JPH0112759B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to biologically active peptides, pharmaceutically acceptable salts thereof, methods for their preparation and use as therapeutic agents. In this specification, symbols and abbreviations are those commonly used in peptide chemistry (J. Biol.
Chem. 1972, Vol. 247, pp. 977-983). Boc is t-butyloxycarbonyl group, Bzl is benzyl group, c is concentration, d is decomposition, HOTcp is trichlorophenol, MeOH is methanol, Met(0) is methionine sulfoxide, (4-Cl)Phe is 4-
Chloro-L-phenylalanine, (4- _NH2 )
Phe is 4-amino-L-phenylalanine, (4
-NO ₂ ) Phe is 4-nitro-L-phenylalanine, Pip is L-pipecolic acid, Thz is 4-L-thiazolidinecarboxylic acid, Pyr is pyroglutamic acid (5-oxopyrrolidine-2-carboxylic acid)
[See Biochemistry, 14 (2), 459 (1975)], TLC
represents thin layer chromatography. The present invention relates to the general formula: represents an enylalanine residue, B represents an L-proline residue, L-pyroglutamic acid residue, L-tyrosine residue, or L-phenylalanine residue, and C represents an
- represents a proline residue or an L-alanine residue, D
represents L-methionine residue, L-valine residue, L-leucine residue or L-isoleucine residue, Y
represents a hydroxy group, an amino group, or a lower alkoxy group. Preferred terminal nitrogen atom-protecting groups that X can represent include aliphatic urethane-type terminal nitrogen protecting groups such as t-butoxycarbonyl group, 1-methyl-cyclobutoxycarbonyl group, adamantyloxycarbonyl group, and isobornyloxycarbonyl group. includes groups. Preferred L-α-imino acid residues that B can represent are the Pro group, and preferred L-α-amino acid residues that B can represent in the absence of A include Pyr, Phe and Tyr groups. include. Preferred lower alkoxy groups that Y can represent include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, and 2,2,2-tri-butyl group. It is an alkoxy group corresponding to a fluoroethyl group or a cyclohexyl group. The present invention also includes salts of the peptides described above with pharmaceutically acceptable acids or bases. Such acid addition salts include sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfamic acid, citric acid, lactic acid, pyruvic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, cinnamic acid, and acetic acid. , trifluoroacetic acid, benzoic acid, salicylic acid, gluconic acid, ascorbic acid and similar acids. Base addition salts can be derived from a variety of inorganic and organic bases such as sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, dicyclohexylamine. Synthesis of the peptides of the invention is accomplished by classical solution methods. This synthetic method essentially consists in the appropriate sequential condensation of protected amino acids or peptides. The condensation is carried out such that the resulting peptide has the desired sequence of 4 or 5 amino acid residues. When amino acids and peptides are condensed by methods known per se in polypeptide chemistry, they have amino and carboxyl groups protected with suitable protecting groups, which do not participate in the formation of peptide bonds.
Protecting groups can be removed by acidolysis, saponification or hydrogenolysis. For protecting amino groups, for example, benzyloxycarbonyl group, t-butoxycarbonyl group, trityl group, formyl group, trifluoroacetyl group,
Using protecting groups such as o-nitrophenylsulfenyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group or 3,5-dimethoxy-α,α′-dimethylbenzyloxycarbonyl group be able to. For the protection of carboxyl groups, protective groups such as, for example, methyl, ethyl, t-butyl, benzyl or p-nitrobenzyl can be used. The reaction forming the peptide bond by condensation between the amino group of one molecule and the carboxyl group of the other molecule is carried out via an activated acyl derivative, such as a mixed anhydride, azide or activated ester, or a condensing agent. , carried out by direct condensation of free amino groups with free carboxyl groups using a condensing agent, e.g. in the presence of dicyclohexylcarbodiimide alone or together with a racemization inhibitor, e.g. N-hydroxysuccinimide or 1-hydroxybenzotriazole. can do. The hydrazides or substituted hydrazide derivatives according to the invention condense an N-protected peptide or amino acid with a suitably substituted hydrazine, such as benzylcarbazate, t-butylcarbazate, adamantylcarbazate, phenylhydrazine or adamantylhydrazine. or an N-protected peptide hydrazide or amino acid hydrazide with a suitable alkylating agent, such as an alkyl chloride, or with a suitable acylating agent, such as benzyl chloroformate, t-butyl fluoroformate, di-t-butyl dicarbonate or Produced by reaction with adamantyl fluoroformate.
