Purified pyrroloquinolinyl-pyrrolidine-2,5-dione compositions and methods of obtaining and application thereof

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to polymorphs of form 1 and form 2 of (-)trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolon-I-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. Invention also relates to methods of obtaining said polymorphs and pharmaceutical composition on their basis.

EFFECT: novel polymorphs of (-)trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolon-I-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione are obtained, useful in cancer treatment.

23 cl, 26 dwg, 2 tbl, 27 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

According to this application claimed priority based on provisional application U.S. 61/289563, filed December 23, 2009. Such application is incorporated herein in its entirety by reference.

The prior art of the INVENTION

Cancer is the second leading cause of death in the United States, second only to heart disease (Cancer Facts and Figures 2004, American Cancer Society, Inc.). Despite recent advances in diagnosis and treatment of cancer, surgery and radiation therapy can cure early cancer detection, but modern drug therapy metastatic tumors were mostly palliative and seldom offer permanent cure. Even with new chemotherapeutic agents entering the market, there remains a need for new drugs effective in monotherapy or in combination with existing tools as first-line therapies and therapies second and third line in the treatment of resistant tumors.

Cancer cells, by definition, are heterogeneous. For example, in one tissue or one cell type multiple mutational mechanisms can lead to cancer. By itself, heterogeneity frequently exists between cancer cells taken from tumors of�Noah and the same fabric and the same type, which originated in different individuals. Frequently observed mutational "mechanisms" that are associated with the same types of cancer may differ between one tissue type and another (for example, frequently observed mutational "mechanisms" that lead to colon cancer may differ from those frequently observed mutational mechanism leading to leukemia). Thus, it is often difficult to predict whether a particular cancer to respond to a particular chemotherapeutic agent. (Cancer Medicine, 5th Edition, Bast et al. eds., B. C. Decker Inc., Hamilton, Ontario)

The components of the transmission of cellular signals that regulate growth and differentiation of normal cells, in case of violation of their regulation can lead to impaired cellular proliferation and cancer. Mutations in signaling proteins can induce the expression or activation of these proteins in unacceptable concentrations or at inappropriate times during the cell cycle that, in turn, may lead to uncontrolled cell growth or changes in the adhesive properties of cell-cell. For example, dysregulation of receptor tyrosine kinases by mutation, gene rearrangement, gene amplification and overexpression and receptor and ligand have been implicated in the emergence and development of cancer in humans.

c-Met tyrosine kinase receptor is a single visokay�tion receptor growth factor hepatocyte (HGF), also known as scatter factor. Binding of HGF to c-Met extracellular ligand binding domain leads to multimerization receptor and phosphorylation of multiple tyrosine residues in the intracellular portion of c-Met. Activation of c-Met leads to the binding and phosphorylation of proteins-mediators such as Gab-1, Grb-2, Shc, and c-Cb1, and successive activation vector of the signal, such as PI3K, PLC-γ, STAT, ERK1 and 2 and FAK. c-Met and HGF is expressed in many tissues, and their expression is normally restricted to cells of epithelial and mesenchymal origin, respectively. Regulation of c-Met and HGF disrupted in cancer person, and they can participate in the dysregulation of cell growth, the spread of cancer cells and tumor penetration in the course of the disease and metastasis (see, e.g., Journal of Clinical Investigation 109: 863 to 867 (2002) and Cancer Cell pp 5-6 July 2004). c-Met and HGF are highly expressed in numerous cancers compared with the surrounding tissue, and their expression corallium with a poor prognosis and lack of response to standard clinical care (see, for example, Journal of Cellular Biochemistry 86: 665-677 (2002); Int. J. Cancer (Pred. Oncol.) 74: 301-309 (1997); Clinical Cancer Research 9: 1480-1488 (2003) and Cancer Research 62: 589-596 (2002)). Without any regard to theory, it is assumed that c-Met and HGF may protect tumors from cell death induced by DNA damaging agents and, thus, mo�et to participate in the resistance to chemical attack and resistance to radiation of tumors. Without any connection with theory believe that inhibitors of c-Met can be used as therapeutic agents in the treatment of proliferative disorders, including breast cancer (see, for example, Cancer and Metastasis Reviews 22: 309-325 (2003)). Thus, new compounds and methods for regulating these factors and treatment of cancer. The present invention is directed to solving these problems.

Summary of the INVENTION

The present invention provides a form 1 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation. In some embodiments, the polymorph may be characterized by powder x-ray diffraction pattern comprising peaks approximately in the area 8,2, 10,8, 14,1, 15,5, 17,8, 19,9 and 25.6 °2θ using Cu Kα radiation. In other embodiments, the polymorph can also be characterized by a powder x-ray diffraction pattern comprising peaks approximately in the area 8,2, 10,8, 14,1, 14,9, 15,5, 17,1, 17,8, 19,4, 19,9, 21,1, 21,9, 23,0, 25,6 and 28.4 °2θ using Cu Kα radiation.

The present invention also provides the form 2 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-in�ol-3-yl)pyrrolidin-2,5-dione, characterized by powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation. In some embodiments, the polymorph can also be characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9,9, 12,0, 16,7, or 20.1 and 22.8 °2θ using Cu Kα radiation. In other embodiments, the polymorph can also be characterized by a powder x-ray diffraction pattern comprising peaks approximately in the area 6,5, 9,9, 12,0, 13,2, 16,4, 16,7, 17,2, 20,1, 20,3, 20,8, 22,8, 23,7, 28,6 and 30.4 °2θ using Cu Kα radiation.

The present invention also provides (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-indichloride and a composition comprising (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-indichloride. The composition may include more than 90%, more than 95% or greater than 99% (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dietilamina.

The present invention also provides (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine or a composition comprising (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-imperiality-2,5-dione·(1S,2S)-(+)-pseudoephedrine. The composition may include more than 90%, more than 95% or greater than 99% (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-·(1S,2S)-(+)-pseudoephedrine. In some embodiments, the composition may include less than 1%, less than 0.5%, or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-diopsideearrings.

The present invention also provides chiral purified (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, comprising less than 1%, less than 0.7%, less than 0.5%, or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

The present invention also provides a method of obtaining (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, comprising: (a) mixing (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion (1S,2S)-(+)-pseudoephedrine in the first solvent to obtain a solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine; (b) washing the solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoeph�Drina, obtained at the stage of (a) a mixture of water with the first solvent; (C) introducing into the reaction of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine with stage (b) with an acid in an organic solvent and isolation of the organic layer of the resulting solution; (d) washing the organic layer from step (C); (e) adding a second solvent to the organic layer; (f) concentrating the organic layer to such an extent that the concentration of the second solvent in the solution was less than 5%; and (g) crystallizing from the organic layer of step (f) and drying the resulting solution of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione under vacuum to give (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Preferably the obtained (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione comprises less than 1%, less than 0.7%, less than 0.5%, or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

The first solvent may be a non-aqueous solvent. Preferably, the first non-aqueous solvent may be methanol, ethanol, cyclohexylethylamine, acetonitrile or a mixture thereof. W�Roy solvent may be a non-aqueous solvent. Preferably, the second non-aqueous solvent may be methanol, ethanol, acetonitrile or a mixture thereof. In some embodiments, the second solvent is a same as the first solvent. In other embodiments, the second solvent different from the first solvent. Organic solvent at the stage (C) may constitute methyltetrahydrofuran. In some embodiments, the organic layer washed at the stage (d) salt solution. Preferably, the salt solution is a sodium chloride solution.

The method may further include washing the crystals of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion after stage (g). In some embodiments, the crystals of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was washed with alcohol. Preferably, the alcohol is selected from methanol and ethanol.

The present invention also provides a method of obtaining (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, comprising (a) mixing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine and acid; (b) adding alcohol to the mixture with� stage (a) to form a suspension; (C) heating and stirring the suspension of step (b); (d) cooling and isolation of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione; (e) irrigation (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion, selected at the stage (d), the first solvent; (f) dissolving (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione from step (e) in the second solvent to obtain a solution; (g) adding a third solvent to the solution at stage (f) and distillation of the solution before reaching the content of the second solvent in the solution is less than 5%; (h) crystallizing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione from a solution from stage (g); (i) optional addition of a fourth solvent (preferably water) for the maturation of the crystals at the stage (h); (j) the allocation of crystals from stage (i) filtering; (k) washing the crystals with stage (j) a third mixture of a solvent and a fourth solvent; and (l) drying the crystals from step (k) under vacuum to give (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Preferably the obtained (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dio� includes less than 1%, less than 0.7%, less than 0.5%, or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

The alcohol may be methanol, ethanol or a mixture thereof. The first solvent may be a non-aqueous solvent. Preferably, the first non-aqueous solvent is a methanol, ethanol or a mixture thereof. The second solvent may be a non-aqueous solvent. Preferably, the second non-aqueous solvent is a tetrahydrofuran. The third solvent may be a non-aqueous solvent. Preferably, the third non-aqueous solvent is a methanol, ethanol or a mixture thereof.

The present invention also provides a method of obtaining (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, comprising (a) dissolving (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione in dichloromethane and the allocation of (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dietilamina; (b) dissolving (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dietilamina in the first solvent; (C) distillation of the solution from stage (b) to achieve concentrations of dichloromethane in Rast�'or less than 0.1% wt.; (d) dilution of the solution from stage (C) in the second solvent; (e) the introduction of the solution from stage (d) in the system multicanonical chromatography containing packing material, suitable for chiral separation; (f) the Association obtained purified product obtained from stage (e); and (g) crystallization of the purified product from stage (f), filtration of the obtained (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or evaporation of the purified product from step (f) to dryness, obtaining, thus, (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Preferably the obtained (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione comprises less than 1%, less than 0.7%, less than 0.5%, or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Preferably, the first non-aqueous solvent may be methanol, ethanol or a mixture thereof. The second solvent may be a non-aqueous solvent. Preferably, the second non-aqueous solvent is a methanol, ethanol, acetonitrile or a mixture thereof. More preferably, the second non-aqueous solvent is a mixture of methanol and acetonitrile.

EU�and not mentioned specifically, all technical and scientific terms used in this description have the meanings understandable to a specialist in the field of technology to which belongs the present invention. In the specification, the singular also includes the plural unless the context clearly indicates otherwise. Although in the practice or testing of the present invention can be used in the methods and materials similar or equivalent described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned in the present description, is included as a reference. References cited in the present description, are not recognized as having priority over the claimed invention. In case of conflict, the materials, methods and examples are presented only as illustrating and not assumed as a constraint.

Other characteristics and advantages of the invention will become apparent from the following detailed description and claims.

BRIEF description of the DRAWINGS

Fig.1 shows a chemical structure (±)-CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.2 shows the effect of (±)-CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-i ]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione on survival of MDA-MB-231 or Paca-2 cells isin vitro.

Fig.3 shows the effect of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione on survival of MDA-MB-231 cellsin vitro.

Fig.4 shows the effect of (±)-CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione on the activity of protein kinase Cin vitro.

Fig.5 on part a shows the inhibition of c-Met of autophosphorylation (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione; part B shows the inhibition induced c-Met phosphorylation (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.6 shows the effect of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione on the induction of apoptosis in cancer cells.

Fig.7 shows the effect of (-)-TRANS-3-(5,6-d�hydro-4H-imidazo[3,2,1- ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione for inhibiting metastatic invasion of cancer cells.

Fig.8 shows the effect of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione in xenograft breast cancer.

Fig.9 shows the effect of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion on xenograft colon cancer (part a), on xenograft pancreatic cancer (part B), on xenograft prostate cancer (part C) and xenograft gastric cancer (part D).

Fig.10 shows the cytotoxic sensitivity of many cell lines to (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.11 shows the reduction in the amount of phosphorylated c-Met in histological samples treated with (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, method of immunohistochem (part a) or Western blotting (part B).

Fig.12 in part a shows the powder diffraction pattern of form 1 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione; part B shows a typical 2θ values for the x ray powder patterns of the form 1 p�limonta (-)- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.13 in part a shows the powder diffraction pattern of form 2 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione; part B shows a typical 2θ values for the x ray powder patterns of the form 2 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.14 shows graphs comparing the x ray powder patterns of forms 1 and 2 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.15 part a and B graphically show the IR spectra of forms 1 and 2 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.16 graphically shows thermal (melting) behavior forms 1 and 2 (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Fig.17 part a and B graphically show the solubility and intrinsic dissolution of forms 1 and 2, respectively, (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

DETAILED description of the INVENTION

Connection pyrroloquinolinequinone-2,5-Dion

The present invention provides (-)-TRANS-3-(5,-dihydro-4H-imidazo[3,2,1- ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% according to HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

The present invention provides a composition comprising (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% according to HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. The composition may contain one or more pharmaceutically acceptable carriers and excipients.

Preferably (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione high purity provided by the present invention has a chiral purity of more than 99.3 percent, more than 99.5%, more than 99.6 percent, more than 99.7 per cent, more than 99,8% or more than 99.9%. Preferably a composition comprising (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione high purity provided by the present invention contains less than 0.7%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2% or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

All forms of the compounds of infusion�him to the invention are proposed or in mixture, or in pure form, including crystalline forms of racemic mixtures and crystalline form of individual isomers. The invention is particularly specifically covers dedicated optical isomers having the specified activity. Racemic forms can be resolved by physical methods, such as separation or crystallization of diastereomeric derivatives, chiral separation column chromatography, or supercritical chromatography with a mobile phase. Individual optical isomers can be obtained from Ruzimatov traditional ways, such as, for example, salt formation with an optically active acid or base, followed by crystallization.

Certain compounds of the present invention can be used in a tautomeric form. All such tautomeric forms of compounds are considered within the scope of the present invention, unless otherwise indicated.

Additionally, the polymorphism of crystals may be present but is not limiting, but any crystal form may be single or a mixture of crystalline forms, or anhydrous or hydrated crystalline form.

The terms "crystal polymorphs" or "polymorphs" or "crystal forms" means crystal structures in which a compound (or its salt and�and solvate) can crystallize in different crystal packing, all of which have the same elemental composition. Different crystal forms usually have different x-ray diffraction pattern, infrared spectra, melting point, density, shape of crystals, optical and electrical properties, stability and solubility. The solvent of crystallization, the rate of crystallization, storage temperature, and other factors can lead to the dominance of one crystal form. Crystalline polymorphs of compounds can be obtained by crystallization under different conditions.

The present invention provides two polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Form 1 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation. In some embodiments, the polymorph can also be characterized by a powder x-ray diffraction pattern comprising peaks approximately in the area 8,2, 10,8, 14,1, 15,5, 17,8, 19,9 and 25.6 °2θ using Cu Kα radiation. In other embodiments, the polymorph can also be characterized by a powder x-ray diffraction pattern comprising peaks at�to be about in the field of 8.2, 10,8, 14,1, 14,9, 15,5, 17,1, 17,8, 19,4, 19,9, 21,1, 21,9, 23,0, 25,6 and 28.4 °2θ using Cu Kα radiation.

The present invention also provides the form 2 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation. In some embodiments, the polymorph can also be characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9,9, 12,0, 16,7, or 20.1 and 22.8 °2θ using Cu Kα radiation. In other embodiments, the polymorph can also be characterized by a powder x-ray diffraction pattern comprising peaks approximately in the area 6,5, 9,9, 12,0, 13,2, 16,4, 16,7, 17,2, 20,1, 20,3, 20,8, 22,8, 23,7, 28,6 and 30.4 °2θ using Cu Kα radiation.

The present invention also provides a composition comprising form 1 polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation. The composition may include one or more pharmaceutically acceptable carriers and excipients.

Additionally, the connections we�oedema to the invention, for example salts of the compounds may exist in hydrated or non hydrated (anhydride) form or as solvates with other solvate molecules. Non-limiting examples of hydrates include monohydrates, dihydrate, etc. non-limiting examples of solvates include solvates with ethanol solvates with acetone, etc.

The present invention also provides (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine. (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine may include less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione pseudoephedrine.

The present invention also provides a composition comprising (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine, having chiral purity having chiral purity greater than 99% according to HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione pseudoephedrine. The composition may include one or more pharmaceutically acceptable carriers or excipients.

Preferably (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-�l)pyrrolidin-2,5-dione pseudoephedrine high purity, provided by the present invention has a chiral purity of more than 99.5%, more than 99.6 percent, more than 99.7 per cent, more than 99,8% or more than 99.9%. Preferably a composition comprising (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione pseudoephedrine high purity provided by the present invention contains less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2% or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione pseudoephedrine.

"Solvates" refer to attached form a solvent containing stoichiometric or stoichiometric amount of solvent. Some compounds have a tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate is a hydrate, when the solvent is an alcohol, the solvate is an alcoholate. The hydrates formed by combination of one or more molecules of water with one or more substances in which the water remains in its molecular form (H2O, such a combination can form one or more hydrate. For example, the solvate may performance�perform dichlormethane (DCM) solvate.

The present invention also provides (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-indichloride and a composition comprising (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-indichloride. The composition may include more than 90%, more than 95% or greater than 99% (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dietilamina. The composition may include one or more pharmaceutically acceptable carriers or excipients.

Some compounds of the present invention can exist in tautomeric form, which is also assumed to be covered by the scope of the present invention. "Tautomers" refers to compounds which structures are significantly different according to the arrangement of atoms, but are quick and easy balance. It should be understood that the compounds of the invention can be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are assumed to be covered by the scope of the present invention and the naming of the compounds does not exclude any tautomeric forms.

The compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, � such tautomeric forms are included in the scope of the present invention. Tautomers exist as a tautomeric mixture of the complex in solution. In solid form usually predominates one of the tautomers. Even if one tautomer may be described, the present invention includes all tautomers of the present compounds.

As used in the present description, the term "salt" is a pharmaceutically acceptable salt and can include acid additive salts, including hydrochloride, hydrobromide, phosphates, sulfates, hydrosulfate, sulfonates, arylsulfonate, acetates, benzoates, citrates, maleate, fumarate, succinates, lactates, and tartrates; cations of alkali metals such as Na+, K+Li+, salts of alkaline earth metals such as Mg,2+Ca2+or salts of organic amines.

As used in the present description, the term "metabolite" means a product of metabolism of the compounds of the present invention or pharmaceutically acceptable salts thereof, polymorph or solvate that exhibits similar activityin vivocompared with the specified connection according to the present invention.

As used in the present description, the term "mixing" means the combining, blending, stirring, shaking, circular stirring or shaking. The term "mixing" means mixing, shaking, stirring or circular �remesiana.

Compounds of the present invention can also be obtained in the form of a prodrug, for example, pharmaceutically acceptable prodrug. The terms "Pro-drug" and "prodrug" are used in the present description are interchangeable and they refer to any compound which releases an active source medicinein vivo. Because the known properties of the prodrug to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can be delivered in the form of Pro-drug forms. Thus, the present invention encompasses prodrugs of the claimed in the present compounds, methods of delivery and compositions containing them. The term "prodrug" includes a compound of the present invention, covalently associated with one or more protective groups such as amino groups or other water-soluble group. The compound of the present invention can be freed from the protective groups by hydrolysis, oxidation and/or enzymatic mechanisms of release. In one of the embodiments, the prodrug composition of the present invention demonstrates an additional advantage of high water solubility, improved stability and �Lucchini pharmakinetics profiles. The protective group can be selected to obtain the desired characteristics of the prodrug. For example, a protective group, such as amino group or other group to improve the solubility, such as phosphate, can be selected on the basis of solubility, stability, bioavailability and/or delivery or absorption ofin vivo. The term "prodrug" is also intended to include any covalently bonded carrier which releases the active source drug of the present inventionin vivo, when administered to a patient such prodrug. The prodrug of the present invention is obtained by modification of functional groups present in the compound in such a way that the modifications are cleaved, or using conventional manipulation, orin vivoto the original connection. Prodrugs include compounds of the present invention, in which the hydroxy-, amino-, sulfhydryl, carboxy or carbonyl group is associated with any group, so you can splitin vivowith the formation of free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively.

