Cyclopeptide, the way they are received, containing their pharmaceutical compositions and method of production thereof

 

(57) Abstract:

The invention relates to new cyclopeptides formula (I): cyclo-(Arg-B-Asp-X-Y), where B, X and Y are specified in paragraph 1 of the claims value, and their salts. These compounds act as inhibitors of integran and can be used in particular for the prevention and treatment of diseases of the pulmonary circulation and in the treatment of tumors. The method of obtaining compounds of formula (I) is that the corresponding linear peptide or a reactive derivative of such a peptide is subjected to cyclization by treatment collisuem agent, followed if necessary by interaction with an acid or base with the formation of salts. Describes a method of obtaining a pharmaceutical composition and pharmaceutical composition antagonist 11b3and 3- integrins containing the compounds of formula (I). 4 C. and 3 h.p. f-crystals.

The invention relates to new cyclopeptides formula (I):

Cyclo-(Arg-In-Asp-X-Y)

where = Gly, Ala, -NH-Q-CO -, and Q =/C-C/ alkylen;

X = Phe, D-Phe, D-(4-Hal-Phe, D-Lys, D-Orn, D-Pro, D-Tic, D-Nal, D-Phg

Y = Gly, Ala, D-Ala, Val, D-Val, Phe, D-Phe, Leu, D-Leu, Nle, Lys, Lys (Ac), Lys (AcSH), Orn, D-Orn;

Ac = alkanol with 1-10 C-atoms;

Hal = chlorine, fluorine, bromine, iodine,

and physiologists obtain new compounds with valuable properties, particularly suitable for the preparation of drugs.

It is shown that the compound of formula (I) and their salts have very valuable properties, namely the antagonist properties 11b3and3-integrins, and in particular they inhibit adhesion receptors3or5-integrin with a ligand. This action can be confirmed, for example, by the method described by J. W. Smith and others, in J. Biol.Chem. 265, 12267-12271 (1990). Additionally have anti-inflammatory effects, which also can be confirmed by 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 circulation, thrombosis, heart attack, arteriosclerosis, inflammations, apoplexy, angina, neoplastic disease, osteolytic diseases, in particular osteoporosis, antiogenesis and restenosis after angioplasty. Further, the compounds can be used to improve wound healing.

Moreover, compounds suitable as antimicrobial biologically active substances, which prevent infections that are excited, for example, a tank is if the active substances in the intervention in organisms, while using foreign substances, as, for example, biomaterials, implants, catheters or electrostimulation of the heart. They act as antiseptics.

Most preferred according to the invention are cyclopeptide formula I, representing

/a/ Cyclo-(Arg-Gly-Asp-D-Lys-Val)

/b/ Cyclo-(Arg-Gly-Asp-D-Phe-Lys)

/c/ Cyclo-(Arg-Gly-Asp-D-Phe-Gly)

/d/ Cyclo-(Arg-Gly-Asp-D-Phe-Phe)

/e/ Cyclo-(Arg-Gly-Asp-D-Phe-Leu)

/f/ Cyclo-(Arg-Gly-Asp-Phe-D-Leu)

Above - and below-reducing amino acid residues indicate residues of the following amino acids:

Abu 4 - aminobutyric acid

Aha 6 - aminohexanoic acid

Ala alanine

Asn asparagine

Asp aspartic acid

Asp (OR), aspartic acid (- ester

Arg arginine

Cha 3-cyclohexylamin

Cit citrullin

Cys cysteine

Dab 2,4-diaminopentane acid

Gln glutamine

Glu glutamic acid

Gly glycine

His histidine

Ile isoleucine

Leu is leucine

Lys lysine

Lys (Ac) N- alcoholized

Lys (AcNH2) N- aminoalcohols

Lys (AcSH) N- mercaptoquinoline

Met methionine

Nal 3-/2-naphthyl-alanine

Nle norleucine

Orn ornithine

Phe FeNi Ser serine

Tia 3-/2-thienyl/-alanine

Tic of tetrahydroisoquinoline-Z-carboxylic acid

Thr threonine

Trp tryptophan

Tyr tyrosine

Val valine

Further, in the following introduces the following notation:

BOC tert.-butoxycarbonyl

CBZ benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

DMF dimethylformamide

Cl N-ethyl-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 ethyl ester

POA phenoxyacetyl

TBTV 2-/1H-benzotriazol-1-yl/-1,1,3,3 - tetramethyleneglutaric

TFK triperoxonane acid

Because of the above amino acids can be in several enantiomeric forms, are included above and below, for example, as a constituent part of compounds of formula (I), all these forms and also their mixtures (for example, DL - forms). Further, amino acids, for example, as an integral part of the compounds of formula (I) may contain relevant, in itself known protective group.

