JPH08225586A - New phosphoric acid derivative, its production and medicinal composition containing the same - Google Patents

Abstract

PURPOSE: To provide a specific new phosphoric acid derivative containing a benzazepine ring, etc., having an inhibiting action against neutral endopeptidase and angioensin transferase activit, and useful for preventing and treating hypertension, cardiac failure, angina pectoris, etc. CONSTITUTION: The new phosphoric acid derivative is represented by formula I [R is a lower alkyl, an ar(lower)alkyl, hydroxyl group; A is a single bond, an lower alkylene, an alkylenecarbonyl, an amino acid residue, a methyleneamino acid residue, etc.; m is 0, 1; p is 0, 1; q is 1, 2; p+q=2], has an inhibiting activity against neutral endopeptidases and angiotensin transferases, and is useful as an agent for preventing and treating hyper tension, cardiac failure, renal failure, hyperandrostronemia, hypercalciuria, hyperleninemia, etc. The compound is obtained by deesterifying an ester derivative of formula II [R<1> is a lower alkyl, an ar(lower)alkyl; R<2> a , R<2> b are each H, an lower alkyl, an ar(lower)alkyl] by a catalytical hydrogenation reaction in the presence of a Pd catalyst.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to novel phosphoric acid derivatives and pharmaceutically acceptable salts thereof. More specifically, the present invention relates to neutral endopeptidase (hereinafter referred to as NEP), for example, neutral endopeptidase EC3.4.
24.11 and angiotensin converting enzyme (hereinafter AC
(Hereinafter referred to as E), a novel phosphoric acid derivative having a dual inhibitory action against E) and a pharmaceutically acceptable salt thereof, a method for producing the same, a pharmaceutical composition containing the same as an active ingredient, and hypertension in humans or animals, heart failure, The present invention relates to a method for treating and / or preventing various cardiovascular disorders such as angina, renal failure, periodic edema, hyperaldosteronism, hypercalciuria and the like. Further, the compound of interest is a therapeutic agent for glaucoma, asthma, inflammation, pain, epilepsy, dementia, obesity and gastrointestinal disorders (particularly diarrhea and irritable bowel syndrome) and / or
Alternatively, it may be useful as a prophylactic agent for the regulation of gastric acid secretion and the treatment of hyperreninemia.

[0002]

OBJECTS OF THE INVENTION One object of the present invention is NEP and A
It is to provide a novel and useful phosphoric acid derivative having an inhibitory effect on CE. Another object of the present invention is to provide a method for producing the phosphoric acid derivative and its salt. Still another object of the present invention is to provide a pharmaceutical composition containing the phosphoric acid derivative and a pharmaceutically acceptable salt thereof as an active ingredient. Another object of the present invention is to provide a method for treating and / or preventing the above-mentioned diseases in humans or animals using the phosphoric acid derivative and a pharmaceutically acceptable salt thereof.

NEP is used for degrading several peptide hormones including atrial natriuretic peptide (ANP) having potent vasodilatory action, diuretic action and natriuretic action and enkephalin which is an endogenous morphine-like peptide. It is well known to be involved. That is, NEP inhibitors can enhance the biological effects of ANP and enkephalin. Therefore, NEP
The compound which inhibits is useful for treating and / or preventing various cardiovascular disorders such as hypertension, heart failure and angina, renal failure, periodic edema, hyperaldosteronism, hypercalciuria and other diseases mentioned above. It is useful.

Further, it is well known that ACE is a peptidyl dipeptidase having a catalytic action for converting angiotensin I into angiotensin II. Angiotensin II is a vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex. That is, ACE inhibitors are also useful for treating and / or preventing various cardiovascular disorders such as hypertension and heart failure.

[0005]

The phosphoric acid derivative which is the object compound of the present invention is novel and is represented by the following general formula [I], and includes pharmaceutically acceptable salts thereof.

Embedded image [Wherein R represents a lower alkyl group, an ar (lower) alkyl group or a hydroxyl group; A represents a single bond, a lower alkylene group, an alkylenecarbonyl group, an amino acid group or a methyleneamino acid group, and methylene in these groups is Optionally substituted with phenyl or ar (lower) alkyl; m
Represents an integer of 0 or 1, p represents an integer of 0 or 1, q represents an integer of 1 or 2, and satisfies p + q = 2] or a salt thereof.

The object compound [I] or a salt thereof can be produced by the method represented by the following reaction formula. Manufacturing method 1

Embedded image

Manufacturing method 2

[Chemical 4]

[In the above formulas, m, p, and q are as defined above; R ¹ is a lower alkyl group or an ar (lower) alkyl group; R ² _a and R ² _b are each hydrogen;
A lower alkyl group or an ar (lower) alkyl group; A means a single bond, an alkylenecarbonyl group or an amino acid group, a lower alkylene group, an alkylenecarbonyl group or a methyleneamino acid group, and methylene in these groups is phenyl or ar ( Lower) may be substituted with alkyl]

In the above and subsequent descriptions of this specification, suitable examples and explanations of the various definitions that fall within the scope of this invention are set forth in detail below.

"Lower" means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl groups" are straight or branched chain alkyls having 1 to 6 carbon atoms,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, te.
Examples thereof include rt-pentyl and hexyl, and among them, preferred are methyl, ethyl and tert-butyl.

Preferable examples of "ar (lower) alkyl group" include benzyl, phenethyl, phenylpropyl, phenylbutyl, benzhydryl, trityl and the like. Among them, preferable ones are benzyl and phenethyl.

Preferable examples of "lower alkylene group" include methylene, dimethylmethylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, pentamethylene, hexamethylene and the like having 1 to 6 carbon atoms. There may be mentioned straight chain or branched chain alkylene groups having 1 (preferably 1 to 4), of which methylene is preferred.

Preferable examples of "amino acid group" include glycyl, L-alanyl, L-valyl, L-leucyl and L-.
Isoleucyl, L-phenylalanyl, L-lysyl and the like can be mentioned.

Preferable examples of "alkylenecarbonyl group" include methylenecarbonyl, dimethylmethylenecarbonyl, ethylenecarbonyl, trimethylenecarbonyl,
1 to 7 carbon atoms (preferably 1) such as propylene carbonyl, tetramethylene carbonyl, methyl trimethylene carbonyl, dimethyl ethylene carbonyl, pentamethylene carbonyl, hexamethylene carbonyl and the like.
To 5) straight-chain or branched-chain alkylenecarbonyl groups, among which methylenecarbonyl is preferred.

Suitable pharmaceutically acceptable salts of the target compound [I] are conventional non-toxic salts such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg salt). Examples thereof include metal salts such as calcium salt and magnesium salt), ammonium salts, salts with organic bases (eg, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, etc.) and the like.

The method for producing the object compound [I] will be described in detail below. Production Method 1 Compound [Ia] or a salt thereof can be produced by subjecting compound [II] to elimination reaction of the ester moiety. Suitable methods for carrying out the elimination reaction of the ester moiety include conventional methods such as hydrolysis and reduction.

Examples of the reduction include chemical reduction with an alkali metal borohydride (eg sodium borohydride etc.) and catalytic reduction with a palladium catalyst (eg palladium-carbon etc.).

