Isoindoline compounds used for treating cancer

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

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1. The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to isoindoline compounds, pharmaceutical compositions containing one or more such compounds, and methods of use thereof for the treatment, prevention or control of various diseases.

2. The LEVEL of TECHNOLOGY

2.1. PATHOBIOLOGY CANCER AND OTHER DISEASES

Cancer is characterized mainly by the increase in the number of atypical cells derived from the original normal tissue, invasion of adjacent tissues data atypical cells or spread through the lymphatic or blood vessels of malignant cells in regional lymph nodes and distant organs (metastasis). Clinical data and molecular biology research indicate that cancer is a multistage process that begins with small preneoplastic changes, which in certain conditions can progress to neoplasia. Neoplastic education can grow in dividing cells and to detect excess capacity for invasion, growth, metastasis and heterogeneity, especially in conditions in which neoplastic (tumor) cells are not recognized by the immune system carrier (Roitt et al, Immunology 17.1-17.12 (3rded., Mosby, St. Louis, Mo., 1993)).

There are many what about the varieties of cancer, which have been described in the medical literature. Examples include lung cancer, colon, rectum, prostate, breast, brain and intestines. The number of cases of cancer continues to grow as the aging population, identifying new cancer and growth in susceptible groups of people (e.g., HIV-infected people or excessively exposed to sunlight). However, treatment options for cancer are limited. For example, in the case of cancer of the blood system (e.g. multiple myeloma) few options available, especially when traditional chemotherapy fails and there is no possibility for a bone marrow transplant. Therefore, there is a huge need for new methods and compositions that can be used to treat patients with cancer.

Most types of cancer is associated with the formation of new blood vessels - a process known as angiogenesis. Identified several mechanisms involved in stimulated tumor angiogenesis. The most direct of these mechanisms is the secretion of tumor cells cytokines with angiogenic properties. Examples of these cytokines include acidic and basic fibroblast growth factor (α,β-FGF (α,β-FGF)), angiogenic factor vascular endothelial growth (VEGF, VEGF and TNF-α (TNF-α). As an alternative the willow, tumor cells can allocate angiogenic peptides through the production of proteases and subsequent cleavage of the extracellular matrix, where some cytokines (e.g., β-FGF (β-FGF)). Angiogenesis may also indirectly through the induction of recruiting cells of inflammation (particularly macrophages) and the subsequent allocation of their angiogenic cytokines (such as TNF-α, β-FGF).

A number of other diseases or disorders associated with, or characterized by, undesired angiogenesis. For example, increased or unregulated angiogenesis is involved in a number of diseases or medical conditions, including, as non-limiting examples, neovascular diseases of the eye, choroidal neovascular disease, neovascular diseases of the retina, rubios (neovascularization of the angle of the anterior chamber), viral diseases, genetic diseases, inflammatory diseases, allergic diseases and autoimmune diseases. Examples of such diseases and conditions include, as non-limiting examples of diabetic retinopathy, retinopathy of prematurity, graft rejection of corneal neovascular glaucoma, retrolental fibroplasia, arthritis and the proliferative vitreoretinopathy.

Accordingly, compounds that can control anguage the ez or to inhibit the production of certain cytokines, including TNF-α, can be useful in the treatment and prevention of various diseases and conditions.

2.2. METHODS of CANCER TREATMENT

Currently, cancer therapy may include surgery, chemotherapy, hormone therapy and/or radiation therapy to destroy neoplastic cells in a patient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy could also include biological therapy or immunotherapy. All these approaches represent significant obstacles for the patient. Surgery, for example, may be contraindicated due to the patient's health or is likely to be unacceptable to the patient. In addition, surgery may not completely remove neoplastic tissue. Radiation therapy is effective only when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often cause serious side effects. Hormone therapy is rarely used alone. Although hormone therapy can be effective, it is often used to prevent or delay recurrence of cancer after other methods of treatment, which removed most of the tumor cells. The number of cases of biological therapy and immunotherapy are limited, and they can p is iodite side effects, such as a rash or swelling, flu-like symptoms, including fever, chills and fatigue, problems with gastrointestinal tract or allergic reactions.

In relation to chemotherapy, there are various hemiterpenes agents proposed for cancer treatment. Mainly drugs for hemoterapia cancer act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of precursors of deoxyribonucleotides to prevent DNA replication and concomitant cell division (Gilman et al., Goodman and Gilman''s: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York)).

Despite the availability of various chemotherapeutic agents, chemotherapy has many obstacles (Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter. 12, sect. 10, 1998). Almost all chemotherapeutic agents are toxic, and chemotherapy causes severe and often very dangerous side effects, including severe nausea, suppression of bone marrow and suppression of the immune system. In addition, even with the introduction of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance against chemotherapeutic agents. In fact, these cells are resistant to specific chemotherapeutic agents used in the treatment Protocol, often nazyvautsa resistant to other medicines, even if these agents act through mechanisms that are different from the mechanisms of drugs used in a particular treatment. Due to drug resistance, many cancers are or become resistant to standard chemotherapeutic treatment protocols.

Other diseases or conditions associated with or characterized by undesirable angiogenesis is also difficult to treat. However, it is assumed that some compounds, such as Protamine, heparin and steroids useful in the treatment of some specific diseases (Taylor et al., Nature 297:307 (1982); Folkman et al., Science 221:719 (1983) and U.S. patent No. 5001116 and 4994443.

There is still a strong need for effective methods of treatment, prevention and control of cancer and other diseases and conditions, particularly for diseases that are unresponsive to conventional treatments such as surgery, radiation therapy, chemotherapy and hormone therapy, along with this you can reduce or avoid toxicity and/or side effects associated with traditional methods of treatment.

3. The INVENTION

Offers isoindoline compounds and their pharmaceutically acceptable salt, solvate, prodrug or stereoisomer.

Also offers pharmaceutical companies the positions, containing the proposed connection, for example a compound of Formula I, including its individual enantiomer, mixture of enantiomers, or a mixture of diastereomers; or its pharmaceutically acceptable salt, MES or prodrug; in combination with one or more pharmaceutically problemami media.

In addition, there are methods of treatment, prevention or control of various diseases in a subject, which include introduction to the subject a therapeutically effective amount of the proposed connection, for example the compounds of Formula I, including its individual enantiomer, mixture of enantiomers, or a mixture of diastereomers, or pharmaceutically acceptable salt, MES or prodrug.

4. DETAILED description of the INVENTION

4.1. DEFINITION

To facilitate the understanding set out in the description of the disclosure given below are definitions of several terms.

In General, the nomenclature used and describes laboratory techniques of organic chemistry, medicinal chemistry and pharmacology are well known and are typically used in the art. Unless otherwise noted, all materials used in the description of the technical and scientific terms usually have the same value, which usually understands any average expert in the field of technology to which this description.

The term "subject" refers to the animal, including, as non-limiting examples of a Primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat or mouse. The terms "subject" and "patient" are used interchangeably in relation to, for example, the subject is a mammal such as man.

The terms "treat", "treating" and "treatment" refer to the eradication or reduction of the intensity of the disease or disorder, or one or more symptoms associated disease or disorder. In General, the treatment occurs after the onset of the disease or disorder. In some embodiments of the invention, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the introduction of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder.

The terms "prevent", "warning" and "prevention" refer to the prevention of the beginning, recurrence or spread of the disease or disorder or one or more of their symptoms. In General, a warning occurs before the onset of the disease or disorder.

The terms "controlling", "controlled" and "controlling" refers to preventing or slowing the progression, spread or worsening of the disease is or disorder, or one or more of their symptoms. Sometimes the positive effects that the subject receives from the preventive or therapeutic agent do not result in treatment of the disease or disorder.

The term "therapeutically effective amount" is intended to encompass a number of compounds that, when introduced is sufficient to prevent development of or alleviate to some extent one or more symptoms of the disorder, disease or condition being treated. The term "therapeutically effective amount" also refers to the amount of the compound that is sufficient to achieve the biological or medical response of a cell, tissue, system, animal or human that is being hunted by a researcher, veterinarian, doctor or Clinician.

The term "IC50" refers to the amount, concentration or dose of a compound required for 50% inhibition of the maximum response in the test in which to evaluate this response.

The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition or environment, such as a liquid or solid is the first filler, the diluent, excipient, solvent or material to encapsulate. In one example implementation, each component is "pharmaceutically acceptable" in the sense that it is compatible with other components of the pharmaceutical composition suitable for use in contact with the tissue or organ of a human or animal without the occurrence of high toxicity, irritation, allergic response, immunogenicity, or other problems or complications, in accordance with appropriate risk/benefit. Cm. "Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; "Handbook of Pharmaceutical Excipients", 5thEdition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association, 2005; "Handbook of Pharmaceutical Additives", 3rdEdition, Ash and Ash Eds., Gower Publishing Company, 2007; "Pharmaceutical Preformulation and Formulation", Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

The term "approximately" means a margin of error for a particular value, which is determined by any average person skilled in the technical field, which depends in part on how the value is measured or determined. In some embodiments of the invention, the term "approximately" means within 1, 2, 3, or 4 standard deviations. In some embodiments of the invention, the term "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0,5%or 0.05% of the given value or range.

The terms "active ingredient" and "active substance" refers to a connection that introduces one or in combination with one or more pharmaceutically acceptable auxiliary substances to a subject to treat, prevent, or reduce one or more symptoms of the condition, disorder or disease. As used, "active ingredient" and "active substance" may be optically active isomer disclose the connection.

The terms "drug", "therapeutic agent" and "chemotherapeutic agent" refers to a compound or pharmaceutical composition that is administered to a subject to treat, prevent, or reduce one or more symptoms of the condition, disorder or disease.

The term "alkyl" refers to linear or branched saturated monovalent hydrocarbon radical, where alkyl may optionally be substituted by one or more substituents. The term "alkyl" also encompasses both linear and branched alkyl, except otherwise specified. In some embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1-15 (C1-15), 1-12 (C1-12), 1-10 (C1-10) or 1-6 (C1-6 ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3-15 (C3-15), 3-12 (C3-12), 3-10 (C3-10) or 3-6 (C3-6) carbon atoms. As used linear C1-6and branched C3-6alkyl groups are also referred to as "lower alkyl". Examples of alkyl groups include, as non-limiting examples methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, tert-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, C1-6alkyl refers to a linear saturated monovalent hydrocarbon radical with 1-6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3-6 carbon atoms.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment one to five carbon-carbon double bonds. Alkenyl may optionally be substituted by one or more substituents. The term "alkenyl" also includes radicals with "CIS" and "TRANS" configurations, or alternatively, "E" and "Z" configurations that clearly experts in this field of technology. As used, the term "alkenyl" coverage which provides as linear, and branched alkenyl, except otherwise specified. For example, C2-6alkenyl refers to a linear unsaturated monovalent hydrocarbon radical with 2-6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3-6 carbon atoms. In some embodiments of the invention alkenyl is a linear monovalent hydrocarbon radical with 2 to 20 (C2-20), 2-15 (C2-15), 2-12 (C2-12), 2-10 (C2-10or 2-6 (C2-6) carbon atoms or a branched monovalent hydrocarbon radical with 3 to 20 (C3-20), 3-15 (C3-15), 3-12 (C3-12), 3-10 (C3-10) or 3-6 (C3-6) carbon atoms. Examples alkenyl groups include, as non-limiting examples, ethynyl, propen-1-yl, propen-2-yl, allyl, butenyl and 4-methylbutanal.

The term "quinil" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds. Quinil may optionally be substituted by one or more substituents. The term "quinil" also encompasses both linear and branched quinil, except otherwise specified. In some embodiments of the invention quinil is a linear od is valenty hydrocarbon radical with 2 to 20 (C 2-20), 2-15 (C2-15), 2-12 (C2-12), 2-10 (C2-10or 2-6 (C2-6) carbon atoms or a branched monovalent hydrocarbon radical with 3 to 20 (C3-20), 3-15 (C3-15), 3-12 (C3-12), 3-10 (C3-10) or 3-6 (C3-6) carbon atoms. Examples etkinlik groups include, as non-limiting examples, ethinyl (-C≡CH) and propargyl (-CH2C≡CH). For example, C2-6quinil refers to a linear unsaturated monovalent hydrocarbon radical with 2-6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3-6 carbon atoms.

The term "cycloalkyl" refers to cyclic saturated bridge and/or nemoricola monovalent hydrocarbon radical, which may optionally be substituted by one or more substituents. In some embodiments of the invention cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 12 (C3-12), from 3 to 10 (C3-10or from 3 to 7 (C3-7) carbon atoms. Examples cycloalkyl groups include, as non-limiting examples, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decaline and substituted.

The term "aryl" refers to monocyclic aromatic group and/or polycyclic monovalent aromatic group which contains at measures what one aromatic hydrocarbon ring. In some embodiments of the invention, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15) or from 6 to 10 (C6-10) atoms in the ring. Examples of aryl groups include, as non-limiting examples of phenyl, naphthyl, fluorenyl, azulene, antril, tenantry, pyrenyl, biphenyl and triphenyl. Aryl also relates to bicyclic or tricyclic carbon ring, where one of the rings is aromatic, and others may be saturated, partially unsaturated or aromatic, for example dihydronaphtho, indenyl, indanyl or tetrahydronaphthyl (tetralinyl). In some embodiments of the invention the aryl may optionally be substituted by one or more substituents.

The term "aralkyl" or "aryl-alkyl" refers to monovalent alkyl group, a substituted aryl. In some embodiments of the invention as alkyl and aryl may optionally be substituted by one or more substituents.

The term "heteroaryl" refers to a monocyclic aromatic group and/or polycyclic aromatic group that contains at least one aromatic ring, where at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Each ring of a heteroaryl group can contain one or diatoma O, one or two atom S and/or one to four N atom, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. Heteroaryl can be attached to the main structure at any heteroatom or carbon atom that leads to the formation of stable compounds. In some embodiments of the invention heteroaryl has from 5 to 20, 5 to 15 or 5 to 10 atoms in the ring. Examples of monocyclic heteroaryl groups include, as non-limiting examples, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolin, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyridinyl, pyridazinyl and triazinyl. Examples of bicyclic heteroaryl groups include, as non-limiting examples, indolyl, benzothiazolyl, benzoxazolyl, benzothiazyl, chinoline, tetrahydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromones, coumarinyl, cinnoline, honokalani, indazoles, purinol, pyrrolopyridine, properidine, thienopyridines, dihydroisoquinolyl and tetrahydroquinolines. Examples of tricyclic heteroaryl groups include, as non-limiting examples, carbazolyl, bunzendahl, financr the Lin, acridines, phenanthridines and xantinol. In some embodiments of the invention heteroaryl may also optionally be substituted by one or more substituents.

The term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-aromatic ring system and/or polycyclic ring system that contains at least one non-aromatic ring, where one or more non-aromatic atoms in the ring are heteroatoms independently selected from O, S or N; and the remaining atoms in the ring are carbon atoms. In some embodiments of the invention heterocyclyl or heterocyclic group has from 3 to 20, 3 to 15, 3 to 10, 3 to 8, from 4 to 7 or 5 to 6 atoms in the ring. In some embodiments of the invention heterocyclyl is monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a condensed or bridged ring system and in which the nitrogen atoms or sulfur may be optionally oxidized, the nitrogen atoms may optionally be quaternity and some rings may be partially or fully saturated or aromatic. Heterocyclyl can be attached to the main structure at any heteroatom or carbon atom that leads to the formation of mobilnogo connection. Examples of such heterocyclic radicals include, as non-limiting examples, acridines, azepine, benzimidazolyl, bunzendahl, benzisoxazole, benzisoxazole, benzodioxane, benzodioxole, benzofuranyl, benzopyranyl, benzenepropanal, benzopyranones, benzopyranyl, bettererererer, betterregulation, benzothiadiazoles, benzothiazolyl, benzothiophene, benzotriazolyl, benzothiophene, benzoxazines, benzoxazolyl, benzothiazolyl, β-carbolines, carbazolyl, bromanil, chromones, cinnoline, coumarinyl, decahydroquinoline, dibenzofurans, dihydromethysticin, dihydroergotoxine, dihydrofuran, dihydropyran, DIOXOLANYL, dihydropyrazine, dihydropyridines, dihydropyrazolo, dihydropyrimidines, dihydropyrrole, DIOXOLANYL, 1,4-ditional furanones, furanyl, imidazolidinyl, imidazolyl, imidazolyl, imidazopyridines, imidazothiazoles, indazoles, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isobenzofurandione, isobenzofuranyl, isopropanol, isocoumarins, isoindolines, isoindolyl, ethenolysis, isothiazolinones, isothiazolin, isoxazolidine, isoxazolyl, morpholinyl, naphthyridine, octahedrally, activitiesunder, oxadiazolyl, oxazolidinyl, oxazolidinyl, oxazolopyridine, oxazolyl, oxiranyl, pyrimidinyl, tenants dinil, fantrainer, phenarsazine, phenazines, phenothiazines, phenoxazines, phthalazine, piperazinil, piperidinyl, 4-piperidinyl, pteridinyl, purinol, pyrazinyl, pyrazolidine, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrimidines, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolyl, hintline, chinoline, honokalani, hinokitiol, tetrahydrofuryl, tetrahydropyranyl, tetrahydroisoquinoline, tetrahydropyranyl, tetrahydrofuryl, tetrazolyl, thiadiazolidine, thiadiazolyl, thiomorpholine, thiazolidine, thiazole, thienyl, triazinyl, triazolyl and 1,3,5-tritional. In some embodiments of the invention, the heterocycle may optionally be substituted by one or more substituents.

The term "halogen" or "halide" refers to fluorine, chlorine, bromine and/or iodine.

The term "optically active" and "active enantiomeric" refers to a collection of molecules, where the enantiomeric excess (enantiomeric purity) is at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%not less than approximately 9.5% or at least about 99.8 per cent.

When describing an optically active compound, the prefixes R and S are used to specify the absolute configuration of the molecule in its chiral(s) centre(s). Signs (+) and (-) are used to specify the optical rotation of the compound, i.e. the direction in which the plane of polarized light is rotated optically active compound. The prefix (-) indicates that the connection is levogyrate, i.e. the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the connection is Pervouralsk, that is, rotates the plane of polarized light to the right or clockwise. However, the sign of the optical rotation (+) and (-) is not associated with the absolute configuration of the molecule - R, and S.

The term "MES" refers to the compound or its salt, which further comprises a stoichiometric or non-stoichiometric amount of solvent bound non-covalent intermolecular forces of interaction. When water is the solvent, the MES is a hydrate.

4.2. CONNECTION

Description offers isoindoline compounds, pharmaceutical compositions containing one or more such compounds, and methods of their use for the treatment, prevention or control of various diseases.

One note is re implementation is provided a compound of the Formula I:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer, where

X represents C(=O) or CH2;

Y represents O, cyanamideor amido (NH);

m is an integer 0, 1, 2 or 3;

R1represents hydrogen or C1-6alkyl;

R2represents hydrogen, -NO2C1-10alkyl, C0-6alkyl-(5-10-membered heteroaryl), C0-6alkyl-(5-6-membered heterocyclyl), C0-6alkyl-OH, C0-4alkyl-NH2, -NHCO-C1-6alkyl, -OR21or -(CH2Z)0-2Is(5-10-membered heteroaryl), where each heteroaryl and heterocyclyl optionally substituted by one or more C1-6alkilani;

R3represents hydrogen, halogen, -NO2C0-6alkyl-(5-10-membered heteroaryl), C0-6alkyl-(5-6-membered heterocyclyl), C0-6alkyl-OH, C0-4alkyl-NH2, -NHCO-C1-6alkyl, -OR21or -(CH2Z)0-2Is(5-10-membered heteroaryl), where each heteroaryl and heterocyclyl optionally substituted by one or more1-6alkilani;

R21represents a C6-10aryl, 5-10-membered heteroaryl, 5-6-membered heterocyclyl or-CO(CH2)0-2R22where aryl, heteroaryl and heterocyclyl, each optionally substituted by one or more 1-6alkilani;

R22represents-NH2or 5-6-membered heterocyclyl; and

Z represents CH2, NH or O;

provided that when R1represents hydrogen, then R2is not hydrogen or C1-10by alkyl;

provided that when Y is O, then R3is not a halogen; and

provided that when Y is O and R3is a halogen, then R2represents a C0-6alkyl-(5-6-membered heterocyclyl).

In some embodiments of the invention X represents CH2. In some embodiments of the invention X represents C(=O).

In some embodiments of the invention Y is O. In some embodiments of the invention Y is cyanamide. In some embodiments of the invention Y is amido.

In some embodiments of the invention Z represents CH2. In some embodiments of the invention Z represents NH. In some embodiments of the invention Z represents O.

In some embodiments of the invention m is 0. In some embodiments of the invention m is 1. In some embodiments of the invention m is 2. In some p is imarah the invention, m is equal to 3.

In some embodiments of the invention R1represents hydrogen. In some embodiments of the invention R1represents a C1-6alkyl, optionally substituted by one, two or three substituents Q as described here. In some embodiments of the invention R1represents methyl.

In some embodiments of the invention R2represents hydrogen. In some embodiments of the invention R2represents a halogen. In some embodiments of the invention R2represents nitro. In some embodiments of the invention R2represents a C1-10alkyl. In some embodiments of the invention R represents a C0-6alkyl-(5-10-membered heteroaryl), where heteroaryl optionally substituted by one or more C1-6alkilani. In some embodiments of the invention R2represents a C0-6alkyl-(5-6-membered heterocyclyl), where heterocyclyl optionally substituted by one or more C1-6alkilani. In some embodiments of the invention R2represents a C0-6alkyl-OH. In some embodiments of the invention R2represents a C0-4alkyl-NH2. In some primarycontent invention R 2represents-NHCO-C1-6alkyl. In some embodiments of the invention R2represents-OR21where R21as described here. In some embodiments of the invention R2represents -(CH2-Y)0-2Is(5-10-membered heteroaryl), where heteroaryl optionally substituted by one or more C1-6alkilani. In some embodiments of the invention R2represents hydrogen, amino, acetamido, hydroxy, nitro, aminomethyl, hydroxymethyl, 2-methyl-1H-imidazol-1-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-(methylpiperazin-1-yl)methyl, 2-methyl-2H-pyrazole-3-yl, 1-methyl-1H-pyrazole-3-yl, 2-methylthiazole-4-yl, 4-methyl-4H-1,2,4-triazole-3-yl, morpholinomethyl, (pyridine-4-yl)methyl, (pyridin-4-yloxy)methyl, phenoxy, pyridine-2-yloxy, piperidine-4-yloxy, 2-aminoacetate or 2-piperazine-1-RECETOX.

In some embodiments of the invention R3represents hydrogen. In some embodiments of the invention R3represents nitro. In some embodiments of the invention R3represents a C0-6alkyl-(5-10-membered heteroaryl), where heteroaryl optionally substituted by one or more C1-6alkilani. In some embodiments of the invention R3represents a C0-6alkyl-(5-6-membered heterocyclyl), where heterocyclyl optionally substituted by one or more 1-6alkilani. In some embodiments of the invention R3represents a C0-6alkyl-OH. In some embodiments of the invention R3represents a C0-4alkyl-NH2. In some embodiments of the invention R3represents-NHCO-C1-6alkyl. In some embodiments of the invention R3represents-OR21where R21as described here. In some embodiments of the invention R3represents -(CH2-Y)0-2Is(5-10-membered heteroaryl), where heteroaryl optionally substituted by one or more C1-6alkilani. In some embodiments of the invention R3represents hydrogen, amino, acetamido, hydroxy, nitro, methyl, aminomethyl, hydroxymethyl, 2-methyl-1H-imidazol-1-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-(methylpiperazin-1-yl)methyl, 2-methyl-2H-pyrazole-3-yl, 1-methyl-1H-pyrazole-3-yl, 2-methylthiazole-4-yl, 4-methyl-4H-1,2,4-triazole-3-yl, morpholinomethyl(pyridine-4-yl)methyl, (pyridin-4-yloxy)methyl, phenoxy, pyridine-2-yloxy, piperidine-4-yloxy, 2-aminoacetate or 2-piperazine-1-RECETOX.

In one embodiment, the connection is:

or its pharmaceutically acceptable salt, MES prodrug and stereoisomer.

In another embodiment is provided a compound of Formula II:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer, where

X represents C(=O) or CH2;

m is an integer 0, 1, 2 or 3;

R4represents a C3-10cycloalkyl, 5-10-membered heterocyclyl, 5-10-membered heteroaryl or C0-4alkyl-NR41R42; where cycloalkyl, heterocyclyl and heteroaryl, each optionally substituted by one or more halogen, C1-6alkilani, -CO-NR43R44, -COOR45or C0-4alkyl-C6-10Allami, where the aryl may optionally be substituted by one or more halogen; and

R41, R42, R43, R44and R45each independently represents hydrogen or C1-6alkyl.

In some embodiments of the invention X represents CH2. In some embodiments of the invention X represents C(=O).

In some embodiments of the invention m is 0. In some embodiments of the invention m is 1. In some embodiments of the invention m is 2. In some embodiments of the invention m is equal to 3.

In some embodiments of the invention R4represents a C3-10cycloalkyl, neo is Astelin substituted by one or more (C 1-6) alkilani or C0-4alkyl-C6-10Allami. In some embodiments of the invention R4is a 5-6-membered heterocyclyl, optionally substituted by one or more (C1-6) alkilani or C0-4alkyl-C6-10Allami. In some embodiments of the invention R4represents a C0-4alkyl-NR41R42where R41and R42each is described here.

In some embodiments of the invention R4represents a 3-(N,N-diethylamino)propyl, 4-acetamidophenyl, 3-(2-aminoethoxy)-4-were 3-aminomethyl-4-were 2-aminomethyl-5-were, 3-AMINOPHENYL, 3-amino-4-were, 3-chloro-4-were, 4-hydroxymethylene, 3-hydroxy-4-were, 3-(2-methyl-1H-imidazol-1-yl)phenyl, 4-methyl-3-nitrophenyl, 3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl, 4-methyl-3-(2-piperazine-1-RECETOX)phenyl, 3-((4-methylpiperazin-1-yl)methyl)phenyl, 3-(1-methyl-1H-pyrazole-3-yl)phenyl, 3-(2-methyl-2H-pyrazole-3-yl)phenyl, 3-(2-methylthiazole-4-yl)phenyl, 4-(4-methyl-4H-1,2,4-triazole-3-yl)phenyl, 3-(morpholinomethyl)phenyl, 4-(morpholinomethyl)phenyl, 4-nitrophenyl, phenyl, 3-(piperidine-4-yloxy)phenyl, 4-(pyridin-4-yl)were, 4-((pyridin-4-yloxy)methyl)phenyl, 3-(pyridine-2-yloxy)phenyl, 3-phenoxyphenyl, 4-tert-butylcyclohexyl, CIS-4-tert-butylcyclohexyl, TRANS-4-tert-butylcyclohexyl, 4-methylcyclohexyl, CIS-4-methylcyclo exil, TRANS-4-methylcyclohexyl, 1-benzylpiperidine-4-yl, 4-methyltetrahydro-2H-Piran-4-yl, piperidine-4-yl, 4-phenylcyclohexyl, CIS-4-phenylcyclohexyl or TRANS-4-phenylcyclohexyl.

