DE2703109A1 - BIOLOGICALLY ACTIVE AMIDES - Google Patents

Description

DR. BERG DIPL.-ING. STAPF DIPL.-ING. SCHWABE DR. DR. SANDMAIk

PATENT LAWYERS P.O. Box 860245, 8000 Munich Dr Bai Dipl-lnf. Sl * rf and Pwtner, PO Box 160245. MX »Munich K '

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Your sign Yourref.

Under our ref.

S MUNICH W

2 a JAN. 197?

Lawyer File 27 Be / Bo

The Welloome Foundation Ltd " London / England

"Biologically Active Amides"

This invention relates to peptides and their derivatives, the production of such compounds, formulations containing such compounds, such as the production of such formulations and the use of the compounds in human and veterinary medicine.

A 480

(OW) «1272 BERGSTAPF PATENT Some »1273 TELEX: «1274 0524JtO BERG d «3310

1433100

3M0002624 k Do »5343-101

709831/1024

In particular, the present invention relates to peptides and their derivatives that exhibit morphine agonate activity. As generally accepted and the designation here is used, a morphine agonist is a compound whose biological activity mimics that of the natural alkaloid.

The pharmacological properties and therapeutic Uses of morphine are described in the literature, see for example "The Pharmacological Basis of Therapeutics ", by Goodmann, L.S. and Gilman, A.eds., published by The MaoMillan Company, New York, J. Edition (1965), particularly Chapter 15, pages 247 bis 266, and "Martindalet The Extra Pharmacopoeia", Blacow, N.W. ed., published by The Pharmaceutical Press, London, 26th edition (1972), particularly pages 1100 to 1106, to which reference is made here as a whole. Ea however, it is well known (see Goodman, L.S. et al. at the specified location, Chapter 16) that repeated administration of morphine to the patient led to the urgency towards the drug and to getting used to it Effects and withdrawal symptoms that occur, when the administration is interrupted. Accordingly, there has been a need for a connection with the activity spectrum of morphine for many years, but with this connection should lack these disadvantages.

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The present invention provides peptides of the general formula (I):

R- (X ¹ ) _m - (X ² ) _n -X ³ -X ⁴ -X ⁵ -X ⁶ - (X ⁷ ) _r - (X ⁸ ) _p - (X ⁹ ) _cl -R ¹ (I)

together with their salts, esters, amides, N-alkylamides and Ν, Ν-dialkylamides and their acid addition salts, the compounds having morphine agonist activity both in vitro and in vivo studies, with the radicals X and X in the general formula (I) are the same or different and each is the residue of a basic amino acid (D or L), X is a D- or L-

Remainder of the general formula is:

W ¹ WR ² - (CH ₂ ) _a '(CH) _b «CH.CO-,

ρ
wherein R is a phenyl or 1,4-cyclohexadien-i-yl group, a = 0, 1 or 2, b = 0 or 1, one of the radicals W and W is a group NR ^ and the other is a hydrogen atom, with the proviso that W is always NR when b = 0, and that when R is a 1,4-Cyolohexadien-1-ylgruppe, a is always 1 and b is always 0, where R is a hydrogen atom or an alkyl, alkenyl , Alkynyl, carboxyalkyl,

Is Garboxyalkenyl- and / or Garboxyalklnylgruppe, and

2 R is optionally substituted by one or several hydroxy, alkoxy, alkanoyloxy, alkyl, nitro, Trifluonnethyl, amino, N-alkylamino, halogen, N, N-dialkylamino and / or benzyloxy group, in which the phenyl

7 0 a): J 1 / '. ii 2 4

ring is optionally substituted by one or more hydroxy, alkoxy, alkanoyloxy, halogen, Alkyl, nitro, trifluoromethyl, amino, N-alkylamino and / or Ν, Ν-dialkylamino groups,

4 5
the radicals X and X are identical or different and each is a glycyl or a D or L radical, namely C-propargylglycyl, alanyl, «-alkylalanyl, β-alanyl, valyl, norvalyl, leucyl , Isoleucyl, norleucyl, prolyl, hydroxyprolyl, tryptophyl, asparaginyl and / or grlutaminyl radicals, each of these radicals being

2 is optionally substituted with an alkyl group,

X is a grlycyl, a D or L radical, namely methionyl, leucyl, isoleucyl, norleucyl, valyl, norvalyl, prolyl, hydroxyprolyl, alanyl and / or histidyl radical, and / or the Can have meanings as they do for J? were specified,

7th
X is a D or L radical, namely a seryl, homoseryl, O-alkylseryl, O-alkylhomoseryl, threonyl, O-alkylthreonyl, methionylsulphoxide, ftlethionylsulphone, β-homovalyl, homoleucyl, β -Homoleucyl, S-methylhomocysteinyl, homomethionyl and / or ß-homomethionyl radical and / or can have one of the meanings given for X,

α is the remainder of a basic amino acid (D or L) and / or a D or L radical of a seryl, threonyl, phenylalanyl and / or tyrosyl radical,

7 0 9: 31 / ΊU2 k

X is a glycyl residue, the residue of a basic amino acid (D or L) and / or a D or L residue of a seryl and / or is threonyl group,

R is a hydrogen atom, an aralkyl, alkyl, alkenyl, Alkynyl, carboxyalkyl, carboxyalkenyl and / or carboxyalkynyl radical is,

R is the hydroxyl radical of the 1-carboxyl group of the C-terminal Is an amino acid residue or a group which restricts the place of the 1-carboxyl group, namely a group

4- 4-CH ₂ OR, where R is a hydrogen atom or an alkanoyl group or the 5-tetrazolyl group which is optionally substituted in the 1- or 2-position with an alkyl and / or benzyl group, and

m, n, p, q and r, independently of one another, are 0 and 1, with the proviso that when r = 0, ρ and q are also 0 and X is a D residue which can be selected from the residues given above, except for the feptides of the general Formula:

HX ⁵ -Gly-Gly-X ⁶ -X ⁷ -OH
and their salts, esters, amides, N-alkylamides and N ₁ N-

• 7

Dialkylamides and their acid addition salts, in which X ^{1 is} an L-eucyl and / or L-methionyl radical, and either the radical Jr is an L-tyrosyl and / or L-3,5-diiodotyroeyl group and X is an L-phenylalanyl group or X is an L-tyrosyl group and X is an L-4-chlorophenylalanyl group.

7 0 9 ⁿ 3 1 / ι 0 2 4

The abbreviations as used here for the amino acids and their residues are used are common in this field and are, for example, in Biochemistry, 11, 1726 (1972). In the preceding and following statements, all statements refer to the L-amino acids and their residues, except in the case of glycine and unless otherwise indicated.

The term "basic amino acid" is to be understood as an amino acid with two basic functions and one carboxyl group and examples of the radicals X, X, Jr and I / are lysyl-, (D and L), homoarginyl- (D and L), Ornithyl (D and L), histidyl (D and L), <x, T-diaminobutyryl (D and L) and arginyl (D and L) radicals are to be understood.

In the formula (I), the alkyl substituents which may occur in the radicals X ⁴ and X ^, the alkyl part of the <x -alkylalanyl radical, provided it has the meaning of X and X, and the alkyl part of the 0-0-alkylhomoseryl and O- AlSylthreonyl residues, which

7th
can have meanings of X, desirably 1 to 4 and preferably 1 or 2 carbon atoms. In

2 the phenyl or 1,4-cyclohexadien-i-yl ring R des Remainder X and in those optionally present therein

Benzylosy substituents can optionally be present Halogen substituents fluorine, chlorine, bromine

709i! 31 / 1Ü24

-A-

and / or iodine atoms and any alkyl and / or alkoxy substituents present together with the Alkyl parts of the optionally present alkanoyloxy, N-alkylamino and Ν, Ν-dialkylamino substituents desirably have 1 to 4, and preferably 1 or 2 carbon atoms.

When the phenyl or cyclohexadien-1-yl ring of the remainder X has one or two substituent groups, take these groups desirably occupy the 3- and / or 4- position or positions of the ring.

The alkyl radical, if it corresponds to the radical R or Έ? of the rest Ί? corresponds, together with the part of the carboxyalkyl radical in the corresponding meaning, can in particular have 1 to 4, for example 1 or 2 carbon atoms, but groups with, for example, 1 to 10 or 1 to 20 carbon atoms are also included. The alkenyl and alkynyl groups can in their meaning as R and R together with the parts in the carboxyalkenyl and carboxyalkynyl groups for this purpose in particular have 2 to 4 carbon atoms, but groups with, for example, 2 to 10 or 2 to 20 carbon atoms are also in the range of general formula (I) fall. Allyl (c <, β or) '*) and propargyl groups should be mentioned as special values for alkenyl or alkynyl groups.

7 0 9 ij 3 1 / I ü 2 4

When R is an aralkyl group, this can, for example be a benzyl group which is optionally substituted in the phenyl ring by one or more groups each group may be selected from the groups as set out above with respect to the optional

existing benzyloxy substituents of the group R in the Remainder X have been described.

1 4th A. ''

When R is a group -CH ₂ OR where R is an alkanoyl-. is radical, the alkyl portion of the alkanoyl group may desirably have 1 to 4, and preferably 1 or 2 carbon atoms. When R is a 5-tetrazolyl group, the optionally present alkyl substituent can desirably have 1 to 5 carbon atoms and the optionally present benzyl substituent can as such optionally be substituted in the phenyl ring by one or more groups as described above with respect to the optionally present -

existing benzyloxy substituents of the group R in the

Remainder X ³ .

Among the esters of the peptides of the formula (I), mention should be made of the alkyl esters and the aryl esters. To the alkyl esters in particular include those in which the alkyl group has 1 to 4 carbon atoms, for example the methyl, ethyl and t-butyl esters, but esters, in which the alkyl group is for example 1 to 10 or

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Contains 1 to 20 carbon atoms, are also considered to be included here. The aryl esters include phenyl esters, for example halophenyl esters, in which the halogen atom is, for example, a chlorine atom, as in p-chlorophenyl

In the N-alkyl and N, N-dialkyl amides of the peptides of In general formula (I), the alkyl groups can in particular have 1 to 5 carbon atoms, but Alkyl groups having, for example, 1 to 10 or 1 to 20 carbon atoms are also considered to be included and in the Ν, Ν-dialkylamides the alkyl groups can be the same or be different. The amides of the peptides are to be understood as meaning those compounds which not only conceptually derive from ammonia, but also heterocyclic bases such as pyrrolidine, piperidine and morpholine, i.e., pyrrolidinamides, piperidinamides and morpholinamides.

