Compounds and methods for inhibiting bcl protein interaction with binding partners

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

 

Applications equivalents

This application is a continuation patent application of U.S. 11/600,332, filed 15.11.2006, which is incorporated here fully by reference.

The technical field

The present invention relates to the field of cancer therapeutics. Specifically, the present invention relates to the field of cancer therapeutics that stimulate apoptosis of tumor cells using analogues of isoxazolidine. Connection isoxazolidine according to the invention is contacted with the protein Bcl and block the anti-apoptotic function of Bcl in cancer cells and tumor tissue expressing Bcl. Compounds and pharmaceutical compositions containing these compounds, can be used for the treatment of cancer alone or in combination with chemotherapy or other drugs.

The level of technology

Apoptosis, or programmed death of cells that are important for normal embryological/anatomical development of protective forces of an organism and the suppression of carcinogenesis. Incorrect regulation of apoptosis occurs in cancer and other human diseases that arise due to the imbalance between the process of cell division and death of cells. Bcl-2 is initially identified at the chromosomal breakpoint of t(14;18)-bearing b-cell lymphoma and belongs to R. studimo family of proteins, that regulate apoptosis (Article Gross, A; McDonnell, JM; Korsmeyer, S.J. BCL-2 family members and the mitochondria in apoptosis. Genes & Development, 1999, 13, cc.1899-1911, Cory, S.; Huang, D.C.S.; Adams, J.M. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene, 2003, 22, cc.8590-8607, Danial, N.N.; Korsmeyer, S.J. Cell death: Critical control points., Cell 2004, 116, cc.205-218, Chao, D..; Korsmeyer, S.J. Bcl-2 family: regulators of cell death., Annu. Rev. Immunol., 1998, 16, cc.395-419), the book of Apoptosis, Christopher Potten, James Wilson, Cambridge University Press, 2004). Family proteins Bcl-2 includes anti-apoptotic molecules such as Bcl-2 and Bcl-XL, and proapoptotic molecules, such as Bax, Bak, Bid and Bad. Bcl-2 is involved in the development of cancer cells by preventing capture of normal cells, caused by physiological mechanisms of cell death. Overexpression of Bcl-2 was observed in 70% of cases of breast cancer and many other cancers (Article Buolaniwini, J.. Novel anticancer drug discovery, Curr. Opin. Chem. Biol., 1999, 3, cc.500-509). The levels of protein expression of Bcl-2 also correspond to resistance to a wide range of chemotherapeutic drugs and γ-radiation treatment (Article Reed, J..; Miyashita, T.; Takayama, S.; Wang, H.-G.; Sato, T.; Krajewski, S.; Aime-Sempe, C.; Bodrug, S.; Kitada, S.; Hanada, M. Bcl-2 family proteins: Regulators of cell death involved in the pathogenesis of cancer and resistance to therapy, J. Cell. Biochem., 1996, 60, cc.23-32; Reed, J.. Bcl-2 family proteins: strategies for overcoming chemoresistance in cancer. Advances in Pharmocology 1997, 41, 501-553; Strasser, A.; Huang, D.C.S.; Vaux, D.L. The role of The Bcl-2/ced-9 gene family in cancer and general implications of defects in cell death control for tumorigenesis and resistance to chemotherapy, Biochem. Biophys. Acta, 1997, 1333, cc. F151-F189; DiPaola, R.S.; Aisner,J. Overcoming Bcl-2 and p53-mediated resistance in prostate cancer, Semin. Oncol., 1999, 26, cc.112-116).

Members of the family proteins Bcl-2 are key regulators of apoptosis with proapoptotic (e.g., Bax, Bak, Bid, Bim, Noxa, Puma) and anti-apoptotic function (for example, Bcl-2, Bcl-xL, Mcl-1). Selective and competitive dimerization between Pro - and anti-apoptotic family members determines the outcome of the cells subjected proapoptotic stimulation. Although the exact role of Bcl-2 and Bcl-xL in cancer is not fully clear, there are several lines of evidence that Bcl-2 and Bcl-xL not only participate in the development of cancer by preventing capture of normal cells, but also play a role in the resistance of cancer cells to current anticancer treatments. Experimental overexpression of Bcl-2 (Bcl-xL) makes resistant cancer cells to a wide range of chemotherapeutic agents and irradiation (Article Bcl-2 family proteins: Regulators of cell death involved in the pathogenesis of cancer and resistance to therapy, J. Cell. Biochem., 1996, 60, cc.23-32; Reed, J.C). Bcl-2 and/or Bcl-xL sverkhekspressiya more than 50% of all tumors, as shown below (from the article Wang, S.; Yang, D.; Lippman, M.E., Targeting Bcl-2 and Bcl-xL with nonpeptidic small-molecule antagonists., Seminars in Oncology, 2003, 5, cc.133-142).

Type of cancerOverexpression of Bcl-2 (%)Overexpression of Bcl-xL (%)
Prostate20-40100
hormoneresistant80-100-
Chest60-8040-60
No small cell lung20-40-
Small cell lung60-80-
Rectum50-10083
Melanoma6590
Multiple myeloma (repeat)-77
Head and neck1352-75
Pancreas2390
Hepatocellular carcinoma-80

It has been shown that biological approaches to modulate the function of Bcl-2, using antisense oligonucleotides or single-chain antibodies, increase heniochus vitelotte tumor cells (Article Ziegler, A.; Luedke, GH; Fabbro, D.; Altmann, PHD; Stahel, R.A.; Zangemeister-Wittke, U. Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the Bcl-2 coding sequence, J. Natl. Cancer. Inst., 1997, 89, cc.1027-1036; Webb, A.; Cunningham, D.; Cotter, F.; Clarke, P. A.; Di Stefano, F.; Ross, P.; Corpo, M.; Dziewanowska, Z. Bcl-2 antisense therapy in patients with non-hodgkin lymphoma, Lancet, 1997, 349, cc.1137-1141; Cotter, F.E. Phase I clinical and pharmacokinetic study of Bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma., J. Clin. Oncol., 2000, 18, cc.1812-1823; Piche, A.; Grim, J.; Rancourt, C.; Gomez-Navarro, J.; Reed, J.C.; Curiel, D.T. Modulation of Bcl-2 protein levels by an intracellular anti-Bcl-2 single-chain antibody increases the drug-induced cytotoxicity in the breast cancer cell line MCF-7, Cancer Res., 1998, 58, cc.2134-2140).

It has been shown that antisense oligonucleotide (G3139) (Article Raynaud, F.I.; Orr, R.; Goddard, P.M.; Lacey, H.A.; Lancashire, H.; Judson, I.R.; Beck, T.; Bryan, C.; Cotter, F.E. Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to Bcl-2, after intravenous administration or continuous subcutaneous infusion to mice, J. Pharmacol. Exp. Ther., 1997, 281, cc.420-427), designed for hybridization with a sequence in the mRNA of Bcl-2, inhibits the expression of Bcl-2, promotes apoptosis and inhibits cell growth in breast cancer cells of a person with overexpression of Bcl-2 (article Chen, NG, Marchall, J.L., Trocky, N., Baidas, S., Rizvi, N., Ling, Y., Bhagava, P., Lippman, M.E., Yang, D., and Hayes, D.F., A Phase I study of Bcl-2 antisense G3139 (Genta) and weekly docetaxel in patients with advanced breast cancer and other solid tumors, Proceedings of American Society of Clinical Oncology, 2000). Important synergistic effects and complete regression of tumors was observed in vivo when combined treatment G3139 and docetaxel. Therefore, Bcl-2 is a very privlekatelnosti to develop a new approach for the treatment of many forms of cancer.

Limitations associated with the use of large molecules, such as oligonucleotides, proteins and polypeptides as therapeutic agents include low oral bioavailability, low stability in vivo and high cost. Desirable would be a therapeutic agent ones, permeable to cells small molecules that bind to Bcl-2 and inhibit anti-apoptotic function in cancer and promotirovat cell death in the tumor.

Have been described various small molecules that inhibit the function of Bcl-2. For example, arylsulfonamides been shown to inhibit the function of Bcl-2 and Bcl-xL in biochemical assays and in vitro, article Nature, 2005, 435, cc.677-681. However, there is a need for more small organic molecules that bind to Bcl-2 and inhibit its anti-apoptotic function in cancer and promotirovat cell death in the tumor. The present invention fulfills these needs and has other benefits.

The invention

One way of implementing the present invention relates to compounds of isoxazolidine. In some embodiments, the nitrogen atom isoxazolidinone rings associated with substituted aranceles group. In some embodiments, substituted kalkilya group substituted benzyl group. In some embodiments, isoxazolidinone ring substituted hydroxymethylene or hydroxyethylene group. In some embodiments, isoxazolidinone ring substituted hydroxymethylene and hydroxyethylene group. In some embodiments, isoxazolidinone ring substituted amide group. The present invention further relates to pharmaceutically active salts of the above compounds of isoxazolidine. Another variant of implementation of the present invention relates to pharmaceutical compositions containing a compound of isoxazolidine according to the invention. Another variant of implementation of the present invention relates to a method of applying the above compounds or pharmaceutically active salts, alone or in combination with other agents for the treatment of cancer. Specifically, the present invention relates to a therapeutic method comprising treating a condition characterized by abnormal proliferation of mammalian cells, such as tumor cells (for example, breast cancer and myeloid leukemia), introduction to the mammal or a human, suffering from such a condition, an effective amount of the compounds of the present invention. In some embodiments, the compound of the present invention is administered with a pharmaceutically acceptable carrier.

Detailed description of the invention

The present invention generally relates to compounds of isoxazolidine, useful for the treatment of cancer. Connection isoxazol the Dean according to the invention is contacted with one or more proteins of the Bcl and block the anti-apoptotic Bcl function in cancer cells and tumor tissue, which expresses Bcl. In some embodiments, implementation, some compounds of the invention selectively inhibit the anti-apoptotic activity of only one member of the subfamily of Bcl-2 of anti-apoptotic proteins. Connection isoxazolidine according to the invention can be used for the treatment of a patient suffering from a disease associated with Bcl. In some embodiments, the compounds of isoxazolidine according to the invention are used to treat a patient suffering from cancer. Connection isoxazolidine according to the invention can be administered to the patient in the form of pharmaceutical compositions. The pharmaceutical composition includes the compound of isoxazolidine according to the invention and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition includes the compound of isoxazolidine according to the invention, the chemotherapeutic agent and one or more pharmaceutically acceptable excipients. In some embodiments, the chemotherapeutic agent is docetaxel, paclitaxel, cisplatin, 5-FU, doxorubicin, epipodophyllotoxin, camptothecin, 17-AAG or cyclophosphamide.

The synthesis of compounds of isoxazolidine

Connection isoxazolidine according to the invention can be obtained by the reaction of [3+2] cyclopamine Nitron and alkene. Nitronyl substrate and alkene may contain functioning of the social group, suitable for the production of chemical derivatives after synthesis isoxazolidinone kernel. In some embodiments, the reaction was added a Lewis acid. In a preferred embodiment, the Lewis acid is a Ti(Ofrom-Pr)4. In some embodiments, the reaction mixture is subjected to microwave radiation. Typically, these reactions are carried out in a liquid reaction medium, but can be done on solid media. The reaction may be carried out in an aprotic solvent, preferably that in which the ingredients of the reaction essentially soluble. Suitable solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diglyme, tert-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, carbon tetrachloride and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, xylene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, pyridine and the like; or combinations of two or more solvents. The reaction can be conducted at different temperatures. Usually, the reaction at lower temperatures take the more time to finish. In some embodiments, the reaction cyclopamine carried out in a range from about 15°to about 60°C. In some embodiments, the reaction cyclopamine carried out in a range from about 15°to about 30°C. In some embodiments, the reaction cyclopamine performed at room temperature. In some embodiments, the reaction cyclopamine carried out in a range from about 80°to about 150°C. In some embodiments, the reaction cyclopamine carried out in a range from about 90°to about 120°C. In some embodiments, the reaction cyclopamine spend in the range of from about 95°to about 105°C. In some embodiments, the reaction cyclopamine is performed using a substrate affixed to a solid support. After synthesis isoxazolidinone kernel of the connection isoxazolidine can be obtained derivatives of different reactions obtain derivatives known from the prior art. Illustrative examples include palladium the condensation reaction with getting alkenylphenol or aryl halides, oxidation, reduction, reaction with nucleophiles, reaction with electrophilic compounds, pericyclic reactions, introduction of a protective group, removing the protective groups and the like.

Analysis of biological activity

The following analyses on binding in vitro and cellular assays can be used to determine the activity and SP is civicnet compounds of the present invention to contact with Bcl-2 and inhibit the function of Bcl-2 in the cell.

