JPS58225047A - N-substituted glycine compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is COOH, alkoxycarbonyl, CN, phenyl, cycloalkyl or benzocycloalkyl; X is straight or branched chain alkylene; R<1>, R<3> and R<4> are H or lower alkyl; R<2> is aralkyl) or a salt thereof. EXAMPLE:N-{N-[1(s)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl}N-[-( 2-ethoxycarbonyl-1-methyl)ethyl]glycine tert-butyl ester. USE:An inhibitor for angiotensin converting enzymes and enzymes hydrolyzing bradykinin (kininase) useful for the diagnosis, prevention or treatment of hypertension. PROCESS:A compound expressed by formula II is condensed with a compound expressed by formula III under reductive conditions or a compound expressed by formula IV is condensed with a compound expressed by formula V or a reactive derivative at the COOH group thereof to afford the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N-substituted glycine metals useful as pharmaceuticals and methods for producing the same.

More specifically, the present invention is based on the formula % formula % [wherein A is a carboxyl L/ group, an alkoxy V carpo 2 μ group, an ano group, a phenylated IV group, a cycloalkyl/I/ group, tfc is a benzoshif 11 alkyl group, and Xt: ti7I
M or a branched 7-kylene group, R1 is hydrogen or a lower alkyl group, R2 is an alkyl group, and R3 and R4 are hydrogen or a lower alkyl group. Item 9 relates to the salt and its manufacturing method.

Regarding the above formula (1), Apcoquina /L/ denoted by A
)Nyl groups include lower 7- to carbon atoms having 2 to 5 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbo=ρ group, ptoquine carbonyl group, and tart-ptoquine carbonyl group. Coxycarbonyl group is a cycloaμ/L/ group such as at's' clopropyμ group, V clopropyl group, V clovenna μ group, cyclohexV~ group, V cloheptyl~ group, V clooctyfi7 group. A cycloagiμ group having 3-8 carbon atoms such as benzo V
Examples of the chloroμkyl group include an indanyl group, a tetrahydronaphthyl group, and a penzocyclohedetenyl p group.

Examples of the linear 7μ xylene group represented by X include a methylene group, an ethylene group, and a trimethylene group.

A lower alkylene group having an elective number of 1 to 4, such as a tetofumethylene group, is used as a branched alkylene group, such as a methyμ group, an ethyl group, a propyl group, or an isopropyl group, at any position of these lower alkylene groups.

Examples include a 9-μ-kylene group substituted with a lower diylkylene group having an elective number of 1 to 4, such as a butyμ group.

Examples of the lower atom group represented by H1, R3 and R4 include a methyl group, an ethyl group, a propy group, an isopropy group, a buty group, and an isobuty group.

Examples of the aralgyl group represented by HE include a benzene μ group, a phenethyl group, a 3-phenylene group, and 〃Propyl'M, (1) f~benji〃
group, α-methy, A/7 enethy p group, 2-methy 41~
Key groups can be mentioned.

Examples of the salt of compound (I) include hydrochloride.

Inorganic acid salts such as hydrobromides, sulfates, nitrates, phosphates, such as acetates, tartrates, citrates, tuma-μ salts, maleic acids &)μ-enesulfonates, methanesulfonic acids Organic acid salts such as salts, such as sodium salts, potassium salts, A/S/U salts, metal salts such as aluminum salts, such as ammonium salts, hydrazone salts, guanidine salts, triethylamine salts, dichlorohexylamine salts, quinine salts, Examples include pharmaceutically acceptable salts such as salts with bases such as s/nkonine salt.

The compound (1) of the present invention is, for example, a compound represented by the formula: By carrying out a condensation reaction with the compound represented by under reductive conditions,
Or a compound represented by the formula % formula % () [wherein A , That power μbogishi/I/,! It can be produced by carrying out a condensation reaction with the reactive derivative of (iii).

