Tri-, tetra-, penta -, and polypeptides and their therapeutic use as an antidepressant agent

 

(57) Abstract:

In the application described new peptides used to treat patients suffering from depression. These new peptides are modifications Tripeptide hormone IF received, including, in the result of the conversion residues from the terminal amino group, residues with terminal carboxyl group and internal amino acid residues, including the addition or substitution of amino acid residues and conversion of peptide bonds and functional side groups of the respective amino acid residues. For the treatment of patients suffering from depression, tri-, Tetra-, Penta -, and polypeptides of the present invention can be applied individually or in composition. 5 S. and 104 C.p. f-crystals, 3 ill., table 1.

Heterogeneous unipolar and bipolar depression is a common psychiatric disorder that is most likely due to neurochemical changes in the Central nervous system. In the past few decades, widespread in medicine for the treatment of unipolar depression has been the use of antidepressant drugs. The present invention relates to new peptides and their application endogenous depression is genetically determined biochemical disorder, leading to inability to withstand stress. This form of depression is often classified as unipolar depression, which is divided into a depressive phase of manic-depressive psychosis and agitated depression. Depressive phase of manic-depressive psychosis is characterized by slowing of psychomotor reactions when the subject to some extent inadequate interacts with the environment. On the other hand, agitated depression is characterized by increased inappropriate activity, such as increased heartbeat, compulsive movement of hands, etc.

Most likely that unipolar depression is a disorder which results in numerous heterogeneous changes in the brain. Specialists one of the scientific schools adhere catecholamine theory, according to which endogenous depression is caused by a decrease in the concentration of norepinephrine in the field of adrenergic receptor sites in the brain. It is also possible that endogenous depression is called absolute or relative deficiency of indolamine, namely 5-hydroxytryptamine, the receptor sites in the brain.

The treatment of endogenous depression is whitesage treat depression, include (1) tricyclic antidepressants, (2) inhibitors of monoamine oxidase (MAO) and (3) second generation antidepressants.

The first drug chosen to treat endogenous depression more than thirty years ago, were the tricyclic drugs. However, these drugs have had limited effectiveness, so two thirds of patients receiving tricyclic drugs, was not a favorable reaction. Tricyclic drugs have numerous side effects, including cholinergic blockade, heart complications, allergic reactions, dry mouth, constipation, blurred eyes, and tachycardia. The structure of the tricyclic drugs characterized by the presence of the tricyclic nucleus. Tricyclic antidepressants include imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, doxepin, and trimipramine. The metabolism of these tricyclic structures through oxidase with mixed functions. The resulting metabolites are pharmacologically active compounds.

With the 50-ies for the treatment of depression have used MAO inhibitors. These compounds are divided into hydrazides, for example, with C-N-N-slice (e.g., phenelzine, isocarb is of serious side effects.

Drugs for so-called second generation represent a group of new drugs, including amoxapine, maprotiline, fluoxetine, trazodone, and bupropion. Most of these drugs probably act the same way as tricyclic drugs.

Antidepressant drugs must cross the blood brain barrier in a pharmaceutically effective concentration. The capillaries of the Central nervous system, in contrast to the capillary bed, supplying other organs, have close ties with the endothelial cells of the cerebral cortex. It is known that the blood-brain barrier in humans is a lipid barrier without pores. Any potential antidepressant medication should be created so that the connection was able to overcome the blood-brain barrier. Compounds with low solubility in lipids, as well as vysokoerudirovannye connection, not able to leave the bloodstream to penetrate the extracellular fluid of the brain. Water-soluble compounds can cross the blood brain barrier only if there is a special membrane transport system. Conversely, for fat-soluble drugs the blood-brain bar the torus inhibition melanocytestimulating hormone and has the following chemical formula: shed-leucyl-glycinamide or Pro-Leu-Gly-NH2has numerous endocrine impact on the brain. In numerous animal models was also shown that the Tripeptide MIF is active in the treatment of depression.

Originally MIF was isolated from extracts of the hypothalamus bull (Nair and others , 1971, Biochem. Biophys. Res. Comm. 43(6): 1376-1381) and extracts of rat hypothalamus (Celis and others , 1971, Proc. Natl. Acad. Sci. USA 68(7): 1428-1433) and characterized. The activity of MIF is associated with suppression of release melanocytestimulating hormone, giovingo hormone, which is known to stimulate the production of melanin. None of the above publications is not intended to be and does not describe any antidepressant activity of MIF.

In U.S. patent 3708593 (issued in the name N. P. Plotnikoff 2 January 1973) described that MIF exhibits antidepressant activity against mice, which was established using the modified DOP-test (Everett and others, 1966, the OEWG. 1st. Int. Sym. Anti-depressant Drugs, page 164).

In U.S. patent 3795738 (issued in the name N. P. Plotnikoff 5 March 1974) described that MIF individually or in combination with other known drugs has increased activity against Parkinson's disease.

In U.S. patent 3931184 (issued in the name of C. G. Lex 6 anaysis by adding diethyl ether, getting a white crystalline precipitate of MIF. This clean MIF is collected, washed with ether and dried under vacuum before use.

In U.S. patent 4278595 (issued in the name of J. H. Cort 14 July 1981) described that the practical application of MIF prevents that MIF rapidly metabolized after administration. Due to this relatively short time-life MIF to obtain effective concentrations is needed injection of large amounts of MIF for extended periods of time. Cort describes similar MIF, characterized by the substitution of Leu at its D-isomer, to obtain similar MIF optional replace Pro pyro-Glu and optional alkylate terminal amide group of Gly-NH2. This analog may have the same antidepressant activity, as MIF, and increased stability. Cort describes the Tripeptide having the formula X-D-Leu-NH2-CH2-CONR1R2where X represents Pro or pyro-Glu and each of R1and R2independently from each other represents H or lower alkyl, preferably methyl or ethyl.

It was found that Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), which is a peptide having the origin of the brain has an effect on the passive mi residue Tight, that leads to the production of Ala-MIF-1, Leu-MIF-1 and Phe-MIF-1) were studied from the point of view of influence on behavior and locomotor activity (Hayashi and others, 1984, Pharmacology Biochemistry &Behavior 21: 809-812). Ala-MIF-1 and Phe-MIF-1, but not Leu-MIF-1, have an impact on the reaction of passive avoidance in rats. It was found that none of these peptides have no effect on the locomotor response.

Kastin and others, (1984, Pharmacology Biochemistry &Behavior 21: 767-777) showed that MIF-1 and Tyr-MIF-1 are active antidepressants. The activity level was determined using the test of the water-wheel, which is a modification of the swimming test Porsolt.

Kastin and others, (1985, Pharmacology Biochemistry &Behavior 23: 1045-1049) found that Tyr-MIF-1 and some analogues of Tyr-MIF-1 have antiopium action. Along with the Tyr-MIF-1, Phe-MIF-1 has been active as an inhibitor analgesic effects of morphine in rats.

Banks and others , (1986, Am. J. Physiol. 251 [Endocrine Metabolism 14]: E477-E482) revealed Mediaroom carrier transport system responsible for the delivery of Tyr-MIF-1 of the system of blood flow in the brain extracellular fluid.

Thus, there is a need in the design and development of modified small peptides for treatment of suffering from Decius barrier, without leading to side effects, inherent to most available, currently used antidepressant drugs.

The present invention relates to a modified small peptides for use as an antidepressant compounds. In accordance with the invention, these new peptides are used to treat patients suffering from depression. These transformations affect residues with a terminal amino group, remains with the terminal carboxyl group and the remains of internal amino acids and include accession and the substitution of amino acid residues and conversion of peptide bonds and functional side groups of the respective amino acid residues, as described in more detail below.

The subject invention are peptides having pharmacological activity.

Another subject of the invention are peptides that are suitable for the treatment of patients exhibiting symptoms of depression.

The hallmark of the invention is the synthesis and preparation of small peptides, characterized by new transformations, substitutions, accessions and/or divisions in the structure of the nucleus MIF, which have antidepressant activity.

the x, than the well-known antidepressants to reduce the potential for harmful side effects.

In one example embodiment of the invention small peptides according to the invention are tripeptides represented by the formula (1)

R1-Pro1-AA1-NR2-CH2-R (1)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is selected from the group including Trp, Orn, Lys, Leu, D-Leu, Arg, D-Arg or Il; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; R1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl; and R2denotes a hydrogen atom or a group of lower alkyl, preferably having 1-3 carbon atoms, provided that if RHS1denotes Pro and AA1represents Leu, both R1and R2cannot signify hydrogen, when R denotes carbamine for use in the treatment of depression in patients are the tripeptides of formula (1A)

Pro1-AA1-Gly-NH2, (1a)

where Pro1and AA1have the values described above for formula (1).

Preferred compositions of the tripeptides of formula (1A) include: RHS-Thr-Gly-NH2Pro-Arg-Gly-NH2Pro-D-Arg-Gly-NH2Pro-Lys-Gly-NH2Pro-Orn-Gly-NH2and Pro-Ile-Gly-NH2but not necessarily limited to.

Another example of the tripeptides of formula (1), declared for use in the treatment of depression in patients who are tripeptides of formula (1b)

R1-Pro1-AA1-Gly-NH2, (1b)

where Pro1, AA1and R1have the values described above for formula (1).

Preferred compositions of the tripeptides of formula (1b) include CIS - or TRANS-4-OH-Pro-D-Arg-Gly-NH2, CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2, CIS - or TRANS-4-OH-Pro-Arg-Gly-NH2, CIS - or TRANS-4-OH-Pro-Trp-Gly-NH2and CIS - or TRANS-4-thio-Pro-Leu-Gly-NH2but not necessarily limited to.

Another example of the tripeptides of formula (1), declared for use in the treatment of depression in patients who are tripeptides of formula (1C)

Prol-AAl-NR2-CH2-R, (1C)

where Pro1, AA1R and R2have the values described above for formula (odorata, if R denotes either a carboxyl group or a hydroxyalkyl group, since these compounds, i.e., Pro-Leu-NHCH2-CO2N (or Pro-Leu-Gly and Pro-Leu-NHCH2-CH2OH, do not fall under the scope of this invention, and also under one condition, that when Pro means Pro and AA1means Thr, R2cannot denote a hydrogen atom when R represents a hydroxyalkyl group, as Pro-Trp-NHCH2-CH2OH is a known connection. Preferred compositions of the tripeptides of formula (1C) include: Pro-Leu-N(CH3)CH2-CONH2(or Pro-Leu-Sar-NH2and Pro-Trp-NHCH2-CO2H (or Pro-Trp-Gly), but not necessarily limited to.

Another example of the tripeptides of the present invention, declared for use in the treatment of depression in patients who are tripeptides of formula (2)

R1-Pro1-AA1-Ala-R, (2)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is selected from the group Arg or D-Arg; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl; and R1denotes a hydrogen atom, a group of lower alkyl, pre is the Rupp, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

An example of the tripeptides of formula (2), declared for use in the treatment of depression in patients who are tripeptides of formula (2A)

Pro1-AA1-Ala-NH2, (2a)

where Pro1and AA1have the values described above for formula (2).

