Cyclopeptide, the method of production thereof

 

(57) Abstract:

Describes new cyclopeptide General formula I

cyclo-(Arg-A-sp-R1-R2)

where A=Gly, R1- the remainder of the 2-carboxy-8-amino-4-capibility-9-it, 0-amino-methyl-01-carboxyphenyl, 2-aminomethyl-5-carboxymethylchitin or the residue of 2-(3-amino-1-pyrrolin-2-IMT)-4-methylpentanoic acid (s)Gly(ANC-2)-Leu or (R)Gly(ANC-2)-Leu, and the remains are respectively connected through a peptide bond, R2missing, as well as their physiologically acceptable salts. These compounds act as inhibitors of integrin and can be applied, in particular, for the prevention and treatment of diseases of the circulatory system, bones and cancer therapy, as well as antiviral active substances. 3 S. and 2 C.p. f-crystals, 1 table.

The invention relates to new cyclopeptides formula I

cyclo-(Arg-A-Asp-R1-R2), I

where A=Glu;

R1denotes the residue of 2-carboxy-8-amino-4 - capibility-9-it (Btd), o-amino-methyl-o'-carboxyphenyl (Biph), 2-amino-methyl-5-carboxy-methylthiophene (Act) or the residue of 2-(3-amino-1-pyrrolin-2-IMT)-4-methylpentanoic acid (S) Gly[ANC-2]-Leu or (R) Gly[ANC-2]-Leu, moreover, residues, respectively, linked via a peptide bond, R2missing the

The task of the invention to provide compounds with valuable properties, in particular those that can be used for the manufacture of medicines.

It is shown that the compounds of formula I and their salts possess valuable properties. First of all, they act as inhibitors of integrin, and they inhibit the interaction of integrin receptors 3or5with ligands. The particular active compounds in the case of integrinsv1,v3,v5,v6and11b3. This action can be demonstrated, for example, by the method, which describe j. Double. Y. Smith and others in J. Biol. Chem. 265, 12267-12271 (1990). Additionally manifest anti-inflammatory effects.

The compounds can be used as active principles of drugs in medicine and veterinary medicine, in particular for the prevention and treatment of diseases of the circulation, thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, neoplastic disease, osteolytic diseases, in particular osteoporosis, with the development of blood vessels and restenosis after plastic surgery on vessels, as well as to improve the healing of wounds.

According to the invention the most preferred cyclopeptide formula I are: a) cyclo-(Arg-Gly-Asp(S)Gly[ANC-2]-Leu); (b) cyclo-(Arg-Gly-Asp-(R)Gly[ANC-2]-Leu), cyclo-(Arg-Gly-Asp-Act); d) cyclo-(Arg-Gly-Asp-Btd).

Since the above-mentioned amino acids can exist in several enantiomeric forms, all these forms, and also their mixtures (for example, DL-forms) are covered by the present invention. Amino acids can include the corresponding known protective group.

The subject invention further is a method of obtaining the compounds of formula I or one of its salts, characterized in that they emit in a free form from one of their functional derivatives by treatment solvolysis or hydrogenolysis means. The subject of the invention is also a method, according to which process the peptide of formula II

H-Z-OH, II

where Z denotes-Arg-A-Asp-R1-R2-; -A-Asp-R1-R2-Arg-; -Asp-R1-R2-Arg-A-; -R1-R2-Arg-A-Asp-; -R2-Arg-A-Asp-R1,

R1the remainder of the 2-carboxy-8-amino-4-capibility-9-it (Btd), O-amino-methyl-,

O1- carboxyphenyl (Biph), 2 - aminoet is Gly[ANC-2]-Leu,

R2no,

A-Gly,

or a reactive derivative of such a peptide is treated collisuem means and/or translate basic or acidic compound of formula I by treatment with an acid or a base in one of its salts.

