え ば た と え ば, 酒, 酒, 酒,,, マ ー, メ タ ン 有 有 有, Potassium, potassium, aluminum, such as tritamine, guadin, danzium, hydrazine, kyune, cynco

-Usology such as salt with ¾¾ 樓 樓 基: acceptable soil. The compound (I) of the present invention has, for example, the formula

[Wherein each symbol is as defined above]] by applying a dehydration-closure reaction κ: The closing of the crotch can be performed, for example, by an amide bond formation in a normal peptide. Either use a peptide-forming reagent such as dicyclohexica posimidide,, 1Ϊ, -force / V pozimidazo, diphenophosphate azide, or ^ thiophosphoric acid alone, or Then, a normal nucleic acid-free (eg, hydrogen chloride,, acid, bromine) is added to brominate the amino group of the compound (I), and then, for example, 2,4,5-trichlorophenol / w , Pentachlorophenol, bentaf phenol, 2-Etropheno or 4-1-trophenol * Which phenols or If hydride Lokisk ^ imid, 1-t-droquin ^ benzotriazole, ir-hydroxy y biveridine ¾ which] ヒ キ シ キ シ 縮合 縮合 縮合 縮合 縮合 縮合 さ せ 縮合 縮合 さ せ 縮合After conversion to ester form t, it is converted to iC to form 2: In the case where the compound is converted to the activated ester of the compound (I) as it is or the compound (I), the organic compound is preferably an organic group, for example, a quaternary ammonium compound or a tertiary amine. (Eg, Triethamin, H-Metibiperidin) can be encouraged. SJSfi degree usually - 2 0 + 5 0 Dea, preferably room location near der, as usually for Ru »medium e.g. Jiokisan, Tet, Dorofuran, Aseto - tri ₉ Pyridine, N, 1I- dimethylcarbamoyl ho Muamido, Η, »—Dimethylacetamide, Dimethisoxide, ir-Methylpyrrolidone Chloroform, Idimethylene *, etc., which may be used alone or as a mixture.

Also, the present compound (I) has the formula (summer)-

 Cn¾ n-C00R °

 Where each ¾ is the same as the previous £.

R ⁶ -A-CH-C00R ³

 I (ΒΓ)

¥ ^a

Wherein, TT ^a halogen or the formula R ^a S0 ₃ - 0 - (wherein, R ^a is a lower A key, preparative riffs Oromechi, Hue - Le or p - shows a bird) a group represented by the other Can be also produced by reacting a compound represented by the formula [epsilon] having the same meaning as defined above. J¾s is usually water or other fiber (eg, acetate-tolyl, dimethiformamide, dimethiformide)

+ Replacement One 1, —

 It can be escaped by keeping the moat in the range of −20 to 115 S in a mixed or mixed solvent of oxide, tet, hydrofuran, benzene, and toluene). For the purpose of the above-mentioned speeds, for example, sodium carbonate, 1H sodium hydroxide, 9 carbon sodium hydrogen, pyridine, and triethamine * any: * groups can coexist in the reaction system.

 The compound (I) of the present invention is, for example, a compound of the formula (V)

 Where each pound sign has the same meaning as above.

¥ ^b -CnH ₂ n-C00R ⁵ (W)

Wherein, lT ^b is halogen or wherein R ^b S0 ₂ - 0- (wherein, R ^¾ lower A key, triflumizole Ruo Russia methyl, Hue - or p- tri showing a) at approval a group I Table However, other ¾ symbols have the same meanings as in the above.). The reaction is carried out in a single or mixed state with water or other exchangeable solvents (eg, acetate, dimethylformamide, dimethylphosphoxide, tetrahydrofuran, benzene, toene). This can be achieved by maintaining the humidity in a moderate range. This K, for example, sodium radicals such as sodium charcoal, sodium hydroxide and sodium hydride can coexist in the ^ system.

In formula (I), compounds Eta ⁴ is hydrogen, for example the formula

 [Wherein each symbol is as defined above]

Spear _s 3 -ocCAR ⁶

 I! II C W)

 0 0

[Wherein each pound sign has the same meaning as described above].

 The reducing conditions include, for example, catalytic reduction using platinum, palladium, -dimethyl or a mixture of these and any carrier. For example, lithitamaminium hydride, lithium borohydride, ^ a Gold hydrides such as lithium borohydride, sodium borohydride, sodium borohydride κ: reduction by gold, sodium sodium, metal magnesium, carrier by doco and alcohols J, iron by iron With metals: ¾δ conditions such as reduction with acid, acid, electrolytic reduction, and reduction with reductase t can be mentioned. The upper £ ®δ is usually measured in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chlohom, penzentoluene, acetic acid, dimethylformamide, dimethylacetamide). Although the reaction humidity varies depending on the source, it is preferably about 120 to +100 per coat. 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

w,

[In the formula, Z represents a protecting group which can be eliminated by hydrolysis or bonding, and other symbols are as defined above. Has the hydrolysis of the compound represented by One IS-i can also be manufactured by the contactor ^ iSic ^. (What

 As the protecting group which can be converted to K by the hydrolysis represented by z, all kinds of α- and trithi groups can be used, but, in particular, benzyloxyboel, tert-butoxycarpo-, trifoacetyl, tri- δ Chi is relatively relaxed. Examples of protecting groups which can be separated from JK, such as benzyl, diphenylmethy, and benzyloxy, are given below. This method ic * hydrolysis is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, vinegar, acetate, methylene dichloride, etc. For acid (

 Cyanide, bromine, hydrogen iodide, hydrogen fluoride, diatom, methanesulfonate, p-toluenesulfonate, trifluoroacetic acid) or a group (eg, sodium hydroxide, sodium hydroxide, carbonic acid) Potassium, sodium bicarbonate, sodium nitrate, and triethamine) can be added. s The above reaction is usually carried out in the range of about −20 to +150. In addition, the contact reduction reaction in this method can be carried out with water or, for example, methano-, ethanol, dioxane, tetrahydrofuran. * Any organic solvent or a mixture thereof, for example, platinum, palladium-carbon, etc. Performed in the presence of a solvent. This reaction is carried out at normal pressure or at a pressure of up to 150 ^ Z ¾ ° C and at a temperature of normal humidity of 0 to 150 ° C.

 In the formula (I), R * is hydrogen, for example,

Replacement (X)

Ca¾ n-C00R ⁶

 [Where each pound sign is as defined above. Can be produced by subjecting the compound represented by the formula

 JJB solvolysis is carried out in water or, for example, in methano-, ethanol, dioxane, viridine, drunk test, acetone, methylene dichloride, or a mixture thereof. Acids (eg, hydrogen iodide, hydrogen bromide, hydrogen iodide, fluorine, «S, methanesulfonate, p-toensulfonate, trifluoro, acidic resin) or の た め

(Eg, sodium sulphide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium cocoate, trietiamin) The reaction which can be performed is usually −20. In the present invention ^ ί (I), the group bonded to the group :: If the atom in ^ is a nitrogen atom, for example, the formula

(¾,

[Wherein each symbol is as defined above]

[In the formula, X represents a constituent atomic group, and-represents a group ⁶ as-<^:> Χ]. — IT—

Can be built.

 Examples of the essential conditions include platinum, palladium, and platinum, which are a mixture of any metal and any carrier as a carrier, for example, lithium aluminum hydride, lithium borohydride, cyanohydrogen. Lithium borohydride, sodium borohydride, sodium anodium borohydride, etc. Gold-shung hydride 4C carrier, gold-sodium sodium, metallic magnesium * Reduction by irons, iron, etc. The reaction conditions can be raised, such as the reduction of any metal and acid or acid such as persulfate, reduction of acid, reduction with the source enzyme t, ordinarily water or organic (eg, methanol, The reaction is carried out in the presence of ethano pendant, ethiate / W, virgin oxane, methylene chloride, glume hom, benzene, toene, rich acid, dimethylformamide, dimethylacetamide. Although I go-between Ru different to one in ¾ -! 2 0 Te ~ + 1 0 0 is preferably about. 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 compound (I) of the present invention, when the atom in the group which associates with the group A is a nitrogen atom, for example, the compound (I) may be a compound represented by the formula (X Xia) wherein W ^c is halogen or Represents a group represented by the formula R ^c S0 ₂ -0-(where R ^c represents lower aki, trifluoromethy, hu- or p-tri); Represents a constituent atomic group, and represents a group R ^e as a formula-: ΐ〕) .The reaction can be carried out using a suitable solvent or a mixed solvent. About 0 ~ 10 15

ΟΜΡΙ Run by keeping in the temperature range. The purpose of maintaining the reaction speed

In the reaction system, for example, potassium groups such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, viridine and triethyamine can be coexisted in the reaction system.

In formula (I), H ³ is of Group wherein Z and E ^S is hydrogen is hydrogen, the formula (I) in, E ³ is lower A key or Z and H ⁵ is a lower A key

M by subjecting it to a hydrolysis reaction or

And in formula (I), I? Can also be produced by contacting with a penge or z and R ^s are penges.

 Can be. The hydrolysis or κ-elimination reaction in this method is water or tobacco, such as methanol, ethanol, brewery, clomethone, tetrahydro: orchid, dioxane, viridin, acetic acid, acetate, and methylene dichloride.

The reaction is carried out in any organic solvent or a mixture thereof, and the acid (eg, hydrogen hydride, hydrogen bromide, fluorinated fc *, hydrogen iodide, «, methanesulfonate, P-toenphone, trifon) Acetic acid or base (eg, sodium hydrate, potassium hydride, potassium carbonate, sodium bicarbonate, carbonate)

It can also be performed by adding sodium and sodium acetate). The above reaction is usually performed in a range of about 120 to about 150. In the present method, the reduction reaction may be carried out with water or a solvent such as methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran or any other solvent or a mixture thereof. It is done in the presence. Under a pressure of the reaction until atmospheric pressure or 1 5 O iv Ot ² about, room temperature

 It is performed at S degree of +150.

In formula (I), is lower alkyl or Araruki some and E ⁵ is a lower A key or a is of meeting product Araruki is In formula (I), O PI Compounds wherein R ³ is hydrogen or Z and R ⁵ are hydrogen

R ³ , -OH (W) or formula

The compound can be produced by condensing SJS with a compound represented by H ⁵ ′ -OH (XV) [wherein 'and H ⁵ ' represent lower aki or araki]. The condensation conditions include, for example, reaction conditions using a condensation reagent (eg, dicyclohexacapide, capodiimidazo, cyanophosphate jet, difluorophosphate azide), or acid transfer arrowhead ( For example, it is possible to increase the conditions under which hydrogen peroxide, t * bromine, and p-toluenesulfonic acid) are used. Anti-appropriate * In a solvent or mixed solvent, or in the absence of a solvent-progresses in a fi degree range of -20 to ₁₅₀

In formula (I), Eta ³ is lower alkyl or § la kill or / and is a lower A key or § la key compounds In formula (I), but in Bruno and R ⁵ are hydrogen is hydrogen Certain compounds have the formula

"-r ^d (XVI) or expression

R ⁵ "-Wi (()

[Wherein, R ³ ″ and R ⁵ ″ represent a lower aki or alkenyl, and ^ represents a halogen or a formula R ^d S 02-0-(where R ^d is a lower aki, a trimethylmethacrylate, a phenol) Or a group represented by p-tolyl)] can be produced. The reaction proceeds in a suitable solvent in a fi degree range of about −20 to +150 in the presence of a base (eg, potassium potassium, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate). ", (_ΟΜΡΙ In the present invention, when (I) iC has a C unsubstituted imino group in the group R ⁶ , a compound having a benzimino group or an acyimino group in the group R ^e in the formula (I) Is a reduction reaction, »鎵 reaction is a decomposition reaction

 And i can be built.

 In this method: * The reduction reaction is performed in water or, for example, methanol, ethyl acetate, ethanol, dioxane, tetrahydrofuran * which is attached in R purple or a mixed solvent thereof, for example, palladium-carbon. Performed in the presence of a medium. This reaction is carried out at normal pressure or at a pressure up to about 150 at a humidity of +150.

 In addition, the reaction is carried out in water or, for example, in water or, for example, methano-, ethanol, thiocyanate, chloroform, tetradro7-lane, dioxane, pyridine, acetic acid, acetate, methylene hydride. * The reaction is performed in any organic solvent or a mixture of them, and is performed in an organic solvent (eg, hydrogen peroxide, hydrogen bromide, hydrogen fluoride, iodine, acid, methanesulfonate, p-transferonic acid, trifluorene). Vinegar, or sodium hydroxide (eg, sodium hydroxide, sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, sodium carbonate, sodium acetate) Can also. The above is usually performed in the range of about 120 to about 150.

Formula (I) in the group R ⁶ in the lower (C i - ₄₎ A key, § La key Moshiku compound having a substituted imino group § Shi, the formula (I) Medium group ^ϋ β Κ No Compounds with substituted imino groups and formulas

 ー (XW)

Wherein, S ⁷ is lower A key indicates § La / w key or § Shi, halogen or the formula E ^ S0 ₂ -0 - (In the formula, H ^e is lower A key, preparative riffs Oromechi, Hue - Or P-tri)) «Replacement OMPI

J Can be obtained by S) S. The reaction proceeds by maintaining the temperature in the appropriate four solvents at a temperature in the range of about 120 to about 150. At this time, for the purpose of promoting the reaction rate, it is possible to coexist, for example, potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine and triethylamine in the system as an acid oxidizing agent.

The compound having a substituted imino group by the formula (I group E in ⁶ 4C in :) lower (an alkylene or § la key has the formula (I) of Group compound having a group iC unsubstituted Imino groups in It can also be obtained by condensing a lower (C _1-4 ) aldehyde or a carboxylic acid under reducing conditions.

 Examples of the reducing conditions include contact reduction using a catalyst such as platinum, palladium, rhodium or the like or a mixture thereof with an optional carrier, such as lithium hydride, lithium borohydride, cyano hydride. Lithium borohydride, sodium borohydride, sodium cyanoborohydride Spectroscopy due to metal hydrides, reduction with sodium metal, gold magnesium and other alcohols, iron, sub-dust It is possible to raise the reaction conditions such as which metal is used, and the reaction conditions are homogeneous by acid such as acetic acid and enzymatic acid; The above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol, ethetate, dioxane, methylene chloride, chloro-T3 hom, benzene, tween, drusic acid, dimethyl / 1 dimethyl amide, dimethyl The reaction is carried out in the presence of (1,000 acetamide), and the reaction temperature is different depending on the reducing means. This reaction can be carried out under normal pressure, but the reaction may be carried out under pressure or under reduced pressure, if necessary.

In the case of a compound having an amino group in the group ミ ノ β of the formula (I), One 2ί_

(I) A compound having an unsubstituted imino group in 0¾R ⁶ and a compound represented by the formula

(E ^7,) in ₂ 0 (XK) formula,: s ⁷ 'can also be leading frame manufacturing Therefore to be represented are of Association was in showing the § shea] ^.

Progress by keeping the rain in the S degree range of about 120 to +150 in water or a suitable twisted solvent, or a mixture thereof. 85, For the purpose of speed ^ i, groups such as carbonated lithium, sodium hydroxide, sodium hydrogencarbonate, bilizine, and triethylamine can be coexisted in the system as an emulsifier. ₀ ·

In formula (I), a compound in which R ⁴ is a lower radical can also be produced by subjecting a compound in which R ⁴ is hydrogen in formula (I) to hydrogen. .

Above £ § key ^: The response, as For instance lower A key (Ci one ₄₎ Kae无A key I Contact reducing conditions for reacting A dehydrogenase and under reducing conditions, such as platinum, palladium, rhodium 4 which gold羼Arrowhead reduction using catalysts and mixtures of these with any carrier, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride Reduction by compounds, sodium metal, magnesium magnesium * Reduction by iron and alcohol, reduction by iron and sub-metals and soil, acetic acid, reduction by acid, electrolysis reduction, reduction by Humoto enzyme Any reaction conditions can be given. The reaction is usually with water or an organic solvent (eg, methanol, ethano-, ethiate, dioxane, methylene chloride, chlorinated hom, benzene, toluene, drunkic acid, dimethylformamide, dimethyl acetate). Toamide), and the reaction temperature varies depending on the means of increasing the concentration, but is generally −20 to

-Replacement — 28—

 About 100 is preferable. Although the present SiS can sufficiently achieve its purpose at normal pressure, the reaction may be carried out under pressure or decompression under circumstances. ], Is a formula

R ⁴ (XX) wherein罾f is halogen or the formula S0 ₂ - 0 - indicates (where the lower A key, triflate Oromechi shows Fueyu or p- tri) groups I Table in, R ⁴ is the same as in the previous section) .Acquis fcSiS (reaction conditions are appropriate: H is mixed. For the purpose of promoting the reaction rate, groups such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine and thiamine are coexistent in the reaction system to promote the reaction rate. You can do that too.) * The compound (I) can be obtained by the reaction for producing the compound (I) itself, but it is also possible to add an acid, an alkali, and a ¾ group as needed to produce the compound (I). .

