JPH057384B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new category of specific substituted 3-
Amino-[1]-benzazepine-2-one-alkanoic acid and its derivatives are angiotensin-
It is based on the discovery that it is a highly effective inhibitor of converting enzyme (ACE). The above properties are achieved by the 3-amino-[1]-
Benzazepine-2-ones are particularly valuable when provided to mammals, singly or in combination, for example in the treatment or prevention of diseases that correspond to the inhibition of angiotensin-converting enzyme, such as hypertension. These include cardiovascular disorders and heart disease conditions such as congestive heart failure. The present invention is a novel 3-amino-[1]-benzazepine-2-one-1-alkanoic acid and its derivatives, which are valuable as inhibitors against angiotensin-converting enzyme, and a process for producing the compound, which is pharmaceutically acceptable. The present invention relates to a method for treating diseases, ie, by providing a mammal with the compound and an adduct, thereby treating the inhibition of angiotensin-converting enzyme. The compound according to the present invention has the general formula [In the formula, R _A and R _B are the following formulas

[expression] and

【formula】 (In the formula, R₀is a carboxy group or a modified functional group
carboxyl group, R₁is hydrogen, lower alkali
Kyl group, amino-(lower) alkyl group, aryl
group, aryl-(lower)alkyl group, cycloal
Kyl group or cycloalkyl (lower) alkyl group
and R₂is hydrogen or a lower-alkyl group
), and R₃and R_FourGermany
vertical hydrogen, lower alkyl group, lower alkoxy group
cy group, lower-alkanoyloxy group, hydroxy group
group, halogen or trifluoromethyl group,
Or R₃and R_Fouris the lower-alk formed by combining
means kylene dioxy group, R_Fiveis hydrogen or
Lower alkyl group, X is oxo group, two water
It is an elementary atom or a hydrogen atom and a hydroxyl group, and hexa
hydro or 6,7,8,9-tetrahydrocarbon
may be a disjoint ring]
Compounds, their stereoisomers, salts and complexes
It is the body. R₀deformed functional carboxy group meaning
Carboxy group or carbamo esterified by
yl group, optionally substituted with a nitrogen atom
be done. one or both R₀The residue is residue R_Ain
C.O.R.₆by and residue R_BCOR at₇year
represented by mutually independent carboxy groups,
Terified carboxy group, carbamoyl group or
specifically refers to a substituted carbamoyl group. Salts and complexes of compounds represented by general formula ()
The body is converted from compounds with salt-forming properties,
be pharmaceutically acceptable salts and complexes;
is preferred. Carboxy group R₀is the COR at residue A₆(In the ceremony
R₆is a hydroxyl group) or a residue R_Bin
C.O.R.₇(R in the formula₇is a hydroxyl group)
Ru. Esterified carboxyl group R₀is especially
Lower-
Alkyl group or substituted phthalidyl group
-COR₆(residue R_A) or formula −
C.O.R.₇(residue R_B) [wherein the residue R₆and R₇
one or both residues are lower-alkoxy
groups (amino, mono- or di-lower-alkyl
(mino)-substituted lower alkoxy group, carboxy
-Substituted lower-alkoxy groups (e.g. α-carboxy
C-substituted-lower-alkoxy group), lower-alco
oxycarbonyl-substituted lower-alkoxy group
(Example α-lower-alkoxycarbonyl-substituted
lower-alkoxy group), aryl-substituted lower-
Alkoxy groups (e.g. optionally substituted benzene)
(or pyridylmethoxy group), (hydrooxy group or pyridylmethoxy group)
roxy, lower-alkanoyloxy, or lower
-alkoxy)-substituted lower-alkoxy group
(e.g. pivaloyloxymethoxy group), (hydroxy
cy, lower alkanoyloxy, or lower-alkaline
(oxy)-substituted lower-alkoxymethoxy group,
Bicycloalkoxycarbonyl-substituted lower-
Alkoxy groups (e.g. bicyclo[2,2,1]
heptyloxycarbonyl-substituted lower-al
Koxy group, especially bicyclo[2,2,
1] Heptyloxycarbonyl-substituted methoxy group
(preferably), 3-phthalidooxy group, (lower-a
(alkyl, lower alkoxy, halo)-substituted 3-
phthalidoxy group]
It is expressed as optionally N-substituted carbamoyl group R₀
In particular, the subexpression −COR₆(residue R_A) if
subexpression −COR₇(residue R_B) [wherein, R₆
and R₇one or both residues are amino groups,
Lower-alkylamino group, di-lower alkylamino group
group (both alkyl groups are connected by a C-C bond)
)] and 5-, 6-, 7-membered complexes
The elemental ring is combined with an amino nitrogen, e.g. pyro-
Lydino group, piperidino group, or perhydroacetate
produces a pino group (amino or acylamino)
-substituted lower-alkylamino group, α-(cal
boxy or lower-alkoxycarbonyl)-
Substituted lower-alkylamino group, aryl-substituted
Substituted lower-alkylamino group (as an aryl group,
Phenyl group or indolyl group is preferred
), and in that case, there is a carboxy group on the α-carbon atom.
Substituted with a group or a lower-alkoxycarbonyl group
means the same kind of group that can be used. Derivatives of the compounds according to the invention, pre-active substances
For example, in a preferred embodiment of the present invention,
Mono- or dicarboxylic acids, respectively, as pharmaceuticals
Conversion to acceptable esters, amides, and solvation
Under decomposition or physiological conditions, the carboxylic acid
For example, the above-mentioned beauty salon
compounds, and amides synthesized for the specific purpose of the invention.
Ru. The ester may be linear or branched, for example.
pivaloy, unsubstituted or substituted in an appropriate manner.
oxymethyl, bornyl, oxycarbony
methyl-, benzyl-, pyridylmethyl-, α
-lower-alkyl ethers such as -carboxyethyl-
ster- or appropriately substituted α-carbo
xyethyl esters and such esters
preferable. This amide can be used, for example, for simple first and second
Mido and alanine, such as from phenylalanine
derived from amino acids or their derivatives.
Amides and similar derivatized amides are preferred.
Yes. In particular, the present invention provides general formula (A) [In the formula, R₁is hydrogen, lower-alkyl group, amino
-(lower)alkyl group, aryl group, aryl-
(lower)alkyl group, or cycloalkyl-(lower)
class) alkyl group, and R₂and R_Fiveis hydrogen or
is a lower-alkyl group, R₃and R_Fouris hydrogen,
Lower-alkyl group, lower-alkoxy group, lower-
Alkanoyloxy group, hydroxyl group, halogen or
is a trifluoromethyl group, or R₃and
R_Fouris a lower-alkylenedioxy group formed by combining
, X is an oxo group, two hydrogen atoms, or
hydrogen atom and hydroxyl group, R₆and R₇are mutually
Independent hydroxyl group, mono- or di-(lower) alkyl
Kylamino group, lower alkoxy group, aryl-
(lower) alkoxy group, lower-alkanoyloxy group
cymethoxy group, (amino, mono- or di-lower
-alkylamino, carboxy or lower-alkyl
(oxycarbonyl)-lower-alkoxy group]
Compounds represented by or pharmaceutically acceptable
obtain their salts or complexes. As a preferred embodiment of the present invention, the general formula
(A) [wherein, R₁is hydrogen, lower-alkyl group,
Amino (lower) alkyl group, aryl (lower)
an alkyl group, in which the aryl group is
substituted phenyl group or lower-alkyl group, hydroxyl group
group, lower-alkoxy group, lower-alkylenedio group
xy group, lower-alkanoyloxy group, halogen
or a moiety substituted by a trifluoromethyl group.
means a no- or di-substituted phenyl group, R₂
and R_Fiveis hydrogen or lower-alkyl group
R, R₃and R_Fouris hydrogen, lower-alkoxy group,
Lower-alkyl group, halogen or trifluorome
chill group or R₃and R_Fouris formed by combining
Kylenedioxy group, X is oxo group, hydroxyl group
and a hydrogen atom, or two hydrogen atoms, and R₆
and R₇are mutually independent hydroxyl groups, amino groups,
Lower alkoxy group, phenyl (lower) alkoxy group
Oxy group, lower-alkoxy-carbonyl- (lower)
is an alkoxy group] or
and its pharmaceutically acceptable salts. General formula A (wherein, R₁is hydrogen, lower-alkyl
group, ω-amino-(lower)alkyl group, aryl
-(lower)alkyl group, in which case the aryl group is
unsubstituted phenyl group or lower alkyl group,
Hydroxyl group, lower alkoxy group, lower alkanoyl group
fluoroxy group, halogen or trifluoromethyl group
a monosubstituted phenyl group substituted by
R₂and R_Fiveis hydrogen or lower-alkyl group
Yes, R₃and R_Fouris hydrogen, lower-alkoxy group,
Lower-alkyl group, halogen or trifluorome
chill group or R₃and R_Fouris a lower grade formed by combining
is an alkylenedioxy group, X is an oxo group, water
An acid group and a hydrogen atom or two hydrogen atoms,
R₆and R₇are mutually independent hydroxyl groups, amino groups,
Lower alkoxy group, phenyl (lower) alkoxy group
cy group, lower-alkoxycarbonyl-(lower) a
(alkoxy group) or its
The pharmaceutically acceptable salts of
Ru. General formula A (wherein, R₁is hydrogen, lower-alkyl
group, ω-amino-(lower)alkyl group, aryl
−(lower) alkyl group, R₂and R_Fiveis hydrogen
or a lower-alkyl group, R₃is hydrogen
Yes, R_Fouris hydrogen, lower-alkoxy group, lower-
Alkyl group, halogen or trifluoromethyl group
, X is an oxo group, a hydroxyl group and a hydrogen atom,
or two hydrogen atoms, R₆and R₇phase
Mutually independent hydroxyl group, amino group, lower alkoxy group
cy group, phenyl (lower) alkoxy group, lower-
Alkoxycarbonyl - (lower) alkoxy group
) as a compound or its pharmaceutical
Acceptable salts are particularly useful. General formula A (wherein, R₁is hydrogen, methyl group, ethyl group
group, isopropyl group, ω-aminopropyl group,
ω-aminobutyl group, aryl-(methyl, ethyl
(propyl, propyl), the aryl group being an unsubstituted
enyl group or methyl group, hydroxyl group, methoxy group
group, methylenedioxy group, acetoxy group, chlorine source
substituted by a child or trifluoromethyl group
is a phenyl group, R₂and R_Fiveis hydrogen or
is a methyl group, R₃and R_Fouris hydrogen, methoxy
group, methyl group, chlorine or trifluoromethyl group
and X is an oxo group, a hydroxyl group and a hydrogen atom, or
are two hydrogen atoms and R₆and R₇is mutual
Independent hydroxyl group, amino group, ethoxy group, meth
Oxy group, benzyloxo group, ethoxycarbonyl
Methoxy group or pivaloyloxymethoxy group
as a compound represented by
Salts that can be tolerated are particularly useful. General formula B (where n is 1-4 and R₈is hydrogen, unsubstituted
Phenyl group or lower alkyl group, lower alkyl group
alkoxy group, lower-alkanoyloxy group, halo
by gen, hydroxyl or trifluoromethyl group
is a substituted monosubstituted phenyl group, R₆Oyo
BiR₇are mutually independent hydroxyl groups C_1-4is a lower class
With rukoxy group, benzyloxy group or amino group
) as a compound or its pharmaceutical
Acceptable salts are very useful. General formula B (wherein, C_oH_2ois ethylene,
R₈is a phenyl group or C_1-4is lower-a
Lukoxy group, C_1-4lower-alkyl group, halo
Gen, moiety substituted by trifluoromethyl group
is a substituted phenyl group, R₆and R₇are mutually
Independent hydroxyl group or C_1-4lower-arco which is
compound or drug represented by
Particularly useful are salts that can be tolerated. The present invention relates to the stereochemistry of compounds represented by the general formula
Also relates to isomers. Some racemates, e.g.
General formula A (wherein, R₁and R₂one side is less
is not hydrogen and/or X is hydrogen (hydroxyl group)
In the compound represented by
Ru. Each enantiomer of the racemate is obtained sequentially.
It will be done. The specificity of these isomers is that angiotene
Preferred as an inhibitor against syn-convertase
stomach. General formula C (In the formula, S means polarizing power, and n is_1-4and
R₈Hydrogen, unsubstituted phenyl group or lower alkyl
Kyl group, lower-alkoxy group, lower-alkanoy
hydroxyl group, halogen, hydroxyl group or trifluoro group
Monosubstituted phenyl substituted by romethyl group
is a group and R₆and R₇are mutually independent hydroxyl groups,
C_1-4lower-alkoxy group, benzyloxy
or an amino group)
or its pharmaceutically acceptable salts have outstanding properties.
There is sex. The general definitions used herein are within the scope of this invention.
has the following meaning: Aryl group is carbocyclic or heterocyclic aromatic
residue, preferably unsubstituted or lower-aryl
alkyl group, lower-alkoxy group, lower-alkylene group
dioxy group, lower alkanoyloxy group, hydroxyl group
by a group, halogen or trifluoromethyl group
with substituted mono- or di-substituted phenyl groups
be. The cycloalkyl group is preferably C_3-8is annular
Hydrocarbon residues, such as cyclopentyl
group, and cyclohexyl group. The aryl-(lower)alkyl group is preferably
ndyl group, 1- or 2-phenylethyl group, 1
-, 2-, or 3-phenylpropyl group, 1
-, 2-, 3- or 4-phenylbutyl group
In this case, the phenyl ring is unsubstituted or lower-
Alkyl, hydroxyl group, lower-alkoxy group, lower-
alkylenedioxy group, lower-alkanoyloxy group
by cy group, halogen or trifluoromethyl group
Mono- or di-substituted. Cycloalkyl-(lower)alkyl groups are preferred
or 1- or 2-(cyclopentyl or cyclopentyl)
chlorohexyl)ethyl group, 1-, 2-, or 3
- (cyclopentyl or cyclohexyl)
Lopyl group, or 1-, 2-, 3- or 4-
(cyclopentyl or cyclohexyl) butylene
is a group. “Lower” refers to compounds with the organic residues listed above and below.
C in compounds and applicable compounds₇Below
means below, preferably C_Fourand C_1-2Good
It's convenient. The lower-alkyl group is preferably C_1-4and example
Examples include ethyl, propyl, and butyl groups.
or a methyl group are convenient. The lower-alkoxy group is preferably C_1-4And
Examples include methoxy, propoxy, iso
Propoxy groups are mentioned, or ethoxy groups are preferred.
It's convenient. Mono-(lower)-alkylamino group
is preferably C_1-4an alkyl group, for example
is N-methylamino group, N-propylamino group or
or an N-ethylamino group. G
The (lower) alkylamino group is preferably C_1-4in
Certain lower alkyl groups, such as N,N-
dimethylamino group, N-methyl-N-ethylamide
and N,N-diethylamino groups.
group is convenient. The lower-alkanoyloxy group is preferably acetic acid.
Toxy group, propionoxy group or pivaloyl
It is an oxy group. The alkylene dioxy group is preferably ethylenedioxy.
oxy group, methylenedioxy group being convenient
be. Aryl-lower-alkoxy groups are, for example,
methyloxy group, methyl group, methoxy group or salt
a benzyloxy group substituted by
The pyridylmethoxy group is convenient. Carboxy-lower-alkoxy group is, for example, 1
-Carboxyethoxy groups are advantageous. Lower-alkoxycarbonyl-lower-alkoxy
The cy group is, for example, 1-(ethoxycarbonyl)-ethyl
Toxy groups are convenient. Amino-lower-alkoxy groups, and mono-
(lower) alkylamino-lower-alkoxy group,
Di-(lower)alkylamino-lower-alkoxy
The group can be, for example, an aminoethoxy group, ethylamino
Ethoxy and diethyl-aminoethoxy groups
is convenient. The lower-alkanoyloxymethoxy group is
For example, a pivaloyloxymethoxy group is convenient.
Ru. Bicycloalkyloxycarbonyl- (lower)
The alkoxy group is preferably unsubstituted or
Bicyclo [2_，
2_，1] Heptyloxycarbonyl-(lower) a
It is a lukoxy group and a bornyloxycarbonyl group.
Toxy groups are convenient. Amino-(lower)-alkyl group and ω-amino
-(lower)alkyl group is preferably amino(ethyl)
(propyl, propyl or butyl) and ω-amino
-(ethyl, propyl or butyl). Halogen is preferably chlorine, bromine,
It can also be elemental or iodine. In an embodiment of the present invention, the dicarboxylic acid
One or both of the boxyl groups, i.e.
General formula A or B (in the formula, R₆and R₇is hydroxy acid
The compound represented by ) is a functional derivative.
exists as an ester or amide
Ru. This functional derivative is preferably mono-
is a bis-lower alkyl ester, for example
methyl-, ethyl-, n- or isopropylene
lopyl, butyl- or benzyl esters are mentioned.
mono- or bis-amide, mono-moshi
is a di-N-alkylated amide, e.g.
Examples include mono- or diethylamide.
mono- or di-substituted lower alkyl ester
Examples include W-(amino, mono- or dimethyl
thylamino, carboxy or carboethoxy)
-(ethyl, propyl or butyl)-ester
Can be mentioned. As a functional derivative, with the general formula A
A monoester of the compound represented, for example (formula
Medium, R₆and R₇is one hydroxyl group, and the other is
(lower-alkoxy group)
Monoesters of are particularly preferred. Pharmaceutically acceptable salts are preferably common
Formula (where R₀is a carboxy group) or
General formula A (wherein, COR₆and/or COR₇teeth
metal compound represented by carboxy group)
salts or ammonium salts, especially alkali-
or alkaline earth metal salts, e.g.
Lithium, potassium, magnesium, and calcium
Includes sia salts or derived from ammonia
easily crystallized ammonium salt or
mono-, di-, or tri-lower (alkyl,
(chloroalkyl or hydroxyalkyl) amino
lower alkylene diamine or lower
Droxyalkyl or aralkyl
(Aralkyl)] Alkylammonium - like a base
organic amines such as methylamine, diethyl
Amine, triethylamine, dicyclohexyl urea
amine, triethanolamine, ethylenediamine
tris-(hydroxymethyl)aminomethane,
or benzyltrimethylammonium hydroxide
Sid is convenient. General formula for forming acid addition salts
Preferably, the compound represented by
organic or inorganic acids that can be tolerated, i.e. strong mineral acids
Acids (e.g. halogens such as hydrochloric acid, hydrobromic acid)
hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid),
Aliphatic or aromatic carbon- or sulfone
Acids (e.g. formic acid, acetic acid, propionic acid, succinic acid, glycan acid)
Licolic acid, lactic acid, malic acid, tartaric acid, glucone
acids, citric acid, ascorbic acid, maleic acid,
Malic acid, hydroxymaleic acid, pyruvic acid,
enyl acetic acid, benzoic acid, 4-aminobenzoic acid,
Antanilic acid, 4-hydroxybenzoic acid, Salicylic acid
Ruic acid, 4-aminosalicylic acid, pamoic acid
(pamoasaure), nicotinic acid, methanesulfone
acid, ethanesulfonic acid, hydroxyethanesulfonate
acid, benzolsulfonic acid, p-trienesulfonic acid
Phonic acid, naphthalene sulfonic acid, sulfanyl
acid, cyclohexylsulfoamic acid)
Ru. Compounds represented by the general formula are drugs that can be evaluated.
Physical properties, e.g. angiote in mammals
In particular, through the selective inhibition of transgenic enzymes,
Cardiovascular effects by inhibiting the release of Ngiotensin
Show the impact of Therefore, this compound is
angiotensin-convertase inhibitor in mammals including
It is useful for treating diseases that correspond to the system. The compounds according to the present invention are primarily antihypertensive/hypotemic.
It has a pressure effect and is effective for heart patients.
This property is in. Vivo, in. animals in vitro
Depending on the experiment, it is preferable to use mammals such as rats.
using isolated organs from cats, cats, dogs, or as samples.
It is possible to demonstrate this. Animals are normotensive or hyperbaric
blood pressure (e.g. in genetically spontaneously hypertensive rats or
in renally hypertensive rats and dogs and sodium-deficient rats.
Scarcity - Can be used as experimental animals such as dogs. transformation
Administer the compound to experimental animals, either intraintestically or parenterally.
Preferably orally or intravenously, gelatin capsules
or in the form of an aqueous solution or suspension containing starch
Administer. The dosage is approximately 0.01-100mg/Kg/day.
within the range, preferably about 0.05-50mg/Kg/day
and particularly preferably about 0.1-25 mg/Kg/day. in. The blood pressure lowering effect in vivo has been shown to be large in experimental animals.
Directly or using a catheter placed in the femoral artery.
or indirectly by a sphygmomanometer in the rat's tail.
Record with . Blood pressure before and after administration in mmHg
Record. The antihypertensive effect in spontaneously hypertensive rats is
revealed by indirect measurement of systolic blood pressure Each unanesthetized rat was placed with restricted movement.
Place in a cage and in a room that can be easily heated.
A cuff that extends the pulse-sensory organs onto the tail of each rat.
Place it inside. The arm cuff is distended due to occlusion of the caudal artery.
Make it tense. The pressure inside the cuff decreases continuously and contracts
The pressure corresponds to the pressure inside the cuff, and the pulse wave is reproduced.
do. After obtaining control values for blood pressure and heart rate,
The compound is administered orally once daily for 4 consecutive days.
give Blood pressure measurements after taking each dose are usually 2.0 and 4.0.
and 23.5 hours later. The obtained value is
Compare with the value when treated with a preparation consisting of As an example of the present invention, the “higher
"1-carboxymethyl-3-(1
-ethoxycarbonyl-3-phenylpropyla
(mino)-2,3,4,5-tetrahydro-1H-
[1] Antihypertensive effect of benzacepin-2-one
Report: Average 40mm after oral administration (3mg/Kg)
Hg lowers blood pressure. Measurements were taken during the last two days of administration.
and 4 hours later. Corresponding to Example 12
S,S-enantiomer is administered orally (1 mg/Kg)
Afterwards, blood pressure drops by about 30mmHg. The compounds according to the present invention can be administered intravenously or orally.
After the injection, the angiotensin-induced positive
Demonstrated inhibitory effect on blood pressure increase in normobaric rats.
vinegar. Angiotensin is activated by the convertase.
Hydrolyzed to angiotensin, a potent vasopressor
It will be done. Inhibition of this enzyme is induced by angiotensin.
Blocks the production of ngiotensin. With this mechanism
Blood pressure caused by angiotensin
The increase decreases. Corresponding in. In ex vivo experiments, 5-E
Thyl-5-(1-methylpropyl)-2-thiopal
Normobaric male rats anesthetized with bituric acid sodium salt
The test compound is injected intravenously into the test tube. thigh
directly into the artery and sural vein for blood pressure measurement.
Insert a cannula and angiotensin
and the compound according to the invention is administered intravenously. base
After the basal blood pressure stabilizes, administer angiotherapy at 5-minute intervals.
for 3 intravenous doses of Nshin (333 mg/Kg).
After stimulation, changes in blood pressure are measured. This blood pressure change
The changes were made after intravenous administration of the test compound at 5, 10, 15, and 30 days.
and measure after 60 minutes. If the blood pressure changes mentioned above occur first
The corresponding decrease in blood pressure compared to the value of angio
Suggests inhibition of tensin-convertase. The present invention
As an example of this, Example 1 “Higher melting point”
“1-carboxymethyl-3-(1-etho
(oxycarbonyl-3-phenylpropylamino)
-2,3,4,5-tetrahydro-1H-[1]ben
nzazepine-2-one and its corresponding counterpart in Example 12.
We report on the S,S-enantiomer. Applicable
The compound was administered intravenously (1 mg/Kg) for 30 minutes, then
Giotensin-stimulus-induced blood pressure increase is completely suppressed.
suppressed. Angioplasty using the compound according to the present invention
Tensin-convertase enzyme. Suppression in mud
Biochim Biophys.Acta volume 293, page 451
(1973) can be shown by a similar method as described in
Ru. Based on this method, the compound was prepared at a concentration of 1 mmM.
Dissolve in phosphate buffer to a certain degree. test
Add 100μ of compound phosphate buffer at desired concentration.
and 5 mmM Hippuryl-Histi
Add dill-leucine-phosphate buffer (100μ).
