Releasing peptides of growth hormone

FIELD: medicine; pharmacology.

SUBSTANCE: releasing peptides of growth hormone are described with formula (I): R112345-R2, where:А1 designates Aib, Apc or Inp; А2 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Тrp; А3 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-2Ser(Bzl) or D-Trp; А4 designates 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); А5 designates Apc, Dab, Dap, Lys, Orn or deleted; R1 designates hydrogen; and R2 designates NH2; and their pharmaceutically acceptable salts.

EFFECT: pharmaceutical compositions and the methods of their application are presented.

25 cl, 1 tbl, 2 ex

 

Pulsating release of growth hormone on the basis of the somatotropic pituitary hormones is regulated by neuropeptides in the hypothalamus: releasing factor, growth hormone and somatostatin. Releasing factor, growth hormone stimulates the release of growth hormone, whereas somatostatin inhibits the secretion of growth hormone (Frohman et al., Endocr. Rev. 1986, 7, 223-253 and Strobi et al., Pharmacol. Rev. 1994, 46, 1-34).

The release of growth hormone from the somatotropic pituitary hormones may also be subject to the releasing peptides of growth hormone (RFRG). It was shown that the Hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys amide (RFRG and 6 (GHRP-6)) dependent on the dose of a way releases the growth hormone of the somatotropic hormones for several species, including humans (Bowers et al., Endocrinology 1984, 114, 1537-1545). Subsequent studies chemistry RPG-6 resulted in the identification of other powerful tools that promote the secretion of growth hormone, such as HRG-1, RPG-2 and hexarelin (Cheng et al., Endocrinology 1989, 124, 2791-2798, Bowers, C.Y. Novel GH-Releasing Peptides. In: Molecular and Clinical Advances in Pituitary Disorders. Ed: Melmed, S. Endocrine Research and Education, Inc., Los Angeles, CA, USA, 1993, 153-157, and Deghenghi et al., Life Sci. 1994, 54, 1321-1328).

RING-1Ala-His-D-(2')-Nal-Ala-Trp-D-Phe-Lys-NH2;
RING-2D-Ala-D-(2')-Nal-Ala-Trp-D-Nal-Lys-NH2;
Hexarelin:His-D-2-MeTrp-Ala-Trp-D-Ph-Lys-NH 2.

HRG-1, RPG-2, RPG-6 and hexarelin are synthetic agents that promote the secretion of growth hormone (cGy). CGy stimulate the secretion of growth hormone by a mechanism that is different from the action of the releasing factor growth hormone (Bowers et al., Endocrinology 1984, 114, 1537-1545, Cheng et al., Endocrinology 1989, 124, 2791-2798, C.Y. Bowers Novel GH-Releasing Peptides. In: Molecular and Clinical Advances in Pituitary Disorders. Ed: Melmed, S.; Endocrine Research and Education, Inc., Los Angeles, CA, USA, 1993, 153-157, and Deghenghi et al., Life Sci. 1994, 54, 1321-1328).

Low oral bioavailability (<1%) peptidergic funds, promote the secretion of growth hormone, stimulated the search for ones compounds that mimic the action RPG-8 of the pituitary gland. There are reports of several benzolactams and sproinging, which stimulate the release of growth hormone in different species of animals and humans (Smith et al., Science 1993, 260, 1640-1643, Patchett et al., Proc. Natl. Acad. Sci. USA. 1995, 92, 7001-7005, and Chen et al., Bioorg. Med. Chem. Lett. 1996, 6, 2163-2169). A concrete example of a small spiropentane is MK-0677 (Patchett et al., Proc. Natl. Acad. Sci. USA. 1995, 92, 7001-7005):

The foregoing cGy (peptide and ones nature), apparently mediated by specific receptor funds, promote the secretion of the growth hormone receptor cGy). (Howard et al., Science 1996, 273, 974-977, and Pong et al., Molecular Endocrinology 1996, 10, 57-61). The specified receptor is present in GI is ofise and hypothalamus different mammalian species (GHSR1a), and differs from the receptor releasing factor and growth hormone (RFRG). Receptor cGy was also detected in other areas of the Central nervous system and in peripheral tissues, such as adrenal and thyroid gland, heart, lung, kidney and skeletal muscle (Chen et al., Bioorg. Med. Chem. Lett. 1996, 6, 2163-2169, Howard et al., Science 1996, 273, 974-977, Pong et al., Molecular Endocrinology 1996, 10, 57-61, Guan et al., Mol. Brain Res. 1997, 48, 23-29 and McKee et al., Genomics 1997, 46, 426-434). There are reports of the presence of a truncated variant of GHSR1a (Howard et al., Science 1996, 273, 974-977).

Receptor cGy represents the receptor-associated G-protein. The effects of activation of the receptor cGy include depolarization and inhibition of potassium channels, increasing intracellular concentrations of Inositol triphosphate (IP) and a temporary increase in the concentration of intracellular calcium (Pong et al., Molecular Endocrinology 1996, 10, 57-61, Guan et al., Mol. Brain Res. 1997, 48, 23-29 and McKee et al., Genomics 1997, 46, 426-434).

Ghrelin is a natural peptide, which is considered as an endogenous ligand for receptor cGy (Kojima et al., Nature 1999, 402, 656-660). The known native structure of greenow obtained from several species of mammals and animals other than mammals (Kalya et al., J. Biol. Chem. 2001, 276, 40441-40448; Application for international patent application PCT/JP00/04907 (WO 01/07475)). It has been shown that present in the ghrelin nuclear site provides the activity of the receptor cGy. Nuclear site includes four N-terminal amino acids, where the serine at position 3 in normal modificarea the N-octanoic acid. However, in addition to acylation of N-octane acid ghrelin, as shown, may be allerban N-decanoas acid (Kalya et al., J. Biol. Chem. 2001, 276, 40441-40448). Analogs of ghrelin have many different therapeutic areas of application and use as research tools.

A BRIEF DESCRIPTION of the INVENTION

The present invention relates to peptidyl analogues active against receptor cGy. Analogs of the present invention can be contacted with the receptor cGy and it is preferable to carry out signal transduction.

Thus, in the first aspect of the present invention relates to the compound of formula (I):

R1-A1-A2-A3-A4-A5-R2

or its pharmaceutically acceptable salts, where:

And1indicates Aib, Apc or Inp;

And2denotes a D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Trp;

A3denotes a D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Trp;

And4means 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl);

A5denotes Apc, Dab, Dap, Lys, Orn or deleterow;

R1denotes hydrogen, (C1-6)alkyl, (C5-14)aryl, (C1-6)alkyl(C5-14)aryl, (C3-8)cycloalkyl or (C2-10)acyl; and

R2denotes OH or NH2;

provided that

when A5indicates Dab, Dap, Lys Il is Orn,

And2denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

A3denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

And4means 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl) or Pff,

when And5deleterows,

A3denotes a D-Bip, D-Bpa, D-Dip; or

And4means 2Fua, Pff, Taz or Thr(Bzl); or

And1denotes Apc and

And2denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

A3denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

And4means 2Thi, 3Thi, Orm, 2Pal, 3Pal or 4Pal.

A preferred compound of formula (I), designated as compound from the group 1, is a compound of formula (I), where:

And1indicates Aib, Apc or N-Inp;

And2denotes a D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Trp;

A3denotes a D-Bal, D-Bpa, D-Dip, D-1Nal, D-2Nal or D-Trp;

And4indicates Orn, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi or Thr(Bzl); and

A5is Apc, Lys, or deleterow

or their pharmaceutically acceptable salts.

The preferred compound of group 1, designated as compound from group 1A, represents a connection, Opredelenie the following formula:

A1denotes Apc or H-Inp;

A2denotes a D-Bal, D-Bip, D-1Nal or D-2Nal;

A3denotes a D-Bal, D-1Nal, D-2Nal or D-Trp;

A4means 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi or Thr(Bzl);

or their pharmaceutically acceptable salts.

Another preferred compound of formula (I), hereafter is obtained as the compound of group 2, is a compound defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-NH2;

H-Inp-D-1Nal-D-Trp-3Pal-NH2;

H-Inp-D-Bip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-Dip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Bal-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Trp-D-2Nal(ψ)-Pim;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-1Nal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH ;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Fua-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Fua-NH2;

H-Apc-D-1Nal-D-Trp-2Pal-NH2;

H-Apc-D-1Nal-D-Trp-3Pal-NH2;

H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-3Thi-Lys-NH2;

H-Apc-D-1Nal-D-Trp-3Thi-NH2;

H-Apc-D-1Nal-D-Trp-4Pal-NH2;

H-Apc-D-1Nal-D-Trp-Pff-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Pff-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Pff-NH2;

H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH2;

H-Apc-D-2Nal-D-Trp-2Fua-Lys-NH2;

H-Apc-D-2Nal-D-Trp-2Fua-NH2;

H-Apc-D-2Nal-D-Trp-2Pal-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-2Nal-D-Trp-3Pal-NH2;

H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH2;

H-Apc-D-2Nal-D-Trp-3Thi-Lys-NH2;

H-Apc-D-2Nal-D-Trp-3Thi-NH2;

H-Apc-D-2Nal-D-Trp-4Pal-NH2;

H-Apc-D-2Nal-D-Trp-Pff-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Apc-D-2Nal-D-Trp-Pff-NH2;

H-Apc-D-2Nal-D-Trp-Taz-Apc-NH 2;

H-Apc-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Bal-2Fua-Apc-NH2;

H-Apc-D-Bal-D-Bal-2Fua-Lys-NH2;

H-Apc-D-Bal-D-Bal-2Fua-NH2;

H-Apc-D-Bal-D-Bal-2Pal-NH2;

H-Apc-D-Bal-D-Bal-2Thi-Apc-NH2;

H-Apc-D-Bal-D-Bal-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Bal-2Thi-NH2;

H-Apc-D-Bal-D-Bal-3Pal-NH2;

H-Apc-D-Bal-D-Bal-3Thi-Apc-NH2;

H-Apc-D-Bal-D-Bal-3Thi-Lys-NH2;

H-Apc-D-Bal-D-Bal-3Thi-NH2;

H-Apc-D-Bal-D-Bal-4Pal-NH2;

H-Apc-D-Bal-D-Bal-Pff-Apc-NH2;

H-Apc-D-Bal-D-Bal-Pff-Lys-NH2;

H-Apc-D-Bal-D-Bal-Pff-NH2;

H-Apc-D-Bal-D-Bal-Phe-Apc-NH2;

H-Apc-D-Bal-D-Bal-Phe-Lys-NH2;

H-Apc-D-Bal-D-Bal-Phe-NH2;

H-Apc-D-Bal-D-Bal-Taz-Apc-NH2;

H-Apc-D-Bal-D-Bal-Taz-Lys-NH2;

H-Apc-D-Bal-D-Bal-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Fua-Apc-NH2;

H-Apc-D-Bal-D-Trp-2Fua-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Fua-NH2;

H-Apc-D-Bal-D-Trp-2Pal-NH2;

H-Apc-D-Bal-D-Trp-3Pal-NH2;

H-Apc-D-Bal-D-Trp-3Thi-Apc-NH2;

H-Apc-D-Bal-D-Trp-3Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-3Thi-NH2;

H-Apc-D-Bal-D-Trp-4Pal-NH2;

H-Apc-D-Bal-D-Trp-Pff-Apc-NH2;

H-Apc-D-Bal-D-Trp-Pff-Lys-NH2;

H-Apc-D-Bal-D-Trp-Pff-NH2;

H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;

H-Inp-D-1Nal-D-Bal-2Fua-NH2;

H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;

H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;

H-Inp-D-1Nal-D-Bal-Pff-NH2;

H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Bal-Taz-Lys-NH2;

H-Inp-D-1Nal-D-Bal-Taz-NH2;

H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;

H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Fua-NH2;

H-Inp-D-1Nal-D-Tp-3Thi-Apc-NH 2;

H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Pff-NH2;

H-Inp-D-1Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;

H-Inp-D-2Nal-D-Trp-2Fua-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;

H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-3Thi-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;

H-Inp-D-Bal-D-Bal-2Fua-NHa

H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;

H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;

H-Inp-D-Bal-D-Bal-Pff-NH2;

H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;

H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;

H-Inp-D-Bal-D-Bal-Taz-NH2;

H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Fua-NH2;

H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;

H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;

H-Inp-D-Bal-D-Trp-Pff-NH2;

H-Inp-D-Bal-D-Trp-Taz-NH2;

H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2;

H-Inp-D-Bip-D-Bal-2Fua-NH2;

H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;

H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;

H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;

H-Inp-D-Bip-D-Bal-Pff-NH2; or

H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;

H-Inp-D-Bip-D-Bal-Taz-NH2;

H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;

H-Inp-D-Bip-D-Trp-2Fua-NH2;

H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;

H-Inp-D-Bip-D-Trp-Pff-Lys-NH2;

H-Inp-D-Bip-D-Trp-Pff-H 2;

H-Inp-D-Bip-D-Trp-Taz-Lys-NH2; or

H-Inp-D-Bip-D-Trp-Taz-NH2;

or its pharmaceutically acceptable salt.