Given in the text abbreviations amino acid residues indicate residues of the following amino acids:

Act 2-aminomethylation-5-acetic acid

Asp Aspartic acid

Arg Arginine

Biph o-Aminomethyl-biphenyl-o'-carboxylic acid

Btd 8-Amino-4-capibility-9-one-2-carboxylic acid

Gly Glycine

Gly[ANC-2]-Leu 2-(3-Amino-1-pyrrolin-2-IMT)-4-methyl - pentane acid

Leu is Leucine

In addition, the following mean:

BOC tert.-Butoxycarbonyl

CBZ Benzyloxycarbonyl

DCCI Dicyclohexylcarbodiimide

DMF Dimethylformamide

EDCl N-Ethyl-N'-(3-dimethylaminopropyl)-carbodiimide

Et Ethyl

FMOC 9-Fluorenylmethoxycarbonyl

HOBt 1-Hydroxybenzotriazole

Me Methyl

Mtz 4-Methoxy-2,3,6-trimetilfenil-sulfonyl

OBut tert-Butoxy

OMe is Methoxy

OEt Ethoxy

POA Phenoxyacetyl

TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3 tetramethyleneglutaric

TFA triperoxonane acid

The residue (S)Gly[ANC-2[-Leu or (R)Gly[ANC-2] -Leu denotes the residue of 3(S)-or 3(R)-(3-amino-1-pyrrolin-2-IMT)-4-methyl - pentanol acid

< / BR>
Biph stands for the remainder of aminomethylphenol-o'-carboxylic acid, and Biph1 and Biph2 indicate possible atropoisomeric.

The compounds of formula I, as well as source materials for their production can be obtained by known methods described in the literature (for example, Houben-Weil. Methods of organic chemistry, Publishing Georgie, Stuttgart). You can also take advantage of the known variants, not mentioned here in more detail.

Peptide structural element Gly[ANC-2]-Leu (R)- or (S)-form obtained by the method of P. M. of Freidinger and others, described in J.Org. Chem. 47, 104(1982), and the synthesis of Btd possible for U. Nagai and other Tetrahedron, 49, 3577-3592 (1993).

The source of the substance, if desired, can also be formed in situ so that they are not isolated from the reaction mixture, and immediately turn further into the compounds of formula I.

The compounds of formula I can be obtained by selecting them in the free form of their functional derivatives by solvolysis, in particular hydrolysis or hydrogenolysis.

The preferred source materials for the solvolysis or EIGRP corresponding protected amino and/or hydroxy-group, preferably such that instead of H-atom, United on the N-atom, are one aminosidine group, for example those which correspond to the formula I, but instead of NH2groups contain other' group (where R' denotes aminosidine group, for example BOC or CBZ.

Further preferred source of substances that instead of the H atom of the hydroxy-group are hydroxyamino group, for example those which correspond to the formula I, but instead of hydroxyphenylpyruvic contain R" O-panelgroup (where R" denotes hydroxyamino group).

In the molecule of the original substance may also be present multiple - same or different - protected amino and/or hydroxyl groups. If the existing protective groups differ from each other, they can be in many cases derived selectively.

The expression "Aminosidine group" is well known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removed after the desired chemical reaction carried out elsewhere in the molecule. Typical of such groups, in particular, unsubstituted or substituted acyl, aryl, Alcoceber or Uralkaliy. So what are the critical values; preferred, however, such groups with 1-20, in particular 1-8 C-atoms. The expression "Acyl group" should be understood in connection with the present method in its broadest sense. It includes acyl groups derived from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxyalkyl and primarily alcoxycarbenium group. Examples of such acyl groups include alkanoyl, such as acetyl, propionyl, butyryl. arkanoid, as phenylacetyl, aroyl, such as benzoyl or toluyl; aryloxyalkanoic, such as POA; alkoxycarbonyl, as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, BOC, 2-iodoxybenzoic, arelaxation, such as CBZ ("carbobenzoxy"), 4-methoxybenzeneboronic, FMOC; arylsulfonyl, such as Mtr. Preferred aminosidine group - BOC and Mtr., next, CBZ, FMOC, benzyl and acetyl.