In one embodiment, the connection is:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer.

In yet another embodiment is provided a compound of Formula III:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer, where

X represents C(=O) or CH2;

m is an integer 0, 1, 2 or 3;

R5and R6each independently represents hydrogen, halogen, C1-6alkyl, oxo, -NO2C1-6alkoxy, -Z-C1-6alkyl, C0-6alkyl-(5-10-membered heteroaryl), C0-6alkyl-(5-6-membered heterocyclyl), C0-6alkyl-OH, C0-4alkyl-NH2, -NHCO-C1-6alkyl, -OR21or -(CH2-Y)0-2Is(5-10-membered heteroaryl),

where Z represents S or SO2;

where R21defined above;

where each heteroaryl and heterocyclyl above, optionally substituted by one or more C1-6alkilani; and

where the alkyl or alkoxy, above, may optionally be substituted by one or more halogen; cyano; nitro; amino; C1-6alkylic is jiaxi, C1-6alkoxy, optionally substituted by one or more halogen, or C1-6alkylthio, optionally substituted by one or more Halogens;

R7represents-COR71or-PO(OR72)(OR73);

R71represents a C1-10alkyl, C6-10aryl or 5-6-membered heterocyclyl, where alkyl, aryl, heterocyclyl may optionally be substituted by one or more amino, C1-6alkylamino, di(C1-6alkyl)amino or-COOR74; and

R72, R73and R74each independently represents hydrogen or C1-10alkyl.

In some embodiments of the invention X represents CH2. In some embodiments of the invention X represents C(=O).

In some embodiments of the invention m is 0. In some embodiments of the invention m is 1. In some embodiments of the invention m is 2. In some embodiments of the invention m is equal to 3.

In some embodiments of the invention R5represents hydrogen. In some embodiments of the invention R5represents a halogen. In some embodiments of the invention R5represents fluorine or chlorine.

In some embodiments of the invention R6before the hat is hydrogen. In some embodiments of the invention R6represents a halogen. In some embodiments of the invention R6represents fluorine or chlorine.

In some embodiments of the invention R7represents-COR41where R41as described here. In some embodiments of the invention R7is a-PO(OR42))(OR43), where R42and R43each, independently described here.

In one embodiment, the connection is:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer, where R5and R6above.

In yet another embodiment is provided a compound of Formula IV:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer, where

X represents C(=O) or CH2;

n represents the integer 0 or 1;

R8represents hydrogen or halogen; and

R9represents hydrogen, amino or 5-10-membered heteroaryl or heterocyclyl;

provided that when m is 0, R9is not hydrogen.

In some embodiments of the invention, X represents the FDS is th CH 2. In some embodiments of the invention X represents C(=O).

In some embodiments of the invention n is 0. In some embodiments of the invention n is 1.

In some embodiments of the invention R8represents hydrogen. In some embodiments of the invention R8represents a halogen. In some embodiments of the invention R8represents fluorine or chlorine.

In some embodiments of the invention R9represents hydrogen. In some embodiments of the invention R9represents amino. In some embodiments of the invention R9is a 5-10-membered heteroaryl. In some embodiments of the invention R9is a 5-10-membered heterocyclyl.

In one embodiment, the connection is:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer.

In yet another embodiment is provided a compound of the Formula V:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer, where

X represents C(=O) or CH2;

m equal the integer 0, 1, 2 or 3;

R10and R11each independently represents hydrogen, halogen, C1-6alkyl or C6-10aryloxy, where the alkyl and aryl, each optionally substituted by one or more Halogens.

In some embodiments of the invention X represents CH2. In some embodiments of the invention X represents C(=O).

In some embodiments of the invention m is 0. In some embodiments of the invention m is 1. In some embodiments of the invention m is 2. In some embodiments of the invention m is equal to 3.

In some embodiments of the invention R10represents hydrogen. In some embodiments of the invention R10represents a halogen. In some embodiments of the invention R10represents fluorine or chlorine. In some embodiments of the invention R10represents a C1-6alkyl, optionally substituted by one or more Halogens. In some embodiments of the invention R10represents a C6-10aryloxy, optionally substituted by one or more Halogens.

In some embodiments of the invention R11represents hydrogen. In some embodiments is subramania R 11represents a halogen. In some embodiments of the invention R11represents fluorine or chlorine. In some embodiments of the invention R11represents a C1-6alkyl, optionally substituted by one or more Halogens. In some embodiments of the invention R11represents a C6-10aryloxy, optionally substituted by one or more Halogens.

In one embodiment, the connection is:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer.

In yet another embodiment is provided a compound of Formula VI:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer, where

X represents CH2or C=O,

m and n each independently is 0 or 1;

p is 0, 1, 2 or 3;

R81is a 5-6-membered heterocyclyl, optionally substituted C1-6by alkyl; and

R82represents a hydrogen or halogen.

In one embodiment, X represents CH2. In another embodiment, X is a C=O.

In one embodiment, m is 0. the another embodiment, m is 1. In another embodiment n is 0. In another embodiment, n is 1.

In one embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is equal to 3.

In one embodiment, R81represents a 5-membered heterocycle. In another embodiment 5-membered heterocycle substituted With1-6the alkyl. In another embodiment, R81represents a 6-membered heterocycle. In another embodiment 6-membered heterocycle substituted With1-6the alkyl.

In one embodiment, R82represents hydrogen. In another embodiment, R82represents a halogen.

In one embodiment, the connection is:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer.

In yet another example implementation of the proposed compound of the following formula:

or its pharmaceutically acceptable salt, MES, prodrug or stereoisomer.

Proposed connection encompass all possible stereoisomers, unless the specific stereochemistry. In cases where the proposed connection contains alkenylphenol or alkenylamine group, the compound may exist as one or a mixture of geometric CIS/TRANS (or Z/E) isomers. In cases where structural isomers are vzaimoprevrascheny, overcoming low energy barrier, the compound may exist as one tautomer or mixture of tautomers. This can take the form of proton tautomerism in the compound, which contains, for example, imino, keto-or oximo group, or so-called valence tautomerism in the compound containing the aromatic fragment. From this it follows that one connection can be more than one type of isomerism.

Proposed in the description of the compounds may be enantiomerically pure, such as a single enantiomer or a single diastereoisomer, or a mixture of stereoisomers, such as a mixture of enantiomers, racemic mixture, or a mixture of diastereomers. In this regard, the specialist in the art it will be clear that the introduction of the compound in its (R)form is equivalent, in the case of compounds that are epimerizationin vivothe introduction of the compound in its (S)-form. Conventional methods of acquisition/allocation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis and the achiral starting compounds or the separation of a mixture of enantiomers, for example, using chiral chromatography, recrystallization, separation, formation of diastereoisomeric salts or derivatization in diastereomeric adducts with further separation.

When offered the compound contains an acidic or basic group, it can also be provided in the form of pharmaceutically acceptable salts (see, Berge et al., J. Pharm. Sci., 1977, 66, 1-19 and "Handbook of Pharmaceutical Salts, Properties, and Use", Stahl and Wermuth, Ed., Wiley-VCH and VHCA, Zurich, 2002).

Suitable acid to obtain pharmaceutically acceptable salts include, as non-limiting examples, acetic acid, 2,2-dichloracetic acid, an acetylated amino acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzosulfimide acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, Caproic acid, Caprylic acid, cinnamic acid, citric acid, reklamowy acid, cyclohexanesulfamic acid, dodecylthio acid, ethane-1,2-disulfonate acid, econsultancy acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactarate acid, entityname acid, glucoheptonate acid, D-gluconic acid, D-glucuronic acid is, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, Hydrobromic acid, hydrochloric acid, yodiewonderdog acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-almond acid, methanesulfonate acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonate acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, butyric acid, Orotava acid, oxalic acid, palmitic acid, pambou acid, perchloro acid, phosphoric acid, L-pyroglutamic acid, sugar acid, salicylic acid, 4-aminosalicylic acid, sabotinova acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, ticinobuy acid, p-toluensulfonate acid, undecylenoyl acid and valeric acid.

Suitable base to obtain pharmaceutically acceptable salts include, as non-limiting examples of inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide, and oranicheskih bases, such as primary, secondary, tertiary, and Quaternary, aliphatic and aromatic is practical amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, Diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, Ethylenediamine, Isopropylamine, N-methylglucamine, geranamine, 1H-imidazole, L-lysine, Marylin, 4-(2-hydroxyethyl)morpholin, methylamine, piperidine, piperazine, Propylamine, pyrrolidine, 1-(2-hydroxyethyl)pyrrolidine, pyridine, Hinkley, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propandiol and tromethamine.

The proposed connection may also be provided in the form of a prodrug, which is a functional derivative compounds and are readily converted to the parent compoundin vivo. Prodrugs are often useful because, in some cases, they can more easily entered than the parent compound. They can, for instance, be bioavailable by oral administration, while the parent compound is not. The prodrug may also have high solubility in pharmaceutical compositions over the parent compound. The prodrug may be transformed in the parent drug by various mechanisms, including enzymatic processes and metabolic transformation by hydrolysis. Cm. Harper,Progress in Drug esearch 1962,4,221-294; Morozowich et al. in Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs", Bundgaard, Elsevier, 1985; Wang et al.,Curr. Pharm. Design1999,5, 265-287; Pauletti et al.,Adv. Drug. Delivery Rev.1997,27,235-256; Mizen et al.,Pharm. Biotech.1998,11,345-365; Gaignault et al.,Pract. Med. Chem.1996,671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems, Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al.,Eur. J. Drug Metab. Pharmacokinet.1990,15,143-53; Balimane and Sinko,Adv. Drug Delivery Rev.1999,39,183-209; Browne,Clin. Neuropharmacol.1997,20,1-12; Bundgaard,Arch. Pharm. Chem.1979,86,1-39; Bundgaard,Controlled Drug Delivery1987,17,179-96; Bundgaard,Adv. Drug Delivery Rev.1992,8,1-38; Fleisher et al.,Adv. Drug Delivery Rev.1996,19,115-130; Fleisher et al.,Methods Enzymol.1985,112,360-381; Farquhar et al.,J. Pharm. Sci.1983,72,324-325; Freeman et al.,J. Chem. Soc., Chem. Commun.1991,875-877; Friis and Bundgaard,Eur. J. Pharm. Sci.1996,4,49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs,1977,409-421; Nathwani and Wood,Drugs1993,45,866-94; Sinhababu and Thakker,Adv. Drug Delivery Rev.1996,19,241-273; Stella et al.,Drugs1985,29,455-73; Tan et al.,Adv. Drug Delivery Rev.1999,39,117-151; Taylor,Adv. Drug Delivery Rev.1996,19,131-148; Valentino and Borchardt,Drug Discovery Today1997,2,148-155; Wiebe and Knaus,Adv. Drug Delivery Rev.1999,39,63-80; and Waller et al.,Br. J. Clin. Pharmac.1989,28,497-507.

4.3. METHODS of TREATMENT, PREVENTION AND CONTROL

p> In one embodiment provides methods of treating, preventing and/or controlling various diseases or disorders using offer in the description of compounds, including a single enantiomer, mixture of enantiomers, or a mixture of diastereomers, or pharmaceutically acceptable salt, MES or prodrug. Not limited to a particular hypothesis, proposed connection can control angiogenesis or inhibit the production of certain cytokines, including, as non-limiting examples of TNF-α, IL-1β, IL-12, IL-18, GMCSF (GM-CSF, granulocyte-macrophage-colony stimulating factor) and/or IL-6. Not limited to a particular hypothesis, proposed connection can stimulate the production of several other cytokines, including IL-10, and dejstvovatj as co-stimulating signal to activate T cells, leading to increased production of cytokines, such as, as non-limiting examples of IL-12 and/or IFN-γ (IFN-γ). In addition, the proposed connection can increase the activity of NK-cells (natural killer cells) and antibody-dependent cellular cytotoxicity (ADCC, ADCC). In addition, the proposed connection can be immunomodulatory and/or cytotoxic and, thus, can be used as chemotherapeutic agents. Therefore, not limited to skretny assumption, some or all of these characteristics, which have proposed connection can make them useful for use in the treatment, control and/or prevention of various diseases or disorders. In one example implementation of the present compounds are cytotoxic.

Diseases or disorders amenable to treatment methods include, as non-limiting examples, cancer, disorders associated with angiogenesis, pain, including complex regional pain syndrome ("crbs"), macular degeneration ("MD") and related syndromes diseases of the skin, disorders of the lungs caused by asbestos disorders, parasitic diseases, immunodeficiency States, disorders of the Central nervous system, CNS injury, atherosclerosis and related disorders, sleep disorders and related disorders, hemoglobinopathies and related disorders (such as anemia), associated with α and other cytokines disorders and other various diseases and disorders.

Examples of cancer and precancerous conditions include, as non-limiting examples are described in U.S. patent No. 6281230 and 5635517 Muller et al., in the publications U.S. patents Zeldis, including publication No. 2004/0220144Al, published on 4 November 2004 (Treatment of Myelodysplastic Syndrome), 2004/0029832A1, published February 12, 2004 (Treatment of Varion Types of Cancer), and 2004/0087546, published may 6, 2004 (Treatment of Myeloproliferative Diseases). Examples also include diseases that are described in PCT/US04/14004, registered on may 5, 2004. All these links are included in this description in full by reference.

Examples of cancer include, as non-limiting examples of skin cancers such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; thyroid; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages and associated with AIDS and cancer. The proposed compounds are useful for the treatment of cancer of the blood and bone marrow, such as myeloma and acute or chronic leukemia, for example, lymphoblastic, myelogenous, lymphocytic and military leukemia. The proposed connection can be used for the treatment, prevention or control of primary or metastatic tumors.

Other examples of cancer include, as non-limiting examples, the tumor at a later stage, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, polymorphic glioblastomas, glioblastoma, glioma, brain stem, poor prognosis brain cancer, malignant gliomas is, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, colorectal cancer stages C and D for Duke, irresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acute myeloid leukemia with different karyotype, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, nehodgkinski lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse both B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma (localized melanoma, including, as non-limiting examples, melanoma of the eye), malignant mesothelioma syndrome pleural effusion in malignant mesothelioma, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cells Langerhans, leimyosarcoma, fibrodysplasia references for additional information progressive, harmonistically prostate cancer, resected soft tissue sarcoma with a high risk, irresectable hepatocellular carcinoma, macroglobulinemia waldenstrom, "smoldering" myeloma, indolent myeloma, cancer of the fallopian tubes, androge the-independent prostate cancer, androgen-dependent non-metastatic prostate cancer stage IV, hormonerefractory prostate cancer, insensitive to chemotherapy prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary carcinoma of the thyroid gland and leiomyoma. In some embodiments of the invention the cancer is metastatic. In some embodiments of the invention the cancer is resistant or refractory to chemotherapy or radiation.

In another exemplary embodiment provides methods of treatment, prevention or control of various forms of leukemia, such as chronic lymphocytic leukemia, chronic miliitary leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia, including leukemia that is recurrent, resistant or resistant, as described in published U.S. patent No. 2006/0030594 published February 9, 2006, which is incorporated into this description by reference in full. The term "leukemia" refers to a cancer of the blood forming tissues. Leukemias include, as non-limiting examples, chronic lymphocytic leukemia, chronic miliitary leukemia, acute lymphoblastic leukemia, acute myelogenous, lakosi acute myeloblastic leukemia. Leukemia can be recurrent, immune or resistant to tradizionnoi therapy. The term "recurrent" refers to a situation where patients who had remission of leukemia after therapy, return leukemia cells in the bone marrow and there is a reduction of normal blood cells. The term "immune or resistant" refers to cases where the patients even after intensive therapy are residual leukemic cells in their bone marrow.

In still another embodiment provides methods of treating, preventing or controlling various types of lymphomas, including nehodgkinski lymphoma (NHL, NHL). The term "lymphoma" refers to a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. "NHL" refers to malignant monoclonal proliferation of lymphoid cells in parts of the immune system, including lymph nodes, bone marrow, spleen, liver and gastrointestinal tract. Examples of NHL include, as non-limiting examples, the lymphoma cells of the mantle zone, MCL, lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma, ILL, diffuse poorly differentiated lymphocytic lymphoma, PDL, centrocytes lymphoma, diffuse small cell with split cores lymphoma, DSCCL, fall is circular lymphoma and any type of lymphoma cells in the mantle zone, which can be seen under the microscope (nodular, diffuse, plasticheskuyu and the region of the mantle lymphoma).

Examples of diseases and disorders associated with or characterized by undesirable angiogenesis include, as non-limiting examples of inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, neovascular diseases of the eye, choroidal neovascular diseases, neovascular diseases of the retina and robes (neovascularization of the angle of the anterior chamber). Specific examples of diseases and disorders associated with or characterized by undesirable angiogenesis include, as non-limiting examples, endometriosis, Crohn's disease, cardiac insufficiency, progression of cardiac insufficiency, renal insufficiency, endotoxicosis, toxic shock syndrome, osteoarthritis, replication of a retrovirus, exhaustion, meningitis, caused by silica gel fibrosis caused by asbestos fibrosis, veterinary disorders caused by cancer hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia syndrome with a deletion of 5q.

Examples of pain include, as non-limiting examples are described in published U.S. patent No. 2005/0203142 published September 15, 2005 which is included in the present description by reference. Specific types of pain include, as non-limiting examples of nociceptive pain, neuropathic pain, mixed pain nociceptive and neuropathic pain, visceral pain, migraine, headache and postoperative pain.

Examples of nociceptive pain include, as non-limiting examples, the pain associated with chemical or thermal burns, cuts on the skin, bruises on the skin, osteoarthritis, rheumatoid arthritis, tendinitis and myofascial pain.

Examples of neuropathic pain include, as non-limiting examples, crbs type I, crbs type II, reflex sympathetic dystrophy (RSD RSD), reflex neurovascular dystrophy, reflex dystrophy, post-traumatic osteoporosis, causalgia, atrophy of sodeca bones, algoneurodystrophy, the syndrome of the shoulder, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia associated with cancer pain, phantom pain in the extremities, fibromyalgia, chronic fatigue syndrome, pain due to spinal cord injury, thalamic pain, radiculopathy, diabetic neuropathy, post-stroke pain, syphilis neuropathy and other painful neuropathic condition such as induced by drugs, such as vincristine and walk the D. As used, the term "complex regional pain syndrome", "crbs" and "crbs and related syndromes" means a chronic pain disorder characterized by one or more of the following: pain, spontaneous or induced, including allodynia (painful response to a stimulus that is not normally painful) and hyperalgesia (abnormally increased response to a stimulus, which is usually only slightly painful), the pain that is disproportionate to the underlying event (e.g., such as years of severe pain after stretching of the ligaments of the ankle joint), regional pain, which is not limited localization of a single peripheral nerve and autonomic dysregulation (e.g., swelling, change in blood flow and increased sweating)associated with trophic skin changes (abnormal growth of hair and nails and skin ulceration).

Examples of MD and related syndromes include, as non-limiting examples are described in published U.S. patent No. 2004/0091455, published may 13, 2004, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, atrophic (dry) MD, exudative (wet) AMD, age-related maculopathy (VMP), the choroidal neovascularization (CNV, CNVM), retinal detachment p is gentoo epithelium (PEI, PED) and atrophy of the retinal pigment epithelium (RPE RPE).

Examples of skin diseases include, as non-limiting examples described in the publication U.S. No. 2005/0214328 A1, published September 29, 2005, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, keratoses and related symptoms, skin diseases or disorders characterized by excessive growth of the epidermis, acne and wrinkles. As used, the term "keratosis" refers to any damage to the epidermis, characterized by the presence of a limited overgrowth of the Horny layer, including as non-limiting examples of actinic keratosis, seborrheic keratosis, keratoakantoma, follicular keratosis (illness Daria), inverted follicular keratosis, palmoplantar the keratoderma (LPK, PPK, keratosis palmaris et plantaris), hair keratosis and stucco keratosis. The term "actinic keratosis" also refers to the senile keratosis, senile keratosis, senile wart, plana senilis, solar keratosis, keratoderma or keratome. The term "seborrheic keratosis" also refers to seborrheic wart, senile wart, or the basal cell papilloma. Keratosis is characterized by one or more of the following symptoms: the appearance of roughness, che is wuchty, erythematous papules, plaques, spicules or nodules on open surfaces (e.g., face, hands, ears, legs and chest), pathological overgrowth of keratin, known as cutaneous horns, hyperkeratosis, telangiectasias, elastosis, pigmented lentigines, acanthosis, parakeratosis, dyskeratosis, papillomatosis, hyperpigmentation of basal cell cellular atypia, mitotic figures, atypical intercellular adhesion, dense inflammatory infiltrates and small spread of squamous cell carcinoma.

Examples of skin diseases or disorders characterized by excessive growth of the epidermis include, as non-limiting examples, any condition, disease or disorder characterized by excessive growth of the epidermis, including, as non-limiting examples of infections associated with human papilloma virus, arsenokoitai, the sign of Leser-Trelat, the warty discreta (DB, WD), pochobradsky hair (PS, TS), erythrokeratodermia variable (EQ, EKV), desquamative erythroderma newborn (harlequin ichthyosis), congenital slowtest fingers, skin melanocytoma, parakeets, psoriasis, squamous cell carcinoma, confluent papular papillomatosis (SPP CRP), soft warts, cutaneous horn, disease Caudina (syndrome polymorphic hamartomas), papular dermatosis blacks (map DPN), syndrome epidermal nevus (SEN, ENS), vulgar ichthyosis, molluscum contagiosum, knotted the prurigo and black acanthosis (CHA, AN).

Examples of disorders of the lung include, as non-limiting examples described in the publication U.S. No. 2005/0239842 A1, published October 27, 2005, which is incorporated into this description by reference. Specific examples include pulmonary hypertension and related disorders. Examples of pulmonary hypertension and related disorders include, as non-limiting examples of primary pulmonary hypertension (MRO, PPH), secondary pulmonary hypertension (VLG, SPH), family MRO, sporadic MRO, precapillary pulmonary hypertension, pulmonary arterial hypertension (LAG, PAH), pulmonary artery hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy (ASHES TPA), plexogenic pulmonary arteriopathy, functional classes I to IV pulmonary hypertension and pulmonary hypertension associated with, related to or which is a complication as a result of dysfunction of the left ventricle, mitral valve heart, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous return, occlusive pulmonary veins, collagenosis vessels, congenital heart disease, HIV viral infections is AI, drugs and toxins, such as fenfluramine, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, disorders of breathing during sleep, alveolar hypoventilation, chronic exposure to high altitude, lung disease in newborns, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorders, chronic thromboembolic disease, connective tissue disease, lupus, including systemic and cutaneous lupus, schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis.

Examples caused by asbestos disorders include, as non-limiting examples described in the publication U.S. No. 2005/0100529, published may 12, 2005, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, mesothelioma, asbestosis, malignant pleural effusion, benign pericardial effusion, pleural plaques, pleural calcification, diffuse pleural layering, round atelectasis, fibrous mass and lung cancer.

Examples of parasitic diseases include, as non-limiting examples described in the publication U.S. No. 2006/0154880, published on 13 July 2006, which is incorporated in the present description the s by reference. Parasitic diseases include diseases and disorders caused by intracellular parasites of man, such as, as non-limiting examples,P. falcifarium, P. ovale, P. vivax, P. malariae, L. donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana, L. braziliensis, T. gondii, B. microti, B. divergens, B. coli, C. parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S. haematobium, Trypanosoma spp., Toxoplasma spp., and O. volvulus.Also covered other diseases and disorders caused by non-human intracellular parasites such as, as non-limiting examples,Babesia bovis, Babesia canis, BanesiaGibsoni, Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp.,Hammondia ssp. andTheileria ssp. Specific examples include as non-limiting examples of malaria, babesiosis, trypanosomes, leishmaniasis, toxoplasmosis, encephalitis, keratitis, amebiasis, giardiasis, cryptosporidiosis, infectious diarrheas, ciclosporin, microsporidiosis, ascariasis, trichocephalosis, hookworm, Strongyloides, toxocariasis, trains, lymphatic filariasis, onchocerciasis, filariasis, schistosomiasis, and dermatitis caused by Schistosoma.

Examples of immune disorders include, as non-limiting examples described in the publication U.S. No. 2006/0188475 published August 24, 2006, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, the lack of adenosines Inez, the antibodies deficiency with normal or elevated levels of immunoglobulins (Ig), ataxia-telangiectasia syndrome bare lymphocyte variable unclassifiable immune deficiency, deficit Ig with excessively high IgM, deletions heavy chain Ig, IgA deficiency, immunodeficiency with thymoma, reticular dysgenesis syndrome Nezelof isolated deficiency of IgG subclasses-type, the transient hypogammaglobulinemia newborn syndrome Wiskott-Aldrich, agammaglobulinemia, coupled with X-linked agammaglobulinemia, severe combined immunodeficiency, coupled with the X-chromosome.

Examples of CNS disorders include, as non-limiting examples described in the publication U.S. No. 2005/0143344 A1, published on 30 June 2005, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neuro disorders, such as Tourette syndrome, delirium or disturbance in consciousness that occur over a short period of time, and amnestic syndrome, or small changes in memory that occur in the absence of other impairments of the Central nervous system.

Examples of CNS injuries and related syndromes include, the quality is TBE non-limiting examples, described in the publication U.S. No. 2006/0122228, published June 8, 2006, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, trauma/damage to the Central nervous system and related syndromes include, as non-limiting examples, the primary brain injury secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, head injury, concussion, post-concussion syndrome, bruising and tearing of the brain, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, full PSM (spinal cord injury, SCI), incomplete PSM, acute PSM, subacute PSM, chronic PSM syndrome Central paralysis syndrome Broun-Séquard syndrome paralysis as a result of violations in the anterior part of the spinal cord, brain syndrome cone, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, vomiting, loss of memory, dizziness, double vision, blurred vision, emotional instability, sleep disturbances, irritability, inability to concentrate, increased anxiety, behavioral disorders, cognitive abilities and seizures.