Reductive conditions for the reaction of compound (1) and (grave) include catalytic reduction using a metal such as platinum badge rum, Raneynicke μ, rhodium, or a mixture of these with an arbitrary carrier as a catalyst, such as lithium aluminum hydride, Reduction with metal hydrides such as lithium borohydride, lithium cyanoborohydride, sodium polhydride, sodium cyanoborohydride, metal
Examples of reaction conditions include reduction using hydrogen, magnesium metal, etc. and alcohols, reduction using metals such as iron or zinc and acids such as hydrochloric acid or acetic acid, electrolytic reduction, and reduction using reductase fC. The above reaction is usually carried out in the presence of water or other solvents (e.g., memenol, ethanol, ethyl needle, dioxane, menalinyl chloride, chloroform, benzene, turquoise, dimenalformamide, dimethylacetylamide, etc.). The reaction temperature during reduction varies depending on W, but is generally between 0°C and +10°C (approximately 10°C).This reaction can be carried out at normal pressure to achieve the desired purpose, but depending on circumstances, The reaction may be carried out under elevated pressure or reduced pressure.

In the degeneracy reaction of compound (fV) and (Y), compound (
Examples of the reactive derivatives at the carboxy V group in (ma) include acid halides such as acid chloride and acid gamide; acid anhydrides obtained by dehydrating one molecule of water from two molecules of (ma); Hydrogen of μbox￥p group is 9, for example, ethoxycarbonyl group, isozotyloxycarbonylμ group,
Derived from derivatives such as mixed anhydrides substituted with benzyloxycarbonyl groups, etc. The reaction is generally carried out in a suitable solvent, and any solvent that does not inhibit the reaction can be used. When (ma) is used as it is without converting it into a reactive derivative, for example, zinclohexylcarbodiimide, carboni-diimidazo 7V, S/diethyl anophosphate, zofenyl! It is advantageous to carry out the reaction in the presence of a dehydrating reagent such as phosphorymu-acid. The reaction can also be carried out in the presence of a base such as pyridine, picoline, triethylamine, sodium hydroxide, or sodium electorate. The reaction temperature is usually about -20 to +1
The reaction is carried out at a temperature of about 50°C, but in most cases the reaction proceeds satisfactorily even at room temperature.

A compound in which R3 and/or R4 are hydrogen in the formula (1) can also be produced by hydrolyzing a compound in which R3 and/or R4 are groups other than hydrogen.

Hydrolysis is generally carried out in water, an organic solvent, or a mixed solvent thereof, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, or trifluoroacetic acid9. In the presence of acids such as benzenesulfonic acid, methanesulfonic acid, p-)μenesulfonic acid, or bases such as ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, pyridine, picoline, etc. The reaction temperature is generally in the range of about -20 to +150°C.
In most cases, the reaction proceeds satisfactorily even at room temperature.

Contrary to the above, the compound (1) in which R3 and/or R4 is 1%/group of lower
It can also be produced by alkylating compounds in which 4 is hydrogen. The oxidation method includes an esterification reaction with a corresponding alcohol compound by a conventional method, such as diazomethane, halogenated a-N, etc.
Usual alkylation reactions using alky-A or aryl sulfonic acid esters of alcohol-p compounds, such as addition reactions of olefin compounds such as isobutyne, etc., can be mentioned.

The target compound (1) or its salt thus obtained is purified from the reaction mixture by conventional purification means such as extraction,
Concentration, neutralization, filtration, recrystallization, column chromatography. It can be isolated by using means such as thin layer chromatography.

The compound represented by formula (1) has an asymmetric leg element in its molecule and has multiple optical isomers, but both of these individual isomers and mixtures thereof naturally fall within the scope of the present invention. These isomers can also be prepared individually if desired. That is, the reaction is carried out by carrying out the above reaction using each one of the optical isomers of the raw material compound that has been optically resolved in advance (I
) It is possible to obtain the optical isomer. When at least one of the starting compounds is a racemate, (1) is usually obtained as a mixture of isomers, but this isomer mixture can be separated as desired by a conventional separation method, such as optical H-NM (e.g. It can also be separated into its respective isomers by forming salts with S/nconidine, Vnconidine, quinine, quinine, etc., or by treating each column with chromatography, fractional recrystallization, etc. .

