Apoctalyptic and/or their salts with acids or bases, or their internal salt synthesis method, pharmaceutical composition

 

(57) Abstract:

Apoctalyptic formula I, where W is a residue of formula (a) ; R6and R9is hydrogen, R7and R8is hydrogen or chlorine; R10the hydroxy - group; Z is a residue of formula (b); Y is a carboxyl group or its derivative lowest Olkiluoto ether; R, R1and R2is hydrogen; or their salts with acids or bases, or their inner salts. The compounds of formula I can be used as active ingredients for antimicrobial drugs used in medicine and veterinary medicine for the prevention and treatment of infectious diseases caused by pathogenic bacteria. 3 S. and 6 C.p. f-crystals, 2 PL.

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The present invention relates to synthetic apoctalyptic General formula /I/:

< / BR>
where W and Z, each independently, represents the corresponding part of the aglycone of antibiotic deliberating group /apoctalyptic/; Y represents a carboxyl group or a functional derivative specified carboxyl group;

R and R1each independently represents hydrogen;

R2represents hydrogen.

The present invention includes salts of the above-mentioned representatives of glucogel of the invention is a method for apoctalyptic antibiotics of the formula /I/, presented earlier, from tetrapeptides formula (II):

< / BR>
where: W and Z each independently represents a relevant part of aglycone antibiotic deliberating group /apoctalyptic/;

Y represents a carboxyl group or a functional derivative specified carboxyl group;

R3and R4each independently represents amino or a protected amino group; and

R5represents hydrogen.

Tetrapeptide General formula (II) above, and their salts and method of receiving presents in the international publication of the application N 09210517. The above-mentioned international application also contains a comprehensive description of naturally occurring deliberately antibiotics and their classification into four subgroups, referred to respectively as deliberately type ristocetin, type vancomycin, type avoparcin and type sermonizing.

Pentapeptidnogo precursors suitable for the above tetrapeptide, disclosed in European patent publication N 409045.

The term deliberately usually refer to all substances antibiotics that contain General strongly modified linear heptapeptide structure consisting of Stora is a determinant common mechanism of action, i.e. specific complexitiy with D-alanyl-D-alanine end of one or more of the intermediate compounds in the synthesis of cell walls, which leads to the destruction of cells /see also: F. Parenti and B. Cavalleri, "Novel glycopeptide antibiotics of the dalboheptide group, Drugs of the future V. 15/1/: 57-72/1990/ u B. Cavalleri., F. Parenti: Cyclopeptides (dalbaheptides)" in Kirk-Othmer's Eucyclopedia of Chemical Technology, V. 2, 995-1018, G. Whiley and Sons. 1992/.

In accordance with a preferred variant of the present invention synthetic apoctalyptic formula /1/ presented earlier, contain such derivatives, which has the following values:

< / BR>
< / BR>
where i/ A is hydrogen or a protective group of a phenolic hydroxyl fragment; R6, R7and R8, each independently, represent hydrogen or halogen, where the halogen preferably is chlorine or bromine, and most preferably, they were in anthopology relative to the ether linkages; R9and R10, each independently, represent hydrogen or a group OR15where R15represents hydrogen or a protective group is benzyl hydroxyl fragment.

As can be seen from the formula /I/, presented earlier, simultaneously connected with the second, fourth and sixth amino acid /sciacchitano, are, respectively, the pair - and ortobalagang in relation to communication, connecting the two phenyl rings, and the radical R11and R12each independently represents hydrogen or a protective group of a phenolic hydroxyflavone; group OR13preferably, is in anthopology in relation to communication, connecting the two phenyl rings and the radical R12represents hydrogen or a protective group of a phenolic hydroxyflavone; R14preferably located in the meta position with respect to the link connecting the two phenyl ring and represents hydrogen or halogen, preferably hydrogen or chlorine.

As represented by formula (I) previously, the group Z is linked to the amino acids corresponding to the fifth and seventh amino acid /counting from the right/ fragments heptapeptide chain apoctalyptic.

Enclosed in a circle the numbers in the aromatic rings indicate the corresponding amino acids apoctalyptic chains, which are attached to specific aryl or kalkilya fragments.

The symbol Y in the formula /I/ represents a hydroxyl group, its functional derivative, preferably an ester. Such derivatives of esters is performance communications group in specific conditions, if which is not affected amino acid chain. These definitions include derivatives of the lower esters, and esters formed during the interaction of the carboxyl function with aliphatic alcohols containing substituents (for example, hydroxy, halogen, lower alkoxy, amino, lower alkylamino, di/lower alkyl/amino/, cyano and phenyl, optionally substituted lower alkyl, lower alkoxy, halogen or nitro/ in the aliphatic chain.

The term "functional derivative of a carboxyl group" includes carboxamide fragments, which are described in international published application N 092/10517, where the symbol Y tetrapeptides starting material of formula (II) is illustrated in more detail. These carboxamidine fragments are functional derivatives formed by the interaction of the carboxyl group of aliphatic, cycloaliphatic and heterocyclic amines. In particular, among the aliphatic amines, the preferred lower alkylamines followed and di-lower-alkylamines followed, which may not necessarily be the Deputy on the aliphatic chain as amino, lower alkylamino, d/lower alkylamino/, pyrrolidino, piperidino, N/a lower alkyl alkyl/carbarnoyl, etc.; among the cycloaliphatic amines preferred C4-C7cycloaliphatic primary amines; among the preferred heterocyclic amines, saturated, nitrogen-containing, 5-7-membered heterocyclic fragments, for example, pyrrolidine, morpholine, piperazine and N-/lower alkyl/piperazine.

Salt of the target compounds of formula (I) and the starting compounds of the formula (II) are salts obtained by reaction with acids major groups of molecules, for example, aminomalonate other and/or NR1R2.

