Novel 3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives of the formula ##STR1## [wherein R.sup.1 and R.sup.2 are independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or both jointly form tri- or tetramethylene; R.sup.3 is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl; R.sup.4 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted cycloalkylalkyl; Y is a carboxyl group which may be esterified or amidated; m is 1 or 2] and salts thereof. These compounds and salts thereof exhibits inhibitory activity on angiotensin converting enzyme and so forth, and are of value as an agent for diagnosis, prevention and treatment of circulatory diseases (e.g. hypertension, cardiopathy, cerebral apoploxy).

TECHNICAL FIELD 
This invention relates to novel 
3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives useful as 
pharmaceuticals. 
BACKGROUND ART 
Several 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 Application 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 (e.g. hypertension, 
cardiopathy, cerebral apoplexy), succeed in the production of novel 
3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives having 
excellent action, and have completed the present invention. 
DISCLOSURE OF THE INVENTION 
The present invention provides novel compounds represented by the formula: 
##STR2## 
[wherein R.sup.1 and R.sup.2 are independently hydrogen, halogen, 
trifluoromethyl, lower alkyl or lower alkoxy, or both jointly form tri- or 
tetramethylene; R.sup.3 is hydrogen, optionally substituted lower alkyl or 
optionally substituted aralkyl; R.sup.4 is hydrogen, optionally 
substituted alkyl, optionally substituted aralkyl or optionally 
substituted cycloalkylalkyl; Y is a carboxyl group which may be esterified 
or amidated; m is 1 or 2] and salts thereof. 
Referring to the above formula (I), the halogen represented by R.sup.1 or 
R.sup.2 includes, for example, fluorine, chlorine, bromine and iodine, and 
the lower alkoxy group represented by R.sup.1 or R.sup.2 includes alkoxy 
groups containing about 1-4 carbon atoms, such as methoxy, ethoxy, 
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. Also, 
R.sup.1 and R.sup.2 may combine with each other to form an alkylene 
bridge, whose examples include those such as trimethylene and 
tetramethylene. 
The lower alkyl group represented by R.sup.1 or R.sup.2 includes alkyl 
groups containing about 1-4 carbon atoms, such as methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. 
The lower alkyl group represented by R.sup.3 includes alkyl groups 
containing about 1-6 carbon atoms, such as methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. The 
said groups may substituted for example by carboxyl, 
lower-(C.sub.1-4)-alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, 
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl), aryloxycarbonyl 
(e.g. phenoxycarbonyl) or aralkyloxycarbonyl such as 
phenyl-lower-(C.sub.1-4)-alkoxycarbonyl (e.g. benzyloxycarbonyl, 
phenethyloxycarbonyl, 3-phenylpropoxycarbonyl, 
.alpha.-methylbenzyloxycarbonyl, .alpha.-ethoxybenzyloxycarbonyl, 
.alpha.-methylphenethyloxycarbonyl, .beta.-methylphenethyloxycarbonyl, 
.beta.-ethylphenethyloxycarbonyl), wherein the phenyl group in the 
aryloxycarbonyl and aralkyloxycarbonyl groups may be substituted by 1 to 3 
substituents such as halogen (e.g. fluorine, chlorine, bromine, iodine), 
C.sub.1-4 alkyl (e.g. methyl, ethyl, propyl, butyl group and the like), 
C.sub.1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, 
methylenedioxy group and the like), amino, nitro or hydroxyl group. 
The aralkyl group represented by R.sup.3 or R.sup.4 includes 
phenyl-lower-(C.sub.1-4)-alkyl groups, such as benzyl, phenethyl, 
3-phenylpropyl, .alpha.-methylbenzyl, .alpha.-ethylbenzyl, 
.alpha.-methylphenethyl, .beta.-methylphenethyl and .beta.-ethylphenethyl, 
wherein the phenyl group in said phenyl-lower-alkyl group may be 
substituted by 1 to 3 substituents such as halogen (e.g. fluorine, 
chlorine, bromine, iodine), C.sub.1-4 alkyl group (e.g. methyl, ethyl, 
propyl, butyl group and the like), C.sub.1-4 alkoxy group (e.g. methoxy, 
ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy, amino, nitro or 
hydroxyl group. Examples of such substituted-phenyl-lower-alkyl groups 
include 2-(4-chlorophenyl)ethyl, 2-(4-hydroxyphenyl)ethyl, 
2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 
2-(3,4,5-trimethoxyphenyl)ethyl, 2-(3,4-methylenedioxyphenyl)ethyl, 
2-(p-tolyl)ethyl, 3,4-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 
3,4,5-trimethoxybenzyl, 4-ethylbenzyl, 4-chlorobenzyl. 
The alkyl group represented by R.sup.4 includes straight chain or branched 
chain alkyl groups containing about 1-16 carbon atoms (e.g. methyl, ethyl, 
propyl, isopropyl, butyl, pentyl, isopentyl, 1-ethylpropyl, hexyl, heptyl, 
octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 
hexadecyl, 3-ethylpentyl, 4-propylhexyl, 2,2-dimethylbutyl, 
3,3-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylhexyl, 
3,3-dimethylhexyl), which may have as substituent moiety substituent 
groups such as hydroxy, lower-(C.sub.1-4)-alkoxy (e.g. methoxy, ethoxy, 
propoxy, butoxy), mercapto, lower-(C.sub.1-4)-alkylthio (e.g. methylthio, 
ethylthio, propylthio, butylthio), amino, mono- or 
di-lower-(C.sub.1-4)-alkylamino (e.g. methylamino, ethylamino, 
propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, 
methylethylamino, methylpropylamino, methylbutylamino, diethylamino, 
ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, 
dibutylamino), acylamino such as alkanoylamino containing not more than 5 
carbon atoms (e.g. formamido, acetamido, propionamido, butyramido, 
valeramido, pyvalamido), benzamido, 
phenyl-lower-(C.sub.1-4)-alkoxycarbonylamino (e.g. benzyloxycarbonylamino) 
and lower-(C.sub.1-4)-alkoxycarbonylamino (e.g. tert-butoxycarbonylamino), 
C.sub.3-8 cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, 
cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino) or a 
hetero-alicyclic group. The heteroalicyclic group includes for example 
condensed or non-condensed hetero-alicyclic groups containing at least one 
atom of N, O and S as a ring-forming atom, and preferably hetero-mono- or 
bialicyclic group having a ring or rings composed by 4 to 8 members, the 
said group being saturated or partially saturated. The said 
hetero-alicyclic group may contains two or more hetero atoms which are the 
same kind or two or more kinds. The hetero-alicyclic group includes, for 
example, oxetanyl, thietanyl, azetidinyl, tetrahydrofuryl, 
tetrahydrothienyl, pyrrolidinyl, oxanyl (3,4,5,6-tetrahydro-2H-pyranyl), 
thianyl, piperidyl, oxepanyl, thiepanyl, perhydroazepinyl, oxocanyl, 
thiocanyl, perhydroazocinyl, dioxanyl, dithianyl, piperazinyl, 
morpholinyl, perhydrothiadinyl, oxathianyl, perhydrodiazepinyl, 
oxathiepanyl, dioxepanyl, dithiepanyl, perhydroxazepinyl, 
perhydrothiazepinyl, perhydroxazocinyl, perhydrothiazocinyl, oxathiocanyl, 
perhydrodiazocinyl, dithiocanyl, dioxocanyl, chromanyl, isochromanyl, 
3,4-dihydro-2H-1-thianaphthyl, 3,4-dihydro-1H-2-thianaphthyl, 
1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 
2,3-dihydrobenzofuryl, 1,3-dihydroisobenzofuryl, 
2,3-dihydrobenzo[b]thienyl, 1,3-dihydrobenzo[c]thienyl, indolinyl, 
isoindolinyl, 2,3,4,5-tetrahydro-1(1H)-benzoazepinyl, 
2,3,4,5-tetrahydro-3(1H)-benzoazepinyl, 
2,3,4,5-tetrahydro-2(1H)-benzoazepinyl, 2,3,4,5-tetrahydro-1-benzoxepinyl, 
1,3,4,5-tetrahydro-2-benzoxepinyl, 1,2,4,5-tetrahydro-3-benzoxepinyl, 
2,3,4,5-tetrahydro-1-benzothiepinyl, 1,3,4,5-tetrahydro-2-benzothiepinyl, 
1,2,4,5-tetrahydro-3-benzothiepinyl, 2,3-dihydro-1,4-benzodioxinyl, 
2,3-dihydro-1,4-dithianaphthyl, 1,2,3,4-tetrahydroquinoxalinyl, 
3,4-dihydro-2H-1,4-benzoxadinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 
2,3-dihydro-1,4-benzoxathienyl, 3,4-dihydro-2H-1,5-benzodioxepanyl, 
2,3-dihydro-5H-1,4-benzodioxepinyl, 
2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 
2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 
3,4-dihydro-2H-1,5-benzodithiepinyl, 2,3-dihydro-5H-1,4-benzodithiepinyl, 
perhydroindolyl, perhydroisoindolyl, perhydroquinolyl, 
perhydroisoquinolyl, perhydro-1-thianaphthyl and perhydro-2-thianaphthyl. 
The said condensed or non-condensed hetero-alicyclic group may have at any 
substitutive position thereof a substituent or substituents such as oxo, 
acyl such as lower-(C.sub.1-5)-alkanoyl (e.g. acetyl, propionyl), benzoyl, 
phenyl-lower-(C.sub.1-4)-alkoxycarbonyl (e.g. benzyloxycarbonyl) or 
lower-(C.sub.1-4)-alkoxycarbonyl (e.g. tert-butoxycarbonyl), 
lower-(C.sub.1-4)-alkyl (e.g. methyl, ethyl, propyl, butyl), aryl (e.g. 
phenyl, naphthyl) and phenyl-lower-(C.sub.1-4)-alkyl (e.g. benzyl, 
phenethyl, .alpha.-methylphenethyl, .beta.-methylphenethyl). The phenyl 
group in the said aryl or phenyl-lower alkyl group may optionally 
substituted by halogen (e.g. fluorine, chlorine, bromine), 
lower-(C.sub.1-4)-alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy) or 
lower-(C.sub.1-4)-alkyl (e.g. methyl, ethyl, propyl, butyl). The 
substituted condensed or non-condensed hetero-alicyclic group include, for 
example, 1-phenylpiperidyl, 1-benzylpiperidyl, 4-phenylpiperidyl, 
4-benzylpiperidyl, 1-acetylpiperidyl, 1-benzoylpiperidyl, 
4-phenylpiperazinyl, 4-acetylpiperazinyl, 4-benzoylpiperazinyl, 
1-oxoisoindolynyl, 1,3-dioxoisoindolynyl, 
1,2,3,4-tetrahydro-1-oxoisoquinolyl and 
1,2,3,4-tetrahydro-3-oxoisoquinolyl. 
When R.sup.4 is a substituted alkyl group, the alkyl moiety containing 
about 2 to 9 carbon atoms is preferable. 
The cycloalkylalkyl group represented by R.sup.4 includes C.sub.3-8 
cycloalkyl-lower-(C.sub.1-4)-alkyl groups such as cyclopropylethyl, 
cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, 
cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylethyl and 
cyclooctylethyl; bicycloalkyl-lower-(C.sub.1-4)-alkyl groups, the 
bicycloalkyl moiety thereof being exemplified by for example norbornyl, 
bicyclo[2,2,2]octyl, bicyclo[3,3,1]nonyl or bicyclo[3,3,0]octyl; 
tricycloalkyl-lower-(C.sub.1-4)-alkyl groups, the tricycloalkyl moiety 
thereof being exemplified by for example adamantyl. Examples of the 
bicycloalkyl-lower-alkyl and tricycloalkyl-lower-alkyl groups include 
norbornylethyl, bicyclo[2,2,2]octylmethyl, bicyclo[3,3,1]nonylpropyl, 
bicyclo[3,3,0]octylbutyl, adamantylethyl, and the like. The cycloalkyl, 
bicycloalkyl, tricycloalkyl and lower alkyl groups in said C.sub.3-8 
cycloalkyl-lower-alkyl, bicycloalkyl-lower-alkyl and 
tricycloalkyl-lower-alkyl groups may be substituted by halogen, C.sub.1-4 
alkyl, C.sub.1-4 alkoxy, methylenedioxy, amino, nitro or hydroxy. 
The esterified carboxyl group represented by Y includes 
lower-(C.sub.1-4)-alkoxycarbonyl groups, such as methoxycarbonyl, 
ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, 
isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl, and 
phenyl-lower-(C.sub.1-4)-alkoxycarbonyl groups, such as benzyloxycarbonyl, 
.alpha.-phenethyloxycarbonyl, .beta.-phenethyloxycarbonyl, 
phenylpropoxycarbonyl and phenylbutoxycarbonyl; the amidated carboxyl 
group includes carboxyl groups amidated with .alpha.-amino acids such as 
glycine, valine, leucine, isoleucine, threonine, N.sup..alpha. -lysine, 
methionine, phenylalanine and tryptophan, wherein the hydrogen atom of the 
carboxyl group in these .alpha.-amino acids may be substituted with 
lower-(C.sub.1-4)-alkyl (e.g. methyl, ethyl, propyl, butyl, tert-butyl) or 
phenyl-lower-(C.sub.1-4)-alkyl (e.g. benzyl, phenethyl, phenylpropyl, 
phenylbutyl). 
The group represented by C.sub.m H.sub.2m includes methylene (--CH.sub.2 
--) ethylene (--CH.sub.2 CH.sub.2 --) or ethylidene 
##STR3## 
The compounds of the present invention are specifically disclosed in the 
following: 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-(p-tolyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Isobutoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid and its benzyl ester, 
7-Chloro-3(S)-[1-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-7-methoxy-4-oxo-2,3,4,5-tetrahy 
dro-1,5-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-7-methyl-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-7-trifluoromethyl-2,3,4,5 
-tetrahydro-1,5-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5,8,9-hexahydro-7H- 
indeno[5,6-b][1,5]oxazepine-5-acetic acid and its benzyl ester, 
3(S)-Ethoxycarbonylmethylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5 
-acetic acid and its benzyl ester, 
3(S)-[1-Benzyloxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-4-methylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin 
e-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepin-5-yl-N-acetyl-L-phenylalanine and its tert-butyl ester, 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-propionic acid, 
3(S)-[1-Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5,7,8,9,10-octahydr 
onaphtho[2,3-b][1,5]oxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-.alpha.-methylacetic acid, 
3(S)-[1-Ethoxycarbonylethyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin 
e-5-acetic aicd and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-4-ethylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz 
oxazepine-5-acetic acid and its benzyl ester, 
3(S)-[3-Cycloheptyl-1-ethoxycarbonylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxaze 
pine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propyl]amino-4-o 
xo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic aic and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-3-(4-thianyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic aicd and its benzyl ester, 
Benzyl 
3(S)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpropyl]amino-4-o 
xo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate, 
3(S)-[1-Ethoxycarbonyl-3-(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro 
-1,5-benzoxazepine-5-acetic acid, 
tert-Butyl 
3(S)-[3-cyclohexyl-1-ethoxycarbonylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetate, 
tert-Butyl 
3(S)-[1-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz 
oxazepine-5-acetate, 
3(S)-[1-Benzyloxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro 
-1,5-benzoxazepine-5-acetic acid and its tert-butyl ester, 
3(S)-[3-cyclohexyl-1-ethoxycarbonylmethoxycarbonylpropyl]amino-4-oxo-2,3,4, 
5-tetrahydro-1,5-benzoxazepine-5-acetic acid and its tert-butyl ester, 
3(S)-[1-Butoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid and its tert-butyl ester, 
3(S)-[1-Carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo 
xazepine-5-acetic acid, 
3(S)-[1-Carboxy-3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propyl]amino-4-oxo-2,3, 
4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-3-(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-3-(4-thianyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz 
oxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic acid and its benzyl ester, 
3(S)-[1-Ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic acid and its tert-butyl ester, 
3(S)-[7-Amino-1-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[7-Amino-1-carboxyheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazep 
ine-5-acetic acid, 
3(S)-[7-tert-Butoxycarbonylamino-1-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5 
-tetrahydro-1,5-benzoxazepine-5-acetic acid and its tert-butyl ester, 
3(S)-[1-Ethoxycarbonyl-3-phthalimidopropyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic acid, 
3(S)-[3-Amino-1-ethoxycarbonylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[3-Amino-1-carboxypropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazep 
ine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-4-phthalimidobutyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid, 
3(S)-[4-Amino-1-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz 
oxazepine-5-acetic acid, 
3(S)-[4-Amino-1-carboxybutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepi 
ne-5-acetic acid, 
3(S)-[5-Amino-1-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[5-Amino-1-carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazep 
ine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid, 
3(S)-[6-Amino-1-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz 
oxazepine-5-acetic acid, 
3(S)-[6-Amino-1-carboxyhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepi 
ne-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid, 
3(S)-[8-Amino-1-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz 
oxazepine-5-acetic acid, 
3(S)-[8-Amino-1-carboxyoctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepi 
ne-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid, 
3(S)-[9-Amino-1-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz 
oxazepine-5-acetic acid, 
3(S)-[9-Amino-1-carboxynonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepi 
ne-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-10-phthalimidodecyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic acid, 
3(S)-[10-Amino-1-ethoxycarbonyldecyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[10-Amino-1-carboxydecyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazep 
ine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-2-(4-piperidyl)ethyl]amino-4-oxo-2,3,4,5-tetrahydro- 
1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-2-(4-piperidyl)ethyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro- 
1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-carboxy-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro 
-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro- 
1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro 
-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-8-(4-piperidyl)octyl]amino-4-oxo-2,3,4,5-tetrahydro- 
1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-8-(4-piperidyl)octyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-ethylaminoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo 
xazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-isopropylaminoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-b 
enzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-dimethylaminoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-diethylaminopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-dipropylaminopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-be 
nzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-dibutylaminopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[7-Acetamido-1-carboxyheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzox 
azepine-5-acetic acid, 
3(S)-[7-Benzamido-1-carboxyheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzox 
azepine-5-acetic acid, 
3(S)-[1-Carboxy-5-cyclopentylaminopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-cyclohexylaminopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-cyclohexylaminoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-dibutylaminoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-ben 
zoxazepine-5-acetic acid, 
3(S)-[5-(1-Acetyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-t 
etrahydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[5-(1-Benzoyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5- 
tetrahydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[5-(1-Benzyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-t 
etrahydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-3-(1-oxo-2-isoindolinyl)propyl]amino-4-oxo-2,3,4,5-t 
etrahydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-piperidinoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo 
xazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-(1-piperazinyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-(4-phenyl-1-piperazinyl)pentyl]amino-4-oxo-2,3,4,5-tetrah 
ydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-(4-(2-methoxyphenyl)-1-piperazinyl)pentyl]amino-4-oxo-2,3 
,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-(4-methyl-1-piperazinyl)pentyl]amino-4-oxo-2,3,4,5-tetrah 
ydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Ethoxycarbonyl-3-(1-oxo-1,2,3,4-tetrahydroisoquinol-2-yl)propyl]ami 
no-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-5-piperidinopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo 
xazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-morpholinoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo 
xazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-(4-benzylpiperidino)heptyl]amino-4-oxo-2,3,4,5-tetrahydro 
-1,5-benzoxazepine-5-acetic acid, 
3(S)-[1-Carboxy-7-(2,3,4,5-tetrahydro-3(1H)-benzazepin-3-yl)heptyl]amino-4- 
oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid. 
