Cyclic peptide analogues of somatostatin

 

(57) Abstract:

The present invention describes a peptide of the formula

< / BR>
where the substituents described in the description, which is the circular analogue of somatostatin, in which a disulfide bond connects the N-terminal residue of the C-terminal residue. 20 C.p. f-crystals, 1 table.

Background of the invention

Native somatostatin includes both isoforms of the 14-amino acid (somatostatin-28), and isoforms of 18 amino acids (somatostatin-18) (Heiman. et al., Neuroendocrinology, 45: 429-436 (1987)). Due to the short half-life of native somatostatin have been developed various its analogs, for example, for the treatment of acromegaly (Raynor, et al., Molecular Pharmacol. 43: 838 (1993)). Were identified and described five different somatostatin receptors. (Hoyer, et al., Naunyn-Schmiedeberg''s Arch. Pharmacol., 350:441 (1994)). Somatostatin causes many reactions, including modulating the release of hormones such as growth hormone, glucagon, insulin, Amylin, and the release of neurotransmitter. Some of these effects of somatostatin are accompanied by its binding with a specific receptor somatostatin. So, for example, inhibition of the growth hormone referred to receptai insulin assign the appropriate role of somatostatin receptor type 5 ("SSTR-5") (Coy, et al., 197:366-371 (1993)). It is preferable to have analog with selective actions with respect to the given subtype-specific receptor somatostatin, responsible for the desired biological response, allowing, thus, to reduce interaction with other receptor subtypes, which could lead to the development of side effects.

A brief description of the invention

The invention relates to a peptide described by the following General formula:

< / BR>
where A1denotes a D - or L-isomer of Cys or IPC;

A2represents ASN, GLn, or aliphatic amino acid, an aromatic amino acid or is missing;

A3denotes an aromatic amino acid;

A4indicates GIS or aromatic amino acid;

A7indicates Tre, Ser or aliphatic amino acid;

A8denotes an aromatic amino acid;

A9denotes a D - or L-isomer of Cys;

each of R1and R2represents, independently of one another, H, C1-12alkyl, C7-20phenylalkyl, C11-20nafcillin, C1-12hydroxyalkyl, C7-20hydroxyphenylethyl, C11-20hydroxynaphthalene or COE1where E1the seat is igenerally or C11-20hydroxynaphthalene; and

R3denotes NH2or NHYCH2Z, where Y represents C1-12hydrocarbon group (divalent, for example, linear or branched alkyl group and Z represents H, OH, CO2H or CONH2;

disulfide bond links the side chains of residues of the A1and A9; or their pharmaceutically acceptable salt.

In one embodiment, the implementation of the present invention each group of A3and A8represents, independently from each other, Hairdryer, p-X-dryer (where X represents halogen, OH, OCH3CH3or NO2), o-X-dryer (where X represents halogen, OH, OCH3CH3or NO2), pyridyl-Ala, TRP, Nal, 2,4-dichloro-dryer, Tyr (I) or F5-Hairdryer, A4is a GIS, Hairdryer, p-X-dryer (where X represents halogen, OH, OCH3CH3or NO2), o-X-dryer (where X represents halogen, OH, OCH3CH3or NO2), pyridyl-Ala, TRP, Nal, 2,4-dichloro-dryer, Tyr (I) or F5-Hairdryer, A2- represents ASN, GLn, Ala, Aim, Val, LEU, Ile, NLE, NCA, AMK, Hairdryer, p-X-dryer (where X represents halogen, OH, OCH3CH3or NO2), o-X-dryer (where X represents halogen, OH, OCH3CH3the sludge is EP, Ala, Aim, Val, LEU, Ile, NLE, NCA or AMK.

In another embodiment of the invention Ar denotes CIS, each of A3and A8independently from each other, represents a Hairdryer, p-X-dryer (where X denotes halogen, OH or CH3), Tyr (I), or TRP; A4indicates GIS, Hairdryer, p-X-dryer (where X represents halogen, OH or CH3), Tyr (I), or TRP, A2represents ASN, GLn or absent and A7indicates Requirements or Ser.