Other diseases or disorders include the, as non-limiting examples of viral, genetic, allergic, and autoimmune diseases. Specific examples include, as non-limiting examples, HIV, hepatitis, acute respiratory distress syndrome in adults, diseases of bone resorption, chronic inflammatory lung diseases, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, postischemic reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft-versus-host graft rejection, autoimmune disease, rheumatoid spondylitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ENL in leprosy, radiation damage cancer, asthma or gipertoksicheskaya alveolar damage.

Examples of atherosclerosis and related conditions include, as non-limiting examples described in the publication U.S. No. 2002/0054899, published may 9, 2002, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, all types of conditions related to atherosclerosis, including restenosis after vascular interventions, such as angioplasty, stenting, ATERA Tome and transplantation. All interventions on vessels described, including diseases of the cardiovascular and urinary systems, such as, as non-limiting examples, angioplasty of the renal vessels, percutaneous coronary intervention (PCI, and PCI, percutaneous transluminal coronary angioplasty (PTCA, PTCA), percutaneous transluminal angioplasty of the carotid artery (ČTK, PTA), transplantation coronary artery bypass grafting, angioplasty with stent implantation, peripheral percutaneous transluminal intervention in the iliac, femoral or popliteal arteries, and the operation with the use of impregnated synthetic grafts. In the next part presents a list of the major systemic arteries, which may be in need of treatment, which are all discussed in the description:

ArteryThe supply part of the body
AxillaryShoulders, armpit
ShoulderThe upper part of the hand
BrachiocephalicHead, neck & hand
The Czech Republic is main Divides into the left gastric, splenic and hepatic artery
Common carotidNeck
Common iliacDivided into external and internal iliac artery
CoronaryHeart
Deep femoralHip
FingerFingers
Dorsal artery of the footFeet
The external carotidThe neck and the outer area of the head
External iliacFemoral artery
HipHip
StomachStomach
HepaticThe liver, gall bladder, pancreas and duodenum
Lower brygian the I The descending colon, the rectum and the pelvic wall
The internal carotidNeck and internal head
Internal iliacRectum, bladder, genitals, thigh muscles, uterus and vagina
The left gastricThe esophagus and stomach
Median sacralThe sacrum
OvarianOvaries
Palmar archHand
Small tibiaCaviar
PoplitealKnees
Hind tibiaCaviar
PulmonaryLight
BeamForearm
Renal Kidney
SplenicThe stomach, pancreas and spleen
SubclavianShoulder
Superior mesentericPancreas, small intestine, ascending and transverse colon
TesticularTesticles
ElbowForearm

Examples of sleep disorders and related syndromes include, as non-limiting examples described in the publication U.S. No. 2005/0222209 A1, published October 6, 2005, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, snoring, sleep apnea, insomnia, narcolepsy, tired leg syndrome, fear of sleep, walking during sleep, eating during sleep and sleep disorders associated with chronic neurological or inflammatory conditions. Chronic neurological or inflammatory condition include, as non-limiting examples, complex regional pain syndrome, chronic pain in lower back, musicnotes the pain, arthritis, radiculopathy, pain associated with cancer, fibromyalgia, chronic fatigue syndrome, visceral pain, pain in the bladder, chronic pancreatitis, neuropathy (diabetic, herpetic, traumatic or inflammatory and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, bradykinesia; muscle rigidity; parkinsonii tremor; parkinsonism gait; physical lethargy; depression; impaired long-term memory syndrome Rubinstein-Taybi (CPT, RTS); dementia; postural instability; hypokinetic disorders; due synuclein disorders; multiple system atrophy; striatonigral degeneration; oligometastases atrophy; syndrome Shay-Drager; motor neuron disease with parkinsonism features; the disease is diffuse Taurus Levi; associated with Tau pathology disorders; progressive supranuclear palsy; kortiko-basal degeneration; frontotemporal dementia; associated with amyloid pathology disorders; mild cognitive impairment; Alzheimer's disease to Parkinson's disease; Wilson's disease; disease Hallervorden-Spitze; disease Chediak-Higashi; spinal-cerebellar ataxia degree 3 SCA-3; X-is plenny syndrome dystonia-parkinsonism"; prion disease; hyperkinesia; horey; ballism; dystonia tremor; amyotrophic lateral sclerosis (ABS, ALS); injury to the Central nervous system and myoclonus.

Examples of hemoglobinopathy and related disorders include, as non-limiting examples described in the publication U.S. No. 2005/0143420 A1, published on 30 June 2005, which is incorporated into this description by reference. Specific examples include, as non-limiting examples, hemoglobinopathies, sickle cell anemia and other disorders related to cell differentiation of CD34+.

Examples of disorders associated with α and other cytokines include, as non-limiting examples are described in WO 98/03502 and WO 98/54170, both included in the present description by reference in full. Specific examples include, as non-limiting examples, endotoxicosis or toxic shock syndrome; cachexia; acute respiratory distress syndrome in adults; diseases of bone resorption, such as arthritis; hypercalcemia; graft-versus-host; cerebral malaria; inflammation; tumor growth; chronic inflammatory lung diseases; reperfusion injury; myocardial infarction; stroke; circulatory shock; rheumatoid arthritis; Crohn's disease; HIV and AIDS; other disorders, such as revmatoidnyi arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions, septic shock, sepsis, endotoxic shock, graft-versus-host wasting, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ENL in leprosy, HIV, AIDS and opportunistic infections in AIDS; associated with camp disorders, such as septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, or oncogenic cancer status, asthma, autoimmune disease, radiation injury and gipertoksicheskaya alveolar damage; viral infections such as caused by herpes viruses; viral conjunctivitis or atopic dermatitis.

In some embodiments of the invention also is the use of the proposed compounds in various immunological applications, in particular as adjuvants in vaccines, especially adjuvant in cancer vaccines, as described in the publication U.S. No. 2007/0048327, published on 1 March 2007, which is incorporated into this description by reference in full. This fitting description also applies to the application of the proposed compounds in combination with vaccines for the treatment or prevention of cancer or infectious diseases, and other various applications immunomodulatory compounds, such as reduction or desensitization of allergic reactions.

Depending on the condition, disorder or disease being treated, and the condition of the subject of the proposed connection may be administered via oral, parenteral (e.g. intramuscular injection, administered intraperitoneally, intravenously, ICV (inside the brain ventricles), intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual and/or local (e.g., transdermal or local) routes of administration and may be composed of one or together in a suitable unit dose with a pharmaceutically acceptable excipient, carrier, diluent, auxiliary substance or mixture suitable for each route of administration.

The dose may be in the form of one, two, three, four, five, six or more subdot, which are inserted through suitable intervals during the day. Dose or subdata can be entered in the form of a unit dose containing from about 0.1 to about 1000 mg, from about 0.1 to about 500 mg, or approximately 0.5 to approximately 100 mg of active agent(s) per unit dose, and, if the patient's condition requires, the dose may, alternatively, be given by continuous infusion.

what some examples of the invention, the suitable level of dose is about 0.01 to approximately 100 mg per kg of body weight of the patient per day (mg/kg / day), about 0.01 to about 50 mg/kg / day, about 0.01 to about 25 mg/kg / day, or about 0.05 to about 10 mg/kg / day, which can be entered in single or multiple doses. Suitable level of dosage may be about 0.01 to about 100 mg/kg / day, about 0.05 to about 50 mg/kg / day, or about 0.1 to about 10 mg/kg / day. Within this range the dosage may be about 0.01 to about 0.1, approximately 0.1 to approximately 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg / day.

For oral administration the pharmaceutical compositions may be provided in the form of tablets containing 1.0 to 1000 mg of active agent, in particular about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1000 mg of active agent for symptomatic dose selection the patient under treatment. Compositions could the t to enter the regimen of 1-4 times a day, including, once, twice, three times or four times a day.

However, it will be understood that the specific dose and dosing frequency for any particular patient may vary depending on a number of factors, including the specific activity of the applied compound, the metabolic stability and length of action of this compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, combination lekarstvennih means, gravity specific state and organism being treated.

4.4. ADDITIONAL ACTIVE AGENTS

The proposed compounds may also be combined or used in combination with other therapeutic agents used in the treatment, prevention and/or control of various diseases or disorders, which are used for the proposed connection. Assume that some combinations can work Energetichesky in the treatment of specific types of diseases or disorders as well as conditions and symptoms associated with such diseases or disorders. The proposed connection, including a single enantiomer, mixture of enantiomers, or a mixture of diastereomers or pharmaceutically acceptable salt, MES or prodrug, can also work to facilitate blagopri the governmental activities, related with certain additional active agents, and Vice versa.

As used, the term "in combination" includes the use of more than one therapeutic agent. However, the use of the term "in combination" does not restrict the order or manner in which therapeutic agents are introduced to the subject with a condition or disorder. First terapeuticas agent (e.g., a therapeutic agent, such as the proposed connection) may be administered prior to (e.g., 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 1 week, 2 weeks., 3 weeks, to 4 weeks., 5 weeks, in 6 weeks., 8 weeks. or 12 weeks. before, simultaneously with, or after (e.g., after 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 1 week, 2 weeks., 3 weeks, to 4 weeks., 5 weeks, in 6 weeks., 8 weeks. or 12 weeks. after the introduction of an additional therapeutic agent to the subject being treated.

Suitable specific route of administration used for the specific active agent will depend on the active agent (e.g., whether it can be administered orally without destruction before getting into the bloodstream) and subjected to treatment of the disease. In some embodiments of the invention, the method of introduction of the proposed compounds is oral. In some embodiments of the invention, methods of introducing additional active ingredients or offer the x components are described in the "Physicians' Desk Reference", 1755-1760 (56thed., 2002).

In one embodiment, the additional active agent is administered intravenously or subcutaneously once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. of a Specific amount of an additional active agent will depend on the specific agent type being treated or controlled disease, the severity or stage of the disease and the number of proposed connections and any optional extension active agents simultaneously injected to the patient.

In some embodiments of the invention features a method of reducing, treating and/or preventing adverse or unwanted effects associated with conventional treatment, including, as non-limiting examples, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy and immunotherapy. The proposed compounds and other active agents can be administered to the patient before, during or after the appearance of adverse effects associated with conventional therapy.

When the proposed connection is used simultaneously with one or more therapeutic agents may note the rise of the pharmaceutical composition, containing such other agents in addition to the proposed connection, but this is not necessary. Thus, the proposed pharmaceutical compositions include compositions that also contain one or more other therapeutic agents, in addition to the proposed connection.

One or more additional active ingredients or agents can be used in the proposed methods or compositions. Additional active agents may represent large molecules (e.g. proteins) or small molecules (e.g., synthetic inorganic, ORGANOMETALLIC or organic molecules).

Examples of active agents with large molecules include, as non-limiting examples, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Specific examples of active agents are monoclonal antibodies against CD40 (such as, for example, SGN-40, Herceptin, rituximab); inhibitors discontiuation (such as, for example, SAHA and lunar abyss 824); inhibitors of heat shock protein 90 (such as, for example, 17-AAG); inhibitors of kinase receptor insulin-like growth factor-1; inhibitors of the kinase growth factor receptor vascular endothelial (such as, for example, PTK787); inhibitors of the receptor, insulin growth factor inhibitors alltran feraz lysophosphatidic acid; inhibitors of IkB kinase, p38MAPK inhibitors; inhibitors REPR (EGFR, the receptor for epidermal growth factor) (such as, for example, gefitinib and erlotinib HCL), antibodies to HER-2 (such as, for example, trastuzumab (Herceptin®) and pertuzumab (Omnitarg™)); antibodies to RRES (receptor of VEGF, VEGFR) (such as, for example, bevacizumab (Avastin®); inhibitors RFRAS (such as, for example, specific inhibitors of the kinase flk-1, SU5416 and ptk787/zk222584); inhibitors of P13K (such as, for example, wortmannin); inhibitors of C-Met (such as, for example, PHA-665752); monoclonal antibodies (such as, for example, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab (Panorex®) and G250) and antibodies against TNF-α. Examples of active agents with small molecules include, as non-limiting examples of anticancer agents with small molecule antibiotics (eg, clarithromycin).

Specific additional active compounds that can be combined with the proposed compounds vary according to specific indications, which are subjected to a treatment, prevention or control.

For example, for the treatment, prevention or control of cancer additional active ingredients include, as non-limiting examples, semaxanib, cyclosporin, etanercept, doxycycline, bortezomib, acivicin, aclarubicin, Hakodate hydrochloride, Cronin, adozelesin, Allesley is in, altretamine, ambomycin, ametantrone acetate, amsacrine, anastrozole, astromicin, asparaginase, aspirin, azacytidine, asettaa, azotomycin, batimastat, benzodepa, bikalutamid, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustin, karubitina hydrochloride, carzelesin, Cedeira, celecoxib, chlorambucil, cirolemycin, cisplatin, cladribine, krishnalila mesilate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, decompletion, deazaguanine, deazaguanine mesilate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, deatomizer, edatrexate, eflornithine hydrochloride, elsamitrucin, angloplats, enpromate, epirubicin, epirubicin hydrochloride, arbolada, zorubicin hydrochloride, estramustin, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, atopen, fadrozole hydrochloride, fazarabine, phenetidine, floxuridine, fludarabine phosphate, fluorouracil, fluorocytosine, voskuilen, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubitsina hydrochloride, ifosfamide, ilmofosine, iproplatin, irinotecan, irinotecan hydrochloride, lanreotide and the Etat, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustin, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, Matorin, maturetube, maintain, miacalcin, mitotropin, mitogillin, mitomycin, mitomycin, mitosis, mitotane, mitoxantrone hydrochloride, mycophenolate acid, nocodazole, nogalamycin, ormaplatin, oxysure, paclitaxel, pegaspargase, polymycin, pentamycin, peplomycin sulfate, perforated, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomelin, porfimer sodium porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ibuprin, safingol, safingol hydrochloride, semustine, contrast, Cartosat sodium, sparsomycin, spirogermanium hydrochloride, spiramycin, spiroplatin, streptonigrin, streptozocin, alienor, talisayan, tecogen sodium, Taxotere, tegafur, Alexandrina hydrochloride], teniposide, teraxion, testolactone, timipre, tioguanin, thiotepa, tianfuan, tirapazamine, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate the glucuronate, triptorelin, tabulate hydrochloride, uracil mustard, uredepa, vapreotide, Vert is porphin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, wikepidia sulfate, singleseat sulfate, villarsia sulfate, vinorelbine tartrate, veneroidea sulfate, ventricina sulfate, vorozole, triplatin, zinostatin and zorubicin hydrochloride.

Other additional active agents include, as non-limiting examples, 20-EPI-1,25 dihydroxyvitamin D3; 5-itinerarary; abiraterone; aclarubicin; allpole; Adelina; adozelesin; aldesleukin; antagonists ALL-TK; altretamin; ambamustine; amidax; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; Andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; entrelacs; antidyslipidemic morphogenetic protein-1; antiandrogen, in the case of prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; gene modulators of apoptosis; regulators apoptosis; apurinovaya acid; ara-CDP-DL-PTBA; arginine-deaminase; Bulacan; atamestane; attemptin; achinstein 1; achinstein 2; achinstein 3; azasetron; anatoxin; asteroid; derivatives baccatin III; balana; batimastat; antagonists BCR/ABL; benzocaine; benzoyltartaric; beta-lactam derivatives, beta-alamin; butaclamol B; Betulinol acid; inhibitor off (bFGF, basic fibroblast growth factor); bicalutamid is; pesantren; besuseradminclient; bisnafide; bitraten A; bizelesin; Brevet; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; derivatives camptothecin; capecitabine; aminotriazol-carboxamide; carboxamidates; CaRest M3; CARN 700; originating from cartilage inhibitor; carzelesin; inhibitors of casein kinase (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chlorphenoxamine the sulphonamide; cicaprost; CIS-porphyrin; cladribine; analogues clomiphene; clotrimazole; colimycin a; colimycin B; combretastatin A4; analogues of combretastatin; convenin; kambezidis 816; Kristol; cryptophycin 8; derivatives cryptophycin a; curacin a; cyclopentadecanone; cyclopean; cephamycin; tsitarabina ocfosfate; cytolytic factor; cytostatin; daclizumab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; Taxifolin; dexrazoxane; dexverapamil; diazinon; didemnin B; detox; diethylnitrosamine; dihydro-5-azacytidine; dihydroxy; dioxazine; diphenylpyraline; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; elastin; edelfosine; edrecolomab; eflornithine; elements; Amateur; epirubicin; epristeride; similar estramustine; agonists of estrogen; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; phenetidine;filgrastim; finasteride; flavopiridol; fileselection; fluasterone; fludarabine; fortunemagazine hydrochloride; forenames; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; Galitsin; ganirelix; inhibitors gelatinase; gemcitabine; inhibitors of glutathione; HaSulam; heregulin; hexamethylene biocetamol; hypericin; ibandronate acid; idarubitsin; idoxifene; Idamante; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod; immunostimulating peptides; inhibitor of receptor insulin-like growth factor-1; interferon agonists; interferons; interleukins; iobenguane; iododeoxyuridine; 4-ipomeanol; isoplast; irsogladine; isomerases; isohemagglutinins B; fusetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; lanemile; lenograstim; lentinan sulfate; leptostachys; letrozole; inhibitory factor leukemia; alpha-interferon leukocyte; leuprolide + estrogen + progesterone; leiprorelina; levamisole; lioresal; similar linear polyamine; lipophilic disaccharide-peptide; lipophilic platinum compounds; lissoclinum 7; lobaplatin; lubricin; lometrexol; lonidamine; losoxantrone; doxorubin; lurtotecan; lutetium texaphyrin; letfullin; lytic peptides; maytansine; sandostatin a; marimastat; masoprocol; maspin; inhibitors matrilysin; inhibitors of matrix metalloproteinases; menage the sludge; merbanan; peterlin; methionine; metoclopramide; inhibitor MYTH (MIF factor, which inhibits the migration of macrophages); mifepristone; miltefosine; Miramistin; mitoguazone; mitolactol; analogues of mitomycin; mitonafide; micotoxin the fibroblast growth factor-saporin; mitoxantrone; Maarten; molgramostim; Erbitux, human chorionic gonadotropin; monophosphorylated lipid A + streptokinase myobacterial cell wall; mopidamol; ipitomy anticancer agent; megaproxy B; extract myobacterial cell wall; mylapore; N-azetidinone; N-substituted benzamide; nafarelin; Agresti; naloxone + pentazocine; nipawin; Natterer; nartograstim; nedaplatin; nemorubicin; Nejdanov acid; nilutamide; nizamul; modulators of nitric oxide; nitroxide antioxidant; nitrolon; oblimersen (Genasense®); O6-benzylguanine; octreotide; okizeme; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; asteron; oxaliplatin; axiomized; paclitaxel; analogues of paclitaxel, derivatives of paclitaxel; palyulin; palmitoylation; pamidronovu acid; panaxytriol; promife; pyrabactin; panelitem; pegaspargase; peltatin; pentosan polysulfate sodium; pentostatin; petrosal; perflubron; perforated; parallelly alcohol; fansinating; phenylacetate; ing bitory phosphatase; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placedin a; placein B; inhibitor of plasminogen activator; a complex of platinum; platinum compounds; complex platinum-triamine; porfimer sodium; porfiromycin; prednisone; propylbis-acridan; prostaglandin J2; inhibitors calpaine; immunomodulator on the basis of protein A, an inhibitor of protein kinase C, inhibitors of protein kinase C, microalgae; inhibitors tyrosinemia proteinopathy; phosphorylase inhibitors of purine nucleoside; purpurin; pyrazoloacridine; conjugate paradoxrecovery hemoglobin-polyoxyethylene; raf antagonist; raltitrexed; ramosetron; inhibitors farnesyl-proteincenter ras; ras inhibitors; inhibitors ras-GAP; demetilirovanny reality; ruthenium Re-186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romantic; roquinimex; rubiginosa B1; robaxin; safingol; sinepin; SarCNU; sarcophyton A; sargramostim; mimetics Sdi 1 (senescent cell-derived inhibitor 1); semustine; causing aging inhibitor 1; senovia oligonucleotides; inhibitors of signal transduction; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solvera; somatomedin-binding protein; sonarmen; sportsbuy acid; spicamycin D; spiramycin; splenopathy; spongistatin 1; squalamine; stipend; inhibitors stromelysin; sulfonation; antagonist overactive vasoactive what about putting peptide; coralista; suramin; swainsonine; tallimustine; tamoxifen-methodid; terramycin; tazarotene; tecogen sodium; tegafur; tolerability; telomerase inhibitors; ]; teniposide; tetrachlorodecaoxide; tetrasomy; teleblaster; thiocoraline; thrombopoietin; mimetic of thrombopoetin; thymalfasin; agonist of the receptor of thymopoietin; timorian; thyrostimulin hormone; tin-utilityperson; tirapazamine; titanocene dichloride; topsentin; toremifene; inhibitors broadcast; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostin; inhibitors UBC; ubenimex; factor inhibiting the growth of urogenital sinus; antagonists urokinase receptor; vapreotide; variolin B; valarezo; vermin; verdini; verteporfin; vinorelbine; Wincanton; vitaxin; vorozole; sonotron; senility; salaskar and zinostatin stimulater.

Specific additional active agents include, as non-limiting examples, 2-methoxyestradiol, teamstation, inducers of apoptosis of multiple myeloma cells (such as, for example, TRAIL), statins, semaxanib, cyclosporine, etanercept, doxycycline, bortezomib, oblimersen (Genasense®), Remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, those who gifted, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Ariz (Arisa®), Taxol, Taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, alpha-interferon, Targeted alpha-interferon (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2 (IL-2), GM-CSF (GM-CSF, granulocyte-macrophage colony-stimulating factor), dacarbazine, vinorelbine, zoledronic acid, palpitant, biaxin, busulfan, prednisone, a bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac and etoposide.

Similarly, examples of specific additional agents depending on the indications for treatment, prevention or control can be found in the following references, which are incorporated in the present description in full: U.S. patent No. 6281230 and 5635517; application for U.S. patent No. 10/411649, 10/483213, 10/411656, 10/693794, 10/699154 and 10/981189; and provisional applications U.S. patent No. 60/554923, 60/565172, 60/626975, 60/630599, 60/631870 and 60/533862.

Examples of additional active agents which may be used to treat, prevent or control pain include as non-limiting examples of traditional medicines with the estva, used for the treatment or prevention of pain, such as antidepressants, anticonvulsants, antihypertensive agents, anxiolytics, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatory agents, inhibitors COX-2, immunomodulating agents, agonists or antagonists of alpha-adrenergic receptors, immunosuppressive agents, corticosteroids, hyperbaric oxygen, ketamine, other anesthetics, agonists of the NMDA (N-methyl-D-aspartate) and other drugs found, for example, in "Physician''s Desk Reference 2003. Specific examples include, as non-limiting examples, acetate, salicylic acid (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin (Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate, hydromorphone, prednisone, griseofulvin, pentony, alendronate, difengidramin, guanethidine, Ketorolac (Acular®), thyrocalcitonin, dimethylsulfoxide (DMSO), clonidine (Catapress®), brutily, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®), imipramine (Tofranil®), doxepin (Sinegvan®), to imipramin (Anafranil ®), fluoxetine (Prozac®)), sertraline (Zoloft®), nefazodone (Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion (Wellbutrin®), meksiletin, nifedipine, propranolol, tramadol, lamotrigine, ziconotide, ketamine, dextromethorphan, benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of additional active agents which may be used for the treatment, prevention or control of MD and related syndromes include, as non-limiting examples, a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neurotrophic factor, a regulator of the formation of new vessels, the antibody against VEGF, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or prevent the development of blood vessels connection or a combination of both. Specific examples include, as non-limiting examples, verteporfin purlytin, angiostatic steroids, ranibizumab (rhuFab, interferon-2α, pentoxifylline, complex tin with atopobium, motexafin lutetium, 9-fluoro-11,21-dihydroxy-16,17-l-methylethylidene(hydroxy)pregna-1,4-diene-3,20-dione, latanoprost (see U.S. patent No. 6225348), tetracycline and its derivatives, rifamycin and its derivatives, macrolides, metronidazole (U.S. patent No. 6218369 and 6015803), genistein, genistin, 6'-O-is lorganisation (6'-O-Mal, genistin), 6'-O-acetylcystein (6'-O-Ac genistin), daidzein, daidzin, 6'-O-malonaldehyde (6'-O-Mal daidzin), 6'-O-acetyldigoxin (6'-O-Ac daidzin), glycitein, glycitin, 6'-O-malonylglucosides (6'-O-Mal of glycitin), biochanin A, formononetin (U.S. patent No. 6001368), triamcinolone of acetonide, dexamethasone (U.S. patent No. 5770589), thalidomide, glutathione (U.S. patent No. 5632984), basic fibroblast growth factor (ORF), transforming growth factor b (TGF-b, TGF-b), neurotrophic factor brain (BDNF), a factor plasminogen activator type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and implant RETISERT (Bausch & Lomb). All of the above references is hereby incorporated into this description in full by reference.

Examples of additional active agents which may be used to treat, prevent and/or monitor diseases of the skin include, as non-limiting examples, keratolytics, retinoids, α-hydroxy acids, antibiotics, collagen, botulinum toxin, interferon, and immunomodulatory agents. Specific examples include, as non-limiting examples, 5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lactic acid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics, collagen, botulinum toxin, interferon, corticosteroids, TRANS-retinoic acid and collagen, such as placental collagen h the rights, placental collagen animal Dermalogen, Alloderm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Isoplast and Isolagen.

Examples of additional active agents which may be used for the treatment, prevention or control of pulmonary hypertension and related disorders include, as non-limiting examples, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, analogues of prostacyclin, endothelin antagonists, phosphodiesterase inhibitors (e.g., inhibitors of PDE V (PDE V)), inhibitors of endopeptidase, hypolipidemic agents, inhibitors of thromboxane and other drugs, which are known to reduce pulmonary artery pressure. Specific examples include, as non-limiting examples, warfarin (Coumadin®), diuretics, cardiac glycosides, digoxin oxygen, diltiazem, nifedipine, vasodilator, such as prostacyclin (for example, prostaglandin I2 (PG (PGI2)), epoprostenol (EPO, Floran®), treprostinil (Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine, epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine, iloprost, beraprost and sildenafil (Viagra®).