It can therefore be a subclass of the amides, the N-alkylamides and Ν, Ν-dialkylamides of the general peptides Formula (I) can be represented by the general formula ρ

H- (x ¹ ) _a - (x ² ) _n -x ³ -x ⁴ -x ⁵ -x ⁶ - (x ⁷ ) _p - (i ^e ) _p - (x ⁹ ) ₄ -i

R wherein the radicals X ¹ , X ² , X ⁵ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , m _f

7 ο η r 31/1 η 2 4

η, ρ, q, r and R those in the general formula (I)

5 6 have given meanings and the radicals R ₁ R and the nitrogen atom with which they are linked together form a group, namely an amino, pyrrolidino, Piperidino, morpholino, N-alkylamino and / or N, N-dialfcylamino group, wherein the "alkyl group" in each Trap has 1 to 20 carbon atoms.

In the acid addition salts of the peptides of the general formula (I) and their derivatives given above the activity in the base and the acid are of less importance! whether for therapeutic purposes they are preferably pharmacologically or pharmaceutically for the Recipients should be compatible. Examples of such suitable acids include (a) mineral acids Hydrochloric, hydrobromic, phosphoric, metaphoephoric, nitric and sulfuric acids, (b) organic acids Wine, vinegar, lemon, apple, Miloh, fumar, benzoin ßlycol, glucon, gulon, amber and aryl sulfone, for example p-toluenesulfonic acids. The pharmaceutical and pharmacologically acceptable acid addition salts together with such salts, which are not suitable (for example salts of hydrofluoric and perchloric acids) are used to isolate and purify the bases suitable and of course unsuitable salts are just as valuable for making suitable salts with ice methods known to those skilled in the art. Peptides and their derivatives

7 0 9 r; 3 1/1 0 2 4

■ ZA '

vates that contain a large number of free amino groups, can be obtained in the form of mono- or polyacid addition salts or as mixed salts of a variety of acids.

In the same way, in the case of the salts of the peptides (which the peptide has as a carboxylate anion together with a cation include) the identity of the cation is less important, although it is preferable for therapeutic purposes, that it is pharmacologically and pharmaceutically acceptable for the patient. Examples of suitable cations include sodium and potassium.

The morphine agonist properties of the peptides of general formula (I) and their derivatives as above defined, result from the following investigations, which serve exclusively for explanation and which Not intended to limit the invention.

(A) In vitrot

(1) Inhibition of the neurally evoked contractions of the isolated vas deferens of mice when examined by the method of Hughes et al. (Brain Reeearoh, 88 (1975) 296) (application of electrical impulses of 0.1 Hz), the inhibition being eliminated by the well-known narcotic antagonist "Naloxon" (1-N-allyl-7,8-dihydro-14-hydroxynormorphinone).

7 0 9 U 3 1 / I 0 2 U

η-

(2) Reduction in electrically-induced contractions of the isolated ileum from guinea pigs during dissection for stimulation according to the method of Paton (Brit. J. Pharmacol., 12 (1957) 119-1ZJ. (Each intestinal segment was impaled using an anode and hung with a 2 to 3 g load. Stimulus parameters: Frequency: 0.1 Hz, duration 0.4 min, voltage (supramaximal) 30-40 V, the contractions were isotonically transferred).

(B) In vivoi

(1) The compounds have analgesic activity, being effective, for example, in the manner that it reduces the phenylbenzoohinone-induced writhing in mice when examined by means of a modification of the method of Hendershot et al. (J. Pharm., exp. Therap., 125 (1959) 237) (wherein the compounds are administered by intracerebroventricular injection) and this reduction is eliminated by "naloxone".

(2) The compounds have antitussive activity, e.g. when used in guinea pigs after the Boura et al. Brit. J. Pharmacol, 39 (1970) 225.

(3) The compounds exhibit antidiarrheal activity

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where they are effective, for example, that they reduce the diarrhea induced by castor oil in rats.

Compounds to be mentioned as subclasses of the peptides of the general formula (I) and their derivatives are wherein:

(1) m and η both O,

(2) ρ and q are both O}

(3) r β O,

(4) X is an L-tyrosyl residue,

(5) X is the residue of a D-amino acid, preferably one D-alanine,

(6) X ^{5 is} a glycyl residue,

(7) X is an L-phenylalanyl radical, and

(8) X is the residue of a D-amino acid, preferably a D-leucine or D-methionine residue.

Peptides and their derivatives of the general formula can be mentioned as a further subclass

wherein R, R, p, q. and r the same meaning as in the have general formula (I),

3 4- '

X is L-tyrosyl, 0 -acetyl-L-tyrosyl- or Hf-methyl-L-

tyrosyl residue,

X * a glyoyl-, L-alanyl-, * -Methyl-alanyl- or D-alanyl-

7 0 9 '"; 3 1/1 0 2 A

27Π'Π (! 9

X is a glycyl, darcosyl or L-asparafjinyl residue,

X is an L-phenylalanyl-, L-tyrosyl- or L-4-chlorophenylalanylreat,

7th
X is an L-leucyl, D-leucyl, L-methionyl, D-methionyl, L-norleucyl, L-threonyl or D-ß-homoleucyl radical,

X is an L-threonyl-, D-threonyl-, L-phenylalanyl-, L-tyrosyl- or L-lysyl residue, and

X is a G3ycyl- or L-Lysylrest.

A further subclass are peptides and their derivatives of the general formula

RX ⁵ .D-Ala.Gly.L-Phe. (X ⁷ ) _r -R ¹

to mention in which the radicals R, R and r have the same meaning as in the general formula (I))

X is an L-TyroByl or N-methyl-L-tyrosyl radical, and

7th
X is D-leucyl or D-methionyl.

The peptides of the general formula (I) and their derivatives, As explained above, all processes known to the person skilled in the art for the preparation of compounds analog structure can be produced. They can be formed by successive coupling of the suitable amino acids using classical isohen Process of peptide synthesis or solid phase process

7 0 ' ■ .. η

or by the initial preparation and subsequent coupling of the peptide lower layers.

Such reactions can be brought about, for example, by activating the carboxylic acid group of the amino acid used initially and not for conversion protects certain amino and carboxylic acid groups. Such procedures are common in the peptide field. details via suitable activation and protection (masking) groups and via suitable reaction conditions (both for the coupling reaction as well as to remove the protecting groups), thus minimizing racemic mixtures can be found in the following literature, to which reference is made here in its entirety and which only is mentioned here by way of illustration, it being understood that it is neither exhaustive nor restrictive.

(a) Published British Patent Application Nos. 1 042 487, 1 048 086 and 1 281 383.

(b) Schröder and Lübke, "The Peptides" (Aoademic Press) (1965).

(o) Bellean and Malek, J. Am. Chem. Soc, 90, 165 (1968).

(d) Tilak, Tetrahedron Letters, 849 (1970)

(e) Beyerman, HeIv. Chim. Acta., 56, 1729 (1973).

(f) Stewart and Young, "Solid Phase Peptide Synthesis" (W.H. Freeman and Co.) (1969).

7Oi) J I / J 24

Depending on the reaction conditions, the peptides of the general formula (I) and their derivatives are in Form of the free base or as its acid addition salt or (in the case of the peptides al3 such) as a salt thereof obtain. The acid addition salts can be converted into the free bases or the salts of other acids and the Bases can be converted into their acid addition salts by methods known to those skilled in the art. In the same, rather tea can convert the peptides into their salts and salts are converted into the peptides or other salts by known methods.

The peptides of the general formula (I) and their derivatives, as described above, and their acid addition salts can therefore be prepared by using a reagent (II) of the general formula

R - Y ¹ - OH (II),

where Y is the radical (X) _m , as defined in the formula (I), and / or a partial radical sequence with the Re3t (X) _m at its !! - terminal end and from here corresponding to the general formula (I), with the reagent (III)

HY ² (III),

v / orin Y corresponds to the remainder of the product defined above, condensed, the reagents (II) and (III) optionally protected and / or activated where and ao-

7 0! J; J I /) 24

27Π'Πίΐ9

because it is necessary, and after that, "as far as necessary and {.""is suitable for removing the Schulz group from the product and converting the products into the base, or a salt or an acid addition salt which follows _o

With regard to the peptides of the general formula (I) and their derivatives in which the radical X is a methionyl (D or L) group int, the reagent (II) described above corresponds to the desired U-terminal fragment thereof with either ( 1) the methionyl radical X in the C-terminal position, with the reagent (ill) then having the I {ect (X) in the N-terminal position, or (?) That reads X in the C-terminal position, the reagent (III) then has the methionyl radical X in the N-terminal position, the former possibility being preferred for reasons of general convenience.

Ea is clear to those skilled in the peptide art that the arginyl- (D- or L-) or homoarginyl- (Har) (D- or Ii-) residues not only in the peptide chain in the above are incorporated in the manner described change that they are also incorporated in the chain or in combination can be formed in situ in one of their subunits by guanidination of an ornithyl (D- or L-) or a lysyl (D or L) residue using

7 0 'ι ? Λ

a reagent such as i-guanyl- ^ S-dimethylpyrazole.

It should also be noted that other in situ conversions of the peptides of the general formula (I) and their derivatives are possible. So can the amides, N-alkylamides and N, N-dialkylamides are prepared, for example, by having a peptide alkyl ester such as the methyl ester with ammonia, a heterocyclic base or a mono- or dialkylamine, depending on suitability, implements. The peptide esters can be derived from the peptides Standard esterification procedures can be prepared and the esters can be converted to peptides by saponification

o the. Substituting hydroxy group (s) in group R of the radical X can be in the alkoxy or benzyloxy group converted using the appropriate diazoalkane, e.g. diazomethane, to form idethoxy groups will. Substituting benzyloxy and alkanoyloxy groups (η) in the group R of the radical X can be removed leaving hydroxyl groups by hydrogenolysis in methanol using a 10bigen palladium on charcoal catalyst or by alkaline Hydrolysis and the hydroxy groups) can be in alkanoyloxy group can be converted using standard alkanoylation procedures. All of these procedures are in that Peptide area customary and with regard to the details of the reaction conditions and the appropriate protective and Protection group elimination process is based on the above

ii . ·; 1 / . J 2 4

27-109

referenced literature.