In yet another implementation of the present invention A2represents ASN or absent, A3denotes a Hairdryer, A4means Hairdryer, GIS, p-X-dryer (where X represents halogen, OH or CH3), Tyr (I), or TRP, A8denotes the dryer or p-X-dryer (where X represents halogen, OH or CH3and each of the groups R1and R2regardless Druta from each other, represents H and R3denotes NH2.

Below are examples of the peptides of the present invention, which correspond to the above formula:

H2-c[D-Cys-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Analog II)

H2-c[Cys-Hairdryer-TRP-D-TRP-Lys-Tre-Hairdryer-CIS)-NH2,

H2-c[D-Cys-Hairdryer-TRP-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[Cys-Hairdryer-GIS-dryer-Hairdryer-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2(Similar to IV),

H2-c[D-Cys-hair dryer-Hairdryer-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-C[Cys-Hairdryer-TRP-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2(Similar to (III),

H2- (D-Cys-Hairdryer-TRP-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[Cys-Hairdryer-GIS-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[D-Cys-Hairdryer-GIS-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Similar to VIII),

H2-c[D-Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[D-Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[Cys-ASN-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Similar to V),

H2-c[D-Cys-ASN-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[Cys-ASN-Hairdryer-TRP-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[D-Cys-ASN-Hairdryer-TRP-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C(Cys-ASN-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[D-Cys-ASN-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[Cys-ASN-hair dryer-Hairdryer-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[D-Cys-ASN-hair dryer-Hairdryer-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[Cys-ASN-Hairdryer-TRP-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[D-Cys-ASN-Hairdryer-TRP-D-TRP-Lys-Ser-Hairdryer-Cys]-NN22,

H2-c[Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[D-Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-c[Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[D-Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-c[Cys-Hairdryer-Tyr-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Similar to VI),

H2-C[Cys-Hairdryer-Nal-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Similar to VII),

H2-c[Cys-Hairdryer-HFA-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Similar to IX),

H2-c[MPa-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Similar to X),

H2-c[Cys-Hairdryer-Tyr-D-TRP-Lys-Tre-Hairdryer-D-Cys]-NH2(Similar XI)

H2-c[Cys-hair dryer-Hairdryer-D-TRP-Lys-Tre-Tyr-Cys]-NH2(Similar XII),

H2-c[Cys-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2(Similar to XIII).

Except for the N-terminal amino acids all abbreviations (e.g., Ala or A2) amino acids in the present description corresponds to the structure-NH-CH(R)-CO-, where R is the side chain of amino acids (for example, represents a CH3in Ala). In the case of the N-terminal amino acids reduction corresponds to the structure = N-CH(CH2SH)-CO-, if it is D - or L-isomer of Cys or C=(-CH2SH)-CO, if it is D - or L-isomer of the IPC, while R represents the side chain of the amino acid the values accordingly: norleucine, Norvaline, -pyridyl-alanine, pendaftar-phenylalanine, and 2,4-dichlorophenylamino-naphthylamine, -aminobutyric acid, mercaptopropionic acid, p-chlorophenylalanine and-aminoadamantane acid. Designation Tyr (I) refers to the iodine-containing residue tyrosine (for example, 3-I-Tyr, 5-I-Tyr, 3,5-I-Tyr), in which iodine can be a radioactive isotope, for example, I125I127or I131. Aliphatic acid is an amino acid that includes one or two side chains which are, independently of one another are a hydrocarbon, for example, represent a linear or branched chain containing from 1 to 6 carbon atoms. Examples of aliphatic amino acids include Ala, Aim, Val, LEU, Ile, NLE, NCA or AMK. Aromatic amino acid is an amino acid side chain which is neutral (i.e., not sour or not alkaline) aromatic Deputy, for example, substituted or not substituted phenyl, naphthyl or aromatic heterocyclic group (e.g. pyridyl or indolyl). Examples of aromatic amino acids include Hairdryer, p-X-dryer (where X denotes a halogen (for example F, Cl or I), OH, OCH3CH3or NO2), o-X-dryer (where X denotes halogen, OH, the residue presents optically active isomer, this is the L-isomer, unless otherwise specified. In addition, in the above General formula hydroxyalkyl, hydroxyphenylethyl and hydroxynaphthalenes can contain from 1 to 4 hydroxyl substituents and COE1-C= OE1. Examples of-C=OE1include, but are not limited to, p-hydroxyphenylpropionic (i.e.,- C=OCH2-CH2-C6H4-OH) and phenylpropionyl. In the above formula not shown disulfide bonds linking the thiol group on the side chain residue of A1(for example, IPC, D-IPC, Cys or D-Cys) and the thiol group on the side chain residue of A9(for example, IPC, D-IPC, Cys or D-Cys). The peptide of the present invention is indicated also in another form, such as H2-c[Cys-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys] -NH2in this case, the two linked by a disulfide bond balance (i.e., CIS) placed in brackets after "c".