Analysis of binding with Bcl-2

Binding of Bcl-2 and Bcl-xL may be determined by various known methods. One such analysis is a sensitive and quantitative assay for binding in vitro using fluorescence polarization (FP), described in the article, J.-L.; Zhang, Z-J.; Choksi, S.; Sjam. S.; Lu, Z.; Croce, S.M.; Alnemri, E.S.; Komgold, R.; Huang, Z., Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells, Cancer Res., 2000, 60, cc.1498-1502.

Cellular analyses

It was shown that the ability of the compounds of isoxazolidine of the present invention to inhibit cell viability of cancer cells with overexpression of the protein Bcl-2. When RL cells were treated with compounds of isoxazolidine of the present invention, the inhibitors show a dose-dependent cell killing in the analysis of cytotoxicity with Alamar blue with values IC50from about 100 μm to about 1 μm (see examples). When cells Panc 1 was treated by the compounds of isoxazolidine of the present invention in combination with camptothecin inhibitors show a synergistic dose-dependent cell killing in the analysis on the survival of cells with the exception of propitiated with values IC50from about 100 μm to about 1 μm (see examples).

It has been shown that inhibitors of Bcl-2 are active against several cancer cell lines as a separate agent, including, but not limited to and the and breast cancer (US 2003/0119894 published application WO 02/097053 and WO 02/13833), lymphoma (article Nature, 2005, 435, cc.677-681), cancer small cell lung (article Nature, 2005, 435, cc.677-681), head and neck cancer (published application WO 02/097053) and leukemia (published application WO 02/13833).

It has been shown that inhibitors of Bcl-2 are active against several cancer cell lines in combination with other anticancer agents and radiation, including, but not limited to, breast cancer (docetaxel published application WO 02/097053), prostate cancer (docetaxel published application WO 02/097053), head and neck cancer (docetaxel published application WO 02/097053) and considerable cancer cells of the lung (paclitaxel, article Nature, 2005, 435, cc.677-681). In addition to the combination of the chemotherapeutic agents, small molecular inhibitors of proteins Bcl-2 exhibit synergy with other anti-cancer agents, including, but not limited to, etoposide, doxorubicin, cisplatin, paclitaxel and radiation (article Nature, 2005, 435, cc.677-681).

The methods of therapy and treatment

The present invention also relates to methods for treating and reducing the severity of cancer, and other disorders or conditions mediated Bcl.

Cancer or neoplastic diseases and related disorders that can be cured by the introduction of the compounds and compositions of the present invention, in luchot, but not limited to, listed in table 1 (for a review of such disorders, see Fishman and others, 1985, Medicine, 2nd edition., J.. Lippincott Co., Philadelphia:

In a preferred embodiment, the compounds of the present invention are used for treating cancer, including, but not limited to, lymphoma (preferably follicular lymphoma, diffuse extensive B-cell lymphoma, lymphoma, epithelial cells and chronic lymphocytic leukemia), prostate cancer (more preferably insensitive to hormones), breast cancer (preferably positive for estrogen receptor), neuroblastoma, colorectal cancer, endometrial, ovarian, lung (preferably small cell), hepatocellular carcinoma, multiple myeloma, head and neck cancer or testicular cancer (preferably embryonic).

Treatment of cancer in combination with chemotherapy or radiotherapy

In some embodiments, the implementation, one or more compounds of the present invention is used to treat or prevent cancer or neoplastic disease in combination with one or more anti-cancer chemotherapeutic agents, including, but not limited to, methotrexate, Taxol, mercaptopurine, tioguanin, GI is roximately, cytarabine, cyclophosphamide, ifosfamide, nitrosamine, cisplatin, carboplatin, mitomycin, dacarbazine, procarbazine, etoposide, prednisolone, dexamethasone, cytarabine, campatelli, bleomycin, doxorubicin, idarubitsin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, Espartinas, vinblastine, vincristine, vinorelbine, paclitaxel and docetaxel. In a preferred embodiment, one or more compounds of the present invention is used to treat or prevent cancer or neoplastic disease in combination with one or more chemotherapeutic or other anti-cancer agents, including, but not limited to, are presented in table 2.

Chemotherapeutic agent and/or radiation therapy may be used in accordance with therapeutic methods that are well known from the prior art. Specialist in the art it is clear that the introduction of the chemotherapeutic agent and/or radiation therapy may vary from treatable diseases and known actions of chemotherapeutic agent and/or radiation therapy for this disease. Also, in the accordance with specialist knowledge in a given field of technology therapeutic techniques (e.g., number of doses and times of administration) can be varied on the basis of the observed effects of the introduced therapeutic agents (i.e antineoplastics agent or irradiation) on the patient and on the basis of the observed responses of the disease to introduce therapeutic agents.

Also, usually compounds of the present invention and the chemotherapeutic agent can be administered in a single pharmaceutical composition, and may be due to different physical and chemical characteristics to be entered in various ways. For example, the compounds of the present invention can be administered intravenously to ensure and maintain high levels in the blood, while the chemotherapeutic agent may be administered orally. The definition of the method of introduction and acceptability of introducing, where possible, in the same pharmaceutical composition known to the person skilled in the art. The initial introduction can be carried out in accordance with methods known from the prior art, and then on the basis of the observed effects, dosage, methods of administration and the time of its introduction can be changed by the treating physician.

The specific choice of the chemotherapeutic agent or radiation will depend upon the diagnosis of the attending physicians and from the analysis of the patient's condition and appropriate methods of treatment, the Oia.

The compound of the present invention and the chemotherapeutic agent and/or radiation can be used competitive (for example, at the same time, almost simultaneously, or one method of treatment) or sequentially, depending on the nature of the proliferative disease, the condition of the patient and the exact choice of chemotherapeutic agent and/or radiation used in combination (i.e. a single method of treatment) with the compound of the present invention.

If the connection of the present invention and the chemotherapeutic agent and/or radiation are not used simultaneously or essentially simultaneously, then the optimal order of introduction of the compounds of the present invention and a chemotherapeutic agent and/or radiation may be different for different tumors. So, in some cases, the compound of the present invention may be introduced before the introduction of the chemotherapeutic agent and/or radiation; and in other cases, the chemotherapeutic agent and/or radiation may be used before the introduction of the compounds of the present invention. This alternate introduction may be repeated during a single treatment. Determination of the order of introduction and the number of repetitions of the introduction of each therapeutic agent in the course of treatment is determined by a specialist in the art after evaluation for treatable is Alemania and condition of the patient. For example, the chemotherapeutic agent and/or radiation may be used first, especially if you use a cytotoxic agent, and then the treatment continued with the introduction of the compounds of the present invention, where it is advantageous, by introducing a chemotherapeutic agent and/or radiation, and so on until the end of the treatment.

Thus, in accordance with experience and knowledge of the attending physician can modify each method the introduction of a component (therapeutic agent, i.e. compounds of the present invention, a chemotherapeutic agent or radiation) of the treatment according to the individual needs of the patient, for the purposes of this treatment.

Definition

For convenience, certain terms used in the description, examples and appended claims, below.

The term "co-administration" refers to competitive introduction (the introduction of two or more therapeutic agents at the same time) and the introduction at different times (introduction of one or more therapeutic agents at a time different from the time of introduction of the additional therapeutic agent or agents) up until therapeutic agents are present in a patient to a certain extent some time.

The term "heteroatom"as used here, describes the AET atom of any element, other than a carbon atom or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term "alkyl" refers to the radical of saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl group and cycloalkylation alkyl groups. In preferred embodiments, implementation, linear or branched chain alkyl has 30 or fewer carbon atoms in the chain (for example, C1-C30for linear chains, With3-C30for branched chain), and more preferably 20 or less. Similarly, the preferred cycloalkyl contain 3-10 carbon atoms in the ring structure, and more preferably contain 5, 6 or 7 carbon atoms in the ring structure.

If the number of carbon atoms specified otherwise, a "lower alkyl", as used here, refers to an alkyl group as defined above, but containing from one to ten carbon atoms, more preferably from one to six carbon atoms in the main structure. Similarly, "lower alkenyl" and "lower quinil have the same length chains. Preferred alkyl groups are lower alkali. In preferred embodiments, implementation, Deputy denoted by ZV the camping as alkyl, represents lower alkyl.

The term "halogenated", as used here, refers to an alkyl group where at any position from 1 to all of the hydrogen atoms replaced by halogen. "Perhalogenated" radical, where all the hydrogen atoms replaced by halogen atoms.

The term "aralkyl", as used here, refers to an alkyl group, substituted aryl group (for example, an aromatic or heteroaromatic group).

The terms "alkenyl" and "quinil" refers to unsaturated aliphatic groups analogous in length and possible substitution to the above alcelam, but that contain at least one double or triple bond, respectively.

The term "aryl", as used here, includes 5-, 6 - and 7-membered adnakolava aromatic groups that may include from zero to four heteroatoms, for example benzene, anthracene, Naftalan, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazin, pyridazine and pyrimidine, and the like. Such aryl groups containing heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatic". The aromatic ring can be substituted at one or more positions of the ring such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, what lkinson, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyla, silicom, simple ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ether complex, heterocyclyl, aromatic or heteroaromatic groups, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbons are common to two joined rings (the rings are "condensed ring"), where at least one of the rings is aromatic, for example, and other cyclic rings can be cycloalkyl, cicloalchil, cycloalkenyl, Ariely and/or heterocyclyl.

The terms ortho, meta, and para applied to 1,2-, 1,3 - and 1,4-the disubstituted benzenes, respectively. For example, the names of 1,2-xylene and ortho-dimethylbenzoyl are synonyms.

The terms "heterocyclyl" or "heterocyclic group" refers to a 3-10-membered ring structures, more preferably 3-7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also introduce politicly. Heterocyclyl groups include, for example, thiophene, tianren, furan, Piran, isobenzofuran, chrome, Xanten, tenacity is h, pyrrole, imidazole, pyrazole, isothiazol, isoxazol, pyridine, pyrazin, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, hemolysin, isoquinoline, quinoline, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthrolin, fenesin, phenarsazine, phenothiazines, furazan, phenoxazine, pyrrolidin, oxolan, tolan, oxazole, piperidine, piperazine, morpholine, lactones, lactams, such as azetidinone and pyrrolidinone, solitary, sultone and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, quinil, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyla, silicom, simple ether, alkylthio, sulfonyl, ketone, aldehyde, ether complex, heterocyclyl, aromatic or heteroaromatic group, -CF3, -CN, or the like.

The terms "politikil" or "polycyclic group" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkenyl, Ariely and/or heterocyclyl), in which two or more carbons are common to two attached rings, such as rings are "condensed ring". The ring with which are closely linked not through neighboring atoms, called "bridge" rings. Each of the rings polycycle can be substituted with such substituents as described above, for example by halogen, alkyl, aralkyl, alkenyl, quinil, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyla, silicom, simple ether, alkylthio, sulfonyl, ketone, aldehyde, ether complex, heterocyclyl, aromatic or heteroaromatic group, -CF3, -CN, or the like.

As used here, the term "nitro" means-NO2; the term "halogen" designates-F, -CL, -Br or-I; the term "sulfhydryl" means-SH; the term "hydroxyl" means -- HE; and the term "sulfonyl" means-SO2-.

The terms "amine" and "amino" are known from the prior art and represent unsubstituted and substituted amines, such as the group which can be represented by the following formula:

where R50, R51 and R52 each independently represents hydrogen, alkyl, alkenyl, -(CH2)m-R61, or R50 and R51, together with the N atom to which they are attached, constitute a heterocycle containing 4 to 8 atoms in the ring structure; R61 represents an aryl, cycloalkyl, cycloalkenyl, heterocycle or politics; and m is zero or has a value of from 1 to 8. In some embodiments, implementing the tvline, only one of R50 or R51 may be a carbonyl, e.g. R50, R51 and the nitrogen atom together do not form an imide. In other embodiments, implementation, R50 and R51 (and optionally R52) each independently represents hydrogen, alkyl, alkenyl or -(CH2)m-R61. Thus, the term "alkylamino" includes an amino group, as defined above, containing a substituted or unsubstituted alkyl attached thereto, i.e. at least one of R50 and R51 is an alkyl group.

The term "acylamino is known from the prior art and denotes a group which can be represented by the General formula:

where R50 is as defined above, and R54 represents a hydrogen, alkyl, alkenyl or -(CH2)m-R61, where m and R61 are as defined above.

The term "amido" is known from the prior art as aminosilanes carbonyl and includes a group that can be represented by the General formula:

where R50 and R51 are as defined above. Some embodiments of the amide in the present invention do not include imides which may be unstable.