The condensation can be carried out in a solvent such as dimethylformamide, pyridine, acetonitrile, tetrahydrofuran or N-methyl-2-pyrrolidone. The reaction temperature may be from -30°C to ambient temperature. The reaction time is generally 1 to 120 hours. Synthetic routes, protecting groups and condensing agents can be chosen to avoid the risk of racemization. The protecting group elimination reaction can be carried out by a method known per se in polypeptide chemistry. Peptides in which Y represents a lower alkoxy group are prepared, for example, starting from a C-terminal amino acid esterified with a suitable alcohol. A peptide in which Y represents OH can be produced, for example, by hydrolysis of a peptide in which Y represents a lower alkoxy group. Y
Peptides in which represents _NH2 can be prepared by ammonolysis of the corresponding ester or starting from a C-terminal amino acid amidated with a suitable amine. Biological Activity The compounds of the present invention are described by K. Kammerer.
and A. Dey-Hazra, Veterina¨r-Medizinische Nachrichten, 99~
It has an interesting growth-promoting activity in animals as shown in an in vitro-in vitro test system regarding protein synthesis in liver tissue as described on page 112 (1980). The compounds of the invention also exhibit interesting endocrine activities, such as prolactin and luteinizing hormone releasing effects. Evaluation of growth promoting activity Peptides of the present invention, e.g. H-Phe-Pro-
Pro-Trp-Met-NH ₂ was given to rats for 1 to 1 day.
The test was carried out by subcutaneous administration at a dose of 100 ng/Kg for 1 to 4 weeks. These compounds showed an increase in hepatic protein synthesis as measured by the Kemmerer and Dey-Hazra method and an increase in body weight at the end of the 4 week experiment. Additionally, the feed conversion ratio was improved. In vivo - In vitro test - Protein synthesis The growth test was carried out in 6 male rats (Wister,
The animals were divided into three subgroups and kept in Makrolon cages lined with sawdust as bedding. Water and feed (Althromin containing 19% crude protein)
1321 Standarddiet (Altromin 1321 Standarddiet)
was given voluntarily. The peptides of the invention can be used at 1, 10 and 100n in solution.
It was administered subcutaneously daily at a dose of g/Kg. Physiological saline was used as the diluent, and dilution was started from a 100 ng/ml stock solution. Preparation of Tissue Samples 3 g of liver in 9 ml of ice-cold TKM buffer-sucrose solution was homogenized in a Potterhomogeniser for 2 min at 600 rpm, then in an ultracentrifuge for 20 min at 10000 g.
Centrifugation was performed at 4°C and the supernatant, ie, microsomal cell juice, was decanted. Procedure: After calculating the protein content in microsonal cell juice by the Biuret method, the protein concentration was adjusted to 1 mg/ml with TKM buffer. The microsomal cell fluid was then further diluted with double-distilled water.
The protein content was 0.25mg per ml (juice). Then, 0.15 ml of reaction medium and 0.05 ml (50 mcg) of pyruvate kinase solution and 0.1 ml of ¹⁴ C amino acid mixture (=1 μCi) were then added. The volume of each incubation mixture was 1 ml. After incubation for 35 minutes at 37°C in a water bath, 2 ml of trichloroacetic acid (10%) was added to precipitate the proteins. Trichloroacetic acid was added several times, then centrifuged (3600g/5) until the supernatant was free of radioactivity.
