AU598105B2 - 4-piperidyl derivatives - Google Patents

Description

if f ~1 L-4 COMMONWEALTH O59 8 1 COMMONWEALTH OF AUSTRAJLIA PATENTS ACT 1952 Form SUBSTITUTE COMPLETE SPECIFICATION FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: This document contains the amendments made under Section 49 and is correct for t 'Jitihig.

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a)t It li I- TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: i Actual Inventor: TAKEDA CHEMICAL INDUSTRIES, LTD.

27, Doshomachi 2-chome, Higashi-ku, OSAKA 541, JAPAN Hirosada Sugihara; Kohei Nishikawa and Katsumi Ito GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000

AUSTRALIA

I It Ir I C Cr

I

Address for Service: Complete Specification for the invention entitled:

(ICC(

C I 1or1 C

II

4-PIPERIDYL DERIVATIVES The following statement is a full description of this invention, including the best method of performing it known to me/us:- 3882A:rk COMMONWEALTH OF AUSTRALIA 9579A/bm S Subject matter disclosed but not claimed herein is disclosed and claimed in parent application number 37602/85 of which this application is a divisional.

Background Art A variety of compounds having angiotensin converting enzyme inhibitory activities are known, but compounds having further condensed seven membered ring as a basic moiety are disclosed only in European Patent Publication of Aplication No. 72352.

The present inventors, after extensive search for compounds which exhibit inhibitory activity on angiotensin converting enzyme and are useful as a therapeutic agent for circulatory diseases such as hypertension, cardiopathy, and cerebral apoplexy, succeeded in the production of condensed seven-membered ring compounds having excellent action.

These condensed seven-membered ring compounds are claimed in parent application number 37602/85.

The parent application discloses compounds represented S" by the formula: 20 R 1 20 T p S~ R 4

A-R

6 1 3

N-CH-COOR

(I)

N

Rz O

IS

CnH 2 n-COOR 1 2 [whereind R and R are independently hydrogen, halogen, 44 trifluoromethyl, lower alkyl or lower alkoxy, or both 3 5 Se jointly form tri- or tetramethylene; R and R are independently hydrogen, lower alkyl or aralkyl; R 4 is 30 hydrogen or lower alkyl; R is a condensed or non-condensed hetero-alicyclic group containing at least one atom of N, O and S as a ring-forming atom which may be I substituted; A is an alkylene chain; n is 1 or 2] and salts thereof, and a process for producing the same.

Referring to the above formula the halogen represented by R or R includes, for example, fluorine, 5895S/bm -lA- GRIFFITH HASSEL FRAZER, SYDNEY, AUSTRALIA 9579A/bm -2chlorine, bromine and iodine, and the lower alkoxy grouip reprsened y Ror Rincludes alkoxy groups containing about I to 4 carbon ;atorrs, such as methoxy, ethoxy, propoxy, 4 isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

Also, R 1 and R 2 both may combine with each other to form an alkylene bridge, whose examples include those such as trimethylene and tetraxnethylene.

The lower alkyl group represented by Rl, R 2 3

R

4 or R' includes alkyl groups containing about 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, V isobutyl, sec-butyl and tert-butyl.

The aralkyl group represented by R 3 or R 5 includes phenyl-lower- (C 1 4 -alkyl groups containing abo~ut 7 to 10 carbon atans such as benzyl, phenethyl, 3-phenyipropyl, a-methylbenzyl, a-ethylbenzyl, a-methylphenethyl, $-rnethylphenethyl,and a- V ethylphenethyl.

The condensed or non-cindensed hetero-alicyclic group containing at least one atom of N, 0 andI S as a ring-forming-atcm, as represented by R includes a saturated or parll aut htr ring or rings cunpose of 4 to 8 memers, and~ may be. hetero rings or not less than two kinds of atoms may exist as the ringforming atom. The hetero-alicyclic group includes hetero-monoor bi-alicyclic groups, such as oxetanyl, thietanyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, oxanyl 4,5,6-tetrahydro-2H-pyranyl) thianyl, piperidyl, oxepanyl, thiepanyl, perhydroazepinyl, oxocanyl, thiocanyl, perhydroazocinyl, dioxanyl, dithianyl, piperazinyl, morpholinyl, perhydrothiazinyl, oxathianyl, perhydrodiazepinyl, oxathiepanyl, dioxepanyl, dithiepanyl, perhydrooxazepinyl, perhydrothiazepinyl, perhydrooxazocinyl, perhydrothiazocinyl, oxathiocanyl, perhydrodiazocinyl, dithiocanyl, dioxocanyl, chromanyl, isochronianyl, 3,4-dihydro-2H-l-thianaphthyl, 3,4-dihydro-IH-2-thianaphthyl, 1,2,3,4-tetrahydroquinolyl, 1,2, 364-tetrahydroisoquinolyl, 2,3-dihydrobenzofuryl, 1, 3-dihydroisobenzofuryl, 2,3-dihydrobenzofblthienyl, l,3-dihydrobenzo(cithienyl, indolinyl, PAEN. OFIC a AC t-3isoindolinyl, 1,3,4,'5-tetrahydro-l(lH)-benzoazepinyl, 2,3 4 te trahydro- 3(1 H)-be nzoa z epi nylI, 2, 3,4 5- tetrahyd ro- 2(1IH) benzoazepinyl, 2,3,4,S-tetrahydro-l-benzoxepinyl, 1,3,4,5tetrahydro-2-benzoxepinyl, l,2,4,5-tetrahydr-o-3-benzoxepinyl, it 2.3,4,5-tetrahydro-l-benzothiepinyl, l,3,4,S-tetrahydro-2benzothiepinyl, l,2,4,5-tetrahydro-3-benzothiepinyl, 2,3dihydro-1,4-benzodioxinyl, 2,3-dihydro-1,4--dithianaphthyl, l,2.3,4-tetrahydroquinoxalinyl, 3 ,4-dihydro-2H--l,4-benzoxadinyl, 3,4-dihydro-2H-,4-benzothiadinyl, 2, 3-dihydro-l..4-benzoxathienyl, 3,4-dihydro--2H-l,5-benzoxepanyl, 2,3-dihydro-51i-l,4-benzoh dioxepinyl, 2,3,4,5-tetrahydro-lH-l,,5-benzodiazepinyl, 2,3,4,5tetrahydro-lH-l, 4-ben zod iazepinyl, 3, 4-dihydro-2H-l.5-benzodithiepihyl, 2,3-dihydro-SH-l, 4-berizodithiepinyl, perhydroindolyl, perhydroisoindolyl, perhydroquinolyl, perhydroisoquinolyl, perhydro-l-thianaphthyl arnd perhydro-2-thianaphthyl.

The said condensed or non-condensed hetero-alicyclic grop n~ay have at any substitutive position thereof a substituent or two substibients, for exanple, lower(C 1 )alkyl(e.q. mrethyl, ethyl, propyl, butyl), oxo, acyl ~Ji such as C 5 aJlcarxyl acetyl, proypionyl), bezoyl, pheny1lor- 1 4 1 aIJ'oxycarbxonyl benzyloxycarbonyl) and lower- (C 1 -a]ThxycarbonyL S tert-btoxycarbonyl), aryl such as phenyl and naphthyl, arid phenyl-lower- (Cl-4)-ky such.

as berizyl, phenethyl, a-methylphenethyl and 6-methylphenthyl.

The phenyl group in the aryl group or phenyl-lower-alkyl group as the said substituent may optionally be substituted by halogen, such as fluorine, chlorine and bromine, lower-

(C

1 4)-alkoxy, such as methoxy, ethoxy, propoxy and butoxy, t or lower- -alkyl, such as methyl, ethyl, propyl and butyl.

Such substituted condensed or non-condensed hetero-alicyclic: g roup-includes, for example, those such as 1-phenylpiperidyl, 1-benzylpiperidyl, 4-phenylpiperidyl, 4-benzylpiperidyl, Iacetylpiperidyl, 1-benzoy11piperidyl, 4-phenylpiperazinyl, 4acetylpiperazinyl, 4 -ben zoylpiperaz inyl, 1-oxoisoindolinyl,' S1,3-dioxoisoindolinyl, l,2,3,4-tetrahydro-l-oxoisoquinolyl and 1,2,3,4-tetrahydro-3-oxoisoquinolyl.

~1 T w i, Me -icl~ liuh S The alkylene chain represented by A includes, for example, straight-chain or branched-chain alkylene chains containing about 1 to 16 carbon atoms, whose examples include divalent groups, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, pentadecamethylene, hexadecamethylene, propylene, ethylmethylene, 4-propylhexamethylene, 3,3-dimethylhexamethylene, 5,5-diethylhexamethylene and The said alkylene chains may have in the chain an unsaturated bonded or unsaturated bonds double bond, triple bond).

The divalent group represented by CnH2n forms methylene, ethylene or ethylidene, depending upon the value of n.

The compounds are specifically disclosed, for example, CC in Table A.

S A 1 q 2 4 6 r Table A R 1 S A-R c 2

N-CH-COOR

3 c c 7 2_ R 51 o I CnH n-COOR CnH 2 n RR 2 3 R 6 No. CnH2n R ,R RI R R R *t c r 11 5 t e 1 CH 2 H H H H -(CH 2 2 2 2 CH 2 H C 2

H

5 H H -(CH 2 2 2- S CH 2 H H H H -(CH2) 2 4 CH 2 H C 2 H H -(CH 2 2- 5 CH 2 H H H H I H 5961S/bm No.' CdHAR1

,R

2

-A-

6 CH 2 H C 2

H

5 H H (CH 2 2 7 H C 2 5 H H (CH 2 2- 8 CH 2 H C 2

H

5 H H (CH 2 2

-CN-C-CH

3 9 C 2 H C 2 5 H H (C 2 2

I

0

CH

2 H C 2

H

5 H H (CH 2 2

C

0

CU

2 H C2HS H H (CH 2 2- 0 12 CU 2 H C 2 5 H H (CU 2

-N

0 13 CU 2 H C 2 5 H H (CH 2 f- 14 CH 2 H C 2

H

5 H H (CH 2

CH

2 H C H 5 H H C24 16 CH 2 H H H H -(CH 2 4

-N

17 CH 2 H C 2

H

5 H H -(CH 2 2 .14C-0CH 2 1-\ tt t t t II V -6

A

A

Vt V t t

I

I

I If I I t I £1

I

I IC -7- No. CngI 2 f RI, R

R

3

A

C

2 H5 H

C

2 H5

(H)

32 CH S Q

N

00 0 5 CH

H

0 37 H Ht 38 C;H H H -(CH2) 2 39 CH2 c r C~ t [1 iiIC

I

A 2 3 4 5 No. CnH 2 n R,R 2

R

3 R R R 6 54 CH 2 H H H HH -(CH 2 3

H

CH

2 H C 2

H

5 H H -(CH2) 5 Y H The compound possesses asymmetric carbon in the molecules, and both stereoisomers of the R and S configurations are included in the scope of the invention claimed in 37602/85. Among others, the compound in which the carbon atom bearing the symbol has the absolute configuration of R and the carbon atom bearing the symbol has the absolute configuration of S is preferable.

t Salts of the compounds include pharmaceutically t acceptable salts, such as salts with inorganic acids being 20 exemplified by hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc. salts with organic acids being exemplified by acetate, tartarate, citrate, fumarate, maleate, toluenesulfonate and methanesulfonate, etc., metal salts being exemplified by sodium salts, potassium salts, calcium salts, aluminum salts, etc., and salts with bases being exemplified by triethylamine salts, guanidine salts, I ammonium salts, hydrazine salts, quinine salts, cinchonine salts, etc.

4 tc S 5895S/bm -9-

O

Preferred are the compounds of the formula A NH L-NHCHCOOH S0 CH COOH wherein A is C2-9 alkylene, and their pharmacentucally acceptable salts.

The compound can be produced, for example, by subjecting a compound of the formula:

R

l

R

4

A-R

6

S-CH

2

CH-N-H-COOR

5 l^ j COOH

T

S

R2 CnH 2 n-COOR [wherein each of the symbols is as defiend hereinbefore] to a dehydrative ring-closure reaction. The said dehydrative ring-closure reaction can be carried out, for example, by means of an ordinary amide bond formation reaction in peptide synthesis. Thus, the reaction can be conducted by employing such a peptide forming reagent as dicyclohexylcarbodiimide,

S(I

C r C t II N,N'-carbonyldiimidazole, diphenylphosphorylazide and diethyl phosphorocyanidate solely or adding an ordinary inorganic acid hydrogen chloride, sulfuric acid, nitric acid, hydrogen bromide) to allow protonation of the amino group of the compound (II) and then condensing the protonated compound with phenols, such as 2,'4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol or 4-nitrophenol, or N-hydroxy compounds, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxypiperidine, in the presence of such a catalyst as dicyclohexylcarbodiimide to convert to the activated ester derivative, followed by cyclization. The crystalizatio reaction, whether the compound (II) is cyclized as such or after converting to its activated ester, can be promoted by adding preferably an organic base, for example, quaternary amnonium salt or tertiary amine triethylamine, N- Smethylpiperidine). The reaction temperature is normally to +50*C, preferably in the neighborhood of room temperature, and a solvent which is normally employed includes, for example, j dioxane, tetrahydrofuran, acetonitrile, pyridine, NN-dimethylformamide, N,N-dimethylacetanide, dimethylsulfoxide, N-methylpyrrolidone, chloroform, methylene chloride, etc., which may I be used alone or as a mixture thereof.

The compound can also be produced, for example, by reacting a compound of the formula: 1

R

4 H (III) R 1 CnH n-COOR5 Sr [wherein each of the symbols is as defined hereinbefore) with a compound of the formula:

R

6 A-CH-COOR3

(IV)

Wa (herein W a is halogen or a group represented by the formula cii'' RaSO2-O- (wherein R a is lower-(C4)-alkyl, trifluoromethyl, phenyl or p-tolyl); other symbols are as defined hereinbefore The reaction can be allowed to proceed by maintaining normLlly 12both of the compounds in the absence or presence of water or other organic solvent (e.g.

acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, benzene, toluene) solely or a mixture thereof within the temperature range of about -20 to +150 0 C. On this occasion, it is possible for the purpose of acceleration of the reaction rate to allow a base, such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine and triethylamine, to coexist in the reaction system.

Also, the compound CI) can be produced, for example, by reacting a compound of the formula:

R

4

A-R

6

N-CH-COOR

3

(V)

2 H o [wherein each of the symbols is as defined hereinbefore] with a compound of the formula: wb -CnH 2 n-COOR 5

(VI)

[wherein W b is halogen or a group represented by the formula e RbSO (wherein Rb is lower-CC )-alkyl, trifluorrethyl, phenyl 2 1-4 S or p-tolyl); other symbols are as defined hereinbefore]. The 0 reaction can be allowed to proceed by maintaining both of the compounds in water or other organic solvent acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, benzene, toluene) solely or a mixture thereof within the temperature range of about -20 to +150 0 C. On this occasion, it is possible to allow a base, such as potassium carbonate, sodium hydroxide and sodium hydride, to coexist in the reaction system.

4 The compound of the formula wherein R is hydrogen can be produced, for example, by subjecting a compound of the formula: t

R(V)

CX 2 (VII) -13- (wherein each of the symbols is as defined hereinbeforel and a compound of the formula: S- O-C-C-A-R 6 I It (V S0 (wherein each of the symbols is as defined hereinbef6re] to a condensation reaction under reductive conditions.

The said reductive conditions include reaction conditions of catalytic reduction using a metal, such as platinum, palladium and rhodium, or a mixture thereof with an aribitrary support as a catalyst; reduction with a metal hydride compound, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride and sodium cyanoborohydride; reduction with metallic sodium, metallic magnesium, etc. and alcohols; reduction with a metal, such as iron and zinc, and an acid such as hydrochloric acid and acetic acid; electrolytic reduction; reducing with a reducing enzyme, and so forth. The above rear :ion is normally carried out in the presence of Swater or an organic solvent methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies with means of reduction S employed, but generally is preferably in the range of S to +100°C. The reaction can be conducted at atmospheric pressure to achieve the desired object satisfactorily but may also be carried out under pressure or under reduced pressure according to the circumstances.

Also, the compound of the formula wherein R 4 is hydrogen can be produced, for example, by subjecting a compound of the formula: I S Z A-R 6

N-CH-COOR

3

(IX)

R2 nH n-COOR *e 2 (wherein Z is a protective group removable by hydrolysis or catalytic reduction; other symbols are as defined hereinbefore] to a hydrolysis or catalytic reduction reaction. As the invention, including the best method of performing it known to me/us:- 3882A:rk t protective group removable by hydrolysis as represented by Z in thbre are used all kinds of acyl groups and trityl groups, and benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, -trityl, etc., among others, are advantageous in the case of reactions under relatively mild reaction conditions.

The protective group removable by catalytic reduction as representedLby Z includes, for example, benzyl, diphenylmethyl, benzyloxycarbonyl, etc. The hydrolysis reaction in the said method is carried out in water or an organic solvent, such as methanol, ethanol, dioxane, pyridine, acetic acid, acetone and methylene chloride, or a mixture thereof, and for the purpose of accelerating the reaction rate, it can also be conducted by adding an acid hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoro- Sacetic acid) or a base Ce.g. sodium hydroxide, potassium i t hydroxide, potassium carbonate, sodium hydrogencarbonate, sodium acetate, triethylamine). The above reaction is carried out normally within the temperature range of -20 to +150'C.

S The catalytic reduction reaction in the said method is conducted in water or an organic solvent, such as methanol, ethanol, dioxane and tetrahydrofurane, or a mixture thereof in the presence of an appropriate catalyst, such as t t' L platinum and palladium-carbon. This reaction is carried out S at atmospheric pressure or under pressure up to about 150 kg/cm 2 and at ordinary temperature or at a temperature up to S° +150*C, but the reaction generally proceeds satisfactorily at ordinary temperature and at atmospheric pressure.

The compound of the formula wherein R 4 is hydrogen can also be produced, for example, by subjecting the cyano group in the compound of the formula:

A-R

NHCHCN (X) CnH 2 n-COOR (wherein each of the symbols is as defined hereinbeforel represented by R1 or R 2 includes, for example, fluorine, represented by R or R includes, for example, fluorine, 5895S/bm -IA- S to solvolysis.

The above solvolysis reaction is carried out in water or an organic solvent, such as methanol, ethanol, dioxane, pyridine, acetic acid, acetone and methylene chloride, or a mixture thereof, and can also be conducted by adding an acid hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, acid resin) or a base sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogencarbonate, sodium acetate, triethylamine) for the purpose of accelerating the reaction rate. The reaction is normally carried out at a temperature within the range of about -20 to +150*C.

The compound wherein the atom in the group R 6 being linked to the group A is a nitrogen atom can also be produced, for example, by allowing a compound of the formula:

R

4

A-NH

2

N-CH-COOR

3

(XI)

SR2" b CnH 2 n-COOR (wherein each of the symbols is as defined hereinbefore] and a compound of the formula:

OHC\

OHC/X (wherein X is a ring-forming atomic group and represents R 6 71 as the formula -NCH2X] to undergo a condensation reaction

'CH

2 S under reductive conditions.

The said reductive conditions include reaction conditions of catalytic reduction using a metal, such as platinum, palladium and rhodium, or a mixture thereof with an arbitrary support. as a catalyst; reduction with a metal hydride compound, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride ,,','--Lucranyaroquinoiy1, 1,,J,4-tetrahydroisoquinolyl, 2 3 -dihydrobenzofuryl, 1,3-dihydroisobenzofuryl, 2,3-dihydrobenzo(blthienyl, 1,3-dihydrobenzo(clthienyl, indolinyl, -16and sodium cyanoborohydride; reduction with metallic sodium, metallic magnesium, etc. and alcohols; reduction with a metal, such as iron and zinc, and an acid, such as hydrochloric acid and acetic acid; electrolytic reduction; reduction with a reducing enzyme, and so forth. The above reaction is normally carried out in the presence of water or an organic solvent methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies with means of reduction employed, but generally is preferably in the range of -20*C to +100*C. This reaction can be conducted at atmospheric pressure to achieve the desired object satisfactorily but may also be carried out under pressure or under reduced pressure according to the circumstances.

Also, the compound wherein the atom in the group being linked to the group A is a nitrogen atom can be produced, for example, by reacting a compound of (XI) with'a compound of the formula: Wc- S[wherein WC is halogen or a group represented by the formula I~ RcS0 2 (wherein Rc is lower(C 1 l 4 )alkyl, trifluoromethyl, phenyl or p-tolyl); Y is a ring-forming atomic group and represents the group R 6 as -N Y] The reaction is allowed to proceed by maintaining both of the compounds in a-.suitable solvent or a mixture thereof within the temperature range of about -20 to +150*C.

On this occasion, it is also possible for the purpose of accelerating the reaction rate to allow a base, such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine and triethylamine, to coexist in the reaction system r: as a deacidifying agent.

(The compound of tie fornula wherein R 3 is hydrogen or/and SC R 5 is hydrogen can be produced by subjecting a compound of the formula henrein R 3 is lower alkyl or/and R 5 is lower and 1,2,3,4-tetrahydro-3-oxoisoquinolyl.

-17subjecting the compound of the formula wherein R 3 is benzyl or/and R 5 is benzyl to a catalytic reduction reaction.

The hydrolysis or elimination reaction in the said method is carried out in water or an organic solvent, such as methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, acetic acid, acetone and methylene chloride, or a mixture thereof, and can also be conducted by adding an acid hydrogen chloride, hydrogen bromide, hydrogen fluoride, hydrogen iodide, sulfuric acid, methanesulfonic acid, ptoluenesulfonic acid, trifluoroacetic acid) or a base (e.g.

sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogencarbonate; sodium carbonate, sodium acetate) The above reaction is normally carried out at a temperature within the range of -20 to +150*C. The catalytic reduction reaction in the said method is carried out in Water or an organic solvent, such as methanol, ethanol, ethyl acetate, dioxane and tetrahydrofuran, or a mixture thereof in the presence of an appropriate catalyst, such as palladium.carbon. This reaction is conducted at atmospheric pressure or under pressure up to about 150 kg/cm 2 and at ordinary temperature or at a temperature up to +150*C.

The compound of the formula wherein R 3 is lower alkyl or aralkyl or/and R 5 is lower alkyl or aralkyl can be produced by allowing the compound of the formula wherein

R

3 is hdyrogen or/and R 5 is hydrogen to undergo a condensation reaction with a compound of the formula:

R

3 OH (XIV) or the formula:

R

5 OH (XV) (wherein R 3 'and R 5 are independently lower alkyl or aralkyl].

The said condensation reaction conditions include, for example, reaction conditions involving the use of a condensing agent cg; dicyclohexylcarbodiimide, carbonyldiimidazole, diethyl phosphorogyanidate, diphenylphosphorylazide) or reaction conditions involving the use of an acid catalyst hydrogen chloride, hydrogen bromide, p-toluenesulfonic

'A

2 I "2'2 H 5961S/bm -4- -1 acid). The reaction is allowed to proceed in a suitable solvent or a mixture thereof or in the absence of a solvent at a temperature within the range of about -20 to +150*C.