Examples of additional active agent is, which can be used for the treatment, prevention or control caused by asbestos disorders include, as non-limiting examples, anthracycline, platinum, alkylating agent, oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, pamidronate, biaxin, busulfan, prednisone, bisphosphonate trioxide arsenic, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline and gemcitabine.

Examples of additional active agents which may be used for the treatment, prevention or control of parasitic diseases include, as non-limiting examples, chloroquine, quinine, quinidine, pyrimethamine, sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine, primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin, suramin, pentamidine, melarsoprol, nifurtimox, benznidazole, amphotericin B, compounds of pentavalent antimony (for example, sodium stibogluconate), gamma-interferon, Itraconazole, conjunction is the dead of promastigote and BCG (Bacillus Calmette-guérin, BCG), leucovorin, corticosteroids, sulfonamide, spiramycin, IgG (serology), trimethoprim and sulfamethoxazole.

Examples of additional active agents which may be used for the treatment, prevention or control of immunodeficiency include, as non-limiting examples of antibiotics (therapeutic or prophylactic), such as, but without limiting this, ampicillin, clarithromycin, tetracycline, penicillin, cephalosporins, streptomycin, kanamycin, and erythromycin; anti-viral agents, such as, but without limiting this, amantadine, rimantadine, acyclovir, and ribavirin; immunoglobulin; plasma; immunoprophylaxis agents, such as, but without limiting this, levamisole and isoprinosine; biologics such as, but without limitations this, gamma-globulin, transfer factor, interleukins, and interferons; hormones such as, but without limitation this timony; and other immunologic agents such as, but without limitation, the stimulators of B-cells (e.g., BAFF/BlyS (B lymphocyte stimulator), cytokines (such as IL-2, IL-4 and IL-5), growth factors (such as TGF-α), antibodies (e.g., anti-CD40 and IgM), oligonucleotides containing neetilirovannye CpG-motifs (CG-motives), and vaccines (e.g., viral and tumor peptide vaccines).

Examples of additional active agents which can be used for the treatment of the Oia, prevention or control of CNS disorders include, as non-limiting examples, the agonist or antagonist of dopamine, such as, but not limited to, levodopa, L-DOPA, cocaine, α-methyltyrosine, reserpine, tetrabenazine, benzotropine, pargyline, vendorama mesilate, cabergoline, pramipexole, the dihydrochloride, ropinerole, amantadine hydrochloride, selegilina hydrochloride, carbidopa, pergolid mesilate, Sinemet-CF (Sinemet CR) and Symmetrel (Symmetrel); a MAO inhibitor, such as, but without limiting this, iproniazid, clorgyline, phenelzine and isocarboxazid; inhibitor COMT (catechin-O-methyltransferase), such as, but without limitation, the tolkapon and entacapone; a cholinesterase inhibitor, such as, but without limiting this, physostigmine salicylate, physostigmine sulfate, physostigmine bromide, neostigmine bromide, neostigmine the methyl sulfate, ambenonium chloride, Adriane chloride, taken, pralidoxime chloride, obidoxime chloride, trimedoxime bromide, diacetylenes, andriani, pyridostigmine and demecarium; anti-inflammatory agent, such as, but without limiting this, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, Rho-D immune globulin, mycophenolate mopete is, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, marennikova acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, timelet gold-sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone or betamethasone and other glucocorticoids; and antiemetic means, such as, but without limiting this, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine salt, alizapride, azasetron, benchenane, batanouny, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxybenzyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, tietilperazin, thioproperazine, tropisetron, and mixtures thereof.

Examples of additional active agents which may be used for the treatment, prevention or control of CNS injuries and associated si is Gromov, include, as non-limiting examples of immunomodulatory agents, immunosuppressive drugs, antihypertensive agents, anti-convulsants, anti-fibrinolytic tools, antiplatelet tools, antipsychotics, antidepressants, benzodiazepines, buspirone, amantadine and other known or conventional agents used in patients with trauma/damage to the Central nervous system and related syndromes. Specific examples include, but without limiting this, steroids (e.g., glucocorticoids, such as, but without limiting this, methylprednisolone, dexamethasone and betamethasone); anti-inflammatory agent, including, but without limiting this, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, immunoglobulin RHo-D, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, methenamine acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbuta is h, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, thiomalate gold-sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone; the analogue of camp, including, but without limiting this, dB-camp (db-cAMP); the agent containing the active ingredient methylphenidate, which contains l-trimethylpentyl, d-trimethylpentyl, dl-trimethylpentyl, l-eletromechanical, d-eletromechanical, dl-eletromechanical and mixtures thereof; and a diuretic, such as, but without limitation to these, mannitol, furosemide, glycerol and urea.

Examples of additional active agent that can be used for the treatment, prevention or control of sleep disorders and related syndromes include, as non-limiting examples, a tricyclic antidepressant, a selective inhibitor of serotonin reuptake, antiepileptic drug (gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam, topiramate), an antiarrhythmic agent that blocks sodium channel means, a selective inhibitor of mediator of inflammation, opioid agent, a second immunomodulatory compound, combined medicine and other known or conventional agents used in the treatment of sleep. Specific examples include, but without limitation, the neuron is in, oxycontin, morphine, topiramate, amitriptyline, nortriptyline, carbamazepine, levodopa, L-DOPA, cocaine, α-methyltyrosine, reserpine, tetrabenazine, benzotropine, pargyline, vendorama mesilate, cabergoline, pramipexole, the dihydrochloride, ropinerole, amantadine hydrochloride, selegilina hydrochloride, carbidopa, pergolid mesilate, sinemet-WED, symmetrel, iproniazid, clorgyline, phenelzine, isocarboxazid, tolkapon, entacapone, physostigmine salicylate, physostigmine sulfate, physostigmine bromide, neostigmine bromide, neostigmine the methyl sulfate, amrinone chloride, Adriane chloride, taken, pralidoxime chloride, obidoxime chloride, trimedoxime bromide, diacetylenes, andriani, pyridostigmine, demerary, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, immunoglobulin RHo-D, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, methenamine acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxia is, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, timelet gold-sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon, benzbromarone, betamethasone and other glucocorticoids, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benchenane, batanouny, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxybenzyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, tietilperazin, thioproperazine, tropisetron, and mixtures thereof.

Examples of additional active agents which may be used for the treatment, prevention or control of hemoglobinopathy and related disorders include, as non-limiting examples, the interleukins, such as IL-2 (including recombinant IL-II ("rIL2) and IL-2 virus Canaries (canarypox)), IL-10, IL-12 and IL-18; interferons, such as interferon Alfa-2a, interferon alpha-2b, interferon Alfa-n1, interferon Alfa-n3, interferon beta-Ia, and interferon gamma-Ib; and G-CSF (G-CSF, granulocyte colony-stimulating factor); hydroxyurea; butyrate or derivatives butyrate; nitrous oxide; GAOXIN THE (NIPRISAN™, see U.S. patent No. 5800819); antagonists Gardos channel (Ca2+-activated K+channel), such as clotrimazole, triarylmethane derivatives; deferoxamine; protein C and blood transfusion or blood products, such as Hemospan™ or Hemospan™ PS (Sangart).

The applied dose will depend on the rate of absorption, inactivation and excretion of drugs, as well as other factors known to specialists in this field of technology. It should be noted that the magnitude of the dose will also vary depending on the severity of the condition, which is easier. In addition, it should be understood that for any particular subject, specific schemes and dosing regimens should be adjusted over time according to individual needs and professional judgment involved the introduction of, or controlling the introduction of songs.

The mass ratio of the proposed connection and an additional active agent depends on the effective dose of each component. Typically, each will be applied in an effective dose. Thus, for example, when the proposed connection combined with a PPAR agonist (receptor-activated proliferation peroxisome) the mass ratio of the proposed connection and PPAR agonist will generally be from about 1000:1 to about 1:1000 or closer is Ino 200:1 - approximately 1:200. The combination of the proposed compounds and other active agents typically will also be within the aforementioned range, but in each case it is necessary to apply an effective dose of each active agent.

4.5. CYCLIC THERAPY

In some embodiments of the invention offer prophylactic or therapeutic agents are injected to the patient cyclically. Cyclic therapy involves the introduction of the active agent over a period of time followed by a rest during the period of time and repeating this sequential administration. Cyclic therapy can reduce the development of resistance to one or more therapies, to avoid or reduce the side effects of one of therapies and/or to improve the effectiveness of the treatment.

In some embodiments of the invention offer the connection is entered daily in single or divided into several doses dose for four to six week cycle with a rest period of approximately one week or two weeks. The invention additionally makes it possible to increase the frequency, number and duration of dosing cycles. In some embodiments of the invention offer the connection is introduced within larger cycles than usual when you enter one. In some examples, the wasp is estline of the invention the proposed connection is entered for a larger number of cycles, what would normally cause a dose-dependent toxicity in a patient, which additional active agent is applied.

In one example implementation of the present compound are introduced daily and continuously for three or four weeks at a dose from about 0.1 mg to about 500 mg per day followed by a break in one or two weeks. In other embodiments, the dose may be from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20 mg followed by a break.

In one example implementation of the present compound and the additional active agent are introduced orally, with the introduction of the proposed connection running for 30-60 minutes up to an additional active component during cycle four to six weeks. In another embodiment, the combination of the proposed connection and the additional active agent is administered by intravenous infusion over about 90 minutes each is of Tcl. In some embodiments of the invention the number of cycles during which the patient is combination therapy ranges from approximately one to approximately 24 cycles, from about two to about 16 cycles, or from approximately four to approximately three cycles.

4.6. PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

The pharmaceutical compositions can be used to generate individual dosage forms for a single injection. We offer pharmaceutical compositions and dosage forms contain the proposed compound or its pharmaceutically acceptable salt, MES, stereoisomer, or prodrug. We offer pharmaceutical compositions and dosage forms may optionally contain one or more auxiliary substances.

We offer pharmaceutical compositions and dosage forms can also contain one or more additional active agents. Examples of optional additional or incremental active agents are disclosed in Section 4.4 above.

The proposed dosage forms for a single injection are suitable for administration to a patient orally, through mucous membranes (e.g., nasal, sublingual, vaginal, buccal or rect the aspects), parenteral (e.g. subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topically (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous. Examples of dosage forms include, as non-limiting examples, tablets, caplet, capsules, such as soft gelatin capsules, starch wafers, cakes, candies, dispersion, suppositories, powders, aerosols (e.g., nasal sprays or inhalers), gels; liquid dosage forms suitable for administration orally or via the mucous membrane of the patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, emulsions oil-in-water or liquid emulsion, water-in-oil"), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient, eye drops or other ophthalmic preparations suitable for topical administration, and sterile solid form (e.g., crystalline or amorphous solid forms), which can be reconstructed to form a liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape and type of the proposed dosage forms will typically vary depending on their application. For example, a dosage form used for emergency treatment of the disease, can have in the howling part of a greater amount of one or more active components, it contains, than a dosage form used in long-term treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more active ingredients that it contains, than oral dosage form used to treat the same disease. These and other ways in which specific dosage forms according to this invention will vary from one another will be readily apparent to experts in this field. See, for example, "Remington''s Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA (1990).

In some embodiments of the invention offer the pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to experts in the field of pharmacy and offers non-limiting examples of suitable auxiliary substances. Whether a particular excipient suitable for introduction in the pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the manner in which the dosage form will be administered to the patient. For example, oral dosage forms such as tablets, may contain the substance of excipients, not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active components may accelerate some excipients, such as lactose, or when exposed to water. The active components, which contain primary or secondary amines, in particular, subject to such accelerated decomposition. Accordingly, this description encompasses pharmaceutical compositions and dosage forms that contain almost no lactose or other mono - or disaccharides. As used, the term "lactose-free" means that the amount of lactose that is present, if it occurs, is insufficient to significantly improve the speed of destruction of the active component.

Offer available from lactose compositions can contain auxiliary substances, which are well known in this area and are listed, for example, in the US Pharmacopoeia (USP) 25-NF20 (2002). As a rule, free from lactose compositions contain active components, a binder/filler, and a moving substance in pharmaceutically compatible and pharmaceutically acceptable amounts. In some embodiments of the invention offer aimie free from lactose dosage forms containing the active components, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The invention additionally encompasses anhydrous pharmaceutical compositions and dosage forms containing the active ingredients, since water can facilitate the destruction of some compounds. For example, the addition of water (for example, 5%) is widely distributed in pharmaceutical technology as a means of simulating long-term storage for assessing characteristics such as shelf-life or the stability of formulations over time. See, for example, Jens T. Carstensen "Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, the water and heat accelerate the degradation of some compounds. Thus, the influence of water on the composition can be of great importance, as are usually encountered with moisture and/or humidity during manufacturing, handling, packaging, storage, transportation and application of structures.

Offer anhydrous pharmaceutical compositions and dosage forms can be obtained by using anhydrous or low moisture content components and low moisture or low humidity. In some embodiments of the invention the pharmaceutical compositions and dosage forms that contain lactose and at least one active component that is going to win a primary or secondary amine, are anhydrous, when it is assumed substantial contact with moisture and/or humidity during manufacturing, packaging and/or storage.

Anhydrous pharmaceutical composition followed to produce and store so as to maintain its anhydrous state. In some examples of the invention, the anhydrous compositions are packaged using materials known as the preclusive effect of the water, so that they can be included in the appropriate formulary kits. Examples of suitable packaging include, as non-limiting examples, hermetically sealed foils, plastics, containers dose for one admission (for example, bottles, blister packaging and blister.

The invention additionally encompasses pharmaceutical compositions and dosage forms that contain one or more compounds that reduce the rate at which would decompose the active ingredient. Such compounds are called "stabilizers"include, as non-limiting examples of antioxidants, such as ascorbic acid, pH buffers, or salt buffers. Like the quantities and type of excipients, the number and specific types of active ingredients in the dosage form may vary depending on factors such as, as pogranicze the operating examples, the way in which they will be introduced to the patients. In some embodiments of the invention offer dosage forms contain the proposed connection in the amount of from about 0.10 to about 500 mg. In some embodiments of the invention offer dosage forms contain the proposed connection in the amount of approximately 0,1, 1, 2, 5, 7,5, 10, 12,5, 15, 17,5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg

In some examples of the invention, the dosage forms contain additional active agent in the amount of 1 - about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. of Course, the specific amount of an additional active agent will depend on the specific agent used, the type of disease being treated or controlled, and the amount of the proposed connection(s) and any optional additional active agents concurrently input to the patient.

4.6.1. ORAL DOSAGE FORMS

We offer pharmaceutical compositions, which are acceptable for oral administration may be presented as divided into several parts dosage forms, such as, but not limited to, tablets (e.g., Eveline tablets), kapley, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined quantity of active ingredients and can be obtained from the pharmaceutical methods, well known to specialists in this field. See, in General terms, "Remington''s Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA (1990).

In some embodiments of the invention offer oral dosage form is obtained by combining the active components when the two are thoroughly mixed with at least one auxiliary substance in accordance with conventional methods of blending in the pharmaceutical industry. Excipients can have a wide variety of forms depending on the form required for injection. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavouring agents, preservatives and dyes. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules and kapley)include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, sliding agents, binders and disinteg yousie agents. Because of the ease of introduction of tablets and capsules represent the most convenient oral dosage form, in which case use solid excipients. If necessary, the tablets can be coated using standard using water or waterless methods. Such dosage forms can be obtained by any of the methods of pharmacy. Typically, the pharmaceutical compositions and dosage forms are produced by uniform and thorough mixing the active ingredients with liquid carriers, finely powdered solid carriers, or both, and then the molded product in a desired to release the form, if necessary.

For example, a tablet may be obtained by extrusion or molding. Molded tablets may be made by molding in a suitable device active components in granular form, such as powder or granules, optionally mixed with auxiliary substance. Trituratsionnye tablets can be obtained by molding, in a suitable device, a mixture of powdered compound moistened with an inert liquid diluent.

Examples of excipients that can be used for the proposed oral dosage forms include, as non-limiting examples of binders, fillers, desint gerousia agents and slip agents. Binders suitable for use in pharmaceutical compositions and dosage forms include, as non-limiting examples, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums, such as Arabian gum, sodium alginate, alginic acid, other alginates, powdered tragakant, guar gum, cellulose and its derivatives (for example, ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hypromellose (e.g., No. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof.

Suitable types of microcrystalline cellulose include, as non-limiting examples, the materials sold under the trademark AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus hook, Pennsylvania), and mixtures thereof. Specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold under the trademark AVICEL RC-581. Suitable anhydrous or low moisture content excipients or additives include AVICEL-PH-103™ and starch 1500 LM.

Examples of fillers suitable for use in pharmaceutical compositions and dosage form is, disclosed in the description, include, as non-limiting examples, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrans, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments binder or filler in the proposed pharmaceutical compositions are present in an amount of from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Dezintegriruetsja agents are used in the proposed compositions to provide tablets that disintegrate when exposed to a water environment. Pills that contain too much dezintegriruetsja agent may decompose during storage, while those that contain too little may not disintegrate with the desired speed or desired conditions. Thus, a sufficient amount of dezintegriruetsja agent, which is either not too large or not too small to harm to modify release of the active components should be used for the formation of the proposed solid oral dosage forms. The number dezintegriruetsja agent varies depending on species composition and pronounced what about any specialist in this field. Some examples of proposed pharmaceutical compositions include from about 0.5 to about 15% of the mass. dezintegriruetsja agent or from approximately 1 to approximately 5% of the mass. dezintegriruetsja agent.

Dezintegriruetsja agents that can be used in the proposed pharmaceutical compositions and dosage forms include, as non-limiting examples, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crosspovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algini, other cellulose, gums and their mixtures.

Sliding substances that can be used in the proposed pharmaceutical compositions and dosage forms include, as non-limiting examples, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulphate, talc, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, etiloleat, Atilla is at, agar and mixtures thereof. Additional sliding substances include, for example, silicagel syloid (AEROSIL 200, produced by W.R. Grace Co., Baltimore, MD.), a coagulated aerosol of synthetic silica (marketed by Degussa Co., Piano, Texas), CAB-O-SIL (a pyrogenic silicon dioxide, a product of Cabot Co., Boston, mA), and mixtures thereof. When using sliding substances are used usually in amounts of less than approximately 1% of the mass. the pharmaceutical compositions or dosage forms to which they are added.

Offer oral solid dosage form contains a proposed connection, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

4.6.2. DOSAGE FORMS WITH CONTROLLED RELEASE

Offer active agents can be introduced by means of controlled-release or devices for delivery, which are well known to the average person skilled in the art. Examples include, as non-limiting examples are described in U.S. patents No. 3845770, 3916899, 3536809, and 3598123 4008719, 5674533, 5059595, 5591767, 5120548, 5073543, 5639476, 5354556 and 5733566, each of which is incorporated into this description by reference. Such dosage forms can be used to provide slow or controlled what about the release of one or more active components, using, for example, hypromellose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination to provide the desired release profile in different proportions. Suitable formulations of controlled release, well known to the average expert in this area, including those described, can be readily selected for use with the proposed active components. The invention also covers the dosage forms to a single injection, suitable for oral administration, such as, as non-limiting examples, tablets, capsules, gelatin capsules and kapley, which modify for controlled release.

All pharmaceutical products with controlled release have a common goal of improving drug therapy relative to what is achieved with the help of their counterparts with uncontrolled release. In the ideal case, the use of optimally composed of drug controlled release medical treatment is a minimum of drugs to cure or control the condition in a minimum period of time. Advantages of the compositions with controlled visuo what ordeniem include extended activity of the drug, reduced the frequency of doses and increased the degree of adherence by the patient. In addition, the composition of controlled release can be used to change the starting time of the action or other characteristics, such as levels of drug in the blood, and can thus affect the incidence side (e.g., adverse) effects.

Most formulations of controlled release are designed to initially release an amount of drug (active ingredient), which will quickly lead to the desired therapeutic effect, and gradually and continually release further amounts of drug to maintain therapeutic or prophylactic effect at this level for a long period of time. To maintain this constant level of the drug in the body, the drug must be released from the dosage form at a rate that will allow us to compensate for the quantity of a drug that metabolizability and excretions from the body. Controlled release of the active ingredient can be stimulated by various conditions, including, as non-limiting examples of pH, temperature, enzymes, water, or other physiological with the standing or connection.

4.6.3. DOSAGE FORMS FOR PARENTERAL administration

Parenteral dosage forms can be administered to patients by various routes, including, as non-limiting examples, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since their introduction usually bypasses the natural protective system of patients against contaminants, parenteral dosage forms are preferably sterile or be sterilized prior to administration to the patient. Examples of parenteral dosage forms include, as non-limiting examples, ready-made solutions for injection, dry products, ready for dissolution or suspension in a pharmaceutically acceptable medium for injection, prepared suspension for injection and emulsions.

Suitable environment that can be used to obtain the proposed parenteral dosage forms well known to the person skilled in the art. Examples include, as non-limiting examples, water for injection (purity in accordance with the U.S. Pharmacopoeia (USP), the water environment, such as, as non-limiting examples, solution for injection sodium chloride, ringer's solution for injection, dextrose injection, dextrose and sodium chloride injection and rest the R ringer's lactate for injection, mix with the water environment, such as, as non-limiting examples, ethyl alcohol, polyethylene glycol and polypropylenglycol, and non-aqueous environment, such as, as non-limiting examples, corn oil, cottonseed oil, peanut oil, sesame oil, etiloleat, isopropylmyristate and benzyl benzoate.

In parenteral dosage form according to the invention can also be added compounds that increase the solubility of one or more active components disclosed in the present description. For example, to increase the solubility of the proposed immunomodulatory compound and its derivatives can be used cyclodextrin and its derivatives. See, for example, U.S. patent No. 5134127, which is included in the present description by reference.

4.6.4. DOSAGE FORMS FOR LOCAL AND MUCOUS APPLICATION

Offer for topical application and injection through the mucous membranes of dosage forms include, as non-limiting examples, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations or other forms known to the person skilled in the art. See, for example, "Remington''s Pharmaceutical Sciences", 16thand 18theds., Mack Publishing, Easton PA (1980 and 1990) and "Introduction to Pharmaceutical Dosage Forms", 4thed., Lea & Febiger, Philadelphia (1985). Dosage forms, suitably the e for the treatment of mucosal tissues in the mouth, can be prepared in liquid form for oral rinse or gel for the mouth.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to obtain for local use and mucosal dosage forms encompassed by this invention are well known to experts in the pharmaceutical industry and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. Given this fact, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropylmyristate, isopropyl, mineral oil and mixtures thereof to obtain the solutions, emulsions or gels that are non-toxic and pharmaceutically acceptable. If desired, can be added moisturizers in the pharmaceutical compositions and dosage forms. Examples of such additional components are well known in the art. See, for example, "Remington''s Pharmaceutical Sciences", 16thand 18theds., Mack Publishing, Easton PA (1980 &1990).

the pH of the pharmaceutical composition or dosage form can also be adjusted to improve delivery of one or more active components. Similarly, to improve the sufficiency of the key may be governed by the polarity of the carrier solvent, its ionic strength or toychest. Also in the pharmaceutical compositions or dosage forms to improve the delivery can be added compounds such as stearates, mainly to change the hydrophilicity or lipophilicity of one or more active components. In this regard, stearates can serve as a lipid environment for the drug compound, as an emulsifying agent or surfactant, and as enhancing the delivery of, or increase the penetration of the agent. You can apply different salt, hydrate or solvate of active components for additional adjustment of the properties of the final composition.

4.7. SETS

The proposed connection can also be provided in the form of products of industrial production, using packaging materials, well known to specialists in this field of technology. See, for example, U.S. patent No. 5323907, 5052558 and 5033252. Examples of packaging materials in the pharmaceutical industry include, as non-limiting examples, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected composition and the intended type of injection or treatment.

Also offers kits, which, when applied by a physician, can make that call for the giving of appropriate amounts of active ingredients to a subject. In some embodiments of the invention offer the kit includes a container and a dosage form of the proposed connection, including a single enantiomer, a mixture of enantiomeric pairs, one diastereoisomer or mixture of diastereoisomers or its pharmaceutically acceptable salt, MES or prodrug.

In some embodiments of the invention, the kit includes a container containing a dosage form of the proposed connection, including a single enantiomer, a mixture of enantiomeric pairs, one diastereoisomer or mixture of diastereoisomers or its pharmaceutically acceptable salt, MES or prodrug, where the container contains one or more other therapeutic agents described herein. We offer the kits can further comprise additional active agents, such as oblimersen (Genasense®), melphalan, G-CSF, GMCSF, EPO (erythropoietin), topotecan, dacarbazine, irinotecan, Taxotere, IFN, a COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-CIS-retinoic acid, or a pharmacologically active mutant or derivative or combination thereof. Examples of additional active agents include, as non-limiting examples, all described here.

We offer the kits may further include devices that are used DL is the introduction of active components. Examples of such devices include, as non-limiting examples, syringes, needleless injectors, packages, drip infusion, transdermal delivery systems and vaporizers. We offer the kits may also contain condoms for administration of active agents.

We offer the kits can optionally contain pharmaceutically acceptable medium that can be used for introducing one or more active components. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may contain a sealed container with a suitable environment in which the active ingredient can be dissolved with the formation of free from particles of a sterile solution that is acceptable for parenteral administration. Examples of pharmaceutically acceptable media include, as non-limiting examples of the water environment, including, as non-limiting examples, water for injection (purity in accordance with the U.S. Pharmacopoeia (USP), solution for injection sodium chloride, ringer's solution for injection, dextrose injection, dextrose and sodium chloride for injection and ringer's solution with lactate for injection; mix with the water environment, such as, as non-limiting examples, ethyl with the IRT, the polyethylene glycol and polypropylenglycol, and non-aqueous environment, such as, as non-limiting examples, corn oil, cottonseed oil, peanut oil, sesame oil, etiloleat, isopropylmyristate and benzyl benzoate.

The invention will be better understood from the following non-limiting example.