Preferred compositions of the tripeptides of formula (2a) include: Pro-Arg-Ala-NH2and Pro-D-Arg-Ala-NH2but not necessarily limited to.

Another example of the tripeptides of the present invention, declared for use in the treatment of depression in patients who are tripeptides of formula (3)

R1-Pro1-AA1-Tyr-R, (3)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1refers to the amino acid Orn; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, or dimethyl - or diethylaminopropyl.

An example of the tripeptides of formula (3), declared for use in the treatment of depression in patients who are tripeptides of formula (3A)

R1-RHS1-AA1-Tight-NH2, (3A)

where Pro1, AA1and R1have the values described above for formula (3).

Preferred compositions of the tripeptides of formula (3A) include: RHS-UCP-Tyr-NH2and CIS - or TRANS-4-OH-Pro-Orn-Tyr-NH2but not necessarily limited to.

The present invention also relates to tetrapeptides and their use for the treatment of depression. One embodiment of the invention relates to compositions of tetrapeptides with increased-end represented by the formula (4)

R1-Pro1-AA1-Gly-AA2-R, (4)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1represents Ile, Leu, Arg, D-Arg or Trp; AA2indicates the amino acid is selected from the group Trp or Taut; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 atoms of plastics technology: turning & is calamine or dialkylamino, preferably methyl or ethylamino, or dimethyl - or diethylaminopropyl.

An example of tetrapeptides formula (4), declared for use in the treatment of depression in patients who are tetrapeptide formula (4A)

R1-Pro1-AA1-Gly-AA2-NH2, (4a)

where Pro1, AA1, AA2and R1have the values described above for formula (4).

Preferred compositions of tetrapeptides formula (4a) include CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 1), CIS - or TRANS-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 2), CIS - or TRANS-4-OH-Pro-D-Arg-Gly-Trp-NH2, 3,4-degidro-Pro-D-Arg-Gly-Trp-NH2and 3,4-degidro-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 62), but not necessarily limited to.

Another example of tetrapeptides formula (4), declared for use in the treatment of depression in patients who are tetrapeptide formula (4b)

Pro1-AA1-Gly-AA2-NH2, (4b)

where Pro1, AA1and AA2have the values described above for formula (4).

Preferred compositions of tetrapeptides formula (4b) include: Pro-Il-Gly-Trp-NH2(SEQ ID NO: 3), 3,4-degidro-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 4), Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 5), Pro-Leu-Gly-Tyr-NH2(SEQ ID NO: 6), Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 7), Pro-Trp-Gly-Trp/P> Another example of tetrapeptide according to the invention are compositions of tetrapeptides with increased N-end represented by the formula (5)

R1-AA1-R2-Pro1-AA2-Gly-R, (5)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is selected from the group TGR, Tight or Phe; AA2indicates the amino acid is selected from the group Leu, Il or Thr; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and each R1and R2independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

An example of tetrapeptides formula (5), declared for use in the treatment of depression in patients who are tetrapeptide formula (5A):

Rl-AAl-R2-Prol-AA2-Gly-NH2, (5A)

where Pro1, AA1, AA2, R1and R and R2cannot denote a hydrogen atom, when AA1indicates Tight and AA2means TGR, because this connection, i.e., Tyr-Pro-Trp-Gly-NH2(SEQ ID NO: 54), is a known compound, and another, under one condition that, if Pro1denotes Pro and AA2represents Leu, both R1and R2cannot denote a hydrogen atom, when AA1represents Phe or Tight, because Phe-MIF-1 and Tyr-MIF-1 are known compounds. Preferred compositions of tetrapeptides formula (5A) include: Trp-Pro-Leu-Gly-NH2(SEQ ID NO: 10), Phe-Pro-Leu-Gly-NH2(SEQ ID NO: 11), 4-F-Phe-Pro-Leu-Gly-NH2(SEQ ID NO: 12), 4-Cl-Phe-Pro-Leu-Gly-NH2(SEQ ID NO: 13), 4-F-Phe-Pro-Ile-Gly-NH2(SEQ ID NO: 14), 4-F-Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 15), 4-F-h-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 16), Trp-Pro-Leu-Gly-NH2(SEQ ID NO: 17), Trp-Pro-Ile-Gly-NH2(SEQ ID NO: 18), Thr-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 19), Thr-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 20) and 4-CL-h-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 60), but not necessarily limited to.

The present invention also relates to pentapeptides and their use for the treatment of depression. In one embodiment, Pentapeptide according to the invention is a composition of pentapeptides with increased N-end submissions to the mean amino acid Pro or degidro-RHS, preferably 3,4-degidro-RHS; AA1and AA2each independently from each other represents an amino acid selected from the group Phe or Taut; AA3indicates the amino acid is selected from the group of Leu or Il; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

An example of pentapeptides formula (6) claimed for use in the treatment of depression in patients who are Pentapeptide formula (6A)

R1-AA1-AA2-R2-Pro1-AA3-Gly-NH2, (6a)

where Pro1, AA1, AA2, R1and R2have the values described above for formula (6).

Preferred compositions of pentapeptides formula (6A) include: 4-F-Phe-Tyr-Pro-Leu-Gly-NH2(SEQ ID NO: 21), 4-Cl-Phe-Tyr-Pro-Leu-Gly-NH2(SEQ ID NO: 22), Phe-Tyr-Pro-Leu-Gly-NH2le-Gly-NH2(SEQ ID NO: 26), Tyr-Tyr-Pro-Leu-Gly-NH2(SEQ ID NO: 27), Tyr-Tyr-Pro-Ile-Gly-NH2(SEQ ID NO: 28), Tight-Tight-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 29) and Tight-Tight-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 30), but not necessarily limited to.

Another example of Pentapeptide according to the invention are compositions of pentapeptides with simultaneously increased N-end and C-end represented by the formula (7)

R1-AA1-R2-Pro1-AA2-Gly-AA3-R, (7)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is selected from the group Phe or Taut; AA2indicates the amino acid is selected from the group Leu, Ile, Arg, D-Arg or Thr; AA3represents the amino acid Trp; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - impressie patients are Pentapeptide formula (7a)

Rl-AAl-R2-Prol-AA2-Gly-Trp-NH2, (7a)

where Pro1, AA1, AA2, R1and R2have the values described above for formula (7).

Preferred compositions of pentapeptides formula (7a) include: Phe-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 31), Tyr-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 32), Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 33), Phe-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 34), Phe-CIS - or TRANS-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 35), Tight-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 36), Tyr-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 37), Tight-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 38), Tyr-Pro-Trp-Gly-Trp-NH2(SEQ ID NO: 39), Tight-CIS - or TRANS-4-OH-Pro-Trp-Gly-Trp-NH2(SEQ ID NO: 40), 4-F-h-CIS - or TRANS-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 41), Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 42), 4-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 43), 4-F-h-CIS - or TRANS-4-OH-Pro-D-Arg-Gly-Trp-NH2, 3-F-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 66); 2-F-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 68); and 4-CL-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 61), but not necessarily limited to.

Another group of preferred compositions of pentapeptides formula (7a) is characterized optional conversion Pro1in degidro-RHS, before-Il-Gl-Thr-NH2(SEQ ID NO: 72) and 4-F-Phe-3,4-degidro-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 55), but are not limited to them.

Another group of examples falling within the scope of formula (7a), includes, but is not limited to, additional optional conversion AA2preferably Arg, His, Homo-Arg, L-ALLO-Il or canavanin; additional optional conversion R1and/or R2(preferably R1, preferably the amino group, carboxyl group, a nitro-group or a phosphonic group (preferably in the form of foston-TSU); additional optional conversion of heterocyclic nitrogen-containing ring Pro1preferably using CIS - or TRANS-4-one or Homo-RHS. Preferred peptides of formula (7a) are 4-NH2-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 63); 4-F-h-CIS - or TRANS-4-OH-Pro-His-Gly-Trp-NH2(SEQ ID NO: 64); 4-NO2-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 65); 4-CH3On-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 59); 4-F-Phe-CIS - or TRANS-4-OH-Pro-Homo-Arg-Gly-Trp-NH2(SEQ ID NO: 71); 4-F-Phe-Homo-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 69); 4-F-Phe-Homo-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 57); and 4-F-h-CIS - or TRANS-4-OH-Pro-L-ALLO-Ile-Gly-Trp-NH2(SEQ ID NO: 73).

Another example of Pentapeptide according to the invention ablauts is UP>1-Pro1-AA1-AA2-Gly-AA3-R, (8)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1and AA2each independently of the other denotes the amino acid from the group of Leu or Il; AA3represents the amino acid Trp; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

An example of pentapeptides formula (8), declared for use in the treatment of depression in patients who are Pentapeptide formula (8A)

Rl-Prol-AAl-AA2-Gly-Trp-NH2, (8A)

where RHS1, AA1, AA2and R1have the values described above for formula (8).

Preferred compositions of pentapeptides formula (8A) include: Pro-Il-Leu-Gly-Trp-NH2(SEQ ID NO: 44) and CIS - or TRANS-4-OH-Pro-Ile-Leu-Gly-Trp-NH2(SEQ ID N what begins as N-terminal amino acids, and C-terminal amino acids, the composition of pentapeptides or their pharmaceutically acceptable salts can be represented by the following formula (9):

R1-AA1-R2-Pro1-AA2-Gly-AA3-R, (9)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is Ala; AA2indicates the amino acid is selected from the group comprising Leu, Ile, Arg, D-Arg, Trp or canavanin; AA3represents the amino acid Trp; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1means peregrinae ring, preferably in the form of such a fragment as 3-(3-pyridyl); R2denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup, or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

The preferred composition of formula (9), which is not ledue the GOM example of carrying out the invention including adding as N-terminal amino and C-terminal amino acids, the composition of hexapeptides or their pharmaceutically acceptable salts can be represented by the following formula (10):

R1-AA1-R2-Pro1-AA2-AA4-Gly-AA3-R, (10)

where Pro1represents the amino acid Pro or degidro-RHS; AA1indicates the amino acid is selected from the group Phe or Taut; AA2indicates the amino acid is selected from the group comprising Leu, Ile, Arg, D-Arg, Trp or canavanin; AA3represents the amino acid Trp; AA4refers to the amino acid Gly or Il; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup, or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

The group p is tion with other peptides, see the description of the present invention, for the treatment of patients suffering from depression are characterized by addition of C-terminal amino acids Thr, optional conversion of heterocyclic nitrogen-containing ring Pro1preferably using CIS - or TRANS-4-Oh-group, the presence of a fluorine atom in position 4 in Phe; preferably Arg as AA2; TGR as AA3; and Il or Gly as AA4; and the fact that the C-terminal amide remains untransformed. The formula (10A) is depicted in the form of

R1-Phe-R2-Pro1-AA2-AA4-Gly-Trp-NH2, (10A)

moreover, the preferred peptides of formula (10A) include, but are not limited to, 4F-Phe-4-OH-Pro-Arg-Gly-Gly-Trp-NH2(SEQ ID NO: 58) and 4F-Phe-4-OH-Pro-Arg-Ile-Gly-Trp-NH2(SEQ ID NO: 67).

