JPH0987291A - New alanine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new specific alanine derivative effective for specifically inhibiting angiotensin converting enzyme, endothelin conversion enzyme and enkephalinase and useful for analgesic, hypotensive diuretic treatment or for the prevention, treatment, etc., of cardiac insufficiency and hypertension. SOLUTION: This new alanine derivative is expressed by the formula I [R<1> is OH, a lower alkoxy or a lower aralkyloxy; R<2> is H, a lower alkyl or a lower aralkyl; R<3> is a lower alkyl; R<4> is OH or a lower aralkyl; Ar is an aryl such as a (substituted)phenyl, a (substituted)naphthyl, thienyl or pyridyl]. The derivative specifically inhibits the action of a metal peptidase such as angiotensin converting enzyme, endothelin converting enzyme and enkephalinase and is useful for analgesic, antidiarrheic and hypotensive diuretic treatment and the prevention, treatment, etc., of cardiac insufficiency and hypertension. The compound can be produced by reacting a substituted alanine compound of the formula II with trichloromethyl chloroformate, reacting the product with a compound of the formula III (R<8> is an alkoxy, etc.; R<9> is an alkyl, etc.) and finally hydrolyzing the reaction product.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a metal peptidase, and more particularly to a novel alanine derivative which specifically inhibits the actions of angiotensin converting enzyme, endothelin converting enzyme and enkephalinase.

[0002]

BACKGROUND OF THE INVENTION Angiotensin converting enzyme is an enzyme which is abundantly present in lung vascular endothelial cell membranes, renal tubules and the like and acts on angiotensin I in vivo to produce angiotensin II having a strong pressor action. Therefore, it is clinically effective in preventing and treating hypertension by inhibiting the activity of angiotensin converting enzyme. Enkephalin is an endogenous peptide that specifically binds to opioid receptors and exerts a morphine-like effect (Nature, 2
58,579, (1975)), consisting of 5 amino acids as shown below,

Tyr ¹ -Gly ² -Gly ³ -Phe ⁴ -A (In the formula, A represents Met or Leu)

Gly ³ -Ph by enkephalinase
It is said that e ⁴ is specifically cleaved and the activity is lost. The enkephalinase inhibitor exhibits excellent analgesic and antidiarrheal effects by inhibiting the enkephalinase and maintaining the effect of enkephalin.
Thiorphan, keratorphan, etc. have been reported (N
ature, 320, 681 (1986)).

On the other hand, enkephalinase is Cys ⁷ -Phe ⁸ of atrial natriuretic hormone (also known as ANP).
It is known to be involved in the inactivation of ANP by cleaving the Ser ²⁵ -Phe ²⁶ bond with the protein (Lancet,
9, 591, (1989)). Therefore, enkephalinase inhibitors have been studied in animal experiments, clinics, etc. as therapeutic agents for heart failure and hypertension (Sybertz, EJ.
et al. , Hypertension, 15, 15
2, (1990), Mavgulies, K .; B. et
al. , Kidney Int, 38, 67, (19
90)).

[0006] The conventional research has mainly been focused on developing a drug having excellent selectivity for either one of the above two enzyme activities. However, if there is a drug with similar inhibitory activity against both enkephalinase and angiotensin converting enzyme, angiotensin
This is extremely advantageous because it can effectively inhibit the action of endogenous ANP while inhibiting the production of II.

[0007] In addition, endothelin is a vasoconstrictor peptide consisting of 21 amino acids whose structure was determined and isolated from the culture supernatant of porcine aortic endothelial cells (Yanagisawa).
et al. , Nature, 332, 411-41
5 (1988)). As a biosynthesis mechanism of endothelin,
From the endothelin precursor, the big endothelin (39
Number of amino acids) is cut out, then mechanism by endothelin converting enzyme Trp ²¹ -Val ²² bond of big endothelin is converted into a specific cleavage endothelin is estimated. Big endothelin has a lower vasoconstrictor activity than endothelin, and since it is thought that big endothelin is converted into endothelin in the body to act, endothelin-converting enzyme inhibitors are circulatory system diseases such as hypertension and ischemic heart. It is expected to be effective against diseases or renal diseases.

[0008] Although research on endothelin converting enzyme inhibitors is new, there are few reports, but the only known phosphoramidon exhibits inhibitory activity by the action of a metal chelate. (JP-A-4-41430)

[0009]

DISCLOSURE OF THE INVENTION The present invention provides a metal peptidase, and more specifically, by specifically inhibiting the actions of angiotensin converting enzyme, endothelin converting enzyme and enkephalinase, analgesia, antidiarrheal, hypotensive diuresis and It is an object of the present invention to provide a novel alanine derivative which is highly effective as a preventive and therapeutic drug for heart failure and hypertension.

[0010]

The present invention has the general formula (I)

[0011]

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(Wherein R ¹ represents hydroxy, lower alkoxy and lower aralkyloxy. R ² represents hydrogen, lower alkyl and lower aralkyl. R ³ represents lower alkyl. R ⁴ represents hydroxy and lower aralkyl. Represents Ar
Represents the following aryl.

[0013]

[Chemical 6]

(In the formula, R ⁵ and R ⁶ are the same or different and each is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower aralkyl, optionally substituted phenyl, lower aralkyloxy, carboxy, halogen, lower alkylthio, Lower alkylsulfonyl, optionally substituted phenylthio, halo lower alkyl, nitro, amino, acetamide, lower aralkyloxycarbonyl, lower alkoxycarbonyl lower alkoxy, R ⁷ represents hydrogen, lower alkyl, lower alkoxy))). The present inventors have completed the present invention by discovering that the novel alanine derivative represented and the pharmacologically acceptable salt thereof have an excellent metal peptidase inhibitory effect.

The present invention will be described in detail below. Unless otherwise specified, the term "lower" in the definition of the general formula in the present specification means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, as the above-mentioned “lower alkyl”, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl and the like can be mentioned.

Specific examples of "lower alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, pentyloxy and the like. “Lower aralkyl” means a group in which any hydrogen of the above “lower alkyl” is substituted with aryl such as phenyl and naphthyl. For example, when phenyl is used as aryl, specific examples thereof include benzyl and phenethyl. .

The salts of the above compound (I) are pharmacologically acceptable salts and may include the following. That is,
Examples of the inorganic base include alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, magnesium salt, etc.), ammonium salt, etc., and examples of the organic base include organic amine salt ( Eg triethylamine salt, pyridine salt, ethanolamine salt etc.) and basic amino acids (eg arginine)
And the like.

The compounds represented by the general formula (I) and the general formula (II) of the present invention can be produced by the following synthetic method. Reaction (a) A method for producing a compound of the general formula (II) according to claim 2, wherein R ¹ is lower alkoxy or lower aralkyloxy.

[0019]

[Chemical 7]

(Each symbol in the formula is the same as in claim 2.) In the reaction (a), the substituted alanine derivative (III) is reacted with trichloromethyl chloroformate to give a compound (IV),
The compound (II) is produced by reacting with the compound (V). The synthetic method of compound (IV) proceeds quantitatively in the presence of a base in an organic solvent. The amount of trichloromethyl chloroformate used is the compound (III)
1-1.5 times the molar equivalent is good, especially 1.1-
A 1.2-fold molar equivalent is preferable. Examples of the organic solvent used include methylene chloride, chloroform, benzene, toluene, tetrahydrofuran and the like, and methylene chloride is particularly preferable. The amount of the organic solvent used is the compound (III)
The amount is preferably 5 to 30 times, and particularly preferably 10 to 15 times. Examples of the base used include triethylamine, pyridine, dimethylaminopyridine and the like, with triethylamine being particularly preferred. The amount of the base used is preferably 1-1.5 times the molar equivalent of the compound (III), and particularly preferably 1-1.2 times the molar equivalent. Further, when the compound (III) is a hydrochloride, the molar equivalent is 2-3 times, and the molar equivalent is preferably 2.2-2.2. Reaction temperature is 0 ℃
To room temperature is good, and the reaction time is 30 to 120 minutes (preferably 40 to 60 minutes). The compound (IV) obtained by such a method can be reacted with the compound (V) without isolation and purification.

The condensation reaction between compound (IV) and compound (V) proceeds in an organic solvent in the presence of a base. The compound (V) has a 1-1.5-fold molar equivalent to the compound (III), and preferably a 1.1-1.2-fold molar equivalent. Examples of the organic solvent used include methylene chloride, chloroform, benzene, toluene, tetrahydrofuran and the like, with methylene chloride and toluene being particularly preferred. The amount of the organic solvent used is preferably 10-20 times the amount of the compound (III). Examples of the base used include triethylamine, pyridine, dimethylaminopyridine and the like, with triethylamine being particularly preferred. The amount of base used is
The molar equivalent is preferably 1-1.5 times the compound (III). The reaction temperature is not particularly limited, but room temperature is preferable, and the reaction time is preferably 16 to 24 hours.

The compound (III) is known, and some of them are commercially available. Others are produced according to known chemical methods. Compound (V) is produced by the following synthetic method. (1) When R ⁸ is lower alkoxy and R ⁹ is lower alkyl

[0023]

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(In the formula, Z represents a general nitrogen protecting group used in peptide synthesis. R ³ is the same as in claim 2.) Compound (VI) is a general nitrogen protecting group used in peptide synthesis. The compound (VII) is protected to give a compound (VIII) by reacting with formalin in the presence of a base such as anhydrous potassium carbonate or anhydrous sodium carbonate. Further, the compound (IX) is obtained by chlorinating with a chlorinating agent and then reacting with a corresponding phosphite. Compound (V) is obtained by subjecting compound (IX) thus obtained to a general deprotection operation. The compound (V) is preferably prepared before use during the reaction with the compound (III).

[0025]

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(In the formula, Tf represents trifluoromethanesulfonyl. R ³ is the same as in claim 2.) Compound (X) is reacted with paraformaldehyde in the presence of a base to give compound (XI). Furthermore, in the presence of pyridine,
After reacting with anhydrous trifluoromethanesulfonic acid to form the compound (XII), it is reacted with the compound (VI) to obtain the compound (V). (2) When R ⁸ is lower aralkyl and R ⁹ is lower alkyl

[0027]

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(In the formula, Z represents a general nitrogen protecting group used in peptide synthesis. R ³ is the same as in claim 2.) Compound (X) is reacted with trimethylsilyl chloride in methylene chloride in the presence of triethylamine. After the reaction, the compound (V) can be reacted with the compound (XIV), and then a general deprotection operation can be performed to obtain the compound (V). The compound (X) is, for example, D.I. S. Karanewsky
J. et al. Med. Chem. (1988), 31, 20
It can be synthesized according to the method of 4-211. In addition, the compound (XI
V) can be obtained by reacting the compound (VIII) with trimethylsilyl bromide in methylene chloride. (3) When R ⁸ is lower alkoxy and lower aralkyloxy and R ⁹ is lower alkyl and lower aralkyl

[0029]

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(In the formula, R ³ is the same as in claim 2.) Compound (VI) is reacted with formaldehyde in a system of ethyl acetate-water to give compound (XV), and then compound (X) is reacted in toluene. By doing so, the compound (V) is obtained.

Reaction (b) The general formula (I) according to claim 1.
1) The reaction for selectively deesterifying the phosphate ester moiety When R ⁸ is lower aralkyl

[0032]

[Chemical 12]

(In the formula, R ¹ represents lower alkoxy and lower aralkyloxy. Other respective symbols are the same as those in claim 2.)

When R ⁸ is lower alkoxy and lower aralkyloxy

[0035]

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(Each symbol in the formula is the same as above.)

The above reaction is a reaction in which the phosphoric acid moiety is selectively deesterified, and easily proceeds by reacting compound (II) with trimethylsilyl bromide in an organic solvent. As the organic solvent used, acetonitrile,
Examples include chloroform and methylene chloride. The amount of trimethylsilyl bromide used is 2 with respect to compound (II).
A -3 fold molar equivalent is preferred. Reaction temperature is room temperature 1-24
It is preferable to do it in time.

When R ¹ is lower alkoxy, R ⁸ is lower aralkyloxy and R ⁹ is lower aralkyl, the reaction proceeds by catalytic reduction in methanol in the presence of palladium / carbon. The palladium content is preferably 5-10% and particularly preferably 10%. The amount used is 0.1-1 times (preferably 0.3-0.5 times) the amount of compound (II), and the reaction proceeds promptly at room temperature and atmospheric pressure. At this time, a sodium salt of phosphoric acid can be obtained by adding a necessary amount of an aqueous solution of sodium hydrogen carbonate.

2) Reaction for deesterification of carboxylic acid ester

[0040]

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(In the formula, R ¹ represents lower alkoxy and lower aralkyloxy. R ⁸ represents lower aralkyl.
The other symbols are the same as in claim 2. )

[0042]

[Chemical 15]

(In the formula, R ¹ represents lower alkoxy and lower aralkyloxy. Other symbols are the same as those in claim 2.) The above reaction is a reaction for converting R ¹ into hydroxy, and R ¹ is In the case of lower alkoxy, the reaction proceeds by hydrolysis with a base in an organic solvent containing 50-80% water at room temperature for 1-24 hours. Examples of the water-containing organic solvent include methanol, ethanol, dioxane, tetrahydrofuran and the like, and alcohols such as methanol and ethanol are particularly preferable. The base used is preferably sodium hydroxide, potassium hydroxide, lithium hydroxide or the like,
It is preferable to use 1-5 times molar equivalents (preferably 2-3 times molar equivalents) of the compounds (XVI) and (XVII).
When R ¹ is lower aralkyloxy, it proceeds by catalytic reduction in methanol in the presence of palladium / carbon. Palladium content should be 5-10%, especially 10
% Is preferred. The amount used is 0.1-1 times amount (preferably 0.3-0.5 times amount) of the compounds (XVI) and (XVII).
The reaction proceeds promptly at room temperature and atmospheric pressure.

At this time, a sodium salt of carboxylic acid and phosphoric acid can be obtained by adding a necessary amount of sodium hydrogen carbonate aqueous solution. The compounds represented by the general formula (I) and the general formula (II) contain at least one asymmetric carbon atom, and optical isomers exist. The compounds of the present invention include isolated isomers of these isomers and mixtures thereof.

The compound of the present invention produced by the above-mentioned method is isolated and purified by applying commonly used chemical operations such as extraction, recrystallization, column chromatography and the like, and is used as an active ingredient of the metal peptidase inhibitor of the present invention. Used. The present compound can be produced by a method known per se, for example, tablets, films, ointments and hard capsules, powders, granules, dragees, pills, suppositories, emulsions, suspensions, eye drops, injections, etc. The dosage form can be

In the case of molding into tablets, various carriers well known in the art can be widely used as carriers. Examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like, and examples of the binder include water, ethanol, propanol, simple syrup, glucose, Starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and the like can be mentioned. Examples of the disintegrant include dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose. Examples of the disintegration inhibitor include sucrose,
Examples include stearin, cocoa butter, hydrogenated oil, and the like. Examples of the absorption promoter include quaternary ammonium base, sodium lauryl sulfate and the like. Examples of moisturizers include glycerin and starch.
Examples of the adsorbent include starch, lactose, kaolin, bentonite, colloidal silicic acid and the like. Examples of the lubricant include refined talc, stearate, boric acid powder, polyethylene glycol and the like. Further, the tablet may be a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multi-layer tablet.

When molding in the form of pills, various carriers well known in the art can be widely used as carriers. Examples of the excipient include glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and the like. As the binder, for example,
Examples thereof include gum arabic powder, tragacanth powder, gelatin and ethanol. As the disintegrant, for example, laminaran,
Examples include agar and the like.

When molding in the form of suppositories, various carriers well known in the art can be widely used as carriers. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides.

Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood, and when molded into these forms, those commonly used in the art as diluents Can all be used, for example water,
Ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. If necessary, colorants, preservatives, fragrances,
Flavors, sweeteners, and other pharmaceuticals can also be included in the pharmaceutical preparation.

In the case of molding in the form of eye drops, various carriers well known in the art can be widely used as carriers. Examples of the isotonicity agent include sodium chloride, potassium chloride, concentrated glycerin, propylene glycol and the like. Examples of the buffer include sodium phosphate, boric acid, epsilon-aminocaproic acid, monoethanolamine and the like. Examples of the stabilizer include sodium edetate and the like. Examples of the preservative include benzalkonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl palmitate, chlorobutanol and the like. Examples of the surfactant include polysorbate 80 and the like. Examples of pH adjusters include sodium hydroxide and hydrochloric acid.

The compounds can be administered in a conventional manner, either orally or parenterally (eg subcutaneously, intravenously, rectally). The amount of active ingredient to be administered is
There is no particular limitation, and a wide range can be selected. The dose can be adapted to the individual needs in each particular case, but generally the amount of free form is from 0.1 mg to 1 mg.
An amount in the range of 000 mg / day is suitable, and this is administered once or in several divided doses.

In order to explain the present invention in detail, formulation examples will be given below, and then, as reference examples, production examples of raw material compounds for producing active ingredient compounds to be incorporated in the formulation,
In addition, production examples of the above-mentioned active ingredient compounds are given as Examples,
Further, the present invention will be described more specifically by giving test examples of active ingredient compounds, but it goes without saying that these do not limit the present invention.

Formulation Example 1 Tablet Compound of Example (8-3) 50 g Anhydrous calcium hydrogen phosphate 40 g Mannitol 73 g Crystalline cellulose 25 g Carboxymethyl cellulose calcium 5 g Hydroxypropyl cellulose 5 g Magnesium stearate 2 g Stirring ingredients other than magnesium stearate Mix with a granulator and add 60 ml of ethanol to granulate. After ventilation drying, the granules are crushed and sized, magnesium stearate is added, and the mixture is compressed into tablets having a diameter of 8 mm and a tablet weight of 200 mg.

Formulation Example 2 Capsule Compound of Example (7-14) 50 g Anhydrous calcium hydrogen phosphate 33 g Crystalline cellulose 70 g Low-substituted hydroxypropyl cellulose 20 g Hydroxypropyl cellulose 5 g Magnesium stearate 2 g Stirring components other than magnesium stearate Mix with a granulator and add 80 ml of ethanol to granulate. After ventilation drying, the mixture is crushed and sized, magnesium stearate is added, and 180 mg each of No. 3 hard capsules is filled into a capsule.

Formulation Example 3 Eye Drop Compound of Example (7-7) 2.17 g Sodium hydroxide 0.40 g ε-aminocaproic acid 0.50 g Methylparaben 0.026 g Propylparaben 0.014 g Chlorobutanol 0 0.25 g propylene glycol 0.30 g 0.2N hydrochloric acid until pH 5.5 Purified water up to 100 ml

The compound of Example (7-7) is dispersed in 10 ml of purified water, sodium hydroxide is added and dissolved by stirring to prepare a stock solution of the compound of Example (7-7). Methylparaben, propylene glycol and chlorobutanol were added to propylene glycol, heated to about 50 ° C and dissolved, and added to 80 ml of purified water preheated to about 60 ° C, and stirred well to dissolve. After cooling this solution to room temperature, ε-aminocaproic acid and the compound stock solution of Example (7-7) are added and dissolved. Adjust the pH to 5.5 with 0.2N hydrochloric acid.
To 100 ml with purified water, and sterilized and filtered to obtain eye drops.

Formulation Example 4 Injectable compound Compound of Example (7-7) 2.17 g Sodium hydroxide 0.40 g Sodium chloride 0.14 g 0.2N hydrochloric acid Until pH 7.4 Water for injection Up to 100 ml Example The compound of (7-7) is dispersed in 90 ml of water for injection, sodium hydroxide is added, and the mixture is dissolved with stirring. Sodium chloride was added to this solution, which was then adjusted to pH 7.
Adjust to 4, make up to 100 ml with water for injection, and filter for sterilization to obtain an injection.

Reference Example 1 2-Bromomethyl-6-methylnaphthalene 2,6-dimethylnaphthalene 3.0 g (19.2 mM)
In 30 ml of anhydrous benzene, 3.59 g (20.2 mM) of N-bromosuccinimide and 47 benzoyl peroxide
0 mg (1.92 mM) was added and the mixture was heated under reflux for 1 hour.
After cooling the reaction solution to room temperature, n-hexane was added and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure, and the obtained concentration residue was subjected to silica gel column chromatography (eluent: n-
990 mg of 2-bromomethyl-6-methylnaphthalene by purifying with hexane / benzene = 19/1)
(Yield 21.9%) was obtained. Melting point: 96-98 ° C N.V. M. R. (CDCl ₃ ) δ: 2.50 (s, 3H), 4.66 (s, 2
H), 7.31-7.34 (m, 1H), 7.44-7.48 (m, 1H), 7.59 (d, 1H, J = 0.9
8Hz), 7.67-7.77 (m, 3H) I. R. ν _KBr cm ^-1 : 1215,895,830,810,660,600

Reference Example 2 2-[(4-bromophenyl) thio] benzyl alcohol
Le Step 1 2 - [(4-bromophenyl) thio] benzaldehyde 2-chloro-benzaldehyde 7.0 g (49.8M
M), p-bromobenzenethiol 10.36 g (5
4.78 mM), anhydrous sodium carbonate 6.86 g (6
4.74 mM) and 100 ml of dimethyl sulfoxide were stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By recrystallizing the obtained concentrated residue from benzene / n-hexane, 11.18 g (yield 76.6%) of 2-[(4-bromophenyl) thio] benzaldehyde was obtained. Melting point: 80-81 ° C N.V. M. R. (CDCl ₃ ) δ: 7.10 (dd, 1H, J = 7.69,1.
46Hz), 7.29 (d, 2H, J = 8.42Hz), 7.32-7.48 (m, 2H), 7.51 (d, 2
H, J = 8.42Hz), 7.86-7.93 (m, 1H), 10.36 (s, 1H) I. R. ν _KBr cm ^-1 : 3450,1680,1590,1570,1470,141
0,1210,1080,1010

Step 2 2-[(4-Bromophenyl) thio] benzyl alcohol
In a nitrogen atmosphere, lithium borohydride 624 mg (2
A solution of 2-[(4-bromophenyl) thio] benzaldehyde 7 g (23.9 mM) obtained in Step 1 in 35 ml of anhydrous THF was added dropwise to a suspension of 8.68 mM of anhydrous THF in 35 ml under ice-water cooling. After completion of dropping, the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, acidified with hydrochloric acid, and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By recrystallizing the obtained concentrated residue from benzene / n-hexane, 2
5.47 g (yield 77.5%) of-[(4-bromophenyl) thio] benzyl alcohol was obtained. Melting point: 48-50 ° C N.V. M. R. (CDCl ₃ ) δ: 2.04 (t, 1H, J = 6.23Hz),
4.77 (d, 2H, J = 5.86Hz), 7.04 (d, 2H, J = 8.43Hz), 7.24-7.32
(m, 1H), 7.34-7.43 (m, 4H), 7.50-7.56 (m, 1H) I. R. ν _KBr cm ^-1 : 3340,3050,1600,1580,1480,146
0,1390,1200,1100,1010 MS-FAB (gly): m / z 294,296 (MH ⁺ ).

Reference Example 3 Phenylalanine methyl ester hydrochloride 3.75 ml of thionyl chloride was added to a suspension of 5 g (30.26 mM) of phenylalanine in 50 ml of methanol under ice-cooling.
(51.7 mM) was added dropwise. After completion of the dropping, the mixture was heated under reflux for 3 hours. The reaction solution was cooled and concentrated under reduced pressure. The concentrated residue thus obtained was recrystallized from methanol / ether to give 5.77 g of phenylalanine methyl ester hydrochloride.
(88.4% yield). Melting point: 161-162 ° C (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 3.11 (dd, 1H, J = 13.
92,7.33Hz), 3.24 (dd, 1H, J = 13.92,5.49Hz), 3.65 (s, 3H),
4.22 (t, 1H, J = 6.41Hz), 7.23-7.36 (m, 5H), 8.80 (s, 3H) I. R. ν _KBr cm ^-1 : 3000,1760,1590,1560,1500,145
0,1240,1150,1080,940,750,700

The following compounds were obtained in the same manner as in Reference Example 3. Phenyl-L-alanine methyl ester hydrochloride Phenyl-D-alanine methyl ester hydrochloride

Reference Example 4 3- (4-methoxyphenyl) alanine benzyl ester
Hydrochloride (DL) -Tyrosine 2.0 g (11.0 mM) DMF
Triethylamine 3.85m in 16ml / 4ml water mixture
After adding 1 (27.6 mM), 3.6 g (16.6 mM) of di-t-butyl dicarbonate was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was dissolved in 15 ml of anhydrous DMF, 1.24 g (8.94 mM) of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature for 30 minutes, and then 1.06 ml of benzyl bromide.
(8.94 mM) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/1) to give N- (t-butoxycarbonyl)-.
2.66 g (yield 64.8%) of 3- (4-hydroxyphenyl) alanine benzyl ester was obtained as an oily substance.

Obtained N- (t-butoxycarbonyl)
-3- (4-hydroxyphenyl) alanine benzyl ester 1.15 g (3.08 mM) anhydrous DMF 10 m
Anhydrous potassium carbonate 470 mg (3.39 mM) in 1 solution
Was added and stirred for 30 minutes, then 0.21 ml of methyl iodide
(3.39 mM) was added dropwise at room temperature. After the dropping was completed, the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained concentrated residue was diluted with water, acidified with a 5% aqueous citric acid solution,
Extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (eluent: benzene / ethyl acetate = 19/1) to give N-.
1.0 of (t-butoxycarbonyl) -3- (4-methoxyphenyl) alanine benzyl ester as an oil.
8 g (yield 90.9%) was obtained.

Next, N- (t-butoxycarbonyl)-
To a solution of 3- (4-methoxyphenyl) alanine benzyl ester in 10 ml of anhydrous benzene was added 10 ml of 4N hydrochloric acid / ethyl acetate solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and crystallized from methanol / ether to give 3- (4-methoxyphenyl) alanine benzyl ester hydrochloride (885 mg, yield 98.2%). Melting point: 184-186 ° C N.V. M. R. (CD ₃ OD) δ: 3.14 (d, 2H, J = 6.84Hz),
3.77 (s, 3H), 4.28 (t, 1H, J = 6.84Hz), 5.20 (d, 1H, J = 12.20H
z), 5.26 (d, 1H, J = 12.20Hz), 6.84 (d, 2H, J = 8.78Hz), 7.07
(d, 2H, J = 8.79Hz), 7.28-7.39 (m, 5H) I.D. R. ν _KBr cm ^-1 : 3000,1760,1590,1560,1500,145
0,1240,1150,1080,940,750,700

The following compounds were obtained in the same manner as in Reference Example 4. 3- (4-methoxyphenyl) -L-alaninebenzyl
Ester hydrochloride 3- (4-methoxyphenyl) -D-alanine benzyl
After the ester hydrochloride tyrosine was BOC-ized and reacted with methyl iodide instead of benzyl bromide, the following compound was obtained in the same manner as in Reference Example 4. 3- (4-methoxyphenyl) -L-alanine methyl ester
Stell hydrochloride 3- (3,4-dimethoxyphenyl) alanine methyl ester
Stell hydrochloride or 3- [N- (t-butoxycarbonyl) -4-hydroxyphenyl] alanine benzyl ester obtained in Reference Example 4 was reacted with various halides and then de-BOC-ized to give the following compound. The compound was obtained. 3- (4-n-butoxyphenyl) -L-alanine ben
Dil ester hydrochloride 3- (4-benzyloxyphenyl) -L-alanine
Benzyl ester hydrochloride 3- [4- (ethoxycarbonylmethoxy) phenyl]
-L-alanine benzyl ester hydrochloride

Reference Example 5 4- (methylsulfonyl) benzyl chloride 4- (methylthio) benzyl alcohol 3.0 g (1
Thionyl chloride (4.25 ml, 58.3 mM) was added dropwise to a solution of anhydrous methylene chloride (9.5 mM) in 30 ml, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and azeotropically distilled with toluene. A solution of the obtained concentrated residue in 30 ml of chloroform was added with 6.71 g (38.9 mM) of metachloroperbenzoic acid.
Was gradually added, and then the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, metachlorobenzoic acid was removed by basic activated alumina (Art. 1097 manufactured by Merck) column chromatography, and the eluate was concentrated under reduced pressure.
The obtained concentrated residue was purified by silica gel column chromatography (eluent: benzene / ethyl acetate = 9/1) to obtain 4- (methylsulfonyl) benzyl chloride (3.0 g, yield 75.4%). . Melting point: 64-65 ° C. N.V. M. R. (CDCl ₃ ) δ: 3.06 (s, 3H), 4.64 (s, 2
H), 7.60 (dd, 2H, J = 6.59,1.96Hz), 7.95 (dd, 2H, J = 6.59,1.9
6 Hz) I. R. ν _KBr cm ⁻¹ : 1410,1320,1300,1140,1085,950 MS-FAB (MNBA): m / z 205,207 (MH ⁺ ).

