Somatostatinoma peptides

 

(57) Abstract:

Describes a new cyclic Hexapeptide of the formula (II) cyclo [A - Zand(D/L)Trp - Lys - X1- X2] (II) where X1means a radical of the formula (a) or (b), where R1means optionally substituted phenyl; R2means Z1-CH2-R1, -CH2-CO-O-CH2-R1; or (C) or (d), where Z1means O or S; X2is an amino acid having an aromatic residue on the side chain Cor is the amino acid level Db; And a represents a divalent residue selected from Pro, where R3represents NR8R9-(C2-C6)alkylen or guanidino (C2-C6)alkylene; R4represents hydrogen or CH3; R11represents an optionally substituted in the ring, benzyl, -(CH2)1-3- HE or -(CH2)1-5-NH2; Rbrepresents -(CH2)1-3; each of R8and R9independently of one another represent hydrogen, (C1-C4)alkyl, acyl or CH2HE(SEN)with-CH2- in which C = 0, 1, 2, 3, or 4, or R8and R9form together with the nitrogen atom to which they paramorphine; Zzandis a link natural or non-natural amino acids are selected from the group comprising Ala, Val, Thr, Ser, Leu, Nle, Jle, His, Trp, Arg, Tyr, Phe and NH2-Phe, in free form or in salt form or complex compounds. The compounds have affinity to somatostatin receptors. 2 s and 5 C.p. f-crystals, 2 PL.

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or

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The invention relates to somatostatinomas peptides, method for their production and pharmaceutical preparations containing them.

Somatostatin is tetradecapeptide having the structure:

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Since the isolation and characterization of somatostatin conducted an intensive search for more potent and more stable analogues.

More specifically, the present invention features an analog of somatostatin containing the amino acid sequence of the formula (I)

(D/L)Trp-Lys-X1-X2(I)

in which X1represents a radical of formula (a) or (b)

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or

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where R1represents a possibly substituted phenyl,

R2is a-Z1-CH2-R1, -CH2-CO-O-CH2-R1,

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or

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where Z1represents O or S, and9natural somatostatin - 14.

These compounds are referred to hereinafter as compounds according to the invention.

As used here is the analogue of somatostatin is remotemachine or cyclic peptide derived from existing in the nature of somatostatin-14, containing a sequence of the formula I and in which optionally one or more than one amino acid unit is removed and/or substituted by one or more than one amino acid radical(s), and/or in which one or more than one functional group substituted by one or more than one other functional group, and/or one or more than one group substituted with one or more other isothermic groups. In a General sense, the term covers all modified derivatives of natural somatostatin-14, containing the above sequence of formula I, which has an affinity binding in the nM range with at least one subtype of somatostatin receptors, as defined hereafter.

According to PR the s 8-11 somatostatin-14 presents the sequence of formula I, as specified above.

More preferably provides an analog of somatostatin, as defined above, containing Hexapeptide unit, and residues in positions 3-6 specified Hexapeptide units contain a sequence of the formula I. the Most preferred is somatostatinomas Hexapeptide in which residues at positions 1 and 2 Hexapeptide units can be any of the known from the prior art (A. S. Dutta, Small Peptides, Vol.19, 292-354, Elsevier, 1993) or, as substituents, residues Phe6and/or Phe7somatostatin-14.

More specifically, provides an analog of somatostatin, which Hexapeptide unit is cyclic, for example, having a direct peptide bond between the carbonyl group of the residue at position 6 and a-amino group of the residue in position 1.

Whereas Lys, X1and X2in the sequence of formula I have the L-configuration, Trp may be D - or L-configuration. Preferably Trp is D-configuration.

X1preferably represents the residue of formula (a) or (b), and R2preferably is

-Z1-CH2-R1< / BR>
or

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When X2contains aromatic mod the measures Phe, Tyr, Trp, Nal, Pal, benzothiazyl-Ala, Tic and Terenina, preferably Phe or Nal, more preferably Phe. X2preferably represents-amino acid bearing an aromatic residue on the side chain Cg.

When R1is a substituted phenyl, it may accordingly be substituted, for example, in the ortho and/or para position by halogen, stands, ethyl, metaxylem or ataxia. More preferably R1represents unsubstituted phenyl.

Z1preferably represents O.

Representative compounds according to the invention is, for example, the compound of formula (II)

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in which X1and X2such as defined above,

A represents the bivalent residue selected from Pro,

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where R3represents NR8R9-C2-6-alkylen, guanidino-C2-6-alkylene or C2-6-alkylene-COOH, R3arepresents H, C1-4alkyl or has independently one of the meanings given for R3, R3brepresents H or C1-4alkyl, Rarepresents OH or NR5R6, Rbrepresents -(CH2)1-3- or-CH(CH3)-, R5and R6independently represents H, C1-4alkyl-amino-C1-4alkylene, -hydroxy-C1-4alkylen or acyl, R7represents a direct bond or C1-6alkylene, each of R8and R9independently represents H, C1-4alkyl-hydroxy-C2-4alkylene, acyl or CH2OH-(CHOH)c-CH2- where c is 0, 1, 2, 3, or 4, or R8and R9form together with the nitrogen atom to which they are attached, heterocyclic group which may contain an additional heteroatom, and R11represents a possibly substituted in the ring, benzyl, -(CH2)1-3-OH, CH3-CH(OH)- or (CH2)1-5-NR5R6and

ZZarepresents a unit of natural or unnatural amino acids.

ZZamay be D - or L-configuration. When ZZarepresents a unit of natural or unnatural amino acids, it may accordingly be, for example, Thr, Ser, Ala, Val, Ile, Leu, Nle, His, Arg, Lys, Nal, Pal, Tyr, Trp, possibly substituted in the ring of Phe or Ng-benzyl-Cly. When ZZarepresents Phe, his benzene ring can be substituted, for example, NH2, NO2CH3, OCH3or halogen, preferably in the para-position is if A contains Pro amino acid residue, any Deputy, is present in prolinnova ring, for example, R3-NH-CO-O -, and so on, is preferably in position 4. Such substituted polynomy residue may exist in the CIS-form, for example

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and in the TRANS-form. The present invention covers each geometric isomer individually, as well as mixtures thereof.