In another exemplary embodiment of the invention, including the addition of a N-terminal amino and C-terminal amino acids, the composition of heptapeptides or their pharmaceutically acceptable salts can be represented by the following formula (11):

Rl-AAl-R2-Prol-AA2-AA4-AA5-Gly-AA3-R, (11)

where Pro1represents the amino acid Pro or degidro-RHS, AA1indicates the amino acid is selected from the group Phe Il refers to the amino acid Thr; AA4and AA5indicate the amino acid Gly or Il; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup, or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl, or phosphonic group (preferably phosphotyrosine).

The preferred composition of formula (11) includes 4-F-Phe-4-OH-Pro-Arg-Gly-Ile-Gly-Trp-NH2(SEQ ID NO: 56), but is not limited to them.

In the scope of the present invention also assumes that the Gly in formulas (7) through (11) optionally may be substituted with Val or l.

The most preferred compositions of the present invention contain small peptides, which exhibit higher activity in the swimming test Porsolt presented in this optici, Pentapeptide, Hexapeptide and heptapeptide. The formula of these the most preferred peptides described in this description may be represented in the form

R1-Phe-Pro1-AA2-AA3-NH2< / BR>
for tetrapeptide, in which R1preferably denotes a halogen atom, most preferably a fluorine atom or chlorine, carboxyl group, amino group or a nitro-group, and all conversions are preferably relate atom C4 in Phe; Pro1means arranged in descending order of preference 3,4-degidro-RHS, Homo-Pro, CIS - or TRANS-4-OH-Pro, or Pro; AA2preferably indicates Il, Leu, or Arg; and AA3preferably represents Gly or Thr.

Other preferred tetrapeptides of the present invention is the Pro-Ile-Gly-Trp (SEQ ID NO: 3).

Formula most preferred pentapeptides, hexapeptides and heptapeptides, also described in this description may be represented in the form

R1-Phe-Pro1-AA2-Gly-AA(n)-AA3-NH2< / BR>
where R1preferably denotes a halogen atom, preferably fluorine atom or chlorine, carboxyl group, amino group or a nitro-group, all of which change the activity of 3,4-degidro-RHS, Homo-Pro, CIS - or TRANS-4-OH-Pro, or Pro; AA2preferably represents Arg, Ile, Leu or His, and Arg is the most preferred; AA(n)indicates 0-2 amino acid residue when n=1, the preferred amino acid residue is Gly, and when n=2, the preferred Il-Gly, Ile-Ile, or Gly-Gly; and AA3preferably indicates Thr or Gly, and Thr is the most preferred.

The present invention also relates to chemical combinations of polypeptides and/or overlapping chemical combinations of any of the peptides represented by the formulas (1) to (11) intended for use in the treatment of depression in patients. These chemically combined polypeptides preferably have at least about three to at least approximately ten modified and/or unmodified amino acids.

The present invention also relates to mixtures of peptides represented by the formulas (1) to (11), with known antidepressant compounds, such as amitriptyline, fluoxetine (Prozac) and sertraline (Zoloft). To a person skilled in the art it is obvious how to create various mixtures of small peptides according to the present IO the present invention can be presented in the form of compositions with a suitable pharmaceutical carrier for administration in vivo to a patient using the standard method, known in the art so that pharmacologically effective concentration reached the scene. Suitable routes of administration include oral (introduction through the mouth or oral), sublingual, parenteral (e.g. intravenous, intraspinal, intrathecal, intraventricularly, epidermal, intracisternally, intracutaneous or intradermal, subcutaneous or intramuscular), nadgorny or transdermal, intranasal or rectal and inhalation (using poly - or microdispersed aerosol), but is not limited by them.

The following terms used in this description have the following meanings.

Pro - L-Proline; Leu - L-leucine; Gly - L-glycine; Tight - L-tyrosine; Ala - L-alanine; Arg - L-arginine; Lys - L-lysine; Phe - L-phenylalanine; Trp - L-tryptophan; Ile - L-isoleucine; Orn - L-ornithine; D-Arg - D-arginine; D-Leu - D-leucine; 3,4-degidro-RHS - 3,4-degidro-L-Proline; pyro-Glu - pyroglutamyl acid; Sar - L-sarcosine (N-methylglycine); 4-OH-Pro - 4-hydroxyproline; 4-thio-RGS - 4-thioproline; 2-F-Phe - 2-forfinally; 3-F-Phe - 3-forfinally; 4-F-Phe - 4-forfinally; 4-Cl-Phe - 4-chlorophenylalanine; 4-NH2-Phe - 4-aminophenylalanine; 3-(3-pyridyl)-l - 3-(3-pyridyl)alanine; Homo-Arg, Homo-arginine; Homo-RHS - d is you or-CO2N; hydroxyalkyl - alcohol group or-ROH, where R denotes the group of lower alkyl, preferably having 1-3 carbon atoms; carbamyl - 1oamide group, or-CONH2; allylcarbamate - 2oor 3oalkilirovanny amide group, or-CONR1R2where each R1and R2independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms; alkoxycarbonyl - ester group or-CO2R, where R denotes the group of lower alkyl, preferably having 1-3 carbon atoms; degidro - angiograph, which removed one or more hydrogen atoms; hydroxyl - alcohol group or is HE or ROH, where R denotes the group of lower alkyl, preferably having 1-3 carbon atoms; sulfhydryl - tylna group-SH or-RSH, where R denotes the group of lower alkyl, preferably having 1-3 carbon atoms; alkylamino - -other, where R denotes the group of lower alkyl, preferably having 1-3 carbon atoms; dialkylamino - -NR2where R denotes the group of lower alkyl, preferably having 1-3 carbon atoms; the patient includes any member of the animal Kingdom, the definition includes people, but is not limited to them is lnyh compositions of small peptides according to the invention and their pharmacological activity as anti-depressants. It is obvious that the invention is not limited presents as examples shown in the drawings, and are presented in table 1 variants of execution of the present invention, and variations in the scope of the following claims.

In Fig. 1 shows the average number of animals reacting appropriately in the swimming test Porsolt to the processing of selected compounds listed under the following numbers 1-15:

1) 4-F-Phe-3,4-degidro-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 55);

2) 4-F-Phe-4-OH-Pro-Arg-Gly-Ile-Gly-Trp-NH2(SEQ ID NO: 56);

3) 4-F-Phe-4-Homo-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 57);

4) Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 3);

5) 4-F-Phe-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 16);

6) Amitriptyline;

7) 4-F-Phe-4-OH-Pro-Arg-Gly-Gly-Trp-NH2(SEQ ID NO: 58);

8) 4-CH3O-Phe-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 59);

9) 4-Cl-Phe-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 60);

10) 4-F-Phe-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 41);

11) 4-F-Phe-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 43);

12) 4-OH-Pro-Ile-Gly-NH2;

13) Zoloft;

14) Prozac;

15) Pro-Leu-Gly-NH2.

In these examples, the peptides were injected at a concentration of 0.1 mg/ml

In Fig. 2 shows the difference between the average motion in the NGC and in groups of animals treated with selected Z-points calculated for the time of motion in animal groups treated with selected compounds listed under the numbers 1-15 described above for Fig.1.

Fragment Tripeptide hormone having the General formula Pro-Leu-Gly-NH2otherwise known as L-prolyl-L-leucyl-glycine, factor inhibiting melanocytestimulating hormone, factor, inhibiting the release of melanotropin or MIF, as you know, has antidepressant activity. Usually in the literature MIF has been described as a Tripeptide having the structure of Pro-Leu-Gly-NH2or Pro-Leu-Gly-amide. In the present description MIF, which has the following chemical structure, known as Pro-Leu-Gly-NH2:

Pro-Leu-NHCH2CONH2or

< / BR>
In accordance with the invention, the conversion tripeptides patterns MIF produce new small peptides, used to treat patients suffering from depression. These transformations affect residues with a terminal amino group, remains with the terminal carboxyl group and the remains of internal amino acids and include accession and the substitution of amino acid residues and conversion of peptide bonds and functional side groups of the respective amino acid residues that more pedrobaraocampos (N-end), on the end with a free carboxyl group (C-end) or internal amino acid residues of the sequence kernel MIF, for the synthesis of small peptides according to the invention may(may) be selected(s) from the group comprising Ala, Arg, D-Arg, Gly, Ile, Leu, D-Leu, Lys, Orn, Phe, Pro, degidro-Pro, Sar, Trp and Tight, or any of the remaining amino acids. Conversion of carboxylic end of small peptides according to the invention may include optional substitution karbonilnoj (amide) group at the carboxyl end of the sequence kernel MIF on the carboxyl (acid) group, hydroxyalkyl (alcohol) group, alkoxycarbonyl (ester) group or acylcarnitine (alkilirovanny amide) group, etc., Converting the terminal amino group and the internal transformation of small peptides according to the invention can include an optional add or remove on heterocyclic, aromatic and other carbon residues of the amino alkyl groups, preferably alkyl groups having 1-3 carbon atoms, digitography (angiography), halogroup, a hydroxyl group, sulfhydryl groups, alkylamino or dialkylamino, etc. in Addition, the amino group of small peptides according to the invention can bitoy engineering obviously, these additions, substitutions, deletions and/or conversion may be carried out by conventional methods of synthesis of polypeptides and organic synthesis.

In the present description detailed data extensive biological experiments, supporting the following position: stated in the present description small peptides are expressed antidepressant activity, measured on the basis of the swimming test Porsolt. The "Example" section contains comparative data for the selected as examples of the peptides of the present invention and the known antidepressants amitriptyline, fluoxetine (Prozac) and sertraline (Zoloft), obtained in a series of outdoor tests Porsolt. Grouping of small peptides according to the invention in the form below formula is made for convenience only and should not be construed as limiting in any way the scope of the invention.

In one example implementation of the invention small peptides are tripeptides, characterized by optional substitution of the Leu residue in the sequence kernel MIF to an amino acid selected from the group including Trp, Orn, Lys, Arg, D-Arg or Il; optional substitution of residue Pro degidro-RHS, predpochtitelno, selected from a carboxyl group, hydroxyalkyl group, preferably hydroxymethylene group, alkoxycarbonyl group or alkilirovanny karbonilnoj group; optional conversion heterocyclic group or dihydroheterocodeine group terminal amino groups with substituent selected from the group including a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup; or aluminumcopper or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl; and/or optional conversion of hydrogen atoms at the nitrogen atoms of the amino acid peptide bonds using the group of lower alkyl, preferably having 1-3 carbon atoms.

