Antagonists of somatostatin receptors

 

(57) Abstract:

Describes new compounds of General formula I: (R1, R2)A1-AND2-AND3-A4-Lys-A6-A7-A8-R9where AND1is D - or L-isomer of an aromatic amino acid; AND2represents the D-isomer selected from the group comprising Cys, Pen, aromatic amino acid or aliphatic amino acid; AND3represents an aromatic amino acid; AND4is D-Trp; AND6is Thr, Thr(Bzl), Gly, Ser or aliphatic amino acid; AND7is Cys, Pen, or aromatic, or aliphatic amino acid; AND8is D - or L-isomer selected from the group including Thr, Ser, aromatic amino acid or aliphatic amino acid; each of R1and R2independently represents H or F, SO2or E, where E1represents a heterocycle lower alkyl, substituted on the heterocycle hydrokinesis-alkyl; and R3represents NH2provided that if a2is D-Cys or D-Pen, and7is Cys or Pen, the side chains AND2and7linked by a disulfide bond, and if a1is n-BUT2-h, AND2is D-Cys, AND3Novye compounds are antagonists of somatostatin receptors and may find application for use for the treatment of diseases or disorders, when activating the secretion of growth hormone or insulin, and somatostatin, for example, in the methods of Radiolaria. 18 C. p. F.-ly, 1 table.

Native somatostatin includes either a 14-amino acid isoforms (somatostatin-14) or 28-amino acid isoforms (somatostatin-28) Heiman et al. , Neuroendocrinology, 45, 429-436 (1987). Because native somatostatin has a short half-life have been investigated by various analogs of somatostatin required, for example, in the treatment of acromegaly. Raynor et al. , Mol. Pharmacol. , 43, 838 (1993). Identified and characterized five different somatostatin receptors. Hoyer et al. , Naunyn-Schmiedeberg''s Arch. Pharmacol. , 350, 441 (1994). Somatostatin has a number of actions, including modulation of the secretion of hormones such as growth hormone, glucagon, insulin, Amylin, as well as the secretion of neurotransmitters. Some of these actions are associated with its binding to specific receptors somatostatin. For example, suppression of growth hormone is associated with somatostatin receptor type (SSTR-2) (Raynor et al. , Mol. Pharmacol. , 43, 838, 1993, Lloyd et al. , Amer. J. Physiol. , 268, G102 (1995)), while inhibition of insulin is associated with somatostatin receptor 5-th type (SSTR-5) (Coy et al. , 197, 366-371, 1993. The present invention predst">

Brief description of the invention

The invention relates to the substance of the formula:

< / BR>
where a1is D - or L-isomer of an aromatic amino acid or is missing;

AND2represents the D-isomer selected from the group comprising Cys, Pen, aromatic amino acid or aliphatic amino acid;

AND3represents an aromatic amino acid;

AND4represents Trp or D-Trp;

AND6is Thr, Thr(Bzl), Gly, Ser, Eaa or aliphatic amino acid;

AND7is Cys, Pen or aromatic, or aliphatic amino acid;

AND8is D - or L-isomer selected from the group including Thr, Ser, aromatic amino acid or aliphatic amino acid;

each of R1and R2represents H or substituted (for example, from one to four substituents) or unsubstituted lower alkyl, aryl, aryl-lower alkyl, heterocycle, heterocyclic lower alkyl, E1SO2or E1CO (where E1represents aryl, aryl-lower alkyl, heterocycle, or heterocycle lower alkyl), where specified, the Deputy is halogen, lower alkyl, hydroxyl, halogen lower alkyl or hydroxyl-lower alkyl; and

R3prawley N, HE CO2H or CONH2or R3together with the carbonyl group AND8attached to it, restored to H, lower alkyl or hydroxyl-lower alkyl; provided that, if a2is D-Cys or D-Pen, AND7is Cys or Pen, linked side chains AND2and7linked by a disulfide bond, or if a1is D-Phe or p-NO2-Phe, AND2is D-Cys, AND3is Phe or Tight, AND6is Thr or Val and A7is Cys, AND8is-Nal.

In one embodiment of the invention AND2is D-Cys, A7is Cys and4is D-Trp. In another embodiment of the invention AND1represents an aromatic amino acid.

In the next version of the invention AND1and3independently are-Nal, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2) m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa or Pal; A6is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, -Ala, Gaba, or Val; A8represents the d-sub>), o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), Igl, Tyr(Bzl) or Nal. In the next version of the invention AND1is-Nal, Npa, Igl, Phe, p-F-Phe, Trp, p-Cl-Phe, or p-CN-Phe; A3is Tyr, Tyr (I), or Pal; A6is Val, Tle, Nle, Ile or Leu; A8is p-F-Phe, -Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R1represents H, CH3C) 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1 - piperazineethanesulfonic; R2is H, and R3represents NH2.

In another embodiment of the invention AND1is a D-aromatic amino acid. In another embodiment of the invention AND1is D-Nal, D-o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), D-p-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), D-m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa or D-Pal; A3is-Nal, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, HE, CH3, UB>, CN or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tight (I), Bta, Bip, Npa or Pal; A6is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, -Ala, Gaba, or Val; A8is D - or L-isomer of Thr, Dip, F5-Phe, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2) m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), Tyr(Bzl), Igl or Nal.

In yet another variant of the invention AND1is D-Nal, D-Npa, D-Igl, D-Phe, D-p-F-Phe, D-Trp, D-p-Cl-Phe or D-p-CN-Phe; A3is Tyr, Tyr (I), or Pal; A6is Val, Tle, Nle, Ile or Leu; A8is p-F-Phe, -Nal, Tyr, Dip, p-Cl-Phe, Igl or g-CN-Phe; R1represents H, CH3WITH, 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1 - piperazineethanesulfonic; R2is H, and R3represents NH2.