Because of their already mentioned morphine agonist effectiveness can peptides of the general formula (I) together with their pharmacologically or pharmaceutically acceptable Salts, esters, amides, N-alkylamides and Ν, Ν-dialkylamides and their pharmacological and pharmaceutical compatible acid addition salts for the treatment of mammals in both the human and veterinary medicine can also be used in such conditions where an agent with a morphine-like effect Effect is indicated. The following are examples of typical uses here mentioned

(1) For pain relief (analgesia), for pain relief caused by smooth muscle spasms such as kidney and biliary colic, pain as a result of terminal diseases such as cancer, pain in the pootoperative Period and pain associated with childbirth.

(2) Sedation, for example in the pre-anaethetic Medication, for calming down, for falling asleep, especially in the case of insomnia due to pain and to relieve anxiety in general o

(3) Heavy back pressure suppression.

(4) To remedy dyspnea, for example acute

709Ü31 / 10 24

- a © - 27Μ: Π09

Failure of the gastric outlet (acute left ventricular failure) or pulmonary edema.

(5) To cause constipation, for example after Ileoatomy or coloatomy and used to treat Diarrhea and dysentery.

(6) To induce euphoria and to treat depression, for example when combined 3ind in relieving pain in terminal states such as cancer.

For each of these uses, I will use the required amount of peptide or its derivative or acid addition salt (hereinafter referred to as the active ingredient) according to the type of administration and the severity of the Treating conditions change, and uie will ultimately be at the discretion of the doctor or veterinarian, in general however, the dosages for each of these uses will be in the range of 0.0025 / Ug to 40 mg per kg Mammalian body weight, preferably 0.025 / Ug to 4.0 mg / kg and most conveniently in the range of 0.25 bia 400 / Ug / kg (with all these dosages in relation to are calculated on the peptide bases).

The active ingredients can be administered in any manner appropriate to the conditions to be treated, with suitable for this purpose are oral, rectal, nasal, local

709 ÜJ 1/10 24

(buccal), vaginal and parenteral (including subcutaneous, intramuscular and intravenous) administrations. It should be noted that the method of administration will change with the conditions to be treated, and that for example to relieve the pain In the case of childbirth, administration directly into the cervical medulla can be advantageous.

While it is possible to administer the active ingredients as is, it is preferred to take them in the form of a pharmaceutical formulation preparation.

The formulations, for both veterinary and human use, of the present invention contain an active ingredient as defined above together with one or more suitable carriers and, optionally, other therapeutic ingredients. Ber carrier or the carrier must be in the sense or "suitable" acceptable that they are compatible with the other ingredients of the formulation and do not act adversely on the Reslpienten. Desirably, the formulations should not contain oxidizing agents and other substances known to be incompatible with feptides.

Formulations include those suitable for oral, rectal, nasal, topical (buccal), vaginal or parenteral (including subcutaneous, intramuscular

and intravenous) administration, although the most convenient mode of administration in a given case will depend on, for example, the active ingredient and the type of substance conditions to be treated. The formulations can expediently be presented in the form of dosage units and they can be replaced by any of the in the Pharmacy known processes are produced. All of these methods involve bringing the active ingredient into association with the carrier, plus one or more additional Can absorb components. In general, the formulations are made by uniformly and intimately mixing together the active ingredient with liquid carriers or finely distributed solid supports or made with both and then, if necessary, the product is put into the mold brought to the desired formulation.

The formulations of the present invention suitable for oral administration can be used as separate Units are presented as capsules, cassettes or tablets, each of which contains a predetermined amount of the active ingredient, as a powder or granules or as a solution or suspension in an aqueous or non-aqueous liquid or as a liquid oil-in-water or water-in-oil emulsion. The active ingredient can also be presented as a pill, latwerge or paste.

A tablet can be made by prepressing

9 ^ 31/1024

27G3109

or deforming, optionally with one or more components. Compressed tablets can be produced by anyone by pre-pressing in a suitable machine, with the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert extender, surface-active agent or dispersants can be mixed. Molded tablets can be made by molding in a ge Suitable machine can be produced, including a mixture of the powdery compound, moistened with an inert liquid diluent, is used.

Formulations for rectal administration can be in the form of suppositories with the usual carriers such as cocoa » Butter, while a suitable formulation for nasal administrations is nasal drops contain the active ingredient in aqueous or oily solution.

Formulations suitable for topical administration in the mouth include fastilles, which contain the active ingredient contained in a flavor base material, usually saooharose and acacia gum or tragacanth, and fastilles, which contain the active ingredient in an inert base such as gelatin and glycerine or Saooharose and acacia gum

Formulations for vaginal administration can be any Fessaries, creams, fasting or spray formulations

709831 / 1U24

are offered which, in addition to the active ingredient, can contain carriers as are known to the person skilled in the art to be suitable.

Formulations for parenteral administration usually contain sterile aqueous solutions of the active ingredient, these solutions are preferably isotonic with the patient's blood. Such formulations can can be conveniently prepared by the fact that the solid active ingredient in water to form an aqueous Solution dissolves, and this solution is sterile and with de «! Makes the patient's blood isotonic. The formulations can be presented in unitary or multi-dose containers, for example in closed ampoules or bottles will.

Formulations for nasal administration wherein the carrier is a solid contain a coarse powder with a particle size of, for example, 20 to 500 µm when administered in such a way that they are snorted should be, e.g. by rapid inhalation through the nasal canal from a powder container that is tight is held under the nose.

It should be noted that in addition to the aforementioned ingredients, the formulations of this invention may contain one or more additional ingredients, such as diluents, extenders, buffers, flavorings, Binders, surfactants,

7 0 9 0 3 1 / I ü 2 4

■ \ s ·

Thickeners, lubricants, preservatives (including antioxidants) and the like.

If the formulations for human or veterinary use are presented in the form of dosage units, for example those unit dosage forms as specifically mentioned above, each contains Unit usually the active ingredient, as defined above, in an amount in the range from 0.125 / ug to 2 g, preferably 1.25 / ug to 200 mg and most suitably from 12.5 / ug up to 20 mg (all weights are calculated on the peptide base).

From the foregoing it can be seen that each new embodiment described here is additionally claimed, primarily and not exclusively for example!

(a) They peptides of the general formula (I), as defined above, together with their salts, esters, amides, N-alkylamides and Ν, Ν-dialkylamides and their acid addition salts.

(b) Process as described above for the preparation of the peptides of the general formula (I) and their derivatives, as indicated above under (a), and their acid addition salts.

(c) Pharmaceutical formulations, provided they contain a pep-

709C31 / 10 24

tid of the general formula (I), a pharmacological and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N, N-dialkylamide or a pharmacologically and pharmaceutically acceptable acid addition salt of a peptide of the general formula together with a suitable carrier.

(d) Process for the preparation of the pharmaceutical formulations as defined under (c) above.

(e) Methods of treating a mammal and the conditions in which an agent having a morphine-like effect is indicated by providing the mammal with a treatment-effective, non-toxic agent Amount of a peptide of the general formula (I), a pharmacologically and pharmaceutically acceptable one Salt, ester, amide, N-alkylamide or N, N-dialkylamide des peptides or a pharmacology and pharmaceutically acceptable acid addition salt thereof administered.

(f) The method according to claim (e) for the treatment of conditions as described in detail above under (1), (2), (5), (4), (5) or (6).

The following examples serve to illustrate the present invention without intending to restrict the invention. All temperatures are in degrees

709C31 / 1024

Celsius indicated.

The following abbreviations are used below!

HOBT 1-Hydroxybenzotriazole

DCCI dicyolohexylcarbodiimide

DCU dicyclohexylurea

NMM N-methylmorpholine

IMP dimethylformamide

Pr isopropanol

Pr ₂ O diisopropyl ether

pe petroleum ether

EtOAc ethyl acetate

Z benzyloxy carbonyl

Bu tertiary butyl

BOC tertiary butyloxycarbonyl

BzI benzyl

The peptides were tested using tlc on Merck silica gel plates with the following solvent systems

1) methyl ethyl ketone

2) n-butanol ι acetic acid (water (3 »1» 1)

5) chloroform: methanol / 32% acetic acid (12 »9» 4)

4) ChloroformsMethanol »0.880 ammonia (12: 9» 4)

5) ethyl acetate / n-butanol / acetic acid / water (Ii1t1: i)

6) chloroform «methanol (8» 1)

All acids were in the! Configuration unless that this is stated otherwise. The optical rotations were measured using a Bendix NPL automatic polarimeter certainly. The amino acid preparations of peptide hydrolysates (6N «HC1 at 110 ° for 24 hours in pumped-out, sealed tubes) were made with a Beokman-SpincoJ model 120C amino acid analyzer or with a

709C31 / 1024

Rank Chromostak amino acid analyzer examined.

The following general procedures were used during the preparation of the peptides.

(a) The couplings were carried out in DMP and duroh DCCI determined.

(b) The amino acid ester hydrochloride was converted into the free ester with the addition of a tertiary one Base, either from triethylamine or N-methyl morpholine.

(c) HOBT was added at the coupling step when fragment condensation resulted in the formation of a peptide in an optically active carboxy terminal amino acid, e.g. the coupling with BOC.Tyr.D-Ala. (JIy.Phe. OH was made.

(d) Couplings were allowed to 24 hours in a cold room to proceed at +4 ⁰ C.

(β) After coupling, purification was carried out by washing with acid or base to remove the unconverted Reaction partner carried out.

(f) The alkaline saponifications were carried out in aqueous methanol with an autotitrator at a p ^ value from 11.5 to 12.0 performed with N.NaOH.

(g) The Benzyloxycarbonyl-Sohutzgruppen were duroh hydrogenolysis in methanol / acetic acid with 10 i »

709031 / 1Ü24

Palladium carried on charcoal.

(h) The acetate salts obtained from the foregoing Hydrogenolysis were converted into the corresponding hydrochlorides by adding methanol-isohemic hydrogen chloride.

(i) The benzyl protecting groups were removed by hydrogenolysis in methanol with 10 # palladium on charcoal.

