TETRAPEPTIDEHYDRAZIDE DERIVATIVES AND PROCESS FOR THEIR PREPARATION

Abstract: Novel tetrapeptidehydrazide derivatives, inclusive of a pharmacologically acceptable acid addition salt thereof, which has the general formula (I): (wherein R₁ is hydrogen or lower alkyl; R₂ is hydrogen or the side chain of a D-α-amino acid; R₃ is hydrogen or lower alkyl; R₄ is hydrogen, or a saturated or unsaturated and straight or branched lower aliphatic acyl group which may optionally be substituted by hydroxy amino lower alkoxy, halogen, oxo, lower alkylthio or lower alkylthiooxide), are useful as analgesics.

Description: This invention relates to new tetrapeptide hydrazide derivatives which have analgesic activity. Hushes et al isolated from the brain of a pig a couple of pentapeptides, generically called enkephalin, which give morphinomimetic activity on intracerebral administration, and identified them to be H-Tyr -Gly-Gly-Phe-Met-OH and H Tyr-Gly-Gly-Phe-Leu-OH, respectively (Nature 258, 577 P (1975)). Although these substances display a morphinemimetic action when directly administered by the intracerebral route, they do not have an analgesic action on intravenous administration. R-Endorphin, which is apparently derived from the carboxyl terminal of -lipotropin, when intravenously administered produces profound analgesic effects but since it is a polypeptide consisting of 31 amino acid residues, it is extremely difficult to produce it by an organic chemical process and, therefore, to make it available as a medicinal product on a commercial scale. The investigation made for commercially advantageous compounds which would be stable and capable of producing an adequate relief of pain on intravenous or subcutaneous administration led us to the finding that certain tetrapeptide derivatives are suitable for the abovestated purpose. The finding was followed by further research which has resulted in this present invention This invention is directed to: (1) a tetrapeptide hydrazide derivative, inclusive of a pharmacologically acceptable acid addition salt thereof, which has the general formula (I): EMI2.1 (wherein 21 is hydrogen or lower alkyl; R2 is hydrogen or the side chain of a r-a-amino acid; R3 is hydrogen or lower alkyl; R4 is hydrogen, or a saturated or unsaturated and straight or branched lower aliphatic acyl group which may optionally. be substituted by hydroxy, amino, lower alkoxy, halogen, oxo, lower alkylthio or lower alkylthiooxide7 (2) a method of producing a tetrapeptide hydrazide derivative of general formula (I) characterized by deprotecting a compound of general formula (II): EMI2.2 (wherein R1 is hydrogen or lower alkyl; R2 is hydrogen or the side chain of a D-a-amino acid which may optionally be protected; F, is hydrogen or lower alkyl; R4 is hydrogen, or a saturated or unsaturated and straight or branched lower aliphatic acyl group which may optionally be substituted by hydroxy, amino lower alkoxy halogen, oxo, lower alkylthio or lower alkylthiooxide and which may be protected; Y1 is A protective group; Y2 and YX, respectively mean hydrogen or a protective group). In this specification, amino acids and peptides are designated either by the abbreviations commonly used in the art or by those adopted by the Committee on Chemical Nomenclature of IUPAC-IUB. Some of such abbreviations are as follows Ala : alanine Gly : glycine Leu : leucine Phe : phenylalanine Methe : N-methyl-phenylalanine Tyr : tyrosine MeTyr : N-methyl-tyrosine Gln : glutamine Thr : threonine Ser : serine Nva : norvaline Met(O) : methionine sulfoxide Met(O2) : methionine sulfone Lys : lysine His : histidine Glu : glutamic acid In the following description, the compounds repeatedly referred to are designated by the following abbreviations DCC : N,N'-dicyclohexylcarbodiimide HONB : N-hydroxy-5-norbornene-2,3-dicarboximide ONB : HONB ester Z : benzyloicycarbonyl OEt : ethyl ester ONP : p-nitrophenyl ester frDs : tosyl BOC : t-butoxycarbonyl But : t-butyl DMF : dimethylformamide Bzl : benzyl HOBT : N-hydroxybenzotriazole MeOH : methyl alcohol AcEt : ethyl acetate TEA : triethylamine THF : tetrahydrofuran TFA : trifluoro acetic acid tCHA : dicyclohexylamine OCH3 : methylester C±-Z : p-chlorobenzyloxycarbonyl Throughout this specification, wherever any amino acid or its residue is designated by an abbreviation in the above manner, it represents the L-form thereof unless otherwise specified, while the D-form of any amino acid or residue thereof is specified by (D)- or D-. Referring, now, to the above general formulas (I) and (II), the lower alkyl R1 is preferably a straight-chain or branched alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, n-pentyl, isopentyl, sec-amyl, tert-amyl, n-hexyl, isohexyl, 3-methylpentyl, neohexyl and 2,3 dimethylbutyl. The side chain of D-&alpha;-amino acid is represented by R2 or R2' is the side chain of any of such amino acids as L-leucine, D-alanine, D-methionine, D-methioninesulfoxide, r-serine, S-threonine, D-phenylalanine, D-histidine, Di- tryptophan, D-tyrosine, D-methioninesulfone, D-glutamine, D-asparagine, D-arginine, D-lysine, D-ornitine, D-glutamic acid, D-aspartic acid, D-cysteine, S-methyl-D-cysteine, Sethyl-D-cysteine, S-methyl-D-cysteinesulfoxide, S-ethyl-Dcysteinesulfoxide, D-a-aminobutyric acid, D-valine, Dnorvaline, r-norleucine D-isoleucine, and S-methyl-D-methionine In this context the side chain of D-a-amino acid includes the amino acids mentioned above having protective group such as tertiary butyl, benzyl, acetyl, formyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, p-nitrobenzyloxy, t-butoxy, methoxy, ethoxy and benzyloxy. The lower alkyl R3 is preferably an alkyl group of 1 or 2 carbon atoms, such as methyl and ethyl. The saturated or unsaturated and straight or branched lower aliphatic acyl group R4 is preferably a group of 1 to 8 carbon atoms, and F4 being particularly preferred is a group of 2 to 6 or 3 to 5 carbon atoms The examples of the saturated and straight or branched lower aliphatic acyl groups are formyl, acetyl, propionyl, isopropionyl, n-butyryl, isobutyryl; n-valeryl, isovaleryl, hexanoyl, isohexanoyl, heptanoyl and octanoyl, as a parent acyl group. The examples of the unsaturated and straight or branched lower aliphatic acyl groups are crotonoyl, methacryl and acryl, as a parent acyl group. As examples of the halogen atom which may be present as a substitutent on acyl groups mentioned above, there may be mentioned chlorine, fluorine or bromine, for instance. The lower alkoxy which may substitute the acyl groups is preferably an alkoxy group of 1 to 4 carbon atoms, such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. Particularly desirable are methoxy, ethoxy and n-propoxy The lower alkylthio which may substitute the acyl groups is preferably an alkylthio group of 1 to 4 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio and tert-butylthio. Particularly desirable are methylthio, ethylthio, n-butylthio and isobutylthio. The lower alkylthiooxide which may substitute the acyl group is preferably an alkylthiooxide group of 1 to 4 carbon atoms, such as methylthiooxide, etbylthiooxide, n-propylthiooxide, isopropylthiooxide, n-butylthiooxide, isobutylthiooxide and tertubutylthiooxide. Particularly desirable are methylthiooxide, ethylthiooxide, n-butylthiooxide and isobutylthiooxide The typical examples of substituted acyl group FS are hydroxyacetyl, 2-hydroxypropionyl, 3-hydroxypropionyl, 2hydroxybutyryl, 3-hydroxybutyryl, 4-hydroxybutyryl, 2,3dihydroxypropionyl, aminoacetyl, 2-aminopropionyl, 3-aminopropionyl, 4-aminobutyryl, ethoxyformyl, methoxyacetyl, 3methoxypropionyl, 3-ethoxypropionyl, 4-methoxybutyryl, chloroacetyl, dichloroacetyl, 2-chloropropionyl, 3-chloropropionyl, 2,3-dichloropropionyl, 2-chlorobutyryl, 3 chiorohutyryl, 4-chlorobutyryl, 3-oxobutyryl, 3-oxovaleryl, 4-oxovaleryl, methylthioacetyl, 3-methylthiopropionyl, ethylthioacetyl, 3-ethylthiopropionyl, methylthiooxideacetyl, 3-methylthiooxidepropionyl, ethylthiooxideacetyl and 3ethylthiooxidepropionyl. As examples of the protective group Y1 in the above general formula, there may be mentioned benzyloxycarbonyl, t-butoxycarbonyl, t-amyloxcarbonyl, isobornyloxycarbonyl, adamantyloxycarbonyl, chloro- or nitro-substituted benzyloxycarbonyl, o-phenylthio and diphenylphosphinomethyl. The protective group Y2 may for example be benzyl and t-butyl As regards the protective groups on R2 and Rq, the protective group for protecting the hydroxy and/or carboxyl group of each parent group may for example be one of the groups mentioned for Y2 and the protective group for the amino group of each parent group may for example be one of those mentioned for v The protective group Y3 may be one of those protective groups mentioned for Y1. A tetrapeptide hydrazide derivative of chemical structural formula (I) is produced by condensing N-terminal amino acid or a peptide fragment of tetrapeptidehydraziyie (I), having a N-terminal amino did, with the remaining part of the tetrapeptidehydrazide (T). Thus, for example, the following alternative methods may be utilized for this purpose. The methods described in M. Bodansky and M.A. Ondetti: Peptide Synthesis, Interscience, New York, 1966; F.N. Finn and K. Hofman: The Proteins, Vol. 2, ed. by H. Nenrath, R. L. Hill, Academic Press Inc,, New York, 1976; or Nobuo Izumiya et al; Peptide Gosei (Peptide Synthesis), Maruzen Inc. , 1975, may be utilized Thus, for example, the azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method, the method involving the use of Woodwar(l's reagent K, carbodiimidazole method, reduction-oxidation method and rCC/HONB method may be mentioned. There are cases in which the NCA (N-carboxy-anhydride) method (the method involving the use of an intramolecular cyclic carbonyl compound corresponding to the amino acid without use of a protective group) may be utilized. Prior to the condensation reaction, the carboxyl or/and amino group in starting material which will not be pertinent to the reaction may be previously protected or the carboxyl or and amino groups of starting material which are pertinent to the reaction may be previously activated. The protective groups for the starting material may be the protective groups mentioned hereinbefore. The carboxyl group of the starting material may also be protected in the form of metal salt (e. g. sodium salt, potassium salt), t-alkylamine salt (e.g. triethylamine salt, N-methylmorpholine salt) or ester (e.g. methyl ester, ethyl ester, benzyl ester, p-nitrobenzyl ester, t-butyl ester, t-amyl ester). As examples of the protective group for the amino group in the starting material, there may be mentioned benzyloxy- carbon, t-butoxycarbonyl and isobornYloxyearbonyl. The imino group of histidine may be protected by benzyl, tosyl, 2,4-dinitrophenyl, t-butyloxycarbonyl and carbobenzoxy. The hydroxy group of tyrosine may be protected in the ether form by benzyl and t-butyl. The guanidino group of arginine may he protected by nitro, tosyl, carbobenzoxy, isobornyloxycarbonyl and adamantyloxycarbonyl. As examples of the activated form of the carboxyl group in the starting material, there may be mentioned the corresponding acid anhydride, azide, active ester (i. e. esters with alcohols (e.g. pentachlorophenol, 2,4,5-- trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, pnitrophenol, N-hydroxy-5-norbornene-2,3-dicarboximide, N hydroxysuccinimide N-hydroxyphthalimide, N-hydroxybenzo triazole)). As an example of the activated form of the amino group in the starting material, there may be mentioned the corresponding phosphoric acid amid. Assuming that the starting materials are A and B, the above combinations of carboxyl and amino groups in starting materials may be as shown in the following table. Combination Starting materials example A B COOH NH COOH NH2 1* Free Protected Protected Free 2 Activated Protected Free Free 3 free Protected Protected Activated Note: In the case of *, a dehydrating agent (e.g. a carbodiimide reagent such as dicyclohexyl carbodiimide) is desirably present in the reaction system. The reaction may be carried out in a solvent. This solvent is selected from among the solvents hitherto-known to be suited for peptide synthesis reactions. Thus, for example, there may be mentioned anhydrous or aqueous dimethylformamide, dimethylsulfoxide, pyridine, chloroform, dioxane, dichloromethane and tetrahydrofuran as well as appropriate mixtures of such solvents The reaction temperature is selected from the range hitherto-known to be suited for peptide synthesis reactions and may normally range from about -200C to about 30 C. The precursor compounds (protected peptides) for the compounds of this invention may be easily produced as well by the solid-phase synthesis procedure The protected compound of formula (II) so obtained is subjected to a deprotecting reaction by which the protective groups are removed. While the deprotecting reaction depends on the type of protective group involved, it is preferred for commercial purposes that this reaction is such that it removes all the protective groups in a single step without affecting the peptide bonds. Thus, protective groups are chosen in consideration of this possibility. Table 1 shows some combinations of different types of protective groups and typical deprotecting conditions 'l'able 1 EMI11.1 <tb> <SEP> protective <SEP> Protective <SEP> Protective <tb> <SEP> group <SEP> group <SEP> on <SEP> group <SEP> on <tb> Conditions <SEP> Yl <SEP> Y2 <SEP> 1 <SEP> R <SEP> 3 <tb> of <SEP> removal <SEP> 2 <SEP> 4 <tb> lI2/catalyst <SEP> Z <SEP> Bzl <SEP> - <SEP> - <SEP> Z <tb> H2/catalyst <SEP> Z <SEP> - <SEP> - <SEP> - <SEP> <tb> CF3COOH <SEP> BOO <SEP> But <SEP> But <SEP> But <SEP> BOC <tb> <SEP> 2N-HCt <SEP> OC <SEP> - <SEP> - <SEP> - <SEP> <tb> (in <SEP> acetic <SEP> acid)(BOC <SEP> - <SEP> - <SEP> - <SEP> BOC <tb> CH <SEP> SO <SEP> H <SEP> z <SEP> - <SEP> - <SEP> - <SEP> BOC <tb> <SEP> 33 <tb> While Table 1 is a listing of some deprotecting reactions such as catalytic reduction involving the use of palladium black, palladium-on-carbon, platinum or the like catalyst and acid hydrolysis with trifluoroacetic acid, dilute hydrochloric acid or methanesulfonic acid, such other processes as reduction with sodium metal in liquid ammonia and acid hydrolysis with the use of trifluoromethanesulfonic acid, a solution of hydrogen bromide in glacial acetic acid, hydrogen fluoride or the like may also be mentioned. These reactions are generally conducted at suitable temperatures from 2000 to 400C, and in the case of acid hydrolysis, the addition of a cation acceptor such as anisole, phenol or thioanisole is advantageous. When the compound (I) is desired to have D-methionine sulfoxide as r-a-amino acid component, the required introduction of oxide may be conducted on any intermediary compound containing