Reference Example 6 3- (2-Methylphenyl) alanine benzyl ester
Hydrochloride Step 1 Diethyl (acetylamino) [(2-methylphenyl)
Methyl] propanedioate In a nitrogen atmosphere, 540 mg (11.2 mM) of 50% sodium hydride (washed with n-hexane) was cooled with ice water to 2.43 g (11.2 m) of diethylacetamide malonate.
A solution of M) in 15 ml of anhydrous DMF was added, and the mixture was stirred at room temperature for 2.5 hours. This reaction solution was cooled with ice water under α-bromo-o-
It was added dropwise to 1.0 ml of xylene (7.46 mM). After the dropping was completed, the mixture was further stirred at room temperature for 17 hours. The reaction solution was poured into ice water and neutralized with 4N-hydrochloric acid. The precipitated crystals were collected by filtration, dissolved in chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By recrystallizing the obtained concentrated residue from ethyl acetate / n-hexane, 1.805 g (yield: 75.3%) of diethyl (acetylamino) [(2-methylphenyl) methyl] propanedioate was obtained. Melting point: 85-89 ° C N.V. M. R. (CDCl ₃ ) δ: 1.28 (t, 6H, J = 7.08Hz),
2.01 (s, 3H), 2.23 (s, 3H), 3.70 (s, 2H), 4.17-4.36 (m, 4H),
6.57 (bs, 1H), 6.94 (d, 1H, J = 7.08Hz), 7.04-7.14 (m, 3H) I. R. ν _KBr cm ^-1 : 3250,2980,1750,1640,1520,137
0,1310,1270,1220,1200,1180,1060

Step 2 3- (2-Methylphenyl) alanine hydrochloride diethyl (acetylamino) [(2-methylphenyl)
Methyl] propanedioate 1.78 g (5.54 m
To M) was added 6N-hydrochloric acid 10 ml, and the mixture was heated under reflux for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained crystals were washed with ether to obtain 1.11 g (yield 92.9%) of 3- (2-methylphenyl) alanine hydrochloride. Melting point: 215-218 ° C N.V. M. R. (DMSO-d ₆ ) δ: 2.31 (s, 3H), 3.12
(d, 2H, J = 6.84Hz), 4.00 (t, 1H, J = 7.33Hz), 7.17-7.22 (m, 4
H), 8.53 (bs, 3H) I.H. R. ν _KBr cm ^-1 : 2900,1740,1495,1210

Step 3 3- (2-Methylphenyl) alanine benzyl ester
Hydrochloride 3- (2-methylphenyl) alanine hydrochloride 1.55 g
(7.19 mM) was converted into BOC, benzyl ester and de-BOC in the same manner as in Reference Example 3 to give 3- (2
2.03 g (yield 92.1%) of -methylphenyl) alanine benzyl ester hydrochloride was obtained. Melting point: 136-138 ° C. N.V. M. R. (CD ₃ OD) δ: 2.31 (s, 3H), 3.14 (dd, 1
H, J = 14.16,7.81Hz), 3.24-3.32 (m, 1H), 4.25 (t, 1H, J = 7.81
Hz), 5.12 (d, 1H, J = 11.72Hz), 5.19 (d, 1H, J = 11.72Hz), 7.09
-7.23 (m, 6H), 7.30-7.35 (m, 3H) I. R. ν _KBr cm ^-1 : 3360,2960,2900,1750,1515,125
0,1220,750

The following compounds were obtained in the same manner as in Reference Example 6. 3- (3-methylphenyl) alanine benzyl ester
Hydrochloride 3- (4-methylphenyl) alanine benzyl ester
Hydrochloride 3- (2-naphthyl) alanine benzyl ester Hydrochloride 3- (6-Methyl-2 -naphthyl) alanine benzyl ester
Stell hydrochloride 3- (4-biphenyl) alanine benzyl ester hydrochloride
Salt 3- (3-trifluoromethylphenyl) alanine ben
Dil ester hydrochloride 3- (4-isopropylphenyl) alanine benzyl ether
Stell hydrochloride 3- (4-nitrophenyl) alanine benzyl ester
Hydrochloride

Reference Example 7 3- (3-Bromophenyl) alanine methyl ester salt
3 obtained in the same manner as Step 1 and Step 2 of Acid Reference Example 6
4 g of (3-bromophenyl) alanine hydrochloride (14.2
6 mM) was methyl-esterified in the same manner as in Reference Example 3 to obtain 4.16 g (yield 99.0%). Melting point: 162-163 ° C (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 3.09-3.24 (m, 2H),
3.69 (s, 3H), 4.31 (t, 1H, J = 6.60Hz), 7.24-7.33 (m, 2H), 7.4
7-7.51 (m, 2H), 8.73 (bs, 3H) I. R. ν _KBr cm ^-1 : 3050,2800,1750,1570,1500,122
0,1070,860,780,700

The following compounds were obtained in the same manner as in Reference Example 7. 3- (4-bromophenyl) alanine methyl ester salt
Salt 3- (3,4-dichlorophenyl) alanine methyl es
Terhydrochloride 3- (4-nitrophenyl) alanine methyl ester salt
Acid salt 3-[(2-chloro-4-methyl) phenyl] alanine
Methyl ester hydrochloride 3- (4-methylsulfonylphenyl) alanine methyl
Ester hydrochloride

Reference Example 8 3- (2-benzylphenyl) alanine benzyl ester
Hydrochloride Step 1 Diethyl (acetylamino) [(2-benzylphenyl
1.4 g (7.0 ) of methyl] propanedioate 2- (benzyl) benzyl alcohol
(6 mM) and 2 ml (14.1 mM) of triethylamine in 30 ml of anhydrous methylene chloride, while cooling with ice water, 1.1 ml (14.1 mM) of methanesulfonyl chloride was added dropwise in 5 ml of methylene chloride. After completion of dropping, the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with saturated sodium hydrogen carbonate, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give mesylate.

Then, 370 mg (7.77 mM) of 50% sodium hydride was added little by little to 70 ml of absolute ethanol, and then 1.69 g of diethyl acetamide malonate.
(7.77 mM) was added, and the mixture was stirred at room temperature for 10 minutes. Further, the mesylate obtained above was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained concentrated residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to dryness. The obtained concentrated residue was purified by silica gel column chromatography (eluent: benzene / ethyl acetate = 9/1) to give 1.25 g of diethyl (acetylamino) [(2-benzylphenyl) methyl] propanedioate ( Yield 44.5%). Melting point: 125-127 ° C N.V. M. R. (CDCl ₃ ) δ: 1.27 (t, 6H, J = 7.08Hz),
1.94 (s, 3H), 3.73 (s, 2H), 3.93 (s, 2H), 4.15-4.35 (m, 4H),
6.61 (bs, 1H), 6.98-7.01 (m, 1H), 7.05-7.19 (m, 6H), 7.22-
7.28 (m, 2H) I. R. ν _KBr cm ^-1 : 3230,2980,2970,1750,1640,153
0,1320,1280,1230,1205,1195,1085,1060

Step 2 3- (2-Benzylphenyl) alanine hydrobromide diethyl (acetylamino) [(2-benzylphenyl) methyl] propanedioate 1.24 g (3.12)
12 ml of 48% hydrobromic acid aqueous solution was added to
Heated to reflux for an hour. After cooling, the reaction solution was concentrated under reduced pressure. By washing the obtained crystals with ether, 3- (2-
Benzylphenyl) alanine hydrobromide 0.91 g
(Yield 86.8%) was obtained. Melting point: 239-240 ° C (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 3.01-3.17 (m, 2H),
3.99-4.03 (m, 3H), 7.13-7.33 (m, 9H), 8.35 (bs, 2H), 13.77
(br, 1H) I. R. ν _KBr cm ^-1 : 3020,2930,1760,1570,1505,145
5,1190,1130,1110,760

Step 3 3- (2-benzylphenyl) alanine benzyl ester
In the same manner as in Reference Example 4, 0.9 g (2.68 mM) of 3- (2-benzylphenyl) alanine hydrobromide hydrochloride was used as BO.
0.96 g (yield 93.4%) of 3- (2-benzylphenyl) alanine benzyl ester hydrochloride was obtained by C-forming, benzyl esterifying, and de-BOCing. Melting point: 152-154 ° C N.V. M. R. (DMSO-d ₆ ) δ: 3.07 (dd, 1H, J = 13.
92,9.16Hz), 3.24 (dd, 1H, J = 13.92,6.23Hz), 3.98 (s, 2H),
4.12 (dd, 1H, J = 9.16,6.23Hz), 4.99 (d, 1H, J = 12.46Hz), 5.1
1 (d, 1H, J = 12.45Hz), 7.08-7.11 (m, 2H), 7.14-7.29 (m, 9H),
7.31-7.36 (m, 3H), 8.75 (bs, 3H) I. R. ν _KBr cm ^-1 : 3030,1740,1495,1250,1225,75
0,735,700

The following compounds were obtained in the same manner as in Reference Example 8. 3- (1-naphthyl) alanine benzyl ester hydrochloride 3- (2-pyridyl) alanine benzyl ester hydrochloride 3- (4-methylthiophenyl) alanine benzyl ester
Telluric hydrochloride 3- (4-n-butylphenyl) alanine benzyl ester
Ter hydrochloride 3- (3-thienyl) alanine benzyl ester hydrochloride Also, the alanine derivative obtained by the same method as in Step 2 of Reference Example 8 was methyl esterified by the same method as in Reference Example 3 to give the following compound. The compound was obtained. 3-[(5-chloro-2-nitro) phenyl] alanine
Methyl ester hydrochloride 3-[(5-bromo-2-methoxy) phenyl] alani
Methyl ester hydrochloride 3- [2-[(4-bromophenyl) thio] phenyl]
Alanine methyl ester hydrochloride 3- (4-methylthiophenyl) alanine methyl ester
Hydrochloride 3- (2-Methylthiophenyl) alanine methyl ester
Hydrochloride

Reference Example 9 3- (6-Methoxy-2-naphthyl) alaninebenzyl
Ester Hydrochloride Step 1 2-Acetamide-3- (6-methoxy-2-naphthyl)
5.0 g of 6-methoxy-2-naphthopropenoic acid (26.
9 mM) in a mixed solution of 15 ml of acetic anhydride, 2.42 g (29.5 mM) of anhydrous sodium acetate and 3.4 of acetylglycine.
6 g (29.5 mM) was added and the mixture was heated under reflux for 2 hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and washed with water. 30 ml of acetone and 10 ml of water were added to the obtained crystals, and the mixture was heated under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crystals were washed with water and then recrystallized from methanol to give 2.37 g of 2-acetamido-3- (6-methoxy-2-naphthyl) propenoic acid (yield 30.9%). )Obtained. Melting point: 235-236 ° C (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 2.03 (s, 3H), 3.89
(s, 3H), 7.18 (dd, 1H, J = 9.28,2.44Hz), 7.31-7.35 (m, 2H),
7.71-7.74 (m, 1H), 7.79-7.85 (m, 2H), 8.06 (s, 1H), 9.51 (s,
1H), 12.61 (br, 1H) I. R. ν _KBr cm ^-1 : 3280,2950,1695,1625,1525,125
5,1235,1185 MS-FAB (MNBA): m / z 286 (MH ⁺ ).

Step 2 N-acetyl-3- (6-methoxy-2-naphthyl) a
Lanine 2-acetamido-3- (6-methoxy-2-naphthyl)
Propenoic acid 1.5 g (5.26 mM) ethanol 30
300 ml of 5% palladium on carbon solution in a nitrogen atmosphere
After adding g, the mixture was stirred under hydrogen substitution at room temperature for 24 hours.
After the reaction was completed, palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The crystals obtained were washed with ether to give N
1.18 g (yield 78.1%) of -acetyl-3- (6-methoxy-2-naphthyl) alanine was obtained. Melting point: 203-205 ° C N.V. M. R. (DMSO-d ₆ ) δ: 1.77 (s, 3H), 2.96
(dd, 1H, J = 13.67,9.28Hz), 3.17 (dd, 1H, J = 13.67,5.37Hz),
3.86 (s, 3H), 4.42-4.51 (m, 1H), 7.12 (dd, 1H, J = 8.79,2.44H
z), 7.26 (d, 1H, J = 2.44Hz), 7.34 (dd, 1H, J = 8.30,1.47Hz),
7.63 (s, 1H), 7.70-7.75 (m, 2H), 8.15 (d, 1H, J = 8.30Hz) I. R. ν _KBr cm ^-1 : 3330,2930,1715,1630,1610,156
0,1260,1240,1035 MS-FAB (gly): m / z 288 (MH ⁺ ).

Step 3 3- (6-Hydroxy-2-naphthyl) alanine hydrochloride N-Acetyl-3- (6-methoxy-2-naphthyl) alanine 1.16 g (4.04 mM) 4N-hydrochloric acid 12 m
The mixture was heated to reflux for 16 hours. The reaction solution is concentrated under reduced pressure,
The crystals obtained are washed with ether and dried to give 3
1.06 g (yield 98.1%) of-(6-hydroxy-2-naphthyl) alanine hydrochloride was obtained. Melting point: 246-247.5 ° C. (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 3.25 (d, 2H, J = 6.35
Hz), 4.20 (t, 1H, J = 6.35Hz), 7.08-7.12 (m, 2H), 7.31 (dd, 1
H, J = 8.79,1.46Hz), 7.63-7.70 (m, 3H), 8.45 (bs, 2H), 9.81
(bs, 1H) I. R. ν _KBr cm ^-1 : 3320,2930,1720,1610,1520,149
0,1400,1290,1240,1220 MS-FAB (gly): m / z 232 (MH ⁺ -HC
l)

Step 4 3- (6-Methoxy-2-naphthyl) alaninebenzyl
Ester hydrochloride 3- (6-hydroxy-2-naphthyl) alanine hydrochloride was converted into BOC, benzyl ester, methoxy and de-BOC in the same manner as in Reference Example 4 to give 3- (6-
0.945 g (yield 65.4%) of methoxy-2-naphthyl) alanine benzyl ester hydrochloride was obtained. Melting point: 193-195 ° C N.V. M. R. (DMSO-d ₆ ) δ: 3.19-3.27 (m, 1H),
3.30-3.38 (m, 1H), 3.88 (s, 3H), 4.39-4.44 (m, 1H), 5.14 (s,
2H), 7.14-7.18 (m, 3H), 7.22-7.34 (m, 5H), 7.63 (s, 1H), 7.6
9-7.76 (m, 2H), 8.66 (br, 3H) I. R. ν _KBr cm ^-1 : 3000,2940,1740,1610,1500,125
0,1240,1200,1035,860,750

Reference Example 10 3- (4-Benzyloxycarbonylphenyl) alanine
Benzyl ester hydrochloride step 1 diethyl (acetylamino) [(4-cyanophenyl)
Methyl] propanedioate 4-cyanobenzyl bromide 2.0 g (10.2 m
M) in the same manner as in Step 1 of Reference Example 6 with diethyl (acetylamino) [(4-cyanophenyl) methyl].
2.02 g (yield 59.6%) of propanedioate was obtained. Melting point: 166-168 ° C N.V. M. R. (CDCl ₃ ) δ: 1.30 (t, 6H, J = 7.33Hz),
2.03 (s, 3H), 3.73 (s, 2H), 4.19-4.36 (m, 4H), 6.53 (bs, 1H),
7.12 (d, 2H, J = 8.79Hz), 7.56 (d, 2H, J = 8.43Hz) I. R. ν _KBr cm ^-1 : 3240,2980,2230,1750,1645,152
0,1300,1275,1220,1210

Step 2 3- (4-Benzyloxycarbonylphenyl) alanine
Benzyl ester hydrochloride diethyl (acetylamino) [(4-cyanophenyl)
Methyl] propanedioate 2.0 g (6.02 mM)
In the same manner as in Step 2 of Reference Example 6 to give 3- (4-carboxyphenyl) alanine benzyl ester hydrochloride,
In the same manner as in Reference Example 4, BOC conversion, benzyl ester conversion,
By de-BOC-ized, 1.80 g (yield 62.5%) of 3- (4-benzyloxycarbonylphenyl) alanine benzyl ester hydrochloride was obtained. Melting point: 177-179 ° C N.V. M. R. (DMSO-d ₆ ) δ: 3.24 (dd, 1H, J = 13.
92,8.06Hz), 3.36-3.41 (m, 1H), 4.47 (dd, 1H, J = 8.06,5.50H
z), 5.20 (s, 2H), 5.45 (s, 2H), 7.19-7.58 (m, 12H), 7.97 (d, 2
H, J = 8.06Hz), 8.82 (bs, 3H) I. R. ν _KBr cm ^-1 : 3150,3025,3000,2850,2800,174
0,1720,1495,1405,1280,1230,1105 MS-FAB (gly): m / z 390 (MH ⁺ -HC
l)

Reference Example 11 3- (4-biphenyl) -L-alanine benzyl ester
Hydrochloride Step 1 N- (t-butoxycarbonyl) -3- [4- (trif
Luoromethanesulfonyloxy) phenyl] -L-alani
N- (t-butoxycarbonyl) -3- (4-hydroxyphenyl) -L-alanine benzyl ester obtained in the same manner as in Reference Example 4 from 5 g of benzyl ester (L) -tyrosine.
2 g (8.62 mM), anhydrous pyridine 2.1 g (26.
2.5 ml of trifluoromethanesulfonic anhydride (8.86 m) in 50 ml of anhydrous methylene chloride (5 mM) at 0 ° C.
M) was gradually added dropwise. After the completion of dropping, the mixture was stirred at 0 ° C for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (eluent: n
4.15 g of N- (t-butoxycarbonyl) -3- [4- (trifluoromethanesulfonyloxy) phenyl] -L-alanine benzyl ester by purification with -hexane / ethyl acetate = 9/1 (yield) Rate 95.7%)
Obtained. Melting point: 58-59 ° C N.V. M. R. (CDCl ₃ ) δ: 1.41 (s, 9H), 3.00-3.19
(m, 2H), 4.58-4.67 (m, 1H), 5.01-5.05 (m, 1H), 5.08 (d, 1H, J
= 11.97Hz), 5.19 (d, 1H, J = 11.97Hz), 7.10 (s, 4H), 7.30-7.3
8 (m, 5H) I. R. ν _KBr cm ^-1 : 3350,2975,1720,1500,1430,122
0,1140,1020,900,750,700

Step 2 N- (t-butoxycarbonyl) -3- (4-biphenyl)
L) -L-alanine benzyl ester N- (t-butoxycarbonyl) -3- [4- (trifluoromethanesulfonyloxy) phenyl] -L-alanine benzyl ester 3.98 g (7.9 mM), phenylboronic acid 2 After stirring a suspension of 0.0 g (16.4 mM) and 1.7 g (12.3 mM) of anhydrous potassium carbonate in 60 ml of anhydrous toluene at room temperature for 30 minutes, 600 mg (0.52 mM) of tetrakis (triphenylphosphine) palladium was added.
Was added and the mixture was heated with stirring at 80 to 90 ° C. for 3 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and water in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (eluent: benzene / ethyl acetate = 19/1) to give N- (t-butoxycarbonyl) -3- (4-biphenyl) -L-alanine benzyl ester. 3.1 g (yield 90.9%) was obtained. Melting point: 97-98 ° C N.V. M. R. (CDCl ₃ ) δ: 1.42 (s, 9H), 3.12 (d, 2
H, J = 5.47Hz), 4.65-4.70 (m, 1H), 5.03-5.06 (m, 1H), 5.11
(d, 1H, J = 12.20Hz), 5.18 (d, 1H, J = 12.20Hz), 7.11 (d, 2H, J =
8.06Hz), 7.27-7.57 (m, 12H)

Step 3 3- (4-biphenyl) -L-alanine benzyl ester
Hydrochloride N- (t-butoxycarbonyl) -3- (4-biphenyl) -L-alanine benzyl ester 3.1 g (7.1
To a 20 ml solution of benzene (8 mM), 10 ml of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature for 3 hours. Ether was added to the reaction solution, and the mixture was stirred for 30 minutes and then filtered under reduced pressure to obtain 2.6 g (yield 98.0%) of 3- (4-biphenyl) -L-alanine benzyl ester hydrochloride. Melting point: 216-217 ° C. (decomposition) N.V. M. R. (DMSO-d ₆ ) δ: 3.14 (dd, 1H, J = 13.
92,7.69Hz), 3.21-3.31 (m, 1H), 4.37-4.40 (m, 1H), 5.20 (s,
2H), 7.23-7.67 (m, 14H), 8.72 (bs, 3H) I. R. ν _KBr cm ^-1 : 3150,2850,1750,1500,1410,138
0,1240,760,750,700 MS-FAB (gly): m / z 332 (MH ⁺ -HC
l) [α] _D = -19.30 ° (c = 1.0152, MeOH)

The following compounds were obtained in the same manner as in Reference Example 11. 3- (4-biphenyl) -D-alanine benzyl ester
Le hydrochloride 3- (4-biphenyl) -L- alanine ethyl ester
Hydrochloride 3- [4- (4-methylphenyl) phenyl] -L-a
Lanine ethyl ester hydrochloride

Reference Example 12 N-benzyl-3-phenyl-L-alanine methyl ester
Ter 3-phenyl-L-alanine methyl ester hydrochloride 1 g
A small amount of Molecular Sieves 3A and 470 mg of triethylamine in 20 ml of methanol (4.64 mM).
(4.64 mM) was added and the mixture was stirred for 30 minutes, then benzaldehyde (500 mg, 4.71 mM) was added at room temperature, and the mixture was stirred for 18 hours. 200 mg (5.29 mM) of sodium borohydride was gradually added to the reaction solution under ice-water cooling, followed by stirring at room temperature for 1 hour. The insoluble matter was filtered off, washed with methanol, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained concentrated residue was acidified with hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (eluent: benzene / ethyl acetate = 19/1 to 9/1) to give N-benzyl-3-phenyl-L-alanine methyl ester as an oily substance 1 .18 g (yield 9
4.5%) was obtained. N. M. R. (CDCl ₃ ) δ: 2.96 (d, 2H, J = 7.08Hz),
3.54 (t, 1H, J = 7.08Hz), 3.63 (d, 1H, J = 13.18Hz), 3.65 (s, 3
H), 3.81 (d, 1H, J = 13.18Hz), 7.14-7.36 (m, 10H) I. R. ν _NaCl cm ⁻¹ : 1740,1500,1460,1200,1170,74
0,700 MS-FAB (MNBA): m / z 270 (MH ⁺ ) [α] _D = −3.56 ° (c = 0.7300, MeOH)

The following compounds were obtained as in Reference Example 12. N-ethyl-3-phenyl-L-alanine methyl ester
Le N-ethyl-3-phenyl-L-alanine benzyl ester
Ter N-ethyl-3-phenyl-L-alanine ethyl ester
Le

Reference Example 13 3- [4- (acetamido) phenyl] alanine methyl ester
N- (t-butoxycarbonyl) was obtained by BOC-converting 3- (4-nitrophenyl) alanine methyl ester hydrochloride 1.0 g (3.04 mM) obtained in Stell hydrochloride in Reference Example 7 in the same manner as in Reference Example 4. ) -3- (4-Nitrophenyl) alanine methyl ester.

Next, 240 mg of 10% palladium carbon was added to a 12 ml methanol solution of BOC in a nitrogen atmosphere, and the mixture was stirred at room temperature for 24 hours under hydrogen substitution. After the reaction was completed, palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (eluent: benzene / ethyl acetate = 9/1) to give N- (t-butoxycarbonyl) -3.
9- (4-aminophenyl) alanine methyl ester
10 mg were obtained.

910 mg (3.09 m) of the obtained amino compound
M) and 0.24 ml (3.4 mM) of acetyl chloride were added dropwise to a solution of 0.47 ml (3.4 mM) of triethylamine in 10 ml of anhydrous methylene chloride while cooling with ice water. After completion of dropping, the reaction solution was concentrated under reduced pressure after stirring at room temperature for 30 minutes. The obtained concentrated residue was dissolved in ethyl acetate, washed with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By de-BOC-converting the obtained concentrated residue in the same manner as in Reference Example 3,
760 mg (yield 72.6%) of [4- (acetamido) phenyl] alanine methyl ester hydrochloride was obtained. Melting point: 214-215 ° C. (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 2.04 (s, 3H), 3.00-
3.16 (m, 2H), 3.68 (s, 3H), 4.22 (bs, 1H), 7.13 (d, 2H, J = 8.42
Hz), 7.55 (d, 2H, J = 8.43Hz), 8.60 (br, 3H), 10.06 (s, 1H) I. R. ν _KBr cm ^-1 : 3000,2920,1760,1745,1665,161
0,1555,1515

Reference Example 14 N- (benzyloxycarbonyl) -N- (diethoxyphosphine)
Sulfolylmethyl) -isobutylamine Method 1 Step 1 N- (benzyloxycarbonyl) isobutylamine Isobutylamine 5 g (68.4 mM) in 20 ml of water was added to 1N-sodium hydroxide while adjusting the pH to 8-9. 7 g (68.6 mM) was added dropwise at 5 to 10 ° C. After completion of dropping, the mixture was stirred at 5 to 10 ° C for 1 hour and further at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, washed with 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 10.77 g of N- (benzyloxycarbonyl) isobutylamine was obtained by purifying the obtained concentrated residue by silica gel column chromatography (eluent: benzene / ethyl acetate = 9/1).
(Yield 76%) was obtained. Melting point: 31-32 ° C N.V. M. R. (CDCl ₃ ) δ: 0.90 (d, 6H, J = 6.59Hz),
1.71-1.81 (m, 1H), 3.02 (t, 2H, J = 6.59Hz), 4.79 (bs, 1H), 5.
10 (s, 2H), 7.30-7.35 (m, 5H) I. R. ν _KBr cm ^-1 : 3320,2950,1700,1550,1460,128
0,1160,1020,750,700

Step 2 N- (benzyloxycarbonyl) -N- (hydroxyl
3. Cyl) isobutylamine N- (benzyloxycarbonyl) isobutylamine 4.
0 g (19.3 mM), 37% formaldehyde 14.
5 ml (0.19M), anhydrous potassium carbonate 2.80 g
A mixed solution of 50 ml of dioxane (20.3 mM) was heated under reflux for 2 hours. The reaction solution was cooled, diluted with ethyl acetate, and the organic layer was washed with water. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the obtained concentrated residue was subjected to silica gel column chromatography (eluent: benzene / ethyl acetate = 19/1).
N- (benzyloxycarbonyl) by purification with
-N- (hydroxymethyl) isobutylamine 2.8
2 g (yield 61.6%) was obtained. N. M. R. (CDCl ₃ ) δ: 0.89 (d, 6H, J = 6.86Hz),
1.85-1.97 (m, 1H), 3.18 (d, 2H, J = 6.96Hz), 4.78 (d, 2H, J = 7.
70Hz), 5.16 (s, 2H), 7.29-7.35 (m, 5H) I. R. ν _KBr cm ^-1 : 3450,2950,1700,1420,1250,116
0,1020

Step 3 N- (benzyloxycarbonyl) -N- (diethoxyphosphine
Suphorylmethyl) -isobutylamine N- (benzyloxycarbonyl) -N- (hydroxymethyl) isobutylamine 1.5 g (6.32 mM) in anhydrous methylene chloride solution was cooled with ice water to thionyl chloride 2.3.
After adding ml (31.6 mM), the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure to dryness and azeotroped with toluene.
To a solution of the concentrated residue in 15 ml of anhydrous toluene, 1.08 ml (6.32 mM) of triethyl phosphite was added, and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure to dryness, and the obtained concentrated residue was subjected to silica gel column chromatography (eluent:
Purification with n-hexane / acetone = 4/1) gave 1.07 g (yield 47.4%) of N- (benzyloxycarbonyl) -N- (diethoxyphosphorylmethyl) isobutylamine. N. M. R. (CDCl ₃ ) δ: 0.85-0.90 (m, 6H), 1.28
(t, 6H, J = 7.08Hz), 1.96 (br, 1H), 3.29 (d, 2H, J = 7.57Hz), 3.
72-3.79 (m, 2H), 4.08-4.14 (m, 4H), 5.15 (s, 2H), 7.35 (s, 5
H) I. R. ν _NaCl cm ^-1 : 2960,1700,1470,1430,1240,120
0,1055,1030,970

The following compounds were obtained in the same manner as in Method 1 of Reference Example 14. N- (benzyloxycarbonyl) -N- (diethoxyphoh
Sulfolylmethyl) -n-propylamine N- (benzyloxycarbonyl) -N- (diethoxyphoh
(Suphorylmethyl) -ethylamine

Method 2 Step 1 Hydroxymethylphosphonic acid diethyl ester Diethyl phosphite 3 g (21.7 mM), paraformaldehyde 660 mg (21.9 mM) and triethylamine 220 mg (2.2 mM) were mixed at 120 ° C. for 2-3 times.
The mixture was heated and stirred for an hour. After cooling, vacuum distillation (130-140
2.9 g (yield 80.0%) of hydroxymethylphosphonic acid diethyl ester was obtained by purification at (° C./4-5 mmHg). N. M. R. (CDCl ₃ ) δ: 1.35 (t, 6H, J = 6.96Hz),
2.26 (bs, 1H), 3.91 (d, 2H, J = 5.86Hz), 4.14-4.20 (m, 4H) I. R. ν _KBr cm ^-1 : 3400,2975,1650,1240,1030,97
0,810

Step 2 N- (benzyloxycarbonyl) -N- (diethoxyphosphine
Sforylmethyl) -isobutylamine hydroxymethylphosphonic acid diethyl ester 2.5 g
(14.9 mM), 1.3 g of anhydrous pyridine (16.4 m)
M) in 30 ml of anhydrous methylene chloride under a nitrogen atmosphere,
4.3 g of trifluoromethanesulfonic anhydride at 0-5 ° C
(15.2 mM) was gradually added dropwise. 0 ° C after dropping
It was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the obtained concentrated residue to separate the layers. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained triflate was dissolved in 20 ml of anhydrous methylene chloride, and diisopropylethylamine 2 g (15.5 mM) and isobutylamine 1.3 were added at 0 to 5 ° C under a nitrogen atmosphere.
5 g (18.46 mM) was sequentially added dropwise. After dropping,
Stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ether was added to the obtained concentrated residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 1.5 g of the obtained amino compound and triethylamine
(14.8 mM) in anhydrous methylene chloride (20 ml) at 0-5 ° C. under a nitrogen atmosphere.
g (14.9 mM) was added dropwise. After dropping, add 2
Stirred for hours. The reaction mixture was concentrated under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 9/1 to 1/1) to give N- (benzyloxycarbonyl) -N- (. Diethoxyphosphorylmethyl) isobutylamine 2.66
g (yield 50.0%) was obtained. Instrumental analysis was consistent with Method 1.