5. EXAMPLES

5.1. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-pyridin-4-ylmethylene)urea

To a suspension of the salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and methanesulfonic acid (0.18 g, 0.5 mmol) in DMF (2 ml) was added to the OED (CDI, 1,1-carbonyldiimidazole) (81 mg, 0.5 mmol). The mixture was stirred at room temperature overnight. Was added to a mixture of 4-pyridine-4-iletilenlerin (92 mg, 0.5 mmol) and the mixture was stirred at room temperature for 4 h and Then the temperature was raised to 40°C and the mixture was stirred at this temperature for 8 hours the Mixture was cooled to room temperature, added water (5 ml) and was stirred for 10 minutes, the Suspension was filtered and the precipitate washed with water (20 ml), EtOAc (20 ml) and CH3CN (20 ml) to give the product in a solid off-white color (100 mg, yield 41%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient 5%-100% over 5 min, CH3CN/0.1% of H3PO4, 4,69 min(94%); TPL: 290-292°C;1H NMR (DMSO-d6) δ 1.93 and e 2.06 (m, 1H, CHH), 2,29 is 2.44 (m, 1H, CHH), 2,54 of 2.68 (m, 1H, CHH), 2,82-to 3.02 (m, 1H, CHH), 3,88 (s, 2H, CH2), 4,24-of 4.54 (m, 4H, CH2CH2), 5,10 (DD, J=5,0, of 13.7 Hz, 1H, NCH), 6,70 (s, 1H, NH), 7,10 (d, J=8,3 Hz, 2H, Ar), 7,22 (d, J=5.3 Hz, 2H, Ar), 7,34 (d, J=8,3 Hz, 2H, Ar), 7,39-of 7.48 (m, 1H, Ar), 7,51 (s, 1H, Ar), of 7.69 (d, J=7.7 Hz, 1H, Ar), 8,40-charged 8.52 (m, 2H, Ar), 8,59 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 31,20, 40,63, 42,76, 47,12, 51,56, 118,03, 121,83, 122,91, 123,99, 126,86, 129,06, 130,27, 132,08, 138,75, 142,36, 144,87, 149,42, 155,22, 163,87, 167,93, 170,98, 172,85; LC-MS MH+=484; analytical calculated for C27H25N5O4+ 1,5 H2O: C, 63,52; H, of 5.53; N, 13,72; S, 6,55; found: C, 63,68; H, 5,24; N, 13,79.

5.2. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-hydroxymethylene)urea

To a suspension of the salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and methanesulfonic acid (0.18 g, 0.5 mmol) in DMF (2 ml) was added to the OED (81 mg, 0.5 mmol). The mixture was stirred at room temperature overnight. Was added to a mixture of 4-aminobenzoyl alcohol (62 mg, 0.5 mmol) and the mixture was stirred at room temperature for 4 h and Then the temperature was raised to 40°C and the mixture was stirred at this temperature for 8 hours the Mixture was cooled to room temperature, added water (5 ml) and was stirred for 10 minutes, the Suspension was filtered and the precipitate washed with water (20 ml), EtOAc (20 ml) is CH 3CN (20 ml) to obtain the solid reddish color (100 mg, yield 41%). The residue was purified by ISCO column of silica gel using methanol and DHM as eluent, to obtain the product in a solid white color (30 mg, yield 15%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient 5%-100% over 5 min, CH3CN/0.1% of H3PO4, 4,99 min (97%); TPL: 309-311°C;1H NMR (DMSO-d6) δ 1,92 is 2.10 (m, 1H, CHH), 2,20-2,47 (m, 1H, CHH), 2,54-2,69 (m, 1H, CHH), 2,80-of 3.07 (m, 1H, CHH), 4,19-of 4.54 (m, 6H, CH2CH2CH2), 4,94-of 5.05 (m, 1H, OH), 5,11 (DD, J=5,1, 13,2 Hz, 1H, CHN), 6,70 (t, J=6.0 Hz, 1H, NH), 7,16 (d, J=8.7 Hz, 2H, Ar), 7,28-7,40 (m, 2H, Ar), 7,39-of 7.48 (m, 1H, Ar), 7,52 (s, 1H, Ar), of 7.69 (d, J=7.7 Hz, 1H, Ar), to 8.57 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 31,18, 42,77, 47,12, 51,56, 62,67, 117,49, 121,89, 122,93, 126,91, 127,05, 130,29, 135,22, 138,99, 142,38, 144,88, 155,25, 167,95, 170,99, 172,85; LC-MS MH+=423; analytical calculated for C22H22N4O5+0,4 H2O: C, 61,50; H, to 5.35; N, 13,04; found: C, 61,21; H, of 5.05; N, 12,80.

5.3. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]urea

To a mixture of 5-(3-isocyanatophenyl)-1-methyl-1H-pyrazole (0,22 g, 1.1 mmol), and salts of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and methanesulfonic acid (0.40 g, 1.1 mmol) in acetonitrile (5 ml) was added tea (at 0.31 ml, 2.2 mmol) at room temperature and the mixture was stirred for the period of 22 hours To the mixture was added water (25 ml) and the mixture was stirred at room temperature for 3 hours, the Suspension was filtered and the precipitate washed with water (20 ml), EtOAc (20 ml) and water (20 ml) to obtain the precipitate. The residue was purified using preparative HPLC to obtain the product in a solid white color (122 mg, 24% yield). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CΗ3CN/0.1% of H3PO4, 3,34 min (99.8 per cent); TPL: 260-262°C;1H NMR (DMSO-d6) δ 1,88 is 2.10 (m, 1H, CHH), 2,27-2,47 (m, 1H, CHH), 2,55-of 2.66 (m, 1H, CHH), 2,80-to 3.02 (m, 1H, CHH), of 3.84 (s, 3H, CH3), 4,30 (d, J=17.6 Hz, 1H, CHH), 4,40-4,50 (m, 3H, CHH, CH2), 5,11 (DD, J=5,2, 13.3 Hz, 1H, NCH), 6.35mm (d, J=1.9 Hz, 1H, Ar), 6,83 (t, J=6,1 Hz, 1H, NH), 7,06 (dt, J=1,4, and 7.6 Hz, 1H, Ar), 7,31-7,38 (m, 1H, Ar), 7,40-of 7.48 (m, 3H, Ar), 7,53 (d, J=0.4 Hz, 1H, Ar), 7,63 (t, J=1.9 Hz, 1H, Ar), of 7.70 (d, J=7.9 Hz, 1H, Ar), 8,82 (s, 1H, NH), 10,98 (users, 1H, NH);13C NMR (DMSO-d6) δ 22,48, 31,19, 37,45, 42,78, 47,11, 51,55, 105,55, 117,62 (2 carbon HMQC method), 121,18, 121,87, 122,93, 126,87, 129,08, 130,29, 130,51, 137,86, 140,73, 142,38, 142,82, 144,76, 155,21, 167,94, 170,98, 172,84; LC-MS MH+=473; analytical calculated for C25H24N6O4: C, 63,55; H, 5,12; N, 17,79; found: C, 63,36; H, to 5.17; N, 17,72.

5.4. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-Mei-1-yl)phenyl]urea; formic acid

The mixture of salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and methanesulfonic acid (0.40 g, 1.1 mmol) icdi (0,19 g, 1.2 mmol) in DMF (5 ml) was stirred at room temperature for 18 hours To the mixture was added 3-(2-Mei-1-yl)phenylamine (0,19 g, 1.1 mmol) at room temperature and the mixture was stirred at 60°C for 24 h To the mixture was added water (25 ml) and a simple ether (20 ml). The mixture was stirred at room temperature for 2 hours, the Suspension was filtered and the precipitate washed with water (20 ml), ethyl acetate (20 ml) and water (20 ml) to obtain the precipitate. The residue was purified using preparative HPLC to obtain the product in a solid white color (100 mg, yield 20%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient of 5%-95% for 5 min, CH3CN/0.1% of H3PO4, 4,48 min (96,8%); TPL: 218-220°C;1H NMR (DMSO-d6) δ 1,89-2,12 (m, 1H, CHH), 2,25-to 2.29 (m, 3H, CH3), 2,30 is 2.46 (m, 1H, CHH), 2,54 of 2.68 (m, 1H, CHH), 2,78 totaling 3.04 (m, 1H, CHH), or 4.31 (d, J=17,4 Hz, 1H, CHH), to 4.38-4.53-in (m, 3H, CHH, CH2), 5,11 (DD, J=5,1, 13,2 Hz, 1H, NCH), 6,89 (d, J=1.3 Hz, 1H, Ar), 6,92-7,05 (m, 2H, Ar, NH), of 7.23 (d, J=1.3 Hz, 1H, Ar), 7,32-7,40 (m, 2H, Ar), 7,41-7,49 (m, 1H, Ar), 7,52 (s, 1H, Ar), EUR 7.57-the 7.65 (m, 1H, Ar), of 7.69 (d, J=7.9 Hz, 1H, Ar), 8,18 (s, 1H, HCOOH), 9,03 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 13,60, 22,49, 31,20, 42,77, 47,12, 51,58, 114,22, 116,89, 117,61, 120,68, 121,88, 122,93, 126,89, 127,13, 129,63, 130,30, 137,90, 141,50, 142,38, 143,43, 144,69, 155,16, 163,44, 167,93, 170,98, 172,85; LC-MS MH+=473; analytical calculated for C25H24N6O4+ HCOOH + 1,5 H2O: C, 57,24; H, are 5.36; N, 15,40; found: C, 57,43; H, 5,11; N, 15,57.

5.5. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-about the co-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[4-(4-methyl-4H-[1,2,4]triazole-3-yl)phenyl]urea

To a stirred suspension of 4-(4-methyl-4H-[1,2,4]triazole-3-yl)phenylamine (0.31 g, 1.77 mmol) in DMF (10 ml) at 40°C was added to the OED (0.32 g, 1.94 mmol). The mixture was stirred for 15 min, then added salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and methanesulfonic acid (0.65 g, 1.77 mmol). Heating was stopped after 1.5 h and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified using preparative HPLC to obtain the product in a solid white color (0,13 g, yield 15%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 14/86 CH3CN/0.1% of H3PO4, 4,70 min (93.9 per cent); TPL: 248-250°C;1H NMR (DMSO-d6) δ 1.93 and e 2.06 (m, 1H, CHH), 2,29 is 2.46 (m, 1H, CHH), 2,55-2,70 (m, 1H, CHH), 2,82-to 3.02 (m, 1H, CHH), and 3.72 (s, 3H, CH3), 4,24-4,55 (m, 4H, CH2CH2), 5,11 (DD, J=4,9, 13,2 Hz, 1H, NCH), to 6.95 (t, J=5.7 Hz, 1H, NH), 7,41-7,81 (m, 7H, ArH), 8,51 (s, 1H, ArH), of 9.02 (s, 1H, NH), 10,99 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 31,20, 31,94, 42,79, 47,13, 51,58, 117,50, 119,49, 121,88, 122,94, 126,91, 128,80, 130,32, 141,84, 142,39, 144,72, 145,76, 153,08, 155,12, 167,95, 170,99, 172,85; LC-MS MH+=474; analytical calculated for C24H23N7O4: C, 60,88; H, the 4.90; N, 20,71, found: C, 58,28; H, of 4.67; N, 19,49. (Note: this analysis was unsuccessful and HPLC and1H NMR showed 6% impurities).

5.6. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-IU is iltiazem-4-yl)phenyl]urea

To a mixture of 4-(3-isocyanatophenyl)-2-methylthiazole (0.25 g, 1.2 mmol), and salts of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and methanesulfonic acid (0,43 g, 1.2 mmol) in acetonitrile (5 ml) was added tea (0.33 ml, 2.3 mmol) at room temperature and the mixture was stirred for 3 hours Water (25 ml) was added to the mixture and the mixture was stirred at room temperature for 3 hours, the Suspension was filtered and the precipitate washed with water (20 ml), ethyl acetate (20 ml) and water (20 ml) to obtain the precipitate. The residue was purified using preparative HPLC to obtain the product in a solid white color (160 mg, 28% yield). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, to 5.93 min (99.4 per cent); TPL: 252-254°C;1H NMR (DMSO-d6) δ 1,92-to 2.06 (m, 1H, CHH), 2,27-2,47 (m, 1H, CHH), 2,54-of 2.66 (m, 1H, CHH), a 2.71 (s, 3H, CH3), 2,81-a 3.01 (m, 1H, CHH), or 4.31 (d, J=17.6 Hz, 1H, CHH), to 4.38-4.53-in (m, 3H, CHH, CH2), 5,11 (DD, J=5,1, 13,2 Hz, 1H, NCH), 6,74 (t, J=6.0 Hz, 1H, NH), 7,20-7,32 (m, 1H, Ar), 7,40 (DDD, J=1,1, 2,3, 8,1 Hz, 1H, Ar), 7,46 (DQC, J=1,4, 7,6 Hz, 2H, Ar), 7,53 (s, 1H, Ar), of 7.70 (d, J=7.9 Hz, 1H, Ar), 7,81 (s, 1H, Ar), 8,02 (t, J=1.9 Hz, 1H, Ar), 8,79 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 18,91, 22,51, 31,18, 42,79, 47,12, 51,56, 113,55, 115,55, 117,28, 118,86, 121,86, 122,94, 126,89, 129,01, 130,29, 134,58, 140,82, 142,39, 144,90, 153,89, 155,21, 165,29, 167,95, 170,99, 172,85; LC-MS MH+=490; analytical calculated for C25H23N5O4S: C, 61,34; H, 4,74; N, 14,31; S, 6,55; found:C, 61,09; H, 4,60; N, 14,19; WITH, OF 6.49.

5.7. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(1-methyl-1H-pyrazole-3-yl)phenyl]urea

To a stirred suspension of 3-(3-isocyanatophenyl)-1-methyl-1H-pyrazole (0.25 g, 1.25 mmol), and salts of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione and methanesulfonic acid (0,46 g, 1.25 mmol) in acetonitrile (5 ml) at room temperature was added tea (0.35 ml, 2.51 mmol). The mixture was stirred for 4 h followed by addition of 1N. HCl (10 ml), which was stirred for 10 minutes the Mixture was purified preparative HPLC to obtain the product as a solid off-white color (0,22 g, yield 38%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 25/75 CΗ3CN/0.1% of H3PO4, of 5.99 min (99,9%); TPL: 232-234°C;1H NMR (DMSO-d6) δ 1.93 and-2,07 (m, 1H, CHH), 2,29 is 2.46 (m, 1H, CHH), 2,55 of 2.68 (m, 1H, CHH), 2,82-a 3.01 (m, 1H, CHH), a 3.87 (s, 3H, CH3), 4,24-4,55 (m, 4H, CH2CH2), 5,11 (DD, J=5.0 and 13.3 Hz, 1H, NCH), to 6.57 (d, J=2.3 Hz, 1H, ArH), 6.73 x (t, J=5,9 Hz, 1H, NH), 7.18 in-7,37 (m, 3H, ArH), 7,46 (d, J=7.9 Hz, 1H, ArH), 7,53 (s, 1H, ArH), 7,65-to 7.77 (m, 2H, ArH), 7,89 (s, 1H, ArH), 8,71 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 31,18, 38,60, 42,79, 47,13, 51,58, 102,33, 114,31, 116,77, 118,16, 121,86, 122,93, 126,89, 128,85, 130,29, 132,17, 133,85, 140,66, 142,39, 144,91, 150,03, 155,22, 167,95, 170,99, 172,85; LC-MS MH+=473; analytical calculated for C25H24N6O4+ 0,5 H2O: C, 62,36; H, 5,23; N, 17,45, Nai the network: C, 62,06; H, 5,19; N, 17,28.

5.8. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(morpholinomethyl)phenyl)urea formate

To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione hydrochloride (from 0.37 g, 1.00 mmol) and 4-(3-isocyanatobenzyl)of the research (0,22 g, 1.00 mmol) in acetonitrile (10 ml) was added tea (of 0.28 ml, 2.00 mmol) at room temperature under nitrogen atmosphere. After 2 h was added optional 4-(3-isocyanatobenzyl)morpholine (0,22 g, 1.00 mmol) and tea (of 0.28 ml, 2.00 mmol). After 12 h of undesirable precipitate was filtered and the filtrate was concentrated. The residue was dissolved in acetonitrile and purified preparative HPLC (gradient: CH3CN + 0.1% of formic acid/H2O + 0.1% of formic acid: 10/90 for 5 min, up to 100/0 for 10 min, 100/0 for 5 min). After evaporation of the solvent the residue was ground in a simple ether (20 ml) for 1 h the Product was then isolated by filtration and dried in vacuum to obtain the product as a solid beige color (0.16 g, 30%yield). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient: CH3CN/0.1% of H3PO4: 10/90-90/10 for 10 min, 90/10 (5 min): with 4.64 min (95,84%); TPL: 198-200°C;1H NMR (DMSO-d6) δ 1,83-2,12 (m, 1H, CHH), 2.21 are 2,47 (m, 5H, CHH, CH2CH2), 2,54-2,69 (m, J=to 11.0 Hz, 1H, CHH), 2,79-3,03 (m, 1H, CHH), to 3.38 (s, 2H, CH2), 3,52 to 3.7 (m, 4H, CH2CH2), or 4.31 (d, J=and 17.2 Hz, 1H, CHH), 4,37-4,55 (m, 3H, CHH, CH2), 5,11 (DD, J=5,1, 13,2 Hz, 1H, CH), 6,83 (d, J=7,6 Hz, 1H, Ar), of 6.99 (t, J=5.6 Hz, 1H, NH), to 7.15 (t, J=7.7 Hz, 1H, Ar), 7,32 (d, J=8,3 Hz, 1H, Ar), 7,39 (s, 1H, Ar), 7,44 (d, J=7.7 Hz, 1H, Ar), 7,52 (, 1H, Ar), of 7.69 (d, J=7.7 Hz, 1H, Ar), 8,29 (users, 1H, HCOO), of 8.90 (s, 1H, NH), 10,98 (users, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 31,20, 42,73, 47,12, 51,56, 53,20, 62,69, 66,17, 116,42, 118,13, 121,72, 121,83, 122,90, 126,86, 128,34, 130,25, 138,24, 140,48, 142,36, 144,99, 155,31, 164,30, 167,95, 170,98, 172,85; LC-MS: MH+=492; analytical calculated for C27H31N5O7+ 3 H2O: C, 54,82; H, 6,30; N, 11,84; found: C, 55,12; H, 6,12; N, 11,72.

5.9. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea

To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione hydrochloride (1,00 g, 2,70 mmol) and 4-methyl-3-nitrophenylacetate (of 0.48 ml, 2,70 mmol) in acetonitrile (20 ml) was added tea (0.75 ml, 5.40 mmol) at room temperature under nitrogen atmosphere. After 2 h was added 1N. HCl (20 ml) and the precipitate was separated by filtration and washed with water (3×20 ml). The crude product is triturated in EtOAc (50 ml) for 12 h, the Product was separated by filtration and dried in vacuum to obtain the product in a solid yellow color (0.74 g, yield 61%): HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient: CH3CN/0.1% of H3PO4: 10/90-90/10 for 10 min, 90/10 (5 min): 7,94 min (96,79%); Tthe l : 230-232°C;1H NMR (DMSO-d6) δ 1,87-of 2.08 (m, 1H, CHH), and 2.26-2,48 (m, 3H, CHH, CH3), 2,60 (d, J=17.6 Hz, 1H, CHH), 2,79-of 3.07 (m, 1H, CHH), or 4.31 (d, J=17,4 Hz, 1H, CHH), to 4.38-4,55 (m, 3H, CHH, CH2), 5,11 (DD, J=5.0 and 13.3 Hz, 1H, CH), 6,92 (t, J=5,9 Hz, 1H, NH), 7,34 (d, J=8,3 Hz, 1H, Ar), was 7.45 (d, J=7.9 Hz, 1H, Ar), 7,49-of 7.60 (m, 2H, Ar), of 7.70 (d, J=7.7 Hz, 1H, Ar), compared to 8.26 (d, J=2.3 Hz, 1H, Ar), 9,07 (s, 1H, NH), 10,99 (s, 1H, NH);13C NMR (DMSO-d6) δ 18,95, 22,49, 31,20, 42,82, 47,12, 51,56, 112,74, 121,92, 122,45, 122,94, 124,71, 126,92, 130,33, 132,84, 139,46, 142,38, 144,59, 148,72, 155,02, 167,93, 170,98, 172,85; LC-MS: MH+=452; analytical calculated for C22H21N4O6: C 58,53; H, 4,69; N, 15,51; found: C, 58,23; H, 4,58; N, 15,34.

5.10. 1-(3-Amino-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea

To a solution of 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea (0,30 g, 0.66 mmol) in DMF (50 ml) was added Pd-C (0.10 g, 10% by weight). The reaction mixture was first made in a Parr shaker at 379 kPa (55 psi). After 16 h the mixture was filtered through a layer of celite, which was washed additionally DMF (20 ml). Then, the filtrate was evaporated and the residue was stirred in water (100 ml) for 3 hours the Precipitate was filtered, washed with additional water (50 ml) and dried. Crude green product was dissolved in DMF (100 ml)was added coal to discoloration and the reaction mixture was stirred for 3 hours the Mixture is then filtered through a layer of celite, which is amywali additional DMF (50 ml). Then, the filtrate was evaporated and the residue was stirred in water (100 ml) for 4 hours the precipitate was filtered, washed with additional water (50 ml) and dried in vacuum. The precipitate was ground in a simple ether for 1 h and the product was separated by filtration to obtain the product as a solid pale green color (0,22 g, yield 79%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient: CH3CN/0.1% of H3PO4: 10/90-90/10 for 10 min, 90/10 (5 min): 4,50 min (96,74%); TPL: 228-230°C;1H NMR (DMSO-d6) δ 1,82 is 2.10 (m, 4H, CHH, CH3in ), 2.25-2,47 (m, 1H, CHH), 2,59 (d, J=18.3 Hz, 1H, CHH), 2.77-to to 3.02 (m, 1H, CHH), 4,30 (d, J=17.6 Hz, 1H, CHH), 4,35-a 4.53 (m, 3H, CH2, CHH), 4,93 (users, 2H, NH2), 5,11 (DD, J=5.0 and 12.9 Hz, 1H, CH), 6,51 (DD, J=1,9, 7.9 Hz, 1H, Ar), to 6.58 (t, J=5.7 Hz, 1H, NH), of 6.75 (d, J=8.5 Hz, 2H, Ar), the 7.43 (d, J=7.9 Hz, 1H, Ar), to 7.50 (s, 1H, Ar), of 7.69 (d, J=7.7 Hz, 1H, Ar), 8,23 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 16,75, 22,49, 31,20, 42,74, 47,10, 51,56, 104,16, 106,57, 114,59, 121,86, 122,90, 126,89, 129,79, 130,25, 138,75, 142,36, 145,06, 146,12, 155,22, 167,95, 170,98, 172,85; LC-MS: MH+=422; analytical calculated for C22H23N5O4+ 0,1 H2O + 0,5 Et2O: C, 62,62; H, 6,17; N, 15,21; found: C, 62,30; H, of 5.89; N, 14,89.

5.11. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(3-phenoxyphenyl)urea

To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione of methansulfonate (of 0.37 g, 1.00 mmol) and 1-Izolan then-3-phenoxybenzene (0,212 g, 1.00 mmol) in acetonitrile (10 ml) under nitrogen atmosphere at room temperature was added TEA (0.20 g, 2.00 mmol). After 3 h was added 1N. HCl (10 ml) and the mixture was stirred for 10 min. the Precipitate was separated by filtration and washed with water (20 ml) and acetonitrile (10 ml). The crude product was dissolved in minimum amount of DMF and the product was besieged by slowly adding water (~30 ml). The precipitate was collected by filtration, washed with Et2O and dried in vacuo for 18 h to obtain the product in a solid white color (422 mg, 87%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 35/65, CH3CN/0.1% of H3PO4, 3,76 min (99,3%); TPL: 224-226°C;1H NMR (DMSO-d6) δ 1,99 (s, 4H, CH, CH3), 2,29 is 2.46 (m, 1H, CH), 2,55-of 2.66 (m, 1H, CH), 2,80-a 3.01 (m, 1H, CH), 4,18-4,56 (m, 4H, CH2CH2), 5,10 (DD, J=4,9, 13,2 Hz, 1H, CH), of 6.71 (t, J=5,9 Hz, 1H, NH), 7.23 percent and 7.36 (m, 1H, Ar), was 7.36-of 7.48 (m, 2H, Ar), 7,51 (s, 1H, Ar), of 7.69 (d, J=7.7 Hz, 1H, Ar), 8,55 (s, 1H, NH), of 9.75 (s, 1H, NH), 10,67-11,27 (m, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 23,82, 31,18, 42,77, 47,12, 51,56, 118,12, 119,57, 121,85, 122,91, 126,88, 130,26, 133,18, 135,70, 142,36, 144,94, 155,29, 167,67, 167,95, 170,98, 172,85; LC-MS: MH+=485; analytical calculated for C27H24N4O5: C, 66,93; H, 4,99; N, to 11.56, found: C, 67,03; H, 4,72; N, 11,41.

5.12. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea

To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-yl)piperidine-2,6-dione of methansulfonate (0,37 g, 1.0 mmol) and 1-isocyanato-4-nitrobenzene (164 mg, 1.0 mmol) in acetonitrile (10 ml) under nitrogen atmosphere was added TEA (0.20 g, 2.0 mmol). The mixture was stirred at room temperature for 3 h, during which she remained in suspension. Added 1N. HCl solution (10 ml) and the mixture was stirred for 10 min. the Precipitate was separated by filtration and washed with additional water (20 ml) and acetonitrile (10 ml). The residue was dissolved in minimum amount of DMF and the product was besieged by slowly adding water (~30 ml). The precipitate was collected by filtration and washed with Et2O to remove most of the remaining yellow. The precipitate was dried in a vacuum oven overnight to obtain a product in the form of a solid off-white color (330 mg, 75%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70, CH3CN/0.1% of H3PO4, 6,15 min (97.1 per cent); TPL: 272-274°C;1H NMR (DMSO-d6) δ 1,84 and 2.13 (m, 1H, CHH), 2,24 is 2.44 (m, 1H, CHH), 2,55-of 2.66 (m, 1H, CHH), 2.77-to to 3.02 (m, 1H, CHH), 4,16-4,55 (m, 4H, CH2CH2), 5,11 (DD, J=4,7, at 13.0 Hz, 1H, CH), 7,07 (t, J=5.6 Hz, 1H, NH), 7,37-7,83 (m, 5H, Ar), 8,15 (d, J=8,9 Hz, 2H, Ar), 9,48 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,48, 31,17, 42,83, 47,11, 51,57, 116,97, 121,94, 122,96, 125,09, 126,93, 130,38, 140,48, 142,41, 144,26, 147,04, 154,51, 167,91, 170,98, 172,85; LC-MS: MH+=438; analytical calculated for C21H19N5O6+ 0,5 H2O: C, 56,50; H, to 4.52; N, 15,69; found: C, 56,45; H, or 4.31; N, 15,71.