 The object I) of the present invention thus obtained can be obtained by using conventional separation and purification means from the reaction mixture, such as extraction, concentration, neutralization, 泸 逷, recrystallization, column chromatography, and thin layer chromatography. Can be separated

 Compound (I) may exist in at least the stereoisomers of 4 Rev. Naturally, these individual isomers and the difference between these compounds are also included in the scope of the present invention. If desired, these isomers can also be produced by a process. For example, starting compounds (I), (summer), (w), (v), (¾),

Using the isomers of (κ), (χ) and (I), respectively, perform the inverse of ε! ), To obtain one optical isomer of compound (I). It is possible to produce two kinds of products, and is a mixture of the above-mentioned isomer mixtures. IC is the usual method, for example, optically active acid (锊, camphorsphonic acid, Meng Tartar, Meng Teng, dipenzo liquor) ), Optically active groups (eg, cinchonine, synchidine, chi & n, chidin, amethypendiamine, dehydroavidiamine *, etc.) Each isomer can also be separated by separation means such as chromatography, separation and recrystallization.

 The compound of the present invention, ie, the condensed 7-membered compound represented by the formula (I) and the compound thereof are referred to as animals]), sputum animals (^, humans, dogs, cats, egrets, momots, Butto) and its inhibitory action on amphoterin converting enzyme, butadiene-decomposing enzyme (quinase).

 It is useful as a diagnosis, prevention or treatment for cardiovascular diseases such as heart fibrosis and stroke due to high pressure. Since the compound of the present invention has low toxicity, absorbs well even when administered orally, has excellent kneading properties, and is also excellent in stability, it can be used by itself or as appropriate pharmacologically when used as a medicament for medical treatment. It can be mixed with an acceptable carrier, pharmaceutical preparation and diluent, and administered as an oral or parenteral pharmaceutical preparation such as powder, granules, pharmaceutical preparations, cabose preparations, and injections. The dosage varies depending on the condition of the target disease and the administration route.For example, when administered to adult breathing subjects for the treatment of Xus or genuine hypertension, one dose is usually 0.02- About 10

About 0.02 to 2WZ * ?, specially about 0.04 to 0.8WZi ?, but about 1 to about 0.002 to 1 for single dose administration, especially about 02 to 1WZ * y, especially about 0.02 to 0.2 It is preferable to administer these crotch doses about 1 to 3 times a day, depending on the symptoms, and about 1 to 2 times. Raw material compounds of the present invention (), (a), (V), (W), (κ), (x) — 2δ— and (21) can be easily manufactured, for example, by a method represented by the following J¾S equation.

S-C? ^HS

S— CH ₂ side

R ⁴ A-R ⁶ CH-K-CH-C00R ³ "

C00H (XV) 2) W¾-Cn¾ n-COOR ⁶ (VI)

as (_OMPI — 2i—

R ²

 OMPI

Replacement W1PO

(x)

00R ^s

OMPI

WIPO Ά One 2 j one

_h £ in Scheme, a halogen or Jiazoyuumu group, ws during halo gen or formula R ^g S0 ₂ -0- (wherein, H ^s is lower A key, preparative riff O b methylate, Hue - or p - tri The other pound signs are as defined above.

 The method for producing the compound (I) represented by the above reaction formula will be described in more detail. When cystine (XXI) is converted into a compound, cysteine is derived, and the compound (XXI) is reacted with the compound (XXI). To produce the compound (ΧΜ). Conversion

(XXM) and (W) are the same as ^ of chemical compounds (W) and (W): 行 & of _β (»0 ^) → (50 ^) that can be performed is usually © key ^ ¾ : Dea D, for example, a lower a key a de κ de corresponding to group R ⁴ reduction ^ under

The compound (2) can be formed by adding the compound (2) to the compound-fe (xv) by applying the following reaction to the normal -toro group to the amino group. You can get it.

 In the method for producing the compounds (1) and (W), the amino group of the compound () is protected with an appropriate amino-protecting group (eg, a phthaloy group) to obtain the compound (II) first. In this reaction, the compound (XXVI) is converted to a compound (CXXVI) in an aqueous solution in the presence of a compound (XXVI) and a base (eg, sodium carbonate, carbon monoxide, potassium hydrogen carbonate), usually at about 0 to about 100. Easily progresses at a temperature of a

The reaction of (XXM) → (XXK) is a transfer reaction of a -toro group to an amino group, H, and a usual well-known method can be used. The reduction can be performed by, for example, paradigm-single-carbon, varium-supported palladium, sulfide-palladium _β- platinum *, or sensitized reduction using sensitized medium, or lotus powder, tin, ^ -tin, iron, etc. Reduction with metals and acids or iron * is used. The water ring-closure reaction of the compound (XXK) thus obtained to the compound ^ * (XXX) is usually performed in the presence of a known condensing agent.

'' -28—

I can. Examples of such hydrocondensation include dicyclohexica pomidide, power poimidimidazo, and ア anoline dijet. As the solvent, for example, dioxane, methylene dichloride, acetate-tri, ΙΤ, dimethyiformamide, tetra-t τ »furan, and the like are used, and the reaction is usually performed at a fi degree range of about 110 to about 100. Be performed. For the purpose of favorably proceeding the reaction of the above, it is also possible to add triethyl / V-amidine pyridine to the anti-nitrogen as a sensitizing agent. Condensation reaction between compound (X) and (w) * Production of compound (xa) by sodium hydride, carbonated lime * W, ίτ-dimethyl _/ «e in the presence of any soil group It can be produced by condensing in a solvent such as muamide, dimethyl sulfoxide, or acetate v in a temperature range of about -10 to about 100. Next, the reaction of (xxa)-(w) is hydrazine hydrate in methanol, ethanol, and dioxane. The processing can be performed within the range of about +100, and the chemical compound (w) can be eliminated.

 ^ In (¾) → (¾) is a normal radical reaction, for example, a method in which a low-acid aldehyde corresponding to the group R * is reacted under reducing conditions, or a compound (XX) is appropriately And the like.

 Compound (V) is obtained by converting compound (XXV) to an amino group

% S: can be produced by subjecting to K water ring closure ^. Compound (XXXI) can be produced by attaching a known amino acid-protected amino group to a compound (XXXI) in the production method of compound (1) (K). The reaction of (XXXI) to → (K) is carried out by keeping the appropriate 4¾ϋ neutralization ^ χχχκ) and (W) in the range of -20 to 10150 *.锐 Acidic agents such as potassium carbonate, sodium hydroxide, sodium hydrogen hydrogen, bilizine, trieti OMPI (1) A group such as an amine can coexist in SJg: system. In the production method of compound CX), compound (X) can be obtained according to known stripping force-(atrecker) SjSi using compounds (W) and (XXHY) and cyan as raw material ^ T. it can.

 In the process for producing compound (π), compound c xxxw) can be obtained by reacting compound () with (XXXV). Examples include aceturi, methyl I ketone, acetone, and tetrahydrofuran.

 Himethylene, dimethyl sulphoxide, dimethyl sulphamide and the like are used, and usually ^ is within a range of about 110 to about 150 in a quantitative range. With tretamine, pyridine, potassium carbonate, sodium carbonate, etc., and potassium iodide, etc. to fend off ^ jg in an advantageous manner: ftr ^

Sale-Can be sold. (XXWO— (XXXW) SJS can be done by * C in the same way as (ΧΧΠΓ) — (XXV) ^), and (XXW) → (2) S is (XXXI) — (VI) SiS The compounds (W) and (W) used in the production of the compound (I) of the present invention can be easily produced, for example, by the method tc represented by the following formula (1). You.

C XX ») ^{11 11}

 0 0

 or)

R ⁶ -A-CH—C00R

 OH

β ₃ ""

R -A-CH-C00R ^s- > R ^6- A— CH— CO OR ³

 a

'' OMP! ヽ -SI—

In the reaction scheme, R ³ ′ and R ³ ″ each represent lower aki or araki, and the other symbols are as defined above.

 The compound (W ') is prepared by combining the compounds (XXXVI) and (XXIX) in the presence of, for example, sodium methoxide or iodine. By doing so, it can be manufactured. The compound (w ′) can be produced by subjecting the compound (ring) to a known halogen 還 or sulfo- ^ by subjecting the compound (ring ′) to a known reduction. .

 The starting compound (XXVM) used here is, for example,

R ⁶ — Α, one CH— C00IT

[Wherein T ¹¹ represents a halogen, A, represents A as A, -C 、, and the other symbols have the same meanings as described above.] It can be easily manufactured.

When R ⁶ contains a group that may affect the reaction, the group may be, for example, low (C i-5) akanoy (eg, aceti), penzoi, fue lower (Cl-14) akoxy Power ^ Po (eg Benji ^

-, Lower (Ci-14) alkoxycarbo (eg, tert-butoxycarbo)-The reaction may be carried out with any protecting group.

In the formulas (W,), (IL) and (ΒΓ,), a compound in which R ³ is hydrogen is obtained by subjecting the compounds (′), (IL) and (ΠΓ ′) to a hydrolysis reaction, respectively)) Can be manufactured.

In the formulas (rings) and (IV), a compound in which R ⁶ is 4-biperidi even if R ⁶ is substituted is a novel compound], and the present invention is useful during the synthesis of 4 novel compounds c I) Is industrially advantageous as .. formula (w) and ■ ― 82―

l In (1), it also includes a compound in which: & ⁶ is 4-biperidi even when substituted.

 In the above method for producing compound (I) and its intermediate, the compound used for anti-JSi does not hinder the reaction, such as acid, hydrogen bromide, sulfuric acid, sulfuric acid, and sulfuric acid. Clay, dephosphoric acid: Which inorganic soils, such as tonacetate, liquor, citric acid, fuma, maleic acid, Tohshong, ¾, methanance; Sodium ash, potassium, potassium, aluminum, etc., for example, sodium chloride, guadin, ammonium: lime, hydrazine, küne,壤 壤 ¾ ： ： ： ： ¾ ： ： ： ¾ ： ： ： ： ：

 The best form to enlighten Ming

 Actual travel example 1

 Dissolve S- (o--trohue-)-L-cysteine 9- in sodium carbonate 1.4-aqueous solution (20) and add stirrer. After stirring at 5 o'clock, remove the insoluble matter by passing through a furnace and make it weakly acidic with concentrated acid.The crystals that grew out were collected and recrystallized from ethanol 3 to give 3- (o- 2- (R) -phthalimidobrobionic acid 8.6- is obtained as pale yellow needles.Melting point 220-222.

0 elementary Q 值 C ₁₇ H ₁₂ ¾0 ₆ S

 Total ft: C 54.84 H 3.25; IT 7.53

 Jitsuwan 傢: C 54.46; Ξ3.26; If 7.46

 [00-79. (, In Methaneau)

 Fine 2

5 3— (0 —-Trohue! -One

 Acidic acid 10 f is catalytically reduced in methanol at 5% palladium on carbon at normal fibre and pressure. After absorbing the calculated amount of hydrogen, the solvent is removed and the methanol is depressurized. Add the residue Athe and petroleum Aether: i. Then, remove the bright blue powder & yield 3-(. 1-aminophenothio-2 (H) —phthalimidobionic acid 8.4 f. Dissolve this product 8.4 in dimethylformamide 5 and add 5.5 g of flanolin-monitor ヱ し な が ら while stirring under ice-cooling.After the performance, stir for 5 minutes and mix. * Triethylamine under ice-cooling Stir under permanent cooling for 30 minutes, then stir in the field at room temperature for 1 hour, add 200 W of water to the solution, leave it overnight, and remove the greasy body. Purification of this S by column chromatography (dichloromethane: acetic acid -2: 1) yields 3 (E) -phthalimid 2,3-dihydro-1,5C5H. 5.4 f of 1-Penzothiazebin-41-one is obtained as colorless prisms. Melting point 202-205

Elemental analysis value C ₁₇ H _{12 20 s As} S

 Calculation 镇: C 62.95? H 3.73; K 8.64

 Jiang Wan: C 63 · 15; H 4.02; Ν8.49

[<<] Page 1 64. (Methanol) Medium) Dimethiformamide 5 Add 0.5% sodium hydride (60 * oily), and stir under ice-cooling. Under rice cooling, fruit; {3 (R) -phthalimido 2,3—dihidro 1,5C 5H obtained in Example 2) 1-benzothiazebin-4-f-one 4 f, add 4 f, 5 minutes Stir. Under ice-cooling, add 2 f of tert-butyl thiocyanate. After stirring for 15 minutes under ice-cooling, add SJS solution iC ice water C 200 «f) and remove the kiide crystal. Inui: »¾, Siri -84—

 When sugar is prepared by column chromatography (hexane: sulphonic acid-3: 1), 4-oxo-3 (H) -phthalimide-2,3,4, δ-tetra-t draw 1,5 Benzothiazebine-5-monoacetic acid tert-butyric ester 4f is obtained as a colorless tangent. When ^ is re-crystallized from Echi-Ete, it becomes colorless brain 蕞. With a melting point of 181-184

Elemental analysis As c ₂₃ ¾ ₂ ο _δ S

 Calculation 傢: C 63.01; Η 5.06; Κ 6.39

 Survey hall: C 62.95; Η 5.10; Η 6-34

 [*] 1 1 56 ° (c-0.9, in black mouth home)

Actually

In fact; * 4-oxo-3 (H) -phthalimido-2,3,4,5-tetra-kappa draw 1,5-pentozothiazevin-5-enzyme ter "buty! Este 4- and okamizu" obtained in Example 3 Add 1.4 f of hydrazine to ethanol and stir the mixture for 1 hour while stirring. ^ Concentrate the solution under reduced pressure, add 300 ml of vinegar and 10 to the remaining mixture, and shake well. After washing the _β- fetish layer with dilute sodium hydroxide water and water, the layer is anhydrous.

Dry with magnesium and decompress. 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, -benzothiazebine-5-vinegar. Tert-butylester 2- is obtained as colorless prisms.

Melting point 8 β—S 9

As elemental Ori值 _{c 15 H 20 ir 2 o s} s

 Kao Ken: C 58.42; H 6.54; N 9.08

 Execution: C 58.73; H 6.48; N 9.13

[Na] ^β — 238f * (c == 1, in Methanow) ― One nine

 When SJS similar to that for synthesizing a ^ -recombinant (fR = fl) is performed using a 0-Trohr-phosphorus derivative having a substituent as a raw material, a compound shown in Table 1 tC is obtained.

実旅例 10 - 13 table 1.

Actual travel example 10-13

 When the S- (2Trop-)-L-cysteine derivative obtained in Examples 5 to 8 was reacted with if-ethoxycaptoimide in the same manner as in Example 1, the compounds shown in Table 2 were obtained. Can be

 table

0ΜΡΪ One ie one real i

 No. * 1 (V) (in methano)

0 4-C R Used for next step or reaction without purification

 4-0C¾ R 157-159 -120 °

12 4.5- (CH ₂ ) ₃ R 219-222 -1 9 °

 13 4— CI R 183-185 -116 * Example 14 -17

 Actually, when the phthalimide derivative obtained in 10-13 is subjected to ^ in the same manner as in the actual trip «2, the compound shown in Table 3: is obtained *

実誠 18 -21 Table a.

Sincerity 18 -21

 When the phthalimide benzothiazepine 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.

Exchange One ST one

)₃

) ₃

 Real 22- 25

 Actual; * When the phthalimidobenzothiazebine acetic acid ert-ester ester derivative obtained in Example 18-21 is subjected to ^ in the same manner as in Example 4, the following chemical formulas are obtained.

Table 5.

