Biologically active carnosine-anserine-containing complex and method for its preparing

FIELD: biotechnology, biochemistry.

SUBSTANCE: invention relates to producing the biologically active complex eliciting antioxidant and immunomodulating activity and used in medicine, cosmetics, veterinary science and food industry. The biologically active complex preparing by enzymatic hydrolysis of muscle tissue represents complex of biologically active compounds involving carnosine and anserine in the amount 85-97 wt.-% of the native content of these components in poultry muscle tissue, 1-7 weight parts of amino acids, 0.5-12 weight parts of oligopeptides of molecular mass 10 kDa, not above, and 0.1-15 weight parts of cyclic and polycyclic phenolic compounds as measured for 1 weight part of carnosine and anserine in the complex. This complex is prepared by enzymatic hydrolysis of milled and homogenized water muscle tissue in preferable dilution homogenate with water in the range 0.2-0.6 and with using proteolytic enzymes in the amount 2-5 wt.-% of the protein content and working at pH 4.5-8.5 and at enhanced temperature being preferably at 45-65°C. Product is isolated as extract or powder prepared in drying the extract. Invention provides enhancing effectiveness of the claimed complex.

EFFECT: improved method for preparing, valuable properties of complex.

7 cl, 6 tbl, 6 ex

 

The invention relates to biotechnology and for the production of biologically active agents, including histidinemia a dipeptide having antioxidant, immunomodulatory activity, obtained on the basis of natural raw materials - muscle chicken, which can be applied in the medical and food industries, cosmetics, veterinary, animal husbandry.

It is known that the antioxidant and immunomodulatory activity have both natural and synthetic products of different structure and composition. Such products include, for example, histidinemia dipeptides, and amino acids. Much attention in recent years has been paid to the study histidinemia of dipeptides with antioxidant activity, namely the production of carnosine, which has the structure of Ala-His and its derivatives, such as anserin patterns Ala-N-MeHis. Carnosine was first isolated and studied already in 1900 (BRI. Carnosine. Biological significance and possible applications in medicine. M, 1998). Currently, natural dipeptide carnosine contained in skeletal muscle of humans and vertebrate animals characterized as an effective water-soluble antioxidant, immunomodulator and pH buffer used as antitumor agents, antihistamines, anti-stress, anti-ulcer, anticataract tool, have what it wound healing and antineoplastics action (RF, patent No. 2084457, From 07 To 5/062, 1997). Carnosine natural was first isolated from the aqueous suspension of ground beef planting ethyl alcohol (Gulewitsh WS Amiradzibi's Uber das Carnosin eine neue organische Base des Fleischxtraktes Ber Deutsch Chem Ges 1900, 33, 1902-1903). In clinical practice, as currently applied, both natural and synthetic carnosine and its homologues, in particular anserin. Synthetic carnosine currently produced by foreign firms, such as SERUA, SIGMA (Italy). However, as it is known from additional experimental studies as well as from existing information sources, synthetic histidinemia dipeptides and their mixtures due to the presence of side formed during the synthesis products have a relatively high toxicity, which limits their applicability (RF patent No. 2084457, From 07 To 5/062, 1997). In 1996, Russia had developed the industrial production of natural carnosine extraction from beef. The product obtained by this method, was entered in the Register of medicines of Russia No. 96/50/02. Natural carnosine is recognized as low-toxic compared to its synthetic counterparts. Its LD 50 was 21 g/kg of body weight. However, carnosine in the absence of adjuvants has a relatively low antioxidant activity, which limits its use as terap whitesage drug and that has led to the search for more active forms of this drug, for example, to the selection of mixes, including carnosine. Thus, the known composition used as a pharmaceutical or dietetic preparation containing carnosine and/or its derivatives, such as homocarnosine, anserine, origin and/or their pharmacologically acceptable salts and/or their acyl derivatives in mixture with amino acids branched structure, selected from the group leucine, isoleucine, valine, and optionally containing salts of organic and inorganic acids, such as carbonates, lactates, sulfates, magnesium gluconate, zinc, iron, and other additives, such as vitamins, flavonoids (EP patent No. 0825871, And 61 To 38/05, 2001). A known composition of carnosine and its homologues are 1-0 .5 wt.%, preferably 15-25 wt.% to the total weight of the whole mixture, and the mixture of three amino acids is 50-70 wt.%, moreover, leucine contained in a mixture of 20 wt.%. This composition is used as an oral medication in the form of tablets, capsules, liquid solutions. The composition is produced by mixing the components, their heat treatment and subsequent isolation. As the source of dipeptides in this part apply to synthetic products. Antioxidant efficacy of this drug was tested on laboratory animals change lipoperoxides in plasma is e blood, liver and found that carnosine in complex with branched amino acids reduces the content of peroxides by 35.5%. The dosage of this well-known drug depends on the nature and extent of the disease and is 0.1-500 mg/kg body weight. This composition is close to the composition and applications of the new tool and therefore selected as the prototype. A disadvantage of the known compositions of the prototype is its lack of effectiveness, which limits its scope.