The compound of the formula wherein R is lower alkyl or aralkyl or/and R 5 is lower alkyl or aralkyl can also be produced.by reacting the compound of the formula (I) wherein R 3 is hydrogen or/and R 5 is hydrogen with a compound of the formula: d3" _wd (XVI) or the formula:

R

5 Wd

(XVII)

[wherein R r and RS are independently lower alkyl or aralkyl;

W

d is halogen or a group represented by the formula RdSO 2

-O-

(wherein R d is lower-(C )-alkyl, trifluoromethyl, phenyl or p-tolyl)] The reaction is allowed to proceed in a suitable solvent at a temperature within the range of about -20 to +150C in the presence of a base potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate).

The compound wherein the group R 6 contains an unsubstituted imino group can be produced by subjecting the compound of the formula wherein the group R 6 contains a benzylimino or acylimino group to a catalytic reduction, elimination or solvolysis reaction.

The catalytic reduction reaction in the said method is carried out in water or an organic solvent, such as methanol, ethyl acetate, ethanol, dioxane and tetrahydrofuran, or a mixture thereof in the presence of an appropriate catalyst, such as palladium-carbon. This reaction is conducted at atmospheric pressure or under pressure up to about 150 kg/cm 2 and at ordinary temperature or at a temperature up to +150*C.

The solvolysis or elimination reaction in the said method is carried out in water or an organic solvent, such as methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, acetic acid, acetone and methylene chloride, or a mixture thereof, and can also be conducted by t C -19adding an acid hydrogen chloride, hydrogen bromide, hydrogen fluoride, hydrogen iodide, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid) or a base sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogencarbonate, sodium carbonate sodium acetate). The above reactions are normally carried out at a temperature within the range of -20 to +150*C.

The compound of the formula wherein the group R 6 has therein an imino group substituted by lower-(Cl-4) -alkyl, aralkyl or acyl can be obtained by reacting the compound of the formula wherein the group R 6 has therein an unsubstituted imino group with a compound of the formula:

R

7 We Cxvni3) [wherein R is lower alkyl, aralkyl or acyl; We is halogen or a group represented by the formula ReSO2-O- (wherein Re is lower (Cl 1 4 alkyl, trifluoromethyl,.phenyl or p-tolyl)]. The reaction is allowed to proceed by maintaining both of the compounds in a suitable solvent within the temperature range of about S -20 to +150*C. On this occasion, it is possible for the purpose of accelerating the reaction rate to allow a base,.such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine,and triethylamine, to coexist in the reaction system as a deacidifying agent.

Also, the compound of the formula wherein the group 6 R has therein an imino group substituted by lower-(Cl-4)alkyl or aralkyl can be obtained by allowing the compound S of the formula wherein the group R 6 has therein an unsubstituted imino group and a lower-(Cl 4 )-alkylaldehyde or aralkylaldehyde to undergo condensation under reductive conditions.

c The said reductive conditions include, reaction conditions of catalytic reduction using a metal, such as platinum, palladium and rhodium, or a mixture thereof with an arbitrary support as a catalyst; reduction with a metal hydride compound, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride and sodium i cyanoborohydride; reduction with metallic sodium, metallic magnesium, etc. and alcohols; reduction with a metal, such as iron and zinc, and an acid, such as hydrochloric acid and acetic acid; electrolytic reduction; reduction with a reducing enzyme, and so forth. The above reaction is normally carried out in the presence of water or an organic solvent methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, diemthylformamide, dimethylacetamide), and the reaction temperature varies with means of reduction, and generally is preferably in the range of to +100*C. This reaction can be conducted at atmospheric pressure to achieve the desired object satisfactorily, but may be carried out under pressure or under reduced pressure depending on the circumstances.

The compound Qf the formula wherein the group R 6 has therein an acylimino group can also be produced by reacting the compound of the formula wherein the group R 6 has therein an unsubstituted imino group with a compound of the I c formula: (R 7 2 0 (XIX) [wherein R 7 is acyl].

The reaction is allowed to proceed by maintaining both of the compounds in water or a suitable solvent or a mixture thereof within the temperature range of about -20 to +150*C. On this occasion, it is possible for the purpose of accelrating the reaction rate to allow a base, such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine, and triethylamine, to coexist in the reaction system as a deacidifying agent.

The compound of the formula wherein R 4 is lower alkyl can also be produced by subjecting the compound of the can formula wherein R 4 is hydrogen to an alkylation reaction.

f t The above alkylation reaction includes, for example, a reductive alkylation reaction involving the reaction with a lower alkyl-(Cl_ 4 )-aldehyde under reductive conditions (the reductive conditions include reaction conditions of I 1 I I llIl -21catalytic reduction using a metal, such as platinum, palladium and rhodium, or a mixture thereof with an arbitrary support as a catalyst; reduction with a metal hydride compound, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride and sodium cyanoborohydride; reduction with metallic sodium, metallic magnesium, etc. and alcohols; reduction with a metal, such as iron and zinc, and an acid., such as hydrochloric acid and acetic acid; electrolytic reduction; reduction with a reducing enzyme, and so forth.

The reaction is normally carried out in the presence of water or an organic solvent methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies with means of reduction employed, and generally is preferably in the range of -20*C to +100°C.

This reaction can be conducted at atmospheric pressure to achieve the desired object satisfactorily, but may also be carried out under pressure or under reduced pressure according to the circumstances] or an alkylation reaction (the.reaction -i conditions include, for example, reaction conditions in which both of the compounds are maintained in a suitable solvent or a mixture thereof 'within the texperature range of -20 to +1500C. On this occasion, it is also possible for the purpose of accelerating the reaction rate to allow a base, such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine,and triethylamine, to coexist in the reaction system as a deacidifying agent) involving the reaction with a compound of the formula: R4 W f

(XX)

[wherein wf is halogen or a group represented by the formula RfSO 2 (wherein R f is lower(C 4 alkyl, trifluoronethyl, phenyl t or p-tolyl); R 4 is as defined hereinbefore].

The salt of the compound can be produced by the reaction per se for producing the compound and if desired, it can also be produced by adding an acid, alkali or base to the compound -22- The object compound (I) thus obtained can be isolated from the reaction mixture oy utilizing conventional separation and purification means, for example, means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and thin layer chormatography.

The compound can exist in at least four stereoisomers.

These individual isomers and a mixture thereof, naturally, all fall within the scope of the present invention, and such isomers can be produced individually, if desired. For example, a single optical isomer of the compound can be obtained by carrying out the above reaction using a single isomer each of the starting compounds (VII), (IX), and and when the product is a mixture of not less than two kinds of isomers, it can also be separated into individual isomers by separating means, such as methods of forming salts with optically active acids camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.) or optically active bases cinchonine, cinchonidine, quinine, quinidine, a-methylbenzylamine, dehydroabiethylamine, etc.), a variety of chromatographic techniques and fractional recrystallization.

The compounds namely the condensed seven-membered ring compounds represented by the formula and salts thereof, exhibit inhibitory activities on angiotensin converting enzyme and bradykinin decomposing enzyme (kininase), etc. in animals, in particular mammals I human, dog, cat, rabbit, guinea pig, rat), and are useful, for example, as drugs for diagnosis, prevention and treatment of hypertensionand hypertension-induced circulatory diseases, such as cardiopathy and cerebral apoplexy. The compound is of low toxicity, well adsorbed on oral administration, excellently long-lasting in effect and highly stable, and it, when being used as the abovementioned drugs, can therefore be safely administered orally or parenterally, per se or in admixture with suitable, pharmaceutically acceptable carriers, excipients or diluents a__ J J 589 5S/bm 9- 23 in various pharmaceutical formulations, such as powders, granules, tablets, capsules and injectable solutions. While the dosage level varies depending upon the conditions of the diseases to be treated as well as the administration route used, in the case of administration to human adult for the purpose of treatment of renal or essential hypertension, for example, the compound may be desirably administered orally at a single dose of normtally about 0.02 to 10 mg/kg, preferably about 0.02 to 2 mg/kg, more preferably about 0.04 to 0.8 mg/kg, or intravenously at a single dose of about 0.002 to I mg/kg, preferably about 0.02 to 1 mg/kg, more preferably about 0 .02 to 0. 2 mg/kg, abutone to 3 H pser cay, preferably once to twice per day, according to the conditions.

The starting compounds (II) (III) MV), (VII),I (IX) M X and (XI) ican be easily prepared,.

for ekample, by the methods as illustrated in the following reaction schema.

'2~ C '2 '2 '2 '2 C C '2 IA

C

C U S-CHZ CHCO0H

S-CH

2 CHC00H 2IX

N"H)

1):Reduction 2) if0

R

2

COOH

R

6 -A-C-C-0R 3 0 0 Ca~) I>SCa CHNH-CH-CO O0R 3 a COOH XY r. C C. I '2 C R4 A-R 6 ~(SCHZ CH- r-CH-COOR 11 O E kI (XX 1).RedUction 2) WbCaH n-COORS (VI)

A

24 Rl

R

4 A-Id NE OOE RnE 2zC1

H)

NO

2

COOR

R:vi c 0 0 0 CCCGL 0 a, 0~ ,o @4 @0 0.

'9 0 *0 P p p P 04 *O 4040

P

Pt t a ii 0 tt 4. 4.

4. 4:4 44 C (4.4.

4. 4.4.

4.4 4.

4 t4.t4.4.

I

0

CEZCEI$ICJ-

COOHO0 =0C( w~a-alr a-cop.5(VI)

R

R 0o (MM~ CnHl -GO Cull n-COORS

~~CH

2 CHk CH-C0R3 0 IRedu zfO 2

COOH

112 (XCy) Off) CalHza-COOR' 11' A 1 6 I I H-N-c H-CO 0 00H C =XII) or p-tolyl) other symbols are as defined hereinbetorej The reaction can be allowed to proceed by maintaining norMLllY 25 I.R FA--t 6 -I7-11-CH-CoOR3

V

R-HO0 Cn.Hzz-COOR Cu H~u-COO R

R

0 C HCO OR 3 PI Z A-R 6

N_-ICOO.R

3 Cnlfu-COOR 5

S

t It g t -A-cHO

AR

CunHzx-COOR 5 R Cn -OOR (C(H-A-CH-COOR 3 0 1 XXV

~CII

C

(C 4 4 1 4

,H

2

MW

cna~n-COOR 3 CnH 2 n-COOR l 26- I R R4 -C0 -CHOO-COR 3 |Cj -zH-H-COOR R2 I C nH n-C 0R 5

OO

In the above reaction formulae, R 8 is halogen or a diazonium group; w is halogen or a group represented by the formula RgSO-O- (wherein Rg is lower (C1_4).alkyl, triflucomr thyl, phenyl or p-tolyl); and other symbols are as defined hereinbefore.

ift Referring in more particuar to the process for producingA- S the compound (II) as shown in the above reaction schema, cystine (XXI) used as a starting compound is derived into cysteine, which is reacted with the compound (XXII) to produce the compound (XXIII). The reaction of the compounds (XXIII) and (VIII) can be carried out in the same manner as the Ireaction between the compounds (VII) and (VIII). The reaction of (XXIV)--+(XXV) is an ordinary alkylation reaction, and can be allowed to proceed, for example, by the reaction with a Slower alkylaldehyde corresponding to the group R 4 under reductive conditions. The compound (XXV) is subjected to a conventional reduction reaction of the nitro group to the amino group, followed by an alkylation reaction to produce the compound (II).

S' In the method for producing the compounds (III) and (VII), the amino group of the compound (XXVI), in the first place, is protected with a suitable amino protecting group phthaloyl group) to produce the compound (XXVIII). This aOL-.ayLjc reauction; otner symbols are as defined hereinbeforej to a hydrolysis or catalytic reduction reaction. As the A 1 -27reaction is allowed to proceed easily by condensation of the compound (XXVI) with the compound (XXVII) in the presence of a base sodium carbonate, potassium carbonate, potassium hydrogencarbonate) normally at a temperature in the range of 0 to +100*C. The reaction of (XXVIII)--(XXIX) is a reduction reaction of the nitro group to the amino group, and conventionally known reduction techniques can be employed. The reduction techniques include catalytic reduction using as a catalyst for example palladium-carbon, palladium supported with barium sulfate, sulfided palladium, platinum, etc., reduction with a metal such as zinc, tin, stannous chloride and iron and an acid or alkali, and so forth. The dehydrative ring-closure reaction of the resultant compound (XXIX) to the compound (XXX) can be advantageously carried out in the presence of a conventionally known dehydrative S, coupling'agent. Such dehydrative coupling agent includes, for example, dicyclohexylcarbodiimide, carbonyldiimidazole, diethyl phosphorocyanidate, etc. As a solvent, there are used, for example, dioxane, methylene chloride, acetonitrile, SN,N-dimethylformamide, tetrahydrofuran,etc., and the reaction I is normally carried out at a temperature in the range of to +100*C. For the purpose of allowing the reaction to proceed advantageously, in such a case, it may also be possible to add such a base as triethylamine and pyridine to the reaction solution as a catalyst. The preparation of the compound (XXXI) through a condensation reaction between the compounds (XXX) and (VI) can be effected normally by condensation in a solvent such as N,N-dimethylformamide,- dimethylsulfoxide and acetonitrile in the presence of such a base as sodium hydride and potassium carbonate at a temperature in the range of -10 to +100*C. Then, the reaction of (XXXI)--(VII) can be conducted by treatment with hydrazine hydrate in a solvent such as methanol, ethanol and dioxane at a temperature in the range of -10 to +100"C to produce the compound (VII).

The reaction of (VII)--(III) is an ordinary alkylation reaction, and such an alkylation method includes, for example,

A

R

I S TNHCHCN (X) R I S CnH 2 n-COOR (wherein each of the symbols is as defined hereinbeforel t I" 2 -2 a procedure of reacting with a lower alkylaldehyde corresponding to the group R 4 under reductive conditions and a procedure of reacting with the compound (XX) in a suitable solvent.

The compound can be prepared by subjecting the compound (XXV) to an ordinary reduction reaction of the nitro group to the amino group, followed by a dehydrative ringclosure reaction.

In the process for producing the compound the compound (XXXIII) can be prepared by subjecting the compound VII) to a per se known amino protecting reaction for amino acids. The reaction of (XXXIII)--(IX) is allowed to proceed by maintaining the compounds (XXXIII) and (IV) in a suitable solvent within the temperature range of -20 to +150*C. In such a case, it is also possible .for the purpose of accelerating the reaction rate to allow such a base as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine and I triethylamine to coexist in the reaction system as a deacidifying Sc agent.

In the process for producing the compound the compound can be obtained from the compounds (VII) and (XXXIV) and hydrogen cyanide as starting compounds according to the Strecker reaction which is per se known.

In the process for producing the compound the compound (XXXVI) can be obtained by the reaction between the compounds (VII) and (XXXV). As a solvent, there are used acetonitrile, methyl ethyl ketone, acetone, tetrahydrofuran, methylene chloride, dimethylsulfoxide, dimethylformamide, etc., and the reaction is normally carried out at a temperature in the range of -10 to +150*C. In such a case, it is also possible for the purpose of allowing the reaction to proceed advantageously t to add a base, such as triethylamine, pyridine, potassium carbonate and sodium carbonate, and potassium iodide, etc.

The reaction of (XXXVI)-*(XXXVII) can be carried out in the same manner as the reaction of (XXIV)-+(XXV), while the reaction of (XXXVII)-(XI) can be conducted in the same manner conditions of catalytic reduction using a metal, such as platinum, palladium and rhodium, or a mixture thereof with an arbitrary support, as a catalyst; reduction with a metal hydride compound, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride T 4- 29 as the reaction of (XXXI)-+(.VII).

The compounds (IV) and (VIII) which are used in the production of the compound can be readily produced, for example, by the process as shown in the following reaction schema.

^OOR

3

R

6

-A-COOR

3 COOR3- R-A -OR J(xxXVi) (VIII')

R

6

-A-CH-COOR

3

OH

(IL)

R

6

-A-CH-COOR

3

R

6

-A-CH-COOR

3 Wa Wa

(IV)

In the above reaction schema, R 3 'and R 3 "are independently lower alkyl or aralkyl corresponding to R 3 other symbols are as defined hereinbefore.

The compound (VIII') can be prepared by allowing the compounds (XXXVII) and (XXXIX) to undergo condensation in the presence of such a.base as sodium ethoxide, followed by S* heating in the presence of aqueous dimethylsulfoxide, lithium S chloride, etc. The compound can be produced by subjecting t the compound (VIII') to a per se known reduction reaction and then subjecting the resulting compound (IL) to a per se known halogenation reaction or sulfonylation reaction.

The starting compound (XXXVIII) can be readily produced, t for example, by subjecting a compound of the formula:

R

6

-H-COOR

3 wh [wherein Wh is halogen; A' represents A as A'-CH 2 other S symbols are as defined hereinbefore] to a per se known t" reduction reaction.

When R 6 has therein a group which may interfere with the reaction, the reaction may be carried out by protecting the said group with a protective group, such as is hydrogen can be produced by subjecting a compouna or cne formula henrein R 3 is lower alkyl or/and R 5 is lower 30 alkanoyl acetyl), benzoyl, phenyl-lower-(C 1 alkoxycarbonyl benzyloxycarbonyl), lower-(C 4 alkoxycarbonyl tert-butoxycarbonyl), etc.

The compounds of the formulae (VIII'), (IL) and (IV') 3 wherein R is hydrogen can be readily produced by subjecting the compounds (VIII'), (IL) and (IV') respectively to a hydrolysis reaction.

The compounds of the formulae (VIII) and (IV) wherein

R

6 is 4-piperidyl which may be substituted are novel compounds, and the present invention provides the compounds 6.

of the formulae (IV) and (VIII) wherein R is 4-piperidyl which may be substituted, which are industrially favoured as an intermediate for the synthesis of the novel compound (I) being useful as a pharmaceutical.

Hence according to one aspect of the present invention, there is provided a compound of the formula: 6 3 R A E-COOR 3 3 6 wherein R is hydrogen, lower alkyl or aralkyl; R is S 4-piperidyl which may be substituted by lower alkyl, oxo, t, '20 C 1 -5 alkanoyl, benzoyl, phenyl-lower alkoxycarbonyl, lower 't alkoxycarbonyl, phenyl, naphthyl or phenyl-lower alkyl; A is •t a Ci-16 alkylene chain and E is-C=0 or a group represented by the formula:

CH-W

wherein W is halogen or a group represented by the formula RaSO2-O- in which Ra is lower alkyl, trifluoromethyl, phenyl or p-tolyl, or a salt thereof.

According to another aspect of the invention there is provided a process for producing a compound of the formula:

R-A-E-COOR

3

(L)

wherein R is hydrogen, lower alkyl or aralkyl; R is S4-piperidyl which may be substituted by lower alkyl, oxo, alkanoyl, benzoyl, phenyl-lower alkoxycarbonyl, lower alkoxycarbonyl, phenyl, naphthyl or phenyl-lower alkyl;; A t '35 is a C -16 alkylene chain and E isZC=0 or a group represented by the formula: iCH-Wa phosphorogyanidate, diphenyiphosphorylazide) or reaction conditions involving the use of an acid catalyst hydrogen chloride, hydrogen bromide, p-toluenesulfonic 4 wherein W ais halogen or a group represented by the formula R aS so20 in which R a.i lower alkyl, trifluoromethyl, phenyl or p-tolyl, or a salt thereof, which comprises a) reacting a compound of the formula: R 6

-A-COOR

3 1 wheeinR 6and A are as defined above and R Vis lower e ~t -I C

C

CL, LII ICC I C 11CC C CCC C I

CC

CC C' C C

CC

C C C CC methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, acetic acid, acetone and methylene chloride, or a mixture thereof, and can also be conducted by alkyl or aralkyl, and a compound of the formula

COOR

3

COOR

3 wherein R 3 is lower alkyl or aralkyl, in the presence of a base, followed by heating, and if desired, b) subjecting a compound of the formula in which E is C=O, to a reduction reaction, followed by a halogenation or sulfonylation reaction, and if desired, c) subjecting a compound of the formula in which R 3 is lower alkyl or aralkyl, to hydrolysis to provide a compound of the formula in which R 3 is hydrogen, and if desired, d) converting the thus obtained compound of the formula into a salt thereof.

The compound of the formula wherein R 4 is hydrogen can also produce, for example, according to the following reaction scheme.

R1 (XXX) NH2 (XL) 2 H O R A-R 6 (IV) or (VIII) RNHCHCOOR 3 R H 0 The reaction (XXX)-M (XL) can be conducted under the same conditions as those of the reaction (XXXI) (VII).

The compound can be produced by reacting the compounds (XL) and (IV) or (VIII) under the same conditions as those 35 of the reaction of the compounds (III) and (IV) or (VII) and

(VIII).

11€ 1 195S/bm platinum, palladium and rhodium, or a mixture thereof with an arbitrary support as a catalyst; reduction with a metal hydride compound, such as lithium aluminum hydride, lithium borohydride.

lithium cyanoborohydride, sodium borohydride and sodium -31- In the above-mentioned processes for producing the compound and its intermediates, the compounds to be used in the reactions may be employed in the form of salts, such as inorganic acid salts being exemplified by hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., organic acid salts being exemplified by acetate, tartarate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate, etc., metal salts being exemplified by sodium salt, potassium salt, calcium salt, aluminum salt, etc., and salts with bases being exemplified by triethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt, etc., so long as they do not interfere with such reactions.

The following Examples, Experiment Examples and Preparation Examples are further illustrative but by no means limitative of this invention.

Example 1 In an aqueous solution (200 mi) of 1.4 g of sodium carbonate is dissolved 2.9 g of S-(o-nitrophenyl)-L-cysteine, and 3.5 g of N-ethoxycarbonylphthalimide is added to the solution under stirring. After the mixture is. stirred at rom tmperature for 5 hours, the insoluble matter is removed by filtration, and the filtrate is made weakly acid with concentrated hydrochloric acid. The crystals which separate out are recovered by filtration, and recrystallized from 30 mt of ethanol to r fr The above alkylation reaction includes, for example, a reductive alkylation reaction involving the reaction with a lower alkyl-(C 1 4 )-aldehyde under reductive conditions (the reductive conditions include reaction conditions of Found C, 54.46; H, 3.26; N, 7.46 Ca2.