The expression "Hidroxizina group" is also generally known and relates to groups which are suitable for the protection of the hydroxy-group from chemical reactions, but which are easily removed after the desired reaction is carried out elsewhere in the molecule. Typical of such groups are the above-mentioned nezamedin the groups do not have critical values, as they are after the desired chemical reaction or series of reactions are removed again; preferred group with 1-20, in particular 1-10, C atoms. Examples hydroxyamine groups, incidentally, are benzyl, p-nitrobenzoyl, p-toluensulfonyl, tert.-butyl and acetyl, and especially preferred benzyl and tert.- butyl. COOH-group in aspartic and glutamic acids are preferably protected in the form of tert. butyl esters (for example, Asp (OBut)).

Used as starting substances functional derivatives of compounds of formula I can be obtained by conventional methods of amino acid and peptide synthesis, as they, for example, described in these standard works and patent applications, for example, also by a solid phase method according to Merrifield (B. F. GISIN and P. B. Merrifield, J. Am. Chem. Soc., 94,310 and trail(1972)). Particularly favorable synthesis according to the FMOC strategy in flow reactor described A. Ionica and j.By Merrifield in the Peptides, Proceedings of the 8th American Symposium on peptides, 73-77 (1983) (editors: C. J. Smith.Hrubý and D. H. rich), Pearce Co., Rockford.

The release of the compounds of the formula I from their functional derivatives is possible - depending on the protective group - for example, c strong acids, feasible, strong organic acids; as trichloroacetic acid or sulfonic acids such as benzene - or p-toluensulfonate. The presence of an additional inert solvent may, but is not always necessary. As inert solvents are particularly suitable organic, for example carboxylic acids, such as acetic acid, ether, such as tetrahydrofuran or dioxane, amides, such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, then also alcohols, such as methanol, ethanol or isopropanol, and also water. Next can be considered a mixture of the above solvents. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1. Reaction temperatures for the cleavage are appropriate between 0 and approx. 50oC, preferably between 15 and 30oC (room temperature).

Group BOC, oBut and Mtr can be derived, for example, triperoxonane acid in dichloromethane or approx. 3-5-normal HCl in dioxane at 15-30oC, FMOC-group of approximately 5-50% solution secondary amines, such as dimethylamine, diethylamine or piperidine in dimethylformamide at 15-30oC.

SaaS hydrogen in the presence of a catalyst (for example, a catalyst made of noble metal, somehow platinum, suitable media, such as charcoal). As the solvent usable above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as dimethylformamide. The hydrogenolysis is carried out usually at temperatures from 0 to 100oC and pressures from approx. 1 to 200 bar, preferably at 20-30oC and 1-10 bar. Hydrogenolysis of CBZ groups can, for example, on 5-10% Pd-C in methanol or with ammonium formate (instead of H2) on Pd-C in methanol/dimethylformamide at 20-30oC.

The compounds of formula I can be obtained by cyclization of compounds of formula II under conditions of peptide synthesis. It is reasonable to work on the usual methods of peptide synthesis as described, for example, in Houben-Weil, Chapter 1, vol 15/11 p. 1-806 (1974).

The reaction is possible mainly in the presence of digitalisierung means, such as a carbodiimide, such as DCCI or EDCl, then anhydride papapostolou acid (compare Angew. Chem.,), 92, 129 (1980), diphenylphosphinite or 2-ethoxy-N - etoxycarbonyl-1,2-dihydroquinoline, in an inert solvent such as halogenated hydrocarbon, such as dichloromethane, ether, such as tetrahydrofuran or dioxane, amide, such as dimethylformamide Il is -10 to 40oC, preferably from 0 to 30oC. to promote intramolecular cyclization in front of intermolecular binding peptide, it is advisable to work in diluted solutions (principle of dilution).

Instead of II can also be introduced into 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. Derivatives of amino acids II can be used, for example, in the form of their activated esters, which are expediently formed in situ, for example, by adding HOBt or N-hydroxysuccinimide.