methionine residue in the course of peptide synthesis of this invention. for example, (1) T)-methionine sulfoxide is used as the starting material, (2) an intermediate of the compound (III) representable by the formula (III) EMI12.1 (wherein R1, R2 and R3 have the same meaning as defined above) is oxidized, and then the resulting compound is subjected to peptide synthesis, or (3) the compound (III) is subjected to oxidation. As examples of the oxidizing agent usable for the oxidation, there may be mentioned hydrogen peroxide, sodium perchloride, sodium perborate, chloramne T, tribromocresol, N-chlorosuccinimid and chloroauric acid The amount of the oxidazing agent is usually not less than about 1 equivalent,preferably about 1 to 10 equivalent to the compound (III). The solvent usable for the reaction is, for example, water, acetic acid, alcohol (e.g methylalcohol, ethylalcohol), or mixtures thereof. The reaction temperature is generally -20"C to 400C. Aster completion of the reaction, the peptide derivative (I) so produced is isolated by procedures which are knows for the separation of peptide derivatives, i 0e by extraction, distribution, reprecipitation, recrystallization or column chromatography. The peptide (I) may be obtained in the form of a salt, e.g. the organic acid salt or inorganic acid salt, preferably acetate, citrate, tartrate, hydrochloride or sulfate. The following is the result of a pharmacological test with the compound (I) of this invention. Hot-plate test: Ta:CF1 mice, 4 weeks old and with body weights 18-22 g, were used When the animal is placed on a hot copper plate maintained at St) + 0.5 C, it shows certain responses to the thermal stimulus such as licking the soles of the hind paws or limping up to escape. The mice showing such responses within 20 seconds after placement on the hot plate were selected into groups of 10 animals. The test drug was injected intravenously or suboutaneously, and after 5, 10, 20, 30, 45 and 60 minutes their response times were measured and compared with the response times of untreated animals (control groups). To avoid irreversible injuries to the soles, 60 seconds was selected as the maximum test time. The indexes of analgesic action(response prolongation rate, %) were derived by means of the following equation and a t-test was carried out to evaluate the effectiveness of the test drug. Response time after - Response time dosing (sec.) before dosing (sec.) x 100 GO - response time before dosing (sec.) In the above test, the compound (I) of this invention in doses of no more than 2 mg/kg preferably 1 mg/kg or 200 ig/kg displayed analgesic actions equivalent to a prolongation rate of not less than 40% with a peak occurring at 5 to 60 minutes preferably 5 to 30 or 5 to 20 minutes and some particularly effective kinds of compound (I) displayed marked pain reliefs even in small doses not exceeding 0.5 mg/kg preferably not exceeding 0.1 mg/kg or not exceeding 20 pg/kg. As mentioned hereinbefore, the compound (I) according to this invention produces a definite analgesic action, as evidenced by results of hot-plate tests in mire, at the dose levels between about 0.05 to 10 mg, preferably about O.05mg to about 2 mg/kg, or about 0.2 to 1 mg/kg and in view of its superior efficacy as compared with ss- endorphine, is of value as an analgesic drug. Therefore, the compound (I) and its pharmacologically acceptable acid addition salts can for instance be used as analgesics for the relief of pains inclusive of the pain of advanced-stage cancer and as medicaments for the treatment of gastrointestinal disorders such as diarrhea, in mammalian animals such as mouse, rat, rabbit, dog, monkey, human being or be used as a medicaments for the treatment of mental disease. The compound (I) and its acid addition salts thereof, which are provided by this invention are extremely low in toxicity and no death is encountered even at 200 mg/kg which is by far beyond the effective dose. The compound of this invention may be administered in its free form or as an acid addition salt thereof. In the case of free compound (I), the proper dosage is generally in the range of 0,01 to 50 mg/kg, preferably 0.05 mg to 30 m/kg or 0.1 to 20 mg/kg. The dosage of the acid addition salt of (I) may also range generally from 0.01 to 50 mg/kg, preferably 0.05 mg to 30 mg/kg or O.1 to 20 mg/kg as free compound (I). The compound and salt according to this invention are mainly administered by routes other than the oral route (e.g. intravenous, subcutaneous, rectal), although they may be orally applied depending on condition. Particularly useful is continuous infusion or instillation in the course of a surgical operation. Useful dosage forms include injections, suppositories, powders and so forth, although instillable preparations are also useful Being stable substances, the compounds according to this invention can be stored as dissolved in physiological saline but they may be provided in the form of lyophilized ampoule preparations as compounded with mannitol or sorbitol for extemporaneous dissolution and use In the case of intravenous and subcutaneous injections, concentrations are preferably within the range of 1 to 25 mg/me preferably 10 to 25 mg/m or 10 to 20 mg/m± in physiological saline The present compound (I) also has activities of prolactin or growth hormone releasing activity, inhibitory effect on motor activity of small intestine and modulating of central nervous system There are some occasions that the present compound (II), which has a protective group, has a similar activity to those of the present compound (I). The following examples are given to describe this invention in further detail. It should be understood that the Sephadex LH-20 used for the purification of final products is the product of Pharmacia (Sweden) and that the purity of each compound prepared was assayed by thin-layer chromatography on Kieselgel 60F-254, Neck, using the following solvent systems: Rf : chloroform-methanol-acetic acid (9:1:0 5) Rf2 : ethyl acetate-pyridine-acetic acid-water (60:20:6:10) Rf3 : n-butanol-acetic acid-water (4:1:1) Reference example 1 Production of Z-Tyr-(D)-Leu-Gly-OH (I) Production of Z-(D)-Leu-Gly-OH In 20 ml of water is dissolved 3.3 g of glycine, and 3.4 g of sodium hydrogen carbonate is added. Then, under stirring, a solution (100 ml) of 17.0 g (40 m mols) of Z(D)-Leu-ONB in DMF is added. The mixture is stirred at room temperature overnight. Next morning the DMF is distilled off and 200 ml of AcOEt and 50 ml of aqueous hydrochloric acid are added to the residue. The AcOEt layer is washed with water and dried over anhydrous sodium sulfate. The AcOEt is then distilled off and the residue is crystallized with petroleum ether. Recrystallization from AcOEt-petroleum ether yields 9.8 g (75 %) of the above indicated compound. m. p. 110-111 C; [&alpha;]D27 + 24.3 (c = 1.0, MeOH); RfÚ=0.42. Elemental analysis, for C16H2205N2 Calcd. C, 59.61; H, 6.88; N, 8.69 Found C, 59.59; H, 6.85; N, 8.74 (II) Production of Z-Tyr-(D)-Leu-Gly-OH In 100 ml of MeOH is dissolved 7.0 g (22 m mols) of Z-(D)-Leu-Gly-OH and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the MeOH is distilled off and the residue is suspended in THF-water (100 ml - 10 ml). The suspension is cooled and dissolved by the dropwise addition of 3 ml oI TBA. To this solution is added 10.5 g of Z-Tyr-ONB and the mixture is stirred at toom temperature overnight. The THF is distilled off and 200 ml of AcOEt and 25 ml of liT aqueous hydrochloric acid are added to the residue The AcOEt layer is washed with water and dried over anhydrous sodium sulfate. The AcOEt is then distilled off and the residue is treated with diethylether and recrystallized from AcOEt. 8.2 g (78 %): m.p. 179-181 C; [a]27 + 45.2 (c = 0.5, MeOH); RfÚ=0.38 elemental analysis, for C25H31O7N3 Calcd. C, 61.68; H, 6.51; N, 8.64 Found C, 61.84; H, 6.44; N, 8.66 Example 1 Production of H-Tyr-(D)-Leu-Gly-Phe-NNH-NH2 (I) Production of Z-Tyr--(D)-Leu-Gly-Phe-OMe In 50 ml of THF are dissolved 1.45 g of Z-Try-(I))- Leu-Gly-OH and 590 mg of HONB, and under cooling at 00C, 680 mg of LCC is added and the mixture stirred for 4 hours. The by-product urea derivative is filtered off, 750 mg of H-Phe-OMe hydrochloride and 0.5 ml of TEA are added to the filtrate and the mixture is stirred at room temperature overnight. The THF is then distilled off, the residue is extracted with 100 ml of AcOEt and the extract is washed with 5% aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The AcOEt is distilled off and the residue is purified by precipitation with petroleum ether and recrystallized from AcOEt-diethylether. 1.73 g (89 %); m. p. 100-101 C; [&alpha;]D22-2.6 (c = 0.5, DMF); RfÚ=0.68. Elemental analysis, for C35H4208N4 Calcd C, 65.00; II, 6.55; N, 8.66 Found C, 64.97; H, 6.95; N, 8.62 (II) Production of Z-Tyr-(D)-Leu-Gly-Phe-NH-NH2 In 5 mf of DMF is added 517 mg of Z-Tyr-(D)-Leu- Gly-Phe-OMe, and after the addition of 0.1 me of NH2-NH2. H20, the solution is allowed to stand at room temperature for 3 days. The DMF is then distilled off and the residue is treated with water, by filtration and purified by reprecipitation eith MeOH-diethylether. 410 mg (80%); m. p. 176-177 C (decomp.); [&alpha;]D22 -22.7 C (c = 0.4, DMF); RfÚ=0.20 Elemental analysis, for C34H4207N6 'kH20 Calcd C, 62.27; H, 6.45; N, 12.82 Found C, 62,03; H, 6.57; N, 12.64 (III) Production of H-Tyr-(D)-Leu-Gly-Phe-NH-NH2 In 50 ml of MeOH is dissolved 350 mg of Z-Tyr-(D)- Leu-Gly-Phe-NH-NH2, and following addition of 0.1 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the filtrate is concentrated and the residue is dissolved in a small amount of 1N-aqueous acetic acid and put on a column of Sephadex LH-20 (2.5 x 120.cm). Elution is carried out with lN-aqueous acetic acid and fractions from 320 through 340 ml are collected and lyophilized. 210 mg (6'); (a 22.6 (c=0.38, MeOH); Rf2=0,34; amino acid analysis (acid hydrolyzate): Gly, 1.00, Leu, 1 00; Tyr, 0.90; Phe, 1.02; mean recovery rate 70%. Example 2 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH2 (I) Production of Z-Tyr-(D)-Ala-Gly-OH In 200 ml of MeOH is dissolved 8.2 g of Z-(D)-Ala- and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the MeOH is distilled off and the residue is dissolved in 70 ml of trifluoroacetic acid and allowed to stand at- room temperature for 40 minutes The trifluoroacetic acid is distilled off and the residue is trea-ted with diethyl ether and collected by filtration. The powders thus obtained are suspended in 50 ml of water and dissolved by the addition of 4.7 g of sodium hydrogen carbonate. To this solution is added 100 mt of a THF solution containing 13.3 g (28 m mols) of Z-Tyr-ONB and the mixture is stirred at room temperature overnight The reaction mixture is neutralized with lN-HCt and extracted with 150 ml of AcOEt The extract is washed with water and dried over anhydrous sodium sulfate The AcOEt is distilled off and the residue is treated with diethyl ether, collected by filtration and recrystallized from AcOEt. 8.5 g (69%); m. p. 184-185 C; [&alpha;]D22 + 25.6 (c = 0.5, MeOH); RfÚ = 0.16. Elemental analysis, for C22II2507NX Calcd. C, 59.58; H, 5.68; N, 9.48 Found C, 59.29; II, 5.81; N, 9.32 (II) Production of Z-Phe-NHNH-BOC In 100 ml of THF are dissolved 18.4 g of Z-Phe-ONB and =.3 g of NH2-NH-BOC. The solution is stirred at room temperature overnight. The THr is then distilled off, the residue is extracted with 150 ml of AcOEt and the extract is washed with aqueous citric acid and 5% aqueous sodium hydrogen carbonate dried over Na2SO4 and distilled to remove the AcOLt The residue is treated with petroleum ether, collected by filtration and recrystallized from AcEOt-Petroleum ether. 13.2 g(80%); m. p. 107-109 C; [&alpha;]D19 - 23.4 (c = 0.5, MeOH); RfÚ = 0.71. Elemental analysis, for C22H2705N3 Calcd. C, 63.90; H, 6.58; N, 10.16 Found C, 64.18; H, 6.61; N, 9.88 (III) Production of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-BOC In 100 ml of MeOH is dissolved 3.6 g of Z-Phe-NH-NH BOC, and following addition of 0.5 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, 10 ml of DMF is added to the filtrate and the MeOH is distilled off On the other hand, 3.5 g of Z-Tyr-(1))-Ala-Gly-0H and 1.56 g of HONB are dissolved in 50 me of THF, and under cooling at 00C, 1.80 g of 1)CC is added The mixture is stirred at 0 C for 6 hours. The insolubles are filtered off, the filtrate is combined with the amine component and the mixture is stirred at room temperature overnight. The THF is distilled off, the residue is extracted with 150 m± of AcOEt and the extract is washed with 5% aqueous sodium hydrogen carbonate and with aqueous citric acid, and dried over anhydrous sodium sulfate. The AcOEt is then distilled off and the residue is treated with petroleum ether and recrystallized from AcOEt-petroleum ether. 3.7 g (67%); m. p. 143-146 C (decomp.); [&alpha;]D22 - 25.4 (c = 0.5, DMF); RfÚ = 0.38. Elemental analysis, for C36H44O9N6 Calcd C, 61.35; H, 6.29; N, 11.93 Found C, 61.05; H, 6.42; N, 11.58 (IV) Production of Z-Tyr-(D)-Ala-Cly-Phe-NH-NH2 In 30 mR of trifluoroacetic acid is dissolved 3.: g of Z-Tyr-(r)-Ala-Gly-Phe-NH-NH-BOC and the solution is allowed to stand at room temperature for 20 minutes The trifluoroacetic acid is distilled off and the residue is treated with dietbyl ether and collected by filtration The resulting powders are dissolved in 10 ml of DMF and stirred with 1.4 me of TEA The DMF is distilled off and the residue is treated with water, collected by filtration and purified by reprecipitation with methanol-diethylether. 2.8 g (96%); m. p. 182-184 C (decomp); [&alpha;]D22 - 23.0 (c = 0.5, DMF); RfÚ = 0.17. Elemental analysis, for C31H3607N6 Calcd. C, 61.58; H, 6.00; N, 13.90; Found C, 61.32; H, 5.91; N, 1.72 (V) Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH2 In 50 m1 of MeOH is dissolved 250 mg of Z-Tyr-(D)- Ala-Gly-Phe-NH-NH2, and following addition of 0.1 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst The catalyst is filtered off, the filtrate is dissolved in a small amount of 1Naqueous acetic acid and the solution is put on a column of Sephadex LH-20 (2.5 x 120 cm). Elution is carried out with lN-aqueous acetic acid and fractions from 310 me through 335 me are pooled and lyophilized. 95 mg (38C/); [&alpha; ;]D22 - 20.4 (c = 0.2, MeOH); RfÚ = 0.22; amino acid analysis (hydrolyzed with HCl): Gly, 1.00; Ala, 1.05,; Tyr, 0.89; Phe, 1.01; mean recovery rate 81%. Example 3 Production of H-Tyr-(D)-Leu-Gly-Phe-NH-NH-CO-CH3 (I) Production of Z-Phe-NH-NH-CO-CH3 In 50 m± of THF is dissolved 2.03 g (6.5 m mols) of Z-Phe-NH-NH2, and under cooling, 1.4 ml of acetic anhydride and 0.9 me of TEA are added dropwise. The mixture is stirred at room temperature for 2 hours The crystals are collected by filtration, washed with diethyl ether and recrystallized from AcEOt. 