The peptides of the present invention can be used for inhibiting the release of insulin from the subject (mammal, such as a sick person). Thus, the peptides can be used in the treatment of physiological conditions in which it is desirable to achieve inhibition of the release of insulin, for example, in diabetes type II. In addition, the peptides according to the present toccatina (for example, SSTR-5). Such peptides of the present invention can be used either in vivo to detect cells bearing receptors somatostatin (e.g., cancer cells) or in vitro as a radioactive ligand in the test for binding to the somatostatin receptor.

The peptides of the present invention can be represented pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, salts formed with organic acids (e.g. acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluensulfonate or pambou acid), inorganic acids (i.e., hydrochloric acid, sulfuric acid or phosphoric acid), polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic acid, polyglycolic or copolymers of polylactic acid - glycolic acid).

A therapeutically effective amount of the peptide of the present invention and a pharmaceutically acceptable carrier substance (e.g., magnesium carbonate, lactose, or a phospholipid with which the medicinal compound forms a micelle) together form a pharmaceutical composition (e.g. in the form of pills, tablets, capsules Rodchenko, nasal, method of iontophoresis, intratracheal) to a subject in need of the peptide. The pill, tablet or capsule can be coated with a substance capable of protecting the composition from the action of gastric juice and digestive enzymes in the stomach of a subject over a period of time sufficient for the composition is passed undigested in the small intestine of the subject. A pharmaceutical composition may also be in the form of prolonged action, which can be biodegradable and not be subject to degradation under the influence of biological factors and which is used for subcutaneous or intramuscular injection. See, in particular, the U.S. patent 3773919 and 4767628 and PCT application N WO 94/00148.

It is also possible to perform the continuous introduction using an implantable or external pump (e.g. pump INFUSAIDTM) suitable for administration of medicinal compositions. The peptide can be administered to the patient before going to sleep.

The dose of the peptide of the present invention, used in the treatment of the above diseases varies depending on the method of administration, age and body weight of the subject, the health of the subject to be treated, and, however, is determined by the attending physician or veterinarian, in the present description will correspond to the term "therapeutically effective amount".

In the framework of the present invention is also a peptide covered by the above General formula, which is used for the treatment of diseases or disorders associated with the need to inhibit the release of insulin, for example, diabetes type II, and for use for the detection of somatostatin receptors, for example, when scanning with the use of radioactive isotopes.

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

Detailed description of the invention

The synthesis and use of somatostatin analogues according to the present invention will not cause difficulties for professionals with an average level of knowledge in this area. Unless specifically stated otherwise, all technical and scientific terms used in the context of the present description, correspond to their values, which experts traditionally assign them. In addition, all publications, patent applications, patents and other mentioned in the description of the references cited in this report as auxil and on the basis described in the application description can make full use of the present invention. Below are specific implementations of the present invention should therefore be understood as merely illustrative and in no way limiting the invention.

The synthesis of analogues of somatostatin

The synthesis of short peptides is well studied in the field of peptide chemistry. (See, in particular, Stewart et al., Solid Phase Peptide Synthesis (Pierce Chemical Co., 2d ed., 1984)). Below is described the method of synthesis of Analogue I. Other peptides of the present invention can be obtained in a similar way any specialist with the average level of knowledge in this field.