Examples of the prodrug include, but are not limited to, esters (e.g., acetates derivatives, dialkylaminomethyl, formato�, phosphates, sulfates and benzoate) and carbamates (e.g., N,N-dimethylaminoethyl) hydroxy functional groups, esters groups (e.g. ethyl esters, morpholinoethyl esters) of carboxyl functional groups, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Chiffony the grounds and enaminone amidofunctional groups, oximes, acetals, kitali and enologia esters of ketone and aldehyde functional groups in compounds of Formula I and the like, see Bundegaard, H. "Design of Prodrugs" p1-92, Elesevier, New York-Oxford (1985).

The synthesis of compounds (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Standard synthetic methods and procedures for the preparation of organic molecules and transformation of functional groups and manipulating them, including the use of protective groups, can be obtained from relevant scientific literature or from standard reference in this field. Although they are not limited to one or more sources deemed guides include: Smith, M. B.; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thed.; John Wiley & Sons: New York, 2001; and Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd; John Wiley & Sons: New York, 1999. The following description of methods of synthesis are intended to illustrate, but not limit, General procedures for obtaining the compounds posovremeni.

The present invention also provides a method of obtaining (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, comprising (a) mixing (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion (1S,2S)-(+)-pseudoephedrine in the first solvent to obtain a solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine; (b) washing the solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine, obtained at the stage of (a) a mixture of water with the first solvent; (C) introducing into the reaction of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine with stage (b) with an acid in an organic solvent and isolation of the organic layer of the resulting solution; (d) washing the organic layer from step (C); (e) adding a second solvent to the organic layer; (f) the concentration of the organic layer to such an extent that the concentration of the second solvent in the solution was less than 5%; and (g) crystallizing from the organic layer of step (f) and drying the resulting solution of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione under WAC�mind obtaining (-)- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. Preferably the obtained (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione comprises less than 1%, less than 0.7%, less than 0.5%, or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

The first solvent may be a non-aqueous solvent. Preferably, the first non-aqueous solvent may be methanol, ethanol, acetonitrile or a mixture thereof. The second solvent may be a non-aqueous solvent. Preferably, the second non-aqueous solvent may be methanol, ethanol, acetonitrile or a mixture thereof. In some embodiments, the second solvent is a same as the first solvent. In other embodiments, the second solvent different from the first solvent. Organic solvent at the stage (C) may constitute methyltetrahydrofuran. In some embodiments, the organic layer washed at the stage (d) salt solution. Preferably, the salt solution is a sodium chloride solution.

The method may further include washing the crystals of (-)-TRANS-3-(5,6-dihydro-4H-pyrrol�[3,2,1- ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione after stage (g). In some embodiments, the crystals of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was washed with alcohol. Preferably, the alcohol is selected from methanol and ethanol.

The present invention also provides a method of obtaining (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, comprising (a) mixing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine and acid; (b) adding alcohol to the mixture from stage (a) to form a suspension; (C) heating and stirring the suspension obtained in (b); (d) cooling and isolation of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione; (e) irrigation (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion, selected at the stage (d), the first solvent; (f) dissolving (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione from step (e) in the second solvent to obtain a solution; (g) adding a third solvent to the solution in (f) and distillation of the solution before reaching the content of the second solvent in the solution is less than 5%; (h) crystallizing (-)-TRANS-3-(5,6 dihydro-4H-imidazo[3,2,1- ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione from a solution from stage (g); (i) optional addition of a fourth solvent (preferably water) for the maturation of the crystals at the stage (h); (j) the allocation of crystals from stage (i) filtering; (k) washing the crystals with stage (j) a third mixture of a solvent and a fourth solvent; and (l) drying the crystals from step (k) under vacuum to give (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

The alcohol may be methanol, ethanol or a mixture thereof. The first solvent may be a non-aqueous solvent. Preferably, the first non-aqueous solvent is a methanol, ethanol or a mixture thereof. The second solvent may be a non-aqueous solvent. Preferably, the second non-aqueous solvent is a tetrahydrofuran. The third solvent may be a non-aqueous solvent. Preferably, the third non-aqueous solvent is a methanol, ethanol or a mixture thereof. Preferably, the fourth solvent is water.

The present invention also provides a method of obtaining (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, comprising (a) dissolving (±)-TRANS-3-(5,6-dihydro-4H-�irolo[3,2,1- ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione in dichloromethane and the allocation of (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dietilamina; (b) dissolving (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dietilamina in the first solvent; (C) distillation of the solution from stage (b) to achieve the concentration of dichloromethane in the solution is less than 0.1% wt.; (d) dilution of the solution from stage (C) in the second solvent; (e) the introduction of the solution from stage (d) in the system multicanonical chromatography containing packing material, suitable for chiral separation; (f) the Association obtained purified product obtained from stage (e); and (g) crystallization of the purified product from stage (f), filtration of the obtained (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or evaporation of the purified product from step (f) to dryness, obtaining, thus, (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. Preferably the obtained (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione comprises less than 1%, less than 0.7%, less than 0.5%, or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Preferably, the first non-aqueous solvent may be methanol, ethanol or a mixture thereof. The second solvent may be a non-aqueous solvent. Preferably, the second non-aqueous solvent is a methanol, ethanol, acetonitrile or a mixture thereof. More preferably, the second non-aqueous solvent is a mixture of methanol and acetonitrile.

In scheme I provides a summary of not requiring the preparation of a composition comprising highly pure (>99% chiral purity) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione with minimal amounts (<1%) of the undesired enantiomer, (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. Preferably the composition comprises (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity of more than 99.3 percent, more than 99.5%, more than 99.6 percent, more than 99.7 per cent, more than 99,8% or more than 99.9%. Preferably, the compositions include less than 0.7%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2% or less than 0.1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

As shown in scheme I and described in detail in the following examples, using various�s procedures for the receipt and allocation of said compositions, include (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion high chiral purity, including, but not limited to, resolution multicanonical chromatography, diastereomeric permission salts or dynamic kinetic resolution.

At stage 1 on the diagram I, linolein (Connect 4) were treated with oxaliplatin with getting acylchlorides in the reaction solvent methyl tert-butyl simple ether (MTBE). The addition of methanol was sufficient to provide the intermediate complex keeeper, methyl ester 5,6-dihydro-4H-imidazo[3,2,1-ij] quinolin-l-yl) oxoacetate acid (Connection 5). In stage 2 the reaction ofConnection 5and indole-3-acetamide (Compound 5A) combined with 3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Compound 6). As described in detail in the following examples, there is no need to allocate an intermediateConnection 5to getCompounds 6. Substitution of the solvent with MTBE in tetrahydrofuran (THF) was necessary before carrying out stage 2, and since5and5Ahave extremely weak solubility in MTBE. After addingCompounds 5Ato absorbConnection 5in THF in the presence of base was added HCl �to finish the reaction to achieve the crude Compounds 6. UntreatedCompound 6then purified from dichloromethane (DCM) and heptane with gettingCompounds 6sufficient purity for the next stage. A detailed description of this method is shown in Example 1.

Compound 6was hydrogenosomal palladium hydroxide, THF and tert-butoxide potassium with gettingTRANSthe racemate (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Compound 8). As described in the examples, the preparation of the compound 8 does not require the discharge of untreatedCISthe racemate (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connection 7). It is preferable in the hydrogenation ofCompound 6the conditions modified in such a way as to affect the isomerization obtainedCompound 7in situ. The resulting method provides mechanisms to control the main impurity inConnection 8especiallyCompounds 6. In particular, the reaction is carried out in THF solvent and catalyst used is a palladium hydroxide. Tert-butoxide potassium was added to the reaction mixture, to promote isomerization. A detailed description of this method is shown in Example 2.

The most common impurity inConnection 8is aSoy�the coalescing 7 . BecauseConnection 7in and of itself is a chiral, particularly difficult to predict the evolution of isomers ofCompound 7from multicanonical chromatography (MCC) when usingCompounds 8lower purity (<99%). To ensure a product of high purity, therefore, it is necessary to increase the purity of the racemateCompounds 8before enantiomeric resolution using JPOs. It was determined that the purity of theCompounds 8can be improved by selective crystallization of the solvate and various solvents. One such solvate obtained from dichloromethane (DCM) leads toCompound 8 DCMhigh chemical purity (>99%). As shown in scheme I,Compound 8 DCMwas obtained by dissolving the crudeCompounds 8in DCM and subsequent priming crystals DCM. After the crystal growth layer to a critical mass of heptane was added to complete crystallization. After separation by filtration, and mass removal of excess solvent under vacuumCompound 8 DCMusually contain of 0.8 to 0.9 mol of DCM in relation toConnection 8. This crystallization of the solvate was removed impurities present in the crude (95-98%)Connection 8as a consequence of the hydrogenation and isomerization. Such description of this method shown in Example 3.

The present invent�tion provides chiral resolution of the two enantiomers Compound 8 DCMwith the help of MCC, as shown in scheme I. method for the separation of enantiomers MCC provides an advantage compared to the separation of the party HPLC chromatography in that it can provide high chiral purity (>99%) at large scale (>20 kg), compared with those obtained by the parties. Permit MCC to conduct or methanol or mixtures of methanol and ethanol (1:1 vol.), or methanol and acetonitrile (9:1 by vol.). Used chiral stationary phase (CSP) the party is or a Chiralpak AD or AZ, available from Chiral Technologies, Inc. The concentration of the loaded solution of the racemate is in the range of 20-50 g/l. Preferably mounted chiral purity for the separation is >99% (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connection 10and the content of <1% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connection 9).

More specifically, the separation is carried out by obtaining a downloadable solution of racemicCompounds 8the selected mobile phase. Said solution is prepared fromCompound 8 DCMby initially dissolving the substance in methanol. Chromatographic parameters were evaluated before and getting conducted a final optimization during the initial hours or days of separation downld�display solution. If the collected initial fraction did not meet the specifications of chiral purity, the material is recycled in a downloadable solution for repeat resolution. Once were set operating parameters that meet the specifications, the conditions used to separate the whole amount of the feed solution. During the operationConnection 10collected as a stream of purified substance were combined and concentrated. Concentrated purified substance is then or was concentrated to dryness (scale <5 kg) or concentrated and injected the priming for the induction of crystallization ofConnections 10(scale >5 kg). A detailed description of this method is presented in example 4.

In addition to the resolution of MSS applied the classical approach to the resolution of chiral acids or bases through the formation of diastereomeric salts. In the case ofConnections 10could be used, or acid, or base, because the molecule is an amphoteric. After a detailed selection of chiral bases, it was shown that the salt formed of enantiomersCompounds 8with pseudoephedrine, have significantly different profiles of solubility in certain solvents. This ratio is optimized to give the possibility of allowing theCompounds 8when using (1S,2S)-(+)-pseudoephedrine d�I selective preparation of (-)- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine (Compound 10 (1S,2S)-(+)-pseudoephedrine). A detailed description of this method is given in Example 6. Another method provided by the present invention is to racemization of the unwanted enantiomer, (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-DionConnection 9)in situwhen using dynamic kinetic resolution (DKR). A detailed description of this method is presented in Example 7.

And in the resolution of the MSS, and in the classic way of resolving the diastereomeric salts were isolated undesired enantiomer,Connection 9. Specified undesired enantiomer can be isomerizate with obtaining racemicCompounds 8. This is accomplished by applying the same procedure isomerization of the CIS-isomer,Compound 7obtaining crudeTRANS-racemate ofCompounds 8. The isomerization is carried out or in methanol or ethanol using sodium hydroxide as the base. A detailed description of this method is presented in Example 5.

The methods of synthesis described in scheme I are easily reproducible on a large scale, for example, 10 kg, 20 kg, 30 kg, 40 kg, 50 kg and 60 kg and more, providing a total output of more than 4% (-)- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connection 10), from indolacetic as a limiting reagent. Preferably 1 kg of linolein (Connect 4) results in the release of approximately 1 kg (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connections 10), having a purity >99%.

The present compound also provides a method of obtaining polimorfo (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. UntreatedConnection 10was dissolved in a solvent such as THF, by heating the mixture to 50°C. the mixture was clarified by filtration followed by the addition of a second solvent, such as methanol and shape of the seed crystal 1Connections 10.

The use of seed crystals specifies the control of polymorphs in the way of crystallization. In the absence of priming or Form 1 or Form 2 can spontaneously crystallize with high purity. Thus, to ensure that Form 1 or Form 2 is allowed spontaneous crystallization; and once formed crystalline product can be characterized by quantitative analysis using x-ray powder diffraction to determine the obtained crystalline Fort�s and polymorphic purity. After such characteristic crystalline product can be used as "seed crystals" or "priming" to control polymorph, or Form 1 or Form 2 obtained during subsequent crystallization, as described here.

The solution is then concentrated azeotropic and at atmospheric pressure by distillation to reduce the volume of the solvent, e.g., THF. The temperature of the solvent was lowered to 50°C and stirred for 4 hours. Aliquots were taken to confirm the formation of the desired polymorph. If you polymorph could be re-dissolved in THF (30% of the lot size), clarified by filtration, concentrated, and he was made a seed crystal for receiving the output of the desired polymorph. After obtaining the desired shape of the polymorph was added 50% aqueous solution of methanol at 50°C and the solution was stirred in the next 2-3 hours. The solution is then cooled to ambient temperature and left to stand for at least 2 hours, allowing to crystallize. After the crystals were isolated by filtration, washed with additional aqueous 50% methanol and dried under vacuum at 65°C for at least 12 hours. Polymorphic Form 1Connections 10allocated in the form of a red-brown solid substance.

Polymorph Form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]�inolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione can also be obtained as described above, if seed crystals of form 1 to replace the seed crystals of Form 2.

Methods of treatment

The present invention provides methods for the treatment of disorders of cell proliferation in a patient in need of such treatment by administration to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising (a) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα emission�, and one or more pharmaceutically acceptable carriers or excipients.

Violation of cell division may be a cancer or a precancerous condition. The present invention additionally provides the use of compositions (a), (- )- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients, to obtain a pharmaceutical product suitable for treatment narushenia.lechenie proliferation.

The present invention also provides methods of protection against violations of cell proliferation in a patient in need, by introducing a therapeutically effective amount of a pharmaceutical composition comprising (a) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, and 9,9 12,0 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients, and one or more pharmaceutically acceptable carriers or excipients patient, nujdayas� such treatment. Violation of cell proliferation may be a cancer or a precancerous condition. The present invention also provides the use of compositions (a), (- )- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, and 9,9 12,0 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients for medical drug suitable for the treatment of disorders of cell proliferation.

As used in this description, "patient, well�given this is a patient having a violation of cell proliferation, or the patient having an increased risk of developing disorders of cell proliferation in relation to the whole population. A patient who needs it, can be in a precancerous state. Preferably a patient who needs it, has cancer. The term "patient" includes a mammal. The mammal may be, for example, any mammal, e.g., human, Primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep or pig. Preferably, the mammal is a human.

As used in the present description, the term "violation of cell proliferation" refers to the conditions in which irregular or abnormal growth of cells, or both that and another, can lead to the development of an unwanted condition or disease, which may or may not be cancerous. Examples of disorders of cell proliferation according to the invention include the various States, where cell division razregulirovki. Examples of disorders of cell proliferation include, but are not limited to, neoplasms, benign tumors, substandard tumors, precancerous lesions, tumors in the place of education, encapsulated tumors, metastatic tumors, liquid tumors,solid tumors, immunological tumors, tumors of the circulatory system, various types of cancers, carcinomas, leukemias, lymphomas, sarcomas and rapidly dividing cells. The term "rapidly dividing cells", as used in this description, is defined as any cell that is divided at a speed that is greater than or more than expected or observed among neighboring or adjacent cells in the same tissue. Violation of cell proliferation includes a precancer or precancerous condition. Violation of cell proliferation include cancer. Preferably, the methods provided in the present description, is used to treat or relieve symptoms of cancer. The term "cancer" includes solid tumors, and tumors of the circulatory system and/or malignant neoplasms. "Precancerous cell" or "precontingency cell" is a cell that demonstrates a violation of cell proliferation, which is a precancer or precarcinogens state. "Cancer cell" or "cancerous cell" is a cell that demonstrates a violation of cell proliferation, which is a cancer. Any reproducible means of measurement can be used to determine whether cancer or precancerosis cells. Cancer cells or precarcinogens cells can be identified by GI�tragicheskomu definition or classification of tissue samples (for example, biopsy specimens). Cancer cells or precarcinogens cells can be identified by the use of suitable molecular markers.

Examples of non-cancer conditions or diseases include, but are not limited to, rheumatoid arthritis, inflammation, autoimmune disease, lymphoproliferative conditions, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, other arthritic condition, sepsis, septic shock, endotoksicski shock, gram negative sepsis, toxic shock syndrome, asthma, acute respiratory distress syndrome in adults, chronic obstructive pulmonary disease, chronic pneumonia, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, fibrosis of the pancreas, liver fibrosis, acute and chronic kidney disease, the irritable bowel syndrome, fever, restenosis, cerebral malaria, stroke, and ischemic injury, brain trauma, Alzheimer's disease, Huntington's chorea, Parkinson's disease, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendant, tenosynovitis syndrome, gr�LM, rupture or prolapse of intervertebral disc disease, Albers-schönberg, thrombosis, restenosis, silicosis, pathological overgrowth of the soft tissues of the lung, diseases of bone resorption, such as osteoporosis, graft-versus-host, multiple sclerosis, lupus, fibromyalgia, AIDS and other viral diseases such as herpes zoster, herpes simplex I and II, influenza virus and cytomegalovirus and diabetes mellitus.

Examples of cancer include, but are not limited to, adrenocortical carcinoma, cancers associated with AIDS, lymphoma, AIDS related cancer of the anus, anorectal cancer, cancer of the anal canal, cancer of the Appendix, childhood astrocytoma of the cerebellum, childhood astrocytoma brain, basal cell carcinoma, skin cancer (non-melanoma) cancer, liver cancer, extrahepatic cancer of the bile ducts, intrahepatic cancer of the bile ducts, cancer of the bladder, vesical cancer, cancer of the bones and joints, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, glioma of the brain stem, astrocytoma of the cerebellum, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway glioma and hypothalamus, breast cancer, bronchial adenomas/carcinoids, carcinoid tumors, gastric Tr�KTA, cancer of the nervous system, lymphoma of the nervous system, cancer of the Central nervous system, lymphoma of the Central nervous system, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cancer of the colon and rectum, cutaneous T-cell lymphoma, lymphoid neoplasm, mushroom granuloma, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial tumor of germ cells, wegonna a germ cell tumor, extrahepatic cancer of the bile ducts, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer (stomach cancer), carcinoid tumor, gastrointestinal tract, gastrointestinal stromal tumor (GIST), embryonic cell tumor, germ cell tumor of the ovary, ovarian gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intracellular melanoma, eye cancer, tumors of the islet cells (pancreas), Kaposi's sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, leukemia hairy cell cancer, lip and oral cavity cancer, liver cancer, lung cancer, numb�kletocny lung cancer, small cell lung cancer, lymphoma, AIDS related, nahodkinskuju lymphoma, primary lymphoma of the Central nervous system, waldenstrom's macroglobulinemia, medulloblastoma, melanoma, intraocular(eye) melanoma, carcinoma, Merkel cells, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, mouth cancer, tongue cancer syndrome multiple endocrine neoplasia, mushroom granuloma, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharynx cancer, neuroblastoma, oral cancer, oral cancer, oropharyngeal cancer, ovarian cancer, cancer of the epithelial cells of the ovary, potentially malignant ovarian tumors, pancreatic cancer, cancer of the island cells of the pancreas, cancer of the paranasal sinus and nasal chambers, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, a neoplasm of plasma cells/multiple myeloma, the pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, cancer of Lynn�th cancer, the family of Ewing's sarcoma, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer, sarcoma cancer, skin cancer (non-melanoma), skin cancer (melanoma), carcinoma Merkel cells, cancer of the small intestine, soft tissue sarcoma, squamous cell carcinoma, gastric cancer (stomach cancer), supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and carcinoma of the thymus, thyroid cancer, transitional cell cancer renal pelvis and ureter and other urinary organs, gestational trophoblast tumor, urethral cancer, endometrial cancer of the uterus, sarcoma of the uterus, cancer of the uterine body, cancer of the vagina, cancer of the female external genitalia and Wilms tumor.