Salts of the compounds (I) include pharmaceutically acceptable salts, such 
as salts with an inorganic acid being exemplified by hydrochloride, 
hydrobromide, sulfate, nitrate, phosphate, etc., salts with organic acid 
being exemplified by acetate, tartarate, citrate, fumarate, maleate, 
toluenesulfonate, 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, ammonium salts, hydrazine salts, quinine salts, cinchonine salts, 
etc. 
The compound (I) of the present invention can be produced, for example, by 
subjecting a compound of the formula: 
##STR4## 
[wherein each of the symbols is as defined hereinbefore] and a compound of 
the formula: 
##STR5## 
[wherein R.sup.3 and R.sup.4 are as defined hereinbefore] to a 
condensation reaction under reductive conditions. 
The said reductive conditions include reaction conditions of catalytic 
reduction using metals, such as platinum, palladium, Raney nickel and 
rhodium, or mixtures thereof with arbitrary supports as a catalyst; 
reduction with metal hydride compounds, 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 metals such as iron or zinc 
and acids such as hydrochloric acid or acetic acid; electrolytic 
reduction; reduction with reducing enzymes, and so forth. The above 
reaction is normally carried out in the presence of water or an organic 
solvent (e.g. 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.degree. C. to +100.degree. 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 (I) of the present invention can be produced, for 
example, by subjecting a compound of the formula: 
##STR6## 
[wherein each of the symbols is as defined 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 peptides synthesis. Thus, the reaction can be conducted by 
employing such a peptide forming reagent as dicyclohexylcarbodiimide, 
N,N'-carbonyldiimidazole, diphenylphosphorylazide and diethyl 
phosphorocyanidate solely or adding an ordinary acid (e.g. hydrogen 
chloride, sulfuric acid, nitric acid, hydrogen bromide) to allow 
protonation of the amino group of the compound (IV), 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 active ester derivative, 
followed by cyclization. The cyclization reaction, in any cases of 
cylizing the compound (IV) as such or after converting to its activated 
ester, can be promoted by adding preferably organic bases, for example, 
quaternary ammonium salts or tertiary amines (e.g. triethylamine, 
N-methylpiperidine). The reaction temperature is normally -20.degree. to 
+50.degree. C., preferably in the neighborhood of room temperature, and 
the solvent which is normally employed includes, for example, dioxane, 
tetrahydrofuran, acetonitrile, pyridine, N,N-dimethylformamide, 
N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, chloroform, 
methylene chloride, etc., which may be used alone or as a solvent mixture. 
The compound of the present invention can also be produced, for example, by 
subjecting a compound of the formula: 
##STR7## 
[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. The protective group removable by hydrolysis 
as represented by Z in (V) includes all kinds of acyl groups and trityl 
group, 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 represented by 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 solvent mixture thereof, and for the purpose of 
accelerating the reaction rate, it can be conducted as well by adding an 
acid (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, 
hydrofluoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic 
acid, trifluoroacetic acid) or a base (e.g. sodium hydroxide, potassium 
hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, 
triethylamine). The above reaction is carried out normally within the 
range of about -20.degree. to +150.degree. C. The catalytic reduction 
reaction in the said method is conducted in water or an organic solvent, 
such as methanol, ethanol, dioxane and tetrahydrofuran, or a solvent 
mixture thereof in the presence of an appropriate catalyst, such as 
platinum and palladium-carbon. This reaction is carried out at atmospheric 
pressure or under pressure up to about 150 kg/cm.sup.2 and at ordinary 
temperature or at a temperature up to +150.degree. C., but the reaction 
generally proceeds satisfactorily at ordinary temperature and at 
atmospheric pressure. 
The compound (I) of the present invention can be produced as well, for 
example, by subjecting the cyano group in a compound of the formula: 
##STR8## 
[wherein each of the symbols is as defined hereinbefore] 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 solvent mixture thereof, and can also 
be conducted by adding an acid (e.g. hydrochloric acid, hydrobromic acid, 
hydroiodic acid, hydrofluoric acid, sulfuric acid, methanesulfonic acid, 
p-toluenesulfonic acid, trifluoroacetic acid) or a base (e.g. sodium 
hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, 
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.degree. to +150.degree. C. 
The compound (I) can also be produced by reacting the compound (II) with a 
compound of the formula: 
##STR9## 
[wherein R.sup.3 and R.sup.4 are as defined hereinbefore; W.sup.a is 
halogen or a group represented by the formula R.sup.a SO.sub.2 --O-- 
(wherein R.sup.a is lower 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 -20.degree. to 
+150.degree. 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 bicarbonate, pyridine and 
triethylamine to coexist in the reaction system. 
The compound (I) of the present invention can also be produced, for 
example, by reacting a compound of the formula: 
##STR10## 
[wherein each of the symbols is as defined hereinbefore] with a compound 
of the formula: 
EQU W.sup.b --C.sub.m H.sub.2m --Y (IX) 
[wherein W.sup.b is halogen or a group represented by the formula R.sup.b 
SO.sub.2 --O-- (wherein R.sup.b is lower alkyl, trifluoromethyl, phenyl or 
p-tolyl); m and Y are as defined hereinbefore]. The reaction is allowed to 
proceed by maintaining both of the compounds in a suitable solvent within 
the temperature ranging about -20.degree. to +150.degree. C. On this 
occasion, the reaction can be conducted by allowing a base, such as 
potassium carbonate, sodium hydroxide and sodium hydride, to coexist in 
the reaction system. 
In the case of the compound (I) wherein R.sup.3 is hydrogen and/or Y is 
carboxyl, the compound (I) can also be produced by subjecting the ester 
compound wherein R.sup.3 is lower-(C.sub.1-4)-alkyl or/and Y is 
lower-(C.sub.1-4)-alkoxycarbonyl to a hydrolysis or elimination reaction, 
or by catalytic reduction of the benzyl ester compound wherein R.sup.3 is 
benzyl or/and Y is benzyloxycarbonyl. 
In the case of the compound (I) wherein R.sup.3 is lower-(C.sub.1-4)-alkyl 
or/and Y is lower-(C.sub.1-4)-alkoxycarbonyl, further, such a compound can 
also be produced by subjecting the compound wherein R.sup.3 is hydrogen 
or/and Y is carboxyl to an esterification reaction. 
In the case of the compound (I) wherein Y is esterified or amidated 
carboxyl, such a compound can also be produced, for example, by condensing 
a compound of the formula: 
##STR11## 
[wherein each of the symbols is as defined hereinbefore] with a compound 
of the formula: 
EQU R.sup.5 --H (XI) 
[wherein R.sup.5 is a lower alcohol residue, phenyl-lower-alcohol residue 
or .alpha.-amino acid residue whose carboxyl group may be protected with 
lower alkyl or phenyl-lower-alkyl]. 
Furthermore, the compound of the formula: 
##STR12## 
[wherein R.sup.5' is an .alpha.-amino acid residue; other symbols are as 
defined hereinbefore] can also be obtained by subjecting the compound 
obtained in the above condensation reaction as represented by the formula: 
##STR13## 
[wherein R.sup.5 is .alpha.-amino acid residue whose carboxyl group is 
protected with lower alkyl or phenyl-lower alkyl and the other symbols is 
as defined hereinbefore], for example, to a hydrolysis reaction, 
elimination reaction or catalytic reduction. PG,22 
In case compounds having a group which may interfere with a reaction are 
used [e.g. reaction of the compound (II) with the compound (III) or (IV)], 
compounds wherein the said group is protected with a known protecting 
group [e.g. benzyloxycarbonyl, tert-butoxycarbonyl, chloroacetyl, 
phthalimide, succinimide] are subjected to the reaction, followed by per 
se known deprotection reaction to give the desired compound. 
In case R.sup.4 in the formula (I) is, for example, an alkyl group 
substituted by amino, mono- or di-loweralkylamino, acylamino or 
cycloalkylamino, the compound (I) can be represented by the formula: 
##STR14## 
[wherein A is straight chain or branched chain alkylene group containing 
about 1-16 carbon atoms, R.sup.c and R.sup.d are independently hydrogen, 
lower-(C.sub.1-4)-alkyl, acyl or cycloalkyl, and the other symbols are as 
defined hereinbefore] and can be produced, for example, by the following 
method. 
The compound (II) is reacted with a compound of the formula: 
##STR15## 
[wherein W.sup.c is halogen or a group represented by the formula R.sup.g 
SO.sub.2 --O-- (wherein R.sup.g is lower alkyl, trifluoromethyl, phenyl or 
p-tolyl); one of R.sup.e and R.sup.f is hydrogen and the other is a 
protective group (e.g. benzoyl, acetyl) or both are cyclized with the 
adjacent nitrogen atom to form phthalimido or succinimido and the other 
symbols are as defined hereinbefore] to give a compound of the formula: 
##STR16## 
[wherein each of the symbols is as defined hereinbefore], and then the 
compound (Ia') is subjected to deprotection reaction to give the compound 
of the formula: 
##STR17## 
[wherein each of the symbols is as defined hereinbefore]. 
A compound of the formula (Ia) wherein R.sup.c and/or R.sup.b is lower 
alkyl or cycloalkyl, can be produced for example by reacting a 
corresponding aldehyde or ketone with the compound (Ib) under reductive 
conditions in water or an organic solvent (e.g. alcohol, ether, 
tetrahydrofuran, dimethylformamide, acetonitrile) or a mixture thereof, at 
a temperature ranging about -20.degree. to +100.degree. C. 
The said reductive conditions include reaction conditions of catalytic 
reduction using metals, such as platinum, Raney nickel, palladium, or 
mixtures thereof with arbitrary supports as a catalyst; reduction with 
metal hydride compounds, 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 metals such as iron or zinc and acids such as 
hydrochloric acid or acetic acid; electrolytic reduction reduction with 
reducing enzymes, and so forth. 
A compound of the formula (Ia) wherein R.sup.c and/or R.sup.d is acyl, can 
be produced for example by reacting an activated organic acid derivative 
such as acid anhydride or acid halide with the compound (Ib) in water or 
an organic solvent (e.g. ethyl acetate, methylene chloride, ether, 
benzene, toluene, triethylamine, dimethylformamide) or a mixture thereof, 
at a temperature ranging from about -20.degree. to +150.degree. C. For 
accelerating the reaction rate, an organic base (e.g. triethylamine, 
picoline, pyridine) or an inorganic base (e.g. sodium bicarbonate) may be 
added. 
The compound of the formula (I) wherein R.sup.4 is an alkyl group 
substituted by a hetero-alicyclic group and the nitrogen atom of the 
hetero-alicyclic group is bound to the alkyl group can be produced by 
subjecting the compound (Ib) and a compound of the formula: 
##STR18## 
[wherein X.sup.1 is a ring-forming group and it represents a 
hetero-alicyclic group as the group of the formula 
##STR19## 
to condensation reaction under reductive conditions. 
The said reductive conditions include reaction conditions of catalystic 
reduction using metals, such as platinum, palladium, Raney nickel and 
rhodium, or mixtures thereof with arbitrary supports as a catalyst; 
reduction with metal hydride compounds, 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 metals such as iron or zinc 
and acids such as hydrochloric acid or acetic acid; electrolytic 
reduction; reduction with reducing enzymes, and so forth. The above 
reaction is normally carried out in the presence of water or organic 
solvent (e.g. 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.degree. C. to +100.degree. 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 depending on 
the circumstances. 
The compound of the formula (I) wherein R.sup.4 is an alkyl group 
substituted by a hetero-alicyclic group and the nitrogen atom of the 
hetero-alicyclic group is bound to the alkyl group can be produced by 
reacting the compound (Ib) and a compound of the formula: 
##STR20## 
[wherein W.sup.d is halogen or a group represented by the formula R.sup.h 
SO.sub.2 --O-- (wherein R.sup.h is lower alkyl, trifluoromethyl, phenyl or 
p-tolyl) and X.sup.2 is a ring-forming group and it represents a 
heteroalicyclic group as the group of the formula --N X.sup.2 ]. The 
reaction is allowed to proceed by maintaining both of the compounds in a 
suitable solvent within the temperature range of about -20.degree. to 
+150.degree. 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 bicarbonate, pyridine and 
triethylamine to coexist in the reaction system. 
The compound of the compound (I) wherein R.sup.4 is an alkyl group 
substituted by a hetero-alicyclic group and the hetero-alicyclic group has 
an unsubstituted imino group therein can be produced by subjecting the 
compound of the formula (I) wherein R.sup.4 is an alkyl group substituted 
by a hetero-alicyclic group and the hetero-alicyclic group has an 
benzylimino or acylimino group, to catalytic reduction reaction, 
elimination reaction or solvolysis reaction. 
The catalytic reduction reaction in the said method is conducted in water 
or an organic solvent, such as methanol, ethyl acetate, ethanol, dioxane 
and tetrahydrofuran, or a solvent mixture thereof in the presence of an 
appropriate catalyst, such as palladium-carbon. This reaction is carried 
out at atmospheric pressure or under pressure up to about 150 kg/cm.sup.2 
and at ordinary temperature or at a temperature up to +150.degree. 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 or 
methylene chloride or a solvent mixture thereof, and for the purpose of 
accelerating the reaction rate, it can be conducted as well by adding an 
acid (e.g. hydrochloric acid, hydrobromic acid, hydrofluoric acid, 
hydroiodic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic 
acid, trifluoroacetic acid) or a base (e.g. sodium hydroxide, potassium 
hydroxide, potassium carbonate, sodium bicarbonate, sodium carbonate, 
sodium acetate). The above reaction is carried out normally within the 
range of about -20.degree. to +150.degree. C. 
The compound of the formula (I) wherein R.sup.4 is an alkyl group 
substituted by a hetero-alicyclic group and the hetero-alicyclic group has 
therein an imino group substituted by lower-(C.sub.1-4)-alkyl, aralkyl or 
acyl can be produced by reacting the compound of the formula (I) wherein 
R.sup.4 is an alkyl group substituted by a hetero-alicyclic group and the 
hetero-alicyclic group has an unsubstituted imino group with a compound of 
the formula: 
EQU R.sup.6 --W.sup.e (XIV) 
[wherein R.sup.6 is lower alkyl, aralkyl or acyl, and W.sup.e is halogen or 
a group represented by the formula R.sup.i SO.sub.2 --O-- (wherein R.sup.i 
is lower 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 -20.degree. to +150.degree. 
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 bicarbonate, pyridine or triethylamine to coexist in the 
reaction system. 
The compound of the formula (I) wherein R.sup.4 is an alkyl group 
substituted by a hetero-alicyclic group and the hetero-alicyclic group has 
therein an imino group substituted by lower-(C.sub.1-4)-alkyl or aralkyl 
can be produced by subjecting the compound of the formula (I) wherein 
R.sup.4 is an alkyl group substituted by a heteroalicyclic group and the 
hetero-alicyclic group has an unsubstituted imino group therein and a 
lower-(C.sub.1-4)-alkylaldehyde or aralkylaldehyde to condensation 
reaction under reductive conditions. 
The said reductive conditions include reaction conditions of catalystic 
reduction using metals, such as platinum, palladium, Raney nickel and 
rhodium, or mixtures thereof with arbitrary supports as a catalyst; 
reduction with metal hydride compounds, 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 metals such as iron or zinc 
and acids such as hydrochloric acid or acetic acid; electrolytic 
reduction; reduction with reducing enzymes, and so forth. The above 
reaction is normally carried out in the presence of water or an organic 
solvent (e.g. 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.degree. C. to +100.degree. 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 depending on 
the circumstances. 
The compound of the formula (I) wherein R.sup.4 is an alkyl group 
substituted by an hetero-alicyclic group and the hetero-alicyclic group 
has an acylimino group therein can be produced by reacting the compound of 
the formula (I) wherein R.sup.4 is an alkyl group substituted by a 
heteroalicyclic group and the hetero-alicyclic group has an unsubstituted 
imino group therein with a compound of the formula: 
EQU (R.sup.7).sub.2 O (XV) 
[wherein R.sup.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.degree. to +150.degree. 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 bicarbonate, 
pyridine or triethylamine to coexist in the reaction system. 
The salt of the compound (I) can be produced by the reaction for producing 
the compound (I) per se, and if desired, it can be produced by adding 
acid, alkali or base to the compound (I). 
The object compound (I) of the present invention thus obtained can be 
isolated from the reaction mixture by utilizing conventional separation 
and purification means, for example, means such as extraction, 
concentration, neutralization, filtration, recrystallization, column 
chromatography and thin layer chromatography. 
Depending on the kind of the substituents represented by R.sup.4, there may 
exist at least two stereoisomers of the compound (I). These individual 
isomers and mixture thereof, naturally, both 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 (I) can be 
obtained by carrying out the above reaction using a single isomer each of 
the starting compounds (II), (IV), (V), (VI), (VII), (VII') and (VIII), 
and when the product is a mixture of two or more isomers, it can be 
separated into individual isomers by a usual separation technique, for 
example, separation means such as methods of forming salts with optically 
active acids (e.g. camphorsulfonic acid, tartaric acid, dibenzoyltartaric 
acid, etc.) or optically active bases (e.g. cinchonine, cinchonidine, 
quinine, quinidine, .alpha.-methylbenzylamine, dehydroabiethylamine, 
etc.), a variety of chromatographic techniques and fractional 
recrystallization. 
