Linear or cyclic oligopeptides having affinity for opiate receptors, pharmaceutical composition

 

(57) Abstract:

Linear or cyclic oligopeptides having the primary amino acid sequence of the formula I

Tyr-X-Phe-Ley-Z

where X and Z - amino acids or their derivatives or their analogues, in which X and Z can be covalently linked, form a heterocyclic structure.

When the linear Oligopeptide, X-Ser, Gly, Pro, D-Ala, Z = Glu or its derivatives, when the cyclic Oligopeptide, X - 2,4-diaminobutane acid, Lys, Cys, Orn, a Z = Glu or its derivatives. The oligopeptides of formula I are potentially useful as analgesics to relieve pain and increase comfort of the individual. 2 c. and 3 C.p. f-crystals, 4 Il., table 2.

The invention relates to new oligopeptides having affinity to the opiate receptors, which may be linear or cyclic Pentapeptide with the primary sequence of amino acids in the skeletal Tyr-X-Hairdryer-S-Z, where X and Z denote amino acids or derivatives of amino acids and/or analogs, and where X and Z can be covalently linked, form a heterocyclic structure in which Z is selected from Cys, Glu, GLn or derivatives of Glu and GLn; X is selected from amino acids or amino acid analogs, such as Ser, Glu, D-Ala, D - or Z-farmatsevticheskii drugs, containing new oligopeptides, which are potentially useful as analgesics to relieve pain and improve comfort for individuals suffering from extraordinary stress or shock, and to reduce depression and possible treatment of persons suffering from opium addiction.

Physicians treating patients with deficiency of growth hormone with the help of human growth hormone, often report that their patients have a noticeable improvement compared with a control group not receiving treatment. Was found a statistically significant difference between these groups in terms of social isolation, physical activity, sleep, and emotional status /see Acta Paed. Scand. (Annex), I. 356, pages 55-59, S. Bjork and others, and Acta Paed. Scand (Appendix), so 356, pages 70-72, 1989, GA Mc Cauley/.

The clinic also observed some secondary effects on the Central nervous system /CNS/, in the treatment of human growth hormone. It has been suggested that opioide active peptide fragments released from the growth hormone can reach the Central nervous system, if the blood plasma of a person possesses proteolytic activity, is able to release them. If so what vidualistic, the human growth hormone affects the Central nervous system and that enzymatic released fragments can interact with opioid receptors.

A number of studies have shown that enzyme-treated preparations of proteins can include peptides with opioid activity, such as-casomorphin, zitohromna and hemamalini. -Casomorphin comes from peptone obtained in the decay of beta-casein, and was discovered earlier in Physiol. Chem., so 360 p. 1211-16, 1979, V. Brantl and others, Pharmacol. Sci., so 4, page 193, 1979, V. Brantl and others, Eur. J. Pharmacol., so 106, pages 213-214, 1884, V. Brantl and others, and J. Chin. Endocrinol. Metab., so 68, page 289-9, 1989, F. Nyberg, etc.

It was also shown that the obtained enzymatic processing of fragments of the mitochondrial cytochrome B contain zitohromna, other opioid peptides /see Eur. J. Pharmacol., so 111 page 293, 1985, V. Brantl and others/. The link to hemamalini see Eur. J. Pharmacol., 125, pp. 309-10, 1986, V. Brantl and other Opioid activity of these peptides was confirmed by testing their ability to inhibit electrically induced contractions of the drug longitudinal muscles and the nervous plexus of the muscular layer of the ileum of the Guinea pig, as well as studies with receptors.

Some cyclic oligopeptides, obladaushi the 7162-6; this article was discussed and prepared a number of cyclic analogs of enkephalins. Cyclic oligopeptides having affinity to opioid receptors, are disclosed in J. Med. Chem., so 35, 1992, pp. 3956-3961, P. Schiller and other U.S. Patent 4254024 (J. Stewart and others) discloses a class of tetrapeptides with opioid activity that has been proven to drug ileum of the Guinea pig General formula H-Tyr-X-Y-z is Another link to linear tetrapeptide linking opiate receptors are located in the European patent publication EP 350221.

