Pharmaceutical echinocandine preparations containing micelle- forming surface-active agents

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

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to pharmaceutical prescription mixtures containing the compound echinocandin, including, in particular, micelle-forming surfactants, to enhance their stability and water solubility.

The LEVEL of TECHNOLOGY

Parenteral (ip) mixture of prescription pharmaceutical drugs can be administered to the patient intramuscularly (im), intravenous (iv) or subcutaneously. Create a mixture of prescription for a given drug depends on the specific problem. In the art, for example, it is well known that any prescription, the mixture must be soluble and stable. Lyophilized prescription the mixture should have the ability to form properly hardened layer of sediment and easily recreated (usually less than one minute). Ultimately, prescription mixture must have an acceptable appearance and to contain officially recognized safe fillers.

Stability is an essential characteristic of the generated prescription mixes, especially for parenteral use. In practice, prescription mixture should be maintained for at least two years. So often prescription mixture, it is desirable to liofilizirovanny to about the ensure greater shelf life and better shelf life at room temperature.

Instability and poor solubility (<0.1 mg/ml) of compounds echinocandin makes them particularly difficult to prepare a mixture of prescription. The majority of prescription compounds tested to date, has a shelf life of less than one year. In General, the shelf life should be two years or more. Therefore, to achieve the required stability of the prescription, the mixture containing the compound echinocandin, you must liofilizirovanny.

Poor solubility of the compounds echinocandin creates an additional challenge when creating a prescription mixtures containing active echinocandin. One way of obtaining such compounds is the addition of a surfactant that enhances the solubility of this drug. However, in the art it is recognized that the use of a certain concentration of surfactant, as a rule, restricts the ability of the drug to liofilizirovanny. Typical lyophilized prescription mixture has a concentration of surfactants less than 5 wt.%. Market research lyophilised pharmaceutical RX mixtures containing surfactant, it was found that the concentration of the surfactant is in the dried product, ka is the rule, less than 5 wt.%. See Carpenter et al., Pharm. Res., 14(8), 969-975, 1977-1997, Physicians' Desk Reference, 50thedition, Medical Economics Co. NJ (1996). It is considered that prescription mixture with a higher concentration of surfactant is unlikely to form a dried product with the desired characteristics. That is, the presence of surfactants causes the deformation of the" freeze-dried sediment layer (cake)obtained at the bottom of the vial (bottle), instead of properly hardened layer. This residue, as a rule, less stable, difficult to recreate and not reproducible.

Due to the poor water solubility of the compounds echinocandin to obtain an acceptable concentration of the compound echinocandin in solution typically requires 2-4% (weight to volume) surfactant. As noted above, when the content of surface-active substances liofilizirovannye difficult. There is therefore a need for prescription of the mixture, which improves the solubility of the compounds echinocandin in the water, and at the same time, allows lyophilization to obtain optimum stability.

The INVENTION

Applicants have found a group of surface-active substances, which solubilizers connection echinocandin at high concentrations and, oddly enough, retain the ability to lyophilization of the appropriate prescription the mixture. In the first embodiment of the present invention was created parenteral pharmaceutical prescription mixture that includes (i) a connection echinocandin (or its pharmaceutically acceptable salt), (ii) pharmaceutically acceptable micelle-forming surfactant (e.g., Polysorbate, lecithin, bile salts, polyoxyethylene castor oil and mixtures thereof), and (iii) non-toxic, water solvent. The solution prescription pharmaceutical optional mixture contains one or more stabilizing agents, toning agent and/or buffer. The mass ratio echinocandin to surfactant is about 1:1.75 to 1:25 (the most preferred ratio is from about 1:2 to about 1:3), and the connection echinocandin present in an amount of greater than or equal to 1 mg/ml of the Appropriate surface-active substance, usually present in excess of 1 wt.% on the volume.

In one embodiment, the present invention is created lyophilized prescription pharmaceutical composition includes (i) a connection echinocandin (or its pharmaceutically acceptable salt), (ii) a pharmaceutically acceptable, micelle-forming surfactant (e.g., Polysorbate, lecithin, bile salts, polyoxyethyl the new castor oil, and mixtures thereof), and (iii) volumetric filler. Micelle-forming surfactant is present in excess in the dried product 5 wt.%, and the ratio echinocandin and surfactant is about 1:1.75 to 1:25 (preferably a ratio from about 1:2 to about 1:3). This lyophilized pharmaceutical prescription optional mixture may contain one or more stabilizing agents and/or buffer. Created as a parenteral pharmaceutical prescription mixture obtained from lyophilized form.

In another embodiment of the present invention, a method of receiving parenteral prescription mixture, which comprises mixing the compound echinocandin (or complex echinocandin/carbohydrate) and pharmaceutically acceptable micelle-forming surfactants in aqueous solvent.

In another embodiment, the present invention developed a method of creating a lyophilized mixture of prescription, including the following order of steps: (i) dissolving in an aqueous solvent compounds echinocandin (or complex echinocandin/carbohydrate) in the presence of a pharmaceutically acceptable micelle-forming surfactants, in which this surface-activeelement in quantities exceeding 1 wt.% volume; (ii) sterile filtration of this solution; (iii) the lyophilization of this solution. In most cases, volumetric filler is added to the resulting solution before lyophilization. Optional front of stage (iii) you can add one or more buffers, stabilizing agents, toning agents, or a combination thereof.

Developed alternative getting dried prescription of a mixture that includes (i) tebufelone non-toxic aqueous solution to a pH between 4.0 and 5.0 s receive buffer solution; (ii) adding a buffered solution pharmaceutically acceptable micelle-forming surfactant; (iii) cooling the solution from step (ii) to a temperature between 5°and 15°With (preferably between 7°and 10° (C) obtaining a cooled solution; (iv) adding to the resulting cooled solution suspension including connection echinocandin or complex echinocandin/carbohydrate and second non-toxic aqueous solvent; (v) sterile filtering the specified solution from step (iv); and (vi) lyophilization of the specified solution from step (v). Before carrying out stage (v) optional can be added one or more bulk agents, stabilizing agents and/or toning agents.

In another embodiment, the infusion is his invention has developed a parenteral pharmaceutical product, which is obtained by dissolving in an aqueous solvent compounds echinocandin (or complex echinocandin/carbohydrate) in the presence of a pharmaceutically acceptable, micelle-forming surfactant with obtaining a solution in which this surface-active substance is present in quantities exceeding 1 wt.% volume; (ii) sterilizing by filtration of the resulting solution; and (iii) the lyophilization of this solution in the ampoule, in which the mass ratio echinocandin and surfactant is about 1:1.75 to 1:25. Before using this vial is poured non-toxic aqueous solution.

In another embodiment, the present invention has developed a method for the treatment of antifungal infection in a mammal in need of it, which includes the introduction of this mammal the above parenteral prescription mixture or parenteral prescription mixture obtained by adding a pharmaceutically acceptable aqueous solvent to one of the above lyophilized mixture of prescription.

The number and percentages given here in the form of mass units, unless specified otherwise.

The term "echinocandin" refers to compounds having the following General structure:

where R is the Wallpaper alkyl group, alkenylphenol group, alkylamino group, aryl group, heteroaryl group, or combinations thereof; R1, R2, R3, R6, R7and R10independently represent hydroxy or hydrogen; R4represents hydrogen, methyl or-CH2C(O)NH2; R5and R11independently represent methyl or hydrogen; R8represents-OH, -ORO3H2, ORO3HCH3, ORO2HCH3or S3N; a R9represents-H, -HE, or S3N.

The term "alkyl" refers to hydrocarbon radical of General formula CnH2n+1containing from 1 to 30 carbon atoms, unless otherwise specified. Alkanoyl radical may be unbranched, branched, cyclic, or multicyclones. This alkanoyl radical may be substituted or unsubstituted. Similarly, the alkyl portion of alkoxygroup or alkanoate have the same meaning as defined above.

The term "alkenyl" refers to an acyclic hydrocarbon containing at least one carbon-carbon double bond. Allenby radical may be unbranched, branched, cyclic or multicyclones. This Allenby radical may be substituted or unsubstituted.

The term "quinil" refers to an acyclic hydrocarbon containing at the ore, one triple carbon-carbon bond. Alkyne moiety may be unbranched or branched. This alkyne moiety may be substituted or unsubstituted.

The term "aryl" refers to aromatic components having a single (e.g., phenyl or a condensed ring system (e.g., naphthalene, anthracene, phenantrene etc). Aryl groups can be substituted or unsubstituted. Substituted aryl groups include chain aromatic components (e.g., biphenylene, terranella, vinylnaphthalene etc).