The subject invention further is a method the first method of synthesis, get a linear peptide of General formula II:

X-Z-OH,

where Z = Arg-B-Asp-X-Y

B-Asp-X-Y-Arg

Asp-X-Y-Arg-B

X-Y-Arg-B-Asp

or

Y-Arg-B-Asp-X

the value of B, Y and X - stated in the 1st paragraph of the claims,

or a reactive derivative of such a peptide is subjected to cyclization by treatment collisuem agent, followed if necessary by interaction with an acid or base with the formation of salts.

How appropriate is carried out according to conventional methods of peptide synthesis are described, for example in Houben-Weyl, cited above, vol 15/11, S. 1-806 (1974).

The reaction is preferably carried out in the presence of dehydrating, such as a carbodiimide, as DSS or ETS: 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 in a 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 of about -10oC to 40oC, preferably at 0-30oC. in order to facilitate vnuh solutions (principle of dilution).

Instead of the compounds of the formula (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 a protective group. 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 the addition of HOBt or N-hydroxysuccinimide.

Educt of the formula (II), as a rule, are new. They can be obtained by known methods, for example the above-mentioned methods of 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 them otscheplaut protective group R' and thereby gain free peptides of the formula H-Z-OH (II).

In the molecule of the original substance may be several identical or different protected amino and/or hydroxyl groups. If the existing protective group different from each other, in many cases, they can be selectively split.

The expression "protection for the amino-GRU is economic transformations, and which, however, can be easily removed after it has been desired chemical reaction in other parts of the molecule. Typical of such groups are unsubstituted or substituted acyl, aryl, arelaxation or kalkilya group. As the protective groups are removed after the desired reaction or sequence of reactions, their family and size, however, is not critical; preferred, however, groups 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 acyl group, aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic or sulfonic acids, 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 toluene; aryloxyalkanoic; alkoxycarbonyl as methoxycarbonyl; etoxycarbonyl, 2,2,2-trichlorocyanuric, BOC, 2 - iodine-etoxycarbonyl; Uralelectromed as CBZ ("carbobenzoxy"); 4 - methoxybenzeneboronic, FMOC; arylsulfonyl as Mtr. Preferred protective DL is a strong group, the group is also well known and refers to groups suitable for protecting a hydroxyl group from chemical interactions, and which, however, can be easily removed after it has been desired 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 sequence of reactions 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-nitrobenzoyl, p-toluensulfonyl, tert. -butyl and acetyl, and especially preferred benzyl and tert.-butyl, COOH-group in aspartic acid and glutamic acid are preferably protected in the form of their complex tert.-butyl esters (for example, Asp [OBut]).

The basis of the formula (I) with acids can be converted to the corresponding salt accession acid. For this interaction, use of acid, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, such as sulfuric acid; nitric sour Ospina 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 acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-or 3-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinoyl acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalene mono - and di-sulfonic acids, louisanna acid. For isolating and/or purifying compounds of formula (I) can be used salts with physiologically unacceptable acids, for example the picrate.

On the other hand, the acid of formula (I) by entering into interaction with the base can be translated into one of its physiologically acceptable metal salts or ammonium. As the salts thus take into wine, as dimethyl-, diethyl - or diiso-propyl-ammonium salt; monoethanol-, diethanol - or triethanol-ammonium salt; cyclohexyl, DICYCLOHEXYL-ammonium salt; dibenzylethylenediamine salt; further, for example, salts with N-methyl-D - glucamine or with arginine or lysine.