"Violation of cell proliferation of the hematopoietic system is a violation of cell proliferation involving cells of the hematopoietic system. Violation of cell proliferation of the hematopoietic system may include lymphoma, leukemia, myeloid neoplasms, neoplasms of the fat cells, myelodysplasia, benign a monoclonal gammopathy, lymphomatoid a granulomatosis, limfoidnye papules, true polycythemia, chronic miliitary leukemia, anagennao myeloid metaplasia essential thrombocythemia and idiopathic. Violation of cell proliferation of the hematopoietic system may include hyperplasia, dysplasia and metaplasia kleptokratiey system. Preferably the compositions of the present invention can be used for the treatment of cancer selected from the group consisting of cancer of the blood system of the present invention or the disruption of cellular proliferation of the hematopoietic system of the present invention. Cancer of the hematopoietic system of the present invention may include multiple myeloma, lymphoma (including Hodgkin's lymphoma, nahodkinskuju lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including children's leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute miliitary leukemia, chronic lymphocytic leukemia, chronic miliitary leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and neoplasms of fat cells.

"Violation of cell proliferation of the lung" is a violation of cell proliferation involving lung cells. Disorders of cell proliferation of the lung can include all forms of disorders of cell proliferation, acting on the lung cells. Disorders of cell proliferation of the lung can include lung cancer, a precancer or precancerous condition of the lung, benign tumors or pathological changes of the lung and malignant tumors or pathological changes in the lungs, and metasta�quarter changes in tissues and organs, different from the lungs. Preferably the compositions of the present invention can be used to treat lung cancer or disorders of cell proliferation of the lung. Lung cancer may include all forms of lung cancer. Lung cancer may include malignant neoplasms of the lung, carcinomain situtypical carcinoid tumors and atypical carcinoid tumors. Lung cancer may include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC"), nesamoney non-small cell lung cancer, squamous non-small cell lung cancer, squamous cell carcinoma, neploskokletochny carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma and mesothelioma. Lung cancer may include "scar carcinoma", bronchioalveolar carcinoma, giant cell carcinoma, spindle carcinoma and large cell neuroendocrine carcinoma. Lung cancer may include neoplasms with histological or ultrastructural heterogeneity (e.g., mixed cell types).

Disorders of cell proliferation of the lung can include all forms of disorders of cell proliferation, acting on the lung cells. Disorders of cell proliferation of the lung can include lung cancer, a precancerous condition of the lung. Violations� cell proliferation of the lung can include hyperplasia, dysplasia and metaplasia of the lungs. Disorders of cell proliferation of the lung can include asbestos-induced hyperplasia, squamous metaplasia and the benign reactive materialului the metaplasia. Disorders of cell proliferation of the lung can include replacement of the columnar epithelium stratified squamous epithelium and mucosal dysplasia. Individuals subjected to the action of inhaled damaging agents such as cigarette smoke and asbestos may be at risk of developing disorders of cell proliferation of the lung. Primary lung disease, which can lead to predisposition of individuals to the development of impaired lung cell proliferation may include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid arthritis, sarcoidosis, interstitial pneumonia, tuberculosis, multiple pneumonias, idiopathic pulmonary fibrosis, granulomatosis, asbestosis, fibrosing alveolitis, and Hodgkin's disease.

"Violation of cell proliferation of the colon" is a violation of cell proliferation, affecting the cells of the colon. Preferably, the violation of cell proliferation of the colon is a colon cancer. Preferably the compositions according to the present� to the invention can be used to treat colon cancer or disorders of cell proliferation of the colon. Colon cancer includes all forms of colon cancer. Colon cancer may include single or hereditary cases of colon cancer. Colon cancer may include malignant neoplasms of the colon, local carcinoma typical carcinoid tumors and atypical carcinoid tumors. Colon cancer may include adenocarcinoma, squamous cell carcinoma and adenosquamous cell carcinoma. Colon cancer may be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis cancer of the colon and rectum, familial adenomatous polyposis syndrome Gardiner, syndrome Peutz-Jeghers syndrome Turko and juvenile polyposis. Colon cancer can be caused by hereditary syndrome selected from the group consisting of hereditary nonpolyposis cancer of the colon and rectum, familial adenomatous polyposis syndrome Gardiner, syndrome Peutz-Jeghers syndrome Turko and juvenile polyposis.

Disorders of cell proliferation of the colon can include all forms of disorders of cell proliferation, acting on cells of the colon. Disorders of cell proliferation of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon and metachronous p�etologicheskie changes of the colon. Disorders of cell proliferation of the colon may include adenoma. Disorders of cell proliferation of the colon can be characterized by hyperplasia, metaplasia or dysplasia of the colon. Primary disease of the colon, which can lead to predisposition of individuals to the development of impaired cell proliferation of the colon may include the primary colon cancer. The current disease that can lead to a predisposition of an individual to the development of impaired cell proliferation of the colon, may include Crohn's disease and ulcerative colitis. Violation of cell proliferation of the colon may be associated with a mutation in a gene selected from the group consisting of p53,ras,FAPandDCC. The individual may have an increased risk of developing disorders of cell proliferation of the colon because of the presence of mutations in a gene selected from the group consisting of p53,ras,FAPandDCC.

"Violation of cell proliferation of the prostate" is a violation of cell proliferation, affecting the cells of the prostate. Disorders of cell proliferation of the prostate can include all forms of disorders of cell proliferation, affecting the cells of the prostate. Disorders of cell proliferation of the prostate may include prostate cancer, a precancer or precancerous condition �rotate, benign enlarged or pathological changes of the prostate and malignant growths or pathological changes of the prostate, and metastatic pathological changes in tissues and organs of the body other than the prostate. Disorders of cell proliferation of the prostate may include hyperplasia, metaplasia and dysplasia of the prostate.

"Violation of cell proliferation of the skin" is a violation of cell proliferation involving skin cells. Disorders of cell proliferation of the skin can include all forms of disorders of cell proliferation, affecting skin cells. Disorders of cell proliferation of the skin can include a precancer or precancerous condition of the skin, benign growths or pathological changes in the skin, melanoma and other malignant growths or abnormal skin changes and metastatic pathological changes in tissues and organs of the body than the skin. Disorders of cell proliferation of the skin can include hyperplasia, metaplasia and dysplasia of the skin.

"Violation of cell proliferation of the ovary is a violation of cell proliferation, affecting the cells of the ovary. Disorders of cell proliferation of ovarian can include all forms of disorders of cell proliferation, affecting the cells of the ovary. Violations of the cellular ProLife�ation of the ovary may include a precancer or precancerous condition of the ovary, benign enlarged or pathological changes of the ovary, ovarian cancer, malignant growth or pathological changes in the ovary and metastatic pathological changes in tissues and organs of the body, distinct from the ovary. Disorders of cell proliferation of ovarian can include hyperplasia, metaplasia and dysplasia cells of the ovary.

"Violation of cell proliferation of the mammary gland is a violation of cell proliferation, affecting the cells of the breast. Disorders of cell proliferation of the breast can include all forms of disorders of cell proliferation, affecting the cells of the breast. Disorders of cell proliferation of breast cancer can include breast cancer, a precancer or precancerous condition of the breast, benign growth or pathological changes, breast cancer, malignant growth or pathological changes, breast cancer, metastatic pathological changes in tissues and organs of the body than the breast. Disorders of cell proliferation of the breast can include hyperplasia, metaplasia and dysplasia of the breast.

Violation of cell proliferation of the breast may represent a precancerous condition of the breast. The compositions according to the present Fig�the plants can be used to treat precancerous conditions of the breast. A precancerous condition of the breast can include atypical hyperplasia of the breast, local intraductal carcinoma (DCIS), intraductal carcinoma, local lobular carcinoma (LCIS), lobular tumor and stage 0 or grade 0 pathological growths or changes in breast cancer (e.g., stage 0 or grade 0 breast cancer or carcinoma). You can highlight the stage of precancerous conditions of the breast according to the TNM classification scheme as accepted by the American joint cancer Committee (American Joint Committee on Cancer) (AJCC, where primary tumor (T) belongs to stage T0 or Tis; and where the local lymph nodes (N) refers to the stage of N0; and where distant metastasis (M) belongs to M0 stage.

Violation of cell proliferation of breast cancer may be a breast cancer. Preferably the compositions of the present invention can be used to treat breast cancer. Breast cancer may include primary epithelial cancers of the breast. Breast cancer may include types of cancer, where the mammary gland is involved in other tumors, such as lymphoma, sarcoma or melanoma. Breast cancer can include cancer of the breast, intraductal carcinoma of the breast, lobular carcinoma of breast, nedeff�entirelynew carcinoma of the breast, features in phyllodes cystosarcoma breast cancer, angiosarcoma of the breast and primary lymphoma of the breast. Breast cancer may include phase I, II, IIIA, IIIB, IIIC and IV breast cancer. Intraductal carcinoma of the breast may include invasive carcinoma, local invasive carcinoma with a predominant intraductal component, inflammatory breast cancer and intraductal carcinoma of the breast with histological type selected from the group consisting of a nodular, slime, medullary, medullary with lymphocytic infiltrate, papillary, scirrhous, and tubular. Lobular carcinoma of the breast may include invasive lobular carcinoma with dominant local component, invasive lobular carcinoma and invasive infiltrating lobular carcinoma. Breast cancer may include Paget's disease, Paget's disease with intraductal carcinoma and Paget's disease with invasive intraductal carcinoma. Breast cancer may include neoplasms of breast cancer with histological and ultrastructural heterogeneity (e.g., mixed cell types).

Preferably, the compound of the present invention may be used to treat breast cancer. Breast cancer, the treatment of which will be set�dit, may include family breast cancer. Breast cancer, the treatment of which will be conducted may include sporadic breast cancer. Breast cancer, the treatment of which will carry out, can occur in male patient. Breast cancer, the treatment of which will conduct that may occur in the patient female. Breast cancer, the treatment of which will carry out, can occur in pre-menopause female patient or in postmenopausal female patient. Breast cancer, the treatment of which will conduct that may occur in the patient, whose age is more than or equal to 30 years, or the patient, whose age less than 30 years. Breast cancer, the treatment of which will conduct that may occur in a patient whose age is equal to or more than 50 years, or in a patient aged less than 50 years. Breast cancer, the treatment of which will conduct that may occur in a patient whose age is equal to or more than 70 years, or in a patient aged less than 70 years.

Breast cancer, the treatment of which will carry out, can be typed to identify a familial or spontaneous mutation in BRCA1, BRCA2 or p53. Breast cancer, the treatment of which will carry out, can be typed as having a gene amplification of HER2/neu, increased expression of HER2/neu �Lee as having low, intermediate or high expression level of HER2/neu. Breast cancer, the treatment of which will carry out, can be typed at the marker selected from the group consisting of estrogen receptor (ER), progesterone receptor (PR), the receptor for the growth factor of human epidermis 2, Ki-67, CA15-3, CA 27-29, and c-Met. Breast cancer, the treatment of which will carry out, can be typed with an unknown level of ER-rich ER or poor ER. Breast cancer, the treatment of which will carry out, can be typed as ER-negative or ER-positive. ER-typing of breast cancer can be performed by any reproducible means. ER-typing of breast cancer can be performed, as set forth in Onkologie 27: 175 to 179 (2004). Breast cancer, the treatment of which will carry out, can be typed as unknown level PR, rich PR or poor PR. Breast cancer, the treatment of which will carry out, can be typed as PR-negative or PR-positive. Breast cancer, the treatment of which will carry out, can be typed as a negative against the receptor or positive relative to the receptor. Breast cancer, the treatment of which will carry out, can be typed as associated with an increased blood level of CA 15-3 or CA 27-29, or both.

Breast cancer, treatment which�will be spending about, may include localized swelling breast. Breast cancer, the treatment of which will be conducted may include a tumor of the breast associated with negative biopsy sentinel lymph node (SLN). Breast cancer, the treatment of which will be conducted may include a tumor of the breast associated with a positive biopsy of the sentinel lymph node (SLN). Breast cancer, the treatment of which will be conducted may include a tumor of the breast associated with one or more positive axillary lymph nodes has been defined stage of axillary lymph nodes in any acceptable manner. Breast cancer, the treatment of which will be conducted may include a tumor of the breast, which was typed as having the status of the absence of lymph node lesions (e.g., without involvement of lymph nodes) or with the status of presence of lymph node lesions (e.g., lymph nodes). Breast cancer, the treatment of which will be conducted may include a breast tumor that has metastasized in other parts of the body. Breast cancer, the treatment of which will conduct classified as having metastases in other departments, selected from the group consisting of bones, lungs, the liver or brain. Breast cancer, the treatment of which will conduct classified according to the characteristics selected from the group consisting of metastatic, localized, local, locally distributed, local-local, local spread, distant, multifocal, bilateral, ipsilateral, contralateral, freshly diagnosed, recurrent and inoperable.

The compound of the present invention can be used in the treatment of disorders of cell proliferation, breast cancer or in treating or preventing breast cancer in a patient having an increased risk of developing breast cancer compared to the population as a whole. The patient with an increased risk of developing breast cancer compared to the population as a whole presents a female patient with a family history or personal history of breast cancer. The patient with an increased risk of developing breast cancer compared to the population as a whole is a female patient with germ-line or spontaneous mutation in BRCA1 or BRCA2, or both. The patient with an increased risk of developing breast cancer compared to the population as a whole is a female patient with a family history of breast cancer and �bearing germ line or spontaneous mutation in BRCA1 or BRCA2 or both. The patient with an increased risk of developing breast cancer compared to the population as a whole represents a female patient aged more than 30 years, 40 years, 50 years, 60 years, 70 years, 80 years or 90 years. The patient with an increased risk of developing breast cancer compared to the population as a whole is a patient with atypical dysplasia, breast cancer, local intraductal carcinoma (DCIS), intraductal cancer, local lobular carcinoma (LCIS), lobular neoplasm, or stage 0 pathological growths or changes in breast cancer (e.g., stage 0 or grade 0 breast cancer or carcinoma).

Breast cancer, the treatment of which can be performed, histology can be divided according to the Scarff-Bloom-Richardson, in which the breast tumor is credited with the value of mitosis 1, 2 or 3; the value of nuclear pleiomorphism 1, 2 or 3; the value of education tubules 1, 2 or 3; and the overall result according to Scarff-Bloom-Richardson in the range from 3 to 9. You can determine the degree of development of breast cancer, the treatment of which can be performed according to the classification of tumors according to the international group to harmonize the treatment of breast cancer selected from the group consisting of grade 1, level 1-2, level 2, grade 2-3, or grade 3.

You can determine the degree of development of breast cancer, l�, the values of which can be performed according to the TNM classification system of the American joint cancer Committee (American Joint Committee on Cancer) (AJCC), where the tumor (T) is assigned a stage of TX, T1 T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) is assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or M1. Stage of cancer, the treatment of which can be performed, can be a according to the classification system of the American joint cancer Committee (American Joint Committee on Cancer) (AJCC) Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. Cancer, the treatment of which can be performed, can be attributed to the stage according to the AJCC classification, Stage GX (e.g., grade cannot be determined), Stage 1, Stage 2, Stage 3 or Stage 4. Cancer, the treatment of which can be performed can be classified according to the pathological stage classification (pN) AJCC as pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, or pN3b pN3c.

Cancer, the treatment of which is expected to be conducted may include a tumor, which was defined as less than or equal to about 2 centimeters in diameter. Cancer, the treatment of which is expected to be conducted may include a tumor, which was defined as from about 2 to about 5 centimeters in diameter. Cancer, treatment which is expected �to hang out, may include tumor, which was defined as more than or equal to about 3 centimeters in diameter. Cancer, the treatment of which is expected to be conducted may include a tumor, which was defined as more than about 5 centimeters in diameter. Cancer, the treatment of which is expected to be conducted can be classified according to the microscopic structure as well-developed, moderately developed, weakly developed or undeveloped. Cancer, the treatment of which is expected to be conducted can be classified according to the microscopic structure from the point of view of the number of mitosis (e.g., cell proliferati) or nuclear pleiomorphism (e.g., change in cells). Cancer, the treatment of which is expected to be conducted can be classified according to the microscopic structure as associated with areas of necrosis (e.g., areas of dying or degrading cells). Cancer, the treatment of which is expected to be conducted can be classified as having an abnormal karyotype with an abnormal number of chromosomes or having one or more chromosomes that are abnormal in appearance. Cancer, the treatment of which is expected to be conducted can be classified as aneuploid, triploid, tetraploid, or as having modified ploidy. Cancer, the treatment of which predpolagaete� conduct, can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome or a region of deletion, duplication or amplification of part of chromosome.

Cancer, treatment is expected to occur, can be evaluated by DNA cytometry, flow cytometry or visual cytometry. Cancer, the treatment of which is expected to be conducted can be classified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the cells at the stage of synthesis of cell proliferation (e.g., in the S-phase of cell proliferation). Cancer, the treatment of which is expected to be conducted can be classified as having a low S-fraction or high S-fraction.

As used in this description, a "normal cell" is a cell that cannot be classified as part of "disorders of cell proliferation". In a normal cell there is no uncontrolled or abnormal growth, or both, which lead to undesirable condition or disease. Preferably normal cells have a well-functioning regulatory control mechanisms.

As used in the present description, "contact cell" refers to a state in which the compound or other composition of matter is in direct contact with the cell or close enough to� to call in the cell, the desired biological effect.

As used in the present description, the "connection applicant" refers to the compound of the present invention to be tested in one or morein vitroorin vivobiological tests to determine whether the specified connection to cause the desired biological or medical response in a cell, tissue, system, animal or human sought by a researcher or practitioner. The connection candidate is a pharmaceutical composition comprising (a) a composition comprising (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically acceptable carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion, kharakterizuyushchemu x-ray diffraction pattern, comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients. Biological or medical response can be a cancer treatment. Biological or medical response can be a treatment or prevention of disorders of cell proliferation. Biological testsin vitroorin vivomay include, but are not limited to, assays of enzymatic activity, methods of electrophoretic mobility shift, test cell viability ofin vitroand tests described here.

As used in this description, "monotherapy" refers to the introduction of the single active or therapeutic compound to a patient in need of such introduction. Preferably monotherapy would imply the introduction of a therapeutically effective amount of an active compound. For example, cancer monotherapy with one of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate to a patient in need of cancer treatment. Monotherapy can be contrasted with the combined treatment, which is administered a combination of several active compounds, preferably each component of the combination, Pris�relevant in therapeutically effective amounts. In one aspect monotherapy compound of the present invention is more effective than combination treatment to achieve the desired biological effect.

As used in the present description, "therapy" or "treatment" describes the control of the disease and patient care in order to combat the disease, condition or violation and includes the introduction of compounds according to the present invention for alleviating symptoms or complications of the disease, condition or violation or to cure the disease, condition or breach.

Compounds of the present invention may also be used to prevent disease, condition or violation. As used in the present description, the "prevention" or "prevent" describes the reduction or elimination of the occurrence of symptoms or complications of the disease, condition or breach.

Cancer treatment may result in reduction in tumor size. Reduction tumor size can also be referred to as "tumor regression". Preferably, after treatment, tumor size is reduced by 5% or more relative to its size prior to treatment; more preferably, reduced by 10% or more; more preferably, reduced by 20% or more; more preferably, reduced by 30% or b�Loei; more preferably, reduced by 40% or more; more preferably, reduced by 50% or more; and most preferably reduced by 75% or more. Tumor size can be measured by any reproducible means. Tumor size can be measured as the diameter of the tumor.