The hydrolysis is preferably carried out in the presence of bases or acids including Lewis acids. Suitable bases used in the reaction include, for example, alkali metals (eg sodium, potassium etc.), alkaline earth metals (eg magnesium, calcium etc.), their hydroxides or carbonates or bicarbonates, ammonia, cysteamine. , Trialkylamines (eg trimethylamine,
Triethylamine), picoline, 1,5-diazabicyclo [4.3.0] nonene-5,1,4-diazabicyclo [2.2.2. ] Inorganic and organic bases such as octane, 1,8-diazabicyclo [5.4.0] undecene-7 can be mentioned.

Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid etc.). The reaction using trihalogenated acetic acid (eg trichloroacetic acid, trifluoroacetic acid, etc.) is accelerated by the addition of a cation scavenger (eg phenol, anisole, etc.).

Suitable salts of the compound [Ia] may be the same as those shown for the compound [I]. For example, reduction in the presence of a base (for example, sodium hydrogencarbonate, 10% palladium-carbon, reaction in the presence of hydrogen) can directly give a salt of compound [Ia] (for example, sodium salt). .

The hydrolysis reaction is usually carried out in a conventional solvent such as water, alcohol (for example, methanol, ethanol and the like), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. It is carried out in another organic solvent. Furthermore, if the acids or bases used are liquids, they can also be used as solvents. These conventional solvents can also be used as a mixture with water. The reaction temperature is not particularly limited and is usually room temperature or heating or heating.

Production Method 2 Compound [Ib] or a salt thereof can be produced by subjecting compound [III] to elimination reaction of the ester moiety. Suitable methods for carrying out the elimination reaction of the ester moiety include conventional methods such as hydrolysis and reduction,
The method of manufacturing method 1 may be referred to. Suitable salts of the compound [Ib] may be the same as those shown for the compound [I].

The compound obtained by the production method 1 or 2 can be isolated and purified by a conventional method such as extraction, pulverization, recrystallization, column chromatography and recrystallization.

The raw material compound of this method can be produced by the method described in the production examples below.

The compound [I] and other compounds described in the present specification may show one or more stereoisomers based on an asymmetric carbon atom. The mixture is also included in the scope of the present invention.

The object compound [I] and its pharmaceutically acceptable salts have a dual inhibitory action on NEP and ACE, and have various cardiovascular disorders such as hypertension, heart failure and angina in humans or animals. It is useful for treating and / or preventing renal failure, periodic edema, hyperaldosteronism, hypercalciuria and the like. Further, the object compound [I] is used as a therapeutic and / or prophylactic agent for glaucoma, asthma, inflammation, pain, epilepsy, dementia, obesity and gastrointestinal disorders (particularly diarrhea and irritable bowel syndrome) and regulation of gastric acid secretion and hyperreninemia. It seems to be useful for the treatment of the disease.

[0028]

To show the usefulness of the target compound [I],
The pharmacological test data of the compound [I] are shown below.

Test 1: Neutral endopeptidase (NE
P) Inhibitory action Method: "Peptide" 9: 173-180 (198)
8) described in J. L. Purified NEP prepared from the kidney of male Sprague-Dawley rats by the method of Sonnenberg et al. Was used. The NEP inhibitory activity was measured as follows.

0.1 was added to the culture mixture (total volume of 262 μl).
M Tris buffer (pH 7.4), 0.1 mg / ml α-
hANP (α-human ANP), test compound (dissolved in 2 μl of N, N-dimethylformamide), NEP (45
-50 U / ml) was included. Reaction mixture at 37 ° C
The mixture was incubated for 15 minutes at 50 ° C. and 50 μl of 10% acetic acid was added to stop the reaction. Add 50 μl of reaction mixture to HPL
Injected into C, C ₁₈ column (YMC, ODS-A200
The hydrolysis of α-hANP was measured by reverse phase HPLC using S). 0.05% trifluoroacetic acid: 60%
CH ₃ CN (70:30) 0.05% trifluoroacetic acid: using a linear gradient elution of 15 minutes to _{60% CH 3 CN (54:46)} . NEP inhibitory action is α-hANP
It was defined as the inhibition of hydrolysis.

Test 2: Angiotensin converting enzyme (AC
E) Inhibitory action Method: "Eur. J. Biochem" Vol. 87, 265
-Carmel and Yar described on page 273 (1978).
The ACE inhibitory activity of the test compound was measured by the on method.

The test compound was dissolved in N, N-dimethylformamide (DMF) and the assay mixture (0.4 Mmo-aminobenzoyl-Gly-p-nitrophenyl-proline in 0.2 M Tris-HCl, pH 8.0) was added. ) Was added. The reaction was initiated by the addition of 50 μl of crude enzyme (guinea pig serum). The reaction mixture was incubated at 37 ° C. for 20 minutes and 0.1M EDTA · 2Na 2.
The reaction was stopped by adding 0 ml. Fluorescence measurement was performed with a fluorescence spectrometer (Hitachi F-2000). The excitation wavelength and emission wavelength were 360 nm and 410 nm, respectively. A
CE inhibitory activity was calculated from the difference in fluorescence intensity between the test mixture of test compounds and the DMF control.

Results: For some of the target compounds of the present invention, double activity inhibitory action against NEP and ACE is shown in [Table 1].

Table 1 2 of phosphoric acid derivatives for NEP and ACE
Heavy activity inhibitory effect

For the purpose of therapy, the object compound [I] of the present invention and pharmaceutically acceptable salts thereof are organic or inorganic solid, semi-solid or liquid suitable for oral administration, parenteral administration and topical administration. It is used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient in admixture with a pharmaceutically acceptable carrier such as an excipient. The pharmaceutical preparation may be solid such as capsule, tablet, dragee, granule, suppository, or liquid such as solution, lotion, suspension, emulsion, gel, ointment and the like. If necessary, auxiliary agents, stabilizers, lubricants or emulsifiers, buffers and other commonly used additives may be contained in the above-mentioned preparation.

The dose of the compound [I] varies depending on the age and condition of the patient, but the target compound [I] has an average of 1
Single dose about 0.1mg, 1mg, 10mg, 50mg,
It was found that 100 mg, 250 mg, 500 mg and 1000 mg were effective in treating the above diseases. Generally, an amount of between 0.1 mg and about 1000 mg per day may be administered.

[0036]

EXAMPLES The present invention will be described in more detail below with reference to production examples and examples.

Production Example 1 tert-butoxycarbonyl- (S) -phenylalanine (2.65 g), (3S) -3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine- 1-benzyl acetate (3.24 g) and 1-
To a mixture of hydroxybenzotriazole hydrate (1.48 g) in methylene chloride (26.5 ml) 1- (3-
Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.11 g) is added at 0 ° C. The reaction mixture is stirred at room temperature for 1.5 hours and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure. The residue was washed with chloroform and methanol.
Purified by silica gel column chromatography using a mixed solution (50: 1) of silica gel as an eluent to obtain (3S) -3- (ter
t-butoxycarbonyl- (S) -phenylalanyl)
Amino-2-oxo-2,3,4,5-tetrahydro-
1H-1-benzazepine-1-benzyl acetate (5.1
4 g) is obtained as a foam. IR (film): 3400, 3320, 1745, 1
660 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.39
(9H, s), 1.75-1.9 (1H, m), 2.4
-2.75 (2H, m), 2.9-3.05 (2H,
m), 3.15-3.35 (1H, m), 4.37 (1
H, d, J = 17.4 Hz), 4.15-4.5 (2
H, m), 4.80 (1H, d, J = 17.3 Hz),
4.85-4.95 (1H, m), 5.14 (2H,
s), 6.89 (1H, br.d, J = 6.8Hz),
7.05-7.35 (14H, m) MASS: 572 (M + 1)

