Epothilone derivative for treatment of hepatome and other cancer diseases

FIELD: medicine.

SUBSTANCE: invention refers to medical products, particularly to application of compound of formula I where A stands for O, R stands for hydrogen or lower alkyl, and Z stands for O to prepare a medicinal agent for treatment of cancer disease chosen from primary cancer of Fallopian tube; primary peritoneal cancer and colorectal cancer progressing after Irinotecan therapy. Besides the invention concerns the pharmaceutical composition including specified compound, therapy of specified diseases and commercial package. formula (I).

EFFECT: agent is characterised with improved effectiveness.

13 cl, 7 ex

 

The present invention relates to a method of treating a warm-blooded animal, especially humans, suffering from cancer, selected from hepatoma; primary cancer of the fallopian tube, primary peritoneal cancer; breast cancer progressing after treatment with hormonal therapy or radiotherapy; renal cell carcinoma, progressing after treatment with the cytokine, radiotherapy and/or nephrectomy; melanoma progressing after radiotherapy; prostate cancer progressing after blindness; of ovarian cancer progressing after treatment with a platinum compound or radiotherapy; and rectal cancer progressing after radiotherapy and/or treatment with oxaliplatin or irinotecan; the method is also applicable for the treatment of metastasizing tumors listed. The method consists in the introduction referred to the animal a therapeutically effective amount of a derivative epothilone formula I, below.

Epothilone, especially epothilone a, b and D, represent a new class of cytotoxic agents, stabilizing microtubules (see K.Gerth and others in J.Antibiot., 49, 1996, SS-563; Hoefle, etc. in DE 4138042).

Unexpectedly, it was found that derivatives epothilone formula I

where a represents an atom of O or NRN, RNmeans a hydrogen atom or lower alkyl, R Osnach is no hydrogen or lower alkyl, a Z denotes O or communication, to be effective in the treatment of such cancers, as hepatoma; primary cancer of the fallopian tube, primary peritoneal cancer; breast cancer progressing after treatment with hormonal therapy or radiotherapy; renal cell carcinoma progressing after treatment with the cytokine, radiotherapy and/or nephrectomy; melanoma, progressive after radiotherapy; prostate cancer progressing after blindness; ovarian cancer progressing after treatment with a platinum compound or radiotherapy; and colorectal cancer progressing after radiotherapy and/or treatment with oxaliplatin or irinotecan; derivatives are also effective in epothilone the treatment of metastasizing tumors listed.

Thus, the invention relates to a method of treating a warm-blooded animal, especially humans, suffering from the above-mentioned cancer. The method consists in the introduction of a warm-blooded animal that is in need, a therapeutically effective amount of a derivative epothilone formula I in which a represents O or NRNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z denotes O or a bond; or its pharmaceutically acceptable salt.

The concept of "hepatoma", as used in the present invention, means cancer C is bolovanje, which is characterized in that at least one of liver tumors derived from malignant hepatocytes. Hepatoma is often the cause of death for residents in some areas of Africa and Southeast Asia. The symptoms of this disease are abdominal pain, weight loss, heaviness in the right hypochondrium and unexpected deterioration in previously stable patient caused by cirrhosis. Sometimes there are systemic metabolic disorders, including hypoglycemia, erythrocytosis, hypercalcemia, and hyperlipidemia. Other diagnostic indicator is the increased level of α-fetoprotein. Such methods of examination of the abdominal cavity, as ultrasound (us), computer tomography (CT) and magnetic resonance imaging (MRI)are important diagnostic tools and sometimes can detect preclinical carcinoma. Treatment of hepatoma, as a rule, is unsatisfactory, because the tumor is not sensitive to ionizing radiation, and chemotherapy usually does not give a positive result.

The concept of "primary cancer of the fallopian tube," as it is used in the present invention include, but are not limited to, malignant disease, which may include one or both fallopian tubes with lesions of the pelvic area or not, and so the e cancer affecting peritoneal implants outside the pelvis and/or metastases.

The term "radiotherapy", as used in the present invention, includes, but is not limited to, treatment with ionizing radiation.

The term "cytokine"as it is used in the present invention include, but are not limited to, interleukin-2 (IL-2) and α-interferon (α-IFN).

The concept of "orchiectomy"as it is used in the present invention, means the removal of one or both testes.

The term "platinum compound", as used in the present invention include, but are not limited to, carboplatin, cisplatin and oxaliplatin.

The term "treatment", as used in the present invention, means the treatment of patients with hepatoma, which is at the preclinical stage of the disease or had undergone resection of the tumor; the result can be a full or partial recovery or stabilization of the patient.

The concept of "full treatment", as used in the present invention means, in particular, the disappearance of all measurable or undergoing evaluation manifestations of the disease.

The term "partial cure"as it is used in the present invention means, in particular greater than or equal to 50% reduction in measurable or podvergalis the assessment of symptoms in the absence of progression in any specific manifestation of the disease.