(J) The tertiary butyl and tertiary butyloxyoarbonyl protecting groups were treated with N-hydrogen chloride in acetic acid in the presence of anisole, which acts as a scavenger seemed removed. The cleavage was allowed to proceed for 60 to minutes.

OBu protective groups on the alcoholic functions of the threonine and serine residues were removed with trifluoroacetic acid containing 10 H> water, the cleavage being allowed to proceed for 90 minutes.

(1) The end peptides were isolated as hydrochlorides and lyophilized from the aqueous solution.

709331/1024

Comparative manufacture 1 BOC.Tyr.Gly.Gly.Phe.OH

This was prepared according to the scheme given in Table I, with the various protective groups have the following meanings

Z t benzyloxycarbonyl

Me t methyl

BOC t-butyloxycarbonyl

All couplings were carried out in dimethylformamide using dicyclohexylcarbodiimide, the reaction mixtures being ^{stirred at 4 °} C. for at least 24 hours.

The Peptiimethylester (1) and (5) were (stat PJJ) in solution in methanol: water (3T1 V / V) by addition of 2N aqueous sodium hydroxide at _pH 11.5 saponified. The protective group Z was cleaved from the protected tripeptide (3) duroh hydrogenolysis in methanol in the presence of 10 ^ palladium on charcoal catalyst.

Characteristic values are given in Table II, where Bf refers to a thin chemical chromatography using Merok silica gel and the specified Solvent system.

Table I.

709031/1024

Table I.

Tyr • Tyr · OH G ^y iy GIy Phe Z. GIy .0H H-GIy .0Me Z. GIy Ü-1 GIy. OMe I Τ * ΙΓΤ Ii ι ι Z .GIy i ^ - GIy. OH H.Phe.OMe Z. GIy Ω- GIy Phe.OMe H. GIy i ^ - GIy Phe.OMe BOO ΠΙ tr 111 _ai y Phe.OMe BOC ■ ^ Gly Phe.OH BOC _-

Comparative production 2 BOC.Tyr.Gly.Gly.Phe.OH

According to the method as described in comparative preparation 1, the compound (4) is prepared and coupled with completely protected tyrosine (BzI is a Benayl group) as detailed in Table III to form the protected tetrapeptide (9). This saponified one described in the same manner as in the comparative preparation 1 to form the compound (10), from which the BzI group by hydrogenolysis in methanol is split off in the presence of a 1Obigen palladium on charcoal catalyst.

709031/1024

Table II

Rf ¹ melting point, crystallization elemental analysis
⁰ C solvent φ

(1) ^{0.65 a} 66-67 ETAc / pe • C ₁₅ H ₁₆ N ₂ O ₅ requires: C, 55.7; H 5.7; N 10.0;

found: C, 55.8; H 5.9; N 10.3}

(2) 0.59 * 180 aq. EtOH C ₁₂ H ₁₄ N ₃ O ₅ requires: C, 54.1; H 5.3; N 10.5;

found: C, 54.3; H 5.6; N 10.4;

(3) 0.40 ^b 58 ethyl acetate / diiso-

propyl ether ^C 22 ^H 25 ^N 3 ° 6 ^requires * ^{c 6} 1 » ⁸ ; H 5.9; N 9.8; J ₀ Found: C 61.6; H 5.8; N 9.6;

S (4) (H.C1) ^{O.77 C} 182.3 methanol / isopropa-

- * nol C ₁₄ H ₂₀ ClN ₅ O ₄ required: C 51.0; H 5.1; N 12.8;

^ found: C, 51.3; H 6.3; N 12.6;

S (5) O, 33 ^b
** (6) 0.8 *

solvent (a) n-butanol; Acetic acid) water (3> 1: 1)
Cb) methyl ethyl ketone (c) chloroform; Methanol) 32 # acetic acid (12: 9: 4)

0 pe: Fetrolether EtAc s ethyl acetate EtOHi ethanol ¹ ^

BOC.

BOC.

BOC, BOC,

Tyr

OBzI

I. Tyr.OH

OBzI
I.
Tyr

Sly

Table III GIy

Ph

OBzI
i
Tyr -

Tyr

H-fGly- ^ GIy -Ul

GIy GIy

GIy GIy

GIy GIy

Phe.OMe Phe.OMe

Phe.OH Phe.OH

Rf melting point

and crystallization solvents

138.2 ⁰ C ETAo

Elemental analysis

^C 24 ^H 40 ^N 4 ° 8

C 64.56} H 6.33 | N 8.86 |

found!

C 64.42 | H 6.46 | H

^ Solvent (a) n-butanol | Acetic acid water (3 »1» 1) (b) methyl ethyl ketone

The characterizing values for the intermediate products (9) and (10) are given in Table III, where Rf is thin-layer chromatography using Merok-Silioagel and the specified solvent systems describe.

709 3 31/1024

_ TJ _

Examples 1 to 3

Peptides of the formula »H.Tyr.GIy.GIy.Phe.X ⁷ .OH

Peptides of this formula are produced by using the protected tetrapeptide BOC.Tyr.Gly.Gly "Phe-OH (comparative preparations 1 and 2) with a suitable carb

7 oxy-protected amino acid derivative H-X-OR condensed

BOC.

BOC,
H,

Tyr
Tyr

Tyr
Tyr

GIy
GIy

GIy
GIy

GIy GIy

GIy GIy

Phe

.0H H X ⁷
X ⁷ .0R
.0R X ⁷ .0H Phe
Phe Phe

where OR can expediently be selected from radicals such as OMe, OEt, OBu *, OBzI, 0Bzl (p-N0 ₂ ) etc., depending on the final choice of the selected removal of the protective group. With the protective groups OMe and OEt, the carboxyl group can be made free by alkaline saponification, with OBU by mild acidolysis, e.g. with trifluoroacetic acid or N-hydrochloric acid in acetic acid, with OBzI and 0Bzl (p-NO ₂ ) by hydrogenolysis.

Step (A) General procedure for the preparation of BOC.Tyr.GIy.GIy.Phe.X ⁷ .OR, where X ⁷ «s is GIy, Ala, VaI and R = Me.

Dissolve BOC.Tyr.GIy.GIy.Phe.OH (0.92 mmol), HCl HX ⁷ .

OMe (e.g. glycine methyl ester «hydrochloride (0.92 mmol) and HOBT (1.84 mmol) in DMF (5 ml) and gives NMM (0.92 mmol)

709 ^ 3 1/1024

270-109

to. The mixture is cooled to -10 ° C. and DCCI (0.92 mmol) is added. The solution is allowed to slowly dissolve Warm to room temperature and stir overnight. DCU is filtered off, washed with a little DMP and evaporated Filtrate under vacuum. The residue is dissolved in ethyl acetate and washes successively with 55% aqueous NaHCO ,, HgO, 5% citric acid and HgO. One dries evaporate the solution over (MgSO.) and crystallize the residue from a suitable solvent.

Melting point
(Crystallization solvent)

Rf

Elemental analysis amino acid analysis

GIy 108-110 °
MeOH /
EtOAc / pe

AIa 115-117
EtOAo

VaI 150-151

Pr / EtOAc /
Pr ₂ O

0.973 0.954 0.85 ⁵

C ₅₀ H ₅₉ N ₅ O ₉ .H ₂

3.08

₊₁ , ₇ o '- Tyr (1.00

^{+ Ί} ° 'C 57.05 H 6.5Of Phe (i, 05J N 11.09

(0 = 0.5, found i C 57.02,
MeOH) H 6.62, N 10.649 *

0.87 '

0.9i

-8.81 ° ^C 31 ^H 41 ^N 5 ° 9 ^L.

(C = 0.5, in MeOH)

GIy AIa

C 59.32 | H 6.58j Tyr N 11.16 Phe

Found: C, 59.19; H 7.06, N 10.7496

0.97 "

-6.08 '

0.95-

(C = 0.5. in MeOH)

O ₃₃ H ₄₅ N ₅ O ₉ I.

GIy VaI

C 60.44} H 6.92j Tyr N 10.68 Phe

found i C 59.94 |
H 7.02 | N 10.3796

1.98)

1.09

1.00,

1.03)

1.97), 0.94)

1.00) (0.999)

0 9 Ί 'J1 / I π 2 4

2 7 Π 3 1 O

Step (B) General procedure for making BOC.Tyr.Gly.Gly.Phe.X ⁷ .OH X ⁷ = GIy, Ala, VaI

The protected pentapeptide BOC.Tyr.GIy “GIy. Phe.X ⁷ .OMe in methanol (6 ml), add water (3 ml), keep the p ^ value at 11.5 to 12.0 with N.NaOH until the theoretical amount of alkali has been added. Concentrate the solution in vacuo to remove methanol and dilute with water. Traces of insoluble material are filtered off, the solution is extracted with ethyl acetate to remove any ester residue, and the aqueous phase is brought to p "3 with 0.7M citric acid solution. The precipitated peptide is extracted into ethyl acetate, the extract is washed with water and dried with MgSO. and concentrated under vacuum »

Rf elemental analysis

GIy amorphous 0.84? ppt. from EtOAoO, 74c with pe 0.83

C ₂₉ H ₃₇ N ₅ O ₉ -H ₂ O, G 56.40,

η ο, 22, N 11.34

found "C 56.33, H 6.41, N $ 11.07

Ala amorphous 0.80; 0, _ο Η ™ Ν, -0η.Η ₂ 0 »C 57.05,

ppt. from EtOAcO, 66c H 16.50

0.87 ^ N 11.09

with Pr ₂ O

VaI amorphous
t

found »C 57.2Of H 6.43J N 1O67 #

p, ppt. from EtOAcO, 85c with pe 093 ³

° · »4 ^Ο 32« 43 ^Ν 5 ° 9

with pe

0.93

found"

C 59.89} H 6.75 |

C 59.98 »H 65O #

709 J J 1 / iü24

Step (θ) General procedure for the preparation of H.lyr.GIy.GIy.Phe.X ⁷ .OH HCl X ⁷ = GIy, Ala, VaI

1, ON hydrochloric acid in acetic acid (5 ml) and anisole (1 ml) are added to the pentapeptide BOC.Tyr.GIy.GIy.Phe.X ^{7 OH (100 mg).} After 90 minutes at room temperature, the solvent is removed in vacuo. An amorphous solid is obtained by triturating the residue with dry ether. Dissolve the product in water, filter, and lyophilize to give the hydrochloride salt of the peptide as a white solid.