Reference Example 15 N- (dibenzyloxyphosphorylmethyl) isobutyla
Min Step 1 1,3,5-triisobutylhexahydro-1,3,5
Triazine isobutylamine 5 g (68.4 mM) ethyl acetate 1
To a mixed solution of 00 ml and 100 ml of water, 5.1 ml (68.4 mM) of 37% formaldehyde was added under ice-water cooling, and the mixture was stirred for 1 hour under ice-water cooling. The reaction solution was separated, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1,3,5-triisobutylhexahydro-1,3,5.
-5.4 g (yield 92.8%) of triazine was obtained. N. M. R. (CDCl ₃ ) δ: 0.89 (d, 18H, J = 6.59H
z), 1.69 (septet, 3H, J = 6.84Hz), 2.20 (d, 6H, J = 7.32Hz), 3.
27 (bs, 6H) I. R. ν _KBr cm ^-1 : 2960,2870,2790,1470,1460,138
0,1365,1210,1115,1015

Step 2 N- (dibenzyloxyphosphorylmethyl) isobutyla
Min 1,3,5-triisobutylhexahydro-1,3,5
-9 g of dibenzyl phosphite in a solution of 2.95 g (11.6 mM) of triazine in 30 ml of anhydrous toluene (34.
70 mM anhydrous toluene 20 ml solution was added to 70-80.
Stirred at C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 19/1) to give 7.12 g of N- (dibenzyloxyphosphorylmethyl) isobutylamine (yield. 59.1%) was obtained. N. M. R. (CDCl ₃ ) δ: 0.85 (d, 6H, J = 6.96Hz),
1.66 (septet, 1H, J = 6.60Hz), 2.42 (d, 2H, J = 6.96Hz), 2.98
(d, 2H, J = 11.72Hz), 5.02 (dd, 2H, J = 11.72,8.06Hz), 5.12 (d
d, 2H, J = 11.72,8.79Hz), 7.30-7.37 (m, 10H) I.D. R. ν _KBr cm ^-1 : 2960,1460,1240,1220,1000,73
5,695 MS-FAB (MNBA): m / z 348 (MH ⁺ ).

The following compounds were obtained as in Reference Example 15. N- (dibenzyloxyphosphorylmethyl) ethylamine N- (diethoxyphosphorylmethyl) isobutylamine N- (diethoxyphosphorylmethyl) ethylamine

Reference Example 16 N- (benzyloxycarbonyl)-[N- [ethoxy]
(4-Phenylbutyl) -phosphorylmethyl]] isobu
Cylamine Step 1 (4-phenylbutyl) phosphinic acid sodium hypophosphite monohydrate 2.7 g (25.47)
(mM) in a suspension of 27 ml of ethanol, 0.7 m of concentrated sulfuric acid
1,4-phenyl-1-butene 1.12 g (8.47 m
M), 2,2'-azobisisobutyronitrile (AIB
N) 140 mg (0.85 mM) was added, the mixture was heated under reflux for 6 hours, AIBN 90 mg (0.55 mM) was added, and the mixture was further heated under reflux for 16 hours. After cooling the reaction solution, the insoluble material was filtered off and washed with ethanol. The filtrate and washings were combined and concentrated under reduced pressure. The concentrated residue obtained was made basic with 4N sodium hydroxide and extracted with ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure (4
Phenylbutyl) phosphinic acid as crude product 1.3
g (yield 77%) was obtained. N. M. R. (CDCl ₃ ) δ: 1.55-1.83 (m, 6H), 2.60
-2.66 (m, 2H), 6.07 (s, 0.5H), 7.14-7.30 (m, 5H), 7.75 (s, 1
H), 8.08 (s, 0.5H)

Step 2 (4-Phenylbutyl) phosphinic acid ethyl ester (4-phenylbutyl) phosphinic acid 1.56 g (8.
47 mM), ethanol 430 mg (9.33 mM) in 20 ml of anhydrous THF at room temperature under a nitrogen atmosphere, and 1.95 g of dicyclohexylcarbodiimide (DCC) (9.
45 mM), dimethylaminopyridine (DMAP) 11
0 mg (0.9 mM) was added, and the mixture was stirred at room temperature for 2 hours.
50 ml of ethyl acetate was added to the reaction solution, the insoluble matter was filtered off,
After washing with ethyl acetate, the filtrate and washings were combined and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (eluent: chloroform / ethyl acetate = 19 /
By purifying in 1), 560 mg of (4-phenylbutyl) phosphinic acid ethyl ester was obtained as an oil (yield: 31.3% from 4-phenyl-1-butene). N. M. R. (CDCl ₃ ) δ: 1.35 (t, 3H, J = 6.96Hz),
1.55-1.85 (m, 6H), 2.64 (t, 2H, J = 7.14Hz), 3.99-4.25 (m, 2
H), 6.10 (s, 0.5H), 7.15-7.31 (m, 5H), 8.05 (s, 0.5H) I. R. ν _KBr cm ^-1 : 3450,2950,1500,1460,1220,103
0,960,700

Step 3 N- (benzyloxycarbonyl) -N- [ethoxy (4
-Phenylbutyl) phosphorylmethyl] isobutylami
Emissions obtained in Step 2 of Method 1 of Reference Example 14 N-(benzyloxycarbonyl) -N- anhydrous acetonitrile 1 (hydroxymethyl) isobutyl amine 1 g (4.22MM)
Trimethylsilyl bromide 1.3 in 5 ml solution at room temperature
A solution of g (8.19 mM) in 5 ml of anhydrous acetonitrile was added dropwise. After completion of the dropping, the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure to give N- (benzyloxycarbonyl) -N- (bromomethyl) isobutylamine.

On the other hand, to a solution of 950 mg (4.2 mM) of (4-phenylbutyl) phosphinic acid ethyl ester and 630 mg (6.23 mM) of triethylamine in 10 ml of anhydrous methylene chloride was added 680 mg (6.72 mM) of trimethylsilyl chloride under ice-cooling. After stirring for 10 minutes, the previously obtained N- (benzyloxycarbonyl)-
A solution of N- (bromomethyl) isobutylamine in 5 ml of anhydrous methylene chloride was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The obtained concentrated residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 19/1) to give N- (benzyloxycarbonyl)-.
710 mg of [N- [ethoxy (4-phenylbutyl) phosphorylmethyl]] isobutylamine as an oil.
(Yield 38%) was obtained. N. M. R. (CDCl ₃ ) δ: 0.93 (s, 6H), 1.32-1.36
(m, 3H), 1.62-1.78 (m, 6H), 2.03-2.08 (m, 1H), 2.60-2.68
(m, 2H), 3.22-3.35 (m, 2H), 3.67-3.86 (m, 2H), 4.07-4.15
(m, 2H), 5.19 (s, 2H), 7.24-7.40 (m, 10H) ¹³ C-N. M. R. (CDCl ₃ ) δ: 156.376,141.89
1,136.39,128.414,128.230,128.010,127.772,125.700,6
7.502,60.507 (d, J = 6.3Hz), 54.814,45.105 (d, J = 98.4Hz),
35.304,32.444 (d, J = 14.9Hz), 28.227,26.851,20.947,19.
829,16.584 (d, J = 5.0Hz) R. ν _NaCl cm ⁻¹ : 3450,2950,1700,1460,1420,126
0,1200,1040,960,860,750,700

Example 1 (1-1) 3-phenyl-N- [N-isobutyl-N- (dietoxy)
Ciphosphorylmethyl) carbamoyl] -L-alanine
Chill ester trichloromethyl chloroformate 430 mg (2.1
After adding 5 ml of anhydrous methylene chloride to (7 mM), 500 mg of L-phenylalanine ethyl ester hydrochloride (2.
18 mM, 450 mg of triethylamine (4.45 m)
A solution of M) in 20 ml of anhydrous methylene chloride was added dropwise under ice-water cooling. After completion of dropping, the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to dryness, and 490 mg (2.18 mM) of N- (diethoxyphosphorylmethyl) isobutylamine was added to a suspension of the obtained concentrated residue in 5 ml of anhydrous methylene chloride.
A solution of 230 mg (2.27 mM) of triethylamine in 5 ml of anhydrous methylene chloride was added dropwise under ice-water cooling. After completion of dropping, the mixture was further stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the obtained concentrated residue and the layers were separated. The organic layer was washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and water in this order, and dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The obtained concentrated residue is purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 9/1) to give 3-phenyl-N-.
750 mg (yield 77.9%) of [N-isobutyl-N- (diethoxyphosphorylmethyl) carbamoyl] -L-alanine ethyl ester was obtained as colorless crystals. Melting point: 36-39 ° C N.V. M. R. (CDCl ₃ ) δ: 0.83 (d, 3H, J = 6.59Hz),
0.85 (d, 3H, J = 6.59Hz), 1.22 (t, 3H, J = 6.96Hz), 1.30 (t, 3H,
J = 6.96Hz), 1.32 (t, 3H, J = 6.96Hz), 1.85-1.95 (m, 1H), 3.09
-3.19 (m, 4H), 3.63 (dd, 1H, J = 16.12,9.52Hz), 3.75 (dd, 1H,
J = 16.12,9.52Hz), 4.13 (q, 6H, J = 6.96Hz), 4.67 (dd, 1H, J = 1
3.56,6.23Hz), 5.47 (bs, 1H), 7.15-7.30 (m, 5H) I. R. ν _KBr cm ^-1 : 3300,2950,1740,1650,1540,139
0,1270,1210,1190,1020,980,830,700 [α] _D = -14.73 ° (c = 1.0136, MeOH)

The following compounds were obtained by the same method as in Example (1-1). (1-2) 3-phenyl-N- [N-ethyl-N- (diethoxyphoh
Suphorylmethyl) carbamoyl] -L-alanine ethyl
Ester yield 30.5% N.E. M. R. (CDCl ₃ ) δ: 1.08 (t, 3H, J = 7.08Hz),
1.23 (t, 3H, J = 7.08Hz), 1.29 (t, 3H, J = 7.08Hz), 1.31 (t, 3H,
J = 7.08Hz), 3.03-3.18 (m, 2H), 3.25-3.42 (m, 2H), 3.53-3.7
1 (m, 2H), 4.07-4.19 (m, 6H), 4.67 (dd, 1H, J = 13.42,6.10H
z), 5.55-5.58 (m, 1H), 7.15-7.31 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 3350,2975,1740,1660,1540,140
0,1240,1200,1030,980,760,710 [α] _D = -15.40 ° (c = 0.8204, MeOH)

(1-3) 3-phenyl-N- [N-isobutyl-N- (dibenzyl
Roxyphosphorylmethyl) carbamoyl] -L-alani
Methyl ester yield 71.6% N. M. R. (CDCl ₃ ) δ: 0.75 (d, 3H, J = 6.59Hz),
0.76 (d, 3H, J = 6.59Hz), 1.75-1.86 (m, 1H), 2.97-3.18 (m, 4
H), 3.66-3.74 (m, 5H), 4.65 (dd, 1H, J = 13.55,6.22Hz), 4.94
-5.08 (m, 4H), 5.42 (bs, 1H), 7.10-7.33 (m, 15H) I. R. ν _NaCl cm ⁻¹ : 3350,2950,1740,1650,1520,122
0,1000,740,700 [α] _D = -11.07 ° (c = 0.8860, MeOH)

(1-4) 3-phenyl-N- [N-isobutyl-N- (dibenz
Roxyphosphorylmethyl) carbamoyl] -L-alani
Ethyl ester yield 84.7% N. M. R. (CDCl ₃ ) δ: 0.76 (d, 3H, J = 6.59Hz),
0.77 (d, 3H, J = 6.59Hz), 1.21 (t, 3H, J = 7.08Hz), 1.79-1.84
(m, 1H), 2.97-3.03 (m, 2H), 3.06 (d, 2H, J = 6.35Hz), 3.61-3.
82 (m, 2H), 4.13 (q, 2H, J = 7.08Hz), 4.64 (dd, 1H, J = 13.43,6.
10Hz), 4.94-5.09 (m, 4H), 5.39 (bs, 1H), 7.10-7.36 (m, 15H) I. R. ν _NaCl cm ⁻¹ : 2975,1740,1680,1520,1460,139
0,1220,1010,740,700 [α] _D = -10.56 ° (c = 0.7726, MeOH)

(1-5) 3- (2-methylphenyl) -N- [N-isobutyl-
N- (diethoxyphosphorylmethyl) carbamoyl] a
Lanine benzyl ester yield 87.3% N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.84Hz),
0.83 (d, 3H, J = 6.84Hz), 1.30 (t, 6H, J = 7.08Hz), 1.89 (septe
t, 1H, J = 6.84Hz), 2.32 (s, 3H), 2.99-3.19 (m, 4H), 3.54-3.6
4 (m, 1H), 3.65-3.74 (m, 1H), 4.05-4.17 (m, 4H), 4.69 (dd, 1
H, J = 14.41,7.57Hz), 5.07 (d, 1H, J = 12.45Hz), 5.13 (d, 1H, J
= 12.45Hz), 5.71 (br, 1H), 7.04-7.08 (m, 2H), 7.11-7.13 (m,
2H), 7.20-7.24 (m, 2H), 7.29-7.33 (m, 3H) I. R. ν _NaCl cm ⁻¹ : 3330,2960,1750,1650,1540,123
5,1175,1055,1030,975,760

(1-6) 3- (3-methylphenyl) -N- [N-isobutyl-
N- (diethoxyphosphorylmethyl) carbamoyl] a
Lanine benzyl ester yield 77.1% N.V. M. R. (CDCl ₃ ) δ: 0.81 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.29 (t, 6H, J = 7.08Hz), 1.87 (septe
t, 1H, J = 6.84Hz), 2.26 (s, 3H), 3.01-3.17 (m, 4H), 3.62 (dd,
1H, J = 16.36,9.77Hz), 3.73 (dd, 1H, J = 16.36,9.28Hz), 4.05
-4.16 (m, 4H), 4.71 (dd, 1H, J = 13.43,6.10Hz), 5.08 (d, 1H, J
= 12.21Hz), 5.17 (d, 1H, J = 12.21Hz), 5.44 (br, 1H), 6.85-6.
90 (m, 2H), 7.02 (d, 1H, J = 7.56Hz), 7.11 (t, 1H, J = 7.56Hz),
7.27-7.35 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 2960,1750,1650,1530,1240,119
0,1170,1050,1030,970 MS-FAB (MNBA): m / z 519 (MH ⁺ ).

(1-7) 3- (4-methylphenyl) -N- [N-isobutyl-
N- (diethoxyphosphorylmethyl) carbamoyl] a
Lanine benzyl ester yield 89.6% N.V. M. R. (CDCl ₃ ) δ: 0.91 (d, 3H, J = 6.83Hz),
0.92 (d, 3H, J = 6.83Hz), 1.39 (t, 6H, J = 7.08Hz), 1.97 (septe
t, 1H, J = 6.84Hz), 2.39 (s, 3H), 3.11-3.28 (m, 4H), 3.71 (dd,
1H, J = 16.11,9.52Hz), 3.85 (dd, 1H, J = 16.36,9.28Hz), 4.15
-4.27 (m, 4H), 4.81 (dd, 1H, J = 13.68,6.11Hz), 5.18 (d, 1H, J
= 12.21Hz), 5.27 (d, 1H, J = 12.21Hz), 5.54 (br, 1H), 7.05 (d,
2H, J = 8.05Hz), 7.13 (d, 2H, J = 8.05Hz), 7.39-7.46 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 3320,2960,2930,2870,1750,166
0,1520,1460,1390,1280,1240,1190,1170,1050,1030,97
0,755

(1-8) 3- (4-isopropylphenyl) -N- [N-isobutane
Cyl-N- (diethoxyphosphorylmethyl) carbamoy
Lu] alanine benzyl ester yield 84.4% N.V. M. R. (CDCl ₃ ) δ: 0.78 (d, 3H, J = 6.59Hz),
0.79 (d, 3H, J = 6.59Hz), 1.21 (d, 6H, J = 6.84Hz), 1.22 (t, 6H,
J = 7.08Hz), 1.79-1.89 (m, 1H), 2.80-2.91 (m, 1H), 3.00-3.1
6 (m, 4H), 3.63 (dd, 1H, J = 16.11,9.52Hz), 3.75 (dd, 1H, J = 1
6.11,9.28Hz), 4.05-4.16 (m, 4H), 4.67-4.75 (m, 1H), 5.09
(d, 1H, J = 12.21Hz), 5.16 (d, 1H, J = 12.21Hz), 5.38 (br, 1H),
6.99 (d, 2H, J = 8.06Hz), 7.09 (d, 2H, J = 8.06Hz), 7.27-7.37
(m, 5H) I. R. ν _NaCl cm ⁻¹ : 3320,2960,1740,1650,1510,123
0,1180,1165,1050,1020,970,750

(1-9) 3- (4-n-butylphenyl) -N- [N-isobutyl
Ru-N- (diethoxyphosphorylmethyl) carbamoy
L] Alanine benzyl ester yield 70.7% N. M. R. (CDCl ₃ ) δ: 0.79 (d, 3H, J = 6.59Hz),
0.80 (d, 3H, J = 6.59Hz), 0.92 (t, 3H, J = 7.33Hz), 1.27-1.40
(m, 8H), 1.50-1.61 (m, 2H), 1.85 (septet, 1H, J = 6.83Hz), 2.
55 (t, 2H, J = 7.57Hz), 3.01-3.16 (m, 4H), 3.62 (dd, 1H, J = 16.
36,9.52Hz), 3.74 (dd, 1H, J = 16.36,9.28Hz), 4.06-4.16 (m,
4H), 4.71 (dd, 1H, J = 13.43,6.10Hz), 5.09 (d, 1H, J = 12.21H
z), 5.17 (d, 1H, J = 12.21Hz), 5.42 (br, 1H), 6.97 (d, 2H, J = 8.
06Hz), 7.03 (d, 2H, J = 8.06Hz), 7.26-7.35 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 3270,2950,2920,1750,1650,154
0,1210,1180,1030,970

(1-10) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Diethoxyphosphorylmethyl) carbamoyl] alani
Benzyl ester yield 66.0% N.V. M. R. (CDCl ₃ ) δ: 0.81 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.28 (t, 3H, J = 7.08Hz), 1.29 (t, 3H,
J = 7.08Hz), 1.81-1.97 (m, 1H), 3.03-3.17 (m, 4H), 3.57-3.7
9 (m, 2H), 4.05-4.18 (m, 4H), 4.77 (dd, 1H, J = 13.67,6.35H
z), 5.10 (d, 1H, J = 12.21Hz), 5.20 (d, 1H, J = 12.21Hz), 5.58
(br, 1H), 7.14 (d, 2H, J = 8.30Hz), 7.26-7.37 (m, 6H), 7.40-
7.46 (m, 4H), 7.52-7.56 (m, 2H) I. R. ν _NaCl cm ⁻¹ : 2950,1740,1650,1520,1490,139
0,1240,1190,1170,1055,1030,970,760

(1-11) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Diethoxyphosphorylmethyl) carbamoyl] -L-
Alanine benzyl ester yield 38.0% Melting point: 85-86 ° C N.V. M. R. (CDCl ₃ ) δ: 0.81 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.28 (t, 3H, J = 7.08Hz), 1.29 (t, 3H,
J = 7.08Hz), 1.86-2.04 (m, 1H), 3.03-3.17 (m, 4H), 3.62 (dd,
1H, J = 16.24,9.64Hz), 3.75 (dd, 1H, J = 16.24,9.15Hz), 4.05
-4.17 (m, 4H), 4.77 (dd, 1H, J = 13.55,6.22Hz), 5.10 (d, 1H, J
= 12.21Hz), 5.20 (d, 1H, J = 12.21Hz), 5.58 (br, 1H), 7.15 (d,
2H, J = 8.30Hz), 7.27-7.56 (m, 12H) I. R. ν _KBr cm ^-1 : 3275,2950,1740,1640,1540,121
0,1180,1030,980,860,820,760,730,690 [α] _D = -24.03 ° (c = 0.8720, MeOH)

(1-12) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Diethoxyphosphorylmethyl) carbamoyl] -D-
Alanine benzyl ester yield 71.1% Melting point: 76-77 ° C N.V. M. R. (CDCl ₃ ) δ: 0.81 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.28 (t, 3H, J = 7.08Hz), 1.29 (t, 3H,
J = 7.08Hz), 1.86-1.93 (m, 1H), 3.06-3.22 (m, 4H), 3.62 (dd,
1H, J = 16.11,9.52Hz), 3.75 (dd, 1H, J = 16.11,9.03Hz), 4.05
-4.17 (m, 4H), 4.77 (dd, 1H, J = 13.43,6.10Hz), 5.10 (d, 1H, J
= 12.21Hz), 5.19 (d, 1H, J = 12.21Hz), 5.59 (br, 1H), 7.14 (d,
2H, J = 8.30Hz), 7.27-7.56 (m, 12H) I. R. ν _KBr cm ^-1 : 3275,2950,1740,1640,1550,149
0,1420,1400,1220,1190,1040,980,760,740,700 [α] _D = + 22.16 ° (c = 1.2240, MeOH)

(1-13) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dibenzyloxyphosphorylmethyl) carbamoyl]-
L-alanine benzyl ester yield 37.3% N.V. M. R. (CDCl ₃ ) δ: 0.74 (d, 3H, J = 6.54Hz),
0.75 (d, 3H, J = 6.54Hz), 1.77-1.84 (m, 1H), 2.92-3.12 (m, 4
H), 3.60-3.82 (m, 2H), 4.70-4.78 (m, 1H), 4.93-5.20 (m, 6
H), 5.50 (bs, 1H), 7.09 (d, 2H, J = 8.31Hz), 7.26-7.44 (m, 20
H), 7.52 (d, 2H, J = 8.31Hz) I. R. ν _NaCl cm ⁻¹ : 2950,1740,1660,1520,1460,122
0,1000,890,760,700 [α] _D = -16.44 ° (c = 0.9110, MeOH)

(1-14) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dibenzyloxyphosphorylmethyl) carbamoyl]-
D-alanine benzyl ester yield 65.2% N.V. M. R. (CDCl ₃ ) δ: 0.74 (d, 3H, J = 6.59Hz),
0.75 (d, 3H, J = 6.59Hz), 1.78-1.85 (m, 1H), 2.98-3.12 (m, 4
H), 3.61-3.83 (m, 2H), 4.67-4.78 (m, 1H), 4.94-5.20 (m, 6
H), 5.50 (bs, 1H), 7.03-7.53 (m, 24H) I. R. ν _KBr cm ^-1 : 3350,2975,1750,1640,1540,121
0,1000,890,740,690 [α] _D = + 17.15 ° (c = 0.8900, MeOH)

(1-15) 3- [4- (4-methylphenyl) phenyl] -N-
[N-isobutyl-N- (dibenzyloxyphosphorylmeth
Cyl) carbamoyl] -L-alanine ethyl ester yield 79.3% N.V. M. R. (CDCl ₃ ) δ: 0.76 (d, 3H, J = 6.59Hz),
0.77 (d, 3H, J = 6.59Hz), 1.23 (t, 3H, J = 7.08Hz), 1.78-1.90
(m, 1H), 2.39 (s, 3H), 2.98-3.12 (m, 4H), 3.62-3.83 (m, 2H),
4.11-4.20 (m, 2H), 4.63-4.71 (m, 1H), 4.94-5.10 (m, 4H), 5.
45 (br, 1H), 7.16-7.47 (m, 18H) I. R. ν _NaCl cm ⁻¹ : 2950,1740,1650,1500,1380,124
0,1000,800,750,700 [α] _D = -11.84 ° (c = 0.91010, MeOH)

(1-16) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (diethoxyphosphorylmethyl) carbamoyl]
-L-alanine methyl ester yield 57.2% N.V. M. R. (CDCl ₃ ) δ: 0.83 (d, 3H, J = 6.59Hz),
0.84 (d, 3H, J = 6.59Hz), 1.31 (t, 3H, J = 7.08Hz), 1.33 (t, 3H,
J = 7.08Hz), 1.85-1.93 (m, 1H), 2.97-3.20 (m, 4H), 3.64-4.0
7 (m, 8H), 4.07-4.19 (m, 4H), 4.59-4.67 (m, 1H), 5.47 (bs, 1
H), 6.81 (d, 2H, J = 8.62Hz), 7.07 (d, 2H, J = 8.62Hz) ¹³ C-N. M. R. (CDCl ₃ ) δ: 172.951,158.42
9,157.201,130.118,128.212,113.708,62.404,62.304 (d,
J = 6.85Hz), 55.217,55.015,54.868,51.898,43.253 (d, J = 1
58.2Hz), 37.082, 26.924, 19.865, 19.810, 16.308, 16.235 I.I. R. ν _KBr cm ^-1 : 3400,2950,1740,1650,1520,125
0,1030,970,760,720 [α] _D = -17.25 ° (c = 1.070, MeOH)