5.13. N-(4-{3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}phenyl)ndimethylacetamide

Stage 1: Obtain 1-(4-AMINOPHENYL)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea. To stir a mixture of 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea (150 mg, 0,343 mmol) in EtOH (2 ml) was added sodium dithionite (597 mg, of 3.43 mmol) in water (2 ml). The resulting mixture was heated to 60°C for 20 min, after which LC-MS showed complete disappearance of the original nitro compounds. The reaction mixture was mixed with the crude product of the individual reactions and concentrated in vacuum. The residue was dissolved in minimum amount of DMF and was chromatographically on a column of C-18 preparative HPLC, equipped with a mass-controlled collector fractions. The desired fractions were combined and concentrated in vacuum to obtain 1-(4-AMINOPHENYL)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea as solid pale yellow color (90 mg, 40% total average output of two separate reactions). TPL: >400°C; LC-MS: MH+=408.

Stage 2: Obtain N-(4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}phenyl)ndimethylacetamide. 1-(4-AMINOPHENYL)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]machev the well (64 mg, of) 0.157 mmol) was stirred at room temperature in acetic anhydride (5 ml) for 2 hours Volatiles were removed in vacuo, the residue was dissolved in minimum amount of DMF and purified on a column of C-18 preparative HPLC. The desired fractions were combined and concentrated in vacuum to obtain the product as a solid, pale yellow (37 mg, yield 52%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 17/83, CΗ3CN/0.1% of H3PO4, 5,19 min (97,4%); TPL: 265-267°C;1H NMR (DMSO-d6) δ 1,99 (s, 4H, CH, CH3), 2,29 is 2.46 (m, 1H, CH), 2,55-of 2.66 (m, 1H, CH), 2,80-a 3.01 (m, 1H, CH), 4,18-4,56 (m, 4H, CH2CH2), 5,10 (DD, J=4,9, 13,2 Hz, 1H, CH), of 6.71 (t, J=5,9 Hz, 1H, NH), 7.23 percent and 7.36 (m, 1H, Ar), was 7.36-of 7.48 (m, 2H, Ar), 7,51 (s, 1H, Ar), of 7.69 (d, J=7.7 Hz, 1H, Ar), 8,55 (s, 1H, NH), of 9.75 (s, 1H, NH), 10,67-11,27 (m, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 23,82, 31,18, 42,77, 47,12, 51,56, 118,12, 119,57, 121,85, 122,91, 126,88, 130,26, 133,18, 135,70, 142,36, 144,94, 155,29, 167,67, 167,95, 170,98, 172,85; LC-MS: MH+=450; analytical calculated for C23H23N5O5+ 1,0 H2O: C, 59,09; H, of 5.39; N, 14,98; found: C, 58,75; H, 4,99; N, 14,59.

5.14. 3-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-1-methyl-1-phenylacetone

To a suspension of the salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.18 g, 0.5 mmol) in CH3CN (10 ml) was added DIPEA (DIPEA) (0.4 ml, 2.5 mmol) and the acid chloride of N-METI phenylcarbinol acid (178 mg, 1.05 mmol). The mixture was stirred at room temperature overnight. The suspension was filtered and the precipitate washed with water (20 ml), ethyl acetate (20 ml) and CH3CN (20 ml) to give the product in a solid white color (200 mg, yield 47%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, of 3.56 min (96%); TPL: 168-170°C;1H NMR (DMSO-d6) δ 1,89-2,07 (m, 1H, CHH), 2,30-2,47 (m, 1H, CHH), 2,55-2,69 (m, 1H, CHH), 2,79-a 3.01 (m, 1H, CHH), 3,18 (s, 3H, CH3), 4,22-4,58 (m, 4H, CH2CH2), 5,11 (DD, J=5.0 and 13.3 Hz, 1H, NCH), of 6.68 (t, J=5,9 Hz, 1H, NH), 7,16-7,35 (m, 3H, Ar), was 7.36-7,44 (m, 3H, Ar), 7,46 (s, 1H, Ar), 7,66 (d, J=7.7 Hz, 1H, Ar), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 31,21, 37,14, 43,76, 47,10, 51,55, 121,85, 122,71, 125,78, 126,54, 126,86, 129,23, 130,04, 142,19, 144,02, 145,41, 156,74, 168,02, 171,02, 172,86; LC-MS MH+=407; analytical calculated for C22H22N4O4+ 0,5 H2O: C, 63,60; H, to 5.58; N, 13,49; C, 6,55; found: C, 63,61; H, 5,51; N.

5.15 1-Biphenyl-4-yl-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

To a suspension of the salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (from 0.37 g, 1 mmol) in DMF (2 ml) was added to the OED (162 mg, 1 mmol). The mixture was stirred at room temperature overnight. Was added to a mixture of 4-phenylaniline (169 mg, 1 mmol) and the mixture was stirred at room temperature for 4 h Then those which the temperature was raised to 40°C and the mixture was stirred at this temperature for 8 hours The mixture was cooled to room temperature. The suspension was filtered, the filtrate was added CH3CN (5 ml) and the resulting suspension was filtered. The collected precipitate was recrystallized from DMF to obtain the product in a solid white color (30 mg, yield 15%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 2,78 min (95%);1H NMR (DMSO-d6) δ 2,02 (users, 1H, CHH), 2,28-2,47 (m, 1H, CHH), 2,60 (d, J=18.5 Hz, 1H, CHH), 2,82 totaling 3.04 (m, 1H, CHH), 4,23-4,59 (m, 4H, CH2CH2), 5,11 (DD, J=4,9, 13,2 Hz, 1H, NCH), 6.73 x-6,83 (m, 1H, NH), 7,22-7,35 (m, 1H, Ar), 7,37-7,66 (m, 10H, Ar), of 7.70 (d, J=7.9 Hz, 1H, Ar), is 8.75 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 31,20, 42,80, 47,13, 51,58, 118,09, 121,89, 122,94, 125,99, 126,64, 126,85, 128,82, 130,30, 132,86, 139,93, 142,40, 144,81, 155,18, 167,95, 170,99, 172,85; LC-MS MH+=423.

5.16 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]urea

To a stirred suspension of 3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenylamine (0,22 g, of 1.09 mmol), and salts of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.40 g, of 1.09 mmol) in acetonitrile (5 ml) at room temperature was added tea (0,31 ml, 2,19 mmol). The mixture was stirred for 3 h followed by addition of 1N. HCl (10 ml), which was stirred for 10 minutes the Mixture was purified preparative HPLC to obtain the product is in a solid white color (0.10 g, yield 19%). HPLC, Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 4,37 min (99,3%); TPL: 242-244°C;1H NMR (DMSO-d6) δ 1,92-2,07 (m, 1H, CHH), 2,30 is 2.46 (m, 4H, CH3, CHH), 2,55-to 2.67 (m, 1H, CHH), 2,82-to 3.02 (m, 1H, CHH), 4,24-4,56 (m, 4H, CH2CH2), 5,11 (DD, J=5,1, 13,2 Hz, 1H, NCH), 6,91 (t, J=5.8 Hz, 1H, NH), 7,39-7,80 (m, 6H, ArH), of 8.37 (s, 1H, ArH), 9,05 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 11,25, 22,49, 31,20, 42,83, 47,12, 51,58, 116,37, 120,24, 121,93, 121,96, 122,94, 123,77, 126,94, 129,90, 130,33, 141,41, 142,39, 144,68, 155,10, 167,61, 167,93, 170,99, 172,85, 174,86, LC-MS MH=475; analytical calculated for C24H22N6O5+ 0,4 H2O: C, 59,85; H, of 4.77; N, 17,45; found: C, 59,53; H, to 4.68; N, 17,30.

5.17. 1-(3-AMINOPHENYL)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea

Step 1: To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione hydrochloride (0.74 g, 2.00 mmol) and 3-nitrophenylacetate (0.33 g, 2.00 mmol) in acetonitrile (20 ml) was added tea (of 0.56 ml, 4.00 mmol) at room temperature under nitrogen atmosphere. After 12 h, the precipitate was filtered and was purified preparative HPLC (gradient: CH3CN/H2O: 15/85 for 5 min, up to 100/0 for 10 min, 100/0 for 5 min). After evaporation of the solvent the residue was ground in a simple ether (20 ml) for 1 h the Product was then isolated by filtration and dried in vacuum to obtain 1-((2-(2,6-dioxopiperidin the n-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-nitrophenyl)urea in a solid yellow (0.34 g, yield 39%).

Stage 2: To a solution of 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-nitrophenyl)urea (0.33 g, 0.80 mmol) in DMF (80 ml) was added Pd-C (0.10 g, <10% by weight). The reaction mixture was first made in a Parr shaker at 379 kPa (55 psi). After 12 h the mixture was filtered through a layer of celite, which was washed additionally DMF (50 ml). Then, the filtrate was evaporated and the residue was stirred in water (150 ml) for 3 hours the Precipitate was filtered, washed with additional water (50 ml) and dried. The crude product was dissolved in DMF (50 ml), was added coal to discoloration and the reaction mixture was stirred for 12 hours the Mixture is then filtered through a layer of celite, which was washed additionally DMF (50 ml). Then, the filtrate was evaporated and the residue was stirred in water (100 ml) for 3 hours the Precipitate was filtered, washed with additional water (50 ml) and dried in vacuum to obtain the product as a solid pale yellow color (0.24 g, yield 77%). HPLC: X-Terra RP 18, of 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, CH3CN/0.1% of (HCO2)NH4: 15/85, 7,95 min (95,27%); TPL: 233-235°C;1H NMR (DMSO-d6) δ 1,78-of 2.08 (m, 1H, CHH), 2,38 (arcs, J=4,5, 13,2 Hz, 1H, CHH), 2,59 (d, J=17,8 Hz, 1H, CHH), 2,79-of 3.06 (m, 1H, CHH), 4,18 is 4.36 (m, 1H, CHH), 4,36-4,60 (m, 3H, CHH, CH2), 4,91 and 5.36 (m, 3H, NH2CH), 6,15 (DDD, J=0,9, 2,1, 7.9 Hz, 1H, Ar), 6,48 return of 6.58 (m, 1H, Ar), 6,63 (t, J=6.0 Hz, 1H, NH), 6,76 (t, J=2.0 Hz, 1H, Ar), 6,85 (t, J=7.9 Hz, 1H, Ar), 7,44 (d, J=7.7 Hz, 1H, Ar), 7,51 (s, 1H, Ar), 7,69 (d,J=7.9 Hz, 1H, Ar), 8,32 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 31,20, 42,73, 47,12, 51,58, 103,78, 106,20, 107,79, 121,86, 122,91, 126,89, 128,89, 130,26, 140,92, 142,38, 144,99, 148,44, 155,16, 167,95, 170,99, 172,85; LC-MS: MH+=408; analytical calculated for C21H21N5O4: C, 61,91, H, 5,20, N, 17,19; found: C, 62,40, H, 5,67, N, 15,59.

5.18. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(pyridine-2-yloxy)phenyl]urea

3-(5-Aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione methanesulfonate (1,11 g, 3.0 mmol) and 1,1'-carbonyldiimidazole (535 mg, 3.3 mmol) suspended in dry DMF (20 ml) and the mixture was stirred at room temperature for 24 hours While stirred, part of the reaction mixture (6,7 ml, ~1 mmol) was transferred into a tube containing 3-(pyridine-2-yloxy)phenylamine (205 mg, 1.1 mmol). The resulting mixture was stirred at room temperature overnight and the reaction was monitored using LC-MS. After 48 h, additional 3-(pyridine-2-yloxy)phenylamine (37 mg, 0.2 mmol) was transferred into the reaction mixture and continued stirring for a further 24 hours the Reaction mixture was acidified with acid and water. Volatiles were removed in vacuo, the residue was dissolved in DMF and purified using C-18 preparative HPLC, to obtain 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(pyridine-2-ylox is)phenyl]urea as solid white (310 mg, yield 64%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, to 4.81 min (98,6%); TPL: 298-300°C;1H NMR (DMSO-d6) δ 1,84-to 2.06 (m, 1H, CHH), 2,19 is 2.44 (m, 1H, CHH), 2,54 of 2.68 (m, 1H, CHH), 2,79 was 3.05 (m, 1H, CHH), 4,08-4,60 (m, 4H, CH2CH2), 5,10 (DD, J=5,1, 13,2 Hz, 1H, CH), only 6.64 (DD, J=1,4, 8.0 Hz, 1H, Ar), for 6.81 (t, J=5,9 Hz, 1H, NH), of 6.99 (d, J=8,3 Hz, 1H, Ar), 7,07-to 7.18 (m, 2H, Ar), from 7.24 (t, J=8,1 Hz, 1H, Ar), 7,33 (t, J=2.1 Hz, 1H, Ar), the 7.43 (d, J=7.7 Hz, 1H, Ar), to 7.50 (s, 1H, Ar), to 7.68 (d, J=7.7 Hz, 1H, Ar), 7,78-of 7.97 (m, 1H, Ar), 8,16 (DD, J=1,5, a 4.9 Hz, 1H, Ar), 8,82 (s, 1H, NH), 10,97 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 31,18, 42,73, 47,12, 51,56, 110,23, 111,51, 113,54, 113,68, 118,99, 121,85, 122,93, 126,86, 129,56, 130,29, 140,10, 141,79, 142,39, 144,77, 147,52, 154,37, 155,09, 163,03, 167,93, 170,99, 172,85; LC-MS: MH=486; analytical calculated for C26H23N5O5+ 0,3 H2O: C, 63,61; H, is 4.85; N, 14,27, found: C, 63,62; H, to 4.62; N, 14,18.

5.19. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(piperidine-4-yloxy)phenyl)urea

Using the methodology described in section 5.15, the product was obtained from 3-(piperidine-4-yloxy)aniline and a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

5.20. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-were)urea

Stage 1: Using the procedure described in section 5.15, 1-(3-(tert-butyldimethylsilyloxy)-4-were)-3-((2-(2,6-di is cooperider-3-yl)-1-occaisonaly-5-yl)methyl)urea was obtained from 3-(tert-butyldimethylsilyloxy)-4-methylaniline and salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

Stage 2: a Mixture of 1-(3-(tert-butyldimethylsilyloxy)-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea (0.54 g, 1.0 mmol) and cesium fluoride (0.15 g, 1.0 mmol) in DMF (10 ml) was heated to 70°C for 8 hours the Mixture was cooled and was diluted with water (10 ml). The solid precipitate was filtered, washed with water (10 ml) and dried under vacuum to obtain the product.

5.21. 5-(3-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ureido)-2-were-2-aminoacetate hydrochloride

Stage 1: Using the procedure described in section 5.15, 5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ureido)-2-were-2-(tert-butoxycarbonylamino)acetate was obtained from 5-amino-2-were-2-(tert-butoxycarbonylamino)acetate and salts of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

Stage 2: To a mixture of 5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ureido)-2-were-2-(tert-butoxycarbonylamino)acetate (0,58 g, 1.0 mmol) in DHM (50 ml) was added 2M HCl in diethyl ether (1 ml) and the mixture was stirred for 24 hours Solid precipitate was filtered, washed DHM (10 ml) and dried under vacuum to obtain the product.

5.22. 5-(3-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ureido)-2-were-2-(piperazine-1-yl)acetate hydrochloride

Stage 1: Using the procedure described in section 5.15, tert-butyl 4-(2-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ureido)-2-methylphenoxy)-2-oxoethyl)piperazine-1-carboxylate was obtained from tert-butyl 4-(2-(5-amino-2-methylphenoxy)-2-oxoethyl)piperazine-1-carboxylate and salts 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

Stage 2: To a mixture of tert-butyl 4-(2-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ureido)-2-methylphenoxy)-2-oxoethyl)piperazine-1-carboxylate (0.65 g, 1.0 mmol) in methylene chloride (50 ml) was added 2M HCl in simple ether (1 ml) and the mixture was stirred for 24 hours Solid precipitate was filtered, washed DHM (10 ml) and dried under vacuum to obtain the product.

5.23. 1-(3-(Aminomethyl)-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea

Stage 1: Using the procedure described in section 5.15, 1-(3-cyano-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea was obtained from 5-amino-2-methylbenzonitrile and salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

Stage 2: a Mixture of 1-(3-cyano-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g) and 5-6M HCl in isopropanol (2 ml) in ssnoi acid (15 ml) was first made when the hydrogen pressure 345 kPa (50 psi) for 48 hours The mixture was filtered through celite, the filtrate was evaporated in vacuum and the residue was purified preparative HPLC to obtain the product.

5.24. 1-(2-(Aminomethyl)-5-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea

Stage 1: Using the procedure described in section 5.15, 1-(2-cyano-5-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea was obtained from 2-amino-4-methylbenzonitrile and salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

Stage 2: a Mixture of 1-(2-cyano-5-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g) and 5-6M HCl in isopropanol (2 ml) in acetic acid (15 ml) was first made when the hydrogen pressure 345 kPa (50 psi) for 48 h the Mixture was filtered through celite, the filtrate was evaporated in vacuo and the residue was purified preparative HPLC to obtain the product.

5.25 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-(morpholinomethyl)phenyl)urea

Using the methodology described in section 5.15, the product was obtained from 4-(morpholinomethyl)aniline and a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

5.26. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea

Using the methodology described in section 5.15, the product was obtained from 3-((4-methylpiperazin-1-yl)methyl)aniline and a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid.

5.27. Isoindoline connection

Isoindoline compounds presented above were obtained using the methodology described in section 5.15.

5.28. Salt of 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[4-(2-pyridin-4-yl-ethyl)phenyl]urea with hydrochloric acid

Stage 1: Obtain 4-[2-(4-nitrophenyl)vinyl]pyridine

For CH3CN to a solution of 1-iodine-4-nitrobenzene (498 mg, 2 mmol) and 4-vinylpyridine) - derivatives (262 mg, 2.5 mmol) was added tea (350 μl, 2.5 mmol) and Pd(OAc)2(0.45 mg, 0.2 mmol). The mixture was heated to 100°C for 48 h in a sealed tube of glass Pyrex. Then cooled to room temperature, extinguished 1H. HCl (20 ml) and concentrated under reduced pressure. The mixture was filtered and the precipitate was transferred into EtOAc (30 ml) and washed with 1N. NaOH (30 ml). The organic layer was concentrated, dried over Na2SO4and concentrated to obtain 4-[2-(4-nitrophenyl)vinyl]pyridine in the form of a solid yellow color (160 mg, 37%).

Stage 2: Obtain 4-(2-pyridin-4-retil)phenylamine

To EtOAc RA is Toru (30 ml) of 4-[2-(4-nitrophenyl)vinyl]pyridine (160 mg, 0.71 mmol) was added palladium-on-coal (0.1 g, 50% wetted). The suspension was first made when the hydrogen pressure 345 kPa (50 psi) for 2 hours. The mixture was filtered through a layer of celite. The filtrate was concentrated to obtain 4-(2-pyridin-4-retil)phenylamine in a solid yellow color (140 mg, 100%).

Stage 3: obtain the salt of 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[4-(2-pyridin-4-retil)phenyl]urea with hydrochloric acid

To a suspension of the salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (from 0.37 g, 1 mmol) in DMF (2 ml) was added carbonyldiimidazole (162 mg, 1 mmol). The mixture was stirred at room temperature overnight. 4-Pyridin-4-iletilenlerin (140 mg, 0.7 mmol) was added to the mixture and the mixture was stirred at 40°C overnight, then at 80°C for 1.5 hours. The mixture was cooled to room temperature, added water (5 ml) and was stirred for 10 minutes, the Suspension was filtered, the filtrate was concentrated and was purified preparative HPLC. Obtained after purification, the solid was stirred with 1N. HCl, filtered and the filtrate was concentrated to obtain salts of 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[4-(2-pyridin-4-retil)phenyl]urea with hydrochloric acid in a solid off-white color (30 mg, 8% yield). In the LC: Waters Symmetry C 18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient 5% to 95% within 5 min, CH3CN/0.1% of H3PO4,: tR=4,70 min (92%); TPL: >400°C;1H NMR (DMSO-d6) δ 1,89-to 2.06 (m, 1H, CHH), 2,37 (users, 1H, CHH), 2,55-to 2.67 (m, 1H, CHH), 2,82-a 3.01 (m, 3H, CH2, CHH), 3,12 (d, J=7.7 Hz, 2H, CH2), 4,20-a 4.53 (m, 5H, CH2CH2), 5,11 (DD, J=4,8, 13.3 Hz, 1H, NCH), 6,89 (users, 1H, NH), 7,07 (d, J=8,3 Hz, 2H, Ar), 7,32 (d, J=8,3 Hz, 2H, Ar), 7,44 (d, J=7.9 Hz, 1H, Ar), 7,51 (s, 1H, Ar), of 7.69 (d, J=7.7 Hz, 1H, Ar), 7,83 (d, J=5,5 Hz, 2H, Ar), 8,71-8,78 (m, 2H, Ar), 8,80 (s, 1H, NH), 10,98 (s, 1H, NH).13C NMR (DMSO-d6) δ 22,44, 31,13, 34,25, 36,52, 42,64, 47,05, 51,49, 117,59, 121,78, 122,84, 126,56, 126,78, 128,49, 130,19, 132,39, 138,59, 142,12, 142,28, 144,86, 155,24, 167,86, 170,91, 172,78; LC-MS MH=498; analytical calculated for C28H27N5O4+ 1,55 HCl + 0,75 H2O + 0,15 CH3CN C, 56.78 has; H, from 5.29; N, 11,64; Cl, 8,87; found: C, 56,47; H, 5,15; N, 11,99; Cl, cent to 8.85.

5.29. Isoindoline connection

Data isoindoline compounds presented above were obtained using the methodology described in section 5.15.

5.30. N-(3-Chloro-4-were-N'-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-N-cyanoguanidine

Stage 1: Getting phenyl ether (3-chloro-4-were)carbamino acid

Dissolve 2-chloro-4-aminotoluene (282 mg, 2 mmol) in THF (10 ml). To the mixture was added sodium hydride (128 mg, 3.2 mmol) and stirred at room temperature than is their 15 minutes. Added diphenyl(N-cyano)amidocarbonyl (715 mg, 3.0 mmol) and the mixture was heated to boiling for 4 hours. The reaction mixture was cooled to room temperature, put a saturated solution of NH4Cl (10 ml), filtered and the precipitate was dried in a drying Cabinet with getting phenyl ether (3-chloro-4-were)carbamino acid as a solid (0.5 g, 87%).

Stage 2: Obtaining N-(3-chloro-4-were)-N'-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-N-cyanoguanidine

To a suspension of the salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.18 g, 0.5 mmol) in DMF (2 ml) was added phenyl ether (3-chloro-4-were)carbamino acid (143 mg, 0.5 mmol) and DIPEA (83 μl, 0.5 mmol). The mixture was stirred at 100°C for 4 hours. The mixture was concentrated under reduced pressure to remove DMF, was purified on a column of silica gel, using as eluent methanol and methylene chloride, to obtain N-(3-chloro-4-were)-N'-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-N-cyanoguanidine in a solid white color (40 mg, yield 17%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 50/50, CH3CN/0.1% of H3PO4,: tR=3,06 min (96,5%); TPL: 325-327°C;1H NMR (DMSO-d6) δ 1.93 and-of 2.09 (m, 1H, CHH), 2,25 of-2.32 (m, 3H, CH3), 2,33 at 2.45 (m, 1H, CHH), 2,55-to 2.67 (m, 1H, CHH),2,82-a 3.01 (m, 1H, CHH), 4,27-of 4.57 (m, 4H, CH2CH2), 5,11 (DD, J=5,1, 13,2 Hz, 1H, NCH), 7,13 (DD, J=2,3, 8,1 Hz, 1H, Ar), 7,32 (d, J=1.5 Hz, 2H, Ar), the 7.43 (d, J=7.7 Hz, 1H, Ar), 7,51 (s, 1H, Ar), 7,71 (d, J=7.7 Hz, 1H, Ar), a 7.85 (s, 1H, NH), 9,20 (s, 1H, NH), 10,99 (s, 1H, NH).13C NMR (DMSO-d6) δ 18,98, 22,49, 31,20, 44,70, 47,15, 51,58, 116,88, 121,98, 122,94, 124,33, 126,97, 130,52, 131,41, 132,08, 133,10, 136,46, 142,36, 142,97, 158,15, 167,86, 170,98, 172,86; LC-MS: 465; analytical calculated for C23H21ClN6O3+ 0,6 H2O + 0,2 EtOAc: C, 57,94; H, a 4.86; N, 17,03; found: C, 57,66; H, to 4.81; N, 17,10.

5.31. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[4-(1H-imidazol-2-yl)phenyl]urea

The mixture of salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.40 g, 1.1 mmol) and CBI (0,19 g, 1.2 mmol) in DMF (5 ml) was stirred at room temperature for 18 hours. To the mixture was added 4-(1H-imidazol-2-yl)phenylamine (0.17 g, 1.1 mmol) at room temperature and the mixture was stirred at 60°C for 1 day. To the mixture was added water (25 ml) and ethyl acetate (20 ml). The mixture was stirred at room temperature for 2 hours, the Suspension was filtered and the precipitate washed with water (20 ml), ethyl acetate (20 ml) and water (20 ml) to obtain the precipitate. The residue was purified using preparative HPLC to obtain 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[4-(1H-imidazol-2-yl)phenyl]urea as solid white is the first color (150 mg, yield 30%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient 5/95-95/5 for 5 min, CH3CN/0.1% of H3PO4, to 4.41 min (95,9%); TPL: 190-192°C;1H NMR (DMSO-d6) δ 1,91-of 2.08 (m, 1H, CHH), 2,27-2,47 (m, 1H, CHH), 2,54-of 2.66 (m, 1H, CHH), 2,81-a 3.01 (m, 1H, CHH), or 4.31 (d, J=17,4 Hz, 1H, CHH), to 4.38-to 4.52 (m, 3H, CHH, CH2), 5,11 (DD, J=5.0 and 13.3 Hz, 1H, NCH), 6,78 (t, J=6.0 Hz, 1H, NH), 7,33-7,76 (m, 9H, Ar), 8,17 (s, 1H, HCOOH), 8,67 (s, 1H, NH), 10,99 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,41, 31,10, 42,69, 47,02, 51,49, 114,17 (OSiR.), 117,80, 121,79, 122,84, 124,55, 126,81, 126,98, 130,19, 135,46, 138,55, 142,31, 144,83, 155,14, 163,19 (HCOOH), 167,88, 170,92, 172,77; LC-MS MH=459; analytical calculated for C24H22N6O4+ 2 H2O + 0,7 HCOOH + 0,3 DMF: C, 56,04; H, 5,42; N, 16,08; found: C, 55,84; H, of 5.34; N, 16,11.