This composition Tripeptide or its pharmaceutically acceptable salt can be represented by the following formula (1):

R1-Pro1-AA1-NR2-CH2-R (1)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1 is ilen group, carbamino group, acylcarnitine group or alkoxycarbonyl group; R1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl; and R2denotes a hydrogen atom or a group of lower alkyl, preferably having 1-3 carbon atoms, provided that when a Pro1denotes Pro and AA1represents Leu, both R1and R2cannot signify hydrogen, when R denotes carbamino (amide) group, because MIF is a known connection.

The following paragraphs describe the composition of tripeptides formula (1), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression.

The first group of preferred compositions of the tripeptides of formula (1), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression, x is the first amide group remain untransformed, can be represented by formula (la). The formula (1A) is represented in the form

Pro1-AA1-Gly-NH2, (1A)

where Pro1and AA1have the values described above for formula (1). The tripeptides of formula (1A) can be used individually or in combination with other peptides described herein, for the treatment of patients suffering from depression. The preferred compositions of the tripeptides of formula (1A) are Pro-Trp-Gly-NH2; Pro-Arg-Gly-NH2; Pro-D-Arg-Gly-NH2; Pro-Lys-Gly-NH2; Pro-Orn-Gly-NH2and Pro-Ile-Gly-NH2.

The second group of preferred compositions of the tripeptides of formula (1), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression, characterized by optional replacement of Leu, and, in addition, characterized by the optional conversion of the N-terminal nitrogen-containing heterocyclic ring Pro1, preferably in position C4 nitrogen-containing heterocyclic ring, preferably by adding CIS - or TRANS-hydroxyl group or a CIS - or TRANS-sulfhydryl groups, and the fact that the C-terminal amide group remains untransformed, can b who/BR> where Pro1, AA1and R1have the values described above for formula (1).

The preferred compositions of the tripeptides of formula (1b) are: CIS - or TRANS-4-OH-Pro-D-Arg-Gly-NH2; CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2; CIS - or TRANS-4-OH-Pro-Arg-Gly-NH2; CIS - or TRANS-4-one-RHS-Thr-Gl-NH2and CIS - or TRANS-4-thio-Pro-Leu-Gly-NH2.

The third group of preferred compositions of the tripeptides of formula (1), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression, characterized by optional replacement of Leu, optional conversion C-terminal amide group optional conversion C-terminal hydrogen atom of the nitrogen included in the peptide bond between Leu and Gly, and the fact that the N-terminal nitrogen-containing heterocyclic ring Pro1remains untransformed, can be represented by the formula (1C). The formula (1C) is depicted in the form of

Prol-AAl-NR2-CH2-R, (1C)

where Pro1, AA1R and R2have the values described above for formula (1), provided that, when Pro1denotes Pro and AA1represents Leu, R2cannot denote an atom in the i.e. Pro-Leu-NHCH2-CO2N (or Pro-Leu-Gly and Pro-Leu-NHCH2-CH2OH, do not fall under the scope of the present invention, and another, under one condition, that when Pro1denotes Pro and AA1represents Trp, R2cannot denote a hydrogen atom when R represents a hydroxyalkyl group, as Pro-Trp-NHCH2-CH2OH is a known connection. The preferred compositions of the tripeptides of formula (1C) are Pro-Leu-N(CH3)CH2-CONH2; and Pro-Trp-NHCH2-CO2H.

In another example embodiment of the invention additional tripeptides are characterized by replacement of Leu Arg or D-Arg; substitution of Gly at l; optional substitution of Pro at degidro-Pro, preferably 3,4-degidro-RHS; optional conversion C-terminal amide group with a functional group selected from the group comprising carboxyl group, hydroxyalkyl group, preferably hydroxymethylene group, alkoxycarbonyl group, or alkilirovanny carbamino group; optional conversion of the N-terminal nitrogen-containing heterocyclic ring Pro1with the help of a Deputy selected from the group including a group of lower alkyl, preferably having the CIS - or TRANS-4-OH-group, sulfhydryl group, preferably a CIS - or TRANS-4-togroup; or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl; and/or optional conversion of hydrogen atoms at the nitrogen atoms of the amino acid peptide bonds using the group of lower alkyl, preferably having 1-3 carbon atoms.

This composition Tripeptide or its pharmaceutically acceptable salt can be represented by the following formula (2):

R1-Pro1-AA1-Ala-R (2)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is selected from the group Arg or D-Arg; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl; and R1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

In the next paragraph describes the DAMI, described in this description, for the treatment of patients suffering from depression.

A group of preferred compositions of the tripeptides of formula (2), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression, characterized by the substitution of Leu and Gly and the fact that the N-terminal residue Pro1and C-terminal amide remain untransformed, can be represented by the formula (2A). The formula (2A) is represented in the form:

RHS1-AA1-Al-NH2, (2A)

where Pro1and AA1have the values described above for formula (2).

The preferred compositions of the tripeptides of formula (2A) are Pro-Arg-Ala-NH2and Pro-D-Arg-Ala-NH2.

In another embodiment according to the invention is small tripeptides are characterized by substitution of Leu at the UCP; substitution of Gly on Tight; optional substitution of Pro at degidro-Pro, preferably 3,4-degidro-RHS; optional conversion C-terminal amide groups with substituent selected from the group comprising carboxyl group, hydroxyalkyl group, preferably hydroxymethylene group, alkoxycarbonyl group, or alkilirovanny is and RHS1with the help of a Deputy selected from the group including a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup; or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl; and/or optional conversion of hydrogen atoms at the nitrogen atoms of the amino acid peptide bonds using the group of lower alkyl, preferably having 1-3 carbon atoms.

This composition Tripeptide or its pharmaceutically acceptable salt can be represented by the following formula (3):

R1-Pro1-AA1-Tyr-R, (3)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1refers to the amino acid Orn; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, halogen atom, predpochtitelno, preferably a CIS - or TRANS-togroup, or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

In the next paragraph describes compositions of the tripeptides of formula (3), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression.

A group of preferred compositions of the tripeptides of formula (3), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression, characterized by the substitution of Leu and Gly, optional conversion of the N-terminal nitrogen-containing heterocyclic ring Pro1and the fact that the C-terminal amide remains untransformed, can be represented by the formula (3A). The formula (3A) is depicted in the form of

R1-RHS1-AA1-Tight-NH2, (3A)

where Pro1, AA1and R1have the values described above for formula (3).

The preferred compositions of the tripeptides of formula (3A) are Pro-Orn-Tyr-NH2and CIS - or TRANS-4-OH-Pro-Orn-Tyr-NH2.

In another embodiment, of the image is inability Thr or Tight to Gly or by adding N-terminal amino acids Thr or Phe to Pro tripeptides, with the sequence kernel MIF; optional replacement of Leu Il, Arg, D-Arg or Thr; optional substitution of Pro at degidro-Pro, preferably 3,4-degidro-RHS; optional conversion C-terminal amide with substituent selected from the group comprising carboxyl group, hydroxyalkyl group, preferably hydroxymethylene group, alkoxycarbonyl group, or alkilirovanny carbamino group; optional conversion of heterocyclic nitrogen-containing ring Pro1and TGR and optional conversion of the aromatic rings of Phe with substituent selected from the group including a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup, or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl; and/or optional conversion of hydrogen atoms at the nitrogen atoms of the amino acid peptide bonds using the group of lower alkyl, preferably having 1-3 carbon atoms.


R1-Pro1-AA1-Gly-AA2-R, (4)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1means Il, Leu, Arg, D-Arg or Thr; AA2means Thr or Taut; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, digitography, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

In the next paragraph describes the composition of tetrapeptides formula (4), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression.

A group of preferred compositions of tetrapeptides formula (4), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression are characterized by addition of Thr or is anyone nitrogen-containing ring Pro1and the fact that the C-terminal amide remains untransformed, can be represented by the formula (4A). Formula (4A) is depicted in the form of

R1-Pro1-AA1-Gly-AA2-NH2(4a)

where Pro1, AA1, AA2and R1have the values described above for formula (4).

The preferred compositions of tetrapeptides formula (4a) are

CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 1);

CIS - or TRANS-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 2);

CIS - or TRANS-4-OH-Pro-D-Arg-Gly-Trp-NH2and

3,4-degidro-Pro-D-Arg-Gly-Trp-NH2.

Another preferred composition of tetrapeptide formula (4a) is 3,4-degidro-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 62).

The second group of preferred compositions of tetrapeptides formula (4), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression are characterized by addition of Thr or Tight to the C-terminal Gly, optional replacement of Leu and the fact that the N-terminal nitrogen-containing heterocyclic ring Pro1remains untransformed, can be represented by formula (4b). The formula (4b) is represented in the form

Pro1-AA1-Gly-AA2-NHEpothilone compositions of tetrapeptides formula (4b) are:

Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 3);

3,4-degidro-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 4);

Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 5);

Pro-Leu-Gly-Tyr-NH2(SEQ ID NO: 6);

Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 7);

Pro-Trp-Gly-Trp-NH2(SEQ ID NO: 8);

Pro-D-Arg-Gly-Trp-NH2and

Pro-Ile-Gly-Tyr-NH2(SEQ ID NO: 9).

In another example implementation, including the addition of N-terminal amino acids, the composition of tetrapeptides or their pharmaceutically acceptable salts can be represented by the following formula (5):

R1-AA1-R2-Pro1-AA2-Gly-R, (5)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is selected from the group TGR, Tight or Phe; AA2indicates the amino acid is selected from the group Leu, Il or Thr; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, hydroxyl group, sulfhydryl group or alkylamino or dialkylamino, predpochtitaemye of tetrapeptides formula (5), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression.

A group of preferred compositions of tetrapeptides formula (5), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression are characterized by addition of Thr, Tight or Phe to N-terminal Pro1, optional replacement of Leu, optional conversion of heterocyclic nitrogen-containing ring Pro1and Thr, and optional conversion of the aromatic rings of Phe and Tight and that the C-terminal amide remains untransformed, can be represented by the formula (5A). The formula (5A) is represented in the form

Rl-AAl-R2-Prol-AA2-Gly-NH2, (5A)

where Pro1, AA1, AA2, R1and R2have the values described above for formula (5), provided that, if Pro1denotes Pro, both R1and R2cannot denote a hydrogen atom, when AA1indicates Tight and AA2means TGR, as the Stiff-Pro-Trp-Gly-NH2is a known compound, and also on one condition that, if Pr is Yes AA1represents Phe or Tight, because Phe-MIF-1 and Tyr-MIF-1 are known compounds. The preferred compositions of tetrapeptides formula (5A) are:

Trp-Pro-Leu-Gly-NH2(SEQ ID NO: 10);

Phe-Pro-Leu-Gly-NH2(SEQ ID NO: 11);

4-F-Phe-Pro-Leu-Gly-NH2(SEQ ID NO: 12);

4-Cl-Phe-Pro-Leu-Gly-NH2(SEQ ID NO: 13);

4-F-Phe-Pro-Ile-Gly-NH2(SEQ ID NO: 14);

4-F-Ph-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 15);

4-F-h-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 16);

Trp-Pro-Leu-Gly-NH2(SEQ ID NO: 17);

Trp-Pro-Ile-Gly-NH2(SEQ ID NO: 18);

Thr-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 19); and

Thr-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 20).

