Cyclopeptide or their salts, a method of production thereof, pharmaceutical compositions and method for their preparation and method of treatment


(57) Abstract:

The invention relates to new compounds of formula I cyclo-(a-b-C-D-Agde), where a-D-Val; (B - L - or D-Phe; C - L-Asp, D-Asp (O-C1-C4-alkyl), D-Gly, or Ala, and at least two of these amino acid residues are in the D-form, and their salts. The compounds act as inhibitors of integrin and can in particular be used for the prevention and treatment of diseases of the pulmonary circulation and therapy of tumors. Describes how to obtain the compounds of formula (I), pharmaceutical compositions based on these compounds and a method of treatment of diseases associated with inhibition of binding of integenerational with legendary, with the use of compounds of formula (I) in a daily dose of 0.01-2 mg/kg of body weight. 5 C. and 1 C.p. f-crystals, 1 table.

The invention relates to new cyclopeptides formula I

cyclo-(A-B-C-D-(L - or D-) Arg/

where A = D - Val;

B = L - or D - Phe;

C = L-Asp, D - Asp or D-Asp (O-C1-C4-alkyl);

D represents Gly or Ala,

moreover, at least two of these amino acid residues are in the D-form,

and also their salts.

Similar compounds are known from Pharmazic 40/8/, 532-535 (1985).

The basis of the invention is put is Holocene medicines.

Found that the compound of formula (I) and their salts have very valuable properties. First of all, they act as integrin inhibitors, and in particular they inhibit interaction 3- integrin receptors with ligands. This action can be detected, for example, by the method specified J. W. Smith and others in J. Biol.Chem., 265, 12267-12271 (1990). Additionally they have anti-inflammatory effects. All of these actions can be detected using known literature methods.

The compounds can be used as a drug biologically active substances in medicine and veterinary medicine, in particular for the prevention and treatment of diseases of the pulmonary circulation, thrombosis, heart attack, arteriosclerosis, inflammations, apoplexy, angina, tumors, osteolytic diseases, in particular osteoporosis, angiogenesis and restenosis after angioplasty.

Above and below the reduction of amino acid residues have values of residues of the following amino acids: Ala = alanine; Asp = aspartic acid; Asp/d = aspartic acid (-ester); Arg = arginin; Cys = cysteine; Glh = glutamine; Glu = glutamic acid; Gly = glycine; His = histidine; Ile = isoleucine; Leu = leucine; Lys = lysine; Met = methionine; Phe = phenylalanine; Pro = the Oia shall have the following meanings: BOC = tert-butoxycarbonyl; CBZ = benzyloxycarbonyl; DCCI = dicyclohexylcarbodiimide; DMF = dimethylformamide; EDC = N-util-N'- /3-dimethylaminopropyl/-carbodiimide; Et = ethyl; FMOC = 9-fluorenylmethoxycarbonyl; HOBt = 1-hydroxybenzotriazole; Me = methyl; Mtr = 4-methoxy-2,3,6-trimetilfenil-sulfonyl; OBUt = tert. -butyl ester; OMe - methyl ester; OEt = complex ethyl ester; POA = phenoxyacetyl; TPA = triperoxonane acid.

Because of the above amino acids can be in several enantiomeric forms, above, and further, for example, as an integral part of the compounds of formula (I), includes all these forms and also their mixtures (for example, DL-forms).

The subject invention further is a method for obtaining compounds of formula (I) under item 1 or one of its salts, characterized in that it is free from one of its functional derivatives by treatment solvolysis or hydrogenolysis tool, or a peptide of the formula (II):

H - Z - OH,

where Z represents: -A-B-C-D-Arg-; -B-C-D-Arg-A-; -C-D-Arg-A-B-; -D-Arg-A-B-C - or-Arg-A-B-C-D,

or a reactive derivative of such a peptide is treated collisium means, and/or a basic or acidic compound of the formula (I) by treatment with acid or base perevious specified in the case of formulas (I) and (II) values.

In the above formulas "alkyl" preferably means methyl, ethyl, isopropyl or tert-butyl.