Representatives salts accession acids are salts, which are formed in reactions with inorganic and organic acids, such as hydrochloric, sulfuric, phosphoric, succinic, citric, lactic, maleic, fumaric, holeva, o-glutamic, camphoric, putarias, phthalic, tartaric, methansulfonate, benzosulfimide, benzoic, salicylic, triperoxonane acid, etc. In another embodiment, the salt can be formed by forming a salt of the carboxylic acid group represented by the symbol A, with such appropriate base, such as, for example, the hydroxide or carbonate of an alkali metal, or such an organic amine as mono-, d is kadalbajoo formula I are those salts, which are obtained when the inner salt formation when simultaneously present main /for example, amino/ acid and /for example, carboxyl functional groups sufficient power in a single connection.

In the above formula (I) and other relevant formulas in this description and in the claims chiral center of each of the five major aryl - and arylmethyl-amino apoctalyptic has the same absolute configuration as the configuration of the corresponding amino acids in the natural dalbeattie, from which was obtained the source material /II/.

Chiral centers, which are apoctalyptic of the present invention in the synthesis marked with indices 3 and 15, respectively, in the formula above, /I/ and can be either in R or S absolute configuration, depending on the absolute configuration of the amino acids, which include in the molecule.

However, in accordance with a preferred variant of the present invention introduce chiral center indicated by the index 3, is S-configuration, whereas the configuration of the chiral center marked with index 15, can be both R and S, but more preferably, R configuratie contains derivatives of the formula /Ia/.

< / BR>
where Y represents a carboxyl group or a derivative of the lower Olkiluoto of ester specified carboxyl group;

R and R1each independently represents hydrogen or a group protecting the amino function, preferably, hydrogen;

R2represents hydrogen;

R6represents hydrogen;

R7and R8each independently represents hydrogen or chlorine;

R9represents hydrogen or hydroxy; preferably, hydrogen;

R10represents hydrogen or hydroxy; and

their salts with acids and bases, preferably their salts with pharmaceutically acceptable acids and bases, as well as their internal salt.

In accordance with the present invention is a method of obtaining apoctalyptic antibiotics of formula (I) are in accordance with reaction scheme 1.

In scheme 1 the reaction of the characters W and Z have the same values as before, whereas the term "options. derived carboxy" relating to the symbol Y indicates that this symbol represents the functional derivative of the carboxyl group, as described previously, including protected carboxyl group, protected which can be removed at the end of the process.

Parapeted /TP/ formula /IIa/ to obtain the TP formula /IIb/.

Specified selective protection can be realized, for example, protecting first the more reactive amino group denoted by the symbol R3in TP formula /IIa/, then, by protecting the amino group denoted by the symbol R4protective group of the other type, which is not cleaved under the conditions required for the subsequent removal of the protection of the amino group represented by the symbol R3.

This latter operation results in connection TP /IIb/, where R4represents a protected amino group, and R3is a free amino group that can react with the selected derived amino acids, i.e., N-protected phenylalanine to obtain Pentapeptide /PP/ in accordance with the stage of a /b/ schema reaction. This stage is completed by removing the N-protecting group of N-protected phenylalanine precursor that leads to the production of PP formulas /III/.

The implementation of the above reaction at the stage of /b/ includes implementation of such reaction conditions, when the presence of the free carboxyl group in position Y has a negative impact on the course of the reaction. Therefore, it is preferable to use this TP derived /IIb/, where Y is the functional derivative of the specified CT is whether the use of the condensation conditions for a combination of N-protected phenylalanine with TP /IIb/ obtaining PP /III/.

For similar reasons, preferably, protected carboxyl group represented by the symbol Y, and also at the subsequent stages, including the education of other peptide bonds.

When carrying out the above reaction stages, as well as the subsequent reactions it is not necessary to ensure the protection of phenol or benzyl carboxylic groups, which may be in parts of the W and Z, TP and PP. However, if these protecting groups present in the original TP formula (II), as obtained in accordance with the international published application WO 92/10517, they can persist for all subsequent reactions and can optionally be split at the end of the whole process, if you get apoctalyptic /Ib/ or /Ic/.

The next stage /c/ includes intramolecular condensation of free amino PP /III/ and carboxyl fragment COOR5where R5represents hydrogen. Also in this case, the reaction course can have a negative impact of the presence of free carboxyl group in position Y PP. Indeed, such an additional carboxyl group can participate in reactions intramolecular condensation with free aminogroup protect such carboxyl groups, as noted previously. Stage /c/ includes the removal of protection for the amino group represented by the symbol R4for intermediate Hexapeptide /HP/ formula /IV/.

The next stage /d/ includes attaching the second amino acid by condensation with NN--protected lysine derivative, to obtain the derived apoctalyptic /Ib/, which, at a subsequent stage /e/ may be subjected to removal of the N-protective group of the lysine of the fragment. Optionally, if Y is easily tsepliaeva protective carboxypropyl, the protection can be removed from the specified protected carboxypropyl that will result in getting apoctalyptic /Ic/, where Y represents a carboxyl group.

The following description provides a more detailed description of each stage of implementation of the method described above.

Stage /and/:

The main point of this stage of /a/ is the selection of a reagent suitable for introducing a protective group of the primary AMINOPHENYL primarily reacts with the amino group represented by the symbol R3formula /IIa/.

In respect of this desirable effect, it was found that satisfactory is found N-protective group.

This reagent is subjected to interaction /in Approximately equimolar ratio/ s TP formula /IIa/ solution consisting of a mixture of water and inert and miscible with water, an organic solvent, preferably chosen from lower alcohols, acetone, tetrahydrofuran, dioxane and dimethoxyethane, at a temperature of from -5 to 20oC, preferably from 0oup to 10oC, at pH 6 to 8, preferably from 6.5 to 7.5.

The ratio of water and organic solvent varies in the range from 1: 9 to 9:1, and preferably from 4:6 to 6:4.

Target product formula /IIa/, where R3represents tert.-butoxycarbonylamino /all other symbols have the same values as indicated in the reaction scheme 1/, usually get together with a small amount of by-product formula /IIa/, where both R3and R4represent tert.-butoxycarbonylamino fragments.

By-product can be easily separated from the target monoamino product, for example, extragere acidic aqueous mixture containing both products, water-immiscible solvent.

Selected by-product can be turned into an unprotected source material by acid hydrolysis /aprimitive with di-tert.-BUTYLCARBAMATE in the above conditions. If necessary, the process of regenerating a by-product after the reaction in di-tert. -BUTYLCARBAMATE can be repeated twice or three times to obtain a high yield of the desired mono-protected product.