4 _79* in methanol)

D

Example 2 In 300 ml of methanol is placed 10 g of 3-(o-nitrophenyl)give 3.6 g of 3-o-nitrophenythio-2(R)-phthalimidopropionic acid, which is catalytically reduced as pale yellow needles, melting atmospheic pressure,220-222 using 5 palladium-carbon as a catalyst. After the calculated Calcd.: C, 54.84; H, 3.25; N, 7.53 amount of hydrogen is absorbed, the catalyst is removed, and7.46 the -79 (c methanol is evaporated off under reduced pressure. Ether and petroleum ether are added to the residue, and the deposited yellowish crystalline powder is collected by Example 2 filtration 300 m of methanol is placed 0 g of 3-(o-nitrophenyl)hio-2(R)-phthalimidopropionic acid which is product (8.4 g) iscally reducissolved at ordinary temperature unmamide and 5tmospheric pressure,thyl phosphorocyanidate is added dropwise to the solution under ice-cooling 5 palladium-carbon as a catalyst. After the addition is completed, the mixture is stirred for 5 minutes, and 2.28 g of triethylamine is further added drogen is abs orbed, the catalyst is removed, and the methanol is evaporated off under reduceand pressure. Etherat room temperature for 1 hour. Water (200 mL) is added to the reaction solution, and the mixture is allowed to t he residue, and t. The A deposited solid is collected by filtration and dried. This product is purified by silica-gel column chromatography (dichltraomethane:ethyl acetate to give 8.42:1) to give 5.4 g of 3(R)- 2(Rphthaimido23d-phthalimidopropionic acid. This product (8.4 g) is d issolved in 50sms, melt of dimethylfo mide, and 20C.f diethyl phosphorocyanidate is added dropwise to the solution under ice-cooling with stirring. After the addition is completed, the mixture is stirredanalysis, for C 1 7H5 minutes, and 228 g of triethylamine Calcd.: C, 62.95; H, 3.73; N, 8.64 is further added dropwise under ice6315;olin The mixture isN, 8.49 stirred under ic-0.9, in for 30 minutes and then at roommethanol) Example 3 temperature for hour. Water 200 mide) is added to the reaction "solution, and the mixture is allowed to stand overnight. The I deposited solid is collected by filtration and dried. This product is purified by silica-gel column chromatography (dichloromethane: ethyl acetate 2:1) to give 5.4 g of 3(R)phthalimido-2,3-dihydro-l,5(5H)-benzothiazepine-4-one as colorless prisms, melting at 202-205C.

Et Elemental analysis, for CITHI2N203S t t t Calcd.: C, 62.95; H, 3.73; N, 8.64 C Found C, 63.15; H, 4.02; N, 8.49 -164 in methanol) Example 3 To 50 mt of dimethylformamide is added 0.5 g of sodium

L

The salt of the compound can be produced by the reaction per se for producing the compound and if desired, it can also be produced by adding an acid, alkali or base to the compound 33 hydride (60 in oil), and the mixture is stirred under ice-cooling. 3(R)-Phthalimido-2,3-dihydro-l,5(SH)benzothiazepine-4-one (4 g) as obtained in Example 2 is added to the mixture under ice-cooling, followed by stirring for minutes. tert-Butyl chloroacetate (2 g) is further added to the mixture under ice-cooling, and after stirring under icecooling for 15 mintues, ice-cold water (200 mt) is added to the reaction solution. The deposited crystals are collected by filtration, dried and purified by silica-gel column chromatography (hexane: ethyl acetate 3:1) to give 4 g of tert-Butyl 4 -oxo-3 -phthalimido-2,3,4, 5-tetrahydro-1, as colorless crystals. Recrystallization from ethyl ether of a part of the compound yields colorless prisms, melting at 181-184°C.

Elemental analysis, for C23H 2 2

N

2 0 5

S

Calcd.: C, 63.01; H, 5.06; N, 6.39 i Found C, 62.95; H, 5.10; N, 6.34 [a]20-156 in chloroform)

D

Example 4 To 100 mi of ethanol are added 4 g of tert-butyl 4oxo-3(R)-phthalimido-2,3,4,5-tetrahydro-, as obtained in Example 3 and 1.4 g of hydrazine hydrate, and the mixture is heated under reflux for.1 hour with stirring. The reaction solution is concentrated under reduced pressure, and 300 mt of ethyl acetate .and 100 mt of water are added to the residue, followed by shaking thoroughly.

The ethyl acetate layer is washed with dilute aqueous sodium hydroxide solution and water, successively, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is crystallized from a 4 t mixture of ether and petroleum ether to give 2 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo-

I

as colorless prisms, melting at 86-89*C.

Elemental analysis, for C5IH20N203S Calcd.: C, 58.42; H, 6.54; N, 9.08 Found C, 58.73; H, 6.48; N, 9.13 t t effect and highly stable, and it, when being used as the abovem, ntioned drugs, can therefore be safely administered orally or parenterally, per se or in admixture with suitable, pharmaceutically acceptable carriers, excipientS or diluent~s 34 (a]20-238* (cml, in methanol)

D

Examples 5 to 9 Using substituted o-nitroaniline derivatives as a starting material, the reaction is carried out in the same manner as in the synthesis of the unsubstituted derivatives (R=Hi) to give the compounds as shown in Table 1.

Table 1: Nfl 2 I6 _,,I.-LCOOH Examnpl1e No.

Con fig. Melting Ipoint, OC CaID in IN hydrochloric acid 4 -CH 3 4 -0CH 3 2* 2 3 166-168 157-158 +440 +240 +330

I

i-I 1± 21 St t t a

I,

St S t *1( S. St

S

S

55 5

IS

tI~ S C St S II Cr C 8 4 -Cl I R J169-171 +46- 9 4-CF 3 R j181-183 f 53o Examples 10 to 13 In the same manner as Example 1, the S-(2-nitrophenyl)- L-cysteine derivatives as obtained in Examples 5 to 8 are reacted with N-ethoxycarbonylphthalimide to give the compounds as shown in Table 2.

Table 2: 0 0 I St 14 -CH 3 4 -OCH 3 4 5 -(Cfi 2 3i 4-Cl

R

I R Melting (a I D point, C Ijin methanol Used in the subsequent reaction without bein puified.

157-159 -1200 219-222 -1490 183-185 -1160 _Z X~qzCH_!{_CHCOOR, 1OR (XV 2) Wb-CnH, ,COORS (VI)

R

2 3- Examples 14 to 17 The phthalimide derivatives as obtained in Examples to 13 are subejcted to a reaction similar to the reaction described in Example 2 to give the compounds as shown in Table 3.

Table 3: 9d Example R Config. Melting point,0C 14 7-CH 3 R 222-225 -1800 7-0Cfl 3 R 255-258 -340 (in chloroform) 16 7,-(CH 2 3 R 240-243 -1360 (in methanol) 17 7-Cl R 256-258 l69* V (in methanol) Examples 187 to' 21 The phthalimidobenzothiazepine derivatives as obtained in Examples 14 to 17 are suxbjected to a rection similar to the reaction described in Example 3 to give the compounds as shown in Table 4.

Table 4: V 8N R CHi 2

COOC(CH

3 3 Example RConfig. Melting [aID No. R*1 pointC in methanol is 7-CH 3 R 140'-143 -1510 t 19 7--OCH 3 R 155-157 -1390 7,8-(CH2)3- R 195-198 -114* 21 7-Cl R 182-184 -1480 Examples 22 to t a t t t t WJ L.L W VL V.

R1 R' A-R 6 R' A-R 6 CH C-COOR 1 Reduction SCH -CH-N-CH-COOR0 (0)rO COOHO 1

R

2 Re H COOH (XC= F- I1

I

i

I

Ii Ii 36- The tert-butyl phthalimidobenzothiazepine acetate derivatives as obtained in Examples 18 to 21 are subjected to a reaction similar to the reaction described in Example 4 to give the compounds as shown in Table Table S s *1 8 /_-NH 2 7 9 CO R6

I

CH

2

COOC(CH

3 )3 R Config *1 Example No.

1 Melting point, °C [a]D (in methanol) 22 23 24 7-CH3 7-OCH3 7,8-(CH 2 )3- 7-Cl 159-160 -1466 oxalate) 175-178 -147' (hydrochloride) I Used in the subsequent reaction without being purified.

158-160 -1020 (oxalate) Example 26 To 67 mL of 0.25N aqueous sodium hydroxide solution is added 5. 3 g of S-(2-nitro-4-trifluoromethylphenyl)-Lcysteine as obtained in Example 9, -and after stirrincj at room temperature for 30 minutes, 2.7 mL of benzyloxycarbonyl chloride and 19 mL of IN aqueous sodium hydroxide solution are simultaneously added dropwise to the mixture under icecooling over the period of 30 minutes, followed by stirring at room temperature for 2.5 hours. The reaction solution is extracted with ethyl ether, and the aqueous solution layer is made weakly acidified with IN hydrochloric acid, and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and ethyl ether is added to the resulting residue to deposit 5.5 g of S-(2-nitro-4-trifluoromethylphenyl)-N-benzyloxycarbonyl-L-cysteine as pale yellow crystals, melting at 150-153*C.

(in methanol) E4 t C tE C(S) K 0 WgV) CnH 2 n-COOER 37- Elemental analysis, for C181H 5

F

3

N

2 0 6

S

Calcd.: C, 48.65; H, 3.40; N, 6.30 Found C, 48.68; H, 3.41; N, 6.27 Example 27 To a mixture of 50 mi of acetic acid and 50 mL of water are added 4.3 g of S-(2-nitro-4-trifluoromethylphenyl)-N-benzyloxycarbonyl-L--cysteine as obtained in Example 28 and 4 g of powdered zinc, followed by stirring at room temperature for 50 minutes. Water (150 mi) and 150 mi of ethyl acetate are added to the mixture, and the insoluble matter is filtered off. The aqueous layer is extracted further twice with 100 ml of ethyl acetate, and the ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in 50 ml of ethyl ether, and 5 ml of hydrogen chlorideethyl acetate solution (5N) is added to the solution to give 3.4 g of S-(2-amino-4-trifluoromethylphenyl)-Nbenzyloxycarbonyl-L-cysteine hydrochloride as yellowish powder.

This product is dissolved in 30 mt of dimethylformamide, and a solution of 0.78 g of triethylamine in 5 mL of dimethyla formamide is added dropwise to the solution under ice-cooling with stirring over the period of 1 minutes, followed by adding dropwise a solution of 1.83 g of diethyl phosphorocyanidate in 5 mt of dimethylf.onnamide over the period of 5 minutes and adding a solution of 0.78 g Sof triethylamine in 5 mt of dimethylformamide. The reaction solution is stirred under ice-cooling for 30 minutes and then at room temperature for 2.5 hours, followed by adding 200 mi of water. The mixture is extracted with ethyl acetate, and Sthe extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silica-gel column chromatography 4 (hexane:ethyl acetate 4:1 to 2:1) to give 1.3 g of 3(R)benzyloxycarbonylamino-7-trifluoromethyl-2,3-dihydro-, 5 benzothiazepine-4-one as colorless crystalline powder, melting at 120-123'C.

(alo-161" (in methanol) 6h I bI a f It compound (II).

S' In the method for producing the compounds (III) and (VII), the amino group of the compound (XXVI), in the first place, is protected with a suitable amino protecting group phthaloyl group) to produce the compound (XXVIII). This -38- Elemental analysis, for C 8 gHI 5

F

3

N

2 0 3

S

Calcd.: C, 54.54; H, 3.81; N, 7.07 Found C, 54.79; H, 3.90; N, 7.09 Example 28 In 20 mt of dimethylformamide is dissolved 1.1 g of 3 -benzyloxycarbonylamino-7-trifluoromethyl-2,3-dihydro- 1,5(5H)-benzothiazepine-4-one as obtained in Example 27, and 0.46 g of'tert-butyl chloroacetate, 0.42 g of potassium carbonate and 0.1 g 6f potassium iodide are added to the solution, followed by stirring at room temperature for 4.5 hours.

Water (100 mi) is added to the reaction solution, and the mixture is extracted with 100 mt of ethyl acetate. The extract is washed with 0.1N hydrochloric acid, aqueous sodium hydrogencarbonate solution and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.4 g of tert-butyl 3(R)-benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-, benzothiazepine-5-acetate as a colorless viscous material.

*nujol -1 IR nujocm: 1680 (amide), 1710 (urethane), 1740 (ester) max IR: (stands for infrared absorption spectrum; the same shall apply thereafter).

Example 29 In 5 mL of acetic acid is dissolved 1.4 g of tert-butyl 3 -benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,3,4,5tetrahydro-1,5-benzothiazepine-5-acetate, and 10 mL of 30 Si hydrogen bromide-acetic acid solution is added to the solution, S followed by allowing the mixture to stand at room temperature for 4 hours. Petroleum ether (100 mi) is added to the reaction solution, and the mixture is thoroughly shaken, followed by decanting the supernatant. After petroleum ether is again added to repeat the same procedure, the residue Sis dissolved in a mixture of ethyl acetate and benzene, and the mixture is concentrated to dryness.under .reduced pressure. Petroleum ether is added to the residue to give 0.75 g of 3(R)-amino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid-

II

i

K

tt -39hydrobromide as crystals.

Melting point; 176-180°C Elemental analysis, for C 12

H

11

F

3

N

2 0 3 S-HBr-H 2 0 Calcd.: C, 34.38; H, 3.37; N, 6.68 Found C, 34.40; H, 3.60; 6.66 Example In 20 mt of methanol is dissolved 1 g of tert-butyl 3(R)-amino-4-ox-2 ,3,4,5-tetrahydro-l,5-benzothiazepine-5acetate as obtained in Example 4, and 0.32 g of potassium cyanide, 1.1 g of N-C4-formylbutyl)phthalimide and 0.3 g of acetic acid are added to the solution, followed by stirring at room temperature overnight. The reaction solution is concentrated to dryness under reduced pressure to yield as a crude product tert-butyl 3(R)-(l-cyano-5-phthalimidopentyl)amino-4oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5-acetate. This product, without being purified, is used as a starting compound for Example 31.

Example 31 To 2 g of tert-butyl amino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5-acetate is added 20 mL of ethanolic hydrochloric acid (11N), and the mixture is stirred under ice-cooling for 6 hours, followed by allowing it to stand at room temperature overnight. The ethanol is evaporated off under reduced pressure, and 50 mI of ethanol and 10 g of Amberlyst 15 ion exchange resin are added to the residue, followed by refluxing with stirring for 7 hours. After cooling, the resin portion is treated with I pyridine-ethanol solution, and the ethanol portions are combined and concentra'ted under reduced pressure. The resulting oily material is dissolved in 300 ml of ethyl acetate, and the solution is washed with 0.1N hydrochloric acid and water successively. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue is purified by silica-gel column chromatography (hexane:acetone 2:1) to give 0.9g of ethyl 3(R)-(l-ethoxycarbonyl- 5-phthalimidopentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5as a colorless oily material.

IRvna cm 1 1770, 1740, 1720, 1710(phthalimide and ester) max Masspectrum 567 (M Example 32 In 25 mt of dimethylformaide is dissolved 6.48 g of 3C(R) -phthalimido-2, 3-dihydro-1, 5 (5H) -benzothiazepine- 4-one is obtained in Example 2, and 6.27 g of tert-butyl 2-bromopropionate, 5.5 g of potassium carbonate and 0.5 g of potassium V iodide are added to the solution, followed by stirring at room temperature overnight. Water C200 mt) is added to the V reaction solution, and the mixture is extracted with 300 m2t V of ethyi-acetate. The extract is washed with 200 m2. of 0. hydrochloric acid and 100 nit of saturated aqueous sodium hydrogencarbonate solution successively, then dried over anhydrous magnesium sulfate and, concentrated under reduced L pressure. The resulting oily material is purified by silica-gel.

column chromatography (hexane:ethyl acetate 3:1 to 2:1) to give 7.8 g of tert-butyl 3(R)-phthalimido-4-oxo-2,3,4,5te trahydro 5-ben zo thia zep ine-5-a -me thylacetate as a colorless powder.

IR nea cm: 1770, 1730, 1720, 1680(.C=O) max Elemental analysis, for C 24

H

24 2 0 5 S-1/2H 2 0 Calcd.: C, 62.46; H, 5.46; N, 6.07 Found C, 62.62; H, 5.14; N, 6.13 Example 33 in the same manner as Example 4, 7.6 g of tert-butyl 3.R)-phthalimido-4-oxo-2,. 245-tetrahydro-l,5-benzothiazepine- -a-.nethylacetate as obtained in Example 32 is treated with hydrazine hydrate to give 5.4 g of tert-butyl 3(R)-amino-4-oxo- C E 2,3,4 ,5-tetrahydro-l,5-benzothiazepine-5-ci-methylacetate as a tt Pale yellow oil, 'a'D -2230 (c-n0.5, in methanol) Mass spectrum 322 Example 34 41 In 20 mi of dimethylformamide is dissolved 3.08 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoas obtained in Example 4, and 7.36 g of ethyl 2-bromo-6-phthalimidohexanoate, 2.76 g of potassium carbonate and 1.66 g of potassium iodide are added to the solution, followed by stirring at room temperature overnight.

Furthermore, 3.68 g of the bromo ester and 1.38 g of potassium carbonate are additionally added to the mixture, followd by stirring for 3 days. Water C100 mi) and 300 mi of ethyl acetate are added to the reaction solution, followed by extraction. The extract is washed with water and concentrated under reduced pressure. Oxalic acid (5 g) and 30 mi of-ethyl acetate are added to the resulting residue to bring into a solution, and 120 mi of petroleum ether is added to the solution, o followed by shaking thoroughly. After allowing the mixture to I'"o stand, the supernatant is decanted, and the same procedure is repeated four times with the residue, followed by addingo the residue 100 m of saturated aqueous sodium hydrogencarbonate solution :and then 300 mi of ethyl acetate, followed by extraction. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silica-gel column chromatography (hexane:acetone 4:1) to give as the first fraction 1.75 g t of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-5-phthalimidopentyl] amino-4-oxo-2,3,4,5-tetrahydro-l, as an oily material.

IR vneat cml 3330(NH), 1780, 1740, 1720, 1680(C=O) max Mass spectrum '595 (M From the second fraction is obtained 2.5 g of tert- (t butyl 3 (R)-(l(S)-ethoxycarbonyl-5-phthalimidopentyl] amino- 4-oxo-2,3,4,5-tetrahydro-l, 5-benzothiazepine-5-acetate as a colorless oil.

IR neat 3330(NH), 1770, 1740, 1720, 1680(C=0) max Mass spectrum 595 (M) a)

D

-119" in methanol) ".~4JY Lne rormula: i2:CH-Wa

~AL

INC 54S 42 4 Example In 5 mi of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.2 g of tert-butyl 3(R)-(l(s)--ethoxycarbonyl- Iamino-4 -oxo-2,3,4,5-tetrehydro-l,S5ben zoth ia zepine-5-acetate as obtained in Example 34, and the solution is allowed to stand at room temperature for 3 hours.

Ethyl ether (50 imi) is added to the reaction solution, and the deposited precipitate is washed with 100 mi. of ethyl ether to give 0.13 g of amino-4-oxo-2, 3, 4, 5-tetrahydro-l, acid-hydrochloride as a colorless powder.

Elemental analysis, for C 27

H

29

N

3 0 7 S8HC1-1/2H 2 0 ifCalcd.: C, 55.42; H, 5.34; N, 7.18 Sound 55.09; H, 5.12; N, 7.15 [a] 0 I -ll4* in methanol) Example 36 In 20 ml. of ethanol is dissolved 1.6 g of tert-butyl 3 (l -ethoxycarbonyl-5-phthalimidopentyl] arnino-4--oxo- 2,3,4 ,5-tetrahydro-l,5-benzothiazepine-5-acetate as obtained in Examnple 34, anrd G. 8g of 85.% hydrazine hydrate is added to the solution, followed by allowing the mixture to stand at room f~ 4temperature overnight. Ethyl acetate (200 ml.) and 200 ml. of water are added to the reaction solution, followed by extraction.

The ethyl acetate portion is washed with 0.lIN aqueous I sodium hydroxide solution and water successively to yield an ethyl acetate solution of tert-butyl ethoxyrcarbonylpentyllamrino-4-oxo-2,3,4,5-tetrahydro-1,5- Sodium hydrogencarbonate (1.6 g) and 50 ml. of water are added to this solution, and a solution of 0.9 g of di-tert-butyl dicarbonate in 5 ml. of ethyl acetate is added dropwise to the :mixture with stirring at room temperature After stirring for 30 pinutes, the ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting oily material is purified by silica-gel column chromatography thexanetacetone to give 1.4 g of tert-butyl amino-1 -ethoxycarbofylpenty 1amino4 oxo- 2, 3, 4, 5- te trahyd roas a colorless oily material.

IR vna cm 1: 3350(NH), 1740, 1710, 1680(C-0) max mass spectrum 565 (M Example 37 In the same manner as Example 36, 2.6 g of tert-butyl 1(S)-ethoxycarbonyl-5-phthalimidopentyllamino-4-oxo- 2 ,3,4,5-tetrahydro-,5-benzbenzothiazepine-5-acetate as obtained in Example 34 is treated with hydrazine, and reacted with di-tert-butyl dicarbonate, followed by purification by silica-gel column chromatography to give 1.87 g of tert-butyl (S)-ethoxycarbonylpentyl] amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material.

IR vneat cm-l: 3350(NH), 1740, 1710, 1670(C=0) max Mblass spectrum 565 (M a] D- 1 36 0 (C=0.8 in methanol) Examole 38 In a mixture of 40 m. of methanol and 25 mZ of 1N aqueous sodium hydroxide solution is dissolved 0.6 g of tert-butyl ethoxycarbonylpentyl] amino-4-oxo-2,3,4,5-tetrahydro-1, S benzothiazepine-5-acetate as obtaiend in Example 37, and ml of water is further added to the solution, followed by stirring at room temperature for 2 hours. The methanol is evaporated off under reduced pressure, and the residual solution is made weakly acidified with phosphoric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.37 g of tert-butyl 5-tert-butoxycarbonylamino-l (S)-carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5-acetate a as a colorless viscous material. This product is treated with ethyl acetate to yield a colorless crystalline powder, melting at 134-1350C.

Elemental analysis, for C 2 6H 39

N

3 07S Cacld.: C, 58.08; H, 7.31; N, 7.82 1w Found C, 58.11; H, 7.22; N, 7.73 e IR vnujolcm-l: 3350(NH), 1730, 1700, 1680(C-0) max *u ~Example 39 In 200 mL of acetonitrile are dissolved 5 g of tertbutyl 3(R)-amino-4-oxo-2,3,,4,5-tetrahydro-1,5-benzothiazepineas obtained in Example 4 and 17.9 g of ethyl 2bromo-6-phthalimidohexanoate, and the solution is refluxed for 45 hours. The acetonitrile is evaporated off under reduced L A pressure, and 200 mt of water and 300 mt of ethyl acetate are added'tho the residue, followed by extraction. The extract i~s washed with water, dried over anhydrous magnesiumi sulfate and c, zncentrated under reduced pressure. Thc resulting oily material is purified by silica-gel column chromatography (heyane:acetone 4:1) to give as a colorless oily material 3.9 g of tert-butyl 3(R)-(l-CR)-ethoiycarbonyl-S-phthalimidopentyl iamino-4-oxo- 2 3,4, 5-tetrahydro-l, acetate and 4.1 g of tert-butyl phthalimidopentyllamino-4-oxo-2,3,4,S-tetrahydro-1,5-benzoth iazepine-5 -acetate, which are the samne products as Zhose obtained in Example 34.

Examoles 40 to 42 tert-Butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahvdro-l,5benzothiazepine-S-acetdte is reacted with the a-bromo esters shown in Table 6 in the same manner as Example 39 to give the following benzothiazepine derivatives.