1.9 g (83%); m. p. 205-206 C; [&alpha;]D23 - 16.4 (c = 0.5, DMF); RfÚ = 0.60. Elemental analysis, for C20H23O5N3 Calcd. C, 62.32; H, 6.02; N, 10.90 found C, 62.38; H, 6.09; N, 10.49 (II) Production of Z-Tyr-(D)-Leu-Gly-Phe-NH-NH-CO-CH3 In 50 ml of MeOH is dissolved 700 mg of Z-Phe-NH-NH CO-CH3, and following addition of 0.2 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst The catalyst is filtered off, the MeOH is distilled off and the residue is dissolved in 20 m± of THF On the other hand, 680 mg (1.4 m mols) of Z-Tyr (L)-Leu-Gly-0H and 300 mg of HONB are dissolved in 20 md of THF, and after cooling, 330 mg of I;CC is added and stirred at 0 C for 5 hours. The insolubles are filtered off, the filtrate is combined with the amine compbnent previously prepared and the mixture is stirred at room temperature overnight The THF is distilled off and the residue is treated with AcOEt, collected by filtration and purified by reprecipitation with methanol-AcOEt, 0.71 g (74%); m. p. 184-185 C; [&alpha;]D23 - 13.4 (c = 0.5, DMF); RfÚ = 0.28 Elemental analysis, for C36H4408N6 Calcd. C, 62,77; H, 6.44; N, 12.20 Wound C, 62.52; H, 8.81; N, 12.04 (III) Production of H-Tyr-(D)-Leu-Gly-Phe-NH-NH-CO-CH3 In 50 ml of MeOH is dissolved 500 ml of Z-Tyr-(D) Leu-Gly-Phe-NH-NH-CO-CH3, and following addition of 1 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst The catalyst is filtered off, the solvent is distilled off, the residue is treated with water and the insolubles are filtered off. The filtrate is lyophilized and the resulting powders are put on a column of Sepbadex LH-20 (2.5 x 120 cm). Elution is carried out with 1N-aqueous acetic acid and fractions from 320 ml through 345 ml are pooled and lyophilized. 245 mg (50%); [&alpha;]D23 + 26.7 (c = 0.3, MeOH); Rfê = 0.41; amino acid analysis (hydrolyzed with HC±): Gly, 1.00; Leu, 1.05; Tyr, 0.93; Phe, 1.02; mean recovery rate 82%. Example 4 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-(CH2)3-CH3 (I) Production of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-(CH2)3-CH3 In 5 ml of LMF are dissolved 604 mg (1 m mol) of Z Tyr-(D)-Ala-Gly-Phe-NH-NH2, 297 mg of HOBT and 0.2 ml of CH3(CH2)3COOH. After cooling the solution to OOC, 454 mg of LCC is added and the mixture is stirred at 0 C for 4 hours and at room temperature overnight. The insolubles are filtered off, the DMF is distilled off and the residue is extracted with 100 ml of AcOEt, washed with 5% aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate The AcOEt is distilled off and the gel residue is treated with diethyl ether, collected by filtration and purified by reprecipitation with methanol AcOEt. 480 mg (70%); m. p. 178-179 C; [&alpha;]D23 - 22.4 (c = 0.16, DMF); RfÚ = 0.46. Elemental analysis, for C36H44O8N6 Calcd. C, 62.77; H, 6.44; N, 12.20 Found C, 62.71; H, 6.77; N, 11,98 (II) Product ion of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-(CH2)3-CH3 In 50 ml of MeOH is dissolved 430 me of Z-Tyr-(D)- Ala-Gly-Phe-NH-NH-CO-(CH2) 3-CH3, and following addition of 1 me of acetic acid, catalytic reduction is carried out with palladium black as the catalyst The catalyst is filtered off, the MeOH is distilled off and the residue is dissolved in a small amount of lN-aqueous acetic acid and put on a column of Sephadex LH-20 (2.C x 120 cm), elution being carried out with 1N-aqueous acetic acid The fractions from 325 ms through 340 ml are pooled and lyophilized 240 mg (56%); [&alpha; ;]D23 - 24.5 (c = 0.2, MeOH); Rfê = 0.47; amino acid analysis (hydrolyzed with HC±); Gly, 1.00; Ala, 0.95; Tyr, 0.88; Phe, 1.01; mean recovery rate 82%. Example 5 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2-CH(CH3)2 (I) Production of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2- CH(CH3)2 The procedure of Example 4-(I) is repeated except that 530 mg (0.88 m mol) of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH2 and 0.15 ml of (CH3)2 CH-CH2-COOH are employed. 320 mg (53%); m. p. 228-230 C; [&alpha;]D23 - 23.9 (c = 0.28, DMF); RfÚ = 0.46 Elemental analysis, for C36H44O8N6 Calcd. C, 62.77; H, 6.44; N, 12.20 Found C, 62.58; H, 6.35; N, 11.95 (II) Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2 CH(CH3)2 The procedure of Example 4-(II) is repeated except that 170 mg of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2-CH(CH3)2 is employed. 105 mg (62%); [&alpha;]D23 - 21.1 (c = 0.18, MeOH); RfÚ = 0.49; amino acid analysis (Hydrolyzed with HCl); Gly, 1.00; Ala, 1.02; Tyr, 0.96; Phe, 1.02; mean recovery rate 80 %. Example 6 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-(CH2)2-Cl (I) Production of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-(CH2)2-Cl The procedure of Examplc 4-(I) is repeated except that 513 mg (0.85 m mol) of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH2 and 120 mg of Cl-CH2-CH2-COOH are employed. 360 mg (59%); m. p. 169-170 C; [&alpha;]D23 - 21.1 (c = 0.37, DMF) Elemental analysis, for C34H39O8N6#Cl Calcd. C, 58.74; H, 5.65; N, 12.09; Cl, 5.10 Found C, 58.61; H, 5.59; N, 11,81; Cl, 4.92 (II) Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-(CH2)2-Cl The procedure of Example 4-(II) is repeated except that 250 mg of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-(CH2)2-Cl is employed. 150 mg (60%); [&alpha;]D23 - 20.5 (c = 0.2, MeOH); I?f2= 0.42; amino acid analysis (acid hydrolyzate): Gly, 1.01; Ala, 0.95; Tyr, 0.88; Phe, 0.98; mean recovery rate 79% Example 7 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2 CH2-OH (I) Production of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2-CH2-OH The procedure of Example 4-(I) is repeated except that 540 mg of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH2 and 0.12 ml of HO-CH2-CH2-COOH are employed. 320 mg (53%); m. p. 178-179 C; [&alpha;]D23 - 22.3 (c = 0.3, DMF); RfÚ = 0.10. Elemental analysis, for C34H40O9N6 Calcd. C, 60.34; H, 5.96; N, 12.42 Found C, 59.98; H, 5.85; N, 12.18 (II) Production of H-Tyr-(D)-Ala-Glly-Phe-NH-NH-CO-CH2 CH2-OH The procedure of Example 4-(II) is repeated except that 250 mg of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2-CH2-OH is employed. Yield 100 mg (40 %); [&alpha;]D23 - 19.5 (c = 0.21, MeOH); RfÚ = 0.32; amino acid analysis (acid hydrolyzate): Gly, 1.00; Ala, 1.05; Tyr, 0,92; Phe, 1.00; mean recovery rate 79y. Example 8 Product ion of H-Tyr- (1)) -Ala-Gly-Phe-NH-NH-CO-CH2-CH3 (I) Production of Z-Tyr-(D)-Ala-Gly-Phe--NH-NH-CO-CH2-CH3 The procedure of Example 4-(I) is repeated except that 495 mg (0.82 m mol) of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH2 and 0.1 ml of CH3-CH2-COOH are employed, 250 mg (65%); m.p. 190-191 C; (&alpha;)D23-20.5 (c=0,3, IMF); Rf1 = 0.26. Elemental analysis, for C34H40=8N6 Calcd. C, 61.80; H, 6.10; N, 12.72 Found. C, 61.53; H, 6.02; N, 12.65 (II) Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2-CH3 The procedure of Example 4-(II) is repeated except that 250 mg of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2-CH3 is employed. 130 mg (52 /,); [&alpha;]D23 - 25.5 (c = 0.23, MeOH); Rfê = 0.42; amino acid analysis (acid hydrolyzate): Gly, 1.00; Ala, 0.95; Phe, 1.01; Tyr, 0.95; mean recovery rate 81%. Example 9 production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2 CH2-NH2 (I) Production of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2- CH2-NH-Z In 10 ml of DMF are dissolved 495 mg (C.82 m mol) of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH2 and 390 mg of Z-ss-Ala-ONB After cooling the solution, 0.14 ml of TEA is added, and the mixture is stirred at room temperature overnight. The DMF is distilled off, the residue is extracted with 100 ml of AcOEt, washed with 5 ,! aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate The AcOEt is distilled off and the residue is treated with diethylether, collected by filtration and purified by reprecipitation with methanol-AcOEt. ; 370 mg (56/ó); m.p.251-2330C; [&alpha;]D23 - 21.5 (c = 0.27, DMF); RfÚ = 0.26 Elemental analysis, for C24H47O10N7 Calcd C, 62.28; H, 5.85; N, 12.10 Found C, 61.99; H, 5.94; N, 11.95 (II) Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH2 CH2-NH2 The procedure of Example 4-(II) is repeated except that 280 mg of Z-Tyr-(D)-Ala-Glly-Phe-NH-NH-CO-CH2-CH2-NH-Z is employed. 160 mg (61%); [&alpha;]D23 + 16.7 (c = 0.27, MeOH); Rfê 0.07; amino acid analysis: Gly, 1.00; Ala, 0.95; t3-Ala, 0.99; Tyr, 0.89; Phe, 1.00; mean recovery rate 79%. Example 10 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-(CH2)2-CH3 11 (I) Production of Z-Phe-NH-NH-C-CH2-CH2-CH3 In 30 ml of b.MF is dissolved 2.5 g (8 m mols) of Z Phe-NH-NH2, and under cooling, 0.9 ml of CH3CH2CH2COCl and 1.1 ml of TEA are added The mixture is stirred at room temperature for 5 hours. To this reaction mixture is added water and the resulting crystals are collected by filtration, dried and recrystallized from AcOEt-petroleum ether 2.6 g (85%); m. p. 150-156 C; [&alpha;]D23 - 27.2 (c = 0.5, MeOH), RfÚ = 0.71 Elemental analysis, for C21-H25-O4-N3 Calcd. C, 65.46; H, 6.48; N, 10.87 Found C, 65.78; H, 6.57; N, 10.96 (II) Production of Z-Tyr-()-Ala-Gly-Phe-NH-NH-CO-Cfl,- CH2-CH3 In 5ss me of MeOH is dissolved 505 mg of Z-Phe-NH-NH CO-CH2-CH2-CH3 and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the MeOH is distilled off and the residue is dissolved in 20 m± of THF On the other hand, 530 mg of Z-Tyr-(D) Ala-Gly-OH and 237 mg of HONB are dissolved in 50 m of THF and under cooling at 00C, 271 mg of DCC is added and the mixture is stirred at 0 C for 4 hours The by-product urea derivative is filtered off, the filtrate is combined with the amine component prepared above and the mixture is stirred at room temperature overnight The THF is then distilled off, the residue is extracted with 100 ml of AcOEt, and the extract is washed with 5% aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The AcOEt is then distilled off and the residue is treated with diethyl ether, collected by filtration and purified by reprecipitation with AcOEt 420 mg (50%); m. p. 203-206 C, [&alpha;]D23 - 0.4 (c = 0.5, MeOH); RfÚ = 0.28. Elemental analysis, for C35H42O8N6 Calcd. C, 62.30; H, 6.27; N, 12.46 Found C, 62.60; H, 6.52; N, 12.18 (III) Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO- CH2CH2CH3 In 50 ml of MeOH is dissolved 250 mg of Z-Tyr-(D) Ala-Gly-Phe-NH-NH-CO-CH2-CH2-CH3, and following addition of 0.2 ml of acetic acid, catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the filtrate is concentrated and the residue is dissolved in a small amount of lN-aqueous acetic acid and put on a column of Sephadex LH-20(2.5 x 120 cm). Elution is carried out with lN-aqueous acetic acid and fractions from 320 ml througt 340 ml are pooled and lyophilized. 110 mg(44%); [&alpha;]D23 + 23.2 (c = 0.5, MeOH); Rfê 0.40; amino acid analysis (hydrolyzed with HCl): Gly, 1.06; Ala, 1.00; Tyr, 0.93; Phe, 0.93; mean recovery rate 90%. Example 11 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-OCH2-CH3 (I) Production of Z-Phe-NH-NH-CO-OCH2-CH3 The procedure of Example 10-(I) is repeated except that 1.8 g (5.7 m mols) of Z-Phe-NH-NH2 and 0,7 ml of ethyl chlorocarbonate are employed. 1.5 g (69%); m. p. 134 C; [&alpha;]D23 - 20.6 (c = 0.5, DMF); RfÚ = 0.69 Elemental analysis, for C2oH2305N3 Calcd. C, 62.32; H, 6.02; N, 10,90 Found C, 62.38; H, 6.09; N, 10.49 (II) Production of Z-Tyr-(L) -Ala-Gly-Phe-NH-NH-CO OC0I2-,H3 The procedure of Example 10-(II) is repeated except that 580 mg (1.3 m mols) of Z-Tyr-(D)-Ala-Gly-OH and 620 mg of Z-Phe-NH-NH-CO-OCH2-CH3 are employed to synthesize the indicated compound. 820 mg (93%); m. p. 154-155 C; [&alpha;]D23 - 24.2 (c = 0.45, MeOH); RfÚ = 0.40. Elemental analysis, for C34H40O9N6 Calcd. C, 60.34; H, 5.96; N, 12.42 Found C, 60.09; H, 5.87; N, 12.21 (III) Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO- OCH2-CH3 The procedure of Example 10-(III) is repeated except that 540 mg of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-OCH2-CH3 is employed to synthesize the above-indicated compuond. 240 mg (53%); [&alpha;]D23 + 18.1 (c = 0.2, MeOH); Rfê = 0.49: amino acid analysis: Gly, 1.00; Ala, 0.98; Tyr, 0.88; Phe, 1.02; mean recovery rate 78%. Example 12 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 (I) Production of Z-Tyr-(D)-Ala-Gly-MePhe-OCH3 In 20 ml of MeOH is dissolved 1.8 g (5.7 m mols) of Z-MePhe-OH, and following addition of 20 m± of 5N-HC±/ dioxane, the solution is allowed to stand at room temperature overnight The solvent is distilled off and the residue is extracted with 100 mz of AcOEt, washed with water and dried over anhydrous sodium sulfate The AcOEt is then distilled off, whereupon 1.5 g of oil is obtained. A 1.1 g portion of this oil is dissolved in 50 ml of MeOH and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the MeOH is distilled off and the residue is dissolved in 20 ml of TrIF. To this solution are added 1.55 g (3.5 m mols) of Z-Tyr-(D)-Ala-Gly-OH and 0.75 g of HONB, and under cooling at 0 C, 0.80 g of DCC is added. The mixture is stirred at OoC for 5 hours and at room temperature overnight. The by-product urea derivative is filtered off and the DMF is distilled off The residue is extracted with 100 ml of AcOEt, washed with 5% aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate The AcOEt is distilled off and the residue is treated with diethyl ether and purified by reprecipitation with MeOH-diethylether. 1.2 g (56%); m. p. 103-104 C; [&alpha;]D23 - 17.2 (c = 0.31, MeOH); RfÚ = 0.68. Elemental analysis, for C33H3808N4 Calcd. C, 64.06; H, 6.19; N, 9.06 Found C, 63.91; H, 6.05; N, 8.89 (II) Production of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 In the same manner as Example 1-(II), 1.0 g (1.6 m mols) of Z-Tyr-()-Ala-Gly-MePhe-OCH, is treated with 0.5 ml of NH2-NH2.HO, whereby the above-indicated compound is obtained. 820 mg (82%); m. p. 95-96 C (decomp.); [&alpha;]D23 - 26.8 (c = 0.5, DMF); RfÚ = 0.29. Elemental analysis, for C32H38O7N6 Calcd. C, 62.12; H, 6.19; N, 13.59 Found C, 61.85; H, 6.28; N, 13.09 (III) Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 300 mg of Z-Tyr-(D)-Ala-Gly-MePhc-NE-NH2 is treated in the same manner as Example 4-(II) to obtain the aboveindicated compound. 