Then the mono-protected product is introduced into the following intermediate process to protect the free amino group represented by the symbol R4, a protective group which is not cleaved under conditions of acid treatment, which is required to remove tert-butoxycarbonyl group. Reagents that can be used to achieve the desired effect, you can choose from those that form the urethane derivative.

Examples of such reagents and the appropriate conditions of the reactions described, for example, in the book T. W. Creene and P. GM.Wuts: "Protectike Croups in Organic Synthesis" Slcoud edition, J. Wiley, N. Y., 1991 /see the pages 315-348/.

Accordingly, the following protective groups are most suitable for protection of an amino group denoted by the symbol R4in TP formula /IIb/: 9-fertilitycare, 9-/2-sulfo/fertilitycare, 9-/2,7-di-bromo/fertilitycare, 2,7-decret. -butyl/9-10,10-dioxo-thioxanthene//methoxycarbonyl, 1,1-dimethyl-2,2-dibromoethenyl, 1,1-dimethyl-2,2,2-trichlorocyanuric, benzyloxycarbonyl and 4-methylsulfonylbenzoyl.

In accordance with a preferred variant of the present invention benzyloxycarbonyl radical is used as a protective group aminophenol, represented by the radical R4formula /IIa/. For this purpose, the above-mentioned mono-protected TP formula /IIa/, where R3represents tert.-butoxycarbonylamino fragment is subjected to interaction with a suitable reagent capable of introducing benzyloxycarbonyloxy group in aminophenol, for example, benzylchloride, in the presence of an excess of a mild base, e.g. sodium bicarbonate, potassium bicarbonate or three/lower alkyl/Amin.

The reagent providing the N-protecting group generally used in equimolar amounts with respect to TP. However, in some cases it may be necessary to use a number slightly higher than the molar equivalent of /up to 20% of such reagent to complete the reaction.

The reaction is usually carried out in the presence of a solvent, preferably consisting of a mixture of water and miscible with water and inert organic solvent, such as those listed previously for the introduction of tert-butoxycarbonyl fragment. The reaction temperature maintained within the interval on the way, put then acid treatment, suitable for the selective removal of tert.-butoxycarbonyl group.

Such processing includes, for example, in the implementation of the interaction of di-protected TP with excess dry triperoxonane acid at a temperature of from 5 to 30oC for 5-25 minutes.

TP formula /IIb/, where R4is oxcarbazepine fragment /all other symbols have the same values that are indicated in the reaction scheme 1/ distinguish then from the reaction medium known per e professionals ways.

Stage /Ib/: This stage consists in the implementation of the interaction of N-protected TP formula /IIb/ with a suitable derivative of phenylalanine. This derivative must be protected on the amino group, and should contain the group, carboxyl activating fragment, for promotion of the condensation process. Protective group aminomalonate in phenylalanine must be different from the protective groups R4part of the TP, as it should be removed at the next stage in conditions that do not affect R4part.

The solution to this problem is to use a group forming a carbamate, which was used at the previous step /a/. Therefore, tert.-butoxide the

The activated group of N-protected carboxyl group of phenylalanine can be selected from groups that form a conventional activated ester fragments.

Examples of activated esters are those that are described as amino acid esters for the reactions of peptide combinations in the book by L. F. Fieser and M. Fieser, "Reagent for organic Synthesis", J. Wiley, New York.

Reagents, which activated esters, which can be used to activate the carboxyl function of the N-protected phenylalanine described, for example, R. Schwyser et al. in Helv. Chim. Acta., 1955, 38, 69-70, and include the following:

ClCH2CN, BrCH2COOC2H5, BrCH/COOC2H5/2, ClCH2COCH3,

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Other groups, carboxyl activating a function of N-protected phenylalanine, which can be used in the method of the present invention are esters of the carboxylic hydroxyl group of the following compounds given in the end of the description ( as specified I. Iones in The Chemical Synthesis of Peptides", pp. 55-58, Clarendon Press-Oxford /1991/).

In accordance with one preferred variant of the present invention an ester of N-protected phenylalanine with N-hydroxysuccinimide is used for react the education of polypeptides. Usually two reagent are contacted in Approximately equimolar amounts of/ in the presence of an Approximately equimolar amount of an organic tertiary amine, for example, three-/lower alkyl/Amin, if the amino group, R3in the connection /IIb/ is in the form of salt accession acid in an organic solvent at a temperature from 5 to 35oC, preferably from 15 to 25oC. inert Organic solvent is generally chosen from organic amides (for example, dimethylformamide/, polyesters (for example, dimethoxyethane/, cyclic ethers (for example, tetrahydrofuran (THF)/, the lower aliphatic esters (for example, ethyl acetate and dimethyl sulfoxide. The preferred solvent is dimethylformamide.

Di-protected PP derived, which participates in the following the condensation reaction, the process then under conditions promoting cleavage of the N-protected amino phenylalanine residue instead of an N-protected amino group, R4, resulting in a gain PP formula /III/. In that case, if the amino group of phenylalanine protected due to the formation of tert.-BUTYLCARBAMATE, a R4is benzyloxycarbonylamino, preferred treatment basically this is the relevant TP.

Stage /c/:

Mono-protected PP /III/, formed in the previous reaction, is subjected to intramolecular condensation to obtain a peptide bond between the free amino group of phenylalanine fragment and a carboxyl group COOR5where R5represents hydrogen.

Intramolecular condensation, obviously, occurs only in well-defined conditions, with the choice of a suitable condensing agent, solvents, proportions of reactants and temperature. Intramolecular reaction occurs due to the activation of the carboxyl group COOR5PP formula /III/ due to the interaction of N-hydroxybenzotriazole in the presence of dicyclohexylcarbodiimide. Conditions for formation of the activated carboxypropanoyl PP require that before the interaction with N-hydroxybenzotriazole was obtained Sol carboxypropyl COOR5with such an organic tertiary amine as diethylamine, N-organic N-methylpiperazine or N-methylmorpholine. PP, organic amine and N-hydroxybenzotriazole use Approximately equimolar amounts, whereas dicyclohexylcarbodiimide use 10-20% molar excess. The reaction, preferably, are in a mixture of solvents, somervale from 10 to 35oC for a sufficient period of time to complete intramolecular condensation. The necessary time can be determined in the course of the reaction using conventional analytical systems that include TLC and HPLC.