The N-substituted glycine compound represented by formula (1) and its salts exhibit angiodensin-converting enzyme inhibitory activity, pubudykinin degrading enzyme (kininase) inhibitory effect, etc. in animals and mammals, and are effective against hypertension, for example. It is useful as a diagnostic, preventive or therapeutic agent for diseases. Compound (1) has low toxicity, good absorption even when administered orally, and excellent stability. Therefore, when used as the above-mentioned medicine, compound (1) may be used alone or in appropriate pharmaceutically acceptable carriers, excipients, and diluents. It can be safely administered orally or parenterally as a pharmaceutical composition such as powder, granules, tablets, capsules, or injections. Although the dosage range varies depending on the condition of the target disease and the administration μ-F, for example, when administered to adult patients for the purpose of treating hypertension, oral administration is usually about 0.02 to 20 m/kg. : Approximately 0.2~2q
/kg, but when administered intravenously, it is 1ljl! If electric approx. 0.0
02~0.2 cape/kg especially about 0402~0.2q
/kg, and it is desirable to administer these tablets about 1 to 3 times a day depending on the symptoms.

Note that the raw material compound (l[)if in the above production method can be produced, for example, by the method shown by the following reaction formula.

[In the formula, A, X, R1, R' have the same meanings as above,
2 indicates Penzyl Ogishika ~ Boni/Vmt] In the above reaction, the reaction between (ff) and (II) involves (1v) and (Y
) The same reaction conditions as for the reaction of
conditions are used.

Further, the starting compound (Y) can be prepared, for example, by the method shown by the following reaction formula.

tBu00cDHN% + (bar) -! ■2
〉(Vll) R1 (IX) x1u4 represents a tert-butyl group] In the above reaction, the reaction between (VMI) and (lid) involves (
The same reaction conditions as for the reaction between 1) and (y) are used, and the reaction conditions for the usual acid hydrolysis reaction are used for the reaction from (IX) to (ma).

The present invention will be explained in more detail by showing reference examples, drainage side and formulation examples below, but the scope of the present invention is not limited thereto.

Reference example/ L-alanine tert-butyl ester oxalate 10
Dissolve 200 g of ethanol-A' in VCl2, 10 s of acetic acid, and 79.9 g of sodium acetate. Ena/L/2-Ogiso 4-Phenylgunarate 13f and Nanashi Gyubusheep 3mu 20f bales, Bunenitsuke 11/10
f and catalytic reduction at room temperature and pressure. After hydrogen absorption has stopped and death, the upper m= is collected diagonally with #A, and the precipitate is washed with ethanol 2 to 3 times. Dissolve the substance in ethyl acetate 300111, add sodium IA acid hydrate, and filter with 20 g of diatomaceous earth.The ethyl acetate layer is separated from the filtrate, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain an oily substance. is obtained.The crystal is chromagraphed on silica gel (hexanenia 7 tons-50=
1 to 20:1), N-(1(R)-ethoxycarbonyl)v-3-phenylphubiμ)-L-alanine tart-butyl ester was extracted from both first effluents at 3.89 is obtained as a colorless oil.

IRshuek)/L/vnaatcm': 3
310 (NH).

&1X 1720 (C=O).

NMR Nuvector (CDC13) δ: 1.1-1.
3 (61 (, m), 1.4 (9H, s), 1.6 2.
2 (3H, u+), Z5-2.9 (2H, n+), 2.
9 3.3 (2H, m), 4.1 (2H, q, J=7H
z), 7.1 (5H, s).

[α] -22,5° (o=l, methano-/v) From both later outflows, a-C1(s)-ethogycin-bonyru-3-pheni-bu-avir)-L-alanine t =r
3.8 g of t-butyl ester are obtained as a colorless oil.

IR spectrum μ ν sub-depression 0(,: l1l-1 = 333
0 (NH) 11720 (C=0).

NMR spectrum/L/(CDC13)δ: J, 1-
14 (1, m), 1.7 2.1 (3t (, u+), 2
．． 5 2.8 (2H, at).

3.0-34 (2H+”), 4.15 (2H, q, J=
7Hz).

7.1 (5H, s).

[a″12b4-17.9°(””to methanol)(
NMR spectrum abbreviations = 8 is Ichito hx, a r
x is a double line, t is a triple line, q is a four-wire line, and 9m indicates a multi-lane line. The same applies to the following reference examples and the backflow side) Reference example λ H-(1(R)-ethoxycarboni/L/-3-phenylglobil)-L-alanine ta obtained in Reference example/
Dissolve rt-butyl ester 2, st total 6ti hydrogen-ethyl acetate solution 40JfC7d and leave at room temperature for 4 hours. Concentrate under reduced pressure, add ether/' l U Oml, and calculate the number of colorless needle crystals that precipitate.
(R)-EtquincarbonyA'-3-phenylpropyl)-L-alanine L[&"AA2,3&gai1
It will be done. Melting point 167-173℃, (a)2 blue 5-26
．． 0° (cml, methanol).