(1-17) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (diethoxyphosphorylmethyl) carbamoyl]
Alanine benzyl ester yield 74.6% N.A. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.83 (d, 3H, J = 6.59Hz), 1.29 (t, 6H, J = 7.08Hz), 1.88 (septe
t, 1H, J = 6.84Hz), 3.02-3.18 (m, 4H), 3.61 (dd, 1H, J = 16.36,
9.52Hz), 3.71-3.80 (m, 4H), 4.05-4.17 (m, 4H), 4.66-4.73
(m, 1H), 5.08 (d, 1H, J = 12.21Hz), 5.18 (d, 1H, J = 12.21Hz),
5.46 (br, 1H), 6.74 (dd, 2H, J = 6.59,1.95Hz), 6.97 (dd, 2H, J
= 6.59,1.95Hz), 7.26-7.37 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 3320,2960,1750,1660,1515,125
0,1180,1030,970,760

(1-18) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (diethoxyphosphorylmethyl) carbamoyl]
-L-alanine benzyl ester yield 33.0% N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.83 (d, 3H, J = 6.59Hz), 1.31 (t, 6H, J = 7.08Hz), 1.86-1.91
(m, 1H), 3.04-3.13 (m, 4H), 3.61 (dd, 1H, J = 16.36,9.52Hz),
3.71-3.81 (m, 4H), 4.06-4.16 (m, 4H), 4.61-4.73 (m, 1H), 5.
08 (d, 1H, J = 12.20Hz), 5.18 (d, 1H, J = 12.20Hz), 5.47 (bs, 1
H), 6.74 (d, 2H, J = 8.55Hz), 6.97 (d, 2H, J = 8.55Hz), 7.28-7.
36 (m, 5H) I. R. ν _KBr cm ^-1 : 3450,2950,1750,1660,1520,144
0,1260,1180,1030,970,830,700 [α] _D = -17.97 ° (c = 1.040, MeOH)

(1-19) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (diethoxyphosphorylmethyl) carbamoyl]
-D-alanine benzyl ester yield 57.0% Melting point: 54-56 ° C N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.83 (d, 3H, J = 6.59Hz), 1.30 (t, 6H, J = 7.08Hz), 1.85-1.92
(m, 1H), 3.03-3.13 (m, 4H), 3.61 (dd, 1H, J = 16.35,9.52Hz),
3.71-3.80 (m, 4H), 4.05-4.17 (m, 4H), 4.69 (dd, 1H, J = 13.4
3,6.11Hz), 5.08 (d, 1H, J = 12.20Hz), 5.18 (d, 1H, J = 12.20H
z), 5.48 (bs, 1H), 6.75 (d, 2H, J = 8.55Hz), 6.97 (d, 2H, J = 8.5
5Hz), 7.28-7.36 (m, 5H) I. R. ν _KBr cm ^-1 : 3300,2950,1750,1650,1550,152
0,1260,1210,1180,1030,960,820,760,700 [α] _D = + 20.65 ° (c = 1.1460, MeOH)

(1-20) 3- (4-methoxyphenyl) -N- [Nn-propyne
Ru-N- (diethoxyphosphorylmethyl) carbamoy
L] -L-alanine benzyl ester yield 25.0% N.V. M. R. (CDCl ₃ ) δ: 0.83 (t, 3H, J = 7.33Hz),
1.29 (t, 6H, J = 6.96Hz), 1.46-1.55 (m, 2H), 3.03-3.09 (m, 2
H), 3.17-3.25 (m, 2H), 3.57-3.71 (m, 2H), 3.76 (s, 3H), 4.06
-4.16 (m, 4H), 4.68 (dd, 1H, J = 13.42,6.10Hz), 5.08 (d, 1H, J
= 12.33Hz), 5.18 (d, 1H, J = 12.33Hz), 5.50 (bs, 1H), 6.74 (d,
2H, J = 8.55Hz), 6.97 (d, 2H, J = 8.55Hz), 7.28-7.36 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 3350,2950,1750,1660,1520,146
0,1400,1260,1180,1040,960,760,700 [α] _D = -18.95 ° (c = 0.9740, MeOH)

(1-21) 3- (3,4-dimethoxyphenyl) -N- [N-iso
Butyl-N- (diethoxyphosphorylmethyl) carbamo
Il] alanine methyl ester yield 75.5% N.V. M. R. (CDCl ₃ ) δ: 0.84 (d, 3H, J = 6.59Hz),
0.85 (d, 3H, J = 6.59Hz), 1.27-1.38 (m, 6H), 1.83-1.98 (m, 1
H), 2.96-3.22 (m, 4H), 3.55-3.79 (m, 5H), 3.85 (s, 6H), 4.05
-4.21 (m, 4H), 4.59-4.68 (m, 1H), 5.52-5.63 (m, 1H), 6.66-
6.82 (m, 3H) I. R. ν _NaCl cm ⁻¹ : 3420,2950,1740,1650,1520,147
0,1400,1240,1160 MS-FAB (gly): m / z 489 (MH ⁺ ).

(1-22) 3- (4-n-butoxyphenyl) -N- [N-isobutane
Cyl-N- (diethoxyphosphorylmethyl) carbamoy
L] -L-alanine benzyl ester yield 62.4% N.V. M. R. (CDCl ₃ ) δ: 0.81 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 0.97 (t, 3H, J = 7.33Hz), 1.29 (t, 6H,
J = 7.08Hz), 1.48 (sextet, 2H, J = 7.33Hz), 1.71-1.80 (m, 2
H), 1.88 (sextet, 1H, J = 6.84Hz), 3.03-3.18 (m, 4H), 3.61 (d
d, 1H, J = 16.11,9.52Hz), 3.76 (dd, 1H, J = 16.11,9.28Hz), 3.
90 (t, 2H, J = 6.59Hz), 4.06-4.17 (m, 4H), 4.69 (dd, 1H, J = 13.
18,6.35Hz), 5.08 (d, 1H, J = 12.20Hz), 5.18 (d, 1H, J = 12.20H
z), 5.45 (br, 1H), 6.74 (d, 2H, J = 8.55Hz), 6.95 (d, 2H, J = 8.5
5Hz), 7.28-7.36 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 2960,1750,1660,1515,1250,118
0,1060,1030,970 MS-FAB (MNBA): m / z 577 (MH ⁺ ) [α] _D = -18.83 ° (c = 1.3212, MeOH)

(1-23) 3- (3-Bromophenyl) -N- [N-isobutyl-
N- (diethoxyphosphorylmethyl) carbamoyl] a
Lanine methyl ester yield 39.7% N.V. M. R. (CDCl ₃ ) δ: 0.85 (d, 3H, J = 6.59Hz),
0.86 (d, 3H, J = 6.59Hz), 1.32 (t, 3H, J = 7.08Hz), 1.33 (t, 3H,
J = 7.08Hz), 1.90-1.95 (m, 1H), 2.99-3.22 (m, 4H), 3.64-3.7
2 (m, 5H), 4.08-4.21 (m, 4H), 4.66 (dd, 1H, J = 12.94,6.84H
z), 5.71 (bs, 1H), 7.04-7.08 (m, 2H), 7.33-7.38 (m, 2H) I. R. ν _NaCl cm ⁻¹ : 3325,2950,1740,1650,1530,144
0,1390,1220,1030,860,760

(1-24) 3- (3-Bromophenyl) -N- [N-isobutyl-
N- [ethoxy (4-phenylbutyl) phosphoryl methyl
Lu] carbamoyl] alanine methyl ester yield 39.3% N.V. M. R. (CDCl ₃ ) δ: 0.83-0.88 (m, 6H), 1.24
-1.32 (m, 3H), 1.69-1.93 (m, 7H), 2.60-2.66 (m, 2H), 3.03-
3.24 (m, 4H), 3.41-3.58 (m, 1H), 3.65-3.74 (m, 4H), 4.03-4.
14 (m, 2H), 4.62-4.69 (m, 1H), 5.65 (bs, 1H), 7.06-7.37 (m, 9
H) I. R. ν _NaCl cm ⁻¹ : 3300,2950,1750,1640,1540,120
0,1040,960,860,760,700 MS-FAB (MNBA): m / z 595,597 (MH ⁺ ).

(1-25) 3- (3-bromophenyl) -N- [Nn-propyl
-N- (diethoxyphosphorylmethyl) carbamoyl]
Alanine methyl ester yield 37.2% Melting point: 85-86 ° C N.V. M. R. (CDCl ₃ ) δ: 0.86 (t, 3H, J = 7.32Hz),
1.32 (t, 3H, J = 7.08Hz), 1.33 (t, 3H, J = 7.08Hz), 1.51-1.59
(m, 2H), 2.98-3.32 (m, 4H), 3.60-3.64 (m, 2H), 3.72 (s, 3H),
4.09-4.21 (m, 4H), 4.65 (dd, 1H, J = 12.94,6.84Hz), 5.76 (b
s, 1H), 7.08-7.19 (m, 2H), 7.33-7.38 (m, 2H) I.s. R. ν _KBr cm ^-1 : 3300,2975,1760,1640,1540,148
0,1450,1400,1240,1180,1040,990,960,830,780,700

(1-26) 3- (4-bromophenyl) -N- [N-isobutyl-
N- (diethoxyphosphorylmethyl) carbamoyl] a
Lanine methyl ester yield 64.4% N.V. M. R. (CDCl ₃ ) δ: 0.85 (d, 3H, J = 6.59Hz),
0.86 (d, 3H, J = 6.59Hz), 1.31 (t, 3H, J = 7.08Hz), 1.32 (t, 3H,
J = 7.08Hz), 1.91 (septet, 1H, J = 6.84Hz), 3.01 (dd, 1H, J = 1
3.92,6.60Hz), 3.08-3.20 (m, 3H), 3.59 (dd, 1H, J = 16.36,9.
77Hz), 3.65-3.98 (m, 4H), 4.06-4.20 (m, 4H), 4.66 (dd, 1H, J
= 13.18,6.59Hz), 5.67 (br, 1H), 7.04 (d, 2H, J = 8.30Hz), 7.4
0 (d, 2H, J = 8.06Hz) I. R. ν _NaCl cm ⁻¹ : 3230,2960,1750,1650,1540,149
5,1230,1060,1030,980,760 MS-FAB (MNBA): m / z 507,509 (MH ⁺ ).

(1-27) 3- (3,4-dichlorophenyl) -N- [N-isobutane
Cyl-N- (diethoxyphosphorylmethyl) carbamoy
Lu] alanine methyl ester yield 54.9% Melting point: 59-62 ° C N.V. M. R. (CDCl ₃ ) δ: 0.86 (d, 3H, J = 6.59Hz),
0.87 (d, 3H, J = 6.59Hz), 1.32 (t, 3H, J = 7.08Hz), 1.33 (t, 3H,
J = 7.08Hz), 1.93 (septet, 1H, J = 6.84Hz), 2.97-3.22 (m, 4
H), 3.62-3.67 (m, 2H), 3.73 (s, 3H), 4.08-4.21 (m, 4H), 4.66
(dd, 1H, J = 12.70,6.84Hz), 5.85 (br, 1H), 7.02 (dd, 1H, J = 8.
30,2.20Hz), 7.28 (d, 1H, J = 2.20Hz), 7.34 (d, 1H, J = 8.30Hz) I. R. ν _KBr cm ^-1 : 3270,2950,1755,1640,1545,120
5,1180,1060,1035,980

(1-28) 3-[(3-chloro-4-methyl) phenyl] -N-
[N-isobutyl-N- (diethoxyphosphoryl methyl
) Carbamoyl] alanine methyl ester yield 50.2% Melting point: 72.5-74 ° C N.V. M. R. (CDCl ₃ ) δ: 0.84 (d, 3H, J = 6.59Hz),
0.85 (d, 3H, J = 6.59Hz), 1.26-1.37 (m, 6H), 1.82-1.98 (m, 1
H), 2.33 (s, 3H), 2.95-3.20 (m, 4H), 3.61-3.74 (m, 5H), 4.06
-4.22 (m, 4H), 4.60-4.68 (m, 1H), 5.55-5.72 (m, 1H), 6.68-
6.97 (m, 1H), 7.01-7.06 (m, 1H), 7.23 (d, 1H, J = 8.06Hz) I. R. ν _KBr cm ^-1 : 3400,3300,2950,1750,1640,155
0,1440,1400,1200,1060,1030 MS-FAB (gly): m / z 476,478 (MH ⁺ ).

(1-29) 3-[(5-Bromo-2-methoxy) phenyl] -N-
[N-isobutyl-N- (diethoxyphosphoryl methyl
Le) Carbamoyl] alanine methyl ester yield 90.6% Melting point: 134-137 ° C N.V. M. R. (CDCl ₃ ) δ: 0.86 (d, 6H, J = 6.96Hz),
1.29 (t, 3H, J = 6.96Hz), 1.31 (t, 3H, J = 6.96Hz), 1.85-2.01
(m, 1H), 2.96-3.22 (m, 4H), 3.55-3.77 (m, 5H), 3.82 (s, 3H),
4.06-4.20 (m, 4H), 4.53-4.63 (m, 1H), 5.63-5.74 (m, 1H), 6.
73 (d, 1H, J = 8.79Hz), 7.25 (d, 1H, J = 2.56Hz), 7.31 (dd, 1H, J
= 8.79,2.56Hz) I. R. ν _KBr cm ^-1 : 3350,2940,1750,1640,1550,150
0,1440,1220,1060,1035

(1-30) 3- (2-benzylphenyl) -N- [N-isobutyl
-N- (diethoxyphosphorylmethyl) carbamoyl]
Alanine benzyl ester yield 79.2% Melting point: 81-83 ° C N.V. M. R. (CDCl ₃ ) δ: 0.83 (d, 6H, J = 6.59Hz),
1.28 (t, 3H, J = 7.08Hz), 1.29 (t, 3H, J = 7.08Hz), 1.82-1.98
(m, 1H), 2.94-3.20 (m, 4H), 3.54-3.74 (m, 2H), 3.96-4.17
(m, 6H), 4.63-4.71 (m, 1H), 5.06 (d, 1H, J = 12.20Hz), 5.12
(d, 1H, J = 12.20Hz), 5.70 (br, 1H), 7.04-7.23 (m, 11H), 7.28
-7.32 (m, 3H) I. R. ν _KBr cm ^-1 : 3330,2950,1750,1650,1540,121
0,1190,1055,1030,975

(1-31) 3- [4- (ethoxycarbonylmethoxy) phenyl]
-N- [N-isobutyl-N- (diethoxyphosphoryl
Methyl) carbamoyl] -L-alanine benzyl ester
Le yield 79.8% N. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.83 (d, 3H, J = 6.59Hz), 1.30 (t, 9H, J = 7.08Hz), 1.89 (septe
t, 1H, J = 6.84Hz), 2.98-3.18 (m, 4H), 3.60 (dd, 1H, J = 16.11,
9.52Hz), 3.74 (dd, 1H, J = 16.11,9.52Hz), 4.06-4.17 (m, 4
H), 4.27 (q, 2H, J = 7.08Hz), 4.56 (s, 2H), 4.69 (dd, 1H, J = 13.
19,5.86Hz), 5.07 (d, 1H, J = 12.21Hz), 5.18 (d, 1H, J = 12.21H
z), 5.53 (br, 1H), 6.75 (d, 2H, J = 8.55Hz), 6.97 (d, 2H, J = 8.5
5Hz), 7.27-7.36 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 2960,1750,1660,1520,1200,113
0,970,760 MS-FAB (MNBA): m / z 607 (MH ⁺ ) [α] _D = -17.16 ° (c = 0.990, MeOH)

(1-32) 3- [4- (benzyloxy) phenyl] -N- [N-i
Sobutyl-N- (diethoxyphosphorylmethyl) carba
Moyl] -L-alanine benzyl ester yield 28.7% N.V. M. R. (CDCl ₃ ) δ: 0.81 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.29 (t, 6H, J = 7.08Hz), 1.82-1.94
(m, 1H), 3.04-3.19 (m, 4H), 3.56-3.79 (m, 2H), 4.04-4.17
(m, 4H), 4.70 (dd, 1H, J = 13.18,6.10Hz), 5.01 (s, 2H), 5.07
(d, 1H, J = 12.20Hz), 5.18 (d, 1H, J = 12.20Hz), 5.47 (bs, 1H),
6.82 (d, 2H, J = 8.54Hz), 6.96 (d, 2H, J = 8.54Hz), 7.28-7.43
(m, 10H) I. R. ν _NaCl cm ⁻¹ : 2950,1750,1660,1520,1460,139
0,1240,1180,1030,980,760,700 [α] _D = -18.55 ° (c = 0.8964, MeOH)

(1-33) 3- [4- (benzyloxy) phenyl] -N- [N-i
Sobutyl-N- (diethoxyphosphorylmethyl) carba
Moyl] -L-alanine ethyl ester yield 86.6% N.I. M. R. (CDCl ₃ ) δ: 0.83 (d, 3H, J = 6.59Hz),
0.84 (d, 3H, J = 6.59Hz), 1.22 (t, 3H, J = 7.33Hz), 1.30 (t, 3H,
J = 7.08Hz), 1.31 (t, 3H, J = 7.08Hz), 1.90 (septet, 1H, J = 6.8
4Hz), 2.98-3.19 (m, 4H), 3.63 (dd, 1H, J = 16.36,9.52Hz), 3.
76 (dd, 1H, J = 16.36,9.28Hz), 4.06-4.19 (m, 6H), 4.62 (dd, 1
H, J = 13.43,6.11Hz), 5.03 (s, 2H), 5.45 (br, 1H), 6.88 (d, 2
H, J = 8.55Hz), 7.07 (d, 2H, J = 8.55Hz), 7.30-7.44 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 2960,1740,1650,1510,1240,119
0,1050,1020,970 MS-FAB (MNBA): m / z 549 (MH ⁺ ) [α] _D = -14.44 ° (c = 1.006, MeOH)

(1-34) 3- [4- (benzyloxy) phenyl] -N- [N-i
Sobutyl-N- (dibenzyloxyphosphorylmethyl) carb
Lubamoyl] -L-alanine benzyl ester yield 67.4% N.V. M. R. (CDCl ₃ ) δ: 0.74 (d, 3H, J = 6.59Hz),
0.75 (d, 3H, J = 6.59Hz), 1.75-1.85 (m, 1H), 2.91-3.08 (m, 4
H), 3.64 (dd, 1H, J = 16.12,9.28Hz), 3.73-3.82 (m, 1H), 4.63
-4.70 (m, 1H), 4.93-5.08 (m, 7H), 5.16 (d, 1H, J = 12.21Hz),
5.41 (br, 1H), 6.76-6.80 (m, 2H), 6.92 (d, 2H, J = 8.54Hz), 7.
26-7.41 (m, 20H) I. R. ν _NaCl cm ⁻¹ : 2960,1740,1650,1510,1455,124
0,1175,1000,750 MS-FAB (MNBA): m / z 735 (MH ⁺ ) [α] _D = -13.13 ° (c = 1.014, MeOH)

(1-35) 3- [2- (methylthio) phenyl] -N- [N-iso
Butyl-N- (diethoxyphosphorylmethyl) carbamo
Il] alanine methyl ester yield 84.9% N.V. M. R. (CDCl ₃ ) δ: 0.83 (d, 3H, J = 6.59Hz),
0.84 (d, 3H, J = 6.59Hz), 1.27 (t, 3H, J = 7.08Hz), 1.30 (t, 3H,
J = 7.08Hz), 1.92 (septet, 1H, J = 6.84Hz), 2.47 (s, 3H), 3.03
-3.28 (m, 4H), 3.60 (dd, 1H, J = 16.36,9.52Hz), 3.71-3.81
(m, 4H), 4.02-4.17 (m, 4H), 4.63-4.71 (m, 1H), 5.64 (br, 1
H), 7.06-7.12 (m, 1H), 7.16-7.24 (m, 3H) I. R. ν _NaCl cm ⁻¹ : 3330,2980,2950,1740,1640,154
0,1440,1205,1195,1180,1020,980,755

(1-36) 3- [4- (methylthio) phenyl] -N- [N-iso
Butyl-N- (diethoxyphosphorylmethyl) carbamo
Il] alanine methyl ester yield 78.1% N.I. M. R. (CDCl ₃ ) δ: 0.84 (d, 3H, J = 6.59Hz),
0.85 (d, 3H, J = 6.59Hz), 1.31 (t, 3H, J = 7.08Hz), 1.32 (t, 3H,
J = 7.08Hz), 1.90 (septet, 1H, J = 6.84Hz), 2.46 (s, 3H), 2.98
-3.20 (m, 4H), 3.61 (dd, 1H, J = 16.36,9.52Hz), 3.68-3.77
(m, 4H), 4.06-4.20 (m, 4H), 4.66 (dd, 1H, J = 13.43,6.35Hz),
5.56 (br, 1H), 7.07 (dd, 2H, J = 6.35,1.95Hz), 7.17 (dd, 2H, J
= 6.35,1.95Hz) I. R. ν _NaCl cm ⁻¹ : 3330,2960,1750,1650,1530,149
5,1230,1050,1025,970,750 MS-FAB (MNBA): m / z 475 (MH ⁺ )

(1-37) 3- [2- (4-bromophenylthio) phenyl] -N
-[N-isobutyl-N- (diethoxyphosphoryl methyl
Le) Carbamoyl] alanine methyl ester yield 57.3% Melting point: 83.5-85.5 ° C N.V. M. R. (CDCl ₃ ) δ: 0.85 (d, 6H, J = 6.96Hz),
1.24-1.35 (m, 6H), 1.85-2.00 (m, 1H), 3.01-3.33 (m, 4H), 3.
52-3.64 (m, 1H), 3.68 (s, 3H), 3.69-3.82 (m, 1H), 4.03-4.19
(m, 4H), 4.66-4.75 (m, 1H), 5.70 (bs, 1H), 7.03 (d, 2H, J = 8.4
3Hz), 7.15-7.41 (m, 6H) I. R. ν _KBr cm ^-1 : 3450,2950,1750,1655,1640,153
0,1480,1390,1230,1160 MS-FAB (gly): m / z 615,617 (MH ⁺ ).

(1-38) 3- [4- (benzyloxycarbonyl) phenyl] -N
-[N-isobutyl-N- (diethoxyphosphoryl methyl
Le) carbamoyl] alanine benzyl ester yield 44.2% N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.83 (d, 3H, J = 6.59Hz), 1.28 (t, 3H, J = 7.08Hz), 1.29 (t, 3H,
J = 7.08Hz), 1.82-1.97 (m, 1H), 3.01-3.24 (m, 4H), 3.57 (dd,
1H, J = 16.36,9.52Hz), 3.65-3.75 (m, 1H), 4.04-4.18 (m, 4
H), 4.75 (dd, 1H, J = 13.43,6.35Hz), 5.06 (d, 1H, J = 12.21H
z), 5.18 (d, 1H, J = 12.21Hz), 5.35 (s, 2H), 5.72 (br, 1H), 7.1
3 (d, 2H, J = 8.30Hz), 7.24-7.47 (m, 10H), 7.90 (d, 2H, J = 8.30
Hz) I. R. ν _NaCl cm ⁻¹ : 2950,1720,1650,1530,1270,118
0,1100,1050,1020,980,755 MS-FAB (MNBA): m / z 639 (MH ⁺ ).

(1-39) 3- (4-nitrophenyl) -N- [N-isobutyl-
N- (diethoxyphosphorylmethyl) carbamoyl] a
Lanine methyl ester yield 84.7% N.V. M. R. (CDCl ₃ ) δ: 0.85 (d, 3H, J = 6.59Hz),
0.86 (d, 3H, J = 6.59Hz), 1.27-1.38 (m, 6H), 1.84-2.02 (m, 1
H), 3.01-3.35 (m, 4H), 3.51-3.70 (m, 2H), 3.72 (s, 3H), 4.06
-4.23 (m, 4H), 4.67-4.78 (m, 1H), 5.98-6.07 (m, 1H), 7.37
(d, 2H, J = 8.80Hz), 8.13 (d, 2H, J = 8.80Hz) I. R. ν _NaCl cm ⁻¹ : 3400,2950,1745,1640,1605,152
0,1390,1350,1125,1020 MS-FAB (gly): m / z 474 (MH ⁺ ).

(1-40) 3- (4-nitrophenyl) -N- [N-isobutyl-
N- (dibenzyloxyphosphorylmethyl) carbamoy
L] alanine methyl ester yield 64.6% N.I. M. R. (CDCl ₃ ) δ: 0.77 (d, 3H, J = 6.59Hz),
0.78 (d, 3H, J = 6.59Hz), 1.83 (septet, 1H, J = 6.84Hz), 2.94
(dd, 1H, J = 14.65,7.56Hz), 3.01-3.13 (m, 2H), 3.23 (dd, 1H,
J = 13.67,5.86Hz), 3.57 (dd, 1H, J = 16.35,9.52Hz), 3.65-3.
74 (m, 4H), 4.68 (dd, 1H, J = 13.18,6.60Hz), 4.94-5.12 (m, 4
H), 5.82 (br, 1H), 7.26-7.38 (m, 12H), 8.09 (d, 2H, J = 8.79H
z) I. R. ν _NaCl cm ⁻¹ : 3330,2960,1750,1650,1520,135
0,1220,1000,750 MS-FAB (MNBA): m / z 598 (MH ⁺ ).

(1-41) 3- (4-nitrophenyl) -N- [N-isobutyl-
N- (dibenzyloxyphosphorylmethyl) carbamoy
Lu] alanine benzyl ester yield 64.7% Melting point: 99-100 ° C N.V. M. R. (CDCl ₃ ) δ: 0.77 (d, 3H, J = 6.59Hz),
0.78 (d, 3H, J = 6.59Hz), 1.78-1.88 (m, 1H), 2.91-3.21 (m, 4
H), 3.57 (dd, 1H, J = 16.60,9.28Hz), 3.71 (dd, 1H, J = 16.11,
9.28Hz), 4.71 (dd, 1H, J = 12.94,6.35Hz), 4.94-5.09 (m, 5
H), 5.22 (d, 1H, J = 11.97Hz), 5.79 (br, 1H), 7.11 (d, 2H, J = 8.
79Hz), 7.26-7.36 (m, 15H), 7.94 (d, 2H, J = 8.79Hz) I. R. ν _KBr cm ^-1 : 3340,2970,1760,1640,1535,151
5,1350,1235,1180,1045,1015

(1-42) 3- (3-trifluoromethylphenyl) -N- [N-
Isobutyl-N- (diethoxyphosphorylmethyl) calc
Vamoyl] alanine benzyl ester yield 93.0% N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.84 (d, 3H, J = 6.59Hz), 1.30 (t, 6H, J = 7.08Hz), 1.83-1.98
(m, 1H), 3.02-3.26 (m, 4H), 3.54-3.73 (m, 2H), 4.06-4.18
(m, 4H), 4.71-4.79 (m, 1H), 5.09 (d, 1H, J = 12.21Hz), 5.17
(d, 1H, J = 12.21Hz), 5.83 (br, 1H), 7.23-7.39 (m, 7H), 7.41-
7.48 (m, 2H) I. R. ν _KBr cm ^-1 : 3350,2970,1745,1650,1535,133
0,1165,1125,1050,1030 MS-FAB (MNBA): m / z 573 (MH ⁺ ).