If A is a where NR8R9forms a heterocyclic group, this group may be aromatic or saturated and may contain one heteroatom nitrogen or a nitrogen heteroatom and a second heteroatom selected from nitrogen and oxygen. Preferably the heterocyclic group represents, for example, pyridyl or morpholino. C2-6-alkylen this balance represents preferably-CH2-CH2-.

Any acyl, such as R5, R6, R8and R9in A may be, for example, R12CO-, where R12represents H, C1-4alkyl, C1-4alkenyl, C3-6cycloalkyl or benzyl, preferably methyl or ethyl. When R4aor R11in A is substituted in the benzyl ring, a benzene ring can be substituted as indicated above for the ZZa.

3-NH-CO-O - or

Another more preferred group of compounds according to the invention is the group of compounds in which the N-terminal amino acid contains substituted Pro, in particular 4-substituted Pro, for example the compounds of formula II in which A represents a 4-substituted Pro.

Preferably A represents a 4-(R3-NH-CO-O)Pro.

Additional representatives of the compounds according to the invention are compounds containing the amino group bearing a chelating group, in particular a compound of formula (II), where A contains the amino group of the side chain, which is a chelating group, in free form, in salt form or complexed with a detectable element. These compounds are designated hereafter as chelate compounds according to the invention.

Suitable chelating groups are physiologically acceptable chelating group capable of complexing with a detectable element. Preferably the chelating group has significant is diaminopropionic acids or anhydrides, for example, a group derived from an acyclic ligands, for example, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol - O,O'-bis(2-amino-ethyl)-N,N,N',N'-tetraoxane acid (EGTA), N, N'-bis (hydroxybenzyl) Ethylenediamine-N, N'-luxusni acid (HBED) and Triethylenetetramine acid (TTHA), groups derived from the substituted EDTA or DTPA, for example parasiticidal-benzyl-EDTA or DTPA, group derived from macrocyclic ligands, such as 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraoxane acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane-N, N',N",N"'-tetraoxane acid (TETA) or 1,4,7,10-tetraazacyclotridecane-N, N', N", N"'- tetraoxane acid (TITRA).

Chelating group can be attached, either directly or through spacer elements group to the amino group of the compounds according to the invention. Suitable spacer elements of the group include known from the prior art (GB-A-2225579) groups, for example the bivalent residue of the amino-carboxylic acids, such as Ala or a bivalent residue derived from 6-aminocaproic acid.

Preferred chelating groups are groups derived from DTPA, DOTA, TETA, or substituted EDTA or DTPA. Chelating group, sex the th element, preferably the metal ion, which exhibits the property of detectable therapeutic or in vivo diagnostic methods, such as metal ion that emits detectable radiation, or metal ion, which is able to influence the NMR relaxation properties.

Suitable detectable metal ions include, for example, ions of heavy elements or rare earth metals, in particular, used CAT scan (computed axial tomography), paramagnetic ions, such as Gd3+, Fe3+, Mn2+and Cr2+, fluorescent ions of metals such as Eu3+and radionuclides, such as radioantenna, in particular-emitting radionuclides-emitting radionuclides-emitting radionuclides, Auger-e--emitting radionuclides, positron-emitting radionuclides, such as68Ga.

Suitable-emitting radionuclides include those which are useful in diagnostic methods. -emitting radionuclides tend to have a half-life of from 1 hour to 40 days, preferably from 5 hours to 4 days, more preferably from 12 hours to 3 days. Examples are the radionuclides obtained from gallium, indium, technetium, Il>Re.

Suitable-emitting radionuclides include those which are useful in therapeutic applications, such as90Y67Cu186Re,188Re,169Er121Sn 127Te143Pr198Au,109Pd165Dy,32P,142Pr and156Sm.

Suitable-emitting radionuclides are those that are used in therapeutic treatment, such as211At,212Bi or201Tl.

Compounds according to the invention can be, for example, in free form or in salt form. Salt include salts obtained by the addition of acids, for example salts of organic acids, polymeric acids or inorganic acids, such as hydrochloride and acetates, and salt forms received from the group of carboxylic acids at their presence, for example, chelating group, such as alkali metal salts, such as sodium or potassium, or substituted or unsubstituted ammonium salts.

The present invention also includes a method of preparing compounds according to the invention. They can be obtained by analogy with known methods.

Compounds according to the invention can be obtained, for example, as follows:

a) remove, is ormula 1, and somatostatinomas peptide is in a protected form, or

b) be bound by an amide bond two peptide units, each of which contains at least one amino acid in protected or unprotected form, with this arrangement, amide bond, in which get the desired amino acid sequence, and, if required, carry out stage a) of the method, or

C) remove the functional group is unprotected or protected somatostatinomas peptide or turn it into another functional group in such a way to get another unprotected or protected peptide and, in the latter case, carry out stage a) of the method, or

g) to obtain a chelate compounds according to the invention sew chelating agent and nichelato connection according to the invention in protected or unprotected form, containing a free amino group, thus to lock the chelating group on the desired amino compound, and then may perform stage a) of the method,

and allocate the thus obtained compound according to the invention in free form, in salt form or perhaps in the form complexed with a detectable element.

Stage b) of the method of prepeptide with the formation of the cyclic peptide, having the desired amino acid sequence. If desired, a side chain, which is present in A, can be introduced into the amino acid to the stage of the peptide combination (b) or at the end of a linear or cyclic peptide according to stage b). Thus, in the latter case, the compound of formula II in which A represents a hydroxy-Pro, can be converted into a compound of formula II in which A is an R3-NH-CO-O-Pro.

The cyclization can also be carried out in the traditional way using hydrazide. When the linear peptide is obtained on the resin, usually no matter what amino acid is selected for placement in the C-terminal position, provided that the sequence of amino acids in the linear peptide corresponds to the sequence in the desired analogue of somatostatin. Once the cyclization of the linear peptide conducted, I do not have to determine which amino acid was on the C-end of the linear peptide. Despite the fact that in the General case, the choice of the first amino acids to start the chain does not play a role, since the linear peptide is cycletour, there may be other factors that may prefer one of the original amino acid to another. Preferably the linear peptide cyclist still is 1 in position 5.