Next, sucrose, magnesium chloride,
Adult male rats in Tris buffer containing potassium chloride
Angiotensin-converting enzyme prepared from human lungs
Add (50μ). Incubate this solution for 30 minutes at 37℃
and 0.6N sodium hydroxide to stop the reaction.
Add um solution (0.75ml). 0.2 in methanol
Solution containing % o-phthalaldetide (100μ)
was added at room temperature, and after 10 minutes, 6N hydrochloric acid (100μ) was added.
Ru. These samples were measured at 360nm using a spectrophotometer.
to be measured (against water). During the 30 minute incubation period
Histidyl-leucine produced in nanomoles
After the conversion factor, the standard curve becomes IC₅₀, Sunawa
, resulting in 50% activity of the control sample containing no reagent.
To determine the concentration of the reagent, the results are
Graph against concentration. Examples of the present invention and
Accordingly, Example 9 “exhibiting a higher melting point” 1-
Carboxymethyl-3-(1-carboxy-3-
phenylpropylamino)-2,3,4,5-te
Trahydro-1H-[1]benzazepine-2-o
and the corresponding S,S enantiomer of Example 19.
- are 5.2×10 each^-9M and 1.7×10^-9M IC₅₀
Show. Example 8 “Exhibits a higher melting point”
The corresponding 1-carboxymethyl-3-(1-cal
boxy-3-phenylpropylamino)-2,3,
4,5-tetrahydro-1H-[1]benzazepi
On-2-on is 5.8×10^-8M IC₅₀Show. Angiotensin - converting enzyme is angiotensin
involved in the conversion of angiotensin to angiotensin
Not only that, but also Bradykinin.
and aldoterone – also plays a role in controlling levels.
Fulfill your share. These factors of the compounds according to the invention
effects on antihypertensive or cardiac properties
Contribute. The above preferred characteristics include humans.
In the present invention, as a specific therapeutic agent for mammals.
This makes such compounds highly valuable. The compounds according to the present invention are useful as antihypertensive agents.
Yes, especially for improving hypertension (regardless of etiology)
and/or heart disease such as congestive heart failure.
and/or other conditions associated with hydrops or ascites.
It is particularly useful in situations where For the synthesis of other useful products
It is also used as an intermediate in
It is particularly useful in the manufacturing process of commercial products. The compound represented by the general formula according to the present invention is
It is manufactured as follows using a known method. (a) General formula (In the formula, the carbocyclic ring is hexahydro or
6,7,8,9-tetrahydro, X,
R_B,R₃,R_Fourand R_Fiveis as defined above)
The compound represented by the general formula A R_A-Z (A) (In the formula, Z is an esterified reactive hydroxyl group.
R, R_Ais as defined above)
compound or general formula R₁−CO−R₀ () (In the formula, R₁and R₀is as defined above)
In the presence of a reducing agent, the compound represented by
primary and secondary amino groups and/or
Temporary formation of hydroxyl and/or oxo groups
protection (residues X, R_A,R_B,R₃,R_Fouroh
and R_Fivereaction (which may exist in any of the following)
Then, alkylate the above compound () or
teeth (b) General formula (In the formula, the carbocyclic ring is hexahydro or
6,7,8,9-tetrahydro, X,
R₃,R_Fourand R_Fiveis as defined above, and R_A′
is a hydrogen atom or R as defined above_AAnd
) to the compound represented by the general formula B R_B-Z (B) (In the formula, Z is a reactive esterified hydroxyl group.
R, R_Bis as defined above)
alkylation with a compound, and at the same time temporarily
and secondary amino groups and/or optionally
Should hydroxyl and/or oxo groups be protected?
(It is residues X, R_A,R_B,R₃,R_Fourand R_Fiveof
) or (c) General formula (In the formula, the carbocyclic ring is hexahydro or
6,7,8,9-tetrahydro, and Y is
Este formed by combining with xo group or hydrogen atom
represents a reactive hydroxyl group, X, R_B,R₃
and R_Fouris as defined above).
The general formula for the compound R_A−NH−R_Five () (In the formula, R_Aand R_Fiveis as defined above)
is condensed with an amine represented by
If it is an oxo group, it can be oxidized in the presence of a reducing agent.
Under temporary protection of oxo group (as substituent
or (d) General formula (In the formula, the carbocyclic ring is hexahydro or
6,7,8,9-tetrahydro, X,
R₁,R₂,R₃,R_Fourand R_Fiveis as defined above.
R, R₀′ and R₀″ is a cyano group, and
and the other is a cyano group or as defined above
R₀In the compound represented by
Solvent decomposition of the cyano group, or (e) General formula (In the formula, the carbocyclic ring is hexahydro or
6,7,8,9-tetrahydro, X,
R_A,R_B,R₃,R_Fourand R_Fiveis as defined above.
) or its ester
cyclize or (f) The odor of the compound represented by the general formula described above.
to the C-3 position or R_Anitrogen atom within the group
and an additional two atoms between it and the adjacent carbon atom.
A compound having heavy bonds is treated with a reducing agent to reduce the
saturate the double bond or (g) General formula (wherein X is oxo
To produce a compound represented by
, the general formula (In the formula, the carbocyclic ring is hexahydro or
6,7,8,9-tetrahydro, R_B,
R₃and R_Fouris as defined above)
The general formula for the compound R_A−NH−R_Five () (In the formula, R_Aand R_Fiveis as defined above)
condensed with an amine represented by and (h) If desired, expressed in a general formula as defined above.
The obtained compound is treated within the range mentioned above.
Is it converted to other compounds represented by the general formula?
and/or (i) if desired, expressed in a general formula as defined above;
Compounds obtained that exhibit salt-forming properties
into salts or liberated from such salts.
liberate the compound and/or (j) If necessary, in a general formula as defined above.
The obtained complex-forming properties are expressed as follows:
converting the compound into a complex and/or (k) If desired, the obtained
from a stereoisomeric mixture of a compound at least
optics with a special configuration with respect to the center of optical power
increasing the content of isomers, A compound represented by the above general formula characterized by
Preparation of compounds, their stereoisomers, salts, and complexes
Law. Tail residue R_Aand R_BIn the process (a) and (b) of inducing
The alkylation based on the general formula
In general, the corresponding starting materials expressed as and
formula R_AZ(A) or R_BZ(B) [In the formula, R_Aoh
and R_Bis as defined above, and Z is aliphatic.
or aromatic sulfonic acids (e.g., lower alkanesulfonic acids)
Fonic acid, especially methanesulfonic acid, trifluorometa
benzenesulfonic acid, especially benzenesulfonic acid, p-t
Luenesulfonic acid, p-benzenesulfone bromide
strong acids such as p-nitrobenzenesulfonic acid)
Reactive hydroxyl groups esterified with organic acids or
sulfuric or hydrohalic acid (e.g., hydrogen chloride)
acid, most preferably hydroiodic acid or water bromide
Reactivity esterified with strong inorganic acids such as
hydroxyl group].
Alkylation is carried out from 0°C under the usual general formula conditions.
within the boiling point of the reaction mixture, preferably from room temperature to
Perform at temperatures up to 100℃. In relation to the reactants,
In the presence of insoluble solvents, i.e. chlorinated lower atom
lucane (e.g., chloroform, methylene chloride), non-
cyclic or cyclic ethers (e.g. diethyl ether)
1,2-dimethoxyethane, dioxane, tetra
(trahydrofuran), especially low molecular weight tert-amide
(e.g., N,N-dimethylformamide, N,N
-dimethylacetamide, N-methylpyrrolid
N-ethylpiperidone, hexamethyl phosphate
It is convenient to carry out in the presence of
Ru. The strong acid HZ liberated during the reaction is preferably
Alkali metal -dicarbonate, -carbonate or -hydroxide
Inorganic acid-scavengers such as compounds, organic quaternary ammonium
salts (e.g. tetrabutylammonium salts),
or triethylamine, N-ethylpiperidine,
Organic tertiary bases such as pyridine or quinoline
are combined by the addition of In step (a), the alkylation is carried out in a conventional and appropriate manner.
Reductive alkylation using methods used in the field.
It can also be done under certain conditions. Performing alkylation
In the general formula R₁−CO−R₀ (In the formula, R₁and R₀is as defined above)
The represented compound is reacted with the starting bicyclic compound.
and simultaneously or subsequently react with a reducing agent. return
When used simultaneously with an alkylating agent under the base agent, sodium
Complex metal hydrides such as muciano borohydride
and formic acid; another sequel
Under the reducing agent mainly used in operations that occur in
In other words, the reduction of the previously formed imine (Schizuf salt)
diborane and sodium boride
Hydride and sodium cyanoborohydride
It is said that the complex metal hydride consists of
Bell. Separate intermediates such as imines
can be added to the first reaction mixture without
It is convenient to In this case, the alkylation is
Aliphatic or cyclic ethers (e.g. diethyl ether
diisopropyl ether, 1,2-dimethoxy
siethane, dioxane, tetrahydrofuran) or
or aliphatic alcohols (e.g. methanol, ethano
alcohol, isopropyl alcohol, glycol, glycol
Recall monomethyl ether, diethylene glyco
Organic solvents that are inert to reducing agents, such as
Among them, it is convenient to carry out the process preferably at a temperature of 0°C to 80°C.
It is. Mains that can be used simultaneously and successively
The reducing agent is hydrogen, especially catalytically activated
It is hydrogen. The catalyst is commonly used as a hydrogenation catalyst
for example on a carrier (e.g. carbon
Calcium, aluminum hydroxide, or sulfate
precious metals (e.g. palladium, platinum,
Even in finely dispersed suspensions of aluminum) without carriers.
Alternatively, it can be used in the form of acrosome and in a homogeneous phase.
preferable. Finely dispersed transition metals, e.g.
Raney metals, especially Raney nickels, are reducing agent alkylenes.
It is suitable for file formatting. Most of the special reaction conditions
minute, it relies on a special hydrogenation catalyst, and its
The exact activity is generally known for hydrogenation.
It's no different than that. Temperature ranges from room temperature to 150
The hydrogen pressure ranges from atmospheric pressure to 300 atm.
This is based on standard operation in the field.
will be applied accordingly. Said above in connection with hydride reduction
Low molecular weight amides, especially tertiary
class amides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyro
-ridone, N-ethylpiperidone, hexamethyl
phosphoric acid triamide), formamide, acetamide
Suitable solvents include It's an oxo group.
Expressed by a general formula with a functional group that is easily reduced, such as
Special treatment should be given to starting materials that are
In order to protect these groups, conventional methods have been used to protect these groups.
Can it be applied under selective reduction conditions known in the field?
or it is desirable to reduce these groups simultaneously
or essential or accordingly active.
It is carried out using chemical reagents and/or conditions. The previously generated imine is preferably a general
Amines represented by the formula and general formula
Compounds are separated from inert solvents (e.g. toluene, methylene chloride).
First, the dehydration catalyst (e.g. boron trifluoride) is
Lloyd ethylate, p-toluenesulfonic acid, min
It is synthesized by condensation in the presence of a child system (Rui). Step (b) preferably comprises an alkali metal hydride.
(e.g. sodium hydride, potassium hydride),
Rukoxide (e.g. sodium methoxide, sodium
potassium tert-butoxide),
or acid (e.g. lithium diisopropylamide)
in the presence of strong alkali metal hydrides such as
The reaction is carried out in the preferred solvent of ether or amide.
cormorant. In the special completed form of process (b), R′_Ais water
using starting materials that are elementary and at least reactants
Use two equivalents of quality B. Obtained product odor
, residue R_Aand R_Bare the same and R_Bdefinition range of
It is within the range. In each alkylation step, the starting material
The primary and secondary amino groups are alkylated.
temporarily during alkylation by removing the secondary amino group
need to be protected. Suitable protecting groups also include:
Induction and release procedures are well known in the art.
has been developed, especially as a general method for peptide synthesis.
As stated in; by Hawbon-Bail: Organicization
Academic method 4th edition, 15/volume edited by E. Vuunciu
Collection: Peptide Synthesis (Georg Thime Publishers, Ste.
Utgard, 1974). Rational selection of protecting groups is
Depends on the specific purpose and the need for starting materials
The characteristics and reaction conditions of the specific process must be considered.
Must be. When protecting some functional groups
It is preferable to select a combination of Like
or for example, the same or better, the residue
R₀and residue R₁, the same aluminum protecting group
is used and simultaneously liberated at the end of the alkylation. As an amino-protecting group, it can be removed in particular by reduction.
Amino-protecting groups that can be removed are preferred, e.g.
Examples include the ndyloxycarbonyl type;
When the benzene ring of the benzyloxycarbonyl group
Halogen atoms, lower alkoxy groups, and
and/or lower-alkyl residues and especially nitro-
substituted by a group, e.g.
and p-bromobenzyloxycarbonyl-, P
-methoxybenzyloxycarbonyl-, p-methoxycarbonyl
Tylbenzyloxycarbonyl- and p-nito
lobenzyloxycarbonyl group, or isonico
Any of the thinyloxycarbonyl groups. a
Three hydrocarbon residues in the β-position as mino-protecting groups
silyl group substituted by (for example, trifium)
enylsilyl group, dimethyl-t-butylsilyl group
or in particular a trimethylsilyl group).
Toxycarbonyl groups are convenient. β-(tri
-lower-alkylsilyl)-ethoxycarbonyl
This type of β-(trihydrocarbon
rubyl-silyl)-ethoxycarbonyl group, and
For example, especially β-(trimethylsilyl)-ethoxylic
The bonyl group is reacted with the amino group to be protected, and the pair
corresponding β-trihydrocarbyl ethoxylic
Bonylamino group (e.g. β-trimethylsilyletho
oxycarbonylamino group) and make it extremely
fluorine ions under very mild conditions specific to
It is possible to release it by a group that can be liberated by acid hydrolysis;
For example, the t-butoxycarbonyl group and similar
group, as well as benzhydryl group, di-(4-methoxy
c)-benz-hydryl group and triphenyl group
Aralkyl such as tyl group (trityl group)
(Aralkyl)-type radical or Swiss patent specification
2-(p-biphenyl) disclosed in No. 509266
)-2-propoxycarbonyl type specific
Examples include aralkoxycarbonyl groups. Cal
Protecting groups derived from esters of bonic acids are often
can be liberated by base hydrolysis.
It is Noh. Optionally, temporary protection of the hydroxyl group can be achieved by reduction.
Protecting groups that can be liberated by
Ben. (see text by Beil), 2-tetrahy
Dropyranyl group, t-butoxycarbonyl and
The t-butyl group can be liberated by acid decomposition.
Wear. Hydroxyl group-protecting group can be liberated by reduction.
is preferable, for example, halo is added to the benzene ring.
Gen, lower alkyl group, lower alkoxy group and
and/or especially nitro groups, especially 4-nitrobenzyl
A benzyl group substituted with a group is preferred. Weak base
Formyl groups or toxins that can be liberated under conditions
Use acyl groups like lyfluoroacetyl groups
It is also possible. Optional protection of oxo groups preferably includes
as a ketal, especially methanol as a ketal.
or lower alkanols such as ethanol or
is preferably derived from ethylene glycol,
or preferably as the corresponding thioketal
Derived from 1,2-ethanedithiol. these
The group releases an oxo group under the conditions shown below.
be able to. Subsequent release of protecting groups in embodiments of the invention
The separation depends on the nature of the compound and is common for derivatives.
It is carried out in the usual way, taking into consideration the nature of the test. similar article
can be released under conditions (particularly here, by acid decomposition).
For groups that can be separated, or for amino and hydroxyl groups
can be liberated by reduction as described in all
(preferably groups), all protecting groups can be removed in a single operation.
Amino groups, hydroxyl groups and
and oxo groups or special
In this case, different types of groups are used and their
It is also possible to release each separately. Groups that can be liberated by reduction are particularly halogenated.
lower-alkyl-residues (e.g., 2,2,2-t
(lichloroethyl residue), isonicotinyl residue (e.g.
isonicotinyloxycarbonyl), and especially
Substituted benzyl residues, all 4-nitrobenes
Groups containing zyl residues are preferably
By reduction with lead, preferably acetic acid and
Normally at room temperature with or without the addition of an inert organic solvent
It is released under By acid hydrolysis (acid decomposition)
In the case of t-butyl-type, the release of the protecting group is
is hydrogen chloride, hydrogen fluoride or trifluoroacetic acid
In the case of acid-sensitive protecting groups, formic acid and
and/or lower aliphatic carboxylic acids such as acetic acid
with water and optionally a polyhalogenated lower atom.
lukanol or lower-alkanone (Example 1,
1,1,3,3,3-hexafluoropropane-2
-ol, hexafluoroacetone)
cormorant. In this method, for example, water can also be used as a solvent.
or formic acid and vinegar in anhydrous trifluoroethanol.
acids, organics like chloroacetic acid, trifluoroacetic acid
by acid (German Publication No. 2346147) or
releases the N-trityl group with an aqueous acetic acid solution.
trifluoroacetic acid or hydrochloric acid
The t-bitoxycarbonyl group is liberated by
and an aqueous acetic acid solution or e.g.
Formic acid (82.8% strength) - water (7:1:2) mixture
Or the method based on German Publication No. 2346147?
2-(p-biphenylyl)-isopropo
Possibility of liberating the xycarbonyl group
It is. β-silylethyl ester group is preferred.
or the aforementioned fluorine-ion reagents, such as tet
Quaternary compounds such as laethylammonium fluoride
It can be liberated by fluoride of organic base. Ketalized and thioketalized oxo groups
is a normal strong inorganic acid or oxal in the presence of water.
Can be converted into free oxo group by acid decomposition with acid.
and the latter is a sulfur-binding agent (e.g. mercury-salt).
and/or cadmium carbonate).
can be released. Protecting groups under basic conditions
For example, formyl group, trifluoro
loacetyl group, carboxylic acid ester group to sodium carbonate
potassium carbonate, sodium bicarbonate, heavy carbon
Potassium acid and ammonia aqueous solution in an organic solvent,
It can be liberated by acting at room temperature.
Wear. Protecting groups are preferably used under the conditions of the examples or
can be released under similar conditions. The final product according to the invention contains two basic groups.
Depending on the method of separation, the base or
or as an acid addition salt. Similarly, acidic groups
The final product with is obtained as a salt. each shape
One state can be converted into another by known methods.
Bases can be obtained from acid addition salts by known methods.
Ru. It can be sequentially converted from a base to an acid addition salt.
Therapeutically useful acid addition salts are formed by reaction with acids.
For example, reaction with acids of the salt-forming types mentioned above.
It is possible to obtain it by acids and them
The salts of are in a similar relationship to each other. free carboxy
Compounds with both radicals and basic groups have intramolecular
May form salts and establish isoelectric point
You can get them by. Starting materials represented by general formulas A, B and
quality, i.e. known or unknown alkylation
The agent can be easily obtained by conventional synthetic processes.
can. Starting materials of the general formula and are usually
The following are the special intermediates obtained by the synthesis process of
A detailed example will be described. The alkylation reaction in step (c) follows the same general considerations.
Accordingly, under the same experimental conditions, the above processes (a) and
and (b), general formula A, B or (substituted
alkylation or reductive alkylation)
The treatment of alkylating agents is described in detail above.
Do as you did. Starting material represented by the general formula
The quality is measured in the usual known ways, e.g. specifically as detailed below.
It is obtained by the method described in detail. expressed by a general formula
Known or unknown amines can be synthesized using conventional methods.
easily obtained. The solvation decomposition in step (d) is carried out under normal conditions.
method to convert cyanide (nitrile) into free carbon.
carbonic acids or their salts, esters, or
Can be converted to mido. Conversion to the free acid is accomplished by water in an inert organic solvent.
Hydrolysis using at least water is advantageous.
Ethers that are miscible with (e.g. diethyl ether)
diisopropyl ether, 1,2-dimethoxy
siethane, especially dioxane or tetrahydrof
or lower alkanols
(For example, methanol, ethanol, isopropylene
Pyl alcohol, butyl alcohol, especially t-butyl alcohol
alcohol (such as alcohol) is used, and then
In the case of
Requires excess water. Hydrolysis is caused by strong acids, especially sulfur
acids or preferably hydrohalic acids (e.g. bromide
Hydrogen acid, hydrochloric acid as the first choice), etc.
inorganic acids or bases, especially alkali metal hydroxides
compounds and carbonates (e.g., sodium hydroxide, hydroxide
This is done with an inorganic base, such as potassium oxide).
It will be done. To obtain the carboxylate salt as the first product,
Bases are usually used in at least stoichiometric amounts.
Acidic catalysts give best results when applied as dilute aqueous solutions.
You can get results. General formula (where R₀is esterified
The final product represented by
The corresponding alcohol (alcohol) of the nitrile
The solvation decomposition by catalyzing anhydrous strong acid
carried out in the presence of a suitable amount of hydrogen chloride, preferably gaseous hydrogen chloride.
It can be obtained by becoming. Usually excess alcohol
is used as a solvent, but inert organic solvents,
i.e. cyclic and acyclic ethers (particularly those mentioned above)
ether), and/or halogenated lower alkyl
Adding alcohol (especially chloroform/dichloromethane)
You can get it. Strictly anhydrous alcohol decomposition
If carried out under conditions, the first product (iminoester
) can be conveniently prepared by adding water to the reaction mixture.
Well hydrolyzed, while at a suitable stoichiometry of water
by performing alcoholysis in the presence of
The desirable esters are obtained directly. expressed by a general formula
corresponding amide (e.g., represented by the general formula
It is a compound with R₀is a carbamoyl group)
To obtain the corresponding nitrile, preferably
Alkaline decomposition is carried out in the presence of hydrogen oxide. The starting material represented by the general formula is a conventional known starting material.
A condensation reaction similar to that in step (c), for example
is obtained by the general formula
The starting compound shown below is expressed by the general formula ′ (In the formula, R₁and R_Fiveis as defined above,
corresponding to the above-mentioned amine represented by the general formula)
React with the amine represented by process (a) and
(b) is also a similar synthesis of nitrile expressed by the general formula
It can be used for. Cyclization in step (e) can be carried out using known methods such as dehydration.
I'll turn over and go. General especially useful for this purpose
The method is described in the above-mentioned edited books, e.g.
15/and 15/vol.
The formation of amide bonds in peptides and
It's related. According to the preferred improvement method, it is cyclized.
Amino groups are inactivated by protonation (i.e.
(i.e. acid addition salt), then the carbonyl group is
For example 2,4,5-trichlorophenol, pen
tachlorophenol, pentafluorophenol,
2-nitrophenol or especially 4-nitrophenol
nor, or N-hydroxysuccinimide, 1
-Hydroxybenztriazole or N-hydro
N-hydroxy compounds such as roxypiperidine
substances, especially N,N'-dicyclohexyl isourea
optionally N,N'-di-substituted isoures such as
or similarly to active esters such as
Convert to commonly known activators. Cyclization is
Preferably an organic base, such as quaternary ammonium
salts or especially tertiary amines (e.g. triethylamine,
N-acetylmorphone, N-methylpiperidi
to make it basic (to cyclize the amino group).
), unprotonated to react
This is done by converting to The reaction temperature is
Usually -20 to +50℃, preferably around room temperature.
An example of a commonly used solvent is dioxane.
ion, tetrahydrofuran, acetonitrile, pyri
gin, dimethylformamide, dimethylaceto
Mido, dimethyl sulfoxide, N-methylpyrroli
Don, hexamethyl phosphate-trisamide, chloro
Roform, methylene chloride and customary mixed solvents
can be mentioned. Especially in the improvement method, dicyclohexane
xylcarbodiimide (N-hydro if necessary)
Roxysuccinimide, unsubstituted or e.g.
halogen-, methyl-, methoxy-substituted 1-
Hydroxybenztriazole, 4-hydroxy
Benzo-1,2,3-triazine-3-oxide
or N-hydroxy-5-norbornene
(norbornen)-2,3-dicarboximide
(under the addition of dicarboximid)
Bodiimide or N,N'-carbonyl-diimide
By the action of free acid with dazole, in. S
Direct activation of carboxyl groups in tow
I can do it. The starting material of the general formula can be, for example,
Known conventions as described in the specific examples below.
