Combinations including epothilones, and their pharmaceutical application

FIELD: medicine.

SUBSTANCE: present invention concerns medical products, particularly pharmaceutical combination for development inhibition or treatment of proliferative disease which contains in therapeutically effective amounts (a) compound PTK787 and (b) epothilone derivative of formula , where A means O or NRN, where RN means hydrogen or lower alkyl, R means hydrogen or lower alkyl, and Z means oxygen or chain, for simultaneous, separate or consecutive application. Besides the invention concerns a pharmaceutical composition, application and commercial package thereof.

EFFECT: specified combination of active components ensures synergetic effect in treatment of proliferative diseases.

7 cl, 6 ex

 

The invention relates to a combination which comprises (a) a bisphosphonate, a platinum compound or soodustatakse connection and (b) derived epothilone formula I and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use, in particular, to slow down the progression or treatment of proliferative diseases, especially diseases of the solid tumor; to pharmaceutical compositions comprising such a combination; the use of such a combination for the preparation of medicines to slow down the progression or treatment of a proliferative disease; the product package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use and to a method of treating a warm-blooded animal, especially a human.

Despite the widespread use of Taxol®and Taxotere®in the treatment of tumors of different types, the influence of taxan on the survival of the patient was moderate, and the vast majority of metastatic tumors did not respond to treatment. Treatment taxonomy associated with some significant side effects, such as peripheral neuropathy, stomatitis, and efficiency taxan can be seriously limited the Jena emerging mechanisms of resistance to drugs, perhaps tubulin mutations or increased expression of phosphoglycoprotein, which act as pumps to drain the medicinal product. Bearing in mind these limitations, and given the side effects commonly observed in the case of standard treatment combinations, it becomes clear need to identify new combinations which exhibit improved public profile, including a broader spectrum of antitumor activity, effective against tumors that are resistant to many drugs, and greater safety and tolerability.

therapeutic efficacy of bisphosphonates has been demonstrated in the treatment of bone disease Paget's disease, tumor-induced hypercalcemia, bone metastases and multiple myeloma (.Fleisch in the collection "Bisphosphonates in Bone Disease. From the Laboratory to the Patient". Ed.: The Parthenon Publishing Group, new York/London, 1997, p.68-163).

Direct proof of the role of factor a vascular endothelial growth" (VEGF) as a factor in tumor angiogenesis in vivo was obtained from studies in which inhibited the expression of VEGF or VEGF activity. This was achieved by using antibodies that inhibit the activity of VEGF, using dominant-negative mutant VEGFR-2, which inhibit the signal transmission, or when using RNA techniques antisense VEGF. MA the s molecules, inhibiting tyrosinekinase VEGF, disclosed in international patent application WO 98/35958. One of these molecules is known as RTG.

The stabilizing effect epothilones on micro canals was first described by Bollag and others in "Cancer Research", 55, 1995, 2325-33. A suitable scheme for the treatment of various types of tumors, especially tumors that are not amenable to treatment with other chemotherapeutic agents, in particular Taxol™, described in the international patent application WO 99/43320.

The present invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises (a) a bisphosphonate, a platinum compound or soodustatakse connection and (b) derived epothilone formula I,

where a represents O or NRNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower alkyl and Z means oxygen or a bond, in which the active ingredients (a) and (b) are present in each case in free form or in pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use.

Unless otherwise stated, in the present disclosure organic radicals and compounds designated as "lower"contain not more than seven, prefer the LNO not more than four carbon atoms.

The compound of formula I, where a represents oxygen, R is hydrogen and Z means oxygen, known as epothilone And; a compound of formula I, where a represents oxygen, R is methyl and Z means oxygen, known as epothilone In; a compound of formula I, where a represents oxygen, R is hydrogen and Z represents a relationship, known as epothilone With; a compound of formula I, where a represents oxygen, R is methyl and Z represents a relationship, known as epothilone D.

The term "a combined preparation", as used in this context means, in particular, the "kit of parts" in the sense that the components (a) and (b) the combination, as defined above can be dosed independently or by use of various set combinations with known quantities of components (a) and (b) combination (simultaneously or at different points in time. Part of the kit of parts may then be applied, for example, simultaneously or chronologically differentiated, i.e. at different time points and with equal or different time intervals for any part of the kit parts. Very preferably the time intervals are chosen so that the effect on the treated disease in the combined use of the parts was greater than the effect that can be obtained by using only either the about of the components (a) and (b) combinations. The ratio of the total amount of the component (a) combination to the total amount of component (b) combinations that should be used in the combined preparation can be varied, for example, to meet the needs of subpopulations of patients undergoing treatment, or the needs of the individual patient, these different needs of patients can be explained by age, gender, body weight, etc. Preferably there is at least one beneficial effect, such as the total magnification effect of the components (a) and (b) combinations, in particular a synergism, e.g. a greater than additive effect, additional beneficial effects, smaller side effects, a combined therapeutical effect in ineffective dosage of one or both of components (a) and (b) combination, and very preferred strong synergism of the components (a) and (b) combinations.

The term "disease is a solid tumor" refers, in particular, breast cancer, ovarian cancer, cancer of the colon and usually cancer of the gastrointestinal tract, including stomach cancer, cervical cancer, lung cancer such as small cell lung cancer and non-small cell lung cancer, pancreatic cancer, kidney cancer, glioma, melanoma, cancer of the head and neck, bladder cancer, liver cell cancer, prostate cancer and sarcoma of the Kapos who. Preferably, the proliferative disease undergoing treatment with a combination comprising a compound of platinum, are ovarian cancer, lung cancer, malignant tumor of head or neck cancer, cervical cancer, prostate cancer, colon cancer, breast cancer, kidney cancer, carcinoid tumors, stomach cancer or liver cell carcinoma. Preferably, the proliferative disease undergoing treatment with a combination comprising a bisphosphonate, is breast cancer, ovarian cancer or lung cancer. According to another preferred variant of the invention, the proliferative disease is treated by a combination according to the invention, including soodustatakse connection, in particular RTK is ovarian cancer, breast cancer, lung cancer, malignant tumor of head or neck, cervical cancer, prostate cancer or cancer of the colon.