The term "heteroaryl" refers to aromatic components containing at least one heteroatom in the aromatic ring system (e.g., pyrrole, pyridine, indole, thiophene, furan, benzofuranol, imidazole, pyrimidine, purine, benzimidazole, quinoline and the like). This aromatic component may consist of one or condensed ring system. Heteroaryl groups can be substituted or unsubstituted.

In organic chemistry, particularly in organic biochemistry usually means that a significant substitution of compounds Pets or even is useful. In the present invention, for example, the term alkyl group allows substitution, which represent the classical the ski alkyl, such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, hexyl, isooctyl, dodecyl, stearyl etc. the Term group, in particular, implies and allows substitution for alcelam that are common in the art, such as hydroxy, halogen, alkoxy, carbonyl, keto, ester, carbamate, etc. and also includes unsubstituted alkyl part. However, experts in this field it is clear that alternates should be selected so as not to adversely impact on the pharmacological characteristics of the connection or to prevent the use of drugs. Suitable substituents for any of the above groups include alkyl, alkenyl, quinil, aryl, halogen, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, mono - and dialkylamino, Quaternary ammonium salts, aminoethoxy, hydroxyethylamino, aminoalkylation, carbamyl, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, and combinations thereof.

"Complex echinocandin/carbohydrate" refers to a crystalline complex comprising echinocandins and carbohydrate during recrystallization echinocandin of the solvent in the presence of carbohydrate. A more detailed description of complexes echinocandin/carbohydrate can be found in the publication Larew, et al., filed March 3, 1999, entitled "Echinocandin/Carbohydrate Complexes."

"Carbohydrate" refers to the aldehyde or economy derivative of polyhydric alcohols with the formula C n(H2O)n(e.g., glucose, C6(H2O)6; sucrose, C12(H2O)n). Carbohydrates include compounds with relatively small molecules such as simple sugars (e.g., monosaccharides, disaccharides, and so on)and macromolecular (polymer) substances such as starch, glycogen, and cellulose are polysaccharides. Sugars and their simple derivatives are carbohydrates (sugars), having the General structure (CH2O)n. Although simple Monomeric sugar (glucose) is described as polyoxyalkylene or ketones, e.g., HOCH2(SNON)4-NSS for aldohexose (e.g., glucose) or NON2(SNON)3-CO-CH2IT is for 2-ketosis (e.g., fructose), their structure, usually represented in the form of five- (furanose) or six- (pyranose) membered ring cyclic ether, e.g.

The term "micelle-forming surfactant" refers to an amphiphilic substance which spontaneously and reversibly forms a water-soluble unit. A more detailed description of the formation of micelles and the list of micelle-forming surfactants look at Attwood. et al. Surfactant Systems. Their Chemistry, Pharmacy and Biology, Chapman and Hall (1983). Block copolymers of propylene oxide and ethylene oxide not established themselves well in obtaining prescription mixtures nastojasih the invention; therefore, these block copolymers are not considered as micelle-forming surfactants.

The term "pharmaceutically acceptable"is used here as an adjective, is essentially non-toxic and mostly not harmful to a specific recipient.

DETAILED description of the INVENTION

Cyclic peptides used in the present invention, can be obtained by culturing various microorganisms. Suitable natural product source materials relating to the family of cyclic peptide echinocandin includes echinocandin, echinocandin With, echinocandin D, Culiacan Andγ, mountainmen, sporophores And pneumocandin A0, WF11899A and pneumocandin0. Most of the cyclic peptides may be characterized as a cyclic Hexapeptide kernel with acylated amino group of one amino acid. The amino naturally meet cyclic peptide usually alleroed fatty acid group forming a side chain of the core. Examples of naturally meet acyl groups include linoleoyl (echinocandin b, C and D), Palmitoyl (aculeates Andγ and WF11899A), stearoyl, 12-metalmeister (mountainin), 10,12-dimethyluracil (sporophores and pneumocandin And0) and the like.

Semi-synthetic production is s can be obtained by removal of the fatty acid side chain of the cyclic peptide nucleus, which forms a free amino group (i.e. an additional acyl group-C(O)R is missing). Then this free amine reallyread a suitable acyl group. For example, the core echinocandin In reallyread some of which are not found in nature, parts of the side chain, which creates a number of antifungal agents. See U.S. Patent No. 4293489. Specialists in the art it is obvious that the N-acyl side chain includes a number of components of the side chain, are known in the art. The corresponding components of the side chain include substituted and unsubstituted alkyl groups, alkeline group, alkyline groups, aryl groups, heteroaryl groups, and combinations thereof. Preferably, this side chain contains a rigid annular part and a flexible alkyl part, which increases up to a limit antifungal effectiveness. Representative examples of preferred acyl side chains include R-groups with the following structures:

where a, b, C and D independently represent hydrogen, C1-C12alkyl, C2-C12quinil, C1-C12alkoxy, C1-C12alkylthio, halogen, or-O-(CH2)m-[O-(CH2)n]p-O-(C1-C12alkyl), or-O-(CH2)q-X-E; m is 2, 3 or 4; n is 2, 3 or 4; a is 0 or 1; q is 2, 3 or 4; X represents pyrrolidino, piperidino or piperazine derivatives; and E represents hydrogen, C1-C12alkyl, C3-C12cycloalkyl, benzyl or3-C12cycloalkylation.

As noted above, the described cyclic peptides can be obtained by fermentation of known microorganisms, which are described in the art. Subsequent diallylamine usually done enzymatically using enzyme deacylase using known materials and method described in this technical field.

For example, U.S. Patent No. 3293482 describes diallylamine and obtain a cyclic peptide of formula I, where R4, R5and R11represent methyl. R9represents hydrogen, a R1, R2, R6, R7, R8and R10each represents hydroxy. U.S. patent No. 4299763 describes diallylamine and obtain a cyclic peptide of formula I, where R4, R5and R11represent methyl, R2represents hydroxy, R7and R9represent hydrogen, a R1, R3, R6, R8and R10each represents hydroxy. U.S. patent No. 3978210 describes obtaining aculeata. U.S. patent No. 4304716 describes diallylamine and obtain a cyclic peptide of formula I, where R 5represents-CH2C(O)NH2; R11represents methyl; R4and R9represent hydrogen; R1, R2, R3, R6, R7, R8and R10each represents a hydroxy, acyl group with the substituent R represents myristoyl.

Cyclic peptides, where R2and R7each represents a hydroxy, can be obtained as a result of exposure to the corresponding connection (where R2and R7each represents hydroxy; alpha-amino group of ornithine may be a free amino group or be acylated) a strong acid and a reducing agent in an appropriate solvent at a temperature between -5°s and 70°C. Suitable strong acids include trichloroacetic acid, triperoxonane acid or athirat of boron TRIFLUORIDE. The preferred strong acid is triperoxonane acid. Suitable reducing agents include Lamborghini sodium or triethylsilane. Preferred regenerating agent is triethylsilane. Suitable solvents include methylene chloride, chloroform or acetic acid, preferably methylene chloride. A strong acid is present in an amount of from 2 to 60 mol per mole of substrate, and the reducing agent is present in amounts which the firmness of from about 2 to 60 mol per mol of substrate. The process of acid recovery selectively removes amine (R2) and benzyl (R7) hydroxy-group.

The acylation α-amino group of ornithine can be made in various ways well known to specialists in this field of technology. For example, the specified amino group can be allievate in the reaction with substituted accordingly acyl halide, preferably in the presence of an acid acceptor such as a tertiary amine (e.g., the triethylamine). Usually the reaction is carried out at a temperature of between approximately -20°and 25°C. Appropriate reaction solvents include polar aprotic solvents, such as dioxane or dimethylformamide. The choice of solvent is not essential, because the solvent is inert to the ongoing reaction and the reactants enough solubilization for carrying out the desired reaction.

The amino group can also be allievate in the reaction with substituted accordingly carboxylic acid in the presence of a binding agent. Appropriate linking agents include dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole, bis(2-oxo-3-oxazolidinyl)fatfingered (THIEF-CL), N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), benzotriazol-1 iloxi-tripyridyltriazine (Rubor) and similar

Alternative amino group can be allerban complex activated ester of carboxylic acid, such as para-nitrophenyl (NOWT. H2O), 2,4,5-trichlorophenyl, hydroxybenzotriazole hydrate, pentafluorophenol, and complex carboxylate esters of N-hydroxysuccinimide. Preferred allerease components are 2,4,5-trichlorophenyl and complex carboxylate esters of NOWT. The reaction usually lasts for 1-65 hours at a temperature of from about 0°With 30°in an aprotic solvent. Typically, the reaction ends after approximately 24-48 hours through at a temperature of between about 15°s and 30°C. Appropriate solvents include tetrahydrofuran and dimethylformamide or mixtures thereof. In most cases, the amino group present in equimolar proportions with respect to activated ether or with a slight excess of an amino group.

