Method for introducing epotilone analogs for treating cancer cases

FIELD: medicine.

SUBSTANCE: method involves preparing composition comprising epotilone analogs by dissolving said epotilone analog in aqueous butanol. The produced solution is dried in two stages to produce lyophilized product being lyophilized epotilone analog and pharmacological means for treating cancer diseases containing lyophilized epotilone analog.

EFFECT: high solubility of obtained product.

20 cl,1 tbl

 

The area to which the invention relates.

Epothilone are macrolide compounds used in the pharmaceutical industry. For example, epothilone a and b having the following structure:

have a stabilizing effect on microtubules similar to paclitaxel (TAXOL®) and, therefore, cytotoxic activity against rapidly proliferating cells such as tumor cells or other hyperproliferative cells, see Hofle et al., Angew. Chem. Int. Ed. Engl., Vol.35, No. 13/14, 1567-1569 (1996); application WO 93/10121, published may 27, 1993; application WO 97/19086, published may 29, 1997.

Were synthesized various derivatives and analogs epothilones a and b, which can be used to treat various types of cancer and other abnormal proliferative diseases. Such analogs are described Hofle et al. Id., Nicolaou et al., Angew. Chem. Int. Ed. Engl., Vol.36, No. 19, 2097-2103 (1997); and Su et al., Angew. Chem. Int. Ed. Engl., Vol.36, No. 19, 2093-2097 (1997).

Analogues epothilones with greater activity described General formula I:

where different radicals mentioned below. Although these compounds have beneficial therapeutic properties, however, obtaining drugs based on them is difficult due to certain properties, which will be described below. According to this invention was izraboten composition, by which the above-described analogs epothilone can be entered easily by injection without appreciable loss of their activity. In addition, many anticancer drugs are toxic.

Indeed, therapeutic profile of many active anticancer drugs is deteriorating due to toxicity. Therefore, there is a need to establish methods of introduction and schemes dosage, which lead to the reduction or elimination of toxicity of anticancer agents. These methods will allow you to apply active antitumor agents, which in other cases cannot be used clinically.

The essence of the invention.

The present invention provides a new scheme dosage epothilones connections, and this scheme is suitable for the treatment of patients with solid tumors, especially developed solid tumors. In addition, the methods according to the invention can be used for the treatment and/or prophylaxis of both metastases and primary tumors. According to one variant of the invention provides a method of treating patients who had previously undergone radiotherapy and/or chemotherapy against solid tumors. It was also found that epothilone compounds according to the invention, especially preferred is the compound [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethynyl]-4-Aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, can be used for the treatment of tumors resistant to radiation therapy or chemotherapy.

The methods according to the invention are suitable for combating cancer cells and, thus, tumors that are by nature insensitive or become insensitive to paclitaxel.

According to one variant, the treatment regimen according to the invention includes a weekly introduction epothilone according to the invention, preferably, in a continuous infusion within one (1) hour each week. According to another variant, the introduction is carried out weekly for three weeks. Dose for weekly infusion is from 1 mg/m2up to 30 mg/m2and, more preferably, 1 mg/m225 mg/m2. According to another variant, the treatment regimen includes both oral and intravenous administration of the same epothilones connection. For example, the weekly introduction may precede or follow oral dose of 20 mg/m or more doses. According to the special way the scheme is the introduction includes a three-week cycle of intravenous infusion once a week for approximately one (1) hour before the loop or after it is administered orally certain dose one or more times in the week prior to the first intravenous, or in the week following the last inside the public administration. Other protocols are also covered by the invention, including, but not limited to, the following schemes:

(a) daily administration for 5-10 days followed by a break, at least for 3 days;

(b) weekly introduction within 2-10 weeks followed by a break for at least one week;

(C) the introduction of once every three weeks followed by a break for at least one week.

The invention also provides for the use of H1and H2antihistamine agents before, after and/or before and after cycle introduction epothilone. Similarly, the invention encompasses the use of other chemotherapeutic agents, particularly anti-tumor agents, together with one epothilone or together with H1and H2blockers and epothilone.

According to another variant of the scheme is the introduction epothilone applied after carrying out the ordinary course using paclitaxel.

The methods according to the invention provide for the treatment of various cancers. According to a preferred variant of the methods according to the invention is used for the treatment of solid tumors, including, but not limited to, tumors of the breast, head and neck, sarcoma, colorectal tumors, tumors of RTIs, melanoma, tumor of the esophagus, kidney, cervix, thyroid gland, anus, ovarian, Obodo the big intestine.

Methods and compositions according to this invention provide for drug and drug-based analogues epothilone described by the formula:

where different radicals defined below.

According to one variation similar epothilone first solubilizer mixture trebuetsya and water and then lyophilizer in optimal conditions. Liofilizirovannoe medicine recreate by adding the first mixture polyethoxyethanol castor oil (surfactant) and anhydrous ethanol and then diluting ringer's solution with lactate for injection to a concentration suitable for injection.

Detailed description of the invention.

According to one variant of the invention provides for the preparation for the introduction of analogues epothilone formula I:

In the formula I and forth in the description of Q is selected from the group consisting of

and

M is selected from the group consisting of oxygen, sulfur, NR8and CR9R10; each of R1, R2, R3, R4, R5, R7, R11, R12, R13, R14and R15independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl and, if R1and R2about the means alkyl, they may together form cycloalkyl;

R6selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclyl and substituted heterocyclyl;

R8selected from the group consisting of hydrogen, alkyl, substituted alkyl, R11C=O, R12OC=O and R13SO2; and

each of R9and R10independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclyl, hydroxy, R14C=O and R15OC=O.

Below are definitions of various terms used in this application to describe the present invention. These definitions apply to terms used throughout the text, unless otherwise agreed in specific cases when the description of individual compounds or part of a large group.

The term "alkyl" refers to substituted linear or branched saturated hydrocarbon groups containing from 1 to about 20 carbon atoms, preferably from 1 to about 7 carbon atoms. The term "lower alkyl" refers to substituted alkyl groups containing from 1 to about 4 carbon atoms.

The term "substituted alkyl" refers to alcelam, samemanner, for example, one to four substituents, such as halogen, trifluoromethyl, triptoreline, hydroxy, alkoxy, PI is alkyloxy, heterocyclic, oxo, alkanoyl, aryl, aryloxy, aralkyl, alkanoyloxy, amino, alkylamino, arylamino, aralkylamines, cyclooctylamine, heterocyclisation, disubstituted amino group in which the substituents are selected from alkyl, aryl, aralkyl, alcanolamines, substituted alkanolamines, substituted killingray, substituted arcanol-amino group, alkylthio, aaltio, Uralkali, cycloalkylation, heterocyclic, alkylthio, aracytine, alkylsulfonyl, arylsulfonyl, Arakishvili, sulfonamide (e.g., SO2NH2), substituted sulfenamidovy, nitro, cyano, carboxy, carbamoyl (for example, CONH2), replaced carbamoyl (for example, CONH, CONH, CONH or cases where there are two substituent at the nitrogen atom, selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclyl, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, etc. In cases where, as indicated above, the substituents themselves contain substituents, the latter selected from the group consisting of halogen, alkyl, alkoxy, aryl and aralkyl. The definitions of alkyl and substituted alkyl, refer also to the alkyl part of alkoxygroup.