Obtained by law. The reduction in step (f) saturates such double bonds.
carried out by known conventional methods used to
be able to. Starting unsaturation corresponding to the general formula
The double bond in a substance is between C-3 and C-4,
or between C-3 and an adjacent nitrogen atom, or
residue R_AThe nitrogen atom and the adjacent carbon atom in
It is localized between. Double bond saturation is preferred
or catalytic hydrogenation, e.g. preferably as described above.
The process is carried out under conditions such as
Metal reduction, such as lead reduction, or especially C
-N In case of double engagement, sodium
Complex hydrides such as borohydrides or dibora
Reduction is carried out by means of This improvement method
Unsaturated starting materials can be used, for example, in steps (a) and (c).
and/or as a special example below.
It can be obtained by known conventional methods. The condensation reaction in step (g) is carried out under normal general conditions.
When using a solvent that is inert to the reactants (e.g., methylene chloride)
1,2-dimethoxyethane, N,N-dimethylene
(formamide) within the temperature range of 0° to 100°C
If necessary, a base e.g. triethylamine
Tertiary amines such as or sodium hydride
It is carried out in the presence of an alkali metal hydride such as The final product obtained, represented by the general formula, is
If necessary, when converting,
Transform within the range defined by the general formula, as follows:
The transformation takes place: the amino group is alkylated and
and/or oxo group, especially the group represented by
to an acid group (+ hydrogen) or by reduction to two hydrogens
atoms and/or hydroxyl groups by oxidation.
Hydrogen atoms can be converted into oxo groups or by reduction.
and/or free hydroxyl or carboxy
The group can be removed by hydrolysis or hydrogenolysis.
released from the esterified form and/or
Hydroxyl or amino groups may be acylated and/or
The free carboxyl group is esterified and/
or the aromatic carbocycle in the general formula is hydrogenated
hexahydro or 6,7,8,9-tetra
hydro and/or hexahydro carbocycle
is dehydrogenated, and 6,7,8,9-tetrahydro is also
or an aromatic carbon ring. All conversions should be made according to well-known routines, if necessary.
Do it according to the law. By alkylation reaction,
For example R_Fivelower alkyl as represented by
The R group is expressed by the general formula (wherein, R_Fiveis hydrogen)
can be derived into the final product that is
Any of the remedies detailed in connection with step (a)
Use either. Substitutional and reductive alkylation
When both are used, the former is an alkyl halide
The latter are lower aliphatic aldehydes and ketones.
and catalytically activated hydrogen or formal
In the case of dehydes, preferably formic acid is used as the reducing agent.
Make it react. In the case of substitutional alkylation, the lower alkyl
Kill group is R₀Component of carbamoyl group represented by
is induced into an amino group. 5-oxo hydroxyl
Reduction to groups can be carried out, for example, by complex-metal hydrides, especially
As a milder alkali metal borohydride
(e.g. sodium borohydride), or
by the Meerwein-Ponndorf method.
or by an improved method using alkanols.
with isopropyl alcohol, solvent and reducing agent.
and a metal alkoxide, preferably a catalyst.
and a reducing agent such as aluminum isopropoxide.
It is carried out using a substance that corresponds to the original alcohol.
Ru. Reduction of oxo group to two hydrogen atoms is convenient
Treatment of amalgam zinc with hydrochloric acid or corresponding
Raney-nickel of dithioketals - by desulfurization
It can be done with Hydroxyl group to oxo group
The oxidation is preferably carried out using chromic acid and its salts.
Hexavalent chromium derivative permanganate
(especially potassium permanganate) or Otupenna
Under conditions of well (openauer) oxidation, an oxidizing agent and
acetone or cyclohexanone, catalyst and
using aluminum isopropoxide.
cormorant. Esterified hydroxyl groups are especially hydroxyl-protecting groups.
by the method described above in detail regarding the release of
specially liberated; both hydroxyl and amino groups
The acylation of the two is carried out in a conventional manner, preferably with the corresponding
Use acid anhydrides or halides. beauty salon
For the diazolysis, the carboxyl group is directly
can, especially diazomethane or strong acid catalysts (e.g. sulfuric acid)
acids, organic sulfonic acids)
and/or dehydrating agents (e.g. dicyclohexyl
cycarbosiimide). As needed
and the carboxyl group is described in relation to step (e).
and its reactive derivatives such as activated esters.
is added to a mixture of anhydrides, e.g. acid halides.
(especially acid chlorides) or converted with trifluoroacetic acid,
This activated intermediate is reacted with the desired alcohol.
make them respond. The free carboxyl group becomes the esterified carboxyl group.
Released from the boxyl group by conventional methods, especially by base-catalyzed
It is carried out by water splitting. Especially interestingly -
C.O.R.₆and −COR₇one special represented by
Carboxy groups can be selectively released.
In such cases, as a carboxyl group-protecting group,
In the field, known ester groups and
and Hoven-Beil, supra, 15/and
Especially for peptide synthesis as in Volume 15/vol.
Using diverse ester groups in combination
I can do it. To selectively release carboxyl groups,
Suitable residues include, for example, cyanomethyl alcohol.
alcohol, benzoyl methyl alcohol, or t-
Derived from alcohols such as butyl alcohol
ester, and the residue is removed by acid hydrolysis.
can be liberated, especially 2,2,2-trichloroethanol
benzyl alcohol, especially 4-nitrobezyl
Alcohol or isonicotinyl alcohol as needed
In the case of alcohols such as alcohol, the residue is
It can be liberated depending on the source. especially convenient
are substituted alkanols, with β-position
Triphenylsilyl, dimethylbutylsilyl,
or especially tri-substituted compounds such as trimethylsilyl.
Ethyl alcohol with a silyl group. parable
As described in Belgian patent number 851576, it
These alcohols are particularly suitable for selective release.
, since the corresponding β-silylethyl ethyl
ster, such as β-(trimethylsilyl)-ethyl
Conventionally, the stability of alkyl esters
fluorine ions under mild conditions.
selectively liberated by the action and other esterification
carboxyl groups, such as alkoxycarbonyl groups
The group remains as is. The liberation of the esterified group depends on its nature;
This is carried out by a conventional method taking into consideration the characteristics of other residues.
groups that can be liberated by reduction, especially halogenated
lower alkyl residues (e.g., 2,2,2-trichloro
ethyl residue), isonicotinyl residue (e.g.
cotinyloxycarbonyl group) and optionally
benzyl residues substituted with
The trobenzyl residue is preferably reduced by zinc reduction.
usually in the presence of an acid, preferably acetic acid.
It is usually liberated at room temperature with or without the addition of an organic solvent.
and benzyl-type, especially unsubstituted benzyl
Zyl ester is customarily used for benzyl groups
Can be liberated by hydrogenolysis. Release of ester group by hydrolysis (acid decomposition)
chloride water, especially in the case of the t-butyl type.
by hydrogen fluoride, trifluoroacetic acid, or trifluoroacetic acid.
Let's do it. β-silylethyl ester group is preferred
is liberated by the fluorine-ion-generating reagent,
For example, the fluoride of a quaternary organic base (tetraethyl
Ammonium fluoride) is used. base anxiety
A specific ester group is sodium bicarbonate or bicarbonate.
Act quickly with an aqueous solution of potassium acid or
Aqueous ammonia, preferably in an organic solvent, usually at room temperature.
Release at warm temperature. The ester group was prepared under the conditions of the example.
Preferably released under or under similar conditions.
stomach. Combining ester groups is an early step in the synthesis
or selection of starting materials and reactants.
For example, at the final step in process (a),
selectively derivatized with the carboxyl group to be released
The ester group to be liberated is selected. The compound represented by the general formula and especially A is
It is convenient to synthesize based on reaction sequence 1,
It includes the selection of starting materials and intermediates, and
It consists of the following stages: (a) Under conditions of base catalysis, general formula XI (In the formula, R₃′ and R_Four′ is hydrogen; lower alkyl
group, lower alkoxy group, lower alkanoyloxy group
cy group, halogen, trifluoromethyl group or
R₃′ and R_Four′ is a lower alkylene that forms as a unit
It is a dioxy group, and X′ is two hydrogen atoms, water
Esterified or etherified with elementary atoms
Hydroxyl, oxo or ketal or thio
It is an oxo group protected in the form of a ketal and R₉
is amino group, lower alkylamino group, azide
groups, or acylamino groups, such as lower alkyl
Canoylamino group or alkyloxycarbo
The compound represented by
General formula'B (In the formula, R₂′ is hydrogen or a lower alkyl group,
Z is an esterified reactive hydroxyl group,
R₇' is a hydroxyl group, a di(lower) alkylamino group,
Lower alkoxy group, aryl (lower) alkoxy
cy group, lower alkanoyloxymethoxy group, or
or lower alkoxycarbonyl (lower) alco
It is condensed with a compound represented by
height, (b) General formula′ if necessary (In the formula, R₃′, R_Four′, X′ are as defined in general formula XI
and R₂′ and R_Five′ is hydrogen or lower alkyl
R group, R₇′ can also be a hydroxyl group, an amino group, or a mono group.
or di(lower) alkylamino group, lower alkyl
Koxy group, aryl (lower) alkoxy group, lower
alkanoyloxymethoxy group, di(lower alkanoyloxymethoxy group)
alkylamino) lower alkoxy group or lower
alkoxycarbonyl (lower) alkoxy group.
) can be obtained to obtain the compound represented by
intermediates can be reduced, hydrogenated, hydrolyzed and
is alkylated, (c) Reduction of the compound represented by the above general formula
Under the conditions of sexual alkylation, the general formula ′ (In the formula, R₁' is hydrogen, lower alkyl group, acyl
amino (lower) alkyl group, aryl
group, aryl group (lower) alkyl group, cycloa
alkyl (lower) alkyl group, R₆′ is hydroxy acid
group, di(lower) alkylamino group, lower alkyl
Oxy group, aryl (lower) alkoxy group, lower
Alkanoyloxymethoxy group or lower alkyl
Koxycarbonyl (lower) alkoxy group
) may undergo a condensation reaction with the compound represented by
under the conditions of alkylation, with the general formula ′ given above.
Compound represented and general formula 'A (In the formula, R₁′ and R₆′ is defined by the general formula ′.
and Z is an esterified reactive hydroxyl group.
conduct a condensation reaction with a compound represented by
mosquito, (d) If necessary, hydrolysis or
or convert it into a derivative, (e) any resulting compound of general formula A;
The compounds can also be converted into other compounds according to the invention. Compounds of general formula
2, substituted and/or derived according to
3,4,5-tetrahydro-1H[1]benzaze
Pin-2-one (J.Chem.Soc, vol. 1937, p. 456)
UK Patent No. 1359285; Liebias's Annalen
Retrieved from Chemie volume 574, page 171 (1951).
Appropriately derived new starting material [1] Benzua
Zapin-2-one is conveniently known in the art.
Methods known in the art and methods in the Examples
The corresponding substituted naphthalene-1-one using
Synthesized by Beckman rearrangement of The tetrahydro-[1]benzazepine-2-
on is 3-halo (example 3-chloro)-2,3,4,
5-tetrahydro-1H-[1]benzazepine-
2-one under the conditions of the example, e.g.
treatment with tantachloride followed by conversion by hydrogenation.
exchange. Substitution of halo derivatives is possible with metal azides (e.g.
azide), and optionally reduced, and
using ammonia or lower alkylamine
and acylation if necessary.
Then, a compound represented by the general formula XI is obtained. General formula XI (where R₉is an amino group, an alkyl group
(mino group, acylamino group)
Compounds can be prepared by reduction and with appropriate substitutions.
and/or derived 4-(o-nitrophenyl)-
Cyclization of 2-aminobutyric acid and optional twitching
By N-alkylation or N-acylation
can be obtained selectively. Other compounds for optically active compounds according to the invention
The synthesis begins with the naturally occurring amino acid tryptophan.
Especially L-4-(o-aminophenyl)-4-oxo
-2-amino-butyric acid (L-kynurenine, J.
Am.Chem.Soc.76, 1708 (1954), L-Tryptopov
) is an optically active starting material
quality, general formula XI (wherein, R₉is an acylamino group
), for example, 3-(s)-t-
Butyloxycarbonylamino-2,3,4,5
-tetrahydro-1H[1]benzazepine-2,
5-Zion (Australian.Journal of
(described in Chemistry volume 33, pages 633-40 (1980))
Convert to Compounds represented by general formula XI and general
Lactanal with a reactant of formula 'B
Killing is well known in the art and is preferred.
or alkali metal hydride compounds (e.g. sodium hydrogen
potassium hydride) alkali metal alkoxy
(e.g. potassium t-butoxide, sodium chloride)
toxides) organometallic reagents (e.g. lithium, diiso
in the presence of a base such as propylamide) and
under phase-transfer-catalytic conditions, e.g.
Preferably in the presence of a tylammonium salt.
For example, tetrahydrofuran, dimethylformamide
in a solvent such as, preferably in the range of about 0°-75°C
Do this at internal temperature. Intermediate products represented by general formula ′ and general formula
Known α-keto acid-derived derivatives denoted by
(Chem. Ber. vol. 31, p. 551, p. 3133)
The condensation reaction by N-alkylation is already known in the art.
Under known conditions, e.g. platinum, palladium
Mu- or nickel-catalyst or single or light
Chemical reducing agents such as metal hydride-complexes, convenient
Nanoha, such as sodium cyanoborohydride,
Contact water in the presence of alkali metal cyanoborohydride
This is done by adding elements. alkali metal cyano
Reductive amination using borohydrides is preferred.
or methanol or acetonitrile.
In an inert solvent, in the temperature range of about 0°-50°C, preferably
or at room temperature, such as hydrochloric acid or acetic acid.
It is conveniently carried out in the presence of a suitable acid. The intermediate product represented by the general formula - amine is
reaction using a reactant represented by the general formula 'A'
Lucylation is carried out under conditions known in the art.
salts like triethylamine or potassium carbonate
an inert solvent in the presence or absence of a basic catalyst.
It takes place inside. The compound represented by the general formula and especially A is
Combined by series 2 and 3. Series 2 consists of the following stages: (a) General formula (XII) (In the formula, R₃′, R_Four′ and X′ are the general formulas above.
As defined in XI, R_Five′ is hydrogen or
is a lower-alkyl group)
A general formula′ In the formula, R₁′ and R₆′ is as defined above).
Conditions for reductive alkylation with the compounds represented
Or the general formula 'A (In the formula, R₁′, R₆' and Z are as defined above.
under alkylation conditions with a compound represented by
So, the general formula ′ (In the formula, R₁′, R₃′, R_Four′, R_Five′, R₆′ and X′ are
As defined above)
condensation reaction for (b) The obtained compound represented by the general formula
General formula'B (In the formula, R₂′, R₇' and Z are as defined above.
) under basic catalytic conditions.
condensation reaction. (c) Hydrolysis of the product obtained if necessary.
or conversion of the obtained products into derivatives. (d) Expressed by a general formula obtained as necessary.
Conversion of a certain compound to another compound according to the present invention
Exchange. Series 3 consists of the following steps. (a) General formula′ (In the formula, R₁″ is hydrogen, lower alkyl group, acyl
amino-(lower) alkyl group, aryl
group, aryl-(lower)alkyl group or
is a loalkyl group, R₆″ is a hydroxyl group, di-(low
class) alkylamino group, lower-alkoxy group,
Aryl(lower)alkoxy group, lower-al
Kanoyloxy-methoxy group, or lower-a
alkoxycarbonyl-(lower)alkoxy group
A compound represented by the general formula ′ (In the formula, R₂″ is hydrogen or lower alkyl group
R, R₃″ and R_Four″ is hydrogen, lower-alkyl group,
lower-alkoxy group, lower-alkanoyloxy group
cy group, halogen or trifluoromethyl group.
R or R₃″ and R_Four” is a low
class-alkylenedioxy group, and X″ is two
Hydrogen atom, etherified with hydrogen atom
is an esterified hydroxyl group, oxo group, ketal
or protected Oki in the form of thioketal.
is a group, R₇″ is a hydroxyl group, di-(lower) alkyl
Kylamino group, lower-alkoxy group, aryl
-(lower)alkoxy group, lower-alkanoyl
Oxymethoxy group or lower-alkoxy group
Rubonyl-(lower) alkoxy group, Y is
oxo group or dichlor)
under the conditions of reductive N-alkylation with
Condensation reaction or compound represented by general formula ′
A substance of the general formula ′ (wherein X″ is an oxo group)
and Y is esterified with hydrogen or esterified with hydrogen.
(reactive hydroxyl group)
Condensation reaction with compounds or these compounds
3,4-dehydro elimination product or 3,4-
Condensation reaction with dihydro derivative. (b) Reduction and hydrolysis of the product obtained as required.
solution, or derivatization. (c) the present invention of a certain compound obtained as necessary;
Conversion to other such compounds. In series 2 and 3 above, the lactam-a
alkylation, reductive N-alkylation and amine
Alkylation is carried out under the conditions described in Method 1.
It is held when In reaction series 1, 2 and 3 described above,
For example, represented by the general formulas 'A,'B and '
The reactant to be converted to the corresponding nitrile (e.g. R₂′CH(Z)
C.N., R.₁CH(Z)CN,R_FiveNHCH(R₁′)CN)
can do. The obtained nitriles correspond to
carboxylic acid and under conditions known in the art.
For esters and amines represented by the general formula
Can be converted. Starting materials of the general formula ′ are known in the art.
List well-known amino acids and derivatives
vinegar. The optically active compound according to this invention has the general formula
An optically active compound represented by ', for example L
-α-aminophenylbutyric acid, L-phenylalani
Notably, it is based on
It is important. General formulas 'A, 'B, ' and ' (wherein,
R₇′, R₆′ or R₆” is a hydroxyl group)
The appropriate carboxylate salt in the reactant
preferably in-situ, with the desired
synthesized before the condensation reaction with the intermediate product. The terms used in the method described above are as follows:
It is defined as follows. The esterified reactive hydroxyl group is a strong inorganic or
Organic acids, primarily hydrohalic acids (e.g. hydrogen chloride)
acids, hydrobromic acid, hydroiodic acid), aliphatic or
is an aromatic sulfonic acid (e.g. methanesulfonic acid, p-
esterified with toluenesulfonic acid)
It is something. The etherified hydroxyl group is preferably a lower alkyl group.
Koxy group (e.g. methoxy group, ethoxy group, t-buto
xy group). If necessary, reduction of the starting materials described above, hydrogen
Addition, hydrolysis or conversion to derivatives and
Transfer of the obtained product to other compounds according to the invention
The conversion is carried out under conditions and chemistries known in the art.
Performed as described in the Examples. General formula or A (where R₆and/or
R₇is a lower-alkoxy group)
Ammonia, mono- or di-(lower)
An alkylamine of the general formula or A (wherein,
R₆and/or R₇is unsubstituted, mono- or di-
− (lower) alkylamino group)
amidation to obtain the compound. General formula or A (where R₆and/or
R₇is lower-alkoxy, aryl-(lower)alkoxy,
Koxy group, amino group, mono- or di-(lower
-alkyl)-amino group)
The general formula of the compound or A (where R₆and/ma
or R₇is a hydroxyl group)
The conversion of hydrohalic acid or sulfuric acid
This is conveniently carried out by hydrolysis with an inorganic acid.
Better or preferably lithium hydroxide
or an alkali metal hydroxide such as sodium hydroxide.
It is carried out by hydrolysis of compounds with an alkaline aqueous solution.
Now. General formula and A (where R₆and/or
R₇is an α-aryl-(lower) alkoxy group, and
(e.g. benzyloxy group)
The general formula of a product or A (where R₆and/also
is R₇is a hydroxyl group) to the compound represented by
Selective conversion is achieved by the presence of a catalyst, e.g. palladium.
By hydrogenolysis under the use of hydrogen
It is done conveniently. General formula or A (where R₆and/or
R₇is not a hydroxyl group).
General formula or A (wherein the residue R₆and R₇is hydroxy acid
The monocarboxylic acid of the compound represented by
Can be converted. Such conversion shall
Selective hydrolysis or
It is carried out by hydrogenolysis, and R₆and
R₇This is done based on the chemical properties of the substitution product. General formula or A (where R₆and/or
R₇is a hydroxyl group)
acid or its salts are well known in the art.
alcohol or its reactivity under
Derivatives, corresponding mono- or di-esters
, that is, the general formula or A (where R₆Oyo
and/or R₇is a lower-alkoxy group, an aryl
(lower) alkoxy group, lower alkanoyl
Oxymethoxy group or lower-alkoxycarbo
is a nyl (lower) alkoxy group)
To obtain the compound, it is esterified. even more free
Carboxylic acid via a reactive intermediate product, the general formula
(In the formula, R₆and/or R₇is an amino group, mono-
or di-(lower) alkylamino group)
Converted to mono- or bis-amide represented by
do. Compounds represented by general formula or A and
Intermediate products, such as the general formula and ′ (wherein
X or X' is an oxo group)
compound to the corresponding compound (X or X' is a hydrogen atom
and hydroxyl group) by reduction, for example,
Catalytic hydrogenation, hydrogen in the presence of platinum catalyst, sodium
Metal hydride-reducing agent such as borohydride
Use to convert. The obtained compound (X or
X' is a hydrogen atom and a hydroxyl group).
or X′ are two hydrogen atoms), for example
by catalytic hydrogenation of carbodiimide adducts.
For example, a compound (X or X' is a hydrogen atom
and hydroxyl group) dicyclohexylcarbodiyl
by a condensation reaction in the presence of cuprous chloride.
Chem.Ber., vol. 107, p. 1353.
(1974). If necessary, the compound (X or X' is hydrogen and
hydroxyl group) first, and the corresponding compound [X or
or X′ is a hydrogen atom and an acyloxy group (e.g. acetate)
to
by catalytic hydrogenation in the presence of a palladium catalyst.
, a compound (X or X' are two hydrogen atoms)
reduce to The above-mentioned reactions are carried out according to conventional methods, preferably
Diluents, catalysts, and condensates that are inert to reagents and solvents.
In the presence or absence of the combination drug and other agents,
and or in an inert atmosphere at low temperatures, room temperature or
is the higher temperature, preferably the boiling point of the solvent used
Atmospheric pressure or above atmospheric pressure at a temperature of
It is done under force. The present invention includes improvements to the above-described method, and any
Intermediates obtained in steps can also be used as starting materials.
and can do the remaining steps or
It can be interrupted at any stage or the starting materials can be
or the reaction components may also contain their salts.
or in optically pure enantiomer form.
I can do it. Primarily their starting materials are these
It is used under the reaction of
used in the formation of the aforementioned compounds.
Ru. The present invention provides new starting materials and their production.
Concerning the process. Depending on the choice of starting materials and methods, novelization
Compounds can be in one form of possible isomers or as a mixture
Depending on the number of asymmetric carbon atoms, for example, the enantiomer
pure optical isomers such as, or racemic or
or a mixture of diastereoisomers
May exist as a mixture of chemical isomers. The resulting mixture of diastereoisomers and
Mixtures of racemates and racemates are prepared using conventional methods, including
Based on differences, pure isomers, diastereoisomers
isomers or racemates, e.g.
splitting by roughy and/or fractional crystallization
Ru. The obtained racemate was further converted to an optical enantiomer by a conventional method.
for example, reconsolidation from optically active solvents.
crystals, microorganisms, and optics that form racemic acids and salts.
due to the reaction of physically active chlorine with acidic end products.
The salt obtained is separated by conventional methods.
for example, based on different solubility.
For astereoisomers, the enantiomer is a suitable agent
It can be released depending on the use. base racemic raw
A compound can be divided into similar enantiomers, e.g.
By separating the diastereomeric salts of, e.g.
Resolution by fractional crystallization of α or L-tartrate
can. Conveniently, the two more active enantiomers are separated.
be done. Finally, the compounds according to the invention are in free form.