Acid precursor R-COOH obtained by hydrolysis of the nitrile of the formula R-CN, or a complex ester of the formula R-COO - (C1-C4alkyl). Intermediate products of the nitrile and ether complex can be obtained using methods known in the art. For example, the intermediate products of the nitrile and ether complex, in which R represents alkoxyaryl component, can be obtained using Method a or IU the ode Century

Method A. One equivalent of allylbromide, iodide, or para-toluensulfonate added to a mixture containing one equivalent of base, such as tert-piperonyl potassium or potash (K2CO3), and one equivalent hidroxiaril connection in 200-300 ml of acetonitrile (CN3CN). This reaction mixture was refluxed for 6 h, and then concentrated under negative pressure to obtain residue, which was dissolved in a mixture of Et2O/2N NaOH. The resulting layers are separated and the organic layer is dried over magnesium sulfate (gS4), filtered and dried to obtain alkoxyaryl product.

Method Century. Diethylazodicarboxylate (1 EQ.) added dropwise to the mixture containing hydroxyaryl compound (1 EQ.), alkilany alcohol (1 EQ.) and triphenylphosphine (1 EQ.) in 200-300 ml of THF. After 17 h at negative pressure to remove the solvent to obtain a residue, which was dissolved in Et2O. the resulting mixture was washed with a solution of 2N NaOH, dried over gSO4filter and concentrate getting the product, which is then crystallized from a mixture of Et2O/pentane or, if this product contains tertiary amine, hydrochloric get salt and crystallized from methanol mixture (Meon)/EtOAc. Intermediate products of the nitrile and ether complex, in which R represents alkynylaryl responsibility of the Yu can be obtained using Method C.

Method C. a Mixture containing Et2O (2 equiv.) dichloride palladium is 0.05 equiv.) triphenylphosphine (0.1 equiv.) iodide copper (0,025 EQ.) and alkyne (1 equiv.) add under nitrogen (N2) to one equivalent of arilbred, iodide, or triftoratsetata in CH3CN (600 ml/0.1 mol of aryl reagent). The resulting mixture was refluxed for 11 h, and then at a negative pressure to remove the solvent to obtain a residue, which is a suspension in 300 ml of Et2O, and then filtered. The obtained filtrate washed with 1N HCl, dried over MgSO4, filtered and then dried to obtain the desired product. Essential intermediates in which R represents terminilogy component can be obtained using the Method of D.

Method R.

1. Getting reagent boric acid

To one equivalent to a cooled (-78° (C) halodrol in THF add utility (1.2 equivalent). After 15 minutes add triisopropylsilyl (2 equiv.). After 10 minutes, this reaction mixture is heated to room temperature and cooled rapidly by addition of water (H2O) followed by addition of 1N HCl. The resulting layers are separated and the organic layer concentrated under negative pressure to obtain solid, which is collected by filtration, and dried using hexane.

2. Received the e terpentinovogo ether

In a mixture containing airborne acid (1 EQ.), To2CO3(1.5 EQ.) and methyl 4-iodobenzoate (1 EQ.) (or trichloranisole ether of iodobenzoate) in toluene blown N2add tetrakis(triphenylphosphine)palladium (0.03 EQ.). The reaction mixture is refluxed for 7 h and then decanted to remove To2CO3and dried at a negative pressure to obtain a residue. The residue is triturated in CH3CN and filtered to obtain the desired product. The above aryl NITRILES and esters can be converted by hydrolysis into the corresponding carboxylic acid using Method E or Method F.

The way that Urinary dissolved in ethanol (EtOH) and in excess of 50%NaOH solution and refluxed for 2 hours In this reaction mixture was added water to obtain a precipitate solids. This solid is collected by filtration, add a mixture of dioxane/6N Hcl and the resulting mixture is refluxed for 17 hours After practical completion of the reaction the resulting product carboxylic acid is crystallized by adding H2O, and then collected by filtration and dried under negative pressure.

Method f complex atilovomu ether in the Meon poured the excess 2N NaOH and the resulting solution is boiled with bratim fridge for 5 h, and then acidified by adding an excess of Hcl. To the obtained reaction mixture, water is added until precipitation of a solid residue (carboxylic acid). Collect by filtration carboxylic acid and dried at a negative pressure. Carboxylic acids can be converted into the corresponding complex 2,4,5-trichlorophenolate esters using the following Method G. Activated esters are used then for the acylation of an amine of the center.

Method G. compound containing Alloway carboxylic acid (1 EQ.), 2,4,5-trichlorophenol (1 EQ.) and DCC (1 equiv.) in CH2Cl2stirred for 17 h and then filtered. The resulting filtrate is concentrated to obtain residue, which was dissolved in Et2O, filtered, and then add pentane until the beginning of crystallization. The crystals are collected by filtration and dried under negative pressure. Alternatively, using the method of N obtained carboxylic acid can be activated by converting it into the corresponding complex hydroxybenzotriazole ether.

Way N. Alloway carboxylic acid (1 EQ.) and a slight excess of N-methylsulfonyl substituted hydroxybenzotriazole (1.2 EQ.) enter into the reaction, under nitrogen, in the presence of a small excess of base in DMF, such as triethylamine (Et3N) (1.3 EQ.). After this reaction mixture is diluted with toluene and washed with H 2O. the Obtained organic portion was diluted with H2O and then filtered using complex tert-butyl methyl ether (MTBE) to move a given substance. The obtained solid residue is washed with MTBE and dried under negative pressure.

Connection echinocandin you can select cleaning and used as such in the form of its pharmaceutically acceptable salt or hydrate or in the form of a complex echinocandin/carbohydrate. The term "pharmaceutically acceptable salt" refers to non-toxic acid additive salts derived from inorganic and organic acids. The corresponding derivatives salts include halide compounds, thiocyanates, sulphates, bisulfate, sulfites, bisulfite, arylsulfonate, alkyl sulphates, phosphonates, disubstituted phosphates, one-deputizing phosphates, metaphosphates, pyrophosphate, alkanoate, cycloalkylcarbonyl, arylalkenes, adipate, aspartate, benzoate, fumarate, glucoheptonate, glycerophosphate, lactates, maleate, nicotinate, oxalates, palmitate, pectinate, picrate, pivalate, succinate, tartratami, citrates, camphorate, camphorsulfonate, digluconate, triptoreline and the like.

"Complex echinocandin/carbohydrate" refers to a crystalline complex formed echinocandin compound and carbohydrate (or sugar) by recrystallization of echinocandin is on of the solvent in the presence of carbohydrate. A more detailed description of complexes echinocandin/carbohydrate can be found in the publication Larew, et al., filed March 3, 1999, entitled "Echinocandin/Carbohydrate Complexes" and incorporated herein by reference. These complexes are formed using standard methods of crystallization, which is usually used for the purification of compounds by recrystallization. Substance echinocandin and the carbohydrate is dissolved at elevated temperature (approximately 45-60°C, preferably below 55° (C) in the solvent. Then the resulting solution is slowly cooled until the beginning of crystallization. To initiate crystallization can add a seed crystal (such as the previously crystallized complex or undissolved sugar). Suitable solvents include any solvent or mixture of solvents, inert to the ongoing reaction, which is enough solubilizing reagents, creating an environment in which there is required the complexation between the carbohydrate and the connection echinocandin, such as proton or ketone solvents, including methanol, ethanol, benzyl alcohol, and mixtures of benzyl alcohol with solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, 2-pentanol, 2-methyl-1-propanol, MEK, acetone, the ethyl acetate, toluene, acetonitrile, Forbes is l, methylene chloride, nitromethane, or cyclic ketones such as Cyclopentanone and cyclohexanone. Preferred solvents include methanol, ethanol, benzyl alcohol, and mixtures of benzyl alcohol with methylethyl-ketone, ethyl acetate and acetonitrile.

Suitable carbohydrates include adonit, arabinose, Arabic, ascorbic acid, chitin, D-cellobiose, 2-deoxy-D-ribose, dulcet, (S)-(+)-eritruloza, fructose, fucose, galactose, glucose, Inositol, lactose, lactulose, lyxose, malitol, maltose, maltotriose, mannitol, mannose, melezitose, melibiose, microcrystalline cellulose, palatinose, pentaerythritol, raffinose, rhamnose, ribose, sorbitol, sorbose, starch, sucrose, trehalose, xylitol, xylose, and their hydrates. Suitable carbohydrates include also the D and L enantiomers, as well as alpha and beta anomers of the above compounds. Preferred carbohydrates are simple sugars (e.g., mono - and disaccharides).