The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine. The term "ring the Wai system" refers to a possibly substituted ring system, containing one to three rings and at least one carbon-carbon double bond in at least one ring. Examples of ring systems include, but are not limited to, aryl or partially or completely unsaturated heterocyclic ring system which may contain substituents.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups containing from about 6 to about 12 carbon atoms in the ring, such as phenyl, naphthyl, biphenyl and diphenyl, each of which may have substituents.

The term "aralkyl" refers to aryl attached to the rest of the molecule through an alkyl group such as a benzyl group.

The term "substituted aryl" refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halogen, trifluoromethyl, triptoreline, hydroxy, alkoxy, cycloalkane, heterocyclics, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, aralkylamines, cyclooctylamine, heterocyclisation, alkanolamine, Tolna group, alkylthio, cycloalkyl, heterocyclic, ureido, nitro, cyano, carboxy, carboxylic, carbamic, alkoxycarbonyl, alkylthio, Aristion, alkylsulfonyl, sulfonamide, aryloxy etc. Deputy, in turn, can be substituted by one the or more substituents, selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, aryl, substituted alkyl, substituted aryl and aralkyl.

The term "cycloalkyl" refers to substituted saturated cyclic ring systems, preferably containing 1 to 3 rings and 3 to 7 carbon atoms in a single ring which may be condensed with an unsaturated With3-C7-carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and substituted. Examples of the substituents include one or more alkyl groups described above, or one or more groups described above as alkyl substituents groups.

The terms "heterocycle", "heterocyclic" and "heterocyclyl" refers to possibly substituted, unsaturated, partially saturated or fully saturated or aromatic and non-aromatic cyclic group, which, for example, is a 4-7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which contains at least one heteroatom in at least one carbon-containing ring. Each ring of the heterocyclic group containing a heteroatom can contain 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, the volume of sulfur, the atoms of nitrogen and sulfur can be oxidized and the nitrogen atoms can also be Quaternary. Heterocyclic group may be attached via any heteroatom or carbon atom.

Examples of the monocyclic heterocyclic groups are pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolines, imidazoles, imidazolines, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, diazolidinyl, isothiazolin, isothiazolinones, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxazepines, azepine, 4-piperidinyl, pyridyl, N-oxopyridine, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydropyranyl, Tetra-hydrocompression, morpholinyl, thiomorpholine, thiomorpholine-sulfoxide, thiomorpholine, 1,3-dioxolane and tetrahydro-1,1-dioxo-thienyl, dioxane, isothiazolinones, titanyl, thiiranes, triazinyl and triazolyl etc.

Examples of bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothiazyl, hinokitiol, chinoline, chinoline-N-oxide, tetrahydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, chromones, coumarinyl, cinnoline, honokalani, indazoles, pyrrolopyridine, properidine(such as furo[2,3-C]pyridinyl, furo[3,1-b]pyridinyl or furo[2,3-b]pyridinyl), dihydroisoquinolyl, dihydroquinazolines, (such as 3,4-dihydro-4-oxo-hintline), benzisothiazole, benzisoxazole, benzodiazines, benzofurazanyl, benzothiophene, benzotriazolyl, benzimidazolyl, dihydrobenzofuran, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, indolinyl, isopropanol, isoindolines, naphthyridine, phthalazine, piperonyl, purinol, iridoviridae, hintline, tetrahydroquinoline, cyanophoric, cyanopyridyl, theNational etc.

Examples of the substituents at the "ring system", "heterocycle", "heterocyclic" moiety and heterocyclyl include one or more of the substituents described above as the substituents for substituted alkyl or substituted aryl, and heterocyclic compounds of smaller size, such as epoxides, aziridines etc.

The term "alkanoyl" refers to the radical-C(O)-alkyl.

The term "substituted alkanoyl" refers to-C(O)-substituted to the alkyl.

The term "heteroatom" includes oxygen, sulfur and nitrogen.

The compounds of formula I form salts with various organic and inorganic acids. Such salts include salts formed with hydrochloric acid, Hydrobromic acid, methanesulfonate, hydroxyethanesulfonic, sulfuric acid, acetic KIS is Auteuil, triperoxonane acid, maleic acid, benzosulfimide, toluensulfonate and various other acids known to the expert in the field of pharmacology. Such salt is produced by interaction of the compounds of formula I with an equivalent amount of acid in the medium in which the salt precipitates or in an aqueous medium followed by evaporation of the solution.

In addition, can be obtained zwitter ions ("inner salts"), they are also covered by the term "salt"used in this description.

Especially preferred analogue epothilone among the compounds of formula I is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,-16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethynyl]-4-Aza-17-oxabicyclo-[14.1.0]heptadecane-5,9-dione, described by formula II:

Compounds described by the above formulas I and II, also called herein "epothilone compounds according to the invention, their receipt as described in the application U.S. No. 09/170582, filed October 13, 1998, and in the application 09/280191 filed March 29, 1999

Compounds represented by formulas I and II may be in the form of numerous optical, geometric and stereoisomers. Although the compounds described in this application are presented in the same optical orientation, the scope of the present invention includes all isomers and mixtures thereof.

With the organisations, represented by formulas I and II above, are agents, stabilizing microtubules. Therefore, they are suitable in the treatment of various cancers and other proliferative diseases including, without limitation, the following diseases:

carcinoma, including bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, neck, thyroid and skin, including squamous carcinoma cells;

gemoliticheskie tumors of the lymphoid system, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, lymphoma B-cell lymphoma T-cell lymphoma Hodgkins, lymphoma non-Jackinsky, lymphoma hairy cell and Burkitt's lymphoma;

gemopoeticescoe tumor myeloid system, including acute and chronic myelogenous leukemia, and promyelocytic leukemia;

tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

other tumors, including melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma;

tumors of the Central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and swannery;

tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma, and

other tumors, including melanoma, xeroderma pigmentation, keratoakantoma, seminoma, thyroid follicular the popular cancer and teratocarcinoma.

Compounds represented by formulas I and II are suitable for the treatment of patients who had been treated for cancer, as well as those, which have not been subjected to such treatment. Indeed, the methods and compositions according to this invention can be used in second-line therapy in the treatment of cancer. In addition, compounds represented by formulas I and II are suitable for treatment of resistant cancer.

Compounds represented by formulas I and II, also inhibit angiogenesis, the effect on tumor growth and providing treatment of tumors and related tumors violations. Such antiangiogenic properties of the compounds of formulas I and II are also useful in the treatment of other conditions susceptible to antiangiogenic agents, including, without limitation, certain forms of blindness related to retinal vascularization, arthritis, especially inflammatory arthritis, multiple sclerosis, restenosis, and psoriasis.