Or it can be obtained as its salt. the base obtained
is preferably a pharmaceutically acceptable acid or
is converted to the corresponding acid addition salt using an anion exchange agent.
can be converted or the resulting base
For example, metals or ammonium hydroxide.
using strong bases or alkali metal hydroxides.
or basic salts such as carbonates or cation exchange
It is converted to the corresponding free base using a chemical agent. general formula
(In the formula, R₀is a carboxy group)
compound or general formula A (wherein COR₆and/
or COR₇is a carboxy group)
Compounds with corresponding metal or ammonium
Convert to salt. These salts or other salts, even
picrate is used for purification of the obtained base.
the base is converted to a salt, the salt is separated, then the base is
is liberated from salt. in free compound and salt form
For a close relationship with a certain compound,
As far as the compounds are concerned, the corresponding salts are
It is intended to be provided under reasonable conditions. The compounds contained in these salts are in the form of hydrates.
containing other solvents obtained or used for crystallization.
I'm here. The pharmaceutical composition according to the present invention is suitable for use in mammals including humans.
For example, oral, rectal or enteral administration to
Suitable for intravenous and parenteral administration;
Prevention of diseases corresponding to the inhibition of enzymes
treatments, such as hypertension and congestive heart failure.
Expressed in a general formula that is effective against cardiovascular diseases such as
as a pharmacologically active compound or drug
The salt may be used in a single or single potency amount.
one or more pharmaceutically acceptable
Contains in combination with the body. The pharmacologically active compounds according to the invention are
Also suitable carriers for intra- or parenteral administration
or mixed with excipients, or the effective amount of the mixture
Useful in the manufacture of pharmaceutical compositions containing
Ru. Tablets and gelatin capsules are preferred;
Along with the active ingredient (a) diluents: e.g. lactose, dextrin;
Strauss, sucrose, mannitol, soybean
Rubitol, cellulose and/or glycine
(b) Lubricants: e.g. silica, talc, stearic acid,
Magnesium or calcium tearate
salt and/or polyethylene glycol, tablets
(c) Binding agent for agent: e.g. magnesium aluminum
Silicate starch pasta, gelatin,
Tragacant, Methylcellulose, Na
Thorium carboxymethylcellulose and/or
or polyvinylpyrrolidone, if desired (d) swelling
Agents: e.g. starch, agar, alginic acid or
sodium salt, foaming mixture and/or (d) absorption
agents, dyes, flavors, sweeteners, and injectable compositions are preferred.
It is an isotonic aqueous solution or suspension and a suppository.
is prepared from a fat emulsion or suspension.
The composition is sterile and/or storage stable;
Lubricants, adjuvants such as emulsifiers, solution promoters
stimulants, salts to control osmotic pressure, and/or
contains a buffer. In addition, other therapeutic properties
Including quality. The composition can be prepared by conventional mixing, granulation, coating,
- It is formulated by the tengu method and has a concentration of approximately 0.1 to 75%.
Preferably, it contains about 1-50% active ingredient. 50~70Kg
The dosage unit for mammals is approximately 10-200 mg.
Contains active ingredients. The following examples are intended to embody the invention:
It does not represent a restriction. Temperature is shown in degrees Celsius
All parts shall be expressed as parts by weight. Record
If not, evaporation is preferably carried out under reduced pressure.
is performed at approximately 15 to 100 mmHg. General formula or A (in which one or more
(with more than one asymmetric center)
If the diastereoisomeric compound obtained is
In the example, A, B, etc. are displayed. each diastereo
Isomeric compounds are characterized by physical properties
e.g. melting point, phase in chromatography.
Pairwise migration, infrared absorption spectrum, nuclear magnetic resonance spectrum
An example is a spectrum. General formula or A (where X is two hydrogen atoms
The asymmetric center is the carbon supporting the nitrogen atom.
of a compound represented by ) present in the side chain at the atom
, A and B are those in chromatography
Each isomer is classified based on the relative movement of
be done. Transfer in thin layer chromatography and
Normal-phase high-pressure liquid tank using silica gel as the stationary phase
Based on romatography, the faster moving isomer is
The slowly moving isomer of isomer A is isomer B.
Ru. Reversed phase (reserser) high pressure liquid chromatograph
Based on the movement in E, the slowly moving isomer is
In isomer A, the faster moving isomer is isomer B. Example 1 1-carboxymethyl-3-(1-ethoxyca
Rubonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benz
azepin-2-one (melting at higher temperatures)
isomer) 3-amino-1-carboxymethyl-2,3,
4,5-tetrahydro-1H-[1]-benzaze
Pin-2-one (10.0 g) and acetic acid (75 ml)
and benzylpyruvate in methanol (75ml)
-Store the solution with ethyl ester (26.4g) for one hour.
Stir at room temperature under nitrogen. 4 hours into the reaction mixture
sodium cyanoboride in methanol within
Add compound (3.4g) dropwise and leave at room temperature for 24 hours.
Stir. Add concentrated hydrochloric acid (4 ml) dropwise to the mixture.
Stir for 1 hour at room temperature and evaporate. residual
Distribute the material between 150 ml of water and 50 ml of ether, 40%
Adjust the pH to 9 with an aqueous sodium hydroxide solution. layer
Separate and discard the ether layer. The water layer is concentrated chlorinated water
Adjust the pH to 4.3 with basic acid and add acetic acid ethyl ester (3
x75ml). Hydrogen chloride gas to methylene chloride
Bubble the solution of crude product in 310 ml of water for 5 minutes.
Evaporate the solution to dryness and dissolve the residue in 225 ml of ether.
Stir and filter the product. High pressure - liquid chromatography
Diastereomers as confirmed by graphie
70:30 is obtained. The product was dissolved in ethanol/acetic acid.
Recrystallize from the methyl ester (1:3). melting point
1-carboxy showing 246−248° (with decomposition)
Methyl-3(1-ethoxycarbonyl-3-phene)
Nylpropylamino)-2,3,4,5-tetra
Hydro-1H-[1]benzazenpin-2-one
-hydrochloride is obtained, racemized isomer B
corresponds to The above hydrochloride salt (0.9 g) and
Propylene oxide (10
ml) solution is stirred under nitrogen for 18 hours. The solution is vaporized
Dry and dissolve the residue in ethanol (3 ml).
Ru. Add ether (75 ml) and add hydrochloric acid as described above.
A small amount of the ride precipitates. Evaporate the filtrate to dryness and remove the residue.
Triturate the distillate with ether/petroleum ether (1:9)
Mix and filter the resulting solid substance. Melting point 139−
1-carboxymethyl-3-(1-
Ethoxycarbonyl-3-phenylpropylamide
-2,3,4,5-tetrahydro-1H-[1]
Benzazepine-2-one is obtained. general formula
B (in the formula, C_oH_2ois ethylene and R₆is Etoki
is a group, R₇is a hydroxyl group, and R₈is phenyl
The higher melting point of the compound represented by
Racemized isomer B shown below. under normal conditions
Resolution of diastereomers with optically active amines
and the pure enantiomer, e.g. the 1-carboxylic acid of Example 12.
oxymethyl-3S-(1S-ethoxycarbonyl-3
-phenylpropylamino)-2,3,4,5-
Tetrahydro 1H-[1]benzazepine-2-o
can be obtained. Inversion phase (solvent system: methanol/acetic acid (3:1)
cylindrical high pressure containing 0.025% acetic acid)
Liquid chromatography (abbreviated as h.p.l.c.)
) shows a lower melting point than Example 5.
Isomer B migrates faster than isomer A. Starting material, i.e. 3-amino-1-carboxy
Dimethyl-2,3,4,5-tetrahydro-1H
- [1] Benzazepine-2-one is as follows:
Manufactured to. 2,3,4,5-tetrahydro-1H-[1]be
nzazepine-2-one (48.3 g; S. britschus
et al., J. Chem. Soc. 1937, p. 456), Phoshopene
Tachloride (188g) and xylene (1300ml)
Stir under nitrogen atmosphere at 90℃ (oil bath temperature)
Cook for 30 minutes while stirring. 30℃ (phosphopentac
(dissolve the loride) and heat at 50°C.
Stop and do it. Generate sufficient hydrogen chloride
Ru. The temperature is held at 90°C for 30 minutes. The reaction mixture is
heat (to remove small amounts of suspended solids)
Filter and evaporate the filtrate to dryness under reduced pressure. residue
Add saturated aqueous sodium carbonate solution under stirring.
(100ml). After completion, filter out the solid product
washed with ethanol (150 ml), then washed with ethanol (150 ml).
Washed with nol (50ml) and ether (50ml)
and dry. 3,3- exhibiting a melting point of 185-187°
Dichloro-2,3,4,5-tetrahydro-1H
-[1]Benzazepine-2-one is obtained. 3,3-dichloro-2,3,4,5-tetrahydrogen
Dro-1H-[1] Benzazepine-2-one (20
g, 0.174 mol) and anhydrous vinegar in acetic acid (920 mg)
Sodium chloride (15.4 g, 0.188 mol) under air pressure
hydrogen over 5% palladium-carbon-catalyst (1.72 g)
Hydrogenate until absorption is complete. Filter the catalyst,
Acetic acid was distilled off under reduced pressure, and the residue was diluted with 10% hydrogen carbonate.
Sodium solution (900ml) and dichloromethane
(300ml). Further dichloromethane water layer (PH8)
Extract with lomethane (3 x 300 ml). combined draw
Dry the extract over anhydrous sodium sulfate and evaporate to dryness.
do. 3-chloro-2, exhibiting a melting point of 163-167°
3,4,5-tetrahydro-1H-[1]benza
Zepin-2-one is obtained. 3-chloro-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one (15.9g,
0.08 mol) and dimethyl sulfoxide (320
Sodium azide (6.36 g, 0.10 mol) in ml)
is kept under nitrogen at 80°C for 3 hours. At this time
The infrared absorption spectrum of this sample reaches its maximum at the point
2150cm in strength^-1shows a peak at , it is azide
It is group-specific. The reaction mixture was poured into ice water (1000
ml) and stir the suspension for 30 min. solid substance
Filter, wash with water (250 ml) and dry. melting point
3-Azide-2,3,4,5 showing 142−145°
-tetrahydro-1H-[S]benzazepine-2
-On is obtained. 3-a in dry dimethylformamide (75 ml)
Dido-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one (8.7g, 0.043
dry dimethylformamide in a solution containing
Oysters with sodium hydride in (250ml)
Mixed suspension [60% dispersion in mineral oil (1.9g)]
was synthesized with petroleum ether (3 x 150 ml).
Wash. ] under nitrogen at 0°C within 30 minutes.
Add. Stir for another 1.5 hours, then dry
Acetic acid bromide in dimethylformamide (75 ml)
ester (10.8 g, 0.047 mol) over 45 minutes.
and maintain the temperature at 0°C. more mixture
Stir for 18 hours while warming to room temperature. Dimechi
The formamide was distilled off under reduced pressure, and the residue was dissolved in water.
(500ml) and dichloromethane (500ml)
do. The aqueous phase was extracted with dichloromethane (3 x 500ml).
put out The combined extracts were dried over sodium acetate.
It is dried and the solvent is distilled off under reduced pressure. as an oily substance
A crude ester-azide is obtained. Tolue them
(500 ml) and mixed with silica gel (48 g).
match. Filter, remove the solvent under reduced pressure, and remove the oil.
3-azido-1-benzyloxycarbo
Nylmethyl-2,3,4,5-tetrahydro-
1H-[1]benzazepin-2-one is obtained,
used in the next synthetic step without further purification.
Ru. Suspension of activated Raney-nickel catalyst in water (15 ml)
Wash the suspension with ethanol (5 x 100 ml) and strain
3-Azide in ethanol (300ml) while stirring.
-1-benzyloxycarbonylmethyl-2,3,
4,5-tetrahydro-1H-[1]benzazepi
Add a solution containing ion-2-one (5.0 g). Hanging
The suspension was stirred for 18 hours at room temperature under nitrogen.
Ru. The catalyst is filtered off and the solvent is distilled off under reduced pressure. Residue
Dissolve the distillate in 2N hydrochloric acid and add the solution to
Extract with tel (2 x 250 ml). Concentrate the aqueous solution
Make it alkaline (PH9) with monia water and evaporate the solution.
Extract with ether (3 x 200 ml). Combined A
Dry the extract over sodium sulfate and remove the solvent.
Distill under reduced pressure. As an oil, 3-amino
-1-benzyloxycarbonylmethyl-2,
3,4,5-tetrahydro-1H-[1]benza
Zepin-2-one was obtained and did not require further purification.
It is then used in the next synthesis step. 3-amino-1-benzyloxycarbonyl
Chil-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one is produced as follows.
Build. 3-amide in dimethylformamide (100 ml)
No-2,3,4,5-tetrahydro-1H-[1]
Benzazepine-2-one (5.0g, 0.028mol)
dimethylformamide in a nitrogen atmosphere to a solution containing
Sodium hydride [mineral oil (1.2
g) within 60% dispersion of
Stir with water (3 x 150 ml)
Add the grated suspension. Incubate the reaction mixture at 50 °C for 15 min.
in dimethylformamide (25 ml).
of acetic acid bromo-benzyl ester (7.2 g, 0.031 mole)
mix with the solution of The reaction mixture was heated for an additional 18 hours.
Wash under 50℃, then cool to room temperature, high
Dimethylformade is distilled off under vacuum. inorganic salt
Add toluene/dichloromethane to the residue for precipitation.
Add tongue (1:1, 500ml) and stir. filtration
After that, the filtrate was distilled off under reduced pressure, and the resulting residue was
Perform chromatography using Lycagel (200g). 0-15
Elute with % acetic acid ethyl ester-toluene. main
As a product, 3-amino-1-benzyloxy
Carbonylmethyl-2,3,4,5-tetrahydride
Rho-1H-[1]-benzazepine-2-one is obtained.
It will be done. 3-Amino-1-beta in ethanol (250 ml)
ndyloxycarbonylmethyl-2,3,4,5
-tetrahydro-1H-[1]benzazepine-2
-10% palladium in a solution containing (1.3 g)
Add carbon-catalyst (0.20g) until hydrogen absorption is complete.
Hydrogenate under air pressure at room temperature until
Ru. The catalyst is filtered off and the solvent is distilled off under reduced pressure. White
A foamy substance (0.90 g) is obtained. crush it
3-amino-1-cal showing F.147-150℃
Boxymethyl-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one was obtained.
Ru. 3-azido-1-beta in ethanol (300ml)
ndyloxycarbonylmethyl-2,3,4,5
-tetrahydro-1H-[1]benzazepine-2
−on (14.0 g, 0.04 mol) at 22 hours.
5% palladium on carbon under 3.1 atm.
Hydrogenate at room temperature in the presence of catalyst (2.0 g).
The catalyst is filtered off and the solvent is distilled off under reduced pressure. residue
Dissolve in water (500ml) and dichloromethane the resulting solution.
Extract with lomethane (2 x 400 ml). Dichloromethane
The tan solution is dried and evaporated under reduced pressure. residue
Dissolve in ethanol (50ml) and remove the solvent under reduced pressure.
Distill and repeat the same operation with the residue. residue
recrystallized from ethanol/ethyl acetate
do. 3-Amino-1 exhibiting a melting point of 147-150°
-carboxymethyl-2,3,4,5-tetrahydrogen
Dro-1H-[1]benzazepine-2-one is obtained
It will be done. Example 2 1-benzyloxycarbonylmethyl-3-
(1-carboxy-3-phenylpropylamide
-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one Benzyl pyruvate in methanol (35 ml)
Ester (0.48g, 0.0028mol) and 1-ben
Zyloxycarbonylmethyl-3-amino-2,
3,4,5-tetrahydro-1H-[1]benza
Contains Zepin-2-one (0.45g, 0.0014mol)
Sodium cyanoboride (0.152g,
0.0014 mol). The reaction mixture was heated with nitrogen for two hours.
Stir at room temperature in a bare atmosphere. reaction mixture
Pyruvate-benzyl ester (0.48g,
0.0028 mol) and stirred for an additional 18 hours. dark
Add hydrochloric acid (0.5 ml) and stir for 1 hour.
The solvent was evaporated under reduced pressure and the residue was dissolved in sodium chloride.
dichloromethane (100ml) to precipitate the
and process it. Filter the mixture and remove the solvent under reduced pressure
Evaporate and the resulting residue is silica gel (30g)
Perform chromatography. Acetate ethyl ester/meth
Elute with ethanol/acetic acid (90:10:0.2). oily
As a substance, 1-benzyloxycarbonylmethylene
Ru-3-(1-carboxy-3-phenylpropylene)
Ruamino)-2,3,4,5-tetrahydro-1H
- [1] Nucleus from which benzazepine-2-one is obtained
Magnetic Resonance Spectrum (CDCl₃) σ7.35 (m, 14H),
5.10 (s, 2H), 4.60 (m, 2H), 3.00 (m, 12H). Example 3 1-benzyloxycarbonylmethyl-3-
(1-ethoxycarbonyl-3-phenylpro
pyramino)-2,3,4,5-tetrahydro
-1H-[1]Benzazepine-2-one 1-benzi in dimethylacetamide (15 ml)
carboxycarbonylmethyl-3-(1-carboxy
C-3-phenylpropyl-amino)2,3,
4,5-tetrahydro-1H-[1]benzazepi
ion-2-one (0.364g, 0.0007mol), bicarbonate
Sodium (0.190g, 0.0022mol) and acetate
Solution containing tyloiodide (0.315 g, 0.002 mol)
Stir at room temperature under nitrogen for 72 hours. reaction mixture
is filtered off and evaporated under reduced pressure. water (100ml)
and dichloromethane (4 x 50
ml). The combined extracts were diluted with sodium sulfate.
The mixture is dried on a vacuum cleaner and the solvent is distilled off under reduced pressure. oily substance
A diester is obtained as a quality. This substance is inverted phase
[Solvent system: methanol/water containing 0.025% acetic acid
(3:1)] using a cylindrical h.p.l.c.
Isomer A moves more slowly than isomer B. Example 4 1-carboxymethyl-3-(1-ethoxy-
carbonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]-benz
azepin-2-one (isomer with higher melting point)
body), 1-benzyloxy in ethanol (150ml)
carbonylmethyl-3-(1-ethoxycarbonyl)
(3-phenylpropylamino)-2,3,4,
5-tetrahydro-1H-[1]benzazepine-
Contains 2-one (0.9 g, isomer B of Example 3)
The solution was diluted with 10% palladium-carbon-catalyst (0.5 g).
hydrogenation at room temperature and atmospheric pressure. hydrogen
After absorption, the catalyst is filtered off and the solvent is evaporated under reduced pressure.
make it emit The resulting solid material is ground. melting point
The target compound showing 138−140° was obtained, and the example
The product is identified as 1. Example 5 1-carboxymethyl-3-(1-ethoxyca
Rubonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benz
azepin-2-one (a variant with a lower melting point)
gender) 1-benzyloxy in ethanol (125 ml)
carbonylmethyl-3-(1-ethoxycarbonyl)
-3-phenyl-propylamino)-2,3,
4,5-tetrahydro-1H-[1]benzazepi
ion-2-one (1.2 g, isomer A of Example 3)
A solution containing 10% palladium-carbon-catalyst (0.5 g)
hydrogenation at room temperature and atmospheric pressure in the presence of .
After hydrogen absorption is completed, the catalyst is filtered off and the solvent is reduced.
Evaporate under pressure. The resulting solid substance is ether
(8 ml). 1 showing a melting point of 126-129°
-carboxytyl-3-(1-ethoxycarbonyl)
(3-phenylpropylamino)-2,3,4,
5-tetrahydro-1H-[1]benzazepine-
Racemic 2-one is obtained and shows a lower melting point
It is chemical isomer A. Inversion phase [Solvent system: methanol containing 0.025% acetic acid]
using a cylindrical h.p.l.c.
Then, isomer A shows a higher melting point than Example 1.
It migrates more slowly than racemized isomer B. Example 6 1-benzyloxycarbonylmethyl-3-
(1-ethoxycarbonyl-3-phenylpro
pyramino)-2,3,4,5-tetrahydro
-1H-[1]Benzazepine-2-one 3- in dry dimethylformamide (20 ml)
(1-ethoxycarbonyl-3-phenylpropyl
Ruamino)-2,3,4,5-tetrahydro-1H
- [1] Contains benzazepine-2-one (5.0g)
Dry dimethylformamide in a nitrogen atmosphere to the solution.
Sodium hydride [mineral oil (0.6
g) from a 60% dispersion in petroleum
Wash with ether (3 x 75 ml).
Zeta suspension and tetrabutylammonium odor
Add compound (4.4g). Bring the reaction mixture to room temperature.
Stir for 30 min with dry dimethylformamide.
Acetic bromo-benzyl ether (3.2 g) in (10 ml)
Mix with a solution containing. Leave the mixture at room temperature for another 30 minutes.
Stir under and heat to 60° and keep this temperature at 18:00.
hold for a while. Cool the reaction mixture to room temperature and remove the solvent.
Evaporate under high vacuum. Add water (150ml) and obtain
The solution was diluted with ethyl acetate (2 x 250ml).
Extract. Combined ethyl acetate extracts
Wash with water (100ml) and dry over magnesium sulfate.
Dry and evaporate under reduced pressure. The resulting brown oil
The substance was chromatographed on silica gel (150 g),
Elute with toluene/ethyl acetate (3:1)
do. Firstly, 1-benzyloxycarboxymethy
-3-(1-ethoxycarbonyl-3-phenylene)
(lupropylamino)-2,3,4,5-tetrahy
Dro-1H-[1] Benzazepine-2-one difference
Form A is obtained. Isomer B is subsequently obtained.
These isomers A and B have an inverted phase [solvent system:
Methanol/water (3:1) with 0.025% acetic acid
determined by the cylindrical h.p.l.c.
It is the same as the compound of Example 3. The starting materials are prepared as follows. ethanol
Acetamide-diethyl malonate in (150ml)
A solution containing the ester (33.2 g) in ethanol
A solution containing sodium ethoxide [sodium ethoxide]
Synthesized from aluminum (3.8g) and ethanol (200ml)
add]. Stir the reaction mixture for 30 minutes at room temperature.
and immerse it in ethanol (100 ml) within 20 minutes.
Trophenylethyl bromide [40.0g; J.Med.
Chem. Vol. 20, p. 1020 (1977)]
down. After the addition, the reaction mixture was boiled under reflux for 18 hours.
Boil, then cool to room temperature and evaporate under reduced pressure.
Ru. Dissolve the residue in water (350ml) and add the resulting solution.
Extract the liquid with ethyl acetate (2 x 350ml)
Ru. The combined acetate ethyl ester extracts are mixed with water.
(200ml) and dry over magnesium sulfate.
Ru. The solvent is evaporated under reduced pressure. exhibits a low melting point
2-acetamido-2-(o-
Nitro-phenyl-ethyl)-malonic acid-diethyl
ester is obtained and without further purification,
used in the synthesis process. 2-acetamide in 3N hydrochloric acid (900 ml)
-2-(o-nitro-phenylethyl)-malonic acid
- a solution containing diethyl-ester (80 g) at 12 o'clock
Boil under reflux for a while. Cool the solution and add ethyl acetate.
Extract with ester (200 ml). Ethyl acetate
The Stell solution is dried and evaporated to dryness under reduced pressure. Residue
The distillate is recrystallized from ethanol/ether.
2-amino- exhibiting a melting point of 219221° (with decomposition)
4-(2-nitrophenyl)-butyric acid-hydrochlora
id is obtained. 2 in 10% ethanolic hydrochloric acid (1200 ml)
-Amino 4-(2-nitrophenyl)-butyric acid-hydro
A solution containing rochloride (38 g) was refluxed for 18 hours.
Bring to a boil. The reaction mixture was evaporated under reduced pressure;
Add water (250ml) and oxidize the resulting aqueous solution with 2N hydroxide.
Make alkaline with sodium solution. Distill this solution
Extract with lolomethane (2 x 500 ml). combined
Wash the dichloromethane solution with water (2 x 150 ml),
Dry with anhydrous sodium sulfate. Distillation of solvent
After that, 2-amino-4(2-nitrophenyl)-butyric acid
- Ethyl ester is obtained and requires no further purification.
It is used in the next synthesis step. 2-Amino-4-(2
-nitrophenyl)-butyric acid-ethyl ester (27
g) a solution containing 10% palladium-carbon-catalyst
(2.5 g) at room temperature and atmospheric pressure.