The solid product isolated from this reaction can be purified by chromatographic column with reversed phase, for example, on silica gel using a linear gradient from 10 to 70% acetonitrile in water, and controlling the collected fractions by HPLC. The fractions containing pure N-protected HP unite, and, after concentration, the product periostat, adding a solvent in which the product is insoluble /for example, diethyl ether/. Inorganic impurities that may be present in the precipitated product can be removed by adding the product to the sulfoxide, filtering the suspension and lyophilize transparent filtrate.

Then N-protected HP turn in HP connection formula /IV/, removing the protective group aminomalonate designated as the radical R4. Specified protective group can be deleted using the methods proposed in the literature relating to the previously mentioned N-protective groups. If the N-protecting group AMINOPHENYL designated as Raut catalytic hydrogenation at atmospheric pressure and room temperature in the presence of an organic solvent or mixture of organic solvents and preferably aqueous mineral acid for example, 1H. HCl/. In this case, HP formula /IV/ allocate from the filtered hydrogenated solution in the form of a salt with the specified mineral acid.

Stage /d/:

HP formula /IV/ stage /c/ condense with NLNE- protected lysine derivative, activated at the carboxyl group. As for the N-protected and activated carboxyl group of lysine using the same reagents as for N-carboxy-activation of phenylalanine at the stage of /b/. Reaction conditions and the overall proportions of the reagents, as well as the allocation method is almost the same as in the previously mentioned case.

As a result of this condensation receive apoctalyptic formula /Ib/, in which each of the two amino groups of lysine side has an N-protective group.

Stage /e/:

This stage is designed to remove the two protective groups apoctalyptic /Ib/. This deletion does not occur any problems. In particular, if such an N-protective groups are tert.-butoxycarbonyl fragments, deletion carry virtually the same processing triperoxonane acid, as described for removal of the tert.-butoxycarbonyl fragment phenylalanine part of the PP obtained at the stage of /c/. Alttok the evaporated solution triperoxonane acid treated with an aqueous alkaline solution at a pH of 8.5. The free base apoctalyptic can be further purified by chromatographic column with reversed phase, using almost the same technique and conditions that at the stage of /c/ to clear HP formula /IV/.

Apoctalyptic formula /Ic/, if Y represents a protected carboxyl function, if desired, can be converted to the corresponding derivative of the free hydroxy, removing the protective group.

For example, if a protected carboxyl group is an ester of a lower alcohol, hydrolysis of such a complex ester can be conducted, suspending the product in tetrahydrofuran and adding a molar excess /10-50%/ 1N NaOH at room temperature. The above conditions do not affect other parts of the molecule.

If the Deputy Y apoctalyptic /Ic/ is the functional derivative of the carboxylic group, which is not easily cleaved under mild conditions, this function is left unmodified in the end the connection, but it is still part of the present invention.

If apoctalyptic /Ic/ as Deputy Y carboxyl group, it can be converted into a derived apoctalyptic formula /Ic/, where Y predno earlier. Methods for such functional derivatives of the corresponding svobodnokonvektivnye connection is described in detail in the literature about deliberation. In particular, see the following patent applications: EPA publication 216775, 340245, 370283, 376041, 351685, 460448 and international patent publication WO 93/0360. In particular the present embodiment, the above reaction scheme 1, TP formula /IIa/ obtained from glucoseinsulin used as source material. The specified TP has the following structural formula:

NN< / BR>
and in the subsequent description of the figures as methyl ester ATTP. For clarity and better understanding of the Examples that follow this description, in the above formula, the nitrogen atoms of two different amino groups are indicated by letters B and A, respectively.

In accordance with the multistage process described earlier, and using the appropriate protected amino acids L-phenylalanine and D-lysine stages of /b/ and /d/, respectively, was obtained the following compound corresponding to the General formula /Ic/:

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in which the chiral centers marked with indices 3 and 15 are, respectively, S and R absolute configuration.

To be identified as the NB-reserved-/L-i.e. phenylalanyl/3-ATPP methyl ester and /L-i.e. phenylalanyl/3methyl ester, respectively.

The above compound can be named /L-i.e. phenylalanyl/3-/D-lysyl/15-allocateandinitializesid methyl ether complex [/L-i.e. phenylalanyl/3-/D-lysyl/15-ATDN methyl ether complex, where figures 3 and 15 show that the amino acid fragments containing the carbon atoms 3 and 15 in glucoseinsulin main skeleton in accordance with the classification of A. Malabaroa et.al.J. Antibiotics 42, 1684-1697 /1989/ replaced by L-phenylalanine and D-lysine fragment, respectively. The absolute configuration of the chiral centers marked by figures 3 and 15, is S and R, respectively, as mentioned previously.

This compound shows significant antimicrobial activity in vitro experiments, as can be seen from table 1, in which the comparative compounds used teicoplanin and teicoplanin.

In vitro antibacterial activity of compounds is determined using standard test dilution agar in microtitre. For all bacteria except Streptococcu /Todd-Wewitt broth, Difco/ and enterococci /Mueller-Hintou, Difco/ use Yso-Seusites bulal/ colony forming units per ml = colony forming units per ml. All microrasbora broth MIC is carried out in the presence of 0.01% bovine serum albumin /Pentax fraction Y. Sigma/. MIC/ minimum inhibitory concentration is the lowest concentration at which there is visible growth after incubation at 37oC for 18-24 hours.

The above synthetically obtained apoctalyptic, while maintaining almost the same level of activity as teicoplanin, against most bacteria, which are usually sensitive to deliberation, unexpectedly is also active against clinical isolates Enterococcus faecalis , which is as resistant to teicoplanin and teicoplanin.

Using the method of the present invention, and selecting as a starting material other TP compounds that can be obtained in accordance with the international patent publication WO 92/10517, you can get a number of synthetic apoctalyptic formula /I/.