Compounds represented by formulas I and II, induce or inhibit apoptosis, a physiological process of cell death is critical for normal development and homeostasis. Changes in apoptotic pathways affect the pathogenesis of various diseases in humans. Compounds represented by formulas I and II, as modulators of apoptosis suitable for treatment of various diseases in people with aberration of apoptosis, including, without limitation, Raco is s disease, precancerous lesions, diseases associated with the immune response, viral infections, degenerative diseases of the musculoskeletal system and diseases of the kidney.

Each of the compounds represented by formulas I and II may be contained in the product or be administered with other therapeutic agents, which are selected because of their special usefulness for combination therapy of the abovementioned conditions. For example, each of the compounds of formulas I and II can type in the product along with agents to prevent nausea, hypersensitivity, irritation of the stomach, such as anti-emetics, H1and H2antihistamines. The above-mentioned therapeutic agents when used in combination with the compounds of formulas I and II can be used in amounts indicated in the Physicians' Desk Reference (PDR) or determined by the expert in this field.

Further, the compounds of formulas I and II can be administered in combination with other anti-cancer and cytotoxic agents and treatment modalities used in the treatment of cancer or other proliferative diseases. Especially useful are combinations of anti-cancer and phytotoxicity medication, when the second selected drug works by a different mechanism or another phase of the cell cycle, such as S-phase compared to link the m formulas I and II, showing its effect in the G2-M-phase. Examples of such classes of anti-cancer and cytotoxic agents include, without limitation, alkylating agents such as nitrogen mustard analogues, alkyl sulphonates, nitrosamine, ethylenimine and triazine; antimetabolites such as folate antagonists, purine analogues, and pyrimidine analogues, antibiotics, such as anthracyclines, bleomycin, mitotyping, dactinomycin and plicamycin, enzymes such as L-asparaginase, inhibitors farnesyltransferase, hormonal agents such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and antagonists of luteinizing hormone releasing hormone, acetate octreotide, agents that Deplete microtubules, such as ecteinascidin or their analogs and derivatives, agents, stabilizing microtubules, such as paclitaxel (Taxol®), docetaxel (Taxotere®); products of vegetable origin, such as alkaloids family Vinca, epipodophyllotoxins, taxanes, and topoisomerase inhibitors, inhibitors Plenipotentiaries and mixed agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, coordination complexes of platinum, such as cisplatin and carboplatin, and other agents used as anti-cancer and cytotoxic agents such as modify atory biological response growth factors, immune modulators and monoclonal antibodies. Compounds represented by formulas I and II may also be used in combination with radiation therapy.

Examples of this group of anti-cancer and cytotoxic agents include, without limitation, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustin, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, tioguanin, mercaptopurine, fludarabine, pentostatin, cladribine, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubitsin, bleomycin sulfate, mitomycin C, actinomycin D, saframycin, chinacartimes, discodermolide, vincristine, vinblastine, vinorelbine tartrate, etoposide, teniposide, paclitaxel, tamoxifen, estramustine, estramustine sodium, flutamide, buserelin, leuprolide pteridine, dieny, levamisole, flacon, interferon, interlatin, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethasone, gemcitabine hydrochloride, altretamin and topotek and any of their analogues and derivatives.

Preferred representatives of these compounds are, without limitation, paclitaxel, cisplatin, carboplatin, doxorubicin, karminomitsin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin is h, 5-fluorouracil, 6-mercaptopurine, gemcitabine, citizenoriented, podophyllotoxin or derivatives podofillotoksina, such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leirosidin, vindesine and Larsen.

Examples of anticancer and other cytotoxic agents include the following compounds: inhibitors of cyclin-dependent kinases, such as described in the application WO 99/24416, and inhibitors Plenipotentiaries described in applications WO 97/30992 and WO 98/54966.

Connections can also enter together with anti-cancer and cytotoxic agents, which is neurotoxic, that is detrimental to the nervous system or after these agents.

Not limited to any theory, considering the mechanism or the morphology of the compounds represented by formulas I and II can also be used to treat diseases other than cancer or other proliferative diseases. Such diseases include, without limitation, viral infections, for example herpes virus, poxvirus, Epstein-Barr virus Sindbis and adenovirus; autoimmune diseases such as systemic lupus erythematosus, immune glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus; neurodegenerative diseases, such as illness who Alzheimer's disease, associated with SPID Ohm dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy of the brain and cerebral degeneration, AIDS, myelodysplastic syndromes, aplastic anemia, myocardial infarction, associated with ischemic injury, brain stroke and damage during reperfusion injury, restenosis, cardiac arrhythmias, atherosclerosis, liver disease caused by toxins or alcohol, hematological diseases, such as chronic anemia and aplastic anemia; degenerative injuries of the musculoskeletal system, such as osteoporosis or arthritis, rhinosinusitis, susceptible to aspirin, cystic fibrosis, multiple sclerosis, kidney diseases and pain in cancer.

Compounds represented by formulas I and II, especially the last, are difficult to obtain formulations based on them, because they have very low solubility in water, quickly decompose upon contact with an aqueous medium, are sensitive to low pH, while in solution, sensitive to the action of light, are cytotoxic (class D) and extremely poorly wetted. Any one or two of these characteristics can be compensated for by obtaining a pharmaceutical preparation for intravenous injection, but the combination of all of these disadvantages is shatrugna the Oia for a specialist in obtaining drugs. Considering the fact that all substances that must be used to obtain the composition for intravenous, must meet the requirements of such components for intravenous injection, was unexpected that the composition obtained according to this invention, made it possible to overcome all the drawbacks epothilone above that make it difficult to obtain formulations based on them.

First, due to the fact that these analogues epothilone poorly soluble in water and rapidly decompose upon contact with this environment, it was decided to use the freeze-dried form of these compounds. It was found that a suitable environment for the solution of these compounds for lyophilization is a mixture trebuetsya and water for injection. This mixture should contain at least about 50%.about., preferably, from about 50% to about 80%.about. tertiary butanol to prevent decomposition of the aforementioned analogues epothilone. In addition, due to very poor wettability of such analogs epothilone the initial solution should be obtained using a mixture of at least about 60% vol./about., preferably, about 60-95%.about. trebuetsya and water. Once the solution is obtained, you can add the required amount of water or a mixture trebute is - water to achieve a final concentration of solution for lyophilization, above.

Unexpectedly, it was found that the stability of such analogs epothilone can be significantly improved by implementing a solution at about 15°more preferably, at a temperature of about 5°C. Further, both process - getting solution and subsequent lyophilization should be conducted in such vessels, that the analogues epothilone were protected from light exposure. Beneficial to lyophilization relatively small batches to analogues epothilone was exposed to the water environment within the minimum span of time.

The first stage of drying by lyophilization solution obtained as described above is carried out at temperatures from about -10°C to about -40°preferably at a temperature of about -25°With, in conditions of high vacuum, that is, from about 50 mtorr to about 300 mtorr, preferably, about 200 mtorr, over an extended period of time, namely, from about 24 hours to about 96 hours, preferably about 48 hours. Lyophilization at the specified temperature results in an amorphous product, which is desirable for intravenous drug. Specialists obvious that the usual methods, such as powder diffr the Ktsia X-rays, can be used to confirm the amorphous nature of lyophilized product.