The concept of "stabilization state", as used in the present invention means, in particular, reduction of not less than 50%or an increase of no more than 25% measurable or undergoing evaluation manifestations of the disease.

The concept of "standard anti-diarrhea"as it is used in the present invention include, but are not limited to, natural opiates, such as tincture of opium; tincture with antiperistaltic action containing powder of opium, anise oil, Bentiu acid, camphor, glycerol, diluted alcohol; codeine; synthetic opiates, such as Diphenoxylate, Difenoxin, loperamide; bismuth subsalicylate, octreotide, especially in the form known under the trade name of product SANDOSTATIN LARTMthe antagonist motilin and such a traditional medicine against diarrhea as kaolin, pectin, berberine and muscarinic agents. The remedy against diarrhea prescribed as a preventive measure during the treatment of the disease or as needed when diarrhoea. This remedy is prescribed to prevent, control or eliminate diarrhea, which is sometimes associated with the introduction of epothilones, especially epothilone Century

Unless otherwise agreed, in the present description organic radicals and compounds designated as "lower"contain not more is it seven, preferably not more than four carbon atoms.

Chemical compound of the formula I, where a represents O, R is hydrogen and Z denotes O, known as epothilone A; chemical compound of the formula I, where a represents O, R is methyl and Z denotes O, known as epothilone; chemical compound of the formula I, where a represents O, R is hydrogen and Z represents a relationship, known as epothilone; chemical compound of the formula I, where a represents O, R is methyl and Z represents a relationship, known as epothilone D.

Derivatives epothilone formula I in which a represents O or NRNwhere RNmeans hydrogen or lower alkyl and Z denotes O or communication, and methods of synthesis of such derivatives in General or in detail, for example, in patents and applications for patent WO 93/10121, US 6194181, WO 98/25929, WO 98/08849, WO 99/43653, WO 99/39694, WO 98/22461 and WO 00/31247 where the specified information, in particular, is given in the claims and in the examples. The essence of the final products, the pharmaceutical preparations and the claims contained in these patents and applications for patent, is set forth in the present description by reference to these publications. Included in the present invention are similar to the corresponding stereoisomers as well as the corresponding crystalline modifications, for example the solvate and polymorph, which describe the camping here. Derivatives epothilone formula I can be entered as described in the cited above publications, for example, epothilone you can enter as a component in the form of pharmaceutical compositions, which are described in WO 99/39694, in particular, epothilone can be used in combination with polyethylene glycol 300 (PEG 300), which must be pre-dissolved in 0.9% sodium chloride solution to obtain a concentration of 1 mg/ml

Transformation epothilone In the corresponding lactam is described in WO 99/02514 figure 21 (s, 32) and in example 3 (SS-50). The transformation of compounds of formula I, different from epothilone In the corresponding lactam can be carried out similarly. Appropriate derivative epothilone formula I, where RNmeans the lower alkyl can be synthesized by means known in the field of methods, such as the reaction of reductive alkylation, using as starting compound derived epothilone, where RNmeans hydrogen.

When discussing the methods in the present description with reference to the active ingredients also means that they include their pharmaceutically acceptable salts. If these active ingredients are, for example, at least one basic center, they can form acid additive salt.

The corresponding acid additive salt, if desired, the can is about to receive, having additional major centre. Active ingredients having an acid group (for example COOH)can also form salts with bases. The active ingredient or its pharmaceutically acceptable salt can also be used in the form of hydrates or include other solvents used for crystallization.

According to the present invention the compound of formula I is also used to create medicines for the treatment of such cancers, as hepatoma; primary cancer of the fallopian tube, primary peritoneal cancer; breast cancer progressing after treatment with hormonal therapy or radiotherapy; renal cell carcinoma progressing after treatment with the cytokine, radiotherapy and/or nephrectomy; melanoma, progressive after radiotherapy; prostate cancer progressing after blindness; ovarian cancer progressing after treatment with a platinum compound or radiotherapy; colorectal cancer progressing after radiotherapy and/or treatment with oxaliplatin or irinotecan; the drug also intended for the treatment of metastasizing tumors listed.

In one of the preferred embodiments of the present invention is applied is derived epothilone formula I, where a represents O, R is lower alkyl, especially methyl, ethyl, n-propyl or hydrogen, Z denotes O or communication. In a more preferred embodiment of the present invention use a derived epothilone formula I, where a represents O, R is methyl and Z means About; this compound is also known as epothilone Century

The present invention also relates to a method of treating a warm-blooded animal having a hepatoma. The essence of this method consists of introducing a therapeutically effective amount of a derivative epothilone formula I or its pharmaceutically acceptable salt, especially for the treatment of hepatoma, which progresses after radiotherapy and/or cannot be removed as a result of resection.

One of the embodiments of the present invention is the treatment of breast cancer progressing after treatment with hormones or after radiotherapy.