155 mg (52%); [&alpha;]D23 + 12.0 (c = 0.2, MeOH); Rfê = 0.46; amino acid analysis (acid hydrolyzate): Gly, 1,00; Ala, 098; Tyr, 0.91; mean recovery rate 79%. Example 13 Production of H-Tyr-(D)-Ala-Gly-Phe-NHNH-COCH2-CH2 CH2-Cl (I) Production of Z-Phe-NHNH-COCH2-CH2-CH2-Cl In 40 me of DMF are dissolved 3.13 g (10 m mols) of Z-Phe-NHNH2 and 1.27 g (10 m mols) of y-chlorobutyric acid, and under cooling at 0 C, 2.2 g of POC is added. The mixture is stirred at room temperature for 20 hours. The reaction mixture is filtered and concentrated under reduced pressure. The residue is dissolved in 150 ml of ethyl acetate, washed with water, lN-HCE and 4% sodium hydrogen carbonate in that order It is then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure and crystallized from ethyl acetate-petroleum ether. By the above procedure are obtained 3.6 g of needles (85.7 %) melting at 185-186 C; RFÚ = 0.32. Elemental analysis, for C21H24O4N2Cl Calcd. C, 60.35; H, 5.79; N, 10.06; Cl, 8.49 Found C, 60.51; H, 5.60; N, 10.15; Cl, 8.27 (II) Production of H-Tyr-(D)-Ala-Gly-Phe-NHNH-COCH2CH2CH2.Cl In 50 ml of methanol, 420 mg of Z-Phe-NHNHCOCH2-CH2 CH2-Cl is catalytically reduced using palladium black as the catalyst The catalyst is filtered off and the filtrate is concentrated to dryness. This residue and 445 mg of Z-Tyr-(D)-Ala-Gly-OH are dissolved in 10 ml of BUMF, followed by addition of 180 mg of HONB. Then, under cooling at 0 C, 250 mg of DCC is added. The mixture is stirred at OOC for 3 hours and at room temperature for 12 hours. The insolubles are filtered off, the DMF is distilled off under reduced pressure and the residue is dissolved in 100 m± of a 1:2 mixture of n-butanol and ethyl acetate The solution is washed with lN-HCE, 4% aqueous sodium hydrogen carbonate and water in the order mentioned The solvent is then distilled off under reduced pressure and the residue is dissolved in 50 m± of methanol After addition of 1 m± of glacial acetic acid, catalytic reduction is carried out with palladium black as the catalyst The catalyst is filtered off, the filtrate is concentrated to dryness under reduced pressure and the residue is dissolved in 10 ml of lN-aqueous acetic acid The insolubles are filtered off and the filtrate is run onto a column of Sephadex LH-20 (3 x 45 cm), elution being carried out with lN-aqueous acetic acid As in the fractions from 215 ml to 236 ml the desired product is eluted, the fractions are pooled and lyophilized to obtain 360 m of the indicated compound. Rfê = 0.485; [&alpha;]D23 + 18.2 (c = 0.28, MeOH); amino acid analysis: Gly, 1.00; Ala, 1.02; Tyr, 0.89; Phe, 1.00; mean recovery rate 78%. Example 14 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH3 (I) Preparation of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO- CH2-CH3 In 5 mp of DMF are dissolved 426 mg of Z-Tyr-(D)-Ala- Gly-MePhe-NH-NH2 and 0,07 ml of propionic acid, and under cooling at OOC, 130 mg of HOBT and 200 mg of DCC are added The mixture is stirred at 0 C for 5 hours and at room temperature overnight. Thc insolubles are filtered off, the DMF is distilled off and the residue is extracted with 50 ml of AcOEt, washed with water and dried over anhydrous sodium sulfate The AcOEt is distilled off and the residue is treated with diethyl ether and collected by filtration, Yield 410 m (87%), m.p.139-l410C, Efl= 0.35; [&alpha;]D24 - 32.0 (c = 0.43, DMF), Elemental analysis, for C35H4208N6: Calcd C, 57.68; H, 6.63; N, 11.53 Found C, 57.55; H, 6.42; N, 11.33 (II) Preparation of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH3 In 50 ml of MeOH is dissolved 250 mg of Z-Tyr-(D)- Ala-Gly-MePhe-NH-NH-CO-CH2-CH3 and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the MeOH is distilled off, the residue is dissolved in 50 ml of water and the insolubles are filtered off, followed by lyophilization. The resultant powder is dissolved in a small amount of N-aqueous acetic acid and put on a column of Sephadex LH-20 (2.5 x 120 cm), elution being carried out with 1N-aqueous acetic acid. The fractions from 290 ml to 315 ml are collected and lyophilized to recover 100 mg of the above-indicated compound. RFê = 0.47; [&alpha;]D24 - 7.7 (c = 0.16, MeOH); amino acid analysis: Gly, 1.00; Ala, 1,03; Tyr, 0.92; man recovery rate 81%, Example 15 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH2-CH3 (I) Preparation of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH2-CH3 Using 426 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 and 0-08 ml of n-butyric acid, the procedure of Example 14-(I) was followed to obtain 395 mg of the indicated compound (83 %). m. p. 135-137 C; RfÚ = 0.37; [&alpha;]D23 - 31.5 (c = 0.3, DMF); Elemental analysis, for C36H44O8N6: Calcd. C, 62.77; H, 6.44; N, 12.20; Found C, 62,48; H, 6.31; N, 11.95 (II) Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH2-CH3 By the same procedure as Example 14-(II), 250 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH2-CH2-CH3 is deprotected and purified to obtain 110 mg of the indicated compound. Rfê = 0.48; [&alpha;]D25 - 7.2 (c = 0.2, MeOH); amino acid analysis: Gly, 1.00; Ala, 0.98; Tyr, O86; mean recovery rate 83% Example 16 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH2 CH2-CO-CH3 Using 482 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 and 0.13 ml of 4-oxo-n-valeric acid, the procedure of Example 14-(I) is followed to obtain the above-indicated compound, 390 mg (70 %); m. p. 139-140 C; RFÚ = 0.49; [&alpha;]D24 - 27.6 (c = 0.27, DMF); Elemental analysis, for C37H44O9N6 H20: Calcd. C, 60.48; H, 6.31; N, 11.44 Found C, 60.19; H, 6.25; N, 11.28 (II) Production of H-Tyr-(D)-Ala-MePhe-NH-NH-CO CH2-CH2-CO-CH3 Using 340 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO- CH2-CH2-CO-CH3, the procedure of Example 14-(II) is followed to obtain 170 mg of the indicated compound. RFê = 0.49; [&alpha;]D24 - 6.0 (c = 0.3, MeOH), amino acid analysis: Gly, 1.00; Ala, 0,98; Tyr, 0.97; mean recovery rate 85%, Example 17 Production of H-Try-(D)-Ala-Gly-Phe-NH-NH-CO CIi2-CH, (I) Preparation of Z-(D)-Ala-Gly-Phe-OEt In 20 ml of DMF are dissolved 0.90 g of Z-(D)-Ala Gly-OH and 0.63 g of HONB and, under cooling at 0 C, 0.75 g of DCC is added. The mixture is stirred for 4 hours, at the end of which time the insolubles are filtered off To the filtrate are added 0.81 g of H-Phe-OEt#hydro- chloride and 0.5 mr of TEA, followed by stirring at room temperature overnight The solvent is distilled off, the residue is extracted with 100 mk of AcOEt and the extract is washed with lN-aqueous hydrochloric acid and with 5% aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. Removal of AcOEt by distillation leaves crystals, which are collected by filtration and recrystallized from AcOEt-petroleum ether0 1.2 g (83 %); m.p,109- 110 C; RfÚ = 0.78; [&alpha;]D27 + 1.6 (c = 0.44, DMF) Elemental analysis, for C24H29O6N3 Calcd. C, 63.28; H, 6.42; N, 9.23 Found C, 63.38; H, 6.47; N, 9,03 (II) Production of Z-(D)-Ala-Gly-Phe-NHNH2 In 50 m± of MeOH is dissolved 3.3 g of Z-(D)-Ala Gly-Phe-OEt and after 1 ml of hydrazine hydrate is added, the solution is allowed to stand at room temperature for 2 days. It is then treated with diethyl ether, collected by filtration and recrystallized from ethanol. 3.0 g (84 %); m. p. 196-197 C; RfÚ = 0.34; [&alpha;]D27 + 2.4 (c = 0.37, DMF). Elemental analysis, for C22H27O5N5 Calcd. C, 59.85; H, 6.16; N, 15.86 Found C, 59.62; H, 6.12; N, 16.13 (III) Production of Z-(D)-Ala-Gly-Phe-NH-NH-CO-CH2-CH3 In 10 ml of DMF are dissolved 1.1 g of Z-(D)-Ala Gly-Phe-NH-NH2 and 0.22 me of propionic acid, and after cooling to OOC, 0.44 g of HOBT and 0.62 g of DCC are added The mixture is stirred at 0 C for 4 hours and, then, at room temperature overnight The insolubles are filtered off, the DMF is distilled off and the residue is extracted with 100 mP of AcOEt The extract is washed with aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate The AcOEt is distilled off and the gel-like residue is collected by filtration The powders are washed by boiling with AcOEt. 0.95 g (77 %); m. p. 197-198 C; RfÚ = 0.46, [&alpha;]D27 + 4.8 (c = 0.27, DMF) Elemental analysis, for C25H31O6N5 Calcd. C, 60,34; H, 6.28; N, 1408 Found C, 60.14; H, 636; N, 13.65 (IV) Production of Z-Metyr(But)-(D)-Ala-Gly-Phe-NH-NH CO-CH2-CH3 In 50 mf of MeOH is dissolved 497 mg of Z-(D)-ala- Gly-Phe-NH-NH-CO-CH2-CH3 and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the MeOH is distilled off and the residue is dissolved in 10 me of DMF. On the other hand, 385 mg of Z MeTyr(But)-OH and 215 m of HONB are dissolved in 10 ml of THF and, after cooling to 000, 227 mg of DCC is added The mixture is stirred at 0 C for 4 hours, at the end of which time the insolubles are filtered off, while the filtrate is combined with the DMF solution of amine component prepared above, followed by stirring at room temperature overnight. The solvent is distilled off, the residue is extracted with 100 mE of AcOEt and the extract is washed with 5% aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate The AcOEt is then distilled off and the gel-like residue is collected by filtration 620 mg (85 %); m. p. 143-144 C; RfÚ = 0.63; [&alpha;]D27 - 43.7 (C = 0.4, DMF) Elemental analysis, for C39H50O8N6 Calcd. C, 64.09; H, 6.90; N, 11.50 Found C, 64.33; H, 7.21; N, 11.40 (V) Production of H-MeTyr-(D)-Ala-Gly-Phe-NH-NH-CO- CH2-CH3 In 50 ml of MeOH is dissolved 500 mg of Z-MeTyr-(D)- Ala-Gly-Phe-NH-NH-CO-CH2-CH3 and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the filtrate is distilled and the residue is dissolved in a small amount of aqueous acetic acid The solution is put on a column of Sephadex LH-20(2.5 x 120 cm) and elution is carried out with 1Naqueous acetic acid The fractions from 330 ml through 370 m± are pooled and lyophilized. 360 mg. A 200 mg portion of the lyophilizate is dissolved in 2 nl of trifluoroacetic acid and the solution is allowed to stand at room temperature for 30 minutes, The solvent is distilled off and the residue is dried, dissolved in 50 ml of water and put on a column of Amberlite IRA-410 (acetate-form, 2 x 6 cm). The eluate and washings are combined and lyophilized, 170 mg, This powdery product is dissolved in a small amount of 1Naqueous acetic acid, The solution is run onto a column of Sephadex LH-20 (2 x 120 cm), elution being carried out with lN-aqueous acetic acid. The fractions from 285 me through 300 mZ are pooled and lyophilized 70 mg, Rf = 0.33; [&alpha;]D27 + 32.8 (c = 0.21, MeOH); amino acid analysis: Cly, 1,00; Ala, 0,92; Phe, 1,02; mean recovery rate 78%. Example 18 Production of H-MeTyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH3 (I) Synthesis of Z-(D)-ALa-Gly-MePhe-NH-NH2 In 50 ml of MeOH is dissolved 1.1 g of Z-MePhe-OMe and catalytic reduction is carried out with palladium black as the catalyst. The catalyst is filtered off, the MeOfi is distilled off and the residue is dissolved in 10 mk of DMF. On the other hand, 0,92 g of Z-(D)-Ala-Gly-OH and 0.71 g of HONB are dissolved in 10 m± of DMF and, under cooling at 000, 0.75 g of LOC is added, The mixture is stirred at 0 C for 4 hours, after which time the insolubles are filtered off, while the filtrate is combined with the above amine component and stirred at room temperature overnight, The DMF is distilled off and the residue is extracted with 100 mk of AcOEt, washed with 5% aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate, The AcOEt is distilled off, whereupon 2,5 g of oil is obtained, This oil is dissolved in 20 ml of MeOH and, following addition of 1,5 ml of hydrazine hydrate, the solution is allowed to stand at room temperature overnight. The MeOH is distilled off, the residue is extracted with 100 mZ of AcOEt and the extract is washed with water and dried over anhydrous sodium sulfate, The AcOEt is distilled off and the residue is treated with diethyl ether and collected by filtration, 2,0 g (80 %); m. p. 85-87 C; RfÚ = 0.55. Elemental analysis, for C23H29O5N5 Calcd , C, 60.64; 11, 6,42; N, 15,38 Found C, 60.51; H, 6,55; N, 15,11 (II) Production of Z-MeTyr(But)-(D)-Ala-Gly-MePhe-NH NH-CO-CH2-CH3 In 20 ml of THF are dissolved 0,91 g of Z-(L)-Ala- Gly-MePhe-NH-NH2 and 0,19 me of propionic acid, and at 000, 0,38 g of HOBT and 0,45 g of LOC are added, The mixture is stirred at 00 for 4 hours and, then, at room temperature overnight, The insolubles are filtered off, the THF is distilled off and the residue is extracted with 100 ml of AcOEt, washed with an aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate, The AcOEt is then distilled off, whereupon 1,0 g of oil is obtained, This oil is dissolved in 50 ml of MeOH and catalytic reduction is carried out with palladium black as the catalyst, The catalyst is filtered off, the MeOII is distilled off and the residue is dissolved in 10 mS of THF. On the other hand, 0.73 g of Z-MeTyr(But)OH and 0,41 g of HONB are dissolved in 10 mf of THF, and with cooling. at OOC, 0,43 g of DCC is added, The solution is stirred at 0 C for 4 hours, The insolubles are filtered off and the filtrate is combined with the ThF solution of amine component prepared above and stirred at room temperature overnight, The THF is distilled off, the residue is extracted with 100 mR of AcOEt and washed with 5% aqueous sodium hydrogen carbonate, After drying over anhydrous sodium sulfate, the AcOEt is distilled off and the residue is purified by precipitation with diethyl ether, 1,2 g (86 %); m. p. 110-112 C; RfÚ = 0.61; [&alpha;]D25 - 54.7 (c = 0.45, DMF) Elemental analysis, for C40H52O8N6 Calcd. C, 64.50; H, 7.04; N, 11.28 Found C, 64,25; H, 7,16; N, 11.35 (III) Production of H-MeTyr-(D)-Ala-Gly-MePhe-NH-NH CO-CH2CH3 In the same manner as Example 17-(V), 600 mg of Z MeTyr(But)-(D)-Ala-Gly-MePhe-NH-NH-CO-CH2-CH3 is catalytically reduced, treated with TFA and purified by gel filtration and the desired product is collected. 