Additional preferred composition of tetrapeptide formula (5A) is 4-CL-h-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 60).

In another example embodiment of the invention the peptides are Pentapeptide characterized by either adding two N-terminal amino acids Phe, Tight, Leu or Il to Pro1adding N-terminal amino acids Phe or Tight to Pro1and adding a C-terminal amino acids Thr to Gly, or the addition of C-terminal amino acids Thr to Gly and internal amino acids between Pro and Gly, tripeptides having the sequence kernel MIF; optional Zelenoe converting a C-terminal amide with Deputy selected from the group comprising carboxyl group, hydroxyalkyl group, preferably hydroxymethylene group, alkoxycarbonyl group, or alkilirovanny carbamino group; optional conversion of nitrogen-containing heterocyclic ring Pro1and the optional conversion of aromatic rings Tight or Phe with substituent selected from the group including a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl; and/or optional conversion of hydrogen atoms at the nitrogen atoms of the amino acid peptide bonds using the group of lower alkyl, preferably having 1-3 carbon atoms.

In one example implementation, including the addition of two N-terminal amino acid compositions of pentapeptides or their pharmaceutically acceptable salts can be represented by the following formula (6):

R1-AA1-AA2<3,4 equipment-degidro-RHS; each AA1and AA2independently from each other represents an amino acid selected from the group Phe or Taut; AA3indicates the amino acid is selected from the group of Leu or Il; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

In the next paragraph describes the composition of pentapeptides formula (6), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression.

A group of preferred compositions of pentapeptides formula (6), which can be used separately or in combination with other peptides described herein, for the treatment SUP> optional conversion of nitrogen-containing heterocyclic ring Pro1and optional conversion of the aromatic rings of Phe or Tight, optional replacement of Leu and the fact that the C-terminal amide of Gly remains untransformed, can be represented by the formula (6A). The formula (6A) is depicted in the form of

R1-AA1-AA2-R2-Pro1-AA3-Gly-NH2(6A)

where Pro1, AA1, AA2, R1and R2have the values described above for formula (6).

The preferred Pentapeptide formula (6A) are:

4-F-Phe-Tyr-Pro-Leu-Gly-NH2(SEQ ID NO: 21);

4-Cl-Phe-Tyr-Pro-Leu-Gly-NH2(SEQ ID NO: 22);

Phe-Tyr-Pro-Leu-Gly-NH2(SEQ ID NO: 23);

Phe-Tyr-Pro-Ile-Gly-NH2(SEQ ID NO: 24);

Phe-Tyr-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 25);

Phe-Tyr-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 26);

Tyr-Tyr-Pro-Leu-Gly-NH2(SEQ ID NO: 27);

Tyr-Tyr-Pro-Ile-Gly-NH2(SEQ ID NO: 28);

Tyr-Tyr-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 29); and

Tight-Tight-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 30).

In another example embodiment of the invention, including the addition of a N-terminal amino and C-terminal amino acids, the composition of pentapeptides or their pharmaceutically acceptable salts mogote Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1indicates the amino acid is selected from the group Phe or Taut; AA2indicates the amino acid is selected from the group Leu, Ile, Arg, D-Arg or Trp; AA3represents the amino acid Trp; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

In the next paragraph describes the composition of pentapeptides formula (7), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression.

A group of preferred compositions of pentapeptides formula (7), which can be used separately and the iej, characterized by the addition of N-terminal amino acids h or Tight to Pro1by adding C-terminal amino acid of Trp to Gly, optional conversion of heterocyclic nitrogen-containing ring Pro and optional conversion of aromatic rings h or Tight, optional replacement of Leu Il, Arg, D-Arg or Trp, and the fact that the C-terminal amide remains untransformed, can be represented by formula 7(a). Formula 7(a) is depicted in the form of

Rl-AAl-R2-Prol-AA2-Gly-Trp-NH2, (7a)

where Pro1, AA1, AA2, R1and R2have the values described above for formula (7).

The preferred Pentapeptide formula (7a) are:

Phe-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 31);

Tyr-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 32);

Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 33);

Phe-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 34);

Phe-CIS - or TRANS-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 35);

Tight-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 36);

Tyr-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 37);

Tight-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 38);

Tyr-Pro-Trp-Gly-Trp-NH2(SEQ ID NO: 39);

Tight-CIS - or TRANS-4-OH-Pro-Trp-Gly-Trp-NH2(SEQ ID NO: 40);

4-F-h-CIS - or TRANS-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 41);

4-F-Phe-CIS - or three-TRANS-4-OH-Pro-D-Arg-Gly-Trp-NH2.

Additional exemplary embodiment includes a preferred Pentapeptide formula (7a):

3-F-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 66);

2-F-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 68);

4-CL-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 61), but is not limited to them.

An additional group of preferred compositions of pentapeptides formula (7a) is characterized optional conversion Pro1in degidro-Pro, preferably 3,4-degidro-RHS. Additional preferred peptides of formula (7a) include: 4-F-h-3,4-degidro-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 72); and 4-F-Phe-3,4-degidro-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 55), but are not limited to them.

Another group of embodiments falling within the scope of formula (7a), includes, but is not limited to, additional optional conversion AA2preferably Arg, His, Homo-Arg, L-ALLO-Ile or canavanin; other additional optional conversion R1and/or R2(preferably R1and preferably to the amino group, carboxyl group, a nitro-group or a phosphonic group (preferably foston-Tight); additional optional conversion heteroseksualnymi preferred peptides of formula (7a) are:

4-NH2-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 63);

4-F-h-CIS - or TRANS-4-OH-Pro-His-Gly-Trp-NH2(SEQ ID NO: 64);

4-NO2-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 65);

4-CH3On-h-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 59);

4-F-h-CIS - or TRANS-4-OH-Pro-Homo-Arg-Gly-Trp-NH2(SEQ ID NO: 71);

4-F-Phe-Homo-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 69);

4-F-Phe-Homo-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 57); and

4-F-h-CIS - or TRANS-4-OH-Pro-L-ALLO-Ile-Gly-Trp-NH2(SEQ ID NO: 73).

In yet another example embodiment of the invention, including the addition of C-terminal amino acids and internal amino acid composition of pentapeptides or their pharmaceutically acceptable salts can be represented by the following formula (8):

R1-Pro1-AA1-AA2-Gly-AA3-R, (8)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1and AA2each independently of the other denotes the amino acid from the group of Leu or Il; AA3represents Trp; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1denotes a hydrogen atom, a group of lower alkyl, preferably occhialino CIS - or TRANS-4-OH-group, sulfhydryl group, preferably a CIS - or TRANS-4-togroup or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl.

In the next paragraph describes the composition of pentapeptides formula (8), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression.

A group of preferred compositions of pentapeptides formula (8), which can be used separately or in combination with other peptides described herein, for the treatment of patients suffering from depression are characterized by addition of C-terminal amino acids Thr to Gly, add internal aminosilane Leu or Il between Pro1and Gly, optional conversion of heterocyclic nitrogen-containing ring Pro1, optional replacement of Leu Il and the fact that the C-terminal amide remains untransformed, can be represented by the formula (8A). The formula (8A) is depicted in the form of

Rl-Prol-AAl-AA2-Gly-Trp-NH2(8a)

where Pro1, AA1, AA2and R1have the values described above for formula (8).

Prieur-NH2(SEQ ID NO: 45).

In another example embodiment of the invention, including the addition of a N-terminal amino and C-terminal amino acids, the composition of pentapeptides or their pharmaceutically acceptable salts can be represented by the following formula (9):

R1-AA1-R2-Pro1-AA2-Gly-AA3-R, (9)

where Pro1represents the amino acid Pro or degidro-Pro, preferably 3,4-degidro-RHS; AA1refers to the amino acid l; AA2indicates the amino acid is selected from the group consisting of Leu, Ile, Arg, D-Arg, Trp or canavanin; AA3refers to the amino acid Thr; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and1means peregrinae ring, preferably in the form of such a fragment as 3-(3-pyridyl); R2denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup, or alkylamino or dialkylamino, preferably methyl - or uchet 3-(3-pyridyl)-l-4-OH-Pro-Arg-Gl-Thr-NH2(SEQ ID NO: 70), but is not limited to them.

In another example embodiment of the invention, including the addition of both N-terminal aminosilane and C-terminal amino acids, the composition of hexapeptides or their pharmaceutically acceptable salts can be represented by the following formula (10):

R1-AA1-R2-Pro1-AA2-AA4-Gly-AA3-R, (10)

where Pro1represents the amino acid Pro or degidro-RHS, AA1indicates the amino acid is selected from the group comprising h or Taut; AA2indicates the amino acid is selected from the group comprising Leu, Ile, Arg, D-Arg, Thr or canavanin; AA3refers to the amino acid Thr; AA4refers to the amino acid Gly or Il; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup, or alkylamino or dialkylamino pactically compositions of hexapeptides formula (10), which can be used separately or in combination with other peptides described in this description of the invention, for the treatment of patients suffering from depression are characterized by addition of C-terminal amino acids Thr, optional conversion of heterocyclic nitrogen-containing ring Pro1preferably using CIS - or TRANS-4-Oh-group, the presence of a fluorine atom in position 4 in Phe; preferably Arg as AA2; TGR as AA3; and Il or Gly as AA4; and the fact that the C-terminal amide remains untransformed, can be represented by the formula (10A). The formula (10A) is depicted in the form of:

R1-Phe-R2-Pro1-AA2-AA4-Gly-Trp-NH2, (10a)

moreover, the preferred peptides of formula (10a) are 4F-Phe-4-OH-Pro-Arg-Gly-Gly-Trp-NH2(SEQ ID NO: 58) and 4F-Phe-4-OH-Pro-Arg-ILe-Gly-Trp-NH2(SEQ ID NO: 67).

In another example embodiment of the invention, including the addition of a N-terminal amino and C-terminal amino acids, the composition of heptapeptides or their pharmaceutically acceptable salts can be represented by the following formula (11):

R1-AA1-R2-Pro1-AA2-AA4-AA5-Gly-AA3-R, (11)

where Pro1oboli Tight; AA2indicates the amino acid is selected from the group comprising Leu, Ile, Arg, D-Arg, Trp or canavanin; AA3refers to the amino acid Thr; AA4and AA5indicate the amino acid Gly or Il; R represents a carboxyl group, hydroxyalkyl group, carbamino group, acylcarnitine group or alkoxycarbonyl group; and R1and R2each independently of one another denotes a hydrogen atom, a group of lower alkyl, preferably having 1-3 carbon atoms, a halogen atom, preferably fluorine atom or chlorine, a hydroxyl group, preferably a CIS - or TRANS-4-OH-group, a sulphydryl group, preferably a CIS - or TRANS-4-togroup, or alkylamino or dialkylamino, preferably methyl - or ethylamino, or dimethyl - or diethylaminopropyl, or phosphonic group (preferably foston-Tight).