CH ₂ COOCCCH3) ₃

M-I

実％例26

Actual% Example 26

 Fruit; It is the S— (2——Tro 4-t 9-Fluorometif obtained in Example 9

 1: L-cysteine 5.3 f was added to 2.5 sodium hydroxide water 67 W, stirred at room temperature for 30 minutes, and then cooled under ice-cooling. At the same time, the poker, the ίηί and the 1Ηaqueous sodium hydroxide solution ¾1 are defeated in a JC30 fight. After stirring the field at 2 to 5 o'clock in Murotori, the extract is extracted with ethyl acetate, and the aqueous solution Φ is acidified with 1 H¾ acid. The extract was extracted with anhydrous manganese, decompressed and removed, and the residue obtained was added with thioate to obtain S- (2-tro-4 σ romechi hu ^ Α ')-1-pentoxyca po- 1: L-cistine 5.5 appears as pale yellow crystals. Melting point 150-153Ό

 [<<] ^ +20. (Medium)

 Elemental Kiken Ci8 His と し て Οβ S

 Calculation 值: C 48.65? H 3-40 ί Η 6.30

 Real sculpture: C 48.68; Ξ3.41; Νβ · 27

 Real it example 27

Replacement of S- (2-trough 4-trifluoromethyl phenol) obtained in the actual example 26 9 Ichimo

-Benzoxy power--L-cysteine 4.3 ί ¹ and sub-I & D 4 f are added to acetic acid 5 and water 50W © S solution iC, and stirred for 50 minutes at room temperature. water

Add 150W and vinegar 15 to remove the residue. The aqueous layer is further extracted twice with vinegar, and then extracted twice. The vinegar is combined with the vinegar, washed with water, dried over anhydrous magnesium, and depressurized. After dissolving the residue in acetic acid 5 OWi and adding acetic acid acetic acid «る と (5Κ), S- (2-amino-4 trifluoromethy phene); -One L-Sistine. 8.4 f of dimethiformamide is obtained as a pale yellow powder. を Dissolve this product in dimethylformamide 3 and stir under rice cooling. * Gara, tridiamine 0.78 f dimethylformamide solution in 10 min. Drip. Further, a 1.83 f dimethyformamide 5W solution of 1.83 f is dropped down with a 5 minute push, and then triethylamine 0.78 dimethyformamide 5W is added. Stir under ice-cooling for 30 minutes, add water 20 to the _α- reaction solution with stirring at room temperature for 5 hours, extract with acetic acid, dry the extract with anhydrous magnesium sulfate, and remove under pressure. Purification of the resulting oil by column chromatography (hexane: vinegar monet-4: 1-2: 1) yields 3 (R) —benzyki ^ kabumamino 7— Trifluorometh-2,3-dihydro 1,5 (5 () -benzothiazebin-4-one 1.3 f is obtained as colorless powder d. Melting point 1 20-123

[ _<< ] _Ώ 1 1 6 1. (Medium)

Elemental analysis 值 Ci8 His 3 ₂ 0 ₃ S

 Calculation 值: C 54.54 i H 3.81; If 7, 07

 Actual SI 值: C 54.79? H 3.90; K 7-09

Example of a real curtain 28

 "BU E U

OMPI

'' One One "one

 3 (R) 1-benzyl oxy-force obtained from the actual footstep 27 · Poly-amino-7-trif-oliomeci; V—2,3-dihydro-1,5 (5H) —Penzothia zebin 4-41-year-old 1.1 -Dissolve dimethylformamide 2 OWiC, add kuguchi vinegar ter "butyester, 0.46ί, carbonate 0.42-, iodine atom 0 · 1-, and stir for 5 hours through the room. Add SIS solution K water 10 and extract with vinegar extract 10. The extract is ft-purified with 0.1% sodium ugly, sodium hydrogen carbonate aqueous solution, dried with anhydrous magnesium, and decompressed.去 r after leaving 3 c R) 1-strength ox-force 4min-year-old oxo- 7-to-IT-format 2,3,4,5-tetradro- 1,5-pentoziazebine ~ 5 ~ ferment acid tert One butyester 1.4 is obtained as a colorless candy.

: 1680 (アミ ド） ， 1710 Cウレタン） ， 1740 (エステ A IR u

: 1680 (amide), 1710 C urethane), 1740 (esthetic A

 * IR: (Infrared absorption spectrum: the same applies hereinafter)

Actual 29

In fact: the 3 (H) -benzyloxy obtained in Example 28 4-amino-4,7-trioxo-2,3,4,5—tetrahydro 1,5—bendachiazebine 5- Dissolve the hydrostatic acid er-butyl ester 1.4- in acetic acid, add 30% hydrogen iodide-acetic acid solution 10 «^, and leave it at room for 4 hours. Add SiS solution I Petroleum ether 10 and mix well, then remove the supernatant by slanting. After adding petroleum ether again and performing the same operation it, the substance is dissolved in ethyl acetate and benzene, and decompressed to dryness. Adding petroleum acetate to the residue gives 3 CR) -amino-4 1-year-old xo-7-trifluoromethyl 2,3,4, δ-tetrahydro-1,5-benzodiazebin-5-vinegar. Bromic acid ¾ 0.75-evolves as crystals. Replacement, i Melting point 1 7 6-18 0 "C

Elemental analysis c ₁₂ ¾!? ₃ ¾ o ₃ s · HBr · Η ₂₀

 Calculation 值: C 34.38; Η3.37; Ν6.68

 Actual rate: C 34.40; Η3-60; If 6.66

 5 Example 3 0

 In Example 4, 3 (R) -amino-4-oxo-1,2,3,4, δ-tetrahydro-1,5, -pentoziazebine-5-enzyme ter-petester 1f obtained in Example 4 was dissolved in methanol 2 to dissolve it. , Potassium cyanide 0.32 f,-(-fomibuti) lid; imid 1.1 and acetic acid 0.3,

Stir at room temperature overnight. When the 液 δ liquid is decompressed to dryness,

 (R)-(1-cyano-5-phthalimidopench)) amino-4-oxo2,3,4,5-tetrahydro-1,5-pentazothiazebine-15-acetic acid tert-butyl ester is obtained. This S is used as a raw material for sugar-producing examples 31.

i s Actual travel example 3 1

 EXAMPLE 3 3 (R) — (1-Cyano-5-phthalimidopentyl) amino-4-1, oxo-1,2,3,4,5-tetrahydro-1,5,4-benzothiazebine-5-acetate 5- (acetic acid) obtained in 30 Esthetic 2 f to etanoic; >> Sulfuric acid (1 1 1ί) 2 O WI: Add, stir under eternal cooling for 6 hours, then release 1 so night in room fi. Remove the ethanol by decompression and leave the residue with ethanol 5

 Add Amberlist 15 Ion Exchange Tree 10 and add to the mixture at 7 o'clock. After cooling, cool down the tree with 5 * bilizine-ethanol ^ «^ S, then ethano-face-to-face and« compress. The obtained oil is dissolved in ethyl acetate 30 and the mixture is diluted with 0.11 acid and water. No acetate layer

25 Water After drying with magnesium, remove and remove the material. Purification by chromatography (hexane: acetone = 2: 1) yields 3 (R) — (1 ethoxy power / w po-5-phthalimid pliers / ^) amino 4—oxo 1,2,3,4 0.3 f of 5,5-tetrahydro-1,5-monopentazothia zebin-5-ethyl acetate is obtained as colorless ¾1fe 4fe. IR p dF ¹ : 1770, 1740, 1720, 1710 (Famid and esthetics), 1670 (Amid)

Mass spectrum (me): 567 CM ⁺ ),

Real example 32

 The 3 (R) -phthalimido-2,3-dihydro-1,5C5H) -pentisothiazebine obtained in step 2 was dissolved in dimethylformamide to give 2-tert-propidobrobionic acid. Petit esthetic

Add 6.27 f, 5.5 f potassium potassium and 0.5 potassium iodide, and stir at room temperature overnight. ^ Liquid I Add 200 W of water and extract with 300 W of vinegar. The extract 洗浄 is washed with 200 W of 0.5H 翁 and 100 W of aqueous sodium bicarbonate, dried over anhydrous magnesium, and removed under reduced pressure. The resulting oil was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1-2: 1), yielding 3 (R) -phthalimid 4-oxo-1,2,3 , 4,5-Tetrahydro-1,5-pentoziazebine-1.5- * methyl methoxide 61 «1? -Buteste 7.8 is obtained as a colorless powder.

IE fg | t αΓ ¹ : 1770, 1730, 1720, 1680

 C C = 0)

Elemental element Qi plant C _Z4 E _Z4 ¾ 0 ₅ S · ¾ 0

 Calculator: C 62.46; Ξ 5.46; Ν 6 · 07

 Really: C 62.62; H 5.14; N 6.13

Difference -4

l Obtained in Example 32 3 C R) 1 -phthalimido-4 1 -oxo 2, 3, 4

, 5-Tetrahydrido-1, 5-pentazothiazebine 5-metiacetic acid ter "petit este 7 · β- was treated in the same manner as * 4. Oxo-1,2,3,4,5—Tetope δHydro1,5—Penzothiazebine-5 — << 1-Met.

IR fJ ** «" ¹ : i 735, 1670 CC = 0)

[<<] _D- 223. (C = 0.5, in Methanow)

Mass spectrum ( _a / _e ): 322 (M ⁺ )

0 Actual foot example 34

 3 (S) -Amino-4 oxo-2,3,4,5-tetrahydro-1,5 — ^^ nzothiazebine-5-Drossic acid tert-butylester 8.08 obtained in Example 4 was converted to dimethylformamide 2 Dissolve the OWiC and add ethyl 2-butane 6-phthalimide hexanoate 7.36 f, potassium carbonate 2.76s-and potassium iodide 1. Add S6- and stir overnight at room temperature. In addition, add K-Bro-Moeste 8.68 f and Sugar Monum Kum 1.38, and stir for 3 days. ^ Add 10 parts of water and 30 parts of vinegar to the liquid to extract, wash the extract with water, and crush it. ・ Add 5 f of vinegar and 3 parts of vinegar to the obtained oil and dissolve it. Add petroleum powder 120 and mix well.)

0 After standing still, the upper S solution was decanted, and the residue was again subjected to the same process.Then, the mixture was extracted with sodium bicarbonate aqueous solution 10 and edge 30, and the extract was dried over anhydrous ifcfi magnesium and then destroyed. Press «Remove. Purification of the obtained product by lizard column chromatography (hexane: aceton = 4: 1) yields 3 (H) — [1 (R) —etoki, nkabo 5—as the first surface. 5—Lid Imi Dopenchi Minnow 4 1 year old Kiso 2, 3 _f 4, 5— Tetrahydro 1,5-benzothiazevin-15-tert-butylester 1.75 f is obtained as an oil.

I S u a ^ a a a O dTH), 1 780, 1 740,

 1720, 1 680 (0 = 0)

Mass spectrum (me): 5 95 CM ⁺ )

3 (R) as the second fraction - [1 (S) - Etoki mosquito board - A 5-off data Imi Dopenchi] amino-4 one year old Kiso 2, 3 _s 4, 5 Tetora draw 1, 5-base Nzochiazebin one 5 —Sulfuric acid tert-butyl ester

 2.5 is obtained as an oil.

 I R υ g ¾ oT ^ a a a O dr H), 1 770, 1 74 0,

 1 720, 1 680 C C = O)

Mass spectrum (mZe): 595 (^ J

[] _11-119 ° (c-0.3 in methanol)

Real 3 5

 3 (R)-[1 (S) -ethoxyca ^ po-1-1-l-d-im-d-in-chi] aminnow obtained in 34. 3,2,4,5-tetratetra-dro 1 , 5-Penzothiazebine 5-Dermal ter-Buty Este <0.2-Dissolve in 5H Hydrogen hydride-Vinegar Sodium Solution and leave at room humidity for 3 hours. When the precipitate 5 is added to the reaction mixture and the precipitate is washed with the precipitate 10, 3 (R)-[1 (S) -ethoxyxa-1-phthalimid-pentamine] minnow 4-1-year-old- 2,3,4,5-Tetrahydro: I, 5-pentazothiazebine-5-acetic acid acetic acid 0.13 / is obtained as a colorless powder.

Elemental analysis 值 C ₂₇ H ₂₉ N ₃ 0 ₇ SHC1

Total recruitment: C 55- 42 j H 5.34; K 7.18 Shiao planting: G 55.09; H 5.12; 1ί 7.15

[] _D —1 14. (C- 0.5, Methaneau medium)

Actual:% example 36

 3 (R)-[1 (R) -Etoki power /! 1-5-phthalimidopench] amino-4oxo-1,2,3,4,5-tetrahydro1,5, -pentoziazebine 51-Si¾tert-butylester

 Dissolve 1.6- in ethanol 20 ·, add water-hydrogen 0.8-0.8 f, and leave it overnight in Muro Emperor. The reaction mixture was extracted by adding ethyl acetate 20 and water 20, and the ethyl acetate was washed with 0.1 if aqueous sodium hydroxide solution and then with water to give 3 (R) — [5-amino-1 (R)- Ethoxy pent pent |] amino-4 oxo-1,2,3,4,5-tetrahydro-11,5-pentazothiazebin δ-acetate tert-butyester g ^ li チ et¾ is obtained. To this solution are added 1.6 'sodium bicarbonate and water 5 and, while stirring at room temperature, add dr. After stirring for 30 minutes, separate the ethyl acetate layer. Dry with anhydrous magnesium sulfate. The oil obtained after decompression distillation was purified by silica gel column chromatography (hexane: aceton = 4: 1) to give 3 (R) — [5-7 ert—butoxyca porminol 1 ( R)-ethoxy-ca-po-pent) mino 4-oxo-1,2,3,4,5-tetrahydro-1,5-pentazothiazebin-5-rich acid ter to butyester 1.4- is obtained as a colorless oil. .

 IR V ^ αΓ ^ Β δ δ Ο ί ΙΤΗ), 1 740, 1710,

 1 680 (C = O)

 Mass spec (mβ): 565 (M ")

Actual travel example 37 One "one

 3 (R)-[1 (S) -etokica-1 5-phthalimidopench] amino-4amino-1,2,3,4,5, -tetra Draw 1,5 obtained from 4 Ε 联 tert-buty Este 2 = «f is real; * K hydrazine ^ S as in Example 3 6 and ^ ig with G-tert" buty-carbonate to purify by force and mutachromatography And 3 (R)-[5-tert-butoxy ^ caponamiminol 1 (S) -toxica bo-bench] amino-41-oxo-1,2,3,4,5-tetrathyl-1-, 5-benzothiazebin 1.5-f-Acetate tert-butyl ester 1.87 f is obtained as a colorless oil

IE y αΓ ¹ : 3350 (ITH), 1T40, 1710,

 1670 (C = 0) mass spec ^ (mZe): 5 6 δ (H ^)

«D _D -1 3 6 ° (, medium methanol)

Real 38

 3 CR) -C 5 -tert-butoki force po-amino-1 (S) -ethoxy-po-pinch] amino-4 1-year-old xo 2,3,4,5-tetrahydro draw 1, 5—Penzothiazebin 51 Sfl

■ Dissolve bert-buty Este 0.6-S solution in 40 W of methanol and 25 W of 1 N sodium hydroxide in water. Add water 1 and stir at 2 o'clock with room weight. The methanol is removed by decompression, acidified by roofing, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 3 CΗ) -C 5 -tert "butoxycavanamine 1 (S) -one-strength pentoxy pentyl] amino-4,2-oxo-3,4. , 5-Tetrahydro-1,5-benzothiazebine-5-acetate ert "buty Este 0.37 f is obtained as a colorless starting material.

 "BU EAU

OMPI i 134-135 ^ C

Elemental analysis C ₂₆ H _S9 K ₃ 0 ₇ S

 Calculation II: C 58.08; H 7.31; IT 7.82

 Actual ««: C 58.11 ϊ H 7.22; Η 7.73

5 IR ^^} °} αΓ ¹ : 33 δ 0 (Κ Η), 1730, 1700,

 1680 (C = 0)

 Actual travel example 39

 3 (E) -Amino-4-oxo-2,3,4,5-tetrahydro-1,5-pentazothiazebine-5-acetic acid tert-butyls 0 te ^ 5f and eth 2 obtained from Example 4 Professional i 6-phthalimidohexanoate

 17.9 was dissolved in an acetate tube, and I;

— 5—フタ イミ ドぺンチ 〕アミノー 4 一才キソー 2 , 3 , 4 , 5—テトラヒ ドロー 1 , 5—べンゾチアゼビン 一 5 -酢酸 セ62^-ブチ ヱステル8.9 f と 3 ( B ) -〔 1 ( S ) -ェ0 トキシカ _/«ボ- 一 5—フタ ィ ミ ドペンチ 〕ァミノー 4一ォキソ一 2 , 3 , 4 , 5—テトラヒドロー 1 , 5—ペンゾチアゼビン一 5—酵酸 tert ^プチ エステ 4.1 -が無色油状物として得られる， 実删 40 -42 , And reflux for 45 hours. Depressurize the acetate and remove the residue by adding water 20 and ethyl acetate 30 to the residue. After the extract is washed with water, it is washed with anhydrous magnesium and vacuum-smeared. The obtained oil was separated and purified by silica gel chromatography (hexane: aceton-4: 1), which was the same product as that obtained in Example 34 (3 CK). 1 (H) —Toxica

— 5—Futaimidunch] amino-4 1-year-old xo 2,3,4,5-tetrahydro-1,5—benzothiazebine 5-5-acetate 62 ^ -butylester 8.9 f and 3 (B)-[1 (S) -E0 Toxica _/ «B-I-5-phthalimidopenti] amino 4-oxo-1,2,3,4,5-tetrahydro-1,5-Penzothiazebin-15-Enzyme tert ^ petite Este 4.1- Obtained as a colorless oil, 40-42

3 (R) -Amino-4-oxo-1,2,3,4,5-tetrahydro 1S, 5-Penzothiazebin-5- 酴 tert-buty Este In the same manner as in 39, when the bloester shown in Table 6iC is used, the following benzothiazebine conductor is obtained.

 Table 6

(CH ₃ )

 * Gia stereomer-Blend ^ ί Real giant example 43-"

When the benzothiazebine derivative obtained in Example 40-42 was treated with a hydrofluoride solution in the same manner as in Example 35, the compounds shown in Table 7 were obtained. difference -41—

Table 7

 * A mixture of diastereomers ^ ^

 Actual flag example 6-48

し 後、 ジー tert—ブチ ジカーポネート と^させると、 表 8に示す化合物が得られる。 Example 40 The benzothiazebine derivative obtained in 40-42 was treated with hydrazine in the same manner as in Example 36.

