JPS5965056A - Peptide amide derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [X is group of formula II or formula III; n is 1 or 0; Y is group of formula IV, formula V (R1 is H or alkyl; m is 1-3; X is H or halogen), etc.] and its salt. USE:An analgesic and central nervous suppressing agent. It has weak agonistic activity to the opiate receptor, and is useful as an analgesic having low narcotic property. PROCESS:The compound of formula I can be prepared from a peptide and the amine compound corresponding to the amine segment denoted by Y in the formula I , by conventional condensation process for peptide synthesis. As an alternative method, the objective compound can be obtained by using the amine compounds as starting substances, and extending the amino acid residues successively by the conventional condensation process for peptide synthesis. The third process for the preparation of the objective compound is condensation of the amino acids or peptide derivatives of the amine compounds with amino acids or peptides by conventional condensation process for peptide synthesis.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel neuropeptide amide derivatives and salts thereof, and analgesic and central depressants containing the same.

L. Hughes et al. CNature, 253,577
(1975)'), a compound called enkephalin, which exhibits morphin-like effects when administered intracerebrally, was extracted from pig brain.
! #! , the pentape fl' of H-T7r-G
l]-Gly-Phe-Met-OH and H-1-yr-Gly-Gly-1'he-
Since Leu-011 was isolated and its structure determined, derivatives in which constituent amino acids are replaced with other natural amino acids and unnatural amino acids (D, H, Goγ et al., Pharmacology
& TherapeuLics 657 (1980; et al.), research on structure-activity relationships has been actively conducted.

The present inventors synthesized various new peptide amide derivatives using various amine compounds with different structures from amino acids and examined their pharmacological effects.
We have discovered a compound that exhibits analgesic and central depressant effects and has weak agonist activity at opiate receptors.1゜That is, the compound of the present invention has the following general formula % (where n is l or O, Y shall indicate one of the following residues:

] These are peptide amide derivatives represented by and salts thereof.

In the above general formula (I), the T-alkyl group of R1 is methyl,
Represents a lower alkyl group such as ethyl or propyl; X represents a hydrogen atom or a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom; , the heterocycle is pyrimidine,
It means a heterocyclic ring containing nitrogen and having aromatic properties such as pyridine.

Representative examples of the derivatives of the present invention are listed below using structural formulas. Amino acids are indicated by the IUPAc and IUB rules and symbols commonly used in the field of peptide chemistry, and those without a special number mean L-type.

The compound of the present invention comprises a peptide obtained by a conventional peptide synthesis method and a general formula (I) obtained by a known synthesis method.
) can be produced by condensing an amine compound corresponding to the amine moiety represented by Y using a conventional condensation method used for peptide synthesis. Furthermore, the compounds of the present invention can be produced by using these amine compounds as starting materials and sequentially extending amino acid residues using the condensation method used for ordinary peptide synthesis, or by producing amino acid or peptide derivatives of these amine compounds. It can also be produced by condensing an amino acid or a peptide with a conventional condensation method used for peptide synthesis.

Conventional condensation methods used in peptide synthesis include the azide method, mixed acid anhydride method, N,N-dicyclohexylcarbodiimide (DCC) method, active ester method, oxidation ring method, diphenylphosphorylamide method, DCC+ Additives (N-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy-5-norbornene-
2,8-dicarboximide, etc.) method.

The solvent is appropriately selected from those known to be used in peptide condensation reactions. Examples include dimethylformamide, dimethylsulfoxide, chloroform, dioxane, tetrahydrofuran, ethyl acetate, and appropriate mixtures thereof.

In the production of the compounds of the present invention, carboxyl groups that do not participate in the reaction of amino acids or peptides are, for example, metal salts (sodium, potassium salts, etc.), (-alkylamine salts (triethylamine, N-methylmorpholine, etc.)
Alternatively, it can also be protected in the form of an ester (methyl, ethyl, benzyl, P-nitrobenzyl, t-butyl, etc.). Examples of protecting groups for amino groups that do not participate in the reaction include benzyloxycarbonyl group, [-butyloxycarbonyl group, P-methoxybenzyloxycarbonyl group, and trifluoroacetyl group. Furthermore, the hydroxyl group of tyrosine, which is an amino acid having a functional group in its side chain, is an acetyl group, a benzyl group, a benzyloxycarbonyl group, a t
-Although it may be protected with a butyl group, etc., it is not always necessary to protect it.

