DE2732451A1 - Peptide morphine agonists - for use as analgesics, sedatives, antitussives, etc. - Google Patents

Abstract

Peptides of formula R-(X1)m-(X2)n-X3-X4-X5-X6-(X7)r-(X8)p-(X9)q-R1(I) and their salts, esters, amides, N-alkyl - and N,N-dialkylamides and acid-addn. salts. In the formula X1 and X2 are D or L basic amino acid radicals, X3 is a D or L radical of formula R2(CH2)a-(CHW1)b-CHW-CO; R2 is phenyl or opt. substd. 1, 4-cyclohexadien-1-yl or opt. benzyloxy ring-substd. a=0-2 and b=0 or 1, provided that a=1 and b=0 when R2 is cyclohexadienyl, one of W and W1 is NR3 and the other is H, provided that W=NR3 when b=3; R3 is H, alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl or carboxyalkynyl; X4 and X5 are glycyl or D or L C-propargylglycyl, alanyl, alpha-alkylalanyl, beta-alanyl, valyl, nor valyl, leucyl, isoleucyl, nor leucyl, prolyl, hydroxyprolyl, tryptophyl, asparaginyl or glytaminyl, each opt. N2-substd. by alkyl. X6 is e.g. glycyl or histidyl, or is as X3. X9 is e.g. D or L seryl, or Beta-homomethionyl, or as defined for X6. X8 is a F or L basic amino acid radical or D or L seryl threonyl, phenylalanyl or tyrosyl; X9 is glycyl, o D or L basic amino acid radical, or D or L seryl or threonyl; R is H, aralkyl, alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl or carboxyalkynyl; R1 is the OH gp. of the 1 - COOH radical of the C-terminal amino acid, or this 1 - COOH radical is replaced by CH2OR4 or 5-tetrazolyl opt. 1- or 2-substd. by alkyl or benzyl; R4 is H or alkanoyl; m, n, p, q and r are each 0 or 1, provided that p=q=0 and X4 is in the D form when r=0. Excluded from the above definition are peptides of formula (Ia) and their derivs. H-X3-Gly-Gly-X6-X7-OH(Ia) where X7 is L-leucyl or L-methionyl and either (a) X3 is L-tyrosyl or L-3, 5-diiodotyrosyl and X6 is L-phenylalanyl or (b) X3 is L-tyrosyl and X6 is L-4-chlorophenylalanyl. Cpds. (I) are morphine agonists useful as analgesics sedatives, antitussives of respiratory stimulants and antidiarrhoeal agents.

Description

Peptide compounds, processes for their preparation and these

Medicinal preparations containing compounds claimed July 27, 1976 - Great Britain - No. 31194t 6 Priorities: November 23, 1976 - Great Britain - No. 48821/76 February 9, 1977 - Great Britain - No. 5247/77 The invention relates to novel peptide compounds, processes for their preparation and containing these compounds Medicinal preparations.

The present invention relates to peptide compounds of the general formula I R1R2Tyr - B - Gly - Phe - W (I) in which R1 is a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 2 to 10 carbon atoms, an alkynyl radical with .2 to 4 Carbon atoms, a cycloalkylmethyl group with 4 to 8 carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl group, R2 denotes a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, W denotes the group -NR8R9 or the group -A-R3, where R8 is a an alkyl radical with hydrogen atom, / 1 to 10 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms, a radical -CH (CN OH) -alkyl with 1 to 5 carbon atoms in the alkyl radical, a cycloalkyl (C3 6) -alkyltC1 5) radical, a phenylalkyl radical with 1 to 5 carbon atoms in the alkyl radical, a radical ~ CpH2pXCqH2q + l with the meanings p = 2 to 6, q = 1 to 9 and X = oxygen or sulfur atom, the phenyl group or the group -CH (CN OH) ( C. ) 2SCH3, R9 denotes a hydrogen atom, the phenyl group or an alkyl group with 1 to 10 carbon atoms or a phenylalkyl group with 1 to 6 carbon atoms in the alkyl group and the group -NR8R9 also denotes the pyrrolidino, piperidino, morpholino, thiomorpholino or the piperazino group which are optionally substituted by alkyl radicals with 1 to 3 carbon atoms or phenyl groups, A denotes GMethionine, L-leucine, L-isoleucine, L-norleucine or L-valine group, R3 denotes the radicals -oR4, -NR4R5, L-proline- or L-proline-NR4R5, where R4 and R5 are hydrogen atoms or alkyl radicals with 1 to 3 carbon atoms, B either, when W is the radical -NR8R9, for the D-serine-, D-proline -, D-valine, D-norvaline, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-tryptophan, phenylalanine, D-methionine or the D-threonine group, the latter also in the form of their alkyl ethers with 1 to 4 carbon atoms, or a di-alkyl-alanine radical or the radical -NH-CR6R7-CO, where R6 is an alkyl radical having 1 to 5 carbon atoms and R7 is a hydrogen atom or the methyl group and the radical preferably has the D configuration, or the radical with the meaning of n = 2 to 5, or, if W is the radical -A-R3, stands for the D-methionine, D-serine, D-threonine or the D- -aminobutyric acid group and Phe on the nitrogen atom at least one alkyl radical having 1 to 10 carbon atoms can be substituted, and their acid addition salts.