The new compounds of formula (I) and their physiologically acceptable salts can be used to obtain pharmaceutical preparations because of their effective number together with at least one carrier or auxiliary substance and, if desired, together with one or more other biologically active substances brought to a suitable dosage forms. The thus obtained composition can be used as a drug in medicine or veterinary medicine. As carriers take into account, for example, inorganic substances which are suitable for enteral (for example oral or rectal], parenteral (e.g. intravenous injection] or local [e.g., topical, and through the skin, eyes, or nose] introduction or for introduction in the form of inhalation drugs and do not react with the new compounds, such as water or an aqueous isotonic solution of sodium chloride is ready fatty acids, gelatin, soy lecithin; carbohydrate as lactose or starch, magnesium stearate, talc, cellulose, vaseline. For oral administration are, in particular tablets, coated tablets, capsules, syrups, juices or drops; of special interest are lacquered tablets and capsules resistant to gastric juice coatings, respectively shells of the capsules. For rectal use candles; for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore, suspensions, emulsions or implants. For topical application suitable, for example, solutions that can be applied in the form of eye drops; then, for example, suspensions, emulsions, creams, ointments or sprays. For use as inhalant drugs can be used sprinklers, which contain biologically active compound either dissolved or suspended in the working gas or a mixture of working gases (such as CO2or perchloroethane). It is reasonable to apply the biologically active agent in micronized form, and you can add one or more additional physiologically acceptable solvents, for example ethanol. Solutions for inhalation can be entered with the th for example, for the preparation of drugs for injection. Injections can be done gradually or as a continuous infusion [e.g., intravenously, intramuscularly, subcutaneously or into the spinal fluid space]. 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 fragrances. If desirable, they can also contain one or more other biologically active substances, for example one or more vitamins.

Proposed according to the invention substances, as a rule, you can enter by analogy with other known, commercially available peptides, in particular similar to the one described in U.S. patent A-4 472305 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 depends, however, on a variety of factors, such as efficiency connections in use, the age, body weight, General condition sdate corresponding disease, which has implications for therapy. Preferably parenteral administration.

Furthermore, the new compounds of formula (I) can be used as integranova ligands for the manufacture of columns for affinity chromatography to obtain pure integrins.

The ligand, i.e., a peptide derivative of formula (I), due to the anchoring functionality covalently bound to a polymeric carrier.

As polymeric carriers suitable in itself known in the chemistry of peptides polymer solid phase preferably hydrophilic properties, such as cross stitched polisher as cellulose, sepharose or Sephadexacrylamide, polymers based on polyethylene glycol or Tentakel - polymers.

As the anchor of the functions that are associated with polymeric carriers which are suitable are preferably linear alkylene chain with 2-12 C atoms, in which one of its end directly connected to the polymer, and on the other end contains a functional group, such as hydroxyl, amino, mercapto, maleinimide or - COOH, and therefore suitable for binding to C - or N-terminal segment of the corresponding peptide.

It is possible that peptide binding is s, which contain amino acid residues with functionalized side chains through them in contact with the anchoring function of the polymer.

Moreover, certain amino acid residues, which are an integral part of the peptides of formula (I), can be modified in their side chains so that they are available for binding, for example, SH-, OH-, NH2- or COOH-groups with anchor polymer.

It is possible unusual amino acids, such as, for example, derivatives of phenylalanine, which in the 4-position of the phenyl ring include mercaptopurine-, amino - or carboxialkilnuyu chain, and the functional group is at the end of the chain.

Examples of amino acid residues, the side chain of which may directly serve as the anchor functions are, for example, Lys, Orn, Arg, Dab, Asp, Asn, Glu, Gln, Ser, Thr, Cys, Cit or Tyr.

Examples of N-terminal anchors are these residues, 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 if necessary it can be replaced, for example, the appropriate aryl or UB>nH2n-OH; -O-CnH2n-NH2; -O-CnH2n-COOH, -NH-CnH2n-SH; -NH-CnH2n-OH; -NH-CnH2n-NH2or-NH-CnH2n-COOH, and n , as well as Allenova chain have already mentioned in the previous paragraph is.