150 mg; Rf2=0.48; [&alpha;]D25 + 14.4 (c = 0.25, MeOH); amino acid analysis: Gly, 1.00; Ala, 0.95; mean recovery rate Bli, Example 19 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH3 (I) Production of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-COCH3 In the same manner as Example 14-(I), 426 m of Z-Tyr (D)-Ala-Gly-MePhe-NH-NH2 and 0.06 ml of acetic acid are used to produce 405 mg of the indicated compound (85 %). m. p. 142-143 C; RfÚ = 0.33; [&alpha;]D27 - 31.8 (c = 0.4, DMF) Elemental analysis, for C34H40O8N6 Calcd, C, 61,80; H, 6,10: N, 12,72 wound C, 61,65; H, 6,02 N, 12,66 (II) Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH3 In the same manner as Example 14-(II), 250 m of Z-Tyr- (L)-Ala-Gly-MePhe-NH-NH-CO-CH3 is deprotected and purified to obtain 130 m; of the indicated compound, RFê = 0.44; [&alpha;]D25 - 6.9 (c = 0.3, MeOH); amino acid analysis: Cly, 1,00; Ala, 0,99, Tyr, 0,32; mean recovery rate 82%. Example 20 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH2-O-CH2-CH3 (I) Production of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO- CH2-CH2-0-CII2-CH3 Using 358 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 and 0,08 ml of ss-ethoxypropionic acid, the procedure of Example 14-(I) is repeated to obtain 300 mg of the above-indicated compound (73 %); m. p. 122-124 C; RfÚ = 0.39; [&alpha;]D25 - 31.6 (c = 0.24, DMF) Elemental analysis, for C37H44O9N6 Calcd. C, 62,00; H, 6,19; N, 11,72 Found C, 61,73; H, 6,24; N, 11,58 (II) Production of H-Tyr-(D)-Ala-MePhe-NH-NH-CO CH2-CH2-0-CH2-CH3 In the same manner as Example 14-(II), 150 mg of Z Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH2-CH2-O-CH2-CH3 is deprotected and purified to obtain 75 mg of the aboveindicated compound, Rfê = 0.47; [&alpha;]D25 + 2.0 (c = 0.2, MeOH); amino acid analysis: Gly, 1,00; Ala, 0,97; Tyr, 0,96; mean recovery rate 81, Example 21 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH(CH3)2 (I) Production of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO- CH2-CH(CH3)2 Using 426 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 and 0,09 ml of isovaleric acid, the procedure of Example 14-(I) is repeated to obtain 390 me of the indicated compound (82 %). m. p. 129-133 C; RfÚ = 0.40; [&alpha;]D25 - 32.0 (c = 0.5, DMF) Elemental analysis, for C37H46O8N6 Calcd. C, 63.23; H, 6.60; N, 11.96 Tound C, 63,05; H, 6.45; N, 11,72 (II) Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-(CH(CH)2 In the same manner as Example 14-(II), 300 mg of Z Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH2-CH(CH3)2 is deprotected and purified to obtain 170 mg of the indicated compound, Rfê = 0.48; [&alpha;]D25 - 7.1 (c = 0.2, MeOH); amino acid analysis: Gly, 1,00; Ala, 1,05; Tyr, 0,89; mean recovery rate 79%. Example 22 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH2-Cl (I) Production of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO- CH2-CH2-Cl Using 482 mg of Z-Tyr-()-Ala-Gly-MePhe-NH-NH2 and 0.12 g of 3-chloropropionic acid, the procedure of Example 14-(1) is repeated to obtain 420 mg of the indicated compound (85 %), m. p. 126-129 C; RfÚ = 0.38; [&alpha;]D25 - 28.6 (c = 0.2, DMF) Elemental analysis, for C35H41O8N6.Cl Calcd. C, 59.27; H, 5.82; N, 11.85; Cl, 5.00 Found C, 59.33; H, 5.94; N, 11,61; Cl 4.88 (I1) Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO- CH2-CH2-Cl In the same manner as Example 14-(II), 250 mg of Z Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH2-CH2-Cl is deprotected and purified to obtain 105 mg of the indicated compound, Rfê = 0.509; [&alpha;]D25 - 6.9 (c = 0.2, MeOH); amino acid analysis: Gly, 1,00; Ala, 0.96; Tyr, 0,92; mean recovery rate 81%, Example 23 Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH(OH)-CH3 (I) Production of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO- CH(OH)-CH3 Using 426 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 and 0,08 ml of lactic acid, the procedure of Example 14-(I) is repeated to obtain 380 mg of the indicated compound (81 %). m. p. 131-134 C; RfÚ = 0.29; [&alpha;]D25 - 29.6 (c = 0.4, DMF) Elemental analysis, for C35H42O9N6 Calcd. C, 60.85; H, 6.12; N, 12.16 Found C, 60,77; H, 5.96; N, 12.03 (II) Production of H-Tyr-(D) -Ala-G ly-MePhe-NH-Nfi-CO- CH(OH)-CH3 In the same manner as Example 14-(II), 300 mg of Z Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH(OH)-CH3 is deprotected and purified to obtain 160 mg of the indicated compound, Rfê = 0.41; [&alpha;]D25 - 7.1 (c = 0.2, Me()H); amino acid analysis; Gly, 1,00, Ala, 0,98; Tyr, 0.91; mean recovery rate 82, Example 24 Production of H-Tyr-()-Ala-Gly-MePhe-NH-NH-CO-O- CH2-CH3 (I) Production of Z-Tyr-(D)-Ala-Gly-MePhe-NH- NH-CO- CH2 CH3 In 5 ml of tMF is dissolved 426 mg of Z-Tyr-(D)- Ala-Gly-MePhe-NH-NH2, and after cooling, 90 mg of ethyl chlorocarbonate and 0,11 ml of TEA are added, The mixture is stirred at 0 C for 2 hours, To the reaction mixture is added an aqueous solution of sodium chloride and the mixture is extracted with 100 ml of AcOEt and washed with water, The AcOEt layer is dried over anhydrous sodium sulfate and distilled under reduced pressure, the residue being then treated with diethyl ether, collected by filtration and repreoipitated from ethanol-diethyl ether, 350 mg (73 %); m. p. 131-133 C; RfÚ = 0.40; [&alpha;]D25 - 32.2 (c = 0.3, DMF) Elemental analysis, for C35H42O9N6 Calcd, C, 60,85; H, 6,13; N, 12,16 found C, 60,67; H, 6.30; N, 12,11 (II) Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO O-CEI2-CH3 In the same manner as Example 14-(II), 250 mg of Z-Tyr-(D)-Ala-Gly.MePhe-NH-NH-CO-O-CH2-CH3 is deprotected and purified to obtain 105 mg of the indicated compound, Rfê = 0.47; [&alpha;]D25 - 6.7 (c = 0.2, MeOH); amino acid analysis: Gly, 1.00; Ala, 0.99; Tyr, 0.88; mean recovery rate 79%. Example 25 Production of H-Tyr-(n)-Ala-ly-MePhe-NH-N-CO- CH2-CH2-CH2-CH3 (I) Product ion of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH-Co- CH2-CH2-CH2-CH3 Using 426 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 and 0.09 mE of n-valeric acid, the procedure of Example 14-(I) is repeated to obtain the indicated compound, 390 mg (82%); m.p. 131-133 C; RfÚ=0.40; D I)MF) Elemental analysis, for C37H46O8N6 Calcd, C, 63,23; H, 6.60; N, 11,96 Tound C, 63,42; H, 6.71; N, 11,72 (II) Production of H-Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO CH2-CH2-CH2-CH3 In the same manner as Example 14-(II), 300 mg of Z Tyr-(D)-Ala-Gly-MePhe-NH-NH-CO-CH2-CH2-CH2-CH3 is deprotected and purified to obtain 150 mg of the indicated compound. Rfê=0.49; [&alpha;)D25-6.4 (c=0.2, MeOH); amino acid analysis: Gly, 1.00; Ala, 1.00 Tyr, 0,94; mean recovery rate 80%, Example 26 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-CH3 (II) Production of Z-Phe-NH-NH2: In 200 m± of MeOH is dissolved 59 g of Z-Phe-OH, followed by adding 5 m± of 6N hydrochloric acid-dioxane, and the mixture is allowed to stand overnight at room temperature. The MeOH is distilled off, and the residue is dissolved in 300 ml of diethyl ether, followed by washing with water, After drying over anhydrous sodium sulphate, the diethyl ether is distilled off, and the residue is dissolved in 150 ml of MOOR, 16 mk of hydrazine hydrate is added to the solution, which is then allowed to stand at room temperature for 2 days. The MeOH is distilled off, and the precipitated crystals are collected by filtration with petroleum ether, washed well with diethyl ether, and recrystallized from AcOEt-petroleum ether, Thus obtained is 49 g (79%) of the desired product, m.p. 159-160 C, RfÚ=0.62, [&alpha;]D21-9.8 (c=0.8, IMF) Elemental analysis, for C17H19O3N3 Calculated: C, 65,16; H, 6,11; N, 13,41 Found C, 65,02, H, 6,32; N, 13,20 (II) Production of Z-Phe-NH-NH-CO-CH2-CH3: In 30 ms of DMF is dissolved 12,5 g of Z-Phe-NH-NH2, followed by the addition of 5,8 m of anhydrous propionic acid and 3 ml of pyridine after cooling, and the mixture is stirred overnight at room temperature. Water is added to the reaction solution, and the precipitate is collected by filtration Fecrystallization from MeOH-acetonitrile yields 9.8 g (68%) of the desired product, m.p. 203-204 C, RfÚ= 0.60, [&alpha;]D21-17.6 (c=0.46, DMF). Elemental analysis, for C20H23O4N3 Calculated: C, 65.92; H, 6.27; N, 10.25 Found : C, 65.87; H, 6.72; N, 9.93 (III) Production of Z-Cly-Phe-NH-NH-CO-CH2-CH3: In 50 ml of MeOH is dissolved 2,2 g of Z-Phe-NlI NH-CO-CH2-CH3 to conduct a catalytic reduction with palladium black used as the catalyst, Following the removal of the catalyst by filtration, the MeOH is distilled off and the residue is dissolved in 10 ml of DMF, 2,2 g of Z-Gly-ONB is added to the solution, which is stirred overnight at room temperature, The DMF is distilled off, and the residue is extracted with 100 ml of AcOEt, followed bg washing with water and dr; ;ying over anhydrous sodium sulphate, The AcOEt is distilled off and the precipitated crystals are collected by filtration and recrystallized from AcOEt-acetonitrile, Thus obtained is 1.8 g (?1 %) of the desired product, m,p, 151-152 C, RfÚ=0.46, [&alpha;]D21 I. à)f, -l,20(c=0,5, tN) Elemental analysis, for C22H26O5N4 Calculated: C, 61,96; H, 6,15; N, 13,14 Found : C, 62,25; H, 6,23; N, 12,85 (IV) Product ion of BOC-(D)-Met(O)-Gly-Phe-NH-NH-CO¯CH2-CH3: In 50 ml of MeOH is dissolved 1,0 g of Z-Gly-Phe NH-NH-CO-CH2-CHz to conduct catalytic reduction with palladium black used as the catalyst. Following the removal of the catalyst by filtration, the MeOH is distilled off and the residue is dissolved in 20 ml of acetonitrile. BOC-D-Met-ONB (prepared by the ICC method from 600mg of BOC-D-Met-OH and 470 mg of HONB) is added to the solution, which is stirred overnight at room temperature, 0.5 ml of a 30% aqueous hydrogen peroxide solution is added to the reaction solution, followed by stirring at room temperature for 10 hours. The excess of hydrogen peroxide is decomposed with palladium black, and the acetonitrile is distilled off, The resultant residue is extracted with 100 ml of n-butanol, and the extract is washed with water. The n-butanol is distilled off and the residue is treated with diethyl ether, Thus obtained is 1,1 g (P!f) %) of the desired product, m,p, 121-122 C, Rfl=0.40, [&alpha;]D21 0 (c=0.5, DMF) Elemental analysis, for C24H37O6N5S # 1/2H2O Calculated: C, 52.53; H, 6,97; N, 12,76; S, 5.84 Found : C, 52.41; H, 6.99; N, 12,46; S, 5,61 Production of BOC-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-CH3: In 10 ml of TFA is dissolved 0,82 g of BOC-(I)- Met(O)-Gly-Phe-NH-NH-CO-CH2-CH3, and the mixture is allowed to stand at room temperature for 20 minutes, The TFA is distilled off and the residue is treated with diethyl ether, followed by recovering by filtration. The resultant powder is dissolved in 10 me of DMF and, followed by the addition of 710 mg of BOC-Tyr-ONB and 0.3 ml of TEA, the mixture is stirred overnight at room temperature, The tMF is distilled off, and the residue is extracted with 100 ml of n-butanol, which is washed with water, The n-butanol is distilled off, and the residue is treated with diethyl ether, Thus obtained is 0.75 g (72%) of the desired product as crystals, m.p. 134-135 C RfÚ=0.20, [&alpha;)D21 0 (c=0.5, DMF) Elemental analysis, for C33H46O9N6S#H2O Calculated: C, 54.98; H, 6.71; N, 11.66; S, 4.44 Found : C, 54.72; H, 6.82; N, 11.16; S, 4.43 (VI) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-CH3: In 4 ml of TII.A is dissolved 400 mg of BOC-Tyr-(D)- Met(O)-Gly-Phe-NH-NH-CO-CH2-CH3, and the mixture is allowed to stand at room temperature for 20 minutes, The TFA is distilled off, and the residue is treated with diethyl ether, followed by collecting by filtration, The resultant powder is dissolved in 30 m of water, and the solution is allowed to pass through a column packed with Amberlite IRA 410 (acetic acid type, 2 x 6 cm), then the effluent and the washing are combined and subjected to freeze-drying. The resulting powder is dissolved in a small amount of 0,lN aqueous acetic acid solution, and the solution is passed through a column packed with Sephadex LH-20, followed by eluting with 0.1N aqueous acetic acid solution, The elution fractions from 310 m± to 330 mB are collected and freeze-dried Thus obtained is 310 mg of the desired product, Ff2-0, 35, [&alpha;]D21+24.3 (c=0.35, MeOll), amino acid analysis (hydrochloric acid hydrolyzate): Gly 1,00, Met 0.57, Tyr 0,88, Phe 1,00, Example 27 Production of H-Tyr-(D)-Met (O)-Gly-Phe-NH-NH-CO- CH2-CH2-CH3 (I) Production of Z-Tyr-(D)-Met(O)-Gly-Phe-OEt-: In 50 ml of acetonitrile is dissolved 4.8 g of H-Phe OEt. hydrochloride. After cooling, 2,8 ml of TEA and 7.4 g of Z-Gly-ONB are added, and the mixture is stirred overnight at room temperature, The solvent is distilled off, and the residue is extracted with 200 ml; of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate, The AcOLt is distilled off, and the residue is dissolved in 100 me of MeOH to conduct catalytic reduction with palladium black used as the catalyst, After removal of the catalyst by filtration, the MeOH is distilled off and the residue is dissolved in 50 mk of acetonitrile BOC-(r)-Met-ONB (prepared by DCC method from 4,7 g of BOC (D)-Met-OH and 3.7 ç of HONB) is added to the solution, which is then stirred overnight at room temperature, One ml of N-aqueous hydrochloric acid solution and 2.2 ml of 30% aqueous hydrogen peroxide solution are added to the reaction solution to be stirred at room temperature for 10 hours. The excess of the hydrogen peroxide is decomposed with palladium black, and the acetonitrile is distilled off, The resultant residue is extracted with 200 ml of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate, The AcOEt is distilled off, and the residue is dissolved in 30 ml of TFA, The solution is allowed to stand at room temperature for 20 minutes, The Th: : is distilled off, and the residue is treated with diethyl ether and collected by filtration, The resultant powder is dissolved in 60 ml of acetonitrile, and after cooling, 2.5 ml of TEA and 7.2 g of 7-Tyr-ONB are added to the solution, which is stirred overnight at room temperature, The solvent is distilled off and the residue is extracted with 200 ml of AcOEt, followed by washing with water and drying over anhydrous sodiiuri sulphate. The AcOEt is distilled off and the precipitated crystals are collected by filtration Fecrystallization from AcOEt yields 6.9 g of the desired product, m.p. 162-163 C, RfÚ=0.42, [&alpha;]D21-3.2 (c=0.37, DMF). Elemental analysis, for C35H4209N4S Calculated: C, 60.50; H, 6.09; N, 8.06; S, 4.61 Found : C, 60,45; H, 6.38; N, 8,07; S, 4,37 (II) Production of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2: 6,0 g of Z-Tyr-(D)-Met(O)-Gly-Phe-OEt is dissolved in a mixed solvent of 20 ml of ethyl alcohol-20 ml of SMF, and 2 ml of hydrazine hydrate is added to the solution, which is then allowed to stand at room temperature for 2 days. The ethyl alcohol is distilled off, followed by adding diethyl ether, and the precipitated crystals are collected by filtration, The crystals are boiled with acetonitrile for washing, The yield of the product is 5,0 g, m.p. 182-184 C, RfÚ=0.10, [&alpha;]D21-13.4 (c=0.44, DMF), Elemental analysis; for C33H40O8N6S Calculated: C, 58.21; H, 5.92; N, 12,34; S, 4,71 Found C, 57.95; H, 5.98; N, 12.10; S, 4.55 (III) Production of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO- CH2-CH2-CH3: In 5 ml of IMIi are dissolved 0,51 g of Z-Tyr-(D)-Met(O)- Cly-Phe-NHNH2 and 0.08 ml of n-butyric acid. After cooling to OOC, 120 mg of HOBT and 190 mg of DCC are added and the mixture is stirred at OOC for 5 hours and then at room temperature overnight, The J)MF is distilled off, and the residue is treated with diethyl ether, followed by purifying by reprecipitation with MeOH-acetonitrile. Thus obtained is 410 mg of the desired product, m,p, 161-163 C, RfÚ=0.31, [&alpha;]D21-8.8 (c=0.34, DMF) Elemental analysis, for C37H46O9N6S Calculated: C, 59.18; H, 6.17; N, 11,19; S, 4.27 Found : C, 58,85; H, 6,02; N, 10,86; S, 4.05 (IV) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-CH2-CH3: EMI57.1 3 ml of methane sulphonic acid in the EMI57.2 presence of 0,3 ml of anisole is 300 mg of Z-Tyr-(D)- Met(O)-Gly-Phe-NH-NH-CO-CH2-CH2-CH3. After standing at room temperature for 30 minutes, diethyl ether is added to the reaction solution, which is then allowed to stand at -20 C for 30 minutes, Following removal of the supernatant solution, the resultant oily substance is dissolved in 30 ml of water to pass through a column packed with Amberlite IRA-410 (acetic acid type, 2 x 6 cm). The effluent