The term "alkylthio" refers to an alkyl group as defined above that contains the attached sulfur-containing radical. N what are the options for implementation, group "alkylthio" represented by one of-S-alkyl, -S-alkenyl, -S-quinil and-S-(CH2)m-R61, where m and R61 are as defined above. Approximate ancilliary include methylthio, ethylthio and the like.

The term "carboxyl is known from the prior art and includes such groups, which can be represented by the General formula:

where X50 is a bond or represents an oxygen atom or a sulfur, and R55 and R56 represents a hydrogen, alkyl, alkenyl, -(CH2)m-R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, alkyl, alkenyl or -(CH2)m-R61, where m and R61 are as defined above.

When X50 represents an oxygen atom and R55 or R56 do not represent hydrogen, the formula represents an "ester". When X50 represents an oxygen atom, and R55 is as defined above, the group designated here as carboxyl group, and in particular, when R55 is a hydrogen, the formula represents a "carboxylic acid". When X50 represents an oxygen atom, and R56 represents a hydrogen, the formula represents a "formate". Typically, where the oxygen atom in the above formula is replaced by a sulfur atom, the formula represents a "tylersville" GRU is PU. When the X50 is an atom of sulfur, and R55 or R56 do not represent hydrogen, the formula represents a "tially ether". When the X50 is an atom of sulfur, and R55 represents a hydrogen, the formula represents a "thiolcarbamate acid". When the X50 is a sulfur atom and R56 represents a hydrogen, the formula represents a "diaformin". On the other hand, when the X50 is a bond, and R55 is not hydrogen, the above formula is a group of "ketone". When the X50 is a bond, and R55 represents a hydrogen, the above formula represents an "aldehyde" group.

The terms "alkoxyl" or "alkoxy", as used here, denotes an alkyl group as defined above that contains the attached oxygen moiety. Exemplary CNS groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. "Plain air" consists of two hydrocarbon covalently linked an oxygen atom. Accordingly, the Deputy of alkyl, which translates in a simple alkyl an ether is or resembles alkoxy, which may be represented by one of-O-alkyl, -O-alkenyl, -O-quinil, -O-(CH2)m-R8where m and R8are as defined above.

The term "sulfonate" is known from the pre is striding prior art and includes a group, which may be represented by the General formula:

in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl or aryl.

Terms trifles, tosyl, mesyl and neatly are known from the prior art and represent trifloromethyl, n-toluensulfonyl, methanesulfonyl and nonoperatively groups, respectively. The terms triplet, toilet, mesilate and nonflat are known from the prior art and represent a functional group triftormetilfosfinov ether, n-toluensulfonate ether, methansulfonate ether and nonafterburning ether, and molecules that contain these groups, respectively.

The term "carbarnoyl" means-O(C=O)NRR', where R and R' independently represent H, an aliphatic group, aryl group or heteroaryl group.

The term "alkylamino" means-other, where R is an alkyl group.

The term "dialkylamino" refers to-NRR', where R and R' represent alkyl groups.

The term "hydroxyalkyl" means-R-OH, where R represents alifaticescoe group.

The term "aminoalkyl" means-R-NH2where R represents alifaticescoe group.

The term "acylaminoalkyl" means-R-NH-R', where R and R' represent the FDS is th alifaticheskie group.

The term "dialkylaminoalkyl" means-R-N(R')-R", where R, R' and R" represent alifaticheskie group.

The term "alluminati" means-R-NH-R', where R represents alifaticescoe group, and R' represents an aryl group.

The term "oxo" refers to a carbonyl oxygen atom (=O).

The terms "dyadically" or "bivalent" are used herein interchangeably and refer to any of divalent groups of alkyl, alkenyl, quinil, alkylamino, alkoxyl, cycloalkyl, geterotsiklicheskie, aryl, aralkyl, heterocyclyl, heteroaryl and heteroaryl. For example,

represents a bivalent alkyl or alkyl diradical;

also represents a bivalent alkyl or alkyl diradical;

is a bivalent aryl or the aryl diradical;

represents a bivalent aralkyl or Uralkaliy diradical; and

represents a bivalent (alkyl)heteroaryl or (alkyl)heteroalkyl diradical.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifloromethyl, nonattributable, n-toluensulfonyl and methanesulfonyl, respectively. A more complete list of abbreviations used x the Mikami-organically with knowledge of the prior art, given in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in the table entitled as a Standard list of abbreviations. Abbreviations contained in said list, and all abbreviations used by chemists organically with knowledge of the prior art, shown here as a reference.

The term "sulfate" is known from the prior art and includes a group that can be represented by the General formula:

in which R41is the same as defined above.

The term "sulfonylamino is known from the prior art and includes a group that can be represented by the General formula:

The term "sulfamoyl is known from the prior art and includes a group that can be represented by the General formula:

The term "sulfonyl", as used here, refers to a group, which may be represented by the General formula:

in which R44selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "sulfoxide", as used here, refers to a group that can be represented in General form the Loy:

in which R44selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, cycloalkyl, heterocyclyl, aralkyl or aryl.

"Selenology" denotes an alkyl group containing substituted attached selenography. Examples of "selenoamino", which can be substituted with the alkyl selected from-Se-alkyl, -Se-alkenyl, -Se-quinil and-Se-(CH2)m-R7where m and R7are as defined above.

A similar substitution can be made for alkenyl and etkinlik groups by obtaining, for example, aminoalkyl, aminoalkyl, aminoalkyl, aminoalkyl, aminoalkyl, aminoalkyl, tolchenov, tyulkanov, carbonization of alkenyl or alkinyl.

As used here, the definition of each expression, such as alkyl, m, n, etc. in the presence of more than once in any structure, is independent of its definition elsewhere in this structure.

It should be understood that "substitution" or "substituted" includes inherent to the condition that such substitution is consistent with the valence of the substituted atom and the substituent, and that the substitution leads to the formation of stable compounds, for example, which is not subject to transformation, such as rearrangement, cyclization, elimination, etc.

As here used is to be the term "substituted" include all possible substituents of organic compounds. In a broad embodiment, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrating the substituents include, for example, the substituents described above. Valid, the Deputy may be one or more and same or different suitable for organic compounds. For purposes of this invention, the heteroatoms such as nitrogen, can contain hydrogen substituents and/or any suitable substituents described here, the organic compounds which satisfy the valencies of the heteroatoms. The present invention is not intended to limit the appropriate substituents of organic compounds.

The phrase "protective group"as used here, denotes temporary deputies, which protect a potentially reaktsionnosposobnykh functional group from undesired chemical transformations. Examples of such protective groups include esters of carboxylic acids, Silovye esters of alcohols and acetals and ketals of aldehydes and ketones, respectively. The field of chemical protective groups are described in detail (book Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2-about the edition; Wiley: New York, 1991). Protected forms of the compounds according to the invention is included in the scope of the present invention.

Some compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention includes all such compounds, including CIS - and TRANS-isomers, R - and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures that fall within the scope of the invention. Additional asymmetric carbon atoms may be present in the Deputy, such as an alkyl group. All such isomers and mixtures thereof are included in the present invention.

If, for example, specific enantiomer of the compounds of the present invention, it can be obtained by asymmetric synthesis or by obtaining derivatives with chiral auxiliary substance, which received diastereomeric mixture is separated and the auxiliary group otscheplaut with getting clean target enantiomers. Alternatively, when the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric a salt formed with an appropriate optically active acid or base, followed by separation of the thus obtained diastereomers by fractional crystallization or chromatography the definition means, well known from the prior art, and the subsequent extraction of the pure enantiomers.

The above equivalents of the compounds include compounds which otherwise correspond and which have the same General properties (for example, act as an analgesic funds), which includes one or more simple variations of substituents which do not prevent the effectiveness of compounds binding to the Sigma receptor. Typically, compounds of the present invention can be obtained by methods shown in the General reaction schemes, for example, as described below, or modifications of them, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions it is also possible to use variants which are in themselves known, but not shown here.

For the purposes of the present invention, the chemical elements are identified in accordance with the periodic table of the elements, CAS version, Handbook of Chemistry and Physics, 67-e edition, 1986-87, the inner part of the cover.

The term "subject"as used here, refers to an animal, usually a mammal or human, which is the object of treatment, observation and/or experiment. When the term is used in conjunction with the introduction of the compound or drug, then the subject is the object is ecene, monitoring and/or administration of compounds or medicinal product.

The term "therapeutically effective amount", as used here, refers to that amount of active compound or pharmaceutical agent that causes the biological or medical response in a cell culture, tissue system, animal or human that is set by the researcher, veterinarian, medical doctor or doctor includes relief of the symptoms of treatable diseases, conditions or disorders. In the present invention, such amount will be sufficient for binding bl-2 in the cell and inhibiting at least part of the anti-apoptotic activity of the protein. This amount may be sufficient for therapeutic efficacy in a patient or can provide the sensitivity of cells to treatment with other anti-cancer agent.

The term "composition" includes a product containing certain ingredients in the specified amounts, as well as any product which is formed, directly or indirectly, from combinations of certain ingredients in certain amounts.

The term "pharmaceutically acceptable carrier" refers to an environment, which is used to obtain a desired dosage forms of the compounds. Pharmaceutically acceptable carrier can include one or bore the only solvent, diluents, or other liquid binder; dispersion or suspendida funds; surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like. In the books Remington''s Pharmaceutical Sciences, 15th edition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, 3rd edition, edited by A.H.Kibbe (American Pharmaceutical Assoc. 2000) describes the different media used to produce pharmaceutical compositions and known techniques for getting them.

The phrase "mediated Bcl violation and the violation is mediated by cells expressing Bcl" refers to a pathological and morbid States, which plays a role of Bcl. Such roles may be directly associated with a pathological condition or can be indirectly connected with this condition. A common feature for this class of States is that they can be facilitated by inhibition activity, function, or binding proteins of the Bcl.

As used here, the term "Bcl" and "Bcl" include one or more subfamilies Bcl-2 anti-apoptotic proteins Bcl-2, Bcl-w, Mcl-1, Bcl-XL, A1, Bfll, Bcl-B, BOO/DIVA, and their homologues.

Compounds according to the invention

In some embodiments, the implementation, the present invention relates to the compound of formula 1:

or f is rmaceuticals acceptable salt;

where independently in each case:

n denotes 0, 1, 2, 3 or 4;

R1independently for each case represents H, alkyl, alkenyl, quinil, aryl, aralkyl, heterocyclyl, geterotsiklicheskikh, heteroaryl, heteroalkyl, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamines, nitro, atillio, carboxamide, carboxyl, nitrile, -COR5, -CO2R5, -N(R5)CO2R6, -OC(O)N(R5)(R6), -N(R5)SO2R6or-N(R5)C(O)N(R5)(R6);

R2and R3independently for each case are H, alkyl, alkenyl, quinil, aryl, aralkyl, heterocyclyl, geterotsiklicheskikh, heteroaryl, heteroalkyl or -[C(R5)(R6)p-R4; or having the formula 1A:

where

m denotes 0, 1, 2, 3, 4 or 5;

R7for each case independently represents H, alkyl, aryl, alkenyl, halide, hydroxyl, alkoxyl, alkenylacyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamines, nitro, atillio, carboxamide, carboxyl, nitrile, -OSO3R5, -SO2R5, -S(O)R5, -SR5, -PO2OR5, -OPO2OR5, -COR5, -CO2R5, -OCH2CO2R5or-OCH2C(O)N(R5)(R6); or two R7together can about razvivat monocyclic ring with 5 to 8 atoms in the ring, of which one, two or three atoms independently represent S, O or N;

R4is a halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamines, nitro, atillio, carboxamide, carboxyl, nitrile, - OSO3R5, -SO2R5, -S(O)R5, -PO2OR5, -OPO2OR5, -COR5, -CO2R5, -N(R5)CO2R6, -OC(O)N(R5)(R6), -N(R5)SO2R6or-N(R5)C(O)N(R5)(R6); and

each of R5and R6independently for each case represents H, alkyl, alkenyl, quinil, aryl, aralkyl, cycloalkyl, heterocyclyl, geterotsiklicheskikh, heteroaryl or heteroalkyl; or R5and R6together form a monocyclic ring of 4-8 atoms in the ring, of which one, two or three atoms in the ring independently represent S, O or N.

The present invention also relates to a compound selected from the group consisting of:

Another variant of implementation of the present invention relates to pharmaceutical compositions comprising a compound as described above, and at least one pharmaceutically acceptable excipient.

The methods according to the invention

One way of implementing the present invention relates to a method of treatment mediated Bcl violations includes stage

introduction to the patient in need, a therapeutically effective amount of the above compounds.