The residual solvent in the resulting product are removed in the second stage of drying, which is carried out at relatively low temperatures, namely from about 10°With up to about 30°preferably at a temperature of about 25°C, under conditions of high vacuum, namely, from about 50 mtorr to about 300 mtorr, preferably at about 150 mtorr, over an extended period of time, namely, in a period of from about 24 hours to about 96 hours, preferably for about 48 hours.

Unexpectedly, it was found that the stability of lyophilised analogues epothilone described in this application does not improve with the use of excipients that are commonly used for these purposes, such as lactose, mannitol, dextrin, etc. Some of these excipients may actually have a negative impact on the stability of the lyophilized product (freeze-dried). Therefore, analogues epothilone, preparative forms which are in accordance with this invention, lyophilizers in pure form, i.e. without any excipient.

Lyophilized analogues epothilone represented by formulas I and II, recreated upon receipt of a mixture of equal parts by volume digidratirovannogo the alcohol, Dehydrated Alcohol, USP, and non-ionic surfactants, preferably polyethoxyethanol castor oil, produced by GAF Corporation, Mount Olive, New Jersey, under the trademark Cremophor EL. Lyophilized product and media to recreate Packed separately in the dark bottles. To minimize the amount of surfactant in the reconstructed solution at getting the solution add only sufficient to obtain a solution, the number of media to obtain a solution having a concentration of similar epothilone from about 2 to about 4 mg/ml once the drug dissolved, the resulting solution is diluted before injection suitable for injecting a diluent. Such diluents are well known in the art. These thinners are usually available in clinics. In the framework of the present invention also provides for the availability of packing analogues epothilone third vial containing a sufficient amount of parenteral diluent to achieve the final concentration. The preferred diluent is a solution of ringer's lactate. The final concentration of the solution for injection is preferably from about 0.1 mg/ml to about 0.9 mg/ml

The final dilution of the reconstituted analog epothilone in the composition according to the invention can about usestat, using other suitable drugs, such as 5% Dextrose Injection, ringer's solution with lactate and dextrose, sterile water for injection, etc. However, due to the narrow range of pH, pH=6,0-7,5, it is preferable to ringer's solution with lactate. The ringer's solution with lactate contains 100 ml: sodium chloride UPS 0.6 g, sodium lactate 0.31 g, potassium chloride UPS 0.03 g calcium chloride × 2H2O UPS of 0.02, Osmolarity equal to 275 mosmol/l, which is very close to isotonic solution.

The resulting preparation according to this invention, namely the solution of similar epothilone in the media, representing the alcohol and surfactant, can be stored for up to about 24 hours before further dilution in the introduction. It was found that the occurrence of allergic reactions due to the presence of surfactants in the composition is reduced to a minimum while maintaining the minimum required for dissolving similar epothilone concentration. In addition, the occurrence of such reactions occur to the same extent as when injecting other drugs, such as cyclosporine. This observed level manifestations of allergic reactions when applying the composition according to the invention is significantly lower than with some other cancer agents such as Paclitaxel.

This image is eenie also provides for methods of treating cancer and other hyperproliferative diseases of the patients, includes introduction to the patient a therapeutically effective amount of one or more compounds represented by formulas I and II. The compounds of formula I and II can be administered intravenously or orally, preferably, orally and intravenously. Preferably the compounds of formulas I and II with one or more additional agents to prevent nausea, hypersensitivity or irritation of the gastrointestinal tract, such as antiemetic or H1or H2antihistamines connection.

The amount of compounds of formulas I and II, entered by each IV infusion or oral, or both, may be determined by the person skilled in the art, for example, for a person use a dose from about 0.01 mg/kg/day to about 200 mg/kg/day, which can be injected once or in divided doses, for example, 1-4 times a day. Preferably the compounds at a dose of less than about 100 mg/kg/day and, more preferably, less than 25 mg/kg/day once or approximately 2-4 divided doses. It should be borne in mind that the specific dose and frequency of use for any particular subject may vary and depend on a number of factors including the activity of the specific compound, the metabolic stability and length of action of that compound, the species of the subject, age, weight, General condition,sex, and diet, the method and time of administration, rate of excretion, drug combination and the degree of development of the disease. Preferred subjects treated are the animals most preferred mammals, such as humans and domestic animals, such as dogs, cats, etc. suffering from these diseases.

Typically, compounds of formulas I and II are administered before until the patient has no reaction occurs, such as a decrease in tumor size, or not yet achieved the dose limiting toxicity. The specialist will be clear when the patient detects the reaction or when you reach the dose determines toxicity. Usually the dose determines toxicity associated with the compounds of formulas I and II is shown but is not limited to, fatigue, arthralgia/myalgia, anorexia, hypersensitivity, neutropenia, thrombocytopenia and neurotoxicity.

When administered intravenously, the compounds of formulas I and II, preferably introduced in the form of compositions according to the invention. Typically, compounds of formulas I and II when injected IV infusion over about 10 minutes to about 3 hours, preferably for from about 30 minutes to about 2 hours, more preferably for about 45-90 minutes and, most preferably, for about 1 hour. Usually the compounds are administered intravenously in a dose of from primer is 0.5 mg/m 2up to 65 mg/m2preferably, from about 1 mg/m2up to 50 mg/m2more preferably, from about 2.5 mg/m2up to 30 mg/m2and, most preferably, at a dose of about 25 mg/m2.

Professionals in this field know how to recalculate the dose of mg/kg per mg/m2if you know the weight and/or height of the patient (see, for example, http://www.fda.gov/cder/cancer/animalframe.htm).

The oral method of introducing the compounds of formulas I and II, preferably, is administered in combination with a pharmaceutically acceptable buffer, neutralizing the acid. The buffer neutralizes the acid in the stomach of the patient, and the rate of decomposition of the compounds of formulas I and II is significantly reduced, and they remain in the gastrointestinal tract over a period sufficient for their absorption. Compounds of formulas I and II can be entered together with antacid, such as aluminium hydroxide and magnesium carbonates, for example sodium carbonate and calcium carbonate, silicates and phosphates, to neutralize acid in the stomach before, during and after administration of the compounds of formulas I and II.

Used in this description, the term "pharmaceutically acceptable buffer, neutralizing the acid"refers to a combination of pharmaceutically acceptable non-toxic acid and pharmaceutically acceptable non-toxic salts of the acids, which when added to the solution provide a solution, of which the first is more resistant to changes in pH compared to the solution without buffer when acid or alkali is added to the solution. The term "pharmaceutically acceptable buffer, neutralizing the acid"also includes compounds such as basic compounds, which when added to the acid solution to neutralize the acid and increases the pH of the solution.

According to one variant of the invention the compounds of formulas I and II and pharmaceutically acceptable buffer, neutralizing the acid, administered orally in the same dosage form at the same time. A composition comprising a combination of compounds of formulas I and II may be administered orally in solid dosage forms (e.g. tablets, capsules or powder) or liquid dosage forms (e.g., solution, suspension or elixir). The solution or suspension can be prepared before the introduction with the use of suitable solvents or co-solvents for dissolving epothilone and components of the buffer.