The preferred composition of formula (11) is 4-F-Phe-4-OH-Pro-Arg-Gly-Ile-Gly-Trp-NH2(SEQ ID NO: 56).

In accordance with the invention it is also assumed that the Gly in formulas (7) through (11) optionally may be substituted with Val or l.

In yet another example embodiment of the invention the peptides are polypeptides, including chemical com is rmul (1) through (11), which can be used separately or in combination with other peptides described in this description of the invention, for the treatment of patients suffering from depression. Declared chemical combination and/or overlapping chemical combination of peptides preferably contain from at least about three to at least about ten amino acids. Examples of such combinations include, but are not necessarily limited to, the following composition: 4-F-Ph-CIS or TRANS-4-one-RHS-Il-Gl-Thr-Gl-NH2(SEQ ID NO: 46); 4-F-Phe-CIS-or TRANS-4-one-RHS-Il-Gl-Thr-Gl-Thr-NH2(SEQ ID NO: 47); 4-F-h-CIS or TRANS-4-OH-Pro-Leu-Gly-Trp-Gly-NH2(SEQ ID NO: 48); 4-F-Phe-CIS-or TRANS-4-OH-Pro-Leu-Gly-Trp-Gly-Trp-NH2(SEQ ID NO: 49); Pro-Ile-Gly-Trp-Pro-Ile-Gly-NH2(SEQ ID NO: 50); 4-F-h-CIS or TRANS-4-OH-Pro-Arg-Gly-Trp-Gly-NH2(SEQ ID NO: 51); 4-F-h-CIS or TRANS-4-OH-Pro-Arg-Gly-Trp-Gly-Trp-NH2(SEQ ID NO: 52); CIS - or TRANS-4-one-RHS-Il-Gl-CIS or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 53); 3,4-degidro-Pro-D-Arg-Gly-3,4-degidro-Pro-D-Arg-Gly-NH2; 3,4-degidro-Pro-D-Arg-Gly-Trp-Gly-NH2; and 3,4-degidro-Pro-D-Arg-Gly-Trp-Gly-Trp-NH2.

The most preferred compositions of the present invention contain small peptides, which exhibit higher activity in the swimming test Porsolt, predstavlyayutsya tetrapeptide, Pentapeptide, Hexapeptide and heptapeptide. The formula of these the most preferred peptides described in this description may be represented in the form

R1-Phe-Pro1-AA2-AA3-NH2,

for tetrapeptide, in which R1preferably denotes a halogen atom, most preferably a fluorine atom or chlorine, carboxyl group, amino group or a nitro-group, and all conversions are preferably relate atom C4 Phe; Pro means arranged in descending order of preference 3,4-degidro-RHS, Homo-Pro, CIS - or TRANS-4-OH-Pro, or Pro; AA2preferably indicates Il, Leu, or Arg; and AA3preferably represents Gly or Thr.

Other preferred tetrapeptides of the present invention is the Pro-Ile-Gly-Trp (SEQ ID NO: 3).

Formula most preferred pentapeptides, hexapeptides and heptapeptides, also described in this description may be represented in the form

R1-Phe-Pro1-AA2-Gly-AA(n)-AA3-NH2< / BR>
where R1preferably denotes a halogen atom, preferably fluorine atom or chlorine, carboxyl group, amino group or a nitro-group, and all conversions of prepact the th, Homo-Pro, CIS - or TRANS-4-OH-Pro, or Pro; AA2preferably represents Arg, Ile, Leu or His, and Arg is the most preferred; AA(n)indicates 0-2 amino acid residue when n=1, the preferred amino acid residue is Gly, and when n=2, the preferred Il-Gly, Ile-Ile, or Gly-Gly; and AA3preferably indicates Thr or Gly, and Thr is the most preferred.

The present invention also relates to mixtures of peptides represented by the formulas (1) to (11), with known antidepressant compounds, such as amitriptyline, fluoxetine (Prozac) and sertraline (Zoloft). To a person skilled in the art it is obvious how to create various mixtures of small peptides according to the present invention in addition to those given in the examples in the present description.

Small peptides, which include the present invention easily get usual methods multistep synthesis of polypeptides (i.e., carbodiimide method, anhydrite mixed method, N,N-carbonyldiimidazole method), and using solid-phase synthesis of peptides. The substituting groups are also easily added to the polypeptide residues in the usual way.

The active ingredient, which may contain one or more of the peptides described in this invention may be represented in the form of a composition with a suitable pharmaceutical carrier for administration in vivo to a patient using any standard method known in the art. Suitable routes of administration include oral (introduction through the mouth or oral), sublingual, parenteral (e.g. intravenous, intraspinal, intrathecal, intraventricularly, epidermal, intracisternally, intracutaneous or intradermal, subcutaneous or intramuscular), nadgorny or transdermal, intranasal or rectal and inhalation (using poly - or microdispersed aerosol), but Ruina dosage form depends on the method of introduction. Oral introduction include the use of tablets, capsules, solutions, suspensions, gels, powders, elixirs or syrups, but are not limited to them. Sublingual introduction includes the use of tablets or pellets, but are not limited to them. Parenteral administration includes the use of solutions or suspensions, but are not limited to them. Nadkarny or transdermal application include the application of ointments, creams, pastes, plasters, powders, sprays, lotions, transdermal patches, disks and solutions, but are not limited to them. Intranasal introduction of the peptide or peptides of the present invention includes the use of solutions, sprayable solutions, inhalants or ointments, but are not limited to them. Rectal administration may include the use of solutions, ointments or suppositories, but not necessarily limited to them. The active ingredient may also be presented in a form for inclusion in liposomes, microcapsules, polymer or wax base and drugs controlled release. For more information concerning ways of introducing and achieving standards of pharmaceutically effective doses, see Chapter 3 in the "Dosage Form Design: Biopharmaceutical Considerations in Pharmaceutical Dosage Forms and Drug Delivery Systems, 1990, Ansel, H. C. and Popovich, N. G. fifth issued the compositions, will depend upon the effective dose and method of administration used to enhance the biological activity. The dose should be sufficient to achieve such concentrations of the active substance in the plasma of the blood system, so that an effective amount to break the blood-brain barrier, has been effective. For example, when the active substance is tetrapeptide Pro-Leu-Gly-Trp-NH2its content in the plasma of the blood system for the average adult should be from about 30 mg to about 90 mg; for the average adult human are preferably a content of approximately 60 mg Effective dose for various routes of administration can be derived from the curves of dose - effect obtained in vitro or using animal as model test systems.

Below the invention is additionally illustrated by the examples represent only an example of the synthesis and application of small peptides on izobreteniya.

EXAMPLE: tri-, Tetra - or Pentapeptide as antidepressant

Materials and methods

Synthesis of peptides

Small peptides according to the present izobreteniya synthesized using methods known for the peptide synthesizer model Applied Biosystem 431A. Used cycles double bind, because the number of the original resin two times higher than that for the standard mode. Carried out the following stages: (1) first, the washing of 20% piperidine was removed group, blocking FMOC on the resin; (2) then the resin was washed with N-methylpyrrolidinone; (3) in reactions vessel was added 2 mm FMOC-Proline together with 0.45 mm hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea in a solution of 1-hydroxybenzotriazole and 1 mm diisopropylethylamine; (4) the resin was washed with N-methylpyrrolidinone; (5) repeated the cycle with FMOC-leucine, then FMOC-glycine and at the end with FMOC-tryptophan; (6) the peptide bond of the resin was split in the following solution: 0.25 ml identicial, 0.25 ml of N2Oh, and 9.5 ml of TFU, time splitting was 3-4 hours; (7) then the peptide was purified using two procedures liquid chromatography high resolution (IHVR) with reversed phase, the first of which as an eluting solution used by 0.1% TFU in the water, and the second as an eluting solution used by 0.1% TFU in acetonitrile.

The purity of the synthesized peptides were analyzed by analytical GHUR using chromatograph type HP1090L, equipped with a 10 nm. Molecular masses were determined using mass spectrometry.

Synthesis of Pro-Are-Glv-NH2< / BR>
Pro-Arg-Gly-NH2synthesized manually using fittowindow funnel, and a sequence of stages specified for the synthesis of Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 5), and applying FMOC-amino acids. During the synthesis of Pro-Arg-Gly-NH2instead of N-methylpyrrolidinone used dimethylformamide and at a stage (6) is a peptide bond resin were digested using the following solvent mixtures: 0.75 g of phenol in 0.25 ml of thioanisole, 0.5 ml of N2O and 10 ml of TFU.

Other peptides presented in this description, except Tripeptide Pro-Arg-Gly-NH2received as described above.

Specialists in the art are aware of any variety of methods that can be applied for synthesis of the peptides of the present invention.

Each purified peptide was stored in a frozen state in the form of white crystalline powder. MIF also synthesized using methods known to experts in this field of technology. This Tripeptide was stored in a frozen state in the form of white crystalline powder.

Modification swimming test Porsolt to identify PEP is gton, Minnesota. Rats were placed individually in cages of stainless steel wire with a cell size of half an inch, made in accordance with the "Guidance on the content and use of laboratory animals Institute of Laboratory Animals Resources, National Research and Counsel. Light regime in the premises for animals was 12 hours of the light phase/ 12-hour dark phase, the temperature was maintained at a level of 18-26oC and a relative humidity of 40-70%. Experimental animals were subjected to acclimatize for at least 7 days before the study began. Daily dose of small peptides according to the present invention was obtained by dissolving 1 mg q.s. to 10.0 ml of the following composition: 0.01 M acetic acid in 0.9% saline solution. Then by intraperitoneal injection once daily for five consecutive days have introduced the corresponding peptide at a rate of 1 mg/kg

The antidepressant activity of the peptides of the present invention was determined by a modified swimming test Porsolt (Porsolt and others, 1977, Nature 266: 730-732). The method is based on the observation that, when rats are forced to swim in a situation from which there is no exit it after the initial period of intense activity completely stops moving t o a state of despair, in which standard rat can't find a way out and submits to the experimental conditions. On the first day of the experiment animals were dipped separately in the vertical Plexiglas cylinder (height 40 cm, diameter 18 cm) filled to the level of 24 cm of water, the temperature of which was maintained at a level 25-26oC. the Cylinder was painted white. The water was changed after the experience with each rat. After 15 minutes in the cylinder of rats were removed and returned to their individual cages without drying it out. An hour after that, the rats were introduced tetrapeptide, MIF or control (0.01 M acetic acid in 0.9% saline solution) in an amount determined based on the weight of each animal. On 2-nd, 3-th and 4-th day in the point in time corresponding to the average processing time of the entire group of experimental animals, rats were injected with either peptide 1 through 39, or the control solution. On the 5th day after weighing each rat was treated with the dose determined on the basis of its own weight. Order dosing regulated in such a way as to provide sufficient time between experiments on each individual animal for evaluation of test results. Fifteen minutes after injection, each rat was placed on a 300 Saty

In table 1 and Fig.1-3 presents the results obtained on the basis of numerous swimming tests Porsolt, with the introduction of the peptides of the present invention, known compounds antidepressants (eg, amitriptyline, fluoxetine [Prozac] and sertraline [Zoloft]), known compounds (for example, Pro-Leu-Gly-NH2Pro-D-Leu-Gly-NH2) and placebo (AMG: treatment of 0.1 M acetic acid in 0.9% saline solution, the dose of 1 ml/kg).