Another embodiment of the present invention is the treatment of ovarian cancer progressing after treatment with a platinum compound or radiotherapy.

Another one of the embodiments of the present invention relates to the treatment of primary cancer of the fallopian tube, especially such a cancer that progressed after treatment with a platinum compound, taxonom or after radiotherapy, preferably cancer, fallopian tubes, namely papillary gray is Noah adenocarcinoma.

One of the embodiments of the present invention relates to the treatment of primary peritoneal cancer progressing after treatment with a platinum compound, taxonom or after radiotherapy.

Also one of the embodiments of the present invention is the treatment of renal cell carcinoma progressing after treatment with the cytokine, radiotherapy and/or nephrectomy.

Also the embodiment of the present invention is the treatment of melanoma, progressing after radiotherapy.

The embodiment of the present invention is the treatment of prostate cancer progressing after blindness.

One of the embodiments of the present invention relates to the treatment of colorectal cancer progressing after treatment with oxaliplatin or irinotecan.

Another one of the embodiments of the present invention relates to the treatment of colorectal cancer progressing after radiotherapy.

As specified in the present invention, a method of treating a warm-blooded animal suffering from cancer, may be in the form of monotherapy, or to be complementary to other forms of therapy, such as irradiation or treatment with conventional diarrhea.

The structure of the active ingredients identified by code nos., having a generic or trade name the reasons, you can find the modern edition of the famous catalogue "The Merck Index" or in such databases, such as Patents International (e.g. IMS World Publications). In the present invention, they are included as references. Any person skilled in the art are fully capable of identify the active ingredients and, on the basis of these links, you may also obtain and test pharmaceutical indicators and properties in standard test models both in vitro and in vivo.

The person skilled in the art can choose the appropriate test of the model in order to confirm the effective action of the compounds of formula I on the hepatoma mentioned previously, or the results which are given below.

The pharmacological activity of the compounds of formula I, especially epothilone, can be demonstrated on the example of a study in which treatment was conducted by epothilones In patients with hepatoma during the 4-week cycles (three weeks of the introduction of drugs/one week without introduction or prior to the termination of disease progression or until unacceptable side effects. Initially, the treatment effect can be estimated after the first two cycles, thus it can be installed, for example, one of the above diagnostic methods and/or on the basis of stabilization or improvement of clinical symptoms. Iincorporate treatment can be performed for example, after every two cycles.

The present invention also relates to pharmaceutical preparations which contain the compound of the formula I as active ingredient and which can be used mainly in the treatment of the diseases mentioned above. For warm-blooded animals, in particular humans, the most preferred drugs enteral administration, such as nasal, transbukkalno, rectal or, especially, oral administration and parenteral administration such as intravenous, intramuscular or subcutaneous administration. The products contain either a single active component or, preferably, together with a pharmaceutically acceptable auxiliary agent. The dosage of the active ingredient depends on the condition being treated and the patient's age, weight and individual condition, individual pharmacokinetic data and method of administration.

The present invention also relates to pharmaceutical preparations for the application of prevention and, especially, the treatment of the human or animal, to a process for their preparation (especially in the form of compositions for the treatment of tumors) and to a method of treatment of the aforementioned diseases, predominantly of neoplastic diseases, especially those mentioned above.

This izopet the tion also applies to the preparation and use of compounds of formula I for the preparation of pharmaceutical preparations which contain compounds of the formula I as active component (active ingredient).

The preferred pharmaceutical compositions that can be used for the introduction of a warm-blooded animal, especially humans or valuable from the point of view of Commerce to a mammal suffering from a disease that causes inhibition of depolymerization of microtubules, such as psoriasis or, especially neoplastic diseases. This composition includes an appropriate effective amount of the compounds of formula I, or its pharmaceutically acceptable salt, while soleobrazutaya groups are present together with at least one pharmaceutically acceptable carrier.

Preferred is a pharmaceutical composition for the prevention or, especially, the treatment of neoplastic and other diseases, which are characterized by proliferation; the composition is intended for warm-blooded animals, especially humans or commercially useful mammal requiring such treatment, especially those suffering from the above diseases; as the active ingredient of the pharmaceutical composition includes a new compound of formula I or its pharmaceutically acceptable salt in an amount effective as a preventive or therapeutic agent in respect of the criminal code of the related diseases.

The pharmaceutical preparations contain approximately from 0.000001% to 95% active ingredient, with the form of single doses predominantly contain from 0.00001 to 90% and the form of multiple doses are predominantly from 0.0001 to 0.5%, in the case of preparations for parenteral administration, or from 1 to 20% of the active ingredient in the preparations for enteral administration. Forms a uniform doses are, for example, tablets, coated or not coated, ampoules, vials, suppositories or capsules. Other dose forms include, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, colloidal solutions, etc. examples are capsules containing from about 0.0002 g to 1.0 g of the active ingredient.