Complexation of the compounds according to the invention containing the amino group, substituted chelating group can be carried out by the interaction of the chelate compound with the compound, giving appropriate detectable element, for example with a metal salt, preferably a water-soluble salt. The interaction can be performed by analogy with the known (Perrin, Organic Ligand, Cemical Data Series 22. NY Pergamon Press (1982); Krejcarit and Tucker, Biophys. Biochem. Res. Com. 77: 581 (1977); Wagner and Welch, J. Nucl. Med. 20: 428 (1979)).

Since the starting materials is not described in detail, the compounds are known or can be obtained by analogy with the known and practiced in the technique of ways.

The invention is illustrated by the following examples.

All temperatures are expressed inoC.

The following abbreviations are used:

Bzl = benzyl(Bzl)= -CH2-phenyl attached to oxygen or sulfur according to (a) or (b)

DFM (DMF = dimethylformamide

BOC = tert-butyloxycarbonyl

Fmoc = 9-fluorenylmethoxycarbonyl

TFA = triperoxonane acid

DIPCI = diisopropylcarbodiimide

DCCI = dicyclohexylcarbodiimide

HOBt = hydroxybenzotriazole

Dab = 2,4-diamine is methyl-2,6-dioxocyclohex-1-ildenafil

RT (KT) = room temperature

HyPro = 4-hydroxy-Pro (TRANS, unless otherwise stated)

Tic = tetrahydroisoquinolinium acid

FAB = fast atom bombardment

M. S. = mass spectrometry

E. S. = emission spectroscopy

EXAMPLE 1

cyclo [HyPro-Phe-DTrp-Lys-Tyr(Bzl)-Phe]:

Resin Fmoc-Phe-SASRIN(1,00 g of 0.65 mmol), subject to the procedures of solid-phase synthesis of Fmoc until you collect in the structure of the peptide resin Fmoc-(D)Tpr-Lys-(Boc)-Tyr(Bzl)-Phe-Pro(y-t-OH)-Phe-SASRIN Fmoc deprived of protection, using piperidine. Cleavage of the peptide resin is carried out with application of hydrazinolysis. To 1.00 g of the peptide resin type of 8.3 ml of DMF and 1,24 ml of hydrazine hydrate (approx.15% hydrazine hydrate in DMF). The mixture is stirred for 15 h at RT. After the reaction the resin was filtered and washed thoroughly with DMF. The filtrate is collected and evaporated in high vacuum to obtain an oily residue hydrazide. The residue is dissolved in water and lyophilizer to obtain 480 mg of the linear hydrazide product H-(D)Trp-Lys(Boc)-Tyr(Bzl)-Phe-HyPro-Phe-NH-NH2. This hydrazide was dissolved in 16 ml of DMF, cooled to -20oand treated with 4N HCl solution in ether (2.4 ml, 11.6 mmol) and then tert-butylnitrite (41,3 μl, 0,348 mmol). The reaction mixture is stirred is at room temperature. After the reaction has ended, the DMF is removed under deep vacuum. To the oily residue water is added and the precipitate discarded. The extraction is carried out between ethyl acetate and water. The organic phase is dried over sodium sulfate, and the product isolated. Protection is removed using a mixture of TFA/water (95/5), and the product emit, using high-performance liquid chromatography (HPLC) with reversed phase. Carry out ion exchange of the product containing fractions, and lyophilizers. The result is the connection specified in the header, in the form of a white powder, MH+(FAB) 975, F = 1,24 []D22= -39,0o(95% AcOH; C = 0,1).

EXAMPLE 2

cyclo [{4-(NH2-C2H4-NH-CO-O-)Pro}-Phe-DTrp-Lys - Tyr(Bzl)-Phe]

Fmoc-HyPro-OMe added dropwise into a solution of triphosgene (0.6 EQ.) in THF. After 1H add dimethylaminopyridine (1.0 EQ.) and N-BOC-diaminoethane (6.0 EQ. ), and the reaction mixture was stirred at RT. After the hold operation thin-layer chromatography (TLC), the solvent is removed in vacuum, and Fmoc-4-(N-BOC-aminoethylaminomethyl)Pro-OMe extracted from the two-phase system ethyl acetate/0.1 M HCl to obtain the crude product (MH+= 554). The crude methyl ester that was previously allocated, then break down to St. purify on silica gel, (MNa+= 562).

Resin Fmoc-Phe-SASRIN(1.0 g, of 0.65 mmol), subject to the procedures of solid-phase synthesis of Fmoc until it is assembled in the structure of the peptide resin Fmoc-(D)Trp(BOC)-Lys(BOC)-Tyr(Bzl)- Phe-Pro(y-t-N-BOC-diaminoethane)-Phe-SASRIN. Fmoc deprived of protection, using piperidine. Cleavage of the peptide resin is carried out by processing it in a glass column of 2% solution of TFA in CH2Cl2. The neutralization is carried out 1M solution of NaHCO3. The solvent is evaporated in vacuum, and protected linear peptide lyophilizer (MH+= 1379,8). The protected linear peptide is subjected to cyclization by treatment with DCCI (6.0 EQ.) and HOBt (6.0 EQ.) over a period of 5 days.

Then remove the protection by treatment with a mixture of TFA:H2O (95:5), and cyclic peptide purified preparative high performance liquid chromatography (HPLC) and subjected to ion exchange with getting acetate salts by ion-exchange resin AG4-X4 with getting the connection specified in the header.

(FAB-MH+= 1061,7).

EXAMPLE 3

cyclo [{ 4-(morpholino-ethyl-aminocarbonyl)-Pro} -Phe-DTrp-Lys - Tyr(Bzl)-Phe]

Synthesis hydroxyproline derived as follows.

Fmoc-HyPro-OMe added dropwise into a solution of triphosgene (0,6 the mixture at RT. After surgery thin-layer chromatography (TLC) the solvent is removed in vacuum and Fmoc-4- (morpholinobutyrophenone)Pro-OMe purify on silica gel, (MH+524). Then methyl ether is cleaved by treatment with 1N NaOH in the system of dioxane/water, and the product, Fmoc-4-(morpholinobutyrophenone)Pro-OH, purify on silica gel, (MH+510).