The preferred compound of group 2, designated as compound from group 2A, is a compound defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Trp-D-2Nal(ψ)-Pim;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Nal-D-1Nal-Phe-Apc-NH 2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;

H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;

H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;

H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;

H-Apc-D-Bal-D-Trp-3Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Fua-Lys-NH2;

H-Apc-D-BalI-D-Trp-Pff-Lys-NH2;

H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;

H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;

H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;

H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;

H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;

H-Apc-D-Bal-D-Bal-Phe-Lys-NH2;

H-Apc-D-Bal-D-Bal-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Bal-3Thi-Lys-NH2;

H-Apc-D-Bal-D-Bal-Taz-Lys-NH2;

H-Apc-D-Bal-D-Bal-2Fua-Lys-NH2;

H-Apc-D-Bal-D-Bal-Pff-Lys-NH2;

H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;

H-Inp-D-1Nal-D-Bal-Taz-Lys-N 2;

H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;

H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;

H-Inp-D-1Nal-D-Trp-3Thi-Apc-NH2;

H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;

H-Apc-D-1Nal-D-Trp-3Thi-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Fua-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Pff-Lys-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-2Nal-D-Trp-3Thi-Lys-NH2;

H-Apc-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-2Nal-D-Trp-2Fua-Lys-NH2;

H-Apc-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;

H-Inp-D-Bip-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;

H-Inp-D-Bip-D-Trp-Pff-Lys-NH2;

H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;

H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;

H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;

H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2;

H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;

H-Apc-D-Bal-D-Trp-3Thi-Apc-NH2;

H-Apc-D-Bal-D-Trp-2Fua-Apc-NH2;

H-Apc-D-Bal-D-Trp-Pff-Apc-NH2;

H-Apc-D-Bal-D-Bal-Phe-Apc-NH2;

H-Apc-D-Bal-D-Bal-2Thi-Apc-NH2;

H-Apc-D-Bal-D-Bal-3Thi-Apc-NH2;

H-Apc-D-Bal-D-Bal-Taz-Apc-NH2;

H-Apc-D-Bal-D-Bal-2Fua-Apc-NH2;

H-Apc-D-Bal-D-Bal-Pff-Apc-NH2;

H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Pff-Apc-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Pff-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-NH2;

H-Inp-D-Bal-D-Trp-2Fua-NH2;

H-Inp-D-Bal-D-Trp-Pff-NH2;

H-Apc-D-Bal-D-Trp-3Thi-NH2;

H-Apc-D-Bal-D-Trp-2Fua-NH2;

H-Apc-D-Bal-D-Trp-Pff-NH2;

H-Apc-D-Bal-D-Trp-4Pal-NH2;

H-Apc-D-Bal-D-Trp-3Pal-NH2;

H-Apc-D-Bal-D-Trp-2Pal-NH2;

H-Inp-D-Bal-D-Bal-Taz-NH2;

H-Inp-D-Bal-D-Bal-2Fua-NH2;

H-Inp-D-Bal-D-Bal-Pff-NH2;

H-Apc-D-Bal-D-Bal-Phe-NH2;

H-Apc-D-Bal-D-Bal-2Thi-NH2;

H-Apc-D-Bal-D-Bal-3Thi-NH2;

H-Apc-D-Bal-D-Bal-Taz-NH2;

H-Apc-D-Bal-D-Bal-2Fua-NH2;

H-Apc-D-Bal-D-Bal-Pff-NH2;

H-Apc-D-Bal-D-Bal-4Pal-NH2;

H-Apc-D-Bal-D-Bal-3Pal-NH2;

H-Apc-D-Bal-D-Bal-2Pal-NH2;

H-Inp-D-1Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-2Fua-NH2;

H-Inp-D-1Nal-D-Trp-Pff-NH2;

H-Inp-D-1Nal-D-Bal-Taz-NH2;

H-Inp-D-1Nal-D-Bal-2Fua-NH2;

H-Inp-D-1Nal-D-Bal-Pff-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Trp-2Fua-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Apc-D-1Nal-D-Trp-3Thi-NH2;

H-Apc-D-1Nal-D-Trp-2Fua-NH2;

H-Apc-D-1Nal-D-Trp-Pff-NH2;

H-Apc-D-1Nal-D-Trp-4Pal-NH2;

H-Apc-D-1Nal-D-Trp-3Pal-NH2;

H-Apc-D-1Nal-D-Trp-2Pal-NH2;

H-Apc-D-2Nal-D-Trp-3Thi-NH2;

H-Apc-D-2Nal-D-Trp-2Fua-NH2;

H-Apc-D-2Nal-D-Trp-Pff-NH2;

H-Apc-D-2Nal-D-Trp-4Pal-NH2;

H-Apc-D-2Nal-D-Trp-3Pal-NH2;

H-Apc-D-2Nal-D-Trp-2Pal-NH2;

H-Inp-D-Bip-D-Trp-Taz-NH2;

H-Inp-D-Bip-D-Trp-2Fua-NH2;

H-Inp-D-Bip-D-Trp-Pff-NH2;

H-Inp-D-Bip-D-Bal-Taz-NH2;

H-Inp-D-Bip-D-Bal-2Fua-NH2; or

H-Inp-D-Bip-D-Bal-Pff-NH2;

or in pharmaceutical preparations is automatic acceptable salt.

Preferred compounds from group 2A, designated as compound from group 2B, is a compound defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-Trp-D-2Nal(ψ)-Pim;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2 ;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2; or

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim;

or its pharmaceutically acceptable salt.

The preferred compound of group 2B, designated as compound from group 2B-1, is a compound defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2; or

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

or its pharmaceutically acceptable salt.

Preferred compounds from group 2B-1, designated as compound from group 2B-1A, is a compound defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH ;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

or its pharmaceutically acceptable salt.

More preferred compound of group 2B-1, designated as compound from group 2B-1b, is a compound defined by the following formula:

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2; or

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

or its pharmaceutically acceptable salt.

Even more preferred compound of group 2B-1, designated as compound from group 2B-1C, is a compound defined by the following formula:

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

or its pharmaceutically acceptable salt.

Special is on the preferred compound of group 2B-1c represents a connection, defined by the formula:

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

or its pharmaceutically acceptable salt.

Another more preferred compound of group 2B-1, designated as compound from group 2B-1d, is a compound defined by the following formula:

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

or its pharmaceutically acceptable salt.

Another preferred compound of group 2B, designated as compound from group 2B-2, is a compound defined by the following formula:

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-Nal-D-Dip-Phe-NH2;

H-Inp-D-Trp-D-2Nal(ψ)-Pim;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim; or

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim;

or its pharmaceutically acceptable salt.

Preferred compounds from group 2B-2, designated as compound from group 2B-2A, is a compound defined by the following formula:

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-1Nal-D-Trp(ψ)-Pim; or

H-Inp-D-Bal-D-Trp(ψ)-Pim;

or their pharmaceutically acceptable salt.

Another before occhialino connection from group 2, identified as the compound of group 2C, is a compound defined by the following formula:

H-Inp-D-2Nal-D-Trp-3Pal-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-NH2;

H-Inp-D-1Nal-D-Trp-3Pal-NH2;

H-Inp-D-Bip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-2Nal-D-Trp-3Thi-NH2;

H-Inp-D-Dip-D-Trp-Phe-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Bal-Phe-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2; or

H-Apc-D-1Nal-D-Trp-Phe-NH2;

or its pharmaceutically acceptable salt.

The preferred compound of group 2C, indicated as the compound of group 2C-1, is a compound defined by the following formula:

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2; or

H-Apc-D-1Nal-D-Trp-Phe-NH2;

or its pharmaceutically acceptable salt.

Especially preferred compound of the present invention, designated as compound from group 3, is a compound defined by the following formula:

H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2; or

H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;

or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a method of determining the ability of the compound to contact the receptor cGy, where the method includes a step definition is of the ability of the compound to affect the binding of the compounds of the present invention of formula (I) or relating to any of the following groups 1, 1A, 2, 2A, 2B, 2B-1, 2B-1a, 2B 1b, 2B 1c, 2B-1d, 2B-2, 2B-2a, 2C or 2C-1, to a specific receptor, a fragment of a specified receptor to the polypeptide comprising the specified portion of the specified receptor, or a derivative of the specified polypeptide.

In another aspect, the present invention relates to a method of achieving a favorable effect in the subject, including the stage of introduction of a specified subject an effective amount of the compounds of formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt, where the specified effective amount is effective for assist in treatment (for example, to cure or reduce the severity of the condition) or prevent (e.g., to reduce the probability of early symptoms or deterioration of the condition or disorder.

In another aspect, the present invention relates to a method of stimulating the secretion of growth hormone in a subject in need of such stimulation, including the stage of introduction of a specified subject an effective amount of a ghrelin agonist of formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, the or group 2C-1, or its pharmaceutically acceptable salt, where the specified effective amount is an amount at least sufficient to achieve a significant increase in the secretion of growth hormone, and preferably to achieve a favorable effect in a patient.

In one embodiment, the specified aspect of the invention, consider the stimulation of growth hormone secretion is indicated for the treatment condition, deficient in growth hormone to increase muscle mass, increase bone density, treatment of disorders of sexual function in men or in women, promote capacity weight for easier weight maintenance to help maintain an active physical state, to facilitate the recovery of physical function and/or to facilitate increase appetite. Preferably specified relief in increasing weight, easy weight maintenance and/or promoting increased appetite is indicated for the patient with relevant disease or disorder, or being prepared for treatment, accompanied by weight loss. More preferably the aforementioned diseases or disorders accompanied by weight loss, includes anorexia, bulimia, cancer cachexia, AIDS, (e.g., depletion), cachexia and wasting in frail elderly people. Also preferably indicated the data types of treatment, accompanied by weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.

In another aspect, the present invention relates to a method of suppressing growth hormone secretion in a subject in need of such inhibition, comprising the stage of introduction of a specified subject an effective amount of a ghrelin antagonist of formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt, where specified the effective amount is at least the amount sufficient to achieve a noticeable decrease in the secretion of growth hormone, and preferably is an amount sufficient to achieve a favorable impact on the patient.

In one embodiment, the specified aspect of suppression of secretion of the growth hormone is indicated for the treatment of a disease or condition characterized by excessive secretion of growth hormone to assist in weight loss, to help reduce appetite, to facilitate weight maintenance to treat obesity, for diabetes, for treatment of complications of diabetes, including retinopathy and/or for the treatment of cardiovascular disease is.

In a preferred embodiment, the specified aspect of the present invention overweight is a factor affecting the disease or condition, including hypertension, diabetes, dyslipidemia, cardiovascular disease, gallbladder stones, osteoarthritis and various types of cancer. More preferably the specified assistance in reducing weight can reduce the likelihood of such diseases or conditions. In addition, more preferably specified assistance in weight reduction includes, at least partially, the treatment of such diseases or conditions.