The term "proliferative disease", as used in this context, includes disease solid tumors such as those listed above and, in addition, a disease of bone Paget's disease, tumor-induced hypercalcemia, bone metastases and multiple myeloma.

The term "disease associated with misaligned angiogenesis" refers specifically to diseases caused GLA is Noah revascularization, in particular retinopathy, such as diabetic retinopathy, or age related macular spots, psoriasis, haemangioblastoma, such as hemangioma, proliferative disorders of cells mesange, such as chronic or acute renal diseases, e.g. diabetic nephropathy, malignant nephrosclerosis, thrombotic syndromes microangiopathy or transplant rejection, or especially inflammatory kidney disease, such as glomerulonephritis, especially mesangiocapillary glomerulonephritis, haemolytic uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial to restenosis, autoimmune diseases, acute inflammation, fibrotic disorders (e.g., cirrhosis), neurodegenerative disorders, especially proliferative diseases, in particular proliferative diseases, including tumors expressing the receptor c-kit, KDR or flt-1.

The term "bisphosphonate", as used in this context includes, but is not limited to this, trigonomy acid, clodronate acid, tiludronic acid, pamidronovu acid, alendronate acid, ibandronate acid, risedronate acid and zoledronic acid. "Trigonomy acid" can be applied, for example, in the form in which it is commercially available, for example under the trademark didronel™. "Cladonema acid" can be applied, for example, in the form in which it is commercially available, for example under the trademark skelidTM. "Panikanova acid" can be applied, for example in the form in which it is commercially available, for example under the trademark arediaTM. "Alendronat acid" can be applied, for example, in the form in which it is commercially available, for example under the trademark fosamaxTM. "Ibandronic acid" can be applied, for example in the form in which it is commercially available, for example under the trademark bondronatTM. "Risedronate acid" can be applied, for example, in the form in which it is commercially available, for example under the trademark actonelTM. "Zoledronicaa acid" can be applied, for example, in the form in which it is commercially available, for example under the trademark zometaTM.

The term "platinum compound", as used in this context, means carboplatin, cisplatin or oxaliplatin.

The term "carboplatin", as used in this context, refers to the antitumor agent CIS-diamine(1,1-cyclobutanedicarboxylate)platinum(II), which is disclosed, for example, in U.S. patent No. 4140707 or R.C.Harrison and others in Inorg. Chim. Acta 46, L15 (1980). This drug can Batiment, for example, in the form in which it is commercially available, for example under the trademark of carbopeatTMor paraplatinTM.

The term "oxaliplatin", as used in this context, refers to the antitumor agent, which is disclosed, for example, in U.S. patent No. 5716988. This drug can be applied, for example, in the form described in the cited U.S. patent, or in the form in which it is commercially available, for example under the trademark EloxatinTMor 1-NROTM.

The term "cisplatin", as used in this context, refers to the antitumor agent, also known as CIS-diaminedichloroplatinum, this compound and its use as antitumor agents disclosed, for example, in German patent DE 2318020.

The term "soodustatakse connection", as used in this context includes, but is not limited to these, the active ingredients that reduce the activity of VEGF, matrix metalloproteinases inhibitors and other compounds with soodustamiseks action.

Active ingredient which decreases the activity of VEGF, selected in particular from the group consisting of compounds which inhibit tyrosinekinase the VEGF receptor, compounds which inhibit the VEGF receptor, and compounds that bind to VEGF. Active ingredient which lowers AK is Yunosti VEGF, in particular, one of those compounds, proteins and monoclonal antibodies, which, in General, and specifically disclosed in international patent applications WO 98/35958 (describing the compounds of formula (II), WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and in the application for the European patent EP 0 769 947, which describes .Prewett and others in Cancer Research 59 (1999) 5209-5218, F.Yuan and others in Proc. Natl. Acad. Sci. USA, vol 93, str-14770, December 1996, Z. Zhu and others, Cancer Res. 58, 1998, 3209-3214, and J.Mordenti and others in Toxicologic Pathology, vol 27, No.1, p.14-21, 1999, from those compounds which in General and specifically disclosed in international patent applications WO 00/37502 and WO 94/10202; and of those compounds which are described .S.O''reilly and others, Cell 79, 1994, 315-328 (angiostatinTMand .S.O''reilly and others, Cell 88, 1997, 277-285 (endostatinTM), in each case, in particular claims for compounds, pharmaceutical products and final products of the working examples, the subject matter of which is included therefore in the present application by reference to these publications. Included likewise corresponding stereoisomers, as well as the corresponding crystalline modifications, such as a solvate and polymorph, there are disclosed. The compounds used as active ingredients in the disclosed here, the combinations can be obtained and applied as described in the documents cited here, is respectively.

The term "RTC", as used in this context, means a compound of formula II,

where r, n and m denote each oxygen, R1and R2together form a bridge of subformula II*,

A, b, D and E mean each SN, G means methylene, X is aminogroup, Y represents 4-chlorophenyl, and relationships shown with a wavy line are double bonds, disclosed, for example, in example 38 international patent application WO 98/35958. Preferably this connection is used in the form of its salt with succinic acid. This drug or its salt can be applied, for example, in such form, as disclosed in the cited PCT application for a patent.

"Inhibitors of metalloproteinases", as defined here, are, for example, marimastat (BB-2516), prinomastat (AG3340), buy 12-9566, BMS-275291, MMV and metastat (NSC 683551).