Benzylhydroxylamine-polystyrene resin (Advanced ChemTech, Inc., Louisville, KY) (1.1 g, 0.5 mmol) in a form containing chloride ion, is placed in the reaction vessel in system programmable synthesis of peptides (Advanced ChemTech ACT 200) to make the following reagents/solvents: (a) methylene chloride; (b) 33% triperoxonane acid in methylene chloride (2 times for 1 and 25 min each); (C) methylene chloride; (d) ethanol: (e) methylene chloride; and (e) 10% triethylamine in chloroform.

The neutralized resin is stirred with BOC-S-4-methylbenzyl-CIS and diisopropylcarbodiimide (each 1.5 mmol) in methylene chloride for 1 hour and the resulting amino acid resin is subjected to cyclic abrogat sequential linking of the following amino acids (1.5 mmol): Side-dryer, BOC-O-benzyl-Tre, Side-by-N-benzyloxycarbonyl-Liz; BOC-D-TRP, BOC-dryer, Side-by-Hairdryer and Side-S-methylbenzyl-CIS. After washing and drying the weight of the finished resin is 1.6,

Then the resin (1.6 g, 0.5 mmol) is mixed with anisole (5 ml), dithiothreitol (100 mg) and anhydrous hydrogen fluoride (35 ml) at 0oC and stirred for 45 minutes. Excess fluoride is rapidly evaporated in a stream of dry nitrogen and precipitated while the free peptide was washed with diethyl ether. After that, the crude peptide is dissolved in 500 ml of 90% acetic acid, which is added to the concentrated solution of I2/MeOH to obtain a consistent brown color. Remove the excess of I2the addition of ascorbic acid and the solution is evaporated to a small volume and applied to a column (2.5 x 90 cm) with Sephadex G-25, which was washed with 50% AcOH. Then combine the fractions containing the main component, on the basis of data about the ultraviolet (UV) absorption and results of thin-layer chromatography, evaporated to a small volume and applied to a column (1.5 x 70 cm) with octadecylsilane-silica gel VYDACTM(10-15 μm). Spend the elution from the column using a linear gradient from 80% a and 20% B to 40% a and 60% B, And where the functions are examined using thin layer chromatography (TLC) and analytical high performance liquid chromatography (HPLC) and then combine so in order to achieve maximum purity. Applying repeated lyophilization of a solution of water, obtain 95 mg of product as a white fluffy powder.

Analysis by TLC and HPLC indicated the homogeneity of the product. Amino acid analysis of an acid hydrolysate and mass spectrometry laser desorption matrix (MALDI MS) confirm the composition of the cyclic oktapeptid (current MB - 1077 received MB - 1080).

Below is a method for the synthesis of Analogue V. Benzylidenemalononitrile resin (Advanced ChemTech, Inc., Louisville, KY) (0,7 r, 0.25 mmol) in a form containing chloride ion, is placed in the reaction vessel in system programmable synthesis of peptides (Advanced ChemTech ACT 200) to make the following reagents/solvents: (a) methylene chloride; (b) 33% triperoxonane acid in methylene chloride (2 times for 1 and 25 min each); (C) methylene chloride; (d) ethanol; (e) methylene chloride; and (e) 10% triethylamine in chloroform.

The neutralized resin is stirred with BOC-S-4-methylbenzyl-CIS and diisopropylcarbodiimide (each 1.5 mmol) in methylene chloride for 1 hour and the resulting amino acid resin is subjected to cyclic processing, which includes stages (a) through (e) above programs. Then using the same is-N-benzyloxyethyl-Liz, BOC-D-TRP, BOC-Dryer, Side-By-Hairdryer. BOC-ASN and BOC-S-methylbenzyl-CIS. After washing and drying the weight of the finished resin is 1.2, Then the peptide resin is subjected to cyclic processing, including cleavage with hydrogen fluoride and processing of I2as explained above. Purification using column chromatography, as described above, leads to obtain 21 mg of cyclic nonapeptide, which, as shown by analysis using HPLC and TLC is homogeneous. Amino acid analysis of an acid hydrolysate and analysis through MALDI MS to confirm the structure of cyclic nonapeptide (the calculated value of MB - 1192; the resulting value MB - 1192).