Phe is preferably substituted by at least one methyl group. Furthermore, the allyl group is an alkenyl radical and the propargyl group is an alkynyl radical preferred.

According to a particular embodiment, the present invention provides peptide compounds of the general formula I in which R1 is a hydrogen atom, the propargyl group, an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 3 to 5 carbon atoms or a cycloalkylmethyl radical with 4 to 8 carbon atoms R2 represents a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, W represents the radical -NR8R9 or the radical -A-R3, where R8 is an alkyl radical with 3 to 6 carbon atoms or the radical - (CH2) 3SCH3 is R9 is a hydrogen atom, A the L-methionine, L-leucine, EIsoleucine, L-norleucine or the L.valine group, R3 represents the radicals -oR4, -NR4R5, L proline-OR4 or L-proline-NR4R5, where R4 and R5 Are hydrogen atoms or alkyl radicals with 1 to 3 carbon atoms, B either, when W is the radical -NR8R9, for the D-serine, D-threonine, D-proline, D-phenylalanine or the D-methionine group or the radical -NH-CR6R7CO, where R6 is an alkyl radical having 1 to 5 carbon atoms and R7 is a hydrogen atom or the methyl group and the remainder preferably has the D configuration, or the remainder with the meaning of n = 2 to 5, or, if W is the radical -A-R3, stands for the D-methionine, D-serine, D-threonine or the di-aminobutyric acid group, and their acid addition salts.

Preferred peptide compounds of the general formula I are those of the general formula Ia in which R1 is a hydrogen atom, the propargyl group, an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 4 to 8 carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl group, R2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms means B for the D-serine, D-proline, D-phenylalanine, D-methionine or the D-threonine group, the latter also in the form of their alkyl ethers with 1 to 4 carbon atoms, or the remainder -NH-CR6R7-C0, where R6 is an alkyl radical having 1 to 5 carbon atoms and R7 is a hydrogen atom or the methyl group and the radical preferably has the D configuration, or the radical where n has the numerical value 2 to 5, R8 is an alkyl radical with 1 to 10 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms, a radical -CH (CHOH) -alkyl with 1 to 5 carbon atoms in the alkyl radical, a cycloalkyl (C3 6 ) -alkyl (C1 5) radical, a phenylalkyl radical with 1 to 5 carbon atoms in the alkyl radical, a radical ~ CpH2pXCqH2q + l with the meanings p = 2 to 6, q = 1 to 5 and X = oxygen or sulfur atom, the phenyl group or the group -CH (CH2OH) (CH2) 2SCH3 and R9 denotes a hydrogen atom, the phenyl group or an alkyl group with 1 to 10 carbon atoms or a phenylalkyl group with 1 to 6 carbon atoms in the alkyl group, where the group -NR8R9 also denotes the pyrrolidino-, Piperidino, morpholino, thiomorpholino or the piperazino group, which may be optionally substituted by alkyl radicals having 1 to 3 carbon atoms, and their acid addition salts.

Furthermore, preferred peptide compounds of the general formula I are those of the general formula Ia in which R1 is a hydrogen atom, the benzyl group, an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 10 carbon atoms or an alkynyl group with 2 to 4 carbon atoms, R2 denotes a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, B denotes D. -Alanine, D-valine, D-norvaline, D-leucine, D-isoleucine, D-norleucine, D-proline, D-tryptophane group or a D-cL-alkylalanine residue, R8 for is a hydrogen atom or an alkyl radical with 1 to 10 carbon atoms, R9 is a hydrogen atom or an alkyl radical with 1 to 10 carbon atoms, where the radical -NR8R9 can also be the pyrrolidino, piperidino or the morpholino group, and Phe on the nitrogen atom by at least one Alkyl radical can be substituted with 1 to 4 carbon atoms, and their acid addition salts.