N - and C-terminal anchors can also serve as anchor links already functionalized side chain amino acid residue. Here take into account, for example, amino acid residues as Lys (CO-C5H10-NH2), Asp (NH-C3H6-COOH) or Cys (C3H6-NH2), and the anchor is always associated with the functional group of the side chain.

Obtaining materials for affinity chromatography for the purification of integrin carried out under conditions, which themselves are known for condensation of amino acids.

Temperatures are indicated in degrees Celsius. In the following examples, "conventional treatment" means add, if necessary, water; neutralize; extracted with ether or dichloromethane; separated, the organic phase is dried over sodium sulfate; filtered; and evaporated and purified by chromatography on silica gel and/or by crystallization. RZ = retention time (minutes) by HPLC on Lichrosorbn at a speed of 1 ml/min Expiration and detection at 215 nm. M+= molecular peak in the mass spectrum; it is produced according to the method of "fast atom bombardment" (FAB).

Example 1

A solution of 0.2 g of H-Arg-Gly-Asp-D-Pro-Val-ONa [e.g., derived from Fmoc-Arg-Gly-Asp-D-Pro-Val-O-Wang, and-O-Wang means used in a modified way Merrifield balance 4-oxymethyl-phenoxymethyl-polystyrene resin by removal of Fmoc group with piperidine in DMF and off the resin using TFA in CH2Cl2(1:1) ] in 15 ml of DMF is diluted with 85 ml of dichloromethane and mixed with 50 mg of sodium bicarbonate. After cooling in a mixture of dry ice with acetone to add 40 ál diphenylphosphinite.

After standing for 16 hours at room temperature the solution is concentrated. The concentrate is subjected to gel filtration (Sephadex GIO-column in a mixture of isopropanol with water in the ratio 8:2) and then purified as usual by HPLC. Get cyclo- (Arg-Gly-Asp-D-Pro-Val); PZ = 13,4; M+= 525. Similarly, by cyclization of the corresponding linear peptides receive

cyclo - (Arg-Gly-Asp-D-Tic-Val); RZ= 18,4; M+587;

cyclo - (Arg-Gly-Asp-D-Phe-Val); M+575;

cyclo - (Arg-Gly-Asp-D-Lys-Val); RZ= 6,8; M+556;

cyclo - (Arg-Gly-Asp-D-Phe-Lys); RZ= 10,9; M+604;

CEC,0; M+623;

cyclo - (Arg-Gly-Asp-D-Phe-Leu); RZ = 21,2; M+589;

cyclo - (Arg-Gly-Asp-D-Nal-Val); RZ = 24,7; M+625;

cyclo - (Arg-Gly-Asp-D-Phg-Val); RZ = 16,5; M+561;

cyclo - (Arg-Gly-Asp-Phe-Gly); RZ = 13,2; M+533;

cyclo - (Arg-Gly-Asp-Phe-D-Ala); RZ = 14,8; M+547;

cyclo - (Arg-Gly-Asp-Phe-D-Phe); RZ = 20,2; M+623;

cyclo - (Arg-Gly-Asp-Phe-D-Leu); RZ= 21,4; M+589;

cyclo - (Arg(Mtr)-Gly-Asp-D-Phe-Lys); RZ = 23,4; M+816;

cyclo - (Arg-Gly-Asp-D-Phe-Lys(H3C-CO); RZ = 17,0; M+646;

cyclo - (Arg(Mtr)--Ala-Asp-Phe-D-Val); RZ = 28,2; M+801;

cyclo - (Arg-Gly-Asp-D-Phe-Nle); RZ = 22,0; M+589;

cyclo - (D-Arg-Gly-D-Asp-D-Phe-Val); RZ = 17,5; M+575;

cyclo - (Arg-Gly-D-Asp-D-Phe-D-Gly); RZ = 18,7; M+575;

cyclo - (Arg-D - Ala-Asp-D-Phe-Val); RZ = 18,9; M+589;

cyclo - (Arg-D-Ala-Asp-Phe-D-Val); RZ = 19,1: M+589;

cyclo - (Arg-Aha-Asp-D-Phe-Val); RZ = 20,8; M+631;

cyclo - (Arg-Abu-Asp-Phe-D-Val); RZ = 17,2; M+603;