Synthesis of iodinated analogues of somatostatin on the basis of the tyrosine residue (for example, using the chloramine-T method) are well described in the literature and available for the implementation of each expert with a medium level of knowledge in this area. (See for example, Czemick, et al., J. Biol Chem. 258:5525 (1993) and the European patent N 389180 B1).

Test for binding to the somatostatin receptor

(1) Test for binding to the human SSTR-2

Cells CHO-K1 (cells Chinese hamster ovary), obtained from American culture Collections (ATCC, Rockville, MD (ATCC N CCL61), subjected to transfection with cDNA from C (ATCC N 79046) using standard techniques known in molecular biology. (See, in particular, Patel, et al., Biochem. Biophys. Res. Commun. 198:605 (1994)). The crude membrane obtained by homogenization of CHO-K1 cells after transfection of the human SSTR-2 in 20 ml of chilled on ice in 50 mm Tris-HCl (buffer A) using a homogenizer transmitter stationTM(Brinkmann Instruments, Westbury, NY) when installed in position 6, for 15 seconds. Add some more buffer a to obtain a final volume of 40 ml, and the homogenate was centrifuged using a rotor SS-34 (DuPont, Newton, CT) in a SORVALTMat 39000 g for 10 minutes at a temperature of 0-4oC. Obtained after centrifugation the supernatant dicentric and drop. Sediment homogenized in chilled on ice buffer And diluted and centrifuged as before. Obtained at the end of the procedure the sediment resuspended in 10 mm Tris HCl and incubated on ice for test binding with the receptor.

Aliquots of the membrane preparation is incubated for 90 minutes at 25oC from 0.05 nm [125I-Tyr]MK-678 (2000 curies/mmol; c[N-methyl-Ala-Tyr(I125)-D-TRP-Lys-Val-Hairdryer] ) in 50 mm HEPES (pH 7,4) containing the analyzed peptide at various concentrations (i.e., from 10-11up to 10-6M), 10 mg/ml bovine serum albumin fraction V (Sigma Chemical Co., St. Louis, the volume is 0.3 ml Incubation finish quick filtration through filters GF/C (pre-soaked in 0.3% polyethylenimine within 30 minutes) using a filtration manifold (Brandel, Gaithersburg, MD). Each tube, and each filter is then washed three times an aliquot of chilled on ice buffer And 5 ml of Specific binding is determined by the level of the total radioactivity of [125I-Tyr] MK-678 minus the value of radioactivity bound in the presence of 200 nm somatostatin-14.

Using this test examined the following peptides: somatostatin-14, somatostatin-28, Analog I, Analog I, Analog III, Similar IV and V. Similar to the Above structure Analogues I-V. the Value of Ki is calculated using the following formula:

Ki = IC50/[1+(LC/LEC)],

where IC50(IR50) denotes the concentration of the investigated peptide, which leads to inhibition by 50 percent specific binding of the radioactive ligand [125I-Tyr]MK-678, LC denotes the concentration of radioactive ligand (0,05 nm) and LEC is the value of the equilibrium constant for the dissociation of the radioactive ligand (0,155 nm). The Ki values calculated for the studied peptides listed in the table in the column indicated by avechicago SSTR-5 method, described by Yamada et al. (Yamada, et al., Biochem. Biophys. Res. Commun. , 195-844 (1993)) using standard techniques known in molecular biology. (See, in particular, Patel et al., Biochem. Biophys. Res. Comm. 198:605 (1994)). The crude membrane obtained by homogenization of CHO-K1 cells after transfection of the human SSTR-5 in 20 ml of chilled on ice in 50 mm Tris-HCI in the homogenizer transmitter stationTM(installation in position 6, 15). Add some more buffer to a final volume of 40 ml, and the homogenate was centrifuged using a rotor SS-34 in SORVALTMat 39000 g for 10 minutes at a temperature of 0-4oC. Obtained after centrifugation the supernatant decanted and discarded. Sediment homogenized in chilled on ice buffer, diluted and centrifuged as before. Obtained at the end of the precipitate resuspended in 10 mm Tris HCl and incubated on ice for test binding with the receptor.