The pharmaceutical preparations of the present invention to prepare a known per se manner, for example by conventional mixing, granulating, coating shell, dissolution or lyophilization.

Preference is given to introducing solutions of the active ingredient, including suspensions or colloidal solutions, especially isotonic aqueous solutions, colloidal solutions, or suspensions which, for example, in the case of lyophilised preparations that contain the active ingredient alone or together with a carrier, for example mannitol, can be prepared directly what about before using. The pharmaceutical preparations can be sterilized and/or may contain eccipienti, for example preservatives, stabilizers, moisturizers and/or emulsifiers, solvents, salts for regulating osmotic pressure and/or buffers, and can be prepared in known per se manner, for example by traditional processes of dissolution or lyophilization. The said solutions or suspensions may contain agents that increase the viscosity, as a rule, the sodium salt of carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin, or solvents such as product ®Tween 80 [polyoxyethylene(20)servicemanual; trademark of ICI Americas, Inc, USA].

Suspensions contain oil as the oil component of the vegetable, synthetic or semi-synthetic oils typically used for injection purposes. In this respect, it can specifically be mentioned esters, liquid fatty acids that contain as the acid component of long-chain fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms; such acids include, for example, lauric acid, traditiona acid, myristic acid, pentadactyla acid, palmitic, margaric acid, stearic acid, arachidonic acid, Bekenova acid or the corresponding n is saturated acid, for example oleic acid, elaidic acid, erucic acid, brassicicola acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, β-carotene or 3,5-di-trebuil-4-hydroxytoluene. The alcohol component of these esters of fatty acids has a maximum of 6 carbon atoms and is mono - or polyodontum, for example mono-, di - or Triodion alcohol, for example methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol and glycerin. As esters of fatty acids are referred to the following: etiloleat, isopropylmyristate, isopropyl, product "Labrafil M 2375" (polyoxyethyleneglycol, the company Gattefosse, Paris), the product "Labrafil M 1944 CS" (unsaturated poliglecaprone glycerides prepared by alcoholysis of oils from seeds of apricot and consisting of glycerides and polietilenglikoli complex ether; the company Gattefosse, France), the product "Labrasol" (and consisting of glycerides and complex ether of polyethylene glycol; the company Gattefosse, France), and/or the product "Miglyol 812" (triglyceride of saturated fatty acids with chain length C8-C12the company Hüls AG, Germany), but especially vegetable oils, such as olive, cottonseed, almond, castor, sesame, soy, and especially peanut.

Preparation of injectable drugs is usual is carried out in sterile conditions, it includes the filling, for example, ampoules or vials and sealing of containers.

Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carrier, optionally, to pelletize the mixture and processing the mixture or granules, if desired, in tablet or core tablets, if necessary, with the inclusion of additional excipients.

Acceptable carriers are mainly fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations of cellulose and/or calcium phosphates, for example tricalcium phosphate or secondary acidic calcium phosphate, and also binders compounds such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hypromellose, sodium salt of carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrating agents, such as the above-mentioned starches, also as carboximetilkrahmal, polyvinylpyrrolidone with crosslinking, alginic acid or its salt, such as sodium alginate. Additional excipients is mainly the speed controllers removing and lubricating compounds, for example silicic acid, talc, stearic acid or their salts, such as the magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

Core tablets can be coated with an acceptable, if necessary intersolubility, shells, using inter alia concentrated solutions of sugars, which may contain gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or covering solutions for shells in acceptable organic solvents or mixtures of solvents, or, for the preparation of intersolubility membranes, solutions acceptable preparations of cellulose such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. In tablets or shell tablets can be added dyes or pigments, for example for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for oral use include hard capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules can contain the active ingredient in the form of granules, for example, in a mixture with fillers, such as corn starch, binding compounds and/or adhesive compounds, such as talc and magnesium stearate, and, optionally, stabilizers. In soft capsules the active ingredient preference is sustained fashion dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, or esters of fatty acids and ethylene or propylene glycol, to which may be added stabilizers and detergents, for example, the type of ester of fatty acid and polyoxyethylenesorbitan.

Pharmaceutical preparations suitable for rectal administration, are, for example, suppositories, which consist of a combination of active ingredient and basis. For the base of the suppositories are suitable, for example, natural or synthetic triglycerides, hydrocarbons of the paraffin series, glycols or higher alcohols.

Pharmaceutical preparations suitable for parenteral administration are primarily aqueous solutions [or, for example, saline solution, obtained by diluting solutions of polyethylene glycol, such as polyethylene glycol (PEG) 300 or PEG 400] water-soluble form of the active ingredient, for example a water-soluble salt, or suitable for injection water suspensions containing agents that increase the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and appropriate stabilizers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilisate and it can be dissolved before the introduction, adding a suitable process is Italy.

Solutions, which are used, for example, for parenteral administration, can also be used as solutions for infusions.

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic or benzoic acid.