For example, the compounds of formulas I and II and pharmaceutically acceptable buffer, neutralizing the acid, can be introduced simultaneously administered orally in the form of a solution epothilone formula I or II, dissolved in a liquid containing propylene glycol:ethanol:phosphate buffer (for example, 1M, pH 8) in a ratio of 58:12:30, respectively.

Compounds of formulas I and II and pharmaceutically acceptable buffer, neutralizing the acid, may also be in the form of section is different pharmaceutical compositions, which is administered separately. Each of these compositions is introduced in the form of a solid dosage form or liquid dosage forms for oral administration. If the compounds of formulas I and II and pharmaceutically acceptable buffer, neutralizing the acid, injected separately, pharmaceutically acceptable buffer, neutralizing the acid, may be administered orally before, after, or before and after of the compounds of formulas I and II. Preferably, the pharmaceutically acceptable buffer, neutralizing the acid, to enter before and after oral administration of the compounds of formulas I and II in a quantity sufficient to neutralize the acid in the stomach. When a pharmaceutically acceptable buffer, neutralizing the acid, is injected before the intake of the compounds of formulas I and II, it is introduced for 5 hours, preferably about 3 hours, more preferably for about 1 hour and most preferably about 10 minutes before the introduction of the compounds of formulas I and II. When a pharmaceutically acceptable buffer, neutralizing the acid, is administered after administration of the compounds of formulas I and II, it is introduced after about 5 hours, preferably about 3 hours, more preferably, approximately 1 hour and, most preferably, approximately 10 minutes after administration of the compounds of formulas I and II.

Compounds of formulas I and II can be introduced in the form of pills or capsules interoperation for the ease in which osvobojdenie epothilone until until you type a pharmaceutically acceptable buffer, neutralizing the acid. Tablets and capsules with interoperation represent these forms coated with substances which are resistant to gastric juice, but crushing in intestine.

Typically, pharmaceutically acceptable buffer, neutralizing the acid, is administered in a quantity sufficient to deliver at least about 20 mEq of acid neutralizer, preferably at least about 30 mEq of acid neutralizer, more preferably at least about 40 mEq of acid neutralizer and, most preferably, about 50 mEq of acid neutralizer.

Typically, pharmaceutically acceptable buffer, neutralizing the acid, is injected in the form of an aqueous solution having a pH between 5 and 9, preferably about 6-8,5 and, more preferably, about 7-8. When implementing methods according to the invention can be applied to any pharmaceutically acceptable buffer, neutralizing the acid, which produces a solution with a pH in the desired range. It is preferable to apply a pharmaceutically acceptable buffer, neutralizing the acid, which represents a dibasic phosphate monotony phosphate or dibasic phosphate - citric acid - citrate.

For example, the oral route of administration of the compounds of formulas I and II may include a first peroral the first introduction to the patient pharmaceutically acceptable buffer, neutralizing acid in 150 ml of an aqueous solution containing anhydrous dibasic sodium phosphate (about 0.2 M), dihydrate sodium citrate (about 0.07 M) and anhydrous citric acid (about 0,008 M) at pH about 7.4, followed by oral administration of the compounds of formulas I and II in the form of liquid dosage forms in a mixture of propylene glycol:ethanol with the ratio of 80:20 with the further introduction of other oral servings (about 150 ml) of an aqueous solution containing anhydrous dibasic sodium phosphate (about 0.2 M), dihydrate sodium citrate (about 0.07 M) and anhydrous citric acid (about 0,008 M) at pH of about 7.4.

As indicated above, the compounds of formulas I and II can be administered orally, intravenously or orally/intravenously. In particular, the methods of the invention include protocols introduction, such as once a day for 2 to 10 days, preferably within 3-9 days, more preferably within 4-8 days and, most preferably, within 5 days. According to one variant of the introduction includes the period from 3 days to 5 weeks, preferably from 4 days to 4 weeks, more preferably, from 5 days to 3 weeks and, most preferably, from 1 to 2 weeks between cycles, when treatment is not performed. According to another variant, the compounds of formulas I and II can be administered orally, intravenously or orally/intravenously once per day is 3 days with a break in 1-3 weeks between cycles, when treatment is not performed. According to another variant, the compounds of formulas I and II can be administered orally and/or intravenously once for 5 days with a break, preferably, within 1-3 weeks, when treatment is not performed.

According to a preferred variant of the cycle of introduction of the compounds of formulas I or II include daily administration once a day for 5 days with a break between cycles of treatment from 2 to 10 days, preferably within one week.

Compounds of formulas I and II can be administered orally and/or intravenously once per week for 1 to 10 weeks, preferably within 2 to 8 weeks, more preferably for a period of 3-6 weeks, even more preferably within 3 weeks.

According to another method according to the invention compounds of formulas I and II administered for 28-day cycle, when the compound of formula I or II are administered intravenously in the 1st, 7th and 14th day and administered orally on the 21st day. Otherwise you can type compounds of formulas I and II during the 28-day cycle, with compounds of formulas I and II administered orally at day 1 and injected at the 7th, 14th and 28th day.

According to the methods according to the invention compounds of formulas I and II is administered as long as the patient does not have the reaction of, for example, there will be a reduction in tumor size or until until you reach the limit toxin the property.

Many anticancer agents are neurotoxic, for example, it is known that they cause side effects affecting the Central and peripheral nervous system. The invention further encompasses the use of compounds of formulas I and II for the treatment of patients who were observed neurotoxicity after use of other anticancer agents. Although the compounds according to the invention can also be neurotoxic in some doses, methods according to the invention can be applied to reduce or eliminate such toxicity.

The following examples serve to illustrate this invention without limiting its scope.

Example 1: IV dosage form.

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-Penta-methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethynyl]-4-Aza-17-oxabicyclo[14.1.0]-heptadecane-5,9-dione, 9,86 g were wet/partially dissolved in 600 ml of a mixture of 9:1 trebuetsya and water for injection USP, which was previously cooled to 5°C. as soon As was achieved complete wetting of the powder medicine, has completed its dissolution by adding 600 ml of a mixture of 9:1 trebuetsya and water for injection and 766 ml of a mixture 1:1 trebuetsya and water for injection, which was pre-cooled to 5°S, with a final solution representing a mixture of 1:1. The dissolution was carried out in conditions of protection from light is A.

The above solution was subjected to lyophilization in liofilizadora Virtis INOTOP at -16°With protection from light for 48 hours. The obtained freeze-dried product (lyophilized) was then dried at 15°C in high vacuum for 48 hours. During the implementation of these procedures was not observed appreciable decomposition of the drug. The lyophilisate was Packed in sterile vials with a volume of 30 ml each vial contained 10 mg of the drug and the standard excess for loss of medication in the vial/syringe.

The lyophilisate was recreated with the help of 5.5 ml of a mixture 1:1 by volume of Dehydrated Alcohol USP and Cremophor EL®that usually comes along with the medicine in a separate vial, to obtain a final concentration of drugs, equal to 2 mg/ml as soon As dissolution with careful rotation of the vial is complete, the resulting solution is diluted to achieve a concentration of 0.2 mg/ml by adding 9 ml of ringer's solution with lactate for each ml of reconstituted drug product.