cyclo - (Arg-Aha-Asp-Phe-D-Val); RZ = 19,8; M+631;

cyclo - (Arg-Abu-Asp-D-Phe-Val); RZ = 17,8; M+603;

cyclo - (Arg-Gly-Asp-D-(4-I-Phe)-Val); RZ = 23,3; M+701;

cyclo - (Arg-Gly-Asp-Phe-Val); RZ = 21,8; M+575;

cyclo - (Arg-Gly-D-Asp-D-Phe-Val); RZ = 20,7; M+575;

cyclo - (D-Arg-Gly-Asp-Phe-D-Val); RZ = 20,8; M+575;

cyclo - (D-Arg-Gly-Asp-D-Phe-Val); RZ = 21,9; M+575;

cyclo - (Arg-Gly-D-Asp-D-Phe-Val); RZ = 20,7; M+575;

Example 2

A solution of 0.28 g of cyclo -(Arg[Mtr]- -Ala-Asp-Phe-D-V the sa at room temperature, then concentrate and after dilution with water is subjected to drying by freezing. Gel filtration on Sephadex G10 (acetic acid/water 1:1) and subsequent purification by preparative HPLC under these conditions give cyclo-(Arg----Ala-Asp-Phe-D-Val); RZ = 17,0; M+589.

Similarly get:

Cyclo-(Arg (Mtr)-Gly-Asp-D-Phe-Lys);

Cyclo-(Arg-Gly-Asp-D-Phe-Lys); RZ = 10,9; M+604

Example 3

80 mg of cyclo-(Arg-Gly-Asp-D-Phe-Leu) dissolved 5-6 times in 0.01 M HCl and after each dissolution process is subjected to drying by freezing. Subsequent purification by HPLC gives cyclo- (Arg-Gly-Asp-D-Phe-Leu)HCl; RZ = 20,6; M+589.

Similarly obtained from cyclo-(Arg-Gly-Asp-D-Phe-Val), cyclo - (Arg-Gly-Asp-D-Phe-Val)HCl; RZ = 18,4; M+575;

from cyclo - (Arg-Gly-Asp-D-Phe-Leu), cyclo - (Arg-Gly-Asp-D-Phe-Leu) HCl;

from cyclo - (Arg-Gly-Asp-D-Phe-Leu) by treatment with acetic acid;

cyclo - (Arg-Gly-Asp-D-Phe-Leu)H3C-COOH; RZ = 19,2; M+589,

from cyclo-(Arg-Gly-Asp-D-Phe-Leu) by treatment with nitric acid,

cyclo -(Arg-Gly-Asp-D-Phe-Leu)HNO3; RZ = 20,4; M+589.

Example 4

For preparation of affinity phases 0.9 g N-maleimido-(CH2)5-CO-NH- (CH2)3-polymer [obtained by condensation of N-maleimido-(CH2)3,- COOH H2N -(CH2)3-Phe-Lys (CO(CH2)2SH)]. Stirred for 4 hours while heating the reaction mixture to room temperature, the solid residue is filtered off and washed twice with 10 ml buffer solution (pH= 7) and then three times with 10 ml water. Get cyclo- [Arg-Gly-Asp-D-Phe-Lys/CO/CH2/2S - 3-(N - maleimido-(CH2)5-CONH (CH2)3-polymer)]

Example 5

Analogously to example 1, by condensing the polymer-O-(CH2)3-NH2- (available in sale) with cyclo-(Arg-Gly-Asp-D-Pro-Lys(CO)CH2)4-COOH) [obtained by condensation alienboy acid with cyclo - [Arg-Gly-Asp-D-Pro-Lys] under specified conditions] get the following polymer phase: cyclo-[Arg-Gly-Asp-D-Pro-Lys-/CO/CH2/4-CO-NH-/CH2/3-O-polymer]

Similarly, by condensation of cyclo - [Arg-Gly-Asp-D-Phe-Lys-/CO-/CH2/5-NH2/] HOOC-CH2-O-polymer receive

cyclo - [Arg - Gly-Asp-D-Phe-Lys-/CO-/CH2/5-NH-CO-CH2-O - polymer/]

The examples below relate to pharmaceutical compositions:

An example of a

Glass vials of medicine for injection

A solution of 100 g of cyclopeptide formula (I) and 5 g of dinitrigenoxide in 3 l of bidistilled water using 2 N. hydrochloric acid ustanavlivaetsya sterile conditions and closed. Each bottle of the drug for injection contains 5 mg of biologically active substances.