7 ²⁵

X Rf D elemental analysis amino

acid -

»- analysis

GIy amorphous. 0.82 ^ +27.9 0.3, H ₉ QN ₁ -O ₁₇ HcI.H _o 0I

(HCl) (Ihili 4 ^{23 29 5 7 2}

y p

(HCl) (lyophili- _{0 6} 4 _{(Ces0 18}

Siert) ° ^'65 ₅ 5 ° ^{C e} Se0H ^{5O' 97 'H'} '

0.60 ^ ^{in Μθ0Η} N 12.93 Tyr

found " C 51.09J ^ _h l ^{0) l} H 6.191 N 12., 54 * (o _f99 )

Oh amorphous. 0.50? + 22.3 ° C ₀ ^ ₁ NcO ₇₀ HCLH ₅ Oi

(HCl) (lyophili- 0.58 ^ (0-0.2. ^{24 31 5 7 2} (

sated) 0.67 ⁵ in MeOH) C 51.85 | H 6.12 | l

^{N 1260}

(tDi found 1 C 52.14 | Tyr-H 6.20 | N 12.10 * (1.00);

Phe (0.98)

VaI amorphous. 0.80 ² +31.7
(HCl) (lhili 067 (CO

VaI amorphous. 0.80 +31.7 C _o »H, cN _k 0tHC1.2H _o 0 $ (HCl) (lyophili- 0.67? (C = 0.1 ^{, ^ '" 5} ' * ffly

sated) O.79 ^p in MeOH C 52.80 | H 6.52 | (2,1) |

N 11.40 VaI

found 1 C 52.89, _v H 6.451 N 11.26 * |

Phe

0 9 ■: n / 10 2 k

The following peptides are prepared with the values characterizing them, which are given in the table below, according to standard methods of peptide chemistry analogous to those in the preceding examples and comparative preparations. Are C-terminal derivatives according to the convention given under the following meanings t

- OMe j methyl ester

- NH ₂ ι amide

- NHEt ι ethylamide

Example 10 solves BOC.Tyr.Gly.Gly.Tyr.Leu.OBu in Methanol / ethylene dichloride, which contains a few drops of boron trifluoride etherate. One gives an ethereal solution of Diazomethane is added in excess and the solution is allowed to stand at room temperature until it reacts with Pauly · s-Heagens is negative. The solution is evaporated and the BOC and Bu protective groups are removed from the solid residue using N-SaIζÄure in acetic acid in the presence of anisole in the normal way. The peptide "HydroChloride" is isolated as a colorless amorphous powder after lyophilization with aqueous solution «

In Example 21, the petide product is purified by chromatography on a silica gel column (Merck) Elute with n-butanol / acetic acid water (31I1I). she

Pauly-political fractions with Rft 0.44 are

7 0 9 ü 3 1 / Ί (J 2

men, evaporated under vacuum and lyophilized the residue from the aqueous solution.

The peptide base of Example 107 is produced by reducing the compound H.Tyr.Qly.Gly.Phe.Leu.OMe. as The reducing agent used is lithium aluminum hydride, but other equivalent agents such as the Known in the art, can also be used.

The peptide bases of Examples 113 and 114 are prepared by (a) Z-leucine amide from the protected Amino acid, (b) the amide into the nitrile (phosphorus oxychloride) converts, (o) the protected leucine tetrazole by reacting the nitrile with nitrogen water chemical acid produces, (d) the protective group of the leucylamino function removed by hydrogenolysis (10 # palladium on charcoal), and (e) the pentapeptide in the usual Chen way collects.

7 0 ^C YYY 1 / i U 2 k

OO C *>

Example ITr.

S (a)

S (b)

10

• 11

12th

15th

Compound H.Tyr.D-Ala.Gly.Pho.Leu.OH HCl

H.Tyr.D-Ala.Gly.Phe.Met.OH HCl H.Tyr.D-Ala.Gly.Phe.Met.OMe H.Tyr.D-Ala.Ala.Phe.Leu.OH HCl H.Tyr.Gly.Gly.Tyr.Leu.OH HCl K.Phe.Gly.Gly.Tyr.Leu.OH HCl

H.Tyr.Gly.Gly.Pha.Leu.OH HCl

T T

H.Tyr.Gly.Gly.Tyr.Leu.OH H.Tyr.Gly.n-Ala.Phe.Leu.OH HCl H.Tyr.Ala.D-AIa.Fhe.Leu.OH HCl H.Tyr.Gly .Gly.Phe.Met.Thr.OH HCl

0.63 '

O.62 ² ; O.6O ³ O.67 ² ; O.7O ³ O.65 ² ; 0.56 ⁴ O.47 ² ; 0.SO ³ O.SS ² ; O.57 ⁴

O.58 ² ; O.62 ⁴

O.64 ² ; O.92 ³ O.6O ² ; 0.90 ³ ; 0.63 ⁴ O.6O ² ; 0.94 ³ ; O.55 ⁴ O.72 ⁱ ; O.65 ³ ; O.6O ⁴ ; O.6O

Ifcthanoli

+ 19.8 ° (c ■ »0.5) + 17.2 ° (c - 0.5) + 10.4 ° Cc - 0.5) + 1.68 ° Cc - 0.5) * 24.4 ° Cc - 0.54) + 26.45 ° (c - 0.54)

'+ .21.77 ° Cc = 0.5)

+ 21.0 ° Cc - 0.51) + .36.67 ° (c - 1) '♦ .6.43 ° (c - 1)

- 44 -

U) IMO

CM U)

CM

CM ΙΛ

CM O

«Ο

CM

ο ο »

O to

(M

IO

U)

O Il

IO

Ut

O ul

to

ΙΛ

ιο

CM

U)

IO

U)

OO ^. OO U) ιΗ > ο ι-Ι 00 00 U) U) d *. O · O O d O CM O IO (O to- IO IO Oil · « 00 ^^ U) CM CM Ct Oil U) U) (O (Ml O OO O O d •
O •
Ö (O ·· IN THE CM CM CM CM ο 00 ι-Ι 00 O «Ο • Η U) . »Ο U) U) ιΗ

CM

(O 09 « ", «Ο Oil OO O IO 00 *
O O OO 'σ κι IO OO . • ο IO «Ο O Ot O »Μ
CM οο . O Ut O CM O ^ " OD UI 1 (1 .
O O

«Μ

> ■ Η

β O

ir

CL ₁

et

Ol i

Λ CU

οι

■ 8

ei οι

• • «Ο
■ Η · ». «Ο cn
H rH tH O
(M tH
PI IN THE
P * ' M. H <· »Λ
ιΗ rl 8th

70983171024

Example Mr. 26 27 28 29 30 31 32 33 34 '35 36 37

link

H.Tyr.GIy.GIy.Phe.Nie.OH HCl

H.Tyr.D-Leu.Gly.Phe.Leu.OH HCl

H.Tyr.Ala.Ala.Phe.Leu.OH HCl

H.Tyr.GIy.Pro.Phe.Leu.CH HCl

H.Tyr.D-AIa.GIy.D-Phe.Leu.OH HCl H.Tyr.Gly.Cly.Phe.D-Leu.OH HCl

H.Tyr.GIy.GIy.D-Phe.Leu.OH HCl

H.Tyr.GIy.GIy.Phe.lie.OH HCl

H.Tyr.D-AIa.GIy.C-Phenylglycyl.Leu.OH HCl H.Phe.D-Ala.GIy.Phe.Leu.OH HCl

H.Tyr.D-Ala.Sar.Phe.Leu.OMe KCl

H. Tyr.GIy.Ala.Phe. Leu.OH HCl Rf

O.S8 ² ; 0.8S ³ ; O.86 ⁴ O.85 ¹ ; O.86 ² ; O.79 ³ O.76 ¹ ; O.62 ² ; O.74 ³ 0.76 ¹ ; O.68 ² ; O.75 ³ O.57 ² ; O.S6 ³ 0.71 ¹ ; O.49 ² ; O.79 ³ O.51 ² ; O.8S ³ ; 0.48 ⁴ O.76 ¹ ; O.85 ² ; O.65 ³ O.64 ² ; O ".8S ³ O.66 ² ; O.93 ³ 0.64 *; 0.90 ⁴ O.62 ² ; O.86 ³ ; 0.63 ⁴

[ex] 2

D (in methanol)

+ 24. .44 ° Cc " (c - • 0.4) .2) 27031 + .17. .3 ° Cc ~ 0, .6) CD
CD - 33, .6 ° (c - 0 .5) - 30 .0 ° (c - 0 -S) + 27 .2 ° (c - 0 • 4) + 28 .7 ° (C = 0 .52) + .24 .5 ° (C - C. .6) + 22 .7 ° Cc - 0 .48) + 43 .7 ° (c - 0 .52) + 21 .2 ° (C. -
⁰ (C- 0 4)
D. + .3.
- 12 69
.07 0.

-43-

rH
O iH
LO d i-H
LO ro
I / I rt O a d d i-> α (J
VJ ■ ■ a U
VJ O υ υ
V- C.
• rt
LO
r-i Q
r-ι O
00
cn
rH 39.6 ° O
LO
rH
Kl

LO

Il

LO
• LO O d rH O d - I. Il U n H υ
v_ * U υ υ U ο O O O O PJ O • ο LO PJ . co i-H • O * ■ LO Kl r-l cn LO PJ PJ

SI

LO

LO

cn

VO

IO

cn oo

LO LO

Pl

cn

PJ

Kl

LO OO

to cn Ο

O vO

d vO OO
vO cn IO
cn O O d • v *
LO
OO d Kl
VO PI
vO Kl
O
t- » O CM
LO d d O PJ
oo
LO d LO a «
PI
ΙΛ d d d

X St? 4) · ** U
X rH - O U
X O U X iH O X Ό
• X ^^ α X r 13th O * O 3 3 O M. Vi
U> » O b ft O . 4) 4 » # O • • • —J χ) 3 tyr I. 3 3 3 ■ Η O H O) I. I. 4> l-H i> 41 • z. • <u -3 Ql Ql ►J _I ►J <a 4) <u <0 41 «J 4> <D O ■ j Cu 4>
υ CU * CU CU EC Ci Cu Cu CU • « t-t ■ I. • • • rH ci
Ul 5k
i-I i-H rH U
CS rH rH CU Cu • O ITJ CJ • r ¹ O CIt • * • * • • • rH CU •H Cj ej «I Cj
,,. J CD
Ή f Vi · £ Oil ■ »H • U oil > » H i oil il Oil Oil Oil Oil i ^ H
υ ^> I ^ υ > s Sn s- H < H t- « 35 X H X X X *** X X X

H Φ ■ Η

• Η Φ

OO IO

O rH

PJ

7098 31/10 24

VO I--

Example no.