Reference Example 3 eReference Example/9N-(1(8)-ethoxycarboni/L'-3-phenylprohyA/)-L-afnin t
When art-butyl ester A/2.59 was treated with a hydrogen chloride ethyl acetate solution in the same manner as in Reference Example λ, N-(1(
8)-EthokiVka-PoniA/-3-phenylderhir)-L-alanine salt WI salt2. zV is obtained as colorless needles. Melting point 136-142. [α)”j5 +2
9.6” (0-1, methano-)v).

Reference example 2-indanecarbaldehyde tart-butyl ester arsenite 1.46F, ￥ anoborohydride sodium fluoride 14 and methano-lv2C)m
1 of the mixture was left overnight at room temperature. The reaction solution was made weakly acidic with a phosphoric acid water bath, then made alkaline with an IN aqueous sodium hydroxide solution, and extracted with 200 ml of ethyl acetate/L'. The extract was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Ethyl rotate/'25 hrl and enalate/L/25- were added and dissolved in the residue, and 204 ethanolic hydrochloric acid was added dropwise little by little to give 11- (Indan-2
-ylmethy/L/)glycine tert-butylente)V hydrochloride precipitates as a colorless crystal.

Yield 1v, melting point 166-1681;.

I R7h) #y”u:J”’cm’: 1
740 (varnish fax fi7) Reference example: Using acetyl 1-acid ethyl A'lf in place of 2-indanecarbaldehyde, the reaction was carried out in the same manner as in the reference inversion, and the crude product was subjected to a V lica gel column chromatography. attached to the fee,
Elution and purification with n-hexane ethyl butyrate/l/(15:1) yields N-[(2-4)oxycarbonyl-1-methyl)ethyl]grin tart-butyl esde/'
1.459 is obtained as a muya oil.

IR SHEK)/L/yn8atcb+”:
1740 (F f[lv) Mass spectrum/L/m/e: 245 (M'-) Reference Example 6 Using bendi/lepropyl ketone]V in place of 2-indanecarbaldehyde, Reference Example G, 3 and Same 1
By reacting and treating as follows, N-((1-
1.1 g of benzene/L/)butyl]chloride tart-punal ester are obtained as a λ(li color oil).

IR Suhe9) A/y”=”cm 1: 17
40 (Aesthetics aX Le) NMR spectrum δ (CDCl2): 1.40 (3
H. a, CH3X3), 2.7 (2H, a, CH
2), &30(2H, a.

CH2), 7.15 (5f(,a,]c2lv) Reference example Z Brom^tate/L'lf and glycine tart
-1 g of butyl ester phosphite in ethanol/1'lOd
Add 1.6 ml of triethylamine and heat to 80°C.
After heating for 2 hours, the reaction solution was transferred under reduced pressure, and the residue was extracted twice with 30 ml of ethyl butyrate. The extract was washed with water, dried, and then distilled off.
Attach to matoguffy, n-hexane/ethyl tonic acid/l
/(3:1) to give 0.3!M of purified salt 1(-1-quincarbonylmenalglycine tart-pnal ester) as a colorless oil.

I R
74Q (Z:ATbX /L/) MMRy. Vector δ(cI)cx3): 1.3
(3 l(, L.

CH3), 1.5 (9H, a, CH3x3)
, :U35(2H, a.

CH2), 3.40 (211, a, Cl12), 4.2
(J(1, q.

(', H2) The same reaction and treatment as Reference Example and Reference Example Z f(, Therefore, 3
- Ethyl bromopropionate/l'0.85&, IJ
- (2-ethoxycarbonylethyl')glycine tart-butyl ester No. It can be obtained as a 13tt mubu oil.

iR spectrum HtcIIl-1: 1 7
40 (Nisder) NMR spectrum δ(tl)cl:s): 1.10
(3H, t, CH3), 1.42 (9”, a
, CH3X3) , 24 4.2 (8H, eHgX
4) Reference Example 2 Same reaction as Reference A ΔI7. from 3-chlor 1S:l bionitri Iv0.4SM by treating
N(2-syanoethyl/L/)glycine tert-glycine/L10.651F can be obtained as a colorless oil.