The way the effect of the ghrelin agonist in a subject, comprising the stage of introduction of a specified subject an effective amount of one or more agonists of the ghrelin of the formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt, where the specified effective amount is an amount least sufficient to achieve a significant increase secretion of growth hormone and preferably is an amount sufficient to achieve a favorable impact on the patient.

In another aspect of the present invention relative to the Xia to the way the effect of the antagonist of ghrelin from the subject, including the stage of introduction to the subject an effective amount of one or more of ghrelin antagonists of formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt, where the specified effective amount is an amount at least sufficient to achieve a noticeable decrease in the secretion growth hormone, and preferably is an amount sufficient to achieve a favorable impact on the patient.

Compounds of the present invention are compounds active against receptor cGy. These compounds can be contacted with the receptor and preferably to stimulate the activity of the receptor. Thus, the connection of the present invention is useful as a functional analog of ghrelin, and as a tool for research and/or as a drug.

In the aspect of application as a tool for research mainly discusses the use of the compounds of the present invention in the presence of receptor cGy or its fragment. Receptor cGy may be present in different environments, such as subject, related either to the mammal, Lieb is to the whole cell, or to a fragment of the cell membrane. Examples of use as a tool for research include screening for compounds active against receptor cGy, the detection of the receptor cGy in a sample or preparation and identification of the role or effect of ghrelin.

One aspect of the present invention relates to a method of screening ghrelin agonists and/or antagonists of ghrelin. Screening for agonists of the ghrelin may be performed, for example, when using the compounds of formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt, in a competitive experiment using the investigated compounds. Screening of antagonists, ghrelin may be performed, for example, when using the compounds of formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt, to generate activity against receptor cGy with subsequent determination of the ability of the compounds to alter the activity of the receptor cGy.

Another aspect of the present invention relates to a method of screening compounds capable of is about to contact the receptor cGy. This method includes a step of determining the ability of the compounds to affect the binding of the compounds of formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt with the ligand, with a fragment of the receptor, including the binding site of ghrelin, a polypeptide, including the selection, or derivatives of such polypeptide.

Agonists of the ghrelin can be used to achieve a favorable effect in the subject. For example, ghrelin induces the release of growth hormone from cells primary cultures of pituitary-dependent dose-dependent manner, without stimulating the release of other pituitary hormones. When intravenous injection shot rats ghrelin stimulates pulsating release of growth hormone (Kojima et al., Nature 1999, 402, 656-660). Thus, a non-exhaustive list of examples for which this benefit can be shown, includes: treatment status, deficient rostovomu hormone, increase muscle mass, increase bone density, treatment of sexual disorders in men or women, assistance for capacity weight, easy weight maintenance, and facilitating the maintenance of vigorous physical state relief for the recovery of physical function and/or assistance increase appetite. Assistance to increase weight, facilitating maintenance of weight loss or increased appetite especially useful in the case of a subject having the respective disease or condition, or which is subjected to treatment, followed by weight loss. Disease or condition accompanied by weight loss include, for example, anorexia, bulimia, cancer cachexia, AIDS, (e.g., depletion), cachexia, wasting in frail elderly people and other Kinds of treatment, accompanied by weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization, dialysis, etc.

Thus, another aspect of the present invention relates to a method of achieving a favorable effect in the subject, where the method includes a step of introducing a specified subject an effective amount of one or more compounds of the formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salt where the specified effective amount is effective to achieve a favorable effect in care (for example, to cure or reduce the severity of the condition) or prevent (e.g., to reduce the probability of early manifestations or approving the surveillance state) of the disease or disorder.

In a preferred embodiment, the above described mode of carrying out the present invention indicated favorable effects include stimulation of the secretion of growth hormone in a subject in need of such stimulation, including the stage of introduction to the subject an effective amount of one or more compounds of the formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or its pharmaceutically acceptable salts, where the specified effective amount is an amount at least sufficient to achieve a significant increase secretion of growth hormone, and preferably is an amount sufficient to achieve a favorable impact on the patient.

In a more preferred embodiment, the above-described method specified stimulation of the secretion of the growth hormone is indicated for the treatment condition, deficient in growth hormone for increasing muscle mass, increasing bone density, for the treatment of disorders of sexual function in men or women, to promote capacity weight for easier weight maintenance to help maintain an active physical state, to facilitate the recovery of physical function and/or purpose of the promotion is the major increase appetite.

In another preferred embodiment, the above-described method specified assistance to the building weight, easy weight maintenance and/or promotion of appetite is indicated for the patient with relevant disease or disorder, or who are being treated, followed by weight loss. More preferably the aforementioned diseases or disorders accompanied by weight loss include anorexia, bulimia, cancer cachexia, AIDS, (e.g., depletion), cachexia and wasting in frail elderly people.

In another preferred embodiment, the above-described method, these kinds of treatment, accompanied by weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization, dialysis, etc.

The ghrelin antagonists can also be used to achieve favorable effects on humans. For example, the antagonist of ghrelin can be used to facilitate weight loss, to help reduce appetite, to facilitate weight maintenance to treat obesity, for diabetes, for treatment of complications of diabetes, including retinopathy, and/or for the treatment of cardiovascular diseases. Overweight is a factor that makes an additional contribution to the development of various diseases, including hypertension, d is the Abete, dyslipidemia, cardiovascular disease, gallbladder stones, osteoarthritis and some forms of cancer. Impact to reduce weight can be used, for example, and to reduce the chance of developing these diseases, and as an integral component of the treatment of such diseases.

Compounds of the present invention can also be used to antagonization effect of ghrelin in vitro and in vivo. Thus, another aspect of the present invention relates to a method for suppressing the secretion of growth hormone in a subject in need of such suppression, including the stage of introduction to the subject an effective amount of one or more compounds of the formula (I), group 1, group 1A, group 2, group 2A, group 2B, group 2B-1, group 2B-1A, group 2B-1b, group 2B-1c, group 2B-1d, group 2B-2, group 2B-2a, group 2C, or group 2C-1, or pharmaceutically acceptable salts, where the specified effective amount is an amount at least sufficient to achieve a noticeable decrease in the secretion of growth hormone, and preferably is an amount sufficient to achieve a favorable impact on the patient.

In a preferred embodiment, the above-described method specified suppression of secretion of the growth hormone is indicated for the treatment of a disease or condition, the characteristic is carsologica by excessive secretion of growth hormone, to assist in weight loss, to help reduce appetite, to facilitate weight maintenance to treat obesity, for diabetes, for treatment of complications of diabetes, including retinopathy, and/or for the treatment of cardiovascular diseases.

In a more preferred embodiment, the above method of excess weight is a factor contributing an additional contribution to the development of the specified disease or condition, including hypertension, diabetes, dyslipidemia, cardiovascular disease, gallbladder stones, osteoarthritis and various forms of cancer.

In another preferred embodiment, the above-described method specified assistance in weight reduction reduces the likelihood of developing such diseases or conditions and/or the specified assistance in weight reduction represents at least part of the treatment of such diseases or conditions.

As can be appreciated by the experts in this field, ghrelin and its agonists can be used to achieve a beneficial effect on the cardiovascular system (Nagaya et al., Regul Pept. 2003 Jul 15: 114(2-3): 71-77). For example, it is known that ghrelin inhibits apoptosis of cardiomyocytes and endothelial cells in vitro that repeated administration of ghrelin improves the structure and function of cardiac tissue and weakens the development is the development of cardiac cachexia in rats with heart failure and that ghrelin reduces systemic vascular resistance and increases cardiac output in patients with heart failure (Id). Thus, it is shown that ghrelin and ghrelin agonists are potential drugs for the treatment of severe chronic heart failure.

In a particularly preferred embodiment, each of these ways of using the ghrelin agonist, in the present invention, a ghrelin agonist is a compound of the formula:

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

or its pharmaceutically acceptable salt.

One or more compounds of the present invention can be administered to a subject. The term "entity" in the context of the present description refers to the mammal or animal, non-mammal, including, without limitation, human, rat, mouse, or farm animals. The reference to the optional subject indicates that the subject has a disease or disorder. Thus, the term "subject" includes in addition to a mammal or an animal, other than a mammal, to which a dose of the analogue of ghrelin in the ongoing experiment, a mammal or an animal, other than a mammal undergoing treatment in order to facilitate disease or condition, as well as a mammal or an animal, other than a mammal undergoing preventive treatment with the purpose of delay or is already active is of manifestations of the disease or disorder.

Other features and advantages of the present invention will become apparent from the following specific description, including various examples. The examples illustrate various components and techniques useful in the practice of implementation of the present invention. These examples do not limit the scope of the invention. Based on the above description, any person skilled in the art can identify and use other components and methods that are useful for implementing the present invention.

Unless explicitly noted, all amino acids that have one chiral center, is given in the form of L-enantiomer. Link to derivative indicates a reference to a modified amino acid, such as the corresponding D-amino acid, N-alkylaminocarbonyl, β-labeled amino acid or amino acid.

DETAILED description of the INVENTION

The present invention relates to peptidyl analogues active against receptor cGy. Human ghrelin is a modified peptide of 28 amino acids in which the hydroxyl group of serine etherification n-octane acid (Kojima et al., Nature 1999, 402, 656-660, and Kojima, (Abstract), Third International Symposium on Growth Hormone Secretagogues, Keystone, Colorado, USA 2000, February 17-19).

The number of amino acids found in the compounds of the present invention, presents the trail the way:

A3c1-amino-1-cyclopropanecarbonyl acid
A4C1-amino-1-cyclobutanecarbonyl acid
A5C1-amino-1-cyclopentanecarbonyl acid
A6C1-amino-1-cyclohexanecarbonyl acid
Abuα-aminobutyric acid
Acc1-amino-1-cyclo(C3-C9)alkalicarbonate acid
Act4-amino-4-carboxytetramethyl, for example:

Aibα-aminoadamantane acid
Ala or Aalanine
β-Alaβ-alanine
Apcaminopiperidine acid, for example:

Arg or Rarginine
hArghomoarginine
Asn or Nasparagine
Asp or Daspartic acid
Bal3-benzothiadiazin, for example:

Bip4,4'-biphenylene, for example:

Bpa4-benzylpenicillin, for example:

Chaβ-cyclohexylamin
Cys orcysteine
Dab2,4-diaminopentane acid, (α,γ-diaminobutane acid)
Dap2,3-diaminopropionic acid, (α,β-diaminopropionic acid)
Dipβ,β-diphenylalanine, for example:

Dhp3,4-dihydropyran
Dmt5,5-dimethylthiazolidine-4-carboxylic acid
2Fuaβ-(2-furyl)alanine, for example:

Gln or Qglutamine
Glu or Eglutamic acid
Gly or Gglycine
His or Hhistidine
3HypTRANS-3-hydroxy-L-Proline, i.e. (2S,S)-3-hydroxypyrrolidine-2-carboxylic acid
4Hyp4-hydroxyproline, i.e. (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid
Ile or Iisoleucine
Incindolin-2-carboxylic acid
Inpisonicotinoyl acid, for example:

Ktp4-metoprolol
Leu or Lleucine
hLeuhemolysin
Lys or Klysine
Met or Mmethionine
1Nalβ-(1-naphthyl)alanine
2Nalβ-(2-naphthyl)alanine
Nlenorleucine
NvaNorvaline
Oicoctahedron-2-carboxylic acid
Ornornithine
2Palβ-(2-pyridyl)alanine, for example:

3Palβ-(3-pyridyl)alanine, for example:

4Palβ-(4-pyridyl)alanine, for example:

Pffpentacarbonyliron, for example:

Phe or Fphenylalanine
hPhehomophenylalanine
Pim2'-(4-phenyl)imidazolyl, for example:

Pippipecolinate acid
Pro or PProline
Ser or Sserine
Tazβ-(4-thiazolyl)alanine, for example:

2Thiβ-(2-thienyl)alanine, for example:

3Thiβ-(3-thienyl)alanine, for example:

Thr or Tthreonine
Thzthiazolidin-4-carboxylic acid
Tic1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
Tletert-leucine
Trp or Wtryptophan
Tyr or Ytyrosine
Val or Vvaline

Some other abbreviations used in the present invention, are defined as follows:

Boc: tert-butyloxycarbonyl

Bzl: benzyl

DCM: dichloromethane

DIC: N,N-diisopropylcarbodiimide

DIEA: diisopropylethylamine

Dmab: 4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohex)-3-methylbutyl)-amino}benzyl

DMAP: 4-(dimethylamino)pyridine

DMF: dimethylformamide

DNP: 2,4-dinitrophenyl

Fmoc: fluorenylmethoxycarbonyl

HMTU: hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium

cHex: cyclohexyl

HOAT: hexaphosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium

HOBt: 1-hydroxy-benzotriazol

HOSu: N-hydroxysuccinimide

Mmt: 4-methoxytrityl

NMP: N-organic

Pbf: 2,2,4,6,7-pentamethylcyclopentadiene-5-sulfonyl

tBu: tert-butyl

TIS: triisopropylsilane

TOS: tosel

trt: trail

TFA: triperoxonane acid

TFFH: hexaphosphate tetramethylguanidine

Z: benzyloxycarbonyl

Unless otherwise specified, the abbreviation of amino acids (e.g., Ala) in this description refers to the structure-NH-C(R)(R')-CO-, where R and R'each, independently denotes hydrogen or a side chain amino acids (for example, R=CH3and R'=H in the case of Ala) R and R' can be connected with the formation of a cyclic system.