Example 2: IV Introduction the compound (II).

The group, consisting of 24 cancer patients (12 men and 12 women), compound II with IV infusion in order to determine the maximum tolerance dose (MTD), dose limiting toxicity (DLT), pharmacokinetics and pharmacodynamics, and to evaluate the antitumor activity Conn is in II. Mean age (range) patients was equal to 57 (34-74). Five patients had breast cancer, 5 - head and neck cancer, 2 patients had sarcoma, 2 - colorectal cancer, 2 - cancer engineers, in 2 patients with melanoma, even in 2 - esophageal cancer, one patient had cancer of the kidney, one - cervical cancer, another one - thyroid cancer and one had cancer of the anus. 21 the patient was previously chemotherapy (18 took neurotoxic agents and 18 had a course of radiotherapy). The average number of lines of chemotherapy, including adjuvant, was equal to 2 (1-3).

Patients received oral compound II in 1 day (in doses of 20 mg/m2and above) with a subsequent 30-minute IV infusion of compound (II) every week, starting from the seventh day. Patients were administered the compound II in doses 1, 2,5, 5, 10, 20, 25 and 30 mg/m2. Conducted monitoring of patients during treatment to determine the dose limiting toxicity (DLT). The results show that the compound II can be administered weekly doses of 30 mg/m2without showing appreciable toxicity.

During the second study in 12 patients, cancer patients (5 men and 7 women), oral introduced compound II on the first day followed a 30-minute IV infusion of compound (II) every week, starting from the 7th day, at a dose of 25 mg/m2to assess the neurotoxicity of compound II. Sredneural patients 51 year (30-65). In 4 patients had cancer of the rectum, 3 breast cancer, 2 patients had melanoma, a cancer of kidney, one - sarcoma and one ovarian cancer. 10 patients have been previously chemotherapy (6 patients received neurotoxic agents and 18 patients underwent a course of radiotherapy). The average number of lines of chemotherapy, including adjuvant, was equal to 2 (0-3). This study showed that the compound II can be entered to the patients who were previously chemotherapy with the use of neurotoxic anti-cancer agents. However, it is preferable that the patients who had taken courses of chemotherapy with the use of neurotoxic anti-cancer agents, the cumulative dose of compound (II) does not exceed about 200 mg/m on one cycle.

Studies have further shown that tumors of the breast and colon in patients previously held chemotherapy, were amenable to treatment by a compound of formula II. In particular, patients with breast cancer who have previously passed courses of treatment with adriamycin and Taxotere with cyclophosphamide, 5-fluoracil, methotrexate; adriamycin and Taxotere with cyclophosphamide, 5-fluoracil, methotrexate or adriamycin, cyclophosphamide, 5-fluoracil to ensure metastases cancer, were amenable to treatment with compound II. Patients suffering from metastases colon cancer, passed earlier course of treatment, the Oia Taxol and carboplatinum; 5-fluoracil and leucovorin or irinotecan, were amenable to treatment with compound II.

Example 3: the Pharmacokinetics of compound (II), administered orally for cancer patients.

Patients with advanced malignant tumors were injected weekly compound of formula II in the form of a 30-minute infusion (rate = 3 weekly intravenous injection). Patients received doses 1, 2,5, 5, 10, 20, 25 or 30 mg/m2. Starting dose is 20 mg/m2patients received a single oral dose of compound II on the 6th day in the media, representing 80% propylene glycol and 20% ethanol (vol./about.) with the subsequent introduction of a citrate/phosphate buffer (22,5 g) before the course 1 to assess the absolute bioavailability of compound II. The dose of compound (II), administered orally on the 6th day, corresponded to a dose of IV compounds II, introduced on the first day. Selected plasma samples on the 6th day and the first day of the course 1 to assess the pharmacokinetics using system LC/MS/MS.

The samples were analyzed by adding an internal standard to 0.2 ml of plasma sample, precipitating acetate and then extragere supernatant 1-chlorbutanol. The organic layer was removed and evaporated to dryness. The residue was recreated and introduced into the system LC/MS/MS. produced chromatographic separation on a column of YMC ODS-AQ (4,6×50 mm, 3 m) with mobile phase acetonitrile:0.01 M ammonium acetate, pH 5.0 (65:35). Detect the W was carried out using tandem mass spectrometry with ionization by elektrorazpredelenie. A standard curve in the range from 2 to 500 ng/ml for all analytes were consistent with model 1/x-weighted quadratic regression.

Compound II for oral administration of 25 mg/vial contained as "medicine in a bottle" ("drug in bottle"). Media (buffer) to recreate the compound (II), 25 mg/vial, was a mixture of 80% propylene glycol and 20% ethanol (vol./vol.). A mixture of propylene glycol/ethanol was prepared by mixing 80 hours By volume of propylene glycol and 20 o'clock on the volume of ethanol in a suitable vessel, and the vessel was gently rotated until complete mixing of the components of the solution.

Citrate-phosphate buffer for oral administration after administration of compound (II) was in a separate vial. The buffer compound II was recreated using water for injection (WFI). Compound II was prepared for administration to patients, using a suitable syringe for slow injection of 2.5, 5 or 10 ml of a mixture of propylene glycol/ethanol in a bottle with a capacity of 20 cm3containing 25 mg/vial of compound II, to obtain solutions with concentrations of 10, 5 or 2.5 mg/ml, respectively, depending on the dose, you need to put the patient. The needle of the syringe was removed and vigorously shook the bottle for 10 seconds. The vial was placed in a bath with ultrasound impact, and this impact was carried out to obtain a clear solution. The vials were grouped depending the dose.

The buffer for the introduction together with the compound II was delivered in a clear glass bottle (8 ounces), it was recreated using water for injection (WFI). The tube was removed from the vial and added 140 ml of water for injection (WFI). The vial was vigorously shaken or subjected to the influence of ultrasound and was shaken to obtain a clear solution.

After oral administration on the 6th day the samples were drawn blood 7 ml tube (Becton Dickinson Vacutainer using as an anticoagulant K3EDTA (the upper part of the color lavender) according to the following scheme (expressed in hours:minutes from the start of oral administration): before the introduction of dose, 00:15, 00:30, 00:45, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00, 48:00 and 72:00. After IV infusion on day 1 was selected samples (7 ml) blood tube (Becton Dickinson Vacutainer using as an anticoagulant K3EDTA (the upper part of the color lavender) according to the following scheme (expressed in hours:minutes from the start of the IV infusion): before the introduction of dose, 00:15, 00:30 (end of infusion), 00:45, 1:00,1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00, 48:00 and 72:00.

Immediately after blood collection tube Vacutainer several times turned to ensure mixing with anticoagulant, and then immediately placed in crushed ice. 30 minutes after sampling the samples were centrifuged for 5 minutes at a speed of about 2000 × g and at a temperature of from 0 to 5°C. Then put the plasma on the individual polypropylene tubes with screw caps and labels and store them at -70° With before bioanalysis. The concentration of compound II in plasma was determined by the method LC/MS/MS.