The effective dosage of the compounds of formula I can vary depending on whether an individual compound or pharmaceutical composition, and depending on the method of administration and the severity of the hepatoma which treatment is carried out. Therefore, the dosage should be selected based on various factors, including route of administration, the kidneys and the liver of the patient. Private physician or veterinarian can readily determine and prescribe the effective amount of the compounds of formula I necessary to prevent, stop or slow down the progression of the disease. The optimal choice is such a concentration of the active ingredient, which falls within the range of concentrations that ensure the effectiveness of treatment in the absence of toxicity; this choice is based on the kinetic ability of the active ingredients to reach the target.

In the case where warm-blooded animal is a human, the dosage of the compounds of formula I is preferably in the range from 0.1 to 75 mg/m2 , more preferably from 0.25 to 50 mg/m2for example 2,5 or 6 mg/m2reception once a week for two to four, for example three weeks, followed by a break in 6-8 days (in the case of an adult patient).

Epothilone In preferably used at a dose that allows for the treatment of cancer, referred to in this invention and which is calculated by the formula (I)

where N means number of weeks between doses, Y means 6, where epothilone In is entered in more than one cycle of treatment after an interval of duration from one to six weeks after the previous treatment.

In one embodiment of the present invention epothilone In administered weekly at a dose, which is in the range from 0.1 to 6 mg/m2, preferably between 0.1 and 3 mg/m2for example 2.5 or 3.0 mg/m2within three weeks after an interval of from one to six weeks, mainly at one week intervals after previous treatment. In another embodiment of the present invention mentioned epothilone In preferably administered to a human every 18-24 days at a dose in the range of concentrations from 0.3 to 12 mg/m2.

The present invention also provides the use of compounds of formula I, as described in the present description, for the treatment of the aforementioned cancer-related disease is evania and for the preparation of drugs for the treatment of such cancers.

The present invention also provides a commercial package comprising as active ingredient a compound of the formula I and instructions for their use for the treatment of cancer.

Examples

Example 1

The purpose of the open two-stage randomized multicenter study is to determine the effectiveness of 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methylthiazole-4-yl)vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, injected at a dose of 2.5 mg/m2by 5-minute bolus infusion, weekly repetition for three weeks followed by a break in one week. Patients have diagnoses of ovarian cancer, primary cancer of the fallopian tube or primary peritoneal cancer. Patients either showed no response to primary Texan/platinum first-line therapy, or had a relapse within six months after completion of therapy. When applying Texan/platinum therapy did not allow the use of other chemotherapeutic agents. The investigated group of patients consists of patients with ovarian cancer, primary cancer of the fallopian tube or primary peritoneal cancer who either showed no response to Texan/platinum first-line therapy (or combination with the use of these funds), either initially positive reaction was the Sabbath., but then within six months after completion of such treatment, these patients had a relapse. The third therapeutic agent is introduced as part of taxan/platinum therapy Pets in case of resistant forms of the disease, provided that all other criteria are taken into account.

This study continues. Some patients in this study show a positive reaction.

Example 2

The purpose of the open two-stage randomized multicenter study is to determine the effectiveness of 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methylthiazole-4-yl)vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, injected at a dose of 2.5 mg/m by 5-minute bolus infusion, weekly repetition for three weeks followed by a break in one week to patients with advanced kidney cancer. 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methylthiazole-4-yl)-vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione is administered once a week for three weeks followed by one week without the use of drugs up until either did not stop the progression of the disease or did not manifest undesirable toxic effects. Each four-week period taken for one cycle. Patients evaluated in tumor one week after the last dose of each of the CSOs from the previous cycle, starting from the second cycle. At any time, patients may reduce the dose of 2.0 mg/m2if , in the opinion of the researcher, the initial dose or exceeds the upper limit, or dangerous to the patient, and without reducing the dose a patient would have to withdraw from the study. All modifications of the dose register. The study period, the assessment of efficiency is up to six cycles. In the study include patients with histologically confirmed transitional cell carcinoma of the kidney. Pets mixed histology component of transitional cell carcinoma. Patients may have either progressive local disease or metastatic disease.

This study continues. Some patients in this study show a positive reaction.