Fmoc-Phe-SASRIN subjected to the procedures of solid-phase synthesis of Fmoc as in the previous example, until it is assembled into the structure of the resin Fmoc-(D)Trp(BOC)-Lys(BOC)-Tyr(Bzl)- Phe(morpholinosydnonimine)HyPro-Phe-SASRIN. Remove the Fmoc protection, using piperidine. Cleavage of the peptide resin is carried out by processing it in a glass column of 2% TFA in CH2Cl2. The neutralization is carried out 1M solution of NaHCO3. The solvent is removed in vacuum, and protected linear peptide lyophilizer. The protected linear peptide is subjected to cyclization by treatment with DCCI (6.0 EQ.) and HOBt (6.0 EQ.) over a period of 5 days. Then remove the protection by treatment with a mixture of TFA:H2O (95:5), and cyclic peptide purified preparative high performance liquid chromatography (HPLC) and subjected to ion exchange with getting acetate salts by ion-exchange resin AG4-X4 to get the connection specified in the header.


cyclo[X-Y-DTrp-Lys-Z-Phe]

in which X, Y and Z are defined below in Table 1.

The peptide of example 29 can be obtained as follows.

The protected peptide, cyclo[(NH2-C(=NH)-NH-C2H4-NH-CO-O-)]-Pro-Tyr-DTrp-Lys(Dde)-Tyr(Bzl)-Phe, collected on the resin, applying the procedure for Fmoc solid-phase synthesis as described in Example 2. Instead of Ng-Boc-Lys use the Ng-Dde-Lys, so it is preferable to introduce the functionality of guanidine in the basic side chain of residue HyPro. After Assembly of the peptide into the structure, finish, end Fmoc group is removed, the peptide is subjected to cyclization and in the end remove protection, as in Example 2. This peptide is dissolved in DMF, add diisopropylethylamine (3 EQ.) and HOBt (4 equiv.) then add 3,5-dimethylpyrimidine nitrate (4 equiv.) and the solution is stirred for 72 h at room temperature. The reaction mixture is evaporated in vacuo, and then treated with anhydrous hydrazine (2% in DMF) for 30 min to remove the Dde group on Lys. The crude peptide specified in the title (Example 29), then purified by high-performance liquid chromatography (H4-NH-CO-O-)Pro-Ala-DTrp - Lys-Tyr(3-Bzl)-Phe]

MH+(E. S.): 984,5

EXAMPLE 42

cyclo[{4-(NH2-C2H4-NH-CO-O-)Pro}- (p-NH2)-Phe-DTrp-Lys-Tyr(3-Bzl)-Phe]

MH+(E. S.): 1076,6

EXAMPLE 43

cyclo[4-HyPro-Phe-DTrp-Lys-Tyr(Bzl)- Nal]

MH+(E. S.): 1025,5

EXAMPLE 44

cyclo[4-HyPro-Phe-DTrp-Lys-Tyr(Bzl)-Tyr]

MH+(E. S.): 991,6

EXAMPLE 45

cyclo[MePhe-His-DTrp-Lys-Tyr(Bzl)-Dab]

MH+(E. S.): 1005

EXAMPLE 46

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a) cyclo[4-(NH2-C2H4-NH-CO-O-) Pro-Phe-DTrp-Lys( -Boc)-Tyr(Bzl)-Phe]

60 mg cyclo [4-(NH2-C2H4-NH-CO-O)Pro-Phe - DTrp-Lys-Tyr(Bzl)-Phe], 12 mg NaHCO3and 12 mg (BOC)2O dissolved in 10 ml of a mixture of DMF/water (7/3) and incubated at room temperature with stirring overnight. After removal of solvent specified in the header of the product emit chromatography on silica gel using the system methylene chloride/methanol/acetic acid50%(8/2/0,25) as mobile phase.

b) cyclo[4-(DTPA-NH-C2H4-NH-CO-O-)Pro-Phe-DTrp - Lys) -Boc)-Tyr(Bzl)-Phe]

120 mg of DTPA-hydrazide are dissolved in 5 ml of DMF and adjusted to pH 3 by adding dropwise a mixture of diethyl ether/3N HCl. After cooling to -15othe reaction mixture was added 4 μl of tert - butylnitrite and a solution of 15 mg of the compound obtained above in (a), in 3 ml of DMF, the ITU obtained residue without any additional purification.

C) cyclo[4-(DTPA-NH-C2H4-NH-CO-O-)Pro-Phe-DTrp-Lys - yr(Bzl)-Phe]

The crude product from step b) is treated with 5 ml of a mixture of TFA/water (95/5) at 0owithin 10 minutes. After dilution with 50 ml water solution directly transferred to the column RP18-HPLC and elute with a gradient of water/acetonitrile/TEA0,1%. Pure fractions are combined and lyophilizers.

FAB-MS: 1436,6

EXAMPLE 47

The compound from Example 46), labeled111In

1 mg of the compound from Example 46) are dissolved in 5 ml of 0.01 M solution of acetic acid. The resulting solution is passed through to 0.22-micron filter Millex-GV (trademark registered), divided into portions of 0.1 ml and stored at -20o.111InCl3(Amersham, 1 mcurie/100 ál) pre-diluted with an equal volume of 0.5 M sodium acetate solution and conduct tagging by mixing the ligand with a solution InCl3and soft homogenization at room temperature.

Then add the buffer HEPES (N-2-hydroxyethylpiperazine-N-2 - econsultancy acid) with a pH of 7.4 and receive a solution concentration of 10-6M

EXAMPLE 48

cyclo[4-(DOTA-NH-C2H4-NH-CO-O)Pro-Phe-DTrp-Lys-Ser (Bzl)-Phe]

M. S.: 1371,57

This connection mark isotope90Y as follows: 20 ál90Y (s albumin), pH 4.5). This solution is incubated at 100owithin 15 minutes. Take an aliquot and dilute it 4 mm DTPA (pH 4.5) before you can analyze using a C18 column HPLC with reversed phase to determine the number of free snehalatha90Y in the reaction mixture (in the presence of [90YDTPA]2-).

EXAMPLE 49

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116 mg of the compound from Example 46 (a), 12 mg NaCNBH3and 2 equivalents of the corresponding aldehyde is dissolved in 25 ml of a mixture of DMF/HOAc1%and incubated at 60oup until the starting material could be detected by thin-layer chromatography (TLC). After removal of solvent the residue is purified by chromatography on silica gel (methylene chloride/methanol/HOAc50%9/1/0,125 ---> 8/2/0,25) in order to separate the mono - and dialkylamines final product.