44C4 Table 6: NH -2 COOR' (CH2)ii- 4 4 ~(CH 3 3 COOC> Ch)f-NV2 I Benzothiaz eoine derivative obtained Eanl a-Bromo ester used Cl neat C- No. R I 3330, 1770.

BrR S 1740, 1710, 1670 002 C1 3320, 1*770, 41 (j"~N(I 2 ~icc 2 Br 2 H R RS 1740 1710, 0 Br 1670 3320, 1770, 4 2 0 15 6 R RS- 1730, 1710, W) N(C31 2 6 ?{fCD 2 1670 1I Dr mixture of diastereomers 7 Examples 43 to The benzothiazepine derivatives as obtained in Examples 40 to 42 are treated with hydrogen chloride-ethyl acetate solution in the same manner as Example 35 to give the compounds as shown in Table 7.

Table 7: JNHN<7C00R"0

C

(CH2)n~ :FOacJ 0 R" n *1 *2Conf ig. I[a]D in methanol Example No.

pq 4~ 4 44 #4 44 4 4444 44 #4 4 4 9* 4 4 44 o *4 p 44,44' 4 4

(CH

2 3

CH

3 4

C

2

H

5 2 C .H 5 6 *mixture of diasterec R S -l06* (c=0.6) R RS* 330 R RS* -lQ5* ~mers #6 6 4 4 44 6& 4 t

II

i 4 C Calcd.: C, 62.95; H, 3.73; N, 8.64 Found 63.15; H, 4.02; N, 8.49 caDg -164* in methanol) Example 3 To 50 mlt of dimethylformamide is added 0.5 qof sodium -46 Examples 46 to 48 The benzothiazepine derivatives as otbained in Examples to 42 are treated with hydrazine in the same manner as Example 36, followed by reaction with di-tert--butyl dicarbonate to give the compounds as shown in Table 3.

Table 8: ND E

COOR"'

(CH

3 3 COOC- j (CH 2 nNHCOOC(CH3) 3 Example R- Config. IR vneat cm 1 No. *1 *2 max 46 (C 2

C

3 4 R S 3350, 1730, (CH23CH31710, 1670 47 c 2 E 2 R RS 3400, 1740, C2 5 1710, 1670 48 C 2

H

5 6 R RS* 3350, 1730, *Mixture of diastereomers 11,17 In 20 mnl of ethanol is dissolved 0.7 g of ethyl 3(R)amino-4-oxo-2,3,4,5as obtained in Example 31, and 0.3 g of 85 hydrazine hydrate is added to the solution. Hydrazine hydrate(0.3 g, 85 additionally added to the reaction mixture 1 hour and 2 hours later, respectively, and the mixture is allowed to stand overnight.

Ethanol is evaparated of f under reduced pressure, and 50 t of water is added to the residue. Sodium chloride is added to the mixture to saturate the aqueous phase, followed by extraction with three 100 mlt portions of ethyl acetate. The extract is wahsed withs 50 LIE of 0.LN aqueous sodium hdyroxide solution and 100 tntof water. successively, and dried over anhydrous mragnesium sulfate. Hydrogen chloride ethyl acetate 0.5 rut) is added to the resulting ethyl acetate solution, and the mixture is concentrated under reduced pressure.

Ethyl ether is added to the residue to give 0.13 g of ethyl 3(R)-(5-amino-l-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5tetrahydro-1, 5-ben zo thia zepine-5-aceta te -dihydrochlo ride as a tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-l,5-benzoas colorless prisms, melting at 86-89*C.

Elemental analysis, for C15H20N203S Calcd.: C, 58.42; H, 6.54; N, 9.08 Found C, 58.73; H, 6.48; N, 9.13 ^l-IC-i. I- l S- 7 colorless powder.

Elemental analysis, for C 2 1

H

3 1

N

3 0 5 S'2HCI H 2 0 Calcd.: C, 47.73; H, 6.67; N, 7.95 Found C, 47.81; H, 6.53; N, 7.83 Mass spectrum 437 (M Example In a mixture of 30 mt of ethyl acetate and 10 mi of water is dissolved 50 mg of ethyl l-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro-, as obtained in Example 49, and 0.15 me of benzyloxycarbonyl chloride and 0.3 g of sodium hdyrogencarbonate are added to the solution, followed by stirring at room temperature for 2.5 hours. The ethyl acetate layer is washed with water, dired over anhydrous magnesium sulfate and concentrated udper reduced pressure. The resulting residue is dissolved in a mixture of 20 mt of ethyl ether and 20 mt of petroleum ether, and 0.2 mt of 5N hydrogen chloride-ethyl acetate solution is added to the solution to give 55 mg of ethyl amino-l-ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetate-hydrochloride as a colorless powder.

Mass spectrum 571 (M Example 51 In a mixture of 3 mi of ethanol and 2 mt of IN aqueous sodium hydroxide solution is dissolved 55 mg of ethyl 3(R) (5-benzyloxycarbonylamino-l-ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5-acetatehydrochloride as obtained in Example 50, and the solution is allowed to stand at room temperature for 1 hour. Water(50 mt) is added to the reaction solution, and after the mixture is extracted with 20 mi of ethyl ether, the aqueous layer is adjusted to pH 4 with IN hydrochloric acid. Armmonium chloride i is added to the solution until it becomes saturated, and the ee aqueous layer is extracted ten times with 20 mt of ethyl acetate. The extract is washed with a small amount of water, dried over anhydrous magnesium sulfate and concentrated under t C C C 4 11 4 -0CH 3 12 4,5-(CH 2 )3- 13 14-Cl Used in the subsequent reaction without being purified.

157-159 -1200 219-222 -1490 183-185 -1160

A

k t 48 reduced pressure to give 40 mg of amino-l-carboxypentyl)axnino-4-oxo-2,3,,4,5-tetrahydro-1,5benzo thia ze pine-5 -acetic acid as a colorless powder.

mass spectrum 515 Example 52 In 1 niL of acetic acid is dissolved 40 mig of 3(R)- -ben zyloxycarbonylamnino-l -carboxypen tyl) amino- 4-oxo 3,4,5 tetrahydro 5-benzo thiazepine- 5-ace tic acid as obtained in Example 51, and 1 ml of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by stirring at room temperature for 1 hour. Ethyl ether(80, nL) and 20 niL of petroleum ether are added to the reaction solution, and the mixture is shaken and allowed to stand. The supernatant is decanted, and the precipitate is collected and dried to give 33 mig of 3 -amino-l -carboxypentyl) amino- 4 -oxo- 2,3, 4,5 tetrahydro-l, 5-benzothiazepine-5 -acetic acid dihydrobromide as a colorless powder.

SIMlS spectrum (nile): 382 (MH addition of KI 420 Examples 53 and 54 The benzothiazepine derivatives as obtained in Examples 36 and 37 are treated with hydogen chloride in the same manner as Example 35 to give the compounds as shown in Table 9 as colorless crystals.

Table 9: r _Nf\)NHCHOOC-)HI -2HC1 C 4 Example No.

Config. (in methanol) *1 *2 D R R -161* (c-0.7) R S I -1280 mL of 1N aqueous sodium hydroxide solution is of 3 -(5-amino-l -ethoxycarbonylpentytllamino- To 4 added 0.2g -49 4 -oxo- 2 3 4 ,5-te trahydro 5-ben zoth iazepine- 5-aceti c acid* dihydrochioride as obtained in Example 54, and the mixture is stirred at room temperature for 1.5 hours. Acetic acid (1 ml) is added to the raction solution to make the solution weakly acidified, followed by purification by Mterlite XAD-2 cnlutn chromatography (methanol:water The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.1 g of anino-4-oxo-2,3,4, 5-tetrahydro-l, acid as a colorless powder.

Elemental analysis, for C 17

H

23

N

3

O

5 S-ff 2

O

Calcd.: C, 51.12; H, 6.31; N, 10.52 Found 50.87; H, 5.83; N, 10.34 (ajo -1490 in 1N hydrochloric acid) *See t SIM4S spectrum 382 addition of KI 420 Example 56 In the same manner as Example 35, 0.32 g of tert-butyl 3 -tert-butoxycarbonylamino-l -carboxypentyl]I amino-4 *oxo- 2 3 4 5-tetrahydro- ,5 -ben zothia zepine-5-..ace ta te as obtained in Example 38 is treated with hydrogen chloride to give 0.26 g a t of 3 (R)-(5-amino-l(S)-carboxypentyllamino-4-oxo-2,3,4,5te trahydro-l, 5-ben zothiazepine- 5-ace tic acid -dihydrochloride as a colorless crystalline powder.

I L CElemental analysis, for C17H 2 3 N30 5 S-2HCl'CH 3

COOC

2

H

Calcd.: C, 46.49; H, 6.13; N, 7.75 Found 46.12; H, 6.16; N, 7.52 This product (0.15 g) is dissolved in 2 ni, of water, *and 0.5 mt of 1N aqueous sodium hydroxide solution and then mi of acetic acid are added to the solution, which is purified iwith Amberlite XAD-2 in the same manner as Example to give 0.096 g of the free derivative which is the same compound as the one obtained in Example Examples 57 to 59 The benzothi.3zepine derivatives as obtained in Examples 46 to 48 are treated with hydrogen chloride-ethyl acetate solution in the same manner as Example 35 to give the compounds phenyl) -N-benzyloxycarbonyl-L-cysteine as pale yellow crystals, melting at 150-153*C.

(QID+

2 00 (in methanol) as shown in Table Table Is HOOC)

(C

2 )nNH 2 Example Cnf ig. i tao 57 (CH 2 )3CHj 4 R S 1230 (c=0.4) 58 CH 5 2 R RS 1440 (c=0.4) V59 C 2

H

5 6 R RS*~ -118* (c=0.4) *Mixture of diastereomers Example In 10 mt. of ethanol is dissolved .A.3 gof sodium, and 5 g of ethyl 3- Cl-benzyloxycarbonyl-.4-piperidyl 1propionate and 2.75 g of diethyl oxalate are added to the solution, The solvent is evaporated off under reduced pressure, while heating on a warm-.water bath at 60 to 70*C for 45 minutes. After cooling, the resulting brown viscous material is treated with 200 m2. of water, andi the mixture is made weakly acidified with onentrated hydrochloric acid. The mixture is extracted with 300 mt of ethyl acetate, and the extract is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

It Ten (10) aqueous dimet-hylformamide (50 mt) and 0.73 g of lithium ii chloride are added to the resulting yellow oily material, followed by stirring at 100*C for 30 minutes, at 120 to 1301C for 30 minutes and then at 1400C for 45 minutes. After cooling, 300 mS. of water is added to the reaction solution, and.the mixture is extracted with 300 mS. of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and con~centrated under reduced pressure to give 4.5 g of -ethyl 4 -ben zyloxycarbonyl- 4-piperidy 1) 2-oxobutyra te as a pale brown oil.

IR V neat cm 1 1730, 1700(C=O) max Mass spectrum 347 (M Examples 61, 62 Using the ethyl propionate derivatives as shown in -51 Table 11 as a starting compound, the reaction similar to the one of Example 60 is carried out to give the corresponding a-keto ester derivatives, respectively.

Table 11: Example Star.ing compound Keto..ester derivative No. obtained bp (mmHg) 61 O7CcH 2

CH

2

COOC

2 H5 O)-CH 2

CH

2 115-125C (2) 6 Or- H2CH2COCOOC2H5 HCH2COOC 148-151C (3) Example 63 In 50 m£ of ethanol is dissolved 2 g of tert-butyl 3(R)amino-4-oxo-2, 3,4, 5-tetrahydro-1, and 0.43 g of acetic acid, 4.5 g of ethyl 4-(1l-benzyloxycarbonyl-4-piperidyl)-2-oxobutyrate as obtained in Example and 10 g of Molecular sieve 3A are added to the solution.

The mixture is stirred at room temperature for 1 hour, and a solution of 0.4 g of sodium cyanoborohydride in 30 mt of ethanol is added dropwise to the mixture at room °0 temperature with stirring over the period of 2.5 hours. A solution of 0.5 g of sodium cyanoborohydride in 20 mt of ethanol is further added dropwise to the mixture over the period of 3 hours. The reaction solution is allowed to stand overnight, and concentrated under reduced pressure, and 300 ml of water and 300 mt of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is filtered off, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ether (50 mL) is added to the residue, to which a solution of 1 g of oxalic acid in 50 mt of ethyl ether e" is added. Petroleum ether (200 mt) is added, followed by shaking thoroughly, and the mixture is allowed to stand. The supernatant is decanted, and 100 mi of petroleum ether is again added to the ppecipitate portion, which is then shaken.

The petroleum ether layer is removed by decantation, and 50 mZ aiiu ciie mixture is concentrated to dryness.under reduced pressure. Petroleum ether is added to the residue to give 0. 75 g of 3(R)7anino-4-oxo-7-trifluoromethyl-2,3, 4 5-tetrahydroI, 5beflzothiazepine5 acetic acid- -52 of water and 200 mX~ of ethyl acetate are added to the precipitate portion, followed by adding excess sodium hydrogencarbonate to the mixture with stirring to effect neutralization. The ethyl acetate layer is washed with water, d~itied over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily material. This product is separated and purified by silica-gel column chromatography (hexane:ethyl acetate- 2: 1 to 4: 3) .to give as the f irst f raction 0. 6 g of tert-butyl 3 (1-benzyloxycarbonyl-4 -piperidyl) -1 -ethoxycarbonyl propyll amino-4-oxo-2, 3,4, 5-tetrahydro-1, acetate as a colorless oily material.

neat IR vma cm :3320 (NH) 1740, 1700, 1680 (C=0) Mass spectrum 639 (M Fror., the subsequent f racion, 1. 3 g of tert-butyl 3 [3-U(-benz,yloxycarbonyl-4 -piperidyl) -1 -ethoxycarbonylpropyl] amino-4 -oxo-2 ,3,4 ,5-tetrahydro-1, 5-b enzothiazepine-5 -acetate is obtained as a colorless oily material.

neat -1 IR v cm :3320(NH), 1740, 1700, 1690, 1670(C0O) max+ mass spectrum 639 (11 Exam~ples 64', The a-keto esters as obtained in Examples 61 and 62 are reacted with tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzothiazepine-5 -acetate in the same manner as Example 63 to give the compounds 9hown in Table 12 as an oily material.

Table 12: I NHCHCOOC 2H

(CH

3 3

COOC

E xamnplIe No.

Mass t #I &t R R R S -l37*(c=0,6) R R -96* (c=0.3) R S -82* 506 506 522 522 magnesium sulfate and concentrated under reeuced pressure, and the residue is purified by silica-gel column chromatography (hexane:acetone 2:1) to give O.9g of ethyl 3 (R)-(l-ethoxycarbonylamino-4-oxo-2, 3,4, 5-tetraliydro-1,5- -53 Example 66 In 20 mY. of SN hydrogen chloride-ethyl acetate solution is dissolved 0.3 g of tert-butyl 3 (R)-(3-(l-benzyloxycarbonyl- 4 -piperidyl) -ethoxycarbonylpropyl Iamino- 4 oxo- 2, 3, 4, as obtained in Example 63, and the solution is allowed to stand at room temperature for 3 hours. Petroleum ether (200 mt) is added to the reaction solution to deposit 3(R)-[3-(l-benzyloxycarbonyl- 4 -piperidyl) -1 -ethoxycarbonyipropyl]I amino -4 -oxo- 2 3 4 ,5-tetrahydro-l, 5-benzothiazepine-5 -acetic acid -hydrochloride.

The supernantant liquid is decanted, followed by drying to give 0.22 g of a colorless powder.

Elemental analysiP7, for C30H 3 7

N

3 0 7 S*HC1*H 2 0 Calcd.: C, 56.46; H, 6.32; N, 6.593 Found C, 56.29; H, 6.31; N, 6.57 [cuD -918 in methanol) Exampl'es *67 to The benzothiazepine derivatives as obtained in Examples 7 64 and 65 are treated with hydrogen chloride in the samte manner as Example 66 to give the compounds shown in Table 13.

Table 13: 1 2 c3s NH-CH-COCH*I N CH CH 2

R

Example R Config. a in methanol No.1 2 []D 6 7 -I:3 R R -1510 68 -11S~ 69f7 R R -1440 70 -jS R S 1080 S Exampl e 71 In 2 mt of acetic acid is dissolved 0.6 g of tert-butyl 3 (1-benzyloxycarbonyl -4 -piperidyl) -1 -e thoxycarbony I- 11K( v cm 1J,1I(0 max 1aJD -223* in methanol) Mass spectrum 322 Example 34 T- 54 pro py I Iamino-4-oxo-2, 3,4 5-tetrahydro-1, 5-ben zothiazepine-Sacetate as obtained in Example 63, and 2 q~t Of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by allowing thermixture to stand at' room temperature for 1 hour.

Ethyl ether (150 mt) is added to the reaction solution, and the mixture is allowed to stand. Then, the supernatant is decanted, and the precipitate is washed with ethyl ether, and dried to give 0.5 g of 3(R)-fl(R)-ethoxycarbonyl-3-(4-piperi'dyl)propyljamino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-Sacetic acid-dihydrobromide as a colorless powder.

Elemental analysis, for C 22

H

31 N 3 0 5 S-2HBr-H 2

O

Calcd. C, 41.98; H, 5.60; N, 6,68 Found 41.43; H, 5.39; N, 6.30 a] 22 2.106* in methanol)

D

Examole 72 In the same manner as Example 71, 0.4.g of tert-butvl 3CR)- Cl-benzyloxycarbonyl-4-piperidyl) -ethoxycar.'onyvlpropyllamino-4-oxo-2,3,4 ,5-tetrah~dro- acetate as obtained in Example 63 is treated with hydrogen bromide to give 0.35 g of 3(R)-(S)-ethoxcycarbconyl-3-.(4piperidyl)propyl]aimino-4-oxo-2,3,4,5-tetrahydro-'l,5-benzothiazepine-5-acetic acid- dihydrobronide as a colorless powder.

Elemental analysis, for C 22

H

31

N

3 0 5 S*2HBr-H 2 0 14 Cacid: C, 40.81; H, 5.76; N, 6.49 Found C, 40.47; H, 5.32; N, 6.28 -860 (c-0.

6 in methanol) Example 73 In 4 in? of 0.1N aqueous sodium hydroxide solution is dissolved 0.15 g of 3(R)-(l(S)-ethoxycarbonyl-3-(4-piperidyl)propyljamino-4-oxo-2,3,4,S-tetrahydro-1,5-benzothiazepine-5- 'A acetic acid -dihydrobromJde as obtained in Example 72, and the solution is aliowed to stand at room temperature for 2 hour s.

The solution is made weaklr- acidified with 1 mlt of acetic acid, and purified by Arnberlite XAD-2 column chromatography (methanol: C water 1:1) The eluate is concentrated Linder reduced pressure, a nd th e re s id ue i s Ilyo ph i Iized t o g iv e 0 .0 6 9 ofE 3 S) carboxy-3-(4-piperidyl) propyljamino-4-oxo-2,3,4,5-tetrahydroacid as a colorless powder.

Elemental analysis, for C 2 0

H

2 7

N

3 0 5

S-H

2 0 Calcd.: C, 54.65; H, 6.65; N, 9.56 Found 54.05; H, 6,17; N, .2l Mass spectrum 422 (1111+): addition of KI, 460 LCaD 28* in met-hanol-water) Examples 74, The benzothiazepine derivatives as obtained in Examples 68 and 70 are hydrolyzed with 1N aqueous sodium hydroxide solution in the same manner as Example 73, followed by purification by Amberlite XAD-2 column chromatography to give the compounds as shown in Table 14 as a colorless powder.

Table 14:

HCHCOOH

i 2

CH

2

R

Example RConfig.

No. *1 2 I D 74 .f~R S -140* in methanol 1:1: 75 S R S -1060 (c=0.2) in methanol+1N HCl EmL.

In 10 mZ of ethanol is .iolved 0.25 q of K>ethoxycarbonyl-3 -piperidyl) ropyl Iamino-4 -oxo-2, 3, 4, .'tetrahydro-l ,5-benzothiazepine-5-acetic acid-dihydrobromide as obtained in Example 72, and 67 mg of sodium acetate and 52 mg of benzaldehyde are added to the solution. A solution of 31 mg of sodium cyanoborohydride in 10 mt of ethanol is added dropwise to the mixture over the period of minutes. The ethanol is evaporated off under reduced pressure t and 50 mnL of water is added to the residue. The mixture is made weakly acidified with acetic acid, andI extracted three tirrms with mX of dichioromethane. The extract is washed with a small amount of water and concentrated under reduced pressure. The amino-.(R) -ethoxycarbofly Ipentyl I amino-4-oxo- 2 3, 4 1,5-benzothiazepife5acetate as a colorless oily material.

IR v nat cm 1:3350(N) 1740, 1710, 1680(C-0) mass spectrum (rn/c) 565 (M) resulting oily material is dissolved in I mt of dichioromethane, and 0.5 mt of 5N hydrogen chloride-acetic acid solution is added to the solution. The deposited colorless Powder is washed with ethyl ether, and dried to give 157 mg of 3(R)-[3-Clbenzyl-4-.piperidyl) -l -e thoxyca rbonylp ropylI] a-nino-4--oxo- 2 3 4 ,5-tetrahydro-l,5-benzothiazepine-5-acetic acid-dihydrochloride.

Elemental analysis, for C 29

H

37

N

3 0 5 -2HC1-Ho Caldd,: C, 55.23; H, 6.55; N, 6.66 Found 54.92; H, 6.74; N, 6.14 t a]D- 7 6 in methanol) Example 77 In 5 mi of ethyl acetate dissolved 0.1 g of 3(R)- (1()-toyabnl3 4pprdy)poy]aio4oo2 te trahydro-l 5 -benzo thia zepine-5 -acetic acid -dihydrobromide as obtained in Example 72, and 65.2 mg of triethylamnine is added to the solution. A solution of 23 mng of benzoyl chloride in 2 wi. of ethyl acetate is added dropwise to the mixture under ice-cooling with stirring over the period of 2 minutes.

The reaction solution is stirred at room temperature for mainutes, and 20 mR. of petroleum ether is added, followed by extracting 6 times with 20 mt of saturated aqueous sodium hydrogencarbonate solution. The aqueous iayer is made weakly acidified with hydrochloric acid, and extracted three times with 30 m2.

of dichLoromethane. The extract is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resiilting oily material is dissolved in 1 mt of ethyl acetate, and 0.3 inS of SN hydrogen chloride-ethyl acetate solution is added to the solution, which is then ,diluted with ethyl ether. The deposited precipitate is washed with ethyl ether and dried to give 28 mng of 3 -(C3 (-benzoyl-4 -piperidyl) -ethoxycarny lp ropyJI.

taiino- 4 -oxo-2, 3 4 -tatrahydro-1, 5-benzothiazepine-5 -acetic acid-hydrochloride as a col.Drless powder.