Example 3

The purpose of the open two-stage randomized multicenter study is to determine the effectiveness of 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methylthiazole-4-yl)vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, injected at a dose of 2.5 mg/m2by 5-minute bolus infusion weekly repetition for three weeks followed by a break in one week to patients with advanced cancer of the rectum. 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-METI is a thiazol-4-yl)vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione is administered once a week for three weeks, followed by one week without medication up until either does not stop the progression of the disease, or do not appear undesirable toxic effects. Each four-week period taken for one cycle. Patients evaluated in tumor one week after the last dose of each previous cycle, starting from the second cycle. At any time, patients can reduce the dose of 2.0 mg/m2if , in the opinion of the researcher, the initial dose or exceeds the upper limit, or dangerous to the patient, and without reducing the dose it would have to withdraw from the study. All modifications of the dose register. The study period, the assessment of efficiency is up to six cycles. In the study include patients with rectal cancer, who did not give a positive result, previous chemotherapy, including ftorpirimidinu (such as 5-FU or xeloda) and either irinotecan or oxaliplatin, which was used either in combination or sequentially (one mode, including 5-FU, and one further mode, including either irinotecan or oxaliplatin). Previous chemotherapy could be conducted either as adjuvant therapy or as treatment of metastasis. Patients who received only the adjuvant therapy of disease, suitable for research in the om case, if they had a relapse within six months after the end of such therapy, and therapy consisted of 5-FU and irinotecan or oxaliplatin used in combination, as part of the study Protocol.

This study continues. Some patients in this study show a positive reaction.

Example 4

The purpose of the open two-stage randomized multicenter study is to determine the effectiveness of 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methylthiazole-4-yl)-vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, injected at a dose of 6.0 mg/m2by 5-minute bolus infusion repeat every three weeks to patients with advanced cancer of the rectum. 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methylthiazole-4-yl)-vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione is administered once every three weeks up until either does not stop the progression of the disease, or do not appear undesirable toxic effects. Each three-week period is considered one cycle. Patients evaluated in tumor one week after receiving their last dose every third cycle, starting with the third cycle. At any time, patients can reduce the dose to 5.4 mg/m2or to 4.8 mg/m2if , in the opinion of the researcher, the original is I dose or exceeds the upper limit, or dangerous to the patient, and without reducing the dose it would have to withdraw from the study. All modifications of doses recorded. The study period, assess the effectiveness of up to nine cycles.

In the study include patients with rectal cancer, who did not give a positive result, previous chemotherapy, including ftorpirimidinu (such as 5-FU or xeloda) and either irinotecan or oxaliplatin, which are used either in combination or sequentially (one mode, including 5-fluorouracil, and one further mode, including either irinotecan or oxaliplatin). Previous chemotherapy could be conducted either as adjuvant therapy or as treatment of metastasis. Patients who received only the adjuvant therapy of disease, suitable for research in if they had a relapse within six months after the end of such therapy, if such therapy consisted of 5-FU and irinotecan or oxaliplatin used in combination, as part of the study Protocol.

This study continues. Some patients in this study show a positive reaction.

Example 5

The purpose of the open two-stage randomized multicenter study is to determine the effectiveness of EPO 906, input int the vein at a dose of 2.5 mg/m 2by 5-minute bolus infusion, once weekly for three weeks followed by a break in one week, patients with androgen-independent prostate cancer, which had not been subjected to chemotherapy, or have previously once held chemotherapy, but did not show a positive result. 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methylthiazole-4-yl)vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione is administered once a week for three weeks followed by a break in one week without drugs or to stop the progression of the disease, either prior to the occurrence of undesirable toxic effects. Each four-week period is considered one cycle. Patients evaluated for tumour response one week after receiving their last dose of each previous cycle, starting from the second cycle. At any time, patients can reduce the dose of 2.0 mg/m, if in the opinion of the researcher, the initial dose exceeds the maximum allowable, or dangerous to the patient, and without reducing the dose a patient would have to withdraw from the study. All modifications of the dose register. The study period, the assessment of efficiency is up to six cycles.

The study group is composed of patients with androgen-independent prostate cancer, which showed signs of progressioni the disease:

To investigate the fit patients with any histologically confirmed prostate cancer with moderate metastasis or the increase in PRA (analysis phase solubility) to levels above 20 ng/ml, after initial hormonal therapy.

- Patients must maintain therapy without androgen with an agonist of luteinizing hormone releasing hormone or should be orchiectomy.

The disease should progress in patients who had recently been abolished bicalutamide or to be; after discontinuation of these drugs must pass at least 6 weeks and 4 weeks, respectively. Patients taking PC-SPES should stop therapy at least 4 weeks.

For patients with disease progression, established only on the basis of increasing PRA: two consecutive slew rate Pras for four week period (each separated from the previous two weeks). The latter figure should be at least 50% higher than the lowest level Pras made after the last therapeutic procedures. For patients who discontinued treatment with bicalutamide prior to the beginning of the study, required third increase of PRA 2 weeks after the second indicator (i.e. during the 6-week period).

Yes the Noah study continues. Some patients in this study show a positive reaction.

Example 6: Soft capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 g of one of the compounds of formula I, prepared as follows:

Composition:

the active ingredient250 g
neuroglial2 l

The cooking process:

Powdered active ingredient is suspended in the product Lauroglycol® (propylene glycol laurate, the company Gattefosse S.A., Saint Priest, France) and is ground in a wet pulverizer to the size of the grains is about 1 to 3 μm. Then portions, each of which contains 0,419 g of the mixture is filled into soft gelatin capsules using an apparatus for filling capsules.