1) Aldehyde: (D)-glucose

X1= HOCH2-(CHOH)4-CH2- X2=H

E. S.-MH+= 1225,4

2) Aldehyde: (D)-glucose

X1= X2= HOCH2-(CHOH)4-CH2-

E. S.-MH+= 1389,6

3) Aldehyde: 2,3-O-isopropylidene-(D)-glyceraldehyde

X1= HOCH2-CHOH-CH2- X2= H

4) Aldehyde: 2,3-O-isopropylidene-(D)-glyceraldehyde

X1= X2= HOCH2-CHOH-CH2-

E. S.-MH+= 1149,4

Both in free form and in the form of pharmaceutically acceptable salts and complexes of the compounds of this invention exhibit valuable pharmacological properties, which is confirmed by tests in vivo and in vitro, and are thus indicated for the treatment.

In particular, the compounds of this invention are associated with at least one subtype of receptors for somatostatin. Cloned and described 5 subtypes of receptors for somatostatin: SST-1, SST-2 SST-3, SST-4 and SST-5.

hSST-1, hSST-2, hSST-3 and their sequence is known (Y. Yamada et al. in Proc. Nat. Acad. Sci., 89, 251-255 (1992)). hSST-4 and its sequence is known (L. Rohrer et al. in Proc. Acad. Sci., 90, 4196-4200 (1993)). hSST-5 and its sequence is known (R. Panetta et al. in Mol. Pharmacol. 45, 417-427, 1993).

Analysis of the binding may be performed as described below using membranes prepared from selective towards hSST-1, hSST-2, hSST-3, hSST-4 or hSST-5 cell lines, such as CHO cells, stably expressing the hSST-1, hSST-2, hSST-3, hSST-4 or hSST-5.

Use the tissue in the brain or pituitary gland, which render hSST through, for example, in situ hybridization and/or autoradiography receptors. Membranes prepared in accordance with investimenti cells, for example CHO cells, stably expressing the hSST-1, hSST-2, hSST-3, hSST-4 or hSST-5, three times, incubated in a total volume of 300 μl at a temperature of 22oC for 30 minutes with increasing concentrations: [125I-Tyr3]-octreotide in Hepes buffer (pH 7,6) with a concentration of 10 mmol/l, containing 0.5% BSA. Incubation is interrupted by rapid filtration through glass fiber filters Whatman GF/B, each of which is then washed four times with 5 ml chilled on ice solution of 10 mmol/l Tris/150 mmol/l NaCl. Filters cheated in counter, LKB with a counting efficiency of 78%. Specific binding represents the total binding minus the nonspecific binding in the presence of 1 µmol/l of somatostatin-14. Experiments performed three times. The affinity constant (Kd) and the number of binding sites is calculated from graphs of data on Statchard.

IR50(the concentration at which inhibition is half of the maximum in the competitive analysis of binding using [125I-Tyr3] -octreotide, i.e. the same radioligand that specified above) of the compounds according to this invention, indicated, for example, above, in the above described assays binding hSST-1, hSST-2, hSST-3, hSST-4 and/or hSST-5 is matched with the means of this invention possess the ability to inhibit the release of growth hormone (GH), as evidenced by the inhibition of release of GH from the culture of pituitary cells in vitro. The front lobe of the hypophysis adult rat males cut into small pieces and dispersed using 0.1% trypsin in 20 mm Hepes buffer. Dispersed cells grown for four days in MEM(Gibco), supplemented with 5% fetal calf serum, 5% horse serum, 1 mm NaHCO3, 2.5 nm dexamethasone, 2.5 mg/ml insulin and 20 U/ml of penicillin/streptomycin. On the day of the experiment adhering cells washed twice with medium Krebs-ringer (Krebs-Ringer), buffered with 2 mm Hepes and supplemented with 5 mm glucose and 0.2% BSA. The cells are then incubated with the test compound in the presence of the factor in the release of growth hormone in a concentration of 310-10M within 2-4 hours. The quantity released into the environment, growth hormone is measured by radioimmune assay (RIA). Compounds of the invention inhibit the release of GH-dependent concentration from 10-11up to 10-6M IR50connection Example 2 is 0.4 nm.

Compounds according to the invention also inhibit the release of insulin and/or glucagon, as evidenced by standard experiments on rats-males. The test substance is administered in the region of okonogi introduction of a test substance to produce blood. Determining the level of insulin and glucagon in the blood produced by radioimmunoassay analysis. This experience of connection according to this invention are active when their introduction in doses of from 0.02 to 1000, for example 10 mg/kg subcutaneously. EC50connection Example 9 in relation to insulin secretion is 1.8 mg/kg subcutaneously.

Compounds according to the invention, respectively, are useful in the treatment of diseases, the etiology of which is excessive secretion of growth hormone or associated with it, for example in the treatment of acromegaly, as well as in the treatment of diabetes (in particular its complications, such as angiopathy, proliferative retinopathy, the phenomenon of "dawn" and nephropathy) and other metabolic disorders associated with the release of insulin or glucagon.

Compounds according to the invention also inhibit the secretion of acidic gastric contents, endocrine and exocrine secretion of the pancreas and secretion of various peptides in the gastrointestinal tract, as evidenced by standard tests, for example on rats with gastric or pancreatic fistula, in which the compounds of this invention are active at doses from 0.01 to 10 mg/kg

Thus, Conn peptic ulcers, intestinal and pancreatic fistula, syndrome and disease "irritated" ulcer, dumping syndrome, syndrome of watery diarrhea, diarrhea AIDS-related or caused by chemotherapy, acute or chronic pancreatitis, tumors secreting gastrointestinal hormones (e.g., VIP, glucagon, insulin, carcinoids and so on), and gastrointestinal bleeding.

Compounds according to the invention is also effective in the treatment of tumors containing the receptors for somatostatin, particularly tumors containing hSST-1, hSST-2, hSST-3, hSST-4 and/or hSST-5, which indicate the results of the study of proliferation of various lines of cancer cells containing somatostatin receptors.