Cancer treatment may lead to reduction of tumor volume. Reduction tumor size can also be referred to as "tumor regression". Preferably, after treatment, tumor volume is reduced by 5% or more relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or more; more preferably, reduced by 20% or more; more preferably, reduced by 30% or more; more preferably, reduced by 40% or more; more preferably, reduced by 50% or more; and most preferably reduced by 75% or more. Tumor volume can be measured by any reproducible way of measuring.

Cancer treatment can lead to a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of tumors is reduced by 10% or more; more preferably, reduced by 20% or more; more preferably, reduced by 30% or more; more preferably at�elsaelsa 40% or more; even more preferably, reduced by 50% or more; and most preferably reduced by 75% or more. The number of tumors can be measured by any reproducible way of measuring. The number of tumors can be measured by counting the tumors visible to the naked eye, or at a particular magnification. Preferably the concrete is increasing 2×, 3×, 4×, 5×, l0× and 50×.

Cancer treatment can lead to a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor. Preferably, after treatment, the number of metastatic pathological changes is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic pathological changes is reduced by 10% or more; more preferably, reduced by 20% or more; more preferably, reduced by 30% or more; more preferably, reduced by 40% or more; more preferably, reduced by 50% or more; and most preferably reduced by 75% or more. The number of metastatic pathological changes can be measured by any reproducible way of measuring. The number of tumors can be measured by counting the tumors visible to the naked eye, or at a particular magnification. Preferably specific HC�rising is 2×, 3×, 4×, 5×, l0× and 50×.

Cancer treatment can lead to increased life expectancy of patients undergoing treatment, compared to only receive media. Preferably, the average life expectancy increases by more than 30 days; more preferably more than 60 days; more preferably by more than 90 days and most preferably for more than 120 days. The increase in average life expectancy of a population can be measured by any reproducible means. The increase in average life expectancy of a population can be measured, for example, by calculating for a population the average life expectancy after initiation of treatment with an active compound. The increase in average life expectancy of a population can also be measured, for example, by calculating for a population the average life expectancy after the completion of the first cycle of treatment with active connection.

Cancer treatment can lead to increased life span in populations of patients with treatment compared with the population of patients not receiving therapy. Preferably, the average life expectancy increases by more than 30 days; more preferably more than 60 days; more preferably by more than 90 days and most preferably for more than 120 days. The increase in average prod�littelest life of a population can be measured by any reproducible means. The increase in average life expectancy of a population can be measured, for example, by calculating for a population the average life expectancy after initiation of treatment with an active compound. The increase in average life expectancy of a population can also be measured, for example, by calculating for a population the average life expectancy after the completion of the first cycle of therapy active connection.

Cancer treatment could increase life expectancy in patients with treatment compared with patients receiving monotherapy drug, which is a compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate. Preferably, the average life expectancy increases by more than 30 days; more preferably more than 60 days; more preferably by more than 90 days and most preferably for more than 120 days. The increase in average life expectancy of a population can be measured by any reproducible means. The increase in average life expectancy of a population can be measured, for example, by calculating for a population the average life expectancy after initiation of therapy active connection. The increase in average life expectancy of popular�and can also be measured for example, by calculating for a population the average life expectancy after the completion of the first cycle of therapy active connection.

Cancer treatment may lead to reduction of mortality rate of patients undergoing treatment, compared to only receive media. Cancer treatment may lead to reduction of mortality rate of patients undergoing therapy, compared with untreated. Cancer treatment may lead to reduction of mortality rate of patients undergoing treatment, compared with patients receiving monotherapy drug, which is a compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate. Preferably, the mortality rate decreases by more than 2%, more preferably more than 5%, more preferably by more than 10% and most preferably more than 25%. Reducing the mortality rate of a population can be measured by any reproducible means. Reducing the mortality rate of a population may be measured, for example, by calculating the average number of deaths related to the disease per unit time after the start of treatment the active connection. Reducing the mortality rate of a population may also be measured, e.g.�measures by calculating for a population the average number of deaths related to the disease per unit time after the completion of the first cycle of therapy active connection.

Cancer treatment can lead to a decrease in the rate of tumor growth. Preferably after cancer treatment, the tumor growth rate is reduced by at least 5% compared to the rate prior to treatment; more preferably, after a cancer treatment, the tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. The rate of tumor growth can be measured by any reproducible means. The rate of tumor growth can be measured by the change in diameter of the tumor over time.

Cancer treatment can lead to reduced re-growth of the tumor. Preferably after cancer treatment, the regrowth of the tumor less than 5%; more preferably, the resumption of tumor growth less than 10%; more preferably less than 20%; more preferably less than 30%; more preferably less than 40%; more p�edocfile less than 50%; even more preferably less than 50%, most preferably the resumption of tumor growth less than 75%. The resumption of tumor growth can be measured by any reproducible means. The resumption of tumor growth can be measured by the increase in diameter of the tumor after previous reduction in size after treatment. Reducing the regrowth of a tumor is determined by the absence of the recurrence of tumors after cessation of treatment.

Therapy or prevention of disorders of cell growth can lead to a decrease in the rate of cell proliferation. Preferably, after treatment, the rate of cell proliferation is reduced by at least 5%; more preferably at least 10%; more preferably at least 20%; more preferably by at least 30%; more preferably by at least 40%; more preferably at least 50%; even more preferably less than 50%, most preferably at least 75%. The rate of cell proliferation can be measured by any reproducible means. The rate of cell proliferation can be measured, for example, by measuring the number of dividing cells in the tissue sample per unit time.

Treatment or prevention of disorders of cell growth may lead to a reduction of Ministers�tion of dividing cells. Preferably, after treatment, the proportion of dividing cells decreases by at least 5%; more preferably at least 10%; more preferably at least 20%; more preferably by at least 30%; more preferably by at least 40%; more preferably at least 50%; even more preferably by at least 50%; and most preferably at least 75%. The proportion of dividing cells can be measured by any reproducible means. Preferably the proportion of dividing cells can be measured, for example, the quantitative expression of the number of dividing cells relative to the number of dividing cells in the tissue sample. The proportion of dividing cells may be equivalent to the mitotic index.

Treatment or prevention of disorders of cell growth may lead to reductions in the size of the area or zone of cellular proliferation. Preferably, after treatment, the size of the area or zone of cellular proliferation is reduced by at least 5% in relation to the size prior to treatment; more preferably, by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; �still more preferably, reduced by at least 50%; and most preferably reduced by at least 75%. The size of the area or zone of cellular proliferation can be measured by any reproducible means. The size of the area or zone of cellular proliferation can be measured as the diameter or width of the area or zone of cellular proliferation.

Therapy or prevention of disorders of cell growth can lead to the reduction of the number or proportion of cells having an abnormal appearance or morphology. Preferably, after treatment the cells having an abnormal appearance or morphology, is reduced with respect to their size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Abnormal appearance and morphology of cells can be measured by any reproducible means. Abnormal appearance and morphology of cells can be measured by microscopy, for example when using an inverted microscope for tissue culture. Abnormal appearance and morphology of cells �can take the form of nuclear pleiomorphism.

As used here, the term "selectively" refers to the tendency of occurrence with higher frequency in one population than in other populations. Compare population may represent a cell population. Preferably, the compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate acts selectively on a cancer or precancerous cell but not on a normal cell. Preferably, the compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate acts selectively, modulating one molecular target (e.g., c-met), but not modulating largely another molecular target (e.g. protein kinase C). The invention also provides a method of selective inhibition of enzyme activity such as kinase. Preferably, the event occurs selectively in population A than population B, if it occurs two times more frequently in population A as compared to population B. an Event occurs selectively if it occurs five times more frequently in population A as compared to population B. an Event occurs selectively if it occurs more than ten times more frequently in population A than population B; more preferably, more than fifty-RA� more frequently in population A than population B; even more preferably more than 100 times more frequently in population A than population B, and most preferably more than 1000 times more frequently in population A as compared to population B. for Example, cell death can be said that it occurs selectively in cancer cells if it occurs more than twice as frequently in cancer cells compared to normal cells.

The compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate can modulate the activity of a molecular target (e.g., c-met). Modulation refers to the stimulation or inhibition of the activity of the molecular target. Preferably, the compound of the present invention modulates the activity of the molecular target by at least 2-fold compared with the activity of the molecular target under the same conditions that differ only in the presence of the compound. More preferably modulates the activity of a molecular target if it stimulates or inhibits the activity of a molecular target by at least 5 times in at least 10-fold, at least 20 times, at least 50-fold, at least 100-fold compared with the activity of the molecular target under the same conditions that differ only in the presence of the compound. Activity mol�Blarney target can be measured by any reproducible means. The activity of the molecular target can be measuredin vitroorin vivo. For example, the activity of the molecular target can be measuredin vitroby analysis of enzyme activity or DNA binding or the activity of the molecular target can be measuredin vivoanalysis to evaluate the expression of the gene.

The compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate does not significantly modulate the activity of a molecular target if the addition of the compound does not stimulate or inhibits the activity of a molecular target by more than 10% relative to the activity of the molecular target under the same conditions that differ only in the presence of a specified connection.

As used in the present description, the term "isozyme selective" means preferred the inhibition or stimulation of the first isoform of the enzyme in comparison with the second isoform of the enzyme (for example, the desired inhibition or stimulation of isozyme alpha-kinase compared with isoenzyme beta kinase). Preferably, the compound of the present invention demonstrates a minimum four-fold difference, and preferably ten-fold difference, more preferably pyatidesyatiletnie difference in the dose required to achieve the biological�quarter. Preferably, the compound of the present invention demonstrates the mentioned difference in the range of inhibition, and an example of the differences is an IC50, i.e., 50% inhibition for molecular target.

Introduction compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate in a cage or needy in this patient may result in modulation (i.e., stimulation or inhibition) of activity for the kinase.

The invention provides methods for evaluation of biological activity of the composition comprising (a) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray�'s the diffraction pattern, comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation.

In one of the ways you can use the analysis of the enzymatic activity. In one particular analysis of enzyme activity enzyme activity is a kinase. As used in the present description, "kinase" refers to a large class of enzymes that catalyze the transfer of γ-phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are directly involved in the control of various important cell functions, perhaps the most significant: signal transduction, differentiation and proliferation. It is estimated that there are approximately 2000 different protein kinases in the human body, and although each of them phosphorylates specific protein/peptide substrates, they all bind the second substrate ATP in highly cavity. About 50% of the known oncogenic products are a protein-tyrosine kinase (PTK) and it was shown that their kinase activity leads to the formation of cells. Preferably analyzed the kinase is a tyrosine kinase.

The change in enzymatic activity caused by the compounds of the present invention, can be measured in the described analyses. The change in enzymatic activity can be characterized as from�eenie phosphorylation of certain substrates. As used in this description, "phosphorylation" refers to the addition of a phosphate group to a substrate comprising proteins and organic molecules, and plays an important role in the regulation of biological activity of proteins. Preferably analyzed and measured phosphorylation involves the addition of phosphate groups to tyrosine residues. The substrate can be a peptide or a protein.

In some tests using immunological reagents, e.g., antibodies and antigens. Fluorescence can be used in the measurement of enzymatic activity in some analyses. As used in this description, "fluorescence" refers to the process in which a molecule emits a photon as a result of absorption by the molecule of the incoming photon with higher energy.

Introduction compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate into the cell or the patient who needs it, may result in modulation (i.e., stimulation or inhibition) activity of c-Met. As used in the present description, the activity of c-Met refers to any biological function or activity which is c-Met. For example, the function of c-Met includes the phosphorylation of target proteins through a cascade way. Other functions of c-Met vklyuchayuschimisya, binding adaptor protein, such as Gab-1, Grb-2, Shc, SHP2 and c-Cb1, and activation of a transmit signal such as Ras, Src, PI3K, PLC-γ, STAT, ERK1 and 2 and FAK.

Introduction compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate into the cell or the patient who needs it, may result in modulation (i.e., stimulation or inhibition) activity of ERK 1 or ERK 2 or both. As used in the present description, the activity of ERK 1 or ERK 2 refers to any biological function or activity that is of ERK 1 or ERK 2, for example, the function of ERK 1 or ERK 2 involves the phosphorylation of target proteins through a cascade paths.

Activation refers to the premises of the composition of the substance (e.g., protein or nucleic acid) in a suitable condition for the realization of the desired biological function. The composition of the substance, which can be activated, also has out-of-tolerance condition. The activated composition of matter can have inhibitory or stimulatory function or both.

The increase relates to an increase in the desired biological activity of the composition of the substance (e.g., protein or nucleic acid). Enhancement can occur by increasing the concentration of the composition of matter.

As used in this description, "path con�real point of the cell cycle" refers to a biochemical pathway, which includes modulation control points of the cell cycle. The way the control points of the cell cycle can have a stimulatory or inhibitory effect on, or both on one or several functions, including the control point of the cell cycle. The way the control points of the cell cycle includes at least two compositions of substances, preferably proteins, both of which affect the modulation path checkpoint of the cell cycle. Preferably, the path control points of the cell cycle is a biochemical signaling pathway.

As used in the present description, the controller control points of the cell cycle" refers to a composition of matter that can participate, at least partially, in the modulation of the control points of the cell cycle. The controller control points of the cell cycle can have a stimulatory or inhibitory effect on, or both on one or several functions, including the control point of the cell cycle. The controller control points of the cell cycle may be a protein or a protein.

Cancer treatment or the impairment of cell growth can lead to cell death and, preferably cell death leads to a reduction of at least 10% of the cells in the population. More preferably, the cell death leads to reduced�Yu-na of at least 20%, more preferably, reduced by at least 30%, more preferably reduced by at least 40%, more preferably reduced by at least 50%, most preferably reduced by at least 75%. The number of cells in a population can be measured by any reproducible means. The number of cells in a population can be measured by sorting fluorescence-activated cell (FACS), immunofluorescence microscopy and light microscopy. Methods of measuring cell death are such as shown in Li et al. (2003) Proc. Natl. Acad. Sci. USA. 100(5): 2674-8. In one aspect of cell death occurs by apoptosis.

Preferably an effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate does not represent a significantly cytotoxic to normal cells. A therapeutically effective amount of the compound is not a significantly cytotoxic to normal cells, if the introduction of compounds in a therapeutically effective amount does not induce cell death more than 10% of normal cells. A therapeutically effective amount of the compound does not significantly impact on the viability of normal cells, if the destination�of compounds in a therapeutically effective amount does not induce cell death more than 10% of normal cells. In one aspect of cell death occurs by apoptosis.

Contact of the cell with a compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate may cause the activation of cell death selectively in cancer cells. Introduction to a patient in need, the compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate can induce or activate cell death selectively in cancer cells. Contact of the cell with a compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate may cause the activation of cell death selectively in one or more cells affected by a disruption of cell division. Preferably, the introduction to a patient in need, the compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate can induce or activate cell death selectively in one or more cells affected by a disruption of cell division.

The present invention relates to a method of treating or preventing cancer by administering compounds of the present invention or its pharmaceutically acceptable�th salt prodrug, metabolite, polymorph or solvate to a patient in need, where the introduction of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate leads to one or more aspects of the following: accumulation of cells in Gl and/or S phase of the cell cycle, cytotoxicity via cell death in cancer cells without a significant amount of cell death in normal cells, antitumor activity in animals with a therapeutic index of at least 2, and activation of the checkpoint of the cell cycle. As used in the present description, the "therapeutic index" is the maximum dose divided by the effective dose.

The person skilled in the art can refer to a common reference texts for detailed descriptions of the known methods discussed here, or equivalent technological means. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3d ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al. , Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, to refer to when cooked�research institutes and using aspects of the present invention.

As used in the present description, "combined treatment" or "soteria" includes the introduction of compounds of the present invention and at least one second agent as part of a special treatment regimen intended to provide a beneficial effect from co-action of these therapeutic agents. A beneficial effect from co-action of these therapeutic agents include, but are not limited to those listed, pharmacokinetic or pharmacodynamic joint action that occurs due to a combination of therapeutic agents. The introduction of these therapeutic agents in combination typically is carried out within a certain time period (usually minutes, hours, days, or weeks, depending on chosen combination). "Combination therapy" may, but usually does not involve the introduction of two or more of these therapeutic agents as part of separate monotherapy regimes that are randomly and arbitrarily result in the combinations of the present invention.

"Combined treatment" is intended to encompass introduction of all these therapeutic agents sequentially, where each therapeutic agent is administered at different times, as well as administration of these therapeutic agents, or at least two of tera�efticiency means substantially simultaneously. Substantially simultaneous administration can be accomplished, for example, by introducing the patient a single capsule having a predetermined ratio of each therapeutic agent or in multiple, single capsules for each of therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be made in any acceptable manner, including, but not limited to, oral methods, intravenous methods, intravenous methods and direct absorption through mucous membrane tissues. A therapeutic agent can be entered in the same way or in different ways. For example, a first therapeutic agent of the combination can be administered intravenously by injection, while the second therapeutic agent of the combination can be administered orally. Alternatively, all therapeutic agents can be administered orally or all therapeutic agents can be administered intravenously by injection. The sequence in which therapeutic agent is administered is not narrowly critical.

"Combined treatment" also encompasses the introduction of therapeutic agents. As described above, in further combination with other biologically active ingredients and non-drug treatment.� (for example, surgery or radiation therapy). If combination therapy further comprises a non-drug treatment non-drug treatment may be performed in any reasonable time, so long as the favorable effect is achieved from the joint action of combinations of therapeutic agents and non-drug treatment. For example, in suitable cases, a positive effect is still achieved when the non-drug treatment is temporarily stopped with the introduction of therapeutic agents, possibly for days or even weeks.

The compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate can be administered in combination with a second chemotherapy agent. Second chemotherapy remedy can be Texan, an aromatase inhibitor, an anthracycline, a drug that is targeted to microtubules, the drug is a topoisomerase poison, a targeted monoclonal or polyclonal antibody, an inhibitor of a molecular target or enzyme (e.g., kinase inhibitor) or a drug analogue of cytidine. Preferably, the chemotherapy agent may be, but is not limited to those listed, tamoxifen, raloxifene, anastrozole, exemestane, letrozole, HERCEPTIN® (trastuzumab), GLEEVEC® (Katan�b), TAXOL® (paclitaxel), cyclophosphamide, lovastatin, minocin, araC, 5-fluorouracil (5-FU), methotrexate (MTX), TAXOTERE® (docetaxel), ZOLADEX® (goserelin), vincristine, vinblastine, nocodazole, teniposide, etoposide, GEMZAR® (gemcitabine), epothilone, navelbine, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin (adriamycin), epirubicin, or idarubicin. Second chemotherapy agent can be a cytokine such as G-CSF (granulocyte colony-stimulating factor). The compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate can be administered in combination with radiation therapy. The compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate can be administered in combination with standard combination chemotherapy such as, but not limited listed, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, monotext, 5-fluorouracil and prednisone).

The compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate can TSBs�'it with an inhibitor of the enzyme, such as a receptor or preceptory kinase. Receptor or preceptory kinase according to the invention are, for example, tyrosine kinase inhibitors or serotonin/threonine kinase. Inhibitors of kinases of the invention are small molecules, polynucleotide acids, proteins or antibodies.