In previous work we studied two different peptidases in terms of their ability to release fragments of human growth hormone that can interact with opioid receptors. These enzymes were commercially available trypsin and endopeptidase isolated from human blood plasma. The fragments were separated by liquid chromatography high-resolution reversed-phase and then studied analysis with opioid receptors made with synaptic plasma membranes from rat brain /cerebellum/. The results showed that the active receptor fragments were released by trypsin, and endopeptidase. About the Winky was detected, these fragments are less active compared with beta-casomorphine /fragments of casein peptone/. These findings were presented at the 4th Congress of the European neuroendocrinological Association (Santiago de Compostela, June 28-30, 1989).

When studied amino acid sequence of peptides obtained trypticase splitting of human growth hormone, it was noted that some sequence was similar to those of beta-casomorphin. These new oligopeptides with suspected opioid activity was a Tetra - or Pentapeptide with the sequence Tyr-Glu-LEU-LEU and Tyr-Ser-Hairdryer-LEU-GLn. These oligopeptides were synthesized and several modified in Pentapeptide, glutamine was replaced by glutamic acid. These peptides were then tested for affinity to opiate receptors with relatively-casomorphin /see table. 1/. Tests unexpectedly showed that the new Oligopeptide Tyr-Ser-Hairdryer-LEU-Glu had almost the same affinity for opiate receptors, as-casomorphin.

As a consequence, this result led us to a larger number of new oligopeptides, which was linear or cyclic analogues Tyr-Ser-Hairdryer-LEU-Glu. These new peptides p is covered in the aforementioned U.S. patent 4254024 /see table. 2/.

The present invention relates to new oligopeptides having affinity to opioid receptors, which are derived from sequences that exist in the natural human growth hormone. These new oligopeptides described General formula Tyr-X-Hairdryer-S-Z, where X and Z denote amino acids, their derivatives or analogs in which X and Z can be covalently linked to form cyclic compounds

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If the Oligopeptide is linear, X is Ser, Glu, Pro, AMC /TRANS-(4-aminomethyl)-cyclohexane carboxylic acid) or D-Ala, and Z is Glu or GLn or their derivatives.

Some preferred linear oligopeptides according to the present invention are Tyr-Ser-Hairdryer-LEU-Glu, Tyr-Ser-Hairdryer-LEU-Glu-NH2, Tyr-D-Ala-Hairdryer-LEU-Glu, Tyr-Pro-Hairdryer-LEU-Glu. These linear oligopeptides can be easily prepared, using the following examples.

Cyclic oligopeptides of the present invention can be collisioning with the side chain of the amino acid or by oxidation of two cysteine groups.

To obtain analogues Tyr-Ser-Hairdryer-LEU-Glu cyclic structure of the amino acid is serine, must be replaced with D - or L-2,4 replaced with glutamine, glutamic acid or their derivatives or cysteine.

In General, the cyclic formula

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according to the present invention can be used following amino acids: X = D - or L-2,4-diaminobutane acid (D - or L-Dame), D-Orn, D - or L-Lys or D - or L-Cys, and Z = Depth or its derivatives or CIS, with the proviso that if X = D - or L-Cys, Z=CIS.

Preferred cyclic oligopeptides according to the present invention are Tyr-cyclo (D-Lys-Hairdryer-Lei-Gli) with a peptide bond between the alpha-carboxyl group of glutamic acid and Epsilon-amino group of lysine, Tyr-cyclo (D-diaminobutane acid-Hairdryer-LEU-Glu) and cyclic peptides

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which tsiklitiria oxidation of two cysteine groups.

These cyclic oligopeptides have a heterocyclic structure, related enkephalins, and described by J. De Maio, etc. in the above article.