Moreover, the compounds of formula (I) with different configurations C3and C15can be obtained using phenylalanine and lysine /source materials/ with the corresponding chirality. If use of racemic materials amino acids, receive a mixture GeoStereo is regienov antimicrobial used in medicine and veterinary medicine for the prevention and treatment of infectious diseases caused by pathogenic bacteria that are exposed to these active ingredients, in particular for the treatment of diseases caused by strains of Streptococci, Susceptible and Enterococci, including Enterococci faecalis strains resistant to teicoplanin, and the antibiotics that are currently used for the treatment of serious infectious diseases.

Compounds of the present invention it is possible to introduce oral, topical or parenteral, preferably parenteral method of administration.

Depending on the method of administration, these compounds can be prepared in various dosage forms.

Preparations for oral administration may be in the form of capsules, tablets, liquid solutions or suspensions. As known in the art, capsules and tablets may contain in addition to the active ingredient, such conventional excipients, as diluents, e.g. lactose, calcium phosphate, sorbitol, etc. ; lubricating agents, e.g. magnesium stearate, talc, polyethylene glycol; binding agents, for example, polyvinylpyrrolidone, gelatin, sorbitol, tragakant, acacia; flavoring agents and acceptable is NSI, may contain such conventional additives as suspendresume agents.

For local application of the compounds of the present invention can also be obtained in suitable forms for absorption through mucous membrane tissues of the nose, throat or bronchial tubes, and typically may be in the form of liquid sprays or drugs for inhalation or for lubricating the throat.

For the treatment of eyes or ears, these drugs can be presented in liquid or semi-liquid form. Preparations for local application can be prepared in hydrophobic or hydrophilic bases as ointments, creams, lotions, suspensions, or powders.

For rectal injection of the compounds of the present invention prepared in the form of suppositories in a mixture with conventional carriers, such as, for example, cocoa butter, beeswax, spermaceti or glycols and their derivatives.

Compositions for injection may take the form of suspensions, solutions or emulsions in oily or aqueous carriers, and may contain such composite agents, as suspendida, stabilizing and/or dispersing agents.

In another embodiment, the active ingredient may be in the form of powder to mix it before applying for pisit on various factors, such as weight and condition of the subject to treatment of a patient, the method and frequency of administration, and the cause of the disease.

Compounds of the present invention is usually effective in doses of from about 1 to about 40 mg of active ingredient per 1 kg of body weight.

Depending on the characteristics of the specific connection, infection and patient effective dose can be administered as a single dose once a day, or 2-4 times a day, dividing this dose into pieces. The most preferred compositions, which are prepared in the form of a unit dose containing from about 30 to about 500 mg of the compound per dose.

Example 1. Obtaining methyl ether complex NB-benzyloxycarbonyl-glycomacropeptide /NB-CBZ-ATTP methyl ether complex; the reaction scheme 1, formula /IIb/

i/ Obtain methyl ether complex NA-tert-butoxycarbonylmethylene /NA-tert.-BOC-ATTP methyl ether complex/

Stir a solution of 3 g (about 3 mmol/ ATTP methyl ether complex /synthesis of this compound is described in international publication WO 92/10517/ 100 ml of a mixture of dioxane:water 1:1 was adjusted to pH 7 by adding NaHCO3. Then was added dropwise a solution of 0.65 g /about 3 mmol/ di-tert.-butylcarbamoyl, and then poured into 400 ml of a mixture water:ethyl acetate 1:1.

After adjusting the pH to 3 with 1N HCl: a/ the organic layer emit, washed with water /3 x 100 ml, dried over sodium sulfate, and then concentrated at 30oC under reduced pressure to small volume (about 25 ml /. After adding diethyl ether /100 ml/ solid precipitate is collected, gaining 1.4 g by-product of NANBdi/tert.-BOC/-ATTP methyl ether complex /HPLC: method A, tR25.2 minutes/;

b/ aqueous phase is extracted with an equal volume of butanol and the butanol layer concentrated at 40oC under reduced pressure to small volume (about 30 ml/. After adding 100 ml of diethyl ether the solid precipitate is collected, obtaining 1.5 g of NA-tert.-BOC-ATTP methyl ether complex (table 2, compound 1; HPLC: method A, and 16.4 minutes/.

The above di-protected by-product of NANBdi/tert.-BOC/-ATTP methyl ester /1.4 g/ handle 50 ml triperoxonane acid at room temperature /10 min/ regeneration ATTP methyl ether complex /1,15 g/, which is then transformed into a 0.7 g of NA-tert.-BOC-ATTP methyl ester and 0.5 g of the above by-product in the same conditions. Repeating this process hat about 80%.

ii/ get the NA-tert-butoxycarbonyl-NB- benzyloxycarbonylglycine-tetrapeptide methyl ether complex -/NA-tert-BOC-NB-CBZ-ATTP methyl ester/.

To a stirred solution of 2.35 g /about 2.3 mmole/ NA-tert-BOC-ATTP methyl complex ester in 100 ml of a mixture of dioxane:water 1:1, the pH of which was adjusted to 7 with solid sodium bicarbonate, was added dropwise a solution of 0.32 ml /about 2.3 mmole/ benzylchloride in 10 ml of dioxane at room temperature for 10 minutes. The reaction mixture was stirred at room temperature for 20 minutes and then poured into 150 ml of water. The obtained turbid solution was adjusted to pH by the addition of 1N HCl, and extracted with 200 ml of ethyl acetate. Allocate the organic layer, dried over sodium sulfate, and then concentrated at 30oC under reduced pressure to small volume (about 20 ml/. Adding diethyl ether /100 ml/ precipitation, which is collected, obtaining 2.4 g of NA-tert. -BOC-NB-CBZ-ATTP methyl ester (table 2, compound 2; HPLC: method B, tR11.8 minutes/.

iii/ Receive NB-CBZ-ATTP methyl ether complex

A solution of NA-tert.-BOC-NB-CBZ-ATTP methyl ether complex /2.4 g/ 100 ml of dry triperoxonane KIS is under reduced pressure. The oily residue is dissolved in 300 ml of a mixture water:ethyl acetate 1:1. The organic layer emit, washed twice with water /2 x 150 ml, dried over sodium sulfate, and then concentrated at 40oC under reduced pressure to small volume (about 15 ml/. Adding 100 ml of diethyl ether the solid precipitate is collected to obtain 2 g of NB-CBZ-ATTP methyl ether complex as trifenatate /table 2, compound 3, the analytical data for the free base; HPLC, method B tR8.3 minutes/.