(1-43) 3-[(5-chloro-2-nitro) phenyl] -N-
[N-isobutyl-N- (diethoxyphosphoryl methyl
Le) carbamoyl] alanine methyl ester yield 48.2% N.V. M. R. (CDCl ₃ ) δ: 0.85 (d, 3H, J = 6.59Hz),
0.86 (d, 3H, J = 6.59Hz), 1.32 (t, 3H, J = 6.96Hz), 1.33 (t, 3H,
J = 6.96Hz), 1.84-2.03 (m, 1H), 3.05 (dd, 1H, J = 14.66,7.33H
z), 3.18 (dd, 1H, J = 14.66,7.70Hz), 3.24-3.35 (m, 1H), 3.44
-3.69 (m, 3H), 3.72 (s, 3H), 4.08-4.23 (m, 4H), 4.68-4.77
(m, 1H), 6.04-6.17 (m, 1H), 7.36 (dd, 1H, J = 8.79,2.20Hz),
7.46 (d, 1H, J = 2.20Hz), 7.91 (d, 1H, J = 8.79Hz) I. R. ν _KBr cm ^-1 : 3340,2960,1760,1640,1610,158
0,1530,1350,1220,1060,1040 MS-FAB (MNBA): m / z 508,510 (MH ⁺ ).

(1-44) 3- [4- (acetamido) phenyl] -N- [N-iso
Butyl-N- (dibenzyloxyphosphorylmethyl) calc
Vamoyl] alanine methyl ester yield 38.5% N.V. M. R. (CDCl ₃ ) δ: 0.77 (d, 3H, J = 6.59Hz),
0.78 (d, 3H, J = 6.59Hz), 1.83 (septet, 1H, J = 6.96Hz), 2.13
(s, 3H), 2.91-3.09 (m, 4H), 3.58-3.80 (m, 5H), 4.62 (dd, 1H,
J = 13.55,6.23Hz), 4.93-5.09 (m, 4H), 5.49 (br, 1H), 7.05
(d, 2H, J = 8.43Hz), 7.26 (br, 1H), 7.29-7.33 (m, 10H), 7.39
(d, 2H, J = 8.43Hz) I. R. ν _KBr cm ^-1 : 3330,2960,1745,1640,1610,154
0,1415,1320,1260,1220,1000 MS-FAB (MNBA): m / z 610 (MH ⁺ ).

(1-45) 3- [4- (methylsulfonyl) phenyl] -N- [N
-Isobutyl-N- (dibenzyloxyphosphoryl methyl
Le) Carbamoyl] alanine methyl ester yield 58.6% N.V. M. R. (CDCl ₃ ) δ: 0.77 (d, 3H, J = 6.84Hz),
0.78 (d, 3H, J = 6.84Hz), 1.78-1.88 (m, 1H), 2.93 (dd, 1H, J = 1
4.65,7.57Hz), 3.01-3.13 (m, 5H), 3.18-3.25 (m, 1H), 3.58
(dd, 1H, J = 16.60,9.52Hz), 3.65-3.74 (m, 4H), 4.67 (dd, 1H,
J = 12.94,6.59Hz), 4.95-5.12 (m, 4H), 5.79 (br, 1H), 7.32-
7.34 (m, 12H), 7.82 (d, 2H, J = 8.30Hz) I. R. ν _NaCl cm ⁻¹ : 2960,1740,1640,1525,1305,122
0,1150,990

(1-46) 3- (1-naphthyl) -N- [N-isobutyl-N-
(Diethoxyphosphorylmethyl) carbamoyl] alani
Benzyl ester yield 80.2% N.V. M. R. (CDCl ₃ ) δ: 0.73 (d, 3H, J = 6.59Hz),
0.75 (d, 3H, J = 6.59Hz), 1.27 (t, 3H, J = 7.08Hz), 1.28 (t, 3H,
J = 7.08Hz), 1.74-1.84 (m, 1H), 3.03 (dd, 2H, J = 7.57,2.20H
z), 3.48-3.79 (m, 4H), 4.03-4.18 (m, 4H), 4.83-4.91 (m, 1
H), 5.05 (s, 2H), 5.65 (br, 1H), 7.14-7.19 (m, 2H), 7.21-7.3
3 (m, 5H), 7.43-7.55 (m, 2H), 7.73 (d, 1H, J = 8.06Hz), 7.82-
7.85 (m, 1H), 8.13 (d, 1H, J = 8.06Hz) I. R. ν _NaCl cm ⁻¹ : 2950,1740,1650,1530,1515,124
0,1180,1055,1030 MS-FAB (MNBA): m / z 555 (MH ⁺ ).

(1-47) 3- (2-naphthyl) -N- [N-isobutyl-N-
(Diethoxyphosphorylmethyl) carbamoyl] alani
Benzyl ester yield 76.0% N.V. M. R. (CDCl ₃ ) δ: 0.75 (d, 3H, J = 6.59Hz),
0.76 (d, 3H, J = 6.59Hz), 1.21-1.29 (m, 6H), 1.78-1.88 (m, 1
H), 3.00-3.16 (m, 2H), 3.21-3.35 (m, 2H), 3.59 (dd, 1H, J = 1
6.36,9.77Hz), 3.71 (dd, 1H, J = 16.36,9.28Hz), 4.00-4.14
(m, 4H), 4.83 (dd, 1H, J = 13.43,6.11Hz), 5.07 (d, 1H, J = 12.2
1Hz), 5.19 (d, 1H, J = 12.21Hz), 5.60 (br, 1H), 7.19-7.31 (m,
6H), 7.42-7.45 (m, 2H), 7.55 (s, 1H), 7.68-7.71 (m, 2H), 7.7
7-7.80 (m, 1H) I. R. ν _NaCl cm ⁻¹ : 2950,1740,1650,1510,1240,119
0,1170,1055,1030,970,750 MS-FAB (MNBA): m / z 555 (MH ⁺ ).

(1-48) 3- (6-Methyl-2-naphthyl) -N- [N-isobutane
Cyl-N- (diethoxyphosphorylmethyl) carbamoy
L] alanine benzyl ester yield 63.6% N. M. R. (CDCl ₃ ) δ: 0.75 (d, 3H, J = 6.59Hz),
0.76 (d, 3H, J = 6.59Hz), 1.21-1.29 (m, 6H), 1.78-1.88 (m, 1
H), 2.50 (s, 3H), 2.99-3.15 (m, 2H), 3.18-3.33 (m, 2H), 3.59
(dd, 1H, J = 16.11,9.77Hz), 3.71 (dd, 1H, J = 16.11,9.03Hz),
4.00-4.14 (m, 4H), 4.81 (dd, 1H, J = 13.67,6.35Hz), 5.07 (d,
1H, J = 12.21Hz), 5.18 (d, 1H, J = 12.21Hz), 5.54 (br, 1H), 7.1
6 (dd, 1H, J = 8.54,1.71Hz), 7.21-7.31 (m, 6H), 7.49 (s, 1H),
7.55-7.62 (m, 3H) I. R. ν _NaCl cm ⁻¹ : 2960,1740,1650,1520,1230,119
0,1170,1050,1030,970,760

(1-49) 3- (6-methoxy-2-naphthyl) -N- [N-iso
Butyl-N- (diethoxyphosphorylmethyl) carbamo
Il] alanine benzyl ester yield 47.2% N.V. M. R. (CDCl ₃ ) δ: 0.75 (d, 3H, J = 6.59Hz),
0.76 (d, 3H, J = 6.59Hz), 1.22-1.29 (m, 6H), 1.78-1.88 (m, 1
H), 3.00-3.15 (m, 2H), 3.17-3.31 (m, 2H), 3.60 (dd, 1H, J = 1
6.11,9.52Hz), 3.71 (dd, 1H, J = 16.11,9.28Hz), 3.91 (s, 3
H), 4.01-4.14 (m, 4H), 4.80 (dd, 1H, J = 13.43,6.10Hz), 5.07
(d, 1H, J = 12.21Hz), 5.19 (d, 1H, J = 12.21Hz), 5.55 (br, 1H),
7.09-7.17 (m, 3H), 7.22-7.33 (m, 5H), 7.16 (s, 1H), 7.59 (d,
2H, J = 8.55Hz) I. R. ν _NaCl cm ⁻¹ : 2960,1745,1650,1610,1510,149
0,1395,1270,1240,1180,1055,1030,970,760 MS-FAB (MNBA): m / z 585 (MH ⁺ ).

(1-50) 3- (2-pyridyl) -N- [N-isobutyl-N-
(Diethoxyphosphorylmethyl) carbamoyl] alani
Benzyl ester yield 69.8% N. M. R. (CDCl ₃ ) δ: 0.87 (d, 3H, J = 6.59Hz),
0.88 (d, 3H, J = 6.59Hz), 1.28 (t, 3H, J = 7.08Hz), 1.29 (t, 3H,
J = 7.08Hz), 1.94-2.10 (m, 1H), 3.12-3.38 (m, 4H), 3.69 (dd,
1H, J = 16.11,9.28Hz), 3.91 (dd, 1H, J = 16.11,9.53Hz), 4.06
-4.17 (m, 4H), 4.83-4.89 (m, 1H), 5.04 (d, 1H, J = 12.20Hz),
5.09 (d, 1H, J = 12.20Hz), 6.85 (d, 1H, J = 7.57Hz), 6.98 (d, 1
H, J = 7.57Hz), 7.12 (ddd, 1H, J = 7.57,4.89,0.98Hz), 7.19-
7.24 (m, 2H), 7.27-7.32 (m, 3H), 7.51 (td, 1H, J = 7.57,1.95H
z), 8.42 (ddd, 1H, J = 4.89,1.95,0.98Hz) I.V. R. ν _NaCl cm ⁻¹ : 3330,2960,1750,1650,1520,124
0,1170,1055,1030,970 MS-FAB (MNBA): m / z 506 (MH ⁺ ).

(1-51) 3- (3-thienyl) -N- [N-isobutyl-N-
(Diethoxyphosphorylmethyl) carbamoyl] alani
Benzyl ester yield 74.9% Melting point: 57-59 ° C N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.84Hz),
0.83 (d, 3H, J = 6.84Hz), 1.24-1.35 (m, 6H), 1.80-1.98 (m, 1
H), 3.05-3.14 (m, 2H), 3.16 (dd, 2H, J = 5.86,3.41Hz), 3.68
(dd, 2H, J = 16.11,9.28Hz), 4.02-4.19 (m, 4H), 4.73 (dd, 1H,
J = 13.18,5.86Hz), 5.15 (d, 1H, J = 12.21Hz), 5.19 (d, 1H, J = 1
2.21Hz), 5.46-5.65 (m, 1H), 6.76-6.83 (m, 1H), 6.90 (d, 1H,
J = 2.93Hz), 7.20 (dd, 1H, J = 4.88,2.93Hz), 7.27-7.41 (m, 5
H) ¹³ C-N. M. R. (CDCl ₃ ) δ: 172.163,157.20
1,136.353,135.308,128.450,128.322,128.267,125.572,
122.583,66.879,62.423,62.313,55.345,54.264,43.400
(d, J = 158.2Hz), 32.499,27.035,19.939,19.902,16.400,1
6.308 I. R. ν _KBr cm ^-1 : 3300,2950,2870,1740,1655,163
5,1490,1450,1390,1210,1170 MS-FAB (gly): m / z 511 (MH ⁺ ).

(1-52) N-benzyl-3-phenyl-N- [N-isobutyl-
N- (diethoxyphosphorylmethyl) carbamoyl]-
L-alanine methyl ester yield 42.1% N.V. M. R. (CDCl ₃ ) δ: 0.75-0.81 (m, 6H), 1.29
(t, 3H, J = 7.08Hz), 1.30 (t, 3H, J = 7.08Hz), 1.93-2.02 (m, 1
H), 3.10-3.18 (m, 3H), 3.45-3.53 (m, 1H), 3.59-3.69 (m, 4
H), 3.76-3.91 (m, 2H), 4.03-4.14 (m, 4H), 4.44 (d, 1H, J = 16.
60Hz), 4.60 (d, 1H, J = 16.60Hz), 7.11-7.26 (m, 10H) I. R. ν _NaCl cm ⁻¹ : 3475,2950,1740,1650,1460,142
0,1240,1050,1020,960,860,750,700 [α] _D = -50.06 ° (c = 0.7720, MeOH)

(1-53) N-ethyl-3-phenyl-N- [N-isobutyl-N
-(Diethoxyphosphorylmethyl) carbamoyl] -L
-Alanine methyl ester yield 46.0% N.A. M. R. (CDCl ₃ ) δ: 0.79 (d, 3H, J = 6.59Hz),
0.80 (d, 3H, J = 6.59Hz), 0.93 (t, 3H, J = 7.08Hz), 1.32 (t, 6H,
J = 7.08Hz), 1.86-1.95 (m, 1H), 2.96-3.12 (m, 3H), 3.24-3.3
2 (m, 2H), 3.39 (dd, 1H, J = 14.16,6.10Hz), 3.55 (dd, 1H, J = 1
6.11,9.03Hz), 3.70 (s, 3H), 3.80 (dd, 1H, J = 16.12,11.23H
z), 4.00-4.16 (m, 5H), 7.20-7.30 (m, 5H) I. R. ν _NaCl cm ⁻¹ : 3425,2975,1740,1640,1420,123
0,1050,1020,960,700 [α] _D = −44.73 ° (c = 0.7140, MeOH)

Example 2 3- (4-hydroxyphenyl) -N- [N-isobutyi
Ru-N- (diethoxyphosphorylmethyl) carbamoy
] -L-Alanine ethyl ester 3- [4- (benzyloxy) phenyl] -N- [N-isobutyl-N- (diethoxyphosphorylmethyl) carbamoyl] -L- obtained in Example (1-33) To a solution of 1.38 g (2.52 mM) of alanine ethyl ester in 14 ml of methanol, 140 mg of 10% palladium carbon was added under a nitrogen atmosphere, and then the mixture was stirred under hydrogen substitution at room temperature for 1 hour. The atmosphere was replaced with nitrogen again, 140 mg of 10% palladium carbon was added, and the mixture was stirred under hydrogen replacement at room temperature for 2 hours. After the reaction was completed, palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (eluent: chloroform / methanol =
99/1), 0.99 g of 3- (4-hydroxyphenyl) -N- [N-isobutyl-N- (diethoxyphosphorylmethyl) carbamoyl] -L-alanine ethyl ester (yield 85. 8%) was obtained. Melting point: 110-112 ° C N.V. M. R. (CDCl ₃ ) δ: 0.83 (d, 3H, J = 6.84Hz),
0.84 (d, 3H, J = 6.84Hz), 1.24 (t, 3H, J = 7.08Hz), 1.31 (t, 6H,
J = 7.08Hz), 1.83-1.98 (m, 1H), 2.96-3.18 (m, 4H), 3.62 (dd,
1H, J = 16.35,9.28Hz), 3.80 (dd, 1H, J = 16.35,9.52Hz), 4.05
-4.21 (m, 6H), 4.63 (dd, 1H, J = 13.43,6.11Hz), 5.42 (br, 1
H), 6.58 (s, 1H), 6.71-6.76 (m, 2H), 6.99 (d, 2H, J = 8.30Hz) I. R. ν _KBr cm ^-1 : 3270,2970,1735,1620,1615,159
0,1540,1520,1210,1200,1190,1060,1030,975 MS-FAB (MNBA): m / z 459 (MH ⁺ ) [α] _D = -17.61 ° (c = 0.9840, MeOH)

Example 3 3-Phenyl-N- [N-isobutyl-N- (dihydro
Xyphosphorylmethyl) carbamoyl] -L-alanine
Ethyl ester 3-phenyl-N- [N- obtained in Example (1-1)
Isobutyl-N- (diethoxyphosphorylmethyl) carbamoyl] -L-alanine ethyl ester 300 mg
To a solution of (0.68 mM) in 10 ml of anhydrous acetonitrile, 320 mg of trimethylsilyl bromide (2.09
A solution of mM) in 5 ml of anhydrous acetonitrile was added dropwise at room temperature over 30 minutes. After completion of dropping, the mixture was stirred for 16 hours.
The reaction mixture was concentrated under reduced pressure to dryness, the obtained concentrated residue was dissolved in ethyl acetate, and the mixture was extracted with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid and then extracted with ethyl acetate.
The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness to give 3-phenyl-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine ethyl ester (250 mg).
(Yield 95.4%) was obtained. N. M. R. (CDCl ₃ ) δ: 0.80 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.24 (t, 3H, J = 7.08Hz), 1.77-1.88
(m, 1H), 3.04 (d, 2H, J = 7.32Hz), 3.12 (d, 2H, J = 5.62Hz), 3.4
9-3.73 (m, 2H), 4.17 (q, 2H, J = 7.08Hz), 4.65-4.69 (m, 1H),
7.09-7.14 (m, 2H), 7.23-7.32 (m, 3H), 7.58 (bs, 2H) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1620,1540,120
0,1010,700 [α] _D = -10.75 ° (c = 0.6520, MeOH)

The following compounds were obtained by the same method as in Example (3-1). (3-2) 3-phenyl-N- [N-ethyl-N- (dihydroxy
Phosphorylmethyl) carbamoyl] -L-alanine ethyl
Luster yield 43.4% N. M. R. (CDCl ₃ ) δ: 1.08 (t, 3H, J = 6.96Hz),
1.24 (t, 3H, J = 6.96Hz), 3.13 (d, 2H, J = 5.49Hz), 3.26-3.36
(m, 2H), 3.54-3.68 (m, 2H), 4.13-4.20 (m, 2H), 4.66-4.73
(m, 1H), 7.09-7.31 (m, 7H) I. R. ν _KBr cm ^-1 : 3400,2975,1730,1630,1540,120
0,1020,740,700 MS-FAB (gly): m / z 359 (MH ⁺ ) [α] _D = -14.56 ° (c = 0.5670, MeOH)

(3-3) 3- (2-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine benzyl ester yield 74.5% N.A. M. R. (CDCl ₃ ) δ: 0.81 (d, 6H, J = 6.60Hz),
1.81 (septet, 1H, J = 6.96Hz), 2.27 (s, 3H), 3.00-3.09 (m, 3
H), 3.16 (dd, 1H, J = 13.92,6.96Hz), 3.50 (dd, 1H, J = 16.12,1
1.36Hz), 3.63 (dd, 1H, J = 16.12,9.89Hz), 4.69 (t, 1H, J = 6.9
6Hz), 5.11 (s, 2H), 6.94 (d, 1H, J = 7.33Hz), 7.01-7.16 (m, 3
H), 7.21-7.24 (m, 2H), 7.30-7.37 (m, 3H) I. R. ν _KBr cm ^-1 : 2960,1740,1635,1540,1190,101
0 MS-FAB (gly): m / z 463 (MH ⁺ ), 485 (M
Na ⁺ )

(3-4) 3- (3-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine benzyl ester yield 80.7% N.A. M. R. (CDCl ₃ ) δ: 0.75-0.79 (m, 6H), 1.73
-1.83 (m, 1H), 2.24 (s, 3H), 3.00-3.13 (m, 4H), 3.53 (dd, 1H,
J = 15.75, 11.36Hz), 3.64-3.73 (m, 1H), 4.71 (t, 1H, J = 5.50H
z), 5.09 (d, 1H, J = 12.09Hz), 5.17 (d, 1H, J = 12.09Hz), 6.75-
6.81 (m, 2H), 7.02 (d, 1H, J = 7.70Hz), 7.07-7.13 (m, 1H), 7.2
6-7.36 (m, 5H), 9.80 (br, 2H) I. R. ν _KBr cm ^-1 : 2950,1740,1620,1560,1190,101
0 MS-FAB (gly): m / z 463 (MH ⁺ ).

(3-5) 3- (4-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine benzyl ester yield 87.7% N.A. M. R. (CDCl ₃ ) δ: 0.74 (d, 3H, J = 6.59Hz),
0.77 (d, 3H, J = 6.59Hz), 1.71-1.81 (m, 1H), 2.27 (s, 3H), 3.0
1-3.06 (m, 4H), 3.45-3.55 (m, 1H), 3.63-3.73 (m, 1H), 4.68-
4.72 (m, 1H), 5.06 (d, 1H, J = 12.09Hz), 5.15 (d, 1H, J = 12.09H
z), 6.86 (d, 2H, J = 8.06Hz), 6.99 (d, 2H, J = 8.06Hz), 7.23-7.
38 (m, 5H), 8.81 (br, 2H) I. R. ν _KBr cm ^-1 : 3440,2960,1740,1640,1530,120
0,1010,950

(3-6) 3- (4-isopropylphenyl) -N- [N-isobutene
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Il] alanine benzyl ester yield 84.1% N.V. M. R. (CDCl ₃ ) δ: 0.70 (d, 3H, J = 6.59Hz),
0.73 (d, 3H, J = 6.59Hz), 1.20 (d, 6H, J = 6.96Hz), 1.67-1.77
(m, 1H), 2.84 (septet, 1H, J = 6.96Hz), 2.99-3.14 (m, 4H), 3.
44-3.54 (m, 1H), 3.67 (dd, 1H, J = 16.12,9.53Hz), 4.68-4.72
(m, 1H), 5.09 (d, 1H, J = 12.09Hz), 5.15 (d, 1H, J = 12.09Hz),
6.90 (d, 2H, J = 8.06Hz), 7.06 (d, 2H, J = 8.06Hz), 7.25-7.36
(m, 5H), 8.80 (br, 2H) I. R. ν _KBr cm ^-1 : 2960,1740,1630,1530,1195,101
0 MS-FAB (gly): m / z 491 (MH ⁺ ).

(3-7) 3- (4-n-butylphenyl) -N- [N-isobutyl
Le-N- (dihydroxyphosphorylmethyl) carbamoy
L] Alanine benzyl ester yield 81.1% N. M. R. (CDCl ₃ ) δ: 0.71-0.76 (m, 6H), 0.91
(t, 3H, J = 7.32Hz), 1.32 (sextet, 2H, J = 7.33Hz), 1.48-1.59
(m, 2H), 1.69-1.79 (m, 1H), 2.53 (d, 2H, J = 7.70Hz), 3.00-3.
07 (m, 4H), 3.44-3.54 (m, 1H), 3.61-3.71 (m, 1H), 4.70 (bs, 1
H), 5.08 (d, 1H, J = 12.09Hz), 5.15 (d, 1H, J = 12.09Hz), 5.66
(br, 2H), 6.88 (d, 2H, J = 8.06Hz), 7.01 (d, 2H, J = 8.06Hz), 7.
26-7.34 (m, 5H) I. R. ν _KBr cm ^-1 : 3450,2950,2930,2870,1740,164
0,1530,1200,1010,950 MS-FAB (MNBA): m / z 505 (MH ⁺ ), 52
7 (MNa ⁺ )

(3-8) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -L
-Alanine benzyl ester yield 83.5% N.V. M. R. (CDCl ₃ ) δ: 0.73-0.78 (m, 6H), 1.74
-1.83 (m, 1H), 2.97-3.15 (m, 4H), 3.47-3.74 (m, 2H), 4.77-
4.82 (m, 1H), 5.09 (d, 1H, J = 11.96Hz), 5.18 (d, 1H, J = 11.96H
z), 7.04 (d, 2H, J = 8.06Hz), 7.27-7.53 (m, 12H) I.I. R. ν _KBr cm ^-1 : 3400,2950,1730,1620,1520,118
0,1000,760,690 MS-FAB (gly): m / z 525 (MH ⁺ ) [α] _D = -17.22 ° (c = 0.6490, MeOH)

(3-9) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -D
-Alanine benzyl ester yield 74.4% N.V. M. R. (CDCl ₃ ) δ: 0.76 (bs, 6H), 1.79 (br,
1H), 3.07-3.15 (m, 4H), 3.55-3.72 (m, 2H), 4.79 (bs, 1H), 5.
07-5.19 (m, 2H), 6.50 (br, 2H), 7.02-7.52 (m, 14H) I. R. ν _KBr cm ^-1 : 3450,2950,1740,1630,1540,120
0,1010,760,700 MS-FAB (gly): m / z 525 (MH ⁺ ) [α] _D = + 17.56 ° (c = 0.7640, MeOH)

(3-10) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
L] -L-alanine methyl ester yield 76% N.I. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.35Hz),
0.84 (d, 3H, J = 6.35Hz), 1.81-1.87 (m, 1H), 3.05-3.07 (m, 4
H), 3.48-3.78 (m, 8H), 4.64-4.67 (m, 1H), 6.25 (bs, 2H), 6.8
2 (d, 2H, J = 8.55Hz), 7.00 (d, 2H, J = 8.55Hz) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1620,1250,118
0,1020,840,750 [α] _D = -13.72 ° (c = 1.1376, MeOH)

(3-11) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
L ] alanine benzyl ester yield 85.4% N. M. R. (CDCl ₃ ) δ: 0.74 (d, 3H, J = 6.23Hz),
0.77 (d, 3H, J = 6.23Hz), 1.72-1.82 (m, 1H), 3.04 (bs, 4H), 3.
46-3.55 (m, 1H), 3.64-3.75 (m, 4H), 4.70 (bs, 1H), 5.04 (d, 1
H, J = 12.09Hz), 5.15 (d, 1H, J = 12.09Hz), 6.71 (d, 2H, J = 8.79
Hz), 6.88 (d, 2H, J = 8.79Hz), 7.24-7.33 (m, 5H), 9.16 (br, 2
H) I. R. ν _KBr cm ^-1 : 3440,2960,1740,1615,1515,125
0,1180,1000,950 MS-FAB (gly): m / z 479 (MH ⁺ ).

(3-12) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
L] -D-alanine benzyl ester yield 83% N.V. M. R. (CDCl ₃ ) δ: 0.76 (d, 3H, J = 6.83Hz),
0.78 (d, 3H, J = 6.83Hz), 1.73-1.82 (m, 1H), 3.02-3.05 (m, 4
H), 3.44-3.56 (m, 1H), 3.65-3.75 (m, 4H), 4.68-4.70 (m, 1
H), 5.07 (d, 1H, J = 12.20Hz), 5.17 (d, 1H, J = 12.20Hz), 6.72
(d, 2H, J = 8.54Hz), 6.88 (d, 2H, J = 8.54Hz), 7.27-7.35 (m, 5
H), 7.60 (bs, 2H) I.H. R. ν _KBr cm ^-1 : 3450,2950,1740,1620,1520,147
0,1260,1180,1010,840,760,700 [α] _D = +17.72 ° (c = 0.7840, MeOH)

(3-13) 3- (4-methoxyphenyl) -N- [Nn-propyne
Le-N- (dihydroxyphosphorylmethyl) carbamoy
L] -L-alanine benzyl ester yield 53.8% N.V. M. R. (CDCl ₃ ) δ: 0.79 (t, 3H, J = 6.96Hz),
1.47-1.55 (m, 2H), 3.05 (d, 2H, J = 5.13Hz), 3.13-3.17 (m, 2
H), 3.53-3.66 (m, 2H), 3.75 (s, 3H), 4.70 (bs, 1H), 5.09 (d, 1
H, J = 11.92Hz), 5.18 (d, 1H, J = 11.92Hz), 6.73 (d, 2H, J = 8.61
Hz), 6.87 (d, 2H, J = 8.61Hz), 7.27-7.35 (m, 5H) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1620,1520,125
0,1180,1010,830,750,700 [α] _D = -18.55 ° (c = 0.7160, MeOH)

(3-14) 3- (3,4-dimethoxyphenyl) -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine methyl ester yield 30.3% N.V. M. R. (CDCl ₃ ) δ: 0.78-0.92 (m, 6H), 1.74
-1.92 (m, 1H), 2.99-3.14 (m, 4H), 3.50-3.69 (m, 2H), 3.73
(s, 3H), 3.84 (s, 6H), 4.60-4.68 (m, 1H), 6.60-6.68 (m, 2H),
6.75-6.83 (m, 1H) ¹³ C-N. M. R. (CDCl ₃ ) δ: 172.750,158.61
3,149.023,148.216,128.139,121.354,112.352,112.306,
56.464,55.840,54.887,52.357,45.481 (d, J = 149.5Hz), 3
7.468,27.127,19.939,19.902 I.D. R. ν _NaCl cm ⁻¹ : 3450,3020,2950,1740,1640,152
0,1470,1440,1260,1220,1140,1030 MS-FAB (MNBA): m / z 433 (MH ⁺ ).