48 49 £ 0 £ 1 52 53 54 55 56

■ 57 58 59

link

H.D-Tyr.D-AIa.GIy.Phe.Leu.OH HCl

H.D-Tyr.D-AIa.GIy.Phe.D-Leu.OH HCl

H.Tyr.Gly.Sar.Phe.Leu.OH HCl

H.Tyr.D-AIa.GIy.Phe.D-Leu.Thr.OH HCl

H.Tyr.D-AIa.GIy.Phe.D-Met.OH HCl

H.Tyr.Pro.GIy.Phe.Leu.OH HCl

H.Tyr.D-Ala.Gly.Phe.D-Met.Thr.OH HCl

H.Tyr.Sar.GIy.Phe.Leu.OH HCl

H.Me Tyr.D-AIa.GIy.Phe.Leu.OH

H.Tyr.GIy.D-Pro.Phe.Leu.OH HCl

H.Tyr.D-Ala.D-Pro.Phe.Leu.OH sodium salt H.MeTyT.GIy.GIy.Phe.Leu.OMe HCl

R £

O.55 ² ; O.68 ³ O.57 ² ; O.62 ³ ; O.SO ⁴ O.59 ^2; O.8O ³ ; O.68 ⁴ O.51 ² ; O.06 ³ ; O.55 ⁴ O.S5 ² ; O.67 ³ ; O.58 ⁴ ; O.82 O.92 ³ ; O.76 ⁴ ; O.66 ⁵ O.61 ² ; O.76 ³ O.72 ³ ; O.91 ⁴ ; O.54 ² O.9O ⁴ ; O.85 ^S ; O.S2 ² O.89 ⁴ ; 0.82 °; O.59 ² 0.74 ⁴ ; O.81 ³ ; O.74 ² O.98 ⁴ ; O.99 ³ ; O.48 ²

2 ⁵

r n2

I-D

(inM ethanol)

- 20.7 ° (c - 0.5)

- 4th sl ° (c - 0.5)

+ 17.1 ° (c »1.0)

51.5 ° Cc " 0.52)

+ 31.0 ° (c - 0.51)

- 8.0 ° (C - 0.2)

+ 47.8 ° (c - 0.51)

+ 20.8 ° f. C - 1.0)

+ 55.0 ° Cc - 1.0)

+ 43.2 ° (c - 1.0)

+ 18.1 ° (c - 0.4) CO

Example Mr.

60 61 62 63 O
(O
OO *
CaJ 64

link

H.MeTyr.D-Ala.Gly.Phe.Leu.OMe HCl H.Tyr.D-MeAIa.GIy.Phe.D-Leu.OMe HCl H.TyT.D-MeAIa.GIy.Phe.D-Leu.OH HCl H.Tyr.D-AIa.GIy.Phe.Leu.OMe HCl

H.Tyr.D-AIa.GIy.Phe.D-Met.OMe HCl

'Rf

Ό.91 ⁴ ; O.89 ⁵ ; O.63 ²

O.91 ⁴ ; O.85 ³ ; O.6O ² ♦ 61.3 ° Cc - 0.39) O.6S ⁴ ; O.72 ³ ; O.62 ² + 49.9 ° Cc - 0.45) O.95 ⁴ ; O.95 ³ ; 0.63 ² + 11.6 ° Cc - 0.44) 0.94 ⁴ ; O.93 ³ ; O.S7 ² + 37.8 ° Cc ■ 0.38]

^25th

(in methanol)

Example No.

CO
CjO

(Λ

«■ 9

7o

72nd • 73rd

75 76

Connect "" Ρί

H.D-Tyr.Gly.Gly.Phe.Leu.OH HCl H.MeTyr.D-AIa.GIy.Phe.D-Leu.OH HCl H.McTyr.D-AIa.GIy.Phe.D-Leu.OMe KCl

H.DOPA.Gly.Gly.Phe.Leu.OH HCl DOPA - 3,4-dihydroxyphenylalanyl

H.Tyr.MeAla.Cly.Phe.D-Leu.OH HCl H.Tyr.D-AIa.GIy.Phe.D-Leu.D-Thr.OH HCl HD-Tyr.GIy.GIy.Phe.Leu. OMe HCl H.Tyr.MeAIa.GIy.Phe.D-Leu.OMe HCl H.Tyr.D-AIa.GIy.Phe.D-Leu.NHEt HCl H.MeTyr.D-AIa.GIy.Phe.D- Leu.NHEt HCl Me-MeTyr .D-AIa.GIy.Phe. Leu . OH acetate Me-MeTyr.GIy.GIy. Tyr .Leu.OH χ acetate Rf

O.5S ² ; 0.81 ³ ; 0.82 ⁴

Ο.52 ² ; O.9O ³ ; Ο.92 ⁴

Ο.49 ² ; 0.85 ³

Ο.51 ² ; Ο.88 ³ ; 0.79 ⁴

0.50 *

Ο.63 ² ; 0.97 ³ ; 0.93 ⁴

O.6I ² ; 0.93 ⁴ ; 0.61 ⁵

Ο.58 ² ; 0.92 ³ ; 0.96 ⁴

Ο.54 ² ; Ο.62 ³ ; Ο.66 ⁴
Ο.35 ² ; 0.63 ³ ; Ο.87 ⁴

Γ "25

^Le -D (in methanol)

-.39.0 ° (c = ■ 1.0)

+ 40.9 ° (C - 1)

+ 54.7 ° (c - 1)

+ 13.8 ° (c - 0.4)

+ 17 ° (c - 1.0) + 48.9 ° (c - 0.5) - 42.7 ° (c = »0.1) ■ + 9.03 ° (c - 0.2) + 46.S ⁰ (c = ■ 0.5) + .50.0 ° ( c - 1) '+ 39.2 ° (c - 0.4)' ♦ .31.3 ° (c - 0.4)

Example no.

19th

link

Μβ-McTyr.Gly.Ala.Phe.Lcu.OH HCl

Me-MeTyr.Gly.Gly.Phe.Leu.OH HCl

Me-MeTyr.D-AIa.GIy.Phe.Leu.OMe HCl

Me-MeTyr.Gly.Gly.Phe.Leu.OMe HCl

Me-MeTyr.D-AIa.GIy.Phe.D-Leu.OH HCl Me-MeTyr.D-AIa.GIy.Phe.D-Leu.OMe HCl

Me-D-MeTyr.Gly.Gly.Phe.Leu.OH HCl

Me-MeTyr.D-MeAIa.GIy.Phe.D-Leu.OH HCl

H.Tyr.GIy.GIy.Phe.Leu.Tyr.GIy.OH HCl

H.Tyr.D-Ala.GIy.His.Leu.OK 2HC1

H.Tyr.D-AIa.GIy.Phe.D-Leu.Phe.GIy.OH HCl

H. Tyr.GIy. GIy.Phe.Met (0) .0H HCl Rf

Ο.55 ² ; Ο.66 ³ ; O.SO ⁴ Ο.45 ² ; Ο.65 ³ ; O.SS ⁴ Ο.45 ² ; Ο.97 ³ ; Ο.97 ⁴ Ο.38 ² ; 0.92 ³ ; 0.96 ⁴ O.4O ² ; Ο.86 ⁵ ; 0.78 ⁴ Ο 41 ² ; Ο.75 ³ ; 0.96 ⁴ .36 ² ; Ο.89 ³ ; O.6O ⁴ p.35 ² ; Ο.76 ³ ; Ο.81 ⁴ Ο.86 ³ ; 0.84 ⁴ Ο.26 ² ; 0.47 ³ ; O.S2 ⁴

Ο.18 ² ; O.56 ³ ; 0.Sl ⁴

Co] p (inM ethanol)

+ .38.2 ° (c - 1.0)

+ 52.4 ° (c - 1.0)

+ 62.4 ° (c = 1.0)% -frill *

+ 66.4 ° (c - 1.0)

- 67.4 ° (c => 0.5)

+ 58.4 ° (c ··> 0.2)

- 4.79 ° (c - 0.1)

+ .20.8 ° (c - ok)

+ 13.4 ° (c - 0.5) -J

* 18.7 ° (c - 0.2) __,

Example no

SO

91

55

96

Link-

H.Tyr.D-AIa.GIy.Phe.D-Leu.Lys.Lys.0H Diacetate

H. Tyr. D-Trp. GIy. Phe. Leu. 0H_Natrium salt

Ac
H.Tyr.D-AIa.GIy.Phe.D-Leu.Tyr.OH

H.Tyr.D-Trp.GIy.Phe.D-Leu.OH HCl

H.Tyr.D-AIa.GIy.Phe.OH HCl

H.Tyr.D-AIa. GIy.Phe.D-Leu. £ - "c] alQrjplienyl ester HCl

H.Tyr.D-AIa.GIy.Phe (4Cl) .D-Leu.OH HCl

Me
H.Tyr.GIy.GIy.Tyr.Leu.OH HCl

Q.44 ³ ; 0.38 ⁴

O.76 ² ; 0.84 ³

O.72 ² ; O.67 ⁵

0.76 '

O.66 ⁴ ; O.23 ^4A ; 0.47 ²

O.75 ² ; O.69 ⁵

4A

0.42

O.S5 ² ; O.93 ³ ; O.79 ⁴

Ca] "" Cir- methanol)

'+ .12.0 ° Cc - 0.5)

- 4.72 ° (c - 1.0)

+ 35.6 ° (c - 0.5)

+ 16.58 ° (c = 2) *

+ 64.6 ° (c - 0.5)

+ ■■ 33.9 ° (c = Ü.5)

- 4.56 ° (c - 0.2)

+ 28.4 ° (c - 0.1)

4A * chloroform »methanol» 0.880 ammonia (120: 90 »5) in glacial acetic acid

Example no .