Cell line tumor of the pancreas of the rat AR42J get from caused by azaserine exocrine tumors of the pancreas (Jessop and Hay, 1980). The absence of Mycoplasma regularly confirmed by using staining bisbenzimide and analysis of hybridization GenProbe (San Diego, CA). Culture spread in DMEM, supplemented with 10% fetal calf serum under 5% CO2. Cells grown without antibiotics or antifungal agents. Merging AR42J cells trypsinized, dissolved in DMEM + 2.5% of petalino the ü 0) determine the number of cells in a separate control tablet, as the count in the counter Coulter, and colorimetric analysis of the SRB. The cells are then exposed to the compounds in various concentrations within 2-5 days, after which calculate. In such conditions, the compounds according to this invention inhibit the proliferation of tumor cells at a concentration of from 10-12up to 10-6M IR50connection Example 2 is 0,7 0,3 (CO) nm.

Studies of tumor growth in vivo

Female hairless mice (nu/nu Balbc-A, IFFA Credo, Lyon, France) weighing 19-22 g contain in groups of 5 animals in macroeonomic cells (type III, HS). Cages placed in ventilated enclosures (IFFA Credo), the temperature of which is maintained at a level 241oC. Animals have unimpeded access to drinking water and does not contain pathogens diet for rodents (Diet A, Kliba, Basel, Switzerland). To initiate tumors from cultured cells, AR42J trypsinized, then 5-10106tumor cells (in 0.2 ml) was injected subcutaneously in both flanks hairless mice. Treatment begin within 2-4 days after inoculation of tumor cells, preferably the introduction of the compounds in the form of a continuous infusion, for example with a speed of 10-50 µg/kg per hour. The size of the tumors Predna x width x height x 0.52 in". For statistical calculations used t-test t-test. In this series of experiments the compound according to Example 2 inhibits tumor growth at day 11 to 51% compared with the control physiological solution.

Thus, the compounds of this invention are useful in the treatment of malignant proliferative diseases, such as cancer tumors, particularly tumors that contain those types of receptors for somatostatin, are sent to the action of these compounds, for example, as described below for compounds.

Compounds according to the invention also have an inhibitory effect on angiogenesis, which indicate the results of standard tests, for example on hairless mice, as described below.

Anaesthetize mice by intraperitoneal administration of 400 mg/kg chloral hydrate (Sigma). Tumor cells in an amount of 0.1-101060.1 ml (cells SiHa cells and MDA-MB-231, prepared as described (Angiogenesis, Ed. by R. Steiner, P. C. Weisz and R. Langer, 1992, Switzerland)), inoculant intradermally. Usually the injection, each mouse is produced in two remote from the main vessels of the skin of the abdomen point in mesogastric, so that the original number of vessels was small. Control grupoesta inhalation of CO2. The leather pull on the plastic ring with a diameter of 40 mm for investigation by means of an inverted microscope (Zeiss IM) from 12.5 - and 25-fold magnification. To measure angiogenesis vessels photograph and count those that are directly related to the tumor. Control animals count the blood vessels associated with a specific area around the injection site. This area corresponds to the average area of skin tumors. The latter is determined with the aid of a compass, in accordance with equation 3,14 x r2. The compounds injected subcutaneously either the day of inoculation of the tumor or three days later. Control animals injected media. In this series of experiments the compounds according to the invention inhibit the formation of blood vessels in the introduction in doses of, for example, 0.01 to 1000 μg/kg subcutaneously.

Thus, the compounds according to the invention are useful for prevention or treatment of angiogenesis, inflammatory diseases and retinopathy.

Compounds according to the invention also have an inhibitory effect on the proliferation and migration of smooth muscle cells, which indicate the results of the following studies.

Chronic rejection of the allograft.

a) orthotopic transplanted to male recipient Lewis (RT11). In General produce transplantation in 24 rats. Within 14 days starting from the day of transplantation, all animals receive cyclosporine A dose of 7.5 mg/kg / day inside to prevent acute rejection of the cells. Nephrectomy on the opposite side do not perform. Each group of experimental animals receiving different doses of the compounds of this invention or placebo, consists of six animals.

Since 53-64 day after transplantation animals-recipients receive a connection according to this invention in the form of infusion or placebo for subsequent 69-72 days. On the 14th day after transplantation of the organ perfusion measured by MRI. This procedure is repeated on 53-64 day after transplantation and at the end of the experiment. After that make the dissection of animals. Application to the model of kidney allograft rats of the compounds according to this invention, for example compounds according to Example 31, in a dose of from 1 to 10 mcg/kg per hour is better perfusion of organs. Also noted a sharp decline in the level of IGF-1.

Angioplasty

Research angioplasty is performed on damage model balloon stateofflorida the Fogarty catheter (Fogarty) 2F injected into the left common carotid artery through the external carotid artery, then inflate the balloon (tensile - about 10 μl of H2O). Inflated balloon is extracted along the common carotid artery three times, and the last two times slightly rotate to achieve uniform endothelization. Then the catheter is removed, the external carotid artery impose a ligature in order to prevent bleeding and the animal allowed to recover.

This study used two groups of 12 rats RoRo (400 g, the approximate age of 24 weeks): one control and one receiving the connection according to this invention. All the care, experimental procedure and the analysis is performed on the basis of complete randomization.

The investigated compound is administered in continuous infusion using minimization speeds of 10-50 µg/kg per hour, starting 3 days before the damaged tank (day -3) and before the end of the study, 14 days after injury (day +14). Rats kept in separate cells and provide them with food and water ad libitum.

Then rats anaesthetize with isoflurane, the left ventricle enter perfusion catheter, which is fixed to the aortic arch, and the suction cannula introduced into the right ventricle. Perform perfusion under perfusion pressure of 150 mm Hg, beginning within one minute the house in phosphate buffer (pH of 7.4). Then excised carotid artery, separated from surrounding tissue, immersed in 0.1 M cacodylate buffer (pH 7,4) containing 7% sucrose, and incubated overnight at a temperature of 4oC. the next laziness carotid artery immersed in 0.05% KMnO4in 0.1 M cacodylate and shaken for 1 hour at room temperature. Then tissue dehydration sequential exposure to different concentrations of ethanol: 2x10 minutes in 75%, 2x10 minutes in 85%, 3x10 minutes in 95% and 3x10 minutes in 100% ethanol. Then digidrirovannye carotid artery is placed in Technovit 7100 in accordance with the manufacturer's recommendations. The environment is left to cure overnight in a desiccator under argon. From the middle of each carotid artery solid metal knife on the disk microtome cut out a slice thickness of 4 μm, which are stained by Giemsa (Giemse) for 2 minutes. So prepare about 5 slices each carotid artery, after which the cross-section of the middle layer, neointima and clearance assess morphometric using system image analysis (MCID, Toronto, Canada).