In the studies described in example 3 and table. 1 and 2, it is clear that the oligopeptides of the present invention have high affinity to opioid receptors and especially - and-receptors. It was also shown that cyclic oligopeptides are functional agonists and have a high biologists is Anenii with normorphine /table. 2/.

Linear peptides showed in comparison with the cyclic peptides significantly lower biological activity, which may impart properties to act as a partial agonist at opiate receptors or, in certain circumstances, as antagonists.

It should be noted that the biological activity of linear peptides significantly reduced, even in those that have high binding affinity to the receptors. Estimated partial agonists inhibited agonistic reaction normorphine and called cyclic peptides equally functional antagonists.

Linear and cyclic oligopeptides of the present invention provide a new opportunity for the preparation of drugs for pain relief, to enhance the comfort of patients suffering from shock or stress, or for the treatment of depression, for introducing persons affected by the violation levels of endogenous morphine and opiate analogues or, potentially, for the treatment of opiomania. The specialist can easily find additional pharmacological methods of use of individual oligopeptides of the present invention, which caused their properties agonists, stannah new forms of oligopeptides. It is possible to make oral, percutaneous and/or parenteral dosage forms with suitable carriers and/or solvents and standard stabilizers and activators.

New oligopeptides can be easily prepared in the form of medicines for different routes of administration such as oral, nasal, parenteral, enteral or transbukkalno.

Various modifications and equivalents of the present invention, such as salts and derivatives of oligopeptides of the present invention, be apparent to specialists and are within the scope of the present invention. The present invention also is not limited to the specific examples and variants of the implementation described in this document.

Fig. 1 shows a typical diagram of liquid chromatography high-resolution products tripticase cleavage of human growth hormone (Crescormon). The distribution of activity against opiate receptors are represented by dark bars.

Fig. 2 shows a sample liquid chromatography high resolution receptor activity using Genotropinas the substrate triptyches the P CLASS="ptx2">

Fig. 3 and 4 show the study of the binding invented oligopeptides. The drawings show the distribution curves of the binding of Tyr-Ser-Hairdryer-LEU-Glu and Tyr-Gli-Lei-Lei membranes of the rat, using as labels (3H)D-AGO /Fig. 3/ and (3H)D-AD-L /of Fig. 4/.

Table. 1 represents the initial data binding oligopeptides of the present invention compared with-casomorphin; PL. 2 represents the results of a study of the affinity to opioid receptors and activity of oligopeptides of the present invention in comparison with the existing data for tetrapeptides.

Example 1. Enzymatic degradation of growth hormone.

Preparations of human growth hormone (Crescormonand Genotropin, m units) were supplied by Kabi Pharmacia AB /Stockholm, Sweden/. Crescormonwas isolated from frozen human hypophysis, while Genotropinwas prepared using gene technology. Trypsin treated TRNC, from the pancreas of cattle was obtained from the company Sigma, St. Louis, Missouri, USA/. Chromatographic materials Sephadex G-100 and Sephadex G-25 /PD-10/ set by the company Pharmacia /Uppsala, Sweden/. All other chemical reagents and Rasta">

20 ml of plasma collected from non-pregnant and not being in the postpartum period in women of childbearing age, was fractionally on a column of Sephadex G-100 /5 90 cm/. The column was suirable 20 mm Tris-HCl, pH 7,4, and collecting 20 ml fractions at a speed of elution of 80 ml/h Aliquots /1 ml fractions were absoluely on columns with Sephadex G-25 /PD 10/ and liofilizirovanny before analysis on enzymes. Active fractions were collected, pooled and kept frozen until the beginning of further research. Further purification was performed by chromatography with DEAE-Separate CZ-6B. Column /2 12 cm/ balanced 20 mm Tris-HCl, pH 7.4 and after application of the sample was suirable linear gradient of NaCl /0 - 0,5 M/, containing the same Tris-HCl buffer. Fractions of 10 ml were collected at a speed of elution of 100 ml/h and processed as described above prior research on enzymes.