Aliquots of the membrane preparation is incubated for 30 minutes at 30oC from 0.05 nm [125I-Tyr11]somatostatin-14 [2000 curies/mmol (Amersham Corp., Arlington Heights, IL) in 50 mm HEPES (pH 7,4) containing the analyzed peptide at various concentrations (e.g., from 10-11up to 10-6M), 10 mg/ml bovine serum albumin (coat the th volume is 0.3 ml Incubation finish quick filtration through filters GF/C (pre-soaked in 0.3% polyethylenimine within 30 minutes) using a filtration manifold firm Brandel. Each tube, and each filter is then washed three times an aliquot of chilled on ice buffer 5 ml Specific binding is determined by the level of the total radioactivity of [125I-Tyr11]somatostatin-14 minus the value of radioactivity bound in the presence of 1000 nm of ligand BIM-23052 of somatostatin receptor type 5. (H2-D-hair dryer-hair dryers-hair dryers-D-TRP-Lys-Tre-Hairdryer-TRP-NH2). The value Ki is calculated using the following formula: IC50/[1+(LC/LEC)], where IC50(IR50) denotes the concentration of the investigated peptide, which leads to inhibition by 50 percent specific binding of the radioactive ligand [125I-Tyr11] somatostatin-14, LC denotes the concentration of radioactive ligand (0,05 nm) and LEC is the value of the equilibrium constant for the dissociation of the radioactive ligand (0.16 nm). The Ki values calculated for the studied peptides listed in the table in the column labeled "SSTR-5".

The table lists the corresponding values of the coefficients Kazda higher values for these coefficients and show greater selectivity for SSTR-5, than for SSTR-2.

Other embodiments of the invention

It should be borne in mind that the above description of the invention has the purpose of illustration of the invention but do not limit it in any way, which is completely defined by the attached claims. All other aspects, advantages and modifications are also covered by the claims.

1. The peptide of the formula:

< / BR>
where a1denotes the D - or L-isomer of Cys or IPC;

AND2represents ASN, GLn, or aliphatic amino acid, an aromatic amino acid or is missing;

AND3denotes an aromatic amino acid;

AND4indicates GIS or aromatic amino acid;

AND7indicates Tre, Ser or aliphatic amino acid;

AND8denotes an aromatic amino acid;

AND9denotes a D - or L-isomer of Cys;

each of R1and R2represents, independently of one another, H, C1-12alkyl, C7-20phenylalkyl,11-20nafcillin,1-12hydroxyalkyl,7-20hydroxyphenylethyl,11-20hydroxynaphthalene or SOY1where E1stands WITH1-12alkyl, C7-20phenylalkyl,11-20R3denotes NH2or NHY2Z, where Y denotes a1-12hydrocarbon group, and Z denotes H, HE, CO2N or NH2;

disulfide bond links the side chains of residues AND1and a9;

or their pharmaceutically acceptable salt.

2. The peptide under item 1, characterized in that each of A3and a8represents, independently from each other, Hairdryer, p-X-dryer (where X represents a halogen, HE, co3CH3or NO2), o-X-dryer (where X represents a halogen, HE, co3CH3or NO2), pyridyl-Ala, TRP, Nal, 2,4-dichloro-dryer, Tyr (I) or F5-Dryer, and a4is a GIS, Hairdryer, p-X-dryer (where X represents a halogen, HE, co3CH3or NO2), o-X-dryer (where X represents a halogen, HE, co3CH3or NO2), pyridyl-Ala, TRP, Nal, 2,4-dichloro-dryer, Tyr (I) or F5-Hair dryers.

3. The peptide under item 2, characterized in that A2absent and a7is a Tre, Ser, Ala, Aim, Val, LEU, Ile, NLE, NCA or AMK.

4. The peptide under item 3, characterized in that A9denotes CIS.

5. The peptide under item 4, characterized in that each of A3and a8represents, who appoints GIS, Hairdryer, p-X-dryer (where X represents a halogen, HE or CH3), Tyr (I) or TRD.