Educt of the formula II, as a rule, new. They can be prepared by known methods, for example the above 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 then Malaysia in acid of the formula R'-Z-OH, for example BOC-Z-OH; from these acids hatshepsuts protective group R' and thereby gain free peptides of the formula H-Z - OH(II).

The basis of the formula I can be converted by acid in the corresponding kalatoodete salt. Genetica inorganic acid, for example sulfuric acid, nitric acid, halogen acids such as hydrochloric or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, then the organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, for example formic, acetic, propionic, trimethyllysine, diethyloxalate, malonic, succinic, Emelyanova, fumaric, maleic, lactic, tartaric, malic, benzoic, salicylic, 2 - or 3-phenylpropionate, citric, gluconic, ascorbic, nicotinic, isonicotinoyl, methane - or econsultancy, ethicality, 2-hydroxyethanesulfonic, benzosulfonate, p-toluensulfonate, naphthalenamine and desulfonema, louisanna acid. Salts with physiologically not flawless acids, such as the picrate, can be used for isolation and/or purification of the compounds of formula I.

On the other hand, the acid of formula I by reaction with a base can be converted into one of its physiologically perfect metal salts or ammonium. As salts may be considered at the same time, in particular, isopropylammonium salt, monoethanol-, diethanol - or triethanolammonium salts, cyclohexyl-, dicyclohexylammonium salt, dibenzylethylenediamine salt, hereinafter referred to, for example, salts with N-methyl-D-glucamine, or arginine, or lysine.

The new compounds of formula I and their physiologically acceptable salts can be used to obtain pharmaceutical preparations by transferring them together with at least one carrier substance or auxiliary substance and, if desired, together with one or more other active substances in a suitable pharmaceutical form. The resulting preparations can be used as drugs in medicine or veterinary medicine. As a matter of media can be considered organic or inorganic substances which are suitable for enteral (for example oral or rectal), parenteral (e.g. intravenous injection) or local (e.g., local, dermal, eyes, or nose) applications or for use in the form of inhalation aerosols 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, glice is, theart magnesium, talc, cellulose, vaseline. For oral administration are, in particular, tablets, coated tablets, capsules, syrups, juices or drops; interesting special lacquer tablets and capsules with resistant to gastric juice coating or shell capsules. For rectal use suppositories, for parenteral use - solutions, mainly oily or aqueous solutions, then suspensions, emulsions or implants. For local applications can be used, for example, solutions that can be applied in the form of eye drops, further, for example, suspensions, emulsions, creams, ointments or comprimate. For use as an inhalation aerosol suitable aerosols containing the active substance, or dissolved or suspended in gas-propellant or a mixture of such gases (such as CO2or perchloroethane). It is advisable to apply the active ingredient in micronized form, and may be additional physiologically compatible solvents, such as ethanol. Inhalation solutions may be introduced using conventional inhalers. The new compounds can also be lyophilized and the resulting lyophilizate, for example, note the and as a continuous infusion (e.g., intravenously, intraperitoneally, subcutaneously or podvoloshino). These preparations can be sterilized and/or contain auxiliary substances, such as preservatives, stabilizers and/or wetting means, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyes and/or fragrances. They can, if necessary, to contain one or more active substances, for example one or more vitamins.

The substances according to the invention can be administered to a patient, as a rule, similar to other known commercially available peptides, in particular, by analogy with the compounds described in US-A 4472305, predominantly at doses of approx. 0.05 to 500 mg, in particular from 0.5 to 100 mg per unit dose. The daily dose is generally from 0.01 to 2 mg/kg of body weight. Special dose for each particular patient depends, however, on various factors, for example on the activity of the compound, the age, body weight, General health, sex, food, time and route of drug administration, on the rate of excretion, combination of drugs and the severity of the disease. Preferably parenteral administration.

Furthermore, the new compounds of the Fort is impressive in its purest form.

The ligand, i.e. the derivative of the peptide of formula 1, with covalently attached via anchor function to the polymeric carrier.

As polymeric carriers suitable known in the chemistry of peptides polymer solid phase with predominantly hydrophilic properties, for example, cross stitched, polisher as cellulose, sepharose or seedcoTMacrylamide, polymers on polietilenglikoli basis or anticentromereTM.