The concentration of plasma depending on time was determined using compartmentally analysis. Pharmacokinetic parameters defined for the compound (II) included maximum plasma concentration (Cmax), time to reach Cmax (TM), area under the curve of the dependence of concentration on time from time 0 to time of last selection of the sample T (AUC(0-T)).

18 patients received connection II oral in the form of a solution on the 6th day and by IV in 1 day. The pharmacokinetic parameters obtained in these patients are presented in Table 1.

the solution for peroral. introduction
Table 1.

Pharmacokinetic parameters in patients who were administered compound II oral and intravenous.
Dose (mg/m2)202530
N3114
MethodIVperoral.IVperoral.IVperoral.
CompositionIVthe solution for peroral. introductionIVIVthe solution for peroral. introduction
CMAXa(ng/ml)251 (108)142 (106)447 (189)180 (110)711 (530)274 (104)
TMb, (h)0,25 (0,25, 0,25)1,0 (0,25, 1,50)0,50 (0,25, 0,50)0,50 (0,25, 3,00)0,50 (0,25, 0,50)0,50 (of 0.25, 0.75 in)
AUC(0-T)a,C(h·ng/ml)796 (587)404 (381)848 (284)533 (577)1155 (292)708 (291)
% F3not ODA.43,5 (16,1)not ODA.55,6 (18,4)not ODA.62,2 (25,1)
athe mean (standard, off.)

bmean (min, max)

creflects the AUC(0-T)

Variants of the invention described above are intended for simple illustration, and specialists in this field can, using nothing except routine experimentation, to make numerous equivalent compounds, materials and methods. All such equivalents are within the scope of this invention, the scope of which is defined by the claims.

1. The method of preparation of the composition on the basis of similar epothilone, is expressed by the formula

and/or geometric, optical and stereoisomers, including

a) dissolving the specified analog epothilone in a mixture containing at least about 50 vol.% trebuetsya in water, obtaining a solution;

b) the first stage of drying the specified solution under high vacuum to about 300 mtorr for a period of time sufficient to obtain primary lyophilized product

in the second stage of primary drying lyophilized product under vacuum for a period of time sufficient to obtain a lyophilized product of similar epothilone.

2. The method according to claim 1, characterized in that the specified analog epothilone represented by formula II

3. The method according to claim 1 or 2, characterized in that in stage (a) the specified analog epothilone first moisten the mixture, at least about 60% trebuetsya with water and then to the resulting product add water or a mixture trebuetsya and water in sufficient quantity to ensure that the resulting solution contains from about 2 mg/ml to about 30 mg/ml of the indicated analog in a mixture containing from about 50 vol.% to about 80 vol.% trebuetsya in the water.

4. The method according to claim 3, characterized in that in stage (a) the specified analog of the early moisten the mixture is from about 60% to about 95% by volume trebuetsya and water.

5. The method according to claim 1 or 2, characterized in that the first stage of drying is carried out at a temperature of about -16°and a pressure of from 200 to 300 mtorr.

6. The method according to claim 1 or 2, characterized in that the second stage of drying is carried out at a temperature of about 16°and a pressure of from 150 to 300 mtorr.

7. The method according to claim 1 or 2, characterized in that at least one of the stages is carried out in the dark.

8. The method according to claim 1 or 2, or 7, further comprising packaging lyophilized product of similar epothilone first bottle and packaging in the second vial, the means for recovery of lyophilized product.

9. The method of claim 8, wherein said means for restoring includes digidrirovanny alcohol and nonionic surfactant.

10. The method according to claim 9, characterized in that the means for recovering contains equal parts by volume digidrirovanny alcohol and polyethoxysiloxane castor oil.

11. The method according to claim 1 or 2, characterized in that stage a) dissolving similar epothilone carried out at a temperature below the ambient temperature.

12. The method according to claim 11, characterized in that in stage (a) the specified analog epothilone first moisten the mixture, at least about 60% trebuetsya with water and then to the resulting product add water or a mixture trebuetsya and water in sufficient quantity to that is Oh, to the resulting solution contains at least 50 vol.% trebuetsya in the water.

13. The method according to claim 11 or 12, characterized in that the dissolution of similar epothilone carried out in the absence of filler.

14. The method according to any of 11 to 13, characterized in that the first stage of drying is carried out at a temperature of about -16°and a pressure of from 200 to 300 mtorr for about 96 hours

15. The method according to any of 11 to 13, characterized in that the second stage of drying is carried out at a temperature of about 16°and a pressure of from 150 to 300 mtorr for about 96 hours

16. Method of lyophilization similar epothilone, namely, that similar epothilone formula (II)

and/or geometric, optical or stereoisomer dissolved in a mixture trebuetsya in the water, and then the resulting solution was dried under vacuum to obtain a lyophilized epothilone equivalent.

17. Lyophilized similar epothilone obtained by the method according to item 16.

18. Pharmaceutical agent for the treatment of cancer containing lyophilized similar epothilone prepared by the method according to any one of claims 1 to 7 or 11-16.

19. Pharmaceutical agent for the treatment of cancer, obtained by the method according to any of PP-10.

20. Pharmaceutical agent for the treatment of cancer, containing at least one bottle with liofilizirovannam similar epothilone Ave is prepared by the method according to any one of claims 1 to 7 or 11-16 and the second bottle with means for recovery of lyophilized similar epothilone.



 

Same patents:

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.

EFFECT: valuable medicinal properties of complexes.

4 cl, 2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the formula (I): m means a whole number from 1 to 3; R1 represents halogen atom or (C1-C3)-alkyl; X1 represents -O-; R2 represents (C1-C5)-alkyl-R3 wherein R3 represents piperidine-4-yl that can comprise one or two substitutes chosen from (C1-C4)-alkyl and to their salts. Also, invention relates to methods for synthesis of these compounds and pharmaceutical compositions comprising compound of the formula (I) or its pharmaceutically acceptable salts as an active component. Compounds of the formula (I) and their pharmaceutically acceptable salts inhibit effect of VEGF that is a valuable property in treatment of different pathological states including cancer and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

28 cl, 14 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to using compound of the formula (I) as the first anti-tumor agent for preparing a medicinal preparation that in administration with the second anti-tumor agent prevents development of resistance of malignant cells to apoptosis as result of activation of NFKB by the indicated second anti-tumor agent. Invention provides enhancing effectiveness of treatment.

EFFECT: improved and valuable medicinal properties of agent.

15 cl, 4 tbl, 3 ex

FIELD: medicine, pharmacology.

SUBSTANCE: agent represents flavolignans chosen from silybinine, silydianine, silycrystine, dehydrosilybinine, their mixtures or extracts prepared from plant spotted milk thistle (Silybium marianum (L.) Gaertn) containing these components. Agent is used for inhibition of excessive or pathological proliferation of vascular endothelium. Proposed agent expands assortment of agents directed for treatment pathologies associated with angiogenesis disorders. Invention can be used in development of medicinal preparations used in therapy of pathologies associated with angiogenesis disorders, namely, for inhibition of excessive or pathological proliferation of vascular endothelium.

EFFECT: valuable medicinal properties of agent.