Liquid chromatography high resolution.

Liquid chromatography high-resolution reversed-phase was performed using Pharmacia /LKB (see F. Nyberg and others, J. Chromatogr. so 359, 1986, pp. 541-551) equipped with a column Spherisorb TSK-ODS-120 DT /4,6 250 mm, particle size 5 µm/. The column was suirable linear gradient of acetonitrile /15 - 60%/, containing 0.04% of tri elution 0.5 ml/min and evaporated prior to study receptors.

Enzymatic cleavage.

Lyophilized trypsin or enzymatic fraction of plasma was dissolved in 100 to 200 μl of a 0.4 M solution of ammonium bicarbonate /pH 7.8/ and incubated with 0.2 - 1.5 mg of human growth hormone at 37oC for 5 to 8 h in a final volume of 250 μl. The reaction was stopped by adding 1 ml of ice-cold methanol. The sample is evaporated in a Savant concentrator Vac /Hicksville, new York, USA/ before further study using liquid chromatography high-resolution reversed-phase.

Results.

Fig. 1 shows a typical GHUR-the chromatogram tripticase splitting hormone human (Crescormon). As you can see, there were two peaks with receptor activity. When the substrate used Genotropinthe sample distribution of receptor activity showed some differences /Fig. 2/. Great pic, suirvey in 31 fractions, continued to dominate. However, the peak observed in 18 fractions cleavage of the drug Crescormon/Fig. 1/, almost fell, as shown in Fig. 2. The only explanation can be the fact that the drug Crescormoncontains more detalizirovannym forms of the hormone, and such forms may be the ys. Acta., so 625, 1980, pages 255-260, F. Nyberg and others/. The plasma enzyme gave a few receptore-active fragments, marked with radioreceptor studies GWHR.

After separation on a column of Sephadex G-100 was found that this enzyme was elyuirovaniya at the position corresponding to a protein with molecular weight of 100-110 ked. Further purification of the enzyme plasma was achieved by ion-exchange chromatography on DEAE-sepharose, in which the enzyme was elyuirovaniya when NaCl concentration of about 0.1 M Receptore-active enzymes released by the enzyme plasma differed from active fragments obtained trypticase splitting with respect to their behavior GWHR chromatography.

It was noted that some parts of the fragments of human growth hormone obtained trypticase splitting, were similar to the amino acid sequence-casomorphin. Partial amino acid sequencing of fragments of human growth hormone obtained trypticase splitting, found that one peptide contained the sequence Tyr-Ser-Hairdryer-LEU-GLn.

Example 2. Preparation of oligopeptides of the present invention.

The oligopeptides of the present invention was originally from politiceskih of pentapeptides overall structure Tyr-X-Hairdryer-LEU-Z using the techniques, described in examples 2.1-2.3.

Example 2.1. Synthesis of Tyr-X-Hairdryer-LEU-Glu (X=Ser I, D - Ala II, Pro III).

For the synthesis of peptides was used by standard solid-phase method using synthesizer Beckman 990. Amino acids were purchased from company Bachem. Inc. , California. The phenolic group of tyrosine defended 2,6-dichlorobenzyl, the hydroxyl group of serine was protected by benzyl and gamma-carboxyl group of glutamic acid was atrificial to cyclohexylamino ether.

Upon completion of the last cycle, the peptide was extracted from the resin and completely removed the protection processing anhydrous liquid HF at 0oC for 60 min in the presence of anisole /30 ml HF and 3 ml of anisole for 1 g resin/. After removal of HF and thorough drying in vacuum, the resin was washed with ether and was extracted with acetic acid /10%/ and the extracts were dried by freezing. The crude peptide was purified by gel-filtration on a column of Fractogel TSKHW-40 or PGM 2000 with acetic acid or triperoxonane acid as eluent. The final product was obtained in lyophilized form. The homogeneity of the peptides was tested by TLC /silica gel 60F-254 Merck; I n-butyl alcohol/acetic acid/EtOAc/water: 1/1/1/1; II pyridine /EtOAc/acetic acid/water: 5/5/1/3; X = Ser Ro, 24 h/ / mass spectrometry, will believe. FAB, made on a mass spectrometer with double focusing (Jeol. Japan/.