The term "other compounds with soodustamiseks action", as defined here, refers in particular to the compounds EMD-121974, doxorubicin, paclitaxel, IM-862, thalidomide®, linomide®, RX, AGM-1470,. and polysulphate of pentosan.

Derivatives epothilone formula I where a is oxygen or NRNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower alkyl and Z means oxygen or communication, the methods of obtaining such derivatives epothilone, in particular, disclosed and in General and specifically in patents and international patent applications WO 93/10121, in U.S. patent No. 6194181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247 in each case, in particular claims for compounds and final products of the working examples, the subject matter of the invention in the form of the final products, the pharmaceutical preparations and the claims are included therefore in the present application by reference to these publications. Included likewise corresponding stereoisomers as well as the corresponding crystalline modifications, such as a solvate and polymorph that here disclosed. Derivatives epothilone formula I, in particular epothilone, can be applied as part of the pharmaceutical compositions disclosed in the international patent application WO 99/39694.

Turning epothilone In the corresponding lactam is disclosed in scheme 21 (p.31, 32) and in example 3 of international patent application WO 99/02514 (p.48-50). The transformation of compounds of formula I, which differs from epothilone In the corresponding lactam can be carried out similarly. Appropriate derivative epothilone formula I, where RNmeans the lower alkyl may be obtained by methods known in this field, as, for example, using the reaction of reductive alkylation, provideno is using as starting substances derived epothilone, in which RNmeans hydrogen.

Moreover, the structure of the active agents mentioned here by name, can be taken from the current edition of the standard quick start guide "The Merck Index" or from databases, e.g. International patents (e.g. IMS World Publications). Relevant content included in this description by reference. Any expert in the art on the basis of these links will be able to get to explore pharmaceutical symptoms and properties in standard experimental models both in vitro and in vivo.

The compounds used as component (a) and (b) combinations and described in this invention can be obtained and entered, respectively, as described in the cited documents.

It will be understood that references describing the components (a) and (b) combinations, as expected, also include pharmaceutically acceptable salts. If these components (a) and (b) combinations are, for example, at least one center, they can form acid additive salt. The corresponding acid additive salts can also be formed, if necessary, with additional existing main centre. Components (a) and (b) combinations having an acid group (e.g.,- COOH)can also form salts with bases. Component (a) or (b) the combination or its formats whitesky acceptable salt can also be used for the formation of hydrates or include other solvents, used for crystallization.

A combination which comprises (a) a bisphosphonate, a platinum compound or soodustatakse connection and (b) derived epothilone formula I, where a represents oxygen or NRNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower alkyl and Z means oxygen or connection, the combination in which the active ingredients are present in each case in free form or as pharmaceutically acceptable salt and optionally present at least one pharmaceutically acceptable carrier, hereinafter will be referred to as the combination according to the invention.

The combination according to the invention inhibits the growth of solid tumors, but also liquid tumors. In one preferred variant of the invention, the disease treated is prostate cancer, in particular resistant to the hormone prostate cancer with metastases in the bone. Moreover, the combinations according to the invention, including soodustatakse connection, in particular RTK, show beneficial effects in the treatment of diseases associated with misaligned angiogenesis.

The nature of proliferative diseases such as diseases, solid tumors, is a multi-factorial. In some circumstances can be combined drugs with different CNAME mechanisms of action. However, any combination of drugs with different mode of action will not necessarily result in combinations with useful effects.

Even more amazing are the experimental data, namely, that the use of in vivo combination according to the invention compared with monotherapy using only one of the pharmaceutically active ingredients used in combination according to the invention not only leads to more useful, in particular energeticheskomu, antiproliferative effect, for example, in relation to the slowdown in the development of proliferative diseases or in respect of changes of tumor volume and/or more useful, in particular energeticheskomu effect warnings related skeletal events (SREs), but also to other unexpected beneficial effects, such as fewer side effects and reduced mortality and morbidity. In addition, depending on the type of tumor and the specific combination of the reduction of tumor volume can be achieved when used in combination according to the invention in cases when monotherapy cannot be achieved by the reduction of tumor volume. The combinations according to the invention is also suitable for the prevention of metastatic spread of tumors and the growth or development of micrometastases the century The combinations according to the invention is particularly suitable for the treatment of patients with poor prognosis, i.e. especially those patients who did not respond to treatment or have had a relapse after previous treatment with one drug or combination other than the combination according to the invention.

Other favorable phenomenon is something that can be used lower doses of the active ingredient combination according to the invention, for example, there is a need for doses not only smaller, but also less frequently used, or a smaller dose can be used to reduce the incidence of side effects. This is carried out in accordance with the desires and requirements of treated patients.

Can be shown by using well-known models for testing and, in particular, models for testing disclosed here that the combination of the invention results in favorable effects described here previously. Specialist in the appropriate field has the full ability to choose an appropriate model to test in order to prove such beneficial effects. The pharmacological activity of the combination according to the invention can, for example, be demonstrated in a clinical study or using testing methods, as generally described below.

Suitable clinical studies are mostly randomized parallel studies using double-blind experience under the supervision placebo. Such studies are particularly suitable for comparison of the effects of monotherapy using active ingredients, and therapy that uses a combination according to the invention, and to prove, in particular, the synergy of active ingredients combination of the invention. Beneficial effects on proliferative diseases, for example, for prevention-related skeletal events (SREs) in patients with prostate cancer with metastatic bone disease in anamnesis can be determined directly through the results of these studies or by changes in the simulation studies, which are known in themselves to the person skilled in the art. SREs are defined as pathological phenomena of fracture, the phenomenon of compression of the spinal cord, surgery to bone, radiation therapy to bone, and the change of antineoplastic therapy to treat bone pain. Preferably SREs are the main boundary points in such studies. In addition, such studies can be estimated impact on the indicators of pain, use of analgesics, health status, quality of life, bone density, the time development of bone lesions and the overall development of the disease.