(3-15) 3- (4-n-butoxyphenyl) -N- [N-isobutane
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Il] -L-alanine benzyl ester yield 87.8% N.I. M. R. (CDCl ₃ ) δ: 0.74-0.79 (m, 6H), 0.96
(t, 3H, J = 7.33Hz), 1.47 (sextet, 2H, J = 7.33Hz), 1.68-1.78
(m, 3H), 3.02 (br, 4H), 3.44-3.54 (m, 1H), 3.62-3.73 (m, 1
H), 3.87 (t, 2H, J = 6.59Hz), 4.68 (bs, 1H), 5.05 (d, 1H, J = 12.
09Hz), 5.16 (d, 1H, J = 12.09Hz), 6.70 (d, 2H, J = 8.43Hz), 6.8
5-7.00 (m, 4H), 7.27-7.33 (m, 5H) I. R. ν _KBr cm ^-1 : 2960,1740,1620,1515,1250,118
0,1010 MS-FAB (MNBA): m / z 521 (MH ⁺ ), 54
3 (MNa ⁺ ) [α] _D = -13.18 ° (c = 0.494, MeOH)

(3-16) 3- (3-Bromophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine methyl ester yield 64.8% N.A. M. R. (CDCl ₃ ) δ: 0.84-0.87 (m, 6H), 1.83
-1.91 (m, 1H), 3.06-3.09 (m, 4H), 3.62 (d, 2H, J = 10.25Hz),
3.73 (s, 3H), 4.65-4.71 (m, 1H), 5.05 (bs, 2H), 7.03 (d, 1H, J
= 7.69Hz), 7.15 (t, 1H, J = 7.69Hz), 7.26 (s, 1H), 7.37 (d, 1H,
J = 7.69Hz) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1640,1540,121
0,1000

(3-17) 3- (3-Bromophenyl) -N- [N-isobutyl-
N- [hydroxy (4-phenylbutyl) phosphorylmeth
Cyl] carbamoyl] alanine methyl ester yield 93.3% N.V. M. R. (CDCl ₃ ) δ: 0.84 (d, 3H, J = 6.60Hz),
0.86 (d, 3H, J = 6.60Hz), 1.70-1.93 (m, 7H), 2.58-2.65 (m, 2
H), 3.03-3.10 (m, 4H), 3.58-3.62 (m, 2H), 3.71 (s, 3H), 4.66
-4.71 (m, 1H), 5.21 (bs, 2H), 7.03-7.38 (m, 9H) I. R. ν _KBr cm ^-1 : 3350,2950,1740,1640,1520,120
0,1180,960,850,750,700

(3-18) 3- (3-Bromophenyl) -N- [Nn-propyl
-N- (dihydroxyphosphorylmethyl) carbamoy
Lu] alanine methyl ester yield 67.7% N.I. M. R. (CDCl ₃ ) δ: 0.85 (t, 3H, J = 7.33Hz),
1.49-1.57 (m, 2H), 3.05-3.09 (m, 2H), 3.19-3.26 (m, 2H), 3.
62 (d, 2H, J = 10.01Hz), 3.73 (s, 3H), 4.64-4.69 (m, 1H), 7.05
(d, 1H, J = 7.33Hz), 7.13-7.19 (m, 2H), 7.38 (d, 1H, J = 7.81H
z) I. R. ν _KBr cm ^-1 : 3400,2975,1740,1640,1540,121
0,1010

(3-19) 3- (4-Bromophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine methyl ester yield 82.5% N.A. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.84 (d, 3H, J = 6.59Hz), 1.79-1.89 (m, 1H), 3.00-3.14 (m, 4
H), 3.50-3.77 (m, 5H), 4.67 (t, 1H, J = 5.50Hz), 6.98 (d, 2H, J
= 8.06Hz), 7.40 (d, 2H, J = 8.06Hz), 7.65 (br, 2H) I. R. ν _KBr cm ^-1 : 3400,2960,1740,1630,1540,121
0,1020 MS-FAB (gly): m / z 451,453 (MH ⁺ ).

(3-20) 3- (3,4-dichlorophenyl) -N- [N-isobutane
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Il] alanine methyl ester yield 93.1% N.V. M. R. (CDCl ₃ ) δ: 0.85 (d, 6H, J = 6.60Hz),
1.82-1.92 (m, 1H), 2.99-3.15 (m, 4H), 3.61-3.73 (m, 5H), 4.
68 (t, 1H, J = 5.49Hz), 6.96 (dd, 1H, J = 8.06,1.84Hz), 7.21
(d, 1H, J = 1.84Hz), 7.34 (d, 1H, J = 8.06Hz), 7.51 (br, 2H) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1630,1540,147
0,1200,1030,1000 MS-FAB (gly): m / z 441,443 (MH ⁺ ).

(3-21) 3-[(3-chloro-4-methyl) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
) Carbamoyl] alanine methyl ester yield 53.1% Melting point: 43-44 ° C N.V. M. R. (CDCl ₃ ) δ: 0.71-0.94 (m, 6H), 1.74
-1.96 (m, 1H), 2.32 (s, 3H), 2.96-3.23 (m, 4H), 3.54-3.80
(m, 5H), 4.56-4.71 (m, 1H), 6.81-6.93 (m, 1H), 7.03-7.15
(m, 1H), 7.23 (d, 1H, J = 8.06Hz) ¹³ C-N. M. R. (CDCl ₃ ) δ: 172.328,158.31
9,135.950,134.410,132.979,131.806,129.624,128.982,
56.134,54.740,52.228,45.178 (d, J = 150.8Hz), 37.120,2
8.960, 26.925, 19.774, 19.444 I. R. ν _KBr cm ^-1 : 3400,2955,1740,1630,1515,144
5,1395,1210,1060 MS-FAB (gly): m / z 421,423 (MH ⁺ ).

(3-22) 3-[(5-Bromo-2-methoxy) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
) Carbamoyl] alanine methyl ester yield 72.1% N.V. M. R. (CDCl ₃ ) δ: 0.81-0.93 (m, 6H), 1.81
-1.95 (m, 1H), 2.99-3.14 (m, 4H), 3.43-3.67 (m, 2H), 3.71
(s, 3H), 3.81 (s, 3H), 4.56-4.64 (m, 1H), 6.74 (d, 1H, J = 8.79
Hz), 7.20 (d, 1H, J = 2.56Hz), 7.32 (dd, 1H, J = 8.79,2.56Hz) R. ν _KBr cm ^-1 : 3450,2950,1740,1630,1540,150
0,1490,1460,1260 MS-FAB (MNBA): m / z 481,483 (MH ⁺ ).

(3-23) 3- (2-benzylphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
Lu] alanine benzyl ester yield 46.3% N.A. M. R. (CDCl ₃ ) δ: 0.79 (d, 6H, J = 6.60Hz),
1.81 (septet, 1H, J = 6.59Hz), 2.93-3.15 (m, 4H), 3.43-3.65
(m, 2H), 3.93 (d, 1H, J = 16.12Hz), 4.00 (d, 1H, J = 16.12Hz),
4.62-4.67 (m, 1H), 5.08 (s, 2H), 6.98-7.21 (m, 12H), 7.28-
7.38 (m, 4H) I. R. ν _KBr cm ^-1 : 2960,1740,1630,1540,1500,146
0,1190,1010,950 MS-FAB (gly): m / z 539 (MH ⁺ ), 561
(MNa ⁺ )

(3-24) 3- [4- (ethoxycarbonylmethoxy) phenyl]
-N- [N-isobutyl-N- (dihydroxyphosphoryl
Lumethyl) carbamoyl] -L-alanine benzyl ester
Tell collection rate 63.6% N.Y. M. R. (CDCl ₃ ) δ: 0.75-0.80 (m, 6H), 1.29
(t, 3H, J = 6.96Hz), 1.75-1.85 (m, 1H), 3.02-3.04 (m, 4H), 3.
44-3.54 (m, 1H), 3.61-3.70 (m, 1H), 4.25 (q, 2H, J = 6.96Hz),
4.53 (s, 2H), 4.70 (bs, 1H), 5.06 (d, 1H, J = 12.09Hz), 5.17
(d, 1H, J = 12.09Hz), 6.50 (br, 2H), 6.72 (d, 2H, J = 8.80Hz),
6.88 (d, 2H, J = 8.80Hz), 7.28-7.35 (m, 5H) I. R. ν _KBr cm ^-1 : 3430,2960,1740,1620,1515,120
0,1015 MS-FAB (gly): m / z 551 (MH ⁺ ) [α] _D = -13.39 ° (c = 0.7726, MeOH)

(3-25) 3- [4- (benzyloxy) phenyl] -N- [N-i]
Sobutyl-N- (dihydroxyphosphorylmethyl) calc
Vamoyl] -L-alanine benzyl ester yield 53.6% N.V. M. R. (CDCl ₃ ) δ: 0.76 (bs, 6H), 1.74-1.8
3 (m, 1H), 2.98-3.10 (m, 4H), 3.52-3.76 (m, 2H), 4.70 (bs, 1
H), 4.97 (s, 2H), 5.06 (d, 1H, J = 12.09Hz), 5.16 (d, 1H, J = 12.
09Hz), 6.77-6.95 (m, 4H), 7.29-7.39 (m, 10H), 8.65 (br, 2H) I. R. ν _KBr cm ^-1 : 2950,1740,1620,1520,1460,139
0,1260,1180,1010,950,840,760,700 [α] _D = -15.56 ° (c = 0.6520, MeOH)

(3-26) 3- [2- (methylthio) phenyl] -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine methyl ester yield 87.5% N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.23Hz),
0.83 (d, 3H, J = 6.23Hz), 1.82-1.93 (m, 1H), 2.45 (s, 3H), 2.9
7-3.16 (m, 3H), 3.26 (dd, 1H, J = 13.93,5.50Hz), 3.41-3.52
(m, 1H), 3.59-3.72 (m, 4H), 4.64-4.69 (m, 1H), 7.07-7.24
(m, 4H), 9.72 (bs, 2H) I. R. ν _KBr cm ^-1 : 3400,2960,1740,1630,1530,144
0,1200,1000 MS-FAB (gly): m / z 419 (MH ⁺ ), 441 (M
Na ⁺ )

(3-27) 3- [4- (methylthio) phenyl] -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine methyl ester yield 81.6% N.V. M. R. (CDCl ₃ ) δ: 0.81 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.78-1.88 (m, 1H), 2.44 (s, 3H), 3.0
0-3.08 (m, 4H), 3.50-3.60 (m, 1H), 3.63-3.70 (m, 4H), 4.64-
4.68 (m, 1H), 7.02 (d, 2H, J = 8.43Hz), 7.16 (d, 2H, J = 8.43H
z), 9.71 (br, 2H) I. R. ν _KBr cm ^-1 : 3440,2960,2930,1740,1630,153
0,1500,1205,1010 MS-FAB (gly): m / z 419 (MH ⁺ ).

(3-28) 3- [2- (4-bromophenylthio) phenyl] -N
-[N-isobutyl-N- (dihydroxyphosphorylmeth
Chill) carbamoyl] alanine methyl ester yield 76.4% Melting point: 64-66 ° C N.V. M. R. (CDCl ₃ ) δ: 0.80-0.94 (m, 6H), 1.82
-1.98 (m, 1H), 3.00-3.36 (m, 4H), 3.45-3.77 (m, 5H), 4.64-
4.77 (m, 1H), 7.01 (d, 2H, J = 8.43Hz), 7.16-7.42 (m, 6H) ¹³ C-N. M. R. (CDCl ₃ ) δ: 172.896,158.77
8,138.333,135.473,133.474,134.043,132.209,131.164,
130.834,128.670,128.340,120.438,56.262,54.740,52.4
67,45.371 (d, J = 149.5Hz), 35.964,27.017,20.764,19.921 I.D. R. ν _KBr cm ^-1 : 3400,2950,1740,1630,1530,147
5,1440,1390,1200 MS-FAB (gly): m / z 559,561 (MH ⁺ ).

(3-29) 3- [4- (benzyloxycarbonyl) phenyl] -N
-[N-isobutyl-N- (dihydroxyphosphorylmeth
Cyl) carbamoyl] alanine benzyl ester yield 84.7% N.V. M. R. (CDCl ₃ ) δ: 0.73 (d, 3H, J = 6.22Hz),
0.75 (d, 3H, J = 6.22Hz), 1.72-1.82 (m, 1H), 2.96-3.12 (m, 4
H), 3.47-3.68 (m, 2H), 4.75 (bs, 1H), 5.00 (d, 1H, J = 12.09H
z), 5.13 (d, 1H, J = 12.09Hz), 5.32 (s, 2H), 6.12 (br, 3H), 7.0
2 (d, 2H, J = 8.06Hz), 7.19-7.44 (m, 10H), 7.85 (d, 2H, J = 8.06
Hz) I. R. ν _KBr cm ^-1 : 2960,1720,1620,1530,1280,118
5,1010 MS-FAB (gly): m / z 583 (MH ⁺ ).

(3-30) 3- (4-nitrophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine methyl ester yield 38.0% Melting point: 163-164 ° C N.V. M. R. (DMSO-d ₆ ) δ: 0.73-0.84 (m, 6H),
1.81-1.97 (m, 1H), 3.04-3.25 (m, 4H), 3.36-3.48 (m, 2H), 3.
63 (s, 3H), 4.40-4.54 (m, 1H), 7.51 (d, 2H, J = 8.79Hz), 8.12
(d, 2H, J = 8.79Hz) ¹³ C-N. M. R. (DMSO-d ₆ ) δ: 172.691,15
8.335,146.710,146.196,130.794,123.441,55.195,54.68
2,52.005,45.221 (d, J = 152.0Hz), 37.501,26.573,20.101 I.D. R. ν _KBr cm ^-1 : 3400,2950,1740,1640,1605,152
0,1350,1200 MS-FAB (gly): m / z 418 (MH ⁺ ).

(3-31) 3- (3-trifluoromethylphenyl) -N- [N-
Isobutyl-N- (dihydroxyphosphorylmethyl) carb
Lubamoyl] alanine benzyl ester yield 40.6% N.V. M. R. (CDCl ₃ ) δ: 0.73-0.75 (m, 6H), 1.78
(br, 1H), 3.06-3.13 (m, 4H), 3.58 (br, 2H), 4.78 (bs, 1H), 5.
04 (d, 1H, J = 12.09Hz), 5.11 (d, 1H, J = 12.09Hz), 7.14-7.31
(m, 8H), 7.43 (d, 1H, J = 7.69Hz), 8.25 (br, 2H) I. R. ν _KBr cm ^-1 : 2960,1740,1630,1530,1330,126
0,1200,1160,1120,1070,1000,940 MS-FAB (gly): m / z 517 (MH ⁺ ), 539
(MNa ⁺ )

(3-32) 3-[(5-chloro-2-nitro) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
L) Carbamoyl] alanine methyl ester yield 78.1% N.V. M. R. (CDCl ₃ ) δ: 0.81-0.94 (m, 6H), 1.85
-2.02 (m, 1H), 3.04-3.17 (m, 2H), 3.23-3.36 (m, 1H), 3.44-
3.67 (m, 3H), 3.73 (s, 3H), 4.71-4.80 (m, 1H), 7.35-7.44 (m,
2H), 7.92 (d, 1H, J = 6.79Hz) I. R. ν _KBr cm ^-1 : 3450,2960,1740,1620,1530,140
0,1350,1210,1010 MS-FAB (MNBA): m / z 452,454 (MH ⁺ ).

(3-33) 3- (4-hydroxyphenyl) -N- [N-isobutyl
Le-N- (dihydroxyphosphorylmethyl) carbamoy
L] -L-alanine ethyl ester yield 56.0% N.V. M. R. (CDCl ₃ ) δ: 0.82 (d, 3H, J = 6.59Hz),
0.84 (d, 3H, J = 6.59Hz), 1.23 (t, 3H, J = 7.33Hz), 1.84-1.94
(m, 1H), 2.93-3.11 (m, 4H), 3.44-3.54 (m, 1H), 3.63-3.73
(m, 1H), 4.09-4.17 (m, 2H), 4.55 (t, 1H, J = 5.86Hz), 6.77 (d,
2H, J = 8.43Hz), 6.96 (d, 2H, J = 8.43Hz), 7.23 (br, 3H) I. R. ν _KBr cm ^-1 : 3380,2960,1730,1615,1535,152
0,1200,1010 MS-FAB (gly): m / z 403 (MH ⁺ ) [α] _D = -13.37 ° (c = 0.994, MeOH)

(3-34) 3- (1-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Ninbenzyl ester yield 81.0% N.V. M. R. (CDCl ₃ ) δ: 0.56 (d, 3H, J = 6.59Hz),
0.60 (d, 3H, J = 6.59Hz), 1.54-1.64 (m, 1H), 2.83-2.99 (m, 2
H), 3.43-3.69 (m, 4H), 4.86 (t, 1H, J = 5.86Hz), 4.99 (s, 2H),
7.10-7.13 (m, 3H), 7.22-7.28 (m, 4H), 7.35-7.51 (m, 2H), 7.
69 (d, 1H, J = 8.06Hz), 7.79-7.82 (m, 1H), 8.03 (d, 1H, J = 8.06
Hz), 8.83 (br, 2H) I. R. ν _KBr cm ^-1 : 2950,1740,1630,1530,1190,100
0,950 MS-FAB (gly): m / z 499 (MH ⁺ ).

(3-35) 3- (6-Methyl-2-naphthyl) -N- [N-isobutane
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Il] alanine benzyl ester yield 75.8% N.I. M. R. (CDCl ₃ ) δ: 0.61-0.67 (m, 6H), 1.68
(septet, 1H, J = 6.96Hz), 2.47 (s, 3H), 3.00 (d, 2H, J = 6.23H
z), 3.23 (d, 2H, J = 5.49Hz), 3.46-3.56 (m, 1H), 3.62-3.72
(m, 1H), 4.81 (bs, 1H), 5.03 (d, 1H, J = 12.09Hz), 5.15 (d, 1H,
J = 12.09Hz), 6.63 (bs, 3H), 7.04 (d, 1H, J = 8.43Hz), 7.19-7.
28 (m, 6H), 7.39 (s, 1H), 7.51-7.57 (m, 3H) I. R. ν _KBr cm ^-1 : 2960,1740,1640,1530,1190,101
0,950 MS-FAB (gly): m / z 513 (MH ⁺ ).

(3-36) 3- (6-methoxy-2-naphthyl) -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine benzyl ester yield 79.7% N.V. M. R. (CDCl ₃ ) δ: 0.61 (d, 3H, J = 6.96Hz),
0.64 (d, 3H, J = 6.96Hz), 1.62-1.72 (m, 1H), 3.03 (d, 2H, J = 6.
23Hz), 3.21 (d, 2H, J = 4.76Hz), 3.48-3.67 (m, 2H), 3.87 (s, 3
H), 4.80 (br, 4H), 4.99 (d, 1H, J = 12.46Hz), 5.12 (d, 1H, J = 1
2.46Hz), 7.03-7.09 (m, 3H), 7.16-7.26 (m, 5H), 7.36 (s, 1
H), 7.52 (d, 2H, J = 8.79Hz) I. R. ν _KBr cm ^-1 : 3430,2950,1740,1635,1610,153
0,1270,1230,1200 MS-FAB (gly): m / z 530 (MH ⁺ ).

(3-37) 3- (2-pyridyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin benzyl ester yield 76.0% N.V. M. R. (CDCl ₃ ) δ: 0.76 (d, 3H, J = 6.59Hz),
0.77 (d, 3H, J = 6.59Hz), 1.83-1.93 (m, 1H), 3.14-3.22 (m, 2
H), 3.54-3.57 (m, 4H), 4.87 (t, 1H, J = 6.96Hz), 5.11 (d, 1H, J
= 12.09Hz), 5.19 (d, 1H, J = 12.09Hz), 7.28-7.37 (m, 5H), 7.6
8-7.73 (m, 2H), 8.13-8.19 (m, 1H), 8.78 (d, 1H, J = 5.50Hz),
9.52 (br, 3H) I. R. ν _KBr cm ^-1 : 3320,2960,1740,1640,1540,147
0,1180,1050,990,950 MS-FAB (MNBA): m / z 450 (MH ⁺ ).

(3-38) 3- (3-thienyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin benzyl ester yield 77.8% N.V. M. R. (CDCl ₃ ) δ: 0.76 (bs, 6H), 1.71 (bs,
1H), 2.81-3.19 (m, 4H), 3.28-3.79 (m, 2H), 4.65 (bs, 1H), 5.
01 (d, 1H, J = 11.72Hz), 5.10 (d, 1H, J = 11.72Hz), 6.57-6.65
(m, 1H), 6.72-6.83 (m, 1H), 7.04-7.14 (m, 1H), 7.15-7.35
(m, 5H) ¹³ C-N. M. R. (CDCl ₃ ) δ: 171.870,158.50
3,135.730,135.070,128.542,128.505,128.432,128.304,
125.938,122.986,67.209,56.372,54.154,45.582 (d, J = 14
8.2Hz), 32.279, 27.072, 19.902 I.D. R. ν _KBr cm ^-1 : 3450,2960,1740,1650,1545,146
0,1405,1395,1200 MS-FAB (gly): m / z 455 (MH ⁺ ).

Example 4 (4-1) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Ninbenzyl ester disodium salt 3- (4-biphenyl) obtained in Example (1-10)
-N- [N-isobutyl-N- (diethoxyphosphorylmethyl) carbamoyl] alanine benzyl ester 60
0 mg (1.05 mM) anhydrous acetonitrile 10 ml
To the solution, 350 mg of trimethylsilyl bromide (2.
69 mM) in 4 ml of anhydrous acetonitrile at room temperature for 3
It was dripped in 0 minutes. After completion of dropping, the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to dryness, the obtained concentrated residue was dissolved in ethyl acetate, and the mixture was extracted with saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 3- (4-biphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine benzyl ester disodium salt as 36%.
5 mg (yield 62.1%) was obtained. N. M. R. (CD ₃ OD) δ: 0.80 (d, 3H, J = 6.59Hz),
0.87 (d, 3H, J = 6.59Hz), 1.99 (septet, 1H, J = 6.96Hz), 3.06-
3.24 (m, 4H), 3.30-3.42 (m, 2H), 4.46 (t, 1H, J = 7.69Hz), 5.0
3 (d, 1H, J = 12.46Hz), 5.11 (d, 1H, J = 12.46Hz), 7.14-7.17
(m, 2H), 7.21-7.25 (m, 3H), 7.29-7.33 (m, 3H), 7.39-7.50
(m, 4H), 7.55-7.58 (m, 2H) I. R. ν _KBr cm ^-1 : 3400,2960,1740,1620,1520,151
0,1190,1070,980 MS-FAB (gly): m / z 569 (MH ⁺ ).

The following compounds were synthesized by the same method as in Example (4-1). (4-2) 3- (2-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin benzyl ester disodium salt yield 93.7% Melting point: 180 ° C. (decomposition) N. M. R. (CD ₃ OD) δ: 0.77 (d, 3H, J = 6.59Hz),
0.83 (d, 3H, J = 6.59Hz), 1.89-2.00 (m, 1H), 3.12 (dd, 1H, J = 1
3.92,7.33Hz), 3.22-3.41 (m, 5H), 4.55 (t, 1H, J = 7.57Hz),
4.98 (d, 1H, J = 12.20Hz), 5.04 (d, 1H, J = 12.20Hz), 6.99-7.0
1 (m, 2H), 7.10-7.22 (m, 3H), 7.36-7.44 (m, 3H), 7.67-7.81
(m, 4H) I. R. ν _KBr cm ^-1 : 3400,2960,1740,1620,1525,119
0,1075,980,750 MS-FAB (gly): m / z 543 (MH ⁺ ).

Example 5 (5-1) N-benzyl-3-phenyl-N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
-L-alanine methyl ester disodium salt N-benzyl-3-phenyl-N- [N-isobutyl-N- (diethoxyphosphorylmethyl) carbamoyl] -L-alanine methyl obtained in Example (1-52) To a solution of 750 mg (1.45 mM) of ester in 10 ml of anhydrous acetonitrile, 560 m of trimethylsilyl bromide
A solution of g (3.66 mM) in 5 ml of anhydrous acetonitrile was added dropwise at room temperature over 30 minutes. After completion of dropping, the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to dryness, and the obtained concentrated residue was diluted with ethyl acetate and extracted with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give N-benzyl-3-phenyl-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine methyl ester. Was obtained in an amount of 550 mg (yield: 82.2%). next,
The obtained phosphoric acid (550 mg, 1.19 mM) was dissolved in a solution of sodium hydrogencarbonate (200 mg, 2.38 mM) in water (10 ml), and then adsorbed on HP-20 (40 ml).
After washing with water until the passing solution became neutral, it was eluted with 70% aqueous methanol solution. The eluates were collected and concentrated under reduced pressure to obtain 300 mg of N-benzyl-3-phenyl-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine methyl ester disodium salt (yield 43. 7%) was obtained. N. M. R. (D ₂ O) δ: 0.96-0.98 (m, 6H), 2.19-2.2
6 (m, 1H), 3.26-3.45 (m, 3H), 3.53-3.71 (m, 2H), 3.78-3.97
(m, 4H), 4.24 (dd, 1H, J = 14.16,7.33Hz), 4.69 (d, 1H, J = 16.6
1Hz), 4.83 (d, 1H, J = 16.61Hz), 7.36-7.62 (m, 10H) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1620,1430,124
0,1180,1040,920,730,700 MS-FAB (gly): m / z 507 (MH ⁺ ) [α] _D = -60.79 ° (c = 0.6840, MeOH)

The following compounds were synthesized by the same method as in Example (5-1). (5-2) N-ethyl-3-phenyl-N- [N-isobutyl-N
-(Dihydroxyphosphorylmethyl) carbamoyl]-
L- alanine methyl ester disodium salt yield 47.5% N. M. R. (D ₂ O) δ: 1.03 (d, 6H, J = 6.59Hz), 1.16
(t, 3H, J = 7.08Hz), 2.12-2.17 (m, 1H), 3.25-3.43 (m, 3H), 3.
54-3.65 (m, 4H), 3.76-3.86 (m, 1H), 4.01 (s, 3H), 4.50 (dd, 1
H, J = 9.52,5.61Hz), 7.57-7.69 (m, 5H) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1620,1430,116
0,1060,910,740,700 MS-FAB (gly): m / z 445 (MH ⁺ ) [α] _D = −44.76 ° (c = 0.7230, MeOH)

Example 6 (6-1) 3- [4- (acetamido) phenyl] -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine methyl ester disodium salt 3- [4- (acetamido) phenyl] -N- [N-isobutyl-N- (dibenzyloxyphosphorylmethyl) carbamoyl] alanine methyl obtained in Example (1-44) To a solution of 0.44 g (0.72 mM) of ester in 9 ml of methanol, 120 mg (1.4
4 ml of 2 ml of water was added dropwise. Under nitrogen atmosphere, 1
After adding 0% palladium carbon (150 mg), the mixture was stirred under hydrogen substitution at room temperature for 1 hr. After the reaction was completed, palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. After azeotropic distillation with ethanol, washing with ether gave 0.33 g of 3- [4- (acetamido) phenyl] -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine methyl ester disodium salt ( Yield 9
6.6%). Melting point: 183-184 ° C (decomposition) N. M. R. (CD ₃ OD) δ: 0.79 (d, 3H, J = 6.59Hz),
0.86 (d, 3H, J = 6.59Hz), 1.97 (septet, 1H, J = 6.96Hz), 2.10
(s, 3H), 2.92-3.38 (m, 6H), 3.65 (s, 3H), 4.33 (dd, 1H, J = 8.0
6,6.59Hz), 7.20 (d, 2H, J = 8.79Hz), 7.46 (d, 2H, J = 8.79Hz) I. R. ν _KBr cm ^-1 : 3400,2960,1735,1670,1630,151
5,1415,1225,1070,970 MS-FAB (gly): m / z 474 (MH ⁺ ), 496
(MNa ⁺ )

The following compounds were synthesized by the same method as in Example (6-1). (6-2) 3- [4- (4-methylphenyl) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
L) Carbamoyl] -L-alanine ethyl ester yield 75.4% N.V. M. R. (CDCl ₃ ) δ: 0.80 (d, 3H, J = 6.59Hz),
0.82 (d, 3H, J = 6.59Hz), 1.26 (t, 3H, J = 7.08Hz), 1.78-1.86
(m, 1H), 2.38 (s, 3H), 3.05 (d, 2H, J = 7.56Hz), 3.16 (d, 2H, J =
5.62Hz), 3.51-3.75 (m, 2H), 4.29 (q, 2H, J = 7.08Hz), 4.69
(t, 1H, J = 5.62Hz), 5.50 (bs, 1H), 7.15 (d, 2H, J = 8.05Hz), 7.
23 (d, 2H, J = 8.30Hz), 7.44 (d, 2H, J = 8.05Hz), 7.50 (d, 2H, J =
8.30Hz) I. R. ν _KBr cm ^-1 : 2950,1740,1610,1520,1190,100
0,800 MS-FAB (MNBA): m / z 477 (MH ⁺ ), 49
9 (MNa ⁺ ) [α] _D = -13.38 ° (c = 0.6146, MeOH)

(6-3) 3- [4- (methylsulfonyl) phenyl] -N- [N
-Isobutyl-N- (dihydroxyphosphorylmethyl)
Carbamoyl] alanine methyl ester disodium
Salt yield 96.6% Melting point: 165-166 ℃ (decomposition) N. M. R. (CD ₃ OD) δ: 0.78 (d, 3H, J = 6.60Hz),
0.84 (d, 3H, J = 6.60Hz), 1.96 (septet, 1H, J = 6.84Hz), 3.04-
3.35 (m, 9H), 3.68 (s, 3H), 4.41 (dd, 1H, J = 8.79,5.86Hz), 7.
56 (d, 2H, J = 8.55Hz), 7.88 (d, 2H, J = 8.55Hz) R. ν _KBr cm ^-1 : 3400,2960,1740,1630,1530,130
5,1150,1090 MS-FAB (gly): m / z 495 (MH ⁺ ), 517
(MNa ⁺ )

(6-4) 3- (4-aminophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine methyl ester disodium salt yield 89.2% Melting point: 107-110 ° C. (decomposition) N. M. R. (DMSO-d ₆ ) δ: 0.76 (d, 3H, J = 6.59
Hz), 0.77 (d, 3H, J = 6.59Hz), 1.91 (septet, 1H, J = 6.96Hz),
2.71 (d, 2H, J = 7.33Hz), 3.01-3.14 (m, 4H), 3.49 (s, 3H), 4.0
1 (bs, 1H), 6.46 (d, 2H, J = 8.42Hz), 6.85 (d, 2H, J = 8.42Hz) I. R. ν _KBr cm ^-1 : 3430,3350,2960,1735,1630,152
0,1205,1180,1060 MS-FAB (gly): m / z 432 (MH ⁺ ).