Production Example 2 (3S) -3- (tert-butoxycarbonyl-
(S) -Phenylalanyl) amino-2-oxo-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-benzyl acetate (1.72 g) in ethyl acetate (17
ml) solution, a solution of hydrochloric acid in ethyl acetate (6 ml) 4N is added at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours,
Pour into a 5% aqueous sodium hydrogen carbonate solution (70 ml) and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solution of chloroform and methanol (50: 1) as an eluent to give (3S) -3-((S) -phenylalanyl) amino-2-oxo as a colorless oil. -2,3,4,5-Tetrahydro-1H-1-benzazepine-1-benzyl acetate (1.24 g) is obtained. IR (film): 3350, 1740, 1650 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.47
(2H, br.s), 1.75-2.0 (1H, m),
2.45-2.75 (3H, m), 3.16 (1H, d
d, J = 3.9, 13.7 Hz), 3.2-3.4 (1
H, m), 3.56 (1H, dd, J = 3.9, 9.2)
Hz), 4.39 (1H, d, J = 17.2 Hz),
4.45-4.65 (1H, m), 4.79 (1H, m
d, J = 17.2 Hz), 5.14 (2H, s), 7.
05-7.45 (14H, m), 8.07 (1H, d,
J = 7.7 Hz) MASS: 472 (M + 1)

Production Example 3 (3S) -3-((S) -phenylalanyl) amino-
2-oxo-2,3,4,5-tetrahydro-1H-1
O-benzyl-P-methylphosphonochloridate (dibenzylmethylphosphonate (1.05 g) was added to a mixture of -benzazepine-1-benzyl acetate (1.20 g) and triethylamine (1.06 ml) in methylene chloride. )
And phosphorus pentachloride (0.88g) from JP1-100183
(Prepared by the method described above) at 0 ° C.
Drop by. The reaction mixture is stirred at room temperature overnight and evaporated under reduced pressure. The residue is purified by silica gel column chromatography using a mixed solution of ethyl acetate and n-hexane (1: 4) as an eluent to obtain the desired product, which is mixed with a mixed solution of diisopropyl ether and ethyl acetate (4: 1). Powdered solid (3S) -3- [N- (O-benzyl-P
-Methylphosphonyl)-(S) -phenylalanyl] amino-2-oxo-2,3,4,5-tetrahydro-1
H-1-benzazepine-1-benzyl acetate (0.33
g) is obtained. Melting point 100-105 ° C (dec.) IR (nujol): 3260, 1740, 1670,
1640, 1540 cm ^-1 NMR (200 MHz, DMSO-d ₆ , δ): 0.8
5-1.05 (3H, m), 1.9-2.1 (1H,
m), 2.1-2.35 (1H, m), 2.5-2.7.
(2H, m), 2.8-3.05 (1H, m), 3.0
5-3.25 (1H, m), 3.7-3.95 (1H,
m), 4.1-4.35 (2H, m), 4.4-4.6.
5 (2H, m), 4.7-5.0 (2H, m), 5.1
1 (2H, s), 7.05-7.45 (19H, m),
8.2-8.4 (1H, m) MASS: 640 (M + 1)

Production Example 4 The following compound was obtained in the same manner as in Production Example 3. (3S) -3- [N- (O-benzyl-P-phenethylphosphonyl)-(S) -phenylalanyl] amino-2
-Oxo-2,3,4,5-tetrahydro-1H-1-
Benzazepine-1-benzyl acetate IR (film): 3380, 3275, 1740, 1
655, 1525 cm ^-1 NMR (200 MHz, DMSO-d ₆ , δ): 1.4
-1.75 (2H, m), 1.85-2.15 (2H,
m), 2.35-2.75 (4H, m), 2.9-3.
3 (2H, m), 3.8-4.1 (1H, m), 4.1
5-4.35 (2H, m), 4.4-4.65 (2H,
m), 4.76 (1H, d, J = 17.4Hz), 4.
9-5.1 (1H, m), 5.11 (2H, s), 6.
95-7.45 (24H, m), 8.25-8.45
(1H, m) FAB-MASS : 730.3 as elemental analysis _{C 43 H 44 N 3 O 6} P, Calculated: C; 70.77, H; 6.08 , N;
5.76 Found: C; 70.54, H; 6.00, N;
5.61

Preparation 5 A mixture of ethyl 2-diethoxyphosphinoyl-3-phenylpropionate (33.30 g) and lithium hydroxide hydrate (4.20 g) in water (100 ml) at room temperature for 4 hours. Stir. The reaction mixture is washed with diethyl ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is dissolved in a mixture of ethyl acetate and diethyl ether (1: 1) (200 ml). Dicyclohexylamine (11.4m
l) is added at 0 ° C. The formed precipitate was collected by filtration, and 2-diethoxyphosphinoyl-3-phenylpropionic acid / dicyclohexylamine salt (18.5 as a white solid) was collected.
8 g) are obtained. Melting point 119-120 ° C IR (nujoule): 1630, 1560 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 0.95-
1.5 (10H, m), 1.29 (3H, t, J = 7.
0 Hz), 1.5-1.8 (6H, m), 1.8-1.
95 (4H, m), 2.75-2.95 (2H, m),
2.95-3.4 (3H, m), 7.05-7.3 (5
H, m) MASS: 287, 182

Production Example 6 2-Diethoxyphosphinoyl-3-phenylpropionic acid / dicyclohexylamine salt (1.47 g), (3
S) -3-Amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate (1.02 g) and 1-hydroxybenzotriazol hydrate (0 .47 g) methylene chloride (15 ml)
1- (3-dimethylaminopropyl) -3 to the mixture in
-Ethylcarbodiimide hydrochloride (0.66g) is added at 0 ° C. The reaction mixture is stirred at room temperature for 1 hour. After removing salts by filtration, the filtrate is evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer is washed successively with 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solution of methylene chloride and methanol (50: 1 → 20: 1) as an eluent to give a colorless oily (3S)-
3- (2-Diethoxyphosphinoyl-3-phenylpropionyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate (1.74 g) is obtained. IR (film): 1750, 1610 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.2-
1.4 (6H, m), 1.75-1.95 (1H,
m), 2.35-2.75 (2H, m), 2.9-3.
35 (4H, m), 4.05-4.25 (4H, m),
4.3-4.55 (2H, m), 4.78 (1H, d,
J = 17.2 Hz), 5.12 (2H, s), 6.85
-7.4 (15H, m) MASS: 593

Production Example 7 (3S) -3- (2-diethoxyphosphinoyl-3-
Phenylpropionyl) amino-2-oxo-2,3,
4,5-Tetrahydro-1H-1-benzazepine-1
-Benzyl acetate (1.55g) in methylene chloride (36m
l) Add trimethylsilyl bromide (1.38 ml) to the solution
Add at ℃. The reaction mixture is stirred at room temperature overnight and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer is washed with diethyl ether, acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate (3 times). The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was triturated with diethyl ether to give a white solid (3S) -3.
-(2-Dihydroxyphosphinoyl-3-phenylpropionyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate (1.26 g) is obtained. Melting point 188-194 [deg.] C. (dec.) IR (nujol): 3325, 3250, 1740,
1675, 1625 cm ^-1 NMR (200 MHz, DMSO-d ₆ , δ): 1.8
-2.6 (3H, m), 2.8-3.25 (4H,
m), 4,1-4.3 (1H, m), 4.2-4.35.
(1H, m), 4.77 (1H, d, J = 17.5H
z), 5.10 (2H, s), 7.05 to 7.4 (14)
H, m), 8.01 (1H , d, J = 6.8Hz) MASS: 537 Elemental analysis C ₂₈ H as _{29 N 2 O 7 P · 0.2H} 2 O, Calculated: C; 62.27, H; 5.49, N;
5.19 Found: C; 62.03, H; 5.57, N;
5.09