The compound of the present invention, namely the condensed, seven-membered 
ring compounds represented by the formula (I) and a salt thereof, exhibit 
inhibitory activities on angiotensin converting enzyme, bradikinin 
decomposing enzyme (kininase), etc. in animals, in particular, mammals 
(e.g. human, dog, cat, rabbit, guinea pig, rat), and are useful, for 
example, as drugs for diagnosis, prevention or treatment of hypertension 
and hypertension-induced circulatory diseases (e.g. cardiopathy, cerebral 
apoplexy). The compound of the present invention is of low toxicity, well 
absorbed even on oral administration and highly stable and has 
long-lasting effect. Therefore, when it is used as the above-mentioned 
drugs, it can be administered orally or parenterally, per se or in 
admixture with suitable, pharmaceutically acceptable carriers, excipients 
or diluents in various pharmaceutical formulations such as powders, 
granules, tablets, capsules injectable solutions, etc. While the dosage 
level generally 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 hypertention, for example, the compound may be desirably 
administered orally at a single dose of about 0.02-20 mg/kg, preferably 
about 0.02-2 mg/kg, more preferably about 0.04-0.8 mg/kg, or intravenously 
at about 0.002-1 mg/kg, preferably about 0.02-0.2 mg/kg, about 1 to 5 
times, preferably about 1 to 3 times, more preferably about once or twice 
per day according to the conditions. 
The starting compounds (II), (IV), (V), (VI) and (VIII) of the present 
invention can be easily prepared, for example, by the methods as 
illustrated in the following reaction schema. 
##STR21## 
In the above reactions, Boc is tert-butoxycarbonyl; DEPC is diethyl 
phosphorocyanidate; and the other symbols are as defined hereinbefore. 
The process for preparing the compound (II) as shown in the above reaction 
schema is now illustrated in more detail. The compound (XVI) as a starting 
compound is treated with 2 equivalents of sodium hydride in a polar 
solvent such as N,N-dimethylformamide and then the compound is reacted 
with the compound (XVII) to give the compound (XVIII). 
The reaction of (XVIII).fwdarw.(XIX) is a reduction reaction of the nitro 
group to the amino group, and conventionally known reduction techniques 
can be employed. Thus, the reduction techniques include catalytic 
reduction using as a catalyst for example palladium-carbon, palladium 
supported with barium sulfate, sulfided palladium, Raney nickel, platinum, 
etc., reduction with such a metal as zinc, tin, stannous chloride or iron 
and acid or alkali, and so forth. The dehydrative ring-closure reaction of 
the resultant compound (XIX) to the compound (XX) can be advantageously 
carried out in the presence of a known dehydrative coupling agent. Such 
dehydrative coupling agent includes, for example, 
dicyclohexylcarbodiimide, carbonyldiimidazole, diethyl phosphorocyanidate, 
etc. As the solvent, use is made for example of dioxane, methylene 
chloride, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, etc. and 
the reaction is normally conducted at a temperature in the range of 
-10.degree. to +100.degree. C. For the purpose of allowing the reaction to 
proceed advantageously, a base such as triethylamine or pyridine can also 
be added to the reaction solution as a catalyst. The preparation of the 
compound (XXI) through a condensation reaction between the compounds (XX) 
and (IX) can be effected normally by condensation in a solvent such as 
N,N-dimethylformamide, dimethylsulfoxide or acetonitrile in the presence 
of such a base as sodium hydride or potassium carbonate at a temperature 
in the range of about -10.degree. to +100.degree. C. Then, the reaction of 
(XXI).fwdarw.(II) can be conducted by treating with hydrogen chloride in a 
solvent such as ethyl acetate at a temperature in the range of about 
-10.degree. to +100.degree. C. 
In the process for producing the compound (IV), the reaction of 
(XVIII).fwdarw.(XXII) can be conducted in a manner similar to the reaction 
of (XXI).fwdarw.(II). The compound (XXIII) can be produced by subjecting 
the compounds (XXII) and (III) to a condensation reaction. The compound 
(IV) can be prepared by subjecting the compound (XXIII) to an ordinary 
reduction reaction of the nitro group to the amino group and subsequently 
a condensation reaction with the compound (IX). 
In the process for producing the compound (V), the compound (XXVII) can be 
produced by applying a per se known amino protecting reaction for amino 
acids to the compound (II). The reaction of the compounds (XXVII) and 
(VII) is allowed to proceed by maintaining both of the compounds in an 
appropriate solvent within the temperature range of about -20.degree. to 
+150.degree. C. On this occasion, a base such as potassium carbonate, 
sodium hydroxide, sodium bicarbonate, pyridine or triethylamine can be 
made to coexist as a deacidifying agent in the reaction system for the 
purpose of accelerating the reaction rate. 
In the process for producing the compound (VI), the compound (VI) can be 
obtained from the compounds (II) and (XXVIII) and hydrogen cyanide used as 
starting compounds according to the Strecker reaction which is per se 
known. 
In the process for producing the compound (VIII), the reaction of 
(XX).fwdarw.(XXV) can be promoted in a manner similar to the reaction of 
(XXI).fwdarw.(II). The compound (VIII) can be produced by subjecting the 
compounds (XXV) and (III) to a reaction similar to that of compounds 
(XXII) and (III). The compound (VIII) can also be produced by subjecting 
the compound (XXIV) to a reaction similar to that of (XIX).fwdarw.(XX). 
The compound (II) can be produced, for example, according to the following 
reaction scheme besides the reaction (XXI).fwdarw.(II). 
##STR22## 
In the above reaction scheme, each of the symbols is as defined 
hereinbefore. 
The reaction (XX).fwdarw.(XXIX) can be conducted under the conditions 
similar to those of the reaction (XXI).fwdarw.(II) and the reaction 
(XXIX).fwdarw.(XXX) can be conducted under the conditions similar to those 
of the reaction (II).fwdarw.(XXVII). 
The compound (II') can be produced by subjecting the compounds (XXX) and 
(IX) to the reaction similar to that of the compounds (XX) and (IX). 
The compound (II) can be produced by subjecting the compound (II') to 
hydrolysis or catalytic reduction under the conditions similar to those of 
the reaction (V).fwdarw.(I). 
This invention also provides the compounds (II) which is industrially 
advantageous as an intermediate for synthesis of the novel compound (I) 
having the remarkable activities. 
The compounds of the formulae (III) and (VII) wherein R.sup.4 is an alkyl 
group substituted by an hetero-alicyclic group, which are used for the 
production of the compound (I), can be produced, for example, by the 
method as shown in the following reaction scheme. 
##STR23## 
In the above reaction scheme, R.sup.3' and R.sup.3" are independently lower 
alkyl or aralkyl and the other symbols are as defined hereinbefore. 
The compound (III') can be produced by subjecting the compounds (XXXI) and 
(XXXII) to condensation in the presence of a base such as sodium ethoxide, 
followed by heating in a mixture of dimethylsulfoxide and water in the 
presence of lithium chloride and so on. The compound (XXXIII), which can 
be produced by subjecting the compound (III') to a per se known reduction 
reaction, is subjected to a per se known halogenation or sulfonation 
reaction to produce the compound (VII"). 
The starting compound (XXXI) of the said reaction can be produced easily, 
for example, by subjecting a compound of the formula 
##STR24## 
wherein R.sup.4' is a hetero-alicyclic group, W.sup.f is halogen, A' 
represents A as A'--CH.sub.2 and the other symbols are as defined 
hereinbefore, to a per se known reduction reaction. 
In case that compounds wherein R.sup.4' has a group which may interfere the 
reactions, the reaction may be conducted after protecting the group with a 
protective group such as C.sub.1-5 alkanoyl (e.g. acetyl), benzoyl, 
phenyl-lower alkoxycarbonyl (e.g. benzyloxycarbonyl) or lower 
alkoxycarbonyl (e.g. tert-butoxycarbonyl). 
The compounds of the formulae (III'), (XXXIII) and (VII") wherein R.sup.3" 
is hydrogen can be produced easily, for example, by subjecting the 
compounds (III'), (XXXIII) and (VII") to hydrolysis, respectively. 
The compounds (VII) and (VII') can be produced easily by known methods 
described in literature references [e.g.; Methoden der Organischen Chemie 
(1960), Halogenverbindungen pp. 197-210 (Georg Thieme Verlag); Japanese 
Patent Unexamined Publication No. 42654/1972; Chemical Abstracts 64 P14139 
e (1966); Chemical Abstracts 47, P4361 c (1953); Chemical Abstracts 50, 
8503 e (1956); Chemical Abstracts 53, P17908 h (1959)]. 
In the processes for producing the compound (I) and intermediates thereof, 
the compounds which are used in the reactions may be used 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.

EXAMPLE 1 
In 200 ml of N,N-dimethylformamide is suspended 10.1 g of 60% sodium 
hydride (oily), and a solution of 25 g of Boc-L-serine in 10 ml of 
N,N-dimethylformamide is added dropwise to the suspension in a stream of 
nitrogen at 0.degree. C. with stirring. After stirring is continued at 
0.degree. C. until the evolution of hydrogen stops, 19 g of 
o-fluoronitrobenzene is added dropwise to the mixture. After the stirring 
at room temperature for 4 hours, the reaction mixture is poured in 
ice-cooled water containing dilute hydrochloric acid, followed by 
extraction with ethyl acetate. The organic layer is washed with water and 
dried, and then the solvent is evaporated off under reduced pressure. The 
resulting residue is purified by silica gel column chromatography 
(hexane-ethyl acetate=1:1) to give 30 g of O-(o-nitrophenyl)-Boc-L-serine 
as a colorless oil. 
EXAMPLE 2 
In 500 ml of methanol is dissolved 30 g of O-(o-nitrophenyl)-Boc-L-serine 
obtained in Example 1, and catalytic reduction is conducted in a stream of 
hydrogen at ordinary temperature and at atmospheric pressure with 1 g of 
10% palladium-carbon used as a catalyst. The catalyst is filtered off, and 
the filtrate is concentrated under reduced pressure. The resulting residue 
is recrystallized from ethyl acetate to give 23 g of 
O-(o-aminophenyl)-Boc-L-serine as colorless crystals, melting at 
90.degree.-91.degree. C. 
Elemental Analysis for C.sub.14 H.sub.20 N.sub.2 O.sub.5 : Calcd.: C, 
56.75; H, 6.80; N, 9.45; Found: C, 56.48; H, 6.82; N, 9.43 
EXAMPLE 3 
In 120 ml of N,N-dimethylformamide is dissolved 21.4 g of 
O-(o-aminophenyl)-Boc-L-serine obtained in Example 2, and 14 g of diethyl 
phosphorocyanidate is added dropwise to the solution with stirring at ice 
bath temperature. The mixture is stirred for 10 minutes, and 7 g of 
triethylamine is added dropwise to the mixture. After stirring for 1 hour, 
the mixture is poured in ice-cooled water. The deposited material is 
collected by filtration, washed with water, dried and recrystallized from 
ethyl acetate-hexane to give 12.3 g of 
3(S)-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one 
as colorless plates, melting at 202.degree.-203.degree. C. 
[.alpha.].sub.D.sup.24.5 -195.degree. (c=0.9 in methanol) 
Elemental Analysis for C.sub.14 H.sub.18 N.sub.2 O.sub.4 : Calcd.: C, 
60.42; H, 6.52; N, 10.07; Found: C, 60.69; H, 6.71; N, 9.99 
EXAMPLE 4 
In 150 ml of N,N-dimethylformamide is dissolved 12.3 g of 
3(S)-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one, 
and 8.7 g of benzyl chloroacetate, 8.7 g of anhydrous potassium carbonate 
and 1 g of potassium iodide are added to the solution. After stirring for 
15 hours, the mixture is poured in ice-cooled water. The deposited 
material is collected by filtration, washed with water and recrystallized 
from ethyl acetate-hexane to give 11.7 g of benzyl 
3(S)-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5 
-acetate as colorless prisms, melting at 122.degree.-124.degree. C. 
[.alpha.].sub.D.sup.24 -180.degree. (c=0.1 in methanol) 
Elemental Analysis for C.sub.23 H.sub.26 N.sub.2 O.sub.6 ; Calcd.: C, 
64.78; H, 6.14; N, 6.57; Found: C, 64.65; H, 6.21; N, 6.69 
EXAMPLE 5 
To 7.6 g of benzyl 
3(S)-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5 
-acetate is added 30 ml of hydrogen chloride-ethyl acetate solution (5N) 
and the mixture stands for 3 hours at room temperature. The mixture is 
concentrated under reduced pressure and the resulting residue is 
crystallized from a mixture of ethyl acetate and ether to give 6.2 g of 
benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride as a colorless crystalline powder, melting at 
169.degree.-172.degree. C. 
Elemental Analysis for C.sub.18 H.sub.18 N.sub.2 O.sub.4.HCl: Calcd.: C, 
59.59; H, 5.28; N, 7.72; Found: C, 59.09; H, 5.12; N, 7.55 
[.alpha.].sub.D.sup.24 -202.degree. (c=0.6 in methanol) 
EXAMPLE 6 
In 100 ml of ethanol is dissolved 4.5 g of sodium, and 27.8 g of ethyl 
4-ethylhexanoate and 29 g of diethyl oxalate are added to the solution, 
and the low-boiling substance is removed by evaporation under reduced 
pressure at about 70.degree. C. for 40 minutes. After cooling, 500 ml of 
water and 300 ml of petroleum ether are added to the brown viscous 
residue, and the mixture is thoroughly shaken. The aqueous layer is 
separated off and the petroleum layer is extracted twice with 50 ml each 
of 1N sodium hydroxide solution. The extracts are combined, acidified 
slightly with concentrated hydrochloric acid and extracted twice with 200 
ml each of ethyl acetate. The extract is dried over anhydrous magnesium 
sulfate and concentrated under reduced pressure. One hundred and ten (110) 
ml of 10% aqueous dimethylsulfoxide and 10 g of sodium chloride are added 
to the oily residue, and the mixture is stirred at 160.degree. C. for 2.5 
hours. After the reaction mixture is cooled, 500 ml of water is added, 
followed by extraction with 300 ml of ethyl acetate. The extract is washed 
with water, dried over anhydrous magnesium sulfate and concentrated under 
reduced pressure. The brown oily residue is distilled under reduced 
pressure to give 16.4 g of ethyl 5-ethyl-2-oxoheptanoate as a pale yellow 
oil. 
Boiling point: 83.degree.-88.degree. C. (2 mmHg). 
EXAMPLES 7-12 
By carrying out the reaction using the carboxylic acid ethyl ester as shown 
in Table 1 as a starting compound similarly to the reaction of Example 6, 
the corresponding .alpha.-keto ester derivative is obtained. 
TABLE 1 
__________________________________________________________________________ 
Ex. No. 
Starting Compound Keto-ester obtained 
__________________________________________________________________________ 
##STR25## 
##STR26## 
8 
##STR27## 
##STR28## 
9 
##STR29## 
##STR30## 
10 
##STR31## 
##STR32## 
11 
##STR33## 
##STR34## 
12 CH.sub.3 (CH.sub.2).sub.7 COOC.sub.2 H.sub.5 
CH.sub.3 (CH.sub.2).sub.7 COCOOC.sub.2 
__________________________________________________________________________ 
H.sub.5 
*Removal of ethoxycarbonyl is conducted with use of lithium chloride. 
EXAMPLE 13 
In 30 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 5 g of 
3(S)-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one, 
and the mixture is allowed to stand at room temperature for 3 hours. The 
deposited crystals are collected by filtration to give 3.8 g of 
3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride as a 
colorless needles, melting at 230.degree.-240.degree. C. (decomposition). 
Elemental Analysis for C.sub.9 H.sub.10 N.sub.2 O.sub.2.HCl; Calcd.: C, 
50.36; H, 5.17; N, 13.05; Found: C, 50.30; H, 5.18; N, 13.02 
[.alpha.].sub.D -277.degree. (c=0.4 in methanol) 
EXAMPLE 14 
To a mixture of 100 ml of ethyl acetate and 50 ml of water is added 1.5 g 
of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride, 
and 1.5 ml of benzyloxycarbonyl chloride is added dropwise to the mixture 
at ice bath temperature with stirring. After stirring for 1 hour, the 
ethyl acetate layer separated, washed with water, dried over anhydrous 
magnesium sulfate and concentrated under reduced pressure. To the residue 
is added ethyl ether and the deposited crystals are collected by 
filtration to give 2 g of 
3(S)-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one. 
This product is recrystallized from a mixture of ethyl acetate and ether 
to give colorless needles melting at 157.degree.-159.degree. C. 
Elemental Analysis for C.sub.17 H.sub.16 N.sub.2 O.sub.4 ; Calcd.: C, 
65.38; H, 5.16; N, 8.97; Found: C, 65.54; H, 5.19; N, 8.95 
[.alpha.].sub.D -175.degree. (c=0.7 in methanol) 
EXAMPLE 15 
3(S)-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one (1.9 
g) obtained in Example 14 is reacted with 1.1 g of tert-butyl 
chloroacetate in a manner similar to that of Example 4 to give 2.5 g of 
tert-butyl 
3(S)-benzyloxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-a 
cetate as a pale yellow oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3350(NH); 1730, 1680 (C=O) 
Mass spectrum (m/e): 426 (M.sup.+) 
EXAMPLE 16 
In 30 ml of ethanol is dissolved 2 g of benzyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride obtained in Example 5, and 0.45 g of sodium acetate, 0.35 g 
of acetic acid, 4.5 g of ethyl 2-oxo-4-phenylbutyrate and 10 g of 
Molecular sieve 4A are added to the solution. After the mixture is stirred 
at room temperature for 30 minutes, a solution of 0.34 g of sodium 
cyanoborohydride in 30 ml of ethanol is added dropwise to the mixture over 
a period of 3 hours. After a solution of 1 g of sodium cyanoborohydride in 
30 ml of ethanol is further added dropwise to the mixture over a period of 
1 hour, the reaction mixture is concentrated under reduced pressure. To 
the residue are added 100 ml of water and 200 ml of ethyl acetate, and the 
mixture is stirred. After the insoluble substance is removed by 
filtration, the ethyl acetate layer is dried over anhydrous magnesium 
sulfate and concentrated under reduced pressure. After 50 ml of ethyl 
ether and 1 g of oxalic acid is added to the residue, the mixture is 
shaken and diluted with 300 ml of petroleum ether. The resulting mixture 
is allowed to stand overnight. The supernatant layer is removed by 
decantation, and 50 ml of water and 300 ml of ethyl acetate are added to 
the precipitate, followed by neutralization with an excess of sodium 
bicarbonate. The ethyl acetate layer is dried over anhydrous magnesium 
sulfate and concentrated under reduced pressure to give an oil, which is 
separated and purified by silica gel column chromatography (hexane: ethyl 
acetate=5:1-2:1) to yield firstly tert-butyl 
3(S)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetate as an oil. This product is dissolved in a mixture 
of 100 ml of petroleum ether and 20 ml of ether, and 1 ml of a solution of 
hydrogen chlorideethyl acetate (5N) is added to the solution to yield 0.9 
g of hydrochloride salt of the product as a colorless powder. 