The term "alkyl" refers to a hydrocarbon group containing one or more carbon atoms, where many atoms of carbon in them is connected by single bonds. Alkyl hydrocarbon group may be linear or contain one or more branched or cyclic groups.

The term "substituted alkyl" refers to an alkyl in which one or more hydrogen atoms in the hydrocarbon group substituted by one or more substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -C1-2of alkyl, substituted by 1-6 atoms of halogen, -CF3, -OCH3, -OCF3and -(CH2)0-4-COOH. In various embodiments of the invention may contain 1, 2, 3, or 4 substituent. The presence of -(CH2)0-4-COOH leads to the formation of alkyl acid. Examples of alkyl acids containing -(CH2)0-4-COOH or consisting of the specified component, include 2-norbornanamine acid, tert-butyric acid and 3-cyclopentylpropionic acid.

The term "heteroalkyl" refers to an alkyl in which one or more carbon atoms in the hydrocarbon group substituted by one or more group of the following: amino, amido, or carbonyl. In other embodiments of the invention have one or two gets the rotoma.

The term "substituted heteroalkyl" refers to heteroalkyl, in which one or more hydrogen atoms in the hydrocarbon group substituted by one or more substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -C1-2of alkyl, substituted by 1-6 atoms of halogen, -CF3, -OCH3, -OCF3and -(CH2)0-4-COOH. In other embodiments of the invention are 1, 2, 3, or 4 substituent.

The term "alkenyl" refers to a hydrocarbon group, constructed from two or more carbon atoms which has one or more carbon-carbon double bonds. Alchemilla hydrocarbon group may be linear or may contain one or more branched cyclic groups.

The term "substituted alkenyl" refers to alkenyl, in which one or more hydrogen atoms substituted by one or more substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -C1-2of alkyl, substituted by 1-6 atoms of halogen, -CF3, -OCH3, -OCF3and -(CH2)0-4-COOH. In other embodiments of the invention are 1, 2, 3, or 4 substituent.

The term "aryl" refers to optionally substituted aromatic group, in which eritza at least one cycle, having a conjugate system of PI electrons, which contains up to two conjugated or condensed cyclic systems. Aryl includes carbocyclic aryl, heterocyclic aryl and burilnye group. Preferably aryl is a 5 - or 6-membered cycle. Preferred heterocyclic atoms for the aryl are one or more sulfur atoms, oxygen and/or nitrogen. Examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, and 9-anthracene. Aryl substituents are selected from the group consisting of-C1-4of alkyl, -C1-4alkoxy, halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NO2, -C1-2the alkyl substituted by 1-5 halogen atoms, -CF3, -OCF3and -(CH2)0-4-COOH. In other embodiments of the invention the aryl contains 0, 1, 2, 3, or 4 substituent.

The term "alkylaryl" refers to alkyl attached to the aryl.

In the presence of s-end connection of the present invention imidazole fragment, a non-amino acid (for example, Pim, defined above), it should be understood that the imidazole fragment is attached to an adjacent amino acid through pseudopeptide bond, where the bond is formed between the carbon in position 2 of the imidazole ring and the alpha carbon of the amino acids. For example, in that case is, when the adjacent amino acid is a D-tryptophan (D-Trp) and imidazole fragment is a Pim-end of the peptide will look as follows:

For clarity it should be noted that in the formula specified connection a connection is denoted by a single Greek letter "ψ". For example, written in the form H-Inp-D-Trp-D-2Nal(ψ)-Pim formula refers to the following structure:

The present invention includes diastereomers, as well as their racemic and resolved enantiomerically pure form. Analogs of ghrelin may contain D-amino acids, L-amino acids or a combination thereof. Preferably the amino acids present in the analogue of ghrelin in the form of L-enantiomers.

Preferred derivatives of analogues of the present invention include D-amino acids, N-alkylaminocarbonyl, β-amino acids and/or one or more labeled amino acids (including the option labeled D-amino acids, N-alkylamines or β-amino acids). The term "labeled derivative" indicates a change of the amino acid or derived amino acids, achieved by using a detectable label. Examples of detectable labels include fluorescent, enzymatic or radioactive label. As the label type and its position in the molecule can affect the activity of the analog. EDI should be selected and built so to not substantially alter the activity of the analogue of ghrelin in relation to receptor cGy. The impact of a specific label and its provisions on the activity of ghrelin can be determined using tests to measure the activity of ghrelin and/or the level of its binding.

The protective group is covalently attached to the C-terminal carboxyl group reduces the reactivity of the carboxyl end in vivo. The protective group for carboxyl end is preferably attached to α-carbonyl group of the last amino acid. Preferred protective groups for carboxyl end include amide, methylamide and ethylamide.

Examples

Below examples are given to further illustrate various features of the present invention. The examples also explain the techniques useful in the practice of implementation of the present invention. These examples do not limit the present invention.

Synthesis

Compounds of the present invention can be obtained using the techniques described in the above examples, as well as methods known in the art. For example, the polypeptide segment similar RING may be chemically or biochemically synthesized and modified. Examples of methods used, the share of biochemical synthesis, including the who, the introduction of nucleic acid into the cell and subsequent expression of the nucleic acid, described in Ausubel (Ausubel, Current Protocols in Molecular Biology, John Wiley, 1987-1998, and Sambrook et al., in Molecular Cloning, A Laboratory Manual, 2ndEdition, Cold Spring Harbor Laboratory Press, 1989). Methods of chemical synthesis of polypeptides are also known to specialists in this field (See, for example, Vincent in Peptide and Protein Drug Delivery, New York, N.Y., Dekker, 1990). For example, the peptides of the present invention can be obtained using standard methods of solid-phase peptide synthesis (See, for example, Stewart, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984)).

Deputy R1in the above formula (I) may be attached to the free amine N-terminal amino acids using standard methods known in the art. For example, alkyl groups such as, in particular, (C1-C30)alkyl, can be attached using reductive alkylation. Hydroxyalkyl group, for example, (C1-C30)hydroxyalkyl, can be attached using reductive alkylation, in which the free hydroxy-group protect using complex t-butyl ether. Acyl group, for example, SOY1can be attached by binding of the free acid, for example, E1COOH, with free amine N-terminal amino acids prepared by mixing the resin with three molar equivalents of free the acid and diisopropylcarbodiimide in methylene chloride for about one hour. If the free acid contains a free hydroxy-group, for example, p-hydroxyphenylpropionic acid, the binding should be done using additional three molar equivalents of HOBT.

The peptides of the present invention can also be synthesized in parallel on the synthesizer AST 396 (Multiple Biomolecular Synthesizer (Advanced ChemTech, Louisville, KY)) as follows. The synthesizer is programmed to conduct the following reaction cycle: (1) washing with dimethylformamide (DMF), (2) removing the protective Fmoc group with 20% piperidine in DMF for 1×, 5 minutes and 1×25 minutes, (3) rinsing with DMF, (4) linking with Fmoc amino acid for 1 hour at room temperature in the presence of diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) and (5) repeating steps (4).

Examples 1-65

Each of the reaction cells contains 0,0675 mmol resin Rink Amide MBHA (substitution level=0,72 mmol/g) (Novabiochem, San Diego, CA). Use the following Fmoc amino acids (Novabiochem, San Diego, CA; Chem-Impex International, Wood Dale, IL; SyntheTech, Albany, OR; Core Pharma, High Point, NC): Fmoc-Lys(Boc)-OH, Fmoc-Phe-OH, Fmoc-H-Inp-OH, Fmoc-D-1Nal-OH, Fmoc-D-2Nal-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-3Pal-OH, Fmoc-4Pal-OH, Fmoc-Orn(Boc)-OH, Fmoc-D-Bip-OH, Fmoc-Thr(Bzl)-OH, Fmoc-Pff-OH, Fmoc-2Thi-OH, Fmoc-Taz-OH, Fmoc-D-Dip-OH, Fmoc-D-Bpa-OH, Fmoc-D-Bal-OH and Fmoc-Apc(Boc)-OH.

Each of Fmoc-amino acid was dissolved in 0,3N solution of HOBt in DMF), where the concentration of the obtained Fmoc-amino acids is 0,3N. For each of the th binding assays using a fourfold excess (0.27 mmol, 0.9 ml 0,3N solution) Fmoc-amino acids. In each binding assays using DICK (0.27 mmol, 0.6 ml 0,45N solution of DIC in DMF) as interfacing reagent for each binding assays. The removal of the protective groups is carried out by using 20% piperidine in DMF (2×1.5 ml per residue).

Peptides segregate from the resin by treating the combination of the peptide-resin 8% triisopropylsilane (TYPE) triperoxonane acid (TFU) (1.5 ml in the reaction cell) at room temperature for 2 hours. The resin is removed by filtration. Each of the obtained filtrate is diluted in a centrifugal tube to 25 ml of ether. Obtained in each test tube and the precipitate centrifuged and the solvent is separated from the precipitate by decantation. Then the precipitate in each tube was dissolved in methanol (3 ml) and diluted with water (1 ml). Cleaning products carried out by the method of preparative HPLC with phase reversal using a column (100×21,20 mm, 5 μm) LUNA 5 μm C8(2) (Phenomenex, Torrance, CA). To obtain each of the peptides are elution of column with a linear gradient from 85% a and 15% to 25% a and 75% b for 15 minutes at 25 ml/min And represents 0.1% of TFU in water and represents 0.1% of TFU in a mixture of acetonitrile/water (80/20, vol/vol). Faction evaluate the analytical method HPLC and the fractions that contain pure product, are combined and lyophilizers dry.

p> The yield varies from 13% to 71% and the purity of each of the products obtained in examples 1-65 exceeds 94% by results of the analysis using the method of analytical HPLC. Analyze the method of spectrometry with ionization by electroepilation (ES-MS), and the obtained value of molecular weight is consistent with the calculated molecular masses. The results are shown in table 1 below.

Examples 66-69

The products of examples 66-69 synthesized by the following procedure.

1.a. BOC-(D)-Trp-OH (4.0 g, 13,1 mmol) (Novabiochem, San Diego, CA) in methanol (36 ml) and Cs2CO3(2.14 g, to 6.57 mmol) in water (10 ml) are combined and the mixture is shaken to the formation of homogeneous mixture. The solvents are removed in vacuo and the residue is dissolved in DMF (45 ml). To the solution was added 2-bromoacetophenone (2,61 g, 13,2 mmol) in DMF (9 ml) and the solution stirred for 30 minutes at room temperature. The cesium bromide is removed by filtration and the filtrate concentrated in vacuo. The obtained concentrate was dissolved in xylene (45 ml), add NH4OAc (17.1 g) and the solution heated at boiling temperature under reflux for 1 hour. The cooled solution is washed several times with saturated solution of NaHCO3(45 ml) and then saturated NaCl. The obtained organic layer is purified flash chromatography with education 4.1 g (77%) of intermediate product 1A, shown in scheme 1A ("EDINENIE 1A").