The precipitate was washed by washing. The residue was dissolved in 1.0 ml of Lumasolve and left overnight at 37°C until clear. The preparations were measured in a PRIAS liquid scintillation counter PL (1.0 ml + 5 ml of scintillation fluid). The results of a test on the effect of the peptide of the present invention on liver protein synthesis in rats and the acute toxicity value of the peptide are shown in the table.

[Table] (a) Control group was treated with physiological saline.
For veterinary use, compounds of the invention may be administered to food-producing animals by conventional veterinary techniques of treating them with metabolic or growth promoting agents, i.e. as subcutaneous implants or in a suitable stabilized form mixed into the feed. ~100ng/
It can be administered in a dosage range of Kg. The invention therefore further provides a pharmaceutical or veterinary composition comprising a compound of the invention or a pharmaceutically or veterinarily acceptable salt thereof in admixture with a pharmaceutically or veterinarily acceptable diluent or carrier substance. do. Furthermore, these formulations can release the active ingredient directly or in a delayed manner. Preferred peptides according to the invention are: Pyr-Pro-Trp-Met-OH Pyr-Pro-Trp-Met-NH ₂ Pyr-Ala-Trp-Met-OH Pyr-Pro-Trp-Val-OH Pyr -Pro-Trp-Val-OMe Pyr-Pro-Trp-Val-NH ₂ H-Tyr-Pro-Trp-Leu-NH ₂ H-Phe-Pro-Pro-Trp-Leu-NH ₂ H-Phe-Pro- Trp-Ile-NH ₂ Next, the present invention will be explained in detail based on Examples. The Rf value is the layer thickness of silica gel 60F ₂₅₄ (Merck)
Measurements were made on pre-coated plates of 0.25 mm and 20 cm length using the following developer system: System A: Benzene/ethyl acetate/acetic acid/water = 100/
100/20/10 capacity ratio (upper phase). System B: Benzene/ethyl acetate/acetic acid/water = 100/
100/40/15 capacity ratio (upper phase). System C: n-butanol/acetic acid/water = 4/1/1 volume ratio System D: Chloroform/methanol/32% ammonium hydroxide = 55/45/20 volume ratio. "E.Merck" is a trademark. TLC analysis was not performed in as-built condition. The Rf value can therefore vary, especially at different temperatures. Melting points were determined in open capillary tubes on a Tottoli apparatus and are uncorrected. Most derivatives soften and decompose before their melting point. Solvents for crystallization, precipitation or grinding are indicated in parentheses. High-pressure paper electrophoresis with Pherograph - Original - Frankfurt Model 64 (Pherograph -
Schleicher and Schull paper No. 2317 using a PH1.2 (formic acid: acetic acid:
water = 123:100:777), 1600V (40V/cm) and
PH5.8 (pyridine:acetic acid:water=450:50:4500),
Perform at 1400V (32.5V/cm). The products were characterized by their mobility at PH 1.2 relative to Glu (E _1.2 ) and at PH 5.8 relative to His in Glu (E _5.8 ) due to migration direction. Example 1 Preparation of Pyr-Pro-Trp-Met- _NH2 () Step 1, Boc-Trp-Met- _NH2 () Boc-Trp- in 30 ml of anhydrous tetrahydrofuran
N-methyl- in a solution of 3.043 g (10 mmol) of OH
1.12 ml (10 mmol) of morpholine and 0.99 ml (10 mmol) of ethyl chloroformate were added sequentially at -12°C. After stirring for 2 minutes, dimethylformamide
H-Met-NH ₂ [F.Chillemi,
Gazz.Chim.Ital., 1963, vol. 93, p. 1079] 1.482g
(10 mmol) was added. The reaction mixture was stirred at -12°C for 1 hour and at 0-15°C for 2 hours,
Salts were removed by filtration and evaporated in vacuo. The residue was dissolved in ethyl acetate and saturated with sodium chloride.