Example 7: Solution for infusion

The connection shown in examples 1, 2, 3 and 4, is dissolved in polyethylene glycol 300 (PEG 300) to a concentration of 1 mg/ml and dispensed in ampoules of 2 ml For infusion of this solution diluted in 50-100 ml of 0.9% saline solution in accordance with the Pharmacopoeia of the United States.

1. The use of the compounds of formula I

where a represents O, R is hydrogen or lower alkyl and Z means that for the preparation of lcars the governmental funds for the treatment of cancer, selected from primary cancer of the fallopian tube, primary peritoneal cancer and colorectal cancer progressing after treatment with irinotecan.

2. A method of treating a warm-blooded animal having a cancer selected from primary cancer of the fallopian tube and primary peritoneal cancer, comprising introducing a therapeutically effective amount of a derivative epothilone formula I

where a represents O, R is hydrogen or lower alkyl and Z means Acting

3. The method according to claim 2, in which a warm-blooded animal is a human.

4. The method according to claim 2, in which injected derived epothilone formula I, where a represents O, R is methyl and Z means Acting

5. The method according to claim 4, consisting in the introduction of this derived epothilone people who need such treatment, in a dose that allows for the treatment of the aforementioned diseases and which is calculated by the formula (I)

where N is the number of weeks between treatments and the means 6, where the specified derived epothilone enter in more than one cycle of treatment with an interval of from one to six weeks after previous treatment.

6. The method according to claim 5, consisting in the introduction of this derived epothilone weekly dose, which is in the range from 0.1 to 6 mg/m2.

7. The method according to claim 5, consisting in the introduction of this derived epothilone weekly dose, which is in the range from 0.1 to 6 mg/m2within three weeks with an interval of from one to six weeks after previous treatment.

8. The method according to claim 5, consisting in the introduction of this derived epothilone every third week in a dose that is in the range from 0.3 to 12 mg/m2.

9. The method according to claim 2, in which the cancer is a primary cancer of the fallopian tube.

10. The method according to claim 2, in which the cancer is a primary cancer of the fallopian tubes, progressing after treatment with a platinum compound, taxonom.

11. The method according to claim 2, in which the cancer is peritoneal cancer progressing after treatment with a platinum compound, taxonom.

12. Pharmaceutical composition for the treatment of primary cancer of the fallopian tube and primary peritoneal cancer, comprising a therapeutically effective amount of the compounds of formula I

where a represents O, R is hydrogen or lower alkyl and Z is O.

13. A commercial package comprising a compound of the formula I

where a represents O, R is hydrogen or lower alkyl and Z is O, and optional standard remedy against diarrhea together with in what tracciati for its use in the treatment of primary cancer of the fallopian tube and primary peritoneal cancer.



 

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FIELD: medicine.

SUBSTANCE: there is described oral pharmaceutical composition containing 9,10-dehydroepothilone combined with a pharmaceutically acceptable carrier. According to the second version, the oral pharmaceutical composition contains trans-9,10-degihydroepothilone D and a pharmaceutically acceptable carrier containing hydroxypropyl-β-cyclodextrine, ethanol and propylene glycol. The concentrate for injection contains 9,10-degihydroepothilone D in the pharmaceutically acceptable carrier.

EFFECT: good bioavailability of epothilone D.

21 cl, 4 ex

FIELD: medicine.

SUBSTANCE: prevention of carcinogenic action of diethyl nitrosamine in experimental animals is ensured by introduction of kaskorutol dosed 0.4 g/kg within 9 months as an anticarcinogen, while diethyl nitrosamine is introduced in a dose 100 mg/l 5 days after introduction of kaskorutol within 4 months.

EFFECT: reduced carcinogenic action of diethyl nitrosamine due to inhibition of blastomogenic process, lowered level of lipid peroxidation, improved activity of antioxidant enzymes.

2 tbl, 8 dwg, 1 ex

FIELD: pharmacy.

SUBSTANCE: antineoplastic preparation which coordination compound on the magnesium gluconate base wherein the ligands are chosen from the group consisting of γ-aminobutyric acid (GABA), 3-hydroxy-GABA, ethylendiaminotetraacetic acid and ethylenglycoltetraacetic acid or binary salt chosen from the group consisting of magnesium butyrogluconate, oxymagnesium butyrogluconate, magnesium glucarate-gluconate, calcium butyrogluconate, calcium oxybutyrogluconate, calcium glucarate-gluconate and their combinations.

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4 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.

EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.

EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.

EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, and can be used in therapy of epidermoid skin cancer without metastases in regional lymph nodes. Said therapy is ensured by close-focus roentgenotherapy of total focal dose 6000 R. The irradiation course is followed with over- and subfascial introduction of Klein solution in tumour projection in a dose 20 ml. Then tumour-associated fascia is removed by endoscopic or surgical technique at the distance at least 1 cm from the irradiation zone.