Scheme 1A

1b. Compound 1A (403 mg) is subjected to unlock using a mixture triperoxonane acid (TFU) (8 ml), dichloromethane (DHM) (8 ml) and triisopropylsilane (TYPE C) (1,4 ml). After stirring for one hour the solution is concentrated in a stream of nitrogen. The residue is dissolved in DHM (40 ml), washed two times with saturated solution of NaHCO3(40 ml) and then dried over Na2SO4obtaining a solution of the intermediate product 1B, shown in scheme 1B below.

Scheme 1B

1C.-f. This solution of the intermediate product 1B is divided into four equal parts, and associated with pre-activated complex HOBT esters of FMOC-protected amino acids, as shown below in reaction schemes 1C, 1D, 1E and 1F. In each of examples 66, 67, 68 and 69 are used amino acid represents the following amino acid:

Example 66: FMOC-D-2Nal-OH (130 mg, 0.30 mmol) (Synthetech, Albany, Oregon)

Example 67: FMOC-D-1Nal-OH (130 mg, 0.30 mmol) (Advanced Chemtech Louisville, KY)

Example 68: FMOC-D-Bal-OH (132 mg, 0.30 mmol) (Chem Impex, Wood Dale, IL)

Example 69: FMOC-DSer(Bzl)-OH (124 mg, 0.30 mmol) (Chem Impex, Wood Dale, IL).

Each of these amino acids is subjected to pre-activation under the action of HOBT (46 mg, 0.30 mmol) and DICK (38 mg, 0.30 mmol) in DHM (5 ml) for ten minutes before adding to one of che is ireh portions of the above solution of the intermediate product 1B. Then spend the binding reaction for 30 minutes at room temperature.

Scheme 1C

Scheme 1D

Scheme 1E

Scheme 1F

1g.-j. The FMOC group is removed from each of the obtained compounds 1C, 1D, 1E and 1F by adding Tris(2-amino-ethyl)amine (0.9 ml) to the respective reaction mixtures obtained in the preliminary stage, and stirred for 30 minutes at room temperature. Then the reaction mixture containing an unlocked connection, washed three times with 10% phosphate buffer, pH 5.5 (10 ml).

The obtained solutions with the free amine is associated with pre-activated complex HOBT esters of FMOC - or BOC-protected amino acids as follows:

Example 66: FMOC-Inp-OH (105 mg, 0.30 mmol) (Chem Impex, Wood Dale, IL)

Example 67: FMOC-Inp-OH (105 mg, 0.30 mmol)

Example 68: BOC-Inp-OH (68,3 mg, 0.30 mmol) (Bachem Torrance, Calif)

Example 69: BOC-Aib-OH (to 60.6 mg, 0.30 mmol) (Bachem Torrance, Calif).

Each of these amino acids is subjected to pre-activation under the action of HOBT (46 mg, 0.30 mmol) and DICK (38 mg, 0.30 mmol) in DHM (5 ml) for ten minutes before adding to the corresponding amine, which removed the protective group. This is followed by a reaction of binding over the od of the CSOs hours at room temperature.

Removing the protective groups: compounds of examples 66-67. The FMOC group is removed from the obtained FMOC-protected compounds by adding Tris(2-amino-ethyl)amine (0.9 ml) followed by stirring for 30 minutes. Unlocked connections washed three times with 10% phosphate buffer, pH 5.5 (10 ml) and collect the crude products in the form of sediment.

Removing the protective groups: compounds of examples 68-69. BOC-protected compounds purified flash chromatography and then subjected to unlock within one hour by adding TYPE C (0,50 ml)TFU (0,50 ml) in DHM (2,75 ml). The crude products are then concentrated and dried in vacuum.

Purification by HPLC gives products with 5% and 29% yield compounds of examples 66 and 67, respectively, and 15% and 43% of the compounds of examples 68 and 69, respectively.

The above reaction the introduction of protective groups, linking and removal of the protective groups is shown below in reaction schemes 1G, 1H, 1I and 1J.

Scheme 1G

Scheme 1H

Scheme 1I

Scheme 1J

Example 70: H-Inp-D-Trp-D-2Nal(ψ)-Pim

The compound of example 70 synthesized by the following procedure.

A and a.: Compound 2A receives the same way to obtain the soedineniya 1A, using BOC-D-2Nal-OH and 2-bromoacetophenone as the original products.

Stage a and a. shown in figure 2A below.

Scheme 2A

2.b.1. Compound 2A (100 mg, 0,242 mmol) is subjected to unlock TFU (2 ml) and DHM (2 ml) for one hour. Volatile products are removed in a stream of nitrogen and the residue is dissolved in DHM (10 ml). The resulting solution was washed three times with saturated solution of NaHCO3(10 ml) to obtain the solution of compound 2A with a free amino group.

2.b.2. The active ester FMOC-D-Trp(BOC)-OH (153 mg, 0,290 mmol) obtained using N-hydroxysuccinimide (HOSu; 33 mg, 0,290 mmol) and DICK (37 mg, 0,290 mmol) in DHM (1.5 ml). After one hour diisopropylamino removed by filtration and the filtrate is added to the compound solution of 2A (in the form of a free amine). The resulting solution was diluted with DHM to 4 ml and carry out the binding reaction for 30 minutes.

Stage 2.b.1 and 2.b.2. shown in figure 2B below.

Scheme 2B

S. Compound 2B is subjected to unblock by adding Tris(2-amino-ethyl)amine (TAEA) (0.9 ml) to the above solution for the reaction the reaction of binding and stirred for 30 minutes at room temperature. Then, the solution is washed three times with saturated NaCl solution (10 ml) and then three times with 10% phosphate buffer, H 5,5 (10 ml) to obtain the solution of compound 2B with a free amino group.

S. The active ester of BOC-Inp-OH to 66.5 mg, 0,290 mmol) obtained using HOSu (33 mg, 0,290 mmol) and DICK (37 mg, 0,290 mmol) in DHM (1.5 ml). After one hour diisopropylamino removed by filtration and the filtrate is added to the compound solution of 2B (with a free amino group). The resulting solution was diluted with DHM to 4 ml and carry out the binding reaction for 12 hours.

The reaction mixture is washed three times with 10% phosphate buffer, pH 5.5 (10 ml) and dried over Na2SO4. The solvent is removed in vacuum and the concentrate purified flash chromatography.

S. The intermediate product is subjected to unlock using TFU (2,75 ml), and TYPE C (0.5 ml) in DHM (2,75 ml) for 30 minutes. Volatile products are removed from the reaction mixture in a stream of nitrogen and the residue triturated with ether (15 ml). After centrifugation, the ether is removed by decantation, and the obtained solid material is subjected to HPLC with obtaining purified connection 70 with the release of 39%.

Stage s and s, and s shown in scheme 2C below.

Scheme 2C

Other peptides of the present invention can be obtained by a specialist with an average level of knowledge in this field, using the synthesis procedures similar to the procedures described primarily above and/or specifically disclosed in the above examples, as connections, pollastrini the data in Table 1.

813,01 99
Table 1
Mol. weightMol. weight
Purity
Ex. No.Sequence(Calc.)(MS-ES)(%)
1H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2787,96787,496
2H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2787,96787,499
3H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2753,94753,498
4H-Inp-D-Bip-D-Trp-Phe-Lys-NH2813,01812,499
5H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2831,03830,498
6H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2876,92876,398
7H-Inp-D-2Nal-D-Trp-Thi-Lys-NH2793,00792.4 M.98
8H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2793,99793,497
9H-Inp-D-Dip-D-Trp-Phe-Lys-NH2812,498
10H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2841,02840,495
11H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2852,04851,399
12H-Inp-D-2Nal-D-Trp-3Pal-NH2659,79659,399
13H-Inp-D-2Nal-D-Trp-4Pal-NH2659,79659,398
14H-Inp-D-1Nal-D-Trp-3Pal-NH2659,79659,398
15H-Inp-D-Bip-D-Trp-Phe-NH2684,84684,399
16H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2702,85702,399
17H-Inp-D-2Nal-D-Trp-Pff-NH2748,75748,299
18H-Inp-D-2Nal-D-Trp-2Thi-NH2664,83664,299
19H-Inp-D-2Nal-D-Trp-Taz-NH2665,82665,398
20H-Inp-D-Dip-D-Trp-Phe-NH2684,84684,398
21H-Inp-D-2Nal-D-Dip-Phe-NH2695,86695,3
22H-Inp-D-Bal-D-Trp-Phe-NH2664,83664,397
23H-Inp-D-2Nal-D-Bal-Phe-NH2675,85675,299
24H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2787,96787,597
25H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2799,03798,499
26H-Inp-D-Bal-D-Trp-Phe-Lys-NH2793,00792.4 M.99
27H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2793,00792.4 M.99
28H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2784,96784,498
29H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2784,96784,498
30H-Inp-D-Bal-D-Trp-Phe-Apc-NH2790,99790,497
31H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2801,99801,498
32H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2808,02807,499
33H-Inp-D-1Nal-D-Trp-2Thi-NH2664,83664,298
34H-Apc-D-1Nal-D-Trp-Phe-NH2673,81673,399
35H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2793,99793,599
36H-Inp-D-Bal-D-Trp-Taz-Lys-NH2800,02799,499
37H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2809,00808,599
38H-Apc-D-Bal-D-Trp-Taz-Lys-NH2815,03814,499
39H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2814,04813,498
40H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2790,99790,597
41H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2797,01796,497
42H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2806,00805,597
43H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2812,03811,498
44H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2801,99801,598
45H-Apc-D-Bal-D-Trp-Phe-Lys-NH2808,02and 807.599
46 H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2799,97799,598
47H-Apc-D-Bal-D-Trp-Phe-Apc-NH2806,00805,598
48H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2811,00810,595
49H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2811,00810,596
50H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2813,01812,599
51H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2817,02816,596
52H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2817,02816,594
53H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2819,04818,599
54H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2819,04818,598
55H-Apc-D-1Nal-D-Trp-2Thi-NH2679,84of 679.298
56H-Apc-D-Bal-D-Trp-Phe-NH2679,84679,399
57H-Apc-D-1Nal-D-Trp-Taz-NH2680,83680,399
58H-Apc-D-Bal-D-Trp-2ThiNH 2685,87685,297
59H-Apc-D-Bal-D-Trp-Taz-NH2686,86686,299
60H-Apc-D-2Nal-D-Trp-2Thi-NH2679,84of 679.295
61H-Apc-D-2Nal-D-Trp-Taz-NH2680,83680,297
62H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2791,97791,598
63H-Inp-D-Bal-D-Trp-Taz-Apc-NH2798,00797,499
64H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2806,99806,599
65H-Apc-D-Bal-D-Trp-Taz-Apc-NH2813,02812,498
66H-Inp-D-2Nal-D-Trp(ψ)-Pim610,77611,499
67H-Inp-D-1Nal-D-Trp(ψ)-Pim610,77611,399
68H-Inp-D-Bal-D-Trp(ψ)-Pim616,79617,399
69H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim564,69565,399
70H-Inp-D-Trp-D-2Nal(ψ)-Pim610,77611,4 99

Biological testing

The activity of the compounds of the present invention in relation to receptor cGy can be determined and was determined using techniques such as described in the following examples section. In different variants of implementation of the present invention, the analogue of ghrelin has activity comprising at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% of the functional activity of ghrelin that is defined using one or more tests on the functional activity, as described below; and/or indicator IR50higher than about 1000 nm, higher than about 100 nm, or greater than about 50 nm when determining under test binding with the receptor, as described below. With regard to indicator IR50its higher value corresponds to higher activity and, thus, indicates a smaller amount required to achieve inhibition of the binding.