In known publications contain information relating to the receipt of natural raw materials of compositions containing as amino acid complex, and histidinemia dipeptides. The use of natural raw protein is widely described for obtaining biologically active amino acid complexes by the method of enzymatic hydrolysis. As a feedstock for the production of well-known enzymatic protein hydrolysates are used, for example, saw the skins of mammals (RF patent No. 2068879, With 12 N 1/00, 1992), the internal organs of birds subjected to hydrolysis under the action of endogenous enzymes of the intestine of the bird in an alkaline environment (USSR, A.S. No. 878780, With 12 N 1/20, 1979), meat or raw meat and bone slaughtered animals, crushed and subjected to enzymatic hydrolysis at pH 6.5-7.8 for using protocolin GH and proteolitic the ski enzymes obtained from the pancreas of slaughtered animals (RF patent No. 2112397 And 23 J 1/10, 1998), the muscle tissue of cattle or pigs (USSR, A.S. No. 1025722, With 12 N 1/00, 1983). In the last cited source carefully shredded muscle tissue of cattle or pigs subjected to enzymatic hydrolysis in the presence of proteolytic enzymes, which use the pancreas of cattle or pigs or Pancreatin activity 45 UNITS. Upon completion of the hydrolysis when the depth component of 0.9 to 1.0, is the precipitation of high-molecular compounds in isoelectric point and subsequent filtration and drying of the drug. Get known dry enzymatic hydrolysate contains at least 18 amino acids, the total number of which is 63-69%. However, this complex does not contain carnosine with anserina, which is the main aim of the new invention. Enzymatic dry hydrolysate of proteins of the muscle of cattle or pigs was used to create a nutrient medium for growing cultures of cells and biological products. However, due to the fact that cattle are vulnerable to disease, so-called cow rabies, able, under certain conditions, be transmitted to man, recently limited the use of meat is rupnagar cattle and pigs for the pharmaceutical and food industries.

As mentioned above, carnosine and its homologues are used in combination with the antioxidant compositions, in particular cosmetic creams with therapeutic effect. For example, known from the composition of carnosine with arnitine and other effective additives used in the treatment and prevention of photo (PCT, patent No. 1175898, a 61 K 7/48, 2002), a cosmetic composition in the form of a cream that has anti-inflammatory effect and is used for skin prone to acne. The amount of carnosine in this cream is 0,0009-0,0011 wt.% (RF patent No. 2045949, a 61 K 7/48, 1995).

To extend the range of biologically active drugs with high efficacy and low toxicity, enzymatic method from the muscle tissue of chicken received the new composition of the biologically active complex containing carnosine and anserine in a mixture with other biologically active ingredients in the following weight parts relative to the content of carnosine with anserina: amino acids - 1-7 weight. parts, oligopeptides in number, constituting 0.5 to 12 weight. parts, and cyclic and polycyclic phenolic compounds in an amount of 0.1-15 weight. parts. Biologically active complex is in the form of extract or solid powder.