Group "A" is preferably Val, in particular D-Val. "B" is preferably Phe, in particular D-Phe. "C" denotes preferably Asp, in particular D-Asp. D is preferably Gly.

Accordingly, the subject invention particularly are the compounds of formula (I) in which at least one of these residues has one of the abovementioned preferred meanings.

A preferred group of compounds can be characterized by partial formula (Ia), which usually corresponds to the formula (I), but where A denotes a D-Val; B denotes Phe; C denotes Asp and D represents Gly or Ala. The compounds of formula (I) and also the source materials for their production receive, however, known methods described in the literature (for example in standard works, as Houben-Weil."Methods of organic chemistry, ed. Georg-Thieme. Stuttgart), namely under reaction conditions which are known and suitable for the specified transformations. You can also use known here more not mentioned options.

The source of the substance, if galatella obtaining compounds of formula (I).

The compounds of formula (I) get so that they release from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

The preferred initial agents for the solvolysis, respectively hydrogenolysis are those which, instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, preferably such that instead of the H atom, which is connected with the N-atom, contain protective for the amino group, for example, those that correspond to the formula (I), but instead of NH2groups contain other'group (where R' denotes a protective for the amino group, for example BOC or CBZ).

Further, preferably the original substance, which, instead of the H atom of the hydroxyl group containing protective for hydroxyl group, for example, those that correspond to the formula (I), but instead hydroxyproline groups contain R"O-phenyl group (where R' denotes a protective for hydroxyl group).

In the molecule of the original substance may be several identical or different protected amino and/or hydroxyl groups. If the existing protective group aminogroup group" is well known and refers to groups which are suitable to protect the amino group from chemical reactions (block it), but that is easy hatshepsuts, after it has been desired chemical reaction in other parts of the molecule. Typical of such groups are especially unsubstituted or substituted acyl, aryl, arelaxation or kalkilya group. As for protective amino group after the desired reaction (or sequence of reactions) are removed, their type and value, however, is not critical; however, a preferred group with 1-20, in particular 1-8 C-atoms. The expression "acyl group" in connection with the present method should be understood in its broadest sense. It covers produced from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulfonic acids acyl group, and in particular alkoxycarbonyl, aryloxyalkyl and primarily alcoxycarbenium group. Examples of such acyl groups are alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluyl; aryloxyalkanoic as POA; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, VOS, 2-iodata the Mtr. Preferred protective for amino groups groups are BOC and Mtr; next, CBZ, FMOC, benzyl and acetyl.

The expression "protection for the hydroxyl group, the group is also generally known and relates to groups which are suitable to protect a hydroxyl group against chemical reactions, but which are easily hatshepsuts after was carried out a chemical reaction in other parts of the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, kalkilya or acyl group; hereinafter, also alkyl groups. The nature and size of the hydroxyl protective for groups of groups is not critical, because after the desired chemical reaction or reaction sequence again remove; preferred group with 1-20, in particular 1-10, C atoms. The examples of protection for the hydroxyl group of the groups are, inter alia, benzyl, p-nitrobenzyl, p-toluensulfonyl and acetyl, and especially preferred benzyl and acetyl. COOH-group in aspartic acid and glutamic acid are preferably protected in the form of tert-butyl esters (for example, Asp/OBut).

Used as starting substances, the functional derivatives of compounds of formula (I) Hartig works and patents, for example, also according to the solid-phase method of Merrifield [B. F. Gysin and R. B. Merrifield, J. Am.Chem.Soc., 94, 3102 and later (1972).

The release of the compounds of formula I from their functional derivatives is possible to make - depending on the protective group, for example using strong acids, expediently using TFA or perchloric acid, but also using other strong inorganic acids as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, as trichloroacetic acid, or sulfonic acids, as benzene - or p-toluensulfonate. The presence of an additional inert solvent may, but is not always necessary. As the inert solvent is preferably suitable organic, for example carboxylic acids, as acetic acid; ethers, like tetrahydrofuran or dioxane; amides as DMF, halogenated hydrocarbons like dichloromethane; hereinafter, also alcohols as methanol, ethanol or isopropanol, and also water. Further, taking into consideration the mixture of the above solvents. TFK preferably used in excess without the addition of another solvent; perchloric acid is used in the form of a mixture of acetic acid and 70% perchloric acid in sootnoshenie at a temperature between 15 30oC (room temperature).