In some embodiments, the implementation, the present invention relates to the above method, where the specified mediated Bcl violation is a cancer or neoplastic disease.

In some embodiments, the implementation, the present invention relates to the above method, where the specified cancer or neoplastic disease is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute malacitana leukemia, myeloblastoma, promyelocytic, myelomonocytic, monocytic leukemia, erythroleucus, chronic leukemia, chronic malacitana (granulocytic) leukemia, chronic lymphocytic leukemia, true polycythemia, Hodgkin's disease, disease non-Hodgkin's lymphoma, multiple myeloma, macroglobulinemia Waldenstrom, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, ehotelier.com, lymphangiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, abnormal Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, Pascale the full carcinoma, basal cell carcinoma, adenocarcinoma, carcinoma of the sweat glands, gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, moshaweng cancer, bronchogenic carcinoma, renal cell carcinoma, hepatoma, carcinoma of the biliary tract, choriocarcinoma, seminoma, embryonal carcinoma, Wilm tumor, cervical cancer, bladder cancer, testicular tumor, lung carcinoma, carcinoma small cell lung carcinoma of the bladder, epithelial carcinoma, glioma, astrocytoma, Protocol, craniopharyngioma, ependymomas, pinealoma, hemangioblastoma, neurilemmoma auditory nerve, oligodendrogliomas, meningiomas, melanoma, neuroblastoma, retinoblastoma and endometrial cancer.

In some embodiments, the implementation, the present invention relates to the above method, where the specified cancer is a follicular lymphoma, diffuse extensive B-cell lymphoma, lymphoma epithelial cells, chronic lymphocytic leukemia, prostate cancer, breast cancer, neuroblastoma, colorectal cancer, endometrial, ovarian, lung cancer, hepatocellular carcinoma, multiple myeloma, head and neck cancer or testicular cancer.

In some embodiments, the implementation, the present invention relates to the above method, where the specified cancer shorecrest the range Bcl.

In some embodiments, the implementation, the present invention relates to the above method, where the specified cancer depends on protein Bcl in respect of growth and survival.

In some embodiments, the implementation, the present invention relates to the above method, where the specified protein Bcl is a Bcl-2.

In some embodiments, the implementation, the present invention relates to the above method, where the specified protein Bcl is a Bcl-xL.

In some embodiments, the implementation, the present invention relates to the above method, where the cancer manifests t(14;18) chromosomal translocation.

In some embodiments, the implementation, the present invention relates to the above method, where the specified compound is administered parenterally.

In some embodiments, the implementation, the present invention relates to the above method, where the specified connection intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically or intranasally.

In some embodiments, the implementation, the present invention relates to the above method, where the specified compound is administered systemically.

In some embodiments, the implementation, the present invention relates to the above method, where the specified patient is a mammal.

In some of the s variants of implementation, the present invention relates to the above method, where the specified patient is a Primate.

In some embodiments, the implementation, the present invention relates to the above method, where the specified patient is the man.

In another variant implementation, the present invention relates to a method of treatment mediated Bcl violations, including the stage of introduction to a patient in need, a therapeutically effective amount of a chemotherapeutic agent in combination with a therapeutically effective amount of the above compounds.

In some embodiments, the implementation, the present invention relates to the above method, where the specified mediated Bcl violation is a cancer or neoplastic disease.

In some embodiments, the implementation, the present invention relates to the above method, where the specified cancer or neoplastic disease is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute malacitana leukemia, myeloblastoma, promyelocytic, myelomonocytic, monocytic leukemia, erythroleucus, chronic leukemia, chronic malacitana (granulocytic) leukemia, chronic lymphocytic leukemia, true polycythemia, Hodgkin's disease, b is Lesni non-Hodgkin's lymphoma, multiple myeloma, macroglobulinemia Waldenstrom, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, ehotelier.com, lymphangiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, abnormal Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, carcinoma of the sweat glands, gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, moshaweng cancer, bronchogenic carcinoma, renal cell carcinoma, hepatoma, carcinoma of the biliary tract, choriocarcinoma, seminoma, embryonal carcinoma, Wilm tumor, cervical cancer, bladder cancer, testicular tumor, lung carcinoma, carcinoma small cell lung carcinoma of the bladder, epithelial carcinoma, glioma, astrocytoma, Protocol, craniopharyngioma, ependymomas, pinealoma, hemangioblastoma, neurilemmoma auditory nerve, oligodendrogliomas, meningiomas, melanoma, neuroblastoma, retinoblastoma, and endometrial cancer.

In some embodiments, the implementation, the present invention relates to the above method, where the specified cancer shorecrest the et protein Bcl.

In some embodiments, the implementation, the present invention relates to the above method, where the specified cancer depends on protein Bcl in respect of growth and survival.

In some embodiments, the implementation, the present invention relates to the above method, where the specified protein Bcl is a Bcl-2.

In some embodiments, the implementation, the present invention relates to the above method, where the specified protein Bcl is a Bcl-xL.

In some embodiments, the implementation, the present invention relates to the above method, where the cancer manifests t(14;18) chromosomal translocation.

In some embodiments, the implementation, the present invention relates to the above method, where the amount of these compounds is such that it reduces the cellular levels of proteins Bcl patient, and the number of the specified chemotherapeutic agent is such that these proteins Bcl patient effectively inhibited the specified chemotherapeutic agent.

In some embodiments, the implementation, the present invention relates to the above method, where the specified compound is administered parenterally.

In some embodiments, the implementation, the present invention relates to the above method, where the specified connection intramuscularly, votive is but subcutaneous, oral, pulmonary, intrathecally, topically or intranasally.

In some embodiments, the implementation, the present invention relates to the above method, where the specified compound is administered systemically.

In some embodiments, the implementation, the present invention relates to the above method, where the specified patient is a mammal.

In some embodiments, the implementation, the present invention relates to the above method, where the specified patient is a Primate.

In some embodiments, the implementation, the present invention relates to the above method, where the specified patient is the man.

The pharmaceutical composition

In another embodiment, the present invention relates to pharmaceutically acceptable compositions, which include therapeutically effective amount of one or more of the above compounds together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail hereinafter, the pharmaceutical compositions of the present invention may be particularly prepared for introduction in solid or liquid form, including the right to: (1) oral administration, for example, medicine (aqueous or non-aqueous solutions or suspensions), tablets, e.g., for buccal is Noah, sublingual, and systemic absorption, bolus injections, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, subcutaneous, intramuscular, intravenous or epidural injection, for example, a sterile solution or suspension, or composition of extended release; (3) topical application, for example, in the form of a cream, ointment or patch controlled release or spray on the skin; (4) intravaginal or intrarectal injection, for example, in the form of a pessary, cream or foam; (5) sublingually; (6) eyes; (7) transdermal; (8) nasal; (9) into the lungs or (10) intrathecal.

The phrase "therapeutically effective amount", as used here, indicates the number of connections, material, or composition comprising the compound of the present invention, is effective to obtain a desired therapeutic effect in at least part of the cells of the animal with a reasonable ratio of risk-to-benefit, applicable to any medical treatment.

The phrase "pharmaceutically acceptable" is used here to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope voiced medical treatment, are suitable for use in contact with the tissues of humans and animals without unwanted toxicity, irritation,allergic reactions or other problems or complications, with a reasonable ratio of benefit/risk.

The phrase "pharmaceutically acceptable carrier", as used here, refers to pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient tool to facilitate the receipt (e.g., lubricant, talc, magnesium stearate, calcium or zinc or stearic acid), or encapsulating material to solvent, participating in the transfer or transportation connections from one organ or body part to another organ or part of body. Each carrier must be "acceptable" in relation to compatibility with other ingredients of the composition and is not harmful for the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; (4) powder tragakant; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes for suppositories; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) the floor is Ola, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as etiloleat and tillaart; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) containing no pyrogen water; (17) isotonic saline; (18) the solution of Ringer; (19) ethyl alcohol; (20) pH-regulatory solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances for use in pharmaceutical compositions.

As described above, some embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this respect refers to the relatively non-toxic, inorganic and organic acid additive salts of the compounds of the present invention. These salts can be obtained in situ in the medium for the introduction or the method of obtaining a dosage form or in separate reaction purified compounds according to the invention in its free base form with a suitable organic or inorganic acid, and the allocation of the salts, followed by purification. Exemplary salts include the hydrobromide, hydrochloride, sulfate, bis hat, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate and laurylsulfate and the like. (See, for example, article Berge and others, "Pharmaceutical Salts", 1977, J. Pharm. Sci., 66, cc.1-19).

Pharmaceutically acceptable salts of the compounds include the conventional nontoxic salts or Quaternary ammonium salt compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, sotynova and the like.

In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically p is yimlamai bases. The term "pharmaceutically acceptable salts" in these cases indicates a relatively non-toxic, inorganic and organic basic salt additive compounds of the present invention. These salts can be similarly obtained in situ in the medium for the introduction or the method of obtaining a dosage form or in separate reaction purified compound in the form of the free acid with a suitable base such as the hydroxide, carbonate or bicarbonate pharmaceutically acceptable metal cations, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Exemplary salts with alkali or alkaline earth metal include lithium salts, sodium, potassium, calcium, magnesium and aluminum and the like. Exemplary organic amines useful for the formation of a basic additive salts include ethylamine, diethylamine, Ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge article and others, above).

Moisturizing agents, emulsifiers and lubricants, such as nutriceuticals and magnesium stearate and coloring agents, agents for release agents for coatings, sweeteners, fragrances and perfume agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water is Astoriya antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, bottled hydroxyanisol (BHA), bottled hydroxytoluene (VIT), lecithin, propylgallate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

The compositions of the present invention include compositions suitable for oral, nasal, local (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The compositions typically may be present in unit dosage form and may be obtained by any methods well known from the prior art of pharmacy. The amount of active ingredient that may be combined with the material of the carrier to obtain a single dosage form will vary depending on the treated patient, the specific route of administration. The amount of active ingredient that may be combined with material media, a unit dosage form, is usually the amount of the compound that has a therapeutic effect. Usually, one hundred PR is cents this amount is from about 0.1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

In some embodiments, the implementation, the composition of the present invention includes excipient selected from the group consisting of cyclodextrins, cellulose, liposomes, micelle-forming agents such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides; and the compound of the present invention. In some embodiments, the implementation of the above composition provides an orally bioavailable compound of the present invention.

Methods of obtaining these formulations or compositions include the stage of introduction of the mixture of compounds of the present invention with the carrier and, optionally, one or more additional ingredients. Typically, the compositions will receive uniform and close by introducing the mixture of compounds of the present invention with liquid carriers, or finely ground solid carriers, or both, and then, if necessary, shaping the product.

The compositions according to the invention suitable for oral administration may be in the form of capsules, sachets, pills, tablets, pellets (using odorants, usually sucrose and acacia or tragakant), powders, granules, or in the form of a solution or suspension in aqueous or non-aqueous liquid, or in the form of emulsionable-in-water or water-in-oil or in the form of an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or in the form of liquids for rinsing the mouth and the like, each of which contains a predetermined quantity of compounds of the present invention as an active ingredient. The compound of the present invention can also be administered as bolus injections, Elektrarne or in paste form.

In solid dosage forms according to the invention for oral administration (capsules, tablets, pills, pills, powders, granules, pellets and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following substances: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) loosening agents, such as agar-agar, calcium carbonate, corn starch or starch paste, alginic acid, certain silicates and sodium carbonate; (5) slow dissolving agents, such as paraffin; (6) absorption accelerators, such as compounds of chetverti the CSOs ammonium and surfactants, such as poloxamer and nutriceuticals; (7) moisturizing agents, such as, for example, cetyl alcohol, glycerylmonostearate and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, nutriceuticals, zinc stearate, sodium stearate, stearic acid and mixtures thereof; and (10) coloring agents; and (11) the agent for controlled release, such as crosspovidone or ethylcellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions can also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft gelatin capsules and gelatin capsules with a hard shell, using such excipients as lactose or milk sugars, as well as glycols of high molecular weight and the like.

The tablet can be obtained by extrusion or molding, optionally with one or more additional ingredients. Compressed tablets can be obtained using a binder (such as gelatin or hypromellose), lubricant, inert diluent, preservative, raising agent (for example, nitroglicerine starch or cross-linked, the sodium carboxymethyl cellulose), over OSTO-active or dispersing agent. Molded tablets can be obtained by molding in a suitable device powder mixture of compounds, hydrated inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as tablets, capsules, pills and granules, may not necessarily be obleceni or obtained with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations. They can also be structured in such a way as to obtain a slow or controlled release of the active ingredient, using, for example, hypromellose in different proportions to obtain the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be formulated for immediate release, for example, by freeze drying. They can be sterilized, for example, by filtration through a retaining bacteria filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable media immediately before use. These compositions also optionally may contain radiopaque agents and can provide a composition, which visualaid the t active ingredient (ingredients) only or mainly in certain parts of the gastrointestinal tract, optional delayed. Examples associated compositions, which can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulating form, if appropriate, with one or more above described excipients.