Then, the compound shown in Table 8 is obtained by reacting with di-tert-butydicarbonate.

 Table 8

 ,

(CH ^ HCOOCCCH ^ s

実篪例 η 立体纪匿

Example η 3D hidden

 R

Numbered the 1 * 2 E S¾ "one ¹

3350, 1730

46 (CH ₂ ) ₃ C¾ 4 RS

 1710, 1670

3400, 1740

47 レ 2 ¾ 2 R ES *

 1710, 1670

3350, 1730

48 β R

 1710, 1670

* Gia stereomer mixture ¾Example 49

3 (R) — (11-ethoxy-po-5-phthalimidopentyl) amino-4 obtained at 31-year-old fall 31-year-old oxo-1,2,3,4,5—tetradihydro-1,5 pentisothiazebin-15 Dissolve 酢 7 in ethanol and add 0.3 hydrazine in 85 water. Add 0.3 f of hydrazine in 85% water after 1 hour and 2 hours, then leave overnight. Ethanol was distilled off under the residue, water 5 was added to the residue, the mixture was further added with food, and the mixture was cultivated, and extracted three times with ethyl acetate 10. The extract was washed with a 0.1 W aqueous sodium hydroxide solution 50 W each. Wash with water 100 W and dry with anhydrous magnesium Magnesium acetate was added with 0.5 W of 5 N hydrogenated sodium acetate solution and decompressed to remove the residue. tweak the 3 (S) - (5-amino-1 one ethoxy ^ Ca ball - pliers) Amino one 4- Okiso one 2, 3, 4, 5 Tetorahi draw 1 _t 5 ^ Zochiazepin - 5 - Yoi黢 E Chi Este dihydrochloride 渲 0.13 f as colorless Powder.

Elemental analysis 值 C ₂ i Hsi ITs Os S- 2HC1

0 PI replacement One Si—

 Calculation ②: C 47.73; H 6.67; if 7-95

 Actual measurement: C 47.81; H 6.53; Ji 7 · 83

Mass spectrum (mZe): 4 3 7 (1 ^)

5 0

 Fruit; * Example 4 3 (R) — (5-amino-1-ethoxy) -amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazebine-5-acetic acid obtained in 9 Ethi Este / V · 2 Soil 5 is dissolved in JC of a mixture of ethyl acetate 3 and water 10 »

 Add 5 W and sodium hydrogen carbonate 0.3 and stir in Muroh for 2.5 hours. The ethyl acetate layer is washed with water, dried over anhydrous magnesium, and evaporated under reduced pressure. The resulting oil is washed with petroleum ether 2 and petroleum ether 20

: Dissolve in ^ liquid and add 0.2 W of 5 N borohydride, 3 CH)-(5 — pendoxyca Λ ノ ー ノ ー 一 一 w; w--pliers) ノ ー ノ ー ノ ー ノ ー2,3,4,5-Tetrahydrido 1,5-benzothiazevin-15-ethyl acetate / »esthetic; u · Furic acid clay 5 is obtained as a colorless powder.

Mass Spectacle w (m / β): 57 1 CM ⁺ )

Actual travel example 5 1

 Actual; St Example 3 CR obtained in 50)-C5-1-pentoxy po-amino-1-ethoxyca-pliers V) amino-4-1-quino 2, 3, 3, 4, 5-tetrahydro-1,5-pentazothiazebine Dissolve the acid sulphate 5 in a mixture of ethanol and 1 Η aqueous sodium hydroxide solution 2 W and leave it in the room for 1 hour. After adding water 5 to the reaction mixture i and extracting with ether 2, the aqueous layer is adjusted to pH 4 with 1 IT hydrochloric acid. After adding ammonium chloride until harmless, add water to the aqueous layer.

^ Change Extract 10 times with 20. The extract is washed with a small amount of water, dried over anhydrous magnesium sulfate, and left to remove. 3 (R)-(5-benzoxyca; w-aminaw) 4-Wave 1,2,3,4,5-Tetrahydrido 1,5-pentazothiazebine-5-monoacetic acid 40 W is obtained as a colorless powder.

Mass spectrum (mZe): 5 15 (M ⁺ )

Defeated 52

 3 (R) — (5— ^) obtained in the magnificent fall 1 1 ン ジ ポ ジ 1, 5 テ ヒ, 1, 5 テ ヒ 1, 5 テ—Penzothiazebine-5—Acetic acid 4 is dissolved in acetic acid 1 and 30 * hydrogen bromide acetic acid solution 1 is added.

After adding Ethiete 8 and Petroleum ether 20 to the SiS solution, mix and settle, remove the supernatant by decanting, collect the precipitate, and dry to obtain 3 (R) — (5 1-amino-l-potoxy-pentoxy-amino-l-oxo-l-2,3,4,5-tetrahydro-l, 5-benzothiazepine-l-5-acetic acid / hydrobromic acid-33 W is obtained as a colorless powder.

M / e): 382 C MH +);

KI added 420 ί M + K) ⁺

Actual travel examples 53, 54

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

Table 9

 Hoo

換 え l replacement ^f O PI One δ 骞 ー

3D configuration

 Real * 锊 number [Ο

 Book 1 book 2

53 R R-161. (c = 0.7)

54 R S -128 * C c = 0.5)

Example 55

Example 54 3 (11)-[5-Amino 1 (S) -ethoxy carboxylic acid] Aminnow 4-oxo-1,2,3,4,5—Tetrahydro-1,5-1-: Add 0.2 f of nzothiazebine mono-δ-acetic acid►2 acid to 1 IT water solution, add sodium tricum solution 4 WiC and stir in room S for 1.5 hours. The solution is made acidic by adding 1 W of tC acetic acid, and then purified by Amberlite AD-2 Cam Chromatography-(Methanol: water-3: 7). The effluent is concentrated under reduced pressure and freeze-dried. 3 (R)-[5-Amino-1 (S) -carboxypentyl]] amino 4-oxo-1,2,3,4,5-tetrahydro-1,5-pentazothiazebine — 0.1 f of 5-acetic acid is obtained as a colorless powder. Elemental圻值CL7 H23 30 Calculated _{5 S * H20: C 51.12;} H 6 · 31; N 10.52 real Sakanobo铤: C 50.87; H 5.83; Ιί 10.34 [Do] _D - 149. (In c- (3,11ί¾ acid)

 S I MS Spectrum (m / e): 382 (MH +)

 ∑ I addition 420 C M + K) '

 3 (H)-[5-tert-Putoxyca-^-amino-ICS] -bacteria obtained in Example 38 38-Amino-41-oxo-2,3,4,

2 £ change O PI 5-Tetrahydro 1,5-Penzothiazebine-5-Vinegar tert-butyl estee 0.32 f in the same manner as in Example 3 5: When hydrogen peroxide is «ί3, 3 (S) — [5-amino-1 (S) —force pent pent amino-4 oxy y—2,3,4,5-tetradraw 1,5—pentoziazebine—5-W · 2 Sulfuric acid soil 0.26 is obtained as colorless powder A .

As elemental圻植 _{C 17 ¾ 3 lf 3 0 5} S · 2HC1 · C¾ C00C 2 ¾

 Calculation fl [: G 46. 49 i H 6 · 13; 7 «75

 Actual: C 46. 12 I Η 6-16 N 7.52

 Dissolve 0.15 f of this product in water, add 9 H aqueous solution of 1H sodium hydroxide and 0.5 W of acetic acid, and then apply imber Amberlite XAD-2 as in Example 55. To give the same free form 0.99β as obtained in Example 55.

 Example 5 7-5 9

 A real giant example 4 6— 4 8 obtained 7t_ Benzothiazebin Satsu conductor! ^! If you change the value to 35 and press S with water chloride acetate, the compounds shown in Table 10 are obtained.

Table 10

* Replacement of mixture of diastereomers One ss—

i Actual * Example 60

Dissolve 0.43 f of sodium in ethanol 1 and add ethyl 3-((one pendioxoca vuluru) one) probionate δf and 2.75 f of oxalic acid, and add 60-70 * C © S Heat on the bath for 45 minutes. After cooling, add water 20 to the obtained green candy and make it acidic with acetic acid. And extracted with acetic acid E Ji 30, the extract was dried over anhydrous magnesium, ¾Ipushiron «the _β resulting yellow oil that supports 10 * water dimethylcarbamoyl scan Hoki ^ de 5 a ¾ lithium 0.73 - added, in 100 In the 30-minute field, 120-130, 30 minutes, then 140, 0 45 minutes. After cooling, add water 30 and add

 The extract was washed with water, dried over anhydrous magnesium, and dried under reduced pressure. After removal of the pressure, the residue was obtained as a light brown oily substance. 5 f is obtained a

s IR ^^ t% "αΓ ^ Ι Τ Β Ο, Ι Τ Ο Ο Γ θ ^ Ο)

Mass spectrum (m / β) 347 (M ⁺ )

 61, 62

 Table 1 li When the brobionic acid ester derivative shown in li was used as the starting material, ^ was performed in the same manner as in Example 60 to obtain the corresponding α-keto ester.

一 se— Five

One se—

Actual: §6 example 63

The 3 (H) -amino-4oxo-1,2,3,4,5-tetrad obtained in Example 4 t Draw 1,5 ^^ <nzothiazebin-1 δ-ft acid ter-butyst 2- 5 Dissolve and enzymatic acid 0.43-, crushed, obtained in Example 60. i Add 4-1-1 (11-pentiocarbo-4- 4-vive) -1-2-oxobutyrate «δ-, recrub 3 A10 After stirring the S solution with _β in the room at room temperature for 1 hour, stir the sodium nanoborohydride 0.4 / ethanol 30 W solution in the room, and then drop at 5 o'clock in the field. Lithium 0.5 f Etano-2

 At 3 o'clock and leave overnight. And then add water 30 and ethyl acetate 30 and stir. To remove the insoluble matter, and dry the magnesium layer with anhydrous magnesium and decompress it. * Add ethylene carbonate δ to the afterimage and add 1 f of sodium hydroxide solution. Add. Add petroleum ether 20 and shake well. After stirring, let it stand still, remove the upper δ liquid by tilting, and add the petroleum ether 10 Owl to the Shentan Yuyu again and mix. After removing the petroleum-te layer by sloping, add water 5 and vinegar to the sediment, neutralize it with stirring 4 and excess sodium bicarbonate. After washing the ethyl acetate layer with water, drying over anhydrous «magnesium» and «iE¾T removal, an oil is obtained. When this product is made from sugar by silica gel column chromatography (Hexane: Ethyl acetate -2: 1 to 4: 3), 3 (R) — [3— (1—Benoxykapo-4-biperidily V) Amino-4-oxo y—2,3,4,5—tetrahydro-1,5—benzothiazebine-5—! ^ tert-butyl ester 0.1S-is obtained as a colorless oil.

: 3320 C ITH ) . 1740 , 1700 , 1680 C C=O ) IR υ

: 3320 C ITH). 1740, 1700, 1680 CC = O)

Mass Spectrum (aiZe): 639 (M ⁺ )

 ^ From the surface area, 3 (:)-[3- (1-Penzoxyca-4-4-bipedi A- 1 (S) -ethoxy ^ carpo-blovi] amino-Xoxo 2,3,4,5-tetrahydro-1 1.3 f of 5,5-Penzothiazebin-5-acetic acid ter-butyl ester is obtained as a colorless oil.

 I R V 5 tar ^ .a S S OCirH), 1740, 1700,

 1690, 1670 C C = 0)

Masuvetato (m / e): 639 (Μ "·")

Actual examples 64, 65

 Fruits obtained using the naketoesthe obtained in Examples 61 and 62; * 3 (R) -Amino-4-oxo-1,2,3,4,5-Tetohydro-1,5-Penzothiazebine-15-acetic acid in the same manner as 63 ter "Petite Este" gives the compounds shown in Table 12 as oils.

 Table 12

 * 2

NHCHC00C ₂ ¾

 C¾ CBLR

(CHs ^ COOC — 53—

実麓例 6 6

Actual foot example 6 6

 3 (R) — [3-(1 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ で _______________sub_ mentioned above_I_I_I_I.I. , 3,4,5-Tetrahydro 1,5-benzothiazepine-1 δ-acetate tert-butyl ester 0.3- is dissolved in 5H hydrogen iodide vinegar in ethyl acetate 20W} C and left in the room for 3 hours I do. When petroleum ether 20 is added to the reaction solution, 3 (R)-[3-((1-benzoxyca-141-bridge)) 1-1 (S) -ethoxycarbonyl-bropi] amino-1-oxo-2, 3,, 5-Tetrahidro 1, 5 -Penzothiazebin-5 -Azumigo After decanting and removing the supernatant, drying yields 0.22 of a colorless powder.

As elemental analysis _{fiE C 30 H 37 N 3 0} 7 S · HCl 'H 2 0

 Calculated: C 56.46; H 6.32; N 6.58.

 Actual measurement: C 56.29; H 6.31; H β · 57

[] _D — 9 1. (, In methanol)

 Fine 67-70

 Using the benzotipzebine derivatives obtained in Examples 64 and 65 as in Example 6 β

7 one-O -St-, and treated with hydrogen hydride, the metal products shown in Table 13 are obtained. <

 Table 13

実旅例 β 3で得た 3 ( R )—〔 3 -（ 1一^？ンジ 才キ 力 ポ- - 4ービペリジ ） ー1 ( R )—エトキシカ ニ ブ口ビ 〕ァミノ - 一ォキソ一 2 , 3 , 4， 5ーテトラヒドロー 1 ， 5—べンゾチアゼ ビン一 5—酢酸 tert—プチ エステ 0.6 fを酔酸 2 Wに溶解し、

Actual travel example 3 (R) obtained from β 3-[3- (1 ^^ ????????-4-biperidi)-1 (R)-ethoxycanib] amino-1oxo-1 2, Dissolve 0.6 f of 3,4,5-tetrahydro-1,5-benzothiazebine-5-acetate tert-petit este in 2 W of sulfuric acid,

 30 * Add 2 W of hydrogen acetate solution and leave it in room S for 1 hour. Add 1 Ο δ Μ 1 反 応 反 応 反 応 反 応 反 応 反 応 反 応 反 応 反 応 反 応 反 応 静 静 静 静 静 静 静 し た し た し た 静 後 後 後 後 後 し た し た し た. After the precipitate was washed with ethanol and dried, 3 (ϋ)-[1 (R) -ethoxycarbonyl-31- (4-vinylidyl) propyl] amino-4oxo-1,2,3, 0.5 f of 4,5-tetrahydro-1,5-benzothiazebine-5-acetic acid / dihydrobromide is obtained as a colorless powder.

Elemental analysis 值 C ₂₂ H ₃₁ U3 O5S.2HBr

 Calculation 傢:-C 41.98; H 5.60? K 6- 68

O PI One SO—

 Actually: C 41.3? H 5-39 \ S 6.30

 One 106 ° (c- 0.6, Methanol)

Actual 72

と、 3 ( R ) -〔 1 ( S ) -エトキシカ ポ- 一 3—（ 4一ビぺリジ )プロビ 〕アミノー 4一ォキソ - 2 , 3 , 4 , 5—テトラヒ ドロー 1 , 5 -«^？ンゾチアゼビン一 5 -酢酸 · 2臭ィ bi 素酸埴 0.35 が無色粉末として得られる _β 3 (E) — [3— (1-one-penji-oki-ryoku-po--4--bi-ri-ji)-l (S) -Ethoxyka-pob] Bi] amino-41-oxo- 2,3,4,5-Tetra-t-Draw 1,5-Benzothiazebin-5-acetate tert-butyl 0.4 f was prepared in the same manner as in Example 71.

And 3 (R)-[1 (S) -ethoxy-PoI-3- (4-biphenyl) provi] amino-4oxo-2,3,4,5-tetrahydro 1,5-«^? Nzochiazebin one 5 - acetic acid 2 Nioii bi Motosanhani 0.35 is obtained as a colorless powder _β

Elemental analysis 值 C ₂₂ ¾i N ₃ 0 ₅ S'2HBr * ¾0

 Total »值: C 40.81; H 5.76; K 6.49

 Real child: C 40.47; H 5.32; N 6.28

[<<] _D — 86 ^β (c -0.6, in Methanow)

Sincerity 73

3 was obtained in real ¾ Example 72 (R) - [1 (S) - Etokishika ball - -3 - (4 Biperiji) prop] amino-4 one Okiso one 2, 3 ₃ 4, 5 Tetorahi mud - 1, 5 one ^: Nzothiazebine-5-acetic acid 'Dissolve 0.15 f of hydrogen dibromide in 1 IT water of sodium bromide and leave it in the Murohori for 2 hours. After adding 1 W of acetic acid to make it acidic, purify by amperite 2 column chromatography f methanolic: water-1: 1). After freeze-drying, 3 (R)-[1 (S) -carboxy-3- (4-bipyridyl) provyl] amino-4-oxo-2,3,4,5, -tetrahydro-1,5-benzothiazebine One 5-monoacetic acid 0.06 f is colorless powder 1 << 1-obtained as the end.