Examples of tyrosine kinases include, but are not limited to those listed, bevacizumab (targets VEGF), BIBW 2992 (targets EGFR and Erb2), cetuximab/Erbitux (targets Erb1), imatinib/Gleevec (targets Bcr-Ab1), trastuzumab (target Erb2), gefitinib/iressa (targets EGFR), ranibizumab (targets VEGF), pegaptanib (targets VEGF), erlotinib/Tarceva, and Masha (targets Erb1), nilotinib (targets Bcr-Ab1), lapatinib (targets Erb1 or Erb2/Her2), GW-572016/lapatinib ditosylate (targets HER2/Erb2), panitumumab/vectibix (targets EGFR), Valentini target (RET/VEGFR), E7080 (multiple targets including RET and VEGFR), Herceptin (targets HER2/Erb2), PKI-166 (targets EGFR), canertinib/CI-1033 (targets EGFR), sunitinib/SU-11464/sutent (targets EGFR and FLT3), matuzumab/Emd7200 (targets EGFR), EKB-569 (targets EGFR), Zd6474 (targets EGFR and VEGFR), PKC-412 (target VEGR and FLT3), vatalanib/Ptk787/ZK222584 (target VEGR), CEP-701 (target FLT3), SU5614 (target FLT3), MLN518 (target FLT3), XL999 (target FLT3), VX-322 target (FLT3), Azd0530 (target, SRC), BMS-354825 (target, SRC), SKI-606 (target, SRC), CP-690 (target JAK), AG-490 (target JAK), WHI-P154 (target JAK), WHI-P131 (target JAK), sorafenib/Nexavar (targets RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-b, KIT, FLT-3 and RET), dasatinib/Sprycel (BCR/ABL and Src), AC-220 (Misha�and Flt3), AC-480 (targets all HER proteins, "panHER"), motesanib diphosphate (target VEGF1-3, PDGFR and c-kit), denosumab (targets RANKL, inhibits SRC), AMG888 target (HER3), and AP24534 (multiple targets including Flt3).

Examples of serine/trainingin include, but are not limited to, rapamune (targets mTOR/FRAP1), deforolimus (targets mTOR), certican/everolimus (targets mTOR/FRAP1), AP23573 (targets mTOR/FRAP1), Eryl/fasudil hydrochloride (target RHO), flavopiridol (targets CDK), seliciclib/CYC202/roscovitine (targets CDK), SNS-032/BMS-387032 (targets CDK), ruboxistaurin (targets PKC), Pkc412 (targets PKC), bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (target PI3K), VX-680 (target Aurora kinase), Azdl 152 (target Aurora kinase), Arry-142886/AZD-6244 (targets MAP/MEK), SCIO-469 (targets MAP/MEK), GW681323 (targets MAP/MEK), CC-401 (target INK), CEP-1347 (target INK) and PD 332991 (targets CDK).

Preferred combined treatment includes, but is not limited to those listed, (a) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approx�flax in the field of 8.2, The 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients, administered in combination with aranibar, (a) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by the powder x-ray diffractogram�, comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients, administered in combination with gemcitabine, and (a) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99% as determined by HPLC and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients, administered in combination with sorafenib. In certain embodiments, the subject or patient receives a combination harlot�nibali, administered in an amount of 150 mg once daily, in combination with (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, is administered in an amount of 360 mg twice daily. In other embodiments, the subject or patient receives a combination gemcitabine, administered in an amount of 1000 mg/m2intravenous injection over 30 minutes weekly, in combination with (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, is administered in an amount of 360 mg orally twice daily or 120 mg orally twice a day. In another embodiment of the subject or patient receives a combination of sorafenib, administered in an amount of 200 mg twice daily, in combination with (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, is administered in an amount of 360 mg twice daily. The preferred dosage form for (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion includes, but is not limited to those listed, capsule and tablet.

The pharmaceutical composition

The present invention also provides pharmaceutical compositions comprising (a) (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione having a chiral purity greater than 99%, as defined�but HPLC, and containing less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and a pharmaceutically effective carrier; (b) polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, to 10.8 and 14.1 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients; or (C) polymorph form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9.9 and 12 °2θ using Cu Kα radiation, and one or more pharmaceutically acceptable carriers or excipients.

"Pharmaceutical composition" is a composition, containing the compounds of the present invention in a form suitable for administration to a patient. In one embodiment of the pharmaceutical composition presents bulk or in the form of a single dosage. Form of a single dosage represents any one of a variety of forms, including, for example, a capsule, a package for intravenous infusion, a tablet, one click on inhaler or bottle. To�amounts of the active ingredient (for example, the composition described compound or its salt, hydrate, solvate or isomer) in a single dose is an effective amount and varies according to the specific treatment. Specialist in the art will understand that sometimes it is necessary to do the routine to change the dose, depending on age and condition of the patient. The dose will also depend on the method of administration. Assume a variety of ways, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, subdermal, intranasal, etc. the dosage Form for local or percutaneous introduction of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and sprays. In one embodiment, the implementation of the active component is mixed under sterile conditions with a pharmaceutically suitable carrier, and with any required preservatives, buffers or propellants.

As used in the present description, the phrase "pharmaceutically acceptable" refers to those components, materials, compositions, carriers, and/or dosage forms which are in the scope of the results of a thorough medical evaluation is suitable for use in contact with tissues of a person�human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with an acceptable ratio of benefit/risk.

"Pharmaceutically acceptable excipient" means excipient, which is used in obtaining pharmaceutical compositions, which in General is a safe, non-toxic and neither biologically nor otherwise non-spam, and includes excipient, which are suitable for veterinary use as well as for pharmaceutical human use. "Pharmaceutically acceptable excipient", as used in the specification and claims includes both one and more such excipients.

The pharmaceutical composition of the present invention is formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, subcutaneous), oral (e.g., inhalation), transdermal (topical) and crosslisted introduction. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; Antibac�realnye agents, such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the achievement of tonicity such as sodium chloride or dextrose. the pH can be set when using acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral drug may be in ampoules, disposable syringes or in vials with multiple doses, made of glass or plastic.

The compound or pharmaceutical composition according to the invention can be administered to the patient when using a large number of well-known methods currently used for chemotherapy. For example, to treat various types of cancer, the compound of the invention can be injected directly into tumors, injected into the bloodstream or a body cavity, or administered orally or applied to the skin using patches. The selected dose should be sufficient to ensure that the treatment was effective, but not so high as to cause unacceptable side effects the State of disease (e.g., cancer, precancer, etc) and the health of the patient should preferably carefully monitored for a sufficient period after Le�termination.

The term "therapeutically effective amount", as used in the present description, refers to the amount of pharmaceutical agent to treat, alleviate or prevent a specific disease or condition, or for the demonstration of defined therapeutic or inhibitory effect. The action may be determined by any analytical method known in this field. The precise effective amount for a patient will depend on body mass, size and health of the patient; the nature and extent of the condition; and therapeutics or combination of therapeutics selected for administration. A therapeutically effective amount for a particular situation can be determined by routine experiment, which is included in the competency and discretion of the Clinician. In a preferred aspect, the disease or condition being treated is a cancer. In another aspect, the disease or condition susceptible to treatment constitutes a violation of cell proliferation.

For any connection a therapeutically effective amount can be estimated initially either in cell culture assays, such as cell neoplasms, either in animal models, usually rats, mice, rabbits, dogs or pigs. The animal model can also be used�Ana to determine an appropriate concentration range and route of administration. Such information can then be used to determine an appropriate doses and routes of administration to man. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50(effective therapeutic dose for 50% of the population) and LD50(lethal dose for 50% of the population). The dose ratio between toxic and therapeutic effect is a therapeutic index and can be expressed as the ratio LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary in this ratio depending on the dosage form, the sensitivity of the patient and the method of administration.

The dose and the introduction of a set to ensure sufficient concentrations of the active(s) agent(s) or to maintain the desired effect. Factors that could be taken into account include the danger of the disease state, General health of the patient, age, weight and sex of the patient, diet, time and frequency of administration, drug(s) combination(s), reaction sensitivities, tolerance/response to therapy. Existing for a long time, the pharmaceutical�ski compositions can be administered daily, every 3 to 4 days, every week or once every two weeks depending on half-life and rate and renal clearance of a particular composition.

Pharmaceutical compositions containing the active compounds of the present invention can be manufactured by well known method, for example, using the methods of conventional mixing, dissolving, granulating, production drops, grinding into powder, emulsifying, encapsulating, enable, or lyophilization. Pharmaceutical compositions can be manufactured by well known manner using one or more pharmaceutically acceptable carriers, including excipients and/or additives which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Of course, suitable formulations depend on the selected method of administration.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the preparation of a sterile solution or injection for immediate introduction. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N. J.) or a physiological solution with phosphate buffer (PBS). In all cases, the composition d�should be sterile and should be fluid to the extent that to allow easy injection through a syringe needle. It must be stable under conditions of manufacture and storage and must be protected from contaminating action of microorganisms, such as bacteria and fungi. The medium should be a solvent or medium for the dispersion containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol and the like) and suitable mixtures thereof. Can be supported by a proper liquid state, for example, through the use of a coating such as lecithin, by maintaining a particle size in the case of dispersion and by using surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases it will be preferable to include in the composition isotonic agents, for example, sugars, property, such as mannitol, sorbitol and/or sodium hydroxide. Prolonged absorption of injectable compositions can be made by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active connection strings required amount of suitable solvent with one or a combination of ingredients, listed above, if required, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium for the dispersion and the required other ingredients from those listed above. In the case of sterile powders for obtaining sterile solutions for injection, methods of preparation are dried under vacuum and lyophilization, which lead to the powder of the active ingredient and, in addition, any additional desired ingredient from their prior solution, sterilized by filtration.

Oral compositions generally include an inert diluent or edible pharmaceutically acceptable carriers. They may be enclosed in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, the active compound can be administered with excipients and used in the form of tablets, lozenges or capsules. Oral compositions can also be obtained using a fluid carrier for use as a mouthwash, where the compound in the liquid carrier is applied orally and rinse my mouth and spit out or swallow. Pharmaceutically applicable binders and/or auxiliary materials can be included�s as part of the composition. Pills, pills, capsules, pastilles, etc., may contain any of the following ingredients or components of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch, pregelatinized starch or lactose, dezintegriruetsja agent, such as sodium croscarmellose, sodium-chromalveolata, alginic acid, primogel, polyplasdone or corn starch; a lubricant such as magnesium stearate, stearic acid, sodium fumarate or Sterotes; glidants, such as colloidal silicon dioxide; a sweetener, such as sucrose or saccharin; or flavoring, such as peppermint, methyl salicylate or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressurized container or dispenser that contains a suitable displacing gas, for example, hydrofluroalkane, chlorofluorocarbons, carbon dioxide, or a nebulizer.

Systemic administration can also be effected crosslisted or percutaneous. For crosslisted or percutaneous introduction into the composition of the used penetrating materials suitable for the barrier, through which it is entering. Such penetrating substances commonly known in the art, for example, for crosslists the introduction, detergen�s, bile salts and derivatives of fusicology acid. Crosslist introduction can be carried out through the use of nasal sprays or suppositories. For percutaneous introduction of the active components are in the form of ointments, salves, gels, or creams as generally known in the art.

The active compounds can be obtained with pharmaceutically acceptable carriers that will protect the compound against rapid withdrawal of the body, such as controlled release formulations, including implants and microencapsulated system of delivery. Can be used biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycol acid, collagen, complex polyarteritis, polylactic acid, or mixtures thereof, or copolymers or polyesters. Methods for obtaining such compositions will be obvious to a person skilled in the art. Substances may also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. As pharmaceutically acceptable carriers may also be used of a suspension of liposomes (including liposomes, targets are virus-infected cells with monoclonal antibodies to viral angiogram). They can be obtained according to methods known to experts in this field, for example, as described� in U.S. patent No. 4522811.

In particular, it is preferable to formulate oral or parenteral compositions in a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form, as used in the present description, refers to physically discrete units suitable for single doses for the treatment of patients; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect and the required pharmaceutical carrier. Specification standard dosage forms of the invention are directed directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the invention vary depending on, among other factors that affect the choice of dose, the means of age, weight and clinical condition of the patient to be treated, as well as experience and address the clinical or practical physician prescribing the treatment. Usually, the dose should be sufficient to cause the slowdown and preferably regression, tumor growth, and also, preferably, causing complete regression of the cancer. Dosage m�may be in the range from about 0.1 mg/kg / day to about 5000 mg/kg / day. In preferred aspects, the dosage can range from about 1 mg/kg / day to about 1000 mg/kg / day. In one aspect, the dose will range from about 0.1 mg/day to about 50 g/day; from about 0.1 mg/day to about 25 g/day; from about 0.1 mg/day to about 10 g/day; from about 0.1 mg/day to about 3 g/day or from about 0.1 mg/day to about 1 g/day, in single, divided or continuous doses (this dose can be adjusted to the patient's weight in kg by the square of body surface per m2and age in years). In preferred applications, the dosage may be about 400 milligrams twice daily (b.i.(d.). In actual applications, the dosage is 360 milligrams (mg) twice daily (b.i.(d.). More preferably, the dosage form is a capsule or tablet and is administered as two or three capsules or tablets with a combined dose of 360 milligrams (mg). This dosage form is injected twice daily with a total dose of 720 milligrams (mg). An effective amount of a pharmaceutical means represents that which provides an objectively established improvement, as seen clinical doctor or other qualified observer. For example, tumor regression in a patient can be measured with reference to the diameter of the tumor. Reducing the diameter �tumor indicates regression. The regression also indicates the inability of the tumor to recur after treatment. As used in the present description, the term "effective dose" refers to the amount of active compound to achieve the desired biological effect on the patient or a cell.

Pharmaceutical compositions may be enclosed in a container, pack, or dispenser together with instructions for administration.

Compounds of the present invention is capable of further forming salts. All of these forms are also assumed to be in the scope of the claimed invention.

As used in the present description, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present invention, where the original connection is modified by the receipt of an acidic or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include traditional non-toxic salts or the Quaternary ammonium salts of the parent compound, obtained, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts on�of despair, but are not limited to, salts derived from inorganic or organic acids selected from 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, a mixture of Benzenesulfonic, benzoic, bicarbonate, carbonic, citric, ethylenediaminetetraacetic, ethicolegal, 1,2-econsultancy, fumaric, glucoheptonate, gluconic, glutamic, glycolic, glycosylations, hexylresorcinol, gerbanova, Hydrobromic, hydrochloric, itestosterone, hydroxymaleimide, hydroxynaphthoic, italianboy, dairy, lactobionate, laurylsulfate, maleic, malic, mandelic, methanesulfonic, naftilos, nitric, oxalic, pambou, Pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, peracetic, succinic, sulfamic, sulfanilate, sulfuric, tannic, tartaric, toluensulfonate and usually occurring amino acids, e.g. glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentylpropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic�hydrothermal acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, 3-phenylpropionate acid, pivalic acid, tert-butylalcohol acid, Mukanova acid, etc. the Present invention also covers salts formed when an acidic proton present in the parent compound, or replaced with a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

It should be understood that all references to pharmaceutically acceptable salts include attach form solvent (solvate) or crystal forms (polymorphs) as defined herein, of the same salt.

Compounds of the present invention can also be obtained in the form of esters, for example pharmaceutically acceptable esters. For example, a functional group of carboxylic acid in the compound can be converted to its corresponding ester, for example methyl, ethyl or other ester. Also alcohol group in the compound may be converted to its corresponding ester, e.g., acetate, propionate or other ester.

Compounds of the present invention can also be obtained in the form of a prodrug, for example, pharmaceutically acceptable price�acceptable prodrug. The terms "Pro-drug" and "prodrug" are used here interchangeably and refer to any compound which releases an active source drugin vivo.Since it is known that the prodrug enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can be delivered in prodrug form. Thus, the invention aims to provide a prodrug claimed in the present compounds, methods of delivery specified prodrug and compositions containing them. "Prodrug" is supposed to include any covalently associated media that original release of the active medicament according to the present inventionin vivowhen such prodrug is administered to the patient. The prodrug of the present invention is obtained by modification of functional groups present in the compound in such a way that the modifications are cleaved or during routine manipulations, orin vivoto the original connection. Prodrugs include compounds of the present invention, in which the hydroxyl, amino, sulfhydryl, carboxy or carbonyl group is associated with any group that can tmeplatesin vivoto form shapes that do not contain hydroxyl, aminor�foam, sulfhydryl, carboxylate or carbonyl group, respectively.

Examples of the prodrug include, but are not limited to, esters (e.g., acetate derivatives, dialkylaminoalkyl, hydroxy, phosphates, sulfates and benzoate) and carbamates (e.g., Ν,Ν-dimethylaminoethyl) of hydroxy functional groups, esters (e.g. ethyl esters, morpholinoethyl esters) carbonyl functional groups, N-acylphosphate (e.g. N-acetyl) N-Mannich bases, Chiffony the grounds and enaminone amidofunctional groups, oximes, acetals, katali and enologia esters of ketone and aldehyde functional groups in compounds according to the invention, etc., see Bundegaard, H., Design of Prodrugs, p.1-92, Elesevier, New York-Oxford (1985).

Compounds or their pharmaceutically acceptable salts, esters or prodrug is administered orally, nasally, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, subdural and parenteral. In one embodiment, the implementation of the compound is administered orally. Specialist in the art will understand the benefits of certain techniques.

Admission scheme, using the connection that is selected in accordance with a variety of factors, including t�p, species, age, weight, sex and medical condition of the patient; the severity of the condition, which is subjected to treatment, method of administration, the renal and hepatic function of the patient, the specific compound or its salt. One of ordinary skill of the physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, confront or stop the progression of the condition.

Technological methods of preparation and administration of the described compounds according to the invention can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In one embodiment of the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. Connections will be presented in such pharmaceutically acceptable compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

All percentages and ratios used herein, unless otherwise indicated, presented by mass.

Other features and advantages of the present invention �onati from various examples. These examples illustrate the various components and the methodology used in the practice of the present invention. The examples do not limit the claimed invention. Based on the description of the person skilled in the art can determine and apply the other components and the methodology used in the practice of the present invention.

EXAMPLES

Example 1

The present example describes the obtaining of 3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Linolein [CAS 102280-97-7] (70 kg) (Connect 4in scheme I) was charged to a properly cleaned and dry reaction vessel was then added and methyl tert-butyl ether (MTBE) (375 kg). Laodicean can be commercially purchased or made, as described in published patent application U.S. No. 2006/0223760. The batch was stirred for at least 10 minutes at 15-25°C. In a separate vessel obtained the solution of oxalicacid (56,6 kg) in MTBE (370 kg). The solution linolein was then added to a solution of oxalicacid at such a rate to maintain the temperature below 32°C. the Vessel was washed with additional MTBE (162 kg) was added to the reaction mixture. The batch was stirred at 15-25°C for a minimum of two hours before HPLC analysis. When the reaction was considered completed, there was added methanol (90 kg) and the party p�remedial for at least two hours. When determined the completion of the reaction by HPLC, the batch was distilled to about 80 gallons. It was not necessary to allocate an intermediate product, methyl ester 5,6-dihydro-4H-imidazo[3,2,1-ij] quinolin-l-yl) oxoacetate acid (Connection 5in Scheme I). To the batch was added tetrahydrofuran (THF) (840 kg) and again reduced the volume by distillation up to about 80 gallons. The method of replacement of the solvent is continued until the number of MTBE present in the party, less than 1% of the mass. The new vessel was loaded with indole-3-acetamide [CAS 879-37-8] (61.3 kg) (Compound 5ain Scheme I) and then THF (840 kg). The resulting solution was then loaded into a party at such a rate that the temperature was maintained at 15-25°C. the Vessel containing a solution of indole-3-acetamide was washed with THF (140 kg) and the rinse was added to the party. An empty vessel then loaded with a solution of tert-butoxide potassium (1.6 M in THF, 581 kg) and THF (350 kg). The solution is also added to the batch and the resulting solution was stirred at 20-32°C for a minimum of three hours. When the starting material was consumed, as was confirmed by HPLC analysis, was added aqueous HCl (conc., 273 kg) at such a rate that the temperature was maintained below 50°C. the Batch was stirred at 40-50°C for at least 30 minutes.