This biologically active carnosine-anseranatidae complex yields fermentation the m by hydrolysis of the muscle tissue of chicken, which after grinding and homogenization in water treated with proteolytic enzymes at pH 4.5-5.5 or 8.0, and 9.0 at a temperature of 45-65°using 2-5 wt.% enzyme relative to the protein content in the homogenate and subsequent cooling and filtration treatment. Thus homogenizing the feedstock is diluted with water, preferably in the range of ratios of 0.2-0.6. At the stage of enzymatic hydrolysis of dilute water homogenate was pre-heated at 45-65°C. Upon receipt of the product in powder form selected purified extract is additionally subjected to vacuum evaporation and/or spray or freeze drying.

Cosmetic composition containing a specified biologically active complex and cosmetically acceptable base, contains a complex of Bio Curator” effective amount, depending on the selected cosmetic forms (cream, emulsion, lotion, etc. (and other factors) destination, age of the client, etc.)

The resulting biologically active complex contains a blend of amino acids such as asparagine, tryptophan, serine, glutamine, Proline, glycine, alanine, cysteine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, hydroxylysine, lysine, histidine, arginine. A new tool, in contrast to the known composition of the prototype, contains always the mixture of two histidinemia of dipeptides (carnosine and anserine), as well as a wider range of amino acids, most importantly, additionally contains oligopeptides, as well as cyclic and polycyclic phenolic compound of indeterminate structure, providing a significant synergistic effect, which is manifested in the increased efficiency of the new complex, far exceeding the known preparations of similar action and composition. These properties of the new biologically active complex are created when a certain sequence of operations and compliance with certain modes in the process of getting it. For the study of the antioxidant effect of the obtained complex was applied method chemiluminescent analysis of peroxidation of lipoproteins of blood induced by iron. The essence of the method is that adding to the sample density of ions of bivalent iron is the induction of reactive oxygen species, causing a chain reaction of formation of free radicals, accompanied by fire chemiluminescence. The test results of antioxidant activity of new biologically active complex, depending on the concentration in the sample of biologically active substances are given in table 3. The final volume of the sample in the studies was 1.0 ml table 3 shows the test results, which are in the sample for comparison participated synthetic carnosine. The results indicate the high effectiveness of the new complex. Already adding samples of biologically active complex in the amount of 10 μl, showed a significant increase in the duration of the latent period and the decrease in the intensity of the main flash chemiluminescence /N/. For comparison, the effective concentration of carnosine and anserine when they are used in this model is 500 mm and above (Boldyrev A.A. - Carnosine and protection of tissues from oxidative stress. Moscow, 1999). Thus, we obtain a new method of preparation of the composition due to its effectiveness may be used in the pharmaceutical and cosmetic industries as a single drug or ingredient of the compositions, for example cosmetic compositions with antioxidant, UV-reflective activity.

Below are examples illustrating the new drug, and the method of its production and cosmetic formulations based on it.

Example 1.

Muscle tissue of chickens in the amount of 1 kg minced in a meat grinder and homogenized. The mixture of homogenate was diluted to 3 liters of purified water when diluted in the range of 0.3 and conduct water extraction at 45°C. thereafter separating the aqueous extract from the precipitate by filtration method, and protein compounds in the floor is when the extract is subjected to enzymatic hydrolysis at pH 5.5 using a proteolytic enzyme Flavourzime, used in the amount of 4 wt.% and at a temperature of 50°until the end of the rise of value of the amine nitrogen. After that, the extract is heated to inactivate the enzyme at 75°C for 30 minutes, then hold the cooling and removal of the precipitate formed, and the nozzle the liquid is filtered through depth filters. Get the product with the figures reported in tables 1-3.

Example 2.

Example 2 carried out analogously to example 1 using chicken breast, the process of water extraction is carried out with the use of 4 liters of water, and the enzymatic treatment is carried out at a temperature of 55°C and pH 8.5 using the same proteolytic enzyme in an amount of 5 wt.% from the protein content in the extract. The obtained product is characterized in tables 1-3.

Example 3

The process of extraction and hydrolysis carried out analogously to example 1. At the end of the extraction of the final product are concentrated to a final concentration of at least 10 wt.% and dried by spray drying at 100°C.

Example 4.