In tests to determine the ability of the compound to contact the receptor cGy use receptor cGy, a fragment of the receptor, including the binding site of ghrelin, a polypeptide comprising a fragment or derivative of the polypeptide. Preferably, in the test use the ut receptor cGy or its fragment. A polypeptide comprising a fragment of the receptor cGy, which binds ghrelin may also contain one or more sections of the polypeptide, non-receptor cGy. A derivative of this polypeptide includes a fragment of the receptor cGy, which binds ghrelin, together with one or more components not peptide.

Amino acid sequence of the receptor cGy involved in the binding, can be easily identified using labeled ghrelin or structural or functional analogs of ghrelin and various fragments of the receptor. Can use different strategies to select fragments to be tested in order to determine the binding site. Examples of such strategies include the identification of sequential fragments containing a length of about 15 amino acids beginning at N-end, and testing of longer fragments. If test longer fragments, the fragment that binds ghrelin, can be subdivided into other areas in order to identify the binding site with ghrelin. Used in studies on binding fragments can be obtained using the techniques of recombinant nucleic acids.

Test linking can be carried out using individual compounds or preparations containing different number of connections. The prep is at, containing a different number of compounds with the ability to bind to the receptor cGy, can be divided into smaller groups of compounds that may be analyzed to identify one or more compounds that bind to the receptor cGy. In one embodiment of the present invention in the test for binding use the study drug, which contains at least 10 connections.

Tests for linkage can be obtained using recombinant methods polypeptide receptor cGy present in different environments. These different types of environments include, for example, extracts of the cells and purified extracts of cells containing the polypeptide receptor cGy expressed on the basis of recombinant nucleic acids or natural nucleic acid, and includes, for example, using a purified polypeptide receptor cGy obtained recombinant methods or natural nucleic acid that is introduced into a different environment.

Screening for compounds active against receptor cGy

Screening for compounds active against receptor cGy, performed using recombinante downregulation of the receptor. Use recombinante downregulation of receptor cGy gives several advantages which, such as the ability to Express the receptor in a particular cell system, so that the reaction on the compound on the receptor cGy can be easily differentiated from the reaction on other receptors. For example, the receptor cGy can be expressed in cell lines, such as HEK 293, COS 7, and CHO, which normally does not expresses the receptor on the basis of the expression vector, whereas the same cell line without the expression vector can act as a control.

Screening of compounds that reduce the activity cGy receptor, carried out using a test functional analog of ghrelin. Using a functional analog of ghrelin in screening supports the activity of the receptor cGy. The influence of the studied compounds such activity may be defined to identify, for example, allosteric modulators and antagonists.

The activity of the receptor cGy can be measured using various techniques, such as detection of changes in intracellular conformation of the receptor cGy, in activities associated with G-proteins and/or intracellular carriers. Preferably the activity against receptor cGy determined using methods such as based on measurements of intracellular Ca2+. Examples of methods known in the art, which can be used in Atisa to determine the level of Ca 2+include the use of dyes, such as Fura-2, and Ca2+-sensitive bioluminescent reporter proteins, such as acorin. An example of a cell line using acorin that is used for determining the activity of a G protein is HEK293/aeq17. (Button et al., 1993. Cell Calcium 14, 663-671, and Feighner et al., 1999, Science 284, 2184-2188).

Chimeric receptors containing the binding site of ghrelin, functionally mated with another G-protein, can also be used to determine the activity of the receptor cGy. Chimeric receptor cGy contains N-terminal extracellular domain, a transmembrane domain, built of transmembrane sites, extracellular loop sections and the intracellular loop sections, and an intracellular carboxyl end. The methodology of the chimeric receptor and evaluation associated with G-protein reactions are described, for example, in the application for international patent WO 97/05252 and in U.S. patent No. 5264565, which are both included in the present description by reference.

Stimulation of the activity of the receptor cGy

Structural and/or functional analogs of ghrelin can be used to stimulate the activity of the receptor cGy. Such stimulation can be applied, for example, to study the effect of modulation of the receptor cGy, to study the effect of the secretion of growth hormone, for search or study and is tagonists ghrelin, or to achieve a favorable effect in the subject. The beneficial effects that can be achieved include one or more effects of the numbers below: treatment status, deficient rostovomu hormone, increase muscle mass, increase bone density, treatment of disorders of sexual function in men or women, to assist in capacity weight, easy weight maintenance, and facilitating the maintenance of vigorous physical condition, facilitating the recovery of physical function and/or assistance in increased appetite.

The increase in weight or appetite can be used to maintain weight, or to increase the weight, or to improve appetite in a subject with reduced weight or the patient having the disease or powergauge treatment, which affects the weight or appetite. In addition, for example, agricultural animals such as pigs, cows and chickens, may be given effect to increase the weight.

Subjects with reduced weight include those entities that have the weight of the body at the level of 10% or less, 20% or less, or 30% or less than the lower limit of the range of normal weight or body mass index (BMI). The BMI is based on measuring the ratio of height/weight and is determined by calculating the weight in kilograms and then dividing by the square of the height in meters. The "normal" range of values SSV is the rate of BMI for a person mainly is within 19-22. The "normal" range is renowned in this field and takes into account such factors as age of the subject, the height and body type.

Biological tests-examples

1. Test for binding to the receptor

A. Obtaining cells CHO-K1 expressing the human recombinant receptor cGy

cDNA for the human receptor means, promote the secretion of growth hormone (hGHS-R or the ghrelin receptor), clone within the polymerase chain reaction using RNA from human brain as template (Clontech, Palo Alto, CA), specific gene primers flanking the coding sequence of the full length hGHS-R (S:5'-ATGTGGAACGCGACGCCCAGCGAAGAG-3'(SEQ ID NO: 1) and AS: 5'-TCATGTATTAATACTAGATTCTGTCCA-3') (SEQ ID NO: 2) and set for PCR Advantage 2 PCR Kit (Clontech). The PCR product clone in the vector pCR2.1 using the kit to clone the Original TA Cloning Kit (Invitrogen, Carlsbad, CA). Human cGy-R full length subcloning in the expression vector mammalian pcDNA 3.1 (Invitrogen). Plasmid transferout the cell line Chinese hamster ovary CHO-K1 (American Type Culture Collection, Rockville, MD) according to the method using calcium phosphate (Wigler M, et al., Cell 11, 223, 1977). Clones of a single cell, stably expressing hGHS-R, is obtained by selection of transfected lines growing in cloning rings in environments RPMI 1640 with the addition of 10% calf serum and 1 mm sodium pyruvate with soda is the content of 0.8 mg/ml G418 (Gibco, Grand Island, NY).

C. Test the binding cGy-R

Membrane to study the binding of radioactive ligand can be obtained and was obtained by homogenizing the above cells CHO-K1 expressing the human recombinant receptor cGy in 20 ml of chilled on ice in 50 mm buffer Tris-HCl using a Brinkman transmitter station (Westbury, NY) (setting 6, 15 sec). The homogenates washed twice when conducting centrifugation (39000 g/10 minutes) and the resulting final centrifugation resuspended in 50 mm buffer Tris-HCl containing 2.5 mm MgCl2and 0.1% BSA. For the dough take an aliquot (0.4 ml) and incubated from 0.05 nm (125I)ghrelin (˜2000 Ci/mmol, Perkin Elmer Life Sciences, Boston, MA) with or without adding 0.05 ml of unlabeled competitive studied compounds in the present invention. After 60 minutes of incubation (4° (C) related (125I)ghrelin is separated from the free ghrelin by rapid filtration through filters GF/C (Brandel, Gaithersburg, MD), which were pre-soaked in 0.5% polyethylenimine/0.1% BSA. Then the filters are washed three times aliquot (5 ml) cooled on ice in 50 mm buffer Tris-HCl with addition of 0.1% bovine serum albumin and associated radioactivity remaining on the filters that determine quantitatively gamma spectrometer (LKB Wallac, Gaithersburg, MD). Specific binding determine the AC common associated ( 125I)ghrelin minus the amount that was linked in the presence of 1000 nm ghrelin (Bachem, Torrence, CA).

2. Test for functional activity cGy-R

A. Activity in vitro receptor cGy,

mediated mobilization of intracellular Ca2+

The above cells CHO-K1 expressing the human receptor cGy, collected after incubation in 0.3% EDTA/phosphate buffer saline (25° (C) and washed twice by centrifugation. The washed cells resuspended in buffered saline Hanks solution (HBSS) for making fluorescent indicator Ca2+Fura-2AM. Cell suspension containing approximately 106cells/ml, incubated with 2 μm Fura-2AM for 30 minutes at 25°C. Unsettled Fura-2AM is removed by two centrifugation in HBSS and the final suspension is transferred to a spectrophotometer (Hitachi F-2000)equipped with a magnetic mechanism for mixing and cuvette holder with adjustable temperature. After equilibration at 37°add compounds of the present invention for measuring the mobilization of intracellular Ca2+. The wavelengths of excitation and emission 340 and 510 nm, respectively.

C. Release/suppression of WG in vivo

As is well known in this field, the compounds can be evaluated for their ability to stimulate or suppress visualaid is the growth hormone (WG) in vivo. (See, for example, Deghenghi, R., et al., Life Sciences 54, 1321-1328 (1994); the Application for international patent No. WO 02/08250). So, for example, to determine the compound's ability to stimulate the release of WG in vivo specified connection can be injected subcutaneously for 10 days to rats at a dose of, for example, 300 mg/kg Circulating in the blood of the WG can be determined, for example, 15 minutes after injection and then a comparison with the level of WG in the control rats, which were injected only solvent.

Similar connections can be assessed on their ability to anlagenservice induced by ghrelin secretion of WG in vivo. Thus, the connection can be injected subcutaneously for 10 days to rats at a dose of, for example, 300 mg/kg together with ghrelin. And again the level of circulating in the blood of the WG can be determined, for example, 15 minutes after injection and then a comparison with the levels of WG in the control rats, which were injected only ghrelin.

Introduction

Compounds of the present invention can be incorporated into compositions and administered to the subject with the use described in this manual in accordance with well-known in this field techniques. The preferred route of administration ensures that an effective amount of the compound reaches the target organ. Guide introduction pharmaceutical prep the drugs, mainly known in this field (e.g., Remington''s Pharmaceutical Sciences, 18thEdition, Ed. Gennaro, Mack Publishing, 1990 and Modem Pharmaceutical 2ndEdition, Eds. Banker & Rhodes, Marcel Dekker, Inc., 1990), which are given in the present description by reference.

Compounds of the present invention can be obtained in the form of acidic or basic salts. Pharmaceutically acceptable salts (in the form of a water - or oil-soluble or dispersible products) include the conventional nontoxic salts or Quaternary ammonium salts formed, for example, with inorganic or organic acids or bases. Examples of such salts include additive salts of acids such as acetate, adipate, alginate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, fumarate, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, and toilet undecanoate; and additive salts of bases, such as ammonium salts, salts of alkaline metal such as sodium and potassium, salts of alkaline earth metal such as calcium salt and magnesium salt obtained is passed using organic bases, such as salts dicyclohexylamine, N-methyl-D-glucamine and salts derived from amino acids such as arginine and lysine.

Compounds of the present invention can be administered using a variety of methods, including oral, nasal ways, injections, percutaneous and cresselia injection. Active ingredients, administered orally in suspension, can be obtained in accordance with known in the field methods used for the manufacture of pharmaceutical compositions, and may contain microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as a means of facilitating suspendirovanie, methylcellulose as an amplifier viscosity and sweeteners/flavoring agents. In the manufacture of quick release tablets used for such purposes, the composition may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, tools, creates volume, disintegrant, thinners and oil.

Composition introduced by using a nasal aerosols or by inhalation, can be obtained, for example, as solutions in saline, using benzyl alcohol or other acceptable preservatives, enhancers su is syvania to increase the bioavailability, using fluorocarbons and/or other solubilizing or dispersing the funds.

Compounds of the present invention can also be administered in a form suitable for intravenous administration by bolus and infusion), intraperitoneal, subcutaneous, local injection, when using occlusive dressings or without it, and in a form suitable for intramuscular injection. In the case of the introduction of the injection of the injectable solution or suspension can be prepared using the appropriate non-toxic parenterally acceptable diluents or solvents, such as ringer's solution or isotonic sodium chloride solution, or using suitable dispersing or wetting and suspendida means, such as sterile, light, fatty oils, including synthetic mono - or diglycerides of fatty acids, including oleic acid.