According to the results of this study, the compounds according to the invention inhibit the proliferation neointima at their introduction PU the time, compounds according to the invention are also useful for the prevention of vascular disease in the graft or combat these diseases, such as vasculopathy ALLO - or xenografts, such as atherosclerosis in the grafts, such as the transplanted organ: heart, lung, combination of the transplant heart-lung, liver, kidney or pancreas, or for the prevention or treatment of restenosis and/or occlusion of vessels after vascular damage, such as angioplasty.

Required to apply for all of these indications dosage will of course vary depending, for example, from applied compounds according to the invention, the recipient, the route of administration and the severity of the subject to treatment status. However, in General satisfactory results are achieved with the introduction of the order of from 1 μg to 0.5 mg/kg / day of the compounds according to this invention. Shows patients a daily dose of from 2 mg to about 20 mg, preferably from 0.01 to about 20 mg, in particular from about 10 to about 5000 μg connection subcutaneously, conveniently injected in divided doses three times per day in the form of a standard dose containing, for example, from 0.5 μg to primeneniya according to the invention can be administered in free form, and in the form of pharmaceutically acceptable salts or complexes. Such salts and complexes can be prepared in the usual way and have the same pronounced activity, like free connection. The present invention also proposed a pharmaceutical composition comprising a compound according to the invention, for example compound of formula II, in free base form or in the form of pharmaceutically acceptable salts or complexes, in combination with a pharmaceutically acceptable diluent or carrier. Such compositions can be manufactured in the form of medication as usual. Compounds according to the invention or their pharmaceutically acceptable salts and complexes can be entered in the usual way, for example parenterally, in the form of solutions or suspensions for injection or nasal form or in the form of candles.

In accordance with the foregoing the present invention additionally suggested:

a) compound according to this invention, for example compound of formula II, or its pharmaceutically acceptable salt or complex for use as pharmaceuticals.

b) a method of preventing or treating disorders, as indicated above, the subject in need of such treatment which measures the compounds of formula II, or its pharmaceutically acceptable salt or complex, or

C) the compounds according to the invention, or its pharmaceutically acceptable salt, or a complex for use in the preparation of pharmaceutical compositions for use according to any defined above in paragraph (b) method.

As indicated by the results of standard tests, chelate compounds of this invention or their pharmaceutically acceptable salts are suitable either for use in conjunction with - or positron-emitting nuclide results, such as 111In161Tb or86Y, as a visualizing agent, for example for visualization contains the receptors for somatostatin tissues and cells, such as containing the receptors for somatostatin tumor and metastasis, inflammatory and autoimmune diseases characterized by the presence of receptors for somatostatin, tuberculosis or rejection of organs after transplantation or for use in conjunction with or emitting a nuclide or a nuclide with Auger-e-cascade, such as90Y61Tb211At,213Bi or201Tl, as a radiopharmaceutical drug for treatment in vivo containing receptors for somatostatin tumors and metastases, revatinandana the invention, for example,111In 88Y90Y153Sm186Re or161Tb chelate compounds according to the invention, associated with a good affinity with receptors for somatostatin with a pKi value from about 8 to 10. IR50connection Example 47 is 1.2 nm for hSST-2, of 0.65 nm for hSST-3, and 0.30 nm for hSST-5.

The affinity of the compounds according to this invention and their complexes to the receptors for somatostatin may also be demonstrated through in vivo studies, in accordance with standard methods the research described (GB-A-2,225,579). Connection Example 47, for example, shows a significant accumulation in the tumor after 4 hours after its injection to mice or rats, with exocrine pancreatic tumor containing receptors SST-2.

After the introduction of the chelate compounds according to the invention in the form of a complex, such as111In88Y or161Tb chelate compounds according to the invention, the labeled 0.1 to 5 MCI, preferably 0.1 to 2 MCI of the radionuclide at a dose of 1-5 mg/kg location of the tumor becomes detectable, as the organs through which there is an allocation.

As indicated by the results of studies in hairless mice, chelate soy is -cascade, have antiproliferative and/or cytotoxic effect on tumor cells containing receptors for somatostatin.

Tumor cells of the pancreas of the rat AR42J cell or small cell human lung cancer NCI-H69 inoculant hairless mice as described above. When the tumors reach a volume of 1-2 cm3animals randomizer in the experimental and control groups. Control animals receive either unlabeled compound or a chelate compound in the form of a complex in the form of intraperitoneal or intravenous injection in doses corresponding to the maximum dose applied in the experimental group. Each mouse receives doses up to 40 MCI/kg the size of the tumor is determined with the aid of a compass, as described above. For statistical calculations used t-test t-test. In this series of experiments marked a temporary reduction of the tumor size by 50% from the original and delay growth of tumors in two weeks after a single injection of the compound in Example 48. In the control group, by contrast, is marked by constant growth of tumors with a doubling of the volume within approximately seven days.

Accordingly, in series or special alternative embodiments of the present invention also suggested:

of the complex for detection of the subject in vivo cells and tissues, contains the receptors for somatostatin, and registering the location of the receptor, which binds to this complex.

Labeled with radioactive labeled compounds according to the invention can be administered intraperitoneally, and preferably intravenously, for example in the form of injection solutions or suspensions, preferably in the form of a single injection. Preferably, the incorporation of radioactive label was made shortly before the introduction of the subject.

Convenient is the introduction of chelate compounds according to the invention in a dose containing 0.2 to 20 MCI, and preferably 1-10 MCI, nuclide in the form of a stable complex.

In animals shows the dose range may be from 0.01 to 1 mg/kg chelate compounds according to this invention in combination with a 0.02-0.5 MCI - emitting nuclide. In larger mammals, for example humans, shows the range of doses may be 1-20 µg chelate compounds in the complex, for example, 1-10 MCI111In or86Y

2. The use of chelating compounds according to this invention, for example, chelate compounds of formula II in the form of a complex for the treatment of in vivo tumors and metastases that contains the receptors for somatostatin.

Dose, primenyaemoi from a particular subject to treatment condition, considering, for example known radiotoxicity relative to normal organs contain receptors for somatostatin, tumor volume and the desired therapy. In General, the dose is calculated from pharmacokinetic, distribution of radioactivity to healthy bodies and the observed absorption targets - emitting complex chelate compounds may be administered repeatedly, for example within a period of 1-3 months.