and the washings are combined and freeze-dried, The resulting powder is dissolved in a small amount of 0.1N aqueous acetic acid solution to pass through a column packed with Sephadex DH-20 (2,5 x 125 cm), followed by eluting with 0.1N aqueous acetic acid solution, The elution fractions from 275 ml to 290 ml are collected and freeze-dried. Thus obtained is 110 mg of the desired product, Rfê=0.37, [&alpha;]D21+23.7 (c=0.32, MeOH), amino acid analysis (hydrochloric acid hyclrolyzate): Gly 1,00, Met 0,38, Tyr, 0.91, Phe 1,05, Example 28 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH(CH3)2 (I) Production of Z-Tyr-(J))-Met (O)-Gly-Phe-NH-NH-CO- CH(CH3)2: Using 0.51 g of the Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 and 0.08 ml of isobutyric acid, obtained in a similar manner to(III) of Example 27 is 440 mg of the desired product, m.p. 181-183 C, [&alpha;]D21-8.3 (c=0.37, DMF), RfÚ=0.32, Elemental analysis, for C37H46O9N6S Calculated: C, 59.18; H, 6.17; N, 11.19; S, 4.27 Found : C, 58.77; H, 6.01; N, 10,82; S, 4.15 (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2(CH3)2: Using 300 mg of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO- CH(CH3)2, obtained in a similar manner to (IV) of Example 27 is 105 mg of the desired product, RfÚ=0.37, [&alpha;]D21+26.8 (c=0.32, MeOH), amino acid analysis (hydrochloric acid hydrolyzate): Cly 1,00, Met 0,38, Tyr 0,89, Phe 1.02. Example 29 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH3 (I) Production of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH3: Using 0.51 g Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 and 0,06 ml of acetic acid, obtained in a similar manner to (III) of Example 27 is 405 m of the desired product, m.p. 180-182 C, RfÚ=0.28, [&alpha;]D21-9.1 (c=0.30, DMF) Elemental analysis, for C35H42O9N6S#H2O Calculated: C, 56,75; H, 5.72; N, 11,34; S, 4.33 Found : C, 56,48; H, 562; N, 11,08; S, 4,05 (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO-CH3 Using 300 mg of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH CO-CH3, obtained in a similar manner to (IV) of Example 27 is 130 mg of the desired product, Rfê=0.30, [&alpha;]D21+19.6 (c=0.27, MeOH), amino acid analysis (hydrochloric acid hydrolyzate): Gly 1.00, Met 0.35, Tyr 0.91, Phe 1.02 Example 30 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO- (CH2)3-CH3 (I) Production of -Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO- (CH2)3-CH3: Using 0.47 g of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 and 0.1 mk of n-valeric acid, obtained in a similar manner to (III) of Example 27 is 0.39 g of the desired product, m.p. 159-161 C, RfÚ=0.33, [&alpha;]D21-8.6 (c=0.4, DMF) Elemental analysis, for C38H48O9N6S Calculated: C, 59.66; H, 6.32; N, 10,98; S, 4.19 Found : C, 59.39; H, 6.42; N, 10.69; S, 4O6 (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO (CH2)3-CH3: Using 300 me of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH- CO-(CH2)3-CH3, obtained in a similar manner to (IV) of Example 27 is 110 mg of the desired product, Rfê=0.38, [&alpha;]D21+24.8 (c=0.32, MeOH), amino acid analysis (acid hydrolyzate): Gly 1.00, Met 0.29, Tyr 0.89, Phe 1.00. Example 31 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO-(CH2)4 CITa (I) Production of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH- CO-(CH2)4-CH3: 0.51 g of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 and 0.09 ml of n-caproic acid, obtained in a similar manner to CIII) of Example 27 is 430 mg of the desired product, m.p. 170 172 C, RfÚ=0.34, [&alpha;]D21-9.1 (c=0.48, DMF) Elemental analysis, for C39H50O9N6S Calculated: C, 60.13; H, 647; N, 10.79; 5, 4.11 Found: C, 59.88; H, 6.42; N, 10.53; S, 4.22 (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO (OH2)4 -OH3: Using 350 mg of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH- CO-(CH2)4-CH3, obtained in a similar manner to (IV) of Example 27 is 210 mg of the desired product, Rfê=0.42, [&alpha;]D21+25.7 (c=0.30, MeOH), amino acid analysis (hydrochloric acid hydrolyzate): Gly, 1.00, Met 0.29, Tyr 0.88, Phe 0.99. Example 32 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO (CH2)2-O-CH2-CH3 (I) Production of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO- (CH2)2-O-CH2-CH3: Using 0.51 g of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 and 0.09 mE of ss-ethoxypropionic acid, obtained in a similar manner to (III) of Example 27 is 440 mg of the desired product, m.p. 159-161 C, RfÚ=0.32, [&alpha;]D21-7.5 (c=0.48, DMF) Elemental analysis, for C38H48O10N6S Calculated: C, 58.44; H, 6.19; N, 10.76; S, 4.10 Found : C, 58.22; H, 6.71; N, 10.59; S, 3.99 (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO (CH2)2-O-CH2-CH3: Using 350 mg of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH- CO-(CH2)2-O-CH2-CH3, obtained in a similar manner to (IV) of Example 27 is 105 mg of the desired product, Rfê=0.40, [&alpha;]D21+25.1 (c=0.37), amino acid analysis (acid hydro lyzcfte): Cly 1.00, Met 0.32, Tyr 0.89, Phe 0.98. Example 33 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO-O CH2-CHss (I) Production of BOC-(D)-Met-Gly-OEt: In 100 ml of THF are dissolved 10.0 g of BOC-(D)- Met-OH and 7.9 g of HONB, followed by cooling at 0 C and addinF 9.0 g of DCC, and the mixture is stirred at 0 C for 6 hours Insoluble matters are filtered out, and 5.9 g of H-Gly-OEt#HCl salt and 5.6 m of TEA are added to the filtrate, which is then stirred overnight at room temperature. The THF is distilled off and the residue is extracted with 100 ml of AcOFt, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off and the residue is crystallized with petroleum ether. iecrystallization from AcOXt-petroleum ether yields 9.8 g of the desired product, m.p. 55-56 C, RfÚ=0.70, [&alpha;]D21+12.5 (c=0.67, DMF) Elemental analysis, for C14H26O5N2S Calculated: C, 50,28; H, 7.83; N, 8.37; S, 9.59 Found : C, 50.88; H, 7.99; N, 8.46; S, 9.42 (II) Production of BOC-Tyr-(D)-Met-Gly-OEt: In 15 ml of TFA is dissolved 3.0 g of BOC-(D)- Met-Gly-OEt, and the mixture is allowed to stand at room temperature for 10 minutes The TFA is distilled off and the residue is treated with diethyl ether, followed by recovering by filtration. The resultant powder is dissolved in 20 ml of THF. After cooling, 1.6 ml of TEA and 4.0 g of BOC-Tyr-ONB are added, and the mixture is stirred overnight at room temperature. The THF is distilled off, and the residue is extracted with 100 mA of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate The AcOEt is distilled off and the residue is crystallized with petroleum ether Recrystallization from AcOEt yields 3.1 g of the desired product, m.p. 121122 C, RfÚ=0.62, [&alpha;]+16.8 (c=0.40, DMF) Elemental analysis, for C23H35O7N3S Calculated: C, 55.51; H, 7.09; N, 8.44; S, 6.44 Found : C, 55,32; H, 6.93; N, 8.25; S, 6727 (III) Production of BOC-Tyr-(D)-Met-Gly-OH: In 30 ml of MeOH is dissolved 2.8 g of BOC-Tyr-(D)- Met-Gly-OEt. After cooling, 12 mA of N-aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hour After cooling, 60 ml of 0.2N-aqueous hydrochloric acid solution is added, and the precipitated crystals are collected by filtration, followed by washing with cold water Thus obtained is 2.3 g of the desired product, m.p. 184-186 C, RfÚ=0.24, [&alpha;]D21+13.3 (c=0.46, DMF) Elemental analysis, for C21H31O7N3S Calculated: C, 53.71; H, 6.65; N, 8.94; S, 6.83 wound : C, 54.32; H, 6.71; N, 8.49; S, 6.70 (IV) Production of BOC-Tyr-(D)-Met(O)-ly-OH: In a mixed solvent comprising 10 m± of MeOH and 5 ml of acetic acid is dissolved 2, g of BOC-Tyr-(D)-Met-Gly- OR, followed by adding 0.6 ml of 30% aqueous hydrogen peroxide solution, and the mixture is stirred at room temperature for 5 hours. Following the addition of a small amount of palladium black, the mixdure is stirred. The catalyst is filtered out, and the solvent is distilled off, whereby the precipitated crystals are collected by filtration. Thus obtained is 2.1 g of the desired product, m.p. 185 C (decomposed), RfÚ=0.20, [&alpha;]D21+1.8 (c=0.5, DMF) Elemental analysis, for C21H31O8N3S#H2O Calculated: C, 50.08; K, 6.20; N, 8.35; S, 6.36 Found : C, 49.77; H, 6.32; N, 8.25; , 6.10 (V) Production of Boc-Tyr-(D)-Met(O)-Gly-Phe-NH-NH CO-O-CH2CH3: In 50 ml of MeOH is dissolved 460 mg of Z-Phe-NH-NH CO-O-CH2-CH3, and the catalytic reduction is conducted with palladium black used as the catalyst. After filtering the catalyst, the MeOH is distilled off, and the residue is dissolved in 10 ml of DMF. On the other hand, 485 mg of BOC-Tyr-(D)-Met(O)-Gly-OH and 215 mg of HONB are dissolved in 5 ml of DMF; after cooling to 0 C, 230 mg of DCC is added, and the mixture is stirred at 0 C for 6 'hours Following filtration of the insoluble matters, the filtrate is combined with the amine component, and the mixture is stirred at room temperature overnight. The tMF is distilled off, and the residue is extracted with 50 ml of nbutanol, followed by washing with water. The n-butanol is distilled off, and the residue is treated with diethyl ether, followed by collecting by filtration, Thus obtained is 630 mg of the desired product, m,p. 145-147 C, RfÚ=0.28, [&alpha;]D21-3.6 (c=0.5, DMF) Elemental analysis, for C33H46O10N6S Calculated: C, 55.13; H, 6,45; N, 11,69; S, 4.46 Found : C, 54.85; H, 6,29; N, 11.45; S, 4.35 (VI) Production of H-Tyr-(D)-Met(O)-Gyl-Phe-NHNH-CO-O-CH2-CH3 Using 350 mg of BOC-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO-O CH2-CH3, obtained in a similar manner to (VI) of Example 26 is the desired product; yield: 205 mg, Rfê=0.39, [&alpha;]D21+15.0 (c=0.38, MeOH), amino acid analysis (acid hydrolyzate); Gly 1.00, Net 0.22, Tyr 0.88, Phe 1.00. Example 34 Production of H-Tyr-(D)-Met(O)-Gyl-Phe-NH-NH-CO OH2 -S -CHs (I) Product ion of BOC-Phe-NH-NH-CO-CH2-S-CH3: In 20 ml of acetonitrile is dissolved 1.4 ml of ethyl thioglycolate, and 1 ml of methyl iodide is added While the mixture is stirred under cooling, 2.1 ml of TEA is added dropwise, and the mixture is stirred at room temperature for 3 hours. The acetonitrile is distilled off, and the residue is extracted with diethyl ether, followed by washing with water and drying over anhydrous sodium sulphate. The diethyl ether is distilled off, and the residue is dissolved in MeOH, followed by adding 0.7 ml of hydrazine hydrate and allowing to stand at room temperature for 2 days. The MeOH is distilled off and the residue is dissolved in 20 mE of DMF. To the solution is added 3.2 g of BOC-Phe-ONB, and the mixture is stirred overnight at room temperature. The DMF is distilled off, and the residue is extracted with 100 ml of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off, and the precipitated crystals are collected by filtration Recrystallization from AcOEt-petroleum ether yields 2.3 g of the desired product, m.p. 151-152 C, RfÚ=0.66, [&alpha;]D21-18.6 (c=0.5, DMF) Elemental analysis, for C17H25O4N3S Calculated: C, 55.55; H, 6.86; N, 11.44; S, 8.73 Found : C, 55.59; H, 6.89; N, 11.23; S, 8.33 (II) Production of BOC-Tyr-(D)-Met(O)-Gly-Phe-NH-NH- CO-CH2-S-CH3: In 4 ml of TFA is dissolved 420 mg of BOC-Phe-NH-NH- CO-CH2-S-CH3, and the mixture is allowed to stand at room temperature for 20 minutes The TFA is distilled off and the residue is treated with diethyl ether, followed by collecting by filtration. The resultant powder is dissolved in 10 mB of DMF, and to the solution is added 0.16 ml of TEA On the other hand, in 5 ml of DMF is dissolved 485 mg of BOC-Tyr-D-Met(O)-Gly-OH and 215 mg of IIONB, to which, after cooling to OOC, 230 ng of DCC is added, and the mixture is stirred at OOC for 6 hours. After filtering the insoluble matters, the filtrate is combined with the previously prepared amine component, and the mixture is stirred overnight at room temperature. The DMF is distilled off, and the residue is treated with dimethyl ether Thus obtained is 630 mg of the desired product, m.p. 154-156 C, RfÚ=0.25, [&alpha;]D21-2.0 (c=0.46, DMF) Elemental analysis, for C33H46O9N6S2 Calculated: C, 53.93; H, 6.31; N, 11."3; S, 8.72 Found : C, 53.64; H, 6.42; N, 11.25; Si 8.45 (III) Production of H-Tyr- (U)-Met (O)-G ly-Phe-NH-NII-CO- CH2-S-CH3: Using 300 mg of BOC-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO- CH2- -CH3, obtained in a similar manner to (VI) of Example 26 is 220 mg of the desired product, Rfê=0.42, [&alpha;]D21+15.4 (c=0.33, MeOH), amino acid analysis (acid hydrolyzate): Gly 1.00, Met 0.38, Tyr 0.58, Phe 1.02. Example 35 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-SO-CH3 In 3 m± of N-aqueous acetic acid solution is dissolved 100 mg of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO-CH2-S-CH3. While the solution is stirred, 0.1 ml of 30% aqueous hydrogen peroxide solution is added, and the mixture is stirred at room temperature for 5 hours The powder produced by freezedrying of the reaction solution is dissolved in a small quantity of O.lN-aqueous acetic acid solution, and the solution is applied to a column of Sephadex LH-20 (2.5 x 120 cm), followed by eluting with 0.1N aqueous acetic acid solution. The elution fractions from 290 m± to 305 ml are collected and freeze-dried Thus obtained is 70 mg of the desired product, Rfê=0.32, [&alpha;]D21+13.5 (c=0.46, MeOH), amino acid analysis (acid hydrolyzate): Cly 1.00, Met 0.29, Tyr 0.65, Phe 1.02. Example 36 Production of H-Tyr-(D)-Met(O)-Gly-MePhe-NH-NH-CO CH2-CH3 (I) Production of BOC-(D)-Met-Gly-OH: In 20 mE of ethyl alcohol is dissolved 4.7 g of BOC (D)-Met-Gly-OEt. After cooling, 16 ml of N-aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hoiir, The ethyl alcohol is distilled off, and the residue, after adding aqueous citric acid solution to neutralize, is extracted with 100 ml of ethyl acetate, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off and the residue is crystallized with petroleum ether Fecrystallization from AcOet-petroleum ether results in a yield of 3.8 g of the desired product, m.p. 124-124 C, RfÚ=0.41, [&alpha;]D21+12.3 (c=0.59, DMF) Elemental analysis, for C12H2205N2S Calculated: C, 47.04; H, 7.23; N, 9.14; S, 10.46 Found : C, 46.79; H, 7.45; N, 9.20; S, 10.21 (II) Production of BOC-(D)-Met(O)-Gly-MePhe-NH-NH-CO CH2-CH3: In 50 m± of MeOH is dissolved 4.7 g of Z-MePhe-OH and 2 ml of 6N-hydrochloric acid-dioxane is added, followed by allowing to stand overnight at room temperature The MeOH is distilled off, and the residue, after washing with water, is extracted with 100 ml of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off, and the residue is dissolved in 50 ml of MeOH, followed by adding 1.5 me of hydrazine hydrate and allowing to stand at room temperature for 3 days. The MeOH is distilled off, and the residue is extracted with 100 ml of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate, The AcOEt is distilled off, and the residue is dissolved in 20 ml of THF, followed by adding 1.4 ml of propionic anhydride After cooling, 1.4 