Elemental elements C ₂ 0 H275 ₃ 0 ₅ S.H20

 Calculated bales: C 5.65; H 6-65; ΪΓ 9.56 Actual values: C 54.05; H 6-17; H 9 · 21 Mass Spect ^ (m / e): 422 (MH +);

KI addition, 460 (M + K) ⁺ [e] _D- 128. (C-0.1, Methaneau AH "underwater")

 The benzothiazebine derivatives obtained in the actual examples 68 and 70 were hydrolyzed with 1N hydrous sodium tricum water in the same manner as in the actual travel example 73, and purified by amberite D-2 column chromatography. ^ Is obtained as fe-free.

 Table 14

立体配置

3D configuration

 Real example number R

 Book 1 book 2

 6)

74 R S one 140. (c = 0.

 Methano

75 Hs one 106. (c = 0.2)

Methaneau + 12JHC1 Medium Example 76 Actual trip example 3 CR obtained in 72) -1 CS) Ethoxyka 3-C4-Bili) Buchibi] Amino 4 years old 2 3, 4, 5 - 1,2, -tetrahydro 1, 5-pentazothiazebine-5-acetic acid 'dihydrobromide

 Dissolve 0.25 f in ethanol 1 and add sodium enzymatic sodium 67 and penzaldehyde 52 Τ Τ ¾ ¾ え る ¾ · ¾ ¾ ¾ * * ¾ C C C C C C C C C Q Q ェ Q 1 Qwe i 0 min. Depressurize the ethanol and remove residual S: K: water 50 50, acidify with vinegar, and extract with dichloromethane 5 three times. The extract is washed with a small amount of water, and then removed. The obtained oil is dissolved in dichloromethane 1W *, and 0.5 W of 5lf i-vinegar ft solution is added. The precipitated colorless powder is washed with ethyl acetate and dried to give 3 fS)-[3- (1-benzyl-4-biperidi) -1 (S) -ethoxy-pubi] amino-4oxo-1,2,3 , 4, 5—Tetrahydro Draw 1, 5— ^? Nzothiazebine-5-acetic acid 'diacid ¾157 W is obtained.

Elemental Ki 值 C ₂₉ ¾ ₇ K _s 0 ₅ S .2HC1 · ¾ 0

 Calculated values: C 55 · 23; E 6.55; IT 6.66

 Measured value: C 54.92 ί H 6.74 ΪΤ 6.14

[<< _D — 76. (C = 0.4 in methanol)

Example 77

Example 3 (R) — [1 (S) —ethoxycarbonyl-3-C4-biperidi) obtained in Example 72] amino-1,4-oxo-1,2,3,4,5-tetra, hydro -1,5-Benzothiazepine mono-5-Hydroacetic acid / dihydrobromic acid lump 0.1 is dissolved in ethyl acetate 5 and triethiamine 66 · 2 W is added, and stirred under ice cooling. Drop 2W¾¾ in a two-part field. Stir in the fi fi for 50 minutes, add petroleum ether 20 and extract 6 times with sodium bicarbonate water 2. Make the aqueous layer weakly acidic with lomic acid, and extract 3 fractions with dichloromethane methane 3. Extract the solution with magnesium anhydride '■ One β8—

After drying with, decompression window. Dissolve the obtained oil in ethyl acetate, add 0.35 W of hydrogen acetate, and wash with ethyl acetate. Clean and dry the viscous slime with ethiete and dry it. 3 (R) — [3— (1—1 pentazoy; w—4—biperidi) —1 (S) —etoki strength; 4 One year old xo 2,3,4,5-tetrahydro 1,5 benzothiazebine-5-acetic acid 'ionion II' is obtained as a blue powder.

Elemental analysis 值 C ₂₉ H ₃₅ ¾0 ₆ S. HC1

 Calculation II: C 57.27; H 6.30; N 6.91

 Execution: C 56.98; H 5.99 K 7.01

EXAMPLE 78

 Example 3 (R)-[1 (S) -ethoxycarb-3- (C4-vinylidyl) brovir] amino-4-4-oxo-2,3,4,51-teto obtained in Example 72 1,5 -Penzothiazebine-5-vinegar 黢 '2bromate ^ 0.12 f was reacted with acetyl chloride in the same manner as in Example 77 to give 3 (R) — [3- 〔1-acetyl-4-biperidyl. ) 1-1 (S) -ethoxy carbamide] minnow 4 1,2,3,4,5-tetrahydro-1,5-pentoziazebine-5 · fumigation 7 is obtained as a colorless powder .

[A] _D -97. (C = 0.3, medium methanol)

Actual travel example 79

Fruit; * 3 (R)-(5-amino-11-ethoxycarbo-pentyl) amino-4 obtained in Example 43 1,2,3,4,5-tetrahydro 1,5,5-pentazothiazepine-5-ethyl acetate · Dissolve 2 hydrochloric acid 氇 6 in ethanol 5 »^ C, and differ from 25 * Galaldehyde water ¾¾0.5 One β4—

Add sodium borohydride 0.3-, stir in room water for 2 hours, add _e -reaction iC water 5, add foods and add, then add twice with ethyl acetate 30 * ^ Extract. After the extract is washed with water, it is dried over anhydrous magnesium isoform. Dissolve the obtained oil in a small amount of ethyl ether and add 5H hydrogen chloride enzymatic acid «« 0.2 W to add 3 (H)-(1-ethoxycarbo-A—5-biperidino bench) amino-4oxo. 1,2,3,4,5-Tetrahydro 1,5,1-Penzothiazebine-15-Rich acid ester, diacid * 5 is obtained as a colorless powder.

Mass spectrum (a / e): 505 (M ⁺ )

Sincerity 80

 3 (R)-(1-ethoxy-po-5-biperidino-pentene) amino-4 obtained from 79. 1,2-oxo 3,2,3,4,5-tetrahydro-1,5-pentazothiazebin-5-acetic acid ester · Dissolve 30 W of 2 acid in a mixture of 1 W of methanol and 1 W of aqueous solution of sodium hydroxide and leave it in the room fi for 1 hour. After depressurizing distillation of methano-, 2 W of water and acetic acid of 0. were added, and the mixture was purified by Amberlite II AD-2 column chromatography (acetone: water-2: 1), and the eluate was depressurized. After concentrating and freeze-drying, 3 (R)-(1Poxy-5-Bilidinopent) amino-4N, 2,3,4,5,5-tetrahydro-1,5, -benzothiazebine-15 —Acetic acid 17 is obtained as a colorless powder.

 S IMS spectrum (m / e): 450 CMH +);

 K I addition: 488 (M + K) +

Actual travel example 81

3 (R) — [5-Amino-1 (S) -ethoxycarboprench] amino-4 obtained in Example 58 1-year-old kiso 2,3,4,5-tetratetrad -i5- 1, 5—Benzothiazepine-15 monohydrogen acid diacid (4 f dissolved in ethanol 1 and guatade td water ¾¾ (25 *) 1.2, nomano sodium borohydride 0.4 f Add water and mix at room temperature at 1 o'clock Add water 5 and acidify with 1 »clay» Extract 2 gardens with ethyl acetate 30 · ^ Neutralize aqueous layer with sodium hydrogencarbonate And extract twice with vinegar 30 »^ The aqueous layer is made of sugar by amber light ∑AD-2 column chromatography (aceton: water = 2: 1) ¾Decompression concentration« ¾ After freeze-drying, 3 (Β)-[1 (S) -ethoxy- 15-bis-pyridino pentamine] amino-4 4-oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazebine-1 5 —0.3 f of acetic acid is obtained as a colorless powder.

 -n-139 ° (, in methanol)

SIMS spectrum (mZe): 478 CMH ^T )

Elemental content 值 c ₂₄ H ₃₅ υ ₃ o ₅ s.¾ o

 Calculation II: G 58.16; H 7.53; N 8.49

 Actual history: C 58.47; H 7.55; IT 8 · 52

Example 82

3 (R)-[1 (S) -ethoxycarbo-5-biperidino pentyl] amino-4oxoxo-2,3,4,5-tetrahedro drawn in Example 81 1,5-Venzothiazebine-5-enzymic acid Dissolve 0.23-in water, add 4 w of 1 IT water sodium hydroxide solution, and leave it for 1.5 hours through a room. After addition of m 1, purification by Amber, It XAD, two-column chromatography yields a colorless powder. This product is dissolved in methanol and concentrated to SS to precipitate agar-like substances. Petano-5 W; take 3 (B) 1 [1 (S)-force boxy 5-biperidino bench] aminow 4-oxo 2, 3, 4, 4, 5-tetrahydro 1, 5-benzothiazebine One five One δβ

 0.09 is obtained as a colorless powder.

[A] _D- 117. (C- 0.2, in Methanow)

 SIM Spect (a / e): 50

Practical example 83

 *; 3 (R)-[1-1ethoxycapro-3-phthalimidobro] amino 4-oxo-1,2,3,4,5-tetrahydro-1,5-pentabenzothiazevin obtained in Example 44 Separation and purification of tert-butyl acetate L8 by silica gel column chromatography (hexane: ethyl acetate = 2: 1) yields 3 (R)-[1 (11) -ethoxy porphyrin from the first surface. 3- (1-phthalimidobro)] amino-4,1,4-iso-5,2,3,4,5-tetra-dro 1,5-^: nzothiazepine 5-1 g-S-ter-butylester 0.8 is obtained as a colorless oil.

¹ : 3320 C H H ) , 1770 , 1 740 , IRV

¹ : 3320 CHH), 1770, 1 740,

 17 1 0, 1 670 (0 = 0)

[ _D ] _D -142. (C-0.4, in methanol)

 Continuing from the two fractions, 3 (R)-[1 (S)-ethoxyca 3-: 7 thyme debut] amino-4-oxo-1, 2, 3, 4, 5-tetrahydro 1, 5 One ^? N-zothiazepine-5-WfWi; ert—butyst 0.9 f is obtained as a colorless oil.

a a a o c K H ) , 1770 , 17 0 , IR fjn *

aaaoc KH), 1770, 17 0,

 1720, 1 680 (C = 0)

[] _D -1 34 ^β C c = 0.4, in methanol

Real journey

3 (R)-[1 (S)-ethoxycapo- /-3-phthalimidobro] amino-4 4-year-old xo 2,3,4,5-tetrahydro-1,5-exchange One ST—

l Dissolve benzothiazepine mono-5-g ^ tert-petit estee 0.2 in soil 素 一 ヱ ， ヱ ヱ ヱ ヱ 、 、 、 放置. When the petroleum ether 10 is added to the reaction liquid and the amount of swelling increases, the amount of 3 () 1-1 [1 (S) -ethoxycarbo-3--3-phthalimidoblobis] amino-4-oxo2 , 3,4,5-TetraDraw 1,5 ^^-zothiazevin-5-acetic acid 18- is obtained as a colorless powder. [<<] ■ 0-102. (C- 0,3, in Methanow)

 Actual travel example 85

 *; 3 (ϋ) -amino-4-oxo-2,3,40,5-tetradihydro-1,5-pentazothiazevin-5-S¾tert-butylester 2 § and ethyl 2-bromo- (11) React with 7.1 f of dodecanecanate. The obtained product was separated and purified by silica gel column chromatography (hexane: ethyl acetate-3: 1) to give

As one fraction, 3 (a)-[1 (E) -ethoxycarbonyl-10-lida-5imidode ^] amino-4-oxo-1,2,3,4,5-tetrahydro1-1,5-pentozthiazebine-5- Tert-butyl ester 1.29 is obtained as a dark oil.

IRV « ¹ : 3320 C HH), 1770, 1740,

 1710, 1680 (0 = 0)

0 [] D-104 (c = 0.5, in Methanow)

 As the second surface, 3 (R)-[1 (S) -ethoxycarbonyl-10-phthalimidode] amino-4oxo-1,2,3,4,5-tetrahydrau 1,5-benzothiazepine-1 5-rich The acid tert-butyl ester 1.29 is obtained as a colorless oil.

5 RV neat αΓ ¹ : 3320 CHH), 1770. 1740

max · ― 1 · 8—

 17 10, 1 670 (0 = 0)

[<<] _D -1 1 3. (C-0.5, medium methanol)

 Real 8 β

 Example 8 3 (R) — [1 (S) -ethoxycarbox 10 1-phthalimidode!] Obtained in 5) AMINO 4 1-year-old oxo-1,2,3,4, δ-tetrahydrodraw 1,5 —Penzothiazebin-5-tert-butyster

0.25 f was prepared in the same manner as in Example 84, and aba ft *

 Then, when RS, 3 (R) — [1 (S) —Ethoxy force—10—Futaimi dodeci] amino—4 years old oxo-1,2,3,4,5-tetrahydro 1,5 Nzothiazebine-5-cocoic acid · ¾ 酸: ¾0.23 f is obtained as a colorless powder.

'[0 ^ — 10 1. ( _C = 0,4, in Methanow)

 Real 87

 3 (E) 1-Amino-4-oxo-1 2,3,4,5-TetraDraw 1,5-Penzothiazebine-5-Drossic acid tert-butyl ester 0,4 ^, Ethi 4--(1 (Lou 4-biverige) A 2-cyclobutyrate 1, triethylamine 0.2 ^, lium iodide 0.3 f and acetonitrile 50 »^ are heated and refluxed for 2 days. The reaction solution was decompressed and the residue was made into sugar by silica gel column chromatography (hexane: ethyl acetate -2: 1), yielding 3 (R) — [3- (1-Penzi). -1 (R)-1 (R)-ethoxy-7 * mouth pi] aminow 4-year old xo 2,3,4,5-tetra-t draw 1, 5-benzothiazebine-5-mono tert-acid —Buchi Esthe

0.15 f and 3 (S) — [3— (1—Penzoki ^ force Po-V 4 1 ridge) 1 1 (S) —ethoxycarbo-probi] aminow 4 1 year old — 6f—

Xiso 2,3,4,5-tetrahydro-1,5-benzothiazebine-5-acetate ter "butyltylester 0.25 is obtained as a colorless oil, respectively.

Real trip 钢 88

 3 (R) -amino-4 4-year-old xo 2,3,4,5-tetrahydro-

1,5-I-Penzothiazebine 5-Vinegar ert-Buchi este 2.1 is dissolved in Ethanol 3, and acetic acid 0.49, ETHI 5-C 1-Penzoxy carb-one-bilge) 1-two-year-old Add kisoparate 2.5 f, molecular sieve 3 A10. After stirring this S solution in the room fi for 20 minutes, a solution of sodium cyanoborohydride 0.4-etano-5 is stirred in the room S and dropped at the 3 o'clock threshold. After leaving the reaction solution in the overnight room fi, the pressure is distilled off, and the residue is mixed with water 30 and pentyl peroxy acid 30 and screw-mixed. After passing through to remove insolubles, the ethyl acetate layer is dried over anhydrous magnesium sulfate and removed under reduced pressure. Add ethyl acetate 2 and oxalic acid 2 f to the residue, mix well, add petroleum ヱ -300 and leave. Slanting to remove the solution Φ, water 100 «?

 Add 20 and neutralize by adding excess sodium hydrogencarbonate. The ethyl acetate layer is dried with magnesium anhydride and evaporated under reduced pressure to obtain an oily substance. A This S is separated and purified by silica gel column chromatography (hexane = vinegar = 2: 1). Then, first, 3 CH) -C 4 -C 1 pendant (11-biphenyl) -1 (R) -ethoxy-carbonibuty] amino-4 oxo-2,3,4,4 0.4 f of tert-butyl ester of 5-tetrahydro 1,5-benzozoazepine monopentate is obtained as a colorless oil.

IRV αΓ ¹ : 331 0 (2ΤΗ); 1730, 1 680 (C = 0) Mass spectrum (m / β): 653 (M ⁺ ).

From the subsequent fractionation, 3 (E) — [4-1 (1-1-hydroxy)-1-1 (S)-ethoxy-capitol] amino-4-1-2, 3 , 4,5-Tetohydro-1,5-^: nzothiazebin-5-acetate teii? "Butyester 0.8- is obtained as a colorless oil _β

IRV m ¹ : 3320; 1 730, 1 690 (C-0) · mass start; 1 (m / e): 653 CM ⁺ ).

89

 3 (R) — [4-1 (1 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ァ 力 力 ポ 力 ァ キ シ 力 ミ ミ ミ ミ ミ ミ ミ ミ ~ 2, 3, Dissolve 4,5-tetrahydrido 1,5-benzothiazebine-5-acetic acid tert-peptiestere 0.4-in acid 2 «^, add 30 * hydrogen bromide acid solution, and leave in the field for 1.5 hours in a room overflow . Add 50 ml of ethanol to the reaction mixture, allow to stand, and remove the supernatant by decanting. After washing the debris with ether, and drying it, 3 (R)-{1 (R) -ethoxy-(-biphenyl) butyl] amino-4-oxo-2,3,4 1,5-Tetrahydro-1,5-pentazothiazebine-5-acetic acid / hydrogen dihydric acid ¾0.4 is obtained as a colorless powder.