In another embodiment of the invention AND1no, R1substituted or not substituted E1CO, and R2represents N. In the following embodiment of the invention R1substituted or not substituted on the E1CO (where E1represents phenyl, -naphthylmethyl-pyridinylmethyl or 3 - indolylmethane); AND3is-Nal, o-X-Phe (g is>, halogen, OCH3, NH2, CN or NO2), m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr (I), Bta, Bip, Npa or Pal; A6is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, -Ala, Gaba, or Val; A8is D - or L-isomer of Thr, Dip, F5-Phe, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), Igl, Tyr(Bzl) or Nal.

In another embodiment of the invention R1is E1CO (where E1is 4-hydroxyphenyl, -naphthyl, methyl or phenyl); AND3is Tyr, Tyr(I), or Pal; AND6is Val, Tle, Nle, Ile or Leu; AND8is p-F-Phe, -Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R3represents NH2.

In another embodiment of the invention R3together with the carbonyl group AND8attached to it restored to H, lower alkyl or hydroxy lower alkyl. In another embodiment of the invention AND1is D - or L-isomer-Nal, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2CN Il is dstanley H, HE, CH3, halogen, OCH3, NH2, CN or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa or Pal; A3is-Nal, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa or Pal; A6is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, -Ala, Gaba, or Val; A8is D - or L-isomer of Thr, Dip, F5-Phe, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), m-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), Igl, Tyr(Bzl) or Nal.

In yet another variant of the invention AND1is D - or L-isomer-Nal, Phe, p-F-Phe, Trp, p-AU-Cl-Phe, or p-CN-Phe; AND3is Tyr, Tyr (I), or Pal; AND6is Val, Tle, Nle, Ile or Leu; A8is p-F-Phe, -Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R1represents H, CH3CO., 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic; R2predstavljen.

In the next version of the invention AND2is a D-aromatic amino acid or D-aliphatic amino acid, A7represents an aromatic amino acid or aliphatic amino acid, and a4is D-Trp. In another embodiment of the invention AND1is L-amino acid, and2is a D-aromatic amino acid. In another embodiment of the invention, AND1AND3and7independently represent-Nal, o-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), m-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr (I), Bta, Bip, Npa or Pal; A2is D-Nal, D-o-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), D-p-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2), CN or NO2), D-m-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), D-F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa or D-Pal; A6is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, -Ala, Gaba, or Val; A8is D - or L-isomer of Thr, Dip, F53, halogen, OCH3, NH2, CN or NO2), m-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), Igl, Tyr(Bzl) or Nal.

In another embodiment of the invention AND1is-Nal or Phe; AND2represents the D-Cpa or D-Phe; AND3is Phe or Taut; AND6is Abu, Thr, or Val; AND7is Phe; AND8is Thr; R1represents H, CH3CO., 4-(2 - hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1 - piperazineethanesulfonic; R2is H, and R3represents NH2.

In another embodiment of the invention AND1represents a D-amino acid, and2is a D-aromatic amino acid.

In another embodiment of the invention AND1and2independently represent D-Nal, D-o-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), D-p-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), D-m-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), D-F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa or D-Pal; A3and A7independently represent-Nal, o-X-Phe (where X is H, OH, CH3, halogen, O2), m-X-Phe (where X is H, OH, CH3, halogen, OCH3, NH2, CN or NO2), F5-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa or Pal; A6is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, -Ala, Gaba, or Val; AND8is D - or L-isomer of Thr, Dip, F5-Phe, o-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), p-X-Phe (where X is H, HE, CH3, halogen, OCH3, NH2, CN or NO2), Igl, Tyr(Bzl) or Nal.

In another embodiment of the invention AND1is D-Nal or D-Phe; AND2represents the D-Cpa or D-Phe; AND3is Phe or Tyr; AND6is Thr or Val; AND7is Phe; and8is Thr; R1represents H, CH3WITH, 4-(2 - hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1 - piperazineethanesulfonic; R2is H, and R3represents NH2.

Examples of compounds of the present invention include the following:

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal - NH2(similar to N 2);

(N) (CH3CO)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2(similar to N 5);

(H)-(4-(2-hydroxyethyl)-1-piperazinylmethyl --Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2< / BR>
(H)-(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2/BR>(H)-(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)-(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)(CH3CO)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr - NH2;

(H)-(4-(2-hydroxyethyl)-1 - piperazinylmethyl)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)-(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;

H--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2< / BR>
(H)(CH3CO)--Nal-D-Cs-Pal-D-Trp-Ls-Val-Cs-Thr-NH2< / BR>
(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H) (CH3CO)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-h-D - Cs-Taut-D-Trp-Ls-Val-Cs--Nal-NH2< / BR>
H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2(similar to # 4);

(H)(CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-h-D-Cys - Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1 - piperazineethanesulfonic)-h-D - Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-Phe-D-Cys-Pal-D-Trp-Ly)-Phe-D-Cys - Pal-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1 - piperazineethanesulfonic)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(CH3CO) -- Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(CH3CO)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(CH3CO)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(CH3CO)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

H2-Phe-D-Cys-Tyr-D - Trp-Lys-Thr-Cys--Nal-NH2;

(H)(CH3CO)-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(onl)-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe-D - Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(CH3CO)-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys - Tyr-D-Tip-Lys-Thr-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1 - piperazineethanesulfonic)-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2(similar to N 6);

(H)(CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys - Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe-D - Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys--Nal-NH2;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys--Nal-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Abu-Cys--Nal-NH2;

H2-Phe-D-Cys-Pal-D-Trp-Lys-Abu-Cys--Nal-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;

H2-Phe-D-Pen-Tyr-D-Trp-Lys-Val-Pen--Nal-NH2; or

H2-Phe-D-Pen-Pal-D-Trp-Lys-Thr-Pen-Thr-NH2;

H2-Dip-D-Cys-Pal-D-Trp - Lys-Val-Cys-Dip-NH2(similar to N-10);