In a suitable plan of examination of patients subjected to randomization using the method of double-blind experience for injection every three weeks or 2 mg zoledronate intravenously in the form of 5-minute infusion or 15-minute infusion, 4 mg zoledronate intravenously in the form of 5-minute infusion or 15-minute infusion or placebo intravenously in the form of 5-minute infusion or 15-minute infusion in addition to the compound of formula I, for example, 6 cycles epothilone, where each cycle consists of doses from 2.5 mg/m2up to 6 mg/m2epothilone, the input in the form of absorbed within 5 minutes of bolus once a week for three weeks followed by 14 days of rest.

Another appropriate plan of examination of patients subjected to randomization using the method of double-blind experience for injection every two weeks to 45 mg oxaliplatin/m2the surface of the body in the form of intravenous injections of 2 to 6 hours or matching placebo in addition to the compound of formula I, for example, 6 cycles epothilone, where each cycle consists of 2.5 mg/m2epothilone, the input in the form of absorbed within 5 minutes of bolus once a week for three weeks followed by 14 days of rest.

According to another appropriate plan of examination of patients subjected to randomization using methods double-blind experience for the introduction of daily, for example, 250 or 500 mg RTC or matching placebo in addition to the compound of formula I, for example, 6 cycles epothilone, where each cycle consists of 2.5 mg/m2epothilone, the input in the form of absorbed within 5 minutes of bolus once a week for three weeks followed by 14 days of rest.

According to another study plan weekly dose of 0.5 mg/m2, 1.0 mg/m2, 1.5 mg/m2, 2.0 mg/m2or 2.5 mg/m2epothilone In are applied in the form of intravenous infusion over 5 minutes and cisplatin is dosed according to standard guidelines, i.e. in the form of a weekly dose of 20-100 mg/m2the area of the surface of the body, for example 30 mg/m2on a weekly basis. Injection of cisplatin diluted before administration and entered immediately after epothilone In by intravenous infusion over 1 hour. One cycle of treatment consists of the administration of both drugs for three weeks followed by one week of rest.

One of the purposes of the present invention is to provide a pharmaceutical composition comprising a quantity, which, when joint action is effective against a proliferative disease, the composition comprising a combination according to the invention. In such compositions the components (a) and (b) combinations can be put together, one after the other or about the individual in the form of one combined dosage form with a uniform dose or in two separate dosage forms with a uniform dose. Dosage form with a uniform dose can also be a combination.

The pharmaceutical compositions according to the invention can be prepared in a way known as such, and such compositions are suitable for insertion through the small intestine, for example, orally or through the rectum, and for parenteral administration mammals (warm-blooded animals), including humans, and contain a therapeutically effective amount, at least, only one pharmacologically active ingredient combinations or in combination with one or more pharmaceutically acceptable carriers, especially suitable for application through the small intestine or parenteral.

A new pharmaceutical composition contains, for example, from about 10% to 100%, preferably from about 20% to about 60% of the active ingredients. Pharmaceutical drugs in combination therapy for the introduction through the small intestine or parenterally include, for example, dosage forms with standardized doses, as, for example, covered sugar pills, tablets, capsules or suppositories, and also ampoules. If not otherwise indicated, these forms are prepared by a method which is known in itself, for example by means of conventional mixing, granulating, coating sugar, through the Yu ways dissolution or lyophilization. It is clear that it is not necessary that the content of units of component combinations in individual dose of each dosage form was in itself an effective amount since the necessary effective amount can be achieved by introducing a variety of standard doses.

Upon receipt of the compositions for oral dosage form can be applied to any of the usual pharmaceutical media, as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating tools, lubricants, binding agents, agents to fracture and the like in the case of solid preparations for oral administration such as, for example, powders, capsules and tablets, with the solid preparations for oral administration are preferable to liquid preparations. Thanks to the convenience of using them, tablets and capsules represent the most preferred dosage form with a uniform dose, in this case explicitly used solid pharmaceutical carriers.

In particular, a therapeutically effective amount of each of the components of the combination according to the invention can be introduced simultaneously or sequentially and in any order, and the components can be the ü introduced separately or in combination installed. For example, a way to slow the development or treatment of proliferative diseases according to the invention may include (i) introduction the first component of the combination in the free form or as pharmaceutically acceptable salt and (ii) the introduction of a second component combinations in free form or in pharmaceutically acceptable salt simultaneously or sequentially in any order in therapeutically effective quantities in their joint action, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the one described here amounts. The individual components included in the combination according to the invention can be applied separately at different points in time during the course of treatment or concurrently in divided form or in a combined form. In addition, the term application also covers the use of prodrugs of component combinations, which is converted in vivo as such component combination. The invention should therefore be seen as encompassing all such schemes joint or alternative treatment and the term "application" should accordingly be interpreted.

The effective dose of each component used in combination according to the invention may vary depending on the specific connection or use aamoi pharmaceutical composition, from a way of introduction, from undergoing the treatment condition, the severity of the treated condition. So, regimen combinations according to the invention is selected in accordance with various factors, including route of administration and the activity of the kidneys and liver of the patient. A physician, Clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the individual active ingredients required to prevent, counter or suppress the development of the state. Optimal precision in achieving concentration of active ingredients in the range, leading to efficiency without toxicity requires a regimen based on the kinetics of the availability of the active ingredients for sites to target. This includes consideration of the distribution, equilibrium, and elimination of the active ingredients.

If a warm-blooded animal is a human, the dosage of the compounds of formula I preferably is in the range from about 0.25 to 75, preferably from 0.5 to 50, for example 2.5 mg/m2once a week for two to four weeks, for example three weeks, then free time from 6 to 8 days in the case of an adult patient.

Epothilone In preferably administered in a dose that is calculated according to the formula (III),

where N means number of weeks between courses cured what I have is 6, where epothilone In use in more than one cycle of treatment after a period of time from one to six weeks after the previous treatment.