6. The peptide under item 5, characterized in that A7is a Third or Middle.

7. The peptide under item 6, characterized in that A3represents a Hairdryer AND4represents a Hairdryer, p-X-dryer (where X denotes a halogen, HE, co3CH3or NO2), GIS, Tyr (I) or TRD and a8represents a Hairdryer or p-X-dryer (where X denotes a halogen, HE, co3CH3or NO2).

8. The peptide under item 6, characterized in that A3represents a Hairdryer AND4represents a Hairdryer, Tyr, Tyr (I) TRD and a8represents a

9. The peptide under item 8, wherein each of R1and R2denotes, independently of one another, H, and R3represents NH2.

10. The peptide under item 9 of the formula:

H2-C[Cys-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[Cys-Hairdryer-TRP-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-C[Cys-hair dryer-Hairdryer-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2or

H2-C[Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

11. The peptide under item 7 of the formula:

H2-C[Cys-Hairdryer-TRP-D-TRP-Lys-Trtc-Liz-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-Hairdryer-TRP-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[Cys-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2or

H2-C[D-Cys-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2.

12. The peptide under item 2, characterized in that A2represents ASN, GLn, Ala, Aim, Val, LEU, Ile, NLE, NCA, AMK, Hairdryer, p-X-dryer (where X represents a halogen, HE, co3CH3or NO2), o-X-dryer (where X represents a halogen, HE, co3CH3or NO2), pyridyl-Ala, TRP, Nal, 2,4-dichloro-dryer, Tyr (I) or F5-Hair dryer and a7indicates Tre, Ser, Ala, Aim, Val, LEU, Ile, NLE, NCA or AMK.

13. The peptide under item 12, characterized in that A9denotes CIS.

14. The peptide according to p. 13, characterized in that each of A3AND4and a8denotes, independently from each other, Hairdryer, p-X-dryer (where X represents a halogen, HE or CH3), Tyr(I) or TRD and a4oboznachaet, characterized in that A2represents ASN or GLn and a7indicates Requirements or Ser.

16. The peptide according to p. 15, characterized in that A3denotes the dryer, AND4means Hairdryer, p-X-dryer (where X represents a halogen, HE, co3CH3or NO2), GIS, Tyr (I) or TRD and a8denotes the dryer or p-X-dryer (where X represents a halogen, HE, co3CH3or NO2).

17. The peptide under item 16, characterized in that A3denotes the dryer, AND4means Hairdryer, Tyr, Tyr (I) or TRD and a8denotes the dryer.

18. The peptide under item 17, characterized in that A2represents ASN, each of R1and R2independently from each other represents H and R3denotes NH2.

19. Peptides under item 18 of the formula:

H2-C[D-Cys-ASN-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

20. The peptide according to p. 16 formula:

H2-C[D-Cys-ASN-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[Cys-ASN-Hairdryer-TRP-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-ASN-Hairdryer-TRP-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[Cys-ASN-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-ASN-Hairdryer-GIS-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[Cys-ASN-hair dryer-Hairdryer-D-TIC-ASN-Hairdryer-TRP-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-C[D-Cys-ASN-Hairdryer-TRP-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-C[Cys-ASN-Hairdryer-GIS-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-C[D-Cys-ASN-Hairdryer-GIS-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2,

H2-C[Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[D-Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2,

H2-C[Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2or

H2-C[D-Cys-ASN-Hairdryer-Tyr(I)-D-TRP-Lys-Ser-Hairdryer-Cys]-NH2.

21. The peptide under item 1 of the formula:

H2-C[Cys-hair dryer-Hairdryer-D-TRP-Lys-Tre-Hairdryer-Cys]-NH2.