Hydrogenation is continued until hydrogen absorption is complete. Filter the catalyst
and evaporate the filtrate to dryness. The obtained 2-amino-
4-(2-aminophenyl)-butyric acid-ethyl-S
The compound can be used in the next synthetic step without further purification.
There is. 2-Amino-4-(2
-aminophenyl)-butyric acid-ethyl ester
(35.0 g) in methanol.
Solution containing ummethoxide [sodium (1.0g)
and methanol (400 ml)] was stirred.
Add in a nitrogen atmosphere. Reaction mixture at 65 hr
Boil under reflux for a while and evaporate under reduced pressure. residue
into water (100ml) and dichloromethane (400ml)
distribute it. Dichloromethane (400ml)
Extract with The combined organic solvent was mixed with water (100 ml).
Wash and dry over magnesium sulfate. The solution is
Evaporate to dryness and triturate the residue in ether. Melt
3-amino-2,3,4, showing the point 161−162°
5-tetrahydro-1H[1]benzazepine 2-
On is obtained. Otherwise, do this:
2-Amino-4-(2-nitrophenyl) in water (200 ml)
Contains (2.5g)
in the presence of a 10% palladium-carbon catalyst.
Then hydrogenation is carried out at room temperature and atmospheric pressure. water
After the elementary absorption is completed, the catalyst is filtered off and the filtrate is evaporated to dryness.
harden Dissolve the residue in water (50ml) and add 10% hydroxy acid
Adjust the pH to 7 with sodium chloride solution. Filter out the sediment.
Separate, wash with water and dry. 2-amino-4-
(2-Aminophenyl)-butyric acid is obtained. 2-a
Mino-4-(2-aminophenyl)-butyric acid (1.0
g), hexamethyldisilazane (5.4g) and
Chlorotrimethylsilane in Silol (125ml)
(0.1g) is boiled under reflux for 65 hours.
Ru. Cool the reaction mixture and add ethanol (200ml)
Pour in and evaporate under reduced pressure. water (100ml)
Add the resulting solution dichloromethane (2 x 125ml)
Extract with Add the combined dichloromethane solution to water.
(500ml) and dried over magnesium sulfate.
and evaporate under reduced pressure. Same 3-ami as above
No-2,3,4,5-tetrahydro-1H[1]be
nzazepin-2-one is obtained. 3-amino-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one is as follows
Manufactured to: 3-Azide-2, in ethanol (3500ml)
3,4,5-tetrahydro-1H-[1]benza
A solution containing zepin-2-one (27 g) (Example 1)
The solution was added to water at room temperature under a nitrogen atmosphere with stirring.
Raney in (50ml, washed with 10x ethanol)
- Add the suspension containing nickel. Bring the mixture to room temperature
Stir for 2 hours, filter off the catalyst, and remove the solvent under reduced pressure.
Evaporate. Add ether to the resulting oily substance.
Eh, it solidifies. 3-A exhibiting a melting point of 161-162°
Mino-2,3,4,5-tetrahydro-1H [1]
Benzazepine-2-one is obtained. Benzylpyruvate in methanol (450ml)
(18.0g) and 3-amino-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
(8.0 g) at room temperature under nitrogen for 30 min.
Stir for a minute. Add concentrated hydrochloric acid to the mixture within 10 minutes
(7 ml) was added dropwise, and the mixture was further stirred for a while. reaction mixture
Evaporate to dryness and add dichloromethane (150ml).
Add and stir the mixture for 30 minutes. Filter out solid substances
Add water (100ml), stir for 15 minutes, then filter.
Filter, wash with water (50 ml) and dry. F.173−
3-(1-kat) as a mixture of isomers exhibiting 175°
ruboxy-3-phenylpropylamino)-2,
3,4,5-tetrahydro1H-[1]benzaze
A pin-2-one is obtained. Ethyl chloride in dimethylacetamide (200ml)
- compound (11.6g), sodium bicarbonate (4.0g),
and 3-(1-carboxy-3-phenylpro
pyramino)-2,3,4,5-tetrahydro1H
- [1] Contains benzazepine-2-one (6.0g)
Stir the solution for 72 hours at room temperature under nitrogen.
filter, and evaporate the filtrate under high vacuum. residual
Add water (250ml) to the mixture and dichloromethane the resulting solution.
Extract with lomethane (2 x 400 ml). combined draw
Dry the effluent over magnesium sulfate and remove the solvent under reduced pressure.
3-(1-ethylate) was distilled off as a mixture of isomers.
(oxycarbonyl-3-phenylpropylamino)
-2,3,4,5-tetrahydro-1H-[1]-
Benzazepine-2-one is obtained. Nuclear magnetism
Sound spectrum (CDCl₃) σ9.22 (s, 1H), 4.10 (2
Overlapping quartet; 2H), 1.13 (2 overlapping triplet;
3H) Example 7 1-benzyloxycarbonylmethyl-3-
(1-benzyloxycarbonyl-3-phenylene
(propylamino)-2,3,4,5-tetra
Hydro-1H-[1]benzazepine-2-one 3-(1-ben) in dry dimethylformamide
Zyloxycarbonyl-3-phenynylpropyl
amino)-2,3,4,5-tetrahydro-1H-
[1] Contains benzazepine-2-one (4.0g)
Dry dimethylformamide under nitrogen to the solution
(100 ml) of sodium hydride [mineral oil (0.42
g) from a 60% dispersion in
(3 x 80 ml)
suspension, and tetrabutylammonium bromide
(3.1g) at room temperature.
Ru. Leave the mixture for another 30 minutes at room temperature to dry.
Acetic acid bromide in dry dimethylformamide (10 ml)
Add a solution containing benzyl ester (2.2 g).
After standing for an additional 30 min at room temperature, the reaction mixture was heated to 50°C.
and maintain this temperature for 18 hours. mixture
Cool to room temperature and remove the solvent under high vacuum. residual
Add water (150 ml) to the mixture and dilute the resulting solution with acetic acid ethyl chloride.
Extract with chill ester (2 x 300 ml). Matching
Wash the acetic acid ethyl ester solution with water (100ml),
Dry over magnesium sulfate and evaporate under reduced pressure.
Ru. The resulting brown oily substance was dissolved in silica gel (250
g) Perform chromatography. Toluene/ethyl acetate
Eluted with ester (1:1, 600ml), oily substance
Isomer A of the target compound is obtained as follows. Nuclear magnetic resonance spectrum (CDCl)₃)σ5.12(s,
4H), 4.50(q, 2H) and further mixed solvent (2000ml)
When eluted, the isomer of the target compound appears as an oily substance.
B is obtained. Nuclear magnetic resonance spectrum (CDCl)₃)σ5.17(s,
2H), 5.03 (d, 2H), 4.60 (q, 2H). The starting material is prepared as follows: dimethylacetic acid.
Benzyl bromide (19.0g) in toamide (750ml),
Sodium bicarbonate (10.0 g), and 3-(1-
Carboxy-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benza
Zepin-2-one (13.0 g, as described in Example 6)
7.2 A solution containing sea urchin) was heated under nitrogen at room temperature.
Stir for an hour. Filter the reaction mixture and under high vacuum
Evaporate. Add water (150ml) to the residue to obtain
Extract the solution with dichloromethane (2 x 400ml)
do. Wash the combined extracts with water (100ml),
Dry over magnesium sulfate and evaporate under reduced pressure.
Ru. The obtained crude benzyl ester was dissolved in ethyl acetate.
Crystallized from ester with melting point of 139-141°
3-1-benzyloxycarbonyl-3-phenylene
(lupropylamino)-2,3,4,5-tetrahy
Dro-1H-[1]benzazepine-2-one is obtained
It will be done. Example 8 1-carboxymethyl-3-(1-carboxy
-3-phenylpropylamino)-2,3,4,
5-tetrahydro-1H-[1]benzazepine
-2-one (isomer with lower melting point) 1-benzyloxy in ethanol (800ml)
Carbonylmethyl-3-(1-benzyloxycarboxylate)
Rubonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benza
Zepin-2-one (2.7 g, isomer A of Example 7)
Add a solution containing 10% palladium at room temperature and under atmospheric pressure.
Hydrogenate over a mu-carbon catalyst (0.5 g). hydrogen
After absorption, the catalyst is filtered off and the solvent is removed under reduced pressure.
to evaporate. Isomer A exhibiting F.256−259°,
That is, a di-acid (target compound) is obtained. The same compound was obtained by hydrolysis of the compound of Example 5.
You can get it. Example 9 1-carboxymethyl-3-(1-carboxy
-3-phenylpropylamino)-2,3,4,
5-tetrahydro-1H-[1]benzazepine
-2-one (isomer with higher melting point) 1-benzyloxy in ethanol (950ml)
Carbonylmethyl-3-(1-benzyloxycarboxylate)
rubonyl-3-phenylpyropylamino)-2,
3,4,5-tetrahydro-1H-[1]benza
Zepin-2-one (5.0 g, isomer B of Example 7)
A solution containing palladium was added at room temperature and under atmospheric pressure.
-Hydrogenation with carbon-catalyst (0.5 g). Hydrogen absorption
After the recovery is completed, the catalyst is filtered off and the solvent is distilled off under reduced pressure.
leave Isomer B exhibiting F.280−282°, i.e.
The di-acid (target compound) is obtained. The same compound is also the compound of Example 1 (isomer B)
or hydrolysis of the compound of Example 10 (isomer B)
obtained by. Example 10 1-ethoxycarbonylmethyl-3-(1-ethylmethyl
Toxicarbonyl-3-phenylpropylamide
-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one 3- in dry dimethylformamide (10 ml)
(1-ethoxycarbonyl-3-phenylpropyl
Ruamino)-2,3,4,5-tetrahydro-1H
- [1] Benzazepine-2-one (3.0g, performed
Example 6) into a solution containing dry dimethyl
Sodium hydride in formamide (100ml)
[Synthesized from a 60% dispersion in mineral oil (0.36 g);
washing with petroleum ether (3 x 75 ml)]
The stirred suspension was placed in a nitrogen atmosphere at room temperature.
Drip in the air. Add dimethylformamide to the mixture.
Concentrate acetic acid-ethyl ester (1.4
Add the solution containing g) and stir for an additional 30 minutes, then leave for 48 hours.
Maintain at 60℃. Cool the reaction mixture to room temperature
and evaporate the solvent under high vacuum. water to the residue
(100ml) and dilute the solution with ethyl acetate.
(2 x 200ml). Pour the combined extracts into water.
After washing with (50 ml) and drying over magnesium sulfate,
The solvent is removed under reduced pressure. Yellow oil obtained
Chromatography treatment of quality (3.8g) on silica gel (120g)
and toluene/ethyl acetate (1:1,
250ml). Isomer A of the desired product
is obtained. Further elute with mixed solvent (250ml)
and an oily substance is obtained. It is mainly isomer B
and a small amount of the desired product isomer A.
[Determined by analytical h.p.l.c. (Example 6)].
Further elution with 250ml of mixed solvent yields an oily substance.
is essentially the pure isomer B (more easily
). This substance was mixed with methanol (25
ml) and an equal amount of maleic acid in methanol
Malate salts (Maleatsalz) by adding a solution containing
Convert to After distilling off the solvent, the residue is dissolved in methanol.
Recrystallized from alcohol/ether to give a melting point of 114-116°.
As the malate salt shown, 1-ethoxycarbonyl
methyl-3-(1-ethoxycarbonyl-3-
phenylpropylamino)-2,3,4,5-te
Trahydro-1H-[1]benzazepine-2-o
The pure isomer B of the compound is obtained. Example 11 1-carboxymethyl-3-carboxymethyl
Amino-2,3,4,5-tetrahydro-1H
-[1]Benzazepine-2-one 1-benzyloxy in ethanol (550ml)
Carbonylmethyl-3-benzyloxycarbonyl
methyl-amino-2,3,4,5-tetrahydride
Rho-1H-[1]benzazepine-2-one (4.8
g, 0.01 mol) at room temperature and atmospheric pressure.
Add 5% palladium-carbon catalyst (0.85 g) to water.
Hydrogenate until the end of elementary absorption. water to the mixture
(300ml), filter out the catalyst, and remove the solvent under reduced pressure.
To leave. The residue is triturated in ether. melting point
The target compound (di-acid) of 232-236° is obtained. The starting material is prepared as follows: dimethylform.
3-amino-2,3,4, in Muamide (100ml)
5-tetrahydro-1H-[1]benzazepine-
Nitrogen was added to a solution containing 2-one (5.0 g, 0.028 mol).
dimethylformamide (400 ml)
Thorium hydride [60% dispersion in mineral oil (1.2 g)
Synthesized from the body, petroleum ether (3 x 150ml)
Tetrabu with the stirred suspension containing [Wash with]
Tylammonium-bromide (10.9g, 0.031mol)
Add the mixture. The reaction mixture was incubated at 50 °C for 15 min.
Hold under dimethylformamide (25ml)
Bromide acetic acid benzyl ester (7.2 g, 0.031 mole)
Also add a solution containing Mix for another 18 hours 50
Stir at ℃, then cool to room temperature and dimethyl
The formamide is distilled off under high vacuum. residue
(To precipitate inorganic salts) Toluene/dichloromethane
Stir with lolomethane (1:1, 500 ml). filtration
Afterwards, the solution is evaporated under reduced pressure. Silica residue
Gel (200ml) chromatographed, 0-15% acetic acid
Elute with ethyl ester-toluene. first fraction
as, 1-benzyloxycarbonylmethyl-
3-benzyloxycarbonylmethylamino-
2,3,4,5-tetrahydro-1H-[1]ben
Zuazepin-2-one is obtained. further elutes
and 3-benzyloxycal showing F.124−127°
Bonylamino-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one and 3-
Amino-1-benzyloxycarbonylmethyl-
2,3,4,5-tetrahydro-1H-[1]-be
Nzuazepin-2-one (Example 1) was obtained.
Ru. Example 12 1-carboxymethyl-3S- (1S-ethoxyca
Rubonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benz
azepin-2-one 3(S)-amino-1-carboxymethyl-2,
3,4,5-tetrahydro-1H-[1]benza
Sodium cyanoboride of zepin-2-one
compound (for the racemized compound described in Example 1)
) in the presence of benzylpyruvate-ethyl
After treatment with ester and purification, 1
-Carboxymethyl-3S- (1S-ethoxycarbo
Nyl-3-phenylpropylamino)-2,3,
4,5-tetrahydro-1H-[1]-benzaze
Pin-2-on is obtained: Sodium hydroxide (2.1g) in water (5ml)
At room temperature, add methanol (150 ml) to the solution containing
3(S)-amino-1-ethoxycarbonylmethylene in
Ru-2,3,4,5-tetrahydro-1H-[1]
Solution containing benzazepine-2-one (14.0g)
is added and the solution is stirred for 2 hours. Distill the solvent,
Carefully dry the residue and wash with ether.
Ru. The obtained 3(S)-amino-1-carboxymethylene
Ru-2,3,4,5-tetrahydro-1H-[1]
Benzazepine-2-one-sodium salt is further
Used without further purification. in methanol (75ml) and acetic acid (100ml)
The above sodium salt (12.9g) and benzylpi
A solution containing rubic acid ethyl ester (31 g),
Stir for 1 hour at room temperature in a dry nitrogen atmosphere.
do. Sodium cyanide in methanol (30ml)
Solution containing borohydride (3.8g) within 4 hours
Add it dropwise. This solution was allowed to stand at room temperature overnight.
Stir and add concentrated hydrochloric acid (10 ml) dropwise.
Ru. The mixture was stirred for 1 hour at room temperature and evaporated.
let Dissolve the residue in water (400ml) and ether
(100ml) and 40% sodium hydroxide to pH9.3.
Adjust with liquid. Separate the layers and discard the ether layer.
Adjust the aqueous layer to PH4.3 with concentrated hydrochloric acid, and add acetic acid.
Extract with chill ester (3 x 100 ml). Matching
The organic phase was dried over magnesium sulfate and evaporated.
let Dissolve the crude product in methylene chloride (150ml)
Then hydrogen chloride gas was introduced for 5 minutes. Distill the solvent
and heat the resulting foam with methyl ethyl ketone.
(100g). Filter off the precipitate. h.p.l.c
95:5 diastereomerism as determined by
- A mixture is obtained. The product is converted into 3-pentanone/
Recrystallize from methanol (10:1). general formula
a (in the formula, C_oH_2ois ethylene and R₆is etho
is a xy group, and R₇is a hydroxyl group, and R₈is Fueni
F.188−190°,
[α]_D= −141.0° (in c=0.9 ethanol)
1-carboxymethyl-3(S)-(1(S)-ethyl)
Toxicarbonyl-3-phenylpropylamide
-2,3,4,5-tetrahydro-1H-[1]
Benzazepine-2-one-hydrochloride
can get. The above hydrochloride and ethanol (4
ml) containing propylene oxide (0.5 ml).
Stir the solution under nitrogen at room temperature overnight.
Evaporate the solution to dryness, add ether (2 ml) and precipitate.
Filter out the starch. Melting point 148−149°, [α]_D=−159°
(in c=1.2 ethanol)
Boxymethyl-3S-(1S-ethoxycarbonyl-
3-phenylpropylamino)-2,3,4,5
-tetrahydro-1H-[1]benzazepine-2
-On is obtained. The optically active starting material is prepared as follows: (a) Bromide vinegar in dry tetrahydrofuran (30 ml)
acid ethyl ester (0.23 g) and 3(S)-t-
Butyloxycarbonylamino-2,3,4,
5-tetrahydro-1H-[1]benzazepine
-2,5-dione (0.4g) [L-kynurein form]
synthesized from Australian J.Chemistry 33
Vol. 633-640 (1980)].
Stir under dry nitrogen atmosphere at 0.degree. Mixed
Potassium-t-butoxide (0.254g) to the compound
was added all at once, left at 0°C for 1 hour, and then
Add brominated acetic acid-ethyl ester (0.23g),
Stir for an additional hour at 0°C. this reaction
Add water (100ml) to the mixture and add ethyl acetate.
Extract with gel (2 x 50 ml). combined extract
was washed with water (100ml) and placed on magnesium sulfate.
and evaporate under reduced pressure. the resulting yellow color
ether - petroleum ether (boiling point
30−60°), F.86−88°, [α]_D=-
203° (in c=1 dimethylformamide)
3(S)-t-butyloxycarbonylamine
Nor-1-ethoxycarbonyl-methyl-2,
3,4,5-tetrahydro-1H-[1]benz
Azepine-2,5-dione is obtained. Sodium cyanogen in ethanol (10ml)
hydride (7 mg) and 3(S)-t-butyl
oxycarbonylamino-1-ethoxycarbonylate
methyl-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2,5-dione
(0.14g) at room temperature for 18 hours.
Stir. Ethanol is distilled off under reduced pressure and the remaining
Dissolve the material in dichloromethane (25 ml). the
The solution was saturated with 2N hydrochloric acid (2 x 20ml).
Extract with sodium chloride aqueous solution (20 ml) and sulfuric acid
Dry over sodium. Distill the solvent under reduced pressure
and triturate the residue with ether. Melting point 167−
169.5°, [α]_D= −193° (c = 0.52 dimethylform
3(S)-t-butyl oxyamide)
Cycarbonylamino-1-ethoxycarbonyl
Methyl-5-hydroxy-2,3,4,5-te
Trahydro-1H-[1]benzazepine-2-
On is obtained. This compound is a benzazepine
-2,5-dione-derivative in ethanol
H₂/Pt can also be obtained by hydrogenation. 3(S)-t-butyloxycarbonylamino-
1-ethoxycarbonylmethyl-5-hydroxy
C-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one (0.076g),
Dicyclohexycarbodiimide (0.064g)
and copper-iodine-chloride (7 mg)
The mixture was incubated at 60° for 32 hours in a nitrogen atmosphere.
Heat. Cool the reaction mixture to room temperature. residual
Dissolve the substance in methylene chloride (50ml) and begin with
Dilute ammonium hydroxide (2 x 15ml) then water
(20ml). Sodium sulfate organic phase
Dry on top and evaporate. Desirable appendages and
and cyclohexycarbodiimide mixture
is obtained. The above mixture (0.100g) was dissolved in ethyl acetate.
(40 ml) and placed in a pressure box.
Add 10% palladium-carbon-catalyst (0.010g)
Then, the mixture was heated to 40°C and 3 atm for 16 hours.
Hydrogenate. Filter off the catalyst and evaporate the filtrate.
Ru. The residue was triturated in ether and dissolved in ether.
Evaporate the medium. F.115−116.5°, [α]_D=-
182° (c=2.6 in dimethylformamide)
3(S)-t-butyloxycarbonyla showing
mino-1-ethoxycarbonylmethyl-2,
3,4,5-tetrahydro-1H-[1]benz
Azepin-2-one is obtained. (b) Tartaric acid (12.6 g) and racemized 3-amino
-1-ethoxycarbonylmethyl-2,3,
4,5-tetrahydro-1H-[1]benzaze
Add pin-2-one (22g) to hot ethanol (200g).
ml). Cool this solution to room temperature overnight
Leave it under. The obtained precipitate was filtered and filtered.
Crystallize twice from Nord (200 ml). 3(S)-
Amino-1-ethoxycarbonylmethyl-2,
3,4,5-tetrahydro-1H-[1]-ben
Zuazepin-2-one tartrate is obtained. child
Dissolve this in water (100ml) and add dilute ammonium hydroxide.
Adjust the pH to 9 with dichloromethane and methylene chloride (2
ml). Add the combined extract to water (75ml)
Washed with water, dried over magnesium sulfate and evaporated
let F.104−106°, [α]_D= −285.5° (c=
0.99 ethanol)
Nor-1-ethoxycarbonylmethyl-2,3,
4,5-tetrahydro-1H-[1]benzaze
A pin-2-one is obtained. (c) 3(S)-t- in ethyl acetate (25 ml)
Butyloxycarbonylami-1-ethoxyca
Rubonyl-methyl-2,3,4,5-tetrahyde
Dro-1H-[1]Benzazepine-2-one
First 45 minutes in a solution containing [0.225g, described in (a)]
Introduce hydrogen chloride gas for 30 min, then nitrogen gas for 30 min.
Enter. Add the acetic acid ethyl ester solution to water (30ml).
and 1N hydrochloric acid (30 ml). acetic acid
Discard the ethyl ester layer and combine the aqueous layers.
Adjust the aqueous solution to PH9 with dilute ammonium hydroxide.
and extracted with ethyl acetate (3 x 50 ml).
Ru. Dry the combined organic phases over sodium sulfate.
and evaporate. F.101−102°, [α]_D=−298°
3(S) showing (at c=0.46 ethanol)
-amino-1-ethoxycarbonylmethyl-
2,3,4,5-tetrahydro-1H-[1]be
nzazepin-2-one is obtained. Ethane-diothyl/borotrifluoride
- etherate or trifluoroacetic acid/anisole
The protecting group is cleaved using a solvent. 3(S)-ami
Nor-1-ethoxycarbonylmethyl-2,3,
4,5-tetrahydro-1H-[1]benzaze
A pin-2-one is obtained. 3(S)-amino-1-ethoxycarbonylamino
Methyl-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one is produced as follows.
Build: 3(S)-t-butyloxy in acetic anhydride (20 ml)
Carbonyl-1-ethoxycarbonylmethyl-5
-Hydroxy-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one (1.0g,
(described above) is held at 80° for 3 hours. anti
The reaction mixture is cooled to room temperature and evaporated under reduced pressure.
Ether (100ml) was added to the residue to obtain
Wash the solution with water (500ml) and add magnesium sulfate.
Dry on top. The solvent is removed under reduced pressure. pale
As an oily substance, 5-acetoxy-3(S)-t-butyl
Tyloxycarbonylamino-1-ethoxycal
Bonylmethyl-2,3,4,5-tetrahydro-
1H-[1]benzazepin-2-one is obtained,
Used without further purification. 5-acetoxy-3 in ethanol (50 ml)
(S)-5-butyloxycarbonylamino-1-e
Toxycarbonyl-methyl-2,3,4,5-te
Trahydro-1H-[1]benzazepine-2-o
(0.7 g) was dissolved in 10% palladium-carbon.
- Catalyst (0.5g) for 24 hours at 70°C, 2.9
Hydrogenate under atmospheric pressure. Filter the catalyst and reduce the solvent.