The BOC group, DBZ and Mtr preferably can be split, for example, using TFA in dichloromethane or using approximately 3 to 5 N. HCl in dioxane at 15 - 30oC; FMDC - group can be split by about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 - 30oC.

Hydrogenations removable protective group (for example, CZ or benzyl) can be split, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst based on a noble metal, such as palladium, expediently on the media, as coal). As solvents if this is suitable to the above, in particular, for example, alcohols, like methanol or ethanol, or amides, as DMF. The hydrogenolysis is carried out, as a rule, at temperatures of about 0 - 100oC and pressures of about 1 to 200 bar, preferably at 20 to 30oC 1 to 10 bar. Hydrogenolysis of CBZ-group flows well, for example, in the presence of 5 to 10% palladium-on-coal in methanol or using ammonium formate (instead of hydrogen) on Pd-C in a mixture of methanol with DMF at 20 - 30oC.

The compounds of formula (I) can also be obtained by cyclization of compounds of formula (II) in the synthesis of peptides. , Methods of organic chemistry", T. 15/II, S. 1-806 (1974).

The reaction is carried out preferably in the presence of dehydrating agents, such as carbodiimide, as DCCl or EDCl, next anhydride papapostolou acid, see Angew. Chem. 92, 129 (1980); diphenylphosphinite or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example, halogenated hydrocarbon like dichloromethane; simple ether, as tetrahydrofuran or dioxane, amide as DMF or dimethylacetamide; nitrile as acetonitrile, or mixtures of these solvents, at temperatures from about -10oC to 40oC, preferably at 0 to 30oC. in order to facilitate intramolecular cyclization in front of intramolecular peptide binding, it is advisable to work in diluted solutions (principle of dilution).

Instead of compounds (II) can also be used in the reaction of suitable reactive derivatives of these substances, for example, those in which the reactive group of the intermediate is blocked by protective groups. Amino acid derivatives of the formula (II) can be applied, for example, in the form of their activated esters, which are expedient receive in situ, for example, by adding HOBt be provided by known methods, for example, the above-described methods peptide synthesis and cleavage of the protective groups.

As a rule, first synthesize protected pentapeptidnogo esters of the formula R'-Z-OR", for example, BOC-Z-OMe or BOC-Z-OEt, which primarily omelet to acids of formula R'-Z-OH, for example, BOC-Z-OH, from the last otscheplaut protective group R' and thereby gain free peptides of the formula H-Z-OH (II).

Basic formulas (I) using acid can be converted to the corresponding salt accession acid. For this transformation take into account in particular acids, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, halogen acids as hydrochloric or bromatologia acid; phosphoric acid as phosphoric acid; sulfamic acid; further, organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova kislota, salicylic acid, 2 - or 3-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalene mono - and di-sulfonic acids, louisanna acid. Salt with physiological unsafe acids, for example, picrate, can be used for identifying and/or purifying compounds of formula (I).

On the other hand, the acid of formula (I) by entering its interaction with the base can be converted to its physiologically acceptable metal salts or ammonium. As salts while taking into account in particular the salts of sodium, potassium, magnesium, calcium and ammonium; next, substituted ammonium salts, e.g. salts of dimethyl-, diethyl-or Diisopropylamine; salt monoethanol, diethanol - or triethanol-ammonium; salts of DICYCLOHEXYL-, cyclohexyl-ammonium; salts of dibenzylethylenediamine; further, for example, salts with N-methyl-D-glucamine or arginine.