Further, in the compound containing a geton among the amine moieties represented by Y in general formula [I], the geton can be protected by an appropriate protecting group (1
, 8-dioquinrane, etc.) and deprotection (90% trifluoroacetic acid water, etc.) at an appropriate step, the amine moiety represented by Y can also be obtained.

Furthermore, some of the compounds of the present invention contain Met(0), but these can also be produced using sulfoxidized methionine, which is one of the raw material compounds, or they may contain Met(0). It can also be produced by oxidizing a peptide intermediate with an oxidizing agent (eg, hydrogen peroxide, perchloric acid, sodium periodate, etc.).

Deprotection of amino acids and peptides with protecting groups, as well as the final peptide derivatives with protecting groups, is carried out by methods commonly used in the field of peptide chemistry, namely catalytic reduction, hydrogen fluoride, and bromide. It is carried out using hydrogen, hydrogen chloride, trifluoroacetic acid, methanesulfonic acid, etc.

Purification of the peptide derivative produced according to the present invention is carried out appropriately using methods frequently used in the field of peptide chemistry, such as recrystallization, ion exchange resin partition chromatography, and gel chromatography.

The compound of the present invention represented by the general formula (I) has been confirmed to exhibit analgesic effects in pharmacological tests, and is expected to be a less narcotic analgesic because of its weak agonist activity at opiate receptors. be.

Furthermore, the derivatives of the present invention exhibit central depressant action and are therefore useful as central depressants.

The compound of the present invention is preferably administered to humans and animals as an injection in the form of a salt. Any pharmacologically inert acid can be used as the salt, and examples thereof include acetate, hydrochloride, and sulfate.

Hereinafter, the method for producing the compound of the present invention will be specifically explained using Reference Examples and Examples. In addition, the following abbreviations are used in Reference Examples and Examples.

Z: benzyloxycarbonyl Boc: t-butyloxycarbonyl Bzl: benzyl osu: N-hydroxysuccinimide ester HON
B: N-hydroxy-5-norpornel-2,8-dicarboximide HOIST: N-hydroxybenzotriazole EDC
I: l-ethyl-8-(8-dimethylaminopropyl)
- Carbodiimide hydrochloride DMF Nidimethylformamide Also, the IT value is silica gel (Merck Kieselgel 6 g)
Thin layer chromatography on p254 (1”
LC) using the following mixed solvent.

Rf, Chloroform: Methanol = 20
: 1kf2...n-butanol:acetic acid:water=4:l:IRE,...chloroform:methanol=4:IRE4...chloroform:methanol:acetic acid=9:l :0.5 Reference Example I Boc-Ty
Production of r-(1% R-D-Ala-Glγ-OH (11
Production of Z-D-Al a-Gly-OH H-Gly-
OH1,5f, triethylamine 2, water containing Of 1
Z-D-Ala-O3u 6 in the solution dissolved in 5+++l
．． A solution of 4 t dissolved in 1) MF 5 Q ml was added, and the mixture was stirred at room temperature for 48 hours. After removing the solvent under reduced pressure, 5%
Citric acid was added and the precipitated crystals were extracted with 50 g of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was powdered with ether and recrystallized from ethyl acetate. Yield 4.8 Elemental analysis Calculated value as C1, H,, N, O,: C55,71
, H5, 75, NIO, OO actual measurement value: C65, 52, H
5,80, NIo, 25(2) Boc-Tyr(B
zl) Production of -D-Ala-Gly-OH Z-D-Al
a-Gly-OH2,8, in methanol 20ml
Dissolve and subject to catalytic reduction over 10% palladium on carbon catalyst for a period of time. After removing 10% palladium on carbon, Okinoha was distilled off under reduced pressure to obtain HD-Ala-Gly-OH1.4f. This HD-Al a-Gly-OH was mixed with triethylamine 1. Add 4.5 t of Boc--Tyr(Bzl)-0Su to a solution containing 1 (1+lI) of water containing Ol.
Add the solution dissolved in 20 ml of ldF and stir at room temperature for 48 hours.
Stir for an hour. After evaporating the solvent under reduced pressure, 5% citric acid was added and the precipitated result was extracted with ethyl acetate (50 sr/trowel), and the ethyl acetate layer was washed with saturated brine using a trowel, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with ether and recrystallized from ethyl acetate.