Elemental Analysis for C.sub.30 H.sub.32 N.sub.2 O.sub.6.HCl; Calcd.: C, 
65.15; H, 6.01; N, 5.07; Found: C, 64.65; H, 6.17; N, 4.94 
[.alpha.].sub.D.sup.24 -86.9.degree. (c=0.5 in methanol) 
From the subsequently succeeding fraction, benzyl 
3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetate is obtained as a colorless oil. This product is 
converted to hydrochloride salt thereof as a colorless powder (yield 1.3 
g) in the same manner as mentioned above. 
Elemental Analysis for C.sub.30 H.sub.32 N.sub.2 O.sub.6.HCl; Calc.: C, 
65.15; H, 6.01; N, 5.07; Found: C, 64.97; H, 6.18; N, 4.99 
[.alpha.].sub.D.sup.24 -62.4.degree. (c=0.5 in methanol) 
EXAMPLE 17 
In 100 ml of ethanol is dissolved 0.7 g of benzyl 
3(S)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetate hydrochloride obtained in Example 16, and 
catalytic reduction is conducted at ordinary temperature and under 
atmospheric pressure using 0.5 g 10% palladium-carbon (containing 50% 
moisture) as a catalyst, when the absorption of hydrogen stops, the 
catalyst is filtered off and the filtrate is concentrated under reduced 
pressure. Petroleum ether is added to the residue to give 0.53 g of 
3(S)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder. 
Elemental Analysis for C.sub.23 H.sub.26 N.sub.2 O.sub.6.HCl.H.sub.2 O: 
Calcd.: C, 57.44; H, 6.08; N, 5.83; Found: C, 57.39; H, 5.97; N, 5.74 
[.alpha.].sub.D.sup.24 -98.6.degree. (c=0.6 in methanol) 
EXAMPLE 18 
Catalytic reduction of 1.1 g of benzyl 
3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetate hydrochloride obtained in Example 16 is carried 
out in a manner similar to that described in Example 17 to give 0.8 g of 
3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder. 
Elemental Analysis for C.sub.23 H.sub.26 N.sub.2 O.sub.6.HCl.1/2H.sub.2 O: 
Calcd.: C, 58.54; H, 5.98; N, 5.94; Found: C, 58.45; H, 6.08; N, 5.71 
[.alpha.].sub.D.sup.24 -69.9.degree. (c=0.6 in methanol) 
To this product is added 10 ml of water and the solution is extracted three 
times with 50 ml each of ethyl acetate. The extract is dried over 
anhydrous magnesium sulfate and concentrated under reduced pressure. To 
the oily residue ethyl ether is added and the resulting mixture is allowed 
to stand. The deposited crystals are filtered off and the filtrate is 
treated with hydrogen chloride-ethyl acetate solution to deposit powder, 
which is collected by filtration to give 
3(S)-[1(S)-ethoxycarbonyl-3-phenyl-propyl]amino-4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic acid hydrochloride which has higher optical 
purity. 
[.alpha.].sub.D -103.degree. (c=0.5 in methanol) 
EXAMPLE 19 
In a mixture of 1 ml of ethanol and 4 ml of sodium hydroxide solution (1N) 
is dissolved 0.15 g of 
3(S)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid hydrochloride obtained in Example 17, and the 
resulting mixture is allowed to stand for 2 hours and acidified slightly 
with 1N hydrochloric acid. The deposited powder is collected by 
filtration, dried and dissolved in 10 ml of ethanol. The insoluble 
substance is filtered off and filtrate is dried under reduced pressure to 
give 0.03 g of 
3(S)-[1(R)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo 
xazepine-5-acetic acid as a colorless powder. 
Elemental Analysis for C.sub.21 H.sub.22 N.sub.2 O.sub.6.3/2H.sub.2 O: 
Calcd.: C, 59.29; H, 5.92; N, 6.59; Found: C, 59.63; H, 5.64; N, 6.73 
[.alpha.].sub.D.sup.25 -112.degree. (c=0.3 in methanol) 
EXAMPLE 20 
Hydrolysis of 0.16 g of 
3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid hydrochloride obtained in Example 18 is 
carried out in a manner similar to that described in Example 19. The 
obtained crystals are recrystallized from ethanol to give 0.1 g of 
3(S)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo 
xazepine-5-acetic acid as a colorless prisms, melting at 
127.degree.-130.degree. C. 
Elemental Analysis for C.sub.21 H.sub.22 N.sub.2 O.sub.6.H.sub.2 O: Calcd.: 
C, 60.57; H, 5.81; N, 6.73; Found: C, 60.44; H, 5.69; N, 6.68 
[.alpha.].sub.D.sup.25 -86.5.degree. (c=0.4 in methanol) 
EXAMPLE 21 
Benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride (1.5 g) and ethyl 4-cyclohexyl-2-oxobutyrate (2.63 g) are 
subjected to reductive alkylation reaction in a manner similar to that 
described in Example 16, and the product is purified by silica gel column 
chromatography (hexane:ethal acetate=5:1-4:1). From the first fraction, 
0.4 g of benzyl 
3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate is obtained as a colorless oil. 
Elemental Analysis for C.sub.30 H.sub.38 N.sub.2 O.sub.6 : Calcd.: C, 
68.94; H, 7.33; N, 5.36; Found: C, 69.03; H, 7.27; N, 5.57 
[.alpha.].sub.D.sup.24 -110.degree. (c=1 in methanol) 
The second fraction gives 0.4 g of benzyl 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate as a colorless oil. 
Elemental Analysis for C.sub.30 H.sub.38 N.sub.2 O.sub.6 : Calcd.: C, 
68.94; H, 7.33; N, 5.36; Found: C, 69.08; H, 7.34; N, 5.60 
EXAMPLE 22 
Catalytic reduction of benzyl 
3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.35 g) obtained in Example 21 is carried 
out using 10% palladium-carbon as a catalyst in a manner similar to that 
described in Example 17. The oily product is dissolved in ether, and 0.5 
ml of hydrogen chloride-ethyl acetate solution (5N) is added dropwise to 
the solution to give 0.18 g of 
3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder. 
Elemental Analysis for C.sub.23 H.sub.32 N.sub.2 O.sub.6.HCl; Calcd.: C, 
58.91; H, 7.09; N, 5.97; Found: C, 58.89; H, 7.23; N, 5.82 
[.alpha.].sub.D.sup.25 -134.degree. (c=0.5 in methanol) 
EXAMPLE 23 
Catalytic reduction of benzyl 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.35 g) obtained in Example 21 is carried 
out in a manner similar to that described in Example 17. Ether is added to 
the oily product to deposit 0.31 g of 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid as colorless prisms, melting at 
135.degree.-139.degree. C. 
Elemental Analysis for C.sub.23 H.sub.32 N.sub.2 O.sub.6.1/2H.sub.2 O: 
Calcd.: C, 62.57; H, 7.53; N, 6.34; Found: C, 62.73; H, 7.38; N, 6.30 
[.alpha.].sub.D.sup.25 -128.degree. (c=0.5 in methanol) 
This product is recrystallized twice from a mixture of ethyl acetate and 
petroleum ether to give 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid as colorless prisms, having higher 
optical purity and melting point of 146.degree.-148.degree. C. 
Elemental Analysis for C.sub.23 H.sub.32 N.sub.2 O.sub.6 : Calcd.: C, 
63.87; H, 7.46; N, 6.48; Found: C, 64.07; H, 7.64; N, 6.45 
[.alpha.].sub.D.sup.25 -166.degree. (c=0.6 in methanol) 
EXAMPLE 24 
In 10 ml of N,N-dimethylformamide is dissolved 0.3 g of 
3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-S4-oxo-2,3,4,5-tetrahydro-1 
,5-benzoxazepine-5-acetic acid hydrochloride obtained in Example 18, and 
tert-butyl phenylalaninate (0.3 g) is added to the solution. A solution of 
0.13 g of diethyl phosphorocyanidate in N,N-dimethylformamide is added 
dropwise to the mixture at ice bath temperature. After the resulting 
mixture is stirred for 10 minutes, a solution of 0.14 g of triethylamine 
in N,N-dimethylformamide is added dropwise at ice bath temperature and the 
mixture is stirred for 30 minutes. To the reaction mixture is added 200 ml 
of ethyl acetate and the resulting mixture is washed successively with 50 
ml of water, 50 ml of 0.1N hydrochloric acid (twice), 50 ml of 0.1N sodium 
hydroxide solution and 50 ml of water. The ethyl acetate layer is dried 
over anhydrous magnesium sulfate and concentrated under reduced pressure 
to give 0.4 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl] 
amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-yl-N-acetyl-L-phenylala 
ninate as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3350(NH), 1730(ester), 1680, 
1690(amide) 
EXAMPLE 25 
In 100 ml of hydrogen chloride-ethyl acetate (5N) solution is dissolved 0.4 
g of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-yl-N-acetyl-L-phenylalaninate obtained in Example 24 and 
the solution is allowed to stand for 4 hours. The reaction solution is 
concentrated under reduced pressure, and 50 ml of ether is added to the 
residue. The resulting mixture is extracted twice with 70 ml each of 
saturated sodium bicarbonate solution and the aqueous layer is extracted 
with 50 ml of ether. The aqueous layer is neutralized with 1N hydrochloric 
acid and extracted with 100 ml of ethyl acetate. The ethyl acetate layer 
is dried over anhydrous magnesium sulfate and concentrated under reduced 
pressure. The oily product is dissolved in 10 ml of ether, and 0.5 ml of 
hydrogen chloride-ethyl acetate (5N) solution is added to the solution to 
give 0.2 g of 
3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-yl-N-acetyl-L-phenylalanine hydrochloride as a colorless 
powder. 
[.alpha.].sub.D.sup.25 -53.5.degree. (c=0.5 in methanol) 
Elemental Analysis for C.sub.32 H.sub.35 N.sub.3 O.sub.7.HCl: Calcd.: C, 
63.00; H, 5.95; N, 6.89; Found: C, 62.75; H, 5.93; N, 6.84 
EXAMPLE 26 
Catalytic reduction of 2.5 g of tert-butyl 
3(S)-benzyloxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-a 
cetate is carried out in a manner similar to that described in Example 17 
to give 1.2 g of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a 
colorless oil. 
Elemental Analysis for C.sub.15 H.sub.20 N.sub.2 O.sub.4 : Calcd.: C, 
61.63; H, 6.90; N, 9.58; Found: C, 61.75; H, 6.91; N, 9.37 
Mass spectrum (m/e): 292(M.sup.+) 
[.alpha.].sub.D -253.degree. (c=0.9 in methanol) 
EXAMPLES 27-34 
Benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride obtained in Example 5 is reacted with ethyl pyruvate or 
.alpha.-ketoester obtained in Examples 6-12 in a manner similar to that 
described in Example 16 to give a compound shown in Table 2 as an oil. 
TABLE 2 
__________________________________________________________________________ 
##STR35## 
Mass 
Ex. config. 
spectrum 
IR 
No. 
R *1 
*2 M.sup.+ (m/e) 
.nu. .sub.max.sup.neat 
__________________________________________________________________________ 
cm.sup.-1 
27 CH.sub.3 S R, S* 
426 3330, 1740 
1680 
28 
##STR36## S R 510 3330, 1730 1680 
##STR37## S S 510 3330, 1740 1670 
29 
##STR38## S R 536 3320, 1730 1670 
##STR39## S S 536 3330, 1740 1670 
30 
##STR40## S R 530 3330, 1740 1680 
##STR41## S S 530 3330, 1740 1680 
31 
##STR42## S R 524 3330, 1740 1680 
##STR43## S S 524 3330, 1740 1680 
32 
##STR44## S R 540 3330, 1740 1680 
##STR45## S S 540 3330, 1740 1680 
33 
##STR46## S R 657 3330, 1740 1690, 1680 
##STR47## S S 657 3330, 1740 1690, 1680 
34 CH.sub.3 (CH.sub.2).sub.7 
S R, S* 
524 3330, 1740, 
1680 
__________________________________________________________________________ 
*mixture of diastereomers 
In the table, Ph represents phenyl. 
EXAMPLE 35 
In 10 ml of ethanol is dissolved 0.5 g of benzyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride obtained in Example 5, and triethylamine (0.49 g) and ethyl 
bromoacetate (0.46 g) are added to the solution. After the solution is 
stirred for 4 days, the solution is dried under reduced pressure. The 
residue is purified by silica gel column chromatography (hexane:ethyl 
acetate=4:3) to give 0.28 g of benzyl 
3(S)-ethoxycarbonylmethylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine- 
5-acetate as a pale yellow oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH), 1740, 1680(C.dbd.O) 
Mass spectrum (m/e): 412(M.sup.+) 
[.alpha.].sub.D -148.degree. (c=0.4 in methanol) 
EXAMPLE 36-48 
Catalytic reduction of benzyl 1,5-benzoxazepine-5-acetate derivative 
obtained in Examples 27-35 is carried out using 10% palladium-carbon as a 
catalyst in a manner similar to that described in Example 17 to give 
1,5-benzoxazepine-5-acetic acid derivative shown in Table 3. 
TABLE 3 
__________________________________________________________________________ 
##STR48## 
Elemental analysis 
C H N Mass 
Ex. config. 
Composition 
calcd. spectrum 
No. 
R *1 
*2 formula (Found) (m/e)M.sup.+ 
__________________________________________________________________________ 
36 CH.sub.3 S S,R* 
C.sub.16 H.sub.20 N.sub.2 O.sub.6 
.sup. 50.33 
.sup. 5.80 
.sup. 7.34 
336 
HCl.1/2H.sub.2 O 
(50.11) 
(5.72) 
(7.32) 
37 
##STR49## S R C.sub.22 H.sub.32 N.sub.2 O.sub.6 HCl.1/2H.sub.2 
56.70 (56.64) 
7.35 (7.34) 
6.01 (5.97) 
420 
38 
##STR50## S S C.sub.22 H.sub.32 N.sub.2 O.sub.6 HCl.1/2H.sub.2 
56.70 (56.81) 
7.35 (7.28) 
6.01 (6.00) 
420 
39 
##STR51## S R C.sub.24 H.sub.34 N.sub.2 O.sub.6 HCl.1/2H.sub.2 
58.59 (58.43) 
7.38 (7.40) 
5.69 (5.60) 
446 
40 
##STR52## S S C.sub.24 H.sub.34 N.sub.2 O.sub.6 HCl.1/2H.sub.2 
58.59 (58.29) 
7.38 (7.41) 
5.69 (5.58) 
446 
41 
##STR53## S S C.sub.23 H.sub.28 N.sub.2 O.sub.6 HCl.1/2H.sub.2 
59.32 (59.29) 
6.22 (6.35) 
5.76 (5.72) 
440 
42 
##STR54## S R C.sub.22 H.sub.30 N.sub.2 O.sub.7 HCl.1/2H.sub.2 
55.06 (55.11) 
6.72 (6.78) 
5.84 (5.38) 
434 
43 
##STR55## S S C.sub.22 H.sub.30 N.sub.2 O.sub.7 HCl.1/2H.sub.2 
55.06 (54.73) 
6.72 (6.66) 
5.84 (5.71) 
434 
44 
##STR56## S R C.sub.22 H.sub.30 N.sub.2 O.sub.6 S. HCl.1/2H.sub.2 
O 53.27 (53.32) 
6.50 (6.47) 
5.65 (5.59) 
450 
45 
##STR57## S S C.sub.22 H.sub.30 N.sub.2 O.sub.6 S. HCl.1/2H.sub.2 
O 53.27 (53.15) 
6.50 (6.20) 
5.65 (5.77) 
450 
46 
##STR58## S S C.sub.22 H.sub.31 N.sub.3 O.sub.6. 2HCl.H.sub.2 
50.39 (50.36) 
6.73 (6.68) 
8.01 (7.56) 
433** 
47 CH.sub.3 (CH.sub.2).sub.7 
S R,S* 
C.sub.23 H.sub.34 N.sub.2 O.sub.6. 
.sup. 57.55 
.sup. 7.56 
.sup. 5.84 
434 
HCl.1/2H.sub.2 O 
(57.60) 
(7.50) 
(5.93) 
48 H S -- C.sub.15 H.sub.18 N.sub.2 O.sub.6 
.sup. 55.90 
.sup. 5.63 
.sup. 8.69 
322 
(55.47) 
(5.62) 
(8.28) 
__________________________________________________________________________ 
*mixture of diastereomers 
**free base is used for measurement. 
EXAMPLE 49 
Reaction of 9.5 g of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained 
in Example 26 and ethyl 4-cyclohexyl-2-oxobutyrate is carried out under 
reductive conditions in a manner similar to that described in Example 16, 
and the product is purified by silica gel column chromatography 
(hexane:ethyl acetate=5:1). From the first fraction, 2.3 g of tert-butyl 
3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate is obtained as a colorless oil. 
Elemental Analysis for C.sub.27 H.sub.40 N.sub.2 O.sub.6 : Calcd.: C, 
66.37; H, 8.25; N, 5.73; Found: C, 66.57; H, 8.57; N, 5.48 
Mass spectrum (m/e): 488 (M.sup.+) 
[.alpha.].sub.D -112.degree. (c=0.5 in methanol) 
From the second fraction, 3.2 g of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate is obtained as a colorless oil. 
Elemental Analysis for C.sub.27 H.sub.40 N.sub.2 O.sub.6 : Calcd.: C, 
66.37; H, 8.25; N, 5.73; Found: C, 66.72; H, 8.72; N, 5.82 
Mass spectrum (m/e): 488 (M.sup.+) 
[.alpha.].sub.D -125.degree. (c=0.4 in methanol) 
EXAMPLE 50 
In 10 ml of ethanol is dissolved 1.5 g of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate obtained in Example 49, and 1N sodium 
hydroxide solution is added dropwise over a period of 15 minutes. After 
stirring for 3 hours, the solution is diluted with water (200 ml) and 
extracted with ethyl ether (100 ml). The aqueous layer is acidified 
slightly with 1N hydrochloric acid to deposit crystals. This product is 
collected by filtration and dried to give 1.2 g of tert-butyl 
3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-b 
enzoxazepine-5-acetate as colorless needles, melting at 
180.degree.-183.degree. C. 