Suitable dosing regimens are preferably determined taking into account such well-known in this field factors as the type of the subject to be treated, age, weight, sex and health condition of the subject, route of administration, the functional state of the kidneys and liver of the subject, the desired effect and the nature of the specific connection.

Optimal precision in creating the concentrations used l the drug money in the range which leads to the achievement of efficiency without signs of toxicity, requires the use of injection mode based on the study of the kinetics of receipt of the medicinal product in the sites of the target. These studies include an assessment of distribution, reaching the equilibrium state and the removal of the drug. It is expected that the daily dosage for the subject should be from 0.01 to 1000 mg per day on the subject.

Compounds of the present invention can be supplied as a set. This set typically contains the active compound in a form suitable for administration of the dose. Dosage form contains a sufficient number of active connections, so that could be achieved the desired effect when administered to a subject at regular intervals, for example, from 1 to 6 times a day, during the course of one or more days. Preferably, the kit contains instructions defining rules that are applied to achieve the desirable impact and indicate the number of dosage forms that should be taken within a certain period of time.

The present invention is described in an illustrative manner, and it should be understood that the terminology used is given for clarification of description and not for limitation. It is obvious that various modifications and variations this is the first invention in the light of the above description. It should also be understood that within the topic specified in the claims, the present invention is independent of a particular description.

The patent and scientific literature cited as references, describes the level of knowledge achieved in this area. All patents, patent publications, and other references cited in the description of the publication is included in its entirety as a reference.

Other embodiments of the invention

It should be understood that although the present invention has been presented in conjunction with the detailed description, this description is given solely for the purpose of explanation, but not to limit the scope of the invention, which is defined by the scope of the attached claims. Other aspects, advantages, and modifications are also defined by the claims.

1. The compound of formula (I)

R1-A1-A2-A3-A4-A5-R2

or its pharmaceutically acceptable salt, where

And1indicates Aib, Ape or Inp;

And2denotes a D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Trp;

And3denotes a D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-2Ser(Bzl) or D-Trp;

And4means 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl);

And5denotes Apc, Dab, Dap, Lys, Orm or deleterow;

R1 denotes hydrogen and

R2denotes NH2;

provided that

when And5indicates Dab, Dap, Lys, or Orn,

And2denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

And3denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

And4means 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl) or Pff,

when And5deleterows,

And3denotes a D-Bip, D-Bpa, D-Dip; or

And4means 2Fua, Pff, Taz or Thr(Bzl); or

And1denotes Apc and

And2denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

And3denotes a D-Bip, D-Bpa, D-Dip or D-Bal; or

And4means 2hi, 3Thi, Orn, 2l, 3l or 4l.

2. The compound according to claim 1, in which

And1indicates Aib, Apc or Inp;

And2denotes a D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Trp;

And3denotes a D-Bal, D-Bpa, D-Dip, D-1Nal, D-2Nal or D-Trp;

And4indicates Orn, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi or Thr(Bzl), and

And5denotes Apc, Lys or deleterow,

or its pharmaceutically acceptable salt.

3. The compound according to claim 2, in which

And1denotes Apc or Inp;

And2denotes a D-Bal, D-Bip, D-1Nal or D-2Nal;

And3denotes a D-Bal, D-1Nal, D-2Nal or D-Trp;

And4means 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi or Thr(Bzl),

or its pharmaceutically acceptable salt.

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2or

H-Inp-D-2Nal-D-Trp-Taz-NH2,

or its pharmaceutically acceptable salt.

5. The compound according to claim 4, where the specified connection is defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH ;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2or

H-Inp-D-2Nal-D-Trp-Taz-NH2,

or its pharmaceutically acceptable salt.

6. The compound according to claim 5, where the specified connection is defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-In-D-Dip-D-Trp-Phe-Lys-NH 2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2or

H-Apc-D-2Nal-D-Trp-2Thi-NH2,

or the pharmacist who Cesky acceptable salt.

7. The connection according to claim 6, where the specified connection is defined by the following formula:

H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-1al-D-Trp-Taz-Apc-NH 2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2or

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2,

or their pharmaceutically acceptable salt.

8. The connection according to claim 7, where the specified connection is defined by the following formula:

H-Inp-D-1Nal-D-Trp-SPal-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2,

or their pharmaceutically acceptable salt.

9. The connection of claim 8, where the specified connection is defined by the following formulas is:

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2or

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

or its pharmaceutically acceptable salt.

10. The connection according to claim 9, where the specified connection is defined by the following formula:

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

or its pharmaceutically acceptable salt.

11. The connection according to claim 9, where the specified connection is defined by the following formula:

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2,

or its pharmaceutically acceptable salt.

12. The connection according to claim 6, where the specified connection is defined by the following formula:

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2,

or its pharmaceutically acceptable salt.

13. The connection section 12, where the specified connection is defined by the following formula:

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2,

or its pharmaceutically acceptable salt.

14. The compound of the formula

H-Inp-D-2Nal-D-Trp-3Pal-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-NH2;

H-Inp-D-1Nal-D-Trp-3Pal-NH2;

H-Inp-D-Bip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-Dip-D-Trp-Phe-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Bal-Phe-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-1Nal-D-Trp-Phe-NH2,

or its pharmaceutically acceptable salt.

15. The compound of the formula

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2or

H-Apc-D-1Nal-D-Trp-Phe-NH2,

or its pharmaceutically acceptable salt.

16. The compound of the formula

H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2or

H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2,

or its pharmaceutically acceptable salt.

17. The compound of the formula

H-Apc-D-2Na-D-Trp-Phe-Lys-NH 2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim and

H-Inp-D-Trp-D-2Nal (ψ)-Pim.

18. The method of treatment or prevention, or reduction of the symptoms or severity of the diseases or disorders accompanied by weight loss, through the introduction of a ghrelin agonist selected from the list consisting of:

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-NH2;

H-Inp-D-1Nal-D-Trp-3Pal-NH2;

H-Inp-D-Bip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-Dip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Bal-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Ly-NH 2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-1Nal-D-Trp-Phe-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim or

H-InpD-Trp-D-2Nal(ψ )-Pim

or its pharmaceutically acceptable salt.

19. Way to stimulate the secretion of growth hormone in a subject in need of such stimulation, including the stage of introduction to the subject an effective amount of a ghrelin agonist of the formula

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-NH2;

H-Inp-D-1Nal-D-Trp-3Pal-NH2;

H-Inp-D-Bip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-Dip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Bal-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-1Nal-D-Trp-Phe-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-Bal-D-TF-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-ZThi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim or

H-Inp-D-Trp-D-2Nal(ψ)-Pim

or its pharmaceutically acceptable salt, where specified the effective amount is at least sufficient for the stijene detectable increase the secretion of growth hormone, and preferably is an amount sufficient to achieve a favorable impact on the patient.

20. The method according to claim 19, where the specified stimulation of the secretion of the growth hormone is indicated for the treatment condition, scarce on rostovomu hormone for increasing muscle mass, increasing bone density, when sexual dysfunction in men or women, to facilitate the increase of weight, for easier weight maintenance to help maintain an active physical form, to facilitate the recovery of physical function and/or to facilitate in increasing the appetite.

21. The method according to claim 20, where the specified relief capacity weight, easy weight maintenance and/or promotion of appetite shown for a patient having a disease or disorder or treatment, followed by weight loss.

22. The method according to item 21, where these diseases or disorders accompanied by weight loss include anorexia, bulimia, cancer cachexia, AIDS, malnutrition, AIDS, cachexia and wasting in frail elderly people.

23. The method according to item 21, where these types of treatments, accompanied by weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.

24. The method of detecting the effect of the ghrelin agonist in a subject, comprising a stage in which edenia to the subject an effective amount of a ghrelin agonist of the formula

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-NH2;

H-Inp-D-1Nal-D-Trp-3Pal-NH2;

H-Inp-D-Bip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-Dip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Bal-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-1Nal-D-Trp-Phe-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Aib-D-Ser(Bzl)-D-Trp (ψ)-Pim or

H-Inp-D-Trp-D-2Nal(ψ)-Pim

or its pharmaceutically acceptable salt, where specified the effective amount is at least the amount sufficient to achieve detectable increase the secretion of growth hormone, and preferably is an amount sufficient to achieve a favorable impact on the patient.

25. The connection of claim 10, where the specified connection is giving is a compound of the formula

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2

or its pharmaceutically acceptable salt.

26. The method according to any of PP-24, where the specified ghrelin agonist is a compound of the formula

H-Inp-D-Bal-D-Trp-Phe-Apc-NH2

or its pharmaceutically acceptable salt.

27. The use of compounds selected from the list consisting of

H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-NH2;

H-Inp-D-2Nal-D-Trp-4Pal-NH2;

H-Inp-D-1Nal-D-Trp-3Pal-NH2;

H-Inp-D-Bip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;

H-Inp-D-2Nal-D-Trp-Pff-NH2;

H-Inp-D-2Nal-D-Trp-2Thi-NH2;

H-Inp-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-Dip-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Dip-Phe-NH2;

H-Inp-D-Bal-D-Trp-Phe-NH2;

H-Inp-D-2Nal-D-Bal-Phe-NH2;

H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;

H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-Nal-D-Trp-2Thi-NH 2;

H-Apc-D-1Nal-D-Trp-Phe-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;

H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;

H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;

H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;

H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;

H-Apc-D-1Nal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Phe-NH2;

H-Apc-D-1Nal-D-Trp-Taz-NH2;

H-Apc-D-Bal-D-Trp-2Thi-NH2;

H-Apc-D-Bal-D-Trp-Taz-NH2;

H-Apc-D-2Nal-D-Trp-2Thi-NH2;

H-Apc-D-2Nal-D-Trp-Taz-NH2;

H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;

H-Inp-D-2Nal-D-Trp(ψ)-Pim;

H-Inp-D-1Nal-D-Trp(ψ)-Pim;

H-Inp-D-Bal-D-Trp(ψ)-Pim;

H-Aib-D-Ser(Bzl)-D-Trp(ψ)-Pim and

H-Inp-D-Trp-D-2Nal(ψ)-Pim

or their pharmaceutically acceptable salts to receive medicines designed to stimulate growth hormone.



 

Same patents:

FIELD: medicine, in particular, agent for prophylaxis and correction of immunodeficiency conditions.

SUBSTANCE: claimed agent represents heptapeptide of general formula Thr-Lys-Pro-Arg-Pro-Gly-Pro.

EFFECT: enhanced assortment of immunomodulating drugs, increased effectiveness of prophylaxis and treatment of immunodeficiency conditions.

5 ex, 5 dwg

FIELD: medicine, oncology, pharmacy, biochemistry.

SUBSTANCE: invention relates to peptides-containing medicinal preparations. Invention relates to using peptide of the formula QMTOVNOG representing analog of α-fetoprotein fragment from 472-d to 479-th amino acid. This peptide is able for selective trapping by tumor cells and to operate as vector molecule for directed delivery of anti-tumor preparations into tumor cells. Also, invention relates to conjugate of indicated peptide with doxorubicin wherein doxorubicin is added to peptide by through thioester bond covalently. Also, invention relates to a pharmaceutical composition used in treatment of oncology diseases that comprises conjugate of doxorubicin with peptide QMNOVNOG as a vector molecule and taken in the effective dose and a pharmaceutical carrier suitable for intravenous administration. Invention provides the selective effect of conjugate that allows expanding sphere for using the preparation. Invention can be used in medicine in treatment of oncology diseases of different etiology.

EFFECT: valuable medicinal properties of peptide and conjugate.

3 cl, 2 tbl, 6 dwg, 6 ex

FIELD: medicine, biotechnology.