Production Example 8 2-Dibenzyloxyphosphinoylmethyl-3-phenylpropionic acid (1.27 g), (3S) -3-amino-2-oxo-2,3,4,5-tetrahydro-1H
-1-Benzazepine-1-benzyl acetate (0.97
g) and 1-hydroxybenzotriazole hydrate (0.44 g) in a mixture of methylene chloride (13 ml) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.63 g). Is added at 0 ° C. The reaction mixture is stirred at room temperature for 3 hours and evaporated under reduced pressure.
The residue is partitioned between ethyl acetate and water. 5 organic layers
% Aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, saturated brine, and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solution of chloroform and methanol (50: 1) as an eluent to give a colorless oil (3S).
-3- (2-dibenzyloxyphosphinoylmethyl-
3-phenylpropionyl) amino-2-oxo-2,
There is obtained 3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate (1.68 g). IR (film): 3280, 1745, 1650 c
m ^-1 FAB-MASS: 731.7

Production Example 9 The following compound was obtained in the same manner as in Production Example 8. (3S) -3-[(2S) -2-Diethoxyphosphinoylmethyl-3-phenylpropionyl] amino-2-
Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-tert-butyl acetate IR (film): 3400, 1735, 1655 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.25
(3H, t, J = 7.1 Hz), 1.26 (3H, t,
J = 7.1 Hz), 1.42 (9H, s), 1.7-
2.3 (3H, m), 2.5-2.8 (4H, m),
2.85-3.0 (1H, m), 3.2-3.4 (1
H, m), 3.85-4.1 (4H, m), 4.23.
(1H, d, J = 17.0 Hz), 4.3-4.45
(1H, m), 4.62 (1H, d, J = 17.0H
z), 6.60 (1H, d, J = 6.8 Hz), 7.0
5-7.35 (9H, m) MASS: 573 [α] ²⁵ _D −106.66 ° (C1.17, CHC
l ₃ )

Production Example 10 Hydroxy (4-phenylbutyl) phosphinoyl acetic acid (0.72 g) was added to a solution of 1,1'-carbonyldiimidazole (0.49 g) in methylene chloride (15 ml) at 0 ° C.
Add in. The reaction mixture is stirred at 0 ° C. for 45 minutes. To this triethylamine (1.25 ml) and (3S)-
3-Amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-tert-butyl acetate (0.72 g) is added sequentially at 0 ° C. The reaction mixture is stirred at room temperature overnight and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and 10% aqueous citric acid solution. The organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the colorless amorphous (3S) -3-[[hydroxy (4-
Phenylbutyl) phosphinoyl] acetyl] amino-
2-oxo-2,3,4,5-tetrahydro-1H-1
-Benzazepine-1-tert-butyl acetate (1.2
9 g) are obtained. IR (film): 3300, 1735, 1650 c
m ^-1 NMR (200 MHz, DMSO-d ₆ , δ): 1.3
5 (9H, s), 1.4-1.75 (6H, m), 1.
9-2.1 (1H, m), 2.1-2.35 (1H,
m), 2.5-2.75 (5H, m), 3.1-3.3.
5 (1H, m), 4.15-4.35 (1H, m),
4.33 (1H, d, J = 17.3Hz), 4.58
(1H, d, J = 17.2 Hz), 7.1-7.3 (1
0H, m), 8.31 (1H, d, J = 7.9Hz) MASS: 529, 473

Production Example 11 The following compound was obtained in the same manner as in Production Example 3. (4S) -4- (O-benzyl-P-phenethylphosphonyl) amino-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-2-diphenylmethyl acetate IR (film): 3310 , 1735, 1650 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 2.0-
2.2 (2H, m), 2.8-3.05 (3H, m),
3.15-3.4 (1H, m), 3.80 (1H, d,
J = 17.0 Hz), 3.85-4.0 (1H, m),
4.14 (1H, dd, J = 4.1, 17.4Hz),
4.49 (1H, dd, J = 8.5, 17.4Hz),
4.8-5.15 (2H, m), 5.17 (1H, d,
J = 17.0 Hz), 6.87 (1H, s), 6.8-
7.45 (20H, m) MASS: 659 (M ⁺ +1)

Production Example 12 Diethoxyphosphinoylmethyl trifluoromethanesulfonate (1.07 g), (3S) -3-amino-2-
Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-tert-butyl acetate (1.03
g) and N, N-diisopropylethylamine (0.
A mixture of 85 ml) in methylene chloride (10 ml) is stirred at room temperature for 3 days. The reaction mixture is washed successively with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was mixed with ethyl acetate and n-hexane (6: 1 →
Purification by silica gel column chromatography using 8: 1) as an eluent to give (3S) -3- (diethoxyphosphinoylmethyl) amino-2-oxo-2, a light yellow oil.
Tert-Butyl 3,4,5-tetrahydro-1H-1-benzazepine-1-acetate (1.28 g) is obtained. IR (film): 1730, 1660 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.2-
1.3 (6H, m), 1.44 (9H, s), 1.9-
2.05 (1H, m), 2.35-2.7 (3H,
m), 3.1-3.3 (3H, m), 4.0-4.2.
(4H, m), 4.37 (1H, d, J = 17.0H
z), 4.52 (1H, d, J = 17.0Hz), 7.
1-7.3 (5H, m) MASS: 441 as elemental analysis _{C 21 H 33 N 2 O 6} P, Calculated: C; 57.26, H; 7.55 , N;
6.36 Found: C; 57.39, H; 8.05, N;
6.07

Production Example 13 In the same manner as in Production Example 1, the following compound was obtained. (S) -3- (N-tert-butoxycarbonyl-L
-Alanyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate IR (film): 3310, 1785, 1655 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.30
(3H, d, J = 7.0Hz), 1.44 (9H,
s), 1.8-2.05 (1H, m), 2.5-2.8.
(2H, m), 3.2-3.4 (1H, m), 4.05
-4.2 (1H, m), 4.38 (1H, d, J = 1
7.3 Hz), 4.45-4.6 (1 H, m), 4.8
4 (1H, d, J = 17.2 Hz), 5.14 (2H,
s), 6.9-7.4 (11H, m) MASS: 496 (M + 1)

Production Example 14 The following compound was obtained in the same manner as in Production Example 2. (S) -3- (L-alanyl) amino-2-oxo-
2,3,4,5-Tetrahydro-1H-1-benzazepine-1-benzyl acetate IR (film): 3330, 1745, 1650 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.29
(3H, s), 1.74 (2H, br.d), 1.85
-2.0 (1H, m), 2.45-2.75 (2H,
m), 3.2-3.55 (2H, m), 4.40 (1
H, d, J = 17.2 Hz), 4.45-4.6 (1
H, m), 4.81 (1H, d, J = 17.2 Hz),
5.15 (2H, s), 7.05-7.4 (9H,
m), 7.94 (1H, br.d, J = 7.6 Hz) MASS: 396 (M + 1)