1M citric acid solution, saturated with sodium chloride
Washed several times successively with 1M sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. 4.041 g (93% yield) of the compound was obtained from ethyl acetate: melting point 143°C, [α] ²⁰ _D = -12.3° (c =
1, MeOH), Rf _A 0.61: Rf _B 0.84. Step 2, 3.911 g (9 mmol) of HCl.H-Trp-Met- _NH2 () Boc-Trp-Met- _NH2 () was dissolved in 40 ml of formic acid at room temperature. After complete removal of Boc (monitored by TLC), remove the solvent in vacuo at 30 °C.
It evaporated. The residue was dissolved in methanol cooled to 0° C. and 3.6 ml (10.8 mmol) of a 3M solution of hydrogen chloride in anhydrous tetrahydrofuran were added. Remove the solvent in vacuo and remove 3 g from MeOH/AcOEt.
(yield 90%) of the compound was obtained. Melting point 114℃
(d), [α] ²⁰ _D = +20.4° (c = 1, MeOH), Rf _C
0.62: E _1.2 0.82. Step 3, Pyr-Pro-OH () Z-Pyr-Pro-OH [Castizhirion (R.
de Castiglione et al., Gazz.Chim.Ital.1964, 94
Vol. 875] 3.604 g (10 mmol) were dissolved in 30 ml of a 1:1 mixture of methanol and dimethylformamide and hydrogenated at room temperature and atmospheric pressure in the presence of 1.2 g of 10% by weight palladium on activated carbon. The catalyst was removed by filtration and the solution was concentrated in vacuo. 2.149 g (95% yield) of the compound was obtained from diethyl ether. Melting point 168℃, [α] ²⁰ _D = -105.1° (c = 1,
MeOH), Rf _C 0.21: Rf _D 0.62: E _5.8 0.98. Step 4, Pyr-Pro-Trp-Met- _NH2 () Pyr-Pro- in 20 ml of anhydrous tetrahydrofuran
0.79 ml (7 mmol) of N-methyl-morpholine and 0.69 ml (7 mmol) of ethyl chloroformate were added sequentially to a solution of 1.584 g (7 mmol) of OH() at -12°C. HCl.H-Trp-Met- _NH2 () in 20 ml of dimethylformamide after stirring for 2 minutes.
A cold solution of 2.596 g (7 mmol) and 0.79 ml (7 mmol) of N-methyl-morpholine was added.
The reaction mixture was stirred for 1 hour at -12°C and 2 hours at 0-15°C, filtered to remove salts and evaporated in vacuo.
Crude product silica gel (Merck) 0.040-0.063
Chloroform:methanol:water 87:13:1 on mm
Purified by column chromatography, eluting with (by volume). 2.545 g (yield 67%) of the compound was obtained from diisopropyl ether. melting point
207-209°C, [α] ²³ _D = −95.3° (c = 1, MeOH),
Rf _C 0.43: Amino acid ratio: Glu1.00; Pro0.98;
Met1.00. Example 2 Hcl.H−Phe−Pro−Pro−Trp−Met−NH ₂
Production process of () 1.Boc-Phe-Pro-OH () 1.151 g (10 mmol) of proline was suspended in 10 ml of water and 10 ml of 1N sodium hydroxide was added.
The resulting solution was diluted with dimethylformamide,
The solvent was evaporated in vacuo. Dimethylformamide was added and evaporated again in vacuo. Boc-Phe-OTcp (4.447
g, 10 mmol) [E.Sandrin and RABoissonnas, Helv.Chim.
Acta, 1963, Vol. 46, p. 1637] was added and the reaction mixture was stirred at room temperature overnight. After removing the solvent by evaporation in vacuo, the crude product was converted into the corresponding free acid at room temperature and silica gel (Merck) 0.040~
Chloroform:methanol = 9:1 on 0.063mm
Purification by column chromatography eluting with (by volume) and evaporation from petroleum ether gave 3.252 g (90% yield) of the compound as a foam. Rf _A 0.67. Step 2, Boc-Pro-Trp-Met-NH ₂ () Boc-Pro-OH 1.722 g (8 mmol) and
Starting from 2.967 g (8 mmol) of Hcl.H-Trp-Met-NH ₂ (), the compound was prepared from isopropyl alcohol in the same manner as in Step 1 of Example 1.