Liquid dosage forms for oral administration of the compounds according to the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the prior art, such as, for example, water or other solvents, dissolving agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, oil of groundnuts, maize, wheat germ oil, olive, castor and sesame oils), glycerol, tetrahydrofuranyl alcohol, polyethylene glycols and esters of fatty acids sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include Advanta, such as moistening agents, emulsifying and suspendresume agents, sweeteners, flavors, coloring agents, perfume agents and preservative is.

Suspensions, in addition to the active compounds, may contain suspendresume agents, for example ethoxylated isostearyl alcohols, polyoxyethylenesorbitan and esters of sorbitol, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant and mixtures thereof.

Formulations of the pharmaceutical compositions but the invention for rectal or vaginal injection can be presented in the form of suppositories, which can be obtained by mixing one or more compounds according to the invention with one or more suitable a non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, wax suppositories or a salicylate, and which is solid at room temperature, but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compound.

The compositions of the present invention, which are suitable for vaginal administration, also include pessaries, tampons, creams, gels, pastes, foams or spray compositions containing such suitable carriers, which are known from the prior art.

Dosage forms for local or transdermal injection of the compounds of the present invention include powders, sprays, ointments, pastes, cream the, lotions, gels, solutions, pastes and inhalers. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or gases-displacers that may be required.

Ointments, pastes, creams and gels may contain, in addition to the active compound of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to the compound of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present invention in the body. Such dosage forms can be obtained by dissolving or dispergirovannom compound in a suitable medium. Amplifiers absorption can also be used to improve the passage of compounds through the skin. Soon is there such a passage may be controlled by controlling the speed of the membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, ointments for the eyes, powders, solutions and the like are also included in the scope of the present invention.

The pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds according to the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be recovered in a sterile injectable solutions or dispersions prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostatic substances dissolved substances, which make the composition isotonic with the blood of the patient or suspendresume or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may be used in the pharmaceutical compositions according to the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures of vegetable oils, such as olive oil, and injectable organic esters, such as etiloleat. Proper fluidity can be achieved, for example, the use of covering materials, such as lecithin, by the provision requiring the CSOs particle size in the case of dispersion, and the use of surfactants.

These compositions can also contain adjuvants such as preservatives, moisturizing agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms on connection can be provided by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, fenolcarbonove acid and the like. Also, it may be desirable inclusion isotonic agents such as sugars, sodium chloride and the like, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be provided by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, to prolong the action of a medicinal product, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by applying a liquid suspension of crystalline or amorphous material with low solubility. The speed of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral forms the input of the medicinal product is process is the group or suspendirovanie drug in an oil medium.

Injectable form extended release get education microencapsulating matrix compounds in biodegradable polymers such as polyactic-polyglycolide. Depending on the ratio of drug and polymer and the nature of the particular polymer used, the rate of release of drug can be monitored. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Injectable formulations of extended release also get the introduction of the drug in liposomes or microemulsions that are compatible with the tissue of the body.

When the compounds of the present invention is administered in the form of pharmaceutical agents to humans and animals, they can be administered per se or as a pharmaceutical composition containing, for example, from 0.1 to 99% (more preferably, from 10 to 30%) of active ingredient in combination with pharmaceutically acceptable carrier.

The preparations of the present invention can be administered orally, parenterally, topically or rectally. Of course, they are entered into forms appropriate for each route of administration. For example, they are introduced in the form of tablets or capsules, injections, inhalation, liquid eyes, ointments, suppositories, etc., introduction by injection, infusion or inhalation; topical by lotion or ointment; and rect the flax by suppositories. Oral administration is preferred.

The phrases "parenteral administration" and "administered parenterally"as used here, refers to the route of administration other than enteral and local administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intra-articular, infraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intradermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

The phrase "system introduction, administered systemically", "peripheral introduction" and "enter peripheral", as here used, means introducing the compound, drug or other material not directly into the Central nervous system, so that they are included in the system of the patient and, thus, are subject to metabolism and other similar processes, for example, subcutaneous administration.

These compounds can be administered to humans and other animals for the treatment of any appropriate manner of administration, including oral, nasal, for example, a spray, rectally, intrawaginalno, parenteral, intracisternally and topically in the form of powders, ointments or drops, including buccal and sublingual.

In relation to the chosen route of administration, the connection is of the present invention, which can be used in a suitable hydrated form, and/or pharmaceutical compositions of the present invention are pharmaceutically acceptable dosage forms by conventional means known from the prior art.

The exact dosage levels of active ingredients in the pharmaceutical compositions of the present invention can be modified in such a way as to obtain an amount of active ingredient that is effective to achieve the target therapeutic response for a particular patient, compositions and mode of administration, without toxicity to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the specific compound of the present invention or a complex ester, salt or amide, the method of administration, time of administration, rate of excretion or metabolism of specific compounds, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the specific compound, the age, sex, weight, condition, General health and primary treatable medical history of the patient, and similar factors well known in medicine.

The physician or veterinarian in danniebelle technique is able to easily identify and evaluate effective amount of necessary pharmaceutical composition. For example, the physician or veterinarian could start the dosage of the compounds according to the invention in the pharmaceutical composition at levels lower is required to achieve the target therapeutic effect, and gradually increase the dosage until the implementation of the target of the effect.

Typically, a suitable daily dosage of the compounds according to the invention is that the number of connections, which is the lowest dose effective for therapeutic effect. This effective dose is usually dependent on the above factors. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the present invention for a patient, when used for its analgesic actions are in the range from about 0.0001 to about 100 mg per kilogram of body weight per day.

If necessary, an effective daily dosage of the active compounds may be administered two, three, four, five, six or more separate doses, administered separately with appropriate intervals throughout the day, optionally, in unit dosage forms. The preferred dosage is the introduction of one time per day.

If it is possible for compounds of the present invention to introduce it separately, it is preferable to enter the compound in the form of a pharmaceutical formulation (composition).

Join in soo is according to the invention may be formulated for administration by any conventional method, for use in medicine for the treatment of human or animal health, like other pharmaceutical agents.

In another embodiment, the present invention relates to pharmaceutically acceptable compositions, which include therapeutically effective amount of one or more compounds as described above, together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail hereinafter, the pharmaceutical compositions of the present invention may be specially prepared for administration in solid or liquid form, including forms, adapted for: (1) oral administration, for example, medicine (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and systemic absorption, bolus injections, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, subcutaneous, intramuscular, intravenous or epidural injection such as a sterile solution or suspension; (3) topical application, for example in the form of a cream, ointment or patch controlled release or spray on the skin, the lungs or mucous membranes; or (4) endovaginal or intrarectal injection, for example, in the form of a pessary, cream or foam; (5) sublingual or buccal; (6) eye; (7) transdermal; or (8) nasal.

The term "treatment" includes the em also prevention, therapy and recovery.

The patient undergoing such treatment is any animal, including primates, in particular humans, and other mammals such as horses, cattle, swine and sheep; and poultry, in particular chickens.

The connection according to the invention can be administered as such or as mixtures with pharmaceutically acceptable carriers and can also be administered in combination with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Joint therapy, thus includes sequential, simultaneous and separate introduction of the active compound so that therapeutic action of the first input means does not completely disappear when you enter the next one.

Adding active compounds according to the invention in animal feed is preferably carried out prior mixture of suitable food containing the active compound in an effective amount, and the introduction of the pre-mixture in a complete diet.

Alternatively, the intermediate compound concentrate, or food Supplement containing the active ingredient may be mixed into food. The way in which such food pre-mixes and full ratio can be obtained and implemented, are described in the prior art (the book "Applied Animal Nutritio", W.H.Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding", books About and, Corvallis, Ore., USA, 1977).

Micelle

Recently, the pharmaceutical industry has introduced technology microemulsification to improve the bioavailability of some lipophilic (water-insoluble) pharmaceutical agents. Examples include trimetric (article Dordunoo, S.. and others, Drug Development and Industrial Pharmacy, 17(12), cc.1685-1713, 1991, and REV 5901, Sheen, R.S., and others, J Pharm Sci, 80(7), cc.712-714, 1991). Among other things, microemulsification refers to increased bioavailability mainly aimed absorption into the lymphatic system instead of the circulatory system, which then passes the liver and prevents the destruction of joints in hepatobiliary circulation.

Although all suitable amphiphilic compounds are included, the preferred carriers are usually those that have the status of generally recognized as safe (GRAS) and which can dissolve the compound of the present invention and microemulsions it at the last stage, when the solution is injected into contact with the integrated water phase (such as a phase in the gastrointestinal tract of man). Usually amphiphilic ingredients that meet these requirements have HLB values (hydrophilic and lipophilic balance) 2-20, and their structures contain linear alifaticheskie radicals in the range from C-6 to C-20. Examples are polietilenglikoli rowanne fatty glycerides and polyethylene glycols.

Commercially available amphiphilic carriers especially included, including series Gelucire, labrafil, Lubrizol or neuroglial (all produced and distributed by Gattefosse Corporation, Saint Priest, France), PEG-monooleate, PEG-dioleate, PEG-monolaurate and dilaurate, lecithin, Polysorbate 80, etc. (produced and distributed by many companies in the United States and around the world).

Polymers

Hydrophilic polymers suitable for use for the present invention are polymers which dissolve easily in water, can be covalently linked to form vesicles with lipid and transferred in vivo without toxic effects (i.e. they are biocompatible). Suitable polymers include polyethylene glycol (PEG), polylactic acid (also called polylactide), polyglycolic acid (also called polyglycolide), a copolymer of polylactic-polyglycolic acid and polyvinyl alcohol. The preferred polymers are polymers with a molecular weight of from about 100 or 120 daltons to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons. In a particularly preferred embodiment, the polymer is a polyethylene glycol with a molecular weight of from about 100 to about 5,000 daltons, and more preferably with a molecular weight of from about 300 to about 5,000 da is ton. In a particularly preferred embodiment, the polymer is a polyethylene glycol with a weight of 750 daltons (PEG(750)). The polymers can also be determined by the number of monomers in them; the preferred implementation of the present invention include polymers of at least three monomers, such as PEG-polymers consisting of three monomers (about 150 daltons).

Other hydrophilic polymers that may be suitable for use in the present invention include polyvinylpyrrolidone, polymyositis, politisation, polyhydroxyethylmethacrylate, polymethacrylamide, polydimethylsilane and derivatives of cellulose, such as hydroxymethylcellulose or hydroxyethylcellulose.

In some embodiments, the implementation, the composition of the present invention includes a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylene, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and their copolymers, cellulose, polypropylene, polyethylene, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butane acid), poly(valerianic acid), poly(lactide-co-caprolactone), polysaccharides, proteins, polyaluminum acids, polycyanoacrylates and the x combinations mixtures or copolymers.

Cyclodextrins

Cyclodextrins are cyclic oligosaccharides consisting of 6, 7 or 8 glucose units, denoted by the Greek letters alpha, beta or gamma, respectively. Cyclodextrins containing less than six units of glucose, is unknown. Units of glucose linked alpha-1,4-glucosidase links. As in the sequence conformation of chains of sugar units, all of the secondary hydroxyl group at C-2, C-3) are located on one side of the ring, while all the primary hydroxyl group at C-6 are on the other side. As a result, the outer surface is hydrophilic, making the water-soluble cyclodextrin. On the contrary, the inner part of the cyclodextrins are hydrophobic because they contain hydrogens atoms C-3 and C-5, and afrophobia oxygen atoms. These matrices allow complexation with various relatively hydrophobic compounds, including, for example, steroid compounds such as 17-beta-estradiol (see, for example, article van Uden and other, Plant Cell Tiss. Org. Cult., 1994, 38, cc.1-3-113). Complexation occurs through interactions van der Waals forces, and the formation of hydrogen bonds. For a General overview of the chemistry of cyclodextrins, see Wenz, Agnew. Chem. Int. Ed. Engl., 1994, 33, cc.803-822.

Physico-chemical properties of derivatives of cyclodextrin forces is but depend on the type and degree of substitution. For example, their solubility in water varies from insoluble (for example, triacetyl-beta-cyclodextrin) to 147% soluble (weight/about.) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents. Properties of cyclodextrins possible to control the solubility of the various components of the composition by increasing or decreasing their solubility.