Example 2. Obtaining methyl ether complex NB-benzyloxycarbonyl-/L-i.e. phenylalanyl/3- glycomacropeptide NB-CBZ-/L-i.e. phenylalanyl/3-ATPP methyl ether complex; the reaction scheme 1, formula /III//

i/ Obtain methyl ether complex NB-benzyloxycarbonyl- /N-tert. -butoxycarbonyl-L-i.e. phenylalanyl/3-glucoseinsulin - Pentapeptide /NB-CBZ-/N-tert.-BOC-L-i.e. phenylalanyl/3-ATPP methyl ether complex/.

To a stirred solution of 1 g /about 0.9 mmol/ NB-CBZ-ATTP methyl ether complex of triptoreline in 20 ml of dimethylformamide, add at room temperature of 0.13 ml /about 0.9 mmole/ triethylamine, and then 0.34 g /about 0.9 Molnia at room temperature add 100 ml of water, and the pH of the resulting solution adjusted to 3 by addition of 1N HCl. In the extraction of n-butanol /100 ml and evaporation of the organic layer obtain 0.9 g of NB-CBZ-/N-tert.-BOC-L-i.e. phenylalanyl/3-ATPP methyl ether complex (table 2, compound 4; HPLC: Method B, tR14.9 minutes/;

ii/ Getting /NB-CBZ-/L-i.e. phenylalanyl/3-ATTP methyl ether complex

A solution of NB-CBZ-N-tert.-BOC-L-i.e. phenylalanyl/3-ATPP methyl ether complex /220 mg/ 10 ml dry triperoxonane acid is stirred at room temperature for 15 minutes and then the solvent is evaporated at 30oWith under reduced pressure. Oily residue is suspended in diethyl ether to obtain 200 mg of NB-CBZ-/L-i.e. phenylalanyl/3-ATPP methyl ether complex as trifenatate /table 2, compound 5, analytical data for the free base; HPLC, Method B, tR10.2 minutes/.

Example 3. Obtaining methyl ether complex /L-i.e. phenylalanyl/3-glucosaminilmuramilpentapeptide /L-i.e. phenylalanyl/3-ATHP methyl ether complex; the reaction scheme 1, formula /IV//.

Obtaining methyl ether complex NB-benzyloxycarbonyl- /L-i.e. phenylalanyl/3-glycotechnology solution of 0.4 g /about 0,34 mmole/ NB-CBZ-/L-i.e. phenylalanyl/3-ATPP methyl ether complex in 40 ml of a mixture of dimethylformamide: dichloromethane 1: 1 add 0,047 g /about 0,34 mmole/ N-hydroxybenzotriazole and 0,038 ml /about 0,34 mmole/ N-methylmorpholine at room temperature, and then of 0.085 g /about 0.4 mmole/ dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature overnight and then the solvent is dichloromethane is evaporated at 30oC under reduced pressure. Then add the mix /200 ml/ water:ethyl acetate 1:1 is added dropwise with stirring, the pH of the resulting mixture was adjusted to 3 by addition of 1N HCl and the insoluble part is filtered off. Allocate the organic layer, and the solvent is evaporated at 35oC under reduced pressure. The solid residue is dissolved in 50 ml of a mixture water:acetonitrile:n-butanol 1:1:2 and with stirring, add 5 g silanizing /Silanized/ silica gel 60 /0.06 to 0.2 mm, Merck/. After 30 minutes the solvent is evaporated at 45oC under reduced pressure and the solid residue is placed in a column with 35 g of the same silanizing silica gel in water. Column show a linear gradient from 10 to 70% acetonitrile in water for 15 hours at a flow rate of 100 ml/h, resulting collect 10 ml fractions, which contrast equal volume of n-butanol. The resulting solution was concentrated at 40oC under reduced pressure to small volume (about 10 ml/, and then add 100 ml of diethyl ether. Precipitated precipitated solid portion is collected and added to 20 ml of dimethylsulfoxide. The resulting suspension is filtered and the clear filtrate lyophilizer getting 0.11 g of pure NB-CBZ-/L-i.e. phenylalanyl/3-ATHP methyl ether complex (table 2, compound 6; HPLC: method B, tR22,6 minutes/.

Data1H-NMR spectrum / ml/ for protons below /identification of the proton carried out in accordance with article J. C. J. Barna et al. J. Am. Chem. Soc. 1984, 106, 4895-4902/: 8,69 /w5/, 8,65 /w7/, scored 8.38 /w4/, 7,87 /6b/, of 7.70 /w3/, 7,45 /w2/, 6,60 /w6/, 6,44 /7d/, 6,23 /4b/, 6,10 /7f/, 5.82 /x4/, 5,40 /4f/, 5,13 /z6/, EQUAL TO 4.97 /CBZ-CH2/, 4,60 /x2/, 4,60 /x5/, 4,54 /x7/, 4,25 /x3/, 4,24 /x6/, 3,71 /COO-CH3/, 2,85, 2,72 /z2, z2'/, 2,43, 2,25 /Phe-CH2/.

ii/ Get /L-i.e. phenylalanyl/3-ATHP methyl ether complex

A solution of 1.8 g /about 1.5 mmole/ NB-CBZ-/L-i.e. phenylalanyl/3- ATHP methyl complex ester in 120 ml of a mixture methanol:1N HCl:dimethylformamide 6:2:1 hydronaut /1 ATM. , 25oC in the presence of 1.5 g of 5% Pd/C. the Catalyst is filtered off and the methanol steam is l of ethyl acetate. The organic layer is poured, and the resulting aqueous suspension is extracted with 130 ml of n-butanol. Botanology phase is isolated and concentrated at 30oWith under reduced pressure to a volume of about 20 ml. After adding 150 ml of diethyl ether precipitated precipitated solid part of the collect, and receive 0.65 g /L, i.e. phenylalanyl/3-ATHP methyl ether complex as hydrochloride /HPLC: method B, tR17,5 minutes, the titer of about 75%/, which is used in the next stage without additional purification.