Distill under pressure. The obtained 3(S)-t-butyloxy
cycarbonylamino-1-ethoxycarbonylmethane
Chil-2,3,4,5-tetrahydro-1H-
[1] Further purification of benzazepine-2-one
Based on the method described above, F.99−
101°, [α]_D=-297° (c=1, ethanol odor
3(S)-amino-1-ethoxycarbo
Nylmethyl-2,3,4,5-tetrahydro-
Converted to 1H-[1]benzazepine-2-one
Ru. (d) Acetic bromo-t-butylene in acetone (700 ml)
ester (10.0g) and 3(S)-t-butyl
Oxycarbonylamino-2,3,4,5-te
Tolahydro-1H-1-[1]benzazepine-
2,5-dione (12.5g) [Australian.J.
Chemistry vol. 33, pages 633-640 (1980)
Synthesized from L-kynurenine as shown above]
The containing solution was placed in a dry nitrogen atmosphere at room temperature.
and stir. Potassium carbonate (12.5g) once
and the resulting suspension was incubated at room temperature for 16 hours.
and stir. Filter out the potassium salts and steam the filtrate.
Dry and harden. The residue was converted into ethyl acetate.
(250ml) and water (250ml). layer
Separate and dry the organic layer over sodium sulfate.
let The solvent was distilled off under reduced pressure and the residue
Triturate in ether (350 ml, boiling point 30-60°).
Ru. F.75−77°.〔α〕_D= −172° (c = 0.96 dimethyl
3(S)-t-butyl (in formamide)
Tyloxycarbonyl-amino-1-t-butylene
2,3,4,5-
Tetrahydro-1H-[1]benzazepine-
2,5-dione is obtained. 3(S)-tert-butyl alcohol in ethanol (500 ml)
Oxycarbonylamino-1-t-butyloxycarboxylate
Rubonyl-methyl-2,3,4,5-tetrahydride
rho-1H-[1]benzazepine-2,5-dione
(8.0g) of platinum oxide (800 g)
mg) for 2 hours at atmospheric pressure and room temperature.
Add. The catalyst is filtered off and the filtrate is evaporated. [α]
_D= -173° (c = 1.8 dimethylformamide odor
3(S)-t-butyloxycarbonyl
Amino-1-t-butyloxycarbonylmethyl
-5-hydroxy-2,3,4,5-tetrahydride
Rho-1H-[1]-benzazepine-2-one is obtained.
It will be done. 3(S)-t-butyloxycarbonylamino-1
-t-butyloxycarbonyl-methyl-5-hyron
Droxy-2,3,4,5-tetrahydro-1H
- [1] Benzazepine-2-one (3.0g), di
Cyclohexycarbodiimide (5.0g) and steel
A suspension containing -iodine-chloride (500 mg)
16 h in a dry nitrogen atmosphere with mechanical stirring.
Heat to 80°. Cool the mixture and add methylene chloride
(100ml) and filter. Discard solid materials;
The filtrate was treated with 7% ammonium hydroxide (4 x 75 ml), then
In water (100ml), add saturated sodium chloride solution.
(100ml). Remove the organic phase with sodium sulfate
Dry on top and evaporate. Desirable additions and surpluses
A mixture of dicyclohexycarbodiimide is obtained.
It will be done. This mixture (5.5g) was mixed with ethyl acetate ester.
(200 ml), place in a pressure box, and 10% para
Add dium-carbon-catalyst (3.0 g) for 16 hours.
Hydrogenate at 40° and under 3 atm. catalyst
Filter and evaporate the filtrate. Residue in ether
Pulverize with. F.145−147° as a white solid substance
[α]_D= 194° (c = 0.46 in dimethylformamide
3(S)-t-butyloxycarbonyl
Ruamino-1-butyloxycarbonylmethyl-
2,3,4,5-tetrahydro-1H-[1]ben
Zuazepin-2-one is obtained. 3(S)-t-butyloxy in acetic anhydride (50 ml)
carbonylamino-1-t-butyloxycarbo
Nyl-methyl-5-hydroxy-2,3,4,5
-tetrahydro-1H-[1]benzazepine-2
-on (3.0 g, described above) for 2 hours.
Heat to 80° in a dry nitrogen atmosphere. acetic anhydride
Evaporate the residue with acetic acid ethyl ester (75ml)
Dissolved in saturated aqueous sodium bicarbonate solution (50
ml), water (50ml) and saturated sodium chloride solution
Wash with solution (50ml). Sodium sulfate organic phase
Dry on top, evaporate and dissolve the residue in ether (50
ml). F.164−166.5°, [α]_D=
0169° (c=0.36 in dimethylformamide)
3(S)-t-butyloxycarbonylamine
No-1-t-butyloxycarbonylmethyl-5
-acetoxy-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one was obtained.
Ru. 3(S)-tert-butyl alcohol in ethanol (300 ml)
Oxycarbonylamino-1-t-butyloxycarboxylate
rubonyl-methyl-5-acetoxy-2,3,
4,5-tetrahydro-1H-[1]benzazepi
A solution containing ion-2-one (2.2 g) was added to 10% palladium.
Add um-carbon-catalyst and place in pressure box.
The mixture was hydrogenated for 3 days at 70° and under 3 atm.
Add. The catalyst is filtered off and the filtrate is evaporated.
F.164−165°, [α]_D= −200.6° (c = 0.64 dimethyl
3(S)-tert-butyl (in formamide)
hydroxycarbonylamino-1-t-butyloxy
C-carbonylmethyl-2,3,4,5-tetra
Hydro-1H-[1]benzazepine-2-one
can get. 3(S)-t-butyl in ethyl acetate (40 ml)
Tyloxycarbonylamino-1-t-butyl
oxycarbonylmethyl-2,3,4,5-tetra
Hydro-1H-[1]benzazepine-2-one
(0.85g) was heated with hydrogen chloride gas for 2 hours.
Introduce nitrogen gas for 30 minutes. Ethyl acetate
The white substance obtained as a residue is distilled off.
Immediately dissolve in methanol (40ml). propyle
oxide (5 ml) was added and the mixture was kept at room temperature for 16 hours.
Stir under White substance obtained as precipitate
filter out. F.275−276°, [α]_D=-287°(c=
0.71, in 1N hydrochloric acid)
Amino-1 carboxymethyl-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
On is obtained. This product was prepared as described above.
Benzene in the presence of sodium cyanoboride
Condensation with lupyruvic acid-ethyl ester. Example 13 1-carboxymethyl-3-(1-carboxy
-3-phenylpropylamino)-5-hydro
xy-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one 1-benzyloxycarbonyl in acetic acid (50 ml)
methyl-3-(1-carboxy-3-phenyl
propyl-amino)-2,5,dihydro-1H-
[1] Benzazepine-2,5-dione (1.00g)
Add platinum oxide (0.10g) to the solution containing
I can do it. The mixture was placed in a pressure box for 5 hours under an atmosphere of 2
Hydrogenate. Filter off the catalyst, evaporate the filtrate,
The resulting oil was triturated in absolute ethanol.
Ru. The solid material obtained is separated, dried and then
Suspend in water (10ml). Stir the suspension for 1.5 hours.
Stir, separate solid material and dry. Melting point 179°
Crude 1-carboxymethyl (with decomposition)
-3-(1-carboxy-3-phenyl-propylene)
(ruamino)-5-hydroxy-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
On is obtained. The starting material is prepared as follows: Acetonitrile
Tetrabutylammonium bromide (1000ml)
(1.29g, 0.004mol), powdered potassium hydroxide
(2.24 g, 0.04 mol), and 3-methoxy-2,
5-dihydro-1H-[1]benzazepine-2,
5-dione [8.13 g, 0.04 mol, (anadian J.
As described in Chem., vol. 52, p. 610, (1974)
brominated acetic acid-benzyl ether to a mixture containing
Stell (9.16 g, 0.04 mol) at room temperature,
Add dropwise while stirring. After dropping, suspend
The solution was stirred at room temperature for 64 hours, filtered, and the filtrate was
Concentrate under reduced pressure. Partially crystallized oily substance
is obtained. This was pulverized in ether and solidified.
Obtain a substance. Add this to ethyl acetate (100ml)
and stir for 1.5 hours. Filter out insoluble substances,
Concentrate the filtrate. The crude 1-benzyloxy obtained
Carbonylmethyl-3-methoxy-2,5-dihydrogen
Dro-1H-[1]Benzazepine-2,5-dio
The sample is used directly in the next step. Potassium-t- in t-butanol (5.7 ml)
1.0 mole containing butoxide (0.64 g, 0.0057 mole)
the solution at room temperature under a nitrogen atmosphere while stirring.
(+)-Homophenylalanine (1.02g,
0.0057 mol) at once. the resulting suspension
was suspended with t-butanol (4.3 ml).
Heat until most of the solid material dissolved. cold
After cooling, a suspension is obtained. Pipette this suspension
t-butanol under reflux boiling in portions at
(40ml) of 1-benzyloxycarbonyl-methane.
Chil-3-methoxy-2,5-dihydro-1H-
[1] Benzazepine-2,5-dione (2.00g)
in a nitrogen atmosphere for 10 min.
Add within. A yellow precipitate forms during the addition. Attachment
The suspension was boiled under reflux for 3 hours and filtered.
Ru. The resulting gummy solid substance was dissolved in petroleum ether.
Wash and dissolve in water (20ml). Filter the solution;
Adjust the pH to 5 with 3N hydrochloric acid. Obtained crude 1
-benzyloxycarbonylmethyl-3-(1-
Carboxy-3-phenyl-propylamino)-
2,5-dihydro-1H-[1]benzazepine-
Separate 2,5-dione and directly produce target compound
used for. Example 14 General formula IA (wherein, X is H₂DeR₂and R_Fiveteeth
H and R₆is an ethoxy group and R₇is hydroxyl group
The following compound represented by
Manufactured by:

Table: Substituted 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one starting materials used for compounds 2-5 are prepared as follows: F 7-chloro-2,3,4, showing .164−165°
5-tetrahydro-1H-[1]benzazepine-
2-one is prepared as described in GB 159285. Huisgen's method [Liebigs Ann.
Based on Chem. vol. 574, p. 171 (1951)]
8-methyl-2,3,4, showing F.153−154°
5-tetrahydro-1H-[1]benzazepine-
Synthesize 2-one. 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is prepared as follows: 6,7-dimethoxy in ethanol (300 ml) and water (60 ml). -α-tetraluon (6,7-dimethoxy-α-
tetralon) (24 g) [Snyder et al.;
OrgPrepProced.Int., Volume 5, Page 291 (1973)]
For the synthesis of the oxime, the solution containing hydroxylamine hydrochloride (16 g) and sodium hydroxide (25 g) is boiled under reflux for 2 hours. Pour the reaction mixture into an ice/water mixture (500ml)
and extracted with dichloromethane (3 x 300 ml). The combined extracts are washed with water (200 ml), dried over anhydrous magnesium sulphate and evaporated. An oxime (25 g) is obtained having a melting point of 154-156°. The oxime was dissolved again in dichloromethane (170 ml) and the polyphosphate ester (170 ml) (by Fuser and Fuser: Reagents for Organic Synthesis,
Wiley.NY1967, page 892). The reaction mixture is boiled under reflux for 18 hours. The dichloromethane layer is separated, treated with activated charcoal and dried over magnesium sulfate. F.7,8- showing 153-156°
dimethoxy-2,3,4,5-tetrahydro-
1H-[1]benzazepine 2-one is obtained. 8-methoxy-2,3, showing F.132−134°
4,5-tetrahydro-1H-[1]benzazepin-2-one was prepared in a similar manner by 7-methoxy-α-
Manufactured from tetraluon. 3-Amino-7-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is synthesized as follows: triethylamine (5 ml), 2- t-Butyloxycarbonyloxyimino-2-phenylacetonitrile (6.1 g) and 3-amino-2,3,4,
A solution containing 5-tetrahydro-1H-[1]-benzazepin-2-one (4.0 g) and dioxane (25 ml) is stirred at room temperature for 18 hours.
The resulting precipitate is filtered off and washed with water. 3-t-Butyloxycarbonyl-amino- showing F.199-201° after recrystallization from ethyl acetate.
2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained. 3-t-Butyloxycarbonylamino-2,3,4,5-tetrahydro- in acetic acid (20 ml)
1H-[1]benzazepine-2-one (1.5g)
Hydrogen chloride gas is introduced into the solution containing the solution for 10 minutes.
The reaction mixture is stirred for a further 10 hours. Separate the precipitate, suspend in water (30 ml) and make basic with aqueous ammonia. After filtration, 3-amino-7-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one having a melting point of 170-171 DEG is obtained. Example 15 Each containing the active substance (mg) of Example 1
10000 tablet manufacturing method: Composition: 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropyl-amino)-2,
3,4,5-tetrahydro-1H-[1]benzazepine-2-one 100g Lactose 1157g Corn starch 75g Polyethylene glycol 6000 75g Talcum powder 75g Magnesium stearate 18g Pure water Appropriate amount Manufacturing method: All ingredients in powder form , the size of mesh
Sieve through a 0.6mm sieve. The active ingredients, lactose, talc and magnesium stearate are mixed together with half the amount of starch in a suitable mixer. The other half of the starch is suspended in water (40 ml) and this suspension is added to the boiling polyethylene glycol in water (150 ml). The resulting paste is added to the powder and, if necessary, further water is added to granulate it. Granules overnight
Dry at 35° and process through a sieve with a mesh size of 1.2 mm to form tablets with a diameter of 6.4 mm.
Press the desired cutting groove. Example 16 Preparation of an injectable preparation containing the active substance of Example 1 (5 mg/5 ml solution): Composition: 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2, 3,
4,5-tetrahydro-1H-[1]benzazepine-2-one-hydrochloride 25.0g Propylparapen 1.0g Water for injection (appropriate amount) 5000.0ml Preparation method: Add active substance and preservative to water for injection (3500ml)
Dissolve in and dilute to 5000ml. The solution is filtered through a sterile filter and filled into ampoules with 5 ml of each solution under sterile conditions. Example 17 Each containing the active substance of Example 9 (20 mg)
Manufacturing method for 10,000 capsules: Composition: 1-carboxymethyl-3-(1-carboxy-
3-phenylpropylamino)-2,3,4,5
-tetrahydro-1H-[1]benzazepine-2
-On 200g Lactose 1700g Talcum powder 100g Manufacturing method: Mix all the ingredients in powder form into a mesh size of 0.6mm.
Sieve with a sieve. First the active ingredient is mixed with the talc and then with the lactose in a suitable mixer. Mixture (200mg)
Each is filled into a capsule (number 3) using a filling machine. In a similar manner, tablets, injectable solutions and capsules of other compounds according to the invention, such as those listed below as further examples, are prepared. Example 18 1-carboxymethyl-3S-(1R-ethoxycarbonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benzazepin-2-one 1-carboxymethyl-3S-(1S-
Ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]
- methyl ethyl ketone crystals of benzazepine-2-one hydrochloride - evaporating the filtrate;
The residue is triturated in ethyl acetate (50 ml). The resulting solid material is partitioned between acetic acid ethyl ester (100 ml) and water (100 ml) and the pH is adjusted to 4.3 with concentrated hydrochloric acid. The layers are separated and the aqueous phase is extracted with acetic acid ethyl ester (2 x 100ml).
The combined acetate ethyl ester solutions are dried over sodium sulfate and evaporated under reduced pressure. The residue is separated into its components by liquid chromatography (hplc) using a C ₁₈ inverted phase cylinder.
A water/methanol (3:7) mixture (containing 0.05% acetic acid) is used as the solvent. Example 12
Additional amounts of the S,S-isomer and S,R-isomer of are included. The substance corresponding to the S,R-isomer is dissolved in dichloromethane (75 ml) and hydrogen chloride gas is introduced into the solution. The solvent is removed under reduced pressure and the residue is recrystallized from methyl ethyl ketone. 1-carboxymethyl- showing F.181−183°, [α] _D = −188° (in c=0.8 ethanol)
3S-(1R-ethoxycarbonyl-3-phenylpropylamino-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one-hydrochloride is obtained. Example 19 1-carboxymethyl-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,
5-Tetrahydro-1H-[1]benzazepin-2-one 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro in methanol (10 ml) Aqueous sodium hydroxide solution (0.27 g/2 ml) is added to a solution containing -1H-[1]benzazepine-2-one-hydrochloride (1 g). The reaction mixture is stirred for 18 hours at room temperature and evaporated under reduced pressure. Dissolve the residue in water (25ml), 4N
Adjust the pH to 3 with hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried. melting point 270−272°,
[ _α ] 1-carboxymethyl-3S- (1S
-carboxy-3-phenylpropylamino)-
2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained. Example 20 1-ethoxycarbonylmethyl-3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
1H-[1]Benzazepin-2-one 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H- in dry dimethylformamide
[1] Sodium hydride [synthesized from a 60% dispersion in mineral oil (0.5 g)] was added to a solution containing benzazepine-2-one (5.0 g) in dry dimethylformamide under a nitrogen atmosphere at room temperature. Add a stirred suspension containing 3×80 ml of petroleum ether. Stir the mixture for another 30 minutes.
Stir at room temperature and then add a solution of acetic acid bromide-ethyl ester (2.0 g) in dry dimethylformamide (10 ml). Add the reaction mixture
Hold at room temperature for 30 minutes, then warm to 50° and hold at that temperature for 18 hours. The mixture is cooled to room temperature and the solvent is distilled off under high vacuum. The residue is dissolved in water (150 ml) and the solution is extracted with acetic acid ethyl ester (2 x 300 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulphate and the solvent is evaporated under reduced pressure. The obtained brown oily substance was chromatographed on silica gel (250 g),
Toluene/acetic acid ethyl ester mixture (9:1600
ml). Isomer A of the target compound is obtained as an oily substance, and further elution with a mixed solvent (1000 ml) yields isomer B of the target compound as an oily substance. Example 21 1-ethoxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benzazepine-2-one 1-ethoxycarbonyl-3-(1-benzyloxycarbonyl-3) in ethanol (150 ml)
-phenylpropylamino)-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
(1.1 g, isomer B of Example 20) is hydrogenated over a palladium-carbon catalyst at room temperature and atmospheric pressure. After hydrogen absorption is completed, the catalyst is filtered off and the solvent is distilled off under reduced pressure. The resulting semi-solid material is triturated in ether. Isomer B of the target compound is obtained, exhibiting F.175-177°. Example 22 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-8
-methoxy-2,3,4,5-tetrahydro-
1H-[1]Benzazepin-2-one (isomer B) Benzylpyruvate-ethyl ester (9.4 g) and 3-amino-1-carboxymethyl-8 in a mixture of acetic acid (35 ml) and methanol (35 ml). -methoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (4.0
Stir the solution containing g) for 1 hour. Sodium cyanoboride (1.1
Add the solution containing g) slowly within 5 hours. The mixture was stirred for a further 16 hours, concentrated hydrochloric acid (4 ml) was added and stirred for a further 1 hour. The solvent is evaporated under reduced pressure and the residue is partitioned between water (75ml) and ether (35ml). Adjust the pH to 9.4, separate the ether phase and discard. The aqueous layer was adjusted to pH 4.3 and extracted with ethyl acetate (3 x 50 ml). The combined ethyl acetate solutions are dried over magnesium sulfate and the solvent is distilled off under reduced pressure.
The crude product is dissolved in methylene chloride (100 ml) and hydrogen chloride gas is introduced for 5 minutes. Evaporate the solution
The residue is stirred with ether (75 ml) and the product is filtered off to give a mixture of diastereomers (approximately 70:30) as determined by hplc. This product is recrystallized from 3-pentanone. 1-Carboxymethyl-8-methoxy-3-(1-ethoxycarbonyl-3-phenylpropylamino) with melting point 240-245° (with decomposition)
-2,3,4,5-tetrahydro-7H-[1]benzazepine-2-one-hydrochloride (isomer B) is obtained. The starting material is prepared as follows: phospentachloride (30.0 g) and 8-methoxy-2,3,4,5 in xylene (200 ml).
-tetrahydro-1H-[1]benzazepine-2
-on (7.0 g, described in Example 14).
Heat to 90° (oil bath temperature) within 30 min under stirring in a nitrogen atmosphere. Heating is carried out at 30° and 50° with pauses. This is sufficient to cause chlorinated water gas evolution. The temperature is held under 90° for 30 minutes.
The reaction mixture is filtered hot to remove a small amount of suspended solid material, and the filtrate is steam-dried under reduced pressure.
Add saturated aqueous sodium carbonate solution (20
ml). After solidification, the product is filtered off, then washed with ethanol (30 ml), ethanol (10 ml) and ether (10 ml) and dried. melting point
3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H- showing 148-150°
[1] Benzazepine-2-one is obtained. 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H- in glacial acetic acid (250 ml)
[1] A solution containing benzazepin-2-one (20 g) and anhydrous sodium acetate (13.2 g) was added to a 10% palladium-carbon catalyst (1 g) under atmospheric pressure.
Then, hydrogen is added until hydrogen absorption is completed. The catalyst is filtered off and the glacial acetic acid is distilled off under reduced pressure. Water (100 ml) is added to the residue and the suspension is stirred for 1 hour.
The solid material is filtered off, washed with water (50 ml) and dried. 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1H- exhibiting a melting point of 162-163°
[1] Benzazepine-2-one is obtained. A solution containing sodium azide (4.3 g) and 3-chloromethoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (12.5 g) in dimethyl sulfoxide (150 ml) was Hold under nitrogen at 80° for 3 hours.
The reaction mixture was poured into ice water (300ml) and the suspension
Stir for 30 minutes. Filter off the solid substance and add water (50ml)
Wash and dry. 3- showing F.136−138°
Azido-8-methoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained. 2-azido-8-methoxy-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
A stirred suspension of tetrabutylammonium bromide (0.7 g) and potassium hydroxide (1.3 g) in tetrahydrofuran is added in one portion under cooling to 0.degree. C. (5 g) under a nitrogen atmosphere. The mixture is stirred for 5 minutes and then a solution of acetic acid bromide-ethyl ester (3.6 g) in tetrahydrofuran (15 ml) is added. The reaction mixture is kept warm at room temperature and stirred for an additional 2 hours. The mixture is filtered and the tetrahydrofuran is distilled off under reduced pressure.
The residue is partitioned between water (50ml) and ether (100ml). The organic phase is washed with 2N hydrochloric acid (10 ml) and dried over magnesium sulphate. The solvent is removed under reduced pressure. 3-azido-1-ethoxycarbonyl-methyl-8-methoxy2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one exhibiting F.90-91° is obtained. 3-azido-1-ethoxycarbonylethyl-8-methoxy-2,3, in methanol (75 ml)
A suspension containing 4,5-tetrahydro-1H-[1]benzazepin-2-one (13.8 g) was mixed with water (75 g).
ml) of sodium hydroxide (1.9 g). The reaction mixture is stirred for 2 hours at 40-45°, water (100 ml) is added, acidified with concentrated hydrochloric acid (10 ml) and extracted with methylene chloride (3×75 ml). The combined methylene chloride solutions are dried over magnesium sulfate and evaporated under reduced pressure. Melting point 145
3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one exhibiting -147° is obtained. 3-and-1-carboxymethyl-8- in a mixture of ethanol (250 ml) and water (50 ml).
Methoxy-2,3,4,5-tetrahydro-1H
- [1] A solution containing benzazepin-2-one (11 g) is hydrogenated at room temperature over a 10% palladium-carbon catalyst under 3 atmospheres. 2N to the mixture
Add hydrochloric acid (50 ml) and filter off the catalyst. The solvent was distilled off under reduced pressure, and the residue was dissolved in a mixture of water (50 ml) and ethanol (50 ml). Propylene oxide (25ml) is added and the mixture is stirred for 1 hour. 3-Amino-1- exhibiting a melting point of 300° or higher
Carboxymethyl-8-methoxy-2,3,4,
5-tetrahydro-1H-[1]benzazepine-
2-one is obtained. Example 23 1-(carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benzazepine-2-one-hydrochloride, benzylpyruvate-ethyl ester (6.5
g) and 3-amino-1-(1-carboxyethyl)-2,3,4,5-tetrahydro-1H-
[1] A solution containing benzazepine-2-one-hydrochloride (3 g) was stirred at room temperature for 1 hour. A solution of sodium cyanoboride (0.8 g) in methanol (10 ml) is added within 4 hours. The reaction mixture was stirred for 24 hours at room temperature, concentrated hydrochloric acid (2 ml) was added and an additional 1 ml was added.