The number of reacting appropriately animals from the total number of 12 animals in each test group are shown in column 4 of table 1 for all the studied compounds, doses and combinations. In Fig.1 presents a graphical analysis of the average number of reacting appropriately animals from the total number of 12 animals in one or more experimental groups in the study of selected compounds of the present invention, as well as for the test compounds. In particular in Fig.1 presents data for the following connections:

1) 4-F-h-3,4-degidro-RHS-AGD-Gl-Thr-NH2(SEQ ID NO: 55), corresponds to 2 in table 1;

2) 4-F-Phe-4-OH-Pro-Arg-Gly-Ile-Gly-Trp-NH2(SEQ ID NO: 56), corresponds to 3 in table 1;

3) 4-F-Phe-4-Homo-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 57), corresponding to 4 in the), corresponds to 8 in table 1;

6) Amitriptyline, corresponds to 9 in table 1;

7) 4-F-Phe-4-OH-Pro-Arg-Gly-Gly-Trp-NH2(SEQ ID NO: 58), corresponds to 11 in table 1;

8) 4-CH3O-Phe-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 59). corresponds to 12 in table 1;

9) 4-Cl-Phe-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 60), corresponds to 13 in table 1;

10) 4-F-Phe-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 41), equivalent to 14 in table 1;

11) 4-F-Phe-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 43), corresponds to 17 in table 1;

12) 4-OH-Pro-Ile-Gly-NH2corresponds to 20 in table 1;

13) Zoloft corresponds to 41 in table 1;

14) Prozac corresponds to 48 in table 1; and

15) Pro-Leu-Gly-NH2corresponds to 55 in table 1.

The above compounds 1-15 correspond to the same numbers in the graphs shown in Fig.2 and 3.

Denote the connection is made only for ease of reference. Used in table 1, the numbering does not correspond to the designations of compounds 1-15 in Fig. 1, 2 and 3. The data presented in Fig.1-3 correspond to tests conducted using a standard dose of 0.1 mg/ml Data in table 1 represent these results and the results of numerous additional tests with other peptides of the present invention, with what atom animals see animal the movement which during curing in the vessel with water for 300 seconds does not exceed the average time motion control inactive group (AMG) plus one standard deviation. For example, if the average motion of the NGC, consisting of 12 Wistar rats, 35 seconds plus or minus one standard deviation in 15 seconds, reacting appropriately animals see animal, the movement of which exceeds fifty seconds. Thus, the value for the control group plus one standard deviation was taken as the threshold response; the number of rats, the movement of which exceeded this level given in the table as the number of reacting appropriately animals.

In table 1 (column 5) shows the difference between the time of the movement in the study of various investigated compounds, combinations of compounds and doses and time of movement in the inactive control group. Presents the average movement for each peptide. Average averages the time the motion for the experimental groups treated with each of the above compounds 1-15 marked with two asterisks, also shown in Fig.2. N is 5. Average results for the treated animals was compared with the average results obtained for the control group (AMG), using odnovalentnogo t-criterion of student. Thus obtained to assess the reliability of differences for all investigated compounds are given in table 1 (column 8).

Z-scores of the average time of movement in the study mentioned above of compounds 1-15 shown in Fig.3 and table 1 (column 9). Z-score is a dimensionless coefficient of efficiency, which was averaged according to many experiments. The average Z-score is defined as the difference between the average motion in the treated group and the average motion in the control group, divided by the standard deviation of the average time of movement in the control group. Thus, for the inefficient connections the Z-score close to zero, and higher Z-scores correspond to greater efficiency.

The data presented in table 1, and image data for the above compounds 1-15 in Fig.1-3 show that many of the peptides of the present invention exhibit higher antidepressant activity when compared with the reliability provided as examples of the peptides of the present invention exhibit higher activity, than MIF. The results also indicate that between the peptides of the present invention and known compounds as antidepressants, such as Prozac, may be Energeticheskie action. For example, the data presented in table 1 No. 1, show that a mixture consisting of 4-F-Phe-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 43) at a concentration of 0.1 mg/ml and Prozac at a concentration of 0.8 mg/ml, results in a corresponding reaction in 12 animals of the 12 studied. In addition, the data presented in table 1 No. 6, show that a mixture consisting of 4-F-Phe-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 43) at a concentration of 0.1 mg/ml and amitriptyline, leads to a corresponding reaction in 10 animals of the 12 studied.

Thus, the applicants describe numerous small peptides for use as an antidepressant compounds, reinforcing the possibility of applying the results of biological experiments.

For specialists in the art based on this description, or shown in this description of the practical application of the invention should be obvious to other embodiments of the invention. It is assumed that the description and examples should be considered only in katsa in the claims.

The sequence listing is provided at the end of the description.

1. Peptides representing (a) a Tripeptide of the General formula (1)

R1-Pro1-AA1-NR2-CH2-R (1)

where Pro1indicates the amino acid is selected from the group consisting of Pro and degidro-Pro;

AA1- amino acid selected from the group consisting of Thr, UCP, Lys, Leu, Arg, D-Arg and Ile;

R is a group selected from karbonilnoj group, carboxyl group and hydroxyalkyl group;

R1selected from the group consisting of hydrogen atom, halogen atom, hydroxyl group;

R2from the group consisting of a hydrogen atom and the group of lower alkyl having 1-3 carbon atoms, provided that when a Pro1denotes Pro and AA1Is Leu, Ile, Lys, Arg, or UCP, R1and R2both denote a hydrogen atom when R represents carbamino group; if Pro1denotes Pro and AA1- Leu, R1and R2both denote a hydrogen atom, when R denotes a carboxyl group, and if Pro1denotes Pro and AA1- Thr, R1and R2both denote a hydrogen atom when R denotes hydroxyalkyl group;

or (b) a Tripeptide of the General formula (2)

R - carbamino group;

R1is a hydrogen atom,

or (C) a Tripeptide of the General formula (3)

R1-Pro1-AA1-Gly-AA2-R, (3)

where Pro1indicates the amino acid is selected from the group consisting of Pro and degidro-Pro;

AA1- amino acid selected from the group consisting of Ile, Leu, Arg and D-Arg;

AA2- amino acid selected from the group consisting of Thr and Tyr;

R - carbamino group;

R1selected from the group consisting of a hydrogen atom and a hydroxyl group;

or (d) tetrapeptide General formula (4)

R1-AA1-R2-Pro1-AA2-Gly-R, (4)

where AA1indicates the amino acid is selected from the group consisting of Thr, Tyr and Phe;

AA2- amino acid selected from the group consisting of Leu and Ile;

R - carbamino group;

R1and R2each independently from each other selected from the group consisting of hydrogen atom, halogen atom and a hydroxyl group, provided that when a Pro1denotes Pro, AA2- Leu and R - carbamino group, R1and R2both denote a hydrogen atom, when AA1Is Phe or Tyr; and if Pro1denotes Pro and R - carbamino group, R1and R2not UP>1
-AA1-R2-Pro1-AA2-Gly-AA3-R (5)

where Pro1indicates the amino acid is selected from the group consisting of Pro and degidro-Pro;

AA1- amino acid selected from the group consisting of Tyr and Phe;

AA2- amino acid selected from the group consisting of Leu, Ile, Arg, D-Arg;

AA3- amino acid Thr;

R - carbamino group;

R1and R2each independently from each other selected from the group consisting of hydrogen atom, halogen atom and a hydroxyl group;

or (e) Pentapeptide General formula (6)

R1-AA1-R2-Pro-AA2-Gly-AA3-R, (6)

where AA1refers to the amino acid la;

AA2- amino acid selected from the group consisting of Arg or D-Arg;

AA3- amino acid Thr;

R - carbamino group;

R1selected from the group consisting of fragment 3-(3-pyridyl);

R2from CIS - or TRANS-4-Oh-group;

or (g) the peptide of General formula (7)

R1-AA1-R2-Pro-AA2-AA4-Gly-AA3-R, (7)

where AA1refers to the amino acid he or Tyr;

AA2- amino acid selected from the group consisting of Arg or D-Arg;

AA3- amino acid Thr;

Gg from each other are selected from the group consisting of fluorine atom, chlorine atom, CIS - or TRANS-4-Oh-group;

or (C) a peptide of General formula (8)

R1-AA1-R2-Pro-AA2-AA4-AA5-Gly-AA3-R, (8)

where AA1indicate the amino acid Phe or Tyr;

AA2selected from the group consisting of AGD or D-Arg;

AA3denote amino acid Thr;

AA4and AA5- amino acid Gly or Ile;

R - carbamino group;

R1and R2each independently selected from the group consisting of hydrogen atom, fluorine atom, chlorine atom, CIS-or TRANS-4-Oh-groups,

or their salts.