Yield is 4.21 Melting point 88-90℃ Rt4=0.70C
α)3 +27.0' (C=0.54.methanol)
Elemental analysis C, 61-1,, N, 0. Calculated value as:
C62,50, 1-16,66, S8.4.1 Actual value:
C62,27, H6,85, S8.26 Reference Example 2 B
oc-Tyr(13zl)-D-Metp)-Gly-
Production of OH (11Boc-D-MeLp)-Gly-O
Production of BzlBoc-D-Met-OH7,5t and N-
Methyl 4-ulfolyl8. Of DMF80. ＋＋＋／Mix with dry ice/methanol to -1θ℃~-15℃
Add 4.11 isobutyl chlorocarbonate while maintaining
Isothermal nasal i trowel reaction for 15 minutes. This thing has H-Gly-O
Bzl p-)luenesulfonic acidjJKto, tr
, N-methylmorpholine3. Add Of, 0℃~-5℃
Reacted for 2 hours. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate 1
Dissolved in 00*t, washed with water, 5% citric acid water, sodium bicarbonate water, and water, and dried over anhydrous magnesium sulfate.
Ethyl acetate was distilled off under reduced pressure to obtain oily Boc-D-Met-
Gly-OBzl l B,6f is obtained.

This Boc-D-Met-Gly-OBzl l B
, 6 P was dissolved in 60 ml of ethyl acetate. This stuff includes 6.4 tons of sodium periodate and 100w of water! Add the solution and react at room temperature for 8 hours. The ethyl acetate layer was washed with water, 5% citric acid, sodium bicarbonate, and water, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was dissolved in ethyl acetate-n-
'Crystallize from hexane to obtain the desired product. Yield 8.8
? Melting point 109-111°C Rf, = 0.65 [α], ;s -22,7° (C = 0.52. Methanol) Elemental analysis C1, H2IN20. Calculated value as S: C: 55.82, H6.84, S6.79
, S'1. '17 Actual value: C: 55. O1, H7,0
2, S6.55. S7.60(2) Boc-Tyr
(13zl)-D-MeLp)-Gly-OBzk7)
Production lsoc-D-Met(0)-Gly-OBzl
4.3 Dissolve y in 20 ml of trifluoroacetic acid and react for 30 minutes under water cooling. Trifluoroacetic acid was distilled off under reduced pressure, and ether was added to the residue to form a powder. This powder is D
1. Dissolve triethylamine in 50 ml of MF and cool with water. Ov and Boc-'ryr (Bzl)-0Su 4
．． Add 2 t and stir at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (100 si!). The extract is extracted with water, washed with 5% citric acid, sodium bicarbonate, and water, dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure.

Add ether to the residue to make a powder. Yield 3.9F Melting point 146-149℃ Rt1=0.45. (λ) +20
．． 8° (c=o1g9.methanol) Elemental analysis Cyo) '41NI o8S Calculated value as I: C68,14, H6,51, H6,81, H4,82
Actual measurements: C62, 87, H6, 70, H6, 0B, 54
．． 55 (8i Boc-Tyr (Bzl)-D-M
Production of ct(O)-Gly-OH Boc-Tyr (Bz
l)-D-MetlO)- to 1y-OBzl 3,54
Dissolve 2 in methanol 3+t, add 6 ttti of IN-caustic soda water under water cooling, and stir at room temperature for 2 hours.

Neutralize with IN-hydrochloric acid 6 at, and methanol is distilled off under reduced pressure. The residual liquid was acidified with 5% citric acid water, the precipitated crystals were extracted with 50 m/m of ethyl acetate, and the ethyl acetate layer was washed with water.
Dry over anhydrous magnesium sulfate and evaporate under reduced pressure. Add ether to the residue to make a powder.

Yield 2.90? Melting point 128-180℃ f4=0.
45 (15+27.7°(C=(1,44.