Production Example 15 In the same manner as in Production Example 4, the following compound was obtained. (S) -3- [N- (O-benzyl-P-phenethylphosphonyl) -L-alanyl] amino-2-oxo-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-benzyl acetate IR (film): 3250, 1745, 1650 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.26
1.32 (total 3H, each d, J = 6.9Hz), 1.75
-1.9 (1H, m), 1.9-2.15 (2H,
m), 2.4-2.7 (2H, m), 2.8-3.0
(2H, m), 3.05-3.35 (2H, m), 3.
7-3.95 (1H, m), 4.33, 4.36 (total 1
H, each d, J = 17.2 Hz), 4.4-4.55 (1
H, m), 4.77, 4.79 (total 1H, each d, J = 1)
7.2 Hz), 4.9-5.15 (2H, m), 5.1
5 (2H, s), 7.0-7.4 (20H, m) MASS: 654 (M + 1) Elemental analysis As C ₃₇ H ₄₀ N ₃ O ₆ P, calculated value: C; 67.98, H; 6 .17, N;
6.43 Found: C; 67.78, H; 6.35, N;
6.38

Production Example 16 In the same manner as in Production Example 1, the following compound was obtained. (S) -3- (N-tert-butoxycarbonyl-L
-Leucyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate IR (film): 3300, 1745, 1650 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 0.91
(6H, d, J = 6.2Hz), 1.43 (9H,
s), 1.45-1.7 (2H, m), 1.85-2.
05 (2H, m), 2.45-2.8 (2H, m),
3.2-3.4 (1H, m), 4.0-4.2 (2H,
m), 4.36 (1H, d, J = 17.2 Hz), 4.
45-4.6 (1H, m), 4.86 (1H, d, J =
17.4 Hz), 4.95 (1H, d, J = 8.4H)
z), 5.13 (2H, s), 6.95 (1H, d, J
= 7.2 Hz), 7.10 (1H, d, J = 7.4H)
z), 7.15-7.4 (8H, m) MASS: 538 (M + 1)

Production Example 17 The following compound was obtained in the same manner as in Production Example 2. (S) -3- (L-Leucyl) amino-2-oxo-
2,3,4,5-Tetrahydro-1H-1-benzazepine-1-benzyl acetate IR (film): 3300, 1745, 1650 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 0.90
(3H, d, J = 6.2 Hz), 0.93 (3H, d,
J = 6.3 Hz), 1.2-1.4 (1H, m), 1.
45-1.8 (4H, m), 1.85-2.05 (1
H, m), 2.45-2.75 (2H, m), 3.2-
3.45 (2H, m), 4.39 (1H, d, J = 1
7.2 Hz), 4.45-4.6 (1 H, m), 4.8
2 (1H, d, J = 17.2 Hz), 5.15 (2H,
s), 7.05 to 7.4 (9H, m), 7.94 (1
H, d, J = 7.6 Hz) MASS: 438 (M + 1)

Production Example 18 In the same manner as in Production Example 4, the following compound was obtained. (S) -3- [N- (O-benzyl-P-phenethylphosphonyl) -L-leucyl] amino-2-oxo-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-benzyl acetate IR (film): 3250, 1745, 1650 c
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 0.8-
0.95 (6H, m), 1.25-1.5 (2H,
m), 1.6-2.15 (4H, m), 2.35-2.
65 (2H, m), 2.75-3.1 (3H, m),
3.15-3.3 (1H, m), 3.65-3.9 (1
H, m), 4.32, 4.34 (total 1H, each d, J = 1)
7.2 Hz), 4.4-4.55 (1 H, m), 4.8
0 (1H, d, J = 17.2 Hz), 4.85-5.1
5 (2H, m), 5.14 (2H, s), 6.95-
7.4 (20H, m) MASS: 696 (M + 1) as the elemental analysis _{C 40 H 46 N 3 O 6} P · 0.5H 2 O, Calculated: C; 68.17, H; 6.72 , N;
5.96 Found: C; 68.11, H; 6.69, N;
5.89

Production Example 19 In the same manner as in Production Example 1, the following compound was obtained. (S) -3- (Nα-tert-butoxycarbonyl-
Nε-carbobenzoyl-L-lysyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate IR (film): 3310, 1745, 1720-1
640 (br.) Cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.25-
1.8 (6H, m), 1.42 (9H, s), 1.85
-2.05 (1H, m), 2.4-2.7 (2H,
m), 3.1-3.35 (3H, m), 4.0-4.1.
5 (1H, m), 4.25 (1H, d, J = 17.2H
z), 4.4-4.6 (1H, m), 4.86 (1H,
d, J = 17.3 Hz), 5.07 (2H, s), 5.
12 (2H, s), 5.05-5.2 (2H, m),
6.84 (1H, d, J = 7.4Hz), 7.03 (1
H, d, J = 7.3 Hz), 7.15-7.4 (13
H, m) MASS: 687 (M + 1)

Production Example 20 The following compound was obtained in the same manner as in Production Example 2. (S) -3- (Nε-carbobenzoyl-L-lysyl)
Amino-2-oxo-2,3,4,5-tetrahydro-
1H-1-benzazepine-1-benzyl acetate IR (film): 3220, 1745, 1710, 1
650 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.25-
1.6 (5H, m), 1.65-2.05 (4H,
m), 2.45-2.7 (2H, m), 3.1-3.4.
(4H, m), 4.35 (1H, d, J = 17.2H
z), 4.45-4.6 (1H, m), 4.81 (1
H, d, J = 17.2 Hz), 4.9-5.05 (1
H, m), 5.13 (2H, s), 5.20 (2H,
s), 7.0-7.4 (14H, m), 7.88 (1
H, d, J = 7.7 Hz) MASS: 587 (M + 1)

Production Example 21 The following compound was obtained in the same manner as in Production Example 4. (S) -3- [Nα- (O-benzyl-P-phenethylphosphonyl) -Nε-carbobenzoyl-L-lysyl]
Amino-2-oxo-2,3,4,5-tetrahydro-
1H-1-benzazepine-1-benzyl acetate IR (film): 3260, 1740, 1710, 1
650 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.2-
1.75 (6H, m), 1.8-2.15 (3H,
m), 2.35-2.6 (2H, m), 2.75-3.
0 (2H, m), 3.05-3.4 (4H, m), 3.
7-3.9 (1H, m), 4.20, 4.22 (total 1
H, each d, J = 17.2 Hz), 4.4-4.6 (1
H, m), 4.81 (1H, d, J = 17.2 Hz),
4.9-5.35 (7H, m), 6.9-7.4 (25
H, m) FAB-MASS: 845.2 Elemental analysis As C ₄₈ H ₅₃ N ₄ O ₈ P, calculated value: C; 68.23, H; 6.32, N;
6.63 Found: C; 68.09, H; 6.30, N;
6.62