3.828g (yield 90%) was obtained. [α] ²⁰ _D = -
70.2° (c=1, MeOH), Rf _A 0.38; Rf _B 0.73. Step 3, HCl.H−Pro−Trp−Met−NH ₂ () Boc−Pro−Trp−Met−NH ₂ () 3.722 g
Starting from (7 mmol) and operating in the same manner as in Step 2 of Example 1, 2.621 g (80% yield) of the compound was obtained from anhydrous ethyl alcohol. [α] ²⁰ _D =
−23.0° (c=1, MeOH), Rf _C 0.41; E _1.2 0.76. Step 4, Boc-Phe-Pro-Pro-Trp-Met-
_NH2 () 2.340 g (5 mmol) of HCl.H-Pro-Trp-Met- _NH2 () in 20 ml of dimethylformamide
The solution of N-methyl-morpholine was cooled to 0°C.
Add 0.56ml then Boc-Phe-Pro-OH
(1.812 g), 0.676 g (5 mmol) of 1-hydroxy-benzotriazole and 1.135 g (5.5 mmol) of dicyclohexylcarbodiimide were added. The reaction mixture was stirred at room temperature for 3 hours, then filtered and evaporated in vacuo. Crude product in ethyl acetate on silica gel (Merck) 0.040-0.063 mm:
Purified by column chromatography eluting with methanol:water 70:30:2 (by volume).
Compounds from ethyl acetate/diethyl ether
1.940 g (yield 50%) was obtained. Rf _A 0.15, Rf _B
0.60. Step 5, HCl.H−Phe−Pro−Pro−Trp−Met−
NH ₂ () Boc−Phe−Pro−Pro−Trp−Met−NH ₂ ()
Starting from 1.552 g (2 mmol) and proceeding as in step 2 of Example 1, 1.282 g of crude product was obtained. Crude product in silica gel (Merck)
Chloroform:methanol = 0.040-0.063mm
Purified by column chromatography eluting with 82:18 (by volume). 0.705 g of compound (50% total yield) was obtained from methanol/diethyl ether. Melting point 205-215℃ (d), [α] ²⁰ _D = -79.8°
(c=1, MeOH), Rf _C 0.39: E _1.2 0.61: Amino acid ratio: Pro 1.99; Met 1.00; Phe 1.00. Example 3 Preparation process 1 of Pyr-Pro-Trp-Val-OMe (XII), Boc-Trp-Val-OMe () Boc-Trp in 100 ml of anhydrous tetrahydrofuran
4.5 ml (40 mmol) of N-methyl-morpholine and 3.96 ml (40 mmol) of ethyl chloroformate were added sequentially to a solution of 12.17 g (40 mmol) of -OH at -12°C. After stirring for 2 minutes, HCl.H−Val−OMe [Smith (EL) in 50 ml of dimethylformamide
Smith) et al., J.Biol.Chem. vol. 199, p. 801, 1952
A cold solution of 6.70 g (40 mmol) and 4.5 ml (40 mmol) of N-methyl-morpholine was added.
The reaction mixture was stirred for 1 hour at -12°C and 2 hours at 0-15°C, filtered to remove salts and evaporated in vacuo.
The residue was dissolved in ethyl acetate and washed several times successively with 1M citric acid solution saturated with sodium chloride, 1M sodium bicarbonate solution saturated with sodium chloride, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. 14.1 g of compound (yield 84.4%) was obtained from isopropyl alcohol/diisopropyl ether. Rf _A 0.81; Rf _B 0.87. Step 2, HCl.H-Trp-Val-OMe (XI) 12.52 g (30 mmol) of Boc-Trp-Val-OMe () was dissolved in 15 ml of formic acid at room temperature. After complete removal of Boc (monitored by TLC), remove the solvent in vacuo for 30 min.