Methanol) Elemental analysis C28jl, N30. Calculated value as S: C
58,42, H6,48, H7,80,55,57 Actual value: C58,15, H6,29, H7,07, H5,8
8 Reference Example 3′Boc-Tyr(ISzl)-D-Ala
-011cr) Manufacture Boc-Tyr (Bzl)-0Su
4. 'ly and l-1-D-A la --O
Using H1, Of, the desired product is obtained in the same manner as in Reference Example 1 (11). Yield: 4. l f Melting point: 158-16
0℃ K[,=0.56 Cα),,'+5.4゜(
C=1. 1O, methanol) Elemental analysis Calculated value as C241I3°N206: C
65,14, J16.8 s, H6,13a Actual value: C65,25,1 (6,75, H6,14 Reference example 4
Boc-;ryr(Bzl)-D-Mctp)-OR
Production of BOC-Tyr (Bzl)-0SU 2. l
Boc- obtained in the same manner as (1) of Reference Example 1 using t and H-p)-Me t -0L19001Ff
j'l'yr (Bz l )-D-Me t-OH2
. After methanol is distilled off under reduced pressure, the residual liquid is extracted with 50 wxl of ethyl acetate, and the ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate. Ethyl acetate is concentrated under reduced pressure, and the precipitated crystals are collected. Yield 1.5flK'l' point 169-172℃
4=0.82 [α'): -)-2,1' (C=0.49, methanol) Elemental analysis Calculated values as C2, H, 4N, O, Sl: C60,21, H6,61, H5 ,40,56,
18 actual measurements: C59,95, H6,87, H5,28,
Preparation of 56,04 (11Boc-Tyr(Bzl)-D-Ala-Gly
-N-(CJ(2), -CH.

Boc-;ryr(Bzl)-D-AJa-Gly-O
500 ml of H and 240 ml of N-methyl-4-(4-fluorophenyl)-4,4-ethylenedioxy-butylamine
Dissolve DM F l Oml Im and add sodium chloride-EDCl 4 Q Q Misaki under ice cooling, and stir at room temperature for 24 hours.
Stir for an hour. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate 5
After washing with 5% citric acid solution, sodium bicarbonate solution, and water, it was dried over anhydrous magnesium sulfate solution and evaporated under reduced pressure. This product is subjected to silica gel chromatography (silica gel 901, developing solvent chloroform:methanol=20:l).

Both parts, equivalent to kf+=0.621, were collected and distilled off under reduced pressure. Add petroleum ether to make a powder.

Yield 401"9 Rf+=0.62 Elemental analysis Calculated value as Cwa, H,, N, 08F: C64,98, H
6,85, NT, T'7 actual value: C65,17, H6,
Preparation of 72, H7,56 To Compound A 889W was added 8.2 M of thioanisole and 12 ml of 90% trifluoroacetic acid water, and the mixture was stirred at room temperature for 16 hours.

Concentrate the solvent under reduced pressure. Addition of n-hexane to the residual solution produces an oil. The supernatant was removed by decantation, 10% hydrochloric acid/methanol was added to the residue, and the mixture was evaporated under reduced pressure. The residue is triturated with methanol ether. Yield 285■ Rf2=0.
48 Rf,=0.17(α]'5+50.1'
(C=0.46 m/-r) Elemental analysis C4tH
uN409 Fl ・HC(1・2 H20(!: L
Calculated value: C5B, 71, H6, 49, NlO, 0
2, C66, 84 actual value: C5B, 40. H6,72,
N9.85. Production of C66,22 (11Boc-Tyr(Bzl)-D-Metp)-
Gly-N-(CH2), -CH.

Boc-Tyr(Bzl)-D-Metp)-Gly
The desired product was obtained in the same manner as in Example 1 (1) using -OH57e)η and N-methyl-4-(4-fluorophenyl)4s4-ethylenedioxy-butylamine (240 μl). Yield 703■ REl=0.15 Elemental analysis C4tHuN40981 Calculated value as Ft: C61,79, H6,70, H7,0B, 54.02
Actual measurements: C61,52, H6,90, H6,77, S8
．． The desired product was obtained in the same manner as in Example 1 (2) using Compound 86110m9 of No. 95. Yield 84519 ft=
OJ6 艮 fl = 0.12 [α] Old + 42.6° (C
=0.46. methanol) elemental analysis C*y11uN4
0sstFt・Hce・2H20tL1: Calculated value: C
51,06, Iie, a5. H8, 82, 55, 05.