In one preferred embodiment of the invention epothilone is entered In a weekly dose of from about 0.1 to 6 mg/m2preferably from 0.1 to 3 mg/m2for example 2.5 or 3.0 mg/m2within three weeks after an interval of from one to six weeks, in particular interval of one week after the previous treatment. According to another variant embodiment of the invention mentioned epothilone In preferably introduced to a man every 18-24 days at a dose of between about 0.3 and 12 mg/m2.

If it does not indicate otherwise, bisphosphonates, described here, can be entered in the following dosages:

Alendronat acid can be administered to the person within dosages ranging from about 5 to 10 mg/day.

Cladonema acid can be administered to the person, for example, in the range of dosages ranging from about 750 to 1500 mg/day.

Trigonomy acid can be administered to the person within dosages ranging from about 200 to 400 mg/day.

Ibandronic acid can be administered to the person within dosages ranging from about 1 to 4 mg, every three or four weeks.

Risedronate acid can be administered to the person in predilatation, ranging from approximately 20 to 30 mg/day.

Panikanova acid can be administered to the person within dosages ranging from about 15 to 90 mg every three to four weeks.

Trojanova acid can be administered to the person within dosages ranging from about 200 to 400 mg/day.

Zoledronicaa acid can be administered to the person within dosages ranging from about 2 to 10 mg, in particular 4 or 8 mg, in the form of intravenous infusion every 3 weeks.

Carboplatin can be administered intravenously to a person within dosages ranging from about 100 to 400 mg/m2for example 200 mg/m2the surface of the body, approximately every four to six weeks.

Oxaliplatin may be administered intravenously to a person within dosages ranging from about 25 to 135 mg/m2for example 45 or 85 mg/m body surface, approximately every two to three weeks.

Cisplatin can be administered to the person within dosages ranging from about 25 to 100 mg/m2approximately every three weeks.

If a warm-blooded animal is a human, dose RTC preferably is in the range of about 50 to 1500, more preferably from about 100 to 750, and most preferably from 250 to 500 mg/day.

In a preferred embodiment of the invention the combination according to the invention which engages a bisphosphonate, selected from africanoboi acid, clodronate acid, tiludronic acid, pamidronic acid, alendronova acid, ibandronic acid administered intravenously, risedronate acid and most preferably zoledronate acid.

In another embodiment of the invention the combination according to the invention includes cisplatin, oxaliplatin or carboplatin.

According to another variant embodiment of the invention the combination according to the invention includes sosudistimi formula II,

where r is 0-2, 0-2 n means that m means 0-4,

R1and R2(i) are the lowest alkilani or

(and) together form a bridge in subformula II*,

the binding is achieved via the two terminal carbon atoms,

or

(iii) together form a bridge in subformula II**,

where one or two of the ring members of T1T2T3and T4mean nitrogen and the others in each case, the mean SN and the binding is established through the T1and T4;

A, b, D and E independently of one another mean nitrogen or CH, provided that no more than two of these radicals are nitrogen;

G means the lowest alkylene, lower alkylene, replaced by allochrony or hydroxyl, -CH2-O-, -CH3-S-, -CH2-NH-, oxa- (-O-), thia- (-S-) or aminogroups (-NH-);

Q means a lower alkyl;

R means hydrogen and lower alkyl;

X is imino, oxa-or thia-group;

Y represents unsubstituted or substituted aryl, pyridyl, or unsubstituted or substituted cycloalkyl; and

Z signifies amino group, mono - and disubstituted an amino group, halogen, alkyl, substituted alkyl, hydroxyl, etherified ether hydroxyl, a nitro-group, langroup, carboxyl, the esterified carboxyl, alkanoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino-, guanidino-, mercapto-, sulfo, phenylthio-, phenyl(ness.)alkylthio, alkylenedioxy, phenylsulfonyl, phenyl(ness.)alkylsulfonyl or alkylresorcinol, the substituents Z are identical or different from each other, if more than one radical Z;

and where due, if present, is indicated with a wavy line are either simple or double bonds;

or N-oxide described compounds, where one or more nitrogen atoms bound to the oxygen atom, or a salt of such a compound having at least one salt-forming group. Preferably used a compound of formula II is RTC.

The terms used to identify the compounds of formula II have the meanings prescribed in the international patent application WO 98/35958, these definitions are included here by reference.

In the compound of formula I And preferably means oxygen. R oznachaet is lower alkyl, for example, the ethyl or preferably methyl. Z preferably denotes oxygen.

The combination according to the invention can be combined preparation or pharmaceutical composition.

Moreover, the present invention relates to a method of treatment of a warm-blooded animal with a proliferative disorder, particularly cancer of the prostate, in particular with not treatable by hormone prostate cancer with bone metastases, including the introduction of the animal a combination according to the invention in amounts that in this combined effect therapeutically effective against a proliferative disease, and in such combinations of components may also be present in the form of their pharmaceutically acceptable salts.

In addition, the present invention relates to the use of the combinations according to the invention to slow down the progression or treatment of proliferative diseases and for the preparation of medicines to slow down the progression or treatment of proliferative diseases.

Additionally this invention relates to the use of bisphosphonates, platinum compounds or soodustamiseks connection in combination with the derived epothilone formula I, where a represents oxygen or NRNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower lcil and Z means oxygen or a bond, for the preparation of medicines to slow down the progression or treatment of proliferative diseases.

Moreover, this invention provides a commercial package comprising as active ingredients combination of the invention together with instructions for simultaneous, separate or sequential applying them to slow down the progression or treatment of proliferative diseases.

The following examples illustrate the invention described above;

it is assumed, however, that they do not limit in any way the scope of the invention. The beneficial effects of combination according to the invention may also be defined using other models for testing, which are known as such to a person skilled in the field.

Example 1: Cell RS-MM carcinoma of the prostate man, grown inside of the tibia in Nude mice.