Stir for an hour. The solvent is removed under reduced pressure and the residue is partitioned between water (50ml) and ether (30ml).
Adjust the pH to 9.4, separate the ether door, and throw it away.
The aqueous solution was adjusted to pH 4.3 and extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and the solvent is distilled off under reduced pressure. Hydrogen chloride gas was introduced into a solution of the crude product in methylene chloride (10 ml) for 2 minutes, and the solvent was distilled off. F.87−
As a mixture of diastereomers showing 94°,
1-(1-carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one-hydroochloride is obtained. The starting material is prepared as follows: 3-azido-2,3,4,5-tetrahydro-
1H-[1]benzazepin-2-one (5 g, prepared according to Example 1) was added with tetrabutylammonium bromide (1.8 g) in tetrahydrofuran (50 ml) under a nitrogen atmosphere at 0°. ) Add the stirred suspension containing potassium hydroxide (1.8 g) all at once. Stirring was continued for a further 5 minutes and then (R)-2-brominated propionic acid tert-butyl ester (5.2 g) [J.
P. Griesstein c. , J.Am.Chem.Soc.76
Volume, 6054 pages (1974), H. Niedrich and
G. Koller, J. Prakt. Chem. vol. 316, p. 729 (1974)] is added within 5 minutes. The reaction mixture is warmed and stirred for an additional 2 hours at room temperature. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is partitioned between water (50ml) and ether (100ml). The organic phase is washed with 2N hydrochloric acid (10 ml), dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. As an oily substance, 3-azido-1-(1
-t-butyloxycarbonylethyl)-2,3,
4,5-tetrahydro-1H-[1]benzazepin-2-one was obtained without further purification.
use. 3-Azide in ethanol (70ml)
1-(1-t-butyloxycarbonylethyl)-
A solution containing 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (7 g) was
Hydrogenate over 10% palladium-carbon catalyst (0.5 g) under atmospheric pressure for 3 hours. The catalyst is filtered off, and the ethanol is distilled off under reduced pressure. As an oily substance, 3
-amino-1-(1-t-butyloxycarbonylethyl)-2,3,4,5-tetrahydro-1H
-[1]Benzazepine-2-one is obtained.
Liquid chromatography under high pressure shows that the product is a diastereomeric mixture (approximately 1:1). This material is used without further purification. The above amino-1 in trichloroacetic acid (25 ml)
-(1-t-butyloxycarbonylethyl)-
A solution containing 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (4.7 g),
Stir for 1 hour at room temperature. Trichloroacetic acid was distilled off under reduced pressure, and the residue was dissolved in ether (100ml).
Add to. Until the end of the formation of precipitate in this solution,
Introduce hydrogen chloride gas. Filter off solid substances.
The product was shown to be a mixture of diastereomers (approximately 1:1) by hplc, as well as F.165-
3-amino-1-(1-carboxyethyl)-2,3,4,5-tetrahydro-1H- showing 176°
[1] Benzazepine-2-one-hydrochloride is obtained. Example 24 1-Ethoxycarbonylmethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H- [1]
Benzazepine-2-one, triethylamine (0.8 ml), 2-bromo-4-phenylbutyric acid ethyl ester (1.6 g) and 3S-amino-1 in dimethylformamide (37 ml).
-ethoxycarbonylmethyl-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
(1.5 g) under nitrogen for 18 hours.
Stir at 70°C. Dimethylformamide is distilled off under reduced pressure. The residue is dissolved in ether (70ml), washed with water (5x25ml), dried over magnesium sulphate and evaporated. The product mixture was separated by chromatography on silica gel, using acetic acid ethyl ester-hexane (40:
60) is used. 1-ethoxycarbonylmethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-, which is the ethone thiomer of the compound of Example 10. On [Nuclear magnetic resonance spectrum (CDCI ₃ ): δ4.52 (q, 2H)]
and its diastereomer 1-ethoxycarbonylmethyl-3S-(1R-ethoxy-carbonyl-3-phenylpropylamino)2,3,
The same amount of 4,5-tetrahydro-1H-[1]benzazepine-2-one [nuclear magnetic resonance spectrum ( _CDCI3 ): δ4.50 (q.2H)] is obtained. Thin layer chromatography (TLC): silica gel; ethyl acetate/hexane (40:60): (S,S)
The Rf value of the -isomer is 0.24 and the Rf value of the (S,,R)-isomer is 0.33. Example 25 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,
3,4,5-1H-[1]Benzazepine-2-
1-Ethoxycarbonylmethyl-3S (1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one (0.25 2N potassium hydroxide (0.26 ml) is added dropwise to the solution containing g) with stirring at room temperature under nitrogen. The mixture was stirred for 1 hour, the ethanol was distilled off and the residue was dissolved in water (5 ml).
Adjust the pH to 2 with 2N hydrochloric acid and extract with ethyl acetate (2 x 30 ml). The combined acetic acid ethyl ester solution was diluted with saturated sodium hydroxide solution (5%
ml), dried over magnesium sulphate and evaporated to dryness. The compound of Example 12, 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, is obtained. . Example 26 1-carboxymethyl-7-chloro-3-(1
-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H
- [1] Benzazepine-2-one (isomer B) 1-carboxy-methyl-3 in acetic acid (25 ml)
-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one (1.5g,
Chlorine gas is introduced into the solution containing isomer B) at room temperature with stirring. A white precipitate forms,
Chlorine gas is introduced until the end of the reaction. The solid material is filtered off and the components are separated by liquid chromatography using a C ₁₈ inverted wood cylinder. The appropriate fractions are dissolved in methanol/ethyl acetate (1:1) (50 ml) and hydrogen chloride gas is introduced. Hydrogen chloride gas is introduced into the solution. The solution is evaporated, the residue suspended in ether (100 ml) and the suspension filtered. Melting point 149−151°
1-carboxymethyl-7-chloro-3
-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
1H-[1]benzazepine-2-one-hydrochloride (isomer B) is obtained. Example 27 1-carboxymethyl-3S (1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,
4,5-tetrahydro-1H-[1]benzazepine-2-one-hydrochloride, absolute ethanol (588 ml) and glacial acetic acid (588 ml)
ml), benzylpyruvate ethyl ester (1960 g), and 3(S)-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-
[1] A solution containing benzazepine-2-one-sodium salt (619 g) [[α] ²⁵ _p = -1304.40C = 1.08, in water)] was mixed, and under 20-25°,
Stir for 1.5 hours. A solution containing sodium cyanoboride in absolute ethanol (2200 ml) was prepared for 24 hours.
Add slowly and regularly within the specified time. After the addition is complete, the reaction mixture is stirred for 24 hours. Add 12N hydrochloric acid (500ml) to the reaction mixture and remove the solvent.
Distill under 3 mmHg at 35-40°. A mixture of ice (3000 g) - water (3000 ml) - diethyl ether (3000 ml) was added to the residual oil and the mixture was
PH9- with 10N sodium hydroxide aqueous solution (1735ml)
Adjust to 9.5. Separate the aqueous phase and add more ether (8000 ml) to obtain a larger amount of product as an oil in the ether layer. Separate the ether and immiscible layers and combine the aqueous layers. The ether extract was washed with water (2 x 1000 ml), the washed water was combined with the water/oil portion from above, and the mixture was
Adjust the pH to 4.25-4.35 with 12N hydrochloric acid (550-650ml). The mixture was diluted with acetic acid ethyl ester (3x
2000ml). The combined acetate ethyl ester extracts are washed with water (2000 ml) and dried over anhydrous magnesium sulfate (500 mg). Filter off the magnesium sulfate and remove the solvent at 40°.
Distill under 3 mmHg. The oil obtained is dissolved in ethyl acetate (4500 ml) and, under vigorous stirring, 28% ethereal hydrogen chloride (309 g) is added. Diethyl ether (1500ml) is added and the mixture is stirred for 1 hour. The solid product is separated and washed with acetic acid ethyl ester (2 x 500 ml) and diethyl ether (3 x 1000 ml). below 3mmHg,
Drying at 50° gives a crude product, with the desired 1-carboxymethyl-3S-(1S-ethoxycarbonyl-
3-phenylpropyl-amino)-2,3,4,
5-tetrahydro-1H-[1]benzazepine-
Consists of 2-one (approximately 65%). It is determined by hple using a C ₁₈ inversion phase cylinder. As solvent, methanol, water and acetic acid (75:25:
A mixture of 0.02) is used. The above crude product was dissolved in dichloromethane (26900ml).
hydrogen chloride gas is introduced at a constant flow rate. After 40 minutes a solution is obtained and the gas introduction is stopped. Traces of undissolved material are removed by filtration and diethyl ether (10750 ml) is added. The suspension is stirred overnight at room temperature and the solid material is filtered off and washed with dichloromethane (4 x 500 ml) and diethyl ether (3 x 1000 ml). After drying,
A pure product is obtained which exhibits F170-178° as the hydrochloride salt. Add dichloromethane (1800 ml) to the above hydrochloride salt (1880 g). Hydrogen chloride gas is introduced again to dissolve the suspension. Diethyl ether (7200 ml) is added and the resulting suspension is stirred for 3 hours and filtered. The solid material is washed with dichloromethane (2 x 1000 ml) and diethyl ether (2 x 1000 ml) and dried. melting point
183-185° (hple means this product is
96%) is obtained. The above salt (1280g) and chloroform (4000ml)
Boil the mixture under reflux for 10 minutes. Stop heating and stir the mixture for 4 hours and filter. The solid material is washed with chloroform (2 x 200 ml) and diethyl ether (3 x 500 ml), dried and sieved. exhibiting a melting point of 184-186°, [α] ^D ₂₅ =-139.26° (C = 0.92, in absolute ethanol),
1-carboxymethyl-3S-(-1S-ethoxycarbonyl-3-phenylpropylamino)-2,
3,4,5-tetrahydro-1H-[1]benzazepine-2-one-hydrochloride is obtained. This product is identical to the hydrochloride salt of Example 12. Example 28 3-(1-benzyloxycarbonyl-3-phenylpropylamine)-1-carboxymethyl-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one-hydrochloride (isomer B) 3-(1-benzyloxycarbonyl-3-phenylpropylano)-1-t-butyloxycarbonylmethyl- in ethyl acetate (100 ml) 2,3,4,5-tetrahydro-1H-[1]penzazepin-2-one (4.0 g, see Example 7)
Hydrogen chloride gas is introduced into the solution containing the mixture for 20 minutes at 0° while stirring. The reaction mixture is evaporated under reduced pressure and the solid material obtained is triturated in ether (50ml). The solid substance was filtered off and ether (15
ml) and acetic acid ethyl ester (15 ml), then boiled with acetic acid ethyl ester (50 ml). The product is recrystallized from methanol/ethyl acetate. The desired compound (isomer B) is obtained, exhibiting a melting point of 197-199°. The starting material is prepared as follows: acetic acid bromide-tert-butyl ester (2.2 g) and 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2, in tetrahydrofuran (100 ml).
A solution containing 3,4,5-tetrahydro-1H-[1]benzazepin-2-one (3.0 g) was heated under dry nitrogen with stirring at room temperature.
Add t-ptoxide (1.2g). The reaction mixture is stirred for 20 hours at room temperature, then poured into water (250 ml) and extracted with dichloromethane (2 x 15 ml). The combined extracts are washed with water (100 ml) and dried over magnesium sulfate. After distilling off the solution, 3-(1-benzyloxycarbonyl-3-
Phenylpropylamino)-1-t-butyloxylcarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained. Example 29 1-Ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropyl-amino-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one A solution containing sodium ethoxide [synthesized from sodium (0.25 g) and methanol (50 ml)] was added with stirring in methanol (100 ml) in a nitrogen atmosphere. -(1-ethoxycarbonyl-3-phenyl-propylamino)-2-[o-(ethoxycarbonylmethylamino)-phenyl]-acetic acid ethyl ester (5.6 g)
Add a solution containing The reaction mixture is boiled under reflux for 65 hours and then evaporated under reduced pressure. The residue is partitioned between water (50ml) and dichloromethane (200ml). Extract the aqueous solution with dichloromethane (200ml). The combined organic phases are washed with water (50 ml) and dried over potassium carbonate. After distilling off the solvent, 1-ethoxycarbonylmethyl-3-(1
-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-
[1] Obtained as a mixture of isomers A and B of benzazepine-2-one, in which case silica gel-
Separated by chromatography and converted to malate in each case according to Example 10. The starting material is prepared as follows: To a solution of 2-amino-4-(o-nitrophenyl)-acetic acid-ethyl ester (17.4 g) in 50% aqueous dioxane (130 ml) is added triethylamine (10.5 g) and Add 2-(t-butyloxycarbonyloxyimino)-2-phenylacetonitrile (18.7 g). The reaction mixture is stirred at room temperature for 4 hours and then diluted with water (300 ml). The mixture was extracted with ether (2 x 150 ml) and the aqueous phase acidified with cold 2N hydrochloric acid.
Extract with acetic acid ethyl ester (2 x 250 ml).
Combine the acetic acid ethyl ester layers, wash with water (150 ml) and dry over sodium sulfate. The solution was distilled off under reduced pressure to give 2-t-butyloxycarbonylamino-4-(o-nitrophenyl)-acetic acid.
The ethyl ester is obtained and used without further purification. 2-t-Butyloxycarbonylamino-4-(o-nitrophenyl) in ethanol (300 ml)
-A solution containing acetic acid-ethyl ester (13.0 g) was heated at room temperature under atmospheric pressure with a 10% palladium-carbon catalyst (1 g) until hydrogen absorption was completed.
Hydrogenate. The catalyst is filtered off, the solution is distilled off,
2-t-butyloxycarbonylamino-4-
(o-amino-phenyl)-acetic acid-ethyl ester is obtained and used in the next step without further purification. A solution of 2-t-butyloxycarbonylamino-4-[o-(ethoxycarbonylmethyl-amino)-phenyl]-acetic acid-ethyl ester (8.5 g) in ethyl acetate (150 ml) was added at room temperature. Then, introduce hydrogen chloride gas for 30 minutes. The solution is evaporated under reduced pressure and the residue is dissolved in ethyl acetate (100ml). The solution was diluted with water (3x
100 ml) and dry over sodium sulfate.
The solvent is distilled off under reduced pressure to obtain 2-amino-4[o-(ethoxycarbonylmethylamino)-phenyl]-butyric acid-ethyl ester, which is used in the next step without further purification. Benzylpyruvate-ethyl ester (12.4 g) and 2-amino-4-[o-(ethoxycarbonylmethylamino)-phenyl]-butyric acid-ethyl ester (4.7 g) in acetic acid (35 ml) and methanol (35 ml). The containing solution is stirred at room temperature for 1 hour under nitrogen. A solution of sodium cyanoboride (1.6 g) in methanol (15 ml) is added dropwise within 4 hours. The reaction mixture is
Stir at room temperature for 24 hours, add concentrated hydrochloric acid (2
ml) dropwise and stirred at room temperature for 1 hour. The mixture is evaporated to dryness and the residue is partitioned between water (75ml) and ether (75ml) and adjusted to PH2 with 6N hydrochloric acid. The layers were separated and the aqueous phase was dissolved in ether (2x
75ml). Discard the ether extract, adjust the pH of the water bath to 9 with 40% aqueous sodium hydroxide solution, and extract with ethyl acetate (3 x 50 ml). The extract is dried over sodium sulfate and evaporated under reduced pressure. The obtained 2-(1-ethoxycarbonyl-3-phenylpropylamino)-4-[o
-[Ethoxycarbonylmethylamino)-phenyl]-butyric acid-ethyl ester can be used directly for the synthesis of the final product. Example 30 2-Amino-4-phenylbutyric acid-ethyl ester was prepared under conditions of reductive alkylation as previously described.
1-ethoxycarbonyl metal-2,3,4,5
-tetrahydro-1H-[1]benzazepine-
Treat with 2,3-dione. 1-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-23,4, of Example 10
5-tetrahydro-1H-[1]benzazepine-
2-one is obtained. The starting material is prepared as follows: embodied acetic acid ethyl ester (0.51 ml) and 3,3-dichloro-2,3,4, in tetrahydrofuran (30 ml).
5-tetrahydro-1H-[1]benzazepine-
To a solution containing 2-one (1.0 g, 4.32 mM), under nitrogen atmosphere and stirring, a solution of sodium hydride (4.76 mM) in tetrahydrofuran (20 ml) is added dropwise within 15 minutes. The mixture is stirred for a further 2 hours. The solution is quenched by the addition of saturated ammonium chloride solution and the solvent is evaporated under reduced pressure. The residue is extracted with ether (3 x 20 ml) and the combined ethereal solutions are washed with saturated sodium chloride solution (20 ml) and dried over magnesium sulfate. The solution was distilled off under reduced pressure and 3,3-dichloro-
1-ethoxycarbonylmethyl-2,3,4,5
-Tetrahydro-1H- [1) Benzazetin-2
-on [Nuclear magnetic resonance spectrum (CDCl ₃ ): δ1.27
(t, 3H); 3.22 (m, 4H); 4.25 (q, 2H); 4.65
(s, 2H) and 7.3 ((m, 4H)] are obtained. Morpholine (0.315 g, 3.6 mM) and 3,3
-dichloro-1-ethoxycarbonylmethyl-
A mixture of 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (0.5 g) is stirred at 110° under nitrogen for 18 hours. Dilute the solution to 10 ml with chloroform and cool to 0°. 20%
Sulfuric acid (1 ml) is added and the mixture is stirred for 2 hours at 0°. The solution was diluted with chloroform (2 x 20
ml), and the extract was diluted with 2N hydrochloric acid (2×10
ml), then saturated aqueous sodium chloride solution (5 ml)
Wash with The solution is dried over magnesium sulphate and evaporated under reduced pressure. 1-Ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H
- [1] Benzazepine-2,3-dione [Nuclear magnetic resonance spectrum (CDC(3): δ1.25 (t, 3H);
2.6 (m, 2H); 3.6 (m, 2H); 4.2 (q, 2H) and 7.3 (m, 4H)] are obtained. Example 31 In the presence of potassium carbonate in methylene chloride, 2
-amino-4-phenylacetic acid ethyl ester 3
-prom-1-ethoxy-carbonylmethyl-
2,3,4,5-Tetrahydro-1H-[1]benzazepin-2-one is treated. Example 10-1
-Ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained. The starting material is prepared as follows: 2,3,4,5-tetrahydro-1H in chloroform (30 ml).
- [1] Phosphopentachloride (3.25 g) is added in portions to a solution containing benzazepin-2-one (2.5 g), maintaining the temperature at 0-5°.
After addition, first iodine (30 mg), then bromine (2.5
g) dropwise within 5 minutes. The mixture is boiled under reduced pressure for 4 hours. Distill the chloroform,
The residue was dissolved in ice water (30 ml) and dichloromethane (75 ml).
ml). The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The crude residue is purified by silica gel chromatography, eluting with ether/hexane (7:3). 3-Prom-2,3,4,5-tetrahydro- exhibiting a melting point of 146-148° after evaporation of a suitable area
1H-[1]benzazepin-2-one is obtained. 3-Prom-2,3,4 was added to a stirred suspension of tetrabutylammonium bromide (40 mg) and potassium hydroxide (90 mg) in tetrahydrofuran (10 ml) at 0° under a nitrogen atmosphere. ，
Add 5-tetrahydro-1H-[1]-penzazepin-2-one (300 mg) in one portion. Stir for 5 minutes and add brominated acetic acid-ethyl ester (200
mg) in one portion, warm to room temperature and stir for a further 3 hours. Tetrahydrofuran was distilled off under reduced pressure,
The residue is partitioned between water (5ml) and ether (25ml). The organic phase is washed with 2N hydrochloric acid (5 ml), dried over magnesium sulphate and evaporated under reduced pressure. 3-brome-1- showing F.114−116°
Ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained. 3-chloro-1-ethoxycarbonyl-methyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is prepared analogously. A solution of 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (1.95 g) in dimethylformamide (10 ml) was dissolved in potassium-t in dimethylformamide (10 ml). - Add dropwise to the stirred solution containing butoxide (1.11 g) at 5°. The solution is stirred for a further 15 minutes at 5° and then a solution of acetic acid bromide-ethyl ester (1.78 g) in dimethylformamide (5 ml) is added dropwise. stir
Run for 30 minutes at 5° and then continue for 3 hours at room temperature. Cool the reaction mixture to 10° and add water (100 ml). Solution in chloroform (100ml)
Extract with water, wash with water (2 x 10 ml) and dry over sodium sulfate. The solvent is removed under reduced pressure. 3
-chloro-1-ethoxycarbonylmethyl-2,
3,4,5-tetrahydro-1H-[1]benzazepine-2-one [Nuclear magnetic resonance spectrum (dimethylsulfoxide- _d6 ): δ1.2 (t, 3H);
2.65 (m, 4H); 2.6 (d, 2H) and 7.3 (m)] are obtained. Example 32 1-Carboxymethyl-3S-(1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one Ethanol ( 1-benzyloxycarbonylmethyl-3S-(1S-pivaloyloxymethoxy-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]
Dissolve benzazepine-2-one (3 g) and add 10
% palladium-on-carbon catalyst (0.3 g) is added.
The solution is hydrogenated under atmospheric pressure for 2 hours at room temperature. The reaction mixture is filtered off and evaporated. 1-Carboxy-methyl-3S-(1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino)
-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained. The starting material is prepared as follows: 1-benzyloxycarbonylmethyl-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,
5-tetrahydro-1H-[1]benzazepine-
2-one (5 g, Example 2) is dissolved in 2N potassium hydroxide solution (5.15 ml) and the solution is evaporated to dryness. Pivalic acid-iodomethyl ester (2.3g)
and dimethylformamide (50ml),
The mixture is stirred at room temperature under nitrogen for 18 hours. The dimethylformamide was distilled off and the residue was taken up in ethyl acetate (100 ml), washed with saturated sodium carbonate solution (3 x 25 ml), water (3 x 25 ml) and saturated sodium chloride solution (25 ml), and washed with magnesium sulfate. Dry on top. After evaporation, 1-benzyl-oxycarbonylmethyl-3S-(1S-pivaloyloxytomethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepine-2 -On is obtained. Prepared in an analogous manner: (a) 1-Carboxymethyl-3S-(1S-1-bornyloxycarbonylmethoxycarbonyl-3 using iodized acetic acid-l-bornyl ester as starting material) -phenylpropylamino)-2,3,4,5-tetrahydro-1H-
[1] Benzazepine-2-one. (b) 1-carboxymethyl-3S-(1S-β-methoxyethoxymethoxycarbonyl-3-phenyl-propylamino)-2,3,4, using β-methoxyethoxymethyl chloride as starting material; 5-tetrahydro-1H-
[1] Benzazepine-2-one. (c) 1-carboxymethyl-3S-[1S-
(3-phthalidoxycarbonyl)-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. (d) 1-carboxymethyl- using 2-pyridylmethyl chloride as starting material
3S-[1S-(3-pyridylmethoxycarbonyl)
-3-phenylpropylamino]-2,3,4,
5-tetrahydro-1H-[1]benzazepin-2-one. Example 33 1-carboxymethyl-3S-(1-ethoxycarbonyl-3-phenylpropylamino)-2,
3,4,5-5a,6,7,8,9,9a-decahydro-1H-[1]benzazepine-2one Benzylpyruvate-ethyl ester (1.5 g) in acetic acid (5 ml) and methanol (3 ml) and 3(S)-amino-1-carboxymethyl-2,
A solution containing 3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepine-2-one-sodium salt (0.6 g) was heated at room temperature for 1 hour in a dry nitrogen atmosphere. Stir under A solution of sodium cyanoboride (0.2 g) in methanol (2 ml) is added within 4 hours. The reaction mixture is stirred for 18 hours at room temperature. Concentrated hydrochloric acid is added and the mixture is stirred for 1 hour. The solvent is removed under reduced pressure and the residue is partitioned between water (20ml) and ether (20ml). Adjust the pH to 9.3 with 40% sodium hydroxide solution, separate the layers, and discard the ether layer. The aqueous phase is adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 25 ml). The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. Dissolve the residue in dichloromethane (70 ml) and add 5 ml of hydrogen chloride gas to this solution.