5.32. 1-[3-(1H-Benzimidazole-2-yl)-4-chlorophenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

The mixture of salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.40 g, 1.1 mmol) and CBI (0.21 g, 1.3 mmol) in DMF (5 ml) was stirred at room temperature for 18 hours To the mixture was added 3-(1H-benzimidazole-2-yl)-4-chlorpheniramine (0.32 g, 1.3 mmol) at room temperature and the mixture was stirred at 100°C for 18 hours. To the mixture was added water (25 ml) and a simple ether (20 ml). The mixture was stirred at room temperature for 2 hours. The solvent decantation. The residue was purified using prep is exploring HPLC to obtain 1-[3-(1H-benzimidazole-2-yl)-4-chlorophenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea as solid white (130 mg, yield 22%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% of H3PO4, of 4.44 min (99,2%); TPL: 275-277°C;1H NMR (DMSO-d6) δ 1,90-2,10 (m, 1H, CHH), 2,23 is 2.46 (m, 1H, CHH), 2,54 of 2.68 (m, 1H, CHH), 2,80-to 3.02 (m, 1H, CHH), or 4.31 (d, J=17,4 Hz, 1H, CHH), 4,37-4,51 (m, 3H, CHH, CH2), 5,11 (DD, J=5.0 and 13.3 Hz, 1H, NCH), 6,89 (t, J=5,9 Hz, 1H, NH), of 7.23 (d, J=4.5 Hz, 2H, Ar), 7,40-7,76 (m, 7H, Ar), 8,07 (d, J=2.5 Hz, 1H, Ar), of 9.02 (s, 1H, NH), 10,98 (s, 1H, NH), 12,64 (users, 1H, NH);13C NMR (DMSO-d6) δ 22,39, 31,10, 42,75, 47,02, 51,48, 111,62, 118,88, 120,11, 120,62, 121,55, 121,83, 122,56, 122,85, 126,85, 129,79, 130,23, 130,35, 134,56, 139,56, 142,29, 143,00, 144,58, 149,12, 154,96, 162,96, 167,86, 170,91, 172,76; LC-MS MH=543, 545; analytical calculated for C28H23N6O4Cl + 3 H2O: C, 56,33; H, the 4.90; N, 14,08; found: C, 56,73; H, of 4.67; N, 14,09.

5.33. N-(3-Chloro-4-were)-N'-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]guanidine hydrochloride

Stage 1: 3-(Chloro-4-were)thiourea

To a solution of 2-chloro-4-isothiocyanato-1-methylbenzol (2 g, 10,89 mmol) in dry acetonitrile (10 ml) was added a solution of NH3in MeOH (2n., 6 ml) and the mixture was stirred at room temperature for 2 hours was Added to the reaction mixture water, causing the formation of sludge. The reaction suspension was concentrated in vacuo to ~1/4 of the volume and a white precipitate was collected by filtration and dried in a vacuum oven to obtain 2.1 g (yield 96%) -chloro-4-were)of thiourea in the form of a solid white color, which was used without further purification. LC-MS: MH=201.

Stage 2: 1-(3-Chloro-4-were)-2-methylisothiazoline hydroiodic

To a suspension of 3-chloro-4-methylphenethylamine (2.1 g, 10,46 mmol) in MeOH (15 ml) was added methyliodide (2.5 ml, 40 mmol) and the mixture was stirred at room temperature for 4 h the Reaction mixture was concentrated to dryness and to the residue was added a small portion of dichloromethane was removed volatiles in vacuum. This process was repeated twice more to obtain a yellowish-brown foam, which was dried in a vacuum oven overnight to obtain 3.5 g (yield 98%) of crude (2×) 1-(3-chloro-4-were)-2-methylisothiazoline hydroiodide. It was found that this substance is very hygroscopic and stored in a desiccator for further use. LC-MS: MH = 215.

Stage 3: N-(3-Chloro-4-were)-N'-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]guanidine hydrochloride

In vitro irradiation with microwaves, equipped with anchor magnetic stirrer, were mixed 1-(3-chloro-4-were)-2-methylisothiazoline hydroiodide (597 mg, of 1.74 mmol), 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione methanesulfonate (560 mg, of 1.52 mmol) and DIEA (DIEA) (1.1 ml, the 6.06 mmol) in anhydrous DMF (5 ml). The tube was sealed and subjected to irradiation in a microwave oven for 30 is in at 120°C. To the reaction mixture was added an additional 100 mg of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione of methansulfonate and the reaction was irradiated for 30 min at 120°C. This process was repeated twice more to trashdolls all starting material 1-(3-chloro-4-were)-2-methylisothiazoline hydroiodic that was discovered by co-elution of the desired product by LC-MS. The reaction mixture was acidified with acetic acid and evaporated volatiles in vacuum. The residue was dissolved in minimum amount of DMF, filtered and purified using C-18 preparative HPLC. Was added to combined fractions containing the desired product, 1 N. HCl and the solvents were removed in vacuum. The obtained white precipitate was dissolved in minimum amount of water and liofilizovane to obtain 180 mg (yield 27%) of N-(3-chloro-4-were)-N'-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]guanidine hydrochloride. HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% of H3PO4, to 3.73 min (97,4%); TPL: >400°C;1H NMR (DMSO-d6) δ 1,91-of 2.09 (m, 1H, CHH), of 2.33 (s, 3H, CH3), is 2.41 (DD, J=4,3, 13,2 Hz, 1H, CHH), 2,54 of 2.68 (m, 1H, CHH), 2,80 was 3.05 (m, 1H, CHH), 4,21-4,56 (m, 2H, CH2), of 4.66 (d, J=5.7 Hz, 2H, CH2), to 5.13 (DD, J=4,9, 13,2 Hz, 1H, CH), 7,14 (DD, J=1,9, 8,1 Hz, 1H, Ar), 7,34 (d, J=1.9 Hz, 1H, Ar), 7,42 (d, J=8,1 Hz, 1H, Ar), 7,51 (d, J=7.9 Hz, 1H, Ar), to 7.61 (s, 1H, Ar), 7,76 (d, J=7.7 Hz, 1H, Ar), 7,98 (users, 1H, NH, 8,62 (users, 1H, NH), 10,16 (s, 1H, NH), 11,00 (s, 1H, NH);13C NMR (DMSO-d6) δ 21,04, 24,19, 32,95, 46,33, 49,85, 54,03, 124,13, 125,48, 125,79, 127,28, 129,17, 132,57, 134,20, 135,82, 135,95, 136,64, 143,17, 144,68, 156,84, 170,94, 173,00, 175,82; LC-MS: MH=440, 442; analytical calculated for C22H23Cl2N5O3+ 2,3 H2O + 1,9 HC1 + 0,2 HCOOH: C, 44,72; H, of 5.05; N, 11,74; Cl, 23,19; found: C, 44,55; H, 4,71; N, 11,48; Cl, 22,92.

5.34. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-were)urea

Stage 1: a Mixture of 2-methyl-5-NITROPHENOL (3.0 g, a 19.6 mmol), TBS-Cl (tert-butyldimethylsilyloxy) (3.0 g, a 19.6 mmol) and tea (2.2 g, 21.6 mmol) in DMF (30 ml) was stirred at ambient temperature for 16 hours the Mixture was evaporated under vacuum. The residue was dissolved in ethyl acetate (100 ml) and washed with water (3×100 ml) and evaporated under vacuum. The residue was chromatographically in the gradient hexane-ethyl acetate, gaining 4.7 g of tert-buildkey(2-methyl-5-nitrophenoxy)silane, with the yield 91%;1H NMR (DMSO-d6) δ a 0.27 (s, 6H), is 1.01 (s, 9H), and 2.27 (s, 3H), 7,47 (d, J=8.5 Hz, 1H), 7,52 (d, J=2.3 Hz, 1H), 7,78 (DD, J=2,3, 8,3 Hz, 1H).

Stage 2: a Mixture of product from step 1 (4.7 g, 17.6 mmol) and 10% Pd-C (1.0 g, 50% wetted) in ethyl acetate was first made when the hydrogen pressure 345 kPa (50 psi) for 16 h the Mixture was then filtered through celite and the filtrate was evaporated under vacuum, obtaining of 3.9 g of 3-(tert-butyldimethylsilyloxy)-4-methylaniline with yield 94%;1NMR (DMSO-d 6) δ 0,17 (s, 6H), of 0.97 (s, 9H), to 1.96 (s, 3H), to 4.81 (s, 2H), 6,00-6,21 (m, 2H), 6,74 (d, J=7.9 Hz, 1H).

Stage 3: a Mixture of 3-(5-(aminomethyl)-1-occaisonaly-2-yl)piperidine-2,6-dione of methansulfonate (0.74 g, 2.0 mmol) and CBI (0.32 g, 2.0 mmol) in DMF (30 ml) was stirred at room temperature for 3 h and then was added the product from step 2 (of 0.47 g, 2.0 mmol). The mixture was heated to 70°C for 16 hours Then the mixture was cooled to room temperature and was suppressed with the help of 1H. HCl (30 ml). The resulting mixture was evaporated under vacuum and the residue was purified using preparative HPLC using a gradient of acetonitrile-water and receiving of 0.38 g of 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-were)urea in a solid white color with a yield of 46%; HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 25/75 CH3CN/0.1% of H3PO4, 4,80 min (100,00%); TPL273-275°C;1H NMR (DMSO-d6) δ 2,02 (s, 4H), 2,27-2,47 (m, 1H), 2.63 in (m, 1H), 2,80 totaling 3.04 (m, 1H), 4,17-4,59 (m, 4H), 5,11 (DD, J=4,7, at 13.0 Hz, 1H), 6,47-6,72 (m, 2H), 6,86 (d, J=7.9 Hz, 1H),? 7.04 baby mortality (s, 1H), 7,44 (d, J=7.7 Hz, 1H), 7,51 (, 1H), 7,69 (d, J=7.7 Hz, 1H), 8,39 (s, 1H), 9,13 (s, 1H), 10,98 (s, 1H);13C NMR (DMSO-d6) δ 15,35, 22,49, 31,20, 42,74, 47,12, 51,58, 104,76, 108,45, 116,48, 121,86, 122,91, 126,91, 130,19, 130,26, 138,92, 142,36, 144,96, 155,18, 155,29, 167,95, 170,99, 172,85; LC-MS MH=423; analytical calculated for C22H22N4O5: C, 62,55; H, a 5.25; N, 13,26; found: C, 62,27; H, 5,15; N, of 13.18.

5.35. 1-((2-(2,6-Dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)--(4-hydroxy-3-were)urea

Stage 1: a Mixture of 2-methyl-4-NITROPHENOL (3.0 g, a 19.6 mmol), TBS-Cl (3.0 g, a 19.6 mmol) and tea (2.2 g, 21.6 mmol) in DMF (30 ml) was stirred at ambient temperature for 16 hours the Mixture was distributed between 10% aqueous sodium bicarbonate solution (100 ml) and ethyl acetate (100 ml) and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with 10% aqueous solution of sodium bicarbonate (3×100 ml) and water (100 ml) and evaporated under vacuum. The residue was chromatographically in the gradient hexane-ethyl acetate, receiving of 3.9 g of tert-buildkey(2-methyl-4-nitrophenoxy)silane with a yield of 75%;1H NMR (DMSO-d6) δ 0,29 (s, 6H), and 1.00 (s, 9H), 2,24 (s, 3H), 7,03 (d, J=8,9 Hz, 1H), 8,02 (DD, J=2,8, and 8.9 Hz, 1H), 8,12 (d, J=2.5 Hz, 1H).

Stage 2: a Mixture of product from step 1 (3,9 g, 14.6 mmol) and 10% Pd-C (0.5 g, 50% wet.) the ethyl acetate was first made when the hydrogen pressure 345 kPa (50 psi) for 18 hours the Mixture was filtered through celite and the filtrate was evaporated, obtaining 3.2 g of 4-(tert-butyldimethylsilyloxy)-3-methylaniline with the release of 93%.

Stage 3: a Mixture of 3-(5-(aminomethyl)-1-occaisonaly-2-yl)piperidine-2,6-dione of methansulfonate (0.74 g, 2.0 mmol) and CBI (0.32 g, 2.0 mmol) in DMF (30 ml) was stirred at room temperature for 3 h and then was added the product from step 2 (of 0.47 g, 2.0 mmol). The mixture was heated to 70°C for 30 hours and Then the mixture was cooled to room temperature and Vasilis through 1H. HCl (30 ml), resulting in precipitate formation. This residue was purified by chromatography was carried out on a column of silica gel using a gradient of methylene chloride-methanol and receiving of 0.59 g of 1-(4-(tert-butyldimethylsilyloxy)-3-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea in a solid off-white color with a yield of 55%;1H NMR (DMSO-d6) δ of 0.16 (s, 6H), of 0.97 (s, 9H), 1,88-to 2.06 (m, 1H), 2,10 (s, 3H), 2,25-2,47 (m, 1H), 2,53-2,70 (m, 1H), 2,80-to 3.02 (m, 1H), or 4.31 (d, J=17,4 Hz, 1H), 4,36-to 4.52 (m, 3H), 5,11 (DD, J=4,9, 13,2 Hz, 1H), 6,51-6,74 (m, 2H), was 7.08 (DD, J=2.5 and 8.6 Hz, 1H), 7,18 (d, J=2.3 Hz, 1H), 7,43 (d, J=7.7 Hz, 1H), 7,50 (s, 1H), 7,69 (d, J=7.7 Hz, 1H), 8,35 (s, 1H), 10,98 (s, 1H).

Stage 4: To a solution of product from step 3 (0.5 g, 0.9 mmol) in methylene chloride (20 ml) was added 2 N. HCl in diethyl ether (2 ml). The mixture was stirred for 16 h at ambient temperature. The precipitated product was separated by filtration and washed with methylene chloride (20 ml) and dried under vacuum, obtaining 0.4 g of 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-hydroxy-3-were)urea in a solid off-white color, with a quantitative yield; HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, a 1.88 min (96,4%); TPL210-212°C;1H NMR (DMSO-d6) δ 1,94-to 2.18 (m, 4H), 2,30 is 2.51 (m, 1H), 2,58-of 2.72 (m, 1H), 2,87-of 3.06 (m, 1H), 4,25-4,56 (m, 4H), of 5.15 (DD, J=5.0 and 13.3 Hz, 1H), to 6.67 (d, J=8.5 Hz, 1H), 7,02 (DD, J=2.5 and 8.6 Hz, 1H), 7,12 (d, J=2.3 Hz, 1H), ,47 (d, J=7.7 Hz, 1H), 7,54 (s, 1H), 7,73 (d, J=7.7 Hz, 1H), 8,32 (users, 1H), 11,02 (s, 1H);13C NMR (DMSO-d6) δ 16,15, 22,51, 31,20, 42,77, 47,12, 51,56, 114,47, 117,11, 121,32, 121,83, 122,88, 123,61, 126,86, 130,22, 131,72, 142,35, 145,17, 150,10, 155,58, 170,99, 172,85; LC-MS MH=423; analytical calculated for C22H22N4O5+ 0,25 CH2Cl2: C, 60,23; H, 5,11; N, 12,63; found: C, 60,14; H, 5,43; N, 12,54.

5.36 1-(4-tert-Butylcyclohexyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

To a stirred suspension of 4-tert-butylcyclohexylamine (0.20 g, 1.28 mmol) in DMF (5 ml) at 40°C was added to the OED (0,23 g of 1.40 mmol). The mixture was stirred for 15 min followed by the addition salts of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0,47 g, 1.28 mmol). Heating was stopped after 1.5 h and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified using preparative HPLC to obtain the product in a solid white color (0,076 g, yield 13%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 35/65 CH3CN/0.1% of H3PO4, 13,37 min (44,7%), 14,68 min (54,3%); TPL: 182-184°C;1H NMR (DMSO-d6) δ of 0.83 (s, 9H, CH3CH3CH3), 0,90-to 1.21 (m, 4H, CH2CH2), 1,30 is 1.58 (m, 2H, CHH, CHH), 1,61-of 1.78 (m, 2H, CHH, CHH), 1,87 (users, 1H, CIS), 1,95-to 2.06 (m, 1H, CHH), 2,28-2,47 (m, 1H, CHH), 2,63 (users, 1H, CH), 2,83-3,00 (m, 1H, CHH), of 3.78 3.27 (2s, 1H, CH), 4,23-4,50 (m, 4H, CH2CH2), 5,11 (DD, J=5.0 and 13.1 Hz, 1H, NCH), 5,79-6,12 (m, 1H, NH), 6,25-6,44 (m, 1H, NH), 7,38 (t, J=6,8 Hz, 1H, ArH), was 7.45 (d, J=6.2 Hz, 1H, ArH), to 7.67 (DD, J=4,1, 7,6 Hz, 1H, ArH), 10,99 (s, 1H, NH); (note:1H NMR showed approximately 55% to 45%, the ratio of isomers);13C NMR (DMSO-d6) δ 21,33, 22,49, 25,95, 27,38, 27,45, 31,02, 31,20, 32,06, 32,26, 33,76, 42,87, 43,43, 46,81, 47,10, 47,42, 48,69, 51,56, 121,76, 121,88, 122,83, 122,90, 126,81, 126,88, 130,11, 130,19, 142,29, 142,35, 145,36, 145,52, 157,35, 167,98, 170,99, 172,85, LC-MS MH+=455; analytical calculated for C25H34N4O4+ 0,7 H2O: C, 64,27; H, of 7.64; N, 11,99; found: C, 63,98; H, 7,98; N, 11,92.

5.37. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methylcyclohexyl)urea

To a stirred suspension of 4-methylcyclohexylamine (mixture of CIS/TRANS isomers, 0.21 g, of 1.86 mmol) in DMF (10 ml) at 40°C was added to the OED (0.33 g, 2.04 mmol). The mixture was stirred for 15 min followed by the addition salts of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0,69 g of 1.86 mmol). Heating was stopped after 1.5 h and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified using preparative HPLC to obtain the product in a solid white color (0.14 g, 18% yield). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 25/7 CH 3CN/0.1% of H3PO4, 11,33 min (59,1%), 12,41 min (39,7%); TPL: 223-225°C;1H NMR (DMSO-d6) δ 0,81 with 0.93 (m, 3H, CH3), of 0.95 and 1.35 (m, 3H, CHH, CHH, CHH), 1,37-of 1.57 (m, 4H, CHH, CHH, CHH, CH), 1,58 is 1.70 (m, 1H, CHH), 1,73-of 1.88 (m, 1H, CIS), 1,92-2,07 (m, 1H, CHH), 2,30-2,47 (m, 1H, CHH), 2,54-to 2.67 (m, 1H, CHH), 2,83-3,00 (m, 1H, CHH), 3,20 of 3.75 (m, 1H, CH), 4,21-4,51 (m, 4H, CH2CH2), 5,11 (DD, J=5.0 and 13.1 Hz, 1H, NCH), 5,78-6,11 (m, 1H, NH), 6,24-6,40 (m, 1H, NH), 7,34-7,42 (m, 1H, ArH), 7,42-to 7.50 (m, 1H, ArH), 7,63-7,72 (m, 1H, ArH), 10,98 (s, 1H, NH); (note:1H NMR showed approximately 60% to 40% ratio of isomers);13C NMR (DMSO-d6) δ 21,47, 22,17, 22,49, 29,42, 29,77, 30,42, 31,20, 31,50, 33,28, 33,73, 42,86, 44,54, 47,09, 48,37, 51,56, 121,78, 122,87, 126,81, 130,16, 142,33, 145,44, 145,52, 157,33, 167,98, 170,99, 172,85; LC-MS MH+=413; analytical calculated for C22H28N4O4+ 0,4 H2O: C, 63,23; H, of 6.90; N, 13,41; found: C, 62,93; H, 6,92; N, to 13.09.

5.38. Salt of 1-(3-Diethylaminopropyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea with formic acid

To a solution of paranitrophenylphosphate (202 mg, 1 mmol) in CH3CN (5 ml) was added dropwise at 0°C a solution of N,N-diethylpropane-1,3-diamine (130 mg, 1 mmol) and DIPEA (0,082 ml, 1 mmol) in CH3CN (5 ml). The mixture was stirred at 0°C for 10 minutes was Added a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (from 0.37 g, 1 mmol) followed by addition of DIPEA (0,082 ml, 1 mmol). A mixture of whom were returned to warm to room temperature and was stirred over night at room temperature. To the mixture was added 1N. HCl (15 ml) and filtered. The obtained residue was purified preparative HPLC to obtain the product as a solid off-white color (280 mg, yield 65%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient 5%-100% over 5 min, CH3CN/0.1% of H3PO4, 4,46 min (97%); TPL: 90-92°C;1H NMR (DMSO-d6) δ is 1.01 (t, J=7,1 Hz, 6H, CH3CH3), 1,58 (the Queen., J=7,1 Hz, 2H, CH2), 1,94-to 2.06 (m, 1H, CHH), 2,39 (arcs, J=4,5, 13,2 Hz, 1H, CHH), 2,55-by 2.73 (m, 7H, CH2CH2CH2, CHH), 2,83-2,99 (m, 1H, CHH), 3,05 (d, J=5.3 Hz, 2H, CH2), 4,15-4,56 (m, 4H, CH2CH2), 5,10 (DD, J=5,1, to 13.4 Hz, 1H, NCH), 6,17 (users, 1H, NH), 6,60 (s, 1H, NH), 7,39 (d, J=7.7 Hz, 1H, Ar), was 7.45 (s, 1H, Ar), to 7.67 (d, J=7.9 Hz, 1H, Ar), 8,25 (users, 1H, HCOOH), 10,98 (users, 1H, NH);13C NMR (DMSO-d6) δ 10,25, 22,49, 26,14, 31,20, 37,39, 42,93, 46,11, 47,09, 51,56, 121,73, 122,81, 126,76, 130,13, 142,27, 145,54, 158,18, 167,99, 171,01, 172,86; LC-MS MH+=430; analytical calculated for C23H33N5O6+ 2 H2O: C, 54,00; H, 7,29; N, 13,69; found: C, 54,04; H, 6,92; N, 13,63.

5.39. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methyltetrahydrofuran-4-yl)urea

To a solution of paranitrophenylphosphate (202 mg, 1 mmol) in CH3CN (5 ml) was added dropwise at 0°C solution of 4-methyltetrahydrofuran-4-ylamine (150 mg, 1 mmol) and DIPEA (0,082 ml, 1 mmol) in CH3CN (5 ml). The mixture was stirred at 0°C for 10 minutes add the Yali salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0,37 g, 1 mmol) followed by addition of DIPEA (0,082 ml, 1 mmol). The mixture was left to warm to room temperature and was stirred over night at room temperature. To the mixture was added 1N. HCl (15 ml) and filtered. The obtained residue was purified preparative HPLC to obtain a solid substance. The solid is recrystallized from DMF (1 ml) and water (1 ml) to give the product as solid white (55 mg, yield 12%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient 5%-100% over 5 min, CH3CN/0.1% of H3PO4, 5,02 min (98%); TPL: 158-160°C;1H NMR (DMSO-d6) δ of 1.29 (s, 3H, CH3), 1,40 is 1.58 (m, 2H, CHH), 1,84 is 1.96 (m, 2H, CHH, CHH), 1,99 (s, 1H, CHH), 2,30 at 2.45 (m, 1H, CHH), 2,55-to 2.65 (m, 1H, CHH), 2,84-2,99 (m, 1H, CHH), 3,44-3,68 (m, 4H, CH2CH2), 4,22-4,58 (m, 4H, CH2CH2), 4,95-of 5.29 (m, 1H, NCH), to 5.85 (s, 1H, NH), between 6.08 and of 6.52 (m, 1H, NH), 7,33-7,42 (m, 1H, Ar), was 7.45 (s, 1H, Ar), to 7.68 (d, J=7,6 Hz, 1H, Ar), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,48, 27,00, 31,20, 36,93, 42,58, 47,10, 48,85, 51,56, 62,92, 120,99, 121,67, 122,88, 126,69, 142,35, 145,48, 157,22, 167,98, 171,01, 172,86; LC-MS MH+=415; analytical calculated for C21H26N4O5+ 0,5 H2O: C, 59,56; H, to 6.43; N, 13,23; found: C, 59,34; H, 6.35mm; N, 13,21.

5.40. 1-(1-Benzylpiperidine-4-yl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

To a solution of paranitrophenylphosphate (202 mg, 1 mmol) in CH3CN (5 ml) to allali dropwise at 0°C solution of 4-aminomethylpyridine (190 mg, 1 mmol) and DIPEA (0,082 ml, 1 mmol) in CH3CN (5 ml). The mixture was stirred at 0°C for 10 minutes was Added a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (from 0.37 g, 1 mmol) followed by addition of DIPEA (0,082 ml, 1 mmol). The mixture was left to warm to room temperature and was stirred over night at room temperature. To the mixture was added 1N. HCl (15 ml) and filtered. The obtained residue was purified preparative HPLC with getting sticky solid. The residue was dissolved in DMF (1 ml) was added dropwise a saturated solution of NaHCO3until then, until the start of the sediment. Left to settle at room temperature for 30 min and the precipitate was filtered to obtain the product as a solid white (55 mg, yield 12%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient 5%-100% over 5 min, CH3CN/0.1% of H3PO4, with 4.64 min (99%); TPL: 208-210°C;1H NMR (DMSO-d6) δ 1,21-of 1.52 (m, 2H, CHH), 1,63-to 1.82 (m, 2H, CHH), 1,89 with 2.14 (m, 3H, CHH, CHH, CHH), 2,39 (d, J=13,6 Hz, 1H, CHH), 2,55-to 2.65 (m, 1H, CHH), 2,64 is 2.75 (m, 2H, CHH, CHH), 2,83-to 3.02 (m, 1H, CHH), 3,37-to 3.41 (m, 1H, CH), 3,43 (s, 2H, CH2), 4,21-4,50 (m, 3H, CH2CH2), 5,10 (DD, J=5.0 and 13.3 Hz, 1H, NCH), 5,94 (d, J=7.9 Hz, 1H, NH), 6,34 (t, J=6.0 Hz, 1H, NH), 7,13-of 7.48 (m, 6H, Ar), 7,66 (d, J=7,6 Hz, 1H, Ar), 10,97 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 31,20, 32,46, 42,86, 46,43, 47,09, 51,55, 51,90, 62,19, 121,78, 122,84, 126,79, 128,10, 128,69, 30,13, 138,64, 142,29, 145,44, 157,32, 167,96, 170,99, 172,85; LC-MS MH+=490; analytical calculated for C21H26N4O5+ 0,5 H2O: C, 59,56; H, to 6.43; N, 13,23; found: C, 59,34; H, 6.35mm; N, 13,21.