Example 2.2. Synthesis of Tyr-Ser-Hairdryer-LEU-Glu-NH2.

This peptide was synthesized on 4-methylbenzhydrylamine resin in exactly the way described in example 2.1. MBHA-resin /0.46 mmol/ g, 1,74 g, Nova Biochem., Switzerland/ reacted with BOC-Glu gammatocopherol ether. The crude product was purified by gel filtration on a column of Fractogel TSK HW-40 0.1% TFU as eluent. TLC: Rf(I) 0,76, Rf(II) 0,79; amino acid analysis: Tyr 0,99; Ser 0,99; Hairdryer 1,01; Lei 1,00; Chap 0,99; FAB-MCM/Z 657,2 [M + H]+.

Example 2.3. Synthesis of Tyr-cyclo(-Liz-Hairdryer-LEU-Glu-).

The synthesis was performed by a solid phase method for the resin of 4-alkoxybenzyl alcohol using the standard Fmoc Protocol. -Amidofunctional groups protected fertilityscore group, except-amidofunctional group Tyr defended benzyloxycarbonyloxy group. -Carboxyl Glu-amino group of Lys and the phenolic group of Tyr protected by benzyl, tert-butyloxycarbonyl and banspy protected, in addition to the-amino group of the Lys and the-carboxyl group of Glu. The cyclization was carried out in DMF at a concentration of 0.1 mm peptide benzotriazol tetramethylurea hexaflurophosphate /gbtu/ and N-ethyldiethanolamine. The cyclic peptide was deprived of the protective group by catalytic hydrogenation at atmospheric pressure in methanol with 10% Pd on charcoal as catalyst. The peptide was characterized using amino acid analysis, idestroy chromatography and high resolution FAB mass spectrometry.

Example 3. Learning new oligopeptides.

In the first study using the described methods were synthesized peptide Tyr-Ser-Hairdryer-LEU-GLn with the replacement of GLn to GLA, and a shorter fragment Tyr-Ser-Hairdryer-Lei and used to study their binding to - opioid receptors.

Receptor study was performed according to Zife Sci., so 16, 1975, p. 1979, Z. Terenius, etc., Brain Res., so 259, 1983, pp. 267-274, F. Nyberg and others , using synaptic membranes of rat taken from whole rat brain without cerebellum, and 3H-labeled dihydromorphine as competing radioligand. Each measurement consisted of a calibration curve with Met-enkephaline and binding activity of the tested fractions expressed in EC the species in the study binding in Red.Peptides, so 34, 1991, pp. 169-179, E-L. Glamsta, etc. used (3H)-(D-Ala2, Mean4,Gli-ol5-enkephalin (D-AGO or D-AMGA) and (3H)-(D-Ala2D-S5-enkephalin (D-AD-L) was purchased from Amersham (Buckinghamshire, England). D AGO - or D-AMGA is ligand-receptor, while D-AD-L is a typical agonist-receptor.

The calculated inhibition constants are listed in table.1. Data show that pentapeptidnogo fragment has a great affinity for-and K-receptors compared with a shorter fragment of growth hormone. Activity Tyr-Ser-Hairdryer-LEU-Glu against receptor was the same as in-casomorphin-5 /see table.1/.