97

too
toi

ΙΟί>

link

H.Tyr.D-AIa.GIy.Phe (4Cl) .D-Leu.OMe HCl H.Tyr.GIy.GIy.Phe.D-Leu.OMe HCl H.MeTyr.D-AIa.GIy.Phe.D -Leu.NH ₂ HCl H.Tyr.Gly.Gly.Phe.D-Met.OMe HCl H.Tyr.GIy.GIy.Phe.D-Met.OH HCl,. /> H.MeTyr.D-AIa. GIy.Phe.D-Met.OMe HCl H.Tyr.Asn.GIy.Phe.D-Met.OH H.Tyr.Asn.Gly.Phe.D-Leu.OH Me-MeTyr.MeAIa.GIy.Phe. D-Leu.OH HCl H.Tyr.D-Ala.Gly.Phe.OMe HCl Rf

0.62 ³ ; Ο.64 ⁵

O.S5 ² ; O.51 ⁵

Ο.62 ² ; Ο.75 ³ ; Ο.92 ⁴

O.S2 ² ; O.S3 ^3A

0.48 ² ; O.S8 ^3A

Ο.43 ² ; O.4S ³

O.S7 ^Z ; 0.63 ⁵ ; 0.88 °

[α] ²⁵ (in methanol)

+ 36.5 ° (c - 0.5)

+ 40.0 ° (c - 0.5)

+ 50.7 ° (c " 1)

+ 43.7 ° (c "0.5)

+ 38.3 ° Cc - 0.5)

+ 59.4 ° Cc - 0.12)

- 11.8 ° Cc - 0.52)

- 21.0 ° Cc - 0.5) + 13.8 ° Cc - 0.1) + S7.2 ⁰ Cc - 0.5)

* 3A t chloroformtMethanol: 32 # iger acetic acid (120: 9015)

Example Mr. 167

Come on

110 ia 112.

nz

link

H.TyT.Gly.Gly.Phe.O-acetylleucinol HCl -O-acetylleucinol - -NH.CH (CH ₂ .CH (CH ₃ ) ₂ ) .CH ₂ -O-CO-CH ₃

H.Tyr.Gly.Gly.Phe.leucinol HCl • leucinol - -NH.CH (CH ₂ .CH (CH ₃ ) ₂ ) -CH ₂ -OH

H.Tyr.Ala (aMe) .GIy.Phe.D-Leu.OH HCl -AIa (eMe) - - -NH.C (CH ₃ ) ₂ -CO-

H.Tyr.Ala (aMe) -GIy.Phe.D-Leu.OMe HCl H.eHomoTyT.Gly.Gly.Phe.Leu.OH HCl H.Tyr.D-Ala.Gly.Phe.D-ßHomoLeu.OH HCl H-TyT.D-Ala.Gly.Phe-Leu-tetraiol HCl H.Tyr.D-Ala.Gly.Phe.D-Leu-tetrazole HCl

JH (CH ₃ ) ₂

Π -Leu-tetrazole - -NH-CH-C-HH Rf
Ο.81 ³ ; 0.84 ⁴ ; Ο.68 ⁵

Ο.81 ³ ; 0.75 ⁴ ; O.68 ^p

Ο.55 ² ; O.77 ^J ; 0.59 ⁴

O.7O ² ; Ο.89 ³ ; Ο.95 ⁴ Ο.53 ² ; Ο.63 ³ ; Ο.52 ⁴ Ο.58 ¹ ; Ο.82 ³ ; 0.49 ⁴ O.6O ² ; Ο.92 ³ ; Ο.96 ⁴ O.6O ² ; O.9O ³ ; 0.94 ⁴

(ojJ ^S (in methanol)

+ 25.4 ° (c - 0.52)

+ 23.5 ° (c - 0.5)

- 5.14 ° (c = 0.5)

. ♦ 10.7 ° (c - 0.5)

+ 4S.2 ^U (c - 0.1)

+ 39.7 ° (c - 0.1)

Example No. 115 116 117 118 119 120 121 122 123

124

Compound -H.DOPA.D-Ala.Gly.Phe.D-Leu.OH HCl

HD-DOPA.D-Ala.Gly.Phe.D-Leu.OH HCl H.Tyr.D-AIa.GIy.Phe .Isoamylamid H.isoBuTyr.D-Ala.Gly.Phe Xso amylamid HCl H.MeTyr.D -AIa.GIy.Phe.D-Met.NHEt HCl H.MeTyr.D-AIa.GIy.Phe.D-Met.OH HCl H.MeTyr.D-AIa.GIy.Phe.D-Met.NH ₂ HCl H.Phe (4Cl) .D-AIa.GIy.Phe.B-Leu.OH acetate H.Tyr.D-AIa.GIy.Phe (4Cl) .D-Leu.NHEt HCl Me

I H.Tyr.GIy.Gly.Tyr.Leu.OMe HCl

O.56 ² ; O.72 ³ O.58 ² ; O.68 ³

O.68 ² ; O.67 ³ ; O.6S ⁵

3A

O.59 ² ; 0.84 ³ ; O.9O ⁴

O.52 ² ; O.71 ³ ; O.69 ⁴

O.52 ² ; O.72 ³ ; O.85 ⁴

O.65 ^3A ; 0.4S ^4A

0.63 ² ; O.68 ^3A ; 0.68 ^p

O.62 ² ; O.96 ³ ; O.15 ⁵

yes] £ ^J Gin M-ethanol) + 29.9 ° (c - 0.1) + 9.8 ° Cc - 0.1) + 28.4 ° (c - 0.5)

+ 40.3 ° Cc - 0.5)

+ 59.7 ° Cc - 1)

+ 34.7 ° Cc-D ς,

+ 48.9 ° Cc-I) *

- 0.78 ° Cc - 0.2)

+ 40.7 ° Cc - 0.5)

+ 18.9 ° Cc - 1)

3Λ t CliloroformiMethajiol: 32 ^ i «er .., ils8igaäure .ί120: 90ι5) 4A: chloroformiUethanoltO _t 980 ammonia. (12Ot 90: 5)

Pharmaceutical formulations

A) tablet formulation (20 mg / tablet)

Compound of formula (I) 20 mg

Lactose 76 mg

Corn starch 10 mg

Gelatin 2 mg

Magnesium stearate 2 mg

The compound of general formula (I), lactose and Corn starch are mixed; granulated with a solution of gelatin dissolved in water. To the dry ones Granules are given magnesium stearate and the mass is compressed into tablets, 110 mg per tablet.

B) SuppoBitorien (5 mg / product)

Compound of general formula (I) 250 mg suppository base (Massa

Bsterinum C) to 100 g

The suppository material is melted at 40 ^° C., the compound of the general formula (I) is gradually added in fine powder form and mixed until homogeneous. Pour into suitable molds, 2 g per mold, and allow to set.

Massa Esterinum C is a commercially available suppository mass, consisting of a Gemisoh of mono-,

709C31 / 1U24

Di- and triglycerides of saturated vegetable fatty acids. It is brought to market by Henkel International, Dusseldorf.

C) Peesariums (5 mg / product)

Compound of general formula (I) 5 mg

Lactose 400 mg

Povidone 5 mg

Magnesium stearate 5 mg

The compound of the general formula (I) and lactose are mixed, and the Gemisoh is granulated with a solution of povidone in 50 # aqueous λ-ethanol. One trooknet the granules and the magnesium stearate and compressed with suitably shaped punches, 415 mg per pessary.

D) Freeze-dried injection ampoule (100 mg / ampoule)

Compound of general formula (I) 100 mg Water for injection to 2.0 ml

Dissolve the compound of the general formula (I) in water for injections, the solution, for which purpose they are passed through a membrane filter, 0.2 / do pore size, tet lei, collects the filtrate is sterilized in a sterile container. Sterile glass ampoules, 2 ml / ampoule, are filled under atmospheric conditions and freeze-drying is carried out. The ampoules are closed with sterile rubber

locks that are secured with an aluminum lock are.

The injection mass is prepared prior to administration by adding a suitable volume of water for injection or topped up by adding a sterile saline solution .

In the previous formulations, the weight is the Compound of general formula (I) based in each case on the feptide base.

709031/1024

Claims (19)