As the anchor functions that connect with polymeric carriers, suitable mainly linear alkylene chain with 2-12 C atoms, attached at one end directly to the polymer and at the other end having a functional group such as hydroxy, amino, mercapto, maleinimide or-COOH and suitable for linking with a functional side chain of the corresponding peptide.

It is possible that the peptide directly or through the second anchor function is connected with the anchor peptide.

In addition, the amino acids forming part of the peptides of formula I, can be modified in their side chains that they will be able to join via, for example, the group of NH2CH-, OH-, directly anchoring function, are, for example, Arg, or Asp.

Examples of the anchor, which can be linked through free NH2groups are residues, such as, for example, - CO-CnH2n-NH2, -CO-CnH2n-OH, -CO-CnH2n-SH or-CO-CnH2n-COOH with n=2-12, and the length of alkalinous circuit is not critical, and it may optionally be substituted, for example, corresponding aryl go alkalline remains.

C-terminal anchors that can be attached to the free acid groups are, for example, the group-O-CnH2n-SH, -O-CnH2n-OH, -O-CnH2n-NH2, -O-CnH2n-COOH, -NH-CnH2n-SH, -NH-CnH2n-OH, -NH-CnH2n-NH2,

-NH-CnH2n-COOH, and n, as well as Allenova circuit has the above value.

Obtaining materials for affinity chromatography for the purification of integrins occurs under conditions normal for condensation of amino acids.

If diastereomer anchors you can use the reactions of addition, as the Michael reaction on derivatives of maleinimide or the formation of disulfide with polimersvarka the thiol.

Values emodiment, water, neutralized, extracted with ether or dichloromethane, separated, the organic phase is dried over sodium sulfate, filtered, evaporated and purified chromatographically on chiseled and/or by crystallization. RT = retention time (min) high-performance liquid chromatography (HPLC) on system A: LichrosorbRP Select B (h; 5 μm) or system LichrosorbRP18 (h; 5 μm); mobile phase (A): 0,3% TFA in water; isopropanolamine gradient 0-80 vol. %; 50 minutes at 1 ml/min flow and detection at 215 nm. The mobile phase (system B): eluent A: 0.1% of TFA in water, eluent B: 0.1% of TFA in acetonitrile/water (9: 1); gradient of 20-90% B; 50 min at 1 ml/min. M+= molecular peak in the mass spectrum, obtained by the method of fast atomic bombardirovki, with specified molecular weight is increased by one unit mass compared with the calculated value.

Example 1

A solution of 0.4 g of H-Arg(Mtr)-Gly-Asp-Btd-ONa (for example, can be obtained from FMOC-Arg(Mtr)-Gly-Asp-Btd-O-Wang), and-O-Wang means used in the modified method of Merrifield balance 4-oxymethylphenyl-polystyrene resin by cleavage of the FMOC group with piperidine/DMF (dimethylformamide) and removal of the resin using TFA/CH2Cl2(1:1) in 15 ml DMF Rabb who ál diphenylphosphinite. After 16 hours of incubation at room temperature the solution is concentrated. The concentrate is filtered (column with Sephadex G10 in a mixture of isopropanol/water 8:2) and then purified by HPLC. Get cyclo-Arg(Mtr)-Gly-Asp-Btd.

Similarly obtained by cyclization of the corresponding linear peptides: cyclo-(Arg(Mtr)-Gly-Asp (S) Gly[ANC-2]-Leu; cyclo-(Arg(Mtr)-Gly-Asp-(R)Gly[ANC-2] - Leu; cyclo-(Arg(Mtr)-Gly-Asp-Biph1); cyclo-(Arg(Mtr)-Gly - Asp-Biph2); cyclo-(Arg(Mtr)-Gly-Asp-Act).