The inhibition constants (Ku), in the table. 1 is defined as the concentration of peptide that leads to a 50% block labeled ligand. In the publication " -casomorphins and related peptides," ed. F. Nyberg and others, pp. 65-75, "Selective peptides --antagonists, analogs of absorbine-casein as a test substance for the study of opioid receptors", S. Loukas, etc. are disclosed various inhibiting peptides and their activity against opiate receptors. In "Regulatory peptides", T. 34, 1991, pp. 169-179 (E-L, Glamsta and others) discloses the inhibition constants for cusomer aniu fragments, able to interact with the opiate receptors. It is also obvious that the blood plasma of a person possesses proteolytic activity capable of release of this hormone peptides active against opiate receptors, which, if they pass through the blood-brain barrier, can affect the Central nervous system /CNS/. In practice, in clinical therapy of human growth hormone watched some secondary effects on the Central nervous system /not published/. Thus, we can assume that the peptide fragments that are active against opiate receptors, release of growth hormone, can reach the Central nervous system and cause these effects.

For tests listed in the table.2, to prepare a number of new pentapeptides and peptides according to example 2. These peptides were used for tests with receptors and biological studies on electrically stimulated ileum slices of the Guinea pig. Studies with receptors was performed as described above, with D-AMGA as radioligand receptors. In studies with (3H)-D-AMGA specific binding was supplanted by the various test substances (10-5M-10-10M/. We calculated the oxygen is you want to make Cmaxwith the help of computer programs /Ligand, Biosoft, Cambridge, United Kingdom/. In studies with drugs ileum of the Guinea pig used techniques and materials, the disclosure Regul. Pept., so 34, 1991, pp. 169-179 /E-L, Glamsta and others/ and The Hemorphins, Compr. Summaries of Uppsala Dissertations from the faculty of pharmacology 108, Acta Unisers. Ups. Uppsala, 1993, E-L. Glamsta. The comparative value of the activity in relation to standard connections, normorphine was determined in that study.

Table. 2 shows that the oligopeptides of the present invention have a high binding affinity against receptors. It should be noted that cyclic oligopeptides have high affinity for these receptors, as well as high opioid activity, suggesting a potent agonistic activity.

Linear Pentapeptide the present invention also have high affinity for the receptors, but reduced biological activity, as evidenced by the results of the test drugs ileum of the Guinea pig. It is possible to Express in this regard, the assumption that these compounds are partial agonists or functional antagonists.

Differences of the values of the constants Engibarov the techniques. However, the relative magnitude of the activity of different compounds in each dimension are the most interesting and informative.

Studies have shown the generation of new oligopeptides, originally derived from trypticase fragments of human growth hormone, which have affinity to the opiate receptors and opioid activity high power.

These new compounds, therefore, have high pharmaceutical potential and give you the opportunity to create new tissue-selective drugs with activity against opiate receptors, potentially with reduced side effects.

Data binding were obtained in experiments with inhibition /dual definition/ definition of parameter binding by computer programs EBDA/Ligand. Was selected as one model for site /Tyr-Pro-Hairdryer-Per-Gli =-casomorphin-5-man/.

1. Linear or cyclic oligopeptides having affinity for opiate receptors, having the primary amino acid sequence of the formula I

Tyr - X - Phe - Leu - Z

where X and Z - amino acids or their derivatives or their analogues, in which X and Z can biohd Oligopeptide is linear, X is chosen from the amino acids Ser, Gly, Pro, D-Ala, and Z = Glu or amino;

b) when the Oligopeptide is cyclic, X is chosen from 2,4-diaminoalkanes acid, Lys, Cys, Orn, D - or L-form and Z = Glu or its derivatives, or Cys, with the proviso that if X = Cys, and Z = Cys.

2. Linear oligopeptides of formula I under item 1, having an affinity for - and-opiate receptors.

3 Linear oligopeptides of formula I on p. 1, representing Tyr - Ser - Phe - Leu - Glu; Tyr - Ser - Phe - Leu - Glu NH2; Tyr - DAla - Phe - Leu - Glu; Tyr - Pro - Phe - Leu - Glu.

4. Cyclic oligopeptides of formula I on p. 1, representing

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5. Pharmaceutical composition having affinity for opiate receptors and including an active ingredient and suitable carriers and/or solvents, characterized in that it contains as active ingredient at least one of oligopeptides on PP.1 to 4 in an effective amount.

 

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