Most preferred are the peptide compounds of the general formula Ia in which R1 is a hydrogen atom, the methyl, cyclopropylmethyl, cyclobutylmethyl, allyl, dimethylallyl or the phenethyl group, R2 is a hydrogen atom or the methyl group, B for the D-alanine, D-leucine, D-valine -, D-dc-amino butyric acid or the i-amino-isobutyric acid group or the rest where n has the numerical value 2 to 5, R8 represents the phenyl group, an alkyl radical with 1 to 8 carbon atoms, a phenylalkyl radical with 1 to 5 carbon atoms in the alkyl radical or the radical -CpH2 gCqH2q + 1, where p has the numerical value 3 to 6 , q has the number 1 to 4 and X is an oxygen or sulfur atom, and R9 is a hydrogen atom, the phenyl group, an alkyl group with 1 to 5 carbon atoms or a phenylalkyl group with 1 to 5 carbon atoms in the alkyl group, and their acid addition salts.

Those in the description and claims for amino acid derivatives Symbols used are commonly used in peptide chemistry like this in the journal "Biochem. J." 126: 773 (1972). All amino acid residues have the natural or the L-configuration, unless otherwise stated.

Another object of the present invention are medicinal preparations, the a peptide compound of the general formula I or its salts, if appropriate together with phramacologically compatible carrier materials, diluents and / or excipients.

The peptide compounds according to the invention show a pharmacological one Effectiveness when attached to preparations of transmurally stimulated vas deferens of Mice are studied as described by G. Henderson, J. Hughes, and H. Kosterlitz in "Brit-.J.

Pharmacol. "46 (1972), pp. 764-766. that show activity in this test are local anesthetics, sedatives for smooth muscle, adrenergic neuron blockers, presynaptic oG receptor stimulants, ß-stimulants and agonist narcotics. The invention Peptide compounds can therefore be used in humans where the aforesaid Funds are applied. In addition, since the compounds according to the invention are peptides they can be used as intermediates in the manufacture of purulent peptides which have such amino acid sequences.

The compounds according to the invention can by customary processes peptide chemistry.

Thus, the connections can be made by coupling together appropriately protected and activated amino acids, usually at the terminal carbon atom, either by the classical methods in solution or by solid phase methods or by coupling fragments of suitable ones way generate protected peptides.

Details regarding selection of protecting groups and procedures for their introduction as well as suitable reaction conditions for the formation of amido (peptide) bonds and cleavage of the protective groups can be found in the literature below are: (a) Houben-Weyl "Methods of Organic Chemistry, Volume 16, Parts I and II, Synthesis of peptides (Thieme-Verlag 1974); (b) Schröder & Lübke "The Peptides", Academic Press (1965).

So you can the peptide compounds of general formula I thereby produce that a compound of the general formula II Y - M1 - OH (11) in Y is an appropriate N-protecting group and M1 is an appropriately protected one Amino acid or peptide residue means with a compound of the general formula XII H - M2 - Q (III) in the M2 a suitably protected amino acid or Is a peptide residue and Q is a suitable agent for protecting the carboxyl group, condensed. This condensation of the compounds of the general formulas II and III can be carried out either with or without conventional methods of peptide synthesis Isolation of the activated compound that of the compound of the general formula II corresponds to achieve. Splitting off either the protecting group Y or the protective group Q from the coupling product then provides a compound those analogous to the compounds of the general formula III or of the general formula II is then in turn with a corresponding compound of the general formula II or III can be coupled. This process is repeated until the desired peptide has been produced.

The following examples illustrate the invention. The following abbreviations are used here: Boc tert-butyloxycarbonyl But tert-butyl Z benzyloxycarbonyl ONSu N-hydroxysuccinimido DCCI dicyclohexylcarbodiimide DCU dicyclohexylurea HONSu N-hydroxysuccinimide NMM N-methylmorpholine-DMF dimethylformamide DCHA-tosylamine 1,2-methylmorpholine-amide-amide-DCHA Tosylate TMG Tetramethylguanidine Abu Dg-aminobutyric acid Cpm Cyclopropylmethyl Aib cl -amino-isobutyric acid The various compounds and intermediates are examined by means of thin-layer chromatography on plates made of silica gel GF254 using the following solvent systems: Lauric acid systems, ratio 7B, ethyl acetate, pyridine, acetic acid, water 60: 20: 6 : 11 7C ethyl acetate, pyridine, acetic acid, water 120: 20: 6: 11 7D ethyl acetate, pyridine, acetic acid, water 240: 20: 6: 11 8A chloroform, isopropanol 3: 1 3A chloroform, methanol, acetic acid, water 60:18 : 2: 3 Example 1 1> -Tyrosyl-D-alanylglycyl-L-phenylalanine-3-methyl-butylamide This compound is nac h made according to the following scheme: (a) N-tert-Butyloxycarbonyl-0-tert-butyl-Ltyrosyl-D-alanine (I) 2.5 g of BOC-Tyr (But) -OH are dissolved in DME. The solution is cooled in an ice-salt bath and then 0.853 g of HONSu and 1.53 g of DCCI are added. The temperature of the reaction mixture is then allowed to rise to room temperature and the mixture is stirred overnight. The DCU is then filtered off and the solvent is evaporated. The residue is dissolved in 5 ml of DMF and a solution of 0.66 g of D-alanine in 5 ml of DMF and 1 ml of water in the presence of 0.86 g of TMG is added to the solution at room temperature.