m± of TEA is added, and the mixture is stirred at room temperature for 5 hours The THF is distilled off, and the residue is extracted with 100 ml of AcOEt, followed by washing with 5% aqueous sodium bicarbonate solution and drying over anhydrous sodium sulphate. The AcOEt is distilled off, resulting in 3.8 g of the oily product of Z-MePhe -NI{-NH-CO-0H2-0H3, out of which 2.3 g is dissolved in 50 ml of MeOH to conduct catalytic reduction with palladium black used as catalyst. The catalyst is filtered out, and the MeOH is distilled off, whereby the resultant residue is dissolved in 10 ml of EMF. On the other hand, in 20 ml of acetonitrile are dissolved 1.85 g of BOC-(D)-Met-Gly-OH and 1.2 g of HONB. After cooling at OO, 1.4 g g of DCC is added, and the mixture is stirred at 0 C for 4 hours. After filtrating out the insoluble matters, the filtrate is combined with the amine component, and the mixture is stirred overnight at room temperature. The solvent was distilled off, and the residue is dissolved in 100 ml of AcOEt and washed with water The AcOEt solution is concentrated to 20 ml, to which 5 ml of acetic acid and 0.5 ml of 30% aqueous hydrogen peroxide solution are added, followed by stirring at room temperature for 5 hours. The reaction solution is extracted with 50 ml of n-butanol, and washed with water. The n-butanol is distilled off, and the residue is treated with dimethyl ether, followed by collecting by filtration. Thus obtained is 1.9 g of the desired product, m.p. 116-117 C, RfÚ=0.20, [&alpha;]D21-25.7 (c=0.38, DMF) Elemental analysis, for C25H3907N5S Calculated: C, 54.22; H, 7.09; N, 12.65; S, 5.79 Found : C, 54,05; H, 6.98; N, 12.41; S, 5.48 (III) Production of BOC-Tyr-(D)-Met(O) -Gly-MePhe-NH-NfI- CO-CH2-CH3: In 4 ml of TFA is dissolved 420 mg of BOC-(D)-Met(O)- Cly-MePhe-NTI-NH-CO-CH2-CHz" and the mixture is allowed to stand at room temperature for 20 minutes The TFA is distilled off, and the residue is treated with diethyl ether, followed by collecting by filtration and drying. The resultant powder is dissolved in 10 ml of DMF and, after cooling, 0.14 me of TLA is added The mixture, after adding 330 mg of BOC-Tyr-ONB, is stirred overnight at room temperature The DMF is distilled off, and the residue is extracted with 50 ml of n-butanol, followed by washing with water. The n-butanol is distilled off, and the residue is treated with diethyl ether to be collected by filtration EMI70.1 Feprecipitation from methanol-ether yields 310 mg of the desired product, m.p. 138-139 C, RfÚ=0.20, [&alpha;]D21-21.3 (c=0.55, I:MF) Elemental analysis, for C;4H4809N6S Calculated: C, 56.96; H, 6.74; N, 11.72; , 4.47 Found : C, 56.58; H, 6.48; N, 11.58; S, 4.23 (IV) Production of H-Tyr-(D)-Met(O)-Gly-MePhe-NH-NH CO-CO2-CH3: In 2 m± of TFA is dissolved 150 mg of BOC-Tyr-(D)-Met(O)-Gly MePhe-NH-NH-CO-CH2-CH3, and the mixture is allowed to stand at room temperature for 30 minutes. The TFA is distilled off, and the residue is treated with diethyl ether, followed by collecting by filtration. The resultant powder is dissolved in a small amount of water, and the solution is passed through a column (2 x 4 cm) of Amberlite IRA-4lO (acetic acid type), whereby the effluent and washing are combined to be freeze-dried The obtained powder is purified in a similar manner to (VI) of Example 26 and, obtained is 60 mg of the desired product, Rfê=0.33, [&alpha;]D21+4.1 (c=0.21, MeOH), amino acid analysis (acid hydrolyzate). Gly 1.00, Met 0,24, Tyr 0.91 Example 37 Production of H-MeTry-(D)-Met(O)-Gly-Phe-NH-NH C,O-CH2-CHf (I) Production of Z-MeTyr(But)-(D)-Met(O)-Gly-Phe-NH-NH- CO-CH2-CH3: In 4 ml of TFA is dissolved 470 mg of BOC-(l))-Met(O)- Gly-Phe-NH-NH-CO-CH2-CH3, and the mixture is allowed to stand at room temperature for 10 minutes. The TFA is distilled off, and the residue is treated with diethyl ether, followed by recovering by filtration, The resultant powder is dissolved in 10 ml of SMF. After cooling, 0.15 m± of TEA and Z-MeTyr(But)-ONB (prepared by DCC method from 380 mg of Z-MeTyr(But)OH and 215 mg of HONB), and the mixture is stirred overnight at room temperature. The IMF is distilled off, and the residue is extracted with 100 mX of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off, and the residue is treated with diethyl ether for collecting by filtration Thus obtained is 450 mg of the desired product, RfÚ=0.46, [&alpha;]D21-30.0 (c=0.5, DMF) Elemental analysis, for C39H51O8N5S Calculated: C, 62.46; H, 6.85; N, 934; S, 4.27 Found : C, 62.15; H, 6.63; N, 9.05; S, 3.91 (II) Production of H-MeTyr-(D)-Met(O)-Gly-Phe-NH-NH CO-CH2-CH3: Using 350 mg of NH-NH-CO-CH2-CH3, obtained in a similar manner to (IV) of Example 27 is 120 mg of the desired product, Rfê=0.34, [&alpha;]D21+19.5 (c=0.20, MeOH), amino acid analysis (acid hydrolyzate): Gly 1.00, net 0.32, Phe 0.98. Example 38 Production of H-MeTyr-(D)-Met(O)-Gly-MePhe-NH-NH CO-CH2-CH3 (I) Production of Z-MeTyr(But)-(D)-Met(O)-Gly-MePhe NH-NH-CO-CH2-CH3: In 4 ml of TFA is dissolved 550 mg of BOC-(D)-Met(O) Cly-MePhe-Nh-NH-CO-CH2-CH3, and the mixture is allowed to stand at room temperature for 10 minutes The TFA is distilled off, and the residue is treated with diethyl ether, followed by collecting by filtration and drying The resultant powder is dissolved in 10 ml of DMF and, after cooling, 0.16 ml of TFA is added Following the addition of Z-MeTyr(But)-ONB (prepared by FCC method from 385 mg of Z-MeTyr(But)-OH and 210 mg of HONB), the mixture is stirred overnight at room temperature. The FMF is distilled off, and the residue is extracted with 100 m± of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off, and the residue is treated with diethyl ether to be collected by filtration Thus obtained is 450 m of the desired product, m.p. 121-123 C, RfÚ=0.48 Elemental analysis, for C42H56O9N6S#H2O Calculated: C, 60.12; H, 6.97; N, 10.01; S, 3.82 Found : C, 59.88; H, 6.86; N, 9.75; S, 3.91 (II) Production of H-MeTyr-(D)-Met(O)-Gly-MePhe-NH-NH CO-CH2-CH3: Using 250 mg of Z-Metyr(But)-(D)-Met(O)-Gly-MePhe NH-NH-CO-CH2-CH3, obtained in a similar manner to (IV) of Example 27 is 105 mg of the desired product, Rfê=0.36, amino acid analysis (hydrochloric acid hydrolyzate): Cly 1.00, Met 0.31. Example 39 Production of R-Tyr-Ct)-Met (O)-Gly-Phe-NH-NH-CO- CH2-CH2-Cl (I) Production of z-Tyr-(D)-Met(O)-Gyl-Phe-NH-NH-CO- CH2-CH2-Cl: Using 510 mg of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 and 100 mg of ss-chloropropionic acid, obtained in a similar manner to (III) of Example 27 is 410 mg of the desired product, m.p. 172-175 C, RfÚ=0.26, [&alpha;]D21-8.9 (c=0.50, DMF) Elemental analysis, for C36H43O9N6SCl#H2O Calculated: C, 5478; H, 5.74; N, 10.65; S, 4.06; Cl, 4,49 wound : C, 54.45; H, 5,62; N, 10.54; S, 4.12; Cl, 4.03. (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO- CH2-CH2-Cl: Using 300 me of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH- CO-CH2-CH2-Cl, obtained in a similar manner to (IV) of Example 27 is 120 mg of the desired product, Rfê=0.37, [&alpha;]D21+25.4 (c=0.40, MeOH), amino acid analysis (acid hydrolyzate): Gly 1.00, Met 0.40, Tyr 0.92, Phe 0.98. Example 40 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-CH2-CO-CH3 (I) Production of Z-Tyr-()-Met(O) -Gly-Phe-NII-NH-CO- CH2-CH2-CO-CH3: Using 510 mg of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 and 110 mg of levulinic acid, obtained in a similar manner to (III) of Example 27 is 380 mg of the desired product, m.p. 161-162 C, RfÚ=0.25, [&alpha;]D21-7.6 (c=0.35, DMF) Elemental analysis, for C38H46O10N6S R20 Calculated: C, 57.27; H, 6.07; H, 10.54; S, 4.02 Found : C, 57.05; H, 6.12; N, 1023; S, 3.85 (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-CH2-CO-CH3: Using 350 mg of Z-Tyr-()-Met(O)-Gly-Phe-NH-NH- CO-CH2-CH2-CO-CH3, obtained in a similar manner to (IV) of Example 27 is 130 mg of the desired product, Rfê=0.35, [&alpha;]D21+26.0 (c=0.25, MeOH), amino acid analysis (acid hydrolyzate): Gly 1.00, Met 0.33, Tyr 0.98, Phe 1,02 Example 41 Product ion of H-Tyr-(D)-Met(O)-ly-I)he-NH-NH-CO- CH2-CH2-OH (I) Production of BOC-Tyr-(D)-Met(O)-Gly-Phe-NH-NH- CO-CH2-CH2-OH: Using 460 mg of Z-Phe-NH-NH-CO-CH2-CH2-OH and 485 mg of BOC-Tyr-(D)-Met(O)-Gly-OH, obtained in a similar manner to (V) of Example 33 is 620 mg of the desired product, m.p. 148-150 C, RfÚ=0.20, [&alpha;]D21-2.6 (c=0.40, DMF) Elemental analysis, for C35H46O10N6S Calculated: C, 55.13; H, 6.45; N, 11.69; S, 4.46 Found : C, 54.86; H, 6.25; N, 11.42; S, 4.19 (II) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH-CO CH2-CH2-OH: By treating 350 mg of BOC-Tyr-(D)-Met(O)-Gly-l'he- NH-NH-CO-CH2-CH2-OH in a similar manner to (VI) of Example 26 is obtained 150 mg of the desired product, Rfê=0.30, [&alpha;]D21+19.4 (c=0.35, MeOH), amino acid analysis: Gly 1.00, Met 0.32, Tyr 0.89, Phe 1.00. Fx'ame 42 Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 (I) Production of H-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2: Using 300 mg of Z-Tyr-(D)-Met(O)-Gly-Phe-NH-NH2 obtained in a similar manner to (II) of Example 27,in a similar manner to (IV) of Example 27 is obtained 140 mg of the desired product, Rfê=0.20, [&alpha;]D21+33.0 (c=0.35, MeOH), amino acid analysis (acid hydrolyzate): Gly 1,00, Met 0.29, Tyr 0.95, Phe 1.00. Example 43 Production of H-Tyr-(D)-Thr-Gly-Phe-NH-NH-CO-(CH2)3 CH3 (I) Production of In 50 ml of THF are dissolved 5.Ogof Z-(D)-Thr-OH and 3.6 g of H-Gly-OBut. After cooling, 3.9 g of HONB and 4.5 g of ICC are added, and the mixture is stirred overnight. The solvent is distilled off, and the residue is extracted with 100 m± of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off, and the residue is treated with petroleum ether. Recrystallization from AcOEt-petroleum ether yields 5.0 g of the desired compound m.p. 56-57 C, [&alpha;]D23+13.8 (c=0.5, MeOH), RfÚ=0.69. Elemental analysis for C18H26O6N2 Calcd C, 59.60; H, 7.15; N, 7.65 Found: C, 58.73; H, 7.11; N, 7.87 (II) Production of Z-Tyr-(D)-Thr-Gly-OH In 100 ml of MeOH is dissolved 4.6 g of Z-(D)-Thrut and catalytic reduction is carried out wird palladium black as the catalyst The catalyst is filtered off, After the MeOH is distilled off, the residue is dissolved in THF (50 ml). To this is added Z-Tyr-ONB (5.9 g) and the mixture is stirred overnight at room temperature. The solvent is evaporated and the residue is dissolved in AcOEt (100 m±), The AcOEt solution is washed with water, followed by drying over anhydrous sodium sulphate The AcOEt is evaporated and the residue is treated with ether to give a powder The powder (3.7 :) is treated with TFA (40 ml) for 40 min at room temperature After evaporation the residue is triturated with diethylether The precipitate is collected After drying, the powder is crystallized from AcOEt; yield 2,9 g. m.p.l43- 144 C, [&alpha;]D23+18.2 (c=0.5, MeOH), Rfê=0.49. Elemental anal sis for C23H27O8N3#1/2H2O Calcd.: C, 57.25; H, 5.85, N, 8.87 Found : C, 57.57; H, 5.92; N, 8.55 (III) Production of Z-Tyr-(D)-Thr-Gly-Phe-OCH3 Using Z-Tyr-(D)-Thr-Gly-OH (1.5 g) and H-Phe-OCH3. hydrochloride (0.73g), 1.7 g of the desired compound j.c obtained in a similar manner to (I) of Example I. m.p. 102- 103 C, [&alpha;]D23+20.3 (c=0.33, MeOH), RfÚ=0.44. Elemental analysis for C33H38O9N4 Calcd.: C, 62.45; H, 6.04; N, 8.83 Found : C, 62.31; H, 6.28; N, 8.59 (IV) Production of Z-Tyr-(D)-Thr-Gly-Phe-NHNH2 Using Z-Tyr-(D)-Thr-Gly-Phe-OCHX (1.5 g) and NH2. NH2#H2O (0.5 ml), 1.4 g of the desired compound is obtained in a similar manner to (II) of Example 1. m.p. 212-213 C, [&alpha;]D23-25.9 (c=0.32 DMF), RfÚ=0.12 Elemental analysis for C32H808N6 Calcd.: C, 60.55; H, 6.04; N, 13.24 Found : C, 60.31; H, 6.25; N, 12.98 (V) Production of Z-Tyr-(D)-Thr-Gly-Phe-NHNH-CO-(CH2)3-CH3 Using Z-Tyr-(D)-Thr-Gly-Phe-NHNH2 (0.54 g) and nvaleric acid (0.14 m), 0.42 g of the desired compound is obtained in a similar manner to (I) of Example 4. m.p.172- 173 C, [&alpha;]D24-17.5 (c=0.39 DMF), RfÚ=0.45 Elemental analysis for C37H46O9N6 Calcd.: C, 61.82; H, 6.45; N, 11.69 Found : C, 61 66; H, 6.44; N, 11.43 (VI) Production of H-Tyr-(D)-Thr-Gly-Phe-NHNH-CO-(CH2)3-CH3 Using Z-Tyr-(D)-Thr-Gly-Phe-NH-NH-CO-(CH2)3-CH3 (0.25g), 105 mg of the desired compound is obtained in a 2 24 similar manner to (it) of Example 4. Ca)t +10.80 (c=0.31 MeOH) Amino acid Anal. (hydrolyzed with HCl): Thr 0.97, Gly 1.00, Tyr 1.10, Phe 1.15. Example 44 Production of H-Tyr-(D)-Met-Gly-Phe-NHNH-CO-CH2CH3 (I) Production of H-Tyr-(D)-Met-Gly-Phe-NHNH-CO-CH2CH3 100 mg of H-Tyr-(D)-Met(O)-Gly-Phe-NHNH-CO-CH2CH3 is dissolved in 4% aqueous thioglycolic acid (6 m±) and kept to stand at 50 C for 10 hr. The solution is applied to a column of Sephadex G-25, which is eluted with 30% aqueous acetic acid The fractions (270-310 ml) are combined and EMI78.1 lyophilized to the desired compound; yield 80 mg, Rfê=0.61, [&alpha;]D21+20.0 (c=0.2 MeOH). Amino acid analysis (hydrolyzed with HC±): Gly 1.00, Met 0.77, Tyr 0.80, Phe 1 02. Example 45 Production of H-Tyr-(D)-Nva-Gly-Phe-NHNH-CO-CH3 (I) Production of z-Phe-NHNH-CO-CH3 115 g of Z-Phe-ONB is dissolved in THF (300 m2) and to this is added 20 g of acetylhydrazine. The mixture is stirred at room temperature for 10 hr The formed crystals are collected by filtration, washed with water and recrystallized from acetonitrile; yield 71 g. m.p. 200-201 C, [&alpha;]D23-17.2 (c=0.5, DMF), RfÚ=0.65. Elemental analysis for C19H21O4N3 Calcd.: c, 64.21; h, 5.96; N, 11.83 Found : C, 64.05; H, 5.83; N, 11.69 (II) Production of Z-Gly-Phe-NHNH-CO-CH3 Z-Phe-NHNH-CO-CH3 (42.6g) is hydrogenated over a Pdblack in MeOH (400 mS The mixture is filtered to remove the catalyst and the filtrate is evaporated. The residue is dissolved in TMF (100 ml). and to this is added Z-Gly-ONB (44 g). The mixture is stirred for 10 hr at room temperature and evaporated The residue is treated with diethyl ether to give a powder, which is crystallized from aqueous acetonitrile; yield 45.2 g. m.p. 154-155 C, [&alpha;]D23-0.9 (c= 0.5, DMF), RfÚ=0.52 Elemental analysis for C21H24O5N4 Calcd.: C, 61.15; H, 5.87; N, 13.59 Found.: C, 60.89; H, 5.62; N, 13.40 (III) Production of Z-(D)-Nva-Gly-Phe-NHNH-COCH3 Z-Gly-Phe-NHNH-COCH3 (5g) is hydrogenated over a Pd-black as a catalyst in MeOH (100 m±). The catalyst is filtered and the filtrate is evaporated to give 3.5 g of h-Gly-Phe-NHNH-COCH3 as crystals, H-Gly-Phe-NHNH-COCH3 (0.89g) and Z-(D)-Nva-ONB, which is prepared from z-(t)- Nva-OH (0,80 g) and HONB (0.63g) by the DCC method, are dissolved in DMF (10 m2). The mix ure is stirred for 10 hr at room temperature and. evaporated. The residue is treated with diethylether to give a powder which is crystallized from acetonitrile; yield 1,3 g. m.p. 235-237 C, [&alpha;]D23+3.4 (c=0.45, DMF), RfÚ=0.44 Elemental analysis for C26II3306N5 Calcd.: C, 61.04; H, 6.50; N, 13.69 Found : C, 61.33; H, 6.62; N, 13.66 (IV) Production of Z-Tyr-(D)-Nva-Gly-Phe-NHNH-CO-CH3 