The new compounds of formula (I) and their physiologically acceptable salts can be used to obtain pharmaceutical preparations, so that they together at their biologically active substances brought to a suitable dosage forms. The thus obtained composition can be used as drugs in medicine or veterinary medicine. As carriers take into account organic or inorganic substances which are suitable for intestinal (e.g., oral or rectal), parenteral (e.g. intravenous injection) or local (e.g., topical, skin, eye or nose) administration, or for administration in the form pulverizing preparations for inhalation and do not react with the new compounds, for example, water or an aqueous isotonic solution of sodium chloride, lower alcohols, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates, as lactose or starch, magnesium stearate, talc, cellulose, vaseline. For oral administration are, in particular tablets, coated tablets, capsules, syrups, juices or drops, are of interest lacquered tablets and capsules resistant to gastric juice coatings, respectively, the shells of the capsules. For rectal use candles; for parenteral administration are solutions, preferably oily or aqueous solutions; further, suspensions, emulsions or drops; further, for example, suspensions, emulsions, creams, ointments or extruded products. For administration in the form of pulverizing preparations for inhalation can be applied spray guns, which contain biologically active compound either dissolved or suspended in the working gas or mixture of working times (for example, CO2or perchloroethane). It is expedient in this case, applying the biologically active agent in micronized form, and can be added one or more additional physiologically acceptable solvents, such as ethanol. Solutions for inhalation can be entered using a conventional inhalers. The new compounds can also be liofilizirovanny and received lyophilizate to apply, for example, for the preparation of drugs for injection. Injections can be done in the form of a large pill or as a continuous infusion (e.g., intravenously, intramuscularly, subcutaneously or nutrilion).

These compositions can be sterilized and/or may contain auxiliary substances, such as preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants and/or aromatizers, for example, one or more vitamins.

Proposed according to the invention substances normally administered analogously to other known, commercially available peptides, in particular, however, similar to the one described in U.S. patent A-4 472 305 compounds, preferably in doses of about 0.05 to 500, in particular from 0.5 to 100 mg per dosage unit. The daily dose is preferably about 0.01 to 2 mg/kg of body weight. Special dose for each particular patient, however, depends on various factors, for example, the effectiveness of used special connections, age, weight, General health, sex, cost, time and route of administration, rate of excretion, drug combination and the severity of the respective disease, which has implications for therapy. Preferably parenteral administration.

Both above and below, all temperatures are given inoC. In the following examples, "conventional treatment" means add, if desired, water, neutralized, extracted with ether or dichloromethane, separated, dried over sodium sulfate the organic phase is filtered, evaporated and purified by chromatography on silica gel and/or the solvent: 0,3% TFA in water; isopropanolic gradient 0 to 80 volume.% for 50 minutes at a speed of 1 ml/min Selection and detection at 215 nm. M+designates the molecular peak in the mass spectrum, obtained by the method of "fast atom bombardment".

Example 1. A solution of 30 mg of cyclo- /D-Val-L-Phe-D-Asp-[OBut]-Gly-D-Arg-[Mtr] obtained by cyclization of H-D-Arg-[Mtr]-D-Val-L-Phe-D-Asp[OBut]-Gly-OH according to the system described in example 2 method in 840 μl TFA, 170 μl of dichloromethane and 85 μl of thiophenol leave to stand for 2 hours at 20oC, then concentrate at 37oC under reduced pressure and after dilution with water is subjected to drying by freezing. After gel filtration on Sephadex G-10 in a mixture of acetic acid with water in a ratio of 1 : 1 and subsequent purification by using preparative HPLC on a column of phase lichrosorb PP8 with isopropanol gradient in a mixture of 0.3% TFA (water, get cyclo- /D-Val-L-Phe-D-Asp-Gly-D-Arg/. RZ 17,9; M+575.

Similarly get:

from cyclo-(D-Val-D-Phe-D-Asp(OBut)-Gly-D-Arg(Mtr));

cyclo-(D-Val-D-Phe-D-Asp-Gly-D-Arg), Rz 18,5; M+575;

from cyclo-(D-Val-D-Phe-D-Asp(OBut)-Gly-D-Arg(Mtr));

cyclo-(D-Val-D-Phe-D-Asp-Gly-D-Arg), RZ 19,3; M+575;

from cyclo-(D-Val-D-Phe-D-Asp(OBut)-L-Ala-D-Arg(Mtr));

cyclo-(D-Val-D-Phe-D-Asp-L-Ala-D-Arg), RZ 20,3; M+589;