The reaction mixture is stirred overnight and the solvent is evaporated and treated the residue with 100 ml of water. The aqueous solution is used twice extracted with 50 ml of ethyl acetate and then with 10 percent citric acid pH 4 acidified.

The mixture is then extracted twice with 100 ml of ethyl acetate each time and washes the combined organic extracts with water until they are free from acid and dry them over anhydrous sodium sulfate. After evaporation of the solvent the gummy substance obtained is crystallized from ethyl acetate.

1.3 g (= 43% of theory) of the dipeptide derivative (I) are obtained from Mp. 186 to 1870C.

Rf (7C) = 0.65; Rr (8A) = 0.25.

(b) Benzyloxycarbonyl-glycyl-L-phenylalanine (II) 20 g of Z-Gly-ONSu become to a solution of 12.36 g of phenylalanine in 50 ml of DMF and 5 ml of water in the presence of 8.69 g TMG given. The solution is stirred for 18 hours at room temperature.

Then you work the reaction mixture in a manner analogous to how protruding specified under (a). The product obtained is crystallized from a mixture of ethyl acetate and petroleum ether. 22 g (= 95% of theory) of the dipeptide derivative are obtained (II) of m.p. 123.5 to 1240C.

Rf (7D) = 0.3.

(c) Benzyloxycarbonyl-glycyl-L-phenylalanine-3-methyl-butylamide (III) 2 g of Z-Gly-Phe-OH and 0.588 g of isoamylamine are dissolved in 15 ml of DMF and placed in an ice-salt bath chilled. Then 1.42 g of HONSu and 1.28 DCCI are added and the temperature is left of the reaction mixture rise to room temperature. Filtered after stirring for 18 hours the DCU is removed and the solvent is evaporated. Then dissolve the residue in 150 ml of ethyl acetate, wash the solution three times with 50 ml of saturated sodium bicarbonate solution each time, three times with 50 ml of 10 percent citric acid each time, then until acid-free with water and finally with saturated sodium chloride solution. The organic Phase is dried over anhydrous sodium sulfate and evaporated. You get a solid which recrystallizes from a mixture of ethyl acetate and petroleum ether will. 1.7 g (= 70% of theory) of compound (III) of melting point 128 bis are obtained 129 ° C.

(d) N-tert-Butyloxyearbonyl-O-tert-butyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanine-3-methylbutylamide (V) (i) 1.5 g of Z-Gly-Phe-NH-i-Am in 15 ml of DMF are overnight at room temperature in the presence of 0.67 g of p-toluenesulfonic acid monohydrate and 0.175 g of a 10 percent strength Hydrogenated palladium-carbon catalyst. After filtering off the catalyst steams the solvent is removed and the residue is triturated with cold water. The tosylate salt (IV) is filtered off and dried over P205 under reduced pressure. M.p. 1250C.

(ii) 0.53 g BOC-Tyr (But) -D-Ala-OH and 0.6 g TosA lyǧ-Phe-NH-i-Am are dissolved in 3 ml of DMF. The solution is cooled in the EisSeuz bath and then with 0.328 g HONSu and 0.29 g DCCI and then with 0.131 g NMM (1.31 ml of a 10 percent Solution in DMF). Then the temperature of the reaction mixture is allowed to rise Rise room temperature and stir the mixture for 18 hours. Then filtered one from the DCU, evaporated the solvent and the residue works as in the Preparation of the compound (III) indicated on. After recrystallizing from a A mixture of ethyl acetate and petroleum ether gives the compound (V) in one yield of 0.68 g (= 77% of theory) with a melting point of 180 to 1820C.

(e) L-Tyrosyl-D-alanylglycyl-L-phenylalanine-3-methylbutyl-amide (VI) 0.65 g of BOC-Tyr (But) -D-Ala-Gly-Phe-NH-i-Am are used for 45 minutes at room temperature Treated 5 ml of a 4 M hydrogen chloride solution in ethyl acetate. Then will the solvent evaporated. The residue is triturated with Xther and filtered.