After it was determined the completion of the reaction by HPLC anal�for, was added an aqueous solution of ammonium hydroxide (conc.), while maintaining the reaction temperature below 40°C until the pH of the mixture does not become 9-10. After addition of ethyl acetate (EtOAc) (462 kg) and mixing party the layers were separated. The organic layer was washed with brine (182 kg NaCl and 1022 kg of water). The resulting organic solution was distilled to about one-third the original volume. Was added ethanol (2B, 1120 kg) and continued distillation to reduce the volume of the batch to about 240 gallons. Again was added ethanol (2B, 1120 kg) and the volume reduced to 240 gallons. Was then added water (1400 kg) to the party to cause precipitation of the product. The batch was stirred for a minimum of two hours and the solids were isolated by filtration. The solids were then taken dichloromethane (DCM) (840 kg) and heptane was added (442 kg) for a cleaning product. After stirring of the party for two hours the product was isolated by filtration. After conditioning on the filter was obtained approximately 115 kg (88%) of 3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Compound 6in Scheme (I) as a red powder. This transformation4inCompound 6shown in Scheme II.

Example 2

The present example describes preparation of (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-ind�l-3-yl)pyrrolidin-2,5-dione.

The palladium hydroxide (20 wt%. Pd-on-carbon, 11.5 kg) was charged to a properly prepared reaction vessel. Was added THF (340 kg) to form a slurry and the catalyst was pre-reduced with hydrogen (50-75 psi).Compound 6(115 kg) were loaded into an empty vessel and loading THF (353 kg). The resulting mixture was stirred until complete dissolution. A solution ofCompounds 6then transferred into a slurry catalyst. Loaded into the empty reactor a solution of tert-butoxide sodium (1.6 M in THF, 36 kg) with subsequent loading THF (21 kg). This resulting solution is also transferred to the reaction mixture, followed by additional washing with THF (340 kg). The batch is then heated to 45-55°C at 65-80 psi of hydrogen. There is no need to allocate intermediate CIS-racemate (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connection 7in Scheme I).

After determining the completion of the reaction by HPLC analysis of the batch was filtered through celite to remove the catalyst and was diluted with isopropylacetate (iPrOAc) (810 kg). The organic solution was washed with aqueous HCl (28 kg conc. HCl, 290 kg of water). This method was repeated a second time. The organic solution is then washed with brine (580 kg) before concentration to about 300 gallons of distilled. AddediPrOAc (1690 kg) and partee� was distilled to about 400 gallons. Method of distillation was repeated by addingiPrOAc (1000 kg), while the content of THF does not become <2% of the mass. solution. Heptane (2000 kg) was then added to induce precipitation of the product. The crude (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Compound 8in Scheme I) was isolated by filtration and was kondicionirovanie with getting 111 kg (95%) with HPLC purity ~96%. This material also contained 1.7% ofiPrOAc and 6.3% heptane. This material was confirmed by laboratory scale usage as having sufficient purity for use in the preparation of (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dietilamina (DCM) and resolution multicanonical chromatography (MCC) or for direct use in crystallization diastereomeric salt, as described in more detail in the following examples.

Example 3

The present example describes preparation of (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion DCM.

It is preferable to carry out chemical cleaningCompounds 8by obtaining crystalline (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion DCM (Compound 8 DCMin Scheme (I) before the resolution of enantiomers using MCC.

In one example, in the reaction vessel was loaded with methanol (125 kg) andCompound 8(52,5 kg) and the mixture was heated to 55-65°C. In a clean reactor was loaded with DCM (557 kg). A solution ofCompounds 8then transferred to the reactor containing DCM via a built-in filter. The reactor was washed with DCM (134 kg) which is also transferred through the filter into the reactor containing the reaction mixture. The batch was stirred for at least 30 minutes before you entered the seedCompound 8 DCM(0.1 kg). The batch was stirred for at least four hours and then took the sample to assess the degree of crystallization. If the concentration in the filtrate ofCompound 8 DCMwas below 65 mg/ml, was added heptane (718 kg) and the batch was stirred for at least one hour. The batch was then cooled to 0-5°C and the product was isolated by filtration. The solids were kondicionirovanie on the filter and dried under vacuum in a vacuum shelf drier at 45-55°C for at least four hours. AllocatedCompound 8 DCM(48,3 kg, 92%, HPLC 99,0%) in the form of a solid reddish-brown color. The transformation ofCompounds 6inCompound 8 DCMdescribed in examples 2 and 3, shown in Scheme III.

Example 4

The present example describes the chiral resolution of (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-�the Ndola-3-yl)pyrrolidin-2,5-Dion DCM using MCC and isolation of (-)- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Downloadable solution for multicoloring chromatography (MCC) was prepared by dissolvingCompound 8 DCMin methanol. The resulting Aristotel DCM/MeOH was subjected to distillation until the residual DCM concentration in the loading solution is not reached a sufficient level, suitable for contact with a chiral stationary phase (CSP), i.e. <0.1% of the mass. The batch was diluted in a mixture of methanol/acetonitrile (9:1) to a concentration of 50 mg/ml and injected in the chromatographic system. Can be used Chiralpak AZ (CSP). Monitored the purified product by chiral HPLC analysis and regulated settings chromatography to obtain >99% chiral purity of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connection 10in Scheme I). The purified product were pooled and concentrated as you progress through the division. Assembled the purified product was placed in a large reactor, and reduced the volume. Then was isolated by crystallizationConnection 10.

Example 5

The present example describes the periodic generation of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione of the unwanted enantiomer (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

In some cases, such as when resolution is achieved by the use of MCC, it is desirable to periodically allocate and racemethionine undesired enantiomer, (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (Connection 9in Scheme I).

In one example of method of obtaining the crudeCompounds 8selectedConnection 9the desired enantiomer (of 6.46 kg) was charged to a 100-l reactor. Loaded ethanol (60 l) followed by the addition of solid NaOH (1.05 kg, 1.5 EQ.). The resulting suspension was heated to 65°C for 13 hours and then allowed to cool to ambient temperature for 4 hours. The mixture was sampled and analyzed by chiral HPLC, showing the ratio of enantiomers 54/46. Chemical purity was determined to 94.6% (AUC) by HPLC. The suspension is then clarified by filtration through celite and the collected substance was washed with ethanol (13 l). The material then was removed was a brown film solids, without coarse fragments. The solution was then charged into a 100-l reactor was added 2 M HCl (13,1 l, 1.5 EQ.) within 35 minutes. During the addition of formed a thin suspension. The mixture was then stirred at room temperature (after 5 hours was obtained a thick orange suspension). Was then added water (25 l) for 45 minutes and the mixture AC�stirred for 2 hours. An aliquot was removed and filtered. The batch was then heated to 60°C and stirred for 8 hours and then allowed to cool slowly to improve the filtration properties of solids. Was allocated untreatedCompound 8[5,12 kg, 75,7% (calculated based on 4.5% of the mass. EtOH)] with a chemical purity 99,39% (AUC) according to HPLC. In this case, the cleanliness was sufficient to further process the material MCC. If necessary, the purity can be improved through the formation of DCM.

Chiral resolution ofCompound 8 DCMCompounds 10,described in Example 4, and recycling ofConnection 9inCompound 8described in Example 5, shown in Scheme IV.

Example 6

The present example describes chiral resolution through education diastereomeric salt and excretion of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Alternatively, chiral resolution of MLS, resolution of enantiomers,Connections 10andConnection 9also can be achieved by preferred education diastereomeric saltConnections 10.

In one example of untreatedCompound 8can be converted into (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine (Link� 10·(1S,2S)-(+)-pseudoephedrine in Scheme (I) using the following representative procedure. (1S,2S)-(+)-pseudoephedrine, (601 g, 0.6 EQ.) was dissolved in acetonitrile (CH3CN) (11,2 l, 5 vol.) at about 50°C and stirred for about 30 minutes after dilution. UntreatedCompound 8[2,24 kg, 96,4% (AUC) by HPLC] was dissolved in CH3CN (11,2 l, 5 vol.) at about 50°C and then clarified by filtration through a layer of celite. A solution ofCompounds 8added drops of upside-down tank to a solution of (1S,2S)-(+)-pseudoephedrine for 20-30 minutes at about 50°C. After the resulting solution began to crystallize immediately after completion of the additionCompounds 8the mixture was stirred until it was slowly cooled down to ambient temperature, then the stirring was continued over night (approximately 11 h General cooling and agitation). The granular solids beige was filtered through an 18" suction filter made of stainless steel and washed, re-suspended when using CH3CN (7 l, 3,2). The suspension was filtered and the solid is again suspended CH3CN (5 l, 2,3.). After drying on the suction filter for 1 hour, the sample was analyzed by HPLC. If the solids contained more than the possible number of unwanted diastereoisomeric salt, solids could be re-suspended and when�using CH 3CN and dried before re-analysis. Solids were then dried under a hot N2(51°C) over night. Usually the analysis ofConnection 10·(1S,2S)-(+)-pseudoephedrineshows the total chemical purity >99% (AUC) by HPLC and chiral purity >99%Connections 10.When using1H NMR analysis estimated that a typical sample contained <0.5% by weight. CH3CN.

Connection 10·(1S,2S)-(+)-pseudoephedrinecan then be converted intoConnection 10by treatment with acid and crystallization from methanol or ethanol. A representative procedure is the following:Connection 10·(1S,2S)-(+)-pseudoephedrine(50 g) is suspended in methyltetrahydrofuran (Methf, MeTHF) (500 ml) and water (250 ml). 1 M HCl (110 ml) was added to the mixture to achieve a final pH of 1.6. The resulting solution with a small amount of solids was stirred for about one hour to dissolve the solids. Organic and aqueous layers were washed with a solution of water/brine (1:1, 250 ml), separated, and add 2-B ethanol (1000 ml). The solution was then concentrated to 200 ml and analyze the content of Methf (4.8% masses.). The solution is then clarified by filtration and added the seedConnections 10(0.2 g) (T=25°C). The mixture is stirred for about three days with periodically taken and analyzed samples on remaining in the mother liquorWith�unity 10 . The resulting mixture was filtered and the solids washed with 2-B ethanol (70 ml). The solids are dried for about three hours in a vacuum oven at about 60°C with obtainingConnections 10[28,84 g, 82.7% of that of 99.60% (AUC) according to HPLC, was 0.54% of the mass. ethanol, of 0.08% of the mass. Methf] in the form of a beige solid.

Diastereomers permissionCompounds 8inConnection 10described in example 6, and the recycling ofConnection 9inCompound 8described in Example 5 and shown in Scheme V.

Example 7

The present example describes chiral separation using dynamic kinetic resolution (DKR).

Alternatively, chiral resolution using MCC or traditional kinetic resolution through education diastereomeric salt, you can also achieve dynamic kinetic resolution (DKR) enantiomersConnections 10andConnection 9due to the preemptive education diastereomeric saltConnections 10with simultaneous ratemyareain situConnection 9.

In this method, the crudeCompound 8can be turned intoConnection·(1S,2S)-(+)-pseudoephedrinewhen using the following representative procedure. UntreatedCompound 8(1.25 kg, 96% AUC, or 9.1% of the mass. the solvent content) and (1S,2S)-(+)-pseudoephedrine (559 g, 1,0 �sq) were transferred to a suspension of 2B-ethanol (11,25 l, 9 vol.) and heated to 50°C for 3 hours. The suspension was treated with 21% of the mass. NaOEt in methanol or ethanol (110 g, 0.1 EQ.) and heated to 50°C. After 40 hours, the mixture was quenched by adding 1 M HCl (338 ml, 0.1 EQ.) in water (786 ml, -10% with respect to ethanol) for 5 minutes. The mixture was stirred at 50°C for 1 hour and then allowed to cool to ambient temperature for 0.5 hours. The suspension was stirred at room temperature for another 3 hours and then filtered. The solids were washed with 10% water/2B-ethanol (3,75 l, 3 vol.) and dried in a vacuum oven (50°C, 2 tray) for 18 hours. The solids were analyzed and showed thatConnection 10·(1S,2S)- (+)-pseudoephedrine[1,22 kg, 74%, 99,3% (AUC) according to WEIHS, 99,2% (AUC) according to chiral HPLC]. This method was carried out on 20 kg ofCompounds 8to getConnection 10·(1S,2S)-(+)-pseudoephedrine[18,9 kg, 70%, 98,8% (AUC) according to HPLC, of 99.1% (AUC) according to chiral HPLC].

Dynamic kinetic resolution ofCompounds 8inConnection 10throughConnection 10·(1S,2S)-(+)-pseudoephedrineshown in Scheme VI.

Example 8

The present example describes chiral separation using dynamic kineticheskoe resolution (DKR).

Alternatively, chiral resolution using MCC or traditional kinetic resolution put�m education diastereomeric salt can also achieve dynamic kinetic resolution (DKR) enantiomers Connections 10andConnection 9due to the preemptive education diastereomeric saltConnections 10with simultaneous ratemyareain situConnection 9.

In this method, the crudeCompound 8(To 111.4 kg), Pd absorbing resin (PL-TMT-MP, 3.5 kg) and methanol (1507 l) were added to a container and heated to 45°C for at least 16 hours. After completion of the reaction the mixture was filtered to remove the Pd absorption resin. The container was washed with methanol (104 l). The combined filtrate was distilled to ~600 L.(1S,2S)-(+)-pseudoephedrine (51,4 kg) and methanol (416 l) was added to the filtrate. The resulting solution was heated at 45°C for 3-4 hours. Solids were precipitated and analyzed by HPLC to ensure that the reaction proceeded selectively. Then was added a solution of sodium methoxide in methanol (21% wt., 6.1 kg) followed by the addition of methanol (11 l) and the mixture was heated at 45°C for an additional 18 hours. The reaction mixture was analyzed by HPLC for completion of crystallization. After completion of the crystallization, the reaction mixture was treated with HCl solution (3.5 kg) to neutralize the base. The resulting mixture was cooled to ambient temperature and was stirred for at least 3 hours. The solids were then isolated by filtration and the residue on the filter was washed with a solution of methanol and water (l to 46 l, respectively). The residue on the filter was colorless (if the solids remained significant color, repeated washing to remove the color). The solids were dried in a desiccant filter at 55°C under vacuum for at least 8 hours and released for use at the next stage in the form ofConnections 10·(1S,2S)-(+)-pseudoephedrine(101 kg).

Example 9

The present example describes a method of producing slurry to obtain (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione

MixedConnection 10·(1S,2S)-(+)-pseudoephedrine(100,7 kg) and a solution of aqueous HCl (1M, 250 kg) and methanol (240 kg) and the resulting suspension was heated to 50°C and was stirred for at least 2 hours. Upon completion of the reaction, the mixture was cooled to ambient temperature and stirred for at least 1 hour. The solids were isolated by filtration, washed with 50% aqueous MeOH solution (200 l) and dried under vacuum at 65°C for at least 6 hours. UntreatedConnection 10was dissolved in THF (96 kg) by heating the mixture to 50°C. the resulting solution was clarified by filtration followed by the addition of methanol (200 kg). The solution is then concentrated azeotropic and at atmospheric pressure by distillation to decrease the content of THF. When the solution volume was reduced to 50 l, was added methanol (200 l) and repeated method of concentration. This method was repeated until the THF content was reduced to less than 5% (about./vol.). During the addition of methanol also introduced one Il a few crystals ofConnections 10(300 g) to facilitate crystallization. The crystals were isolated by filtration, washed with additional 50% aqueous methanol and dried under vacuum at 65°C for at least 12 hours. UntreatedConnection 10(60,6 kg) were allocated in the form of a red-brown solid substance.

Example 10

The present example describes a method of producing the suspension to obtain the polymorph form 1 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo [3,2,1-ij] quinolin-1-yl)-4-(lH-indol-3-yl)pyrrolidin-2,5-dione

UntreatedConnection 10received as described in Example 9. UntreatedConnection 10was dissolved in THF (96 kg) by heating the mixture to 50°C. the resulting solution was clarified by filtration followed by the addition of methanol (200 kg) and the Form 1Connections 10in the form of priming for polymorphic control method of crystallization. Priming for polymorphic control were selected from representative batches in which the characteristic data confirmed that the crystalline material was a desired polymorphic form. The solution was then concentrated and atmospheric azeotropic Yes�made by distillation to reduce the content of THF. Once the solution volume was reduced to 250 liters, was added methanol (200 l) and the method of concentration was repeated. This method was repeated until the THF content was reduced to less than 5% (about./vol.). Then the temperature of the solution was reduced to 50°C and was stirred for at least 4 hours. Aliquots were taken to confirm the formation of the desired polymorph. If necessary, the polymorph can be dissolved in THF (30% of the lot size), clarified by filtration, concentrated and can be made the seed to produce the desired polymorph. Upon receipt of the desired polymorph is added a solution of 50% aqueous methanol at 50°C and the solution was stirred for an additional 2-3 hours. The solution is then cooled to ambient temperature and left to stand for at least 2 hours for crystallization. Upon completion, the crystals were isolated by filtration, washed with additional 50% aqueous methanol and dried under vacuum at 65°C for at least 12 hours. Polymorph Form 1Connections 10(60,6 kg) were allocated in the form of a red-brown solid substance.

Polymorph Form 2 of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione may also be obtained as described above, if the seed crystals of Form 1 replace with seed crystals of Form 2.

Example 11/p>

Example 11 describes a method of generating XRPD x-ray patterns of the polymorphs of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Powder x-ray diffraction pattern was obtained on a Siemens D5000 diffractometer using Cu Kα radiation (40 kV, 40 mA), θ-θ goniometer, divergence of V20 and returns slits, a graphite secondary monochromator and scintillation counter. Performance of the instrument was checked using certified standard corundum (NIST 1976). The software used for data collection was a Diffrac Plus XRD Commander v2.3.1, and the data were analyzed and presented using Diffrac Plus EVA v 11,0.0.2 or v 13.0.0.2.

Powder samples were obtained as samples of flat plates. Approximately 35 mg of sample was gently Packed in a slotted cavity polished with zero background intensity (510) silicon wafer. During analysis, the sample was rotated in its plane. Details of data collection the following:

Angular range: 2 to 42 °2θ

Stride length is: 0.05 °2θ

Data collection time: 4 s/step

Example 12

Example 12 describes a method of generating XRPD x-ray patterns of the polymorphs of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Powder x-ray diffraction, high-resolution Paul�Chali on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), θ-2θ goniometer, divergence V4 and receiving slits, a Ge-monochromator and a Lynxeye detector. Performance of the instrument was checked using certified standard corundum (NIST 1976). The software used for data collection was a Diffrac Plus XRD Commander v2.5.0, and the data were analyzed and presented using DiffracPlusEVA v 11,0.0.2 or v 13.0.0.2.

The samples were driven under the conditions of the environment in the form of samples of flat plates when using powder in the same condition as it was received. Approximately 100 mg of sample was gently Packed into the annular cavity cut into polished, zero-background intensity (510) silicon wafer. During analysis, the sample was rotated in its own plane. Details of data collection the following General procedure:

Angular range: 2 to 42 °2θ

Stride length is: 0.05 °2θ

Data collection time: 5 sec/step

Example 13

Example 13 describes XRPD x-ray patterns of the polymorphs of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

Two resolutiony polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione: Form 1 and Form 2 (see Fig.12 and 13).

Form 1 shows the XRPD diffraction pattern comprising 2θ values in degrees of 8.2, to 10.8 and 14.1 (see Fig.12 and Table 1).

�Orme 2 shows the XRPD diffraction pattern, comprising 2θ values in degrees of 6.5, 9.9 and 12.0 V. (see Fig.13 and Table 1).

6,608
Table 1
Form 18,210,814,1JustForm 26,59,912,0Just
AreaAreaAreaAreaAreaAreaAreaArea
13,92514,086,64624,65116,433Is at 5,28410,4022,117
23,86613,9824,45426,4375,365Is 10.5122,312
33,84714,036,62524,50236,5045,34110,4922,335
43,88013,996,55624,42646,4675,32110,4422,228
53,889For 13.886,61924,38856,4845,33110,5022,315
63,85413,926,58624,360 66,5025,281To 10.3822,163
average3,8814,06,6124,464average6,47Of 5.32Of 10.4522,245
Residual standard deviation (RSD(%))0,730,520,480,43Residual standard deviation (RSD(%))0,000,000,010,02

Example 14

Form 1 is a more thermodynamically stable than Form 2, as determined in experiments by mutual transformation. Form 1 pre�provide an orthorhombic and contains four molecules of (-)- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione in the elementary cell. Form 1 has a melting point of ~218°C, documented in DSC (see Fig.16) experiments.