from cyclo-(D-Val-D-Phe-D-Asp(OMe)-Gly-L-Arg(Mtr));

cyclo-(d CR cyclo-(L-Val-D-Phe-D-Asp(OBut)-Gly-L-Arg(Mtr))


from cyclo-(D-Val-L-Phe-D-Asp(OBut)-Gly-L-Arg(Mtr));


from cyclo-(L-Val-D-Phe-L-Asp(OBut)-Gly-D-Arg(Mtr));


from cyclo-(D-Val-L-Phe-L-Asp(OBut)-Gly-D-Arg(Mtr));


from cyclo-(L-Val-L-Phe-D-Asp(OBut)-Gly-D-Arg(Mtr));


from cyclo-(L-Val-D-Phe-L-Asp(OBut)-D-Ala-L-Arg(Mtr));


from cyclo-(D-Val-L-Phe-L-Asp(OBut)-D-Ala-L-Arg(Mtr));


from cyclo-(L-Val-L-Phe-D-Asp(OBut)-D-Ala-L-Arg(Mtr));


from cyclo-(L-Val-L-Phe-L-Asp(OBut)-D-Ala-D-Arg(Mtr));


Example 2. A solution of 80 mg of H-L-Arg-D-Val-D-Phe-D-Asp(OMe)-Gly-OPA (obtained by removal of FMOC group from FMOC-L-Arg-D-Val-D-Phe-D-Asp(OMe)-Gly-O-Wang (and O-Wang means used in the synthesis errifield balance-4-oxymethylene-methyl-polystyrene, which is sewn to 1% with p-divinylbenzene) using the research and off Pentapeptide from the polymer using TFA (dichloromethane and 1:1 ratio) in 8 ml of DMF is diluted with 72 ml of dichloromethane and mixed with 34 mg melkopomolotogo NaHCO3. After cooling in a mixture of dry ice with acetone add 34 μl diphenylphosphinite. After incubation for 16 hours at 20oC dichloromethane removed by 37+589.

To acknowledge receipt of the salt forms of the example 3. Salt often prefer those that are easier to crystallize, which is essential for subsequent dispensing and manufacturing of dosage forms.

Example 3. A solution of 130 mg of cyclo-(D-Val-D-Phe-D-Asp(OMe)-Gly-L-Arg), obtained according to example 2, dissolved in 10 ml of isopropanol and water act triperoxonane acid (conc.) before the formation of sludge. Sucked off the formed salt, washed twice with 5 ml of isopropanol and subjected to freeze-drying.

Get cyclo-(D-Val-D-Phe-D-Asp(OMe)-Gly-L-Arg) TFA, M+575.

The following examples relate to pharmaceutical compositions.

Example A. Glass containers for injectables.

In a solution of 100 g of cyclopeptide formula (I) and 5 g of dinitrigenoxide in 3 l of double-distilled water using 2 N. hydrochloric acid set pH = 6,5, sterile filtered, filled glass containers for injectable drugs, lyophilizer in sterile sterile conditions and closed. Each glass container for injectable preparations containing 5 mg of biologically active substances.

Example B. Candles.

Example B. A Solution.

Prepare a solution of 1 g of biologically active substances of the formula (I), 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. Set pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example, The Ointment.

500 mg of Biologically active substances of formula I are mixed with 99.5 g of vaseline under aseptic conditions.

Example D. Tablet.

A mixture of 100 g of cyclopeptide formula (I), 1 kg of lactose, 600 g of microcrystalline cellulose. 600 g of corn starch, 100 g of polyvinylpyrrolidone and 10 g of magnesium stearate as usual pressed into tablets, so that each tablet contained 10 mg of biologically active substances.

Example E. Bean.

Pressed tablets as described in example D, and then the usual manner, cover them with a coating of sucrose, corn starch, talc, tragant and dye.

Example J. Capsules.

As usual hard gelatin capsules filled the matter.

Example 3. Inhalation spray guns.

14 g of Biologically active substances of the formula (I) are dissolved in 10 l of isotonic NaCl solution and the solution is filled standard vessels for comminution with a pumping mechanism. The solution can be pulverizate in the mouth or in the nose. One portion pulverizing solution (approximately 0.1 ml) corresponds to a dose of approximately 0,14 mg

To demonstrate the industrial applicability and suitability of the compounds attached pharmacological report.