Yield: 0.53 g. This residue is placed on a silica column (48 cm x 2.5 cm) chromatographed with the 7C solvent system. The one after the chromatography The residue obtained is dissolved in 15 ml of 1-M hydrochloric acid and freeze-dried. Yield: 0.4 g, m.p. 156 to 161 ° C.

Rf (7C) = 0.4.

Example 2 N-Methyl-L-tyrosyl-D-alanyl-glycyl-L, phenylalanine-3-methylbutyl-amide This compound is prepared according to the following reaction scheme: (a) N-Methyl-N-tert-butyloxycarbonyl-0-tert-butyl-L-tyrosyl -D-alanine Analogously to the method described in Example 1 (a), this dipeptide is prepared by converting 2.5 g of N- Me-N-BOC-Tyr (But) -OH in its ester activated with ONSu and prepared by coupling the product obtained with 0.731 g of D-alanine in the presence of 0.954 g of TMG. The dipeptide is recrystallized from a mixture of ethyl acetate and petroleum ether. Yield: 2 g; Mp. 109 to 110 ° C.

Rf (7D) = 0.50.

(b) N-methyl-N-tert-butyloxycarbonyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-3-methyl-butyl-amide The abovementioned compound is analogous to the process given in Example l (d) (ii) prepared by adding 0.846 g of N-Me-N-BOC-Tyr (But) -D-Ala-OH with 0.928 g of Tos (3Gl p-Phe-NH-i-Am in DMF using 0.454 g DCCI and 0.506 g HONSu in the presence of 0.202 g of NMM (2.02 ml of a 10 percent solution in DMF). After working up a rubber-like substance is obtained which solidifies when rubbed with ice water. Yield: 1.2 g.

(c) N-methyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanine-3-methyl-butyl-amide 0.6 g of N-Me-N-BOC-Tyr (But) -D-Ala-Gly-Phe-NH-i-Am are 40 minutes at room temperature treated with an excess of a 4 m hydrogen chloride-ethyl acetate solution. Afterward the solvent is evaporated. The residue is placed on a silica column (45 cm x 2.5 cm) chromatographed with the solvent system 7C. The residue will freeze dried. 0.28 g of a white solid with a melting point of 90 ° to 940 ° C. is obtained.

Rf (7B) = 0.50.