IR spectrum 2"cIo": 2240, tolyl mass spectrum 7, n+/e: 185 (M") Reference example 10 L-alanine tar L-butyl ester/L/oxalate 19,
v0.6g,) ethylamine 2.2f, ethanol/L
/12m was reacted and treated in the same manner as in Reference Example 7 to obtain 0.6 g of N-tert-ptomethylpolymethyl-L-afnin-tex-t-glyester I as a colorless oil. When this is treated with nigenolic hydrochloric acid-butyl ether, a hydrochloride condensate is obtained at a temperature of 165-168°C (decomposition). Cm-3”lp-0.so(Cm
1.

Ethanol/L/) Reference j// r4-benzyl-N-7 clobentylmethylamine 1.
5f and Chloro/L'autoic acid tert-glutyl ester~i
．． By reacting and treating st under the reaction conditions of Reference Example 7, N-benzyl-N-cyclopentylmethymu glycine tart. - Zonal ester oil 2.259
get. Dissolve the crystal in 30aJ of methanol and add 5m palladium atom. BytmL was catalytically reduced in a hydrogen stream at room temperature and pressure for 2 hours, the catalyst was removed, and the furnace liquid was distilled off to give 1(-
Cyclobenalmenalglycine tart-butyl esde/L'1.4f71 Obtained as a colorless oil. # When converted to hydrochloride in the same manner as in Example 10, the melting point is 1 8 5
−187t; becomes a crystal.

Reference example/2 6g of N-benzyloxycarbonyl-L-alanine)
Ligutylamine 3,5v to tetobuhydrofuran 50I &
Dissolve in water and -1 (kiln with l)
J (acid isobutylene/L'3.24M chloroporm 10d
#After dropping the solution, add N-benzi to glycine
1" 1ch μ Esthe A/69 Chloroform 50w
rl m M t Add dropwise at -5°C. -5℃ for 1 hour
After stirring at room temperature, 300*Z of water is added, and the chloroform layer is separated, dried, and distilled off. Convert the residue into ethanol/L
Dissolved in /20ml, INN hydroxide natwau 20s? After stirring for 10 minutes at room temperature, add 100 d of water and extract with ~50 ml of Enalleate. The aqueous layer was acidified with hydrochloric acid, extracted with 10011 t of chloroform, and the extract was dried and evaporated under reduced pressure to give N-pene! //I/-ni-(
N-benzyloxyglycine is obtained as a colorless powder. This was dissolved in 30% hydrobromic acid-acetic acid solution 50#11K, stirred for 30 minutes at 30°C, 300 JIIt of ethyl ether was added, and the precipitate was recrystallized from a mixture of ethanol and ethyl alcohol. , N-L-abdiρ-N-benzip-glycan hydrobromide 8f is obtained as colorless prismatic crystals. Melting point 171
-173℃.

Flow side/N-((2-EthoVcarbonyl-l-methyl)ethylcoglycine tart-glutyl ester lv0.

45 g and n-(l-(s)-ethoxy V carbon 2-3-
Phenylpropy, A/)-L-abunine hydrochloride 0,6f
was dissolved in dimethylformamide 811, and while stirring under ice cooling, cyanophosphoric acid die f/vO. Add 45f and 0.8v of triethylamine.

After stirring at room temperature for 4 hours, ice water was added to the reaction mixture, and the mixture was extracted with two wells of acetic acid Guchi/'L730IIt. The extract is washed with dilute hydrochloric acid, then water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to column chromatography on Silicage A'30f, and the fractions eluted with a solvent system of n-hexane/ethyl acetate (5:1) were collected and concentrated. , N-(N-(1(S)-ethoxycarboniμm
3-Fueni/I/10 Building)-L-Atsuni#)-N-(
0.54 g of (2-ethylglycine--1-methy/V)ethylglycine, A', is obtained as a free oil.