Connection echinocandin may be included in the prescription, the mixture of the present invention to lyophilization at concentrations greater than or equal to 1 mg/ml is Usually a connection echinocandin is present in the range from about 1 mg/ml to about 50 mg/ml, preferably in the concentration range from about 1 mg/ml to about 40 mg/ml, more preferably from about 1 mg/ml to about 30 mg/ml and most preferably from about the olo 8 mg/ml to about 12 mg/ml

Prescription mixture of the present invention contain a micelle-forming surfactant, which is an amphiphilic pharmaceutically acceptable excipient, having hydrophobic and hydrophilic elements or groups who have the ability to solubilisate in water insoluble drug. In most cases, the HLB values 10-18 most favorable to solubilize compounds echinocandin. Surfactant represented in the prescription of the mixture mass ratio echinocandin and surfactant from about 1:1.75 to about 1:25, more preferably in a ratio from about 1:2 to about 1:3. The upper limit to be added to the prescription of a mixture of surfactants may be limited due to its toxicity as applied to pharmaceutical drug; therefore, the upper limit may vary depending on the specific surfactant. Suitable surfactants include Polysorbate (e.g., Polysorbate 80, Polysorbate 40, Polysorbate 20), derived polyoxyethylenated castor oil (e.g., Chemophors™ (castor oil polyoxyl 35, hydrogenated castor oil polyoxyl 40 hydrogenated castor oil polyoxyl 60), access the s from BASF)), polyoxyethylenated (e.g., Solutol™ HS 15 (macrogol-660-hydroxystearate, available from BASF), sorbifolia, salts of bile acids (e.g., cholic acid, desoxycholate acids and their salts) (e.g., nitridization or nutritionological)), lecithin, and the like. Preferred surfactants include Polysorbate 80, Polysorbate 40, Polysorbate 20, and polyoxyethylenesorbitan, having recovered Histaminum effects (e.g., Solutol™ HS 15). Surfactants, which solubilizers unsatisfactory, include poloxamer, which are a group of copolymers of propylene oxide and ethylene oxide.

"Polysorbate" refers to substances having the following General formula:

where x+y+w+z is an integer between 5 and 20.

Commercial product twin™ 20, 40 and 80 (available from ICI Americas Inc., Wilmington, DL) represented by the above structure, when x+y+w+z=20.

"Lecithin" refers to substances having the following General structure:

R represents a typical residue of stearic acid, palmitic acid or oleic acid.

"Bile salts" refer to substances having the following General structure:

where R, R7, and R12 represents a group-HE, H or SO3a R24 represents HE or alkaline salt FROM

-
2
With(O)NH(CH2)nSO
-
3
or-C(O)NH(CH2)nFROM
-
2
and n is an integer between 1 and 4.

A typical solution mixture of prescription includes connecting echinocandin and micelle-forming surfactant. Applicants have observed that the inclusion of micelle-forming surfactants not only optimizes the solubilization of compounds echinocandin, but also improves the stability of this solution. Prescription mixture may optionally include one or more components in the form of a buffer, a stabilizing agent, and/or toning agent. If this prescription the mixture is in the form of a solution, it is also a solvent. Solvents are usually chosen with regard to their safe (GRAS) parenteral administration to a mammal. Generally safe solvents are non-toxic aqueous solution of the teli, such as water and other non-toxic solvents that are soluble in water or mixed with water. Suitable solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The preferred solvent is water.

Typical lyophilized prescription mixture comprises echinocandin compound, pharmaceutically acceptable surfactant, volumetric filler and/or a stabilizing agent. This drug may optionally include one or more bafarawa agents. Applicants have observed that the addition of the micelle-forming surfactants not only optimizes the reconstruction of the dried prescription of the mixture in a non-toxic aqueous solvent, but also gives greater stability liofilizirovannam materials.

Solution and lyophilized prescription mixture may optionally contain a stabilizing agent. The stabilizing agent is usually in the range of concentrations from about 0.5% to about 40% (wt./vol.), more preferably in the range of concentrations from about 1% to about 6%. The term "stabilizing agent" refers to a pharmaceutically acceptable filler, which increases the chemical or physical stability of the active ingredient in the prescription of the mixture. On the walking stabilizing agents include polyols (e.g., polyethylene and propylene glycols, and carbohydrates such as sucrose, trehalose, fructose, lactose and mannitol), amino acids and surfactants, such as Polysorbate and bile salts. Preferred stabilizing agents for lyophilized mixture of prescription include mannitol, sucrose, trehalose, fructose, lactose and combinations thereof. In solution the most preferred stabilizing agents are salts of bile acids, glycols and propylene glycol.

And the solution, and lyophilized preparations may also optionally contain a buffer. The buffer is present in a concentration range from about 0.03% to about 5.0% (mass/vol.), more preferably in the concentration range from about 0.1% to about 1.0%. The term "buffer" refers to a pharmaceutically acceptable filler, which maintains the pH of the solution in a specific range, specific to tabularium system. A suitable pH range is in the range from 3.0 to 7.0. The preferred range of pH is in the range of 4.0 to 5.5, the most preferred of 4.0 to 5.0. Suitable buffers include acetates, citrates, phosphates, tartratami, lactates, succinate, amino acids, and the like. Preferred buffers for soluble drug include acetate, citrate, tartratami, phosphate salts and combinations thereof. For freeze-dried mixture of prescription before occhialini buffer is tartaric acid.

Soluble prescription mixture can optionally contain one or more toning agents. The toning agent is present, typically in the concentration range from about 1 to about 100 mg/ml, more preferably in the range of from about 9 to about 50 mg/ml, the Term "toning agent" refers to a pharmaceutically acceptable filler, which makes this solution is compatible with blood. Preferably, toning agents are present in mixtures prescription for injection. Suitable toning agents include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol and the like. Preferred toning agents include mannitol, lactose and sodium chloride, and combinations thereof.

When lyophilization these prescription mixture can optionally contain volumetric filler. Such volumetric filler is present in the preparation in a concentration range from about 2% to about 10% (wt./vol.), more preferably in the concentration range from about 3% to about 6%.

The term "volumetric filler" refers to a pharmaceutically acceptable filler, which increases the amount of prescription of the mixture, forming during lyophilization correctly hardened sludge (cake). Suitable volumetric fillers include mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl the wet starch, ficoll and gelatin. The preferred volumetric fillers include mannitol, sucrose, trehalose, lactose and combinations thereof.

Prescription mixture can be obtained by using the traditional methods of dilution and mixing. For example, a large number of medicinal substance (e.g., echinocandin compound or complex echinocandin/carbohydrate) is dissolved in a non-toxic aqueous solvent in the presence of a pharmaceutically acceptable micelle-forming surfactants and optionally one or more volumetric fillers, buffers, stabilizing agents and/or toning agents. Then the resulting solution was sterile filtered and to create the required prescription mixture preferably lyophilizer. As a rule, before lyophilization solution is surfactant in excess of 1% (wt./vol.).

Alternative pharmaceutical solution can be obtained by producing the aqueous buffer solution, buffered, approximately, to a pH of from 3.0 to 7.0, preferably from 4.0 to 5.5, more preferably from about 4.0 to a 5.0). Used the buffer can be any of the previously described buffer. Then buffered solution add micelle-forming surfactant and the solution is cooled approximately to 5°-15°With(preferably about 7° C-10°). Suspension connection echinocandin or complex echinocandin/carbohydrate in a non-toxic aqueous solvent (which may or may not be the same solvent that is used in the buffer solution) is added to a chilled solution containing an appropriate surfactant. Before lyophilizate to this solution it is possible to add one or more volumetric fillers, stabilizers and/or toning agents. Then the resulting solution is diluted with solvent, filtered and lyophilizer until you get the desired mixture of prescription.

A suitable way of lyophilizate described in Nail et al. Freeze Drying Principles and Practice in Pharmaceutical Dosage Forms, 2ndEd., Marcel Dekker, Inc. NY, pp.163-233 (1993). Prescription mixture preferably lyophilizer vials that can be stored before use. Before use a vial poured non-toxic aqueous solvent for dissolving the lyophilized material, thus obtaining a solution which can be used for parenteral therapeutic applications. Specialists in this field of technology it is obvious that the water solvent includes other traditional solutions used for this application (e.g., saline, dextrose etc., etc.).