Ce 5.58 Actual value: C50,7B, H6,42, H8,59,S
Preparation of 4.77°CI 5.25 Boc-1”yr(Bzl)-D-Ala-OH444
jsrq and N-methyl-4-(4-fluorophenyl)
-4,4-Ethylenedioxy-butylamine 2891 and HONB858 were dissolved in DM FLOwl, and EDC1894 was added under cooling with salt and ice, followed by stirring for 4 hours under water cooling and 12 hours at room temperature. After removing the solvent under reduced pressure, the residue was washed with 5% citric acid water, sodium bicarbonate, sodium hydroxide, and water, dried over anhydrous magnesium sulfate, and then distilled off under reduced pressure. , perform silica gel chromatography (silica gel 100 f, developing solvent chloroform:methanol = 20:L).R
Fractions corresponding to f, = 0.57 were collected and evaporated under vacuum. Add petroleum ether to the residue to make a powder. Yield 660■”
1=0.57 Elemental analysis C, H46N, 0. Calculated value as Fl: C
66,95, H6,99, H6,88 Actual value: C66,
Preparation of 78, H7,28, H6,02 The desired products were obtained in the same manner as in Example 1 (2) using compound caoo■. Yield 171■
艮tt=o, 80 Rfs= 0.55[α]■+4
9.7° (C=0.50.methanol) elemental analysis C,
, H, N, 04F1・HCl, H20 Calculated values:
C57.08, H6.46, N8.68, CJ7.8
1 Actual measurement value: C56,79, H6,72, N8.51. C
#7. Preparation of ll (Preparation of compound D) Boc-Tyr (Bz l )-D-Me tp)
-OI 5194 and N-methyl-4-(4-
The desired product is obtained in the same manner as in Example 8 (1) using fluorophenyl)-4,4-ethylenedioxy-butylamine 24ON9 and HOBT 270 Cape. Collection it 5
91 WqR[s=0.15 elemental analysis C5oH6oN
Calculated value as sOsS 1F t: C: 6B, 81
, H6,81, N5.68, S4.8B actual measurement value:
C6B, 04. H6,98, N5.5B, 84.28
Compound 1) The desired compound was obtained in the same manner as in Example 1 (2) using 550 ml. Yield 810 ``t'fm=
o, f35 Rfs=0. l l〔α〕廿+54.8
°(C=0.58.methanol) elemental analysis C, sH,
,N,0,51F1. Calculated value as HCe, 3H,0: C60,87,1-16,59, N7.05
, S5.88.

Cg 5.95 Actual value: C50.02, H6.71, N6.88,
S5.05.

G g 5.80, production Boc-: l'yr (Bz l )-D-Al
a-OH4Q lq and 1-C4-C4-fluorophenyl)-4゜4-ethylenedioxybutylcopiperazine 2
The desired product was obtained in the same manner as in Example 8 (11) using
O,62 elemental analysis C40HII, N40. Calculated value as F: C66.8B, H7.15, N7.79 Actual value: C6, LV16 @'+Rice7.02, N7.
6 Bo Preparation The desired product is obtained in the same manner as in Example 1 (2) using Compound E407■. Yield 261■
Eg=0.80, Rfi=0.09 [α)”
+88.8° (C=0.49.methanol) elemental analysis
C! 611. , N404F, , 20C (1, 21-
1,0 binding calculation value: C52,61,1 (6,62,N
9.44, cgt 1.95 actual value: C52, H9,
H6,77, N9.02. Production of Ce11.77
O Boc-Tyr(Bzl)-D-MetlO)-OH4
11tq and 1-(4-(4-fluorophenyl)-4,
4-ethylenedioxybutyltwopiperazine 28811
Example 8 (1) using Ig and HOBT214t11g
) to obtain the desired object. Yield 484■ Rfl
=0.19 Elemental analysis C4, HssN40sS, F
Calculated values as 1: C6B, 46, H6,97, N7
．． 05, S4.0B actual measurement value: C6B, 27.1 (
7,05, N6.77, 58.85 The desired product is obtained in the same manner as in Example 1 (2) using Compounds F450~. Yield 278”
f ”i=0.25 1Lfs=0.08(α),;
'+41.2° (C=0.49.methanol) elemental analysis C2,H,, N406S1F1.2Hc/@9H,
Calculated value as 0: C48, 90, H6, 60, N8.15°I4
．． 66, Ce1O, 81 Actual values: C48,75, H6,77, N8.0B.