SUBSTANCE: invention proposes variants of antibodies showing specificity to peptide domain located by both side of hinged site R76S77 in pro-BNP(1-108). Indicated antibodies recognize specifically also circulating pro-BNP(1-108) in human serum or plasma samples but they don't recognize practically peptides BNP(1-76) or BNP(77-108). Also, invention describes variants of peptides used in preparing antibodies. Amino acid sequence is given in the invention description. Also, invention discloses methods for preparing indicated antibodies and among of them by using indicated peptides. Also, invention describes methods for preparing antibody-secreting hybridoma, and hybridoma is disclosed prepared by indicated method. Also, invention describes a monoclonal antibody secreted by hybridoma 3D4 and deposited at number CNCM I-3073. Also, invention discloses variants for diagnosis of cardiac insufficiency in vitro and by using antibodies proposed by the invention. Also, invention describes a set used for detecting pro-BNP(1-108) in a biological sample. Using this invention simplifies detection of pro-BNP(1-108) circulating in human serum or plasma samples and provides specific detection of pro-BNP(1-108) that can be used in early diagnosis of human cardiac insufficiency.

EFFECT: valuable medicinal properties of antibodies.

24 cl, 16 dwg, 5 tbl, 20 ex

FIELD: pharmaceutical chemistry, chemistry of peptides, hormones.

SUBSTANCE: invention relates to a method for preparing analogs of adrenocorticotropic hormone (ACTH) (4-10) possessing neurotropic activity. Method for preparing analogs of adrenocorticotropic hormone (ACTH), a sequence (4-10), of the general formula (I): A-Glu-His-Phe-Pro-Gly-Pro-OH (I) wherein A means hydrogen atom (H), Met, Met(O), Lys, Ser, Trp, Ala, Gly, Thr is carried out by liquid-phase method by step-by-step splicing peptide chain beginning from C-terminal protected tetrapeptide of the formula: H-Phe-Pro-Gly-Pro-OH (II) wherein X means a protective group and using corresponding fully protected amino acids in activated form followed by removal of protective groups at each step and purification of the end product by liquid chromatography. Method provides simplifying the process and to enhance the yield of the end product.

EFFECT: improved preparing method.

5 cl, 1 tbl, 5 ex

FIELD: bioorganic chemistry.

SUBSTANCE: disclosed is oligonucleotide-peptide conjugate of general formula 3'TTCTCTAGG5'-dRib-dRib-dRib-N-terminal-Leu-Arg-Leu-Arg-Leu-Arg-Arg-Gly-NH2-C-terminal (wherein T is thymine residue; C is cytosine residue; A is adenosine residue; G is guanosine residue; drib is deoxyribose residue; Leu is leucine residue; Arg is arginine residue; Gly is glycine residue). Said conjugate cleaves phosphodiester bonds in single-stranded RNA sites in 5'GpN3' (wherein G is guanosine; N is any ribonucleotide) sequences only.

EFFECT: new conjugate being functional analog of T1 ribonuclease.

3 dwg, 4 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of heptapeptide of general formula: H-Thr-Lys-Pro-Arg-Pro-Gly-Pro-OH having psychostimulating activity. Synthesis is carried out by condensation of C-terminal protected tripeptide of formula HCl.H-Pro-GlY-Pro-OX, wherein X is protective group, with protected N-terminal tetrapeptide of formula Y-Thr-Lys(Y1)-Pro-Arg-OH, wherein Y and Y1 are protective groups, and obtained protected heptapeptide of formula Y-Thr-Lys(Y1)-Pro-Arg-Pro-Gly-Pro-OX is treated with deprotecting reagents to remove protective groups and target product is isolated by chromatography method. Also described are tripeptide of formula HCl.H-Pro-GlY-Pro-OBzl and tetrapeptide of formula Boc-Thr-Lys-(Boc)-Pro-Arg-OH as intermediates for synthesis of heptapeptide of general formula: H-Thr-Lys-Pro-Arg-Pro-Gly-Pro-OH.

EFFECT: simplified process; increased yield of target product.

4 cl, 7 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention provides novel compounds of general formula (I) and pharmaceutically acceptable salts thereof, wherein G represents glycin; D aspartic acid; R1 group -(CH2)n- or -(CH2)n-C6H4-; n is integer from 1 to 10; h is 1 or 2; X1 represents amino acid residue having one functional deviation such as amine; X2 and X4 independently represent amino acid residue capable of forming disulfide bond; X3 represents hydrophobic amino acid such as phenylalanine; X6 represents group -NH-[CH-]-C(O)-; X7 is missing or represents biomodifying grouping consisting of monodisperse poly(ethylene glycol): (II), wherein is integer from 1 to 10; C-end unit represents amide group or 1-10 amino acid residues; Z1 chelating group or reporter group; and W1 is missing or represents spacing moiety derived from glutaric or succinic acid. Compounds of invention are designed as diagnostic agents for visualization or as therapeutic agents, the two agent types being directional vectors capable of binding to integrin receptors.

EFFECT: expanded diagnostic and therapeutic possibilities.

19 cl, 3 tbl, 5 ex

FIELD: chemistry of peptides, chemical technology.

SUBSTANCE: invention relates to a method for purification of nona- or decapeptide representing antagonist of luteinizing hormone releasing factor (LHRH) from residual organic solvent. Method involves dissolving nona- or decapeptide in a water-containing solvent and at least one (C1-C3)-alcohol followed by precipitation in a solvent under condition with intensive stirring wherein this solvent represents carboxylic acid alkyl ester comprising from 3 to 6 carbon atoms and one or some nonpolar compounds chosen from hexane, heptane, octane, cyclohexane and methylcyclohexane and, possibly, up to 5% of acetic or propionic acid. Then precipitate of nona- or decapeptide is washed out with a mixture of (C3-C5)-esters and dried. The water content in water-containing solvent used and at least one alcohol is less 8% (vol./vol.) and in the volume ratio of solvents mixture used for dissolving and solvents mixture used for precipitation is 1:10 or above.

EFFECT: improved purifying method.

8 cl, 1 tbl, 6 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to immunomodulator representing pentapeptide of formula Val-Val-Tyr-Pro-Asp and drug in liquid and dry forms based on the same. Both pentapeptide and pharmaceutical composition containing the same have antitumor activity in small doses and have no side effects.

EFFECT: new low molecular peptide with immunomodulating activity and antitumor preparation based on the same.

2 cl, 6 ex, 4 tbl

FIELD: medicine, polypeptides.

SUBSTANCE: invention relates to fusion polypeptides with enhanced pharmacokinetic properties. Fusion polypeptides comprising enhancing peptide sequences associated with the core polypeptide possess with the enhanced pharmacokinetic properties, such as prolonged half-time period. Also, invention relates to methods for enhancing pharmacokinetic properties of any core polypeptide by binding the enhancer peptide sequences with the core polypeptide. Proposed core polypeptides can comprise any pharmacologically useful peptide that can be used, for example, the therapeutic or prophylactic agent. The advantage of invention involves the enhancing of pharmacokinetic properties of polypeptides.

EFFECT: enhanced pharmacokinetic properties of polypeptides.

52 cl, 18 dwg, 14 tbl, 11 ex

The invention relates to oligopeptides derivative containing amino acid D-2-alkyltrimethyl, which is capable of releasing growth hormone (GH) from the somatotropic cells and active when administered orally

The invention relates to Bioorganic chemistry, namely the synthesis of peptides possessing anxiolytic activity (the ability to control an alarm condition)

FIELD: biotechnology, immunology.

SUBSTANCE: invention reports about preparing and characterizing two forms of Nogo protein bound with the natural myelin with respect to the presence of immunogenic properties in their. These two forms correspond to natural products of alternative splicing, their fragments and derivatives, in particular, derivatives comprising deletions in amino acid residues, and chimeric protein also and comprising novel immunogenic polypeptides and their fragments. Invention can be used in medicine for diagnostic and curative aims.

EFFECT: valuable medicinal properties of protein.

18 cl, 79 dwg, 3 tbl, 8 ex

FIELD: biotechnology, gene engineering, pharmaceutical industry, medicine.

SUBSTANCE: method for production of recombinant placental growth factor (PLGF) includes culturing of modified prokaryotic cells containing inducible expression system of PLGF to produce OD600 of 14-50, followed by expression inducing, extraction, purification and solubilizing of inclusion bodies; enriching of obtained mixture with dimer a multimer form of expressed protein by anion exchange chromatography and isolation of PLGF preferably in dimmer form by reversed-phase chromatography.

EFFECT: method for PLGF production with high specific activity and high yield.

27 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: agents are used modulating stem cells proliferation when treating people and animals and accelerating recovery process after peripheral blood chemotherapy.

EFFECT: enhanced effectiveness of treatment.

79 cl, 28 dwg, 44 tbl

FIELD: biotechnology, peptides.

SUBSTANCE: invention relates to a method for preparing antibodies raised to human leukocyte differentiation factor (HLDF) or to HLDF fragment (31-38) representing peptide of the following structure: Arg-Arg-Trp-His-Arg-Leu-Glu-Lys possessing with antigenic and nucleic acids-hydrolyzing properties, and for diagnostic aims also. Antibodies are prepared from rabbit plasma blood immunized with three injections of antigens wherein synthetic HLDF factor or conjugate is used as antigens. Diagnosis of anaplastic state of human cells is carried out by using solutions of antibodies to HLDF factor or HLDF fragment (31-38) in the concentration 0.0013 mg/ml as biological markers. Invention provides carrying out the differential diagnosis of tumors and normal organs and effective detecting initial stages in cell differentiation disturbances.

EFFECT: improved preparing method of antibody, improved method for diagnosis.

6 cl, 21 dwg, 1 tbl

FIELD: biotechnology, veterinary science.

SUBSTANCE: invention proposes nucleic acid molecule GDF-9B of wild and mutated types, polypeptide encoding by these nucleic acids, vector, construction, ligand and methods for using such nucleic acids and polypeptides. Proposed group o invention provides carrying out the modulation of the ovary follicle growth via activity of homodimers of GDF-9B and heterodimers of GDF-9B/GDF-9 both in vivo and in vitro. Invention can be used in animal husbandry for aim of active and passive immunization against these polypeptides for the follicle growth change.

EFFECT: valuable properties of factors.

35 cl, 9 dwg, 4 tbl, 4 ex

FIELD: biotechnology, in particular epithelial cell growth factors useful in production of new keratinocyte growth factor (KGF).

SUBSTANCE: KGF protein is obtained by cultivation of recombinant host cell, transformed with vector containing DNA which encodes amini acid sequence of KGF protein. Obtained KGF protein in pharmaceutical composition is used for forcing of epithelial cell proliferation. Method of present invention makes it possible to produce KGF protein with specific mitogenic activity of 3.4 x 104 U/mg of protein in relation to keratinocyte cells.

EFFECT: new keratinocyte growth factor.

52 cl, 14 dwg, 3 tbl

FIELD: biotechnology, molecular biology, medicine, genetic engineering, pharmacy.

SUBSTANCE: the hemopoietic protein comprises the amino acid sequence of the formula: R1-L1-R1, R2-L1-R1, R1-R2 or R2-R1 wherein R1 represents the modified ligand flt-3; R2 represents the modified human IL-3, the modified or unmodified colony-stimulating factor. Modification of R1 is carried out by addition of N-end with C-end directly or through linker (L2) that is able to join N-end with C-end to form new C- and N-ends. The modified human IL-3 is prepared by replacing amino acids at positions 17-123. The human G-CSF is modified by exchange of amino acids. The hemopoietic protein is prepared by culturing cells transformed with vector comprising DNA that encodes the hemopoietic protein. The hemopoietic protein stimulates producing hemopoietic cells and this protein is used as a component of pharmaceutical composition used in treatment of humans suffering with tumor, infectious or autoimmune disease. Invention provides preparing multifunctional hemopoietic proteins eliciting the enhanced activity with respect to stimulation of hemopoietic cells and eliciting the improved physical indices. Invention can be used for preparing chimeric multifunctional hemopoietic proteins.

EFFECT: improved preparing and producing method, valuable medicinal properties of protein.

22 cl, 19 dwg, 18 tbl, 117 ex

Up!