Numerous cyclodextrins and methods for their production have been described. For example, Parmeter (I) and others (US 3,453,259) and Gramera and others (US 3,459,731) describe electrically neutral cyclodextrins. Other derivatives include cyclodextrins with cationic properties [Parmeter (II), US 3,453,257], insoluble transverse cross-linked cyclodextrins (Solms, US 3,420,788) and cyclodextrins with anionic properties [Parmeter (III), US 3,426,011]. Among the cyclodextrin derivatives with anionic properties of carboxylic acid, phosphoric acid, phosphinic acid, phosphonic acid, phosphoric acid, thiophosphonate acid, thiosulfinate acid and sulfonic acid are linked to the source cyclodextrin [see Parmeter (III)above]. In addition, sulfoalkyl ether cyclodextrin derivatives described Stella and others (US 5,134,127).

Liposome

Liposomes are composed of at least one lipid bisloinoi membranes, including internal water phase. Liposomes can be characterized by the type of membrane and its razmerennaya adnyamathanha vesicles (SUVs) have a single membrane and usually from 0.02 to 0.05 microns in diameter; large adnyamathanha vesicles (LUV) is usually more than 0.05 microns. Oligomineralnye large vesicles and multilamellar vesicles usually contain several concentric membrane layers and the size is usually more than 0.1 μm. Liposomes with multiple concentrically membranes, i.e. several smaller vesicles contained in the larger vesicles, called multivesicular vesicles.

One way of implementing the present invention relates to compositions comprising liposomes containing the compound of the present invention, where the liposomal membrane composed with obtaining liposomes with high load capacity. Alternative or in addition, the compound of the present invention may contain or be adsorbed on the liposomal bilayer liposomes. The compound of the present invention may be aggregated with the lipid surfactant and transferred into the internal space of the liposomes; in these cases, liposomal membrane is prepared to resist the destructive action of the unit is the active agent is a surfactant.

In accordance with one embodiment of the present invention, the lipid bilayer of the liposome contains lipids that form derived from polyethylene glycol (PEG), so that the chain PEG-act with the inner surface of the lipid bilayer in the inner space, encapsules the cell by liposome, and protrude from the external surface of the lipid bilayer into the surrounding space.

The active agents contained in the liposomes of the present invention are solubilizing form. Aggregates of surfactant and active agent (such as emulsion or micelle that contains interesting active agent) can be included in the inner space of the liposomes in accordance with the present invention. The surfactant acts to disperse and solubilize the active agent and may be selected from any suitable alifaticescoe, cycloaliphatic or aromatic surfactant, including, but not limited to, biocompatible lysophosphatidylcholine (LPC) with different chain length (for example, from about14to about20). Lipids, modified polymer, such as PEG-lipids can also be used for the formation of micelles, because they act to inhibit the fusion of micelles/membranes and because adding polymer to the surfactant molecules decreases the CMC of the surfactant leads to the formation of micelles. Preferred are surfactants with CMC in the micromolar range; surfactants with higher CMC can be used to obtain micelles included in the liposomes of the present invention, however, the monomers of surfactant micelles can act on the stability of the liposomal bill who I am and can be a factor for the design of liposomes with the desired stability.

Liposomes in accordance with the present invention can be obtained by any of the methods known from the prior art. See, for example, US patent 4,235,871; published patent application WO 96/14057; book New RRC, Liposomes: A practical approach, IRL Press, Oxford, 1990, cc.33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.

For example, the liposomes of the present invention can be obtained by the diffusion of lipid, forming derivative with a hydrophilic polymer, prior liposomes, for example, by pre-processing the obtained liposomes in micelles, consisting of associated with lipid polymers, at concentrations of lipid, the relevant final molar percentage of lipid derivative, which should be in the liposome. Liposomes containing hydrophilic polymer can also be obtained by homogenization, the hydration of the lipid area or extrusion methods known from the prior art.

In one embodiment of the present invention, the resulting liposomes are essentially homogeneous sizes in a selected size range. One effective method of sizing includes the extrusion of aqueous suspension of liposomes through a series of polycarbonate membranes having a selected uniform pore size; pore size in the membrane corresponds approximately to the largest size l what bosom, obtained by extrusion through that membrane. See, for example, US patent 4,737,323 (12.04.1988).

Modifiers release

The characteristics of the release composition of the present invention depend on the encapsulating material, the concentration encapsulate the drug and the presence of modifiers release. For example, the release may be pH-dependent, for example, using pH-sensitive coating, which releases only at low pH values, as in the stomach, or at high pH values, as in the intestine. Enteric coating can be used to prevent the release as long as the substance does not pass the stomach. Several coatings or mixture of cyanamide, encapsulated in a variety of materials may be used to provide initial release in the stomach with subsequent release into the intestine. The release also can be modified by the inclusion of salts or forming pores agents that can increase the capture of water or the release of drug by diffusion from the capsule. Excipients which modify the solubility of a drug can also be used to control the rate of release. Agents that increase the destruction of the matrix or the release of the matrix, may also be included. They can be on the Balleny to medicinal drug, added as a separate phase (i.e. in the form of particles) or can be dissolved in the polymer phase, depending on the connection. In all cases, the number should be from 0.1 to 30% (wt./weight. polymer). Amplifier type fracture include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate and zinc hydroxide, and organic bases, such as protaminensulin, spermine, choline, ethanolamine, diethanolamine and triethanolamine and surfactants such as Tween® and Pluronic®. Forming pores agents that add microstructure in the matrix (i.e. water-soluble compounds such as inorganic salts and sugars), add in the form of particles. The range should be from 1 to 30% (wt./weight. polymer).

The capture can also be modified by changing the residence time of particles in the intestine. This can be done, for example, coated particles or choice as encapsulating polymer material, communicating with mucous. Examples include most of the polymer with free carboxyl groups such as chitosan, cellulose and especially polyacrylates (as used here, the polyacrylates oboznacheniyalari, including acrylate groups and modified acrylate group, such as cyanoacrylate and methacrylates).

Examples

The present invention, generally described above, are described in more detail using the following examples, which are included only for purposes of illustration, some embodiments of the present invention, and are not intended to limit the invention.

Example 1

Part a

To a solution of 3-identilied 2 (5.8 g, 25 mmol, 1 EQ.) in a mixture of Meon/THF (40 ml, 3:1) was added an aqueous solution of NH2OH·HCl (2,04 g of 29.5 mmole, 1.2 equiv., in 10 ml of water). The pH was brought to 9 with 6 N KOH solution. The reaction mixture was stirred at RT for 2 h and added NaCNBH3(1.5 g, 25 mmol, 1 equiv.), then crystal methylorange. The pH value of 2 was brought to 2, and the resulting bright red color is maintained during the reaction by addition of 1 N HCl solution. After 2 h was added another portion of NaCNBH3(1.5 g, 25 mmol, 1 equiv.). The mixture was stirred for 14 h, then 2/3 of the solvent was evaporated, and the pH value was increased to 9-10 by addition of 6 N aqueous solution of KOH. This mixture was extracted with DHM (3×100 ml). The organic layers were combined, washed with water, then saturated sodium chloride solution. The organic layer was dried MgSO4, was filtered and Aravali in vacuum to obtain 5.7 g of compound 3 in the form of a whitish solid. Yield 85%.

Part B

To a solution of N-(3-jobensis)hydroxylamine 3 (16 g, 64 mmole, 1 equiv.) in benzene (320 ml) was added methylglyoxal (6.8 g, 80 mmol, 1.25 equiv.). The mixture was heated at 120°C for 3 h, using a nozzle Dean-stark. The solution was cooled to CT, and the solvent was concentrated in vacuum with the receipt of 19.1 g of compound 4 as a yellow solid. Yield 93%.

Part b

A solution of methyl ester bis(2,2,2-triptorelin)phosphonooxy acid 5 (28 g, 0.1 mmole, 1 equiv.) and 18-crown-6 (132 g, and 0.50 mmole, 5 equiv.) in THF (2 l) was cooled to -78°C. in a nitrogen atmosphere. To the cooled solution was added bis(trimethylsilyl)amide and potassium in toluene (20 g, 0.6 M in toluene, 0.1 mmole, 1 equiv.). Then was added (S)-2-(tetrahydropyranyloxy)propane 6 (synthesis described in the article in J. Chem. Soc., Perkin. Trans., 1, 1994, s) (16 g, 0.1 mmole, 1 equiv.), and the resulting mixture was stirred for 30 min at -78°C. Then was added a saturated aqueous solution of NH4Cl, and the product was extracted with diethyl ether (3×500 ml). The organic phases were combined, dried Na2SO4that was filtered and concentrated in vacuum. The crude material was purified by chromatography on silica gel to obtain 13.5 g of compound 13 in the form of oil. Yield 63%.

Part G

Methyl ester 4(S)-(tetrahydropyran-2-and the hydroxy)Penta-2-ene acid 7 (10 g, 46,7 mmole, 1 equiv.) restored DIBAL-H in accordance with the methodology described in the article in J. Chem. Soc., Perkin. Trans., 1, 1994, s, to obtain 7.6 g of 4(S)-(tetrahydropyran-2-yloxy)Penta-2-EN-1-ol 8. Yield 88%.

Part D

To a solution of 4(S)-(tetrahydropyran-2-yloxy)Penta-2-EN-1-ol 8 (4.0 g, 22 mmole, 1 equiv.) in THF (20 ml) was added imidazole (3,66 g, 53,5 mmole, 2.4 equiv.), then TBSCl (to 3.89 g of 25.8 mmole, 1.2 equiv.). The reaction mixture was stirred at RT for 4 h, extinguished with water (20 ml) and was extracted with diethyl ether (3×10 ml). The combined organic extracts were washed with water (5×50 ml), saturated sodium chloride solution (50 ml), dried MgSO4that was filtered and concentrated in vacuum. The oil was purified by chromatography on silica gel (30% hexane/EtOAc) to obtain 5.9 g of the compound (9) in the form of oil. Yield 92%.

Part E.

The protective group TNR removed from tert-butultimately-[4(S)-(tetrahydropyran-2-yloxy)Penta-2-enyloxy]silane 9 (10 g, 33 mmole, 1 equiv.) in accordance with the methodology described in article Tetrahedron Letters, 1984, 25, s to obtain 5.9 g of compound 10 in the form of oil. Yield 83%.

Part W

To a solution of methyl ester of Nitron 4 (8,1 g, 38 mmol, 1 equiv.) and alcohol 10(12 g, 38 mmol, 1 equiv.) in toluene (40 ml) was added Ti(och(CH3)2)4(16 g, 17 ml, 56 mmol, 1.5 equiv.). Susp is SIU was heated in a microwave oven at 140°C for 30 min and left to cool down to CT. The solution was diluted with EtOAc (150 ml) and 3-(dimethylamino)-1,2-propandiol (7 g, 7 ml, 58 mmol, 5 equiv.) and stirred at RT for 8 h To the solution was added water (100 ml), the organic phase was separated and the aqueous layer washed with EtOAc (3×30 ml). The combined organic extracts were washed with water (100 ml), saturated solution of sodium chloride (100 ml), dried Na2SO4that was filtered and concentrated in vacuum. The crude material was purified by chromatography on silica gel (1:29 Et2O/DHM) to obtain 13.5 g of compound (11) in the form of solids. Yield 71%.

To a solution of TBS-protected isoxazolidine (13.5 g, 26 mmol, 1 equiv.) in THF (120 ml) was added 6 N HCl solution (67 ml). The solution was stirred at RT for 1.5 h, diluted with water (25 ml) and was extracted with EtOAc (3×80 ml), the organic extracts were combined and washed with saturated solution of NaHCO3(50 ml), saturated sodium chloride solution (50 ml), dried Na2SO4and concentrated in vacuum. The crude material was purified by chromatography on silica gel (20-33% DHM/diethyl ether) to give 9.5 g of compound 9 as a yellow solid. 64% of the total output of the two stages.

Part C

To a solution of (+)-isopinocampheol 12 (0.2 g, 1.3 mmole, 6.5 equiv.) in DHM (10 ml) at RT was added dropwise AlMe3(0,85 ml of 2 M solution in toluene, 1.7 mmole, 8.5 equiv.) within 2.5 minutes Rest the R was stirred at RT for 10 min, then was added dropwise a solution of lactone 11 (0.5 g, 0.02 mmole, 1 equiv.) in DHM (10 ml). The reaction mixture was stirred for 1 h, diluted DHM (125 ml) and saturated aqueous salt of Rosella (125 ml). The mixture was intensively stirred for 2 h until the formation of two phases. The organic phase was separated, washed with water, saturated sodium chloride solution, dried MgSO4that was filtered and concentrated in vacuum to obtain a solid substance. This material was used without additional purification.