H2-F5-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-F5-Phe-NH2(analogs (similar to N 14);

H2-o-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-o-F-Phe-NH2(similar to N 15);

H2-p-p-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-F-Phe-NH2(similar to N 12);

H2-F5-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-F5-Phe-NH2(similar to # 16);

H2-F5-Phe-D-Cys-2-Pal-D-Trp-Lys-Val-Cys-F5- Phe-NH2(similar to N 17);

H2--Nal-D-Cys-His-D-Trp-Lys-Val-Cys-D-Dip-NH2(similar to No. 19);

H2-Dip-D-Cys-His-D-Trp-Lys-Val-Cys--Nal-NH2(similar to N 20);

H2-Dip-D-Cys-His-D-Trp-Lys-Val-Cys-Dip-NH2(similar to N 21);

H2--Nal-D-Cys-His-D-Trp-Lys-Val-Cys--Nal - NH2(similar to N 22);

H2-Trp-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D--Nal-NH2(similar to N 24);

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D--Nal-NH2(similar to N 25);

H2--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-n-F-Phe-NH2(similar to N 28);

H2--Nal-D-Cs-Pal-D-Trp-Ls-Val-Cs--Nal-NH2(similar to N 29);

H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2(similar to N 30);

H2--Nal-D-Cys-Pal-D-Trp - Lys-Nle-Cys--Nal-NH2(similar to N 31);

H2--Nal-D-Cys-Pal-D-Trp-Lys-Ile-Cys--Nal-NH2(similar to N 32);

H2--Nal-D-Cys-Pal-D-Trp-Lys-Gly-Cys--Nal-NH2(similar to N 33);

H2--Nal-D-Cys-Pal-D-Trp-Lys-Ala-Cys--Nal-NH2(similar to N 34);

H2--Nal-D-Cys-Pal-D-Trp-Lys-Leu-Cys--Nal-NH2(similar to N 35)

H2-Bip-D-Cys-Tyr-D-Trp-Lys-Ile-Cys-Bip-NH2(similar to # 36);

H2-p-F-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-n-F-Phe-NH2(similar to N 38);

H2-Npa-D-Cys-Pal-D-Trp-L-Cys-His-D-Trp-Lys-Val-Cys-o-F-Phe-NH2(similar to N 41);

H2--Nal-D-Cys-Pal-D-Trp-Lys-Nle-Cys-Dip-NH2(similar to N 42);

H2-Cpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Cpa-NH2(similar to N 43);

H2-Igl-D-Cys-Pal-D-Trp-Lys-Val-Cys-Igl-NH2(similar to N 44);

H2--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-Dip-NH2(similar to N 45);

H2--Nal-D-Cys-3-I-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2(similar to N 46);

H2-p-CN-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-CN-Phe-NH2(similar to N 47);

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-Dip-NH2(similar to N 48);

H2--Nal-D-Cys-Bta-D-Trp-Lys-Vyl-Cys--Nal-NH2(similar to N 49);

H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys--Nal-NH2(similar to N 50);

H2-Bpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Bpa-NH2(similar to N 52);

H2-Iph-D-Cs-Pal-D-Trp-Ls-Val-Cs-Iph-NH2(similar to N 53);

H2-Trp-D-Cys-Pal-D-Trp-Lys-Tle-Cys--Nal-NH2(similar to N 54);

H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2(similar to N 55);

H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys--Nal-NH2(similar to N 56);

H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-p-Cl-Phe-NH2(similar to N 57);

H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Cha-Cys-p-Cl-Phe-NH2;

H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2;

H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Tle-Cys--Nal-NH2;

H2-p-F-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-p-F-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Tle-Cys--Nal-NH2;

H2--Nal-D-Cys-TyrLys-Abu-Cys--Nal-NH2;

(H)(CH3CO)-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys--Nal-NH2;

H2-n-NO2-Phe-D-Cs-Tight(Bzl)-D-Trp-Ls-Thr(Bzl)-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-n-NO2-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-n-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Tyr-NH2;

H2-n-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-n-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

H2--Nal-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys--Nal-NH2;

H2-D-Phe-D-Pen-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;

H2-D--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;

H2-D--Nal-D-Cs-Taut-D-Trp-Ls-Val-Cs--Nal-NH2(similar to N 9);

H2-D--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

H2-D-Phe-D-Cys-Pal-D-Trp-Lys-Cys-Thr-NH2;

H2-D-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;

H2-D---Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;

H2-D--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D--Nal-NH2(similar to N 26);

H2-D-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-p-F-Phe-NH2(similar to N 27);

H2-D-Bip-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2(similar to N 37);

H2-D-Dip-D-Cys-Pal-D-Trp-Lys-Vays-Pal-D-Trp-Lys-Tle-Cys-p-Cl-Phe-NH2(similar to N 7);

n-NO2-D-Phe-D-Cys-Pal-D-Trp-Lys-Thr(Bzl) - Cys-Tyr(Bzl)-NH2;

n-NO2-D-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Val-Cys-Tyr(Bzl)-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-n-NO2-D-Phe - D-Cys-Pal-D-Trp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-n-NO2-D - Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Val-Cys-Tyr(Bzl)-NH2< / BR>
(H)(3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(3-phenylpropionyl)-D-Cys-Pal-D-Trp - Lys-Val-Cys--Nal-NH2;

(H)(3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)(3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)(3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys--Nal-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(3-[2-naphthyl] propionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

(H)(3- (H)(3-[2-naphthyl] propionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;

(H)(3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys--Nal-NH2;

(H)(3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(CH3CO)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy) propylamide;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(CH3CO)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(CH3CO)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R, 3R;

(N)(CH3CO)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(CH3CO)-Phe-D-Cs-Tyr-D-Trp-Ls-Val-Cs-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R, 3R-(2 - hydroxymethyl)-3-hydroxy)propylamide;