Muscle tissue in quantities of 1 kg of crushed and homogenized, and then the homogenate was mixed with purified water at a rate of 4 liters and placed in a reactor. Use comprehensive aminopterine the Protease enzyme “With” at pH 8.0 at a temperature of 50-55°With the number Mas.% from the protein content in the homogenate. Hydrolysis lead until the end of the rise of value of the amine nitrogen. The resulting product is characterized in tables 1-3.

Examples 5, 6. Medical cosmetics on the basis of the drug, Bio Curator” (discussed above biologically active complex).

In the cosmetically acceptable base, containing the following components, introducing an effective amount of an aqueous extract of the drug, Bio Curator”, mixed components to obtain a homogeneous mass and packaged. Below are examples of compositions on the basis of the drug, Bio Curator”. However, these examples in no way limit the possibility of creating other medical cosmetics on the basis of this medication.

Example 5. Sunscreen composition (wt.%):

Claret 25-2 .0, Claret 6 - 2.0, clearily alcohol - 3.0, ethylhexylacrylate - 5.0, benzophenone 3-1 .0, butylperoxybenzoate - 1.0, seturiresolver - 6.0, cocoglyceride - 2.0, glycerin - 5.0, carbomer - 0.3, triethanolamine - 0.4, tocopherol acetate - 0.5, glucan - 0.5, cyclomethicone - 1.5, Dimethicone - 0.5, methylparaben - 0.3, propylparaben - 0.2, Biocurator - 0.5 (in the form of a 7%aqueous solution), water - the rest to 100%.

Example 6. Anti-inflammatory balm composition (wt.%):

Phytosterin - 1.0, lipid complex - 2.0, propylparaben - 0.2. methylparaben - 0.3, glycerin - 5.0, allantoin - 0.2, carbomer - 0.4, triethanolamine - 0.5, Bio Curator” - 1.0 /in the form of a 5%aqueous solution, D-panthenol - 0.3, bisabolol - 0.3.

Below are tables showing the effectiveness of biologically active complex.

Table 1.

The content of carnosine and anserine a biologically active complex depending on the method of its production.
Name of indicatorExamples 1-2Example 4
Carnosine, mg/ml1.5-4.51.6-6.5
Anserin, mg/ml2.5-102.5-13.5

Table 2.

Physico-chemical characteristics of the biologically active complex depending on the method of its production.
Name of indicatorExamples 1-2Example 4
The content of dry substances in neopreno extract, % wt., not less than47
Mass fraction of total nitrogen, % wt., not less than2.64.7
Amine nitrogen, mg/ml, not less than1.63.5

Table 3.

Study the antioxidant activity of the biologically active complex for various examples.
OptionVolume, ál/sampleAnserin, ug/sampleCarnosine, ug/sampleThe gidroperekisi (h)% of controlThe latent period (τ), % of controlOxidizability (H)% of control
Example 1-2103.22.56012596
The composition of the sample: Carnosine: 2.45 mg/ml2586.255417585
Anserin: 3,19 mg/ml501612.55030087
Solids: 45.8 mg/ml For analysis, the sample was diluted 10-fold1003225.03332565
Example 410116.27012398
The composition of the sample: Carnosine: 6.2 mg/ml253015.563.514395
Ansari is: 11 mg/ml 5055At 33.755015491
Solids: 65.8 mg/ml For analysis, the sample was diluted 10-fold10011062.004918355
Without extractControl105±12, mV90±8, s1524±85, mV
Carnosine1 mM 2264016090
0.5 mM 1135214494
0.25 mM 56.55712595
0.1 mM 11.33696100

Table 4

The composition of drugs “BIOCURATOR” industrial designs
SampleDry (%)

70 mg/ml
Dipeptides (mg/ml) (Dunn the m HPLC) The balance of amino acids (mg/ml) (data obtained on the amino acid analyzer)The hardware efficiency of hydrolysis broth

(%)
AnserinCarnosineAmountFree IAfter complete hydrolysis II 
No. 17,21,4520,8072,25910,29and 36.8028
No. 27,41,7800,8202,615,0746,9031
No. 37,21,8450,7352,58to 28.5747,0444

According to amino acid analysis, we can conclude that the process hardware hydrolysis is not until the end: in the 1st and 2nd samples the degree of hydrolysis was 28 and 31%, respectively, in 3-em - 44%. The output of the dipeptides in the 2nd and 3rd samples are almost identical.