I4.52. Preparation of CglO,07 (Compound G) Boc-Tyr(Bzl)-D-Ala-Gl
Using 500"V of y-OH and 185q of 2-oxo-2-phenylethylamine, the desired product is obtained in the same manner as in (1) of Example 1. Yield: 289wq"l = 0.42 Elemental analysis Calculated value as Cl4H40N407 : C6
6,21, H6,54, N9.09 Actual value: C66,1
6,H6,85,N8.71 To compound G258q, 10 m/g of thioanisole 8 Nj1 trifluoroacetic acid was added and reacted at room temperature for 2 hours. After trifluoroacetic acid is distilled off under reduced pressure, n-hexane is added to the residual solution to produce an oily substance. The supernatant was decanted and drained, 10% hydrochloric acid/methanol was added to the residue, and the mixture was evaporated under reduced pressure. The residue was triturated with methanol-ether. Collection ff
1l12qRf1=0.65 Rfs=0.82
(12)"+47.26 (C=0.25.methanol) Elemental analysis C,, H,, N, Os-HCl -H,0
(!: L”i (calculated value: C54,94, H6,08,
N11.65°C1,87 Actual value: C54,77, H6,89, N11.152°C# 7.12 Production of (Compound H)j3oc-;ryr(Bzl)-D-Metp)-Gl
A desired product was obtained in the same manner as +11 of Example 1 using 576η of y-OH and 185μ of 2-oxo-2-phenylethylamine. Yield 287■, "s" 0.88 Elemental analysis C111844N408 s, Calculated values: C62.4t, H6.40, N8.09. I4.6B
Actual measurements: C62.25, H6.6B, N7.85. I4
．． 82 Using compound H90119, (2) of Example 7
Obtain the object in the same way as . Yield 54■, Rt2=Q
, 41, Rfs=0.18 [α], %'+44.5°
(C=0.81.methanol) Elemental analysis C2, HvN
Calculated value as 406S1*HC#, 2H, O: C5
0,12,H6,1B,N9.74. I5.58゜cg
6. t7 Actual value: C49.85, H6.89, N9.5B, 85
．． 2B.

Preparation of Ce 6.02 (Compound I) Hoc-Tyr(Bzl)-D-Ala-Gly-OH
5QQ+y and 1-(2-pyrimidyl)piperazine 1
The desired product was obtained in the same manner as in Example 1 (11) using 64.

Yield 877wqs Rft=0.44 Elemental analysis CI4 H48” Calculated value as 011: C68,24, H6,71, N15.1B Actual value: C
68,05,H6,95,N15.02 Compound l846
The target product is obtained in the same manner as in Example 7 (2) using η. Yield 201 ml
Rft=0.56 %=0.27 [α]+46
．． 5° (C=0.28.methanol) Elemental analysis C22
1-'2* N709 ・2 tl C(1・2 H
2otot, te calculation value: C50,04,H6,68,N
18.57. Ce18.4B actual value: C49,82,
Production of H6,87, N18.8B, C71!1B, OL (Compound J) Boc-Tyr (Bz I)-D-Me tp
'FGl y-OH5761F1? The desired product was obtained in the same manner as in Example 1 (11) using and 1-(2-pyrimidyl)piperazine 164η.

Our company 44.4 Q Rf1=0. L O elemental analysis c
*a”aNvOvS 1 (!: L Te calculated value: C
59,90, H6,56, NlB, 58, 54.44
Actual value: C59.75, H6.77, N18.22.5
4.02 Compound J, 892■ was used in Example 7 (2
) to obtain the desired object. Yield 285■ 艮fz
=0.4.8 Rfl=O, 1B [α] is also 5+88.
6° (C=0.48, m/-r) elemental analysis C2
4H Leopard N, O, S, , Calculated value as 2HCe-3H20: C4B, 77, H6, 28, N14.89. S
4.87° Celo, 77 Actual value: C48,59, H6,58, N14.89. S
4.65゜C#IO,58 (Compound K) Production Boc -Tyr (Bzl)-D-Ala-
The desired product was obtained in the same manner as in Example 1 (1) using 500'Gly-OH and 1621 ng of ■-phenyl-piperazine.