(N)(CH3CO)-Phe-D-Cys - Tyr-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy) propionic;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe - D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3 - hydroxy)propylamide;

H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl) -3-hydroxy)propylamide;

(N)(CH3CO)-Phe-D-Cys-Pal-D - Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy) propylamide;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys-Pal - D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(N)(4-(2-hydroxyethyl)-1 - piperazineethanesulfonic)-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(N)(CH3CO)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl) ethylamide;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(H)(CH3CO)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R- (2-naphthyl)ethylamide;

(N)(4-(2-hydroxyethyl)-1 - piperazinylmethyl)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl) ethylamide;

(H)(CH3CO)--Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

(H)(4-(2-hydroxyethyl)-1-p-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

(N)(CH3CO)--Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R- (2-naphthyl)ethylamide;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)- -- Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic) -- Nal - D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R- (2-naphthyl)ethylamide;

(H)(CH3CO-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl) ethylamide;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D - Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe-D-Cys-Tyr-D-Trp - Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

H2-Phe-D-Cys-Pal-D-Trp - Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(H)(CH3CO)-Phe-D-Cys - Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val - Cys-2R-(2-naphthyl)ethylamide;

(H)(4-(2-hydroxyethyl)-1 - piperazineethanesulfonic)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl) ethylamide;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2 - naphthyl)ethylamide;

(H)(CH3CO)-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys - 2R-(2-naphthyl)ethylamide;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)-Phe-D - Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe-D-Cys-Tyr-D-Trp - Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl) ethylamide;

(N)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)-Phe-D-Cys-Pal-D - Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

H2---Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R-(2-naphthyl) ethylamide;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R-(2-naphthyl) ethylamide;

H2---Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R, 3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R, R-(2-hydroxymethyl)-3-hydroxy)propylamide;

H2-Phe-D-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;

H2-Phe-D-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

H2-Phe-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

H2--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2< / BR>
(H) (CH3CO)--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

H2--Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;

(H)(CH3CO)--Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1 - piperazineethanesulfonic)--Nal - D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;

H2--Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;

(H)(CH3CO)--Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;

(N)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal - Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)---Nal-D-Cpa-Pal-D-Trp-Lys-Thr-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;

H2-- Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe--Nal-NH2;

(H)(CH3CO) -- Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazinylmethyl)--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe--Nal-NH2;

(H)(4-(2-hydroxyethyl)-1-piperazineethanesulfonic)--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe--Nal-NH2;

H2--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe--Nal-NH2(similar to N 23);

H2--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

H2-D--Nal-D-Cpa-Phe-D-Trp-Lys-Val-Phe-Thr-NH2;

H2-D---Nal-D-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;

H2-D-Phe-D-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

H2-D--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2(similar to N 8); or

H2-D--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe--Nal-NH2or their pharmaceutically acceptable salt.

Except for the N-terminal amino acids, all abbreviations (e.g., Ala or A2) amino acids in this text correspond to the structure-NH-CH(R)-CO-, where R represents the side chain of amino acids (for example, CH3for alanine). For N-terminal amino acid abbreviations correspond to the structure = N-CH(R)-CO-, where R represents the side chain of amino acids. Abbreviations Pen, -Ala, Gaba, PIM-amino acids: penicillamine, 3-aminopropionic acid, 4-aminobutyric acid, norleucine, Norvaline, --[3 - pyridyl] -alanine, -[2,3,4,5,6-pentafluorophenyl] -alanine, -[2,4-dichlorophenyl] -alanine, -[4-chlorophenyl] -alanine, -[2-naphthyl] -alanine, -[1-naphthyl] -alanine, 2-aminobutyric acid, 3,3'- diphenylalanine, -[2-pyridyl] -alanine, 4,4'-biphenylene, n-NO2-phenylalanine, 2-intergrity, 3-sensationally, -[tert-butyl] -glycine, 4-brompheniramine, 4-itfinally, -(cyclohexyl)-alanine, O-benzylation, O-sensitising and 2-aminoadamantane acid. Reduction of Tyr (I) denotes audirovannyj residue tyrosine (for example, 3-I-Tyr, 5-I-Tyr, 3,5-I-Tyr), where iodine can be a radioactive isotope, for example,125I127I or 131I. Aliphatic amino acid is --amino acid having one or two side chains, which, independently are a hydrocarbon, for example, straight or branched chain containing 1-6 carbon atoms. Examples of aliphatic amino acids are Ala, Aib, Val, Leu, Tle, Ile, Nle, Nva or Abu. Aromatic amino acid is an amino acid side chain which has a neutral (i.e. non-acidic and ponownie) aromatic component, for example, substituted or unsubstituted phenyl, naphthyl or aromatic heterocyclic group (e.g., emer, F, Cl, Br or I), HE, OCH3CH3or NO2), o-X-Phe (where X is halogen, HE, OCH3CH3or NO2), m-X-Phe (where X is halogen, HE, OCH3CH3or NO2), His, Pal, Trp, -Nal, 2,4-dichloro-Phe, Tyr(I)- [3,4,5-tryptophanyl] -alanine, Bta -[3-cyanophenyl] - alanine, -[4-cyanophenyl] -alanine, -[3,4-differenl] -alanine, -[3,5-differenl] -alanine, -[2-forfinal] -alanine, -[4 - thiazolyl] -alanine, Bip, Dip, Npa, Igl, Bpa, Iph, homophenylalanine, 2-Pal -[4-pyridyl] -alanine, -[4 - thiazolyl] -alanine, -[2-thiazolyl] -alanine, para-(CF3)- phenylalanine and F5-Phe. The abbreviation "EA" refers to the amino acid having the formula-NH-[CH(R)n] -CO- (where n is 2-6, a R is H, lower alkyl or hydroxyl-lower alkyl). Examples Eaa are-Ala and Gaba.