Example B:

Candles

A mixture of 20 g of biologically active substances of the formula (I) with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and leave to cool. Each suppository contains 20 mg of biologically active substances.

Example:

Solution

Prepare a solution of 1 g of biologically active substances of formula 1, 9, 38 g of NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g of benzylaniline in 940 ml of bidistilled water. Set pH 6.8, made up to 1 l and sterilized by irradiation. This solution is used in the form of eye drops.

Example D:

Ointment

Mix 500 mg of biologically active substances of formula I with 99.5 g of vaseline under aseptic conditions.

Example D:

Tablets

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, 80 g of talc and 10 g of magnesium stearate as usual pressed into tablets so that each tablet contained 10 mg of biologically active substances.

Example E:

Pills

Pressed tablets,like, tragant and dye.

Example G:

Capsules

As usual hard gelatin capsules filled with biologically active substance of the formula (I) so that each capsule contains 5 mg of biologically active substances.

Example 3

Inhalation spray

14 g of biologically active substances of the formula (I) are dissolved in 10 l of isotonic NaCl solution and the solution is poured into selling vessels for spraying with a pump. The solution can be sprayed into the mouth or nose. One injection (approximately 0.1 ml) corresponds to a dose of approximately 0,14 mg

1. Cyclopeptide General formula I

cyclo-(Arg-B-Asp-X-Y)

where B = Gly, Ala, -NH-Q-CO-, and Q = (C1- C6) alkylen;

X = Phe, D-Phe, D-(4-Hal-Phe, D-Lys, D-Orn, D-Pro, D-Tic, D-Nal, D-Phg;

Y = Gly, Ala, D-Ala, Val, D-Val, Phe, D-Phe, Leu, D-Leu, Nle, Lys, Lys(Ac), Lys(AcSH), Orn, D-Orn

Ac = alkanoyl with 1 to 10 C-atoms;

Hal = chlorine, fluorine, bromine, iodine, or their physiologically acceptable salts.

2. Cyclopeptide formula I on p. 1 representing:

(a) Cyclo-(Arg-Gly-Asp-D-Lys-Val);

(b) Cyclo-(Arg-Gly-Asp-D-Phe-Lys);

(c) Cyclo-(Arg-Gly-Asp-D-Phe-Phe);

(d) Cyclo-(Arg-Gly-Asp-D-Phe-Gly);

(e) Cyclo-(Arg-Gly-Asp-D-Phe-Leu);

(f) Cyclo-(Arg-Gly-Asp-Phe-D-Leu).

3. Cyclopeptide formula I under item 1 or a physiologically acceptable salt, obladaushi inhibitor of adhesion.

5. The method of producing cyclopeptides formula I under item 1 or their physiologically acceptable salts, which consists in the fact that the use of solid-phase synthesis method, get a linear peptide of General formula II:

X-Z-OH,

where Z = Arg-B-Asp-X-Y

B-Asp-X-Y-Arg

Asp-X-Y-Arg-B

X-Y-Arg-B-Asp

or

+Y-Arg-B-Asp-X

the value of B, Y, X is said in the 1st paragraph of the claims, then this peptide or a reactive derivative of such a peptide is subjected to cyclization by treatment collisuem agent, followed if necessary by interaction with an acid or base with the formation of salts.

6. A method of obtaining a pharmaceutical composition, characterized in that cyclopeptide formula I under item 1 or one of its physiologically acceptable salts is mixed with at least one solid, liquid or semi-liquid carrier or auxiliary substance.

7. The pharmaceutical composition antagonist 11b3and 3-integrins containing the active ingredient and a carrier or excipient, wherein the active ingredient it contains one of cyclopeptides General formula I under item 1 or one of its physiologically acceptable salt in an effective amount.

 

Same patents:

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 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 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 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

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