1 tbl, 2 dwg, 2 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a method for enhancing availability of epotilone analog. Method involves oral administration of epotilone analog or its pharmaceutically acceptable salt, solvate, clathrate, hydrate or a prodrug in mammal in combination with pharmaceutically acceptable buffer neutralizing acid in the amount providing at least 20 mequiv. of capacity for acid neutralization that results to improving bioavailability of epotilone.

EFFECT: improved properties of formulations of drug.

20 cl, 5 tbl, 2 dwg, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a composition used in solubilization of paclitaxel. The composition comprises the following components, wt.-%: monoolein, 40-89.99 (or 40-64.7 as variants); oil, 10-59.99 (or 25-49.7 as variants), and paclitaxel, 0.3-4 (or 0.01-10 as variants), and to a method for preparing such composition. Paclitaxel-containing compositions don't comprise potentially toxic surface-active substances, show stability for prolonged time and possess high mucoadhesive capacity and high bioavailability.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

22 cl, 5 tbl, 3 dwg, 19 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out combined chemotherapy according to AC-scheme of adriamycin+cyclophosphane. Bioorganic preparation of animal origin is intramuscularly introduced in parallel to chemotherapy to a group of rats at a dose of 0.3 ml/100 g of body weight every day during 30 days.

EFFECT: enhanced effectiveness of treatment.

1 tbl

FIELD: medicine, oncology.

SUBSTANCE: one should carry out endoliquor therapy, moreover, after surgical removal of cerebral tumor, in early post-surgical period, it is necessary to fulfill catheterization of subarachnoidal cerebrospinal space at L4-L5 level and apply an endolumbar catheter. Then one should sample 5 ml cerebrospinal fluid and mix it with methothrexate at the dosage of 5 mg and hydrocortisone suspension at the dosage of 50 mg. The mixture should be incubated for 30 min at 37° C to be introduced into subarachnoidal space through endolumbar catheter by flow-type technique. There are 5 such infusions during one therapeutic course at 3-d-long interval. Totally, it is necessary to conduct 3 mentioned courses in combination with 5 cycles of adjuvant systemic polychemotherapy at injecting cytostatics upon autoblood. Application of such complex therapy enables to stabilize generalized tumoral process, increase relapse-free and metastases-free periods and prolong patient's life duration.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, oncology.

SUBSTANCE: one should carry out endoliquor therapy, moreover, after surgical removal of cerebral tumor, in early post-surgical period, it is necessary to fulfill catheterization of subarachnoidal cerebrospinal space at L4-L5 level and apply an endolumbar catheter. Then one should sample 5 ml cerebrospinal fluid and mix it with methothrexate at the dosage of 5 mg and hydrocortisone suspension at the dosage of 50 mg. The mixture should be incubated for 30 min at 37° C to be introduced into subarachnoidal space through endolumbar catheter by flow-type technique. There are 5 such infusions during one therapeutic course at 3-d-long interval. Totally, it is necessary to conduct 3 mentioned courses in combination with 5 cycles of adjuvant systemic polychemotherapy at injecting cytostatics upon autoblood. Application of such complex therapy enables to stabilize generalized tumoral process, increase relapse-free and metastases-free periods and prolong patient's life duration.

EFFECT: higher efficiency of therapy.

3 ex

Fumaric acid amides // 2290946

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to using fumaric acid amides of the formula (I): These compounds are used in preparing a medicinal agent designated for treatment of autoimmune diseases, response reactions "transplant against host", treatment of diseases mediated by NfkappaB, and to fumaric acid amides of the formula (I) and to a medicinal agent comprising fumaric acid amide of the formula (I) taken in the dose corresponding to 1-500 mg of fumaric acid as measured for a single dose and designated for treatment abovementioned diseases. Fumaric acid amides and a medicinal agent comprising thereof are characterized by absence of systemic adverse effect of body and resistance against hydrolysis that allows avoiding their multiply dosing.

EFFECT: valuable medicinal properties of agents.

19 cl, 2 tbl, 3 ex

FIELD: chemical-and-pharmaceutical industry, in particular production of drugs for joint disease treatment.

SUBSTANCE: claimed agent represents lyophilizate containing glucoseamine salt, chondroitin sulfate and trisaminum in specific component ratio.

EFFECT: agent with increased active ingredient content; diffusion of active substance into joint region with increased rate and effectiveness.

2 cl, 3 ex, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the present innovation deals with new stabilized pharmaceutical composition in its lyophilized form including the compound of formula I

as an active ingredient and lactose disaccharide as a stabilizing agent. The present pharmaceutical compositions are of high stability at storage. As for active ingredient it is not destroyed in the course of time.

EFFECT: higher efficiency.

10 cl, 15 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: preparation comprises echinocandine substance of formula I or its pharmaceutically permissible salt, pharmaceutically permissible micelle-forming surface-active agent and non-toxic aqueous solvent and stabilizing agent.

EFFECT: improved stability and bioaccessibility properties.

48 cl, 4 tbl

FIELD: medicine, hematology, pharmacy.

SUBSTANCE: invention relates to the composition of factor VIII composed without addition of albumin and comprising the following excipients of composition in addition to factor VIII: from 4% to 10% of filling agent taken among group consisting of mannitol, glycine and alanine; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance about between 6 and 8. Alternatively, the composition can comprise from 2% to 6% of hydroxyethylstarch; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance between 6 and 8. In additional variant of realization of invention the composition can comprise: from 300 mM to 500 mM of NaCl, from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose and arginine; from 1 mM to 5 mM of calcium salt, and buffer agent. The composition provides stability in the absence of albumin or other proteins.

EFFECT: valuable properties of compositions.

35 cl, 11 tbl, 7 ex

The invention relates to new pharmaceutical compositions that contain the basis or agonist of the basis for the treatment of diabetes, slowing of gastric emptying or reduce food intake, and their dosage forms and methods for their introduction

The invention relates to the field of medicine and relates to a stable form of anti-cancer drug containing paclitaxel, and how it is received by dissolving crystalline paclitaxel in a neutral organic solvent selected from the group consisting of acetonitrile, dioxane, ethanol or mixtures thereof, provided that the contents of the individual solvents in the mixture is in the range from 5 to 95%, whereas the water content is in the range from 0 to 60%, optionally filtering the resulting solution, freezing and removal of the solvent by sublimation under reduced pressure at low temperature, and optional separation of dose in terms providing sterility

The invention relates to pharmaceutical industry
The invention relates to lyophilizate with increased dissolution rate, which can be restored without the formation of particles, which is achieved by re-heating of selected solutions in bottles to a temperature of from 30 to 95With directly in the freeze-dryer for 10 min to 4 h

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a method for enhancing availability of epotilone analog. Method involves oral administration of epotilone analog or its pharmaceutically acceptable salt, solvate, clathrate, hydrate or a prodrug in mammal in combination with pharmaceutically acceptable buffer neutralizing acid in the amount providing at least 20 mequiv. of capacity for acid neutralization that results to improving bioavailability of epotilone.

EFFECT: improved properties of formulations of drug.

20 cl, 5 tbl, 2 dwg, 9 ex

Up!