Elemental analysis value C ₂₃ ¾ ₃ W ₃ 0 ₅ S. As 2ΗΒΓ · 2Η ₂ 0

 Calculation 值: C 41.76; Η5, 94; S 6.35

 Measurement 值: C 42.07; Η 6.16 JST 6-09

[ _Na ] _Ώ一 1 1 1. (Medium)

Mass spectrum (m / e): 463 (M ⁺ ).

Example 90 3 (R) 1 [4-1 (1-1-benzene-1-(1)-1-benzyl-1-(S)-ethoxyka-butyl] amiso 4 1, no 2, 4, 5-tetrahydrid 1 , 5-Penzothiazebine-1-tert-butyl ester, 0.8-acetic acid, dissolve 0.8-acetic acid, add 30 * hydrogen acetic acid acetic acid solution, and let it stand at room temperature for 1.5 hours. And then remove the supernatant by decanting. Wash the sediment with ethyl ether, and then dry it to obtain 3 (R)-{1CS) -ethoxycarbo-4-1 ( [4-Bibenzyl) butyl] amino-4-oxo-1,2,3,4,5-tetra, hydro-1, 5-pentoziazebine-5-acetic acid.Hydrogen bromide 0.75-is obtained as a colorless powder. Can be

Elemental Qi 镊 C ₂ 3 Has K ₃ 0 ₅ S.2HBr-¾ ¾ 0

 Lonely son: C 42.34; H 5-87; U 6-44

 Measurement: C 42.35; H 6 · 03 ;. »6.12

[] _D -89 ° (Meanau medium)

Mass spectrum (mZe): 463 (M ⁺ )

Actual travel example 91

 3 (R) — {1 (S) —ethoxycarbox 4- (4-biphenyl-A-butyl) amino-4-oxo-1,2,3,4,5-tetrahydro-1,5-pentazothiazebine-δ-acetic acid 2 Dissolve 0.5-hydrogen oxalate in 1 U sodium hydroxide aqueous solution, leave it in room humidity for 30 minutes, then add 2W¾r of vinegar and neutralize, then add MCI gel (C St? 20 f>, 150 ~

MITSUBISHI CHEMICAL) Purify by column chromatography (water: methano-= 2: 1). The effluent is decompressed and concentrated and freeze-dried to give 3 (R)-{1 (S) -force. Key 4-4-1 (4-biperidyl) butyl} amino-4 4-year-old oxo 2,3,4,5-tetrahydro-1 , 5—Venzo Thiazebin-5—0.3 f is obtained as a colorless powder.

Elemental analysis 值 C ₂₁ H _2S W ₃ 0 _S S

 Calculation 值: C 53.49; H 7.05 g. 91

 Execution: C 53.77; H 7.11; K 8-96

[E _D — 1 1 7. (Methanolau underwater)

S Γΐί S spectrum (mZe): 436 (MH ⁺ )

9 2,

3 amino-4-oxo-1,2,3,4,5-tetrahydro

1,5-Penzothiazebine-5-acetate tert-butyl ester 3-is dissolved in ethanol 3 O Wi, and the enzymatic acid 0.58 9, eti 6 -C 1 ^^: Ndoki garbo-4-biperidi) — 2 —Add oxohexanoate «4 f, ¾ recursive sieve 3 A 10 f. This mixture is stirred at room temperature for 15 minutes, and then a solution of sodium cyanoborohydride 0.61 in ethanol 5 is stirred in a room and added dropwise over 3 hours.

 After leaving the reaction solution in a room fi overnight, decompressor buds are removed, and water 100 and acetic acid 20 are added to the residue, and the mixture is mixed. Remove the insoluble matter by passing through a furnace, wash the vinegar layer with 10 * U aqueous solution of phosphoric acid, 0.1N aqueous solution of sodium hydroxide and water, dry with anhydrous magnesium, and remove pressure. . The residue was separated and purified by sieving force and mutaromatography (hexane: ethyl acetate / 2: 1). First, 3 (R) — [5 (1-benzi) was obtained. Rigi) 1 1 (H) — ethoxy borpentyl] a minnow 4oxo-1,2,3,4,5—tetrahydro-1,5—benzothiazebine-5-acetate tert-butyl ester 0.45 f is a colorless oil Obtained as a product.

IRV 5¾ αΤ ¹ : 333 0 (1ΤΗ); 1 74 0, 170 0 (0 = 0). One T one

Mass spectrum (mZe): 667 (M ⁺ ).

 From the following orchids, 3 (R)-[5-(1-1-Penoxykabo-4-biperidi)-1 (S)-Ethoxykapo-pliers] Ami No 4-Iki, No -2, 3,, 4,5-Tetrahydro-1, δ-Benzothia zevin-5-Azumamon Uer-Butieste 0,8- is obtained as a colorless oil.

IRV g ¾ ": 3320 (NH); 1740, 1690 (C = 0). Mass spectrum (m / e): 667 (M ⁺ ).

Fruit paste 93

 3 (R) — [5— (1-year-old xycarbol-ru 4-biperidyl) 1 1 (R) —etoki ^ capo-pliers /! /] Amino 4 4-oxo-1 2,

3,4,5-Tetrahydrido 1,5-pentazothiazevin-5-acetate 0.45 f of tert-butyl ester dissolved in 1 W of acetic acid, 30 * bromine vinegar

 Add ^ and release for 1.5 hours at room temperature. To the reaction mixture is added Ethiete 20 and the mixture is left to stand. The precipitate is washed with ether and dried to obtain 3 (H)-{1 (B) -ethoxycarb-5- (4-biphenyl) pliers I Amino-4 1-year-old 1,2,3 , 4,5-Tetrahydro-1,5 ^^ Cnzothiazebine-5-acetic acid / dihydrogen peroxide 0.3 f is obtained as a colorless powder.

Elemental elements C ₂₄ H3 ₅ N ₃ 0 _{5 As} S.2HBr-H ₂₀

 Calculated values: C43 · 85; H5 · 98; 56 · 39

 Actual M: C 43.95; H 6.29; 2Ϊ 6.47

[<<] _D -1 08 ° (Methaneau)

Masusupeku door (m / e): 477 ( Μ τ)

 Example 94

OMPI 3 (R) 1 [5 1 (1 penge ^ 力 力 力 力 4 4 一 一 一 一) 1 1 (S)-ト ^ ^ カ ボ ボ ア ミ ノ ア ミ ノ ー amino 4 4 キ 1 2 2, 3, 4, 5 1,5-hydro-1,5-benzotriazebine 5-vinegar

 Dissolve 75 tert of tert-butyesthesia, add 80 * 2D hydrobromide, and place at room temperature for 1.5 hours. SiS «i € e エ ー te

Add 20 and allow to stand, then remove the upper S solution by rusting. The precipitate is washed with ether and dried to obtain 3 (R)-(1 (S) -etoki.

 3 Power Po-I 5- (4-Bridge) Pliers "Amino-4oxo-1,2,3,4,5-tetra-t-Draw 1,5-benzothiazebin-5- ゼ

 · 2 ^^ * acid * 0.6f is obtained as a colorless powder.

[Α] _π — 89 ^β (in methanol)

Mass Spect ^ (mZe): 477 CM ⁺ ).

Fine 95

 3 (E) 1 {1 (S) —ethoxycapo-5-C 4 -biperidine) wj amino-4 4-oxo-1,2,3,4,5-tetrahydro 1,5 benzothiazebine-5-acetic acid 2 Dissolve hydrobromic acid ¾ 0.45 in lii water sodium hydroxide ¾ ¾ Dissolve OWiC and leave in a moat for 30 minutes. Vinegar

And neutralized by adding MCI I / w column chromatography (water: methano

 : Purify in 1). The effluent is concentrated under reduced pressure and freeze-dried to give 3 (R)-{1CS) oxy-1- (4-biperidi) pliers 1 amino-4 oxo-2,3,4,5-tetrahydro-1,5 » Panzothiazebin-5-acetic acid OSf is obtained as a colorless powder.

Elemental analysis: C ₂₂ ¾i H ₃ 0 ₅ S-2¾ 0

 Total: C 54.42; H 7.27; H 8.66

Miina 值: C 54.84? H 7- 38; 1Γ 8.61 0 ^1ΛΡι ' [Ot] _D — 131 ^β (Methanolau in water)

SIMS spectrum (m / e): 450 CMH ⁺ )

Actual travel example 96

 3 (R) -Amino-4oxo-1,2,3,4,5-tetrahydro-1,5-benzothiazevin-5-acetate ter-butyrate X Step 2.5 is dissolved in ethanol-3, and 0.5 f-ethyl acetate is dissolved. ~ 7— (1 ^^: ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ _ ^ _ ^ ______________ in lower more more than that is surpassed. After stirring the mixed solution for 10 minutes through the room, lower the mixture at 3 o'clock in the field while stirring a solution of sodium borohydride 0.51 f in ethanol 5 in the room fi.

After leaving the reaction solution to pass through the room overnight, decompress the mixture, add water sow and ethyl acetate 20 to the residue, and shake. After passing through to remove insoluble matter, the vinegar-containing layer is washed with 0.1N-acid, 0.1-ml aqueous sodium hydroxide solution and water in this order, dried with magnesium anhydride, and then removed. When the residue was purified by silica gel chromatography (hexane: ethyl acetate -2: 1), the residue was first purified by 3 (R) — [6- Peridi) 1-1 (H) -ethoxycapoxy-amino) amino-4,3-, 4-, 5-tetrahydro-1,5-pentazothiazebine-5-acetic acid hepta-butyester 0.5 f is a colorless oil Obtained as a product. IH or-i: 3320 (KH); 1730 _f 1680 CC = 0). Mass spectrum (a / e): 681 CM ⁺ ).

From the following plane, 3 (R) — [6— (11-year-old penguin-one-one-one-one-one-one-be-li-ji) -one-one (S) —Ethoxyka-one-two-one- , 3,4,5-Tetrahydro-1,5-monopentazothia zebin-5-acetate tert-butyl ester 0.9- as a colorless oil -79—

 Can be

1R αΓ ¹ : 3330 (KH); 1730, 1690 CC = O). Mass spectrum (me): 681 (M ⁺ ).

Actual example 97

 3 (H)-6-f l

— 1 (S) —Ethoxykapo- ^ hexaminamine 4 1-year-old oxo-1,2,3,4,5-tetrahydro-1,5-pentazothiazebin-5—static H ter—petit este 0.5—dissolved in acetic acid, 30 Add * 类 ^ k elementary solution and leave at room temperature for 1 hour. After adding 200 W of Ethiete to the reaction solution, settle the upper S solution and remove. The sediment was dissolved in 1 M aqueous sodium hydroxide solution 20 and neutralized by adding a glue 2 to the mixture at room temperature for 30 minutes, and then purified by MCI-ge 1 column chromatography (water: methanol-1: 2). The concentrated _β- effluent is concentrated by MflE and freeze-dried to give 3 (H)-[1 (R) -force] oxy-6- (4-biperidiq ^) amino-4-oxo-1,2,3,4,5- Tetrahydro-1,5 monobenzothiazebine-5-acetic acid 0.23 is obtained as a colorless powder.

[<<] _D -144. (Underwater)

Fine 93

 3 (B) — [6-1 (1-1-benzene power)-1-(S)-ethoxy power; po-hex] aminow 4 1-year-old xo 2, 3, 4, 5-tetrahydro draw 1,5-Venzothiazebine-5-monoacetate ter-petite 0.9 f was dissolved in acetic acid IWt, 30 * hydrogen bromide acetic acid solution was added, and the mixture was left standing for 1.5 hours in a moat moat. Reaction solution

M C I -ゲ^クロマトグラフィー（水： メタノ - - 1 ： 2 )で精製する。 流出液を ^濃縮した後、 凍結乾燥 すると、 3 ( R )—〔 1 ( S )一力 ~ポキシ— 6—（ 4ービペリジ ） へキシ^〕アミノー 4ーォキソー 2 , 3 , 4 , 5—テトヲ ドロー 1,5Add 200 »and allow to stand, then remove the supernatant by slanting. Dissolve the moat in 1 U sodium hydroxide water, and stir at room temperature for 30 minutes. 0MPI i Acetic acid 3

Purify by MCI-gel chromatography (water: methano--1: 2). The effluent is concentrated and freeze-dried to give 3 (R)-[1 (S) -l-poxy-6- (4-biperidi) hexy] amino-4-oxo2,3,4,5-tetrad 1,5

5-Penzothiazebin-1 5-vinegar mon 0 · 43- is obtained as a colorless powder.

[<<] _D -121. (Underwater) ·

 SIM Spectrum (mZe): 464 (MH ")

 Actual foot example 99

 3 (R)-amino-4-oxo, no 2,3,4,5-tetrahydro

10 1, 5—Venzothiazebin-5—cocoic acid tert-butyl ester 2 I ¹

 Dissolve in Tano-3, add 0.479 acetic acid, ethi 8-(1-benzy / V-year-old-boni ^ -14-biperidi) -1-2-year-old kiso-tanoate 3, molecular sieve 3 A 10 f. After stirring this solution for 10 minutes in room humidity, 0.45 f of a solution of sodium cyanoborohydride in ethanol is added dropwise at 3 o'clock with stirring under room humidity.

 After leaving the reaction solution in the room fi overnight, decompressive distillation is performed, and water 10 and ethyl acetate 20 are added to the residue and shaken. After treatment to remove insolubles, the acetic acid layer is washed with water, dried over magnesium anhydride, and decompressed. The residue is subjected to column chromatography (hexane: ethyl acetate).

Separation and purification by 20 -3: 1 to 2: 1) yields 3 (R)-[7-(1-

 / キ シ 力 ポ ^ ^ ^ ^ ^ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ノ ー ノ ー ノ ー ノ ー 1 S S S ノ ー S カ ァ ノ ー ノ ー ノ ー-Acetate tert-buty; V Este 0.3 ^ is obtained as a colorless oil.

αΓ¹: 3320 ( ΪΓ-Η ) , 1730 , 1690 C C=0 ) マススペクト^ ( m/e ) ： 695 ( M⁺) 25 IR

αΓ ¹ : 3320 (ΪΓ-Η), 1730, 1690 CC = 0) Mass spec ^ (m / e): 695 (M ⁺ )

 Real 100

 3 (S) 1 [7 1 (1 1 ^: N- oxy-force-1-4-biperidi) 1 ICS)-ethoxyca-hepti / v] amino-4-year old y-2, 3, 4, 5-tetrahydro 1,5 ^^: nzothiazebine-δ-acetic acid

Dissolve 0.3 tert-butylester in 1.5 Wi, add 30 * hydrogen bromide acetic acid solution, leave it in the field for 0.5 hours in a room, and add _β SJS solution Κ: The supernatant is decanted and removed. Dissolve the sediment in 11 W of 10% sodium hydroxide solution and release in room humidity for 30 minutes. After neutralization by adding 2 W of acetic acid, the product is purified by -2 force, mucography-(water: methano--1: 1). After the spill 流出 was compressed and dried, 3 (3) — [1 (S) —force boxy 7-C 4 -beverage; hept ^] amino-1 4-oki, no-2, _Β [a] _D -116, which gives 0.1,3,4,5-tetrad 1,5-pentoziazepine-15-acetic acid as a colorless powder. (Underwater) ''

SIHS Start (m / β): 478 (MH ⁺ )

Real example 101

Stir the mixture of iso-cotinaldehyde 25 ^, ethi (triffe-phospho-redene) acetate 82-and toene 30 at 100 "C for 3 o'clock. After cooling, remove the crystal grown and remove the liquid. After that, add 1: 1, 40 of a mixture of K vinegar and petroleum ether and extract with δ% 500 W. After extracting the aqueous solution with 50 acetic acid, Neutralize with potassium carbonate and cool to give a crystallized crystal.The spear crystal is removed and dried to give ethyl 3- (4-bilidine A acrylate-34 as a colorless prism. Melting point 64 — In S6-3mf-i _ Example 102

 Dissolve 28 f of 3- (4-bili) atarylate in acetic acid at 30 aCK, and use 1 f of platinum monoxide as a wrinkle medium to carry out the reaction of sensitization at normal humidity and pressure. After the hydrogen collection stops, the solution is removed by passing it through an iridium medium and decompressed. Add 500 ml of water and 30 ethyl acetate to the residue, add sodium bicarbonate while stirring, and add until the mixture becomes clear. Add the mixture of pentacarboxylic acid and chloride to the resulting mixture. After stirring at 1 o'clock, add 20 watts of benji genki potato. Stir in Chamber S ¾ ら Add sodium charcoal hydrogen hydrogen 30-little by little. After stirring at room temperature for 2 o'clock, the ethyl acetate layer is separated, washed with water, dried over anhydrous magnesium sulfate, and decompressed. When the obtained oily substance is made into sugar by silica gel column chromatography, FI (hexane: cocoon monkey / u = 2: 1), it is obtained as follows. Rigi) is obtained as a colorless oil.