Elemental Analysis for C.sub.25 H.sub.36 N.sub.2 O.sub.6 : Calcd.: C, 
65.20; H, 7.88; N, 6.08; Found: C, 65.18; H, 7.83; N, 6.14 
[.alpha.].sub.D -122.degree. (c=0.5 in methanol) 
EXAMPLE 51 
In 10 ml of N,N-dimethylformamide is dissolved 0.25 g of tert-butyl 
3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-b 
enzoxazepine-5-acetate obtained in Example 50, and benzyl bromide (0.14 g), 
sodium bicarbonate (0.7 g) and potassium iodide (0.05 g) are added to the 
solution. The reaction solution is stirred at room temperature for 6 hours 
and diluted with water (100 ml) and extracted with ethyl acetate. The 
extract is washed successively with 1N hydrochloric acid and water, dried 
over anhydrous magnesium sulfate and concentrated under reduced pressure. 
The oily product is purified by silica gel column chromatography 
(hexane:ethyl acetate=5:1) to give 0.25 g of tert-butyl 
3(S)-[1(S)-benzyloxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrah 
ydro-1,5-benzoxazepine-5-acetate as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH), 1740, 1680 (C.dbd.O) 
[.alpha.].sub.D -155.degree. (c=0.6 in methanol) 
Mass spectrum (m/e): 550(M.sup.+) 
EXAMPLES 52-53 
Reaction of tert-butyl 
3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-b 
enzoxazepine-5-acetate and halide shown in Table 4 is carried out in a 
manner similar to that of described in Example 51 to give a benzoxazepine 
derivative shown in Table 4. 
TABLE 4 
______________________________________ 
##STR59## 
[.alpha.].sub.D 
Ex. Halogenated Config 
(in 
No. compound used 
R *1 *2 methanol) 
______________________________________ 
52 BrCH.sub.2 COOC.sub.2 H.sub.5 
CH.sub.2 COOC.sub.2 H.sub.5 
S S -145.degree. 
(C = 0.7) 
53 I(CH.sub.2).sub.3 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
S S -200.degree. 
(C = 0.5) 
______________________________________ 
EXAMPLE 54 
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.5 g 
of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate obtained in Example 49, and the solution is 
allowed to stand at room temperature for 4 hours. To the solution is added 
200 ml of petroleum ether and the resulting mixture is shaken thoroughly. 
After the supernatant is removed by decantation, the residue is diluted 
with 50 ml of water and extracted three times with 100 ml each of ethyl 
acetate. The extract is washed with water, dried over anhydrous magnesium 
sulfate and concentrated under reduced pressure. Ethyl ether is added to 
the viscous residue to give 0.37 g of 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid as colorless crystals melting at 
135.degree.-139.degree. C. 
[.alpha.].sub.D -144.degree. (c=0.3 in methanol) 
This product is recrystallized from ethyl acetate and petroleum ether to 
give 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid as colorless prisms, which is identical 
with the compound obtained by recrystallization in Example 23. 
EXAMPLES 55-57 
Benzoxazepine-5-acetic acid tert-butyl ester derivatives obtained in 
Examples 51 to 53 are treated with hydrogen chloride in a manner similar 
to that described in Example 54 to give benzoxazepine-5-acetic acid 
derivatives shown in Table 5. 
TABLE 5 
______________________________________ 
##STR60## 
Ex. Config [.alpha.].sub.D 
No. R *1 *2 (in methanol) 
______________________________________ 
55 
##STR61## S S -115.degree. C = 0.5 
56 CH.sub.2 COOC.sub.2 H.sub.5 
S S -114.degree. 
C = 0.6 
57 (CH.sub.2).sub.3 CH.sub.3 
S S -106.degree. 
C = 0.4 
______________________________________ 
EXAMPLE 58 
In 1 ml of ethanol is dissolved 0.2 g of 
3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid obtained in Example 54, and 3 ml of 1N 
sodium hydroxide solution is added to the solution. After stirring at room 
temperature for 2 hours, the solution is acidified slightly with 1N 
hydrochloric acid. The deposited crystals are collected by filtration, 
washed with water, dried and recrystallized from ethanol to give 0.14 g of 
3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-b 
enzoxazepine-5-acetic acid as colorless crystals, melting at 
202.degree.-205.degree. C. 
Elemental Analysis for C.sub.21 H.sub.28 N.sub.2 O.sub.6.H.sub.2 O: Calcd.: 
C, 59.70; H, 7.16; N, 6.63; Found: C, 59.81; H, 7.03; N, 6.68 
[.alpha.].sub.D -131.degree. (c=0.4 in methanol) 
EXAMPLE 59 
In 5 ml of 1N sodium hydroxide solution is dissolved 0.2 g of 
3(S)-[1(S)-ethoxycarbonyl-3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propyl]amino 
-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride 
obtained in Example 43, and the solution is allowed to stand at room 
temperature for 1 hours. The solution is neutralized with 1.5 ml of acetic 
acid and purified by Amberlite XAD-2 column chromatography 
(acetone:water=1:1). The eluate is concentrated under reduced pressure and 
lyophilized to give 0.16 g of 
3(S)-[1(S)-carboxy-3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propyl]amino-4-oxo- 
2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as a colorless powder. 
Elemental Analysis for C.sub.20 H.sub.26 N.sub.2 O.sub.7.1/2H.sub.2 O: 
Calcd.: C, 57.82; H, 6.55; N, 6.74; Found: C, 57.41; H, 6.01; N, 6.36 
[.alpha.].sub.D -128.degree. (c=0.4 in methanol) 
EXAMPLE 60 
3(S)-[1(S)-Ethoxycarbonyl-3-(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahy 
dro-1,5-benzoxazepine-5-acetic acid obtained in Example 46 is subjected to 
hydrolysis in a manner similar to that described in Example 59, purified 
and lyophilized to give 
3(S)-[1(S)-carboxy-3-(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid as a colorless powder. 
[.alpha.].sub.D -132.degree. (c=0.6 in methanol) 
SIMS spectrum (m/e): 406 (MH.sup.+) 
EXAMPLE 61 
3(S)-[1(S)-Ethoxycarbonyl-3-(4-thianyl)propyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid hydrochloride obtained in Example 45 is 
subjected to hydrolysis in a manner similar to that described in Example 
60 and purified by Amberlite XAD-2 column chromatography. The eluate is 
concentrated under reduced pressure to give 
3(S)-[1(S)-carboxy-3-(4-thianyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid as crystals. 
Elemental Analysis for C.sub.20 H.sub.26 N.sub.2 O.sub.6 S.H.sub.2 O: 
Calcd.: C, 54.53; H, 6.41; N, 6.36; Found: C, 54.12; H, 6.32; N, 6.30 
EXAMPLE 62 
In 150 ml of acetonitrile are dissolved 5 g of benzyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride and 13 g of ethyl 2-bromo-5-phthalimidohexanoate, and 3.2 g 
of triethylamine is added to the solution. After heating at 80.degree. C. 
for 4 days, the solution is concentrated under reduced pressure and 
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. Ethyl acetate (15 ml) and oxalic acid 
(3 g) is added to the residue. Petroleum ether (200 ml) is added to the 
solution and the resulting mixture is shaken. After standing, the 
supernatant is removed by decantation and 100 ml of water and 150 ml of 
ethyl acetate are added to the precipitate. The resulting mixture is 
neutralized with sodium bicarbonate and the ethyl acetate layer is dried 
over anhydrous magnesium sulfate and concentrated under reduced pressure. 
The resulting oil is separated and purified by silica gel column 
chromatography (hexane:ethyl acetate=2:1-3:2) to give firstly 2.3 g of 
benzyl 
3(S)-[1(R)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH), 1770, 1740, 1720, 1680 
(C.dbd.O) 
[.alpha.].sub.D -104.degree. (in methanol) 
From the succeeding fraction, benzyl 
3(S)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH), 1760, 1710, 1680(C.dbd.O) 
[.alpha.].sub.D -100.degree. (in methanol) 
EXAMPLE 63 
In 20 ml of ethanol is dissolved 0.15 g of benzyl 
3(S)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate obtained in Example 62 and catalytic 
reduction is carried out at ordinary temperature and under atmospheric 
pressure using 0.1 g of 10% palladium-carbon as a catalyst. After the 
absorption of hydrogen stops, the catalyst is filtered off and the 
filtrate is concentrated under reduced pressure. The oily product is 
dissolved in 3 ml of ethyl ether, and 0.5 ml of hydrogen chloride-ethyl 
acetate solution (5N) to the solution to give 0.12 g of 
3(S)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder. 
Elemental Analysis for C.sub.26 H.sub.29 N.sub.3 O.sub.8.HCl.1/2H.sub.2 O: 
Calcd.: C, 56.07; H, 5.61; N, 7.54; Found: C, 56.19; H, 5.31; N, 7.44 
[.alpha.].sub.D -104.degree. (in methanol) 
EXAMPLE 64 
In 100 ml of acetonitrile are dissolved 2.8 g of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate and 7.6 g 
of ethyl 2-bromo-8-phthalimidooctanoate, and 1.3 g of triethylamine is 
added to the solution. After heating at 80.degree. C. for 3 days, the 
reaction solution is concentrated under reduced pressure, diluted with 200 
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. Ethyl acetate (10 ml) and oxalic acid (2.8 g) are added 
to the residue, and 200 ml of petroleum ether is added to the solution. 
After shaking, the resulting solution is allowed to stand. The supernatant 
is removed by decantation and 150 ml of water and 200 ml of ethyl acetate 
are added to the precipitate. The mixture is neutralized with sodium 
bicarbonate and the ethyl acetate layer is dried over anhydrous magnesium 
sulfate and concentrated under reduced pressure. The oily product is 
separated and purified by silica gel column chromatography to give 1.5 g 
of tert-butyl 
3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate from the first fraction. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3340(NH), 1770, 1740, 1710, 1670 
(C.dbd.O) 
[.alpha.].sub.D -104.degree. (in methanol) 
From the second fraction, 1.7 g of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate is obtained. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3340(NH), 1775, 1740, 1720, 
1680(C.dbd.O) 
[.alpha.].sub.D -115.degree. (in methanol) 
EXAMPLE 65 
In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.12 g 
of tert-butyl 
3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate obtained in Example 64, and the solution is 
allowed to stand at room temperature for 3 hours. Petroleum ether (100 ml) 
is added to the solution and the deposited precipitate is dried under 
reduced pressure to give 0.08 g of 
3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder. 
[.alpha.].sub.D -128.degree. (in methanol) 
Elemental Analysis for C.sub.29 H.sub.33 N.sub.3 O.sub.8.HCl.1/2H.sub.2 O: 
Calcd.: C, 58.34; H, 5.90; N, 7.03; Found: C, 58.25; H, 5.75; N, 7.08 
EXAMPLE 66 
In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.11 g 
of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate obtained in Example 64, and the solution is 
allowed to stand at room temperature for 3 hours. Petroleum ether (100 ml) 
is added to the solution and the deposited precipitate is dried under 
reduced pressure to give 0.095 g of 
3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder. 
Elemental Analysis for C.sub.29 H.sub.33 N.sub.3 O.sub.8.HCl.1/2H.sub.2 O: 
Calcd.: C, 58.34; H, 5.90; N, 7.03; Found: C, 58.43; H, 6.02; N, 6.80 
[.alpha.].sub.D -104.degree. (in methanol) 
EXAMPLE 67 
In 10 ml of ethanol is dissolved 0.7 g of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate obtained in Example 64, and hydrazine 
hydrate (0.29 g) is added to the solution. After standing overnight, the 
solution is concentrated under reduced pressure, diluted with 50 ml of 
water and extracted five times with 30 ml each of ethyl acetate. To the 
ethyl acetate layer are added 50 ml of water and 0.7 g of sodium 
bicarbonate and 0.38 g of di-tert-butyl dicarbonate is added dropwise to 
the resulting mixture with stirring. After the mixture is stirring at room 
temperature for 0.5 hour, the ethyl acetate layer is dried over anhydrous 
magnesium sulfate and concentrated under reduced pressure. The residue is 
purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to 
give 0.51 g of tert-butyl 
3(S)-[7-tert-butoxycarbonylamino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3 
,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740, 1710, 1680(C.dbd.O) 
[.alpha.].sub.D -122.degree. (in methanol) 
EXAMPLE 68 
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 1.1 g 
of tert-butyl 
3(S)-[7-tert-butoxycarbonylamino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3 
,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 67 and the 
solution is allowed to stand at room temperature for 3 hours. Petroleum 
ether (100 ml) is added to the solution and the deposited precipitate is 
dried under reduced pressure to give 0.9 g of 
3(S)-[7-amino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid dihydrochloride as a colorless powder. 
[.alpha.].sub.D -108.degree. (in methanol) 
EXAMPLE 69 
In 15 ml of 1N sodium hydroxide solution is dissolved 0.5 g of 
3(S)-[7-amino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid dihydrochloride obtained in Example 68, and 
the solution is allowed to stand at room temperature for 30 minutes. 
Acetic acid (3.5 ml) is added to the solution and the mixture is purified 
by Amberlite XAD-2 column chromatography (methanol:water=1:2). The eluate 
is concentrated under reduced pressure and lyophilized to give 0.31 g of 
3(S)-[7-amino-1(S)-carboxyheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzox 
azepine-5-acetic acid as a colorless powder. 
[.alpha.].sub.D -159.degree. (in methanol) 
SIMS spectrum (m/e): 394(MH.sup.+) 
EXAMPLE 70 
A mixture of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2 g), 
ethyl 2-bromo-7-phthalimidoheptanoate (3.9 g), acetonitrile (100 ml) and 
triethylamine (0.9 g) is heated at 80.degree. C. for 3 days. After 
evaporation of acetonitrile, water (150 ml) and ethyl acetate (200 ml) is 
added to the residue, and the mixture is agitated thoroughly. The ethyl 
acetate layer is dried over anhydrous magnesium sulfate and concentrated 
in vacuo. The oily residue is dissolved in a mixture of ethyl acetate (10 
ml) and oxalic acid (2 g). The resulting solution is diluted with 
petroleum ether (200 ml) and agitated thoroughly. The supernatant layer is 
removed by decantation. To the precipitate are added water (150 ml), ethyl 
acetate (200 ml) and sodium bicarbonate with stirring. The ethyl acetate 
layer is separated, dried over anhydrous magnesium sulfate and 
concentrated in vacuo. The oily residue is chromatographed on silica gel 
using hexane-ethyl acetate (2:1-1:1) as an eluent. Evaporation of the 
first fraction affords tert-butyl 
3(S)-[1(R)ethoxycarbonyl-6-phthalimidohexyl[amino-4-oxo-2,3,4,5-tetrahydro 
-1,5-benzoxazepine-5-acetate (0.65 g) as a colorless oil 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH); 1770, 1740, 1710, 1680 
(C.dbd.O) 
[.alpha.].sub.D -110.degree. (in methanol). 
Mass spectrum (m/e): 593(M.sup.+) 
Evaporation of the second fraction gives tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-6-phthaliminohexyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.75 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH):; 1770, 1740, 1710, 
1670(C.dbd.O) 
[.alpha.].sub.D -123.degree. (in methanol) 
Mass spectrum (m/e): 593(M.sup.+) 
EXAMPLE 71 
A mixture of 5N hydrogen chloride-ethyl acetate solution (5 ml) and 
tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.1 g) is allowed to stand at room 
temperature for 3 hours. The mixture is diluted with petroleum ether (80 
ml) to precipitate colorless powder, which is collected and dried in vacuo 
to give 
3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid hydrochloride (0.08 g). 
[.alpha.].sub.D -108.degree. (in methanol) 
Elemental Analysis for C.sub.28 H.sub.31 N.sub.3 O.sub.8.HCl.1/2H.sub.2 O: 
Calcd.: C, 57.68; H, 5.53; N, 7.21; Found: C, 57.65; H, 5.65; N, 7.13 
EXAMPLE 72 
A mixture of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.65 g), hydrazine hydrate (0.27 g) and 
ethanol (10 ml) is allowed to stand overnight at room temperature. The 
mixture is concentrated in vacuo, diluted with water (50 ml) and extracted 
with ethyl acetate (50 ml.times.4). To a mixture of the organic extract, 
water (50 ml) and sodium bicarbonate (0.65 g) are added dropwise 
di-tert-butyl dicarbonate (0.36 g) with stirring at room temperature. 
After stirring for 30 minutes, the ethyl acetate layer is separated, dried 
over anhydrous magnesium sulfate and concentrated in vacuo. The residue is 
subjected to silica gel column chromatography using hexane:ethyl acetate 
(2:1-1:1) as an eluent to yield tert-butyl 
3(S)-[6-tert-butoxycarbonylamino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3, 
4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.54 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740, 1720, 1680(C.dbd.O) 
[.alpha.].sub.D -128.degree. (in methanol) 
Mass spectrum (m/e): 563(M.sup.+) 
EXAMPLE 73 
A solution of tert-butyl 
3(S)-[6-tert-butoxy-carbonylamino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3 
,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.5 g) in 5N hydrogen 
chloride-ethyl acetate solution (10 ml) is allowed to stand for 3.5 hours 
at room temperature. Petroleum ether (80 ml) is added to the solution, and 
the resulting precipitate is collected and dried in vacuo to give 
3(S)-[6-amino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid dihydrochloride (0.4 g) as colorless powder. 
[.alpha.].sub.D -118.degree. (in methanol) 
Mass spectrum (m/e): 407(M.sup.+) 
EXAMPLE 74 
A solution of 
3(S)-[6-amino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid dihydrochloride (0.35 g) in 1N sodium hydroxide 
solution (10 ml) is allowed to stand for 30 minutes at room temperature. 
After addition of acetic acid (2.5 ml), the mixture is subjected to 
Amberlite XAD-2 column chromatography eluting with methanol-water (1:10). 
The eluate is concentrated under reduced pressure and lyophilized to yield 
3(S)-[6-amino-1(S)-carboxyhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxa 
zepine-5-acetic acid (0.17 g) as colorless powder. 