Example 2

A solution of 0.28 g of cyclo-Arg(Mtr)-Gly-Asp-Btd (can be obtained by cyclization in accordance with example 1) 8.4 ml of TFA, 1.7 ml of dichloromethane and 0.9 ml of thiophenol leave to stand for 4 hours at room temperature, then concentrated and diluted with water, dried by freezing. Gelfiltration on Sephadex G10 (acetic acid/water 1:1) and subsequent purification by preparative HPLC under these circumstances can lead to selection of cyclo-(Arg-Gly-Asp-Btd); RT=13,2; M+527.

Similarly receive from cyclo-(Arg(Mtr)-Gly-Asp(S) Gly[ANC-2]-Leu: cyclo-(Arg-Gly-Asp(S) Gly[ANC-2] -Leu, RT= 4,8; M+525; from cyclo-(Arg(Mtr)-Gly-Asp-(R) Gly[ANC-2] -Leu: cyclo-(Arg-Gly-Asp-(R) Gly[ANC-2]-Leu, RT=6,3; M+525; from cyclo-(Arg(Mtr)-Gly-Asp-Biph1): cyclo-(Arg-Gly-As-Biph1); RT-20,7; M+538; of cyclo-(Arg(Mtr)-Gly-Asp-Biph2): cyclo-(Arg-Gly-Asp-Biph2); RT= 20,8; M+538; of cyclo-(Arg(Mtr)-Gly-Asp-Act): cyclo-(Arg-Gly-Asp-A is e of each dissolution process cleanse freezing. Subsequent purification via HPLC gives cyclo-(Arg-Gly-Asp-Btd) x HCl.

Similarly receive from cyclo- (Arg-Gly-Asp-Aha): cyclo-(Arg-Gly-Asp-Aha) x HCl; cyclo-(Arg-Gly-Asp-Aha) x HNO3;

Example 4

To obtain affine phases suspended 0.9 g (Cl- (CH2)3-CO-NH-(CH2)3-polymer (can be obtained by condensation of (Cl-(CH2)3-COOH H2N-(CH2)3-polymer) in 10 ml of 0.1 M nutrifaster buffer at pH 7 and add in 4oC 1 equivalent of cyclo-(Arg(Mtr)-Gly-Asp(ONa)-Btd). Stirred for 4 hours while heating the reaction mixture to room temperature, the solid residue is filtered off and washed twice each time with 10 ml of buffer solution (pH 7) and then three times with water each time to 10 ml. Receive cyclo cyclo-(Arg(Mtr)-Gly-Asp-(O(CH2)3)-CONH- (CH2)3-polymer-Btd).

Example 5

Analogously to example 2 receive, from cyclo- (Arg(Mtr)-Gly-Asp-(O(CH2)3)-CONH-(CH2)3-polymer-Btd), the removal of the group Mtr cyclo-(Arg-Gly-Asp-(O(CH2)3)-CONH-(CH2)3- polymer-Btd).

Example 6

Analogously to example 4 is obtained by condensation polymer(O(CH2)3)-NH2(commercially available) and cyclo-(Arg-Gly - Asp-Biph1) the following polymer phase: cyclo-(Arg-Gly-Asp P CLASS="ptx2">

Example a: Flask for injection

A solution of 100 g of cyclopeptide formula I and 5 g of secondary sodium phosphate in 3 l of double-distilled water was adjusted to pH 6.5 using 2n. hydrochloric acid, sterile filtered, dispensed into vials for injection, lyophilizer in sterile sterile conditions and closed. Each vial contains 5 mg of active substance.

Example B: Suppositories

Melt a mixture of 20 g of the active substance of the formula I with 100 g of soya lecithin in 1400 g of cocoa butter, poured into moulds and allow to cool. Each suppository contains 20 mg of active substance.

Example C: a Solution of

Prepare a solution of 1 g of the active substance 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 to 6.8, made up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

Mix 500 mg of active substance of the formula I with 99.5 g of vaseline under aseptic conditions.

Example E: Tablets

A mixture of 100 g of pelobatid formula I, 1 kg of lactose, 600 g of microcrystalline cellulose, 600 g of corn starch, 100 g of polyvinylpyrrolidone, 80 g tal is active substances.