EFFECT: method allows ensuring greatest possible therapeutic radicalism, removing lymphatic capillaries and postcapillaries assisting in dissemination of cancer cells, reducing metastasis probability with maintaining the cosmetic effect.

2 ex

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: chemistry.

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EFFECT: new compound is characterised with useful biological activity.

2 tbl, 1 ex

FIELD: chemistry.

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EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: medicine.

SUBSTANCE: there is described oral pharmaceutical composition containing 9,10-dehydroepothilone combined with a pharmaceutically acceptable carrier. According to the second version, the oral pharmaceutical composition contains trans-9,10-degihydroepothilone D and a pharmaceutically acceptable carrier containing hydroxypropyl-β-cyclodextrine, ethanol and propylene glycol. The concentrate for injection contains 9,10-degihydroepothilone D in the pharmaceutically acceptable carrier.

EFFECT: good bioavailability of epothilone D.

21 cl, 4 ex

Solid medication // 2357757

FIELD: pharmacology.

SUBSTANCE: invention relates to pharmacon immediately dealing with preparation of a solid medication for treatment of diabetes and its sequela. The medication contains metformin or a salt thereof, pioglitazone or a salt thereof, homogenously dispersed, as well as target admixtures. The ratio of the average particle size of metformin or the salt thereof to the average particle size of pioglitazone or the salt thereof varies from 2.23:1 to 8.06:1.

EFFECT: provision for high homogeneity and dissolution degree of the active ingredient.

5 cl, 3 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: method relates to medicine, namely to oncology, and can be used for treating patients with locally spread or generalised lung cancer. Essence of invention lies in the following: sample of bone marrow from posterior spine of iliac crest in amount 150-180 ml is taken, incubated at 37°C during 24 hours with 1 mln ronkoleikin IU (IL-2), after that autohemochemical therapy (AHCT) is performed together with automieloimmunotherapy (AMIT), medications are introduced intravenously with drip-feed, two courses of treatment are performed with 3 week interval. In case of small cell cancer the following medications are introduced: cysplatin - 80 mg/m2 on the 1-st day, vepesid - 120 mg/m2 on the 1-st, 2-nd, 3-rd day, ronkoleikin - 1 mln IU on the 2-nd, 3-rd, 4-th, 5-th day. In case of non-small cell cancer the following medications are introduced: cysplatin - 80 mg/m2 on the 1-st day, vepesid - 120 mg/m2 on the 1-st, 3-rd, 5-th day, ronkoleikin - 1 mln IU on the 2-nd, 4-th, 6-th, 7-th day.

EFFECT: method allows enhancing anti-tumor activity of immune system and stabilising neoplastic process.

3 cl, 2 ex

FIELD: medicine.

SUBSTANCE: claimed is application of group of epothilone compounds, which have coefficient of average distribution between plasma and brain 0.3-1.5 in mice analysis by intravenous bolus injection, for obtaining medication for therapy of diseases of primary and secondary brain tumors. Epothilones efficiency with respect to xenotransplanted and intracranial human glioma is demonstrated.

EFFECT: compounds are distinguished not only by high anti-tumor activity with respect to brain tumor, but also by good penetration in brain tissues (areas under pharmacokinetic curves for blood plasma and for brain were similar in average).

10 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention claims pellet with enterosoluble shell, including ixabepilone with structure (A). Also a capsule containing multiple pellets with enterosoluble shell is claimed. Pellet includes particle with coating, containing main particle and active component layer distributed completely or partially on or in the main particle. Active component layer includes ixabepilone of structure (A) and binding agent. In addition, versions of obtaining pellet with enterosoluble shell are claimed.

EFFECT: reduced or prevented ixabepilone powder flaking, possible oral administration of ixabepilone without combined acid-neutralising buffer administration.

14 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: medicine; oncology.

SUBSTANCE: thoracic lymphatic duct is drained with lymph collected, incubated at temperature 37°C within 24 hours with Ronkoleukine 1 million ME (IL-2). It is followed with combined autolymphoimmunotherapy and autolymphochemotherapy.

EFFECT: stimulation ensured by generation of lymphokine-activated killers, antineoplastic cell-mediated immune response stimulating tumour lysis with low toxicity and good tolerance to chemotherapy.

3 cl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to combination, composition and set designed for treatment of proliferative diseases, containing epothilones and antimetabolites chosen from 5-fluorouracil, tegafur, gemcitabine and capecitabine and, optionally antidiarrheal agent.

EFFECT: higher efficiency of treatment.

9 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to compounds of formula where one of R6, R7 or R8 means , and X, Y, substitutes of R1-R13 and n are as it is defined in item 1 of formula of invention, and to all their enantiomers, to pharmaceutically acceptable salts and/or esters.

EFFECT: production of compounds for treatment and/or prevention of diseases modulated by PPARδ and/or PPARα agonists.

26 cl, 1 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

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