Cell suspension (2×105cell line PC-MM carcinoma of the prostate man injected into the tibia of Nude mice. Tumor growth in this model leads to destruction of the bone that is clearly visible after 4 weeks. Treatment of compounds begins 7 days after injection of tumor cells. At this time, animals are divided into groups with the same average and maximum size of the tumor. Processing the ZAT is carried out randomly to different groups and treated only fillers; using (a) bisphosphonates, such as zoledronate acid; component of the combination (b), for example epothilones; or combined components (a) and (b), for example zoledronate acid and epothilones Century Analysis after 3-4 weeks of treatment involves assessment of bone destruction and tumor burden.

Example 2: Test of bisphosphonates and epothilone on tumor fragments carcinoma DU145 prostate man, grown subcutaneously in Nude mice.

Cancer DU145 prostate man grown subcutaneously in Nude mice. Fragments of the tumor (approximately 25 mg each) are implanted subcutaneously in the left flank of Nude mice. Handling connections starting when tumors reach a size of 80-100 mm2(usually 10-15 days). At this time, animals are divided into groups with the same average and maximum size of the tumor. Processing is then carried out randomly to different groups and treated only fillers; using (a) bisphosphonates, such as zoledronate acid; component of the combination (b), for example epothilones; or combined components (a) and (b), for example zoledronate acid and epothilones Century tumor Size (measured using a compass) and body weight determine every 3-5 days.

Example 3: Test oxaliplatin and epothilone In tumor fragments of carcino the s DU145 prostate cancer man grown subcutaneously in Nude mice.

Cancer DU145 prostate man grown subcutaneously in Nude mice. Fragments of the tumor (approximately 25 mg each) are implanted subcutaneously in the left flank of Nude mice. Handling connections starting when tumors reach a size of 80-100 mm2(usually 10-15 days). At this time, animals are divided into groups with the same average and maximum size of the tumor. Processing is then carried out randomly to different groups and treated only fillers; using (a) oxaliplatin; (b) epothilones In or combined components (a) and (b), administered either simultaneously or sequentially in any order. Tumor size (measured using a compass) and body weight determine every 3-5 days.

Example 4: Test carboplatin and epothilone In the fragments of the tumor human lung cancer NCI-H596, grown subcutaneously in Nude mice.

On the same model, which is used in example 3, but using the cell line NCI-H596 tumors of the lung, can be demonstrated high efficiency combination consisting of carboplatin and epothilone, compared with the individual drugs.

Example 5: Test RTC and epothilone In subcutaneous xenografts carcinoma DU145 prostate cancer a man at estimating mice.

Cells DU145 carcinoma of the prostate of a man grown subcutaneously in Nude mice. Tumor cells (106) is injected subcutaneously into the left and right flank of Nude mice. Handling connections begin through 25-32 days, when the tumors reach a size of 80-100 mm2. At this time, animals are divided into groups with the same average and maximum size of the tumor. Processing is then carried out randomly to different groups and treated only fillers; with 2 mg/kg epothilone In, injected once a week intravenously; 50 mg/kg RTC, administered once a day orally, or combined components of epothilones In and RTC. Changes in tumor size and body mass are measured with the aid of compasses on a weekly basis. The results demonstrate additive inhibition of tumor growth without concomitant increased loss of body weight.

Example 6: Test epothilone In and RTC on subcutaneous xenografts isogenic murine B16 melanoma black mice.

Cells of the murine melanoma B16 (5×104) injected subcutaneously into the ears of black mice. Handling connections begin after 7 days. At this time, animals are divided into groups with the same average and maximum size of the tumor. Processing is then carried out randomly to different groups and treated only fillers; using aptilo the while, enter once per week intravenously; using RTK, administered once a day orally, or combined components of epothilones In and RTC. The growth of the primary tumor is controlled on a weekly basis with the help of computer analysis of photographic images of melanoma. Animals subjected to autopsy after 3 weeks of stimulation treatment. The distribution of metastases was determined by weighing the cervical lymph nodes.

1. Pharmaceutical combination to slow down the progression or treatment of proliferative diseases, which include therapeutically effective amounts of (a) compound RTC and (b) derived epothilone formula I

where a represents O or RNNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower alkyl and Z means oxygen or a bond,
for simultaneous, separate or sequential use.

2. The combination according to claim 1, including derivative epothilone formula I, where a represents oxygen, R is lower alkyl or hydrogen, and Z means oxygen or link.

3. The combination according to claim 1, where the proliferative disease is ovarian cancer, lung cancer, malignant tumor of head or neck, cervical cancer, prostate cancer or cancer of the colon.

4. Pharmaceutical composition for process plants the possible development or treatment of proliferative diseases containing a therapeutically effective amount of a combination according to claim 1 and at least one pharmaceutically acceptable carrier.

5. The use of a combination according to claim 1 for the preparation of medicines to slow down the progression or treatment of proliferative diseases.

6. Pharmaceutical composition that includes a therapeutically effective quantities soodustatakse connection representing RTC, in combination with the derived epothilone formula I

where a represents O or NRNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower alkyl and Z means oxygen or a bond,
for the preparation of medicines to slow down the progression or treatment of diseases associated with impaired regulation of angiogenesis.

7. Commodity packaging, including therapeutically effective amounts of (a) soodustatakse connection representing RTC, and (b) derived epothilone formula I

where a represents O or NRNwhere RNmeans hydrogen or lower alkyl, R is hydrogen or lower alkyl and Z means oxygen or a bond,
together with instructions for simultaneous, separate or sequential applying them to slow down the progression or treatment of proliferative Zab the diseases.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention concerns pharmacology, veterinary science and medicine and covers a cytostatic composition containing coordination compounds of platinum, ascorbic acid and phenanthroline derivatives where as coordination compound of platinum, it contains cisplatin, as ascorbic acid and phenanthroline derivatives - ascorbate phenanthrolinate complex of platinum of formula [PtPhen2]Asc and ascorbate phenanthrolinate complex of europium of formula EuAscNO3Phen·4·H2O at the following mass ratio: cisplatin - 1; ascorbate phenanthrolinate complex of platinum - 2; ascorbate phenanthrolinate complex of europium - 3.