The table below gives details of further peptide compounds of the general formula I which have been prepared by the methods described in the preceding examples or by other methods known in peptide chemistry. The Rr values were determined using solvent systems 7B, 7C or 3A. Table 1 1 e "- Fp. Der Example compounds RWte Hydrochloride 3 H Tyr D-Ala Gly Phe N (Me) t-amyl 78: 0.4 1590 4 Me Tyr NAla Gly Phe N (Me) i-amyl 7B: 0135 1350 5 H Tyr D-Ala Gly Phe NH (CH2) 2Ph 78: 014 1500 6 Me Tyr q = Ala Gly Phe NH (CH2) 2Ph 78: 04 1220 7 H Tyr D-Ala Gly Phe NH (CH2) 3SMe 7C: 0a35 1ngO 8 Me Tyr OAla Gly Phe NH (CH2) 35Me 7C: 0155 1250 9 H Tyr D-Ala Gly Phe NH (CH2) 3Ph 7C: 0.2 138-140 10 Me Tyr D-Ala Gly Phe NH (CH2) 3Ph 7C: 0162 124-131 11 H Tyr D-Ala Gly Phe N9Ph 70: 066 1660 12 Me Tyr D-Ala Gly Phe 7B: 0t86 154 13 cpm Tyr D-Ala Gly Phe NH t-amyl 7C: 0.5 1600 14 Allyl Tyr D-Ala Gly Phe NH i-amyl 7C: 0135 15 H Tyr D-Ala Gly Phe 78:01 24 16 H Tyr D-Met Gly Phe NH i-amyl 78: 0t69 17 H Tyr NAIa Gly Phe NH Me 78: 0t21 18 H Tyr D-AbuGly Phe Met NH2 3A: 046 19 H Tyr lfAla Gly Phe N (i-amyl) 2 20 Opm Tyr D-Ala Gly Phe NH (CH2) 3SMe 21 H Tyr D-Ala Gly Phe N (Me) (CH2) 3SMe 22 Me Tyr D-Ala Gly Phe N (Me) (CH2) 35Me 23 H Tyr D-Ala Gly Phe N (Me) (CH2) 3Ph 24 Opm Tyr D-Ala Gly Phe NH (CH2) 3Ph 25 H Tyr D-Ala Gly Phe NH CH (CH2OH) (CH2) 25Me 26 H Tyr D-Ala Gly Phe NH CHMe (CH2) 2SMe 27 H Tyr D-Ala Gly Ph Phe ^ NH, sg; Hp, CHMe2 Continued table Example connections 28 H Tyr Atb Gly Phe NH (CH2) 3SMe 29 H Tyr Atb Gly Phe NH t-amyl 30 Me Tyr D »Ala Gly MePhe N (Me) i-amyl 31 H Tyr Atb Gly Phe NH (CH, Ph 32 Me2 Tyr D-Ala Gly Phe NH {-amyl 33 Ph (CH2) 2 Tyr D "Ala Gly Phe NH t-amyl 34 Propargyl Tyr D = Ala Gly Phe NH i-amyl 85 H Tyr D "Ala Gly Phe NH Pr 36 H Tyr D »Ala Gly Phe NH octyl 87 H Tyr D-Ala Gly Phe NH cyclo pentyl 88 H Tyr D-Met Gly Phe 89 H Tyr D-SerGly Phe NH t-amyl 40 H Tyr D "Ser (O-Me) Gly Phe NH t-amyl 41 H Tyr D-Ala Gly Phe h50 42 H Tyr D-Ala Gly Phe 43 H Tyr l} Phe Gly Phe NH t-amyi 44 H Tyr D "Ala Gly Phe NH CH (CH 2 O H) i-butyl 45 H Tyr D "Met Gly Phe Met NHPr 46 H Tyr E> Met Gly Phe Met Pro NH2 47 H Tyr D-Ser Gly Phe Leu Pro NHPr 48 H Tyr D-Thr Gly Phe Nle Pro O Me 48 H Tyr D-Met Gly Phe Ile NH2 50 H Tyr Abu Gly Phe Leu Pro N Me2 51 Me Tyr D-Ser Gly MePhe NH i-amyl 52 H Tyr D-Met Gly MePhe According to the aforementioned research method by Henderson and co-workers, male white mice (OLA MFI strain) are killed by a blow on the head. The vas deferens are removed from the mice and placed in an isolated organ bath of 2.5 ml. Then a twitching stimulus is generated by stimulation at a low frequency (0.1 Hz) with 0.1 m / sec straight current impulses. The stimulus is attenuated by a wide variety of pharmacologically active agents, such as local anesthetics, smooth muscle sedatives, neuron adrenergic blockers, presynaptic receptor stimulants, β stimulants, and agonist narcotics; however, it is possible to distinguish between a weakening of a twitch caused by agonist narcotics and a weakening that has been produced by other mechanisms by performing the test in the presence of the antagonist narcotic 'Naloxon2' (iN-Allyl-7, 8-dihydro-14-hydroxy-normorphinone) repeated. This test has proven to be an extremely specific method for determining agonist narcotics and antagonistic activity (see J. Hughes, H. Kosterlitz and FM Leslie in "Brit.J.Pharmacol." 51, pp. 139-140).

The test compound is dissolved in distilled water so that one can a starting solution with a concentration of 1 mg / ml is generated.

Then serial dilutions are made using Krebs solution Prepare concentrations of 10, ug, 1 rg and 0.1 pg / ml. the Compound is made by adding 0.1 to 0.3 ml of these solutions to the organ bath examined. Then a dose stimulus curve is drawn up and that of dihydromorphine compared. In this test, the compound of the invention possesses H-Tyr-D-Ala-Gly-Phe-NH-i-Am approximately 11 times more activity than dihydromorphine, based on weight, while the compound according to the invention Me-Tyr-D-Ala-Gly-Phe-NH-i-Am approximately one Shows 9-fold activity The compounds according to the invention are also with regard to activity against diarrhea according to the method of A.L.A. Boura and A.E. Fitzgerald in "Brit.J.Pharmac." 26, p. 307 (1966). Owns this test the compound of the invention Tyr-D-Ala-Gly-Phe-NH-i-Am when given intravenously to mice is administered, an ED50 value of 4.7 mg / kg body weight, while the inventive Compound Me-Tyr-D-Ala-Gly-Phe-NH-i-Am had an ED50 value of 0.39 mg / kg body weight Has.

The medicinal preparations can be in a suitable form for an oral Administration or in a suitable form for parenteral administration. Such oral medicinal preparations can be in the form of capsules, tablets, granules or liquid preparations such as elixirs, syrups or suspensions are present.