 

Same patents:

The invention relates to compounds of the formula I

R1-Q1-X-Q2-R2(I)

in which Q1, Q2in each case, independently of one another are either absent or represent-NH-(CH2)n-CO-,

R1, R2in each case, independently of each other either absent or represent a cyclo-(Arg-Gly-Asp-Z), where Z is linked to the side chain of Q1or Q2or, if Q1and/or Q2missing (et), with X and where at least one of the radicals R1or R2must always be present,

X represents a-CO-R18-CO-, and if R1-Q1or R2-Q2- no, there is an R10, R13, R16, Het-CO -, or the residue of a fluorescent dye that is chemically linked through CONH-, -COO-, -NH-C(=S)-NH- -NH-C(=O)-NH-, - SO2NH -, or-NHCO-bonds

Z in each case independently represents an amino acid residue or di-, tri - or tetrapeptides balance, where amino acids independently selected from the group comprising Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val or M

where these amino acids can be derived and amino acid residues connected to one another like xilinix groups, and where M is always present,

M represents NH(R8)-CH(R3)COOH,

R3- R5-R4, -R6-R4or-R7-R4< / BR>
R4is a HE, NH2, SH or COOH,

R5- alkylene containing 1-6 carbon atoms,

R6- alkaliphiles containing 7 to 14 carbon atoms,

R7- alkylenediamine containing 8-15 carbon atoms,

R8-H, a or alkylether containing 7-12 carbon atoms,

A is alkyl containing 1-6 carbon atoms,

R10- alkanoyl containing 1-18 carbon atoms, which is unsubstituted or contains one Deputy from among COOH, COOA, SR11or NR12R12,

R11- H or trityl, pyridyl-2-thio - or allylthiourea containing 1-6 carbon atoms,

R12, R12'each, independently of one another, represent H, alkyl containing 1-8 carbon atoms or a protective group of amino group,

R13- aroyl, which contains 7 to 11 carbon atoms and is unsubstituted or substituted and contains one or two substituent selected from the group comprising alkyl containing 1-6 carbon atoms, alkoxygroup containing 1-4 carbon atoms, alkanoyl containing 1-8 tomsche independently of one another H or A,

R16is arkanoid, which contains 7-19 carbon atoms and which is not substituted or substituted in the aryl fragment of one, two or three deputies, including Hal, alkoxygroup containing 1-6 carbon atoms, or HE, and in which the aryl fragment may also represent a group:

< / BR>
E - CH2or,

D is carbonyl or [C(R17R17')]m,

R17R17'each independently represents H or A,

R18is absent or is an R19, R20, R19-R20-R19or phenylene, which is not substituted or substituted and contains one or two substituent R5the length of the chain which is in each case independently of each other,

R19is alkylene containing 1-8 carbon atoms, where 1 or 2 methylene groups can be replaced with S, -CH=CH - or,

R20- cycloalkyl containing 3-7 carbon atoms,

Hal is F, Cl, Br or I,

Het is a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle which contains from 1 to 4 atoms of N, O and/or S, attached cherepy, including Hal, A, R3, NR4R4', CN, NO2and/or carbonyl oxygen,

n- 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and

m is 1 or 2,

where, assuming that residues are residues of optically active amino acids and derivatives of amino acids, contain both D and L forms, and their salts

Cyclopeptide // 2171260
The invention relates to cyclopeptides and to their therapeutic use as inhibitors of the expression of adhesion molecules

The invention relates to new methods of chromatography, designed for the purification of crude extracts containing cyclosporine, for use in the pharmaceutical industry

The invention relates to cyclopentapeptide formula (I):

cyclo (A-B-C-E-F-(D)-Ala)

in which A, B, C, E and F, independently of one another, may be the same or different and represent a residue of a natural amino acid except cysteine (Cys) and tryptophan (Trp), and accordingly can be an alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), Proline (Pro), serine (Ser), tryptophan (Thr), tyrosine (Tyr) or valine (Val), as well as their physiologically compatible salts

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

The invention relates to new cyclopeptides formula cyclo-(pad-nGly-nAsp-nD-nE), where n, D, and E have the meanings indicated in the claims, and to pharmaceutical compositions based on them having inhibitory activity againstv3and/orv5-integrins and to a method for producing a pharmaceutical composition having inhibitory activity

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

The invention relates to medicine, in particular to the creation of analogues of hormonal drugs protein nature

The invention relates to therapeutic peptides

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

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
The invention relates to medicine and relates to tools for parenteral protein nutrition and removal of toxemia

The invention relates to the field of biotechnology
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