Used in the present description, the term "lower alkyl" includes both straight and branched saturated aliphatic hydrocarbon group having 1-6 carbon atoms. Examples of the lower Akilov groups are: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, sec-butyl and the like.

Used in the present description, the term "aryl" includes any stable monocyclic, bicyclic or tricyclic carbon ring (ring) with the number of carbon atoms on the t phenyl, naphthyl, anthracene, biphenyl, tetrahydronaphthyl, indanyl, phenanthrene and the like.

The term "heterocycle" used in the present description, represents a stable 5 to 7-membered monocyclic or stable 8 to 11-membered bicyclic or stable 11 to 15-membered tricyclic heterocyclic ring, which may be either saturated or unsaturated and which contains carbon atoms and from one to four heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and including any bicyclic group in which any of the above heterocyclic rings condensed with the benzene ring. Heterocyclic ring may be attached at any heteroatom or carbon atom, resulting in a stable structure. Examples of such heterocyclic elements include (but are not limited to): azepines, benzimidazolyl, benzisoxazole, benzofurazanyl, benzopyranyl, benzopyranyl, benzofuran, benzothiazole, Bastiani, benzoxazolyl, bromanil, cinnoline, dihydrobenzofuran, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, furyl, imidazolidinyl, imidazolyl, imidazolyl, indolinyl, indolyl, isopropanol, Salil, 2-oxoethyl, 2 - oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, piperidyl, piperazinil, pyridyl, pyridyl-N-oxide, inexamined, tetrahydrofuryl, tetrahydroisoquinoline, tetrahydroisoquinoline, tetrahydroquinoline, thiomorpholine, themorphological, thiazolyl, thiazolyl, tinfoil, theNational, thienyl and the like.

The term "substituted" means that the above-mentioned chemical groups (for example, lower alkyl, heterocycle, aryl, cycloalkyl and so on ), substituted from one to four above substituents (e.g. halogen, hydroxyl, lower alkyl, and so on ). The Deputy can be attached to any atom of the chemical group.

The structure of 4-(2-hydroxyethyl)-1-piperazinylmethyl and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic is, respectively, the following:

< / BR>
and

< / BR>
Compounds of the present invention can be presented in the form of pharmaceutically acceptable salts. Acceptable salts include, but are not limited to, inorganic salts such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate, or organic acid salts such as acetate, mateut, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, the go salts formed with bases such as sodium hydroxide and potassium hydroxide. Other examples of pharmaceutically acceptable salts can be found in "Pharmaceutical Salts", 1977, J. Pharm. Sci. , 66,1.

In the case where the remaining amino acid is optically active, it is assumed that it is the L-isomer, unless specifically indicated otherwise. In the formulas presented here are not shown disulfide bond between Tilney group in the side chain residue of A2(for example, Cys, Pen, D-Cys or D-Pen) and Tilney group of the side chain of residue AND7(for example, Cys or Pen).

The peptides of the present invention can be used to activate the secretion of growth hormone or insulin in a subject (e.g. a mammal such as man, which is the patient). Thus, the peptides are applicable for the treatment of disturbances of the physiological state in which favorable activating the secretion of growth hormone or insulin. The peptides of the present invention can also be used to accelerate wound healing and activation of angiogenesis. The peptides of the present invention, with the residue Tyr (I), can be used for labeling cells bearing receptors somatostatin. Such peptides on nastoyashimi, cancer cells), and as radioligand test in vitro for binding to the somatostatin receptor.

The peptide of the present invention can be used as vectors for the transport of radioactive isotopes in the target cell.

A therapeutically effective amount of the peptide of the present invention and pharmaceutically acceptable carrier (e.g., magnesium carbonate, lactose, or a phospholipid with which therapeutic compound may form the shape of the micelles) together form a therapeutic composition (e.g., in the form of pills, tablets, capsules or liquid preparation intended for administration (e.g. oral, intravenous, cutaneous, light, vaginally, subcutaneously, nasal, electrophoretic or nutritarian) to a patient in need of this peptide. Pills, tablets or capsules can be coated with a substance which protects the composition from gastric acid and digestive enzymes in the stomach of the patient for a time sufficient to allow the composition to achieve in undigested form of the small intestine of the patient. therapeutic composition can also be in the form biorazlagaemykh or binarytreenode preparer, U.S. patents 3773919 and 4767628 and PCT application WO 94/00148.

Continuous introduction can also be carried out using an implanted or external pump (for example, INFUSAID pump TM) for introducing therapeutic composition.

The dose of the peptide of the present invention for the treatment of these diseases varies depending on the method of administration, age and body weight of the patient, as well as the General condition of the patient who is undergoing treatment, and exactly can be defined directly by the attending physician or veterinarian. This amount of peptide, which is determined by the treating physician or veterinarian, here referred to as "therapeutically effective amount".

Also in the scope of the present invention enabled the peptide denoted by the above General formula, intended for use for the treatment of diseases or disorders where activation is required for the secretion of growth hormone or insulin, and to be used for the determination of somatostatin receptors, for example, by the method of radiolabelling.

Other characteristics and advantages of the present invention will be seen from the detailed description and claims.

Detailed described the Oia to use the present invention to its fullest extent. The following specific variants of the invention selected as the most illustrative, non-limiting other uses of the invention in any possible direction. Except as expressly provided herein, all technical and scientific terms used herein have the meaning known to specialists in the art to which it relates. Also, all publications, patent applications, patents and other works mentioned here are included in the present invention by reference.

Synthesis of

The synthesis of short peptides is well studied in the field of technology related to the study of proteins. Cm. for example, Stewart et al. Solid Phase Peptide Synthesis (Pierce Chemical Co. , 2d ed. 1984). The following describes the synthesis of D-Nal-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2and D--Nal-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2. Other peptides of the present invention can be synthesized in a similar way by an expert in the field of technology.