Usually, lyophilized mixture of prescription contain surround ispolnitel, and deliverydiovan prescription mixture contain one or more toning agents. When using these prescription mixture is usually diluted or recreate (if the product dried) and further, if necessary, before the introduction of the dilute. Exemplary instructions reconstitute the lyophilized product is added to ten ml of water for injection (WFI) in a vial and careful shaking to dissolve. Usually reassembly is less than one minute. Then, before the introduction of this resulting solution was further diluted with infusion solution such as 5%dextrose in water (D5W).

The active ingredient, usually prepared in the form of a pharmaceutically dosage forms to get easily controllable dosage of the product and to provide the patient with a simple and easy to use product. Prescription mixture can include an active ingredient from 0.1 wt.% up to 60 wt.%, more preferably from about 10 wt.% to about 30 wt.%.

Used herein, the term "unit dose" or "dosage unit" refers to physically discrete elements that contain a predetermined amount of the active ingredient, designed to obtain the desired therapeutic effect. If the unit dose is administered parenterally, it is usually sozdaut the form of measured units in capsules (or in bottles).

The dose for administration may vary depending on the physical characteristics of the patient, the severity of the pain symptoms of the patient and used routes of administration of medicines. The specific dose for a given patient is usually set based on the opinion of the treating physician.

Suitable carriers, diluents and excipients known in the art, include materials, such as carbohydrates, ointments, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like. The choice of the particular carrier, diluent or excipient depends on the methods and goals, to which is applied the active ingredient. Consider prescription mixture may also include moisturizing agents, lubricating agents, emulsifiers, suspendresume tools, preservatives, sweeteners, flavors, fragrances, and combinations thereof.

The pharmaceutical composition can be administered using different methods. Suitable methods include injection. Used a particular method of treatment depends on the type of infectious disease that can be cured.

It is established that echinocandin and semi-synthetic compounds echinocandin exhibit antifungal and antiparasitics activity, inhibiting the growth of various infectious fungi, including in the waters of Candida (i.e., .Albicans, .silosis, .Krusei, .Glabrata, .Tropicalis or .Lusikaniaw); types Torulopus (i.e., T. Glabrata); Aspergillus species (i.e., A. Fumigatus); Histoplasma species (i.e., H. Capsulatum); Cryptococcus species (i.e., .Neoformans); Blastomyces species (i.e., B. Dermatitidis); Fusarium species; Trichophyton species, Pseudallescheria boydii, Coccidioides immits, Sporothrix schenckii, etc.

These compounds also inhibit the growth of some organisms, responsible mainly for opportunistic infections in individuals with depressed immunity, suppressing, for example, the growth of Pneumocystis carinii (which is the cause of the disease organism Pneumocystis pneumonia (PCP) in patients with AIDS and other patients with damaged immune systems. Other protozoa, the activity of which is inhibited by the compounds echinocandin type, include species of Plasmodium, Leishmania species, Trypanosoma species, Cryptosporidium species, species of Isospora, Cyclospora species, Trichomonas species, species Microsporidiosis, etc., etc.

Therefore, these prescription mixture of the present invention are suitable for combating systemic fungal infections or fungal skin infections. In accordance with these methods and prescription of the mixture of the present invention can be used for the production of medicines described here for therapeutic applications. For example, fungal activity (preferably the activity of Candida albicans or Aspergillus fumigakis) or parasitic activity may Inga is to aromatise in the contact of a pharmaceutical product obtained in the present invention, respectively with fungus or a parasite. The term "contacting" includes a merger, or connection, or the apparent touching or mutual contact of the compounds of the present invention with a parasite or fungus. This term does not imply any additional limitations to this method, as, for example, the mechanism of suppression. These methods relate to the suppression of parasitic and fungal activity as a result of action of these compounds and their inherent antiparasitics and antifungal properties.

Also developed a method of treating a fungal infection, which includes the introduction of an effective amount of the pharmaceutical prescription mixture of the present invention to a host in need of such treatment. The preferred method involves the treatment of infections caused by Candida albicans or Aspergillus fumigatis. The term "effective amount" refers to the number of active connections, which has the ability to inhibit fungal activity. Enter the dose varies depending on such factors as the nature and severity of the infection, the age and General health of the host and the tolerance of the host to this antifungal agent. The mode of introduction of separate doses may also vary according to these factors. This medicine is a great remedy can be given as a single daily dose or in multiple doses during the day. Assigned mode can last from 2-3 days to 2-3 weeks or longer. A typical daily dose (injected once or divided into subdata) limited dose threshold between about 0.01-100 mg of active compound per 1 kg of body weight. Preferred daily doses generally be between about 0.1-60 mg/kg and more preferably between about 2.5-40 mg/kg

In the following examples, which illustrate but do not limit the present invention. All presented here links included therefore in the description of the invention, as if they were right in it reproduced.

EXAMPLES

Echinocandins connection used to illustrate RX mixtures of the present invention, receive as described for the following drugs. In particular, the following sequence describes obtaining an antifungal compound 6 (a), having the following structure:

Specialists in the art should note that the following serves as an illustrative example and that other semisynthetic compounds echinocandin, suitable as antifungal agents can be synthesized using similar methods or techniques described in the previously cited the references, presented in this description. The materials used in the following samples, available from Aldrich Chemicals (Milwaukee, Wisconsin), unless otherwise specified.

Preparations connections

Getting 4-Bromo-4'-pentylaniline 1(a)

Anhydrous K2POPs (416 g, 3 mol) is added to a mixture of 4-bromo-4'-hydroxybiphenyl (300 g, 1.2 mol), 1-iodopentane (234 ml, 1,79 mol) and 2-butanone (600 ml). The reaction mixture is refluxed for 44 h until TLC (hexane/EtOAc 85:15) shows complete absorption of bromine alcohol. After boiling the mixture is cooled to about 30°With, dilute it with CH2CL2(600 ml) and then filtered. The filtrate is washed twice with N2O and twice with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and then dried under reduced pressure to obtain a solid substance. This solid substance produce by filtration, repeatedly washed with a total volume of 2 l of ice-cold heptane to remove all traces of iodopentane and then dried overnight under high negative pressure. Output: 340 g (88%) of white powder.

Alternative obtain 4-bromo-4'-pentylaniline 1(a):

4-Bromo-4'-hydroxybiphenyl (12.5 g, a 50.2 mmol) contribute in a NaOH solution (2.28 g, purity 97%, 55.2 mmol) in deionized H2O (150 ml) followed by addition of 1-iodine is pentane (11.9 g, a 60.2 mmol) and tetrabutylammonium (0,82 g, 2.51 mmol). The resulting mixture was stirred at 90°C for 3.75 hours before a solution of the solid particles. Then, as the reaction proceeds, starts to precipitate the desired product. This mixture is slowly cooled and then filtered to obtain a solid, which was washed with deionized water until a neutral pH in the filtrate and then dried for 16 h at a negative pressure in thermostat at 30°C.

Output: 15,41 g (96%) 5A. Rfof 0.5 (hexane/EtOAc 97:3).1H NMR: δ of 0.93 (t, 3H, J=6.9 Hz); of 1.41 (m, 4H); to 1.79 (m, 2H); of 3.97 (t, 2H, J=6.6 Hz); 6,98 (m, 2H); 7.23 percent (m, 6N).13With NMR: δ 14,03: 22,43: 28,22; 28,98; 68,12; 114,91; 120,71; 127,93; 128,27; 131,77; 132,24; 139,82; 159,03. MS(FAB+); m/z 320. IR(l3): 2960, 2936, 2874, 1608, 1518, 1485, 1475 cm-1. Analysis17H19Ged: Theoretical calculation: C, 63,96; N, 6,00; VG, 25,0; in fact, found: C, 64,10; N, 5,97; VG, 25,28.

Getting 4-boric acid-4'-pentylaniline 2 (a)

To a cooled (-20° (C) mixture of compound 1 (a) (100 g, 0.31 mol) in tert-butylmethylether (MTBE) (1 l) was slowly added dropwise under N2poured n-utility (150 ml of a 2.5 M hexane solution of 0.37 mol) while maintaining the internal temperature between -19°and -18°C. the resulting mixture was stirred for 3.5 h at temperatures between -17°and -16°that gives a bright yellow-green solution. This solution is cooled to -78° With and diluted with 100 ml anhydrous THF, resulting white precipitate. Then, for 1.5 h dropwise under nitrogen poured chilled (-78° (C) a solution of triisopropylsilane (145 ml of 0.62 mol) in MTBE (200 ml), maintaining the reaction temperature between -78°and -74°C. the resulting reaction mixture is stirred for 1.5 h at -78°C, then warmed to -50°C for 1 h, and then remove the cooling bath and the mixture is stirred overnight (16 to 21 h), which leads to the precipitation of a white powder. The mixture is vigorously shaken with 2 M Hcl (1000 ml) for 5 minutes, the resulting layers are separated and the organic layer is dried under reduced pressure to obtain a residue. The residue is diluted with MUTE (100 ml), then with heptane (800 ml) and receive a white powder, which is marked with a suction filtration and washed 3 times with heptane (300 ml).