Z-(D)-Nva-Gly-Phe-NHNH-COCH3 (0.92g) is hydrogenated over Pd-black in MeOH (50 m±). The catalyst is filtered off and the filtrate is evaporated. The residue is dissclved in LMF (10 ml) and to this is added Z-Tyr-ONB (0.86 g) The mixture is stirred for 10 hr. at room temperature and evaporated The residue is treated with diethylether to give a powder, which is crystallized from acetonitrille; yield 0.85g. m.p. 210-211 C, [&alpha;]D23-18.3 (c=0.48, DMF), RfÚ=0.38. Elemental analysis for C35H42O8N6 Calcd.: C, 62.30; H, 6.27; N, 12.46 Found : C, 62.15; H, 6.06; N, 12.33 (V) Production of H-Tyr-()-Nva-Gly-Phe-NH-NH-COCH, Using Z-Tyr-(D)-Nva-Gly-Phe-NH-NH-COCH, (0.40 g), the desired compound (0.16 g;) is obtained in a similar manner to (II) of Example 4. Rfê=0.36, [&alpha;]D23+22.6 (c=0.30, MeOH). Amino acid analysis (hydrolized with HO±) : Gly 1.00, Nva 1.10, Tyr 0.99, Phe 1.07. Example 46 Production of H-Tyr-(D)-Gln-Gly-Phe-NHNH-COCH3 (I) Production of BOO- (D)-Gln-Gly-Phe-NHNH-COCH3 Using BOC-(D)-Gln-ONP(0.96g) and H-Gly-Phe-NHNH COCH3 (0.72g), the desired compound (0.95g) is obtained in a similar manner to (III) of Example 45 m.p. 198-199 C, [&alpha;]D23-0.8 (C=0.50, DMF), RfÚ=0.19. Elemental analysis for C23H34O7N6 Calcd.: C, 54.53; H, 6.77; N, 16.59 found : C, 54.29; H, 6.81; N, 16.65 (II) Production of Z-Tyr-(D)-Gln-Gly-Phe-NHNH-COCH3 Using BOC-(&gamma;)-Gln-Gly-Phe-NHNH-COCH3 (O.55g) and Z-Tyr-ONB (0,52g) the desired compound (0.60 g) is obtained in a similar manner to (V) of Example 26. m.p. 209-210 C, [&alpha;]&gamma;23-21.5 (c=0.40, IMF), Rf1 = 0.12 Elemental analysis for C35H4109N7 Calcd,: C, 59,73; H, 5.87; N, 13.93 Found : C, 59.72; H, 5.92; N, 13.86 (III) Production of H-Tyr-(D)-Gln-Gly-Phe-NHNH-COCH3 Using Z-Tyr-(D)-Gln-Gly-Phe-NHNH-COCH3 (0.40 g), the desired compound (0.18 g) is obtained in a similar manner to (II) of Example 4.Rfê = 0.25, (&alpha;)D23 + 14.5 (c=0.35, MeOH). Amino acid analysis (hydrolized with Hoe): Glu 0.88, Gly 1.00, Tyr 0.90, Phe 0.98. Example 47 Production of H-Tyr-(D)-Phe-Gly-Ph-NHNH-COCH3 (I) Production of BOC-(D)-Phe-Gly-Phe-NHNH-COCH3 Using H-Gly-Phe-NHNH-COCH3 (0.44 g) and BOC-(L)-Phe ONB (O.68g), the desired compound (0.68g) is obtained in a similar manner to (III) of Example 45, m.p. 208-209 C, (&alpha;)L23 + 3.3 (c = 0.45, DMF), RfÚ = 0.51 Elemental analysis for C27H35O6N5 Calcd : C, 61.70; H, 6.71; N, 13.33 Found : C, 6145; H, 6.65; N, 13,46 (II) Production of Z-Tyr-(D)-Phe-Gly-Phe-NHNH-COCH3 Using BOC-(D)-Phe-Gly-Phe-NHNH-COCH3(0.51g) and Z Tyr-ONB(0.46g), the desired compound is obtained in a similar manner to (V) of Example 26, m.p. 203-204, (&alpha;)I23 - 13.0 (c = 0.44, DMF), RfÚ = 0.38 Elemental analysis for O39R4208I46 Calcd.: C,64.80; H,5.86; N,11.63 Found : C,64.70; H,5.95; N,11.40 (III) Production of H-Tyr-(D)-Phe-Gly-Phe-NHNH-COCH3 Z-Tyr-(D)-Phe-Gly-Phe-NHNH-COCH3 (0.45g) is hydrogenated in MeOll (50 m±) over Pd-black as a catalysist. The catalysist is filtered off and the filtrate is evaporated. The resulting residue is treated with diethylether to give a powder, which is crystallized from acetonitrile; yield 0.22 g, Rfê = 0.37. (&alpha;)D23 - 11.4 (c = 0.35 MeOH). Amino acid analysis (hydrolized with HCl): Gly 1,00, Tyr 0.98, Phe 0.9 Example 48 Production of H-Tyr-(D)-Glu(OCH3)-Gly-Phe-NHNH-COCH3 (I) Production of BOC-(D)-Glu(OCH3)-Gly-Phe-NHNH-COCH3 Using H-Gly-Phe-NHNH-COCH3 (0.44g) and BOC-(D)-Glu(OCH3) Phe-ONB(0.68g), the desired compound (0.50 g) is obtained in a similar manner to CIII) of Example 45. m.p. 205- 206 C, (&alpha;)L23 + 2.8 (c = 0.42, DMF), RfÚ = 0.43 Elemental analysis for C24H35O8N5 Calcd C, 55.26; H, 6.76; N, 13.43 Found : C,55.31; H,6.55; N,13.46 (II) Production of Z-Tyr-(D)-Glu(OCH3)-Gly-Phe-NHNH-COCH3 Using BOC-(D)-Glu(OCH3)-Gly-Phe-NHNH-COCH3 (0.46 g) and Z-Tyr-ONB(0.42 g), the desired compound is obtained in a similar manner to (V) of Example 26 m.p. 200-202 C, (&alpha;)L23 -14.8 (c =0.44, DMF), RfÚ = 0.31 Elemental analysis for C36H42O10N6 Calcd.: C,60.16; H,5.89; N,11.69 Found : C,59.53; H,5.78; N,11.51 (III) Production of H-Tyr-(D)-Glu(OCH3)-Gly-Phe-NHNH-COCH3 Using Z-Tyr-(D)-Glu(OMe)-Gly-Phe-NHNH-COCH3 (0.40 g), the desired compound (0.28g) is obtained in a similar manner to (III) of Example 47, Rfê = 0.27, (&alpha;)D23 + 17.5 (c = 0.38, MeOH), Amino acid analysis (hydrolized with HCl); Clu 0.95, Gly 1,00, Tyr 0.92, Phe 0.98. Example 49 Production of H-Tyr-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 (I) Production of BOC-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 Using H-Gly-Phe-NHNHCOCH3(0.58) and BOC-(D)-Lys (Cl-Z)-ONB (l.15g), the desired compound (1.05 g) is obtained in a similar manner to (III) of Example 45 , m.p. 169-171 C, (&alpha;)D23 + 4.7 (c = 0.47, DMF), RfÚ = 0.45. Elemental analysis for C32H42O8N6Cl Calcd.: C,57.00; H,6.27; N,12.46, Cl,5.26 Found : C, 56.88; H, 6.05; N, 12.29; CR, 5.35 (II) Production of BOC-Tyr-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 Using BOC-(&gamma;)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 (0.70 g) and BOC-Tyr-ONB (0.50 g), the desired compound (0.71 g) is obtained in a similar manner to (V) of Example 26. m.p 196-198 C, (&alpha;)D23 - 2.0 (c = 0.47, DMF), RfÚ = 0.46 Elemental analysis for C41H51O10N7Cl Calcd.: C,58.80; H,6.13; N;11.70 Found : C, 58.69; H, 6.25; N, 11.49 (III) Production of H-Tyr-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 Using BOC-Tyr-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 (0.65 g) the desired compound (0.33g) is obtained in a similar manner to (VI) of Example 26. Rfê = 0.42, (alpha;)D23 + 16.5 (c = 0.26, MeOH). Amino acid analysis (hydrolized with HC±): Lys, 0.85, Gly 1.00; Tyr 0.88, Phe 1.00. Example 50 Production of H-Tyr-(D)-Lys-Gly-Phe-NHNH-COCH3 H-Tyr-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 (0.18 g) is hydrogenated over Pb-black in MeOH (50 ml). The catalyst is filtered off and the filtrate is evaporated to give to crude product, which is purified in a similar manner to (II) of Example 4; yield 0.10 g, Rf = 0.15, (&alpha;)D25 +26.1 (c=0.36, MeOH). Amino acid analysis (hydrolized with HCl): Lys 0.98, Gly 1.00, Tyr 0.99, Phe 1.02. Example 51 Production of H-Tyr-(D)-Ser-Gly-Phe-NHNH-COCH3 (I) Production of Z-(D)--Ser-Gly-Phe-NHNH-COCH3 Using H-Gly-Phe-NHNH-COCH3 (0.69 g) and Z-(D)-Ser ONB(1.08 g), the desired compound (1.25 g) is obtained in a similar manner to (III) of Example 45. m.p. 168-169 C, (&alpha;)I23 + 3.4 (c = 0.5 , DMF), RfÚ = 0.25 Elemental analysis for C24H29O7N5 Calcd.: C,57.72; H,5.85; N,14.02 Found : C, 57.48; H, 5.99; N, 13.80 (II) Production of Z-Tyr-(D)-Ser-Gly-Phe-NHNH-COCH3 Using Z-(I)-Ser-Gly-Phe-NHNH-COCH3 (0.75 g) and Z Tyr-ONB (0.72 g), the desired compound is obtained in a similar manner to (IV) of Example 45. m.p. 184-186 C, (&alpha;)L23 -18.3 (c = 0.30, DMF), RfÚ = 0.19 Elemental analysis for C 33H3809N6 Calcd C, 59.81; H, 5.78; N, 12.68 Found : C, 59.69; H, 5.82; N, 12.51 (III) Production of H-Tyr-(D)-Ser-Gly-Phe-NHNH-COCH3 Using Z-Tyr-(D)-Ser-Gly-Phe-NHNH-COCH3 (O.40g), the desired compound (0.21 g) is obtained in a similar manner to (II) of Example 4. RFê = 0.21, (&alpha;)D23 +11.4 (c = 0.31, MeOH) Amino acid analysis (hydrolized with HC±); Ser 0.85, Gly 1.00, Tyr 0.90, Phe 0.92 Example 52 Production of H-Tyr-(D)-His-Gly-Phe-NHNH-COCH2CH3 (I) Production of BOC-(D)-His(Tos)-Gly-Phe-NHNH-COCH2CH3 Using Z-Gly-Phe-NHNH-COCH2CH3 (0.85 g) and BOO-CF)- His(Tos)-ONB (1.15 g), the desired compound is obtained in a similar manner to (IV) of Example 26. m.p. 178-179 C, (&alpha;)L23 - 1.7 (c = 0.47, MeOH), RfÚ = 0.48 Elemental analysis for C32H41O8N7S Calcd.: C,56.21; H, 6.04; N,14.34; S, 4.69 Found : C, 56.32; H, 6.01; N, 14,15; S, 4.38 (II) Production of BOC-(D)-His-Gly-Phe-NHNH-COCH2CH3 BOC-(D)-His(Tos)-Gly-Phe-NHNH-COCH2CH3 (0.55 g) is suspended in MeOH (15 m) and to this is added 1N-sodium hydroxide solution (1 m) at 0 C, The mixture is stirred for 60 min at room temperature and evaporated. The residue is treated with acetonitrile to give a powder, which is washed with water and dried; yield 0.29 g. m.p. 261-263 C, (&alpha;)D23 + 9.5 (c = 0.40, DMF), Rfê = 0.38 Elemental analysis for C25H35N7H2O Calcd : C, 54.83; H, 6.44; N, 17.90 lound : C, 54.61; H, 6.13; N, 17.80 (III) Production of Z-Tyr-(D)-His-Gly-Phe-NHNH-COCH2CH3 Using BOC-(D)-His-Gly-Phe-NHNH-COCH2CH3 (0,25 g) and Z-Tyr-ONB (0.24 g), the desired compound (0.31 g) is obtained in a similar manner to (V) of Example 26, m.p 181-182 C, (&alpha;)D23 - 10.5 (c = 0.38, DMF), Rfê = 0.56 Elemental analysis for C37H42O8H8H2O Calcd.: C,59.67; H, 5.68; N,15.03 sound : C, 59.31; H, 5.92; N, 14.81 (IV) Production of H-Tyr-(D)-His-Gly-Phe-NHNH-COCH2CH3 Using Z-Tyr-(D)-His-Gly-Phe-NHNH-COCH2CH3 (0.20 g), the desired compound (90 mg) is obtained in a similar manner to (II) of Example 4. Rfê = 0.15, Amino acid analysis His 0.95, Gly 1.00, Tyr 0.85, Phe 1.02 Example 53 Production of H-Tyr-(D)-Met(O2)-Gly-Phe-NHNH-CO-CH3 (I) Production of BOC-(D)-Met(O2)-OHDCHA BOC-(D)-Met-OH(1.7 ) is dissolved in a mixture of MeOH (10 ml), acetic acid (10 m±) and lN-sulfuric acid (10 ml). To this is added 30% aqueous hydrogen peroxide (5 ml). The mixture is stirred for 24 hr at room temperature and evaporated The residue is extracted with AcOEt (50 m±). The AcOEt solution is washed with water and dried over anhydrous sodium sulphate. To the AcOEt solution is added DOHA (0.9 m) and the formed crystals are collected by filtration; yield 1.8 g. m.p. 201 C, (&alpha;)D23 - 16.5 (c = 0.18, DMF), Rfê = 0.61. Elemental analysis for C22H42O6N2S Calcd. : C, 57.11; H, 9.14; N, 6.05; S, 6.93 Found : C, 57.43; H, 9.25; N, 6.10; S, 7.08 (II) Production of BOC-(D)-Met(O2)-Gly-Phe-NHNH-COCH3 Using H-Gly-Phe-NHNH-COCH3 (0.69 g) and BOC-(D) Met(02)-OH (0.66 g), the desired compound (0.67 g) is obtained in a similar manner to (III) of Example 45. m.p. 198-199 C(decomp.), (&alpha;)D23 - 2.5 (c = 0.49, DMF), RfÚ = 0.25. Elemental analisys for C23H35O8N5S Calcd.: C, 51.00; H, 6.51; N, 12.93; S, 5.92 Found : C, 50.92; H, 6.63; N, 12.75; S, 5.68 (III) Production of BOC-Tyr-(D)-Met(O2)-Gly-Phe-NHNH-COCH3 Using BOC-(D)-Met(O2)-Gly-Phe-NHNH-COCH3 (0.52 g) and BOC-Tyr-ONB (0.46 g), the desired compound is obtained in A similar manner to (V) of Example 26. m.p. 176-177 C. (&alpha;)D23 - 2.9 (c = 0.24, DMF), RfÚ = 0.23. Elemental analysis for C32H44O10N6S Calcd.: C, 54.52; H, 6.29; N, 11.92; S, 4.55 Found : C, 54.61; H, 6.32; N, 11.99; S, 4.62 (IV) Production of H-Tyr-(D)-Met(O2)-Gly-Phe-NHNH-COCH3 Using BOC-Tyr-(D)-Met(O2)-Gly-Phe-NHNH-COCH3 (0.35 g), the desired compound (0.21 g) is obtained in a similar manner to (VI) of Example 26. Rfê = 0.19, (&alpha;)D23 + 19.0 (c=0.33, MeOH), Amino acid analysis: Gly 1.00, Tyr 0.95, Phe 1.05. Example 54 Production of H-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH3 (I) Production of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-CO-CH3 Using 0.66 g of Z-Tyr-(D)-Ala-Gly-OH and 0.59 g of Z-Phe-NH-NH-COCH3, obtained in a similar manner to (II) of sample 11 is 0.82 g of the desired product, m.p. 210-211 C, [&alpha;]D23 - 22.9 (c+0.31, DMF), RfÚ = 0.20, Elemental analysis for C33H38O8N6H2O Calcd. C 59.63, H 6.07, N12.64 Found C 59.99, H 6.28, N 12.62 (II) Production of H-Tyr-(D)-Ala-Gly-Phe-NHNH-CO-CH3 Using 0.35 g of Z-Tyr-(D)-Ala-Gly-Phe-NHNH-CO-CH3, obtained in a similar manner to (III) of Example 10 is 0.16 g of the desired product, Rfê = 0.40, [&alpha;]D23 + 21.6 (c = 0.3, MeOH) amino acid analysis (hydrochloric acid hydrolyzato): Gly 1.00, Ala 1.02, Tyr 0.85, Phe 0.99. Example 55 Production of H-Tyr-(D)-Ala-Gly-Phe-NHNH-CO-CH2CH2CH3 hydrochloride. 80 mg of H-Tyr-(D)-Ala-Gly-Phe-NHNH-CO-CH2CH2CH3 obtained in a similar manner to Example 10 is dissolved in 0.02N-hydrochloric acid solution (7.5 ml), and the solution is lyophilized to give a fine powder, which is crystallized from a mixture of ethanol and acetonitrile; yield 55 mg, mp. 169-170 C, [a]t24 + 33.10 (c=0.26 DMF).

Claims: What we claim is: 1. A tetrapeptidehydrazide derivative, inclusive of a pharmacologically acceptable acid addition salt thereof, which has the general formula: EMI90.1 (wherein 1 is hydrogen or lower alkyl; R2 is hydrogen or the side chain of a F-a-amino acid; R3 is hydrogen or lower alkyl; P4 is hydrogen, or a saturated or unsaturated and straight or branched lower aliphatic acyl group which may optionally be substituted by hydroxyl, amino lower Alkoxy, halogen, oxo, lower alkylthio or lower alkyl thiooxide7 2. The tetrapeptidehydrazide as claimed in Claim 1, wherein F1 is lower alkyl having 1 to 6 carbon atoms. The tetrapeptidehydrazide as claimed in Claim 1, wherein R2 is the side chain of D-methionine 4 The tetrapeptidehydrazide as claimed in Chain 1, wherein R2 is the side chain of D-methionine sulfoxide. 5 The tetrapeptidehydrazide as claimed in Claim 1, wherein 13 is lower alkyl having 1 or 2 carbon atoms. 6. The tetrapeptidehydrazide as claimed in Claim 1, wherein the parent lower aliphatic acyl R4 has 1 to 8 carbon atoms. 7. The tetrapeptidehydrazide as claimed in Claim 6 wherein the parent lower aliphatic acyl R4 is propionyl. 8. The tetrapeptidehydrazide as claimed in Claim 6, wherein the parent lower aliphatic acyl R4 is butyryl. 9. The tetrapeptidehydrazide as claimed in Claim 1, wherein R1 is hydrogen, R2 is the side chain of D alanine, R3 is hydrogen and R4 is n-butyryl. 10. 'lhe tetrapeptidehydrazide as claimed in Claim 1, wherein His hydrogen, R2 is the side chain of D alanine, R3 is methyl and R4 is propionyl. 11. The tetrapeptidehydrazide as claimed in Claim 1, wherein Fl is hydrogen, R2 is the side chain of D methionine sulfoxide ,P3 is hydrogen and R4 is propionyl. 12. A method of producing. a tetrapeptidehydrazide derivative of the general formula: EMI92.1 (wherein R1 is hydrogen or lower alkyl; R2 is hydrogen or the side chain of a D-a-amino acid; R3 is hydrogen or lower alkyl; R4 is hydrogen, or a saturated or un- saturated and straight or branched lower aliphatic acyl group which may optionally be substituted by hydroxy, amino, lower alkoxy halogen, oxo, lower alkylthio or lower alkylthiooxide 3 characterized by deprotecting a compound of the general formula: EMI92.2 wherein F1 and R3 are each as defined above; R2 is hydrogen or the side chain of a F-a-amino acid which may optionally be protected; 94 is hydrogen, or a saturated or unsaturated and straight or branched lower aliphatic acyl group which may optionally be substituted by hydroxy, amino, lower alkoxv halogen, oxo, lower alkylthio or lower alkylthiooxideand which may optionally be protected; Y1 is a protective group; Y2 and Y3, respectively, mean hydrogen or a protective group 3

Inventors: KIYOHISA, KAWAI, MASAHIKO, FUJINO, SUSUMU, SHINAGAWA
Applicants: TAKEDA CHEMICAL INDUSTRIES, LTD.
Application year: 1979
Main classification: C07C103
IPC codes: C07K5