(a) Synthesis of H2--Nal-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2,

1) Boc--nafcillin-S-methylbenzyl-D-cysteine-3-pyridyl-2-alanine-D-tryptophan-Ne-benzyloxycarbonyl-lysine-valine-S-methylbenzylidene--nafcillin-benzhydrylamine resin.

Benzhydrylamine-polystyrene resin (Advanced ChemTech Inc. , Louisvil programmirovanie on the next cycle of reactions: (a) methylene chloride; (b) 33% triperoxonane acid in methylene chloride (twice for 1 and 25 min); (C) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) 10% triethylamine in chloroform.

The neutralized resin was stirred with Boc-O-naphtylamine and diisopropylcarbodiimide (1.5 mm each substance) in methylene chloride for 1 hour, and the resulting amino acid resin is then treated in accordance with the stages (a) to(f) above rinsing programme. The following amino acids (1.5 mm each), then successfully added using the same technique: Boc-S-methylbenzyl-Cys, Boc-Val, Boc-Ne-benzyloxycarbonyl-lysine, Boc-D-Trp, Boc-Pal, BOC-S-methylbenzyl-D-Cys and Boc--Nal. After washing and drying the formed resin weighed 2,0,

2) - nafcillin-C[D-cysteine-3-pyridyl-2-alanine-tryptophan: lysine-valine-cysteine] --nafcillin-NH2< / BR>
Formed resin described above in (1) (1.0 g, 0.25 mm) was mixed with anisole (5 ml), dithiothreitol (100 mg) and anhydrous hydrogen fluoride (35 ml) at 0oC and was stirred for 45 minutes. The excess hydrogen fluoride quickly evaporated under the stream of liquid nitrogen, and the free peptide was besieged and washed with ether. The crude peptide was then dissolved in 500 ml of 90% acetic kislotno color. The excess of I2was removed by the addition of ascorbic acid and the resulting solution evaporated to a small volume, which was transferred to a column (2.5 x 90 cm) of SephadexTMG-25, which was suirable 50% AcOH. Fractions containing accordance with the data spectrum UV absorption and TLC were collected, evaporated to a small volume and was transferred to a column (1.5 x 70 cm) VydacTMwith octadecylsilane silicon (10-15 μm). Was suirable linear gradient of acetonitrile in 0.1% aqueous solution triperoxonane acid. Fractions were analyzed by TLC (thin layer chromatography) and analytical HPLC (liquid chromatography high resolution pressure and purified for maximum purity. The desired product as a white fluffy powder was obtained by repeated lyophilization of a solution of water. Data TLC and HPLC confirmed the homogeneity of the resulting product. Elemental analysis of amino acid composition of acid hydrolysate and mass spectroscopy using laser desorption matrix (MALD) confirmed the composition of octapeptide.

(b) Synthesis of H2-D--Nal-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2,

1) BOC--D-nafcillin-D-4-chlorophenylalanine-O-diclorbenzimidazol-D-tryptophan-Ne-benzyloxy the new resin (Advanced ChemTech Inc. , Louisville, KY) (1.2 g; 0.5 mm) in chlorine-ion form was placed in the reaction vessel of the peptide synthesizer Advanced ChemTechTMprogrammed to conduct the following reaction cycle: (a) methylene chloride; (b) 33% triperoxonane acid in methylene chloride (twice for 1 and 25 min); (C) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) 10% triethylamine in chloroform.

The neutralized resin was stirred with Boc-O-benzyltoluenes and diisopropylcarbodiimide (1.5 mm each) in methylene chloride for 1 hour, and the resulting amino acid resin was then treated in accordance with the stages (a) through (f) above rinsing programme. The following amino acids (1.5 mm) and then successfully added using the same technique: Boc-phenylalanine, Boc-Val, Boc-Ne-benzyloxycarbonylglycine, Boc-D-Trp, BOC-O-dichlorobenzyl-Tyr, Boc-D-4-chlorophenylalanine and Boc-D-Nal. After washing and drying the formed resin weighed 2,1,

2) - D-nafcillin-D-4-chlorophenylalanine-tyrosine-D-tryptophan-lysine-valine-phenylalanine-thereonin-NH2< / BR>
The peptide resin obtained in (1) were subjected to HF cleavage, as described above. Purification by column, described above, gives the desired compound in the form of a white fluffy powder (170 mg), and mass spectrometry (MALD) confirm the composition of the peptide.

Peptides containing C-terminal substituted amides can be obtained by solid-phase methods of the corresponding peptide in solid phase corresponding amine. On the other hand, these analogs can be synthesized by methods of peptide synthesis in phase solvent, in which the growing peptide chain is in solution in an organic solvent during the synthesis and increased through repeated cycles of "attaching/removing protection". The final removal of the protective groups of the side chain leads to the production of the desired peptide after appropriate treatment. Peptides containing N-terminal substituents (for example, when R1is E, or E1SO2(where E is a heterocycle lower alkyl), substituted hydroxy lower alkyl, a R2represents H, 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic)) can be synthesized as described in PCT application WO 95/04752.