Output: 88 g (98%). Rf0,45 (CH2Cl2/MeOH 95:5).1H NMR: δ to 0.92 (m, 3H); of 1.41 (m, 4H); of 1.80 (m, 2H); 4,00 (m, 2H); 6,99 (m, 2H); 7,45-7,63 (m, 3H); to 7.67 (m, 2H); 8,24 (d, 1H, J=8,3 Hz).13With NMR: 14.01; 22,26; 28,03; 28,77; 39,61; 39,89; 40,17; 40,45; 67,82; 114,77; 125,32; 127,83; 132,93; 134,84; 141,88; 158,71. MS(FD-): m/z 284/ IR(l3): 2959, 2952, 2874, 1606, 1526, 1500 cm-1.

Obtain compound 3(a):

A solution of toluene (174 ml) and propanol (20 ml) Tegaserod 3 times, adding to this solution a negative pressure within 20-30 CE is und with the subsequent purge of N 2. Tegaserod 2 M solution of Na2CO3. To a mixture of methyl 4-identity (14,12 g, 53,9 mmol) and compound 2 (a) (15.0 g, of 52.8 mmol) is poured a solution of toluene/propanol (97 ml) followed by degassing 2 M solution of Na2CO3(29 ml, 58,0 mmol). The resulting mixture Tegaserod 2 times for 20-30 seconds each time under the pressure of N2above atmospheric and then adding acetabularia (II) (0.24 g, 1.1 mmol) and triphenylphosphine (0.84 g, 3.2 mmol), and then Tegaserod more than 2 times. Then this reaction mixture is refluxed under N2within 5 h, receiving light yellow mixture. This mixture is cooled to 23°with formation of a precipitate, which is collected by filtration, successively washed with toluene (123 ml), MTBE/EtOAc 2:1 (143 ml), deionized water (123 ml) and MTBE/EtOAc 2:1 (42 ml)and then dried for 16 h in a vacuum thermostat at 35°C. Yield: 18.7 g (94%). Rf0,48 (benzene).1H NMR: δ of 0.93 (t, 3H, J=6,80 Hz); of 1.42 (m, 4H); is 1.81 (m, 2H); of 3.95 (s, 3H); 4,00 (t, 2H, J=6.48 in Hz); 6,97 (d, 2H, J=charged 8.52 Hz); at 7.55 (d, 2H, J=charged 8.52 Hz); 7,66 (m, 6N); 8,10 (d, 2H, J=8,20 Hz); MS(FD+): m/z 374. IR(KBR): 2938, 1723-1. Analysis25H26O3: Theoretical calculation: C, 80,18; N, 7,00;

Actually found: C, 79,91; N, 6,94.

Obtaining Compounds 4(a):

A mixture of compound 3(a) (80 g, 0.21 mmol), 5 M KOH (160 ml) and cetyltrimethylammonium is dibromide (4.8 g, 0,013 mol) in xylene (800 ml), refluxed for 3 h, and then cooled to 10°and filtered, obtaining a white solid. This solid is washed 3 times with H2O (each 500 ml) to remove the catalyst and the greater part of the grounds. The resulting material is treated with DME (500 ml). Adjusted to the desired pH by addition of 6 M Hcl (100 ml). The resulting mixture is refluxed for 30 minutes, periodically measuring the pH to ensure the level of acidity, then cooled and filtered. The obtained solid is successively washed with MTBE (400 ml) and water (4×400 ml) to obtain (litmus paper) neutral values of drilling fluids. Output: 76 g (98%yield).1H NMR δ to 0.89 (t, 3H, J=6,82 Hz)to 1.38 (m, 4H), at 1.73 (m, 2H), 3.96 points (t, 2H, J=6.3 Hz), to 6.95 (d, 2H, J=8,56 Hz), EUR 7.57 (d, 2H, J=8,54 Hz), of 7.64-7,74 (m, 6N), of 8.00 (d, 2H, J=8,21 Hz), of 8.09 (s, 1H). MS (FD+) m/z 360. IR(KBR): 2958, 2937, 2872, 1688 cm-1. Analysis24H24O3: Theoretical calculation: C, 79,97; N, of 6.71;

Actually found: C, 80,50; N, 6,77.

Getting complicated NOWT ester compounds 4(a):

A. Obtaining NOT-nelfinavir

To a cooled (0° (C) a mixture consisting of hydroxybenzotriazole (200 g, 1.48 mol) in anhydrous CH2Cl2(1.5 l), slowly poured Et3H (268 ml, 1.92 mol), keeping the temperature 0-10°Since, then, maintaining the temperature between 0-5&x000B0; To add methanesulfonanilide (126 ml, and 1.63 mol). The resulting mixture was stirred for 3 h at 0°and sequentially washed with cold water (2×1.2 l) and salt solution (1.2 l). The combined organic extracts are concentrated under reduced pressure to obtain a solid substance. This substance is recrystallized from CH2Cl2(100 ml) and heptane (1 l). The resulting crystals are collected by filtration with suction and repeatedly washed with heptane, a total volume of 1 l, and then dried overnight under high vacuum (0.5 mm Od). Output: 245 g (78%). Rf0,55 (hexane/CH2CL21:1).1H NMR: δ to 3.58 (s, 3H), 7,46 (t, 1H, J=7,60 Hz), 7,60 (d, 1H, J=8,28 Hz), the 7.65 (d, 1H, J=8,56 Hz), to 7.68 (d, 1H, J=8,20 Hz), with 8.05 (d, 1H, J=to 8.41 Hz).

C. Obtaining a complex NOWT ether

A mixture consisting of the compounds 4(a) (50 g, 0.14 mol) and described above in part a substance (36 g, to 0.17 mol) in DMF (650 ml), subjected to drip effect of Et3N (25 ml, 0.18 mol), N2. The resulting mixture was stirred for 4 h at room temperature until complete consumption of the acid, which was determined by TLC (CH2Cl2/MeOH 95:5). After spending the whole acid aliquot of this reaction mixture (~3 pipetochnoe drops) when it is diluted in 3 ml of CH2Cl2/THF 1:1 gives a transparent homogeneous solution. Then this reaction mixture is diluted with toluene (500 ml). Organically the layer (containing the solid product) diluted with water (500 ml) and filtered using MTBE to move. The solid is rinsed MTBE (2×400 ml) and dried under negative pressure to obtain a greenish-white flakes substances. NOTE: This substance can be dissolved in THF and filtered to remove residual metallic impurities. Output: 61 g (92%). Rf0,68 (CH2CL2/hexane 1:1).1H NMR: δ of 0.93 (t, 3H, J=7, 0 Hz)to 1.42 (m, 4H), of 1.81 (m, 2H), 4.00 points (t, 2H, J=6,53 Hz), of 6.99 (d, 2H, J=8.6 Hz), 7,42-to 7.59 (m, 5H), 7,71 (DD, 4H, J=13,91 Hz to 8.40 Hz), 7,86 (d, 2H, J=8,30 Hz), 8,11 (d, 1H, J=8,31 Hz), 8,35 (d, 2H, J=8,33 Hz),13H NMR: δ 14,03, 22,44, 28,18, 28,94, 40,10, 40,37, 68,11, 108,45, 110,11, 114,95, 118,71, 120,48, 123,04, 124,94, 124,99, 127,00, 127,23, 127,51, 127,73, 128,06, 128,82, 128,86, 131,35, 132,30, 137,15, 141,43, 143,54, 147,85, 159,15, 162,73. MS(FD+); m/z 477. IR(l3): 2960, 2936, 2874, 1783, 1606 cm-1. Analysis of C30H27N3O3: Theoretical calculation: C, 75,45; N, 5,70; N, 8,80; in fact, found: C, 75,69; N, To 5.58; N, 8, 92.