[.alpha.].sub.D -157.degree. (in methanol) 
SIMS spectrum (m/e): 380(MH.sup.+) 
EXAMPLE 75 
A mixture of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.1 g), 
ethyl 2-bromo-9-phthalimidononanoate (3 g), acetonitrile (100 ml) and 
triethylamine (0.96 g) is heated at 80.degree. C. for 3 days. After 
evaporation of the solvent, ethyl acetate (200 ml) and water (150 ml) are 
added to the residue. The ethyl acetate layer is separated, dried over 
anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is 
chromatographed on silica gel using hexane-ethyl acetate (2:1-1:1) as an 
eluent. Evaporation of the first eluate gives tert-butyl 
3(S)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.6 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH); 1770, 1740, 1710, 
1680(C.dbd.O) 
[.alpha.].sub.D -106.degree. (in methanol) 
From the second eluate is obtained tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-8-phthalimido-octyl]amino-4-oxo-2,3,4,5-tetrahyd 
ro-1,5-benzoxazepine-5-acetate (0.65 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1770, 1740, 1710, 
1680(C.dbd.O) 
[.alpha.].sub.D -110.degree. (in methanol) 
Mass spectrum (m/e): 621(M.sup.+) 
EXAMPLE 76 
A mixture of 5N hydrogen chloride-ethyl acetate solution (5 ml) and 
tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.1 g) is allowed to stand at room 
temperature for 3 hours. The mixture is diluted with petroleum ether (80 
ml) to precipitate colorless powder, which is collected and dried in vacuo 
to give 
3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetic acid.hydrochloride (0.067 g). 
[.alpha.].sub.D -100.degree. (in methanol) 
Elemental analysis for C.sub.30 H.sub.35 N.sub.3 O.sub.8.HCl.1/2H.sub.2 O: 
Calcd.: C, 58.97; H, 6.10; N, 6.88; Found: C, 59.10; H, 6.26; N, 6.72 
EXAMPLE 77 
A mixture of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.55 g), hydrazine hydrate (0.22 g) and 
ethanol (10 ml) is allowed to stand overnight at room temperature. After 
evaporation of ethanol, the residue is dissolved in water (50 ml) and 
extracted with ethyl acetate (50 ml.times.4). Water (50 ml) and sodium 
bicarbonate (0.6 g) are added to the organic extract, and to the resulting 
mixture is added dropwise di-tert-butyl dicarbonate (0.29 g) with 
stirring. After stirring for 30 minutes at room temperature, the ethyl 
acetate layer is separated, dried over anhydrous magnesium sulfate and 
concentrated in vacuo. The residue is purified by silica gel column 
chromatography using hexane:ethyl acetate (2:1-1:1) as an eluent to give 
tert-butyl 
3(S)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3, 
4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.48 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740, 1720, 1680 (C.dbd.O) 
[.alpha.].sub.D -102.degree. (in methanol) 
Mass spectrum (m/e): 591 (M.sup.+) 
EXAMPLE 78 
A mixture of tert-butyl 
3(S)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3, 
4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.45 g) and 5N hydrogen 
chloride-ethyl acetate solution (10 ml) is allowed to stand for 3.5 hours 
at room temperature. The mixture is diluted with petroleum ether (80 ml) 
to precipitate colorless powder, which is collected and dried in vacuo to 
give 
3(S)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid.dihydrochloride (0.37 g). 
[.alpha.].sub.D -114.degree. (in methanol) 
Mass spectrum (m/e): 435(M.sup.+) 
EXAMPLE 79 
A solution of 
3(S)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid.dihydrochloride (0.3 g) in 1N sodium hydroxide 
solution (10 ml) is allowed to stand for 30 minutes at room temperature. 
After addition of acetic acid (2.5 ml), the mixture is subjected to 
Amberlite XAD-2 column chromatography eluting with methanol-water (1:2). 
The eluate is concentrated under reduced pressure and lyophilized to yield 
3(S)-[8-amino-1(S)-carboxyoctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxa 
zepine-5-acetic acid (0.2 g) as colorless powder. 
Elemental analysis for C.sub.20 H.sub.29 N.sub.3 O.sub.6.H.sub.2 O: Calcd.: 
C, 56.46; H, 7.34; N, 9.87; Found: C, 56.61; H, 6.86; N, 9.85 
[.alpha.].sub.D -147.degree. (in methanol) 
SIMS spectrum (m/e): 408(MH.sup.+) 
EXAMPLE 80 
A mixture of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (1.65 g), 
ethyl 2-bromo-10-phthalimidodecanoate (2.4 g), acetonitrile (100 ml) and 
triethylamine (0.75 g) is heated at 80.degree. C. for 4 days. After 
evaporation of the solvent, ethyl acetate (200 ml) and water (100 ml) are 
added to the residue. The ethyl acetate layer is dried over anhydrous 
magnesium sulfate and evaporated in vacuo. The oily residue is 
chromatographed on silica gel using hexane-ethyl acetate (2:1) as an 
eluent. Evaporation of the first fraction gives tert-butyl 
3(S)-[1(R)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.45 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1770, 1740, 1710, 
1680(C.dbd.O) 
[.alpha.].sub.D -100.degree. (in methanol) 
Mass spectrum (m/e): 635(M.sup.+) 
From the second fraction is obtained tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.55 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1770, 1740, 1710, 
1680(C.dbd.O) 
[.alpha.].sub.D -98.degree. (in methanol) 
Mass spectrum (m/e): 635(M.sup.+) 
EXAMPLE 81 
A mixture of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.08 g) and 5N hydrogen chloride-ethyl 
acetate solution (5 ml) is allowed to stand at room temperature for 3 
hours. The mixture is diluted with petroleum ether (80 ml) to precipitate 
colorless powder, which is collected and dried under reduced pressure to 
yield 
3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tertrahyd 
ro-1,5-benzoxazepine-5-acetic acid hydrochloride (0.066 g). 
[.alpha.].sub.D -101.degree. (in methanol) 
Elemental analysis for C.sub.31 H.sub.37 N.sub.3 O.sub.8.HCl.1/2H.sub.2 O: 
Calcd.: C, 59.56; H, 6.29; N, 6.72; Found: C, 59.29; H, 6.48; N, 6.51 
EXAMPLE 82 
A mixture of tert-butyl 
3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydr 
o-1,5-benzoxazepine-5-acetate (0.46 g), hydrazine hydrate (0.18 g) and 
ethanol (10 ml) is allowed to stand overnight at room temperature. The 
mixture is concentrated under reduced pressure, diluted with water (50 ml) 
and extracted with ethyl acetate (50 ml.times.4). Water (50 ml) and sodium 
bicarbonate (0.5 g) are added to the organic extract, and to the resulting 
mixture is added dropwise di-tert-butyl dicarbonate (0.24 g) with 
stirring. After stirring for 30 minutes at room temperature, the ethyl 
acetate layer is dried over anhydrous magnesium sulfate and concentrated 
in vacuo. The residue is purified by silica gel column chromatography 
using hexane-ethyl acetate (2:1) as an eluent to yield tert-butyl 
3(S)-[9-tert-butoxycarbonylamino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3, 
4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740, 1710, 1680(C.dbd.O) 
[.alpha.].sub.D -116.degree. (in methanol) 
Mass spectrum (m/e): 605(M.sup.+) 
EXAMPLE 83 
A mixture of terty-butyl 
3(S)-[9-tert-butoxycarbonylamino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3, 
4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.33 g) and 5N hydrogen 
chloride-ethyl acetate solution (8 ml) is allowed to stand for 2.5 hours 
at room temperature. The mixture is diluted with petroleum ether (80 ml) 
to deposit colorless powder, which is collected and dried under reduced 
pressure to give 
3(S)-[9-amino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid dihydrochloride (0.25 g). 
Elemental Analysis for C.sub.23 H.sub.35 N.sub.3 O.sub.6.2HCl.H.sub.2 O: 
Calcd: C, 51.11, H, 7.27; N, 7.77; Found: C, 51.17; H, 7.57; N, 7.34 
[.alpha.].sub.D -110.degree. (in methanol) 
EXAMPLE 84 
A solution of 
3(S)-[9-amino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetic acid dihydrochloride (0.2 g) in 1N sodium hydroxide 
solution (6 ml) is allowed to stand for 30 minutes at room temperature. 
Acetic acid (1.5 ml) is added and the resulting mixture is subjected to 
Amberlite XAD-2 column chromatography using methanol-water (1:2) as an 
eluent. The eluate is concentrated in vacuo and lyophilized to yield 
3(S)-[9-amino-1(S)-carboxynonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxa 
zepine-5-acetic acid (0.15 g) as colorless powder. 
Elemental Analysis for C.sub.21 H.sub.31 N.sub.3 O.sub.6.H.sub.2 O: Calcd.: 
C, 57.39; H, 7.57; N, 9.56; Found: C, 57.42; H, 7.27; N, 9.58 
[.alpha.].sub.D -142.degree. (in methanol) 
SIMS spectrum (m/e): 422(MH.sup.+) 
EXAMPLE 85 
A mixture of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one 
hydrochloride (2 g), ethanol (100 ml), sodium acetate (0.8 g), acetic acid 
(0.6 g), molecular sieves 4A (5 g) and ethyl 4-cyclohexyl-2-oxo-butyrate 
(5 g) is catalytically hydrogenated over Raney nickel at room temperature 
under atmospheric pressure. After the absorption of hydrogen ceases, the 
catalyst is removed by filtration and the filtrate is evaporated in vacuo. 
To the residue are added water (50 ml) and ethyl acetate (200 ml), and the 
mixture is agitated thoroughly. The ethyl acetate layer is dried over 
anhydrous magnesium sulfate and evaporated in vacuo to yield an oily 
residue containing 
3-(1-ethoxycarbonyl-3-cyclohexylpropyl)amino-2,3,4,5-tetrahydro-1,5-benzox 
azepine-4-one. A mixture of this oil, potassium carbonate (4 g), tert-butyl 
chloroacetate (3 g), potassium iodide (0.2 g) and N,N-dimethylformamide 
(20 ml) is stirred overnight at room temperature, and then diluted with a 
mixture of water (300 ml) and ethyl acetate (200 ml). The organic layer is 
separated, dried over anhydrous magnesium sulfate and evaporated in vacuo 
to yield an oil, which is purified by silica gel column chromatography 
using hexaneethyl acetate (4:1) as an eluant to yield tert-butyl 
3-(1-ethoxycarbonyl-3-cyclohexylpropyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5- 
benzoxazepine-5-acetate (1 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH); 1730, 1680(C.dbd.O) 
EXAMPLE 86 
A mixture of benzyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride (2.5 g), ethanol (30 ml), sodium acetate (0.57 g), acetic 
acid (0.4 g), ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate (2.5 
g) and molecular sieves 3A (10 g) is stirred for 10 minutes at room 
temperature. To the stirred mixture is added dropwise a solution of sodium 
cyanoborohydride (0.4 g) in ethanol (50 ml) for 2 hours. After standing 
overnight at room temperature, the mixture is concentrated in vacuo and 
diluted with a mixture of water (300 ml) and ethyl acetate (300 ml). The 
resulting mixture is agitated thoroughly and filtered. The ethyl acetate 
layer is separated, dried over anhydrous magnesium sulfate and 
concentrated in vacuo. The residue is dissolved in a mixture of ethyl 
acetate (20 ml) and oxalic acid (2 g). This solution is diluted with 
petroleum ether (300 ml), and the supernatant layer is removed by 
decantation. To the precipitate are added water (100 ml), ethyl acetate 
(200 ml) and excess sodium bicarbonate. The ethyl acetate layer is 
separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. 
The oily residue is subjected to silica gel column chromatography using 
hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction 
gives benzyl 
3(S)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4 
-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) as a colorless 
oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1740, 1690, 1680(C.dbd.O) 
Mass spectrum (m/e): 671(M.sup.+) 
From the second fraction is obtained benzyl 
3(S)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1-(S)-ethoxycarbonylbutyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.75 g) as a 
colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1740, 1690, 1680(C.dbd.O) 
Mass spectrum (m/e): 671(M.sup.+) 
EXAMPLE 87 
A solution of benzyl 
3(S)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4 
-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) in ethanol (50 
ml) is subjected to catalytic hydrogenolysis over 10% palladium-carbon (1 
g, 50% wet) at room temperature under atmospheric pressure. After the 
absorption of hydrogen ceases, the catalyst is removed by filtration and 
the filtrate is evaporated in vacuo. The residue is triturated four times 
with ethyl ether (100 ml) and then dissolved in ethanol (5 ml). To this 
solution is added 5N-hydrogen chloride-ethyl acetate solution (1 ml) and 
the resulting mixture is diluted with ethyl ether to deposit 
3(S)-[1(R)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahy 
dro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.12 g) as colorless 
powder. 
Elemental analysis for C.sub.23 H.sub.33 N.sub.3 O.sub.6.2HCl.2H.sub.2 O: 
Calcd.: C, 49.64; H, 7.06; N, 7.55; Found: C, 49.17; H, 6.99; N, 7.52 
[.alpha.].sub.D -121.degree. (in methanol) 
EXAMPLE 88 
A solution of benzyl 
3(S)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylbutyl]amino-4 
-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.75 g) in ethanol is 
subjected to catalytic hydrogenolysis over 10% palladium carbon (1 g, 50% 
wet) at ambient temperature and pressure until the absorption of hydrogen 
ceases. After removal of the catalyst by filtration, the filtrate is 
concentrated and diluted with ethyl ether (30 ml) to precipitate colorless 
powder, which is collected by filtration and then dissolved in ethyl 
acetate (10 ml). To the solution is added 5N hydrogen chloride-ethyl 
acetate solution (2 ml), and the resulting mixture is diluted with ethyl 
ether (50 ml) to deposit colorless powder, which is collected by 
filtration to yield 
3(S)-[1(S)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahy 
dro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.45 g). 
Elemental analysis for C.sub.23 H.sub.33 N.sub.3 O.sub.6.2HCl.2H.sub.2 O: 
Calcd.: C, 49.64; H, 7.06; N, 7.55; Found: C, 49.83; H, 7.07; N, 7.29 
[.alpha.].sub.D -93.degree. (in methanol) 
EXAMPLE 89 
A solution of 
3(S)-[1(S)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahy 
dro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.35 g) in 1N sodium 
hydroxide solution (8 ml) is allowed to stand for 30 minutes at room 
temperature. After addition of acetic acid (1.5 ml), the mixture is 
subjected to column chromatography on MCI gel (CHP 20P, 150-300.mu., 
Mitsubishi Chemical) using water-methanol (2:1) as an eluent. The eluate 
is concentrated in vacuo and lyophilized to yield 
3(S)-[1(S)-carboxy-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid (0.2 g) as colorless powder. 
Elemental analysis for C.sub.21 H.sub.29 N.sub.3 O.sub.6.3/2H.sub.2 O: 
Calcd.: C, 56.49; H, 7.22; N, 9.41; Found: C, 56.86; H, 7.31; N, 9.41 
[.alpha.].sub.D -133.degree. (in methanol) 
SIMS spectrum (m/e): 420(MN.sup.+) 
EXAMPLE 90 
A mixture of benzyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate 
hydrochloride (3.4 g), ethanol (30 ml), sodium acetate (0.77 g), acetic 
acid (0.56 g), ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate 
(4.4 g) and molecular sieves 3A (10 g) is stirred for 10 minutes at room 
temperature. To the stirred mixture is added dropwise a solution of sodium 
cyanoborohydride (0.6 g) in ethanol (50 ml) for 3 hours. After standing 
overnight at room temperature, the mixture is concentrated in vacuo and 
diluted with a mixture of water (100 ml) and ethyl acetate (200 ml). The 
resulting mixture is agitated thoroughly and filtered. The ethyl acetate 
layer is separated, dried over anhydrous magnesium sulfate and 
concentrated in vacuo. The residue is dissolved in a mixture of ethyl 
acetate (20 ml) and oxalic acid (3 g). This solution is diluted with 
petroleum ether (100 ml), and the supernatant layer is removed by 
decantation. To the precipitate are added water (50 ml), ethyl acetate 
(200 ml) and excess sodium bicarbonate. The ethyl acetate layer is 
separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. 
The oily residue is subjected to silica gel column chromatography using 
hexame-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction 
gives benzyl 
3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a 
colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1730, 1680(C.dbd.O) 
Mass spectrum (m/e): 685(M.sup.+) 
From the second fraction is obtained benzyl 
3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) as a 
colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3330(NH); 1730, 1680(C.dbd.O) 
Mass spectrum (m/e): 685(M.sup.+) 
EXAMPLE 91 
A solution of benzyl 
3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in ethanol 
(20 ml) is subjected to catalytic hydrogenolysis over 10% palladium carbon 
(0.5 g, 50% wet) at ambient temperature and pressure until the absorption 
of hydrogen ceases. After removal of the catalyst by filtration, the 
filtrate is concentrated. To the residue is added 5N hydrogen 
chloride-ethyl acetate solution (1 ml), and the resulting mixture is 
diluted with ethyl ether (50 ml) to deposit 
3(S)-[1(R)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrah 
ydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.25 g) as the 
colorless precipitate. This acid is dissolved in 1N sodium hydroxide 
solution (10 ml), and the resulting solution is allowed to stand for 30 
minutes at room temperature. After addition of acetic acid (2 ml), the 
mixture is subjected to MCI gel column chromatography using water-methanol 
(2:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to 
yield 
3(S)-[1(R)-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid (0.5 g) as colorless powder. 
Elemental analysis for C.sub.22 H.sub.31 N.sub.3 O.sub.6.3/2H.sub.2 O: 
Calcd: C, 57.38; H, 7.44; N, 9.13; Found: C, 57.39; H, 7.62; N, 9.06 
[.alpha.].sub.D -149.degree. (in water) 
SIMS spectrum (m/e): 434(MH.sup.+) 
EXAMPLE 92 
A solution of benzyl 
3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) in ethanol 
(40 ml) is subjected to catalytic hydrogenolysis over 10% palladium carbon 
(1 g, 50% wet) at ambient temperature and pressure until the absorption of 
hydrogen ceases. After removal of the catalyst by filtration, the filtrate 
is concentrated. To the residue is added 5N hydrogen chloride-ethyl 
acetate solution (2 ml), and the resulting mixture is diluted with ethyl 
ether (50 ml) to deposit 
3(S)-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrah 
ydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.45 g) as a 
colorless precipitate. This acid is dissolved in 1N sodium hydroxide 
solution (15 ml), and the resulting solution is allowed to stand for 30 
minutes at room temperature. After addition of acetic acid (3 ml), the 
mixture is subjected to MCI gel column chromatography using water-methanol 
(2:1) as an eluent. When eluate is concentrated in vacuo and lyophilized 
to yield 
3(S)-[1(S)-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid (0.3 g) as colorless powder. 