2. The Tripeptide under item 1, which is a Pro-D-Arg-Gly-NH2.

3. The Tripeptide under item 1, which is a Pro-Thr-Gly-NH2.

4. The Tripeptide under item 1, which is CIS - or TRANS-4-OH-Pro-D-Arg-Gly-NH2.

5. The Tripeptide under item 1, which is CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2.

6. The Tripeptide under item 1, which is CIS - or TRANS-4-OH-Pro-Arg-Gly-NH2.

7. The Tripeptide under item 1, which is CIS - or TRANS-4-OH-Pro-Thr-Gly-NH2.

8. The Tripeptide under item 1, which is CIS - or TRANS-4-thio-Pro-Leu-Gly-NH2. the that is a Pro-Trp-NHCH2-CO2N.

11. The Tripeptide under item 1, which represents Pro-Arg-Ala-NH2.

12. Tetrapeptide under item 1, which is 3,4-degidro-Pro-D-Arg-Gly-Trp-NH2.

13. Tetrapeptide under item 1, which is CIS - or TRANS-4-OH-Pro-D-Arg-Gly-Thr-NH2.

14. Tetrapeptide under item 1, which is CIS - or TRANS-4-OH-Pro-Leu-Gly-Thr-NH2(SEQ ID NO: 1).

15. Tetrapeptide under item 1, which is CIS - or TRANS-4-OH-Pro-Ile-Gly-Thr-NH2(SEQ ID NO: 2).

16. Tetrapeptide under item 1, which is a Pro-Ile-Gly-Thr-NH2(SEQ ID NO: 3).

17. Tetrapeptide under item 1, which represents Pro-Leu-Gly-Thr-NH2(SEQ ID NO: 5).

18. Tetrapeptide under item 1, which represents Pro-Arg-Gly-Thr-NH2(SEQ ID NO: 7).

19. Tetrapeptide under item 1, which is a Pro-D-Arg-Gly-Thr-NH2.

20. Tetrapeptide under item 1, which is a Pro-Trp-Gly-Thr-NH2(SEQ ID NO: 8).

21. Tetrapeptide under item 1, which represents Pro-Leu-Gly-Tight-NH2(SEQ ID NO: 6).

22. Tetrapeptide under item 1, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 15).

23. Tetrapeptide under item 1, which is 4-F-Phe-CIS - SUB>2
(SEQ ID NO: 12).

25. Pentapeptide under item 1, which represents Tyr-Tight-Pro-Leu-Gly-NH2(SEQ ID NO: 27).

26. Pentapeptide under item 1, which is a Phe-Tight-Pro-Leu-Gly-NH2(SEQ ID NO: 23).

27. Pentapeptide under item 1, which represents Tyr-Pro-Thr-Gly-Trp-NH2(SEQ ID NO: 39).

28. Pentapeptide under item 1, which is a Phe-Pro-Leu-Gly-Thr-NH2(SEQ ID NO: 31).

29. Pentapeptide under item 1, which is a Tight-Pro-Leu-Gly-Thr-NH2(SEQ ID NO: 32).

30. Pentapeptide under item 1, which is a Tight-Pro-Thr-Gly-Thr-NH2(SEQ ID NO: 39).

31. Pentapeptide under item 1, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Ile-Gly-Thr-NH2(SEQ ID NO: 41).

32. Pentapeptide under item 1, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-Thr-NH2(SEQ ID NO: 42).

33. Pentapeptide under item 1, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Thr-NH2(SEQ ID NO: 43).

34. The Tripeptide under item 1, which is 3,4-degidro-Pro-D-Arg-Gly-NH2.

35. Tetrapeptide under item 1, which is 3,4-degidro-Pro-Arg-Gly-Thr-NH2(SEQ ID NO: 62).

36. Tetrapeptide under item 1, which is 4-Cl-Phe-Pro-Ile-Gly-NH2(SEQ ID NO: 60).

37. Pentapeptide is Ted by p. 1, which is 2-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Thr-NH2(SEQ ID NO: 68).

39. Pentapeptide under item 1, which is 4-CL-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Thr-NH2(SEQ ID NO: 61).

40. Pentapeptide under item 1, which is 3-(3-pyridyl)-Ala-CIS - or TRANS-4-OH-Pro-Arg-Gly-Thr-NH2(SEQ ID NO: 70).

41. The peptide under item 1, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Gly-Thr-NH2(SEQ ID NO: 58).

42. The peptide under item 1, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Ile-Gly-Thr-NH2(SEQ ID NO: 67).

43. The peptide under item 1, which is 4-F-Phe-4-OH-Pro-Arg-Gly-Ile-Gly-Thr-NH2(SEQ ID NO: 56).

44. Hexapeptide under item 1, representing 4-F-Phe-CIS - or TRANS-4-OH-Pro-Ile-Gly-Thr-Gly-NH2(SEQ ID NO: 46).

45. Heptapeptide under item 1, representing 4-F-Phe-CIS - or TRANS-4-OH-Pro-Ile-Gly-Thr-Gly-Thr-NH2(SEQ ID NO: 47).

46. Hexapeptide under item 1, representing 4-F-Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-Thr-Gly-NH2(SEQ ID NO: 48).

47. Heptapeptide under item 1, representing 4-F-Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-Thr-Gly-Thr-NH2(SEQ ID NO: 49).

48. Heptapeptide under item 1, representing Pro-Ile-Gly-Thr-Pro-Ile-Gly-NH2(SEQ ID NO: 50).

49. Hexapeptide under item 1, representing the battle 4-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Thr-Gly-Thr-NH2(SEQ ID NO: 52).

51. Hexapeptide under item 1, representing 4-OH-Pro-Ile-Gly-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 53).

52. Hexapeptide under item 1, which represents a 3,4-degidro-Pro-D-Arg-Gly-3,4-degidro-Pro-D-Arg-Gly-NH2.

53. Hexapeptide under item 1, which represents a 3,4-degidro-Pro-D-Arg-Gly-Thr-Gly-Thr-NH2.

54. Pentapeptide under item 1, which represents a 3,4-degidro-Pro-D-Arg-Gly-Thr-Gly-NH2.

55. Pentapeptide (7) or its salt under item 1, in which Pro1denotes 3,4-degidro-Pro.

56. Pentapeptide on p. 55, which is 4-F-Phe-3,4-degidro-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 72).

57. Pentapeptide on p. 55, which is 4-F-Phe-3,4-degidro-Pro-Agr-Gly-Trp-NH2(SEQ ID NO: 55).

58. Pentapeptide (7) or its salt under item 1, including the additional optional conversion AA2with the help of amino acids selected from the group consisting of Agr, His, Homo-Arg and L-ALLO-Ile; additional optional conversion R1with the help of a group selected from the group consisting of amino group, carboxyl group and nitro group, or additional optional conversion of nitrogen-containing heterocyclic ring with CIS - or TRANS-4-one or Homo-RHS.

59. Pentip is 0. Pentapeptide on p. 58, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-His-Gly-Trp-NH2(SEQ ID NO: 64).

61. Pentapeptide on p. 58, which represents 4-NO2-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 65).

62. Pentapeptide on p. 58, which is a 4-CH3O-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 59).

63. Pentapeptide on p. 58, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Homo-Arg-Gly-Trp-NH2(SEQ ID NO: 71).

64. Pentapeptide on p. 58, which is 4-F-Phe-Homo-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 69).

65. Pentapeptide on p. 58, which is 4-F-Phe-Homo-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 57).

66. Pentapeptide on p. 58, which is 4-F-Phe-CIS - or TRANS-4-OH-Pro-L-ALLO-Ile-Gly-Trp-NH2(SEQ ID NO: 73).

67. Composition for treating depression comprising as active ingredient the peptide under item 1 of General formula 7 in an effective amount and a pharmaceutically suitable carrier.

68. The composition according to p. 67, where the specified peptide is 4-F-Phe-cis-4-OH-Pro-Arg-Gly-Trp-NH2or 4-F-Phe-trans-4-OH-Pro-Arg-Gly-Thr-NH2(SEQ ID NO: 43).

69. The composition according to p. 67, further including Fluoxetine.

70. The composition according to p. 67, updat the>

72. A method of treating depression by introducing a peptide or peptides of formula (1) under item 1 in an effective amount.

73. The method according to p. 72, characterized in that the injected peptide or peptides represented by formulas 2 through 11 listed in the above claims.

74. The method according to p. 72, in which the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2(SEQ ID NO: 16).

75. The method according to p. 72, in which the peptide is a Pro-Leu-Gly-Thr-NH2(SEQ ID NO: 5).

76. The method according to p. 72, in which the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-NH2(SEQ ID NO: 15).

77. The method according to p. 72, in which the peptide is a 3,4-degidro-Pro-D-Arg-Gly-NH2.

78. The method according to p. 72, in which the peptide represents a CIS - or TRANS-4-OH-Pro-D-Arg-Gly-Thr-NH2.

79. The method according to p. 72, in which the peptide represents a CIS - or TRANS-4-OH-Pro-Ile-Gly-NH2.

80. The method according to p. 72, in which the peptide represents a CIS - or TRANS-4-OH-Pro-D-Arg-Gly-NH2.

81. The method according to p. 72, in which the peptide is 4-F-Phe-Pro-Leu-Gly-NH2(SEQ ID NO: 12).

82. The method according to p. 72, where the peptide is a Tight-RHS-Thr-Gly-Trp-NH2(SEQ ID NO: 39).

83. The way p is p. 72, where the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 41).

85. The method according to p. 72, where the peptide is a Phe-CIS - or TRANS-4-OH-Pro-Leu-Gly-Trp-NH2(SEQ ID NO: 42).

86. The method according to p. 72, where the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 43).

87. The method according to p. 72, where the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-D-Arg-Gly-Trp-NH2.

88. The method according to p. 72, including the stage of introduction of the peptide Pro-Ile-Gly-NH2.

89. The method according to p. 72, in which the peptide is a 3,4-degidro-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 62).

90. The method according to p. 72, in which the peptide is 4-Cl-Phe-Pro-Ile-Gly-NH2(SEQ ID NO: 60).

91. The method according to p. 72, in which the peptide is a 3-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 66).

92. The method according to p. 72, in which the peptide is a 2-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 68).

93. The method according to p. 72, in which the peptide is 4-CL-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 61).

94. The method according to p. 72, in which the peptide is 4-F-Phe-3,4-degidro-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 72).

95. The method according to p. 72, in which the peptide is 4-F-P 2-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 63).

97. The method according to p. 72, in which the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-His-Gly-Trp-NH2(SEQ ID NO: 64).

98. The method according to p. 72, in which the peptide is a 4-NO2-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 65).

99. The method according to p. 72, in which the peptide is a 4-CH3O-Phe-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 59).

100. The method according to p. 72, in which the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Homo-Arg-Gly-Trp-NH2(SEQ ID NO: 71).

101. The method according to p. 72, in which the peptide is 4-F-Phe-Homo-Pro-Ile-Gly-Trp-NH2(SEQ ID NO: 69).

102. The method according to p. 72, in which the peptide is 4-F-Phe-Homo-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 57).

103. The method according to p. 72, in which the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-L-ALLO-Ile-Gly-Trp-NH2(SEQ ID NO: 73).

104. The method according to p. 72, in which the peptide is a 3-(3-pyridyl)-Ala-CIS - or TRANS-4-OH-Pro-Arg-Gly-Trp-NH2(SEQ ID NO: 70).

105. The method according to p. 72, in which the peptide is 4-F-Phe-4-CIS - or TRANS-HE-Pro-Arg-Gly-Gly-Trp-NH2(SEQ ID NO: 58).

106. The method according to p. 72, in which the peptide is 4-F-Phe-CIS - or TRANS-4-OH-Pro-Arg-Ile-Gly-TrpB>2(SEQ ID NO: 56).

108. The peptide of the formula

R1-Phe-Pro1-AA2-AA3-NH2,

where R1is a halogen atom, preferably fluorine atom or chlorine, or a nitro-group, and all conversions are preferably relate atom C4 in Phe;

Pro1- 3,4-degidro-Pro, Homo-Pro, CIS - or TRANS-4-OH-Pro, or Pro;

AA2Is Ile, Leu or Arg;

AA3Is Gly or Thr,

or its salt.

109. The peptide of the formula

R1-Phe-Pro1-AA2-Gly-AA(n)-AA3-NH2,

where R1is a halogen atom, preferably fluorine atom or chlorine, or a nitro-group, and all conversions are preferably relate atom C4 in Phe;

Pro1- 3,4-degidro-Pro, Homo-Pro, CIS - or TRANS-4-OH-Pro, or Pro;

AA2- Arg, Ile, Leu or His;

AA(n)- 0-2 amino acid residue, and when n= 1, the preferred amino acid residue is Gly, and when n= 2, the preferred Ile-Gly, Ile-Ile, or Gly-Gly;

AA3- Thr or Gly, or its salt.

 

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