Evaporated at °C. The residue was dissolved in methanol cooled to 0° C. and 11 ml (33 mmol) of a 3M solution of hydrogen chloride in anhydrous tetrahydrofuran were added. Remove the solvent in vacuo and add isopropyl alcohol/
9.55g of compound from diisopropyl ether
(yield 90%). Rf _C 0.69, E _1.2 0.89Glu. Step 3, Pyr-Pro-Trp-Val-OMe (XII) Pyr-Pro- in 60 ml of anhydrous tetrahydrofuran
2.81 ml (25 mmol) of N-methyl-morpholine and 2.48 ml (25 mmol) of ethyl chloroformate were added sequentially to a solution of 5.66 g (25 mmol) of OH() at -12°C. HCl.H−Trp−Val−OMe(XI) in 60 ml of dimethylformamide after stirring for 2 min.
A cold solution of 8.85 g (25 mmol) and 2.81 ml (25 mmol) of N-methyl-morpholine was added. The reaction mixture was stirred for 1 hour at -12°C and 2 hours at 0-15°C, filtered to remove salts and evaporated in vacuo. Crude product silica gel (Merck) 0.040~0.063mm
Methylene dichloride: methanol: water = 92:8:
Purified by column chromatography, eluting with 1 (by volume). Isopropyl alcohol/
8.37 g (yield 63.7%) of compound XII was obtained from diisopropyl ether. Melting point 120℃, [α] ²⁴ _D = -
76.3° (c=1, MeOH), Rf _B 0.21: Rf _C 0.56: Amino acid ratio: Glu 1.00; Pro 0.98; Val 1.00. Example 4 Production of Pyr-Pro-Trp-Val-OH () Pyr-Pro-Trp produced in Step 3 of Example 3
2.63 g (5 mmol) of -Val-OMe (XII) was dissolved in 15 ml of methanol and saponified with 7.5 ml of 1N sodium hydroxide at room temperature. The reaction was completed within 4 hours. The solution was diluted with 40 ml of water, concentrated to half in vacuo, diluted again with 40 ml of water, cooled to 0 °C,
The mixture was made acidic to pH 2 with 5N hydrochloric acid, and finally extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution until neutral, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. 2.1 g (yield: 82%) of compound () was obtained from isopropyl alcohol/diisopropyl ether. [α] ²⁵ _D =
−47.6° (c=1, MeOH), Rf _B 0.11: Rf _C 0.48:
E _5.8 0.43Glu, amino acid ratio: Glu1.00; Pro0.99;
Val1.00. Example 5 Production of Pyr-Pro-Trp-Val-NH ₂ () Pyr-Pro-Trp produced in Step 3 of Example 3
-Val-OMe (XII) 2.63 g (5 mmol) in methanol 20 ml and ethylene glycol 0.4 ml (2%
V/V). The solution was saturated with ammonia gas at 5° C. and stored in the refrigerator until the reaction was completed (TLC monitoring). Excess ammonia was removed in vacuo and the solution was concentrated in vacuo. Column chromatography (silica gel 0.040-0.063mm;
The desired compound was obtained from isopropyl alcohol/diisopropyl ether after purification with the eluent system CH ₂ Cl ₂ :MeOH=87:13). (1.99
g, yield 78%). Melting point 128℃, [α] _D = -69.3° (c =
1, MeOH), Rf _B 0.10: Rf _C 0.43, amino acid ratio:
Glu0.99; Pro0.97: Val1.00. Working similarly to the previous example, the following other peptides were synthesized: ()H-Phe-Pro-Pro-Trp-Leu-
_NH2・HCl Rf _C 0.43:E _1.2 0.61. () Pyr−Ala−Trp−Met−OH Rf _C 0.57. () Pyr−Pro−Trp−Met−OH Rf _C 0.42. () H-Tyr-Pro-Trp-Leu- _NH2.HCl Melting point 160-170°C (d) (methanol/diethyl ether); E _1.2 0.63. () H-Phe-Pro-Trp-Ile-NH ₂ HCl melting point 125-130°C (d) (diethyl ether);
E _1.2 0.60.