Medicinal preparations intended for parenteral administration can be in the form of sterile preparations, such as solutions in water or physiological Saline solution.

For the sake of simplicity and dosage accuracy, the medicinal preparations preferably used in single dosage forms.

Claims (18)

P atent claims 1. Peptide compounds of the general formula I RlR2Tyr - B - Gly - Phe - W (I) in which R1 is a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 2 to 10 carbon atoms, an alkynyl radical with 2 to 4 carbon atoms, a cycloalkylmethyl group with 4 to 8 carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl group, R2 denotes a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, W represents the group -NR8R9 or the group -A-R3, where 8 is an alkyl radical with R8 a hydrogen atom, 1 to 10 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms, a -CH (CH2OH) -alkyl radical with 1 to 5 carbon atoms in the alkyl radical, a cycloalkyl (C36) -alkyl (C15 ) Radical, a phenylalkyl radical with 1 to 5 carbon atoms in the alkyl radical, a radical ~ CpH2pXCqH2q + l with the meanings p = 2 to 6, q = 1 to 5 and X = oxygen or sulfur atom, the phenyl group or the group -CH ( Is CH20H) (CH2) 2SCH3, R9 denotes a hydrogen atom, the phenyl group or an alkyl radical with 1 to 10 carbon atoms or a phenylalkyl radical with 1 to 6 carbon atoms in the alkyl radical, and the radical -NR8R9 also denotes the pyrrolidino, piperidino, morpholino, thiomorpholino or the piperazino group, which is optionally through Alkyl radicals with 1 to 3 carbon atoms or phenyl groups are substituted, A denotes the L-methionine, Ia-leucine, L-isoleucine, L-norleucine or the L-valine group, R3 denotes the radicals -oR4, -NR4R5 , L-proline-OR4 or L-proline-NR4R5, where R4 and R5 are hydrogen atoms or alkyl radicals with 1 to 3 carbon atoms, B either, if W is the radical -NR8R9, for the D-serine-, D-proline- , D-valine, D-norvaline, D-alanine, D-leucine, D-isoleucine, D-norleucine, D-tryptophan, D-phenylalanine, D-methionine or the D-threonine group , the latter also in the form of their alkyl ethers with 1 to 4 carbon atoms, or a Dd-alkyl-alanine radical or the radical -NH-CR6R7-CO, where R6 e in is an alkyl radical with 1 to 5 carbon atoms and R7 is a hydrogen atom or the methyl group and the radical preferably has the D configuration, or the radical with the meaning of n = 2 to 5, or, if W is the radical -A-R3, for the D-methionine, D-serine, D-threonine or the D4-amino-butyric acid group and Phe on the nitrogen atom may be substituted by at least one alkyl radical having 1 to 10 carbon atoms, and their acid addition salts. 2. Peptide compounds of the general formula I, in the Phe on the nitrogen atom is substituted by at least one methyl group. 3. Peptide compounds of the general formula I in which the radical R1 is the allyl group. 4. Peptide compounds of the general formula I in which the radical R1 is the propargyl group. 5. Peptide compounds of the general formula R1R2-Tyr-B-Gly-Phe-W in which R1 is a hydrogen atom, the propargyl group, an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 3 to 5 carbon atoms or a cycloalkyl radical with 4 to 8 carbon atoms , R2 represents a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, W represents the radical -NR8R9 or the radical -A-R3, where 8 R8 is an alkyl radical with 3 to 6 carbon atoms or the group - (CH2) 3SCH3, R9 is a Hydrogen atom denotes, A represents the L-methionine, L-leucine, L-isoleucine, L-norleucine or L-valine group and R3 represents the radicals -oR4, -NR4R5, L-proline-OR4 or L-proline -45 4 NR R, where R4 and R5 are hydrogen atoms or alkyl radicals with 1 to 3 carbon atoms, and B either, when W is the radical -NRR, for the D-serine, D-threonine, D-proline, D-phenylalanine or the D-methionine group or the radical -NH-CR6R7-CO, where R6 is an alkyl radical having 1 to 5 carbon atoms and R7 is a W is hydrogen atom or the methyl group and the remainder preferably has the D configuration, or the remainder with the meaning of n = 2 to 5, or, if W is the radical -A-R3, for the D-methionine, D-serine, D-threonine or the D-amino-butyric acid group, and their Acid addition salts. 