EFFECT: composition with antioxidant activity.

1 cl, 1 dwg, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a new derivative of sulfonamide substituted imidazoquinolines, and specifically to N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-c]-qunolin-1-yl]-1,1-dimethylethyl}-methanesulfonamide and its pharmaceutically acceptable salts, as well as to a pharmaceutical composition based on this compound.

EFFECT: invention also relates to a method of inducing biosynthesis of cytokines in an animal organism and methods of treating viral and oncological diseases in animals using said compound and pharmaceutical composition based on said compound.

5 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula: which is N-{2-tert-butyl-1-[(4,4-diflurocyclohexyl)methyl]-1H-benzimidazol-5-yl}ethanesulfonamide and its pharmaceutically acceptable salt, their diastereomers, enantiomers or their mixture. The invention also relates to use of this compound in making a medicinal agent with modulator activity of CB1 receptors; to a pharmaceutical composition based on this compound; to a method of modulating CB1 receptors, based on use of effective quantities of this compound, as well as to a method of producing the compound described above.

EFFECT: obtaining a new derivative of benzimidazole with useful biological activity.

8 cl, 1 tbl, 28 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely oncology and can be used for treating prostate intraepithelial neoplasia. The methods according to the invention involve introduction of a composition containing therapeutically effective amounts of supercritical extracts of rosemary, turmeric, origanum and ginger; and therapeutically effective amounts of water-alcohol extracts of holy basil, ginger, turmeric, Scutellaria baicalensis, rosemary, green tea, Polygonum cuspidatum, Coptis chinensis and barberry.

EFFECT: invention allows inhibiting growth of intraepithelial neoplasia cells due to antineoplastic activity of herbal extracts of the composition, inhibition of cyclooxygenase 2 and induction of apoptosis.

43 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to oncology, and can be used for optimisation of treatment tactics in case of Hodgkin's lymphoma in children and teenagers. Method is realised in the following way. Such unfavourable prognostic factors as: age over 10 years, IV stage of disease, conglomerate dimensions more than 5 cm and/or value of mediastinal-thoracic index greater than 0.33, number of affected zones more than 4, symptoms of intoxication and biological activity of process. After that three risk groups are determined by the sum of detected unfavourable factors. In the first group, if 0-2 factors are detected, 2 cycles of polychemotherapy in accordance with regimen VBVP are carried out, in the second group, if 3-4 risk factors are detected - 4 cycles in alternating regimen VBVP-ABVD-VBVP-ABVD, in the third group, if 5-6 factors are detected - 6 cycles in alternating regimen VBVP-ABVD-VBVP-ABVD-VBVP-ABVD. Two weeks after carrying out polychemotherapy in all groups irradiation of all earlier affected zones is performed.

EFFECT: method allows to reduce risk of post-cytostatic and radiation complications development due to reduction of treatment loading in patients.

1 tbl, 1 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: new pyrrolotriazine derivatives of general formula (I) are described, where R1 is possibly substituted piperidinyl or piperazinyl; R2 is possibly substituted phenyl; R3 is hydrogen; X is -NH-; Y is -CH2-; as well as their pharmaceutically acceptable salts or steroisomers, and pharmaceutical compositions containing said compounds.

EFFECT: given compounds are kinase inhibitors and can be used in medicine, for example as anticancer agents.

9 cl, 267 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, oncology, and can be used for thermochemoradiation therapy of oesophagus cancer. That is ensured by local transoesophageal hyperthermia, gamma-ray teletherapy and chemotherapy as preoperative actions. Herewith gamma-ray therapy is carried out within 2 weeks in average fractionation mode at 3 Gy 5 times a week to total focal dose 30 Gy. Chemotherapy accompanies the whole course of gamma therapy by daily introduction of fluorouracil dosed 300 mg/m2 to the central vein in continuous infusion mode and daily intravenous introduction of cisplatin dosed 6 mg/m2 daily within 1 hour. Hyperthermia is applied on 4th, 8th and 12th days of gamma therapy immediately before irradiation session at temperature 42-44°C within 60 minutes.

EFFECT: method allows optimising treatment of the patients suffering from oesophagus cancer and improving clinical effectiveness owing to advanced local control.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a cyclic bioisostere of purine system derivatives, with general structural formula given below , where R = , Li, Na or K, R1 = -H, -NH2, -Br, -Cl, -OH, -COOH; A = -N- for B=-N=, Z = -CH-; A = -CH= for B = -N=, Z = -CH-; A = -CH= for B = -N=, Z = -N=; A = -CH= for B = -CH=, Z - -CH=; A = -CH= for B = -CH=, Z = -N=, except compounds in which A = -CH= for B = -CH=, Z = -CH=, R= Li, Na or K and R1= -NH2 in the 5th position of the benzo[d]-3H-pyridazine-1,4-dione nucleus, and its pharmacologically acceptable salts, with normalising effect on intracellular processes.

EFFECT: obtaining compounds which can be used for normalising intracellular processes in therapy of disorders, caused by intracellular acidosis and/or oxygen deficiency and/or excess formation of free radicals and/or excess formation of free radical forms of oxygen and/or high thrombocyte aggregation and/or erythrocytes and/or adverse effects and/or nitrergic cell mechanism disorder.