Part And

Arylated 13 (1.44 g, to 2.65 mmole, 1 equiv.), winsborrow acid 14 (1,57 g, 10.6 mmole, of 10.0 equiv.), Na2CO3(1.12 g, 10.6 mmole, of 10.0 equiv.) and tetragonality (0,61 g of 0.53 mmole, 0.2 equiv.) were weighed into a flask with a volume of 100 ml. Flask was then filled with argon, and the content was dissolved in a mixture of 4:1 toluene/water (30 ml) and heated at 65°C for 3 hours the Organic layer was separated, and the aqueous layer was extracted with EtOAc (3×20 ml). The organic layers were combined, washed with a saturated solution of sodium chloride, dried MgSO4and concentrated in vacuum. The crude material was purified by chromatography on silica gel (solvent system) to obtain 1,17 g of compound 15. Yield 85%.

Part of It

To a solution of compound 15 (0.11 g, of 0.21 mmole, 1 equiv.) in tert-BuOH (16 ml), THF (8 ml), water (2 ml) EXT is ulali NMO (0.11 g, of 0.82 mmole, 4 equiv.) and 2.5% solution OsO4(2 ml, 0.21 g, 0,021 mmole, 1 equiv.) in tert-BuOH. After 4 h of stirring the reaction was suppressed by a solution of Na2S2O3and separated between EtOAc/saturated solution of sodium chloride. The aqueous layer was washed organic layers were dried MgSO4that was filtered and concentrated in vacuum to obtain oil.

The crude material (10 mg, 18 µmol, 1 equiv.) then transferred in THF (0.2 ml), to the mixture was added water (20 ml) and periodate sodium (4,1 mg, 19 mcmole, 1.05 equiv.), and the reaction mixture was stirred over night. The reaction was suppressed Na2S2O3off , washed with a saturated solution of sodium chloride, dried MgSO4and concentrated in vacuum. The crude material was purified by chromatography on silica gel with getting to 6.8 mg of compound 16 in the form of a whitish solid. Yield 85%.

Part L

A solution of aldehyde 16 (40 mg, 90 mcmole, 1 equiv.) in 1% aq. the solution Meon (2 ml) was treated with the amine 17 (41 μl, of 0.23 mmole, 2.6 equiv.) and was stirred for 1 h was Added NaBH4(4 mg, 90 mcmole, 1 equiv.), and the mixture was stirred for 0.5 h, and the reaction was suppressed Asón (10 μl).

Half of this crude reaction mixture was treated with 2,3-methylenedioxybenzene 18 (34 mg, 0,23 mmole, 5 equiv.); after 0.25 h was added NaBH3CN (12 mg, 0,23 mmole, 5 equiv.), and stirring is continued during the night. The reaction mixture was purified directly by HPLC reverse phase (CH3CN/water with 40 mm NH4HCO3), with 20 mg of compound 1 as a white solid. Yield 63%. MS (ESI(+)) m/z 707,76 (M+H)+.

Example 2

Compound 19 was obtained in accordance with the procedure described in example 1, using the aldehyde 3-amoxicillinbuy acid instead of 2,3-methylenedioxybenzene. The output is 34%. MS (ESI(+)) m/z 723,82 (M+N)+.

Example 3

Compound 20 was obtained in accordance with the procedure described in example 1, using the aldehyde 6-methoxysilanes acid instead of 2,3-methylenedioxybenzene. Yield 29%. MS (ESI(+)) m/z 709,79 (M+N)+.

Example 4

Compound 21 was obtained in accordance with the procedure described in example 1, using the aldehyde 6-floralicious acid instead of 2,3-methylenedioxybenzene. Yield 38%. MS (ESI(+)) m/z 711,83 (M+N)+.

Example 5

Compound 22 was obtained in accordance with the procedure described in example 1, using 2-chlorobenzaldehyde instead of 2,3-methylenedioxybenzene. Yield 35%.

MS (ESI(+)) m/z 740,68 (M+H)+.

Example 6

Compound 23 was obtained in accordance with the procedure described in example 1, using 2-allyloxymethyl the place of 2,3-methylenedioxybenzene. The yield is 50%. MS (ESI(+)) m/z 719,82 (M+H)+.

Example 7

Compound 24 was obtained in accordance with the procedure described in example 1, using 2-ethoxybenzaldehyde instead of 2,3-methylenedioxybenzene. Yield 25%. MS (ESI(+)) m/z 707,82 (M+H)+.

Example 8

Compound 25 was obtained in accordance with the procedure described in example 1, using 2-(methylthio)benzaldehyde instead of 2,3-methylenedioxybenzene. Yield 38%. MS (ESI(+)) m/z 709,72 (M+H)+.

Example 9

Compound 26 was obtained in accordance with the procedure described in example 1, using 4-formylindole instead of 2,3-methylenedioxybenzene. Yield 25%. MS (ESI(+)) m/z 702,80 (M+H)+.

Example 10

Compound 27 was obtained in accordance with the procedure described in example 1, using 3-hydroxybenzaldehyde instead of 2,3-methylenedioxybenzene and (S)-N1N1-dimethyl-2-Penilaian-1,2-diamine instead of the amine 17. Yield 45%. MS (ESI(+)) m/z 666,89 (M+H)+.

Example 11

Compound 28 was obtained in accordance with the procedure described in example 1, using 3-hydroxybenzaldehyde instead of 2,3-methylenedioxybenzene and (S)-N1N13 trimethylbutane-1,2-diamine instead of the amine 17. Yield 47%. MS (ESI(+)) m/z 665,85 (M+N)+.

Example 12

Compound 29 was obtained in accordance with the procedure described in example 1, using cyclopentanecarboxaldehyde instead of 2,3-methylenedioxybenzene and (S)-N1N1,4,4-tetramethylpentane-1,2-diamine instead of the amine 17. Yield 37%. MS (ESI(+)) m/z 669,91 (M+H)+.

Example 13

Compound 30 was obtained in accordance with the procedure described in example 1, using 3-hydroxybenzaldehyde instead of 2,3-methylenedioxybenzene and amine (S)-N1N1,4,4-tetramethylpentane-1,2-diamine instead of the amine 17. Yield 48%. MS (ESI(+)) m/z 693,92 (M+H)+.

Example 14

Compound 31 was obtained in accordance with the procedure described in example 1, using 2-chloro-6-forbindelse instead of 2,3-methylenedioxybenzene and (S)-N1N1,4,4-tetramethylpentane-1,2-diamine instead of the amine 17. Yield 52%. MS (ESI(+)) m/z 729,86 (M+N)+.

Example 15

Compound 32 was obtained in accordance with the procedure described in example 1, using 2-chloro-6-forbindelse instead of 2,3-methylenedioxybenzene and (S)-N1N13 trimethylbutane-1,2-diamine instead of the amine 17. Yield 35%. MS (ESI(+)) m/z 701,79 (M+H)+.

Example 16

Compound 44 was obtained in accordance with the procedure described in example 1, using 2-chloro-6-forbindelse instead of 2,3-stands is of dioxybenzene and (S)-N 1N1-dimethyl-2-Penilaian-1,2-diamine instead of the amine 17. The output of 21%. MS (ESI(+)) m/z 735,83 (M+H)+.

Example 17

Compound 34 was obtained in accordance with the procedure described in example 1, using 2-chlorobenzaldehyde instead of 2,3-methylenedioxybenzene and (S)-N1N1-dimethylpentane-1,2-diamine instead of the amine 17. Yield 53%. MS (ESI(+)) m/z 683,75 (M+H)+.

Example 18

Compound 35 was obtained in accordance with the procedure described in example 1, using 2-chloro-6-forbindelse instead of 2,3-methylenedioxybenzene and (S)-1-(1-pyrrolidinyl)-2-amino-4-methylpentan instead of amine 17. A 30%yield. MS (ESI(+)) m/z 741,86 (M+H)+.

Example 19

Compound 36 was obtained in accordance with the procedure described in example 1, using 2-trifluoromethyl-6-forbindelse instead of 2,3-methylenedioxybenzene and (S)-1-(1-pyrrolidinyl)-2-amino-4-methylpentan instead of amine 17. Yield 23%. MS (ESI(+)) m/z 775,90 (M+H)+.

Example 20

Compound 37 was obtained in accordance with the procedure described in example 1, using the anhydride of 6-floralicious acid instead of 2,3-methylenedioxybenzene and (S)-1-(1-pyrrolidinyl)-2-amino-4-methylpentan instead of amine 17. Yield 31%. MS (ESI(+)) m/z 723,89 (M+H)+.

Example 21

Part a

To a solution of ketone 39 (500 mg, 2,42 mmole, 1 equiv.) in EDC (5 ml) was added N1N1-dimethylated-1,2-diamine (641 mg, 7,27 mmole, 3 equiv.), then Na(SLA)3NR (771 mg, 3.64 mmole, 1.5 equiv.), and the reaction mixture was heated at 40°C. After stirring for 48 h, the reaction mixture was diluted with water (100 ml), EtOAc (100 ml), saturated solution of sodium chloride (100 ml)and the pH value was brought to 12 with 6 N NaOH. The mixture was extracted with EtOAc (2×100 ml)and the combined organic layers were dried MgSO4that was filtered and concentrated in vacuum to obtain 200 mg of diamine 40 in the form of a dark brown oil. Crude oil was used directly without further purification.

Part B

To a solution of aldehyde 16 (30 mg, 0.07 mmole) in EDC (1 ml) was added to the diamine 40 (0.02 mg, 0.07 mmole), then Na(SLA)3NR (20 mg, 0.1 mmole)and the reaction mixture was heated at 40°C. After stirring for 48 h, was added additional aldehyde (30 mg, 0.02 mmole) and Na(OAc)3BH (20 mg, 0.1 mmole)and the reaction mixture was stirred at 40°C. After 24 h the reaction mixture was purified directly by HPLC reverse phase (CH3CN/water with 40 mm NH4HCO3) to obtain 20 mg of compound 38. Yield 42%. MS (ESI(+)) m/z 707,5. (M+N)+.

Example 22

Compound 41 was obtained in accordance with the methodology described in PR is as 1, using 2-bromo-5-(hydroxyl)benzaldehyde instead of 2,3-methylenedioxybenzene. Yield 38%. MS (ESI(+)) m/z 757,6 (M+H)+.

Example 23

Compound 42 was obtained in accordance with the procedure described in example 1, using 2-formylthiophene-2-carboxylic acid instead of 2,3-methylenedioxybenzene. Yield 48%. MS (ESI(+)) m/z 713,8 (M+H)+.

Example 24

Compound 43 was obtained in accordance with the procedure described in example 1 using 2,4-dichloro-6-hydroxybenzaldehyde instead of 2,3-methylenedioxybenzene. The output is 27%. MS (ESI(+)) m/z 747,8 (M+H)+.

Example 25

Compound 44 was obtained in accordance with the procedure described in example 1, using 2-formylphenoxy acid instead of 2,3-methylenedioxybenzene. Yield 47%. MS (ESI(+)) m/z square 737,7 (M+H)+.

Example 26

Compound 45 was obtained in accordance with the procedure described in example 1, using thiophene-2-carboxaldehyde instead of 2.3 methylenedioxybenzene. Yield 69%. MS (ESI(+)) m/z 669,8 (M+H)+.

Example 27

Compound 46 was obtained in accordance with the procedure described in example 1 using o-tolualdehyde instead of 2,3-methylenedioxybenzene. Yield 51%. MS (ESI(+)) m/z 677,9 (M+H)+.

Example 28

Compound 47 was obtained in accordance with the procedure described in example 1, using 1-methylpyrrole-2-carbox aldehyde instead of 2,3-methylenedioxybenzene. Yield 43%. MS (ESI(+)) m/z 666,9 (M+N)+.

Example 29

Compound 48 was obtained in accordance with the procedure described in example 1, using 2-carboxyaldehyde instead of 2,3-methylenedioxybenzene. Yield 65%. MS (ESI(+)) m/z 707,9 (M+H)+.

Example 30

Compound 49 was obtained in accordance with the procedure described in example 1, using thiophene-3-carboxaldehyde instead of 2,3-methylenedioxybenzene. Yield 69%. MS (ESI(+)) m/z 669,8 (M+H)+.

Example 31

Compound 50 was obtained in accordance with the procedure described in example 1, using 4-fluoro-2-hydroxybenzaldehyde instead of 2,3-methylenedioxybenzene. Output 15%. MS (ESI(+)) m/z 697,8 (M+H)+.