Receiving antifungal compounds 6(a)

Deionized water is used everywhere. A mixture of compound 5 (a) (11 g, 23 mmol) and the centre of compounds 6 (a) (where R is a hydrogen - 92% purity according to HPLC, 19,25 g of 22.2 mmol) in anhydrous DMF (275 ml)was stirred under N2within 4 h (until HPLC indicates a full expenditure of cyclic peptide of the original substance). This mixture is filtered through a layer of celite and the resulting filtrate concentrated under reduced pressure at 35°to obtain pastes is, that mix. This paste is poured into MTBE (500 ml), resulting in loss of fine-grained powder, which is collected by filtration at a negative pressure and dried to obtain 27 g of the crude substance. This substance is pulverized into a powder with the pestle in the mortar, pulpit for 5 minutes in toluene (200 ml), filtered with suction (slow filtration), rinsed MTBE (100 ml) and then dried at a negative pressure to obtain a solid yellow color. Yield: 23 g (95% purity by HPLC, retention time=7,79 min).

Alternatively, this conversion can be carried out using an excess of the cyclic nucleus (1.1 EQ.). After practical completion of this reaction, which is determined by HPLC, the crude substance parts injected into vigorously stirred mixture of acetone/water 9:1 (60 ml). In the resulting suspension is added celite (2.5 g celite, pre-washed with a mixture of acetone/water 9:1). After stirring for 2 minutes the mixture is filtered through a layer of celite (previously washed with a mixture of acetone/water 9:1) and the resulting Packed double-layer rinsed with a mixture of acetone/water 9:1 (10 ml). The filtrate was poured into a beaker with deionized water (200 ml) with gentle turbulent stirring this mixture, which leads to the formation of sludge. The precipitate is collected by filtration with suction, polaskia H 2O (4×25 ml) and then dried at a negative pressure at room temperature. Output: for 6.81 g (97% purity by HPLC).

Further, this product emit purification preparative HPLC. Rf0,29 (CHCl3/MeOH 80:20). MS(FAB+): m/z58H74N7About7Theoretical calculation: 1140,5141; in fact discovered: 1140,5103. IR(KBR): 3365, 2934, 1632, 1518 cm-1.

Pharmaceutical compositions

The following primary prescription illustrate the mixture of the present invention and methods for their preparation. These examples in no way limit the scope of the present invention and they should not be construed as such restrictions.

Following the prescription of the mixture obtained by method A, method b or method C. the Number of compounds 6 (a) is determined by calculating theoretical efficiency needed for experiments, and dividing this value by the actual HPLC - effectiveness of this connection.

Method A. After adjusting pH in 50 ml of 0.1 M citrate source buffer solution to a value of 4.0 in it add 2.5 g of Polysorbate 80 and the resulting mixture is stirred to dissolve, followed by addition of 1 g of compound from sample 6 (a) (effective). This mixture is stirred to dissolve, followed by addition of 3 g of mannitol (body filler) and 2 g of trehalose (a stabilizing agent). The resulting mixture is again p is remediat to dissolve. The resulting solution was diluted with water in a volumetric flask to the 100 ml 3 ml of this solution is transferred into a vial and then dried by freezing in liofilizadora.

Method C. a Solution of 0,3005 g of acetic acid in 50 ml of water adjusted to pH 4.0 using 1 N sodium hydroxide solution, In the process of stirring 2.5 g of Polysorbate 80 and 5.0 g of mannitol (body filler) and the resulting mixture is stirred to dissolve, followed by addition of 1 g of Compound 6 (a) (effective). This mixture is again stirred until dissolution. The resulting solution was diluted with water in a volumetric flask to 100 ml, filtered and placed in capsules. The solution in the ampoule can be dried by freezing in liofilizadora or stored at 5°C.

Method C. a Solution of 0,113 g of tartaric acid in 50 ml of water adjusted to a pH of 4.3, using 10% sodium hydroxide solution. In the process of mixing add the Polysorbate 80 and continue to stir until dissolution. The temperature of the solution was lowered to 5°-15°C, followed by addition of 1 g of compound 6 (a) (effective) in the form of a suspension in water. The resulting mixture is again stirred to dissolve, followed by addition of 1.0 g of fructose (stabilizing agent) and 5.0 g of mannitol (body filler). This mixture is again stirred until dissolution. The resulting solution was diluted with water in a volumetric flask to 100 ml, filtered and then poured into ampoules in injectable Solution may be dried by freezing in liofilizadora or stored at 5° C.

The following prescription examples 1-27 obtained as described above in methods a and B. symbol "-" means that the ingredient is excluded from the composition. In table 1 and subsequent tables, all weights given are in (grams); concentration ([]) are indicated in mg/ml; SA means citric acid; Y means Yes, N means no; Man means mannitol; The means trehalose; Col. means deformation layer; means citrate; VA means of volumetric filler; means In the buffer; PEG " means polyethylene glycol; PPG - means propylene glycol; SA means stabilizing agent; ACE means acetate; Poly means 80 Polysorbate 80; Com connection means; means Suc, sucrose; His means histidine; Sur means surfactant; Lac means lactose; means Fru, fructose; THAT means tartaric acid and AA means of acetic acid.

Study of the solubility

Studies on the solubility carried out at room temperature after the transfer of the test solution (surface-active substance, optionally containing a volumetric filler, buffer or stabilizing agent) and 50 mg of compound 6(a) in a glass test tube. The test tube is shaken out during the night and check on the availability of excess solids. Tubes containing excess solid fuel is Dogo substances, removed for analysis. In tubes that do not contain an excess of solids, advanced, add 50 mg of compound 6(a) and the resulting mixture was stirred by shaking. This operation is repeated until such time as the in vitro observed excess solids. All samples leave for 1 hour, remove the supernatant, filtered and analyzed by reversed-phase HPLC to determine the effectiveness of compounds 6(a) to 1 ml of solution.

The stability of the solution and lyophilized compositions evaluated by monitoring the sample composition on the percentage increase related substances in reversed-phase HPLC at the beginning and after 2 weeks and after 4 weeks storage at 40°C.

1. Parenteral stable pharmaceutical composition comprising (i) echinocandin compound or its pharmaceutically acceptable salt; (ii) pharmaceutically acceptable micelle-forming surfactant; (iii) non-toxic aqueous solvent and (iv) a stabilizing agent, where the aforementioned surface-active substance is present in the composition in a ratio (wt.) from about 1:1.75 to about 1:25 to the connection echinocandin and echinocandin compound is present in amount greater than or equal to 1 mg/ml, and where asany stabilizing agent is a carbohydrate.

2. The composition according to claim 1, in which the connection echinocandin has the following structure:

where R represents alkyl, alkenylphenol, alkenylphenol, aryl, heteroaryl group, or a combination thereof;

R1, R2, R3, R6, R7and R10independently represent hydroxy or N;

R4represents H, methyl or-CH2C(O)NH2;

R5and R11independently represent methyl or H;

R8represents-OH, -ORO3H2, ORO3HCH3, ORO2HCH3or S3N;

R9represents-H, -HE, or S3N

and their pharmaceutically acceptable salts.

3. The composition according to claim 2, where R4, R5and R11each represents methyl, R2and R7independently represent-H or hydroxy; R1, R3, R6and R10each represents a hydroxy: R8is a HE, ORO3HCH3or ORO2HCH3; R represents linoleoyl, Palmitoyl, stearoyl, myristoyl, 12-metalmeister, 10,12-dimethylpyrazol or a group having the General structure

where a, b, C and D independently represent-H, (C1-C1 )alkyl, (C2-C12)quinil, (C1-C12)alkoxy, (C1-C12)alkylthio, halogen, or-O-(CH2)m-[O-(CH2)n]p-O-(C1-C12)alkyl, or-O-(CH2)q-X-E; m is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1; q is 2, 3 or 4; X represents pyrrolidino, piperidino or piperazine derivatives; E represents-H, (C1-C12)alkyl, (C3-C12)cycloalkyl, benzyl or (C3-C12)cycloalkylation.

4. The composition according to claim 3, where R2and R7each represents hydroxy; R8represents hydroxy and

5. Composition according to any one of the preceding paragraphs in which the specified micelle-forming surfactant selected from the group consisting of polysorbates derived polyoxyethylene castor oil, polyoxyethylene-stearates, sorbitrate, bile salts, lecithin, and combinations thereof.

6. Composition according to any one of the preceding paragraphs in which the specified connection echinocandin is present in an amount of from about 1 to 50 mg/ml

7. Compsize according to claim 6, in which the specified connection echinocandin is present in an amount of from about 1 to 30 mg/ml

8. The composition according to claim 1, in which the specified surfactant has the formula

where x+y+z+w is an integer between 5 and 20.

9. Composition according to any one of the preceding paragraphs in which the specified surface-active substance is present in quantities exceeding 1% (wt./vol.).