Example 4. Obtaining methyl ether complex /L-i.e. phenylalanyl/3-/D-lysyl/15allocateandinitializesid[/L-i.e. phenylalanyl/3- /D-lysyl/15-ATDH methyl ether complex; the reaction scheme 1 formula /lc/].

i/ Obtain methyl ether complex /L-i.e. phenylalanyl/3- tert.-butoxycarbonyl/-D-lysyl/15-allocateandinitializesid [/L-i.e. phenylalanyl/3-(NNdi) /tert.-/BOC-D-lysyl/15-ATDH methyl ether complex/].

To a stirred solution of 0.29 g of crude /L-i.e. phenylalanyl/3-ATHP methyl ester hydrochloride is added at room temperature, 3 ml of dimethylformamide, of 0.07 ml of triethylamine and 0,19 g of ester -(NNoWith under reduced pressure to small volume (about 3 ml/. After adding diethyl ether /30 ml/ fallen precipitated solid part of collecting, receiving 0.27 g /L, i.e. phenylalanyl/3-[NNdi/tert. - /BOC-D-lysyl/15-ATDN methyl ether complex /HPLC: method B, tR22.5 minutes, the titer of about 45%/. The compound is used without further purification in the final stage.

ii/ Get /L-i.e. phenylalanyl/3-/D-lysyl/15-AND methyl ether complex.

Crude /L-i.e. phenylalanyl/3-[NNdi/tert. - /BOC-D-lysyl/15-ATDN methyl ester /0.27 g/ dissolved in 10oC in 5 ml of dry triperoxonane acid. After 10 minutes the solvent is evaporated under 15oC under reduced pressure. The oily residue is dissolved in 30 ml of a mixture methanol: water 1: 1 and the pH of the resulting solution adjusted to 3 by addition of 1N HCl; then it is introduced into the column with 50 g silanizing silica gel.UP>B-CBZ-/L-i.e. phenylalanyl/3-ATHP methyl ether complex in Example 3, resulting in a gain of 0.05 g of pure specified in the title compound in the form of triptoreline. The product is then dissolved in 1 ml of water and pH was adjusted to 8.5 by addition of 1N HCl. The solid precipitate is collected and washed with water /2 x 2 ml/ receiving specified in the title compound as free base.

/Table 2, compound 7, HPLC, method B, tRof 18.3 minutes/.

These NMR1H / MD/ for protons are next /triptorelin/: 1,28, 1,45, 1,68, 2,93 /Lys-CH2/, 3,71/COO-CH3/, 4,14-5,34 /peptide alpha-CH /x1-x7, 4,14 MD attributed to X1and 5,34 MD - x4/, 6,64-8,59 /aromatic protons and peptidic NH/.

Analytical techniques

1/ HPLC Methods

The reaction solutions, eluate and the final products are checked by HPLC on a column LiChroCART /125 x 4 mm, Merck/ pre-filled LiChrospher RP /5 μm/ using liquid chromatography pump Varian model 5500 equipped with a 20 µl looped injector Rheodyne model 7125 and UV detector with variable wavelength. Chromatogram recorded at 254 nm. Elution is carried out at a flow rate of 1.5 ml/min, mixing eluent a: 0.2% aqueous ammonium formate with eluent /b/: acetonitrile, in accordance % /b/ s /a/: 5 23 26 35 75 5

Method B:

Time /minutes/ 0 30 35 40 45

% /b/ /a/: 20 60 75 75 20

2/ Acid-base titration

Acid-base titration is carried out in the following conditions: the sample is dissolved in a mixture of methyl cellulose: water 4:1, then add an excess of 0.01 M HCl in the same solvent mixture, and the resulting solution titrate with 0.01 n NaOH.

3/1H-NMR

Spectra1H-NMR spectrum recorded in DMSO solution-d6at 303 K /30oC/ spectrometer Bruker AM 500, equipped with a computer Aspect 3000 using /CH3/4Si /W, 0,00 MD/ as an internal standard.

4/ FAB-MS /Mass spectrum by fast atom bombardment/

FAB-MS positive ion spectra get mass spectrometer Kratos MS-50 double focusing mass interval 3000 daltons, using an accelerating voltage of 8 kV. The device works under the control of the computer. To obtain results with high accuracy using the data system DS-90 in the "raw data" collections (collection of raw data). For FAB use of atomic cannon with saddle-type field with gas Xe /210-5Torr = 2,6710-3N/m2pressure indicators on the ion source when a voltage of 6 kV and a current of 1 mA. The sample is dissolved in a mixture of methanol:water 1:1, containing 0.2 n HCl, or, in another in the but containing 1N acetic acid at a target.

Example 5.

Obtaining internal salts.

Obtain (L-i.e. phenylalanyl)3(D-lysyl)15-ATDN (Compound 8) by saponification of the ester methyl group.

To a stirred suspension of 120 mg (0.1 mmol) of compound 7 (table 2), in the form of a free base, in 3 ml of tetrahydrofuran, added dropwise a solution of 0.5 ml of 1N sodium hydroxide in 1.5 ml of H2O at room temperature for 5 minutes. After stirring the mixture at room temperature for 15 minutes, add 10 ml of n-butyl alcohol, the pH of the mixture was adjusted to 3.5 1N HCl, and then the solvent is evaporated at 45oC under reduced pressure. The solid residue is dissolved in 2 ml of H2O and the pH of the resulting solution was adjusted to 7.25 0.1 N NaOH. The precipitated solid product is collected by filtration, washed with 1 ml of H2O and then dried at room temperature under vacuum over night. Obtain 77 mg of pure compound indicated in the title, in the form of internal salts.

GHUR, Method B, tR14.7 minutes.

Data1H-NMR spectrum confirm the absence of methyl ester groups (no signal on Delta 3.71 ppm).

The internal structure of salt (no PA and Cl, neorganic the ri 800oC in oxygen atmosphere) 0.1%;

analysis on the content of Cl in %: calculated 6.10 found 6.05.