Form 2 is a birefringent starinavity crystal. No pronounced changes in the crystal form or the purity was not noted during the storage of numerous parties Form 2 at 40°C/75% humidity for a period of time up to six months and at 25°C/60% humidity within the time of up to 12 months. Space group form 2 was a or P21or P2: there are two molecules of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion on unit cell (one molecule in the asymmetric cell), and there is no excess volume in the unit cell, which is a molecule of solvent. Form 2 has a melting point at ~216°C, documented in DSC (see Fig.16).

When scaling of obtainingConnections 10to >5 kg as a single party spontaneously dropped Form 1. Infrared (IR) x-ray powder diffraction (XRPD) was determined to be an effective analytical tools for identification and distinction of these two forms (see Fig.14 and 15). The method was easy to control through priming, as shown in the scale of 7 kg.

Two polymorph can�about vzaimoprevrascheny, if the control method of crystallization using the correct terms. Form 2 can be obtained by dissolution of Form 1 in methanol, priming of Form 2 and evaporating the mixture to dryness with rotary evaporation. Successful transformation was identified as Form 2 by IR analysis and confirmed by XRPD analysis.

Example 15

The IR spectrum of Form 1 demonstrates intense vibration centered at -3300 cm-1that was not observed in Form 2 (Fig.15, panel A), whereas the IR spectrum of Form 2 showed a relatively intense peak, centered at -800 cm-1that was not observed in Form 1 (Fig.15, panel B).

Form 1 and Form 2 have different equation rastvorimosti: Form 2 = 0,61 mg/ml and the Form 1 = 0,51 mg/ml Fig.17, panel A shows the solubility of Forms 1 and 2 in methanol from 0-70°C. Fig.17, panel B shows the actual solubility of Forms 1 and 2 in 50 mm pH 6,8 phosphate buffer/1% SLS.

Example 16

Exponentially growing MDA-MB-231 cells or MIA PaCa-2 (also known as PACA-2) cells were seeded at 1000 cells per well in tablets on six holes, and left to attach for 24 hours. MDA-MB-231 and MIA PaCa-2 cells were cultured in DMEM with addition of 10% (vol./about.) fetal bovine serum (FBS) and 5 ml of penicillin/streptomycin at 37°C in 5% CO2. MDA-MB-231 and MIA PaCa-2 incorporated in cell lines, estrogen receptor-negative mammary glands� person and pancreatic carcinoma, respectively. (±)-CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione are each dissolved in a concentration of 10 mm in DMSO separately and added to the cells at a concentration of 0,1, 0,25, 0,5, 1 or 2 Μ. Control plates were received only DMSO, in the same percentage to the total volume of the culture that introduced in combination with the highest drug concentration. Cell cultures were observed daily for 10-15 days, then fixed and stained with a modified painting by Wright-Giemsa (Sigma). Treatment of (±)-CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione leads to cell death of MDA-MB-231 cells or Paca-2. See, for example, Fig.2. It was found that the IC50for (±)-CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was 0.5 Μ. It was found that the value of IC50for (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was 0.5 Μ.

Example 17

MDA-MB-231 cells (ATCC #HTB-26), grown in DMEM with addition of 15% inactivated by heating fetal bovine syware�Ki with the addition of 10 mm HEPES pH 7,5, were placed in 60-mm2tablets (2×105holes in the pad). Two days later the connection candidate in DMSO at various concentrations was diluted in medium and added to the individual tablets so that the final concentration of DMSO in the culture medium of the cell cultures was 0.1%. After two days of incubation, cultures were trypsinization, the cells were washed with medium, counted using hemocytometer and 500 cells, including the cell body, were seeded in 100 mm2tablets on Wednesday. Two weeks later, the medium was removed and cell colonies were fixed with methanol for 10 minutes, dyed with 1% crystal violet for 10 minutes, washed with water and dried in air. Cell colonies were counted visually, if the colony was attended by more than 50 cells. The effectiveness of seeding in downloading is defined as the average number of formed colonies divided by 500. The surviving fraction was determined as the effectiveness of seeding in downloading connection candidate divided by the efficiency of seeding in downloading DMSO, multiplied by 100. For titles of candidate compounds was determined by the value of IC50by substituting the equation y=AeBxto the experimental points and the extrapolation of concentration, where the surviving fraction was 50. Treatment of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (+)-Tran� -3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione leads to cell death of MDA-MB-231. See, for example, Fig.3. It was found that the IC50for (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione is 0,62 Μ. It was found that the IC50for (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione is 4.1 Μ.

Example 18

Recombinant protein kinase C (Calbiochem) (100 ng) were incubated with (±)-CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione at 0.05, 0.5 or 10 Μ for 15 minutes at room temperature. Then to each sample was added to the radioactive solution for ringing in kinase buffer (20 mm Tris-HCl pH 7,5, 10 mm MgCl2) containing 20 Μ ATP and 0.2 μci/μl γ32Ρ-ΑΤΡ, 0.2 mg/ml Histone H1 (Upstate Biotechnology/Millipore, Bedford, MA). Kinase raccio was performed for 5 minutes at room temperature. The reaction products were analyzed by 12% SDS-PAGE and autoradiography.

Processing of recombinant protein kinase C for 15 minutes at room temperature, (±)- CIS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-<> ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione at the studied concentrations did not reduce kinase activity compared with treatment with a single carrier. See, for example, Fig.4.

Example 19

MDA-MB-231 cells were without serum overnight (16 hours) in the absence or in the presence of certain concentrations of the individual enantiomers (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione and (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. Cells treated with 100 ng/ml recombinant growth factor of hepatocytes man/scatter factor (HGF/SF) (R&D Systems #294-HG) for 10 minutes. All cell extracts were obtained in lysing buffer (20 mm Tris-HCl pH 7,5, 150 mm NaCl, 1 mm Na2EDTA, 1 mm EGTA, 1% Triton X-100, 2.5 mm sodium pyrophosphate, 1 mm beta-glycerophosphate, 1 mm Na3VO4And 1 µg/ml leupeptin, 1 mm phenylmethylsulfonyl) and destroyed the cells with ultrasound. The concentration of protein was measured by Bradford analysis using BioRad reagent (BioRad, Hercules, CA) according to the manufacturer's instructions. Samples (50 µg protein) were resolved using 8% SDS-PAGE under reducing conditions and transferred to PVDF membrane (BioRad). The membrane were incubated for 1 hour in TBS-T (50 mm Tris-HCl (pH=7,6), 200 mm NaCl, 0,05% Tween 20) with 5% milk. Protein was determined by incubation in t�chenie night at 4°C in TBS-T with 5% milk and or polyclonal antibody to phosphorylated c-Met (#3121), or a monoclonal antibody to β-actin (A-5441) (Sigma) was used as control saturation of total protein. After extensive washing in TBS-T for one hour was added horseradish peroxidase, conjugated against rabbit IgG (1:5000) or mouse IgG (1:2000) (Amersham Biosciences), and visualized specific protein connection when using an enhanced chemiluminescent detection system (Amersham Biosciences) according to the manufacturer's instructions. See, for example, Fig.5.

Treatment of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione simultaneously inhibits both basal and HGF-induced autophosphorylation c-Met at a concentration of at least 30 nm. In contrast, (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione demonstrates only a minimal inhibitory effect on c-Met phosphorylation at considerably higher concentrations (20 Μ). See, for example, Fig.5.

Example 20

A549 cells are human lung cancer in a plate of 96 wells (Costar 3603, 5000/well) were treated with one of (A) DMSO as a control; (B) 1,2 Μ (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione for 38 hours before adding 1:200 flurorescence of annexin V (green) and 1:500 propitiated (crimson, final conc�ntrace 1 μg/ml). The tagging procedure was carried out at 37°C for 20 minutes followed by image acquisition and analysis using IC100 Image Cytometer (Beckman Coulter, Inc) with 10X amplification.

To determine whether (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione primarily cytostatic mechanism or by a mechanism of apoptosis, cancer cells are exposed to (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion when stained with fluorescently labeled annexin V (green fluorescence) and propitiation (bright crimson fluorescence). Annexin V is a well-proven reagent that is specific binds with high selectivity with the outer membrane phosphatidylserine, an early marker of apoptosis occurring, whereas propitiated is a marker of dead cells. The incubation of cells human lung cancer (A549) with 1.2 Μ (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione for 38 hours induced apoptosis of cells, as proven by the strong staining with annexin V. a Small percentage of cells (~10-20%), simultaneously dyed and by annexin V and propitiation, shows that a subpopulation of cells treated with (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-i ]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion had already been dead for 38 hours. These data are consistent with the fact that (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione induces cell death mainly via activation of the mechanisms of apoptosis (see Fig.6)

Example 21

Cells MDA-MB-231 were pre-treated with specified concentrations of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione for 24 hours. 300 μl of each cell suspension (at a concentration of 0.5×106cells/ml in not containing serum medium) were placed in individual inserts and incubated for 24 hours at 37°C. At the bottom of the hole, in which there were inserts that contained 500 μl 10% FBS-containing medium. After 24 hours, the medium from each insert was aspirated and the cells that had not invasively, carefully removed from an inside of the insertion stroke with a cotton tip. Each insert is then transferred to a clean well containing a solution for staining of cells and incubated for 10 minutes at room temperature. Insert bottom decoloured by incubation in extraction solution and OD was measured at 560 nm. (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione inhibited the migration through the interconnecting voids� at confluent cultures of cancer cells MDA-MB-231. Data represent average of two independent experiments (see Fig.7).

Morbidity and mortality from most cancers is a result of local invasion and metastases from primary tumors in other tissues. This process mainly depends on the mobility and growth of tumor cells. Activation of c-Met HGF induces various cellular responses, including motility, invasion, wound healing and tissue regeneration. It was found that aberrant activation of c-Met plays a critical role in the development and progress of primary tumors and secondary metastases. HGF has the ability to dissociate epithelial layers and stimulate cellular motility and invasion through the substrate extraclean matrix, and production of HGF correlates with tumor metastasisin vivo.

As shown above, (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione inhibits the invasive phenotype of MDA-MB-231 breast cancer cells with an installed value of IC50about 500 nm. Similar results were obtained for cancer cells in the brain and lung. Thus, the results indicate that (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione inhibits metastatic invasion of cancer cells.

Example 22

(-)-TRANS-3-(5,6-d�hydro-4H-imidazo[3,2,1- ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione shows effectiveness in xenotransplanted breast cancer person. Cancer cells human breast MDA-MB-231 were inoculated subcutaneously females Nude thymus of mice (8,0×l06cells/mouse) and left before the formation of palpable tumors. When the tumors reached approximately 60 mm3, animals received oral (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione at a dose of 200 mg/kg or control media daily (5 consecutive days followed by a break in the dose for 2 days). (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was in PEG 400:20% Vitamin E TPGS (60:40). Animals received a total of 20 doses of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or control media. Tumors were measured during treatment and post-therapeutic follow-up period. Each point represents mean ± SEM for ten tumors. (see Fig.8).

Treatment of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione as monotherapy was effective in slowing tumor growth. Inhibition of tumor growth (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was calculated as 79% and it was statistically significant (p=0.009). There were no significant changes in body weight due to oral administration of carrier or (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione at a dose of 200 mg/kg.

Example 23

In xenotransplantation models of cancer of the human colon HT-29 cancer cells of the human colon were inoculated subcutaneously females Nude thymus of mice (5,0×106cells/mouse) and left before the formation of palpable tumors. When the tumors reached approximately 60 mm3, animals received oral (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione at a dose of 200 mg/kg or 300 mg/kg, or control media daily (5 consecutive days followed by a break in the dose for 2 days). (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was in PEG 400:20% Vitamin E TPGS (60:40). Animals received a total of 20 doses of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione or control media. Tumors were measured during treatment and post-therapeutic follow-up period. Each point represents mean ± SEM for ten tumors (see Fig.9, panel A).

In specified highly aggressive xenotransplantation models of colon cancer humans, animals receiving the dose or 200 mg/kg, or 300 mg/kg ka�ETS monotherapy, demonstrated significant inhibition of tumor growth, with 300 mg/kg were more effective than 200 mg/kg (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione in doses of 200 mg/kg showed optimal inhibition of tumor growth by 39% (p=0.006), whereas 300 mg/kg showed optimal inhibition of tumor growth 55% (p=0.00001). There were no significant changes in body weight due to oral administration of carrier or (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione at a dose of 200 mg/kg or 300 mg/kg.

The effectiveness of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was tested on xenotransplantation model with several other cancer cell lines: cancer of human pancreatic MIA PaCa2 (Fig.9, panel B), cancer of the human prostate PC3 (Fig.9, panel C) and gastric cancer MKN45 human (Fig.9, panel D). Cells were treated with (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione as monotherapy at the indicated concentrations. In all these models, (- )- TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione significantly inhibited the growth of tumors.

Example 24

(-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-yl)pyrrolidin-2,5-dione showed significant cytotoxicity against multiple cancer cell lines. Various cancer cell lines were subjected to treatment (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione at the indicated concentrations in the range from 0.03 to 30 Μ. The sensitivity of these cells to (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was measured with a standard MTS analysis on cytotoxicity (Fig.10). Cell lines human cancer expressing c-Met and/or phospho-c-Met, were sensitive to (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione. In contrast, cell lines human cancer without immunodetection c-Met or phospho-c-Met (Fig.10, SK-MEL-28, MCF-7 and NCI-H661) showed a low sensitivity.

Example 25

(-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was analyzed from the point of view of its activity in the inhibition of a large group (n=230) of human kinases. The data presented in table 2, show that (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione inhibits only c-Met to a large extent and shows moderate activity against a small number of other kinases. (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione demonstrates the constant inhibited�I (Κ i) at ~360 nm relative to c-Met.

Table 2
KinaseIC50
CAMKIIδ~10 µm
Flt4~16 mm
PAK3~6,6 µm
Pim-110 µm (33% inhibition)

Example 26

Was installed xenotransplantation model of cancer of the human colon HT-29 colon cancer cells and human rights, as described in example 23. Mice having a tumor, were treated with a single dose of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione (300 mg/kg). The decrease in phospho-c-Met were registered immunohistochemically after 24 hours. Significant decrease in the number of phospho-c-Met visualized using immunoperoxidase system using diaminobenzidin that leads to an insoluble brown reaction product (Fig.11, panel A). Western blotting sample of the tumor on the phospho-c-Met confirmed the results of the immunohistochemical analysis (Fig.11, panel B).

Example 27

The present example describes ingabire�R c-Met receptor tyrosine kinase inhibitors in clear cell carcinoma sarcoma and tumors, associated with MiT (Microphtalmia transcription factor). Compounds according to the invention has also demonstrated efficacy in patients with clear cell carcinoma sarcoma. The research described in this example used the (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, small molecule inhibitor of c-Met receptor tyrosine kinase.

(-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione represented by sooy selective inhibitor of c-Met receptor tyrosine kinase. When abnormal activation of c-Met plays numerous roles in the aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. The data described above demonstrate that (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione inhibits the activation of c-Met in a wide range of cell lines of human tumors, including clear cell carcinoma sarcoma, and demonstrates antitumor activity against several xenograft human tumors. In clinical studies, treatment of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was well tolerated and resulted in a response from the tumor and prolonged stable condition in a wide range of�not tumors and doses.

(-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was administered to patients with clear cell carcinoma sarcoma. In particular, (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione showed a partial response, as determined by the RECIST (Criteria for evaluation of the response of solid tumors to treatment (Response Evaluation Criteria in Solid Tumors)), in a patient with clear cell carcinoma sarcoma.

Objective response to the introduction of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was seen in a group of patients affected molecular-linked group of tumors like sarcomas, for which there is no effective treatment. Based on the specified response (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was administered at a dose of 360 milligrams (mg) twice daily (b.i.(d.).

(-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was administered to patients with MiT (microphtalmia transcription factor)-associated tumors. MiT tumors, which may include clear cell carcinoma sarcoma (CCS), alveolar soft tissue sarcoma (ASPS) and renal cell carcinoma associated with translocation (RCC), biologically related through a common chromosomal abnormality that is responsible for the increased ex�ressio c-Met, leading to the development of these tumors. Tumors with this anomaly are resistant to existing treatments and in the absence of successful surgical procedures invariably fatal.

During the first stage of the study, 23 patients were registered and they were treated with 120 mg (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione b.i.d. It was shown that fourteen of the patients were evaluated on the effectiveness of treatment. In addition to the patient with a confirmed partial response, ten of the evaluated patients demonstrated stable disease.

Objective clinical response shown for (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion, is built around data that show that the knock-out MiT expression by sh inhibits c-Met expression and inhibits the growth of cell sarcoma clear cell carcinoma of manin vitroandin vivo. This finding leads to the development of clinical trials in patients with MiT-associated tumors using (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, which has shown anticancer activity, including objective tumor response as well as the ability to inhibit c-et protein in biopsies of tumors from patients treated by this drug.

1. Polymorph of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(lH-indol-3-yl)pyrrolidin-2,5-dione, characterized by:
(i) powder x-ray diffraction pattern comprising peaks approximately in the region of 8.2, 10,8, 14,1 °2θ using Cu α radiation; or
(ii) a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9,9, 12,0 °2θ using Cu α radiation.

2. Polymorph according to claim 1, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the area 8,2, 10,8, 14,1, 15,5, 17,8, 19,9 and 25.6 °2θ using Cu α radiation.

3. Polymorph according to claim 1, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the area 8,2, 10,8, 14,1, 14,9, 15,5, 17,1, 17,8, 19,4, 19,9, 21,1, 21,9, 23,0, 25,6 and 28.4 °2θ using Cu α radiation.

4. Polymorph according to claim 1, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the region of 6.5, 9,9, 12,0, 16,7, or 20.1 and 22.8 °2θ using Cu α radiation.

5. Polymorph according to claim 1, characterized by a powder x-ray diffraction pattern comprising peaks approximately in the area 6,5, 9,9, 12,0, 13,2, 16,4, 16,7, 17,2, 20,1, 20,3, 20,8, 22,8, 23,7, 28,6 and 30.4 °2θ using Cu α radiation.

6. (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5 indichloride.

7. (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine.

8. A method of producing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, including:
(a) mixing (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion (1S,2S)-(+)-pseudoephedrine in the first solvent to obtain a solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine;
(b) washing the solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine, obtained in stage (a), a mixture of water with the first solvent;
(c) the interaction of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine with stage (b) with an acid in an organic solvent and isolation of the organic layer of the resulting solution;
(d) washing the organic layer from step (C);
(e) adding a second solvent to the organic layer;
f) concentrating the organic layer to achieve a concentration of the second solvent in the solution is less than 5%; and
(g) crystallizing from the organic layer from step (f) and drying the resulting solution of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrol�Dean-2,5-dione under vacuum to give (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

9. A method of producing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, including:
(a) mixing (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione with cyclohexylethylamine in the first solvent to obtain a solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione of cyclohexylethylamine;
(b) washing the solid substance (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione of cyclohexylethylamine obtained at stage (a), a mixture of water with the first solvent;
(c) the interaction of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione of cyclohexylethylamine from stage (b) with an acid in an organic solvent and isolation of the organic layer of the resulting solution;
(d) washing the organic layer from step (C);
(e) adding a second solvent to the organic layer;
f) concentrating the organic layer to achieve a concentration of the second solvent in the solution is less than 5%; and
(g) crystallizing from the organic layer from step (f) and drying the resulting solution of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione under vacuum to give (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin�-2,5-dione.

10. A method according to claim 8 or 9, where the first solvent is a nonaqueous solvent, which preferably represents acetonitrile.

11. A method according to claim 8 or 9, where the specified second solvent is a same solvent as the first solvent; or the specified second solvent different from the first solvent.