As for the results, the clinical ability of the compounds summarized as follows:

1. Various diseases manifesting the main pathological correlate of increased platelet aggregation, i.e. the formation of blood clots, are of potential clinical indications for use3- antagonists.

These include myocardial infarction and apoplexy. Both of these life-threatening diseases originally caused by occlusion of aggregates of platelets in coronary heart or brain circulation, respectively.

2. Atherosclerotic syndrome, including the formation of atherosclerotic plaques in the damaged vessels, rupture of plaques, and targets adhesion and aggregation of platelets. Therefore, as has been shown, these antagonists have potential therapeutic benefit in these clinical assignments.

In addition, it was postulated prevent metastasis of tumor cells with3- antagonists, in accordance with the following observations.

Circulating tumor cells can form microaggregate with platelets and in this form can adhere to the vessel wall.

Through this mechanism facilitates the adhesion and subsequent penetration of tumor cells into the tissue.

In addition, microaggregate tumor cells screened and protected from recognition by cells of the immune system.

Thus, by inhibiting the formation of platelets3antagonists should be effective in preventing adhesion of tumor cells and the formation of metastases.

Materials and methods.

Vitronectin (Yatohogo and others 1988) and fibrinogen (Kazal and others, 1963) from human blood plasma,3from human placenta (Smith and Cheresh, 1988) and human platelets (Pytela and others 1986), was purified as described above. A test of competing ligands using immobilized integrin and processed b the tion of manganese was 10 μm.

The following results are obtained (see table).

The described compounds can be used in Oncology. The compounds of formula I inhibit the interaction integranova receptors and ligands, such as fibrinogen and fibrinogenesis receptor, inhibit the proliferation of tumor cells with the formation of metastasis, which is confirmed by research.

In addition, the compounds of formula I can inhibit the binding metalloproteinase the integrin and discourage the use of cell enzymatic activity of proteases.

An example of a slow-binding MMP-2 (matrix metalloproteinase 2) vitronectin receptor3through cyclo-RGD-peptide described (P. C. Brooks et al. Cell 85, 683 - 693 (1996)).

The distribution of cells local tumor vascular system occurs through the formation of microaggregates (microthrombi) by the interaction of tumor cells with platelets. Tumor cells are protected microaggregate and are not recognized by the immune system.

Microaggregate can be fixed on the surface of the walls of blood vessels, resulting in further penetration of tumor cells into the tissue. As bombasity, GP IIA/IIIb antagonists can be used as an effective inhibitor of metastasis.

1. Cyclopeptide formula I

cyclo- [A - B - C - D - (L - or D-) Arg],

where A = D - Val;

B = L - or D - Phe;

C = L - Asp, D - Asp or D - Asp (O - C1- C4-alkyl);

D = Gly or Ala,

at least two of these amino acid residues are in the D-form,

and also their salts.

2. Cyclopeptide formula I on p. 1 representing: cyclo- [D - Val - L - Phe - D - Asp - Gly - D - Arg]; cyclo- [D - Val - D - Phe - D - Asp - Gly - L - Arg]; cyclo- [D - Val - D - Phe - L - Asp - Gly - D - Arg]; cyclo- [D - Val - D - Phe - D - Asp - L - Ala - D - Arg]; cyclo- [D - Val - D - Phe - D - Asp (OMe) - Gly - L - Arg].

3. The method of producing cyclopeptides formula I under item 1:

cyclo- [A - B - C - D - (L - or D - Arg)]

where A = D - Val;

B = L - or D - Phe;

C = L - Asp, D - Asp, D - Asp (O - C1- C4-alkyl);

D = Gly or Ala

at least two of these amino acid residues are in the D-form,

and also their salts, which consists in the fact that the peptide of formula II

H - Z - OH, where Z represents-A - B - C - D - (L - or D - Arg)- ; -B - C - D - (L - or D - Arg) - A - ; -C - D - (L - or D - Arg) - A - B - D - (L - or D - Arg) - A - B - C - ; - (L - or D - Arg) - A - B - C - D - ,

or a reactive derivative of such a peptide is treated collisuem means, and the pharmaceutical compositions, inhibiting the binding of integrin receptors with ligands, characterized in that the compound of formula I under item 1 and/or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary substance is brought to a suitable dosage forms.