6. Peptide compounds of the general formula Ia in which R is a hydrogen atom, the propargyl group, an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkylmethyl group with 4 to 8 carbon atoms or a phenylalkyl group with 1 to 3 carbon atoms in the alkyl group, R2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, B denotes the D-serine, D-proline, D-phenylalanine, D-methionine or the D-threonine group, the latter also in the form of their alkyl ethers with 1 to 4 carbon atoms, or the remainder - NH-CR6R7-CO, where R6 is an alkyl radical having 1 to 6 carbon atoms and R7 is a hydrogen atom or the methyl group and the radical preferably has the D configuration, or the radical with the meaning of n = 2 to 5, R8 represents an alkyl radical with 1 to 10 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms, a radical -CH (CH 2 O H) -alkyl with 1 to 5 carbon atoms in the alkyl radical, a Cy cl oalkyl (C-3 ~ 6) -alkyl 5) radical, a phenylalkyl radical with 1 to 5 carbon atoms in the alkyl radical, a 'radical ~ CpH2pXCqH2q + 1 with the meanings p = 2 to 6, q = 1 to 5 and X = oxygen or sulfur atom, the phenyl group or the group -CH (CH20H) (CH2) 2SCH3 and R9 is a hydrogen atom, the phenyl group or an alkyl group with 1 to 10 carbon atoms or a phenylalkyl group with 1 to 6 carbon atoms in the alkyl group or the group -NR8R9 also the pyrrolidino, piperidino, morpholino, thiomorpholino or the piperazino group, which may be substituted by alkyl radicals having 1 to 3 carbon atoms, and their acid addition salts. 7. Peptide compounds according to claims 1 to 4 with the general formula Ia in which R1 is a hydrogen atom, the benzyl group, an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 10 carbon atoms or an alkynyl group with 2 to 4 carbon atoms, R2 denotes a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, B denotes D. -Alanine, D-valine, D-norvaline, D-leucine, D-isoleucine, D-norleucine, D-proline or the D-tryptophane group or a Dd, alkyl-alanine residue, R8 for a Hydrogen atom or an alkyl radical with 1 to 10 carbon atoms, R9 is a hydrogen atom or an alkyl radical with 1 to 10 carbon atoms, where the radical -NR8R9 can also be the pyrrolidino, piperidino or morpholino group, and Phe on the nitrogen atom by at least one alkyl radical with 1 to 10 carbon atoms may be substituted, and their acid addition salts. 8. Peptide compounds of the general formula Ia in which R1 is a hydrogen atom or the methyl, cyclopropylmethyl, cyclobutylmethyl, allyl, dimethylallyl or the phenethyl group, R2 is a hydrogen atom or the methyl group, B is D-alanine, D-leucine-> D-valine- , Dlr (-amino-butyric acid- or the dGAmino-isobutyric acid group or the rest represents, in which n has the numerical value 2 to 5, R8 stands for the phenyl group, an alkyl radical with 1 to 8 carbon atoms, a phenylalkyl radical with 1 to 5 carbon atoms in the alkyl radical or the radical CpH2pXCqH2q + 1, where p has the numerical value 3 to 6 , q has the number 1 to 4 and X is an oxygen or sulfur atom, and R9 is a hydrogen atom, the phenyl group, an alkyl group having 1 to 5 carbon atoms or a phenylalkyl group having 1 to 5 carbon atoms in the alkyl group, and their acid addition salts. 9. L-Tyrosyl-D-alanyl-glycyl-L-phenylalanine-3-methyl-butylamide. 10. L-Tyrosyl-D-alanyl-glycyl-L-phenylalanine-3-thiomethylpropyl-amide. 11. N-Methyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanine-3-methyl-butyl-amide. 12. N-Methyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanine-3-thiomethyl-propyl-amide. 13. L-Tyrosyl-D-alanyl-glycyl-L-phenylalanine-N1 -methyl-N '-3-methyl-butyl-amide. 14. L-Tyrosyl-D-alanyl-glycyl-L-phenylalanine-N'-methyl-N'-3-thiomethyl-propyl-amide. 15.N-Methyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanln-N'-methyl-N ' -3-methyl-butyl-amide. 16.N-methyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanine-N'-methyl-N ' -3-methyl-butyl-amide. 17. Verrahren for the preparation of the peptide compounds according to the claims 1 to 16, characterized in that a compound of the general formula II Y - M1 - OH (11) in which M1 is an amino acid or peptide residue and Y is an N-protecting radical, with a compound of the general formula III H - M2 - Q (III) in which M2 is an amino acid or peptide residue and Q is a suitable one Rest for the protection of the carboxyl group means condensed, whereby the compound of general formula II can be activated, and then the protective groups of the compound obtained splits off. 18. Medicinal preparations containing a peptide compound according to the claims 1 to 17 or their acid addition salts, optionally together with pharmacological compatible diluents, carrier materials and / or excipients.