Table-5

The antioxidant activity of drugs “BIOCURATOR”
SampleThe dipeptides concentration in the samples (mm)Antioxidant act shall want to make
End-of Oia in the test sample (mm)Restoring a pair of charmed mesons (nmol/min)End-of Oia in the test sample (mm)The suppression of the accumulation of MDA (%)
AnserinCarnosineAmount
No. 16,023,579,590,191,760,9616,4±0,48
No. 27,383,63br11.010,221,711,126,8±0,88
No. 3the 7.653,25,10,90,223,191,0933,6±1,16
Carnosine20 mm  0,400,261,00%
   0,80,392,016,5±0,55

Antioxidant (AO) activity of preparations of BIOCURATOR was determined in two tests:

- The speed of recovery of stable radical diphenylpicrylhydrazyl [Schlesier, K., Harwat M,öhm V, Bitsch R. Assessment of antioxidant activity by using different in vitro methods // Free It. Res., 36, pp.177-187, (2002)]

On podavini the accumulation of MDA in the reaction induced by iron in peroxidation of lipoproteins in the serum of blood donors [Ohkawa H., Ohishi n, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction.//Anal Biochem, 95(10), 351-358 (1979)]

The results indicate that compared with carnosine drugs of BIOCURATOR provide greater JSC activity than one would expect based on the total content histidinemia of dipeptides (SRS). When included in the reaction system in a test restore of a pair of charmed mesons aliquot of drugs BIOCURATOR providing active concentration HSD to 0.19-0.22 mm. AO activity in 20-40 times higher than observed for carnosine. Given the fact that the used test reveals the antioxidant activity of compounds with certain hydrophobic properties, it can be assumed that the AO activity of the drug BIOCURATOR largely depends on the presence in their structure other (not SRS) antioxidants. This is indicated by the data obtained in the test for the suppression of the accumulation of MDA: in this test, drugs of BIOCURATOR 2-4 times higher than in their AO activity of carnosine.

1. Biologically active carnosine-anseranatidae complex, including amino acids, characterized in that it further contains oligopeptides and cyclic and polycyclic phenolic compounds and represents a complex of biologically active substances of natural origin, obtained by enzymatic guide what Alison muscle chicken, characterized as the weight ratio of the components of the mixture weight. including:

Carnosine and anserine 1

Amino acids 1-7

The oligopeptides of 0.5-12

Cyclic and polycyclic

phenolic compounds is 0.1-1

2. Biologically active complex according to claim 1, characterized in that it is made in the form of an aqueous extract or powdered solid product.

3. Biologically active complex according to claims 1 and 2, characterized in that it is part of the externally-cosmetic remedies.

4. The method of obtaining biologically active carnosine-anseranatidae complex, characterized in that the feedstock used crushed gomogenizirovannogo muscle chicken, which is subjected to enzymatic hydrolysis, followed by cooling and filtration purification allocated to the final product, after grinding and homogenization, the homogenate was diluted with water and treated with proteolytic enzymes operating at pH 4.5-5.5 or 8.0-9.0 and a temperature of 45-65°and used in a quantity amounting to 2-5 wt.% from the protein content in the homogenate.

5. The method according to claim 4, characterized in that the crushed homogenized feedstock is diluted with water preferably in the range of relation equal to 0,2-0,6.

6. The method according to claim 4, characterized those who, before stage enzymatic hydrolysis diluted with water and the homogenate was heated at 45-65°and subjected to filtration treatment.

7. The method according to any of claims 4 to 6, characterized in that upon receipt of the product in powder form selected purified extract is additionally subjected to vacuum evaporation and/or spray or freeze drying.



 

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10 cl, 70 ex

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: organic chemistry, medicine.

SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.

EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to medicine, infectious diseases and can be used for the treatment of brucellosis

The invention relates to medicine, infectious diseases and can be used for the treatment of brucellosis

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

The invention relates to medicine, in particular to chemotherapy of metastatic brain lesions
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