Elemental analysis for C.sub.22 H.sub.31 N.sub.3 O.sub.6.3/2H.sub.2 O: 
Calcd.: C, 57.38; H, 7.44; N, 9.13; Found: C, 57.01; H, 7.76; N, 9.00 
[.alpha.].sub.D -118.degree. (in water) 
SIMS spectrum (m/e): 434(MH.sup.+) 
EXAMPLE 93 
A mixture of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.4 g), 
ethanol (30 ml), acetic acid (0.5 g), ethyl 
7-(1-benzyloxycarbonyl-4-piperidyl)-2-oxoheptanoate (3.2 g) and molecular 
sieves 3A (10 g) is stirred for 10 minutes. To the stirred mixture is 
added dropwise a solution of sodium cyanoborohydride (0.51 g) in ethanol 
(50 ml) for 3 hours at room temperature. After standing overnight at room 
temperature, the mixture is concentrated in vacuo and diluted with a 
mixture of water (50 ml) and ethyl acetate (200 ml). The resulting mixture 
is agitated thoroughly and filtered. The ethyl acetate layer is washed 
successively with 0.1N hydrochloric acid, 0.1N sodium hydroxide solution 
and water, dried over anhydrous magnesium sulfate and concentrated in 
vacuo. The oily residue is chromatographed on silica gel using 
hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction 
affords tert-butyl 
3(S)-[6(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4- 
oxo-2,3,4,5 -tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless 
oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1730, 1680(C.dbd.O) 
From the second fraction is obtained tert-butyl 
3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]amino-4 
-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.5 g) as a colorless 
oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1730, 1680(C.dbd.O) 
Mass spectrum (m/e): 665(M.sup.+) 
EXAMPLE 94 
To a solution of tert-butyl 
3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4 
-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic acid 
(1 ml) is added 30% hydrogen bromide-acetic acid solution (2 ml). The 
resulting mixture is allowed to stand for 1 hour at room temperature and 
then diluted with ethyl ether (100 ml). The supernatant layer is removed 
by decantation and the precipitate is dissolved in 1N sodium hydroxide 
solution (10 ml). The solution is allowed to stand for 60 minutes at room 
temperature. After addition of acetic acid (1 ml), the mixture is 
chromatographed on MCI gel using water-methanol (1:2) as an eluent. The 
eluate is concentrated in vacuo and lyophilized to give 
3(S)-[1(R)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid (0.13 g) as colorless powder. 
[.alpha.].sub.D -139.degree. (in water) 
SIMS spectrum (m/e): 448(MH.sup.+) 
EXAMPLE 95 
To a solution of tert-butyl 
3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]amino-4 
-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.5 g) in acetic acid 
(1 ml) is added 30% hydrogen bromide-acetic acid solution (2 ml). The 
resulting mixture is allowed to stand for 1 hour at room temperature and 
then diluted with ethyl ether (100 ml). The supernatant layer is removed 
by decantation and the precipitate is dissolved in 1N sodium hydroxide 
solution (20 ml). The solution is allowed to stand for 30 minutes at room 
temperature. After addition of acetic acid (4 ml), the mixture is 
chromatographed on MCI gel using water-methanol (1:2) as an eluent. The 
eluate is concentrated in vacuo and lyophilized to give 
3(S)-[1(S)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 
-benzoxazepine-5-acetic acid (0.23 g) as colorless powder. 
[.alpha.].sub.D -133.degree. (in water) 
SIMS spectrum (m/e): 448(MH.sup.+) 
EXAMPLE 96 
A mixture of tert-butyl 
3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2 g), 
ethanol (10 ml), acetic acid (0.49 g), ethyl 
8-(1-benzyloxycarbonyl-4-piperidyl)-2-oxooctanoate (3 g) and molecular 
sieves 3A (10 g) is stirred for 10 minutes. To the stirred mixture is 
added dropwise a solution of sodium cyanoborohydride (0.47 g) in ethanol 
(40 ml) for 3 hours at room temperature. After standing overnight at room 
temperature, the mixture is concentrated in vacuo and diluted with a 
mixture of water (100 ml) and ethyl acetate (200 ml). The resulting 
mixture is agitated thoroughly and filtered. The ethyl acetate layer is 
washed with water, dried over anhydrous magnesium sulfate and concentrated 
in vacuo. The oily residue is chromatographed on silica gel using 
hexane-ethyl acetate (5:2-2:1) as an eluent. Evaporation of the first 
fraction affords tert-butyl 
3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylheptyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a 
colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1740, 1700, 1680(C.dbd.O) 
From the second fraction is obtained tert-butyl 
3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a 
colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3320(NH); 1740, 1690, 1680(C.dbd.O) 
EXAMPLE 97 
To a solution of tert-butyl 
3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylheptyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic 
acid (1.5 ml) is added 30% hydrogen bromide-acetic acid solution (1.5 ml). 
The resulting mixture is allowed to stand for 0.5 hour at room temperature 
and then diluted with ethyl ether (100 ml). The supernatant layer is 
removed by decantation and the precipitate is dissolved in 1N sodium 
hydroxide solution (10 ml). The solution is allowed to stand for 30 
minutes at room temperature. After addition of acetic acid (2 ml), the 
mixture is chromatographed on Amberlite XAD-2 using water-methanol (1:1) 
as an eluent. The eluate is concentrated in vacuo and lyophilized to give 
3(S)-[1(R)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid (0.1 g) as colorless powder. 
[.alpha.].sub.D -119.degree. (in water) 
SIMS spectrum (m/e): 462(MH.sup.+) 
EXAMPLE 98 
To a solution of tert-butyl 
3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl]amino- 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic 
acid (1.5 ml) is added 30% hydrogen bromide-acetic acid solution (1.5 ml). 
The resulting mixture is allowed to stand for 0.5 hour at room temperature 
and then diluted with ethyl ether (100 ml). The supernatant layer is 
removed by decantation and the precipitate is dissolved in 1N sodium 
hydroxide solution (10 ml). The solution is allowed to stand for 30 
minutes at room temperature. After addition of acetic acid (2 ml), the 
mixture is chromatographed on MCI gel using water-methanol (1:1) as an 
eluent. The eluate is concentrated in vacuo and lyophilized to give 
3(S)-[1(S)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 
5-benzoxazepine-5-acetic acid (0.15 g) as colorless powder. 
[.alpha.].sub.D -108.degree. (in water) 
SIMS spectrum (m/e): 462(MH.sup.+) 
EXAMPLE 99 
A mixture of isonicotinaldehyde (25 g), 
ethyl(triphenylphosphoranylidene)acetate (82 g) and toluene (300 ml) is 
stirred for 3 hours at 100.degree. C. After cooling, the crystals that 
precipitated are removed by filtration, and the filtrate is concentrated 
in vacuo. The residue is dissolved in a mixture of ethyl acetate and 
petroleum ether (1:1, 400 ml), and the resulting solution is extracted 
with 5% hydrochloric acid (500 ml). The aqueous layer is extracted with 
ethyl acetate (50 ml) and neutralized with potassium carbonate. After 
cooling, the resulting crystals are collected by filtration and dried to 
give ethyl 3-(4-pyridyl)acrylate (34 g) as colorless prisms, mp 
64.degree.-66.degree. C. 
EXAMPLE 100 
A solution of ethyl 3-(4-pyridyl)acrylate (28 g) in acetic acid (300 ml) is 
catalytically reduced at room temperature under atmospheric pressure over 
platinum oxide (1 g). After absorption of hydrogen ceases, the catalyst is 
filtered off, and the filtrate is evaporated in vacuo. The residue is 
dissolved in a mixture of water (500 ml) and ethyl acetate (300 ml). 
Sodium bicarbonate is added portionwise to the stirred solution until the 
generation of carbon dioxide ceases. Benzyloxycarbonyl chloride (5 ml) is 
added and the resulting mixture is stirred for 1 hour at room temperature. 
After further addition of benzyloxycarbonyl chloride (20 g), sodium 
bicarbonate (30 g) is added portionwise to the stirred mixture. After 
stirring for 2 hour at room temperature, the ethyl acetate layer is 
separated, washed with water, dried over anhydrous magnesium sulfate and 
concentrated in vacuo. The oily residue is purified by silica gel column 
chromatography using hexane-ethyl acetate (2:1) as an eluent to give ethyl 
3-(1-benzyloxycarbonyl-4-piperidyl)propionate (37 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1700 (C.dbd.O) 
EXAMPLE 101 
To a stirred mixture of ethyl 
4-(1-benzyloxycarbonyl-4-piperidyl)-2-oxobutyrate (17 g), acetic acid (4.5 
g) and ethanol (30 ml) is added sodium cyanoborohydride (3 g) at room 
temperature. After stirring for 3 hours at room temperature, the mixture 
is diluted with water (500 ml) and extracted with methylene chloride. The 
organic extract is dried over anhydrous magnesium sulfate and concentrated 
in vacuo. The residue is purified by silica gel column chromatography 
using hexane-ethyl acetate (2:1-1:1) as an eluent to give ethyl 
4-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxybutyrate (11.5 g) as a 
colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3430(OH); 1730, 1690(C.dbd.O) 
NMR(in CDCl.sub.3 -D.sub.2 O) .delta.: 7.3(5H), 5.1(2H), 3.9-4.4(5H), 
2.5-3.1(2H), 1.0-2.0(12H) 
EXAMPLE 102 
To a mixture of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxybutyrate 
(11.5 g), ethyl acetate (200 ml) and pyridine (12 g) is added thionyl 
chloride (5 ml), and the resulting mixture is refluxed for 1 hour with 
stirring. After cooling, the mixture is diluted with water (500 ml) and 
ethyl acetate (100 ml). The organic layer is separated, washed 
successively with 0.1N hydrochloric acid and water, dried over anhydrous 
magnesium sulfate, treated with activated carbon and then evaporated in 
vacuo to give ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate 
(10.5 g) as a pale yellow oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740, 1690(C.dbd.O) 
EXAMPLE 103 
A solution of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate 
(10.5 g) in ethanol (20 ml) is catalytically hydrogenated over 10% 
Palladium-carbon (5 g, 50% wet) as a catalyst at ordinary temperature 
under atmospheric pressure. After the absorption of hydrogen ceases, the 
catalyst is removed by filtration and the filtrate is concentrated in 
vacuo to yield ethyl 4-(4-piperidyl)butyrate, which is dissolved in a 
mixture of ethyl acetate (200 ml) and water (100 ml). To the solution is 
added sodium bicarbonate (6 g), and the resulting mixture is stirred at 
room temperature. Benzyloxycarbonyl chloride (6 ml) is added dropwise to 
the stirred mixture, and the stirring is continued for 1.5 hours at room 
temperature. The ethyl acetate layer is separated, dried over anhydrous 
magnesium sulfate and concentrated in vacuo. The residue is purified by 
silica gel column chromatography using hexane:ethyl acetate (3:1) as an 
eluent to yield ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)butyrate (5.3 g) 
as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1700(C.dbd.O) 
EXAMPLE 104 
To a solution of sodium (0.48 g) in ethanol (10 ml) are added ethyl 
4-(1-benzyloxycarbonyl-4-piperidyl)butyrate (5.3 g) and diethyl oxalate 
(2.8 g). The mixture is evaporated under reduced pressure at 
60.degree.-70.degree. C. for 30 minutes. After cooling, water (300 ml) is 
added to the brown residue, and the resulting mixture is acidified with 1N 
hydrochloric acid and extracted with ethyl acetate (100 ml.times.2). The 
organic extract is dried over anhydrous magnesium sulfate and concentrated 
in vacuo. The oily residue is dissolved in a mixture of dimethylsulfoxide 
(45 ml), water (5 ml) and lithium chloride (0.8 g). The resulting mixture 
stirred for 1.5 hours at 135.degree.-140.degree. C. and then for 30 
minutes at 140.degree.-145.degree. C. After cooling, the mixture is 
diluted with water (500 ml) and extracted with ethyl acetate (300 ml). The 
extract is dried over anhydrous magnesium sulfate and concentrated in 
vacuo to give ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate (5 
g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1700(C.dbd.O) 
Mass spectrum (m/e): 361(M.sup.+) 
EXAMPLE 105 
To a stirred mixture of methylene chloride (400 ml) and water (40 ml) are 
added dropwise benzyloxycarbonyl chloride (100 g) and a solution of 
3-(4-piperidyl)propanol (84 g) and triethylamine (65 g) in methylene 
chloride (100 ml) for 45 minutes at room temperature. After addition is 
completed, stirring is continued for further 1 hour. The methylene 
chloride layer is separated, washed with water, dried over anhydrous 
magnesium sulfate and concentrated under reduced pressure. Vacuum 
distillation of the oily residue is carried out to remove the low boiling 
material (50.degree.-60.degree. C./5 mmHg). 
3-(1-Benzyloxycarbonyl-4-piperidyl)propanol (110 g) is obtained as a 
yellow oily residue. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3400(OH), 1680(C.dbd.O) 
EXAMPLE 106 
To a chilled mixture of 3-(1-benzyloxycarbonyl-4-piperidyl)propanol (110 g) 
and pyridine (500 ml) is added portionwise tosyl chloride (100 g) for 2 
hours with stirring. After stirring for further 1 hour, ice water (1 l) is 
added dropwise to the mixture. The resulting mixture is acidified by 
dropwise addition of concentrated hydrochloric acid at ice-bath 
temperature and extracted with ethyl acetate (1 l). The extract is washed 
successively with diluted hydrochloric acid and water, dried over 
anhydrous magnesium sulfate and concentrated in vacuo. The residue is 
crystallized from ethanol to give 
3-(1-benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (99 g) as a 
colorless crystals, mp 59.degree.-60.degree. C. 
Elemental analysis for C.sub.23 H.sub.29 NO.sub.5 S: Calcd.: C, 64.01; H, 
6.77; N, 3.25; Found: C, 64.25; H, 6.78; N, 3.26 
EXAMPLE 107 
To a solution of sodium (5.8 g) in ethanol (300 ml) are added diethyl 
malonate (40 g) and 3-(1-benzyloxycarbonyl-4-piperidyl)propyl 
p-toluenesulfonate (90.5 g). The resulting mixture is refluxed for 2 hours 
with stirring, cooled, diluted with water (1 l) and extracted with ethyl 
acetate (500 ml). The extract is dried over magnesium sulfate and 
evaporated in vacuo to give ethyl 
5-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylvalerate as an oil. To 
the stirred solution of this oil in ethanol (200 ml) is added dropwise a 
solution of sodium hydroxide (34 g) in water (200 ml). After the addition 
is complete, the mixture is diluted with water (300 ml) and extracted with 
a mixture of ether and petroleum ether (1:1, 300 ml). The aqueous layer is 
acidified with concentrated hydrochloric acid and extracted with ethyl 
acetate (500 ml). The extract is washed with water, dried over anhydrous 
magnesium sulfate and evaporated in vacuo to yield 
5-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyvaleric acid as an oil. This 
oil is heated at 160.degree.-170.degree. C. for 45 minutes with stirring 
to give 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid (50 g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1700(C.dbd.O) 
EXAMPLE 108 
A mixture of 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid (54.8 g), 
sodium bicarbonate (29 g), ethyl iodide (21 ml) and N,N-dimethylformamide 
(150 ml) is stirred for 3 hours at 70.degree.-80.degree. C. After further 
addition of ethyl iodide (10 ml), the stirring is continued for further 3 
hours at 90.degree.-100.degree. C. After cooling, the mixture is diluted 
with water and extracted with ethyl acetate (1 l). The extract is washed 
successively with water, 1N hydrochloric acid and sodium bicarbonate 
solution, dried over anhydrous magnesium sulfate and evaporated in vacuo 
to yield ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)valerate (58 g) as a 
pale yellow oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1700(C.dbd.O) 
NMR (in CDCl.sub.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 109 
To a solution of sodium (2.2 g) in ethanol (50 ml) are added ethyl 
5-(1-benzyloxycarbonyl-4-piperidyl)valerate (30 g) and diethyl oxalate (14 
g). The mixture is evaporated under reduced pressure at 60.degree. C. for 
1 hour and then at 60.degree.-70.degree. C. for 30 minutes. After cooling, 
water (500 ml) is added to the brown residue. The resulting mixture is 
acidified with hydrochloric acid and extracted with ethyl acetate (300 
ml). The extract is dried over anhydrous magnesium sulfate and evaporated 
in vacuo to yield an oil. This oil is dissolved in a mixture of 
dimethylsulfoxide (150 ml), water (15 ml) and lithium chloride (5 g) and 
the mixture is stirred for 35 minutes at 150.degree.-155.degree. C., 
cooled, diluted with water (500 ml) and extracted with ethyl acetate (300 
ml). The extract is dried over anhydrous magnesium sulfate and evaporated 
in vacuo to give ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate 
(26 g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1690(C.dbd.O) 
Mass spectrum (m/e): 375(M.sup.+) 
EXAMPLE 110 
To a chilled mixture of ethyl 
6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate (26 g), ethanol (40 ml) 
and acetic acid (6.2 g) is added sodium cyanoborohydride (4.4 g) with 
stirring. After being stirred for 1 hour, the mixture is allowed to stand 
overnight at room temperature, diluted with water (500 ml) and extracted 
with methylene chloride. The extract is dried over anhydrous magnesium 
sulfate and concentrated in vacuo. The residue is purified by silica gel 
column chromatography using hexane-ethyl acetate (2:1) as an eluent to 
yield ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (16 g) 
as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3450(OH); 1730, 1690(C.dbd.O) 
EXAMPLE 111 
To a mixture of ethyl 
6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (12.8 g), ethyl 
acetate (120 ml) and pyridine (13 g) is added thionyl chloride (5.1 ml). 
The mixture is refluxed for 45 minutes with stirring. After cooling, the 
mixture is diluted with water (500 ml) and extracted with ethyl acetate 
(200 ml). The extract is washed successively with 0.1N hydrochloric acid 
and water, dried over anhydrous magnesium sulfate and concentrated in 
vacuo. The oily residue is chromatographed on silica gel using 
hexane-ethyl acetate (4:1) as an eluent to yield ethyl 
6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate (10 g) as a 
colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740, 1690(C.dbd.O) 
EXAMPLE 112 
A solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate 
(10 g) in ethanol (200 ml) is catalytically hydrogenated over 10% 
palladium-carbon (5 g, 50% wet) at ordinary temperature under atmospheric 
pressure. After the absorption of hydrogen has ceased, the catalyst is 
removed by filtration and the filtrate is evaporated in vacuo to yield 
ethyl 6-(4-piperidyl)hexanoate. This ester is dissolved in a mixture of 
water (100 ml), ethyl acetate (200 ml) and sodium bicarbonate (10 g). 