Elemental analysis, for C29H35N 3 0 6

S*HCI.H

2 0 Calcd.; C, 57.27; H, 6.30; N, 6.91 Found 56.98; H, 5.99; N, 7.01 57 Example 78 In the same manner as Example 77, 0.12 g of 3CR)-fl(S)ethoxycarbonyl-3-(4-piperidyl)propyllamino-4-oxo-2,3,4,5tetrahydro-l, 5-benzo thiazepine- 5 -acetic acid -dihydrobromide as obtained in Example 72 is reacted with acetyl chloride to give 77 mg of 3(R)-(3-(l--acetyl-4-piperidyl)--l(S)-ethoxycarbonylpropyl] amino-.4-oxo-2, 3, 4, 5-tetrahydro-l, acid -hydrochloride as a colorless powder.

a1-970 in methanol) E~xa-mple 79 In 5 ml. of ethanol is dissolved 60 mg of ethyl 3(R)-CS-amino- 1-ethoxycarbonylpentyl) amino-4-oxo-2, 3, 4 ,5-tetrahydro-1 -acetate dihydrochloride, and 0.5 g of aqueous glutaraldehyde solution and 0.3 g of sodium cyanoborohydride are added to the soltition, followed by stirring at room temperature for 2 hours. Water C50 niL) is added to the t~reatio. solu Lion, followed by adding sodium chloride to saturate the solution. The solution is extracted twice with 30 mt of' ~,ethyl acetate,.tand the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is dissolved in a small amount of ethyl ether, and 0.2 mL of SN hydrogen chlorideethyl acetate solution is added to the solution to give 50 mg of ethy. (l-ethoxycarbonyl-5-piperidi.nopentyl) amino-4oxo-2 ,3,4 ,5-tetrahyciro- chloride as a colorless powder.

In a mixture of l,'mt of methanol and g o 4-oxo-2, 3, 4,5-tetrahydro-l, dihydrochloride as obtained in Example 79, and the solution is allowed to stand at room temperature for 1 hour. After methanol is evaporated off under reduced pressure, 2 ml of water and 0.5 ml of acetic acid are adden' to the residue, 1-a 2 6 ?jiiCOx 2 s 1670 mixture of diastereomerS -58 followed by purification by Amberlite KAD-2 column chromatography (acetone:water The eluate is concentrated under reduced pressure, and the residue is lyophilized to give 17 mg of 3(R)-(l-carboxy--5-piperidinopentyl)amino-4--oxo-2,3,4,5acid as a colorless powder.+ SIMS spectrum 450 (Mlii addition of KI: 488 (M+K) Example 81 In 10 mt of ethanol is dissolved 0.4 g of amino-i (5)-ethoxycarbonylpentyl] amino-4-oxo-2,3,4 ,S-tetrahydro- I 1 ,5-benzothiazepine-5-acetic acid -dihydrochloride as obtained in Example 58, and 1.2 g of aqueous glutaraldehyde solution and 0.4 g of sodium cyanoborohydride are added to the solution, followed by stirring at room temperature for 1 hour.

Water (50 is added to the mixture, which is made acidic with I-N hydrochloric acid and extracted twice with 30 raZ 6f ethyl acetate. The aqueous layer is neutralized with sodium hydrogencarbonate, and extracted twice with 30 r4. of ethyl acetate. The aqueous layer is purified by Amberlite )AD-2 clL=r chromatography Cacetone:water and the eluent is..

it concentrated under reduced pressure and lyophilized to give 9 1 t L0.3 g of 3 -ethoxycarbonyl-5-piperidinopentylI amino- 4-oxo-2,3, 4, 5-tetrahydro-l, 5-benzothiazepine-5-acetic acid as a colorless powder.

(OL]D-

1 3 9 0 in methanol) if SIMS spectrum 478 (MH d Elemental analysis, for C 24

H

3 5

N

3 0 5 Calcd.: C, 58.16; H, 7.53; N, 8.49 Found 58.1:7; H, 7.55; N, 8.52 Example 82 In 5 mt of water is dissolved 0. 23 g of 3 ethoxycarbonyl-5-piperidinopentyllamino-4-oxo-2. 3,4,5-eta hydro-1,5-benzothiazepine-5.-acetic acid as obtained in Example 81, and 4 mt of 1N aqueous sodium hydroxide solution is added to the solution, followed by allowing the mixture to stand at room tmeperature for 1.5 hours. Acetic acid lmt.) -59 is added to the reaction solution, which then purified by Amberlite XAD-2 column chromatography to give a colorless powder. This product is dissolved in methanol., and the solution is concentrated under reduced pressure to give an agar-like material. The material is treated with 5 mL of ethanol and collected by filtration to gove 0.09 g of 3C(R) S) -carboxy-5-piperidinopentyl] amino-4-oxo-2, 3,4, acid as a colorless powder.

(olD -ll7* in methanol) SIMS spectrum 450 (MH+) Example 83 A 1.8 g quantity of tert-butyl 3(R)-f 1-ethoxycarbonyl- 3-phthalimidopropyl] amino-4 -oxo-2, 3, 4 ,5-tetrahydro-l, as obtiined in Example 44 is separated and purified by silica-gel column chromatography (hexane: ethyl acetate 2:1) -to give from the first fraction 0.8 g of tert-butyl 3 (1 ethoxycarbonyl--3-phthalimidopropyl] amino-4-oxo- 2, 3, 4, 5-tetrahydro -1,S5-ben zo thia zepine-5-acetate is obtained as a colorless oily material.

I neat 1l IR cm 3320(NH), 1770, 1740, 1710, 1670(C0O) (oD1 42 in methanol) From the second fraction, 0.9 g of tert-butyl ethoxycarbonyl-3-phthalimidopropyl] anino-4 -oxo-2, 3, 4, hydro-l, 5 -benzothia zepine--5-acetate is obtained as a colorless #At oily material.

IR mna cm 3330(NH), 1770, 1740, 1720, 6(CO D l 34* (c=0.

4 in methanol) Ex'ample 84 In hydrogen chloride-ethyl acetate solution (SN, 5 znL) is dissolved 0.2 g of tert-butyl 3(R)-(l(S)-ethoxycarbonyl-3phhliiopoy.aio--x-234,-erSyro15benzo-a room temperature for 4 hours. Petroleum ether (100 mt) is added to the reaction solution, and the deposited precipitate is collected by filtration to give 0.18 g of 3(R)-(l(S)-ethoxycarbonyl-3 -ph thalimidopropyl Iamino -4-oxo--2, 34,5-tetrahydro- -benzothia zepine-5-ace tic acid-hydrochloride as a-colorless powder.

IO2* in methanol) Example In the same manner as Example 39, 2 g of tert-butyl 3 -amino -4 -oxo-2, 3, 4,5-tetrahydro-1, 5-benzo thiazepine-5 acetate is reacted with 7.1 g of 2-bromo-ll-phthalimidoundecanate.

The resulting product is separated and purified by silica-gel column chromatography (hexane:ethyl acetate to give from the first fraction 1.2 g of tert-butyl 3CR)-fl(R)-ethoxycarbonylimidodecyl I amino-4 -oxo-2, 3, 4, 5-tetra-hyiro-l, 5 -ben zo I thiazepine-5-acetate as a c6lorless oily material.

IR Vnat cm 1 3320(M{), 1770, 1740, 1710, 1680(C0O) [a 1 D -1040 in methanol) From the second fraction, there is obtained 1.2 g of tert- I butyl (l(S)-ethoxycarbonyl-1O-phthalimidodecyllamino-4oxo-2..3,4,5-tetrahydro-l,5-benzothiazepine-5-acetate as a colorless oily material.

IR Vneat 71l: 3320(NH), 1770, 1740, 1710, 1670(C-0) may, t t 1130 in methanol) A Example 86 In the same manner as Example 84, 0.25 g of tert-butyl 3 (I CS) -ethoxycarbonyl-l0-phthalinidodecyl]I axaino-4-oxo- 2,3, 4, 5-tetrahydro-l, 5-benzothiazepine--5-acetate as obtained in Example 85 is treated with hydrogen chloride-ethyl acetate solution (SN) to give 0.23 g of 3(R)-(l(S)-ethoxycarbonyl-10phthalimidodecyllamino-4-oxo-2,3,4 thia zepine-5 -acetic ac fd'hydrochloride as a colorless powder.

fa]D-1 0 l@ in methanol) Example 87 'P A mixture of 0.4 g of tert-butyl 3 -amino-4-oxo-2,3,4, 5-tetrahydro-l, acetate, I g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl) 2-chlorobutyrate, 0.2 g of triethylamine, .0:9 a of potassium iodide and 50 ml of acetonitrile is heated under reflux for acetate. The extract is washed witn a small. amounlu u w dried over anhydrous magnesium sulfate and concentrated under -61- 2 days. After cooling, the reaction solution is concentrated under reduced pressure, and the residue is purified by silicagel column chromatography (hexane:ethyl acetate 2:1) to give 0.15 g of tert-butyl 3(R)-[3-(l-benzyloxycarbonyl-4piperidyl) -1 -ethoxycarbonylpropyl amino-4-oxo-2,3,4,5tetrahydro-1,5-benzothiazepine-5-acetate and 0.25 g of tertbutyl 3(R)-[3-(l-benzyloxycarbonyl-4-piperidyl)-l(S)-ethoxycarbonylpropyl] amino-4-oxy-2,3,4,5-tetrahydro-1,5-benzothiazepineas a colorless oily material, respectively.

Example 88 In 30 mi of ethanol is dissolved 2.1 g of tert-butyl 3 (R)-amino-4-oxo-2,3,4,5-tetrahydro-, acetate, and 0.4 g of acetic acid, 2.5 g of ethyl oxycarbonyl-4-piperidyl)-2-oxovalerate and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 20 minutes,, and a solution of 0.4 g of sodium cyanoborohydride in 50 mi of ethanol is added S dropwise to the mixture at roan temperature with stirring over the period of 3 hours. The reaction solution is allowed to stand at room temperature overnight, and concentrated under reduced pressure, and 300 m£ of water and 300 mt of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 'Ethyl acetate (20 ml) and 2 g of oxalic acid are added to the residue, and the mixture is shaken thoroughly and admixed with 300 ml of petroleum ether, followed by allowing the mixture to stand. The solution portion is removed by decantation, and 100 mt of water and 200 mt of ethyl acetate are added to the precipitate portion, followed by adding excess S sodium hydrogencarbonate to conduct: neutralization. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily material.

This product is separated and purified by silica-gel column chromatography (hexane:ethyl acetate 2:1) to give from the first fracticn 0.4 9 of tert-butyl 3(R)-(4-(l-benzyloxycarbonyL-4- 54 R S I 128* Example To 4 mL of IN aqueous sodium hydroxide solution is added 0.2 g of -62 piperidyl)-1(R)-ethoxycarbonylbutyllamino-4-oxo2,3,4,5-tetraas a colorless oily material.

IR vneacm~l 33l0(NH) 1730, 1680(C=O).

max+ Mass spectrum 653 (M From the subsequent fraction there is obtained 0.8 g of tert-butyl 3 -[4-(l-benzyloxycarbonyl-4-piperidyll-l CS) ethoxycarbonylbutyllaxnino-4-oxo-2,3, 4,5-tetrahvdro-l,5-benzo- -acetate as a colorless oily material.

IR neacm~l 3320 1730, 1690(C=O):.

Mass spectrum 653 CM Example 89 In 2 mR. of acetic acid is dissolved 0.4 g of tert-butyl 3 (1l-ben zyloxycarbo nyl 4-piper idyl) -1 -ethoxycarbonylbutyl] amino-4-oxo-2,3,4, 5-tetrahydro-l, acetate, and 2 mI. of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether m.Z) is added to the reaction solution, which is then V allowed to stand. The supernatant is decanted, and the precipitate is washed with ethyl ether and dried to give 0.4 g of 3(R)-(lJ(R}-ethoxycarbonyl-4-(4-piperidyl)butyl] amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiaiepine-5-acetic acid-dihydrobromide as a colorless powder.

Elemental analysis, for C 23

H

33

N

3 0 5 S'2HBr-2H 2

O

Calcd.: C, 41.76; H, 5.94; N, 6.35 Found 42.07; H, 6.16; N, 6.09 D-1110 (in methanol) Mass spectrum I63 (M) Example In 2 niL of acetic acid is dissolved 0.8 g of tert-butyl 3 (1 -benzyloxycarbonyl 4-piper idyl) -1 -ethoxycarbonylbutyljamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate, and 3 mL of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1. 5 hours.

-63 Ethyl ether (50 mi) is added to the reaction solution, which is then allowed to stand, The supernatant is decanted, and the precipitate is washed with ethyl etherand dried o give 0.75 g of 3(R)-iI(S)-ethoxycarbonyl-4-(4-piperidyl)butyljamino-4 -oxo-2 5-tetrahydro- acid-dihydrobromide as a colorless powder.

Elemental analysis, for C23,H 3 3 N305S*2HBrK3/2H 2

O

Calcd.: C, 42.34; H, 5.87; N, 6.44 Found 42.35; H, 6.03; N, 6.12 -890 (in methanol)

D

Mass spectrum 463 (M+ Example 91 in 12 mR. of 1,4I aqueous sodium hydroxide solution is Vt dissolved 0.5 g of 3(R) -ethoxycarbonyl-4-C4-piperidyl) butyl] amino-4 -oxo- 2 3,4 ,5-tetrahydro-1, acetic acid dihydrobromide, and the solution is allowed to stand at room temprature for 30 minutes. The solution is neutralized with 2 ml2 of acetic acid, and purified by MCI-gel (CHP 20P, 150 to 300 Mitsubishi Chemical Industries, Japan) column chorinatography (water:methanol The eluent is concentrated under reduced pressure, and the H residue is lyophilized to give 0.3g of [1(S)-carb~oxy-4- (4 -piperidyl) butyli amino-4 -oxo-2, 3,4, 5-tetrahydro-l, acid as a colorless powder.

Elemental analysis, for C 2 lH 2 9

N

3 0 5 S-2H 2 0 Calcd.: C, 53.49; H, 7.05; N, 8.91 Found C, 53.77; H, 7.11; N, 8.96 LI (nD -1170 (in methanol-water) SIMS spectrum 36 (MH+) Example 92 In 30 mt of ethanol is dissolved 3 g of tert-butyl 3 -amino -4-oxo- 2 3, 4, 5-tetrahydro-.l, acetate, and 0.58 g of acetic acid, 4.4 g of ethyl 6-Clbenzyloxycarbonyl -4 -pipe ridyl) 2-oxohexanoa te and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 15 minutes, and 64 a solution of 0.61 g of sodium cyanoborohydride in 50 mt of ethanol is added dropwise to the mixture at room temperature with stirring over the period of 3 hours.

The reaction is allowed to stand at room temperature overnight and then concentrated under reduced pressure, and 100 mL of water and 200 mt of ethyl acetate are added to the residue, followed by shaking thoroughly. The insoluble matter is removed by filtration, and the ethyl acetate layer is washed with 10 aqueous phosphoric acid solution, 0.1N aqueous sodium hydroxide solution and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by silica-gel column chromatography (hexane:ethyl acetate 2:1) to give from the first fraction 0.45 g of tert-butyl 3CR)- (l-benzyloxycarbonyl-4-piperidyl) -1 (Ri -ethoxycarbonylpentyl] amino-4 -oxo-2,3,4, 5-tetrahydro-l, 5-benzothiazepine-5-acetate as a colorless oily material.

IR neatcm 3330(NH), 1740, 1700(C=0).

max Mass spectrum 667 (M From the subsequent fraction, 0.8 g of tert-butyl 3(R)- [5-(l-benzyloxycarbonyl-4-piperidyl) -l(S)-ethoxycarbonylpentyl] amino-4 -oxo-2,3,4,5-tetrahydro-l, 5-benzothiazepine-5-acetate is obtained as a colorless oily material.

IR uneat cm- 1 3320(NH), 1740, 1690(C=0) max Mass spectrum 667 (M Example 93 In 1 mi of acetic acid is dissolved 0.45 g of tert butyl 3(R)-(5-(l-benzyloxycarbonyl-4-piperidyl)-l(R)-ethoxycarbonylpentyl]amino-4-'oxo-2,3,4,5-tetrahydro-, 5-benzothiazepine- 5-acetate, and 1 mt of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 mi) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is washed with ethyl ether and dried to give 0.3 g of 3(R)-[((R)-ethoxycarbonyl-5-(4-piperidyl)pentyllaminoacid -d Elem Mass butyl carbony is adde to stan C200 ml to stan .O is wash, -el .4 .1 o tetrahy( as a col [a]D a Mass S

I

dissolve S. pentyl)a S acetic a S stand at is neutr.

MCI gel eluent i: S is lyophj piperidy thiazepir Element Ca Fo t 0: t 1 I 65 amino-4--oxo-2,3,4,5-tetrahydro-I,5-benzothiiazepine-5-acetic acid-dihydrobromide as a colorless powder.

Elemental analysis, for C 24 ff 35

N

3 0 5 S-2IHr-f 2

O

Calcd. C, 43.85; 11, 5.98; N, 6.39 Found 43.95; If, 6.29; N, *6.47 faj 0 -108 0 (in methanol) mass spectrum 477 Example 94 In 1 m4g of acetic acid is dissolved 0.75 g of tertbutyl 3(R)-f5-(l-benzyloxycarbonyl-4-piperidyl)-l(S)--ethoxvcarbonylpen tylI Iamino -4-oxo-2, 3 4,5-"tetrahydro-1 5 -ben zothiaze.pineand 2 mi. of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether C200 mnil is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is washed with ethyl ether and dried to give 0.6 g of 3(R)- -e thoxycarbonyl -5 -pi peridyl) pentyll amino -4 -oxo-2, 3,4 00 OP 0 tetrahydro-l,S-benzothiazepine-5-acetic acid-dihydrobromide as a colorless powder.

La3D -890 (in methanol) oMass spectrum 477 (M Example In 10 mt of 1N aqueous sodium hdyroxide solution is dissolved 0.45 g of 3(R)-(l(S)-ethoxycarbonyl-5-.(4-piperidyl)pentyllaxino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5acetic acid-dihydrobromide, and the solution is allowed to stand at room temperature for 30 minutes. The reaction solution is neutralized with 2 ml. of acetic acid and purified by MCI gel column chromatography (water:methanol 2:1) The eluent is concentrated under reduced pressure and the residule is lyophilized to give 0.3 g of 3(R)-(1(S)-carboxy-5-(4piperidyl) pentyl Jamino-4-oxo-2, 3 4 5-tetrahydro-1, acid as a colorless powder.

Elemental analysis, for C 22 1 3

IN

3 0 5 S-2" 2 0 Calcd. 54.42; If, 7.27; N, 8.66 Found C, 54.84; H, 7.38; N, 8.61 66 c[]0-131° (in methanol-water) SIMS spectrum 450 (M Example 96 In 30 mi of ethanol is dissolved 2.5 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5acetate, and 0.5 g of acetic acid, 3.2 g of ethyl 7-(l-benzyloxycarbonyl-4-piperidyl)-2-oxoheptanoate and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 10 minutes, and a solution of 0.51 g of sodium cyanoborohydride in 50 mi of ethanol is added dropwise to the mixture at room temperature with stirring over the period of 3 hours.

The reaction solution is allowed to stand at room temperature dvernight, and concentrated under reduced pressure, and 5Q.0-m of water and 200 mt of ethyl acetate are added to the residue, followed by shaking thoroughly. The insoluble matter is removed by filtration, and the ethyl acetate layer is washed with 0.1N hydrochloric acid, 0.1N aqueous sodium hydroxide solution and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by silica-gel column chromatography (hexane:ethyl acetate 2:1) to give from the first fraction 0.5 g of tert-butyl benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbony1hexyl]amino- 4-oxo-2,3,4,5-tetrahydro-,5-benzothiazepine-5-acetate as a colorless oily material.

IR neat cm-: 3320(NH), 1730, 1680(C0).

max Mass spectrum :/681 (M From the subsequent fraction, 0.9 g of tert-butyl 3(R)- [6-(l-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]- Samino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate is obtained as a colorless oily material.

IR vneat cm 3330(NH), 1730, 1690(C=0) max Mass spectrum 681 (M Example 97 In 1 ml of acetic acid is dissolved 0.5 g of tart-butyL F~ V- I -67- 3(R)-[6-(l-benzyloxycarbonyl-4-piperidyl)-l(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate, and 2 me of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1 hqur. Ethyl ether (200 mi) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 20 mt of IN aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized by adding 2 ml of acetic.-.acid, and purified by MCI-gel column chromatography (water:methanol The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.23 g o° of 3(R)-[1(R)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5- 0 O0 *o tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless s powder.

[a]D -144" in water) Example 98 In 1 me of ace-ic acid is dissolved 0.9 g of tert-butyl (6-(-benzyloxycarbonyl-4-piperidyl) -(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate, and 2 mi of 30 hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture I to stand at room temperature for 1.5 hours. Ethyl ether (200 mi) is added to the reaction solution, which is then allowed to stand. The supenatant liquid is decanted, and the precipitate is dissolved in 30 mt of IN aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized by adding 3 mi of acetic acid, and purified by MCI-gel chromatography S(water:methanol The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.43 g of 3(R) -l(S)-carboxy-6-(4-piperidyl)hexyl amino-4-oxo-2,3,4,5tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.

(nID -121* (in water)

I-

68- SIMS spectrum 464 (MH1+) Example 99 In 30 m- of ethanol is dissolved 2 g of tert-butyl 3(R)-amino-4-oxo- 2 5-tetrahyd.ro-1,5-benzothiazepine-5acetate, and 0.47 g of acetic acid, 3 g of ethyl 8-(l-benzyloxycarbonyl-4-piperidyl)-2-oxooctanoate and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 10 minutes, and a solution of 0.45 g of sodium cyanoborohydride in 40 ml of ethanol is added to the mixture at room temperature with stirring over the period of 3 hours.

The reaction solution is allowed to stand at room temperature overnight, and then concentrated under redcued pressure, and 1l0 mt of water and 200 mi of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residde is separated and S* purified by silica-gel column chromatography (hexane:ethyl acetate 3:1 to 2:1) to give 0.3 g of tert-butyl (l-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonyheptyll amino-4-oxo-2,3,4,5 7 tetrahydro-1,5-benzothiazepine-5-acetate Sas a colorless oily material.

a c neat -I 'IR mnax cm 3320(N-H), 1730, 1690(C=0).

IR Vmax Mass spectrum 695(M Example 100 In 1.5 mi of acetic acid is dissolved 0.3 g of tertbutyl 3(R)-[7-(l-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl ]amino-4-oxo-2,3,4,5-tetrahydro-l, and 1 m of 30 hydrogen-bromide acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 0.5 hour.

Ethyl ether (80 mi) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 10 mt of IN aqueous sodium hydroxide solution, followed by allowing the solution to stand -69at room temperature for 30 minutes. The solution is neutralized with 2 mi of acetic acid, and purified by XAD-2 column chromatography (water:methanol The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.1 g of 3(R)-(l(S)-carboxy-7-(4-piperidyl)heptyl]amino- 4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5-acetic acid as a colorless powder.

a [ID- 116 (in water) SIMS spectrum 478 (MH Example 101 A mixture consisting of 25 g of isonitotine aldehyde, 82 g of ethyl (triphenylphosphoranilidene)acetate and 300 me of toluene is stirred at 100 0 C for 3 hours. After cooling, the deposited crystals are removed by filtration, and the filtrate is concentrated under reduced pressure. A mixture of ethyl acetate and petorleum ether 400 mt) is added to the residue, and the mixture is extracted with 500 mt of 5% hydrochloric acid. The aqueous solution portion S is extracted with 50 mZ of ethyl acetate, followed by neutralization with potassium carbonate and cooling. The deposited crystals are collected by filtration and dried to give 34 g of 3-(4-pyridyl)acrylate as colorless prisms.

m.p. 64-660C.