I RZ9)/L/ν”8atcv 1: 1
740 (x) iraX /I/), 1640 (amide) Mass Spect/I'm/8: 506 (M4 → Example using N-substituted glycine tart-1 nal ester corresponding to Example code) By carrying out reactions and treatments similar to those described above, all of the compounds shown in Table 1 can be obtained as colorless candy-like substances.

■-CM-(1(13)-ethoxyVcarbonyl-3-pheni-propylA/)-L-abnyl]-N-(indan-2-ylmethyllv)glycine tert-butyl ester μ0.5f 3 .5N Hydrogen chloride and ethyl acetate lv solution 10
Dissolve in ml and leave at room temperature overnight.

The reaction solution was concentrated under reduced pressure, and the residue was diluted with ether/'10 m
When l is added, a-(N-(i(s)-ethoxyca~boniA/-3-pheniμpropy~)-I, -7rani~)-
N-(indan-2-ylmethy/V)glycine hydrochloride 0
．． 45f is obtained as a colorless powder. (a)'
j"-13,9° (c=t+memeno/1/) elemental analysis value" C27H34N206・HCI and [2 calculated value
C64, 47, H7, 01, M 5.57 dormitory measurement C6
4,16,H6,95,N 5.36HMR spectrum~
δ (nuso-C6): 1.1-1.6 (6H=m
), 2.1-4.6 (17H,, m), 7.15 (4H
, a).

7.3 (5H, a).

Example 10-/! Performed using the corresponding N-substituted By performing the same reaction and treatment as in Example Z, the compound of Example 10-/j can be obtained as a colorless powdery substance.

Example 10 N-(n-(t(8)-ethoxy-μ-3-phenylpropyl)-L-7-p)-N-[(2-ethoxyVcarbonyl-1-methy71I/) Ethiμ] Glycine hydrochloride. Melting point 161-163°C.

IR spectrum s/v”, :rxcva”: 37
00-2200 (carboxylic acid), 1740 (ester, μ acid), 1640 (amide) Elemental analysis value Calculated value as 23H34N207・HCI C56,72, H7,25, N 5.75 Expected value
to 56.33. H7,17,N 5.66 Example/
/ N-(N-(1(S)-ethoxyca~boniμ-3-phenylpropy~)-N-(1-hendippunal)glycine hydrochloride (a)%, '-32° (c=1+ethano- μ) IR SCHECK) A/y"rcM+-': 3700-220
0ax (carboxylic acid), 1740 (ester, force~boxylic acid),
1640 (amide) Elemental analysis value "C28H38N205・HCl-%H2
Calculated as 0 MC63, 68, H7, 63, N 5
．． 30 median value C63,52,H7,34,N b,
44 Example 12 a-(n-(1(El)-ethoxycarbony~=3-phenylpropyl]-L-abnyl)-N-ethoxyV carbonylmethylglycine hydrochloride mass [α) V-12,7'
(c=0.5, ethanol) IRsubekF ν”
"cIll": 37L)Ll 2200 (la
X force/l' bond d), 1740 (ester, force! levonic acid).

1640 (amide) Elemental analysis value: C21H3QN207.14C1・”,
41 (calculated value as 20 C53,90, H6,89,
N 5.90 Actual value C54, 12, H7, 08, r i 5.70 East Example/3 N-(N-(i(s)-Etkin force μboni fi' -3
-Phenyl 1 μpyl]-L-alanyl]-N-(2-ethoxycarbonyl ethyl/L/)glycine hydrochloride [α] 1?0° (c=0-33.ethano-/I/)I
R 9) A/l/K"rCIO': 370
0 22001LX (Power ~ Bonic acid), 1740 (Esthetic/L/, Carboxylic acid), 1640 (Amide)
・In '20 as old Sanmin C53, 82, H7, 19
,N 5.70 estimated value C53,63,H6,86,N
5.45 Fire Example/R-N-(a-(l(s)-ethoyaccarbonyl-3-phenylpropyl)-I,-alanyl)-N-(2-cyatzenaμ.)glycine hydrochloride (a) V t;, 5°((
3=, 0.7B, eta/-fi/) elemental analysis i & 2C
2+) H27N305 ・HCI ・Calculated as 2H20 C52,06,l (6,98,N 9.10 Jitsunsha 51.88. H7,10,N 8.95 Example/j N-[1- (1(S)-Etho:31-4/Carbonyl-V clobench μm hexaμglycine Cabv-1i, s° (c = 0.c), xp
) /L/) Elemental analysis tit: c23”34N
205 ・HC'L ・'AH20 if calculated
C59, 54, H7, 82, I (6,00 estimated ff
C59, 43, H7, 52, N 5.90 East Example/A.