5. The pharmaceutical composition inhibiting the binding of integrin receptors with ligands, characterized in that it contains at least one compound of General formula I on p. 1 or one of its physiologically acceptable salts in a dose of 0.05 - 500 mg, and a carrier or excipient.

6. A method of treating diseases associated with inhibition of the binding of integrin receptors with ligands, wherein the applied compound of formula I under item 1 or its physiologically acceptable salt in a daily dose of 0.01 - 2.0 mg/kg of body weight.


Same patents:

The invention relates to certain Aza cyclopentapeptide compounds having a nitrogen atom attached to cyclohexadienone ring on the 5th carbon atom of the component 4-hydroxy-ornithine (C-5-orn"), formula I, where R1Is H or OH; R2- H, CH3or OH; R3- H, CH3CH2CN, CH2CH2NH2or CH2CONH2; RI- C9-C21-alkyl, C9-C21alkenyl, C1-C10-alkoxyphenyl or C1-C10alkoxyaryl; RII- H, C1-C4-alkyl, C3-C4alkenyl, (CH2)2-4OH, CO(CH2)1-4NH2, (CH2)2-4NRIVRV; RIIand RIIItaken together, -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2-, -(CH2)2NH(CH2)2-; RIV- H or alkyl; RVIs H or alkyl and salt additive

The invention relates to new polypeptide compound and its pharmaceutical acceptable salts

The invention relates to certain Aza cyclopentapeptide compounds having a nitrogen atom attached to cyclohexadienone ring on the 5th carbon atom of the component 4-hydroxy-ornithine (C-5-orn"), formula I, where R1Is H or OH; R2- H, CH3or OH; R3- H, CH3CH2CN, CH2CH2NH2or CH2CONH2; RI- C9-C21-alkyl, C9-C21alkenyl, C1-C10-alkoxyphenyl or C1-C10alkoxyaryl; RII- H, C1-C4-alkyl, C3-C4alkenyl, (CH2)2-4OH, CO(CH2)1-4NH2, (CH2)2-4NRIVRV; RIIand RIIItaken together, -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2-, -(CH2)2NH(CH2)2-; RIV- H or alkyl; RVIs H or alkyl and salt additive

The invention relates to the field of medicine

The invention relates to new peptides with high biological activity of the same type, which is inherent in the known natural compound BPC, but with a shorter amino acid chain

The invention relates to new polypeptide compound and its pharmaceutical acceptable salts

The invention relates to polypeptides or their salts, with a strong tool to lipopolysaccharides, particularly endotoxins

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: medicine, pharmacology, biochemistry.

SUBSTANCE: invention relates to the highly purified enzyme α-galactosidase A (α-Gal A) and to different methods for its purification. Invention relates to the development of α-Gal A preparation with changed charge and to methods for preparing such preparations. Also, invention relates to α-Gal A preparations with prolonged half-time life in blood current of mammal-host, to methods for their preparing, to methods and doses in administration of α-Gal A preparations in patient. Invention provides expanding assortment used for treatment of patients suffering with α-galactosidase A insufficiency.

EFFECT: improved method for treatment, valuable medicinal properties of preparations.

15 cl, 9 tbl, 10 dwg, 5 ex

FIELD: biochemistry.

SUBSTANCE: method relates to new cyclopeptides of general formula cyclo(R1-Arg-Ile-Lys-Pro-His-R2) selected from group containing: P11: cyclo(DPhe-Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly-Glu) (SEQ ID NO:5), P16: cyclo(Arg-Ile-Lys-Pro-His-Gln-Gly (SEQ ID NO:8), P17: cyclo(Pro-Arg-Ile-Lys-Pro-His-Gln-Gly) (SEQ ID NO:9), P19: cyclo(Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly-Glu) (SEQ ID NO:10), P20: cyclo(Dphe-Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly) (SEQ ID NO:11), P23: cyclo(DPhe-Pro-Arg-Ile-Lys-Pro-His-Gln) (SEQ ID NO:13), P24: cyclo(Gly-Arg-Ile-Lys-Pro-His) (SEQ ID NO:25), as well as P11, P20 and P23 with DPhe substituted by DTyr. Cyclopeptides are useful in systems for angiogenesis inhibition. System includes substrate with cyclopeptides attached by organic spacer arm optionally containing group cleavable by any fermentation system.