Example 32

Part a

To a solution of Boc-L-leucine 53 (5 g, 22 mmole, 1 equiv.) and Rumor (15 g, 28 mmol, 1,3) in DHM (60 ml) was added pyrrolidin at 0°C. the Solution was stirred for 10 min, then was added dropwise DIPEA (6 g, 8 ml, 48 mmol, 2.2 equiv.). After stirring for 6 h, the solution was diluted feast upon. a solution of NaHCO3(40 ml)and the aqueous phase was extracted with DHM (2×50 ml). Unite the military organic phase was washed with a saturated solution of sodium chloride, was separated, dried MgSO4that was filtered and concentrated in vacuum to obtain oil. The resulting oil was purified by chromatography on silica gel (50-100% hexane/EtOAc) to give compound 53 as a clear oil.

Part B

To a solution of amide 53 (4.5 g, 15.8 mmole, 1 equiv.) in DHM (100 ml) was added TFOC (10 ml) at 0°C. After stirring for 2 h at RT, the solvent was removed in vacuum to obtain oil. The resulting oil is suspended in THF and cooled to 0°C. to the mixture was added LiAlH4(4 g, 108 mmol, 6.8 equiv.) portions and heated at the boil under reflux for 12 h in an argon atmosphere. The solution was cooled to CT and extinguished with water (4 ml)was left to mix for 5 min, then added 15% NaOH (4 ml) and was stirred for 5 min, and finally added water (12 ml), and the suspension was stirred until a white precipitate. The solid was filtered and washed with EtOAc, and the filtrate was concentrated in vacuum to obtain compound 54 in the form of oil, which was used without further purification.

Part b

To a solution of compound 16 (250 mg, of 0.56 mmole, 1 equiv.) in the Meon (25 ml) was added compound 54 (96 mg, of 0.56 mmole, 1 equiv.) and stirred at RT for 3 h, then was added NaBH4(21 mg, of 0.56 mmole, 1 equiv.). After stirring Ave is in CT for 12 h, the reaction mixture was diluted Asón (0,08 ml) and concentrated in vacuo to obtain an oil, which was used without further purification.

Part G

To a solution of compound 55 (15 mg, 25 mcmole, 1 equiv.) in DHM (1.0 ml) was added 2-hydroxybenzaldehyde (5 mg, 38 mcmole, 1.5 equiv.), then was added Na(SLA)3NR (11 mg, 50 mcmole, 2 equiv.). After stirring at RT for 12 h, the reaction mixture was diluted Asón (0.1 ml) and was stirred for 10 min. the Reaction mixture was diluted DHM (2.5 ml) and washed the feast upon. a solution of NaHCO3(2.5 ml), the organic phase was separated, dried Na2SO4and concentrated in vacuum to obtain oil. The oil was purified directly by HPLC reverse phase (CH3SN/water with 40 mm NH4HCO3) to obtain 7 mg of compound 51 as a white solid. Yield 40%. MS (ESI(+)) m/z 705,9 (M+N)+.

Example 33

Compound 57 was obtained in accordance with the procedure described in example 32 using 2-formylbenzenesulfonic acid instead of 2-hydroxybenzaldehyde. Yield 39%. MS (ESI(+)) m/z 705,9 (M+H)+.

Example 34

Compound 58 was obtained in accordance with the procedure described in example 32 using 2-(2-hydroxyethoxy)benzaldehyde instead of 2-hydroxybenzaldehyde. Yield 32%. MS (ESI(+)) m/z 749,9 (M+H) +.

Example 35

Compound 59 was obtained in accordance with the procedure described in example 32, using a 5-bromothiophene-2-carboxaldehyde instead of 2-hydroxybenzaldehyde. Yield 54%. MS (ESI(+)) m/z 775,7 (M+H)+.

Example 36

Compound 60 was obtained in accordance with the procedure described in example 32 using 2-(2-formylphenoxy)ndimethylacetamide instead of 2-hydroxybenzaldehyde. Yield 35%. MS (ESI(+)) m/z 762,9 (M+H)+.

Example 37

Compound 61 was obtained in accordance with the procedure described in example 32 using 2-formylphenoxy acid instead of 2-hydroxybenzaldehyde. Yield 59%. MS (ESI(+)) m/z 775,7 (M+H)+.

Example 38

To a solution of compound 61(10 mg, 10 mcmole, 1 equiv.) in DMF (0.5 ml) was added Rumor (10 mg, 20 mcmole 2 equiv.), the research (2 mg, 30 mcmole, 3 equiv.) and Et3N (4 mg, 5 ál, 40 mcmole, 4 equiv.). The solution was stirred for 12 h, diluted with water (0.5 ml)and the reaction mixture was purified directly by HPLC reverse phase (CH3CN/water with 40 mm NH4HCO3) with 3 mg of compound 62 in the form of a white solid. The output of 28%. MS (ESI(+)) m/z 833 (M+H)+.

Example 39

Compound 63 was obtained in accordance with the methodology description is authorized in example 38, using dimethylamine instead of the research. Yield 59%. MS (ESI(+)) m/z 775,7 (M+H)+.

Example 40

Compound 64 was obtained in accordance with the procedure described in example 21, using cyclohexyl(phenyl)methanon instead of cyclohexyl(2-forfinal)methanone. Yield 29%. MS (ESI(+)) m/z 689,49 (M+H)+.

Example 41

Data binding with Bcl-2 below for the various compounds according to the invention. As shown in the table below, "****" indicates that the Ki value is <1 nm; "***" indicates that the value of Ki is 1-5 nm; "**" indicates that the Ki value of about 5-9 nm; and "*" indicates that the Ki value is >9 nm.

Data binding with Bcl-xL below for the various compounds according to the invention. As shown in the table below, "†††" indicates that the Ki value is <0.2 μm; "††" indicates that the value of Ki is 0.2-1 μm; and "†" indicates that the Ki value is >1 micron.

Activity against Bcl-2Symbol
<1 nm****
1-5 nm***
5-9 nm**
>9 nm*
Activity against Bcl-XLSymbol
<0.2 μm†††
0.2 to 1 μm††
>1 μm

ConnectionBcl-2Bcl-XL
1***††
19***††
20**††
21*††
22*†††
23***††
24***††
25***††
26 *††
27**†††
28**††
29****††

ConnectionBcl-2Bcl-XL
30***†††
31****†††
32***†††
33***†††
34**†††
35***†††
36**†††
37***†††
38*** ††
41**†††
42***†††
43*†††
44**†††
45***†††
46***†††
47***†††
48***††
49***††
50***††
51***†††
57**††
58*††
59*** †††
60***†††
62***†††
63***†††
64***

The incorporation by reference

All these are published by the U.S. patents and applications for U.S. patents incorporated by reference.

Equivalents

The person skilled in the art known in the art, or it can install using routine experimentation, numerous equivalents to the specific options described here implement according to the invention. Such equivalents are also included in the following claims.

1. A compound selected from the group consisting of:
,,
,,
,,
,,
,,
,,
,,
,,
,,
,,
,
,,
,,
,,
,,
and

2. Pharmaceutical composition having binding activity against protein Bcl comprising the compound according to claim 1 in an effective amount and at least one pharmaceutically acceptable excipient.

3. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment of cancer.

4. The use according to claim 3, in which the cancer is a follicular lymphoma, diffuse extensive b-cell lymphoma, lymphoma epithelial cells, chronic lymphocytic leukemia, prostate cancer, breast cancer, neuroblastoma, colorectal cancer, endometrial, ovarian, lung cancer, hepatocellular carcinoma, multiple myeloma, head and neck cancer or testicular cancer.

5. The use according to claim 3, in which the cancer sverkhekspressiya protein Bcl.

6. The use according to claim 3, in which growth and vyjivaemosti dependent protein Bcl.

7. The use according to claim 5 or 6, wherein said protein Bcl is a Bcl-2.

8. The use according to claim 5 or 6, wherein said protein Bcl is a Bcl-xL.

9. The use according to claim 3, in which the cancer manifests t(14;18) chromosomal translocation.

10. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment of Bcl-mediated disorders.

11. The use of claim 10, in which Bcl-mediated violation is a cancer or neoplastic disease.

12. The application of claim 11, wherein said cancer or neoplastic disease is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute malacitana leukemia, myeloblastoma, promyelocytic, myelomonocytic, monocytic leukemia, erythroleucus, chronic leukemia, chronic malacitana (granulocytic) leukemia, chronic lymphocytic leukemia, true polycythemia, Hodgkin's disease, disease non-Hodgkin's lymphoma, multiple myeloma, macroglobulinemia Waldenstrom, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, ehotelier.com, lymphangiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, tumors Avnega, leiomyosarcoma, rhabdomyosarcoma, carcinoma thick the second colon, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, moshaweng cancer, bronchogenic carcinoma, renal cell carcinoma, hepatoma, carcinoma of the biliary tract, choriocarcinoma, seminoma, embryonal carcinoma, Wilm tumor, cervical cancer, bladder cancer, testicular tumor, lung carcinoma, carcinoma small cell lung carcinoma of the bladder, epithelial carcinoma, glioma, astrocytoma, Protocol, craniopharyngioma, ependymomas pinealoma, hemangioblastoma, neurilemmoma auditory nerve, oligodendrogliomas, meningiomas, melanoma, neuroblastoma, retinoblastoma, and endometrial cancer.

13. The use according to claim 3 or 10, in which the indicated compound or compounds is administered parenterally.

14. The use according to claim 3 or 10, in which the indicated compound or compounds is administered intramuscularly, intravenously, subcutaneously, orally, topically or intranasally.

15. The use according to claim 3 or 10, in which the indicated compound or compounds is administered systemically.

16. The use according to claim 3 or 10, in which the patient is a mammal.

17. The use according to claim 3 or 10, in which a specified person who is
the primacy.

18. The use according to claim 3 or 10, in which the specified patient is a man.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an immunodepressant based on a heterocyclic compound of formula

or to its pharmaceutically acceptable salt where X represents a nitrogen atom or CH, both or one of R1 or R2 represents a hydrogen atom, hydroxyl, a halogen atom, an amino group, C1-C6 alkoxy or C1-C6 alkyl: R3 represents a hydrogen atom, difluoromethyl, an amino group, methyl or hydroxymethyl; R4 or R5 represents a hydrogen atom or C1-C6 alkyl; R6 represents morpholino (optionally substituted by one or two C1-C6 alkyl groups), pyrrolidinyl (optionally substituted by hydroxy C1-C6 alkyl), piperidine (which is optionally substituted by an oxygen atom, hydroxyl, formyl or C1-C6 alkyl), piperazinyl (optionally substituted by one or two oxygen atoms, where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a groups consisting of formyl, C1-C6 hydroxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 oxoalkyl, furoyl, benzoyl, methoxybenzoyl, benzylcarbonyl, dimethylcarbamoyl, diethylcarbamoyl, morpholinocarbonyl and methoxyacetyl) or 1,4-diazepano (optionally substituted by one oxygen atom where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a group consisting of formyl, C1-C6 oxoalkyl). Also, the invention refers to a heterocyclic compound of general formula

and to an anticancer drug based on the compound of formula (II).

EFFECT: there are produced new immunodepressant based on the compound of formula (I) and compound of formula (II) which can be used as anticancer drugs.

12 cl, 8 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the chemistry of N,N-disubstituted nicotinamide-(Z)-O-methyloximes with the general formula I where if X denotes a methylene group, then R denotes phenyl, benzyl or 2-furyl, R' denotes methyl or n-chlorophenyl, if X denotes a carbonyl group, then R denotes styryl, n-chlorostyryl or benzyl, R' denotes methyl that is characterized by the fungicidal activity.

EFFECT: new compounds that can be efficient against maleficent fungi.

1 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1, compounds of formula 5 and pharmaceutically acceptable salts thereof. In formulae 1 5 Y denotes -C(O)-, X denotes -N(R11)-, R1 denotes a residue of formula 1a or 1b - for formula 1 or residue of formulae 5a or 5b - for formula 5 1a 1b 5a 5b, R2 and R7 independently denote H, hydroxyl or (C1-C6)alkyl; R3 and R6 each independently denotes H, hydroxyl or (C1-C6)alkyl; R4 and R5 each independently denotes H or (C1-C6)alkyl; the rest of the radicals are described in the formula of invention. The invention also relates to separate compounds given in the formula of invention, a pharmaceutical composition having Bcl bound protein inhibiting properties, which contains a therapeutically effective amount of the disclosed compound, a method of treating a bc1 mediated disorder, involving introduction of a therapeutically effective amount of the disclosed compound and a method of treating a bc1 mediated disorder involving administration to a patient in need of treatment of an effective amount of camptothecin and therapeutically effective amount of the disclosed compound.

EFFECT: high efficiency of the composition.

84 cl, 12 tbl, 1 dwg, 217 ex

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