Introduce for minutes. The solution is evaporated and the residue is recrystallized from ethanol/ether. As a mixture of isomers, 1-carboxymethyl-3S-(1-ethoxycarbonyl-3-phenylpropylamino)
-2, 3, 4, 5, 5a, 6, 7, 8, 9, 9a-
Decahydro-1H-[1]benzazepine-2-one-hydrochloride is obtained. The starting material is prepared as follows: Acetic acid (50ml)
3(S)-t-butyloxycarbonylamino-
1-ethoxycarbonylmethyl-2,3,4,5
-tetrahydro-1H-[1]benzazepine 2,
A solution containing 5-dione (3.6 g) was added to the
Hydrogenation is carried out under atmospheric pressure over platinum oxide (1.2 g) as catalyst. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is partitioned between dichloromethane (200ml) and saturated sodium bicarbonate (100ml). The dichloromethane solution is washed with water (50 ml), dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue was treated with silica gel chromatography and 0-50
Elute with % acetic acid ethyl ester-toluene. 50
Collect the fractions eluted with % acetic acid ethyl ester-toluene. 3(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,
4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepine-2,5-dione is obtained and used in the next synthetic step without further purification. Sodium borohydride (0.2 g) and 3(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,8, in ethanol (100 ml) 9,9a-
Decahydro-1H-[1]benzazepine-2,5
-A solution containing the dione (2.7 g) is stirred for 18 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is dissolved in dichloromethane (100ml). The solution is extracted with ice-cold 2N hydrochloric acid (2 x 50 ml) and saturated aqueous sodium chloride solution (50 ml) and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the residue is triturated in ether. 3(S)-t
-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,
4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one is obtained. 3(S)-t-butyloxycarbonylamino-1
-ethoxycarbonylmethyl-5-hydroxy-
2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one (2.1 g), dicyclohexylcarbodiimide (1.8
A mixture of g) and copper-iodine-chloride (0.2 g) is heated under nitrogen at 80° for 32 hours.
The reaction mixture is cooled to room temperature, the residue is dissolved in methylene chloride (200 ml) and washed with dilute ammonium hydroxide solution (2 x 50 ml) and water (50 ml). The organic phase is dried over sodium sulphate and evaporated. A mixture of the desired adduct and excess dicyclohexylcarbodiimide is obtained. This mixture is dissolved in ethyl acetate (100 ml) and placed in a pressure box. 10% palladium-carbon-catalyst (0.4 g) was added and the mixture was heated under 3 atmospheres for 16 hours.
Hydrogenate at 40°. The catalyst is filtered off and the filtrate is evaporated. 3(S)-t-butyloxycarbonylamino-1-ethoxycarbonyl-methyl-
2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one is obtained and used in the next synthetic step without further purification. . The above compound (1.1 g) is dissolved in ethyl acetate (50 ml) and hydrogen chloride gas is introduced into this solution for 45 minutes. The reaction mixture is evaporated under reduced pressure and the residue is dissolved in ethyl acetate (50 ml) and washed with water (3 x 30 ml). The acetic acid ethyl ester solution is dried over sodium sulfate and the solvent is distilled off under reduced pressure. 3(S)-amino-1-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,
8,9,9a-decahydro-1H-[1]benzazepin-2-one is obtained and used in the next step without further purification. Sodium hydroxide (0.1g) in water (0.25ml)
A solution containing methanol (7.5
ml) of the above amine (0.6 g) and stirred for 2 hours. The solvent is evaporated and the residue is carefully dried and washed with ether. 3(S)-amino-1-carboxy-methyl-2,3,4,5,
5a,6,7,8,9,9a-decahydro-1H-
[1] Sodium salt of benzazepine-2-one is obtained. Example 34 N-[1-(1-carboxymethyl)-2,3,
4,5-tetrahydro-2-oxo-1H-
[1] Benzazepine-3S-ylamino)-3
-Phenylpropyl-1-carbonyl]-L-
Phenylalanine L-phenylalanine-methyl ester-hydrochloride was added to 1-benzyloxycarbonylmethyl-3S-(1N -carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazenpin-2-one is condensed in methylene chloride at room temperature. After reaction, N-[1-(1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-2-oxo-1H-[1]benzazepine-3S-ylamino)-3-phenylpropyl-1-carbonyl ]−
L-phenylalanine-methyl ester is obtained. N-[1-(1-carboxymethyl-2,3,4,5-tetrahydro-2-oxo-1H-[1]benzazepine- 3S-ylamino)-3-phenylpropyl-1-carbonyl]-
L-phenylalanine-methyl ester is obtained. N-[1-(1-carboxymethyl-2,3,4,5-tetrahydro-2-
Oxo-1H-[1]benzazepine-3S-ylamino)-3-phenylpropyl-1-carbonyl]
-L-phenylalanine is obtained. Example 35 1-Ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-
[1] Benzazepin-2-one 3-(1-carboxy-3-phenylpropylamino)-1-cyanmethyl-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
1-ethoxycarbonyl-
Methyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (identical to the compound of Example 10) can get. The starting material is prepared as follows: 3-(1-carboxy-3-phenyl-propylamino)-2,
3,4,5-tetrahydro-1H-[1]benzazepin-2-one is alkylated with a solution of acetonitrile bromide in dimethylformamide in the presence of sodium hydride. After reaction, 3-
(1-Carboxy-3-phenyl-propylamino)-1-cyanmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one is obtained and used directly in the next step. . Example 36 Preparation of 10,000 tablets each containing 10 mg of the active substance of Example 12: Composition: 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino-2,3,
4,5-tetrahydro-1H-[1]benzazepine-2-one 100g Lactose 1157g Corn starch 75g Polyethylene glycol 6000 75g Talcum powder 75g Magnesium stearate 18g Pure water Appropriate amount Production method: Same as described in Example 15 Example 37 Preparation of 10,000 capsules each containing 20 mg of the hydrochloride salt of the active substance of Example 12: Composition: 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino-2,3,
4,5-tetrahydro-1H-[1]benzazepine-2-one 200g Lactose 1700g Talcum powder 100g Manufacturing method: Same as described in Example 17 Cardiovascular pharmacology of the compound according to the present invention ) - conversion - carried out by a method for evaluating the inhibition of enzyme (ACE). Biochemical evaluation of ACE inhibition in vitro is standardized by inhibition of peptidic degradation of this compound in rabbit lung tissue. Studies of angiotensin I (AI) vasopressors corresponding to the inhibition of this compound in vivo are performed in rats. In an in vivo test method, an increase in blood pressure
It is induced by first administering angiotensin I (IA) to test animals. The inhibitory effect of each compound on this increase in blood pressure is determined. Biochemical Test Methods Rabbit Lung Tissue [Co-authored by Das Sahua, J.
Biol.Chem.Volume 250, Page 6762, (1975)]
Chiyuung and Kutsuyuman's method [Chiyuungu and Kutsuyuman co-author, Biochim.Biophys.
Acta vol. 293, p. 451 (1973)]
Used for evaluating ACE. In this method, the amount of histidyl-leucine (which is liberated from the synthesized substance after 30 minutes of incubation at 37° C.) is determined by spectrophotometry. ACE-
_IC50 -values of inhibition are calculated graphically. The IC ₅₀ value is expressed in terms of the concentration (in mol) of the compound to be tested, reducing the amount of histidyl-leucine produced in the absence of the test compound to 50%. By intravenous administration of test compound (%AI)
Method of Suppression of Blood Pressure Increases Caused by Angiotensin (AI) In this experiment, catheters are introduced into the femoral artery and peroneal vein of rats as described above. Arterial pressure is recorded from the arterial catheter while angiotensin I (AI) and a single test compound are injected through the intravenous catheter.
The suppression of the increase in blood pressure caused by angiotensin I is expressed as the percent decrease in the control value of the blood pressure increase obtained before treatment and as the mean value of suppression within 30 minutes after administration of the test compound. Shown here. Result

【table】

Claims (1)

[Claims] 1 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; Compounds represented by [possible], salts or complexes thereof, or optical isomers of all such compounds. 2 General formula (A) [In the formula, R ₁ is hydrogen, a lower-alkyl group, or an aryl-(lower) alkyl group, and R ₂ and
R ₅ is hydrogen or a lower-alkyl group, R ₃ and R ₄ are hydrogen, lower-alkoxy, or halogen, X is an oxo group, two hydrogen atoms,
or a hydroxyl group and a hydrogen atom at the same time, and
R ₆ and R ₇ are each independently a hydroxyl group, a lower alkoxy group, an aryl-(lower) alkoxy group, or a lower-alkanoyloxymethoxy group. complex or salt. 3 In the above formula A, R ₁ is hydrogen, lower alkyl,
or aryl (lower) alkyl (where aryl represents unsubstituted phenyl or phenyl monosubstituted by halogen), R ₂ and R ₅ are hydrogen or lower alkyl, R ₃ and
R ₄ represents hydrogen, lower alkoxy or halogen, X represents oxo, one hydrogen and one hydroxy, or two hydrogens, and
3. A compound according to claim 2, wherein R ₆ and R ₇ independently represent hydroxy, lower alkoxy, or phenyl (lower) alkoxy. 4 In the above formula A, R ₁ is hydrogen, lower alkyl,
or represents aryl (lower) alkyl, R ₂
and R ₅ is hydrogen or lower alkyl, R ₃ is hydrogen, R ₄ represents hydrogen, lower alkoxy, or halogen, and X represents oxo, one hydrogen and one hydroxy, or two represents hydrogen, and R ₆ and R ₇ independently represent hydroxy,
The compound according to claim 2, which represents lower alkoxy or phenyl (lower) alkoxy. 5 In the above formula A, R ₁ represents hydrogen, methyl, aryl (methyl, ethyl, propyl) (where aryl is unsubstituted phenyl or phenyl substituted with one chloro group), R ₂ and
R ₅ is hydrogen or methyl, R ₃ and R ₄ are hydrogen,
Represents methoxy or chloro, X is oxo,
Claim 2, wherein R ₆ and R ₇ independently represent hydroxy, ethoxy, methoxy, benzyloxy, or pivaloyloxy-methoxy. compound. 6 General formula (B) (In the formula, n is an integer from 1 to 4, R ₈ is hydrogen,
It is an unsubstituted phenyl group or a phenyl group monosubstituted with halogen, and further R ₆ and
2. The compound according to claim 1, wherein each R ₇ is independently a hydroxyl group, a C _1-4 lower alkoxy group, or a benzyloxy group. 7 In the above formula B, C _o H _2H represents ethylene,
7. The compound according to claim 6, wherein R ₈ represents phenyl or a phenyl group monosubstituted with halogen, and R ₆ and R ₇ independently represent a hydroxyl group or a C ₁ to C ₄ lower alkoxy group. 8 In the above formula A, X is two hydrogens, R ₂ and R ₅ are hydrogen, R ₆ is ethoxy, R ₇ is hydroxy, and other symbols are represented by the following table: [Table] The compound according to claim 2, which means: 9 General formula (C) (In the formula, S means chirality, n represents an integer from 1 to 4, R ₈ is hydrogen, an unsubstituted phenyl group, or a phenyl group substituted with monohalogen,
Furthermore, R ₆ and R ₇ are independently a hydroxyl group, a C _1-4 lower alkoxy group, or a benzyloxy group), or a pharmaceutically acceptable compound thereof; salt. 10 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
The compound according to claim 1, which is 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, an optical isomer thereof, or a salt thereof. 11 Claim 1 which is a racemic compound or an enantiomer thereof exhibiting a higher melting point
Compound according to item 0. Claim 1, which is a racemic compound or an enantiomer thereof, exhibiting a lower melting point than 12.
Compound according to item 0. 13 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-
Claim 1 which is 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one
Compounds described in Section. 14 1-benzyloxycarbonylmethyl-3
-(1-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]
A compound according to claim 1, which is a benzazepin-2-one. 15 1-benzylcarbonylmethyl-3-(1
-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-
[1] The compound according to claim 1, which is benzazepine-2-one. 16 1-benzyloxycarbonylmethyl-3
The compound according to claim 1, which is -(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. 17 1-carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,
The compound according to claim 1, which is 4,5-tetrahydro-1H-[1]benzazepin-2-one, or an optical isomer thereof. 18. The compound according to claim 17, which is a racemized compound exhibiting a melting point higher than 18 and an enantiomer thereof. 19 Claim 1 which is a racemized compound exhibiting a lower melting point or an enantiomer thereof
Compound according to item 7. 20 1-ethoxycarboxymethyl-3-(1
-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-
[1] The compound according to claim 1, which is racemic isomer B of benzazepine-2-one. 21 1-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-
The compound according to claim 1, which is 1H-[1]benzazepin-2-one. 22 1-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-5-hydroxy-2,3,4,5-tetrahydro-1H-
[1] The compound according to claim 1, which is benzazepine-2-one. 23 1-carboxymethyl-3S-(1R-ethoxycarbonyl-3-phenylpropylamino)-
The compound according to claim 1, which is 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. 24 1-carboxymethyl-3S-(1S-carboxy-3-phenylpropylamino)-2,3,
The compound according to claim 1, which is 4,5-tetrahydro-1H-[1]benzazepin-2-one. 25 1-ethoxycarboxymethyl-3-(1
-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
The compound according to claim 1, which is 1H-[1]benzazepin-2-one. 26 1-ethoxycarboxymethyl-3-(1
-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
The compound according to claim 1, which is racemic isomer A of 1H-[1]benzazepin-2-one. 27 1-ethoxycarboxymethyl-3-(1
-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
The compound according to claim 1, which is racemic isomer B of 1H-[1]benzazepin-2-one. 28 1-ethoxycarbonylmethyl-3-(1
-carbonyl-3-phenylpropylamino)-
The compound according to claim 1 or an optical isomer thereof, which is 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. 29 1-ethoxycarbonylmethyl-3-(1
-carbonyl-3-phenylpropylamino)-
The compound according to claim 1, which is racemic isomer compound B of 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. 30 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
8-Methoxy-2,3,4,5-tetrahydro-
The compound according to claim 1, which is a racemic isomer compound of 1H-[1]benzazepin-2-one. 31 1-(1-carboxyethyl)-3-(1-
Ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]
A compound according to claim 1 which is a benzazepin-2-one. 32 1-ethoxycarbonylmethyl-3S-(1S
-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-
[1] The compound according to claim 1, which is benzazepine-2-one. 33 1-ethoxycarbonylmethyl-3S-(1R
-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H [1]
A compound according to claim 1, which is a benzazepin-2-one. 34 1-carboxymethyl-7-chloro-3-
(1-ethoxycarbonyl-3-phenylamino)
The compound according to claim 1, which is -2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. 35 3-(1-benzyloxycarbonyl-3
-phenylpropylamino)-1-carboxymethyl-2,3,4,5-tetrahydro-1H-
[1] The compound according to claim 1, which is benzazepin-2-one or an optical isomer thereof. 36 1-carboxymethyl-3S-(1S-pivaloyloxymethoxycarbonyl-3-phenyl-
The compound according to claim 1, which is propylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. 37 1-Carboxymethyl-3S-(1S-l-bornyloxycarbonylmethylcarbonyl-3-
Phenyl-propylamino)-2,3,4,5-
Tetrahydro-1H-[1]benzazepine-2-
2. A compound according to claim 1, wherein the compound is 38 1-Carboxymethyl-3S-(1S-β-methoxyethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H
-[1] The compound according to claim 1, which is benzazepine-2-one. 39 1-Carboxymethyl-3S-[1S-phthalidoxycarbonyl 1-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-[1]
A compound according to claim 1, which is a benzazepin-2-one. 40 1-carboxymethyl-3S-[1S-(3-
pyridylmethoxycarbonyl)-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one,
A compound according to claim 1. 41 1-Carboxymethyl-3S-(1-ethoxycarbonyl-3-phenylpropylamino)-
The compound according to claim 1, which is 2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one. 42 N-[1-(1-carboxymethyl)-2,
3,4,5-tetrahydro-2-oxo-1H-
[1] Benzazepine-3S-ylamino)-3-
The compound according to claim 1, which is phenylpropyl-1-carbonyl]-L-phenylalanine. 43. A salt of the compound according to claim 1, which is a pharmaceutically acceptable salt. 44 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; Antihypertensive and cardiotonic effects obtained by mixing or formulating a compound represented by the following formula, or an optical isomer thereof, or a pharmaceutically acceptable complex thereof or a salt thereof in each case, and a pharmaceutically acceptable carrier. A pharmaceutical formulation having 45 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; or an optical isomer thereof, or in each case a pharmaceutically acceptable complex thereof or a salt thereof, and an angiotensin-converting enzyme mixed or blended with a pharmaceutically acceptable carrier. Suppressant. 46 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (In the formula, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy (lower) alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy (lower) alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy (lower) alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; A method for producing optical isomers of compounds represented by the general formula (), their salts or complexes, or all of these compounds, (wherein the carbocyclic ring may also be hexahydro, and X, R _B , R ₃ , R ₄ and R ₅ are as defined above), a hydroxy group while protecting the compound, reacting with a compound represented by the general formula (A) R _A -Z (A) (wherein Z is a halogen and R _A is as defined above),
The above compound ( ) is alkylated and then, if desired, the resulting compound of general formula ( ) exhibiting salt-forming properties as defined above is converted into a salt or such a salt is liberated. and/or, if necessary, the resulting compound of the general formula as defined above, which exhibits complex-forming properties, is converted into a complex and/or /or If desired, from the mixture of optical isomers of the obtained compound represented by the general formula (), at least one
The above process, in which the content of optical isomers with a particular configuration with respect to the two chirality centers is increased by chromatography and/or fractional crystallization. 47 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; A method for producing optical isomers of compounds represented by the general formula (), their salts or complexes, or all of these compounds, (wherein the carbocyclic ring may also be hexahydro, and X, R _B , R ₃ , R ₄ and R ₅ are as defined above), a compound represented by the general formula () R ₁ —CO A compound represented by -R ₀ () (in which R ₁ and R ₀ are as defined above) is reacted in the presence of a reducing agent, optionally with temporary protection of the oxo group X. The above compound () is then alkylated to introduce R _A , and then, if desired, the resulting compound of general formula () exhibiting salt-forming properties as defined above is converted into a salt. , or converting this species liberated into a compound of the formula and/or optionally converting the resulting compound exhibiting complex-forming properties of the general formula as defined above.
and/or if desired, from the mixture of optical isomers of the resulting compound of general formula ()
The above process, in which the content of optical isomers with a particular configuration with respect to the two chirality centers is increased by chromatography and/or fractional crystallization. 48 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; A method for producing optical isomers of compounds represented by the general formula (), their salts or complexes, or all of these compounds, (wherein the carbocyclic ring may also be hexahydro, X, R _B , R ₃ , R ₄ and R ₅ are as defined above and R _A ' is a hydrogen atom or R _A as defined above ) is alkylated with a compound represented by the general formula (B) R _B -Z (B) (wherein Z is a halogen and R _B is as defined above),
In this case, if necessary, the hydroxyl group X is temporarily protected, and then, if desired, the obtained compound represented by the general formula ( Salts of this type are liberated and converted into compounds of the formula and/or optionally the resulting compounds exhibiting complex-forming properties of the general formula as defined above.
and/or if desired, from the mixture of optical isomers of the resulting compound of general formula (), at least one
The above process, in which the content of optical isomers with a particular configuration with respect to the two chirality centers is increased by chromatography and/or fractional crystallization. 49 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; A method for producing optical isomers of compounds represented by the general formula (), their salts or complexes, or all of these compounds, (wherein the carbocyclic ring may also be hexahydro, Y represents an oxo group, and X, R _B , R ₃ and R ₄ are as defined above) in the presence of a reducing agent. By temporarily protecting _the oxo _group which may be _present as _the substituent and then, if desired, the resulting compound of the general formula () exhibiting salt-forming properties as defined above is converted into a salt or such a salt is liberated. and/or optionally the resulting compound exhibiting complex-forming properties of the general formula as defined above,
and/or if desired, from the mixture of optical isomers of the resulting compound of general formula (), at least one
The above process, in which the content of optical isomers with a particular configuration with respect to the two chirality centers is increased by chromatography and/or fractional crystallization. 50 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen; R ₅ is hydrogen or a lower alkyl group; X is an oxo group, two hydrogen atoms, or simultaneously a hydroxyl group and a hydrogen atom; A method for producing optical isomers of compounds represented by the general formula (), their salts or complexes, or all of these compounds, (In the formula, the carbocyclic ring is hexahydro, Y represents a halogen group Z together with hydrogen, and X, R _B , R ₃
and R ₄ are as defined above), and an amine represented by the general formula () R _A -NH-R ₅ () (wherein R _A and R ₅ are as defined above). and then, if desired, converting the resulting compound of general formula () exhibiting salt-forming properties into a salt, or converting such a salt into a compound of formula and/or optionally, the resulting compound exhibiting complex-forming properties of the general formula as defined above,
and/or if desired, from the mixture of optical isomers of the resulting compound of general formula (), at least one
The above process, in which the content of optical isomers with a particular configuration with respect to the two chirality centers is increased by chromatography and/or fractional crystallization. 51 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy (lower) alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy (lower) alkoxycarbonyl group, a phthalidoxycarbonyl group;
R ₁ is hydrogen, lower alkyl group, or aryl-
a (lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group), R ₃ and R ₄ are each independently hydrogen, a lower alkoxy group, or a halogen, and R ₅ is hydrogen or a lower alkyl group, and X is an oxo group, two hydrogen atoms, or a hydroxyl group and a hydrogen atom at the same time, and may be a hexahydrocarbocyclic ring; or a method for producing optical isomers of all such compounds, which has the general formula () (wherein the carbocyclic ring may also be hexahydro, X, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above and one of R ₀ ′ and R ₀ ″ is cyano and the other is a cyano group or R ₀ as defined above,
The cyano group is treated with an acid or a base in the presence of a solvent, and then, if desired, the resulting compound of general formula () exhibiting salt-forming properties as defined above is converted into a salt. or liberating such salts into compounds of the formula and/or optionally converting the resulting compound exhibiting complex-forming properties of the general formula as defined above into
and/or if desired, from the mixture of optical isomers of the resulting compound of general formula (), at least one
A process as described above, in which the content of optical isomers with a particular configuration with respect to the two chirality centers is increased by chromatographic methods and/or separate crystallization methods. 52 General formula () [In the formula, R _A and R _B are respectively the following formulas: [Formula] and [Formula] (wherein, R ₀ is a carboxy group, a lower alkoxycarbonyl group, an aryl (lower) alkoxycarbonyl group, a lower alkanoyloxy (lower) an alkoxycarbonyl group, a lower alkoxy(lower)alkoxy-methoxycarbonyl group, a bicyclo[2.2.1]heptyloxy(lower)alkoxycarbonyl group, a phthalidoxycarbonyl group or an aryl-substituted α-carboxy(lower)alkylaminocarbonyl group; ; R ₁ is hydrogen, a lower alkyl group, or an aryl-(lower) alkyl group; R ₂ is hydrogen or a lower-alkyl group)
is a residue represented by, and R ₃ and R ₄ are each
independently hydrogen, a lower alkoxy group, or a halogen, R ₅ is hydrogen or a lower alkyl group, and X is an oxo group, which may further be a hexahydro carbocyclic ring, salts thereof or A method for producing a complex or an optical isomer of all compounds thereof, comprising the general formula () (wherein the carbocyclic ring may also be hexahydro, and X, R _A , R _B , R ₃ , R ₄ and R ₅ are as defined above) or an ester thereof is cyclized, Then, if desired, the resulting compound of general formula () exhibiting salt-forming properties as defined above is converted into a salt, or such a salt is converted into a compound of formula and/or or, if necessary, the resulting compound exhibiting complex-forming properties of the general formula as defined above,
and/or if desired, from the mixture of optical isomers of the resulting compound of general formula (), at least one
The above process, in which the content of optical isomers with a particular configuration with respect to the two chirality centers is increased by chromatography and/or fractional crystallization.