Production Example 22 (S) -3-Amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate (0.55 g) in dry methylene chloride (2. 5 ml)
Triethylamine (0.26 ml) is added to the solution at 0 ° C., then a solution of O-benzyl-P-phenethylphosphorous acid chloride (0.41 g) in dry methylene chloride (1.5 ml) is added at the same temperature. The reaction mixture is stirred at room temperature for 16 hours and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer is washed successively with 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel (40 g) column chromatography using a mixed solution (1: 1) of ethyl acetate and n-hexane as an eluent to obtain (S) -3- (O-benzyl-P-phenethylphosphonyl) amino-. 2-Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate (0.15 g), a low polar product (diastereomer
A) and the polar product (diastereomer-B) are obtained. Low polar product (diastereomer A) IR (film): 1740, 1660, 1595, 1
490 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.9-
2.1 (3H, m), 2.2-2.6 (2H, m),
2.7-3.0 (2H, m), 3.1-3.3 (1H,
m), 3.3-3.5 (1H, m), 3.8-4.1.
(1H, m), 4.40 (1H, d, J = 17.2H
z), 4.71 (1H, d, J = 17.2 Hz), 4.
96 (1H, d, J = 7.6Hz), 4.97 (1H,
d, J = 7.5 Hz), 5.11 (2H, S), 7.0
-7.4 (19H, m) MASS: 583 (M + 1) Polar product (diastereomer-B) IR (film): 1735, 1655, 1595, 1
485 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.8-
2.1 (3H, m), 2.2-2.6 (2H, m),
2.8-3.0 (2H, m), 3.1-3.3 (1H,
m), 3.3-3.5 (1H, m), 3.9-4.1.
(1H, m), 4.46 (1H, d, J = 17.2H
z), 4.71 (1H, d, J = 17.2 Hz), 4.
93 (1H, d, J = 7.5 Hz), 4.94 (1H,
d, J = 7.5 Hz), 5.10 (2H, S), 7.0
-7.4 (19H, m) MASS: 583 (M + 1)

Production Example 23 N-benzyloxycarbonyl-L-phenylalanine (10.0 g), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (7.05 g) and 1-hydroxybenzotriazo. -Hydrate (5.0
(S) -to a mixture of g) in methylene chloride (80 ml).
3-Amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid tert-
Butyl is added at 0 ° C. The reaction mixture is stirred at room temperature for 3 days and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent to give solid (S) -3- (N-benzyloxycarbonyl-). L-phenylalanyl) amino-2-oxo-2,3,4,5
-Tetrahydro-1H-1-benzazepine-1-tert-butyl acetate (19.5 g) is obtained. IR (nujoule): 1720-1730 (br.),
1650 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.42
(9H, s), 1.7-2.0 (1H, m), 2.5-
2.8 (2H, m), 3.03 (2H, d, J = 6.3
Hz), 3.2-3.4 (1H, m), 4.23 (1
H, d, J = 17.0 Hz), 4.3-4.5 (2H,
m), 4.64 (1H, d, J = 17.0 Hz), 5.
06 (2H, s), 5.24 (1H, d, J = 8.0H
z), 6.91 (1H, d, J = 6.5 Hz), 7.0
-7.4 (14H, m) MASS: 572 (M + 1)

Production Example 24 (S) -3- (N-benzyloxycarbonyl-L-phenylalanyl) amino-2-oxo-2,3,4,5
-Tetrahydro-1H-1-benzazepine-1-tert-butyl acetate (19.5 g) in ethanol (25
0 ml) solution of 10% Pd-carbon (water content 50%) (2
g) is hydrogenated under 3 atm of hydrogen for 2.5 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give an oily (S) -3- (L-phenylalanyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1. -Benzazepine-1-tert-butyl acetate (15.5
g) is obtained. IR (film): 1735, 1655 cm ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.41
(9H, s), 1.73 (2H, s), 1.8-2.1
(1H, m), 2.5-2.7 (2H, m), 2.69
(1H, dd, J = 9.2, 13.6Hz), 3.16
(1H, dd, J = 4.0, 13.6Hz), 3.3-
3.5 (1H, m), 3.58 (1H, dd, J = 4.
0, 9.2 Hz), 4.23 (1H, d, J = 17.0)
Hz), 4.4-4.6 (1H, m), 4.67 (1
H, d, J = 17.0 Hz), 7.0-7.4 (9H,
m), 8.07 (1H, d, J = 7.6 Hz) MASS: 438 (M + 1)

Production Example 25 (S) -3- (L-phenylalanyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-tert-butyl acetate (7. 0
g), a mixture of diethyl trifluoromethanesulfonyl phosphite (4.8 g) and N, N-diisopropylethylamine (3.6 ml) in methylene chloride (50 ml) is stirred at room temperature overnight. The reaction mixture is washed successively with water, 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by silica gel (200 g) column chromatography using a mixed solution of methylene chloride and methanol (50: 1) as an eluent to give an oily (S) -3-
[N- (diethylphosphonomethyl) -L-phenylalanyl] amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid ter-
Butyl (5.1 g) is obtained. IR (film): 3300-3330 (br.), 1
720, 1640-1645 (br.), 1600 c.
m ^-1 NMR (200 MHz, CDCl ₃ , δ): 1.25
(3H, t, J = 7.0 Hz), 1.28 (3H, t,
J = 7.0 Hz), 1.41 (9H, s), 1.5-
1.8 (1H, m), 1.8-2.1 (1H, m),
2.5-2.9 (4H, m), 3.0-3.2 (2H,
m), 3.3-3.5 (2H, m), 3.9-4.2.
(4H, m), 4.19 (1H, d, J = 17.0H
z), 4.4-4.6 (1H, m), 4.69 (1H,
d, J = 17.0 Hz), 7.1-7.4 (9H,
m), 7.78 (1H, d, J = 7.9 Hz) MASS: 588 (M + 1)

Example 1 (3S) -3- [N- (O-benzyl-P-methylphosphonyl)-(S) -phenylalanyl] amino-2-oxo-2,3,4,5-tetrahydro -1H-1-benzazepine-1-benzyl acetate (0.30 g), sodium hydrogen carbonate (79 mg) and 10% palladium-carbon (60 mg, 50% water) in methanol / water mixture (1
0: 1) (6.6 ml) under hydrogen at 3 atm.
Stir for hours. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure and lyophilized to give a white solid (3S) -3- [N
-(Hydroxy-P-methylphosphonyl)-(S) -phenylalanyl] amino-2-oxo-2,3,4,5
-Tetrahydro-1H-1-benzazepine-1-acetic acid disodium salt is obtained. Melting point 178-185 ° C (dec.) IR (nujoule): 1650, 1630 cm ^-1 NMR (200 MHz, CD ₃ OD, δ): 0.82
(3H, d, J = 15.6 Hz), 1.9-2.1 (1
H, m), 2.3-2.65 (2H, m), 2.75-
2.9 (1H, m), 2.95-3.1 (1H, m),
3.3-3.6 (1H, m), 3.7-4.05 (1
H, m), 4.2-4.5 (3H, m), 7.1-7.
3 (9H, m) FAB-MASS: 504.1 (M ⁺ ), 526.1.
(M ^{+ +} Na) as Elemental Analysis _{C 22 H 24 N 3 Na 2} O 6 P · 2.7H 2 O, Calculated: C; 47.87, H; 5.37 , N;
7.61 Found: C; 48.12, H; 5.38, N;
7.48

Example 2 In the same manner as in Example 1, the following compound is obtained. (3S) -3- [N- (Hydroxy-P-phenethylphosphonyl)-(S) -phenylalanyl] amino-2-
Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid disodium salt Melting point 200 ° C. or higher IR (nujol): 1640, 1600 cm ⁻¹ NMR (200 MHz, CD ₃ OD, δ): 1.3-
1.55 (2H, m), 1.9-2.1 (1H, m),
2.15-2.65 (4H, m), 2.84 (1H, d
d, J = 7.9, 13.6 Hz), 2.95-3.1.
(1H, m), 3.3-3.5 (1H, m), 3.8-
3.95 (1H, m), 4.29 (1H, d, J = 1
6.6 Hz), 4.3-4.45 (1H, m), 4.4
8 (1H, d, J = 16.6 Hz), 6.95-7.3
5 (14H, m) FAB-MASS: 593.9 (M ⁺ ), 616.1.
(M ^{+ +} Na) as Elemental Analysis _{C 29 H 30 N 3 Na 2} O 6 P · 3H 2 O, Calculated: C; 53.79, H; 5.60 , N;
6.49 Found: C; 53.89, H; 5.48, N;
6.37