Example F: Bean

Pressed tablets as described in example E, and then cover them in the usual way by a coating of sucrose, corn starch, talc, tragant and dye.

Example G: Capsules

Capsules of hard gelatin fill in the usual way active substance of the formula I, so that each capsule contains 5 mg of active substance.

Example H: Inhalation aerosol

Dissolve 14 g of the active substance of the formula I in 10 l of isotonic saline and inject the solution into commercially available spray the blood vessels by the pumping mechanism. The solution can be sprayed into the mouth or nose. Spray quantity (approx. 0.1 ml) corresponds to a dose of approx. 0,14 mg

Pharmacological data supporting the biological activity of the compounds according to the invention (see table).

The binding of vitronectin (VN) to the receptor was determined according to the method described by Smith and al. in J. Biol. Chem., 265,1267-71 (1990).

IC50-value (concentration nmol/l, corresponding to a 50% increase inhibition of the binding of vitronectin to the receptor) characterizes the activity of the compounds of formula I.

According to the applicant compounds according to the invention the character>) (I),

where A = GLy;

R1- the remainder of the 2-carboxy-8-amino-4-capibility-9-it (Btd)-amino-methyl-O'-carboxyphenyl (Biph), 2-aminomethyl-5-carboxymethylchitin (Act) or the residue of 2-(3-amino-1-pyrrolin-2-IMT)-4-methylpentanoic acid (s) Gly (ANC-2)-Leu or (R) Gly(ANC-2)-Leu, and the remains are respectively connected through a peptide bond;< / BR>
R2no,

and their physiologically acceptable salts.

2. Cyclopeptide formula I on p. 1, representing: a) cyclo-(Arg-Gly-Asp(S)Gly/ANC-2/-Leu); (b) cyclo-(Arg-Gly-Asp-(R)Gly/ANC-2/-Leu), cyclo-(Arg-Gly-Asp-Act); d) cyclo-(Arg-Gly-Asp-Btd).

3. Enantiomer or diastereomer the compounds of formula I according to p. 1.

4. The method of obtaining compounds of formula I on p. 1 or one of its salts, characterized in that they emit in a free form from one of their functional derivatives by treatment solvolysis or hydrogenation means.

5. The method of obtaining the compounds of formula I according to p. 1 or one of its salts, characterized in that the peptide of formula II:

H-Z-OH,

where Z = -Arg-A-Asp-R1-R2-; -A-Asp-R1-R2-Arg-; -Asp-R1-R2-Arg-A-; -R1-R2-Arg-A-Asp-; -R2-Arg-A-Asp-R1- where R1- the remainder of the 2-carboxy-8-amino-4-capibility-9-it(Type-2 IMT)-4-methylpentanoic acid (S)Gly((ANC-2)-Leu, or (R)Gly[ANC-2] -Leu;

R2- no;

A = Gly

or a reactive derivative of such a peptide is treated collisuem means and/or translate basic or acidic compound of formula I by treatment with an acid or a base in one of its salts.

 

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The invention relates to medicine

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them

The invention relates to a new radiopharmaceutical drugs, which are radioactivedecay cyclic compounds containing carbocyclic or heterocyclic ring system and acting as antagonists of glycoprotein complex IIb/IIIa

The invention relates to new oligopeptides having affinity to the opiate receptors, which may be linear or cyclic Pentapeptide with the primary sequence of amino acids in the skeletal Tyr-X-Hairdryer-S-Z, where X and Z denote amino acids or derivatives of amino acids and/or analogs, and where X and Z can be covalently linked, form a heterocyclic structure in which Z is selected from Cys, Glu, GLn or derivatives of Glu and GLn; X is selected from amino acids or amino acid analogs, such as Ser, Glu, D-Ala, D - or Z-2,4-diaminobutane acid, AMCC, CIS or their derivatives
The invention relates to new cyclopeptides formula (I): cyclo-(Arg-B-Asp-X-Y), where B, X and Y are specified in paragraph

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
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