IRV αΓ ¹ : 1730, 1700 (0 = 0).

Real giant 103

Dissolve C-one penge (1 year old) and dissolve 17-year-old oxobutyrate (17-) in ethanol, add δf acetic acid and stir. Add sodium 3-. After stirring at 3 o'clock in room S, add water 50 and extract with methylene chloride. The extract was dried over anhydrous magnesium and depressurized, and the resulting oil was purified by silica gel column chromatography (hexane: vinegar -2: 1-1: 1). H- (11-Penzi / w-year-old xycarb-4-biperidi) -1-hydroxybutyrate 11.5 is obtained as a colorless oil. Redemption ^ f> _OMPl IR neat ^ -i; 3430 (OH ); 1730, 1690 (CO) ·] ί R -spectrum (CDC1 ₃ + D ₂ of 0) ί: 7.3 (5Η) , 5 · 1 (2Η), 3.9 one 4.4 (5Η), 2.5-3.1 (2Η), 1.0-2-0 (12Η).

Actual translation 104

 A mixture of 20-pyridine and 12-pyridine with 2-hydroxybutyrate (11.5-biphenyl)-2-hydroxybutyrate 11.5- Ji-Shi-5 In addition, at 1 o'clock, stir the mixture. After cooling, add 500W of liquid K water and 10 vinegar to extract. The extract is washed with 0.11 f acid and water, dried with anhydrous magnesium sulfate and activated carbon. * After removing the ethyl acetate under reduced pressure, the ethyl acetate is removed. 1-Clobutyrate 10.5 is obtained as a pale yellow oil.

IRV αΓ ¹ : 1740, 1690 C = 0).

Real 105

 Echiru 4-1

Dissolve 2-chlorobutyrate 10 «5 in ethanol 20W, and perform tandem reversion under normal humidity and normal pressure using 10 * paradium-carbon (50 * water-containing) 5f as a medium. After the absorption of hydrogen has ceased, the catalyst is removed by passing through the catalyst, and the aqueous solution is removed by ES to obtain 4- (4-biperidi) butyrate. Dissolve this product in a mixture of ethyl acetate ^ 200 »^ and water 10, add 6 f of charcoal sodium salt and stir with a mud. The pentacarboxylic chloride is added dropwise, and after the completion of the addition, the mixture is stirred for 1.5 hours at room s.

Separate the layers, dry-image with anhydrous magnesium, and completely remove. The residue was purified by silica gel column chromatography (hexane: ¾! Acid-3: 1) to obtain ethyl 4-41 -4-Bi, Jdi) butyrate 5.3 is obtained as a colorless oil.

IB gf * α ¹ : 1780, 1700 (0 = 0).

Real example 106

 Dissolve 0.48 f of sodium in ethanol 1 and add ethyl oxalate 8 with eth- (1-pentoxyca-bo 4--biperidi ^) butyrate δ 3 f and add 60-70 ¾ Remove the pressure for 30 minutes and remove the low boiling point Φ. After cooling, add 300 W of water to the obtained yellow candy, acidify it with 1 molly, and extract 2 orchards with 10 vinegar. The extract is dried over magnesium sulfate and then removed. To the obtained oil is added 45 W of dimethyl sulfoxide, 5 W of water, 0.8-lithium lithium oxide, and the mixture is stirred at 135 to 10 for 1.5 hours, and further stirred at 140 to 145 * C for 30 minutes. After cooling, water 50 was added to the reaction solution, and the mixture was extracted with ethyl acetate 30. The extract was dried over anhydrous magnesium, and then removed in Shanghai to remove ethyl 5- (1-1-pen-lo-q-carb--1-viperidyl) -1. 2-five years of foliage are obtained as an oil.

IRV gf * ci " ¹ : i 730, 1700 (C = O).

 Mass spectrum (m / e): 361 C +).

Actual * Example 107

 Methylene chloride of methylene chloride 40 and water 40 »^ in 3- (4-biveridi) propano 84 and triethylamine β 5-

 Stir 100W¾¾ at the same time as the 100-year-old Xi-Kalbo-Yuk mouth lid at room S and drop at 45 minutes. After dropping, stir for 1 hour at room temperature. The methylene chloride layer was separated, dried with magnesium sulfate, and then «pressed off». The resulting oil was evaporated and the bp 50-6 OtZSwHf was removed. — (1—Penoki force

"BUREAU difference One "one

 Poly-4-biperidi) -Pupano 110 is obtained as a yellow oil.

 I R neat: 3400 C 0 layer), 1680 (C-O).

 Β & Χ

Actual foot example 108

 3-C 1—Penzi

Stir the solution of / V I 10 f and pyridine 50 under ice-cooling, and add 100 f of totalolide in small Jt at 2 o'clock. After stirring the field for another 1 hour under ice-cooling, the perishable water 14 is removed.

 Subsequently, 500 W of acid is added dropwise under ice cooling, and then extracted with 1 M of ethyl acetate. The extract is washed with dilute acid and water, dried with magnesium sulfate anhydride, and then removed. When ethanol is added to the obtained oily substance and allowed to stand, 3- (11-pentoxycapo-4-biphenyl) 7 * σ-biρ-to-enthone 99- is obtained as colorless crystals. Melting point 59 — 60

Elemental element Q 值 C ₂₃ H ₂₉ ITO5 S

 Calculated value: C 64 · 01 H 6-77 N 3 · 25

 Actual charge: C 64.25 H 6.78 N 3- 26

Real 109

Dissolve sodium 5.8-in 300 W of Ethanor, and add 40 g of malonic acid and stir. Main mix K 3— C 1 ^^: N-doxyka ^^-4-biphenyl) Bi ^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^ 加 え 9 9and add 加 え を ス ス ス ス ス ス ス ス ス ス ス ス ス ス ス ス ス エ ン 9 9 ス 9 9 9 9 9 ス ス 9 ス ス 9 9 ス ス 9 9 9 9 9 9 9 9 9. After cooling, add water 1 and extract with ethyl acetate Α 'δ 0, dry with anhydrous magnesium sulfate, and decompress to obtain ethyl 5- (1-pentyl carboxylic acid) 1 2 —Ethoxycarbo-valerate is obtained as an oil. This product -8S-Tano-20 OWi Dissolve, stir 34 f sodium 20 f water 20 Qait and add dropwise. After the completion of the dropwise addition, water 30 is added to the reaction solution, and the mixture is extracted with water and petroleum ether (1: 1 and 30. The aqueous layer is made energized by enrichment, and the acid drenched at 500 M). The extract is washed with water, dehydrated with anhydrous magnesium, and decompressed to give 5- (11-benzoxycarbonyl-biperidi) -12-ka-poki ^. The product is stirred with 16-17 0 and heated briefly for 4-4 δ to give 5-(1-benzylic acid-1-4-biperidi) valeric acid 50-as an oil. Can be

IR S¾7 α ¹ : 173 0, 1 700 (0 = 0).

Real example 1 1 0

 5— (1-Benoxy power / Boy 4)

 54.89, Sodium hydrogen hydrogen 29 f, iodine 21 1 ^^-,-Heat the S solution of dimethyformamide 15 at 70-80 for 3 hours with stirring. On the other hand, add baking agent 1 and heat at 90-100 ° C for 3 hours. After cooling, add 1 ^ water and extract with 1 ^ acetate. The extract is washed with water, 1% hydrochloric acid and dilute aqueous sodium hydrogencarbonate, dried with anhydrous magnesium oxide, and then removed. Etch 5-(1-year-old 1-biperidi ^) palerate 58 f is obtained as a pale yellow oil.

 I E υ αΓ ^ Ι δ δ Ο, E Τ Ο Ο ί Ο ^ Ο).

 ^ MR Sect C CDC) d: 7 3 (5Η), 5 1 (2Η), 3 9-4 4 (4Η), 2 5-3. 1 ぐ 2Η), 2 1 -2.5 (2Η), 1- 0-1.9 (14Η).

Example 1 1 1

Dissolve 2.2 f of sodium in ethanol 5 OWiC and add ethyl 5— (1 difference 1 Benzoxykabo 4 4 Beverage) Add 14 f of oxalic acid and 14 f of valerate, 60 o'clock at 1 o'clock, 60 -70 at 30 o'clock, remove pressure and remove low boiling point. After cooling, 500 W of water is added to the brown candy obtained. * The mixture is acidified with folic acid and extracted with 300 ml of enzyme. The extract is dried over anhydrous «Madane» and then dried with MfiES. The obtained oily substance fc Dimethisoxide 150 ", water 1 and 5 f 9-iodide were added, and the mixture was stirred with 150-155 for 35 minutes. After cooling, water δ0 was added to SJS¾ and extracted with ethyl acetate / 30. The extract is dried over anhydrous magnesium isoform and then «depressurized» to give 2- (1 -pentene xicapo-4-biperidi) -2-oxohexanoate 26 as an oil. .

^{IRV g * αΓ 1: 1730,} 1690 (C = 0).

Mass spectrum ^ (mZe): 375 (M ⁺ ).

Actual * Example 112

 チ 一 一 1 1 1 1 1 1 1 1 1 1

(2) Dissolve 26-oxohexanoate (26 f) in ethanol (4), add vinegar 6.2-and stir. Add 4 f of sodium cyanohydride under ice-cooling, stir for 1 hour, and leave overnight in Muroto. Add 500 of water to the reaction solution and extract with methylene tallide. The extract is dried over anhydrous magnesium and «pressed off». The resulting orange oil was purified by silica gel chromatography (hexane: ethyl acetate -2: 1) to give ethyl 6-C 1 -benzocarbyl 4-biphenyl. ^) One 2-t droxyhexanoate 1 s is obtained as a colorless oil.

IE "g | ^ cm ¹ : 3450 (OH); 1730, 1690C C-0) Getty V 6-1 (1 year old)

Dissolve 2-hydroxyhexanoate 12.8 in S-solution of ethyl acetate 12 and viridin 13-, add 5.1 W of thiol chloride, and stir for 45 minutes. Wei, add 500 W of water and 200 W of vinegar to the reaction mixture and extract. The extract is washed with water for 0.1 H, washed with water, dried over anhydrous magnesium and removed. Purification of the resulting oil by column chromatography (hexane: enzyme = 4: 1) yields 6-C 1 benzene. D) One 2-chlorohexanoate 10 f is obtained as a colorless oil.

 I R fgH * «": 1740, 1690 C C = 0).

Real 114

Dissolve the hexanoate 10 in the ethanol 20 by dissolving the hexanoate 10 in the ethanol 20 and permanently using 10% powder carbon (containing 50% water) δ as the sensitizing agent. Perform contact reduction at normal pressure. After the absorption of hydrogen has ceased, the solvent is removed by passing through a sensitizing medium, and the liquid is decompressed and distilled off to obtain ethyl 6- (4-biperidi) hexanoate. This product: Add 10 W of water and 200 mL of acetic acid, add 7.2 W of sodium bicarbonate and stir with 7.2 W of penzoxyca-podichloride in the _β chamber moat and stir overnight. Separate the ethyl acetate layer, ¾ | ¾ with anhydrous magnesium, and decompress. When sugar is used to produce residual sugars by column chromatography (hexane: hydrochloric acid = 4: 1), the sugar is converted to 6- (one pendioxane-force-one-peelage). -7.7 is obtained as a colorless oil.

IRS | t αΓ ¹ : 1780, 1690 (C = 0).

Actual travel example 115 OMPI One 8β—

Sodium 0 · 56 was dissolved in ethano 2 OWtC, and ethyl 6— (1 1-benzo-force 1-boni 1- 1-bridge) was added to oxanoate 7.8 and 3.5-3.5. 60 -70 ^β for 20 minutes, 75 for 20 minutes. After cooling, blue-colored starting material * C Add 10 with water, make it moisturizing with berries, and extract with malic acid ^ 80. The extract is dried over anhydrous magnesium and then pressed. The obtained oily substance is stirred for 40 minutes with 140-160 of dimethyl sulfide 5, 5W of water, and 1.5 f of potassium chloride. After cooling, add 30 βί of water to the reaction solution, extract with 30 g of vinegar, dry the extract with anhydrous magnesium sulfate, and extrude to remove 7- (1-pentoxycarbol-4). -Biperidi) ~ 2-oxohexanobutanoate 6.5 I ¹ is obtained as an oil.

: 1720 ， 1690 ( C -ひ） . IH

: 1720, 1690 (C-H).

Mass spectrum (iii e): 389 (Μ ^τ ).

Real example 1 16

Dissolve 200 mL of tetrahydrofuran (2 W / 8 f), and add 18.4 f of sodium borohydride, and stir with 70-80. -4 drops at 1.5 hours. After the completion of the dropwise addition, reflux for another 2 hours. Remove the reaction solution, add 800 W of water and extract with 300 W of acid. The extract was washed with 1 IG壌酸50W and water 5, and after drying over anhydrous Gune Shiumu, when removed by flashing圧留, 5 i (1-Penji O key Ka port - _-4 one Biperiji) Bentano one ^ 23 # is Obtained as a colorless oil.

IR f cm ¹ : 3400 (OH), ie90 CC = 0).

irilS bitch in capital equipment _{CDC1 3) d: 7.3 (5H} ), 5 · 1 (2Η), 3 · 9-4 · 4 presumed dead, switch C2H), 3.5-3.8 (2H), 2.4-1 3, 0 (3Η), 1 0-1 9 (13Η).

Example 1 1 τ

 5-C 1 Benzoxy force Poyu-biperidi ^) Stir the pentano 18- and pyridine 1 S solution under ice-cooling, and add a small amount of lip 116- Add with 颺. After stirring for another hour under ice cooling, 2 W of ice water is added dropwise. Washed 2 strokes with 50% ow, 1N-m 500W, and further washed with dilute aqueous sodium hydrogen carbonate solution and water, dried with anhydrous magnesium sulfate, and added with castle pressure. «Leave. The obtained oily substance was purified by silica gel column chromatography (hexane: ethyl acetate ^ -3: 1-2: 1) to give 5-(1-pen-year-old sica-po-14-biperidi) pliers; p —Tohens; V phosphate 18- is obtained as an oil.

^R "SI *" 1 ¹ '170 0 (0 = 0).

Real 1 1 8

 Dissolve sodium 0.95-in ethanol 8

Add 7.2 and stir. To this mixture, add 5—C 1 penge o キ kaburu 4 4vii) Pliers / Vr »-ホ ホ ス ホ 1 1 加 え 加 え 加 え 加 え 2 2 2 2 2 2 2 2 2. In addition, sodium

Add a mixture of 2 ml of ethanol and 1.8 f of malonic acid jet, and stir for 2 hours while stirring. Ethanor is decompressed and removed, water is added at 200 W, cocoon acid is extracted with 300 W, dried over anhydrous magnesium, and decompressed, and then decompressed to remove Echino 7— ( 2-4-biperidi) -butanoate is obtained as an oily substance. This product was dissolved in ethanol 3 and lower 4 grounds moat stirring water 50 «^ solvent solution of sodium hydroxide β ί ^1. After shaking, add 150 W of water to the reaction solution, One 38—

Extract with the liquid of petroleum and petroleum ether (1: 1).

Was acidified with sulfuric acid, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and removed to give 7- (1-pentoxykapo-4-biphenyl). ^) One-two-carboxyheptane is obtained as an oil. Stir the book S between 160 and 165, add 1 hour, and add H to the resulting oil. ! When sugar is produced by force chromatography (hexane: ethyl acetate ^ -3: 1-1: 1), it is possible to obtain 7- (1-1-pentoxy carb-1-4-biperidi) 1-butane 6.4 f Is obtained as an oil.

IR ^ SJ ** cm ¹ : 1730, 1710 (C = 0).

Actual H example 1 1 9

 7 ~ C 1 Pendioxy force ^ Poly-vinylidene) heptanoic acid 6.4, sodium bicarbonate 3.1, iodide chill 8.6 / and IT, — Mix the S-solution of dimethyformamide 2, 100 Heat at 8 o'clock. In addition, add 1 f of sodium hydrogencarbonate to f ^ JS solution 2.9-and heat the mixture at 100 for 2.5 hours. After cooling, add 200 ml of water to the reaction solution, and extract with 30 g of vinegar. The extract was washed sequentially with water, 0.1 ir and sodium hydrogen carbonate aqueous solution, dried with non-permanent magnesium itate, and then decompressed to remove ethyl 7-C1-pentoxyca. 4-Biperidite A hebutanoate 5- is obtained as a tribute.

IR yg || "toT ¹ : l 730, 1700 CC = 0).

NHR solid (in CDC1 _S ) 3: 7.3 (5Η), 5.1 (2Η), 4.0-4.3

C4H), 2.5-3.0 (2Η), 2 1 12 4 (2Η), 1, 0-1- 9 (18Η).