In animals shows the dose range may be from 20 to 100 µg/kg chelate compounds in complex with 15-70 MkI90Y or161Tb.

Chelate compounds of this invention in the form of complexes can be administered by any conventional method, in particular, intraperitoneally or intravenously, for example in the form of injection solutions or suspensions. They can also be conveniently applied in the form of infusions, for example, within 30-60 minutes. Depending on the tumor location, they can be introduced as close as possible to the tumor, for example, through a catheter.

Chelate compounds of this invention in the form of complexes may be suitable for imaging or treatment of such tumors as pituitary and gastroenteropancreatic tumors, kartiki, small cell lung cancer, paraganglioma, kidney cancer, skin, neuroblastoma, pheochromocytoma, medullary carcinoma of the thyroid gland, myeloma, Hodginsii and non-Hodginsii lymphomas, bone tumours and their metastases, and also rheumatoid arthritis.

In accordance with a further aspect of the present invention proposed a pharmaceutical composition comprising a chelate compound according to this invention in free form or in the form of a complex with one or more pharmaceutically acceptable carriers or solvents. Such compositions can be manufactured by conventional methods and is represented, for example, imaging studies, in the form of a set containing two separate dosing instructions mixing: one representing the radionuclide and the other free chelate compound. For, radiotherapy preferably, the chelate compound according to this invention in free form or in the form of the complex was presented in the form of hot liquid drug.

1. The cyclic Hexapeptide of the formula II

< / BR>
where X1(means a radical of the formula (a) or (b),

< / BR>
or

< / BR>
where R1means optional zameshannye Z1means O or S;

X2is an amino acid having an aromatic residue on the side chain Cor is the amino acid level Dab;

A represents the bivalent residue selected from Pro, where R3represents NR8R9-(C2-C6)alkylen or guanidino(C2-C6)alkylen;

R4represents hydrogen or CH3;

R11represents an optionally substituted in the ring, benzyl, -(CH2)1-3-OH, or -(CH2)1-5-NH2;

Rbrepresents -(CH2)1-3;

each of R8and R9independently of one another represent hydrogen, (C1-C4)alkyl, acyl or CH2OH-(CHOH)c-CH2- in which c = 0, 1, 2, 3, or 4, or R8and R9form together with the nitrogen atom to which they are attached, heterocyclic group which may contain an additional heteroatom, for example, pyridyl or morpholino;

ZZais a link natural or non-natural amino acids are selected from the group comprising Ala, Val, Thr, Ser, Leu, Nle, Jle, His, Trp, Arg, Tyr, Phe and NH2-Phe,

in free form or in salt form or complex compounds.

s-Tyr(benzyl)-Phe], cyclo[{4-(NH2-C2H4-NH-CO-O-)Pro} -Tyr-DTrp-Lys-Thr(benzyl)-Phe] and cyclo[{ 4-(NH2-C2H4-NH-CO-O-)Pro}-Phe-DTrp-Lys-Ser(benzyl)-Phe].

3. Cyclic Hexapeptide under item 1, in which A contains an amino group bearing a chelating group, in free form or in salt form or complexed with a detectable element.

4. Cyclic Hexapeptide under item 3, wherein the chelating group is selected from diethylenetriaminepentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-N, N', N", N"'-tetraoxane acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraoxane acid (TETA), in free form or in salt form or complexed with a detectable element.

5. Cyclic Hexapeptide under item 2, in which the amino acid end group of the side chain represented by the RHS link, which, in addition, attached to a chelating group, in free form or in salt form or complexed with a detectable element.

6. Cyclic Hexapeptide according to any one of paragraphs.1 - 5 or its pharmaceutically acceptable salt or complex with a detectable element, intended for use as pharmaceuticals.

7. Pharmaceutical kunoe the number of cyclic Hexapeptide according to any one of paragraphs.1 - 5, or its pharmaceutically acceptable salt or complex with a detectable element in combination with one or more pharmaceutically acceptable carriers or diluents.

 

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< / 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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FIELD: organic chemistry, amino acids.

SUBSTANCE: invention claims new compounds that elicit both high affinity and selectivity with respect to neuromedin B and somatostatin receptors. Compounds has the following formula: wherein α-atom in each group among AA1, AA2, AA3, AA4, AA5, AA6, AA7 and AA8 is substituted optionally and independently with (C1-4)-alkyl-(C3-4)-alkenyl, (C3-4)-alkynyl or (C1-6))-alkyl-C(O)-; AA1 is absent or means Ac-D-Phe or D- or L-isomer of R11, Pip, Pro or aromatic α-amino acid taken among the group consisting of Cpa, Dip, Nal and Phe; AA2 is absent or means Pal, Phe, Tyr; AA3 means D- or L-isomer of Cys; AA4 means D- or L-isomer of Trp; AA5 means Lys; AA6 means D- or L-isomer of Cys; AA7 is absent or means A3c, A4c, A5c, A6c, Abu, Aic, β-Ala, Gaba, Nle, Pro, Sar, Thr, Thr(Bzl) or Val; AA8 is absent or means R11, Nal, Thr, Tyr, Phe or Nle; each among R1 and R2 represents independently hydrogen atom (H) or absent; R5 means -NH2,; R11 means D- or L-amino acid independently in each case and AA3 and AA6 are bound by disulfide bond.

EFFECT: valuable biological properties of compounds.

9 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying agonists of somatostatin receptors in case of thyroid carcinoma and, it also, deals with the method for modulating the rate of cell proliferation of medullary thyroid carcinoma (MTC) due to combined impact upon cells with either one or several agonists of somatostatin receptors of type 2 (SSTR2)or either with one or several agonists of somatostatin receptors of type 5 (SSTR5). Moreover, the mentioned SSTR5 agonist can be represented with D-Phe-Phe-Trp-D-Trp-Lys-Thr-Phe-Thr-NH2 or its pharmaceutically acceptable salt. The present innovation enables to enhance suppression of MTC cell proliferation due to antagonism between mediated SSTR2 and SSTR5 effects to the proliferation mentioned.

EFFECT: higher efficiency of modulation.

1 cl, 8 dwg, 2 tbl

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