Yield 4811rQ RE1=0.45 Elemental analysis Cu
Calculated value as H, 1IN606: C67, 16, H7,
05, N10.88 Actual value: C67,01, H7,19
, NlO, 65, using 458~ as the compound, the desired product is obtained in the same manner as in Example 7 (2). Yield 344 ■ 艮 f2' = 0.56 Rfs = 0.27 (2) 25+
35.5° (C=0.66, methanol) elemental analysis C
24H,,N,04.2 HCe, Calculated value as H20: C52,94,H6,48,N12.86. (J
18.02 actual measurement value: C52,7B, H6,66, N12
．． 99. Production of Ce12.75 (compound L) Boc -Tyr (Bz l )-D-Me tp
) -Gly-OH 576 mg and l-phenylpiperazine 1621F to obtain the desired product in the same manner as in Example 1 (11). Yield: 508 cm "s=o, 19 elemental analysis C, H4, N, 0.S, as.

Calculated value: C6B, 40. H6, 86, H9, 7B, 8
4.45 Actual value: C6B, 02. H7,0B, H9,6
5, S4.1l (2) Old ry r -D-Me tlo
)-G1'y-@Production of A The desired product is obtained in the same manner as in Example 7 (2) using compound L419■. Yield 872mg
Rfg=0.54 Rf*=0.20(12),
;' +24.9° (C=0.27, metal/-r)
Elemental analysis C25HssNsOsS, -2HCl
・2l-120(!: L ”'C calculated value: C48,
90, H6, 47, NlO, 97, 55, 02°C#1
1. IO actual measurements: C48,64, H6,79, NlO,58,
Production of 54,89°Ce10.95 (Compound M) Boc-'ryr(Bzl)-D-Ala-GJ y
-OH500W and 4-phenyl-piperidine 161m9
The desired product is obtained in the same manner as in Example 1 (1) using

Yield 425η 艮f+=0.72 Elemental analysis Calculated value as 87846N406: C69
, 1B, H7, 21, H8, 72 Actual value: C69,0
The desired product is obtained in the same manner as in Example 7 (2) using 1, H7,29, H8,65 compound M400+v. Yield 239'9''2=0.76 Rfg=0.52
[α) 25+51.4° (C=0.51.methanol) Elemental analysis C2, Hs2N, 04e HCl, ■,
Calculated value as 0: C59,22, H6,96, Nl
1.05, C7?6.99 Actual value: C58,96,
l17.29, NIo, 97, Ce6.54 Example 14 H-Tyr-D-Metp)-Gly→Two Σ()
of! I! i! Shin (1) Boc-Tyr (Bzl)-D-MetpHy
-N<(Preparation of compound N) Boc-Tyr (Bz l )-D-Me tp)-
Gly-OH576W and 4-phenyl-piperidine 1
The desired product was obtained in the same manner as in Example 1 (11) using 61■.

Yield 438 ■ 艮fl=0.86 Elemental analysis C3, H, ON, 0. Calculated value as S:
C65,16, H7,ol, H7,79,54,4
6 actual measurements: C64,91, H7,42, H7,52,
54,09(21H-'ryr-D-MetlO)-G
Production of ly -N(J)-Q The desired product is obtained in the same manner as in Example 7 (2) using compound N848Wq. 1
Also, the amount 288rngRf2=0.60 Rf3=0.2
6 [α) 25 + 88.1' (to = 0.22,
Methanol) Elemental analysis C, H36N, 0. S, -1-
1c5-2H20 calculation value: C5B, 94,)
16.87, H9,82, H5,8B.

Ce 5.90 Actual value: C58, 51, H7, 19, H9, 01, H6
-05°C115,77

Claims (1)

[Claims] H 11) 1 5=Q Tomic acid, n represents 1 or O, and Y represents any of the following residues. ] A peptide amide derivative represented by these and its salt. 0 1 CH. Peptide amide derivatives and salts thereof. +4) The peptide amide derivative and its salt according to claim 1, wherein n=1. (6) The Vepti H fiber according to claim 1, where n=0, where n represents l or 0, and Y represents any of the following residues. An analgesic and central depressant containing a peptide amide derivative or a salt thereof represented by the following.