Example 6.

Getting acidic - and basic-additive salts and pharmaceutically-acceptable salts.

6.1 Obtaining the acid additive salts (General method).

The compound of formula I in free base or inner salts can be converted into the corresponding acid additive salt suspendirovanie or by dissolving it in an aqueous solvent and adding a slight molar excess of the desired acid. The resulting solution or suspension further lyophilized to highlight the target of an acid additive salt.

In some cases, instead of lyophilization perhaps the selection of the final salt precipitation her when adding a solvent immiscible with water. When the final salt is not soluble in an organic solvent in which the free base or inner salt is soluble, the final salt can be isolated by filtration from the organic solution mesolevel form after adding a stoichiometric amount or a slight molar excess of the required acid.

6.2. Obtain hydrochloride of compound 7.

With the .25 ml). Formed a clear solution, which lyophilized to obtain compound 7 (0.1 mmol) as hydrochloride. Analysis on the content of Cl in %: calculated 11.35 found 11.43.

Similarly, the salts with Hydrobromic, sulfuric, phosphoric, acetic, triperoxonane, ascorbic and salicylic acids.

6.3. Obtaining major additive salts.

6.4. Obtaining the sodium salt of compound 8.

Compound 8 in the form of an internal salt (0.1 mmol) dissolved in a mixture (10 ml) methanol/water (8/2 V/V), then add 1N NaOH (0.1 ml) under stirring at room temperature. After adding 5 ml of n-butyl alcohol, the solvent is evaporated at 45oC under reduced pressure, obtaining the target compound 8 in the form of sodium salt (0.1 mmol, the solid residue after evaporation of the solvent). The salt formation is confirmed by acid-base titration with hydrochloric acid (3 equivalents of HCl required to complete the titration one COO-and two NH2groups). In a similar manner were prepared the other major additive salt.

Example 7. The preparative form.

The compound of the formula I can be formulated for parenteral (intravenous, subcutaneous or vnutr">

The composition for injection, the composition containing the compound 7, is prepared by dissolving 10 mg of compound 7 in the form of dihydrochloride in 1 ml of distilled, not containing heavy hydrogen water. After ultrasonic add about 30 ml of dimethyl sulfoxide and the pH of the resulting solution was adjusted to 5.2 0.1 N potassium hydroxide. The osmotic pressure of the resulting solution close to the osmotic pressure of physiological solution of 1% NaCl in water.

Composition for injection containing other compounds of the present invention is prepared in the same way.

7.2 example of a formulation for oral administration.

The composition for oral administration, the composition B containing compound 7, is prepared by suspendirovanie 150 mg of compound 7 in the form of the free base in 10 ml of purified water. Then, under stirring, add 5 ml of 90% ethanol, followed by addition of 90% (weight/weight) solution of lactic acid in water to obtain a transparent end solution with a pH of 4.0. Formulation for oral administration containing other compounds of the present invention obtained in the same way.

Example 8. The toxicity study of compound 7 in mice.

Toxicity 150 mg/kg of composition B. No signs of toxicity nor immediately after injection or at the end of two weeks was observed.

1. Apoctalyptic General formula I:

< / BR>
where W

< / BR>
where R6and R9each independently represents hydrogen;

R7and R8each independently represents a hydrogen or chlorine;

R10represents a hydroxy-group;

Z represents a

< / BR>
Y represents a carboxyl group or its derivative lowest Olkiluoto ether; R, R1and R2each independently represents hydrogen;

and/or their salts with acids or bases, or their internal salt.

2. Apoctalyptic General formula I under item 1, in which the absolute configuration of the chiral center indicated by the numeral 3, is S-configuration, and the absolute configuration of the chiral center indicated by the numeral 15, is R - or S-configuration, preferably, the R-configuration.

3. The method of producing apoctalyptic General formula I on p. 1, or their salts with acids or bases, or their internal salts, which includes:

a) condensation of tetrapeptide formula II (b)

< / BR>
where W and Z have the above meanings;
R4represents a protected amino group;

R5represents hydrogen;

with N-protected derivative of phenylalanine, and then removing the protection of the amino group of phenylalanine part of the received Pentapeptide, obtaining Pentapeptide formula III:

< / BR>
where W, Z, Y, R4and R5specified above;

b) intramolecular condensation of Pentapeptide formula III, and then remove protection from protected amino group, R4derived Hexapeptide with obtaining a Hexapeptide of the formula IV:

< / BR>
where W, Z, Y described above;

R4represents NH2;

C) condensation of the Hexapeptide of formula IV with the derived NN-protected lysine, and then removing the protection of the amino groups of lysine side received apoctalyptic with getting apoctalyptic General formula (Ic)

< / BR>
where W and Z described above;

Y represents a functional derivative of a carboxyl group;

R, R1and R2each independently represents hydrogen;

g) if necessary, remove protection from easily degradable protected carboxyl group Y to obtain the corresponding carboxypropanoyl;

d) in the case neobhodimosti phenyl or benzyl hydroxy-group;

e) if necessary, converting the free compounds of formula Ic or its corresponding internal salts in its salts with acids and/or bases.

4. The method according to p. 3, characterized in that stage a) N-protected derivative of phenylalanine is a derivative of L-phenylalanine, and on stage) NN- protected lysine derivative is a derivative of D-lysine.

5. The method according to any of the p. 3 or 4, characterized in that the N-protective group derived phenylalanine is removed under conditions that do not affect the N-protective group of the protected amino group, R4.

6. The method according to any of paragraphs.3-5, characterized in that the N-protective group derived phenylalanine is tert.-butoxycarbonylamino, and N-protective group of the protected amino group, R4is benzyloxycarbonylamino.

7. The method according to any of paragraphs.3-6, wherein the N-protected derivative of phenylalanine and NN-protected lysine derivative activated carboxyl function groups suitable for the formation of peptide bonds.

8. The method according to p. 7, characterized in that the group, carboxyl activating function, t is a mini-composition, having antimicrobial activity, comprising the active agent and excipients, characterized in that as the active agent it contains apoctalyptic formula I under item 1 in an effective amount.

 

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