Patent claims s R- (X ¹ ) _m - (X ² ) _n -X ⁵ -X ⁴ -X ⁵ -X ⁶ - (X ⁷ ) _r - (X ⁸ ) _p - (X ⁹ ) _q -R ¹ (I), its salt, ester, amide, N-alkylamide or N, N-dialkylamide or their acid addition salt, wherein 1 2 the radicals X and X are identical or different and each is the radical of a basic amino acid (D or L), x 'is a D or L radical of the general formula ι W ¹ W ι ι R ² - (CH ₂ ) _a . (CH) _b .CH.Co, 2
wherein R is a phenyl or 1,4-cyolohexadien-1-yl group, a = O, 1 or 2, b = 0 or 1, one of the radicals W and W is an NR group and the other is a hydrogen atom, with the proviso that W is always an NR group if ρ
b = O, and that when R is a 1,4-cyclohexadien-i-yl group, a is always 1 and b is always O, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carboxyalkyl , Carboxyalkenyl and / or oxyallcinyl group 2
and in which R is optionally substituted by a hydroxy, alkoxy, alkanoyloxy, alkyl, nitro, trifluoromethyl, amino, N-alkylamino, halogen, N, N-dialkylamino and / or benzyloxy group, wherein the phenyl ring is optionally substituted by one or more 709831/1024 -, Λ ' Hydroxy, alkoxy, alkanoyloxy, halogen, alkyl, nitro, trifluoromethyl, amino, N-alky! Amino and / or N, N-dialkylamino groups, 4 5 the radicals X and X are the same or different and each a glyoyl group or an L or L radical of C-propargylglycyl, Alanyl-, ot-alkylalanyl-, ß-alanyl-, Valyl, norvalyl, leucyl, isoleucyl, narleucyl, Prolyl, hydroxyproIyI, tryptophyl, asparaginyl and / or glutaminyl radicals, wherein each of these radicals is optional is N -substituted with an alkyl group, X is a G-lycyl radical or a D or L radical of methionyl, leucyl, isoleucyl, norleucyl, valyl, norvalyl, prolyl, hydroxyprolyl, alanyl and / or hietidyl radicals or can have the meanings as defined under Jr above, 7th
X is a D or L radical of seryl, homoseryl, O-alkylseryl, O-alkylhomoseryl, threonyl, O-alkylthreonyl, methionyl sulphoxide, methionylsulphone, β-homovalyl, homoleucyl, J3-homoleuoyl -, S-methylhomocyeteinyl, homomethionyl, β-homomethionyl radicals, and / or can have the meanings as defined above under X, λ the best of a basic amino acid (D or L) or is a D or L radical of seryl, threonyl, phenylalanyl and / or Tyroey! radicals, 7 0 9 J 3 1/1 0 2 4 X is a glycyl residue, the residue of a basic amino acid (D or L) and a D or L residue of seryl and / or threonyl residues, R is a hydrogen atom, an aralkyl, alkyl, alkenyl, Is alkynyl, carboxyalkyl, carboxyalkenyl and carboxyalkynyl groups, R is the hydroxyl group of the 1-carboxyl group of the 0-terminal amino acid residue or a group which the Takes place of the 1-carboxyl group, namely a group 4- 4- ■ CH ₂ OR, where R is a hydrogen atom or an alkanoyl group, and / or a 5-tetrazolyl group, which is optionally in the 1- or 2r-position with an alkyl, and / or benzyl group is substituted, and m »n, p, q. and r = O or 1, with the proviso that when r = 0, q and ρ. then are also 0 and X is a D radical selected from those mentioned above, except for the peptides of the general formula HX ³ -Gly-Gly-X ⁶ -X ⁷ -OH and their salts, esters, amides, N-alkylamides and N, N-dialkyl amides and their acid addition salts, in which X is an L-leucyl- and / or L-methionyl radical and X is either an L-tyroayl and / or L-3 _f 5-diiodotyrosyl radical and X is an L-phenylalanyl • X g rest or Jr is L-tyrosyl and X is L-4-chlorophenylalanyl. 709 G31 / 1024 1- 2. Peptide of the general formula H- (X ¹ ) _m - (X ² ) _n -X ⁵ -X ⁴ -X ⁵ -X ⁶ -I ⁷ - (X ⁸ ) _p - (X ⁹ ) _q -OH or its salt, ester, amide, N-alkylamide or N ₁ N-bialkylamide or its acid addition salt, in which 1 2 the radicals X and X are the same or different and each is the radical of a basic amino acid (D or L), X is a phenylalanyl (D or L) and / or C-phenylglycyl- (D or L) residue, and each of these residues is given- if N is substituted by an alkyl group and optionally in the 3- and / or 4-position of the phenyl ring is substituted by a group or groups, namely hydroxy, alkoxy, aoyloxy and / or benzyloxy groups, X ^4- a glycyl-, alanyl- (D or L), valyl-, (D or L), norvalyl-, (D or L), leucyl-, (D or L), isoleuoyl- (D or L), Norleucyl-, (D or L), Prolyl- (D or L) and / or hydroxyprolyl radical (D or L) in which each these radicals optionally with an alkyl group N - is substituted, X is an aeparaginyl, (D or L), glutaminyl (D or L) - 2 radical, in which each of these radicals optionally N- is substituted with an alkyl group and / or the can have the same meaning as described for X, X is a methionyl (D or L), leucyl (D or L), isoleuoyl (D or L), norleucyl (D or L), valyl (D or L), noryalyl (D or L), prolyl (D or L), hydroxy 709031/1 024 ■ ζ ' prolyl- (D or L), glycyl-, alanyl- (D or L) and / or can have the same meaning as described for X, X ^{7 is} a LIethionyl- (D or L), Seryl- (D or L), Threonyl- (D or L), Leucyl- (D or I), Isoleucyl- (D or L), Norleucyl- (D or L) , Valyl (D or L), rlorvalyl (D or L), prolyl (D or L), hydroxyprolyl (D or L), glycyl, alanyl (D or L) and / or the same meaning 3 can have direction as described for X, the radicals λ and X are identical or different and each is a seryl (D or L) and / or threpnyl (D or L) radical, and m, η, ρ and q. = 0 or 1, with the proviso that if m, η, ρ and q are all 0 and the radicals X ⁵ , X ⁴ , X ⁵ and X ⁶ tyrosyl or glycyl, Are glycyl and phenylalanyl radicals, X is not a llethionyl or leucyl radical. 3. Peptide of the general formula: H- (I ¹ ) _a - (X ² ) _n -X ³ -X ⁴ -X ⁵ -X ⁶ -X ⁷ - (I?) P- (X ⁹ ) _il -OH or its salt, ester, amide, N-alkylamide or N, N-dialkylamide or its acid addition salt, in which 1 2 the radicals X and X are identical or different, and each is the remainder of a basic amino acid, the radicals X and X are identical or different and each is a phenylalanyl and / or C-phenylglycyl radical, 709331/1024 wherein each of the radicals is optionally N-substituted by an alkyl group and optionally in 3- and / or 4-position of the phenyl ring is substituted by, a group bzv /. Groups, namely hydroxy, alkoxy, Acyloxy and / or benzyloxy groups, X and X are identical or different and each represents a glycyl, alanyl (D or L) valyl ₁ (D or L) norvalyl, (D or L), leucyl (D or L), isoleucyl (D or L), norleucyl (D or L), prolyl (D or L) and / or hydroxyprolyl radical (D or L), in which each of the radicals is optionally N-substituted by an alkyl group, X is a methionyl, leucyl, isoleucyl, norleucyl, valyl, norvalyl, prolyl, hydroxyprolyl, glycyl, alanyl radical and / or has the same meaning as described for X and X, the radicals X ^ and 1 are identical or different and each is a seryl and / or threonyl radical, and m, η, ρ and q. = O or 1, with the proviso that if m, η, ρ and q are all O and the radicals X, X ^4- , X ⁵ and X tyrosyl or glycyl, Are glycyl and phenylalanyl radicals, X is not a methionyl or leucyl radical. 4. Peptide according to claim 1 of the general formula RX ³ -X ⁴ -X ⁵ -X ⁶ - (X ⁷ ) _r - (X ⁸ ) _p - (X ⁹ ) _q -R ¹ 709 3 31 / JU24 -V or its salt, ester, amide, N-alkylamide or N, N-dialkylamide or its acid addition salt, in which Rf R »Pi Ο. and r have the meaning defined in formula (I), J? an L-tyrosyl, Cr-acetyl-L-tyrosyl or N-methyl-L-tyrosyl radical, X * is a glyoyl, L-alanyl, ci-methylalanyl or D-alanyl radical, X is a glycyl, sarcosyl or L-asparaginyl residue, X is an L-phenylalanyl, L-tyrosyl or L-4-chlorine phenylalanyl radical, X ^I an L-leucyl-, D-leucyl-, L-methionyl-, D-methionyl-, L-horleuoyl, L-threonyl or D-ß-homoleucyl radical, X ^ an L-threonyl, D-threonyl, L-phenylalanyl, L-tyrosyl or L-lysyl radical, and tr is a glyoyl or L-lysyl solid. 5. Peptide according to Claim 1 of the general formula RX ⁵ .D-AIa.GIy.L-Phe. (X ⁷ ) _r -R ¹ or its salt, ester, amide, N-alkylamide or N, H-dialkylamide or its acid addition salt, in which R, R and r have the meaning defined in formula (I), J? an L-tyrosyl- or N-methyl-L-tyrosylreet, and 7th X is D-leuoyl or D-methionyl. 709C31 / 102A 6. Peptide or its derivative according to any one of claims 1, 4 and 5 or its acid addition salt, wherein R is hydrogen is. 7. Peptide according to any one of claims 1 and 4 to 6 or a salt or acid addition salt thereof, wherein R is the Is the hydroxyl group of the! -Carboxyl group of the G-terminal amino acid residue. 8. Ester, amide, N-alkylamide or N, N-dialkylamide one Peptides according to claim 7 or their acid addition salts. 9. Pharmacologically or pharmaceutically acceptable salt or acid addition salt of a peptide or its Derivative according to one of claims 1 to 8. 10. A method for producing a peptide or its Derivative according to one of Claims 1 to 8 or its acid addition salt, characterized that a reagent of the general formula (II): RY ¹ -OH (II), wherein R has the meaning defined in formula (I) and Y ^{1 is} the radical (X ¹ ) _m , as defined in formula (I), and / or a partial sequence of radicals, with the radical (X) _m on the N- terminal end and from there corresponds to the general formula (I) with a reagent (III) t '' HY ² (III), 709831/1024 • S · wherein Y is the balance of the product defined above corresponds, reacts, whereby the reagents (II) and (III) are protected where appropriate and according to their suitability, and / or activated and then, if necessary and suitable, the protective group is removed from the product and / or converting the product to the base or to a salt or acid addition salt thereof. 11. Peptide or derivative thereof according to one of claims 1 to 8 or acid addition salt thereof, if they are produced by a method according to claim 10. 12. Pharmaceutical formulation, characterized in that it is a peptide according to a of claims 1 to 7 or its pharmacological and pharmaceutically acceptable salt, ester, amide, N-alkylamide or Ν, Ν-dialkylamide or a pharmacological and pharmaceutically acceptable acid addition salts thereof with a suitable carrier. 13 · Formulation according to claim 12, characterized that they are for oral, rectal, nasal, buccal, vaginal and parenteral administration suitable is. 14. Formulation according to Claim 12, characterized in that it is used for oral, rectal, 709031/1024 vaginal and parenteral administration is suitable. 15. Formulation according to claim 12, characterized in that it contains the peptide or its derivative or its acid addition salt in solution in an aqueous medium. 16. Formulation according to one of Claims 12 to 15, characterized in that it is in the form of dosage units. 17 · Formulation according to claim 16, characterized in that each dosage unit the peptide or its derivative or its acid addition salt in an amount of 0.125 / µg to 2 g as a peptide base. 18. Formulation according to claim 12, characterized in that it is in the form of a tablet suitable for oral administration. 19. A method for producing a formulation according to any one of claims 12 to 18, characterized in that the ingredients of the formulation are mixed and, if necessary, the product is brought into a certain form. 709031/1024