Biotest in vitro secretion of growth hormone

(a) obtaining a dispersion Geofizik cells of rats

Hypophysis adult male rats Charles River-CD (Wilmington, MA) contained in controlled conditions, was dispersively and cultivated, using aseptic technique , 103, 249, 1983; Heiman et al. , Endocrinology, 116, 410, 1985). Hypophysis had removed the dead rats, cut into segments and then were placed in siliconized scintillation tubes containing 2 ml of 0.2% trypsin (Worthington Biochemicals, Freehold, NJ) in sterile filtered bicarbonate-buffered Krebs-ringer with the addition of 1% bovine serum albumin, 14 mm glucose, fortified mortar modified eagle medium (MEM) and MEM amino acids (Gibco Lab. , Grand Island, NY) (KRBGA). All glassware was siliconserver as described in Sayers et al. , Endocrinology, 88, 1063, 1971. The fragments were incubated in a water bath for 35 minutes at 37oC while stirring. Then the contents of the tube were poured into a scintillation vial containing 2 ml of 0.1% Gnkazy (Sigma Chemicals Co. St. Louis, MO) in KRBGA, and incubated for 2 minutes at 37oC while stirring. After incubation, the tissue decantation in a 15-ml centrifuge tube and allowed to settle. The medium was decanted, and the segments of the pituitary washed three times with 1 ml fresh KRBGA. Then the cells were dispersible in 2 ml of 0.05% LBI (trypsin inhibitor beans Lima: Worthington Biochemicals) using neat retracting fragments in blow siliconized, burned in the fire Pasteur pipettes. Disperser the CGS for centrifugation. Additionally, used 2 ml of 0.05% LBI for washing the first test tube, which was transferred to the second tube by means of filtration.

(b) Culturing cells

Dispersed cells were then diluted to approximately 15 ml sterile filtered modified by Dulbecco environment Needle (GIBCO), to which was added 2.5% fetal bovine serum (GIBCO), 3% horse serum (GIBCO), 10% fresh rat serum (stored on ice no more than 1 hour) taken from individuals-donors pituitary, 1% MEM nonessential amino acids (GIBCO) and gentamicin (10 ng/ml; Sigma) and nystatin (10000 u/ml; GIBCO). The cells were then transferred into a 50 ml round-bottom glass flask with a wide neck for extraction and then placed on the tablet with a density of 200 000 cells per 1 well (Co-star cluster 24; Rochester Scientific Co. , Rochester, NY). Placed in the tablet of cells maintained in the above-described environment, Dulbecco in a humid atmosphere of 95% air and 5% CO2at 37oC for 4-5 days.

(C) Experimental incubation and determination of the IC50< / BR>
To obtain a sample for analysis of the output of the hormone, the cells were washed three times with medium 199 (GIBCO) to remove the old environment and emergent cells. The total volume of each wash was 1 ml of medium 199, with the th estimated antagonist was tested using one 24-hole tablet, designed for cell culture. Each test was replicated in triplicate. Each plate consisted of 8 treatment groups: a control group with stimulated (1-29)-NH21 nm releasing factor, growth hormone GRF; one control group, with 1 nm inhibited by somatostatin in the presence of GRF (1-29) NH2; and 6 doses of the antagonist in the presence of 1 nm SRIF, and 1 nm GRF on 1 tablet. After 3 hours at a temperature of 37oC in an atmosphere with a ratio of the air/carbon dioxide 95/5% of the medium was removed and stored at -20oC before radioimmunotherapy on the content of growth hormone. The values of the IC50for each antagonist to the 1 nm SRIF was calculated using a computer program (SigmaPlot, Jandel Scientific, San Rafael, CA) at the maximum value of the response in relation to the value of this indicator in the control stimulated (1-29)-NH21 nm. The obtained values IC50shown in the table.

It is apparent that although the invention is described using detailed descriptions, such description is intended to illustrate it, but not to limit the scope of the invention, which is defined by the scope of the claims. The claims included also the others who ly

< / BR>
where a1is D - or L-isomer of an aromatic amino acid;

AND2represents the D-isomer selected from the group comprising Cys, Pen, aromatic amino acid or aliphatic amino acid;

AND3represents an aromatic amino acid;

AND4is D-Trp;

AND6is Thr, Thr(Bzl), Gly, Ser or aliphatic amino acid;

AND7is Cys, Pen, or an aromatic or aliphatic amino acid;

AND8is D - or L-isomer selected from the group including Thr, Ser, aromatic amino acid or aliphatic amino acid;

each of R1and R2independently represents H, or E1SO2or E1CO, where E1represents a heterocycle lower alkyl, substituted on the heterocycle hydrokinesis-alkyl;

R3represents NH2provided that if a2is D-Cys or D-Pen, and7is Cys or Pen, the side chains AND2and7linked by a disulfide bond, and if a1is p-NO2-Phe, AND2is D-Cys, AND3is Phe or Tight, AND6is Thr or Val and7is Cys, AND8is-Nal.

2. Link 3. Connection on p. 2, wherein A1is L-aromatic amino acid.

4. Connection on p. 3, wherein A1is-Nal, o-X-Phe (where X is H, halogen or CN), p-X-RPE (where X is H, halogen or CN), m-X-Phe (where X is H, halogen or CN), F5-Phe, Trp, Dip, Igl, Bip or Npa; AND3is 2-Pal, Tyr(Bzl), His, Tight (I) Bta or Pal; A6is Thr, Tle, Thr (Bzl), Ala, Ile, Leu, Gly, Nle or Val; A8is D - or L-isomer of Thr, Dip, F5-Phe, p-X-h (where X is H, halogen or CN), o-X-Phe (where X is H, halogen or SP), m-X-Phe (where X is H, halogen or CN), Igl, Tyr(Bzl) or Nal.

5. Connection on p. 4, in which AND1is-Nal, Npa, Igl, Phe, p-F-Phe, Trp, p-Cl-Phe, or p-CN-Phe; AND3is Tight, Tight(I) or Pal; A6is Val, Tle, Nle, Ile or Leu; AND8is p-F-Phe, -Nal, Tight, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R1represents N, CH3WITH, 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic; R2is H and R3represents NH2.