Benzyloxycarbonyl chloride (7.2 ml) is added dropwise at room temperature 
and the resulting mixture is stirred overnight. The ethyl acetate layer is 
separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. 
The residue is purified by silica gel column chromatography using 
hexane-ethyl acetate (4:1) as an eluent to give ethyl 
6-(1-benzyloxycarbonyl-4-piperidyl)hexanoate (7.7 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1690(C.dbd.O) 
EXAMPLE 113 
To a solution of sodium (0.56 g) in ethanol (20 ml) are added ethyl 
6-(1-benzyloxycarbonyl-4-piperidyl)hexanoate (7.3 g) and diethyl oxalate 
(3.5 g). The mixture is evaporated under reduced pressure at 
60.degree.-70.degree. C. for 20 minutes and then at 75.degree. C. for 20 
minutes. After cooling, water (100 ml) is added to the brown residue, the 
resulting mixture is acidified with hydrochloric acid and extracted with 
ethyl acetate (300 ml). The extract is dried over anhydrous magnesium 
sulfate and evaporated in vacuo to give an oil. This oil is dissolved in a 
mixture of dimethylsulfoxide (50 ml), water (5 ml) and lithium chloride 
(1.5 g). The mixture is stirred for 40 minutes at 140.degree.-160.degree. 
C., cooled, diluted with water (300 ml) and extracted with ethyl acetate 
(300 ml). The extract is dried over anhydrous magnesium sulfate and 
evaporated in vacuo to yield ethyl 
7-(1-benzyloxycarbonyl-4-piperidyl)-2-oxoheptanoate (6.5 g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1720, 1690(C.dbd.O) 
Mass spectrum (m/e): 389(M.sup.+) 
EXAMPLE 114 
To a stirred mixture of ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)valerate 
(26.8 g), tetrahydrofuran (200 ml) and sodium borohydride (13.4 g) is 
added dropwise methanol (40 ml) for 1.5 hours at 70.degree.-80.degree. C. 
After the addition is complete, the mixture is refluxed for 2 hours with 
stirring. After evaporation of solvent, the residue is diluted with water 
(300 ml) and extracted with ethyl acetate (300 ml). The extract is washed 
successively with 1N hydrochloric acid and water, dried over anhydrous 
magnesium sulfate and evaporated in vacuo to give 
5-(1-benzyloxycarbonyl-4-piperidyl)pentanol (23 g) as a colorless oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 3400(OH), 1690(C.dbd.O) 
NMR (in CDCl.sub.3) .delta.: 7.3(5H), 5.1(2H), 3.9-4.4(2H), 3.5-3.8(2H), 
2.4-3.0(3H), 1.0-1.9(13H) 
EXAMPLE 115 
To a chilled mixture of 5-(1-benzyloxycarbonyl-4-piperidyl)pentanol (18 g) 
and pyridine (150 ml) is added portionwise tosyl chloride (14.6 g) for 30 
minutes with stirring. After stirring for further 1 hour at ice-bath 
temperature, ice water (2 ml) is added dropwise and the resulting mixture 
is dissolved in ethyl acetate (500 ml). This solution is washed 
successively with 2N hydrochloric acid (500 ml), 1N hydrochloric acid (500 
ml.times.2), sodium bicarbonate solution and water. The organic layer is 
dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily 
residue is purified by silica gel column chromatography using hexane-ethyl 
acetate (3:1-2:1) to give 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl 
p-toluenesulfonate (18 g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1700(C.dbd.O) 
EXAMPLE 116 
To a solution of sodium (0.95 g) in ethanol (80 ml) are added diethyl 
malonate (7.2 g) and 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl 
p-toluenesulfonate (13.7 g). The mixture is refluxed for 2 hours with 
stirring. After the further addition of a mixture of sodium (0.25 g), 
ethanol (25 ml) and diethyl malonate (1.8 g), the reflux is continued for 
further 2 hours. After evaporation of ethanol, the residue is diluted with 
water (200 ml) and extracted with ethyl acetate (300 ml). The extract is 
dried over anhydrous magnesium sulfate and evaporated in vacuo to give 
ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an 
oil. To a mixture of this ester and ethanol (30 ml) is added dropwise a 
solution of sodium hydroxide (6 g) in water (50 ml). After the addition is 
complete, the mixture is diluted with water (150 ml) and extracted with a 
mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is 
acidified with concentrated hydrochloric acid and extracted with ethyl 
acetate (300 ml). The organic extract is washed with water, dried over 
anhydrous magnesium sulfate and evaporated in vacuo to give 
7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oil. 
This acid is heated for 1 hour at 160.degree.-165.degree. C. with 
stirring. The resulting oil is purified by silica gel column 
chromatography using hexane-ethyl acetate (3:1-1:1) as an eluent to yield 
7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid (6.4 g) as a colorless 
oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1710 (C.dbd.O) 
EXAMPLE 117 
A mixture of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid (6.4 g), 
sodium bicarbonate (3.1 g) and ethyl iodide (8.6 g) and 
N,N-dimethylformamide (20 ml) is stirred for 3 hours at 100.degree. C. 
After further addition of ethyl iodide (2.9 g) and sodium bicarbonate (1 
g), the stirring is continued for further 2.5 hours at 100.degree. C. 
After cooling, the mixture is diluted with water (200 ml) and extracted 
with ethyl acetate (300 ml). The extract is washed successively with 
water, 0.1N hydrochloric acid and sodium bicarbonate solution, dried over 
anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 
7-(1-benzyloxycarbonyl-4-piperidyl)heptanoate (5 g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1700(C.dbd.O) 
NMR (in CDCl.sub.3) .delta.: 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 118 
To a solution of sodium (0.48 g) in ethanol (30 ml) are added ethyl 
7-(1-benzyloxycarbonyl-4-piperidyl)heptanoate (6.5 g) and diethyl oxalate 
(3 g). The mixture is evaporated under reduced pressure at 
60.degree.-70.degree. C. for 1 hour. After cooling, water (150 ml) is 
added to the residue. The mixture is acidified with hydrochloric acid and 
extracted with ethyl acetate (300 ml). The extract is dried over anhydrous 
magnesium sulfate and evaporated in vacuo. The oily residue is dissolved 
in a mixture of dimethylsulfoxide (54 ml), water (6 ml) and lithium 
chloride (1 g). The resulting solution is stirred for 1 hour at 
140.degree. C., cooled, diluted with water (150 ml) and extracted with 
ethyl acetate (300 ml). The extract is washed with water, dried over 
anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 
8-(1-benzyloxycarbonyl-4-piperidyl)-2-oxooctanoate (6 g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730, 1700(C.dbd.O) 
Mass spectrum (m/e): 403(M.sup.+) 
EXAMPLE 119 
A mixture of 4-(3,4,5,6-tetrahydro-2H-pyran)carbaldehyde (13.2 g), 
ethyl(triphenylphosphoranylidene)acetate (44 g) and toluene (200 ml) is 
stirred for 3 hours at 100.degree. C. After the mixture is concentrated in 
vacuo, petroleum ether (200 ml) is added to the residue. The resulting 
precipitate is removed by filtration and the filtrate is concentrated in 
vacuo. The oily residue is purified by vacuum distillation to give ethyl 
3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)acrylate (17 g) as an oil. 
bp 132.degree.-134.degree. C. (16 mmHg) 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1720(C.dbd.O), 1650(C.dbd.C) 
NMR (in CDCl.sub.3) .delta.: 6.6-7.1(1H), 5.6-6.9(1H), 3.7-4.4(4H), 
3.2-3.7(2H), 2.0-2.7(1H), 1.1-1.9(7H) 
EXAMPLE 120 
A solution of ethyl 3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)acrylate (17 g) in 
ethanol (200 ml) is catalytically hydrogenated over 10% palladium-carbon 
(4 g, 50% wet) at room temperature under atmospheric pressure. After the 
absorption of hydrogen has ceased, the catalyst is removed by filtration 
and the filtrate is concentrated in vacuo. The oily residue is purified by 
vacuum distillation to give ethyl 
3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propionate (15 g) as an oil. 
bp 121.degree.-123.degree. C./16 mmHg 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740(C.dbd.O) 
NMR (in CDCl.sub.3) .delta.: 3.7-4.4(4H), 3.0-3.7(2H), 2.1-2.7(2H), 
1.0-1.9(10H) 
EXAMPLE 121 
To a stirred solution of oxalyl chloride (10.2 ml) in methylene chloride 
(200 ml) is added dropwise a solution of dimethylsulfoxide (18.2 ml) in 
methylene chloride (200 ml) at -65.degree. C. for 10 minutes. After 
stirring for 10 minutes, a solution of 4-thianylmethanol (14.1 g) in 
methylene chloride (100 ml) is added dropwise for 10 minutes, and the 
mixture is stirred for 20 minutes at -65.degree. C. Triethylamine (74 ml) 
is added dropwise for 10 minutes and the resulting mixture is stirred for 
15 minutes under cooling. After the cooling bath is removed, the stirring 
is continued for 10 minutes at room temperature and 3N hydrochloric acid 
(215 ml) is added. The resulting mixture is stirred for further 1 hour at 
room temperature. The organic layer is separated, washed with water, dried 
over anhydrous magnesium sulfate and evaporated in vacuo to yield 
4-thianylcarbaldehyde (11 g) as a pale yellow oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1730(C.dbd.O) 
NMR (in CDCl.sub.3) .delta.: 9.5(1H), 3.0-4.5(1H), 2.5-3.0(4H), 1.0-2.5(4H) 
EXAMPLE 122 
A mixture of 4-thianylcarbaldehyde (11 g), 
ethyl(triphenylphosphoranylidene)acetate (32.3 g) and toluene (200 ml) is 
stirred at 100.degree. C. for 4 hours. After removal of the solvent, 
petroleum ether (200 ml) is added to the residue and the resulting 
precipitate is removed by filtration. The filtrate is concentrated in 
vacuo to give an oily residue, which is purified by vacuum distillation to 
yield ethyl 3-(4-thianyl)acrylate (10.4 g) as an oil. 
bp 155.degree.-157.degree. C. (15 mmHg) 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1720(C.dbd.O), 1650(C.dbd.C) 
NMR (in CDCl.sub.3) .delta.: 6.6-7.1(1H), 5.6-6.0(1H), 4.0-4.4(2H), 
2.6-2.9(4H), 1.5-2.4(5H), 1.2-1.5(3H) 
EXAMPLE 123 
A solution of ethyl 3-(4-thianyl)acrylate (10 g) in ethanol (150 ml) is 
hydrogenated over 10% palladium-carbon (9 g, 50% wet) under atmospheric 
pressure. After the mixture is stirred for 20 minutes at room temperature 
and then for 8 hours at 50.degree. C., the catalyst is removed by 
filtration. To the filtrate 10% palladium carbon (9 g, 50% wet) is added 
and the mixture is hydrogenated at 50.degree. C. for 1 day. After the 
catalyst is removed by filtration, the filtrate is evaporated in vacuo to 
give ethyl 3-(4-thianyl)propionate (9.1 g) as an oil. 
IR .nu..sub.max.sup.neat cm.sup.-1 : 1740(C.dbd.O) 
NMR (in CDCl.sub.3) .delta.: 3.9-4.3(2H), 2.4-2.8(4H), 1.8-2.4(4H), 
1.0-1.8(8H) 
EXPERIMENT EXAMPLE 1 
Experiment of 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). That is, 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 dissolved in 0.02 to 0.5% dimethylsulfoxide-100 mM 
borate-HCl buffer solution (pH 8.3, containing 300 mM sodium chloride) was 
added to 100 .mu.l of ACE (protein concentration, 20 mg/ml) and 100 .mu.l 
of 1.25 mM HHL. In this experiment, a borate-HCl buffer solution 
containing dimethylsulfoxide at a concentration equal to that of the test 
solution was used as a control. After warming the solution at 37.degree. 
C. for 1 hour, 150 .mu.l of 1N hydrochloric acid was added to the solution 
to terminate the reaction. After 0.8 ml of ethyl acetate was added the 
solution was centrifuged at 11500 rpm for 2 minutes. A 0.5 ml aliquot was 
separated from the ethyl acetate layer and dried at a temperature below 
40.degree. C. under nitrogen gas streams. The residue was mixed thoroughly 
with 4.5 ml 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 6. 
TABLE 6 
______________________________________ 
ACE inhibitory 
Ex. No. of Concentration 
activity 
tested compound 
(.mu.M) (%) 
______________________________________ 
20 0.1 91 
1 99 
58 0.1 95 
1 100 
59 0.1 93 
60 0.1 95 
1 99 
61 0.1 93 
69 0.1 99 
1 100 
89 0.1 95 
92 0.1 99 
95 0.1 99 
98 0.1 99 
______________________________________ 
EXPERIMENT EXAMPLE 2 
Effect of the Compounds of the Present Invention against Hypertensive 
Activity of Angiotensin I 
Experimental Method 
Male rats (Sprague-Dawley) weighing 250 to 350 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, 
Type 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, 10 mg/kg of the compound of the present invention was 
administered orally as an aqueous solution or an aqueous gum arabic 
suspension, and 20, 60 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 7. 
TABLE 7 
______________________________________ 
Inhibition against hypertensive 
Dose reaction by angiotensin I (%) 
Ex. No. of mg/kg After After After 
tested compound 
(orally) 20 min. 60 min. 
120 min. 
______________________________________ 
18 10 82 58 60 
23 10 97 89 86 
57 10 98 96 86 
55 10 87 78 82 
38 10 93 73 63 
______________________________________ 
EXPERIMENT EXAMPLE 3 
Effect of the Compounds of the Present Invention against Hypertensive 
Activity of Angiotensin I 
Experimental Method 
Male rats (Sprague-Dawley) 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, 
Type 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 ng/kg of the compound of the present invention were 
administered intravenously as a saline 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 8. 
TABLE 8 
__________________________________________________________________________ 
Inhibition against hypertensive reaction 
Dose 
by angiotensin I (%) 
Ex. No. of 
.mu.g/kg 
After 
After 
After 
After 
After 
After 
tested compound 
(i.v.) 
5 min 
10 min 
30 min 
60 min 
90 min 
120 min 
__________________________________________________________________________ 
60 300 100 98 97 74 52 26 
68 300 100 100 97 93 82 65 
69 300 99 100 93 86 75 65 
79 300 100 100 100 99 85 71 
92 300 100 100 100 100 100 100 
95 300 100 100 100 99 96 78 
__________________________________________________________________________ 
Preparation Example 
The compounds (I) of the present invention can be used, for example, for 
treatment of hypertention in the following examples of formulation. 
______________________________________ 
1. Tablets 
______________________________________ 
(1) 3(S)--[1(S)--Ethoxycarbonyl-3-phenylpropyl]- 
10 g 
amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz- 
oxazepine-5-acetic acid hydrochloride 
(2) Lactose 90 g 
(3) Corn starch 29 g 
(4) Magnesium stearate 1 g 
130 g 
for 1000 tablets 
______________________________________ 
The above ingredients (1) and (2) and 17 g of (3) are blended, and 
granulated together with a paste prepared from 7 g of the ingredient (3). 
Five g of the ingredient (3) and the ingredient (4) are added to the 
resulting granules, and the mixture is compressed by a tabletting machine 
to prepare 1000 tablets of a diameter of 7 mm each containing 10 mg of the 
ingredient (1). 
______________________________________ 
2. Capsules 
______________________________________ 
(1) 3(S)--[1(S)--Ethoxycarbonyl-3-cyclohexylpropyl]- 
10 g 
amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine- 
5-acetic acid hydrochloride 
(2) Lactose 135 g 
(3) Finely powdered cellulose 70 g 
(4) Magnesium stearate 5 g 
220 g 
for 1000 capsules 
______________________________________ 
All of the above ingredients are blended and filled into 1000 capsules of 
Gelatin Capsule No. 3 (X Japanese Pharmacopoiea) to prepare 1000 capsules 
each containing 10 mg of the ingredient (1). 
______________________________________ 
3. Injectable solution 
______________________________________ 
(1) 3(S)--[1(S)--Carboxy-3-(4-piperidyl)propyl]- 
10 g 
amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxa- 
zepine-5-acetic acid 
(2) Sodium chloride 9 g 
______________________________________ 
All of the above ingredients are dissolved in 1000 ml of distilled water 
and charged into 1000 brown ampoules each containing 1 ml of the solution. 
The air in the ampoules is replaced with nitrogen gas and the ampoules are 
sealed. The entire preparation steps are conducted under sterile 
conditions. 
______________________________________ 
4. Tablets 
______________________________________ 
(1) 3(S)--[1(S)--Carboxy-6-(4-piperidyl)hexyl]amino- 
10 g 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine- 
5-acetic acid 
(2) Lactose 90 g 
(3) Corn starch 29 g 
(4) Magnesium stearate 1 g 
for 1000 tablets 
______________________________________ 
The above ingredients (1) and (2) and 17 g of (3) are blended, and 
granulated together with a paste prepared from 7 g of the ingredient (3). 
Five g of the ingredient (3) and the ingredient (4) are added to the 
resulting granules, and the mixture is compressed by a tabletting machine 
to prepare 1000 tablets of the diameter of 7 mm each containing 10 mg of 
the ingredient (1). 
______________________________________ 
5. Capsules 
______________________________________ 
(1) 3(S)--[1(S)--Carboxy-5-(4-piperidyl)pentyl]amino- 
10 g 
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine- 
5-acetic acid 
(2) Lactose 135 g 
(3) Finely powdered cellulose 70 g 
(4) Magnesium stearate 5 g 
for 1000 capsules 
______________________________________ 
All of the above ingredients are blended and filled into 1000 capsules of 
Gelatin Capsule No. 3 (X Japanese Pharmacopoiea) to prepare 1000 capsules 
each containing 10 mg of the ingredient (1). 
______________________________________ 
6. Injectable solution 
______________________________________ 
(1) 3(S)--[8-Amino-1(S)--ethoxycarbonyloctyl]- 
10 g 
amino-4-oxo-2,3,4,5-tetrahydro-1,5-benz- 
oxazepine-5-acetic acid dihydrochloride 
(2) Sodium chloride 9 g 
______________________________________ 
All of the above ingredients are dissolved in 1000 ml of distilled water 
and charged into 1000 brown ampoules each containing 1 ml of the solution. 
The air in the ampoules is replaced with nitrogen gas and the ampoules are 
sealed. The entire preparation steps are conducted under sterile 
conditions.