Example 7 (7-1) 3- (2-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt 410 mg (0.89 mM) of 3- (2-methylphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine benzyl ester obtained in Example (3-3) A solution of 220 mg (2.66 mM) of sodium hydrogen carbonate in 3 ml of water was added dropwise to a solution of 5 ml of methanol. In a nitrogen atmosphere, 140 mg of 10% palladium carbon was added, and then at room temperature under hydrogen substitution.
Stirred for hours. After the reaction is completed, palladium carbon is filtered off,
The filtrate was concentrated under reduced pressure. After azeotropic distillation with ethanol, 340 mg of 3- (2-methylphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt was obtained by crystallization from methanol / ether (yield 87 .5%) was obtained. Melting point:> 300 ° C. N.V. M. R. (D ₂ O) δ: 1.00-1.05 (m, 6H), 2.05-2.1
5 (m, 1H), 2.64 (s, 3H), 3.21 (dd, 1H, J = 13.91,8.55Hz), 3.29
-3.51 (m, 4H), 3.56-3.65 (m, 1H), 4.53 (dd, 1H, J = 8.54,6.35
Hz), 7.45-7.57 (m, 4H) I. R. ν _KBr cm ^-1 : 3400,2960,1620,1590,1520,140
0,1085,990,980

The following compounds were synthesized by the same method as in Example (7-1). (7-2) 3- (3-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt yield 87.9% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.92 (d, 3H, J = 6.59Hz), 0.93
(d, 3H, J = 6.59Hz), 1.92-2.02 (m, 1H), 2.51 (s, 3H), 3.04-3.
12 (m, 1H), 3.19-3.42 (m, 4H), 3.55-3.67 (m, 1H), 4.45 (dd, 1
H, J = 8.30,5.37Hz), 7.29-7.33 (m, 3H), 7.42-7.48 (m, 1H) ¹³ C-N. M. R. (D ₂ O) δ: 183.226, 162.286,14
1.511,132.985,131.537,130.161,129.263,60.907,57.31
3,49.117 (d, J = 142.0Hz), 41.177,29.021,23.465,22.328,
22.218 I. R. ν _KBr cm ^-1 : 3400,2950,1620,1590,1530,140
0,1260,1090,990,980 MS-FAB (gly): m / z 439 (MH ⁺ ), 461
(MNa ⁺ )

(7-3) 3- (4-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt yield 79.1% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.98-1.03 (m, 6H), 2.00-2.1
0 (m, 1H), 2.58 (s, 3H), 3.16 (dd, 1H, J = 13.92,8.54Hz), 3.26
-3.52 (m, 4H), 3.57-3.67 (m, 1H), 4.50 (dd, 1H, J = 8.54,5.37
Hz), 7.45-7.51 (m, 4H) I. R. ν _KBr cm ^-1 : 3400,2960,1620,1595,1530,140
5,1260,1090,990,980 MS-FAB (gly): m / z 439 (MH ⁺ ), 461
(MNa ⁺ )

(7-4) 3- (4-n-butylphenyl) -N- [N-isobutyl
Le-N- (dihydroxyphosphorylmethyl) carbamoy
Le] alanine 3 sodium salt yield 82.5% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.98 (d, 3H, J = 6.60Hz), 1.00
(d, 3H, J = 6.60Hz), 1.17 (t, 3H, J = 7.33Hz), 1.52-1.65 (m, 2
H), 1.79-1.90 (m, 2H), 2.02 (septet, 1H, J = 6.84Hz), 2.87
(t, 2H, J = 7.57Hz), 3.15 (dd, 1H, J = 13.91,8.79Hz), 3.25-3.
52 (m, 4H), 3.58-3.68 (m, 1H), 4.51 (dd, 1H, J = 8.79,5.37H
z), 7.50 (s, 4H) I. R. ν _KBr cm ^-1 : 3400,2960,2930,1620,1600,153
0,1410,1090 MS-FAB (gly): m / z 481 (MH ⁺ ), 503
(MNa ⁺ )

(7-5) 3- (4-isopropylphenyl) -N- [N-isobu
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Yl] alanine 3 sodium salt yield 94.3% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.98 (d, 3H, J = 6.59Hz), 0.99
(d, 3H, J = 6.59Hz), 1.49 (d, 6H, J = 7.08Hz), 1.98-2.08 (m, 1
H), 3.11-3.52 (m, 6H), 3.59-3.69 (m, 1H), 4.51 (dd, 1H, J = 8.
79,5.13Hz), 7.54 (s, 4H) I. R. ν _KBr cm ^-1 : 3400,2960,1620,1590,1520,140
5,1260,1080,985,975 MS-FAB (gly): m / z 467 (MH ⁺ ), 489
(MNa ⁺ )

(7-6) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin trisodium salt yield 70.1% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.91-0.96 (m, 6H), 1.92-2.0
2 (m, 1H), 3.19-3.69 (m, 6H), 4.61 (dd, 1H, J = 9.04,5.37Hz),
7.68-7.72 (m, 3H), 7.77-7.83 (m, 2H), 7.91-8.00 (m, 4H) I. R. ν _KBr cm ^-1 : 3400,1620,1590,1530,1400,109
0 MS-FAB (gly): m / z 501 (MH ⁺ ), 523
(MNa ⁺ )

(7-7) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -L
- alanine 3 sodium salt yield 88.5% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.91-0.97 (m, 6H), 1.97 (br,
1H), 3.21-3.70 (m, 6H), 4.61-4.66 (m, 1H), 7.71-8.01 (m, 9
H) I. R. ν _KBr cm ^-1 : 3400,2950,1600,1520,1410,126
0,1080,980,820,760,690 MS-FAB (gly): m / z 501 (MH ⁺ ), 523
(MNa ⁺ ) [α] _D = −50.15 ° (c = 0.6190, MeOH)

(7-8) 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -D
- alanine 3 sodium salt yield 98.1% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 1.05-1.11 (m, 6H), 2.07-2.1
6 (m, 1H), 3.34-3.70 (m, 6H), 4.77 (dd, 1H, J = 9.04,5.37Hz),
7.80-8.14 (m, 9H) I. R. ν _KBr cm ^-1 : 3400,2950,1600,1520,1400,126
0,1070,760,700 MS-FAB (gly): m / z 501 (MH ⁺ ) [α] _D = + 46.04 ° (c = 0.5940, MeOH)

(7-9) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
Le] alanine 3 sodium salt yield 79.7% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.96-1.02 (m, 6H), 1.97-2.0
7 (m, 1H), 3.14 (dd, 1H, J = 13.92,8.54Hz), 3.25-3.51 (m, 4
H), 3.62 (br, 1H), 4.10 (s, 3H), 4.50 (dd, 1H, J = 8.55,5.37H
z), 7.24 (d, 2H, J = 8.78Hz), 7.54 (d, 2H, J = 8.78Hz) I. R. ν _KBr cm ^-1 : 3400,2960,1615,1595,1520,140
0,1260,1090,980 MS-FAB (gly): m / z 455 (MH ⁺ ), 477
(MNa ⁺ )

(7-10) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
Le]-D-alanine 3 sodium salt yield 98.0% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.91 (d, 6H, J = 6.59Hz), 1.92
-1.97 (m, 1H), 3.02-3.60 (m, 6H), 4.02 (s, 3H), 4.04-4.47
(m, 1H), 7.15 (d, 2H, J = 8.54Hz), 7.45 (d, 2H, J = 8.54Hz) I. R. ν _KBr cm ^-1 : 3400,2950,1600,1510,1400,124
0,1070,970,820,750 MS-FAB (gly): m / z 455 (MH ⁺ ), 477
(MNa ⁺ ) [α] _D = + 67.38 ° (c = 0.5700, MeOH)

(7-11) 3- (4-methoxyphenyl) -N- [Nn-propene
Le-N- (dihydroxyphosphorylmethyl) carbamoy
Le] -L- alanine trisodium salt yield 95.9% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.94 (t, 3H, J = 7.33Hz), 1.52
-1.61 (m, 2H), 3.02-3.10 (m, 1H), 3.27-3.53 (m, 5H), 4.02
(s, 3H), 4.38-4.43 (m, 1H), 7.17 (d, 2H, J = 8.61Hz), 7.47 (d,
2H, J = 8.61Hz) I. R. ν _KBr cm ^-1 : 3400,1600,1520,1410,1250,108
0,980,830 [α] _D = −73.90 ° (c = 0.7300, MeOH)

(7-12) 3- (4-n-butoxyphenyl) -N- [N-isobutane
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Yl] -L- alanine trisodium salt yield 89.9% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.87-0.92 (m, 6H), 1.13 (t, 3
H, J = 7.32Hz), 1.64 (sextet, 2H, J = 7.33Hz), 1.88-1.98 (m, 3
H), 3.01-3.09 (m, 1H), 3.13-3.52 (m, 5H), 4.27 (t, 2H, J = 6.6
0Hz), 4.43 (dd, 1H, J = 8.79,5.61Hz), 7.16 (d, 2H, J = 8.54H
z), 7.45 (d, 2H, J = 8.54Hz) I. R. ν _KBr cm ^-1 : 3400,2960,1600,1515,1410,125
0,1080,980 MS-FAB (gly): m / z 497 (MH ⁺ ), 519
(MNa ⁺ ) [α] _D = −46.46 ° (c = 1.024, MeOH)

(7-13) 3-[(4-ethoxycarbonylmethoxy) phenyl]
-N- [N-isobutyl-N- (dihydroxyphosphoryl
Lumethyl) carbamoyl] -L-alanine 3 sodium
Salt-free yield 87.9% Melting point:> 300 ℃ N. M. R. (D ₂ O) δ: 0.88-0.93 (m, 6H), 1.47 (t, 3
H, J = 7.08Hz), 1.92-1.97 (m, 1H), 3.06 (dd, 1H, J = 13.92,8.5
5Hz), 3.14-3.42 (m, 5H), 4.39-4.51 (m, 3H), 4.96 (s, 2H), 7.
14 (d, 2H, J = 8.54Hz), 7.46 (d, 2H, J = 8.54Hz) R. ν _KBr cm ^-1 : 3350,2960,1760,1600,1515,141
0,1205,1080,980 MS-FAB (gly): m / z 527 (MH ⁺ ), 549
(MNa ⁺ ) [α] _D = −53.85 ° (c = 0.864, MeOH)

(7-14) 3- (2-benzylphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
Le] alanine 3 sodium salt yield 87.3% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 1.01-1.06 (m, 6H), 2.06-2.1
6 (m, 1H), 3.23 (dd, 1H, J = 14.16,8.54Hz), 3.29-3.54 (m, 4
H), 3.60-3.70 (m, 1H), 4.41 (s, 2H), 4.54 (dd, 1H, J = 8.55,6.
35Hz), 7.44-7.56 (m, 6H), 7.59-7.66 (m, 3H) I. R. ν _KBr cm ^-1 : 3300,2960,1595,1520,1400,111
0,1070,990 MS-FAB (gly): m / z 515 (MH ⁺ ), 537
(MNa ⁺ )

(7-15) 3- (4-carboxyphenyl) -N- [N-isobutyi
Le-N- (dihydroxyphosphorylmethyl) carbamoy
Le] alanine tetrasodium salt yield 84.9% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.94 (d, 3H, J = 6.59Hz), 0.97
(d, 3H, J = 6.59Hz), 1.90-2.00 (m, 1H), 3.20-3.52 (m, 5H), 3.
59-3.69 (m, 1H), 4.59 (dd, 1H, J = 8.79,5.61Hz), 7.63 (d, 2H,
J = 8.30Hz), 8.09 (d, 2H, J = 8.30Hz) R. ν _KBr cm ^-1 : 3370,1590,1555,1540,1405,108
0,1065 MS-FAB (gly): m / z 491 (MH ⁺ ), 513
(MNa ⁺ )

(7-16) 3- (1-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin trisodium salt yield 90.4% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.91 (d, 3H, J = 6.59Hz), 0.96
(d, 3H, J = 6.59Hz), 1.97 (br, 1H), 3.26-3.50 (m, 3H), 3.56-
3.79 (m, 2H), 3.98 (dd, 1H, J = 14.16,6.10Hz), 4.77-4.82 (m,
1H), 7.84-8.02 (m, 4H), 8.16-8.20 (m, 1H), 8.30 (d, 1H, J = 8.
06Hz), 8.62 (d, 1H, J = 8.30Hz) ¹³ C-N. M. R. (D ₂ O) δ: 183.336, 162.469,13
7.716,136.616,134.819,131.702,130.803,130.161,129.
373,128.878,126.916,60.316,57.221,49.337 (d, J = 142.0
Hz), 38.647,28.892,22.255,22.108 I.D. R. ν _KBr cm ^-1 : 3400,1620,1590,1520,1400,109
0,980 MS-FAB (gly): m / z 475 (MH ⁺ ), 497
(MNa ⁺ )

(7-17) 3- (2-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin trisodium salt yield 77.4% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.68 (d, 3H, J = 6.59Hz), 0.72
(d, 3H, J = 6.59Hz), 1.70-1.80 (m, 1H), 3.11-3.37 (m, 4H), 3.
46-3.64 (m, 2H), 4.59 (dd, 1H, J = 8.79,5.37Hz), 7.66-7.76
(m, 3H), 7.93-8.12 (m, 4H) ¹³ C-N. M. R. (D ₂ O) δ: 183.244, 162.323,13
9.439,136.231,135.039,130.932,130.803,130.712,130.
638,130.547,129.190,128.658,60.778,57.148,49.346
(d, J = 140.7Hz), 41.581, 28.856, 22.126, 21.943 I.D. R. ν _KBr cm ^-1 : 3400,2950,1615,1590,1520,140
0,1260,1080,995,980

(7-18) 3- (6-Methyl-2-naphthyl) -N- [N-isobutane
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Yl] alanine 3 sodium salt yield 93.0% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.69 (d, 3H, J = 6.59Hz), 0.73
(d, 3H, J = 6.59Hz), 1.71-1.81 (m, 1H), 2.67 (s, 3H), 3.12-3.
37 (m, 4H), 3.48-3.55 (m, 2H), 4.57 (dd, 1H, J = 9.04,5.37H
z), 7.58-7.66 (m, 2H), 7.88 (s, 1H), 7.94 (s, 1H), 7.97-8.03
(m, 2H) I. R. ν _KBr cm ^-1 : 3350,2950,1620,1590,1530,140
5,1080,980 MS-FAB (gly): m / z 489 (MH ⁺ ), 511
(MNa ⁺ )

(7-19) 3- (6-methoxy-2-naphthyl) -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moil] alanine 3 sodium salt yield 80.6% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.70 (d, 3H, J = 6.59Hz), 0.74
(d, 3H, J = 6.59Hz), 1.74 (br, 1H), 3.13-3.39 (m, 4H), 3.51-
3.58 (m, 2H), 4.16 (s, 3H), 4.59 (dd, 1H, J = 9.03,5.37Hz), 7.
42 (dd, 1H, J = 9.03,2.69Hz), 7.57 (d, 1H, J = 2.69Hz), 7.67 (d
d, 1H, J = 8.30,1.71Hz), 7.95 (s, 1H), 8.00-8.08 (m, 2H) I. R. ν _KBr cm ^-1 : 3400,1610,1525,1400,1270,108
0,980 MS-FAB (gly): m / z 505 (MH ⁺ ), 527
(MNa ⁺ )

(7-20) 3- (2-pyridyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin trisodium salt yield 95.1% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 1.00 (d, 3H, J = 6.59Hz), 1.04
(d, 3H, J = 6.59Hz), 2.02-2.12 (m, 1H), 3.30-3.52 (m, 4H), 3.
57-3.68 (m, 2H), 4.69 (dd, 1H, J = 9.52,5.61Hz), 7.62 (ddd, 1
H, J = 7.57,5.13,1.22Hz), 7.73 (d, 1H, J = 8.05Hz), 8.12 (td,
1H, J = 7.57,1.71Hz), 8.75 (ddd, 1H, J = 5.13,1.69,0.73Hz) ¹³ C-N. M. R. (D ₂ O) δ: 182.875, 162.444,16
0.946,151.285,141.004,127.527,125.339,60.085,57.30
7,49.452 (d, J = 141.83Hz), 43.383,28.942,22.319,22.189 I.D. R. ν _KBr cm ⁻¹ : 3400,1600,1530,1405,1080,980 MS-FAB (gly): m / z 426 (MH ⁺ ), 448
(MNa ⁺ )

(7-21) 3- (3-thienyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] ara
Nin trisodium salt yield 98.2% Melting point: 290 ° C. (decomposition) N. M. R. (D ₂ O) δ: 0.97 (d, 3H, J = 6.60Hz), 0.98
(d, 3H, J = 6.60Hz), 1.94-2.17 (m, 1H), 3.11-3.68 (m, 6H), 4.
37-4.48 (m, 1H), 7.27 (d, 1H, J = 4.76Hz), 7.42 (s, 1H), 7.53-
7.67 (m, 1H) ¹³ C-N. M. R. (D ₂ O) δ: 183.152, 162.598,14
1.676,131.793,128.841,125.504,60.430,57.386,49.493
(d, J = 140.8Hz), 35.842,29.039,22.365,22.291 I. R. ν _KBr cm ^-1 : 3400,1620,1600,1530,1410,126
0,1080,980 MS-FAB (gly): m / z 431 (MH ⁺ ).

(7-22) 3- (3-trifluoromethylphenyl) -N- [N-
Isobutyl-N- (dihydroxyphosphorylmethyl) carb
Rubamoiru] alanine 3 sodium salt yield 86.6% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 0.95 (d, 3H, J = 6.59Hz), 0.99
(d, 3H, J = 6.59Hz), 1.98-2.08 (m, 1H), 3.24-3.39 (m, 3H), 3.
44-3.67 (m, 3H), 4.57-4.62 (m, 1H), 7.76-7.89 (m, 4H) I. R. ν _KBr cm ^-1 : 3400,1600,1530,1400,1330,117
0,1125,1075,980 MS-FAB (gly): m / z 493 (MH ⁺ ), 515
(MNa ⁺ )

(7-23) 3- (4-hydroxyphenyl) -N- [N-isobutyi
Le-N- (dihydroxyphosphorylmethyl) carbamoy
Le] -L- alanine trisodium salt yield 100% Melting point: 189 ° C. (decomposition) N. M. R. (D ₂ O) δ: 1.00 (d, 3H, J = 6.59Hz), 1.01
(d, 3H, J = 6.59Hz), 1.98 (septet, 1H, J = 6.84Hz), 3.17 (dd, 1
H, J = 13.92,8.54Hz), 3.29-3.44 (m, 3H), 3.56 (dd, 1H, J = 16.
11,8.79Hz), 3.83-3.93 (m, 1H), 4.61 (dd, 1H, J = 8.54,5.37H
z), 7.13 (d, 2H, J = 8.54Hz), 7.44 (d, 2H, J = 8.54Hz) I. R. ν _KBr cm ^-1 : 3430,2960,1610,1520,1260,117
0,1060 MS-FAB (gly): m / z 441 (MH ⁺ ) [α] _D = -18.38 ° (c = 0.9300, MeOH)

(7-24) 3- (4-aminophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt yield 93.8% Melting point:> 300 ° C. N. M. R. (D ₂ O) δ: 1.01 (d, 3H, J = 6.59Hz), 1.03
(d, 3H, J = 6.59Hz), 2.07 (septet, 1H, J = 7.08Hz), 3.09 (dd, 1
H, J = 13.91,8.30Hz), 3.27-3.51 (m, 4H), 3.59-3.69 (m, 1H),
4.45 (dd, 1H, J = 8.30,5.61Hz), 7.07 (d, 2H, J = 8.30Hz), 7.40
(d, 2H, J = 8.30Hz) I. R. ν _KBr cm ^-1 : 3400,2970,1620,1590,1520,140
0,1090,980 MS-FAB (gly): m / z 440 (MH ⁺ ).

Example 8 (8-1) 3-phenyl-N- [N-isobutyl-N- (dihydro
Xyphosphorylmethyl) carbamoyl] -L-alanine 3-phenyl-N- [N- obtained in Example (3-1)
Isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine ethyl ester 250 mg
To a solution of (0.65 mM) in 5 ml of methanol was added dropwise a solution of 70 mg (1.06 mM) of 85% potassium hydroxide in 5 ml of water and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to dryness to give 3-phenyl-N-.
[N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine as an amorphous substance 1
60 mg (yield 69%) was obtained. N. M. R. (CDCl ₃ ) δ: 0.71-0.74 (m, 6H), 1.71
-1.83 (m, 1H), 2.95-3.03 (m, 2H), 3.19-3.45 (m, 3H), 3.61-
3.75 (m, 1H), 4.64 (bs, 1H), 7.17-7.24 (m, 5H), 7.24-7.28
(m, 2H) I. R. ν _KBr cm ^-1 : 3400,2950,1700,1620,1530,120
0,1000,940,750,700 [α] _D = −6.84 ° (c = 1.0044, MeOH)

The following compounds were synthesized by the same method as in Example (8-1). (8-2) 3-phenyl-N- [N-ethyl-N- (dihydroxy
Phosphorylmethyl) carbamoyl] -L-alanine yield 32.2% N.V. M. R. (DMSO-d ₆ ) δ: 0.94 (t, 3H, J = 6.96
Hz), 2.84-3.05 (m, 2H), 3.26-3.40 (m, 4H), 4.18-4.26 (m, 1
H), 6.70-6.75 (m, 1H), 7.18-7.30 (m, 5H) I. R. ν _KBr cm ^-1 : 3400,1720,1630,1540,1450,122
0,1020,810,750,700 [α] _D = -13.13 ° (c = 0.4380, MeOH)

(8-3) 3- (4-methoxyphenyl) -N- [N-isobutyl
-N- (dihydroxyphosphorylmethyl) carbamoy
L] -L-alanine yield 51.8% N.V. M. R. (DMSO-d ₆ ) δ: 0.73 (d, 6H, J = 6.60
Hz), 1.83-1.91 (m, 1H), 2.76-2.98 (m, 2H), 3.06-3.09 (m, 7
H), 4.64-4.67 (m, 1H), 6.25 (bs, 2H), 6.82 (d, 2H, J = 8.55H
z), 7.00 (d, 2H, J = 8.55Hz) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1620,1250,118
0,1020,840,750 MS-FAB (gly): m / z 389 (MH ⁺ ), 411
(MNa ⁺ ) [α] _D = -6.32 ° (c = 0.6020, MeOH)

(8-4) 3- (3,4-dimethoxyphenyl) -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine yield 87.2% Melting point: 65-67 ° C N.V. M. R. (CD ₃ OD) δ: 0.82-0.91 (m, 6H), 1.83
-1.97 (m, 1H), 2.90-3.27 (m, 4H), 3.32-3.45 (m, 2H), 3.79
(s, 3H), 3.83 (s, 3H), 4.40-4.52 (m, 1H), 6.78-6.96 (m, 3H) ^13C -N. M. R. (CD ₃ OD) δ: 177.589,160.99
5,150.489,149.481,132.080,123.205,114.642,113.249,
57.545,56.811,56.316,45.031 (d, J = 145.7Hz), 38.805,2
8.207,20.763,20.634 I.D. R. ν _KBr cm ^-1 : 3400,2950,1620,1540,1500,147
0,1390,1260,1240 MS-FAB (gly): m / z 419 (MH ⁺ ).

(8-5) 3- (3-butylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine yield 73% N. M. R. (DMSO-d ₆ ) δ: 0.71-0.74 (m, 6H),
1.81-1.81 (m, 1H), 2.86-3.11 (m, 4H), 3.28-3.51 (m, 2H), 4.
22-4.29 (m, 1H), 6.78 (bs, 1H), 7.19-7.27 (m, 2H), 7.37-7.4
3 (m, 2H) I. R. ν _KBr cm ^-1 : 3400,2950,1720,1620,1530,120
0,1000,940 MS-FAB (gly): m / z 437,439 (MH ⁺ ),
459,461 (MNa ⁺ )

(8-6) 3- (3-Bromophenyl) -N- [N-isobutyl-
N- [hydroxy (4-phenylbutyl) phosphorylmeth
Chill] carbamoyl] alanine yield 80.2% N.V. M. R. (CDCl ₃ ) δ: 0.75-0.83 (m, 6H), 1.61
-1.78 (m, 7H), 2.57-2.65 (m, 2H), 3.00-3.30 (m, 5H), 3.70-
3.78 (m, 1H), 4.54-4.62 (m, 1H), 6.78 (bs, 1H), 7.11-7.32
(m, 9H) I. R. ν _KBr cm ^-1 : 3400,2950,1720,1620,1520,117
0,1070,960,850,700 MS-FAB (gly): m / z 553,555 (MH ⁺ ).

(8-7) 3- (3-Bromophenyl) -N- [Nn-propyl]
-N- (dihydroxyphosphorylmethyl) carbamoy
Le] alanine yield 88.6% N. M. R. (DMSO-d ₆ ) δ: 0.76 (t, 3H, J = 7.33
Hz), 1.34-1.44 (m, 2H), 2.86-3.06 (m, 2H), 3.16-3.26 (m, 2
H), 3.32-3.49 (m, 2H), 4.21-4.27 (m, 1H), 7.20-7.25 (m, 2
H), 7.38-7.44 (m, 2H) I. R. ν _KBr cm ^-1 : 3400,2950,1740,1630,1540,120
0,1010,950,700 MS-FAB (gly): m / z 423,425 (MH ⁺ ).