EFFECT: angiogenesis inhibiting cyclopeptides.

23 cl, 4 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: preparation comprises echinocandine substance of formula I or its pharmaceutically permissible salt, pharmaceutically permissible micelle-forming surface-active agent and non-toxic aqueous solvent and stabilizing agent.

EFFECT: improved stability and bioaccessibility properties.

48 cl, 4 tbl

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the present innovation deals with new stabilized pharmaceutical composition in its lyophilized form including the compound of formula I

as an active ingredient and lactose disaccharide as a stabilizing agent. The present pharmaceutical compositions are of high stability at storage. As for active ingredient it is not destroyed in the course of time.

EFFECT: higher efficiency.

10 cl, 15 ex, 6 tbl

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes agonists of somatostatin of the formula (I): X-A1-cyclo-(D-Cys-A3-A4-Lys-A6-A7)-A8-Y or its pharmaceutically acceptable salt wherein X represents hydrogen atom (H); A1 represents L-Cpa, L-Phe, L-Trp or L-Nal; A3 represents L-3-Pal or L-4-Pal; A4 represents D-Trp; A6 represents -NH-(CHR1)n-CO- wherein n = 2, 3 or 4; A7 represents L- or D-Cys; A8 represents D- or L-isomer of amino acid taken among the group consisting of Nal, Phe, Cpa and Trp; Y represents NH2; R1 represents hydrogen atom (H), and Cys in A3 is bound by disulfide bong in A wherein this disulfide bond is formed by thiol groups of each Cys residue.

EFFECT: valuable biological properties of compounds.

9 cl, 2 ex

FIELD: organic chemistry, polypeptides.

SUBSTANCE: invention relates to new antagonists of urotensin-II. Invention represents group of cyclic polypeptides of the general formula: (R1)a-AA1-cyclo-[AA2-AA3-AA4-AA5-AA6-Cys]-AA7-R2 wherein AA1 means L-isomer of aromatic amino acid; AA2 means L- or D-isomer of Cys; AA3 means L-isomer of aromatic amino acid; AA4 means L- or D-isomer of Trp; AA5 means L- or D-isomer of Lys, N-Me-Lys or Orn; AA6 means L- or D-isomer of Val, Thr, Leu, Ile, Tle, Nle or aromatic amino acid; AA7 means L- or D-isomer of Val, Thr, Leu, Ile, Tle, Abu, Nle or aromatic amino acid; R1 means hydrogen atom (H), lower alkyl, lower alkanoyl or lower acyl; a = 1 or 2; R2 means hydroxyl; group (OH), OR3, N(R3)2 or NHR3 wherein R3 means H, lower alkyl or arylalkyl. These cyclic polypeptides are used as antagonists of urotensin-II.

EFFECT: valuable biological properties of compounds.

24 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: preparation belongs to decapeptides considered to be an analog of receptor-binding fragment of TGFα from 22 to 31 amino acids in which the eighth amino acid residue Lys is substituted with Ser residue. The analog is bindable to wide range of cytotoxic agents and operate as vector in directed delivery of antitumor agents to tumor cells. The preparation also comprises decapeptide conjugate with a cytotoxic agent showing selective action with respect to tumors and capable of reducing tumor cells resistivity to cytotoxic agents. Conjugated parts are bound by a bond scissile with respect to acid hydrolysis. Another embodiment of the invention is related to pharmaceutical composition containing effective quantity of conjugate and carrier applicable as intravenous injections.

EFFECT: enhanced effectiveness of treatment; high antitumor action selectivity.

6 cl, 2 dwg, 2 tbl