6. Connection on p. 5, where a3is Pal.

7. Connection on p. 4 formula

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

(H)(CH3CO--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NHUB>-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;

H2-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH2;

H2-F5-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-F5-Phe-NH2;

H2-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-m-F-Phe-D-ys-Pal-D-Trp-Lys-Val-Cys-m-F-Phe-NH2;

H2-o-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-o-F-Phe-NH2;

H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-F-Phe-NH2;

H2-F5-h-D-s-PAL-D-Thr-Ls-Vl-s-F5-h-NH2;

H2-F5-Phe-D-Cys-2-Pal-D-Trp-Lys-Val-Cys-F5-Phe-NH2;

H2--Nal-D-Cys-His-D-Trp-Lys-Val-Cys-D-Dip-NH2;

H2-Dip-D-Cys-His-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-Di-D-s-is-D-Thr-Ls-Vl-s-Dip-NH2;

H2--Nal-D-Cys-His-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-Trp-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D--Nal-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D--Nal-NH2;

H2--Nl-D-s-PAL-D-Thr-Lys-Vl-s-D-p-F-h-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Tle-Cys--Nal-NH2;

H2-p-F-he-D-s-PAL-D-Thr-Ls-Vl-s--Nl-NH2;

H2--Nl-D-s-PAL-D-Thr-Ls-Nl-s--Nl-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Ile-Cys--Nal-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Gly-Cys--Nal-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Ala-Cys--Nal-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Leu-Cys--Nal-NH2;

H2-Bip-D-Cys-Tyr-D-Trp-Lys-Ile-Cys-Bip-NH2;

H2-p-F-Phe-D-Cys-His-D-Trp- 2
;

H2-o-F-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-o-F-Phe-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH2;

H2-CPA-D-s-PAL-D-Thr-Ls-Vl-s-CPA-NH2;

H2-Iql-D-s-PAL-D-Thr-Ls-Vl-s-Iql-NH2;

H2--Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-Dip-NH2;

H2--Nl-D-s-3-I-Taut-D-Thr-Ls-Vl-s--Nl-NH2;

H2-p-SP-h-D-s-PAL-D-Thr-Lys-Vl-s-p-SP-h-NH2;

H2--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-Dip-NH2;

H2--Nal-D-Cys-Bta-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys--Nal-NH2;

H2-BPA-D-s-PAL-D-Thr-Ls-Vl-s-BPA-NH2;

H2-Ih-D-s-PAL-D-Thr-Ls-Vl-s-Ih-NH2;

H2-Thr-D-s-PAL-D-Thr-Ls-l-s--Nl-NH2;

H2-p-CL-h-D-s-PAL-D-Thr-Ls-Vl-s--Nl-NH2;

H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys--Nal-NH2;

H2-p-CL-h-D-s-PAL-D-Thr-Ls-l-s-p-CL-h-NH2,

or its pharmaceutically acceptable salt.

8. Connection on p. 2, wherein A1is a D-aromatic amino acid.

9. Connection on p. 8, in which AND1is D-Nal, D-p-X-Phe (where X represents halogen), D-Dip or D-Bip; AND3is 2-PAL, Tyr(Bzl), His, Tyr(I), Bta or Pal; AND6is Thr, Tle, Thr(Bzl), Ala, Ile, Leu, Gly, Nle or Val; AND8is the and CN), m-X-Phe (where X is H, halogen or CN), Igl, Tyr(Bzl) or Nal.

10. Connection on p. 9, in which AND1is D-Nal, D-p-F-Phe; D-p-Cl-Phe; AND3is Tight, Tight(I) or Pal; AND6is Val, Tle, Nle, Il or Leu; AND8is p-F-Phe, -Nal, Tight, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R1represents N, CH3WITH, 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic; R2is H and R3represents NH2.

11. Connection on p. 10, in which AND3is Pal.

12. Connection on p. 8 formula

H2-D--Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D--Nal-NH2;

H2-D-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-p-F-Phe-NH2;

H2-D-Bip-D-Cys-Tyr-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-D-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys--Nal-NH2;

H2-D-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys--Nal-NH2;

H2-D-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-p-Cl-Phe-NH2< / BR>
or its pharmaceutically acceptable salt.

13. Connection on p. 1 AND2is a D-aromatic amino acid, D-aliphatic amino acid, AND7represents an aromatic amino acid or aliphatic amino acid, and4is D-Trp.

14. Connection on p. 13, in which AND1predstavlyala AND1is-Nal or Phe; A2represents the D-Cpa; AND3is Tight; AND6is Thr or Val; A7is Phe; AND8is Thr; R1represents N, CH3WITH, 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic; R2is H and R3represents NH2.

16. Connection on p. 14 formula

H2--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;

H2--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe--Nal-NH2< / BR>
or its pharmaceutically acceptable salt.

17. Connection on p. 13, in which AND1represents a D-amino acid, and2is a D-aromatic amino acid.

18. Connection on p. 17, in which AND1is D-Nal or D-Phe; AND2represents the D-Cpa or D-Phe; AND3is Phe or Taut; AND6is Thr or Val; AND7is Phe and8is Thr; R1represents N, CH3WITH, 4-(2-hydroxyethyl)-1-piperazinylmethyl or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic; R2is H and R3represents NH2.

19. Connection on p. 17 formula

H2-D--Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2< / BR>
or its pharmaceutically acceptable salt.

 

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The invention relates to compounds of General formula I

< / BR>
in which X represents a hydrogen atom or halogen, (C1-C3)alkyl group, one or two (C1-C3)alkoxy group, or triptorelin group, Y is a hydrogen atom or halogen, (C1-C3)alkyl or (C1-C3)alkoxygroup, R represents a hydroxy group, a methoxy group, or a group of the General formula NR2R3in which R2and R3each independently represents a hydrogen atom, (C1-C4)alkyl group, 2-methoxyaniline group, 3-methoxyaniline group, 3-aminopropyl group, group 2-(dimethylamino)ethyl group, 3-(dimethylamino)propyl or 2-piperidine-2-retil, or R2and R3form together with the nitrogen atom to which they are connected, morpholine, pyrolidine or pieperazinove ring which may have in position 4 Deputy in the form of a methyl group or groups (1,1-dimethylmethoxy)carbonyl, in the form of free bases or salts formed by the addition of acid
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