Example 102 In 300 mi of acetic acid is dissolved 28 g of ethyl 3-(4-pyridyl)acrylate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using 1 g of platinum oxide as a catalyst. After absorption Sof hydrogen stops, the patalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. Water (500 mi) and 300 mL of ethyl acetate are added to the residue, and sodium hydrogencarbonate is added to the mixture under sfirring until no foaming is observed. Benzyloxycarbonyl chloride (5 mi) is added to the resulting mixture, followed by stirring at room temperature for 1 hour, and mi oi benzyloxycarbonyl chloride is further added. Sodium hydrogencarbonate (30 mg) is added portionwise to the reaction solution at room temperature with stirring, and after the mixture is stirred at room temperature for 2 hours, the ethyl acetate layer is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silicagel column chromatography (hexane:ethyl acetate 2:1) to give 37 g of ethyl 3-(l-benzyloxycarbonyl-4-piperidyl)propionate as a colorless oily material.

neat -1 IR va cm 1730, 1700(C=0) max Examole 103 In 30 m£ of ethanol is dissolved 17 g of ethyl 4-(1benzyloxycarbonyl-4-piperidyl)-2-oxobutyrate, and 4.5 g of acetic acid is added to the solution. Sodium cyanoborohydride (3 g) is added to the mixture at room temperature with stirring, followed by stirfing at room temperature for t 3 hours, and 500 m of water is added to the reaction mixture, which is extracted with methylene chloride. The extract is Sdried over anhydrous magnesium sulfate and concentrated under S reduced pressure, and the resulting residue is purified by silica-gel column chromatography (hexane:ehhyl acetate 2:1 to 1:1) to give 11.5 g of ethyl 4-(l-benzyloxycarbonyl-4piperidyl)-2-hydroxybutyrate as a colorless oily material.

I r .IR vneatcm-: 3430(OH), 1730, 1690(CO).

max NMR spectrum (in CDC13+D20) 7.3(5H), 5.1(2H), 3.9-4.4 (5H) 2.5-3.1 2H) 1.0-2.0(12H) Stc Example 104 SIn a mixture of 200 mL of ethyl acetate and 12 g of pyridine is dissolved 11.5 g of ethyl 4-(l-benzylt, oxycarbonyl-4-piperidyl)-2-hydroxybutyrate, and 5 mt of thionyl chloride is added to the solution, followed by refluxing with .stirring for 1 hour. After cooling, 500 mt of water and 100 mt of ethyl acetate are added to the reaction solution, followed by extraction. The extract is washed with 0.1N hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and treated with activated carbon. The ethyl acetate is evaporated i; :L IiY-l..-l..li i -71 off to give 10.5 g of ethyl 4-(l-benzyloxycarbonyl-4-piperidyl)- 2-chlorobutyrate pale yellow oil.

neat -1 IR v cm 1740, 1690(C=0) max Example 105 In 20 mi of ethanol is dissolved 10.5 g of ethyl 4-(1benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmosphereic pressure using 5 g of 10 palladium-carbon in water as a catalyst. After absorption of hydrogen stops, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give ethyl 4-(4-piperidyl)butyrate. This product is dissolved in a mixture i of 200 mi of ethyl acetate and 100 ml of i water, 6 g of sodium hydrogencarbonate is added to the solution, followed by stirring at room temperature. Benzyloxycarbonyl chloride (6 mi) is added dropwise to the mixture, and after the addition is completed, the mixture is stirred at rom teparature for hours. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica-gel column chromatography (hexane:ethyl acetate 3:1) to give 5.3 g of ethyl 4-(l-benzyloxycarbonyl-4-piperidyl)butyrate as a colorless oily material.

neat -1 IR v cm 1730, 1700(C=0) max Example 106 In 10 mL of ethanol is dissolved 0.48 g of sodium, and 5.3 g of ethyl 4-(l-benzyloxycarbonyl-4-piperidyl)butyrate and 2.8 g of diethyl oxalate are added to the solution, followed by evaporation under reduced pressure at 60 to 70°C to remove the low-boiling substance. After cooling, the resulting brown viscous material is treated with 300 ml of water, and the mixture is made acidic with IN hydrochloric acid and extracted twice with 100 mi of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dimethylsulfoxide (45 mi), 5 mi of water and 0.8 g of lithium chloride are added to the resulting oily material, -72and the mixture is stirred at 135 to 140*C for 1.5 hours and further at 140 to 145°C for 30 minutes. After cooling, 500 mt of water is added to the reaction solution, and the mixture is extracted with 300 m of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl carbonyl-4-piperidyl)-2-oxovalerate as an oily material.

neat -1 IR v cnm 1730, 1700(C=0) max Mass spectrum 361 (M Example 107 A solution of 84 g of 3-(4-piperidyl )propanol and 65 g of triethylamine in 100 m of methylene i t chloride, simultaneously with 100 g of benzyloxycarbonyl I chloride, is added dropwise to a mixture S I of 400 mt of methylene chloride and 40 mz of water at room temperature with stirring over the-period of 45 minutes. After S the addition is completed, the reaction solution is stirred Sat room temperature for 1 hour. The methylene chloride layer is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.tThe resulting I oily material is distilled under vacuo to remove i the fraction of b.p. 50 to 60*C/5 mmHg, to give S110 g of 3-(l-benzyloxycarbonyl-4-piperidyl) as pale ,t yellow oil.

IR vneatcm-: 3400(OH), 1680(C=0) max t mx Example 108 A mixture of 110 g of 3-(1benzyloxycarbonyl-4-piperidyl)propanol and 500 mi of pyridine is stirred under ice-coolir, and 100 g of tosyl chloride is added portionwise to the mixture over the period of 2 hours. The reaction solution is further stirred under ice-cooling for 1 hour, and 1 tof ice cold water is added dropwise to the solution.

Successively, 500 mi of cone. hydrochloric acid is added dropwise to the reaction mixture under ice-cooling, followed by extraction with 1 tof ethyl acetate. The extract is washed with dilute hydrochloric acid and water successively, dried I S73 over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethanol is added to the resulting oily material, and the mixture is allowed to stand to give 99 g of 3-(l-benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate as colorless crystals, melting at 59-60 0

C.

Elemental analysis, for C 23

H

2 9

NO

5

S

Calcd.: C, 64.01; H, 6.77; N, 3.25 Found C, 64.25; H, 6.78; N, 3.26 Example 109 In 300 mL of ethanol is dissolved 5.8 g of sodium, and g of diethyl malonate is added to the solution, followed by stirring. 3-(l-Benzyloxycarbonyl-4-piperidyl)propyl ptoluenesulfonate (90.5 g) is added to this mixture followed by refluxing with stirring for 2 hours. After cooling, 1 1 of water is added to the reaction solution, which is then extracted with 500 mi of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 5-(l-benzyl.oxycarbonyl-4-piperidy)- .t 2-ethoxycarbonylvalearate as an oily material. This product is dissolved in 200 ml of ethanol, and a solution of 34 g of sodium hydroxide in 200 mi of water is added dropwise to the solution with stirring. After the addition is completed, 300 mi of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1:1, 300 ml). The aqeuous layer is made acidic with cone. hydro- S chlori acid,. followed by extraction with 500 mt of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-(l-benzyloxycarbonyl-4-piperidyl- 2-carboxyvaleric acid as an oily material. This product is heated at 160 to 170°C with stirring for 45 minutes to give 50 g of carbonyl-4-piperidyl)valeric acid as an oily material.

IR vneat cm 1730, 1700(CO) max Example 110 A mixture of 54.8 g of oxycarbonyl-4-piperidyl)valeric acid, 29 g of sodium hydrogen- -74carbonate, 21 mt of ethyl iodide and 150 mi of N,N-dimethylformamide is heated at 70 to 80°C with stirring for 3 hours.

Ethyl iodide (10 mi) is additionally added to the reaction solution, followed by heating at 90 to 100 0 C for 3 hours.

After cooling, 1 t of water is added to the reaction solution, and the mixture is extracted with 1 t of ethyl acetate. The extract is washed with water, IN hydrochloric acid and dilute aqueous sodium hydrogencarbonate solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 58 g of ethyl (l-benzyloxycarbonyl-4-piperidyl)valerate as pale yellow oil.

neat -1 IR v cm 1730, 1700(C=0) max NMR spectrum (in CDC1 3 7.3(5H), 5.1(2H), 3.9-4.4(4H), 2.5-3.1(2H), 2.1-2.5(2H), 1.0-1.9(14H) Example 111 In 50 m£ of ethanol is dissolved 2.2 g of sodium, and g of ethyl 5-(l-benzyloxycarbonyl-4-piperidyl)valerate and 14 g of diethyl oxalate are added to the solution, followed by evaporation under reduced pressure at 60 0 C for 1 hour and at 60 to 70°C for 30 minutes to remove a low boiling substance.

After cooling, 500 mi of water is added to the resulting brown viscous material, and the mixture is made acidic with hydrochloric acid and extracted with 300 mt of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dimethylsulfoxide (150 mi), 15 mi of water and 5 g of lithium chloride are added to the resulting oily material, followed by stirring at 150 to 155 0 C for minutes. After cooling, 500 mt of water is added to the reaction, and the mixture is extracted with 300 mt of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 26 g of ethyl 6-(l-benzyloxycarbonyl-4-piperidyl) -2-oxohexanoate as an oily material.

IR vneat cm 1730, 1690(C-0)' max Mass spectrum 375 (M Example 112 In 40 mt of ethanol is dissolved 26 g of ethyl 6-(1benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate, and 6.2 g of acetic acid is added to the solution. Sodium cyanoborohydride (4.4 g) is added to the mixture under ice-cooling, and the mixture is stirred for 1 hour and allowed to stand at room temperature overnight. Water (500 mt) is added to the reaction solution, followed by extraction with methylene chloride.

The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown viscous material is purified by silica-gel column chromatography (hexane:ethyl acetate 2:1) to give 16 g of ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate as a colorless oily material.

neat -l IR veacm-: 3450(OH), 1730, 1690(C=0) max Example 113 In a mixture of 120 mL of ethyl acetate and 13 g of pyridine is dissolved 12.8 g of ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate, and 5.1 mt of thionyl chloride is added to the solution, followed by refluxing with stirring for 45 minutes. After cooling, 500 mt of water and 200 mt of ethyl acetate are added to the reaction solution, and extraction is carried out. The extract is washed with 0.1N hydrochloric acid and water successively,..dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The resulting oily material is purified by silica gel column chromatography (hexane:ethyl acetate 4:1) to give 10 g of ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate as a colorless oily maferial.

IR vneatcm-1: 1740, 1690(C=0) max Example 114 In 200 mL of ethanol .is dissolved 10 g of ethyl 6- (l-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using Sg of 10% palladiumcarbon 50 I in water as a catalyst. After absorption of hydrogen stoos, the catalyst is removed by filtration, and -76the filtrate is concentrated under reduced pressure to give ethyl 6-(4-piperidyl)hexanoate. Water (100 mt) and 200 me of ethyl acetate are added to this-product, and 10 g of sodium hydrogencarbonate is added to the mixture, followed by stirring. Benzyloxycarbonyl chloride (7.2 mi) is added dropwise to the mixture at room temperature, followed by stirring overnight. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica-gel column chromatography (hexane:ethyl acetate 4:1) to give 7.7 g of ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)hexanoate as a colorless oily material.

neat -1 IR v cm 1730, 1690(C=0) max Example 115 In 20 mt of ethanol is dissolved 0.56 g of sodium, and 7.3 g of ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)hexanoate and 3.5 g of diethyl oxalate are added to the solution, followed by evaporation under reduced pressure at 60 to 70°C for minutes and at 75"C for 20 minutes to remove a low-boiling substance. After cooling, 100 mi of water is added to the resulting brown viscous material, and the-~mixture is made acidic with hydrochloric acid and extracted with 300 mt of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dimethylsulfoxide mt), 5 mt of water and 1.5 g of lithium chloride are added to the resulting oily material, followed by stirring at 140 to 160'C for 40 minutes. After cooling, 300 mt of water is added to the reaction solution, which is then extracted with 1 300 -m of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6.5 g of ethyl 7 (l-benzyloxycarbonyl-4-piperidyl)-2oxoheptanoate as an oily material.

neat -1 IR v acm 1720, 1690(C0) max Mass spectrum 389 (M Example 116 rn 200 m4 of tetrahydrofuran is dissolved 26.3 g of -77 ethyl 5-(l-benzyloxycarbonyl-4-piperidyl)valerate, and 13.4 g of sodium borohydride is added to the solution. Methanol mi) is added dropwise to the mixture at 70 to with stirring over the period of 1.5 hours, and after the addition is completed, refluxing is effected for another 2 hours. The reaction solution is concentrated under reduced pressure, and 300 m£ of water is added to the residue, followed by extraction with 300 mi of ethyl acetate. The extract is washed with 50 mi of IN hydrochloric acid and 50 m£ of water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 23 g of 5-(1benzyloxycarbonyl-4-piperidyl)pentanol as a colorless oily material.

IR vueat cm- 1 3400(OH), 1690(C=0) max NMR spectrum (in CDC1 3 7.3(5H), 5.1(2H), 3.9-4.4(2E), 3.5-3.8(2H), 2.4-3.0(3H), 1.0-1.9(13H) Example 117 A mixture of 18 g of 5-(l-benzyloxycarbonyl-4-piperidy)pentanol and 150 mt of pyridine is stirred under ice-cooling, and 14.6 g of tosyl chloride is added portionwise to the mixture over the period of 30 minutes. After stirring for another 1 hour under ice-cooling, 2 mi of ice-cold water is added dropwise. 2thyl acetate (500 ml) is added to the reaction solution, which is then washed with 500' m of.

2N-hydrochloric acid and 500 ml of IN hydrochloric acid successively, further with dilute aqueous sodium hydrogencarbonate solution and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material. is purified by silica-gel column chromatography to give 18 g c F 5-(l-benzyloxycarbonyl-4piperidyl)pentyl p-toluenesulfonate as an oily material.

IR n e a t cm-l: 1700(C=0) max Example 118 In 80 mi of ethanol is dissolved 0.95 g of sodium, and 7.2 g of diethyl malonate is added to the solution, followed by stirring. 5- (-Benzyloxycarbonyl-4-piperidyl)mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 mt) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is washed with ethyl ether and dried to give 0.3 g of 3(R)-[1(R)-ethoxycarbonyl-5-(4-piperidyl)pentyll- 78pentyl p-toluenesulfonate (13.7 g) is added to the mixture.

followed by refluxing with stirring for 2 hours. Further, a mixture of 0.25 g of sodium, 25 mi of ethanol and 1.8 g of diethyl malonate is added, and the reaction solution is refluxed with stirring for 2 hours. Ethanol is evaporated off under reduced pressure, and 200 mi of water is added to the residue, which is then extracted with 300 me of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 7-(l-benzyloxycarbonyl-4-piperidyl) -2-ethoxycarbonylheptanoate as an oily material. This product is dissolved in 30 mE of ethanol, and a solution of 6 g of sodium hydroxide in 50 me of water is added dropwise to the solution with stirring. After the addition is completed, 150 mt of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether-:(.l:, 150 The aqueous layer is made acidic ,.th conc. hydrochloric acid and extracted with 300 mt of ethyl acetate, and the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 7 -(l-benzyloxycarbonyl-4-piperidyl) 2-carboxyheptanoic acid as an oily material.This product is heated at 160 to 165*C with stirring for 1 hour, and the resulting oily material is purified by silica-gel column chromatography (hexane:ethyl acetate 3:1 to 1:1) to give 6.4 g of 7-(l-benzyloxycarbonyl-4-piperidyl)heptanoic acid as an oily material.

neat -1 IR vnea t cm 1730, 1710(C0O) max Example 119 A mixture of 6.4 g'of 7-(1benzyloxycarbonyl-4-piperidyl)heptanoic acid, 3.1 g of sodium hydrogencarbonate, 8.6 g of ethyl iodide and 20 mt of N,Ndimethylformamide is heated at 100*C with stirring for 3 hours.

Further, 2.9 g of ethyl iodide and 1 g of sodium hydrogencarbonate are added to the reaction solution, followed by heating at 100*C for 2.5 hours. After cooling, 200 me of water is added to the reaction solution, and the mixture is extracted 79 with 300 mE of ethyl acetate. The extract is washed with water, 0.1N hydrochloric acid,and dilute aqueous sodium hydrogencarbonate solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl 7-(l-benzyloxycarbonyl-4piperidyl)heptanoate as an oily material.

IR v cm: 1730, 1700(C=0) max NMR spectrum (in CDC13)6 7.3(5H), 5.1(2H), 4.0-4.3(4H), 2.5-3.0(2H), 2.1-2.4(2H), 1.0-1.9(18H) Example 120 In 30 mZ of ethanol is dissolved 0.48 g of sodium, and g of ethyl 7-(l-benzyloxycarbonyl-4-piperidyl)heptanoate and 3 g of diethyl oxalate are added to the solution, followed by evaporation udder reduced pressure at 60 to 70 0 C for 1 hour to remove a low-boiling substance. After cooling,.150 mi of water is added to the resulting viscous material, and the mixture is made acidic with hydrochloric acid and extracted with 300 mi of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated unddr reduced pressure. Dimethylsulfoxide (54 mi), 6 mi of water and 1 g of lithium chloride are added to the resulting oily material, followed by stirring at 140*C for 1 hour. After cooling, 150 mi of water is added to the reaction solution, and the mixture is extracted with 300 mi of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6 g of ethyl 8-(1benzyloxycarbonyl-4-piperidyl)-2-oxooctanoate as an oily material.

neat 1 IR vmat cm- .1770, 1700(C=0) max Mass spectrum 403 (M Example 121 c A mixture of 13.2 g of 4-(3,4,5,6-tetrahydro- 2H-pyrane)carbaldehyde, 44 g of ethyl (triphenylphosphoranilidene)acetate and 200 mt of toluene is stirred at 100*C for 3 hours.

Toluene is evaporated off under reduced pressure, and 200 mt of petroleum ether is added. The insoluble matter is removed by filtration, and the filtrate is concentrated under reduced amino-4-oxo-2,3,4, 5-tetrahydro-1., is obtained as a colorless oily material.

IR v etcm- 3330(NH1), -1730, 1690(C=O) max+ Mass 3pectrum 681 (M Example 97 In I m 9 k of acetic acid is dissolved 0.5 g of at-u7 80 .4 04 0 4 4444 04 *4 @4 4 0 *44 0 4.

*404*4 0 04 0 0 4 tL *0 tt 0 4( t~t I.

I I II I.

101110 0 1 pressure. The residue is distilled under vacuum to give 17 g of ethyl 3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)acrylate (bp 122- 1340/16mm~g) as an oily material.

IR v mat cm- 1720(C0O), l650(C=C) NMR (in..CDCl 3 6 6.6-7.1(111), 5.6-6.9(111), 3.7-4.4(4H), 3.2-3.7(2H1). 2.0-2.7(111), 1.1-1.9(7H) Exampl'e 1*22 In 200 ml. of ethanol is dissolved 17 g of ethyl 3- 4,5,6-tetrahycdro-2H-pyran -4-yl)acrylate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using 4 g of 10 palladium-carbon in water) as a catalyst. After absorption of hydrogen stops, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The re-sidue is distilled under vacuum to give l5-.g*.(bp.l2-1-l4'3' /l6mmH4')of ethyl. 3- C3 4,5, §-tetrahydro-21-pyran -4-yl) propionate as an oily-material.

IR Vna cm_ 740(C=O) max NMR (in CDCl 3 6: 3.7-4 .4(4H1), 3.0-3.7C(2H1), 2.1-2.7 (2H), Example 123 A solution of 10.2 mt of oxalyl chloride in 200 mL. of methylene chloride is cooled to -65*C, and a solution of 18.2ml of dimethylsulfoxide in 50 ml. of methylene chloride-is added dropwise over the period of 10 minutes, followed by stirring for 10 minutes. A solution of 14.1 g of 4-thianylmet.'Lnol in 100 ml. of methylene chloride is added dropwise over tlie period of 10 minutes, followed by stirring for 20 minutes, and 74 ml.

of triethylarnine is added dropwise over the perioJ of minutes, followed by stirring for 15 minutes. After a cooling bath is removed. and stirring iseffected at room temperature for 10 minutes, 215 mL of 3N4 hydrochloric acid is added, followed by stirring at room temperature for another 1 hour.

The methylene chloride layer is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to qive 11 Q of 4-thianylcarb3ldeiyde as a 31 iwaer~ecnno -i -LAUct-L reduced pressure, and the residue is .yophilized to give 0.43 9 of -carboxy-6-(4 piperidyl) hexyl Iamn-4ox2,3 tetrahydro-1,5-beflzothiazepine5acetic acid as a colorless powder.

(fl D -l21* (in water) pale yellow liquid.

IRvmax m NMR(in CDC1 3 9.5(lH), 3.0-4.5(lH), 2.5-3.0(4H), 2.5(4H).

Example 124 A mixture of 11 g of 4-thianylcarbaldehyde, 32.3 g of ethyl (triphenylphosphoranilidene)acetate and 200 mt of toluene is stirred at 100 0 C for 4 hours. Toluene is evaporated off under reduced pressure, and 200 ml. of petroleum ether is added. The insoluble matter is remov'ed by filtration, and the filtrate is concentrated under reduced pressure. The residue is distilled under vacuum to give 10.4 g (bp 155- 157C/15ImrHg) of ethyl 3-(4-thianyl)acrylate as an oily material.

ofa ety-1(tianl a cmyae an a70C catalytc rdcio ecto s are Iater) is adde aethol he fiatsollowe by sftirring4t lat c frlone, da. Th catalytis remto e cio by filtrtion C an (C out fritr temipcetrated unde rtopeuc pressure toin gie U 9~1 g ofaethylum-carboian(50 propate as an otlysmteral The~f Ir eatonmixur i tire aOoo(tmprtueQor2 by irti n Nineh5 1014allaium-arbo in -18(H wae)i de nwt h ilrtfloe ysirn tniazepine-a-a''- 1 acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 0.5 hour.

Ethyl ether (80 mt) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, S.and the precipitate is dissolved in 10 mt of IN aqueous sodium Shydroxide solution, followed by allowing the solution to stand 2- Example 126 A mixture of tert-butyl 3(R)-amino-4-oxo- 2 3 tetrahydro-1,5-benzothiazepine-5-acetate (3.0 acetonitrile (100 mt), ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)- 2-chlorohexanoate (4.0 triethylamine (1.0 g) and potassium iodide (1.6 g) is stirred for 3 days at 80 0

C.