Actual translation 120

Sodium 0 · 48 was dissolved in ethanol 3 ^ OWtC, and Add 1-butene v ok ^ carbo-4-biperidi) to a mixture of butanoate 6.5 and oxalic acid 3 f, and decompress at 60-70 o'clock for 1 hour to remove the low boiling point. Add 15 pieces of water to the candy, make it acidic with, and extract with 30 ethyl acetate. Extract! : After drying with magnesium anhydride, depressurize the window. Dimethis foxide on oily ring obtained

5 m £. Water ββ Add lithium iodide 1 and stir with 140 for 1 hour. After cooling, add 1 δ of SJS solution K water, extract with dilute acid 80, wash the extract with water, dry with magnesium anhydride, and remove the indentation window. ^ Po-4-biperidyl) -1 2-oxooxotanoate 6 I ¹ is obtained as an oil.

IRV Λ " ¹ : 1730, 1700 (C = 0).

Masusupeku DOO (m / e): 408 ( Μ τ)

Example 121

 4-(3,4,5,6-tetrahydro-2H-bilan) carbamide 13.2f, ethyl (triffe-phosphora-lidene) acetate

Stir for 44 hours with 100 of the dip of 44 f and Tween 20. «Depresses the Tween, Petroleum Ether 200W¾: Additionally, removes insoluble matter by passing through and decompresses the liquid. When the remaining material is vacuum steamed, ethyl 3- (3,4,5,6-tetrahydro 2H-pyran-14-1) acrylic acid 17 f (bp 132 to 184; Z16 騮) is obtained. Obtained as

I Η "^ ί ^ α» " ¹ : 1720 CC = 0), 1650 CC = C). HH C CDC1 ₃ ) S: 6.6-7.1 (15), 5 6-6, 9 (1Η), 3 7-4.4 (4Η), 3.2-3.7C2H), 2.0-27C1H), 1.1-1.9C7H)

Real judge 122 — 9β—

 Dissolve 3- (3,4,5,6-tetrahydro-2Η-pyran-14-1) atalylate 17- in ethanol 20 OWt and use 10 * palladium-carbon (50 50 <water-containing) f as a sensitizing agent. Normal water, normal pressure Τ¾ Perform a reduction reaction. After the absorption of hydrogen has ceased, remove it through the medium and remove the solution ¾ES. Vacuum evaporation of the residue yields ethyl 3— (3,4,5,6-tetrahydro 23: —biran 4i) y bionate 15 f (bp 121-128 / 6 縳) as an oil. Can be

1 HV Iff * cm ¹ : 1740 (C = 0).

IT MR (CDC1 in _{3): 3- 7-4.4 (4Η)} , 3 · 0-3 · 7 (2Η), 2 · 1-2.7

(2Η), 1 0-1 9C10H).

Real It Example 123

Ogizari chloride 10 * 2 »methylene chloride 20

 Cool with 65, add methysulfoxide 1 methylene 5 ^ chloride 50W «« in 10 minutes, and stir for 10 minutes. 4 michi no methylene black! Depress 100 100f¾ «for 10 minutes 阇 t ^

Stir for 20 minutes, then add tridiamine 7 in 10 minutes and stir for 15 minutes ^). Remove the cooling bath, stir at room temperature for 10 minutes, add 3H-folic acid 215 »^, and stir in Room C for 1 hour. Methyleneta

 The U layer is separated, washed with water, dried with anhydrous magnesium sulfate, and removed to give 4-thia-capaldehyde 11f as a pale yellow liquid.

IR 2 * αΓ ¹ : 1780 (C = 0).

 NMS (in CDCUg) a: θ ^ δίΐΗ) ^. 0H 5 (1Η), 2 * 5-3 0 (4Η),

 1.0-2 »5 (4Η).

Fine 124

, QMPI l Stir the mixture of 4 チ ア 1 カ 、 デ 11 、 、 、 チ ト ト ト ト ト ト ト 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 at 4 o'clock. The toluene pressure is removed, and petroleum ether 20 is added to remove the insoluble matter by passing through, and the liquid is decompressed. Vacuum evaporation of the remaining window 5 * yields ethyl 3- (4-thia) atarilat 10.4 f (¾ρ 155-157 / 1 δ 鱅) as an oil.

IE V 51 * aT ¹ : l 720 i C = O), 1 650 CC = C).

 KMR (during CDCOe): 6 6-7 1 (1Η), 5 6-6 0 (1Η), 4 0-4.4 2ί), 2 6-2.9C4H), 1 5—2 4 (5Η), 1 · 2—1 · 5 (8Η).

 Ethyl 3- (4-thia-) atalylate 10- is dissolved in ethanol 15 OWi, and 10ϋ palladium-carbon (50 * water-containing) 9 f is used as a sensitizing medium to perform contact reduction at normal pressure. Stir for 20 minutes at Murohori, then at 8:00 at 50, remove the medium through the furnace, add 10% palladium is-carbon (containing 5056 water) 9, and stir at 50 for 1 day. Removal of the catalyst by filtration through the furnace and depressurization of the effluent yielded ethyl 3- (4-thia) -blobionate 3.1- as an oil.

IR f glx ^{t arl} : 1740 (C = 0).

 KM H (CDClj Φ): 3 9-4.8 (2Η), 2 4-2.8 (4Η), 1 8-2.4 20 (4Η), 1.0-1.8 (8Η).

 Actual »Example 1

 Angiotensin I-enzyme (ACE) of the compound of the present invention

 C method D

Cushm & n et al.'S method I Biochemical Pharmacology, 2 _} 25 1637 (1971). Supachi, -9S ~

Hybri / v—L-¾-stige; L-isine as substrate and A C

Ei] Ϊ 馬 The production of hippuric acid produced by adding the compound of the present invention with respect to the amount of uric acid to produce urine was required. ACE 100 e4 (roofing density 2 ^ n / mi), 1.25 aMHHL 100 / <0.d 2 ~ 5 »Dimethysoxide 100 aM boric acid monochloride buffer (pH 8.8, 800 (Including the aM food) «<i> The dissolved compound of the present invention was added. As a control, a boric acid-¾acid rod mouth liquid containing dimethysulfoxide equivalent to the specimen was used. After the solution was thresholded at 37 ° C for 1 hour,

 The reaction was stopped by adding ISOμ, and ethyl acetate was added, followed by centrifugation at 11,500 rpm for 2 minutes. The hydrophobic acid layer 0-5W was dried under nitrogen gas under i 40, and the remaining substance was sufficiently added with steam water to be sufficiently diluted, and colorimetrically quantified at a wavelength of 228 nm.

 〔Experimental result〕

 The experimental adult crab prepared according to the present invention was shown in Table 15].

 Table 15

Replacement O PI One ₉₈ one

Experimental example 2

 The effect of the present invention on the pressor action of angiotensin I

[Actual method]

 Sprague-Dawley, a body weight of 300-400, which was kept free of food and water, was used. On the day before the experiment, the rats were injected with pentobium bitter sodium (5 OWZ ^) in JC and injected into the body. The vein {"t † L each dedicated polyethylene tube was provided.

 Actual »The average pressure of the same day was measured using an electric pressure gauge (SEC-San-Ei, MPϋ-0.5-290-0—0—Summer), and Ridala 7 (HEC-San-Ei, 365-type or Nihon Kohden) (4 δ type), then angiotensin I (800 ng, and then angiotensin) [100 ng ^] was injected into the crotch vein and its pressor action was called. Next, the present invention ^

 Intravenous administration of 300 ^ ^ as a physiology, and 5,10,30,60,90, and 120 minutes after administration, repeated injections of angiotensin I and 2: to increase blood pressure ^. *did. Inhibition rate was corrected based on the field fluctuation ft of angiotensin I on the pressor action of angiotensin I.

 〔Performance〕

 The experimental results of the compound of the present invention are shown in Table 16K].

 Table 16

OM ^P P ^I I Test compounding: The pressure rise of Anjinshin I

 After 5 minutes 10 60 碰 After 90 minutes After 120 minutes

90 300 1 Θ 100 100 90 β 7 β 2

95 806 96 94 99 89 9 β 91

 s

 98 300, 100 100 100 100 95 79

Mist

 For example, the compound (I) of the present invention can be used according to a method of treating hypertension, for example, as a method for treating hypertension 8.

 1. Disintegrant

 (1) 3 (R)-[1 (S) -carboxy-8- (4-biperidi) butyl] amino-4oxo-1,2,3,4,5-tetrahydro

1,5 Benzothiazebin-5 Monobasic acid 109

 (2) Sugar 90 #

 (3) Corn 29

 (4) Magnesium stearate

 30

 Ingredients (1), (2) and 17 f of component (3) are mixed and granulated together with a paste made from 7 f of component (3) .The granules: 5 f © ¾ ^ (3) and component ( Add 4) and mix. Compress the SJ with a compression key machine and use it as a disintegrant.)) Delivery 1000 tablets of direct suspicion T 鳙 containing one component (1).

 2. Injection Xiang

 (1) 8 (R)-1 C S) Poki, n-3-(4-Biberidi) pu mouth building] amino-4-oxo-1, 2, 3, 4, 5-tetrahydro

: Oh, OP-I 1,5-Penzothiazebine δ-recommended acid 10 /

 (2) Na BaBa 9 f

 Dissolve components (1) and (2) in steam water (100), dispense into blue amber 1000 wounds, replace with nitrogen gas, and seal. All processes are performed in sterile wisteria.

 3. Disintegrant

 (1) 3 (R)-[1 (S) -force poxy ^ 6- (4-biperidi) hexy] amino-4oxo-1,2,8,4,5-tetrahydro-1,5-benzothiazebine-15 — ¾ £ 酸 10

 (2) ¾ sugar 90-

(3) Toe mouth flour 29 f

 (4) Stealin Meng Magne, Ndum 1-

130 /

Ingredients (1), (2) and 17 f ingredient (3) are mixed together and K: 顯 fc fc と も と も と も と も with the paste made from 7 f ingredient (3)

Mix, compress the mixture, and pressurize it with a dispensing machine to deliver 1 agent of the agent]) and deliver 1,000 pieces of agent with a diameter of 7 mm containing one component (1).

4. Injection ^

 (1) 3 (R) — [1 (S) -force oxy-5- (4-biperidin) inch] amino-4 1-year-old oxo-2,3,4,5-tetrahydro-1,5-benzothiazebine-1 — Acid 10

 (2) Sodium sodium 9 f

Dissolve components (1) and (2) in distilled water (100 OWi), dispense into 1000 green tumbles, replace with nitrogen gas, and seal. All processes are performed in sterile form. One if—

Industrial applicability

 The Hakogo 7 kaiyu compound (I) provided by the present invention has excellent action and is useful as a pharmaceutical.

Claims

-9T- Scope of request

Wherein, H ¹ spare each hydrogen, halogen, preparative riff O main switch, lower A key or诋級§ Koki or shown ¾, rain's 3 comes to Application Benefits or shown tetramethylene ¾ in,: R ³ And R ⁸ are hydrogen, 0 lower aki or araki, respectively, are hydrogen or lower aki, and R6 is a condensate or chromium containing at least one Ν, 0 or S as an agricultural constituent. A condensed heteroalicyclic group, Α represents an alkylene chain, a represents 1 or 2] or a compound thereof. 2. Compounds as described in claim 1, wherein R ¹ and are hydrogen.  3. The compound according to claim 1, wherein I S 3. is hydrogen.  4. is a fused or condensed heterocyclic group containing at least 1 of ΪΓ, 0 or S as a constituent of the table, which may be substituted with 0 or 1 substituent; Chair The compound described in clause 8. 5. R ⁶ may be substituted. Ji ^ 20 or 1, 3-dioxoisoindole- ^  Section 8 6. The compound according to claim 1, wherein R ⁶ is oxa-, thia-, or piperidine which may be substituted. 7. The scope of the course in which R ⁶ is 41 bip ^ ^ 1 * 25 objects ¾ Λ OMf? 一 ^, 'V1PO — 9 * ~ l 8. The compound according to claim 1, wherein n is 1.  9.Formula (a)

[Wherein each pound sign has the same meaning as in claim 笫 1], by adding K water-closed Jt ^ JSi to the compound represented by  Equation (b)

 [Wherein each symbol is the same as in claim 1] R ⁶ -A-CH-C00R ³ 5 W ^a [In the formula, Jia ^& represents a halogen or a group represented by the formula R ^a S0 ₂ -0— (wherein R 4 represents lower aki, trifluoromethy, phe- or P-tri ^); Is equivalent to [請求] in the claim], or is contrary to the compound represented by [1], or o (c)

Wherein the symbol is as defined in claim 1 and the compound represented by the formula δ V¾ -Cn¾ n-C00R ^s OMPI ^^^-, ipo One a, one Wherein the halogen or the formula RBS0 ₂ - 0- (wherein, R ^b is lower alk kill, preparative riffs Oromechi, Hue - or p - DOO Lil showing a) at the indicated a group I table, other Contact No. is equivalent to the scope of the course (1).)), Or  Equation (d)

[Wherein each symbol is equivalent to claim 笫 1] — 0— C-C-C-A—R ^e  II II  0 0 [Wherein each symbol is as defined in claim 1] under reducing conditions: condensation reaction to obtain a compound in which in formula (I) is hydrogen, Or  Equation (e)

[Wherein, Z represents a hunger group which can be separated by hydrolysis or contact reduction, and the other symbols have the same meanings as in claim 1]. Or ¾ reduction κΐδ: to give a compound in which in formula (I) is hydrogen, or (t) expression

[Wherein each pound sign is the claim 1 and the threshold significance] 加 ^ Decomposition by SJS to obtain a compound of formula (I) in which is hydrogen, or ,  (g) expression

[Wherein the symbol ¾ is equivalent to claim 笫 1] and the formula

Wherein indicates the x «¾ t ¾ atomic group, wherein - represents a group as _<n _ ^2>,  £ ¾ The other symbols by Chijimikai react under matter reductive conditions the compound represented by the range笫1 wherein the same meaning as defined above claims, in formula (I), the atom in the group H ⁶ to Yuikai the group A Obtain a compound that is a nitrogen atom, or

O PI- One 1W— [Formula, where each pound sign is the same as the first item of the scope of fungus] and formula sale. \  Ύ  Blame c [Wherein, W ^c represents a halogen or a group represented by the formula: E ^ SC ^ -O- (wherein represents lower aki, trifluoromethy ^, phen- or p-tri); indicates纖configuration屎子group of formula - as by a compound represented by a group s ^6] HY, atoms in groups Yuikai the middle group a formula (I) provides compounds where the nitrogen atom Or or (i) In the formula (I), is a lower alkyl or / and a compound in which H ^S is a lower alkyd by hydrolysis or t-attachment. I In the formula (I), B ³ is hydrogen Obtains a compound in which Z and R ⁵ are hydrogen, or (j) A compound in which R ³ is benzyl or / and R ⁵ is benzyl in the formula (I) is subjected to contact reduction, whereby R ³ is hydrogen or Z and are hydrogen in the formula (I). Get a compound, or (k) In the formula (I), a compound in which R ³ is hydrogen or R and R ⁵ is hydrogen, and a compound represented by the formula R ³ '1 0H Or expression  R5 '1 0H [Wherein, 'and H ⁵ ' denote lower-rank or lower-rank] by condensing the compound represented by the formula [I] with Or or and / or 化^δ is a lower arq or lower arq, or (1) In the formula (I), Η ³ is hydrogen or R ⁵ is hydrogen. One 1β— Things and formulas R ³ "-¥ ^d Or the formula [wherein: R ³ "and S ⁵ " represent ft-class or aryl, and \ ^d is halogen or the formula R ^d S0 ₂ — 0— (where R ^d is the bag space. , Or a compound represented by the formula: ## STR1 ## wherein B ³ is a lower alkyl or aryl group in the formula (I). Obtain a compound in which Z and Z are lower or lower, or (m) In formula (I), a compound having a benzimimino or imino in the group R ⁶ is subjected to tangible reduction ^, convulsive SIS or ifeKKJe]. or obtaining a compound having an IC unsubstituted imino within [delta] ^beta, or, (η) In the formula (I), the base Ε ^β is absent. R ⁷ - W ^e Wherein, R ⁷ is a lower A key, § la key or Ashiru, W ^e is a halogen or the formula! ^ S0 ₂ -0-(in the formula, represents lower aki ^, trif-methyl, phenyl or p-tri)]. ?, In the formula (I), to obtain a compound having in the group E ⁶ a lower alkyl, an alkyl or an imino «» (0) In the formula (I), a compound having an unsubstituted imino in the group R ⁶ is condensed with a lower alkyl aldehyde or an aralkyl aldehyde under elementary conditions]), the formula ( I) Medium bag, low bag acryl or core difference in ^{β- 0MP} — 108— Obtaining a compound having an imino substituted with a alkyl, or  (P) In the formula (I), a compound having an unsubstituted imino in the group is represented by the formula In the formula (I), a compound having an acyl imino in the group R ⁶ is obtained by subjecting a compound represented by the formula:  ) In the formula (I), a compound in which is a hydrogen is subjected to an acetylation reaction to obtain a compound in which is a lower aki in the formula (I).  (r) A method for producing a parent compound or a soil thereof by subjecting the obtained compound represented by the formula (I) to iC conversion. BUREAU OMPI  WIIPPOO.,, Ν