(8-8) 3- (4-Bromophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine yield 73.3% N.A. M. R. (DMSO-d ₆ ) δ: 0.78 (d, 6H, J = 6.83
Hz), 1.91 (septet, 1H, J = 6.84Hz), 2.93 (dd, 1H, J = 13.67,8.
79Hz), 3.06 (dd, 1H, J = 13.67,5.37Hz), 3.13 (d, 2H, J = 6.32H
z), 3.34-3.53 (m, 2H), 4.31 (bs, 1H), 5.72 (br, 3H), 6.86 (b
s, 1H), 7.25 (d, 2H, J = 8.30Hz), 7.49 (d, 2H, J = 8.30Hz) ¹³ C-N. M. R. (DMSO-d ₆ ) δ: 173.590,15
7.821,137.487,131.454,130.849,119.389,55.122,54.02
2,44.827 (d, J = 150.7Hz), 36.511, 26.060, 19.572 I.D. R. ν _KBr cm ^-1 : 3400,1960,1730,1620,1540,149
0,1200,1015 MS-FAB (gly): m / z 437,439 (MH ⁺ ).

(8-9) 3- (3,4-dichlorophenyl) -N- [N-isobutane
Cyl-N- (dihydroxyphosphorylmethyl) carbamo
Il] alanine yield 88.8% N. M. R. (DMSO-d ₆ ) δ: 0.72 (d, 3H, J = 6.83
Hz), 0.73 (d, 3H, J = 6.83Hz), 1.85 (septet, 1H, J = 6.84Hz),
2.91 (dd, 1H, J = 13.68,8.79Hz), 3.01-3.17 (m, 3H), 3.29-3.
48 (m, 2H), 4.30 (bs, 1H), 6.87 (br, 1H), 7.24 (dd, 1H, J = 8.3
0, 1.95Hz), 7.46-7.49 (m, 2H) I. R. ν _KBr cm ^-1 : 3400,2960,1720,1630,1540,147
5,1200,1135,1035,1010,945 MS-FAB (gly): m / z 427,429 (MH ⁺ ),
449,451 (MNa ⁺ )

(8-10) 3-[(3-chloro-4-methyl) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
Le) carbamoyl] alanine yield 50.4% N. M. R. (CDCl ₃ ) δ: 0.69-0.87 (m, 6H), 1.64
-1.85 (m, 1H), 2.30 (s, 3H), 2.85-3.27 (m, 4H), 3.61-3.77
(m, 2H), 4.50-4.68 (m, 1H), 6.83-7.24 (m, 3H), 9.07 (br, 3H) ¹³ C-N. M. R. (CDCl ₃ ) δ: 172.493,158.52
1,135.968,134.355,132.888,131.916,129.826,129.055,
56.409,54.777,45.389 (d, J = 149.5Hz), 37.266,29.198,2
7.127,19.682,19.590 I. R. ν _NaCl cm ⁻¹ : 3400,2950,1720,1620,1530,122
0,1010 MS-FAB (gly): m / z 408,410 (MH ⁺ ).

(8-11) 3-[(5-Bromo-2-methoxy) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
Le) Carbamoyl] alanine yield 45.2% N.V. M. R. (CDCl ₃ ) δ: 0.65-0.90 (m, 6H), 1.72
-1.96 (m, 1H), 2.84-3.75 (m, 6H), 3.81 (s, 3H), 4.48-4.67
(m, 1H), 6.66-6.78 (m, 1H), 7.17-7.38 (m, 2H) I. R. ν _KBr cm ^-1 : 3400,2960,1730,1630,1540,150
0,1470,1250 MS-FAB (MNBA): m / z 467,469 (MH ⁺ ).

(8-12) 3- [2- (4-bromophenylthio) phenyl] -N
-[N-isobutyl-N- (dihydroxyphosphorylmeth
Chill) carbamoyl] alanine yield 56.6% Melting point 283 ° C. (decomposition) N.C. M. R. (D ₂ O) δ: 0.92 (d, 3H, J = 6.96Hz), 0.94
(d, 3H, J = 6.96Hz), 1.93-2.07 (m, 1H), 3.14-3.60 (m, 6H), 4.
56-4.67 (m, 1H), 7.36 (d, 2H, J = 8.42Hz), 7.41-7.71 (m, 6H) ¹³ C-N. M. R. (D ₂ O) δ: 183.061, 162.396,14
3.528,138.798,136.927,136.047,135.222,134.452,134.
159,131.830,130.968,122.937,60.247,57.240,49.392
(d, J = 142.0Hz), 39.876, 29.039, 22.438, 22.291 I. R. ν _KBr cm ^-1 : 3400,1600,1520,1470,1390,126
0,1070,980 MS-FAB (gly): m / z 545,547 (MH ⁺ ),
567,569 (MNa ⁺ )

(8-13) 3- (4-nitrophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine yield 94.8% Melting point: 75-77 ° C N.A. M. R. (CD ₃ OD) δ: 0.81 (d, 6H, J = 6.59Hz),
1.82-1.98 (m, 1H), 3.11-3.43 (m, 4H), 3.53-3.67 (m, 2H), 4.
60-4.68 (m, 1H), 7.40 (d, 2H, J = 8.42Hz), 8.04 (d, 2H, J = 8.42
Hz) ¹³ C-N. M. R. (CD ₃ OD) δ: 175.297,159.87
7,148.215,146.895,131.585,124.324,56.078,52.759,4
5.800 (d, J = 155.7Hz), 38.420, 27.840, 20.194, 20.139 I.D. R. ν _KBr cm ^-1 : 3400,2950,1720,1605,1520,135
0,1200 MS-FAB (gly): m / z 404 (MH ⁺ ).

(8-14) 3-[(5-chloro-2-nitro) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
Le) Carbamoyl] alanine yield 75.3% N.V. M. R. (CDCl ₃ ) δ: 0.64-0.92 (m, 6H), 1.66
-1.88 (m, 1H), 3.00-3.78 (m, 6H), 4.64-4.86 (m, 1H), 7.36
(d, 1H, J = 8.79Hz), 7.49 (s, 1H), 7.92 (d, 1H, J = 8.42Hz) I. R. ν _KBr cm ^-1 : 3400,2950,1720,1600,1570,152
0,1340,1200 MS-FAB (MNBA): m / z 438,440 (MH ⁺ ).

(8-15) 3- [4- (4-methylphenyl) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl
Le) carbamoyl] -L-alanine yield 69.3% N.V. M. R. (CDCl ₃ + DMSO-d ₆ ) δ: 0.82
(d, 3H, J = 6.59Hz), 0.83 (d, 3H, J = 6.59Hz), 1.87-1.97 (m, 1
H), 2.38 (s, 3H), 3.03-3.25 (m, 4H), 3.46-3.71 (m, 3H), 7.23
(d, 2H, J = 8.06Hz), 7.30 (d, 2H, J = 8.06Hz), 7.45-7.50 (m, 4
H) I. R. ν _KBr cm ^-1 : 3400,2950,1720,1610,1530,119
0,1000,800 MS-FAB (gly): m / z 449 (MH ⁺ ) [α] _D = -7.41 ° (c = 0.6090, MeOH)

Example 9 (9-1) 3- [4- (acetamido) phenyl] -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine 3- [4- (acetamide) obtained in Example (6-1)
Phenyl] -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine methyl ester disodium salt 0.265 g (0.56 mM)
85% potassium hydroxide 0.1% in 3 ml methanol solution
A solution of 1 g (1.68 mM) in 2 ml of water was added dropwise at room temperature for 1
Stir for 9 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in a small amount of water. In addition to this, cationic resin (Amberlite 12
0-B (H ⁺ )) was added little by little until the liquid property reached pH 2-3, and the mixture was stirred at room temperature for 10 minutes. The resin was transferred to a column tube and slowly eluted with water. The crystals obtained by concentrating the elution part of the target substance under reduced pressure were washed with ether, collected by filtration, and dried to give 3- [4- (acetamido) phenyl] -N- [N-isobutyl-N- (dihydroxyphosphoryl). 0.10 g of methyl) carbamoyl] alanine
(Yield 43.0%) was obtained. Melting point: 185 ° C. (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 0.73 (d, 3H, J = 6.35
Hz), 0.75 (d, 3H, J = 6.35Hz), 1.87 (septet, 1H, J = 6.84Hz),
2.02 (s, 3H), 2.77-3.16 (m, 4H), 3.19-3.36 (m, 2H), 4.15 (b
s, 1H), 7.01 (br, 1H), 7.14 (d, 2H, J = 8.30Hz), 7.46 (d, 2H, J =
8.30Hz), 9.88 (s, 1H) I. R. ν _KBr cm ^-1 : 3250,2960,1740,1675,1600,154
0,1415,1320,1190,930 MS-FAB (gly): m / z 416 (MH ⁺ ), 438
(MNa ⁺ )

The following compounds were synthesized by the same method as in Example (9-1). (9-2) 3- [4- (methylsulfonyl) phenyl] -N- [N
-Isobutyl-N- (dihydroxyphosphorylmethyl)
Carbamoyl] alanine yield 85.0% Melting point: 174-176 ° C (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 0.68 (d, 3H, J = 6.84
Hz), 0.73 (d, 3H, J = 6.84Hz), 1.82 (septet, 1H, J = 6.84Hz),
2.92-3.04 (m, 2H), 3.11-3.34 (m, 7H), 4.28 (bs, 1H), 7.21 (b
r, 1H), 7.53 (d, 2H, J = 8.30Hz), 7.80 (d, 2H, J = 8.30Hz) I. R. ν _KBr cm ^-1 : 3400,2970,1735,1600,1530,133
0,1305,1160,1045 MS-FAB (gly): m / z 437 (MH ⁺ ), 459
(MNa ⁺ )

(9-3) 3- [2- (methylthio) phenyl] -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyle] Alanine yield 91.6% N. M. R. (DMSO-d ₆ ) δ: 0.69 (d, 3H, J = 6.84
Hz), 0.75 (d, 3H, J = 6.84Hz), 1.81 (septet, 1H, J = 6.84Hz),
2.45 (s, 3H), 2.84-3.29 (m, 6H), 4.26 (bs, 1H), 5.99 (bs, 3
H), 7.01-7.07 (m, 1H), 7.17-7.25 (m, 3H) I. R. ν _KBr cm ^-1 : 3400,2970,1720,1620,1520,126
5,1240,1200,1170,1070,1055,920

Example 10 3- [4- (Methylthio) phenyl] -N- [N-iso
Butyl-N- (dihydroxyphosphorylmethyl) carba
Moyl] alanine disodium salt 0.52 g of 3- [4- (methylthio) phenyl] -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine methyl ester obtained in Example (3-27) (1.24 mM) methanol 5
0.27 g (4.10%) of 85% potassium hydroxide in a ml solution.
3 mM water solution of (mM) was added dropwise and stirred at room temperature for 1 hour.
The reaction solution was diluted with water, acidified with hydrochloric acid, and extracted with ethyl acetate. This organic layer is washed with Brine, and the precipitated crystals are collected by filtration, washed with ethyl acetate and dried to give 3-
0.34 g of [4- (methylthio) phenyl] -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine disodium salt (yield 6
4.6%) was obtained. Melting point: 154 ° C. (decomposition) N.C. M. R. (DMSO-d ₆ ) δ: 0.70 (d, 3H, J = 6.84
Hz), 0.76 (d, 3H, J = 6.84Hz), 1.82 (septet, 1H, J = 6.84Hz),
2.43 (s, 3H), 2.77-3.26 (m, 6H), 4.15 (bs, 1H), 7.12-7.21
(m, 4H) I. R. ν _KBr cm ^-1 : 3520,3400,2960,1730,1600,153
0,1230,1170,1040 MS-FAB (gly): m / z 449 (MH ⁺ ), 471
(MNa ⁺ )

Example 11 (11-1) N-benzyl-3-phenyl-N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
-L-alanine trisodium salt N-benzyl-3-phenyl-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine methyl ester disodium obtained in Example (5-1) To a solution of 260 mg (0.51 mM) of salt in 5 ml of methanol, 70 mg of 85% potassium hydroxide
A solution of (1.06 mM) in 5 ml of water was added dropwise, and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with water and extracted with ether.
The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness to give N-benzyl-3-phenyl-N- [N.
-Isobutyl-N- (dihydroxyphosphorylmethyl)
200 mg of carbamoyl] -L-alanine (yield 8
6.9%). Next, 200 mg of the obtained phosphoric acid
(0.45mM) sodium bicarbonate 115mg
After dissolving in a solution of (1.37 mM) in 5 ml of water, the solution was concentrated under reduced pressure to dryness. After azeotropic distillation with ethanol, 10 ml of ethanol
By recrystallization from a mixed solution of 4 ml of water, 130 mg of N-benzyl-3-phenyl-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine trisodium salt (yield 49.2% )Obtained. N. M. R. (D ₂ O) δ: 0.90 (d, 3H, J = 6.59Hz), 0.93
(d, 3H, J = 6.59Hz), 2.11-2.21 (m, 1H), 3.31 (dd, 1H, J = 13.3
1,8.18Hz), 3.40-3.64 (m, 4H), 3.80 (dd, 1H, J = 15.01,12.08
Hz), 4.41-4.46 (m, 1H), 4.67-4.89 (m, 2H), 7.48-7.66 (m, 10
H) I. R. ν _KBr cm ^-1 : 3400,2975,1580,1440,1400,107
0,980,700 MS-FAB (gly): m / z 515 (MH ⁺ ) [α] _D = + 25.65 ° (c = 0.7760, MeOH)

The following compounds were synthesized by the same method as in Example (11-1). (11-2) N-ethyl-3-phenyl-N- [N-isobutyl-N
-(Dihydroxyphosphorylmethyl) carbamoyl]-
L- alanine trisodium salt yield 68.0% N. M. R. (D ₂ O) δ: 0.93 (d, 3H, J = 6.59Hz), 0.98
(d, 3H, J = 6.59Hz), 1.25-1.33 (m, 3H), 1.93-1.99 (m, 1H), 3.
20-3.63 (m, 8H), 4.46-4.51 (m, 1H), 7.54-7.64 (m, 5H) I. R. ν _KBr cm ⁻¹ : 3400,1580,1400,1060,980,700 MS-FAB (gly): m / z 453 (MH ⁺ ), 475
(MNa ⁺ ) [α] _D = + 7.19 ° (c = 0.6200, MeOH)

The compounds shown in the above examples are shown in Tables 1 to 3.

[0253]

[Table 1]

[0254]

[Table 2]

[0255]

[Table 3]

[0256]

[Table 4]

[0257]

[Table 5]

[0258]

[Table 6]

[0259]

[Table 7]

[0260]

[Table 8]

[0261]

[Table 9]

[0262]

[Table 10]

[0263]

[Table 11]

[0264]

[Table 12]

[0265]

[Table 13]

[0266]

[Table 14]

[0267]

[Table 15]

[0268]

[Table 16]

[0269]

[Table 17]

[0270]

[Table 18]

[0271]

[Table 19]

[0272]

[Table 20]

[0273]

INDUSTRIAL APPLICABILITY The metal peptidase inhibitor of the present invention has an excellent metal peptidase inhibitory action and is low in toxicity, so that it is a remedy for analgesia, antidiarrheal, heart failure and hypertension in mammals including humans. Can be used as Hereinafter, the effects of the compound of the present invention will be described in detail with reference to test examples.

Test Example 1 1) Test Method Measurement of Enkephalinase Inhibitory Activity Enkephalinase was determined by the method of Malfroy and Schwartz (J. Bio).
l. Chem. vol. 259, 14365-1437
0, (1984)), and a microsomal fraction was prepared from rat kidney, followed by addition of Triton X-10.
Partially purified by extraction with 0. Enzyme activity can be measured by the method of J. B. Mumford et al.
iol. Chem. vol. 255, 2227-223
0, (1980)), and succinyl-alanyl-alanyl-phenylalanyl- (7-amido-4-methyl) coumarin was used as a substrate for measurement by a fluorometric method. That is, a total volume of 250 μl of a 50 nmoles substrate (manufactured by Sigma), an enzyme, a sample of each concentration, and a 0.05 M Hepes-sodium hydroxide buffer solution (pH 7.4) was reacted at 37 ° C. for 30 minutes, and then reacted. The reaction was stopped by adding 10 μl of 30 μM thiorphan (manufactured by Sigma), and heated at 95 ° C. for 15 minutes. Furthermore, aminopeptidase M (from pig kidney, Boehringer Man
0.75 μl) was added and reacted at 56 ° C. for 60 minutes, then, excitation wavelength was 367 nm, fluorescence wavelength was 440.
The fluorescence intensity at nm was measured, and the amount of AMC produced was calculated. The inhibition rate was calculated from the fluorescence (a) of the reaction solution containing the sample, the fluorescence (b) not containing the sample, and the blinded fluorescence (a 'and b') that did not react with each other by the following formula. Inhibition rate = (bb ')-(aa') / (bb ') *
The 100 (%) IC ₅₀ value was defined as the concentration (M) of the sample required to inhibit the enzyme activity by 50%.

Measurement of Angiotensin-Converting Enzyme Inhibitory Activity The enzyme activity can be measured by a modified method of Hayakari et al. (Anal. B.
iochem. vol. 84, 361-369, (19
78)) and was measured by an absorption spectrophotometric method using hippuryl-histidine-leucine as a substrate. That is, 0.5μ
moles substrate (manufactured by Peptide Lab), enzyme (rabbit lung-derived, manufactured by Sigma) 0.05 M Tris-hydrochloric acid buffer solution (pH) containing each concentration of sample and 0.3 M sodium chloride
The total amount of 250 μl of the mixed solution of 8.2) was incubated at 37 ° C. for 20
After reacting for 1 minute, 1N sodium hydroxide aqueous solution 15μ
The reaction was stopped by adding 1 and left at room temperature for 30 minutes.
Then, 60 mM sodium phosphate buffer (pH 7.
2) 1 ml of 2-methoxyethanol containing 1% of 1% cyanuric chloride was added, and 15 minutes later, the absorbance was measured at 382 nm to calculate the amount of hippuric acid produced. Also, the absorbance (a) of the reaction solution containing the sample and the absorbance (b) not containing the sample
The inhibition rate was calculated by the following formula from the blinded absorbance (a 'and b') that did not react with each other. Inhibition rate = (bb ')-(aa') / (bb ') *
The 100 (%) IC ₅₀ value was defined as the concentration (M) of the sample required to inhibit the enzyme activity by 50%.

Measurement of Endothelin-Converting Enzyme Inhibitory Activity The enzyme activity was measured by the method of Takada et al. (Biochem.
Biophys. Res. Commun. vol. 18
2, 1383-1388, (1992)), using high-performance liquid chromatography using the microsomal fraction of the porcine renal tubular cell line (LLC-PK ₁ ) as an enzyme and human big endothelin-1 as a substrate. It was measured by the absorption spectrometry used. That is, 0.5 nmol
A mixture of es substrate (manufactured by Peptide Institute), enzyme, various concentrations of specimens, and 0.2 M Tris-hydrochloric acid buffer solution (pH 7.0) containing 2 mM parachloromercuryphenyl sulfonic acid in a total amount of 50 μl at 37 ° C. for 5 hours. After reacting,
Stop the reaction by adding 0.5 μl of 0.1 M EDTA,
It was centrifuged at 8000 xg for 5 minutes. Then 1μ of the supernatant
1 is a reverse phase ODS column (Capcell-pak C-
18 AG, 4.6 x 150 mm, SHISEIDO)
And elution with an aqueous solution of acetonitrile containing 0.1% trifluoroacetic acid in a two-step linear concentration gradient of 10% to 34% and 34% to 45%. Absorbance of the resulting eluent at 214 nm was measured, and the amount of endothelin-1 produced was calculated.

Further, the inhibition rate was calculated from the absorbance (a) of the reaction solution containing the sample and the absorbance (b) not containing the sample by the following formula. Inhibition rate = (ba) / b × 100 (%) The IC ₅₀ value was defined as the concentration (M) of the sample required to inhibit the enzyme activity by 50%.

2) Test Results Table 4 shows the results of this test. The test compounds are shown by the example numbers. Each of the test compounds specifically inhibited the actions of metal peptidases, more specifically, the actions of angiotensin converting enzyme, endothelin converting enzyme and enkephalinase.

[0279]

[Table 21]

[0280]

[Table 22]

Test Example 2 Single-dose toxicity test 1) Test method A group of 10 male ICR mice (4 weeks old) was suspended in physiological saline and then pH was adjusted to 7.0-7.4 with 1N sodium hydroxide.
The test compound prepared as above was intraperitoneally administered at a dose of 200 mg / kg, and the mortality rate on the 14th day after the administration was determined.

2) Test Results The results of this test are shown in Table 5. The test compounds are shown by the example numbers. No deaths were observed with any of the test compounds.

[0283]

[Table 23]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/675 ABU A61K 31/675 ABU C07F 9/30 9450-4H C07F 9/30 9/32 9450 -4H 9/32 9/40 9450-4H 9/40 C 9/58 9450-4H 9/58 Z 9/6553 9450-4H 9/6553 (72) Inventor Toyofuku Hatsunori 1-Nihonbashi Muromachi, Chuo-ku, Tokyo 1- 5-3 Wakamoto Pharmaceutical Co., Ltd. (72) Inventor Kiyoshi Akiha 1-5 Nihonbashi Muromachi, Chuo-ku, Tokyo 5-5-3 Wakamoto Pharmaceutical Co., Ltd. (72) Inventor Koji Agata 1-Nihonbashi Muromachi, Chuo-ku, Tokyo 1- 5-3 Inside Wakamoto Pharmaceutical Co., Ltd. (72) Inventor Takeshi Maeda 1-5-3 Nihombashi Muromachi, Chuo-ku, Tokyo Inside Wakamoto Pharmaceutical Co., Ltd.

Claims (15)

[Claims] 1. A compound of the general formula (I) (In the formula, R ¹ represents hydroxy, lower alkoxy and lower aralkyloxy. R ² represents hydrogen, lower alkyl and lower aralkyl. R ³ represents lower alkyl. R ⁴ represents hydroxy and lower aralkyl. Represents the following aryl: embedded image (In the formula, R ⁵ and R ⁶ are the same or different and each is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower aralkyl, optionally substituted phenyl, lower aralkyloxy, carboxy, halogen, lower alkylthio,
Lower alkylsulfonyl, optionally substituted phenylthio, halo lower alkyl, nitro, amino, acetamide, lower aralkyloxycarbonyl, lower alkoxycarbonyl lower alkoxy. R ⁷ represents hydrogen, lower alkyl or lower alkoxy. )) A novel alanine derivative and a pharmacologically acceptable salt thereof. 2. A compound of the general formula (II) (In the formula, each symbol of R ¹ , R ² , R ³ and Ar is defined by
Same as. R ⁸ represents lower alkoxy, lower aralkyloxy, or lower aralkyl. R ⁹ represents lower alkyl or lower aralkyl. ) An intermediate of the compound according to claim 1, which is represented by 3. A compound represented by the general formula (I): A pharmaceutical composition comprising a compound represented by the formula (each symbol in the formula is the same as in claim 1) and a pharmaceutical carrier. 4. A metal peptidase inhibitor comprising the compound of general formula (I) according to claim 1 as an active ingredient. 5. 3- (2-Methylphenyl) -N- [N
-Isobutyl-N- (dihydroxyphosphorylmethyl)
Carbamoyl] alanine trisodium salt 3- (3-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt 3- (4-n-butylphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-biphenyl) -N- [N-isobutyl- N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -L
-Alanine trisodium salt 3- (4-methoxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (2-benzylphenyl) -N- [N-isobutyl- N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (1-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (2-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (6-methyl-2-naphthyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (6-methoxy-) 2-naphthyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (3-trifluoromethylphenyl) -N- [N-
Isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-hydroxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine trisodium salt 3-phenyl -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine 3-phenyl-N- [N-ethyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine 3- (4- Methoxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine 3- (3-bromophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine 3- (3-bromophenyl) -N- [N-isobutyl-
N- [Hydroxy (4-phenylbutyl) phosphorylmethyl] carbamoyl] alanine 3- (3-Bromophenyl) -N- [Nn-propyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3- (4-bromo Phenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine 3- (3,4-dichlorophenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3-[(3-chloro-4-methyl) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3- [2- (4-bromophenylthio) phenyl] -N
-[N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3- (4-nitrophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine 3-[(5-chloro-2-nitro) phenyl] -N-
A compound according to claim 1 selected from [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine. 6. An enkephalinase inhibitor containing the compound according to claim 5 as an active ingredient. 7. 3- (4-Biphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine benzyl ester disodium salt 3- (2-methylphenyl) -N- [N-isobutyl −
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt 3- (3-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt 3- (4-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt 3- (4-n-butylphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-isopropylphenyl) -N- [N-isobutyl -N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -L
-Alanine trisodium salt 3- (4-methoxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-methoxyphenyl) -N- [N-n- Propyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine trisodium salt 3- (4-n-butoxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine 3 Sodium salt 3- [4- (ethoxycarbonylmethoxy) phenyl]
-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine trisodium salt 3- (1-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (2-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (6-methyl-2-naphthyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (6-methoxy- 2-naphthyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-hydroxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine trisodium salt 3- (4-aminophenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt 3-phenyl-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine 3- (4-methoxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) ) Carbamoyl] -L-alanine 3- (3,4-dimethoxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3- (3-bromophenyl) -N- [N-isobutyl −
N- [hydroxy (4-phenylbutyl) phosphorylmethyl] carbamoyl] alanine 3- (3,4-dichlorophenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3-[(3-chloro -4-Methyl) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3- [4- (4-methylphenyl) phenyl] -N-
[N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine Selected from 3- [4- (acetamido) phenyl] -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine. The compound according to claim 1. 8. An angiotensin converting enzyme inhibitor comprising the compound according to claim 7 as an active ingredient. 9. 3- (2-Methylphenyl) -N- [N
-Isobutyl-N- (dihydroxyphosphorylmethyl)
Carbamoyl] alanine trisodium salt 3- (3-methylphenyl) -N- [N-isobutyl-
N- (dihydroxyphosphorylmethyl) carbamoyl]
Alanine trisodium salt 3- (4-n-butylphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-biphenyl) -N- [N-isobutyl- N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -L
-Alanine trisodium salt 3- (4-methoxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (1-naphthyl) -N- [N-isobutyl-N −
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (2-naphthyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (6-methyl-2-naphthyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (6-methoxy-) 2-Naphthyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-hydroxyphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine trisodium salt 3-phenyl-N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] -L-alanine 3- (4-methoxyphenyl) -N- [N-isobutyl-N- ( Dihydroxyphosphorylmethyl) carbamoyl] L- alanine 3- (3-bromophenyl)-N-[N-isobutyl -
N- [hydroxy (4-phenylbutyl) phosphorylmethyl] carbamoyl] alanine 3- (3,4-dichlorophenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3-[(3-chloro -4-Methyl) phenyl] -N-
A compound according to claim 1 selected from [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine. 10. A drug, which comprises the compound according to claim 9 as an active ingredient and simultaneously inhibits both enkephalinase and angiotensin converting enzyme enzymatic activities. 11. 3- (4-Biphenyl) -N- [N-
Isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (4-biphenyl) -N- [N-isobutyl-N-
(Dihydroxyphosphorylmethyl) carbamoyl] -L
-Alanine trisodium salt 3- (2-benzylphenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (1-naphthyl) -N- [N-isobutyl-N −
(Dihydroxyphosphorylmethyl) carbamoyl] alanine trisodium salt 3- (3,4-dichlorophenyl) -N- [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine 3-[(5-bromo-2-methoxy) Phenyl] -N-
A compound according to claim 1 selected from [N-isobutyl-N- (dihydroxyphosphorylmethyl) carbamoyl] alanine. 12. An endothelin converting enzyme inhibitor comprising the compound according to claim 11 as an active ingredient. 13. The enkephalinase inhibitor according to claim 6, which is useful as an analgesic, antidiarrheal, diuretic, and prophylactic and therapeutic drug for heart failure. 14. The angiotensin converting enzyme inhibitor according to claim 8 and the endothelin converting enzyme inhibitor according to claim 12, which are useful as antihypertensive agents. 15. The enzyme inhibitor according to claim 10, which is useful as a hypotensive diuretic.