Ethyl 6- (l-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate g) and potassium iodide (0.8 g) are added, and the stirring is continued for further 1 day at 80 0 C. The mixture is concentrated in vacuo, diluted with water (100 mi) and extracted with ethyl acetate (300 mt). The extract is washed with water, dried over anhydrous magnesium l sulfate and evaporated in vacuo. Purification of the residual oil by silicagel column chromatography (hexane: ethyl acetate 2:1) gives tert-butyl carbonyl-4-piperidyl) -1 CR) -ethoxycarbonylpentyl'] amino-4oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5-acetate (3.1g) as a colorless oil and tert-butyl 3CR)-15-(1-benzyloxycarbonyl-4-piperidyl) -1(S)-ethoxycarbonylpentyl] amino-4oxo-2,3,4,5-tetrahydro-l,5-benzothiazepine-5-acetate (2.1g) as a colorless oil.

Example 127 To a stirred solution of ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (5 g) in methanol mi) is added dropwise a solution of sodium hydroxide (2.6 g) in water (20 mi) at room temperature. After completing addition, the mixture is stirred for 30 minutes, diluted with water (300 mt) and extracted with ethyl ether mt). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (200 mt) The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 6-(1benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid g) as a colorless oil.

IR v neat cm-: 3400 1670 max and sodium hydrogencarbonate is added to the mixture under stirring until no foaming is observed. Benzyloxycarbonyl chloride (5 mi) is added to the resulting mixture, followed by stirring at room temperature for 1 hour, and mk or benzyloxycarbonyl chloride is further added. Sodium 83- Example 128 To a stirred solution of ethyl 6-(l-benzyloxycarbonyl- 4-piperidyl)-2-hydroxyhexanoate (1.0 g) in pyridine ml) is added dropwise methanesulfonyl chloride (0.92 g) at ice-bath temperature. After stirring for 1 hour at ice-bath temperature, the mixture is stirred for 30 minutes at room temperature, and then cooled. After addition of water (1 mt), the mixture is stirred for 30 minutes at icebath temperature, and ice bath is removed. The mixture is stirred for 30 minutes at room temperature, diluted with water (50 mi) and extracted with ethyl acetate (50 mi).

The extract is washed successively with 10% hydrochloric acid, water, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)- 2-methanesulfonyloxyhexanoate (1.1 g) as a colorless oil.

IR heat cm-l: 1750, 1690 max NMR spectrum (in CDCL 3 7.3 4.9-5.1 (3H), 3.9-4.5 3.1 1.0-3.1 (18H) S Example 129 A mixture of tert-butyl 3 CR).-amino-4-oxo-2,3,4,5- (2.05 g) and ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (1.5 g) is heated at 90*C for 1 day. After S. cooling, ethyl acetate (300 ml) is added to the mixture, and the resulting solution is washed with 5% phosphoric acid solution (30 mi x 2) and water (20 ml) successively.

The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuo to yield an oily residue, which is purified by silicagel column chromatography (hexane: ethyl acetate 2:1) to give tert-butyl carbonyl-4-piperidyl) -1 -ethoxycarbonylpentyl] amino-4oxo-2,3,4,5-tetrahydro-, (0.7 g) as a colorless oil. From the subsequent fraction, tert-butyl 3(R)-(5-(l-benzyloxycarbonyl-4-piperidyl)-1(S)ethoxycarbonylpentyllamino- 4 oxo-2,3,4,5-tetrahydro-l,5- (0.55 g) is obtained as a colorless oil.

stirring for 1 hour. Arter cooling, Duu mt or waur; allu LUu -L Sof ethyl acetate are added to the reaction solution, followed by extraction. The extract is washed with 0.1N hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and treated with activated carbon. The ethyl acetate is evaporated -84 Example 130 6-(l-Benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid (4.7 g) and quinine (4.4 g) are dissolved in hot acetone (150 mit). After removal of the insoluble substance by filtration, the solution is allowed to stand in a refrigerator. The precipitating crystals are collected by filtration and recrystallized three times from acetone to yield quinine salt (1.9 g) as colorless crystals. This salt (1.2 g) is added to a mixture of ethyl acetate (200 mt) and IN hydrochloric acid (50 mi), and the resulting mixture is agitated throughly. The ethyl acetate layer is washed with 1N hydrochloric acid (30 mt, 20 mi) and water successively, dried over anhydrous magnesium sulfate and evaporated in vacuo. To the oily residue (0.6 g) are added toluene (50 mi) ethanol (10 mi) and p-toluenesufonic *I acid (0.05 The resulting mixture is stirred for 3 hours at 100°C, cooled, diluted with ethyl acetate, washed with water (50 mt x 2) and dried over anhydrous magnesium sulfate. Evaporation of the solvent gives ethyl ester (0.5 g) as a colorless oil, which is dissolved in pyridine (5 mi). To the stirred solution is added dropwise methanesulfonyl chloride (0.5 at ice-bath temperature. After stirring for 2 -hours at ice-bath temperature, the mixture is stirred at room temperature for 30 minutes and cooled i again by ice-bath. Water (0.5 m) is added and the mix- S ture is stirred at ice-bath temperature for 30 minutes and then at room temperature for 30 minutes. The mixture is diluted with water (20 mi) and extracted with ethyl acetate mi). The extract is washed by 10% hydrochloric acid, water, 0.1N sodium hydroxide solution and water successively, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)- 2-methanesulfonyloxyhexanoate(0.6 g: [a]D-12.8" in methanol) as a colorless oil. The mixture of this sulfonate (0.5 g) and tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-l,5- (0.71 g) is heated at 80-100*C mixture is made acidic with 1N hydrochloric acid and extracted twice with 100 mt of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dimethylsulfoxide (45 mt), 5 mi of water and 0.8 g of Lithium chloride are added to the resulting oily material, 85 for 1 day. After cooling, ethyl acetate (200 mt) is added, and the resulting solution is washed with 5% phosphoric acid solution (30 mt, 20 mi) and water successively, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield a yellow oil, which is purified by silicagel colum chromatography (hexane: ethyl acetate From the first fraction is obtained tert-butyl 3(R)-[5-C1benzyloxycarbonyl-4-piperidyl-i(R)-ethoxycarbonylpentyl] amino-4-oxo-2,3;4,5-tetrahydro-l,5-benzothiazepine-5acetate (0.45 g) as a colorless oil. From the second fraction, tert-butyl 3(R)-[5-(l-benzyioxycarbonyl-4piperidyl)-l(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5- (0.09 g) is obtained as a colorless oil from the second fraction.

Example 131 6-(l-Benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid (5 g) and cinchonidine (4.2 g) are dissolved in hot acetone (50 mt). After cooling, the solution is diluted with ethyl ether (50 mt) and allowed to stand in a refrigerator. The precipitates are removed by filtration, and the filtrate is concentrated in vacuo. The residue is dissolved in acetone (5 mt) and the resulting solution is diluted with ethyl ether (35 mi). After standing in a refrigerator, the resulting precipitates are collected by filtration to give cinchonidine salt (1.4 This salt (1.3 g) is added to a mixture of ethyl acetate (200 mt) and IN hydrochloric acid (50 mt), and the resulting mixture is agitated throughly. The ethyl acetate layer is washed with IN hydrochloric acid (50 mt) and water (50 mi) successively, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield an oily residue, which is dissolved in a mixture of toluene (30 mt), ethanol (3 mi) and ptoluenesulfonic acid (0.05 The solution is stirred for 1 hour at 90-100 0 C, cooled, diluted with ethyl acetate (200 mt) and washed with water (50 mt x The organic layer is dried over anhydrous magnesium sulfate and solution is further stirred under ice-cooling for 1 hour, and 1 tof ice cold water is added dropwise to the solution.

Successively, 500 mi of cone. hydrochloric acid is added dropwise to the reaction mixture under ice-cooling, followed by extraction with 1 tof ethyl acetate. The extract is washed with dilute hydrochloric acid and water successively, dried S- 6 evaporated in vacuo to yield the ethyl ester as a colorless oil, which is dissolved in pyridine (5 mi). To the stirred solution is added dropwise methanesulfonyl chloride (0.4 mi) at ice-bath temperature. After stirring for 30 minutes, water (1 mi) is added to the mixture, and the resulting mixture is stirred for 30 minutes at ice-bath temperature and diluted with ethyl acetate (150 mi). The organic layer is washed with IN hydrochloric acid (50 mi x sodium bicarbonate solution (50 mt) and water successively, dried over anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 6- Cl-benzyloxycarbonyl-4-piperidyl) -2methanesulfonyloxyhexanoate (0.8 g: [a] D +13.7 in methanol) as a colorless oil. A mixture of this mesylate (0.72 g) and tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-l,5- (1.46 g) is stirred overnight at 90-100°C, After cooling, the reaction mixture is dissolved in ethyl acetate (200 mL) and the solution is washed by 5% phosphoric acid solution (30 mt x 2) and water successively, dried over anhydrous magnesium ,sulfate and evaporated in vacuo to give a yellow oil, which is purified by silica gel column chromatography (hexane: ethyl acetate= 2:11. t-Butyl 3(R) -5-(l-benzyloxycarbonyl-4-piperidyl)- 1 -ethoxycarbonylpentyl] amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetate (0.12 g) is obtained as a colorless oil from the first fraction. The second fraction gives t-butyl [5 (l-benzyloxycarbonyl-4-piperidyl)- 1 (S)-ethoxycarbonylpentyl] amino-4-oxo-2,3 1,5-benzothiazepine-5-acetate (0.52 g) as a colorless oil.

Example 132 A mixture of 3 (R)-phthalimido-2,3-dihydro-l,5-(SH)benzothiazepin-4-one (10 ethanol (500 mt) and hydrazine hydrate (6.2 g) is refluxed for 1 hour. After ethanol is t removed by evaporation under reduced pressure, water (300 is added, and the mixture is extracted with ethyl acetate (400 mt). The extract is washed with 0.1N sodium hydroxide solution (100 mi x 2) and water (100 successively, with stirring for 45 minutes to give 50 g of S-(l-benzyloxycarbonyl-4 -piper idyl) vaIer ic acid as an oily material.

IR v neat cm- 1730, 1700(C-0) Example 110 A mixture of 54.8 g of oxycarbonyl-4-piperidyl)valeric acid, 29 g of sodium hydroejen- 87i dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3 -amino-2, 3-dihydro-, 5 -ben zothiazepin-4-one (3.75 g) as colorless leaflets.

mp. 170-173*C (az] D -367* (in methanol) Elemental Analysis for C H 1 2 O Calcd: C,55.65; H,5.19; N,14.42 Found: C,55.73; H,5.09; N,14.51 Example 133 A mixture of 3 -amino ,3-dihydro-1, (Sa) -benzothiazepin-4-one (1.0 ethyl 6-(l-benzyloxycarbonyl-4piperidyl)-2-oxohexanoate (6.0 acetic acid (0.37 g), molecular sieves 3A (3.0 g) and ethanol (25 mX) is stirred at room temperature for 20 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.66 g) in ethanol (20 mu) over a period of hours. After the reaction mixture is concentrated under reduced pressure, the residue is diluted with a mixture of ethyl acetate (80 mt) and water (100 in?) After the insoluble substance is removed by filtration, the ethyl acetate layer is washed with diluted hydroch".oric acid, V water and sodium bicarbonate solution successively, dried over anhydrous sodium sulfate and concentrated in vactio.

V The residue is purified by silica gel column chromatography (hexane: ethyl acetate 2:1) to yield oxycarbonyl-4-piperidyl) -l-ethoxycarbonylpentyll amino-2 dihydro-1 5 -benzothiazepin-4 -one (1.1 g) as a colorless oil.

IR anat c-l NR mv c 3230 1730, 1700, 1680 (C=o) NR(in CDC 3 6: 7.3(511), 7.0-7.7(4H), 5.1(2H1), 3.9-4.3 (SH) 2. 4-3.7 (7H1), 1. 0-1. 8(16H1) Mass spectrum (ni/e) 553 Example 134 A mixture of 3 -amino-2,3-dihydro-l, 5 (51)-benzo- 'Lhiazepin-4-one (2.7 g) and ethyl 6-(l-benzyloxycarbonyl- 4 -pipe ridyl) -2-methanesulf onyloxyhexanoa te (5.4 g) is under reduced pressure to give 26 g of ethyl 6-(l-benzyloxycarbonyl-4 -pipe ridyl) 2-oxohexanoate as an oily material.

IR v na cm -11730, 1690(C-0)' max Mass spectrum 375 (M Example 112 -88 heated at 100-130 0 c for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 mRt) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane: ethyl acetate to give 3(R)-[5-(l-benzyloxycarbonyl-4-piperidyl)-lethoxycarbonylpentyll amino-2, ,3-dihydro-l 5 (5H) -benzothiazepin-4-one (2.9 g) as a colorless oil.

Example 135 A mixture of 3 (l-benzyloxycarbonyl-4-piperidyl) ethoxycarbonylpentyl] amino- 2, 3-dihydro-l, 5(5H) -benzothiazepin-4-one 0 g) tert-butyl chioroacetate 27 g), potassium iodide 3 g) potassium carbonate 24 g) and N,N-dimethylformamide (10 mt) is stirred for 15 hours at room temperature. The mixture is poured into water (50 niL) and extracted with ethyl acetate (40 The extract is washed with diluted hydrochloric acid, sodium bicarbonate C solution and water successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is puiidby silica gel column chromatography (hexane: ethyl acetate 2:1) togive firstly tert-butyl ben zyloxycarbonyl- 4-piperidyl) -1 -ethoxycarbonylpentyl] amino-4-oxo- 2 ,5-tetrahydro-l, acetate (0.45 g) as a colorless oil.

From the second fraction is obtained tert-butyl 3 (1 -ben zyloxycarbonyl-4 -piperidyl) -1 -ethoxycarbonylpen tyl]I amino- 4-oxo-2, 13,4, ,5-tetrahydro-l1 5-ben zo- (0.42 g) as a colorless oil.

In 200 mt of ethanol .is dissolved 10 g of ethyl 6- (l-benzyloxycarbonyl-4-piperidyl)- 2 -chlorohexanoate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using 5g of10 palladiumcarbon 50 in water as a catalyst. After absorption of hydrogen stops, the catalyst is removed by filtration, and S9- Example 136 In 10 ml of acetic acid is dissolved 5.2 g of tert-butyl [5-(l-benzyloxycarbonylpiperidyl)-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepineand 10 ml of 30% hydrogen bromide-acetic acid is added to the solution. After the mixture is left standing at room temperature for 1.5 hours, 200 ml of ethyl ether is added to the mixture and the resulting mixture is left standing. The supernatant liquid is removed by decantation and the precipitate is dissolved in 90 ml of lN aqueous sodium hydroxide solution. After the mixture is left standing at room temperature for 1.5 hours, the mixture is neutralized with 10 ml of acetic acid and purified by MCI gel column chromatography Cwater:methanol=l:l). The eluate is concentrated under reduced pressure to a volume of about ml, and the deposited crystals are collected by filtration and dried to give 2.1 g of 3CR)-[1CS)-carboxy-5-(4-piperidyl) pentyl]amino-4-oxo-2,3,4,5-tetrahydro-, acetic acid as a colorless crystalline powder, melting at a temperature higher than 270 0 C (decomposition) [a]D-130- (in water)

D

Elemental Analysis for C 22

H

31

N

3 0 5

S

Calcd.: C, 58.78; H, 6.95; N, 9.35 Found C, 58.59; H, 6.99; N, 9.37 IR V KB r cm 1 1670 (amide), 1635, 1610 (carboxylate) max Example 137 To a mixture of 5.4 g of 9-phthalimidononanoic acid, f 1.1 g of red phosphorus and 25 ml of carbon tetrachloride is added 2.8 ml of bromine dropwise for the period of 30 minutes and the mixture is stirred for 15 minutes. Further, 2.8 ml of bromine is added dropwise for the period of 15 minutes et and the resulting mixture is heated at 80"C for 30 minutes and at 100*C for 4.5 hours. After cooling, the mixture is poured into 150 ml of water and extracted with 150 ml of ether. The ether layer is extracted with 350 ml of saturated sodium bicarbonate solution and the aqueous layer is acidified oxoheptanoate as an oily material.

neat -1 IR v cm 1720, 1690(C=0) max Mass spectrum 389 (M Example 116 In 200 mi of tetrahydrofuran is dissolved 26.3 g of with conc. hydrochloric acid. The deposited crystals are collected by filtration, washed with water and dried to give 6.8 g of 2-bromo-9-phthalimidononanoic acid, melting at 97-98 0 C (recrystallized from petroleum ether and ether).

KBr -1 IR v K cm 1770, 1710 (C=O) max Example 138 In 50 ml of ethanol is dissolved 6.8 g of 2-bromo-9phthalimidononanoic acid, and 5 ml of conc. sulfuric acid is adced to the solution. After the solution is left standing overnight, the solution is diluted with 100 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is washed with 50 ml of aqueous sodium bicarbonate solution and 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is purified by silicagel column chromatography (hexane: ethyl acetate 6:1) to give 6.3 g of ethyl 2-bromo-9-phthalimidononanoate as a colorless oil.

IR neatcm: 1770, 1735, 1710 (C=O) max NMR (in CDC13)6: 7.6-8.1(m,4H), 4.1-4.5(m,3H), 3.6-4.0 1.4(t,3H), 1.2-2.4(m,12H) Example 139 In 100 ml of acetonitrile are dissolved 2 g of tertbutyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepineand 7.4 g of ethyl 2-bromo-7-phthalimidoheptanoate, and 0.85 g of triethylamine is added to the solution. After the mixture is heated at 80-100*C for 2 days, the mixture is concentrated under reduced pressure, diluted with 100 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane ethyl acetate 2:1) to give from the first fraction 1.0 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl- 6-phthalimidohexyllamino-4-oxo-2,3,4,5-tetrahydro-l,5as a colorless oil.

IR vneatcm 1 3320(NH); 1770, 1730, 1710, 1680 (C=0) max S-91- -950 (in methanol)

D

Mass spectrum 609 (M From the second fraction, 1.15 g of tert-butyl 3(R)- (1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5tetrahydro-1,5-benzothiazepine-5-acetate is obtained as a colorless oil.

neat -l IR vnacm: 3320 1770, 1740, 1700, 1670 (C=0) max 1 2 5 (in methanol) Mass spectrum 609 (M Example 140 In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.12 g of tert-butyl 3(R)-[l(S)-ethoxycarbonyl- 6-phthalimidohexyl amino-4-oxo-2,3,4,5-tetrahydro-, and the solution is left standing at room temperature for 1 hour. Petroleum ether (50 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.1 g of 3(R)-[l(S)-ethoxycarbonyl-6-phthalimidohexyll3 -ino-4-oxo-2,3,4,5-tetrahydroe 1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.

(a -109° (in methanol)

D

Elemental Analysis for C28 H31N30S-HCl-H20 Calcd.: C, 55.30; H, 5.64; N, 6.91 Found C, 55.65; H, 5.72; N, 6.95 Example 141

S,*

1 In 100 ml of acetonitrile are dissolved 2.0 g of tertbutyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-l,5-benzothiazepineand 3.0 g of ethyl 2-bromo-9-phthalimidononanoate, y L and 0.85 g of triethylamine is added to the solution. The mixture is heated at 80 0 C for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted 1 with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:

A,-L

-92ethyl acetate 3:1 2:1) to give from- the first fraction 0.9 g of tert-butyl 3(R)-(1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- acetate as a colorless oil.

neat -1 IR v cm 3340 1775, 1740, 1710, 1680 (C=O) Smax -11" (in methanol) D Mass spectrum 637 (M) From the second fraction, 1.1 g of tert-butyl 3(R)fl(S)-ethoxycarbonyl-8-phthalimidooctyllamino-4-oxo-2,3,4,5tetrahydro-1,5-benzothiazepine-5-acetate is obtained as a colorless oil.

neat -1 IR v neatcml: 3330 1770, 1735, 1710, 1665 (C=0) max [al] -1170 (in methanol)

D

Mass spectrum 637 Example 142 In 100 ml of acetonitrile are dissolved 1.7 g of tertbutyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepineand 2.4 g of. ethyl 2-bromo-1l0-phthalimidodecanoate, and 0.75 g of triethylamine is added to the solution. The mixture is heated at 80 0 C for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane: ethyl acetate 3:1 2:1) to give from the first fraction 0.9 g of tert-butyl 3(R)-[l(R)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate as a colorless oil.

:It t neat 1 IR vneatcml: 3330 1770, 1740, 1715, 1680 (C=O) max -1020 (in methanol) Mass spectrum 651 (M From the second fraction, 0.95 g of tert-butyl 3(R)- [l(s)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo- 2,3,4,5-tetrahydro-1, 5-benzothiazepine- 5 -acetate as a colorless oil.

2 H-pyrane)carbaldehyde, 44 g of ethyl Ctriphenylphosphoranilidene)acetate and 200 mt of toluene is stirred at 100-c for 3 hours.

Toluene is evaporated off under reduced pressure, and 200 mt of petroleum ether is added. The insoluble matter is removed byv filtration, and the filtrate is concentrated under reduced -93 IP. vnetcm- 1 3330 1770, 1740, 1710, 1670 (C=O) max (in methanol)

D+

mass spectrum 651 (M Example 143 In S ml of SN hydrogen chloride-ethyl acetate solution h is dissolved 0.12 g of tert-butyl 3(R)-[l(S)-ethoxycarbonyl-8phthalimidooctylj amino-4-oxo-2,3, 4,5-tetrahydro-l,5and the solution is left standing at room temperature for 3 hours. Petroleum ether (70 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.10 g of 3(R)-lSetoy jj r~narbonyl-.8-phthalimidooctyllamino--4-oxo-2, 3 4, acid hydrochloride as a colorless powder.

1080 (in methanol)

D

KElemental Analysis for C H N0 Hl 30 35 3 o 7 Sl KCalcd.: C, 58.29; H, 5.87; N, 6.80 VFound C, 57.98; H, 5.90; N, 6.60 Example 144 In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.1 g of 3CR)- -ethoxycarbonyl-9-phthalimidononyli amino-4-oxo-2 5-tetrahydro-l, acetate, and the solution, is left standing at room temperature for 3 hours. Petroleum ether (50 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.076 g of 3(R)-[l(S)-ethoxycarbonyl-9-phthalimfido- [4 nonyl] amjno-4-oxo- 2 3,4, 5-tetrahydro-l, acetic acid hydrochloride as a colorless powder.

Ii(a] 1050 (in methanol) Elemental Analysis for C 31

H

37 N 0 S.Hll2 Calcd.: C, 58.07; H, 6.13; N, 6.55 rFound C, 58.26; H, 6.31; N, 6.34 Example 145 In 10 ml of ethanol is dissolved 0.9 g Of tert-butyl 3 l(S) -ethoxycarbonyl- 8 ph tha limidooctyl] amino- 4-oxo- 2, 3, 4, 5 -tetrahydro-1, 5-benzothia zepine5-ace ta te, and 0.35 g for 10 minutes, 215 mL of 3N hydrochloric acid is added, followed by stirring at room temperature for another 1 hour.