12. A method according to claim 8 or 9, where the specified organic solvent at the stage (C) is methyltetrahydrofuran.

13. A method according to claim 8 or 9, where the specified organic layer was washed with salt solution at stage (d), preferably where the specified salt solution is a sodium chloride solution.

14. A method according to claim 8 or 9, further comprising washing the crystals of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion, after step (g), preferably where the crystals of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione was washed with alcohol, selected from ethanol and methanol.

15. A method of producing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4 -(1H-indol-3-yl)pyrrolidin-2,5-dione, including:
(a) mixing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione·(1S,2S)-(+)-pseudoephedrine and acid;
(b) adding alcohol to the mixture from stage (a) with the formation susp�nsii;
(c) heating and stirring the suspension of step (b);
(d) cooling and isolation of (-)-TRANS-3-(5,6-dihydro-4H-imidazo[[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione;
e) irrigation (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-Dion, selected at the stage (d), the first solvent;
f) dissolving (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4 -(1H-indol-3-yl)pyrrolidin-2,5-dione from step (e) in the second solvent to obtain a solution;
(g) adding a third solvent to the solution from stage (f) and distillation of the solution before reaching the content of the second solvent in the solution is less than 5%;
(h) crystallizing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione from a solution from stage (g);
(i) optional addition of a fourth solvent for the maturation of the crystals from step (h);
(j) the allocation of crystals from stage (i) by filtration;
(k) washing the crystals with stage (j) a third mixture of a solvent and a fourth solvent; and
l) drying the crystals from step (k) under vacuum to give (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione;
where the specified alcohol preferably is a methanol, ethanol or a mixture thereof.

16. A method according to claim 15, where the specified second solvent is not�odny solvent, which preferably represents tetrahydrofuran;
where the specified third solvent is a nonaqueous solvent, which preferably is a methanol, ethanol or a mixture thereof; or
where specified, the fourth solvent is an aqueous solvent, which preferably is water.

17. A method of producing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, including:
(a) dissolving (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione in dichloromethane and isolation of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione dichloromethane;
(b) dissolving (±)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione dichloromethane in the first solvent;
c) distillation of the solution from stage (b) to achieve the concentration of dichloromethane in the solution is less than 0.1% wt.;
(d) dilution of the solution from stage (C) in the second solvent;
(e) the introduction of the solution from stage (d) in the system multicanonical chromatography containing packing material, suitable for chiral separation;
(f) the Association obtained purified product obtained from the system from stage (e); and
g) crystallization of the purified product from stage (f), filtration poluchennogo� (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione with obtaining (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

18. A method according to claims.8, 15 or 17, wherein the first solvent is a nonaqueous solvent, which preferably is a methanol, ethanol or a mixture thereof.

19. A method according to claim 8, 9 or 17, wherein the second solvent is a nonaqueous solvent, which preferably is a methanol, ethanol, acetonitrile or a mixture thereof.

20. A method according to claim 8, 9, 15 or 17, where the resulting (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione contains less than 1% of (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, preferably contains less than 0.7% (+)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

21. A method of producing (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione, which includes stages (a-f) according to claim 14 and the phase g' phase g' includes evaporation of the purified product from stage (f), to obtain (-)-TRANS-3-(5,6-dihydro-4H-imidazo[3,2,1-ij]the quinoline-1-yl)-4-(1H-indol-3-yl)pyrrolidin-2,5-dione.

22. Pharmaceutical composition for treating cancer, comprising a polymorph according to any of claims.1-5 and a pharmaceutically acceptable carrier or excipient.

23. Polymorph according to any of claims.1-5 is designed for use in a method for treating cancer in combination with a pharmaceutically acceptable carrier or excipient, �de not necessarily cancer is selected from lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, chronic myelogenous leukemia, melanoma, ovarian cancer, renal carcinoma, hepatoma, brain cancer and multiple myeloma.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrroloquinolinyl pyrrolidine-2,5-diones of formula IVa, IVb, Va or Vb possessing the properties of cancer cell inhibitor properties, to a based pharmaceutical composition, and to a method of treating using them. In general formulas

,

R1, R2 and R3 mean hydrogen, F, Cl, Br, I, -(C1-C6) alkyl, CF3, -O-(C1-C6) alkyl, or -OCF3; R4 means hydrogen, - (C1-C6) alkyl or -CH2R7; R7 means -O-P(=O)(OH)2, -O-P(=O)(-OH)(-O-(C1-C6) alkyl), -O-P(=O)(-O-(C1-C6)alkyl)2, -O-P(=O)(-OH)(-O-(CH2)-phenyl), -O-P(=O)(-O-(CH2)-phenyl)2, groups of carboxylic acid, groups of aminocarboxylic acid or peptide; Q represents aryl, heteroaryl, -O-aryl, -S-aryl, -O-heteroaryl or -S-heteroaryl; X means -(CH2)- or -(NH)-; Y means -(CH2)- or a bond; wherein the above aryl, heteroaryl, -O-aryl, -S-aryl, -O-heteroaryl and -S-heteroaryl groups can be substituted by one or more substitutes, and m is equal to 1 or 2.

EFFECT: preparing the substances possessing the properties of cancer cell growth inhibitor.

26 cl, 2 tbl, 12 dwg, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I)CE, wherein "-----" means a bond, V represents CH, and U represents CH or N, or "-----" means a bond, V represents CR6 and U represents CH, or also "-----" means a bond, V represents N and U represents CH, or "-----" is absent, V represents CH, and U represents CH2, NH or NR9; R0 represents H, or provided "-----" means a bond, can also represent C1-3alkoxygroup; R1 represents H, halogen, cyanogroup, C1-3alkyl or ethinyl; R2 represents H, acetyl or a group of formula -CH2-R3; R3 represents H, C1-3alkyl or C1-3hydroxyalkyl; R4 represents H, or provided n is other than 0, and R5 means H, can also represent OH; R5 represents H, C1-3alkyl, C1-3hydroxyalkyl, C1-3aminoalkyl, C1-3alkoxyC1-3alkyl, carboxyl group or C1-3alkoxycarbonyl; R6 represents C1-3hydroxyalkyl, carboxyl group, C1-3alkoxycarbonyl or a group -(CH2)q-NR7R8, wherein q is 1, 2 or 3 and each of R7 and R8 independently represents H or C1-3alkyl, or R7 and R8 together with a nitrogen atom to which they are attached, form a pyrrolodinyl or piperidinyl ring; R9 represents C1-3alkyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl; A represents -(CH2)p-, -CH2CH2CH(OH)- or -COCH2CH(OH)-; G represents a phenyl group which is mono- or disubstituted in m- and/or n-position(s)by substitutes independently specified C1-4alkyl, C1-3alkoxygroup and halogen, or G means a group of one of formulas below G1 and G2, wherein Q means O or S, and X means CH or N; and each Y1, Y2 and Y3 represents CH, or one of Y1 and Y3 represents N, and the other one represents CH; and n is equal to 0, provided A represents -CH2CH2CH(OH)- or -COCH2CH(OH)-, and n is equal to 0, 1 or 2, provided A represents (CH2)p, wherein p is equal to 1, 2, 3 or 4, provided a sum of n and p is then equal to 2, 3 or 4; or a pharmaceutically acceptable salt of this compound.

EFFECT: compound of formula (I)CE or its pharmaceutically acceptable salt are applicable as a therapeutic agent for preventing or treating a bacterial infection.

29 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to substances preventing malignant regeneration of mammal (including human) normal cells in malignant cells. Aaptos sp. sponge is used to produce an aaptamine analogue, namely 3-N-morpholinyl-9-demethyloxyaaptamine exhibiting ability to prevent mammal normal cell transformation in malignant cells. What is offered is use of 3-N-morpholinyl-9-demethyloxyaaptamine, and also its analogues 9-demethyloxyaaptamine, isoaaptamine, 3-phenethylamino-9-demethyl oxyaaptamine and 3-isopentyl amino-9-demethyloxyaaptamine as such agent. Besides, these substances are used for preparing pharmaceutical compositions preventing mammal normal cell transformation in malignant cells. 3-N-morpholinyl-9-demethyloxyaaptamine and its analogues have a cancer-preventive effect in the concentration nontoxic for normal cells.

EFFECT: reduced risk of toxic action on body after prolonged administration of the substances.

3 cl, 1 dwg, 10 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrroloquinolinyl-pyrrolidine-2,5-diones of formula IVa, IVb, Va or Vb or pharmaceutically acceptable salts thereof: where: R1, R2, R3 and R4 independently denote H; Q denotes a benzo-condensed 5-member heteroaryl with one N atom; X denotes -(CH2)-; Y denotes -(CH2)-, a bond; m equals 1 or 2.

EFFECT: compounds inhibit growth of cancerous cells, which enables their use in pharmaceutical compositions.

12 cl, 2 tbl, 12 dwg, 88 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds of formulae and , in which radicals and symbols assume values defined in the formula of invention, e.g. to 1H-indazoles, 1,2-benzisoxazoles and 1,2-benzisothiazoles. Said compounds are receptor ligands of the α-7 nAChR subtype. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: possibility of using the said compounds to make medicinal agents for treating diseases associated with impaired functioning of nicotinic acetylcholine receptors and their abnormal functioning, primarily in brain cells.

46 cl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: medicine; veterinary science.

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

R1=-H, -NH2, -Br, -Cl, -ОН, -СООН,

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

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

A=-CH- at В=-СН=, Z=-CH=,

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

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

A=-CH= at В=-СН=, Z=-N=.

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

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

4 ex, 3 tbl, 8 dwg

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of imidazolyl derivative of the general formula (I) wherein each Ra and Rb represents independently (C1-C6)-alkyl, (C1-C6)-alkoxyalkyl, optionally substituted aryl or heteroaryl, or wherein Ra and Rb form in common additional homocyclic or heterocyclic system comprising one or some rings; each Ra' and Rb' represents hydrogen atom, or they in common form a carbon-carbon double bond wherein indicated carbon-carbon double bond is optionally part of aromatic system; Rc represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxyalkyl or halogen atom; Rd represents hydrogen atom or (C1-C4)-alkyl; Re represents hydrogen atom or (C1-C4)-alkyl; m = 1 or 2; R1 represents hydrogen atom or (C1-C4)-alkyl, and its salts after addition of acid and wherein compound of the general formula (II) wherein values Ra, Ra', Rb, and Rb' are given above is subjected for interaction with compound of the formula (III) wherein R represents hydrogen atom, (C1-C4)-alkyl group optionally substituted with hydroxy-group, or optionally substituted aryl group; each R', R'', R''' and R'''' represents independently hydrogen atom or (C1-C4)-alkyl group followed by interaction with compound of the formula (IV) wherein R, Rd and Re have values given above and the following optional interaction with the corresponding acid. Proposed method shows high effectiveness for synthesis of ondansetron and cilansetron.

EFFECT: improved method of synthesis.

10 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of [1,4]diazepino[6,7,1-IJ]-quinoline of the general formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkanoyl or (C7-C11)-carboarylalkoxy-group; each R2 and R3 represents independently hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, (C2-C6)-carboalkyloxy-group, (C1-C6)-perfluoroalkyl, (C2-C6)-alkanoyloxy-group, (C2-C6)-alkanoyl, (C6-C8)-aroyl, (C5-C7)-aryl, (C6-C13)-alkylaryl having 5-7 carbon atoms in aryl moiety; R4 and R5 represents independently hydrogen atom or (C1-C6)-alkyl, or R4 and R5 taken in common with carbon atoms with which they are bound form cyclic group chosen from (C4-C8)-cycloalkane, (C4-C8)-cycloalkene; each R6 and R7 represents independently hydrogen atom or (C1-C6)-alkyl; n = 1 or 2; a dotted line means a double bond optionally. Also, invention describes using compounds of the formula (I) in preparing a drug used in treatment of different psychotic disorders. Also, invention relates to a pharmaceutical composition possessing activity as 5-HT2C antagonist based on proposed compounds, and a method for synthesis of compounds of the formula (I). Invention provides synthesis of novel compounds, preparing a pharmaceutical composition and a drug based on thereof.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

53 cl, 1 tbl, 34 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to biotechnology and represents an immunogenic composition for preventing and treating cancer diseases, which contains the non-functional BORIS protein, a sequence of which is free from the zinc finger protein. The present invention also discloses an immunotherapeutic cancer composition containing the above non-functional BORIS protein or a bacterial, mammalian or yeast cell, or a viral particle able to express the above non-functional BORIS protein. The present invention also discloses a method for immunising a patient by administering an effective amount of the above immunotherapeutic composition, as well as using the above immunotherapeutic composition for preparing the cancer vaccine.

EFFECT: invention enables increasing the efficacy of the immunoprophylactic and therapeutic cancer vaccine.

22 cl, 7 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely, to novel heterocyclic compounds of the general formula or to their pharmaceutically acceptable salts, where R1 stands for cyano, nitro, amino, -NHCOOR4 or -NHCOR4; R2 stands for a halogen, C1-alkyl, halogenC1-alkyl or C1-alkoxy; R3 stands for C1-alkyl; or both radicals R3 form a cycloalkyl, containing 3 members, together with carbon atom, which they are bound to; X stands for either an alkylene chain of 4-7 carbon atoms, linear or branched, and the said chain can contain one or several similar or different additional units, selected from -O-, -N(R5)-; either a group where n1 and p1 stand for two integer numbers, the sum of which n1+p1 is an integer number, selected from 2; R6 and R7 together form a covalent bond or R6 and R7 together with carbon atoms, which they are bound to, form a cycle or a cycloalkyl, containing 3 members; R4 stands for C1-alkyl; R5 stands for C1-alkyl. The invention also relates to particular compounds, a pharmaceutical composition based on formula (I), application of the formula (I) compound.

EFFECT: obtained are the novel heterocyclic compounds, useful in treating cancer.

23 cl, 10 dwg, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a combination of leucine source and ω-3 polyunsaturated fatty acid source applicable in therapeutic or preventive treatment of hypercalcemia.

EFFECT: invention provides extending the range of products applicable in the therapeutic or preventive treatment of hypercalcemia.

19 cl, 8 dwg, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with an immunobiological agent for treating urinary bladder cancer, based on BCG vaccine, including a peptidoglycan fragment, which contains diaminopimelic acid as a part of its structure. The group of inventions also deals with a method of applying the claimed immunobiological agent for the treatment of urinary bladder cancer.

EFFECT: group of inventions provides an increased anti-tumour activity.

5 cl, 5 ex, 5 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and aims at preventing, treating or managing cancer, preferentially metastatic cancer, in a patient. The method involves administering an effective amount of Axl inhibitor in a combination with an effective amount of one or more chemotherapeutic substance. The Axl inhibitor represents 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine in the form of a recovered stereoisomer or a mixture thereof, or in the form of a tautomer or a mixture thereof, or their pharmaceutically acceptable salt or N-oxide. The chemotherapeutic substance is specified in a group consisting of: cisplatin, lapatinib, erlotinib, gemcitabine, doxorubicine, paclitaxel, cytarabine and docetaxel.

EFFECT: method enables increasing the clinical effectiveness in cancer, reducing side effects.

5 cl, 11 ex, 16 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a new derivative of anthrafurandione of formula I or its pharmaceutically acceptable salts possessing high antitumour effect and activity on tumours resistant to other drug preparations. Besides, the invention refers to antitumour pharmaceutical compositions containing the compound of formula I, a pharmacologically acceptable carrier and one or mode excipients specified in co-solvents, solubilisers, filling agents, emulsifiers, preserving agents, antioxidants, buffer compounds, substances for maintaining isotonicity.

EFFECT: effective use of anthrafurandione, as it possesses high storage stability as a lyophilisate, and as a solution, and also other improved characteristics, including solubility, efficacy and acceptability.

10 cl, 6 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula (I), possessing properties, making it possible to inhibit phosphorylation of AKT (proteinkinase B; PKB), to versions of method of their obtaining, as well as to intermediate products for their obtaining. In particular compounds can be applied in treatment of different tumours and/or metastases, as well as in case parasitic diseases such a malaria. In formula (I), R1 stands for -L-phenyl or -L-heteroaryl, with term "heteroaryl" standing for bicyclic radical, containing from 9 to 12 units, L stands for either linear or branched alkyl, containing 1-6 carbon atoms, optionally substituted with hydroxyl, or CO group, or group L'-X, where L' stands for linear or branched alkyl, containing 1-6 carbon atoms, and X stands for oxygen or sulphur atom; with phenyl and heteroaryl being optionally substituted with one or several radicals, similar or different, selected from halogen atoms, -NRxRy, alkoxy and alkyl; with said alkyl being optionally substituted with one or several halogen atoms; R2 stands for hydrogen atom or alkyl; R3 stands for alkyl, optionally substituted with one or several halogen atoms; R4 stands for hydrogen atom or halogen atom; with NRxRy being such that Rx and Ry form together with nitrogen atom, which they are bound to, cyclic radical, including 3-10 units, and optionally oxygen atom; and all alkyl or alkoxy radicals, mentioned above, are linear or branched and contain 1-6 carbon atoms.

EFFECT: compounds can be applied as active component for obtaining medications, intended for treatment or prevention of disease, characterised by deregulation of protein- or lipidkinase activity.

25 cl, 3 tbl, 43 ex

FIELD: medicine.

SUBSTANCE: what is presented is using Histochrom (same as echinochrome A or pentahydroxyethyl naphthoquinone) as an agent able to prevent pulmonary fibrosis developed under cytostatic agents. The invention can be used for the pharmacological prevention and correction of the pulmonary tissue disorders caused by administering the cytostatic agents.

EFFECT: preventing hypertrophy of interalveolar connective tissue in the lungs associated with administering bleomycin.

4 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: additional intravenous introductions of preparation of recombinant hybrid protein of tumour necrosis factor alpha - thymosin-alpha-1 (TNF-T)-Refnot before starting chemotherapy and after finishing chemotherapy. On the first day of the course of induction (neoaduvant) chemoimmunotherapy content of Refnot preparation vial is dissolved with 2 ml of injection water with further dilution of obtained solution in vial with 200 ml of isotonic (0.9%) sodium chloride solution in dose 50.000 IU per m2 of patient's body, but not more than 100.000 IU per one introduction, with immediate introduction after solution preparation intravenously by drop infusion during 1-hour infusion. On the second day infusion of cytoxics is performed. Analogous Refnot infusion is performed a day after chemotherapy completion.

EFFECT: method makes it possible to reduce toxic side reactions and improve tolerability of induction polychemotherapy.

2 ex

FIELD: medicine.

SUBSTANCE: invention can be used for treating early breast cancer (BC) involving a radical mastectomy. To this effect, blood in an amount of 8-10 ml is sampled before the surgical intervention and on the first day following the surgical intervention to detect tumour cells. If the blood is found to contain circulating tumour cells on the first postoperative day with a zero level, the therapeutic setting is added with early postoperative FAC-based polychemotherapy.

EFFECT: invention enables assessing the activity of the tumour process accompanying BC and planning the further therapeutic approach.

1 ex

FIELD: medicine.

SUBSTANCE: dexamethasone 8 mg and ketoprofen 100 mg is administered intravenously once prior to the operation. A lumbar plexus is blocked in a combination with a parasacral block and inserting perineural catheters to administer weak 0.2% Ropivacaine, local anaesthetic 20 ml. Paracetamol 1,000 mg is administered intravenously 30 minute before the operation is completed. After the operation is completed, the perineural catheter of the lumbar plexus is used to infuse 0.2% Ropivacaine 300 ml at 6-8 ml/hour for 4-5 days. Ketoprofen 100 mg is administered intramuscularly twice a day for 3 days. Through the perineural catheter of the parasacral plexus, 0.2% Ropivacaine 10 ml is administered twice every 12 hours.

EFFECT: method provides the adequate anaesthesia in the given category of patients by having an effect on primary pain components, as well as ensures the continuous and prolonged anaesthesia both intra-, and postoperatively, prevents the stable and chronic pain syndrome and the motor block of the extremities, reduces a rate of toxic complications.

1 ex

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