N-(N-(1(8)-Etogishiki!Levonyl-3-phenylglobin~)-L-Ab2A/) -N-(t
N-(N-(1
(S)-Ethoxycarbonyl-3-7eni-globil]
-L-alanyl]-N-carbogisimethi μmL ~ 0.4 f of a colorless powdery substance of abunin hydrochloride is obtained.

I R, 1, hel) /L” KBrc+u-1:
3700-2300πaχ (')J A/7j,'! ) + ] 740 ('
−”7'/L', :b)'>N>2
""), 166 (1 (amide) elemental analysis i1 [C20H2BN20-711C1・)4
M2 (L% (C2H5) Calculated value as 20 C53,81, H7,19, N 5.71 Measurement value C54,11, III 7.28. N 5.47
East Example/Z l(-ab2μ-to-benziμglylene hydrobromide 2
f is ethyl-μsomKm, ethyl 2-ogiso4
-Fenibutyrate 6- and Moreyular V-butyrate 3A1
Add Of and stir.

After adding 2fI of sodium saranidianoborohydride and stirring at room temperature for 15 hours, ethyl A/2-oxo 4-
Add 6d of phenylbutyrate and 0.59 of sodium V-anoborohydride and continue for another 24 hours. Add 300 wIl of water to the reaction solution, and add 100 wIl of water.
The aqueous layer was adjusted to pH 4 with IN hydrochloric acid and diluted with ethyl acetate/'100m? Extract with

The extract was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (methanol-μ/re-μroform-1:20).
Refine with. Adding alcoholic hydrochloric acid in ethyl needles to the obtained oil and leaving the formed precipitate to give N-
Bendiμ-N-(N-(1-ethoxyca!bonyl-3-
phenylpropylene/l/)-L-arani μ
! When drunk, 1 F precipitates as colorless crystals. -1 point
00-105℃.

Massspect/'11/6: 408 (M-1420
).

Preparation Example When compound (1) is used, for example, as a therapeutic agent for hypertension, it can be used, for example, in the following formulation.

18 tablets (1) H-CM-CI (8)-ethoxycarbony/L'
-3-pheniμpropyl)-L-alanyl]-N-(indan-2-μmena/L/)glycine hydrochloride
10f (2) Lactose 90f (3) Corn V starch 29g (4)
Magnesium stearate 1v100
130 f (4), (2) and 17 g of corn flour were mixed together and granulated with a paste made from corn starch of 79, and the rice grains of
1. Add V-sushi powder and (4). The mixture was then compressed using a tablet compression machine to produce 1000 tablets with a diameter of 7 mm, each containing (1) lOJv.

2. Capsule (1) N-(N-1(S)-ethoxycarbonyl-
3-phenylpropyl]-L-abdiμ)-N-cyclobenziμglycline hydrochloride 0 g (2) Lactose 135 g (3) Cellulose fine powder 709 (4)
Magnesium stearate 5f1000
Kadese/l'220f All ingredients are mixed and filled into 1000 gelanan Kadese/I/3 (10th revision H present pharmacopoeia) to produce capsules containing 1) 1Oq per capsule.

3. Injection (11N-(N-(1(s)-ethoxycarbonyl-3-phenylpropyl)-L-abinoL',)-
N-C (2-ethoxycarpo diμm 1-methino ν) F'-/L') glycine hydrochloride 1 (1 (2) Sodium chloride 9v (3
) Chlorobutano/L 15g Dissolve all ingredients in 1000d of distilled water 7.
Dispense 1 d into 1000 pieces, replace with nitrogen gas, and seal. The entire process is performed under sterile conditions.

Claims (1)

[Claims] Formula % Formula % [In the formula, A is a force~boxyμ group, 1μoxycarbonyμ group, anano group, phenyl L'M yvl&; N-substituted glycine compound represented by [shown] or 7Ic & other salts.