17 cl, 14 tbl, 15 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel diazaindoledicarbonylpiperazinyl compounds of formula I, including its pharmaceutically acceptable salts, which possess antiviral activity and can be used for HIV-infection treatment. In compounds of formula I Q represents , T represents -C(O)- or -CH(CN)-; R1 represents hydrogen; R3 represents hydrogen; R5 is independently selected from group including halogen, cyano, XR9 and B; R2 and R4 are absent; R6 represents hydrogen; -- represents carbon-carbon bond; -Y- is selected from group including , each of R10, R11, R12, R13, R14, R15, R16 and R17 represents H; R18 is selected from group including C(O)-phenyl, isoquinolyl, quinazolyl; D is selected from group including cyano, 5-member heteroaryl containing 3 heteroatoms selected from nitrogen and oxygen; A is selected from group including phenyl, pyridinyl; B is selected from group including -C(O)CH3; piperazinyl; 5-, 6-member heteroaryl containing 1-3 N atoms and possibly O atom; where said heteroaryl optionally is substituted with from one to three similar or different substituents selected from F; F is selected from group including (C1-6)alkyl, phenyl, pyridinyl, COOR26, -COR21, and -CONR24R25; where phenyl is optionally substituted with (C1-6)alkoxy, CF3, or halogen atom; R9, R24, R25 and R26 each is independently selected from group including hydrogen and (C1-6)alkyl; X represents O; R27 represents piperazinyl, N-methylpiperazinyl, or 3-pirazolyl. Invention also relates to pharmaceutical composition.

EFFECT: obtaining compounds and pharmaceutically acceptable salts, which possess antiviral activity and can be used for treatment of HIV infection.

19 cl, 50 dwg, 4 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel inhibitor of phosphodiesterase (PDE) IV and/or to the tumor necrosis factor (TNF) production inhibitor, which corresponds to the compound with formula (I), where R1 is: (1) mono- or di(inferior)alkylamino, (2) phenyl, (3) saturated or unsaturated 5-or 6-membered heteromonocyclic group, selected from a group which includes pyrrolidinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl and piridinyl, or (4) inferior alkyl not necessarily substituted with (i) inferior alkoxi or (ii) saturated 5- or 6-membered heteromonocyclic group, selected from the group, consisting of piperazinyl and morpholinyl, where the inferior alkoxi is not necessarily substituted with cyclo(inferior)alkyl or piridinyl, R2 corresponds to R7 or - A2R7 , where A2 is -(CH2)n- or -(CH=CH)m- [where n is an even number within 2 to 6, and m is an even number 1 or 2], and R7 is a hydrogen, inferior alkylsulfonyl, carboxy, etherificated carboxy or piridinyl; R3 is: (1) phenyl, not necessarily substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, halogen, cyano or carbamoyl; or (2) quinolinyl; or piridinyl, substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, carbamoyl or halogen, and R4 corresponds to the inferior alkyl, or its pharmaceutically acceptable salt. The application of the compound with formula is invented, for producing the therapeutic agent with the PDE IV and/or TNF production inhibiting activity and the pharmaceutical composition containing the effective amount of compounds with formula (I) mixed with the pharmaceutically acceptable carriers. The method for prevention and treatment of the diseases where the application of the PDE IV and/or TNF production inhibitor is considered to be reasonable, including the administration of the therapeutically effective amount of the compound with formula (I). The method for prevention and treatment of asthma, chronic obstructive pulmonary disease, fibrous disorders, acute and fulminant hepatitis, hepatic steatosis, chronic hepatitis, cirrhosis, autoimmune hepatitis, autoimmune inflammatory intestine disease, atopic dermatitis, Alzheimer's disease or viral infection, including the administration of the therapeutically or preventively effective amount of the compound with formula (I).

EFFECT: compound with the PDE IV and/or TNF production inhibiting activity.

11 cl, 2 tbl, 672 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to medicinal agents containing combined inhibitor of dipeptidylpeptidase IV (DPPIV) and biguanide agent. Offered application of pharmaceutical agent implies production of preventive and therapeutic agent and method of intensified effects of active circulating GLP-1 and/or active circulating GLP-2. Besides, invention concerns method of prevention or treatment of disease connected with active circulating GLP-1 and/or active circulating GLP-2, specifically diabetes, obesity, hyperlipidemia, gastrointestinal diseases. Combined inhibitor DPPIV of formula (I) and biguanide agent, specifically phenformine, methformin or buformine stimulates action of active circulating glucagon-like peptide-1 (GLP-1) and/or active circulating glucagon-like peptide -2 (GLP-2) and, therefore inhibits destruction of GLP-1 and GLP-2, with their levels raised up with biguanide agent.

EFFECT: agent has improved efficiency.

17 cl, 12 tbl, 425 ex

FIELD: medicine; veterinary science.

SUBSTANCE: invention refers to application of compounds with common structural formula

R1=-H, -NH2, -Br, -Cl, -ОН, -СООН,

B=-N=, -CH=, Z=-CH=, -N=,

A=-CH- at B=-N=, Z=-CH-,

A=-CH- at В=-СН=, Z=-CH=,

A=-N= at B=-N=, Z=-CH-,

A=-CH- at B=-N=, Z=-N=,

A=-CH= at В=-СН=, Z=-N=.

Structures of specified formula are active for nitrergic and dopaminergic systems of mammal body including human body. These compounds can be applied as neuroprotectors, to improve cognitive function and to normalise psychophysiologic state, to treat consequences of substance abuse, as well as to treat wide range of diseases including neuropsychic, cardiovascular, immune, inflammatory and gastro-intestinal disorders.

EFFECT: application of new and well-known compound to effect nitrergic and dopaminergic systems for treatment purposes.

4 ex, 3 tbl, 8 dwg

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

The invention relates to medicine, therapy, and can be used for treatment of pain

The invention relates to 7-chloro-4-hydroxy-2(2-chloro-4-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione, its pharmaceutically acceptable salts, methods for treating pain, when administered pain relieving effective amount of this compound, and pharmaceutical compositions containing this compound

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

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