10. Composition according to any one of the preceding paragraphs in which the specified mass ratio echinocandin and surfactant is from about 1:2 to about 1:3.

11. Composition according to any one of the preceding paragraphs in which the specified solvent selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol and mixtures thereof.

12. Composition according to any one of the preceding paragraphs in which the specified stabilizing agent is a beckoning, sucrose, fructose, trehalose, lactose, or a mixture.

13. The composition according to item 12, which specified the stabilizing agent is present in an amount of from about 0.5 to about 10% (wt./vol.).

14. The composition according to item 12, which specified the stabilizing agent is present in an amount of from about 1 to about 6% (wt./vol.).

15. The composition according to item 12, which specified the stabilizing agent further comprises histidine, lysine, glycine, or a mixture.

16. Composition according to any one of the preceding paragraphs, further containing a buffer.

17. The composition according to item 16, in which the specified buffer selected from the group consisting of acetates, zither is s, the tartratami, lactates, succinates, phosphates and amino acids.

18. Composition according to any one of the preceding paragraphs, further comprising a toning agent.

19. The composition according to p in which the specified toning agent selected from the group consisting of glycerol, lactose, mannitol, dextrose, sodium chloride, sodium sulfate and sorbitol.

20. The composition according to p in which the specified toning agent is present in an amount of from about 1 to about 100 mg/ml

21. The composition according to p in which the specified toning agent is present in an amount of from about 9 to about 50 mg/ml

22. Freeze-dried stabilized composition comprising (i) echinocandin compound or its pharmaceutically acceptable salt; (ii) pharmaceutically acceptable micelle-forming surfactant; and (iii) bulk agent, where the specified micelle-forming surfactant is present in a given composition of the mixture in excess of 5 wt.% and where specified volumetric agent selected from the group consisting of mannitol, sucrose, trehalose, lactose and mixtures thereof, as well as dextran, hydroxyethylamide starch, picola and gelatin.

23. The composition according to item 22, which specified volumetric filler selected from the group consisting of mannitol, sucrose, trehalose, lactose and mixtures thereof.

24. The composition according to item 22 or 23, in which asanee connection echinocandin presents the following structure

where R represents alkyl, alkenylphenol, alkenylphenol, aryl or heteroaryl group, or a combination thereof.

R1, R2, R3, R6, R-, and R10independently represent hydroxy or N;

R4represents H, methyl or-CH2C(O)NH2;

R5and R11independently represent methyl or H;

R8represents-OH, -OPO3H2, ORO3HCH3, ORO2HCH3or S3N;

R9represents-H, -HE or S3N

and their pharmaceutically acceptable salt.

25. The composition according to paragraph 24, where R4, R5and R11each represents methyl; R2and R7independently represent-H or hydroxy; R1, R3, R6and R10each represents hydroxy; R8represents-OH, -ORO3HCH3or ORO2HCH3; R represents linoleoyl, Palmitoyl, stearoyl, myristoyl, 12-metalmeister, 10,12-dimethylpyrazol or a group having the General structure

where a, b, C and D are independently-H, (C1-C12)alkyl, (C2-C12)quinil, (C1-C12)alkoxy, (C1-C12)alkylthio, what alogena, or-O-(CH2)m-[O-(CH2)n]p-O-(C1-C12)alkyl, or-O-(CH2)q-X-E; m is 2, 3 or 4; n is 2, 3, or 4; p is 0 or 1; q is 2, 3 or 4; X - pyrrolidino, piperidine or piperazine derivatives; E is-H, (C1-C12)alkyl, (C3-C12)cycloalkyl, benzyl or (C3-C12)cycloalkyl the stands.

26. The composition according A.25, where R2and R7each is hydroxy, R8represents hydroxy and

27. Composition according to any one of p-26, which specified micelle-forming surfactant is chosen from the group consisting of polysorbates derived polyoxyethylenated castor oil, polyoxometalates, sorbitrate, bile salts, lecithin, and combinations thereof.

28. Composition according to any one of p-26, which specified surfactant has the formula

where x+y+z+w is an integer between 5 and 20.

29. Composition according to any one of PP-28, in which the specified surfactant is present in this composition in a mass ratio echinocandin and surfactant from about 1:1.75 to about 1:25.

30. The composition according to clause 29, in which the specified mass ratio echinocandin and surface-active substances the leaves from about 1:2 to about 1:3.

31. Parenterally stable pharmaceutical composition containing lyophilized composition according to any one of p-30 and an aqueous solvent.

32. The composition according to p, optionally containing a stabilizing agent.

33. The composition according to p, which indicated a stabilizing agent selected from the group consisting of mannitol, histidine, lysine, glycine, fructose, sucrose, trehalose, lactose and mixtures thereof.

34. The composition according to p, in which the surface-active substance is present in a weight ratio of from about 1:1.75 to about 1:25 with echinocandins and surfactants.

35. The composition according to p, optionally containing buffer.

36. The composition according to p in which the specified buffer selected from the group consisting of acetates, tartratami, citrates, phosphates and amino acids.

37. Method of preparation of stable parenteral pharmaceutical composition, comprising a stage of mixing echinocandin compound or complex echinocandin/carbohydrate that contains the specified connection echinocandin, pharmaceutically acceptable micelle-forming surfactant and a stabilizing agent in an aqueous solvent, where the specified micelle-forming surfactant is present at a ratio (wt.) from about 1:1.75 to about 1:25 to echinocandin and connection ahin Cantina is present in a quantity greater than or equal to 1 mg/ml, and where specified the stabilizing agent is a carbohydrate.

38. The method according to clause 37, in which the specified connection echinocandin is present in an amount of from about 1 to about 50 mg/ml

39. The method according to clause 37, in which the specified connection echinocandin is present in an amount of from about 1 to about 30 mg/ml

40. Method of preparation of stable lyophilized composition comprising the following order of steps: (i) dissolving in an aqueous solvent compounds echinocandin or complex echinocandin/carbohydrate that contains the specified connection echinocandin, in the presence of a pharmaceutically acceptable micelle-forming surfactants and bulk agent to form a solution, where the aforementioned surface-active substance is present in quantities exceeding 1% (wt./vol.); where specified volumetric agent selected from the group consisting of mannitol, sucrose, trehalose, lactose and mixtures thereof, as well as dextran, hydroxyethylamide starch, picola and gelatin; (ii) sterilizing filtration of the specified solution and (iii) the lyophilization of the specified solution.

41. The method according to p additionally includes the stage of adding one or more buffers, stabilizing agents, tinting agents, or combinations thereof prior to stage (ii).

42. The method according to p or 41, to the torus specified micelle-forming surfactant selected from the group consisting of polysorbates derived polyoxyethylenated castor oil, polyoxyethyleneglycol, sorbitrate, bile acids, lecithin and combinations thereof.

43. Method of preparation of stable lyophilized composition comprising the following stages: (i) tebufelone non-toxic aqueous solution to a pH of between about 4.0 n 5,5 education buffered solution; (ii) adding to the specified buffered solution pharmaceutically acceptable micelle-forming surfactants: (iii) cooling the solution from step (ii) to a temperature of between 5 and 15°obtaining a cooled solution; (iv) adding to the suspension, including a connection echinocandin or complex echinocandin/carbohydrate agent and the second non-toxic aqueous solution to the specified cooled solution: (v) sterile filtering the specified solution from step (iv) and (vi) the lyophilization of the specified solution from step (v).

44. The method according to item 43, in which the specified temperature stage (iii) is from about 7 to about 10°C.

45. The method according to item 43 or 44, further comprising the stage of adding one or more bulk agents, stabilizing agents, tinting agents, or combinations thereof, prior to stage (v).

46. Method of preparation of stable parenteral pharmaceutical product by (i) races the of its in aqueous solvent echinocandin compound or complex echinocandin/carbohydrate containing the specified echinocandins connection, in the presence of a pharmaceutically acceptable micelle-forming surfactant with the formation of a solution, where the aforementioned surface-active substance is present in quantities of more than 1% by weight to solution volume and where the specified solution further comprises a bulk agent or a stabilizing agent; where the specified volumetric agent selected from the group consisting of mannitol, sucrose, trehalose, lactose and mixtures thereof and dextran, gidroksietilirovannogo starch, picola and gelatin and where specified the stabilizing agent is a carbohydrate; (ii) sterile filtering the solution and (iii) freeze-drying the specified solution after stage (ii) in the ampoule.

47. The method according to item 46, further comprising adding a non-toxic aqueous solvent in a specified capacity after stage (iii).

48. The method according to item 46 or 47, in which the mass ratio of the compounds echinocandin to surfactant is from 1:1.75 to 1:25.



 

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