Example 3 (3S) -3- (2-dihydroxyphosphinoyl-3)
-Phenylpropionyl) amino-2-oxo-2,
Hydrogenate a mixture of 3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate (0.54 g) and 10% palladium-carbon (0.11 g, 50% water) in ethanol (22 ml). Stir for 2 hours under 3 atm. After filtering off the catalyst, the filtrate is evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give (3S) -3- (2-dihydroxyphosphinoyl-3) as a white solid.
-Phenylpropionyl) amino-2-oxo-2,
There is obtained 3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (0.33 g). Melting point 155-162 [deg.] C. (dec.) IR (nujol): 3280, 2750-2400,
1720, 1635 cm ^-1 NMR (200 MHz, CD ₃ OD, δ): 1.9-
2.15 (1H, m), 2.3-2.65 (1H,
m), 2.95-3.4 (5H, m), 4.2-4.4.
5 (2H, m), 4.69 (1H, d, J = 17.5H
z), 7.05-7.4 (9H, m ) MASS: 445 Elemental analysis _{C 21 H 23 N 2 O 7} P · 0.5EtOH · H 2 O
As calculated: C; 54.21, H; 5.79, N;
5.75 Found: C; 54.43, H; 5.90, N;
5.62

Example 4 (3S) -3- (2-Dibenzyloxyphosphinoylmethyl-3-phenylpropionyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine- 1-benzyl acetate (1.42 g) and 10
% Palladium-carbon (0.14 g, 50% water) in ethanol (30 ml) under hydrogen at 3 atm.
Stir for hours. After filtering off the catalyst, the filtrate is evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give colorless amorphous (3S) -3- (2-dihydroxyphosphinoylmethyl-3-phenylpropionyl) amino-2-.
Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid (0.71 g) is obtained. IR (nujoule): 1720, 1630 cm ^-1 NMR (200 MHz, CD ₃ OD, δ): 1.05-
1.3 (1H, m), 1.55-2.1 (3H, m),
2.25-3.05 (4H, m), 3.15-3.45
(1H, m), 4.1-4.45 (2H, m), 4.7
1 (1H, d, J = 17.4 Hz), 7.05-7.4
(9H, m) MASS: 460 as elemental analysis _{C 22 H 25 N 2 O 7} P, Calculated: C; 57.39, H; 5.47 , N;
6.08 Found: C; 57.38, H; 5.84, N;
5.79

Example 5 (3S) -3-[[hydroxy (4-phenylbutyl)]
Phosphinoyl] acetyl] amino-2-oxo-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-tert-butyl acetate (1.25 g) in methylene chloride (7.5 ml) was added to trifluoroacetic acid (3.7 m).
l) is added at room temperature. The reaction mixture is stirred at the same temperature for 3 hours and the solvent is distilled off under reduced pressure. The residue was triturated with diethyl ether to give colorless amorphous (3S) -3-[[hydroxy (4-phenylbutyl) phosphinoyl] acetyl] amino-2-oxo-2,3,4,5-tetrahydro-. 1
H-1-benzazepine-1-acetic acid (0.80 g) is obtained. IR (film): 3300, 1720, 1640 c
m ^-1 NMR (200 MHz, CD ₃ OD, δ): 1.5-
1.9 (6H, m), 2.0-2.2 (4H, m),
2.3-2.5 (1H, m), 2.35-2.5 (3
H, m), 2.85 (2H, d, J = 17.0 Hz),
3.35-3.55 (1H, m), 4.35-4.5
(1H, m), 4.41 (1H, d, J = 17.5H
z), 4.72 (1H, d, J = 17.4 Hz), 7.
05-7.4 (9H, m) MASS: 473 Elemental analysis C ₂₄ H ₂₉ N ₂ O ₆ as P · 0.6H ₂ O, Calculated: C; 59.65, H; 6.30 , N;
5.80 Found: C; 59.34, H; 6.10, N;
5.72 [α] ²⁶ _D -155.00 ° (C1.00, CH ₃ O
H)

Example 6 In the same manner as in Example 1, the following compound is obtained. (4S) -4- (Hydroxy-P-phenethylphosphonyl) amino-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-2-acetic acid disodium salt IR (nujol) : Not specifiable NMR (200 MHz, D ₂ O, δ): 1.8-2.0
(2H, m), 2.75-3.1 (3H, m), 3.2
-3.4 (1H, m), 3.77 (1H, d, J = 1
7.0 Hz), 4.02 (1H, d, J = 16.7H)
z), 4.24 (1H, d, J = 16.9 Hz), 4.
8-5.0 (1H, m), 5.30 (1H, d, J = 1
6.6 Hz), 7.1-7.45 (9H, m) FAB-MASS: 447.1 (M ⁺ ), 469.1.
(M ⁺⁺ Na)

Example 7 (3S) -3- (diethoxyphosphinoylmethyl) amino-2-oxo-2,3,4,5-tetrahydro-1
H-1-benzazepine-1-tert-butyl acetate (1.06 g) and 25% hydrobromic acid in acetic acid (1
0 ml) of the mixture is stirred at room temperature for 5 days and evaporated under reduced pressure. The residue is partitioned between water and ethyl acetate. HP-20 using a 15% aqueous methanol solution as an eluent for the aqueous layer
Treat with (160 ml). The compartments containing the target compound are collected and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give colorless powdery (3S) -3- (dihydroxyphosphinoylmethyl) amino-2-oxo-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-acetic acid (0.15 g) is obtained. Melting point 230 ° C or higher IR (nujoule): 1720, 1660 cm ^-1 NMR (200 MHz, D ₂ O + NaOD, δ):
1.85-2.0 (1H, m), 2.25-2.7 (4
H, m), 2.95-3.1 (1H, m), 3.35.
(1H, t, J = 9.6 Hz), 4.20 (1H, d,
J = 17.0 Hz), 4.50 (1H, d, J = 17.
0Hz), 7.2-7.4 (4H, m ) FAB-MASS: 329.0 Elemental analysis C ₁₃ H ₁₇ N ₂ O ₆ as P · 1.5H ₂ O, Calculated: C; 43.95, H; 5.67, N;
7.88 Found: C; 43.80, H; 5.70, N;
7.73

Example 8 The following compound was obtained in the same manner as in Example 1. (S) -3- [N- (phenethylphosphonyl) -L-alanyl] amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid disodium salt IR ( KBr): 1645 cm ^-1 NMR (200 MHz, CD ₃ OD, δ): 1.27.
(3H, d, J = 7.0 Hz), 1.65-1.9 (2
H, m), 1.95-2.15 (1H, m), 2.2-
2.5 (1H, m), 2.5-2.65 (1H, m),
2.7-2.9 (2H, m), 3.35-3.55 (1
H, m), 3.6-3.8 (1H, m), 4.29 (1
H, d, J = 16.5 Hz), 4.3-4.45 (1
H, m), 4.43 (1H, d, J = 16.4 Hz),
7.05-7.35 (9H, m) FAB- MASS: 518.1 Elemental analysis C ₂₃ H as _{26 N 3 Na 2 O 6 P} · 3H 2 O, Calculated: C; 48.34, H; 5 .64, N;
7.35 Found: C; 48.35, H; 5.42, N;
7.27