Claims (1)

[Claims] 1 Formula (): X-A-B-C-Trp-D-Y () [In the formula, bond or L-phenylalanine residue, B represents L-proline residue, L-pyroglutamic acid residue, L-tyrosine residue or L-phenylalanine residue, and C represents L-phenylalanine residue.
- represents a proline residue or an L-alanine residue, D
represents L-methionine residue, L-valine residue, L-leucine residue or L-isoleucine residue, Y
represents a hydroxy group, an amino group or a lower alkoxy group] and pharmaceutically or veterinarily acceptable salts thereof. 2 X represents a hydrogen atom or a t-butyloxycarbonyl (Boc) group, A is present or absent, and if present, represents a Phe residue, and B is
Represents Pro, Pyr, Phe or Tyr residue, C represents Pro or Ala residue, D represents Val, Leu, Met or Ile
Represents a residue, and Y is a hydroxy group, an amino group, or a formula
The peptide according to claim 1 representing a group of OR (wherein R represents a lower alkyl group) or sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfamic acid, citric acid , lactic acid, pyruvic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, cinnamic acid, acetic acid, trifluoroacetic acid, benzoic acid, salicylic acid, gluconic acid, ascorbic acid; Sodium hydroxide, potassium hydroxide, diethylamine,
Base addition salts of said peptides derived from bases such as triethylamine, dicyclohexylamine. 3. The compound according to claim 1 or 2, wherein X is a hydrogen atom. 4 Peptide is H-Phe-Pro-Pro-Trp-Met
_-NH2 , or a pharmaceutically or veterinary acceptable salt thereof. 5 Pry−Pro−Trp−Met−OH Pyr−Pro−Trp−Met−NH ₂ Pry−Ala−Trp−Met−OH Pyr−Pro−Trp−Val−OH Pyr−Pro−Trp−Val−OMe Pyr−Pro Selected from the group consisting of -Trp-Val-NH ₂ H-Tyr-Pro-Trp-Leu-NH ₂ H-Phe-Pro-Pro-Trp-Leu-NH ₂ H-Phe-Pro-Trp-Ile-NH ₂ The compound according to claim 1, which is a compound according to claim 1. 6 Formula (): X-A-B-C-Trp-D-Y () [In the formula, X represents a hydrogen atom, A represents a valence bond or L-phenylalanine residue, and B represents Represents a proline residue or an L-pyroglutamic acid residue,
C represents an L-proline residue, D represents an L-methionine residue or L-valine residue, and Y represents a hydroxy group, an amino group or a lower alkoxy group] or its veterinary acceptable peptides Animal growth promoters containing salt. 7 Formula (): X-A-B-C-Trp-D-Y () [In the formula, represents an alanine residue, B represents an L-proline residue, L-pyroglutamic acid residue, L-tyrosine residue, or L-phenylalanine residue, and C represents an L
- represents a proline residue or an L-alanine residue, D
represents L-methionine residue, L-valine residue, L-leucine residue or L-isoleucine residue, Y
represents a hydroxy group, an amino group or a lower alkoxy group, or a veterinarily acceptable salt thereof, as an activation method, a mixed anhydride,
A compound of formula () below is condensed with a compound of formula () below using an azide, an active ester or dicyclohexylcarbodiimide to give X-A-B-W-OH () H-J-Trp-D-Y ( ) [If W is C in the formula, J does not exist and J is C
, then W does not exist and A, B, C, D, X
and Y represents the above, but X does not represent H,
Y does not represent OH], the generated peptide of the formula () is converted into a compound of the formula () in which Y is different by esterification, hydrolysis or ammonolysis as necessary,
The protecting group of the resulting compound of formula () is optionally removed, and/or the free compound of formula () is optionally converted into a salt, and/or the salt of the compound of formula () is optionally converted to a salt of the compound of formula (). A method for producing a peptide, the method comprising: obtaining a free compound thereof. 8. The method according to claim 7, wherein W represents C and J is absent. 9. The method according to claim 7 or 8, wherein the produced compound of formula () is as defined in claim 3, 4 or 5.