The methylene chloride layer is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 11 q of 4-thianylcarbaldehyde as a I -94- 94 of hydrazine hydrate is added to the solution. After the mixture is left standing at room temperature overnight, the mixture is concentrated under reduced pressure, diluted with water and extracted four times with 50 ml of ethyl acetate. Water (50 ml) and 1.0 g of sodium bicarbonate are added to the ethyl acetate layer, and 0.46 g of di-tertbutyl dicarbonate is added to the resulting mixture with stirring. After the mixture is stirred at room temperature for 30 minutes, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane:ethyl acetate 2:1) to give 0.79 g of tert-butyl 3(R)-[8-tert-butoxycarbonylamino-l(S)-ethoxycarbonyloctyl] amino-4-oxo-2,3,4,5-tetrahydro.-1,5-benzothiazepineas a colorless oil.

IR neatcm- 1 1740, 1710, 1670 (C=O) max [a]D-133 0 (in methanol) Mass spectrum 607 (M Example 146 In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.72 g of tert-butyl 3(R)-[8-tert-butoxycarbonylamino-l -ethoxycarbonyloctyl] amino-4-oxo- 2 3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 3.5 hours. Ether (10 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.50 g of 3(R)-[8-amino- 1 (S)-ethoxycarbonyloctyl]amino- 4 -oxo- 2 3 ,4,5-tetrahydro-l, acid dihydrochloride as a colorless powder.

a]D -1 2 5° (in methanol) Mass spectrum 451 (M Elemental Analysis for C 2 2

H

3 3

N

3 0 5 S-2HCl-1/2H 2 0 Calcd.: C, 49.44; H, 6.98; N, 7.86 Found C, 49.39; H, 6.61; N, 7.73 Example 147 In 10 ml of IN aqueous sodium hydroxide solution is dissolved 0.35 g of 3(R)-[8-amino-l(S)-ethoxycarbonyloctyllamino- 4-oxo- 2, 3,4, 5-tetrahydro-1, U acid dihydrochloride, and the solution is left standing at room temperature for 30 minutes. Acetic acid (2.5 ml) is added to the solution and the resulting mixture is purified by Amberlite XAD-2 column chromatography (methanol:water The eluate is concentrated under reduced pressure and lyophilized to give 0.24 g of 3(R)-f8--amino-l(S)-carboxyoctyl]- 1<amino- 4-oxo- 2, 3,4, 5- tetrahydro- 1,S5-benzothiazepine-5-ace tic acid as a colorless powder.

[a]i 1410 (in methanol) II! D SIMS spectrum Wme): 424 (MH (Ct tt C t DenzyLoxycarDonyj.--piperlay) -a-nyaroxynexanoic acdu g) as a colorless oil.

IR v ne at cm- 1 3400 1670 max 96 Examole 148 In a mixture of ethanol (40 ml) and water (30 ml) is dissolved S-(o-nitrophenyl)-L-cysteine (0.5 g) with heating. After cooling to room temperature, ethyl benzyloxycarbonyl- 4 -piperidyl)-2-oxohexanoate (2.3 g) is added to the solution.

A solution of sodium cyanoborohydride (0.38 g) in ethanol ml) is added dropwise to the mixture over the period of two hours, and the reaction mixture is allowed to stand overnight. The reaction mixture is concentrated under reduced pressure, and ethyl acetate (100 ml) and 1% aqueous phosphoric acid solution (50 ml) are added to the residue, followed by extraction. The ethyl acetate layer is washed with 1% aqueous phosphoric acid solution (50 ml) and water ml), to which hexane (100 ml) and saturated sodium hydrogencarbonate solution (50 ml) are added, followed by agitating. The deposited yellow oil is separated, weakly acidic with 10% hydrochloric acid and extracted with ethyl acetate (200 ml). The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

Ethyl ether is added to the residue to give benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyllamino- 3 -(o-nitrophenyl)thiopropionic acid (0.6 g) as a yellow powder.

Elemental Analysis for C 30

H

39

N

3 0 3 S-1/2H 2 0 Calcd.: C, 59.00; H, 6.60; N, 6.88 Found C, 59.06; H, 6.58; N, 7.33 NMR spectrum 6(DMSO-d 6 7.3-7.6, 7.4, 7.65-7.8, 8.1-8.3(9H, phenyl proton); 5.1(2H, methylene proton of the benzyl group) Example 149 c In a mixture of acetic acid (4 ml) and water (2 ml) is 1« dissolved 2(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-lethoxycarbonylpentyllamino-3-(o-nitrophenyl)thiopropionic acid (0.3 and powdered zinc (0.3 g) is added to the solution. The reaction mixture is stirred at room temperature v va-cecranydro-1, (0.7 g) as a colorless oil. From the subsequent fraction, tert-butyl 3(R)-[5-(l-benzyloxycarbonyl-4-piperidyl)-l(S)ethoxycarbonylpentylamino-4oxo-2,3,4,5tetrahydro-1,5benzothiazepine-S-acetate (0.55 g) is obtained as a colorless oil.

97 for 1 hour, diluted with water (50 ml) and extracted with ethyl acetate (200 ml). The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue are added ethyl ether (30 ml) and 5N hydrogen chloride-ethyl acetate solution (0.5 ml). The deposited colorless powder is collected by filtration to give 3-(o-aminophenyl)thio- 2(R) (l-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyllaminopropionic acid dihydrochloride (0.3 g).

NMR spectrum 6(DMSO-d 6 6.8-7.6, 7.4(9H, phenyl proton); 5.1(2H, methylene proton of the benzyl group) Elemental Analysis for C 30

H

4 1

N

3 0 6 S-2HC11/2H 2 0 Calcd.: C, 55.12; H, 6.78; N, 6.43 Found C, 54.82; H, 6.84; N, 6.68 Example 150 In N,N-dimethylformamide (5 ml) is dissolved 3-(oaminophenyl)thio-2 (R)-[5-(1l-benzyloxycarbonyl-4-piperidyl)- 1-ethoxycarbonylpentyl]aminopropionic acid dihydrochloride (0.16 and diethyl phosphorocyanidate (0.3 ml) is added dropwise to the solution. To the mixture is added triethylamine (0.2 ml) and the reaction mixture is stirred under ice-cooling for I hour. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (50 ml).

The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue is purified by silicagel column chromatography (hexane: acetone=2:) to give 4-piperidyl)-1-ethoxycarbonylpentyllamino- 2 ,3-dihydro-1,5(5H)benzothiazepin-4-one (0.09 g) as a colorless oil.

neat -1 IR v cm 3230, 1730, 1700, 1680 max J iA- >tt 1 .uAy~rDoriy.L-i LUyj.

2-methanesulfonyloxyhexanoate (0.

6 g: -12.8° in methanol) as a colorless oil. The mixture of this sulfonate (0.5 g) and tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5- (0.71 g) is heated at 80-100"C .4 98 Examole 151 In 1.21 of 0.1M phosphate buffer (0.1M KH 2

PO

4 600 ml and 0.1M K2HPO 4 600 ml) are added ethyl 6-(l-benzyloxycarbonyl- 4-piperidyl)-2-hydroxyhexanonate (40g) and Lipase PN (200mg: Wako Pure Chemicals, Japan), and the mixture is agitated at room temperature for 3.5 hours. The mixture is made acidic with cone. hydrochloric acid and extracted twice with a mixture of ethyl acetate and petroleum ether The ethyl acetate layer is washed with saturated sodium hydrogencarbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6-(1benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (14.6g) as a colorless oil. The aqueous sodium hydrogencarbonate layer is extracted with ethyl ether made acidic with cone. hydrochloric n acid and extracted with ethyl acetate (500 ml). The ethyl Sacetate layer is washed with water, dried over anhydrous t magnesium sulfate and concentrated under'reduced pressure to I give S-isomer-rich 6-(l-benzyloxycarbonyl-4-piperidyl)-2hydroxyhexanoic acid (23.5g).

In pyridine (30 ml) is dissolved R-isomer-rich ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (7 g), and methanesulfonyl chloride (2.9 ml) is added dropwise, with stirring, under ice-cooling over the period of 5 minutes.

The mixture is stirred under ice-cooling for 1.5 hours, and water (5 ml) is added dropwise to the mixture. The reaction Smixture is stirred for 30 minutes, diluted with ethyl acetate (300 ml) and washed with IN hydrochloric acid, saturated sodium hydrogencarbonate solution and water. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6-(1benzyloxycarbonyl-4-piperidyl) -2-methanesulfonyloxyhexanoate (8.2 g) as a pale yellow oil.

150 (in methanol)

D

toluenesulfonic acid (0.05 The solution is stirred for 1 hour at 90-100 0 C, cooled, diluted with ethyl acetate (200 mt) and washed with water (50 mi x The organic layer is dried over anhydrous magnesium sulfate and 1.

I

S- 99- Example 1.52 In toluene (50 ml) is dissolved S-isomer-rich 6-(1benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid (3.6 g), and ethanol (10 ml) and p-toluenesulfonic acid (0.2 g) are added to the solution, followed by agitating at 90°C for hours. The mixture is diluted with ethyl acetate (100 ml), washed with saturated sodium hydrogencarbonate solution (100 ml) and water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give Sisomer-rich ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2hydroxyhexanoate (3.7 g) as an oil. This product (1.0 g) is dissolved in pyridine (5 ml), and methanesulfonyl chloride (0.4 ml) is added dropwise to the solution with stirring over the period of 5 minutes under ice-cooling. After stirring is continued for 15 minutes under ice-cooling, water (3 ml) is added to the mixture, followed by stirring for 30 minutes.

*0o Ethyl acetate (150 ml) is added to the mixture, and the Sresulting mixture is washed with IN hydrochloric acid x saturated sodium hydrogencarbonate solution (50 ml) S and water (50 ml). The ethyl acetate layer is dried over Sanhydrous magnesium sulfate and concentrated under reduced pressure to give S-isomer-rich 6-(1-benzyloxycarbonyl-4piperidyl)-2-methanesulfonyloxyhexanoate [1.2 g [a]D -16.6° (in methanol)] as a pale yellow oil. This product (1.2 g) I and cesium propionate [prepared from cesium carbonate (0.47 g) Sand propionic acid (0.32 are added to N,N-dimethyl- S iI formamide (30 ml), and the mixture is stirred at 90°C for I hour. After cooling, ethyl acetate (150 ml) is added to the mixture, and the mixture is washed with 0.1N hydrochloric acid (50 ml x sodium hydrogencarbonate solution (50 ml) and water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily product is purified by silica gel column chromatography (hexane-ethyl acetate 3:1) to give R-isomer-rich ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-propionyloxyhexanoate (1.07 g) as a SLjv=u uy evaporation under reduced pressure, water (300 mt) is added, and the mixture is extracted with ethyl acetate (400 mt). The extract is washed with 0.1N sodium hydroxide solution (100 mi x 2) and water (100 mt) successively, :-4 100 colorless oil. This product (1.05 g) is dissolved in ethanol (10 ml), and iN aqueous sodium hydroxide solution ml) is added dropwise to the solution over the period of 5 minutes, followed by agitating for 30 minutes. The mixture is made acidic with conc. hydrochloric acid and extracted with ethyl acetate (100 ml). The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give Risomer-rich 6-(l-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid as an oily product. This product is dissolved in toluene (30 ml), and ethanol (5 ml) and p-toluenesulfonic acid (0.1 g) are added to the solution, followed by stirring at 90 0 C for 1.5 hours. Ethyl acetate (1,O ml) is added to the mixture, and the resulting mixture is washed with saturated sodium hydrogencarbonate solution (50 ml) and water ml), dried over anhydrous magnesium sulfate and concenrated under reduced pressure to give R-isomer-rich ethyl 6- (l-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (0.84 g) S as a colorless oil. This product (0.3 g) is dissolved in pyridine (3 ml), and methanesulfonyl chloride (0.15 ml) is S added dropwise to the solution with stirring under ice-cooling over the period of 2 minutes. The mixture is stirred for 1 hour under ice-cooling, and ethyl acetate (70 ml) is added to the mixture. The resulting mixture is washed with IN hydrochloric acid (30 ml x saturated sodium hydrogencarbonate solution ml) and water (30 ml). The ethyl acetate layer is dried r. over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate [0.35 g (a[D +16.60 (in methanol)] as a colorless oil.

o tLL Example 134 A mixture of 3 (R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6 -(l-benzyloxycarbonyl- 4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is 101 Exoeriment Example 1 Experiment on Inhibition of Angiotensin I Converting Enzyme (ACE) by the Compounds of This Invention (Experimental Method] The experiment was conducted in accordance with a modification of the method described by Cushman et al.

(Biochemical Pharmacology, Vol. 20, pp. 1637, 1971). Thus, using hippuryl-L-histidyl-L-leucine (HHL) as the substrate, the ACE inhibitory activity was determined in terms of percent inhibition on the amount of hippuric acid produced by ACE when the compound of the present invention was'added. A solution of the compound of the present invention in 0.02 to dimethylsulfoxide-100 mM borate-EC1 buffer solution (pH 8.3, containing 300 mM sodium chloride) was added to 100 ul of ACE (protein concentration, 20 mg/mE) and 100 uL of 1.25 mM HHL. In this experiment, a borate-HCI buffer solution containing dimethylsulfoxide at a concentration equal to that of the test solution was used as a control. After warming the solution S at 37'C for 1 hour, 150 up of IN hydrochloric acid was added to the solution to tsahinate the reaction.' After 0.8 mt of Sethyl a:etate was added, the solution was centrifuged at 11,500 rpm for 2 minutes. A 0.5 mi aliquot was separated from the ethyl acetate layer and dried at a temperature of not more than Sa under nitrogen gas streams. The residue was mixed thoroughly with 4.5 me of distilled water, and the mixture was subjected to colorimetry at a wavelength of 228 nm.

(.Test. Results] The test results obtained with regard to the compounds of the present invention are as shown in Table Table Examole No. of Concentration ACE inhibitory test comoound I activity 73 0.1 92 74 0.1 94 0.1 89 ocL 82 0.1 92 91 0.1 92 0.1 93 93 0.1 93 100 0.1 93 ~I -r I ~I :iL. 1IPILI s 102 Experiment Example 2 Effect of the Compounds of the Present Invention against Hypertensive Activity of Angiotensin I: [Experimental Method] Male rats (Sprague-Awley) weighing 300 to 400 g which were fed under free access to drinking water and feed were used as experimental animals. The rats were anesthetized with intraperitoneal administration of pentobarbital sodium (50 mg/kg) on the day before the test day, and a polyethylene tube was inserted into each of the femoral artery for measurement of blood pressure and the femoral vein for injection of angiotensin I and II. And the tubes were fixed.

On the test day, an average blood pressure in the control phase was measured by an electric hemodynamometer (MPU-0.5-290-0-III model, manufactured by NEC-Sanei, Japan) and recorded by a polygraph (NEC-Sanei, Tupe 365, or Nippon Kohden Type RM-45), and thereafter; angiotensin I and then angiotensin II were injected through the femoral vein at a dose of 300 ng/kg and 100 ng/kg, respectively, to measure the hypertensive activity. Then, 300 ug/kg of the compound of the present invention was administered intravenously as an isotonic salinie.,solution, and 5, 10, 30, 60, 90 and 120 minutes after the administration, angiotensin I and II were injected repeatedly to trace hypertensive reactions. In calculating the percent inhibition to the hypertensive activity of angiotensin I, the percent inhibitory value was corrected based on the variation with time in the hypertensive reaction by angiotensin II.

[Test Results] The test results obtained with regard to the compounds of the present invention are as shown in Table 16.

t r t t *1 'It.

C, I~ 4 t 4.

41 4.

f L 4.

114.414 I 4.

-103 Table 16: Inhibition against hypertensive Example No.; Dose reaction by angiotension 1, of tested pg/kg: Length of time elapsed compound after 'the administration min. 10 min.'3Q min. 60mmn. 90 mindI 120 min.

JQl00 100 900 6 o o7 62 9580 96~ 94 99 89 9: 91 0 0 100 9 Preoaration Examule The compounds of the present invention can be used, for example, for the treatment of hypertension in the following formulation examples.

1. Tablets.

3(R)-(l(S)-Carboxy-3-(4-piperidyl)propyl]--: amjno-4--oxo-2, 3,4, 5-tetrahydro-1, thiazepine-5-acetic acid 10 g Lactose 90 g Corn starch 29 g Mangesium stearate -1 130 g .The ingredients and and 17 g of are blended, and granulated together with a paste prepared from 7 g of the~ingredient Five g of the ingredient and the ingredient are added to the resulting granules, and the mixture is compressed by atabletting machine to prepare 1000 tablets of a diameter of 7 mm each containing 10 mg of the ingredient-. 2. Injectable solution.

3(R)-(l(S)-Carboxy-3-(4-piperidyl)propylJamino-4-oxo-2,3,4,5-tetrahydro-l,5-benzo- 10 g acid Sodium chloride 9g The ingredients and are dissolved in 1000 mRt of distilled water, and cahrged into 1000 brown ampoules cacti containijng 1 n of the solution. The air in the ampoules L.ALLvI L.LdC~rJ.Or1 9 0; r-ert-outyJ. jt kw-iitK)-eznoxycarDonyiL- 6-phtha limidohexyl I amino- 4-oxo- 2, 3, 4, 5- tetrahydro- 1, as a colorless oil.

IR v neat cm- 1 3320(NHi); 1770, 1730, 1710, 1680 (C=O) max 4' 104 is replaced with nitrogen gas, and the amnpoules are sealed.

The entire preparation steps are conducted under strile conditions.

0@ 0 *090 S. 00 a a *0 0 0 00 000*S0 0

I

I

4 C C C C '4 1

I

C t

Claims (15)

1. A compound of the formula: R -A-E-COOR 3 3 6. wherein R is hydrogen, lower alkyl or aralkyl; R is

4-piperidyl which may be substituted by lower alkyl, oxo, alkanoyl, benzoyl, phenyl-lower alkoxycarbonyl, lower alkoxycarbonyl, phenyl, naphthyl or phenyl-lower alkyl; A is a C 1 -C16 alkylene chain and E is-C=O or a group represented by the formula: .TCH-Wa wherein Wa is halogen or a group represented by the formula Raso2-O- in which Ra is lower alkyl, trifluoromethyl, ph&nyl or p-tolyl, or a salt thereof. 2. A compound according to Claim 1, wherein R 3 is hydrogen, C4 alkyl or phenyl-C 1 4 alkyl, 6 R is 4-piperidyl optionally substituted with C 1 -4 alkyl, oxo, C15 alkanoyl, benzoyl, phenyl-C14 alkoxycarbonyl or C1-4 alkoxycarbonyl, A is C 1 16 alkylene, and E isZ.C=O or a group represented by the formula: =CH-Wa wherein W a is halogen or a group represented by the formula RaSO in which Ra is C 1 -4 alkyl, trifluoromethyl, phenyl or p-tolyl, or a salt thereof. 3. A compound according to Claim 1, wherein R 3 is hydrogen or C 1 4 alkyl. 4. A compound according to Claim 1, wherein R 3 is t I 4$ 4 44 4o t i 1-4 alkyl. A 5. A compound according to Claim 1, wherein R is 4-[l-(phenyl-C 1 -4 alkoxycarbonyl)]piperidyl.

6. A compound according to Claim 1, wherein A is SC 2 -9 alkylene.

7. A compound according to Claim 1, wherein A is tetramethylene.

8. A compound according to Claim 1, wherein R a is C1-4 alkyl.

9. The compound according to Claim 1, which is ethyl %1r RAr 7 54S o 0v2 7 1 In 10 ml of ethanol is dissolved 0.9 g of tert-butyl 3 -ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo- 2, 3 4 ,5-tetrahydro-l,5-benzothiazepine-5-acetate, and 0.35 g 6-(l-benzyloxycarbonyl-4-p:' ridyl)-2-methanesulfonyloxy -hexanoate. The compound according to Claim 1, which is ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate.

11. The compound according to Claim 1, which is ethyl 6-(l-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate.

12. A process for producing a compound of the formula: 6 3 R -A-E-COOR (L) wherein R is hydrogen, lower alkyl or aralkyl; R is 4-piperidyl which may be substituted by lower alkyl, oxo, alkanoyl, benzoyl, phenyl-lower alkoxycarbonyl, lower alkoxycarbonyl, phenyl, naphthyl or phenyl-lower alkyl; A is a C 1 1 6 alkylene chain and E isZ:C=O or a group represented by the formula: ICH-Wa wherein Wa is halogen or a group represented by the formula RaSO2-o in which R a is lower alkyl, 0 o trifluoromethyl, phenyl or p-tolyl, or a salt thereof, which O aB 20 comprises a) reacting a compound of the formula: R6 3' *o 6R -A-COOR Swherein R and A are as defined above an R is lower 0 alkyl or aralkyl, and a compound of the formula: COOR 3 3" 4.43 COOR t 111 I tt wherein R is lower alkyl or aralkyl, in the presence of Sa base, followed by heating, and if desired, S 30 b) subjecting a compound of the formula in S 1 which E is-C=O, to a reduction reaction, followed by a ha~ogenation or sulfonylation reaction, and if desired, c) subjecting a compound of the formula in 3. which R is lower alkyl or aralkyl, to hydrolysis to S 35 provide a compound of the formula in which R 3 is hydrogen, and if desired, d) converting the thus obtained compound of the 54S -106a- formula into a salt thereof. 1.3. A process according to Claim 12, wherein the product is a compound of the formula in which R 3is hydrogen, C 1 4 alkyl or phenyl-C 1 -4 alkyl, 6is 4-piperidyl optionally substituted with C alkyl, oxo, C 5 alkanoyl, benzoyl, pey- 1-4 pheny 4 alkoxycarbonyl or C 4 alkoxycarbonyl, A is Cm alkylene, and 1-1 54S .I, E is C=0 or a group represented by the formula SCH-Wa Oi 0 0 05a J, of S* S Ic~ a a wherein W a is halogen or a group represented by the formula RaSO 2 in which Ra is C 1 -4 alkyl, trifluoromethyl, phenyl or p-tolyl, or a salt thereof.

14. A process according to Claim 12, wherein the product is a compound of the formula in which R 3 is hydrogen or C_-4 alkyl.

15. A process according to Claim 12, wherein the product is a compound of the formula in which R 3 is C1-4 alkyl.

16. A process according to Claim 12, wherein the product is a compound of the formula in which R 6 is 15 4-[l-(phenyl-C 1 4 alkoxycarbonyl)]piperidyl.

17. A process according to Claim 12, wherein the product is a compound of the formula in which A is C2 9 alkylene.

18. A process according to Claim 12, wherein the 20 -product is a compound of the formula in which A is tetramethylene.

19. A process according to Claim 12, wherein the product is a compound of the formula in which R a is C1 4 alkyl. 25 20. A compound as defined in Claim 1 and substantially as herein described with reference to any Example.

21. A process as defined in Claim 12 and substantially as herein described with reference to any Example. S IL r DATED this 17th day of February, 1988 TAKEDA CHEMICAL INDUSTRIES, LTD. By their Patent Attorneys GRIFFITH HASSEL FRAZER 5895S/bm -107-