Example 9 The following compound was obtained in the same manner as in Example 1. (S) -3- [N- (phenethylphosphonyl) -L-leucyl] amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid disodium salt IR ( KBr): 1645 cm ^-1 NMR (200 MHz, CD ₃ OD, δ): 0.93
(6H, d, J = 5.6Hz), 1.35-1.6 (2
H, m), 1.6-1.95 (3H, m), 2.0-
2.15 (1H, m), 2.15-2.35 (1H,
m), 2.4-2.55 (1H, m), 2.7-2.9.
(2H, m), 3.35-3.55 (1H, m), 3.
6-3.75 (1H, m), 4.26 (1H, d, J =
16.6 Hz), 4.3-4.45 (1 H, m), 4.
48 (1H, d, J = 16.6 Hz), 7.05-7.
4 (9H, m) FAB- MASS: 560.2 as elemental analysis _{C 26 H 32 N 3 Na 2} O 6 P · 3H 2 O, Calculated: C; 50.90, H; 6.24 , N;
6.85 Found: C; 50.99, H; 5.98, N;
6.70

Example 10 The following compound was obtained in the same manner as in Example 1. (S) -3- [Nα- (phenethylphosphonyl) -L-
Lysyl] amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid disodium salt IR (KBr): 1645 cm ^-1 NMR (200 MHz, CD ₃ OD, δ) : 1.3-
1.9 (8H, m), 1.95-2.15 (1H,
m), 2.15-2.35 (1H, m), 2.45-
2.6 (1H, m), 2.65-2.9 (4H, m),
3.35-3.45 (1H, m), 3.55-3.75
(1H, m), 4.25-4.5 (3H, m), 7.0
-7.4 (9H, m) FAB- MASS: 575.4 as elemental analysis _{C 26 H 33 N 4 Na 2} O 6 P · 3H 2 O, Calculated: C; 49.68, H; 6.25 , N;
8.91 Found: C; 49.39, H; 6.13, N;
8.64

Example 11 (S) -3- (O-benzyl-P-phenethylphosphonyl) amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-benzyl acetate ( A mixture of diastereomer A) (100 mg) and sodium hydrogen carbonate (29 mg) in ethanol / water (5 mg) was reduced with 10% Pd-carbon (water content 50%) (20 mg) under hydrogen at 3 atm for 3 hours. To do. The reaction mixture was filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and powdered (S) -3-
P-phenethylphosphonylamino-2-oxo-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-acetic acid disodium salt (diastereomer A)
(60.0 mg) is obtained. IR (KBr): 1640, 1600 cm ^-1 NMR (200 MHz, CD ₃ OD, δ): 1.5-
1.8 (2H, m), 1.9-2.1 (1H, m),
2.3-2.6 (2H, m), 2.6-2.9 (2H,
m), 3.4-3.7 (1H, m), 3.7-4.0.
(1H, m), 4.18 (1H, d, J = 16.5H
z), 4.67 (1H, d, J = 16.5 Hz), 7.
0-7.4 (9H, m) FAB- MASS: 447.1 as (M + 1) Elemental Analysis _{C 20 H 21 N 2 Na 2} O 5 P · 5.5H 2 O, Calculated: C; 44.04, H; 5.91, N;
5.14 Found: C; 43.86, H; 5.51, N;
4.92

Example 12 The following compound was obtained in the same manner as in Example 11. This compound was obtained by lyophilization and is in NMR analysis consistent with that obtained from diastereomer A. (S) -3-P-phenethylphosphonylamino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid disodium salt (diastereomer-B) IR (KBr): 1640, 1600 cm ^-1 NMR (200 MHz, CD ₃ OD, δ): 1.5-
1.8 (2H, m), 1.9-2.1 (1H, m),
2.3-2.6 (2H, m), 2.6-2.9 (2H,
m), 3.4-3.7 (1H, m), 3.7-4.0.
(1H, m), 4.18 (1H, d, J = 16.5H
z), 4.66 (1H, d, J = 16.5 Hz), 7.
0-7.4 (9H, m) FAB-MASS: 447.1 (M + 1)

Example 13 (S) -3- [N- (diethylphosphonomethyl) -L-
Phenylalanyl] amino-2-oxo-2,3,4
5-Tetrahydro-1H-1-benzazepine-1-tertiary butyl acetate (1.0 g) in 25% hydrobromic acid /
A solution of acetic acid solution (22 ml) is stirred at room temperature for 4 hours and evaporated under reduced pressure. The residue is purified by liquid chromatography using a mixed solution of acetonitrile and a 0.1% trifluoroacetic acid aqueous solution (22:78) as an eluent to obtain two solid compounds. Low polarity product (S) -3- [N- (O-ethylphosphonomethyl) -L
-Phenylalanyl] amino-2-oxo-2,3
4,5-Tetrahydro-1H-1-benzazepine-1
-Acetic acid IR (nujol): 1650 cm ^-1 NMR (200 MHz, DMSO-d ₆ , δ): 1.1
0, 1.26 (total 3H, each t, J = 7.1Hz), 1.
9-2.2 (1H, m), 2.1-2.4 (1H,
m), 2.5-2.8 (1H, m), 2.7-3.0
(2H, m), 3.0-3.3 (3H, m), 3.7
8, 3.82 (total 2H, each q, J = 7.1Hz), 4.
0-4.2 (1H, m), 4.1-4.4 (1H,
m), 4.40 (1H, d, J = 17.5 Hz), 4.
58 (1H, d, J = 17.5 Hz), 7.1-7.4
(10H, m), 8.79 (1H, d, J = 7.7H
z) MASS: 501 (M- 2) Elemental analysis C ₂₄ H ₂₆ N ₃ O ₇ as P · 2H ₂ O, Calculated: C; 53.43, H; 6.34 , N;
7.79 Found: C; 53.32, H; 5.45, N;
7.61 Polar Product (S) -3- [N- (phosphonomethyl) -L-phenylalanyl] amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid IR (nujoule): 1650 cm ^-1 NMR (200 MHz, DMSO-d ₆ , δ): 1.9
-2.1 (1H, m), 2.1-2.4 (1H, m),
2.5-2.7 (1H, m), 2.7-2.9 (2H,
m), 3.0-3.3 (3H, m), 4.0-4.1.
(1H, m), 4.1-4.4 (1H, m), 4.39
(1H, d, J = 17.5Hz), 4.58 (1H,
d, J = 17.5 Hz), 7.1-7.4 (12H,
m), 8.7 (1H, d , J = 7.4Hz) FAB-MASS: as 476.1 Elemental Analysis _{C 22 H 26 N 3 O 7} P · 3H 2 O, Calculated: C; 51.70, H; 5.90, N;
8.21 Found: C; 51.54, H; 5.31, N;
7.70

Claims (1)

[Claims] 1. The formula: [Wherein R represents a lower alkyl group, an ar (lower) alkyl group or a hydroxyl group; A represents a single bond, a lower alkylene group, an alkylenecarbonyl group, an amino acid group or a methyleneamino acid group, and methylene in these groups is Optionally substituted with phenyl or ar (lower) alkyl; m
Represents an integer of 0 or 1, p represents an integer of 0 or 1, q represents an integer of 1 or 2, and satisfies p + q = 2] or a salt thereof.