5.41. 1-[2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-piperidine-4-rocephine hydrochloride

Stage 1. The mixture of salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (1.25 g, 3,39 mmol) and CBI (0,61 g, 3.73 mmol) in DMF (10 ml) was stirred at room temperature overnight. Then was added tert-butyl ether 4-aminopiperidin-1-carboxylic acid (0.68 g, 3,39 mmol) and the mixture was stirred over night. The mixture was purified preparative HPLC to obtain tert-butyl ester 4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}piperidine-1-carboxylic acid in the form of a solid off-white color (0,46 g, yield 27%). The product was used in the next stage without additional purification. HPLC, Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CΗ3CN/0.1% of H3PO4, 4,35 min (99,4%).

Stage 2: a Mixture of tert-butyl ester 4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}piperidine-1-carboxylic acid (0.45 g, 0.90 mmol) in 2M solution of hydrochloride in diethyl ether (30 ml, 9,01 mmol) was stirred over night. Bel is Yu, the suspension was filtered and washed with diethyl ether. The obtained white precipitate was stirred in acetonitrile (80 ml) at 50°C during the night. The suspension was filtered, washed with acetonitrile and dried under vacuum to obtain the product in a solid white color (0.34 g, yield 86%). HPLC: Waters Xterra C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient from 5/95 CH3CN/0.1% of HCOONH4to 95/5 in 5 minutes, continuing for 5 min, 3,10 min (95,1%); TPL: 340-342°C;1H NMR (DMSO-d6) δ 1,46-of 1.65 (m, 2H, CHH, CHH), 1.85 to 2.05 is (m, 3H, CHH, CHH, CHH), 2,30-2,47 (m, 1H, CHH), 2,55-to 2.67 (m, 1H, CHH), 2,83-3,03 (m, 3H, CHH, CHH, CHH), 3,15-of 3.27 (m, 2H, CHH, CHH), 3,59-of 3.77 (m, 1H, CH), 4,23-4,51 (m, 4H, CH2CH2), 5,11 (DD, J=4,9, 13,2 Hz, 1H, NCH), 6,40-to 6.57 (m, 2H, NH, NH), 7,39 (d, J=7.9 Hz, 1H, ArH), was 7.45 (s, 1H, ArH), to 7.67 (d, J=7.7 Hz, 1H, ArH), 8,75 (users, 2H, ClH2N), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 28,92, 31,20, 41,96, 42,82, 43,95, 47,09, 51,55, 121,76, 122,84, 126,76, 130,14, 142,29, 145,35, 157,32, 167,98, 171,01, 172,87; LC-MS MH+=400; analytical calculated for C20H26N504Cl + 1,7 H2O: C, 51,49; H, 6.35mm; N, 15,01; Cl, 7,60; found: C, 51,18; H x 6.15; N, The 14.90; Cl, 7,51.

5.42. Isoindoline connection

Isoindoline compounds presented above were obtained in accordance with the methodology described in Section 5.15.

5.43. Amide 4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}cyclohexanecarboxylic acid

To a solution of paranitrophenyl is chloroformate (200 mg, 1 mmol) in CH3CN (5 ml) was added dropwise a solution of CH3CN (5 ml) amide 4-aminocyclohexanecarboxylic acid (210 mg, 1 mmol) and DIPEA (0.3 ml, 2 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes was Added a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (from 0.37 g, 1 mmol) followed by addition of DIPEA (0.15 ml, 1 mmol). The mixture was stirred over night at ambient temperature. Then the mixture was filtered. The filtrate was purified preparative HPLC to obtain amide 4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}cyclohexanecarboxylic acid in a solid white color (130 mg, 30%yield). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient of 5%-95% for 5 min, CH3CN/0.1% of H3PO4,: tR=4,78 min (92%); TPL: 195-197°C;1H NMR (DMSO-d6) δ 1.32 to at 1.73 (m, 8H, CHH+CHH+CHH+CHH), 1,97 (users, 1H, CHH), 2,09-of 2.21 (m, 1H, CHH), is 2.40 (d, J=a 13.4 Hz, 1H, CHH), 2,62 (users, 1H, CHH), 2,80-3,03 (m, 1H, CHH), 3,70 (users, 1H, CHH), 4,18-4,58 (m, 4H, CH2+CH2), 5,11 (DD, 1H, CHN), x 6.15 (d, J=7.9 Hz, 1H, NH), 6,38 (t, J=5,9 Hz, 1H, NH), 6,67 (users, 1H, NH), 7,19 (users, 1H, NH), 7,38 (d, J=7.7 Hz, 1H, Ar), was 7.45 (s, 1H, Ar), to 7.67 (d, J=7.9 Hz, 1H, Ar), 10,98 (users, 1H, NH);13C NMR (DMSO-d6) δ 0,03, 22,42, 24,06, 24,19, 29,73, 41,73, 42,79, 44,16, 47,03, 51,49, 121,68, 122,80, 126,71, 130,09, 142,26, 145,37, 157,28, 163,37, 167,89, 170,92, 172,78, 176,83; LC-MS: 442; analytically is ycycline for C 22H27N5O5+ 0,5 HCOOH + 1 H2O + 0,2 CH3CN: C, 56,05; H, 6,21; N, 14,84; found: C, 55,70; H, 6,46; N, 14,78.

5.44. 1-(6-Chloropyridin-3-yl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

To a suspension of the salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (from 0.37 g, 1 mmol) in DMF (3 ml) was added carbonyldiimidazole (162 mg, 1 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 5-amino-2-chloropyridine (128,5 mg, 1 mmol) and the mixture was heated at 80°C for 6 hours. The mixture was then concentrated under reduced pressure and the resulting mixture was purified on a column of silica gel, elwira with methylene chloride and methanol, to obtain 11-(6-chloropyridin-3-yl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea as solid off-white color (20 mg, yield 5%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient of 5%-95% for 5 min, CH3CN/0.1% of H3PO4, tR=5,43 min (97%); TPL: 224-226°C;1H NMR (DMSO-d6) δ 1,89-of 2.09 (m, 1H, CHH), 2,29 is 2.44 (m, 1H, CHH), 2,54-of 2.66 (m, 1H, CHH), 2,83 totaling 3.04 (m, 1H, CHH), 4,20-of 4.57 (m, 4H, CH2CH2), 5,11 (DD, J=5.0 and 13.3 Hz, 1H, NCH), of 6.99 (t, J=6.2 Hz, 1H, NH), 7,37 (d, J=8.5 Hz, 1H, Ar), was 7.45 (d, J=7.7 Hz, 1H, Ar), 7,52 (s, 1H, Ar), of 7.70 (d, J=7.7 Hz, 1H, Ar), 7,95 (DD, J=2,8, and 8.7 Hz, 1H, Ar), 8,42 (d, J=2.3 Hz, 1H, Ar), 9,03 (s, 1H, NH), 10,98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22,49, 31,18, 42,86, 47,12, 51,58, 121,91, 122,94, 123,89, 126,92, 128,37, 130,42, 136,75, 139,04, 142,39, 144,50, 154,97, 167,93, 171,01, 172,86, 215,61; LC-MS: 428; analytical calculated for C20H18N5O4Cl + 0,1 H2O C, 55,91; H, 4,27; N, 16,30; Cl, of 8.25; found: C, 56,31; H, 4,51; N, 15,92; Cl, of 8.47.

5.45. 1-[4-(2,4-Differenl)thiazol-2-yl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

The mixture of salt 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.40 g, 1.1 mmol) and CBI (0.18 g, 1.1 mmol) in DMF (5 ml) was stirred at room temperature for 18 hours To the mixture was added 4-(2,4-differenl)thiazol-2-ylamine (to 0.23 g, 1.1 mmol) at room temperature and the mixture was stirred at 100°C for 2 days. To the mixture was added water (25 ml) and ethyl acetate (20 ml). The mixture was stirred at room temperature for 2 hours. The suspension was filtered and the precipitate washed with water (20 ml), ethyl acetate (20 ml) and water (20 ml) to obtain the precipitate. The residue was purified preparative HPLC to obtain 1-[4-(2,4-differenl)thiazol-2-yl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea as solid white (70 mg, yield 13%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, to 6.43 min (97,7%); TPL: 264-266°C;1H NMR (DMSO-d6) δ 1,932,05 (m, 1H, CHH), 2,30 at 2.45 (m, 1H, CHH), 2,55 of 2.68 (m, 1H, CHH), 2,82-3,00 (m, 1H, CHH), 4,32 (d, J=17,4 Hz, 1H, CHH), to 4.41-of 4.54 (m, 3H, CH2, CHH), 5,11 (DD, J=5,1, 13,2 Hz, 1H, NCH), 7,09-7,24 (m, 2H, Ar, NH), 7,28-7,41 (m, 2H, Ar), 7,46 (d, J=7.7 Hz, 1H, Ar), 7,53 (s, 1H, Ar), 7,71 (d, J=7.9 Hz, 1H, Ar), 7,93-8,10 (m, 1H, Ar), 10,85 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,48, 31,18, 42,94, 47,12, 51,57, 104,54 (t, JC-F=26,4 Hz), 110,67 (d, JC-F=14,3 Hz), 111,81 (DD, JC-F=3.3, which is 20.9 Hz), 118,91 (DD, JC-F=2,8, to 11.6 Hz), 121,95, 123,03, 126,95, 130,29 (DD, JC-F=4,4, 9.9 Hz), 130,49, 141,44, 142,45, 143,95, 154,02, 159,48 (DD, JC-F=252,2, 12.1 Hz), 159,36, 161,24 (DD, JC-F=246,9, 13,2 Hz), 167,88, 170,98, 172,85; LC-MS MH=512; analytical calculated for C24H19N5O4F2S: C, 56,36; H, 3,74; N, 13,69; found: C, 56,16; H, of 3.80; N, 14,07.

5.46. Tert-butyl ester 6-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

Suspended 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione methanesulfonate (1,11 g, 3.0 mmol) and 1,1'-carbonyldiimidazole (535 mg, 3.3 mmol) in dry DMF (20 ml) and the mixture was stirred at room temperature for 24 hours while stirring part of the reaction mixture (6,7 ml, ~1 mmol) was transferred into a tube containing tert-butyl-6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (273 mg, 1.1 mmol). The resulting mixture was stirred at room temperature overnight and the reaction was monitored using LC-MS. After 48 h in the reaction mixtures is ü contributed additional tert-butyl-6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 0.2 mmol) and stirring continued for a further 24 hours the Reaction mixture was acidified with acid and water. Volatiles were removed in vacuum and the residue was dissolved in DMF and purified using C-18 preparative HPLC, to obtain tert-butyl ester 6-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid in the form of a solid white color (290 mg, yield 53%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 5,02 min (96,5%); TPL: 230-232°C;1H NMR (DMSO-d6) δ of 1.42 (s, 9H, (CH3)3), 1,90-2,11 (m, 1H, CHH), 2,23-2,47 (m, 1H, CHH), 2,60 (d, J=and 17.9 Hz, 1H, CHH), 2,70 (t, J=5.6 Hz, 2H, CH2), 2,81-of 3.06 (m, 1H, CHH), 3,51 (t, J=5.7 Hz, 2H, CH2), 4,18-4,58 (m, 6H, CH2CH2CH2), 5,11 (DD, J=4,9, 13,2 Hz, 1H, CH), 6,72 (t, J=5,9 Hz, 1H, NH), 7,00 (d, J=8,3 Hz, 1H, Ar), 7,17 (d, J=8,1 Hz, 1H, Ar), 7,27 (users, 1H, Ar), 7,44 (d, J=7.9 Hz, 1H, Ar), 7,51 (s, 1H, Ar), of 7.69 (d, J=7.9 Hz, 1H, Ar), 8,56 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,46, 28,07, 28,44, 31,16, 41,51, 42,75, 45,04, 47,08, 51,55, 78,81, 116,01, 117,49, 121,87, 122,90, 126,20, 126,36, 126,88, 130,25, 134,70, 138,56, 142,35, 144,86, 153,97, 155,21, 167,93, 170,96, 172,83; LC-MS: MH=548; analytical calculated for C29H33H5About6+ 1,1 H2O: C, 61,39; H, 6,25; N, 12,34, found: C, 61,38; H, 6,11; N, 12,29.

5.47. Isoindoline the compounds of Formula III

Isoindoline the compounds of Formula III were obtained as PR is dostavleno in figure 1.

Scheme 1

To a solution of 5-aminomethylpyridine-glutarimide 1 (1,134 mmol) in dry DMF (10 ml) was added Cs2CO3(406 mg, 1,248 mmol). After 5 minutes stirring was added the appropriate klimatotvorennya reagent 2 (1,248 mmol) and the resulting mixture was stirred at 50°C during the night. The reaction mixture was neutralized with a 0.5 N. HCl and then concentrated to dryness in vacuo. The residue was purified preparative HPLC, followed by removal of protective groups, if necessary, under standard conditions to obtain the compounds of Formula III.

5.48. 3-{5-[3-(3-Chloro-4-were)freedomites]-1-oxo-1,3-dihydroindol-2-yl}-2,6-dioxopiperidin-1-ymetray ether of 2,2-dimethylpropionic acid

To a solution of 1-(3-chloro-4-were)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea (500 mg, 1,134 mmol) in dry DMF (10 ml) was added Cs2CO3(406 mg, 1,248 mmol). After 5 min stirring was added chlorocyphidae (188 mg, 1,248 mmol) and the resulting mixture was stirred at 50°C during the night. The reaction mixture was neutralized with a 0.5 N. HCl and then concentrated to dryness in vacuo. The residue was dissolved in acetonitrile and slowly added water, which leads to the formation of a precipitate. The precipitate was collected by filtration and was dissolved in DMF on what I purification on a column for preparative HPLC C-18 (50/50 CΗ 3CN/water). Combined fractions containing the desired product were concentrated in vacuo to remove most of CH3CN and then liofilizovane to obtain a product in the form of a solid white (81 mg, 13% yield). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 55/45 CH3CN/0.1% of H3PO4, 4,58 min (97,2%); TPL: 155-157°C;1H NMR (DMSO-d6) of 0.95 δ is 1.23 (m, 9H,tBu)1,96-of 2.15 (m, 1H, CH), of 2.23 (s, 3H, CH3), 2,31-2,47 (m, 1H, CH), and 2.83 (d, J=16.6 Hz, 1H, CH), 3.00 and-up 3.22 (m, 1H, CH), 4,17-4,60 (m, 4H, CH2CH2), and 5.30 (DD, J=5.0 and 13.3 Hz, 1H, CH), 5,47-of 5.83 (m, 2H, CH2), 6,79 (t, J=5,9 Hz, 1H, CH2NH), 7,02-7,28 (m, 2H, Ar), was 7.36-of 7.60 (m, 2H, Ar), 7,60-7,86 (m, 2H, Ar), a total of 8.74 (s, 1H, NH);13C NMR (DMSO-d6) δ 18,73, 21,56, 26,62, 31,21, 38,21, 42,79, 47,04, 52,01, 63,39, 116,45, 117,66, 121,95, 123,01, 126,98, 127,42, 130,11, 131,00, 132,99, 139,58, 142,36, 144,87, 155,07, 167,96, 170,13, 171,23, 176,51; LC-MS: MH+=555, 557; analytical calculated for C28H31C1N4O6+ 0,2 H2O: C, 60,20; H, 5,67; N, there is a 10.03; Cl, 6.35mm; found: C, 60,20; H, 5,74; N, 9,94; Cl, 6,39.

5.49. (3-(5-((3-(3-Chloro-4-were)ureido)methyl)-1-occaisonaly-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidin-4-carboxylate hydrochloride

1-tert-Butyl-4-(3-(5-((3-(3-chloro-4-were)ureido)methyl)-1-occaisonaly-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidin-1,4-in primary forms (300 mg, 0.44 mmol, obtained as described in the previous example) was added 2 N. HCl in Et2O (15 ml). Suspense is intensively stirred for 2 h at room temperature. The precipitate was filtered, washed abundantly Et2O, and dried in a vacuum oven overnight to obtain (3-(5-((3-(3-chloro-4-were)ureido)methyl)-1-occaisonaly-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidin-4-carboxylate hydrochloride in the form of a solid white color (285 mg, 105% yield). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 3,26 min (98.2 per cent); TPL: 234-236°C;1H NMR (DMSO-d6) δ 1,62-of 1.81 (m, 2H, CHH, CHH), 1,87 is 2.01 (m, 2H, CHH, CHH), 2,02-of 2.16 (m, 1H, CHH), 2,16-to 2.29 (m, 3H, CH3), 2,32-2,47 (m, 1H, CHH), 2,59 was 2.76 (m, 1H, CHH), 2.77-to 2,99 (m, 3H, CHH, CHH, CHH), 3,00 of 3.28 (m, 3H, CHH, CHH, CHH), 4,15-of 4.66 (m, 4H, CH2CH2), of 5.26 (DD, J=4,9, 13,2 Hz, 1H, CH), 5,55-5,80 (m, 2H, CH2O)7,02 (t, J=5,9 Hz, 1H, NH), 7,09-7,29 (m, 2H, Ar), was 7.45 (d, J=7.9 Hz, 1H, Ar), 7,53 (s, 1H, Ar), 7,62-of 7.82 (m, 2H, Ar), to 8.41-8,96 (m, 2H, NH, NH), which is 9.09 (s, 1H, NH);13C NMR (DMSO-d6) δ 18,73, 21,46, 24,31, 31,24, 37,30, 42,00, 42,73, 47,20, 52,09, 63,40, 116,31, 117,50, 121,91, 122,99, 126,97, 127,27, 130,09, 130,99, 132,96, 139,69, 142,38, 144,94, 155,21, 167,96, 170,19, 171,29, 172,20; LC-MS: MH=582, 584; analytical calculated for C29H33Cl2N5O6+ 1,6 H2O + 0,6 HCl + 0,2 Et2O + 0,4tBuCl: C, 53,35; H, equal to 6.05; N, To 9.91; Cl, 13,04, found: C, 53,13; H, the 6.06; N, 9,70; Cl, 13,25.

5.50. 1-Tert-butyl-4-(3-(5-((3-(3-chloro-4-were)ureido)methyl)-1-occaisonaly-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidin-1,4, in primary forms

Stage 1: 1-tert-butyl-4-chloromethylpyridine-1,4, in primary forms/p>

To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 g, of 13.1 mmol) in dichloromethane (40 ml) and water (50 ml) was added NaHCO3(4.4 g, 52,3 mmol) and Tetra-butylammonium the hydrosulfate (444 mg, 1.3 mmol). After stirring the mixture in a bath of ice at 0°C for ~10 min was added dropwise chlormethiazole (2,59 g, 15.7 mmol) in 10 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature and stirred intensively during the night. The mixture was transferred into a separating funnel with dichloromethane and water (200 ml each). The organic layer was additionally washed with water and saturated salt solution, dried (Na2SO4) and concentrated in vacuo to obtain 1-tert-butyl-4-chloromethylpyridine-1,4-in primary forms in the form of a clear oil (3.5 g, yield 96%). This substance is used without additional purification.1H NMR (DMSO-d6) δ of 1.26 to 1.48 (m, 11H, CHH, CHH, tert-Bu)and 1.83 (DD, J=3,0, 13,2 Hz, 2H, CHH, CHH), 2,58 is 2.75 (m, 1H, CH), 2,74-to 2.99 (m, 2H, CHH, CHH), 3,61-was 4.02 (m, 2H, CHH, CHH), by 5.87 (s, 2H, CH2O);13C NMR (DMSO-d6) δ 27,16, 27,98, 39,58, 42,35, 69,41, 78,67, 153,75, 172,25; LC-MS: MH=278.

Stage 2: 1-tert-butyl-4-iodotoluene-1,4, in primary forms

To a solution of NaI (1.6 g, 11,09 mmol) in dry acetonitrile (8 ml) was added dropwise 1-tert-butyl-4-chloromethylpyridine-1,4, in primary forms (2.8 g, 10,08 mmol) of the 2 ml of acetonitrile. The mixture became dark orange and was stirred at room temperature in the dark for 24 h, the Reaction mixture was filtered to remove NaCl and the filtrate was concentrated in vacuum. The remaining residue was redistributed between DHM and 5% aqueous solution of NaHSO3. The organic layer was washed with water and saturated salt solution, dried (Na2SO4) and concentrated in vacuo to obtain 1-tert-butyl-4-iodotoluene-1,4-in primary forms in the form of a pale yellow oil (3.5 g, 94%). Attempts to characterize by NMR in DMSO-d6led to rapid decomposition. The substance kept in the dark at -20°C to minimize degradation before use. LC-MS: MH = 370.

Stage 3: 1-tert-butyl-4-(3-(5-((3-(3-chloro-4-were)ureido)methyl)-1-occaisonaly-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidin-1,4, in primary forms

1-(3-Chloro-4-were)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea (400 mg, 0,907 mmol) and NaH (43,5 mg, 1.82 mmol) was stirred in dry DMF (15 ml) for ~10 minutes To the mixture was added 1-tert-butyl-4-iodotoluene-1,4, in primary forms (402 mg, of 1.09 mmol) and the reaction was stirred the dark at room temperature for 2 hours the Reaction was suppressed by using acetic acid (5 ml) and concentrated in vacuum. The residue was distributed between water and EtOAc (100 ml each of the CSOs). The separated organic layer was additionally washed with water and saturated salt solution, dried (Na2SO4) and concentrated in vacuum to obtain 1.4 g of a yellowish solid, which was dissolved in DMF for purification on a column of C-18 preparative HPLC. Combined fractions containing the desired product were concentrated in vacuo to remove most of CH3CN and then liofilizovane to obtain 1-tert-butyl-4-(3-(5-((3-(3-chloro-4-were)ureido)methyl)-1-occaisonaly-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidin-1,4-in primary forms in a solid white color (380 mg, 49% of theoretical yield of two separate reactions, which were United before preparative HPLC). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 55/45 CH3CN/0.1% of H3PO4, of 5.82 min (99.4 per cent); TPL: 157-159°C;1H NMR (DMSO-d6) δ 1,23-is 1.51 (m, 11H, (CH3)3, CHH, CHH), 1,68-of 1.84 (m, 2H, CHH, CHH), 1,97 and 2.13 (m, 1H, CHH), 2,15-2,31 (m, 4H, CH3CH), 2,32 is 2.46 (m, 1H, CHH), 2,68-to 2.94 (m, 3H, CHH, CHH, CHH), 2,98-is 3.21 (m, 1H, CHH), 3,69-to 3.89 (m, 2H, CHH, CHH), 4,20-of 4.57 (m, 4H, CH2CH2), at 5.27 (DD, J=5.0 and 13.3 Hz, 1H, CH), of 5.53-5,73 (m, 2H, CH2O), for 6.81 (t, J=5,9 Hz, 1H, NH), 7,06-7,24 (m, 2H, Ar), was 7.45 (d, J=7.9 Hz, 1H, Ar), 7,53 (s, 1H, NH), to 7.67 (d, J=1.9 Hz, 1H, Ar), 7,71 (d, J=7.7 Hz, 1H, Ar), 8,76 (s, 1H, NH);13C NMR (DMSO-d6) δ 18,66, 21,39, 27,38, 27,97, 31,16, 42,72, 47,08, 51,98, 63,15, 78,60, 116,37, 117,60, 121,88, 122,93, 126,91, 127,34, 130,06, 130,94, 132,91, 139,52, 142,32, 144,82, 153,74, 155,01, 167,90, 170,11, 171,18, 17297 (two signals in 13C from a ring of piperidine were not observed due to overlap with DMSO-d6); LC-MS: MH=682, 684; analytical calculated for C34H40ClN5O8+ 1,0 H2O: C, 58,32; H, equal to 6.05; N, 10,00; Cl, 5,06 found: C, 58,41; H, to 5.93; N,9,96; Cl, 5,22.

5.51. N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-imidazol-1-ylbenzene

A mixture of 4-imidazol-1-eventing acid (0.21 g, 1.1 mmol) and CBI (0,19 g, 1.2 mmol) in DMF (14 ml) was stirred at 40°C for 2 hours To the suspension was added a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.40 g, 1.1 mmol) and the mixture was stirred at 40°C for 20 hours To the reaction mixture were added water (20 ml) and the mixture was stirred at room temperature for 30 minutes, the Suspension was filtered and the precipitate washed with water (20 ml), ethyl acetate (20 ml) and water (20 ml) to give the product in a solid white color (340 mg, 71%yield). HPLC: Waters Xterra C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient of 5%-95% for 5 min, CH3CN/0.1% of NH4OOCH, to 3.92 min (99,0%); TPL: 268-270°C;1H NMR (DMSO-d6) δ 1,90-of 2.08 (m, 1H, CHH), 2,24-2,47 (m, 1H, CHH), 2,54-to 2.67 (m, 1H, CHH), 2,82-to 3.02 (m, 1H, CHH), or 4.31 (d, J=17,4 Hz, 1H, CHH), of 4.45 (d, J=17,4 Hz, 1H, CHH), to 4.62 (d, J=5.7 Hz, 2H, CH2), 5,11 (DD, J=5,1, 13,2 Hz, 1H, NCH), 7,14 (s, 1H, Ar), 7,49 (d, J=7.9 Hz, 1H, Ar), 7,56 (s, 1H, Ar), 7,71 (d, J=7.7 Hz, 1H, Ar), to 7.77-to $ 7.91 (m, 3H, Ar), with 8.05 (d, J=8.7 Hz, 2H, Ar), 8,39 (s, 1H, Ar), and 9.4 (t, J=5,9 Hz, 1H, NH), 10,98 (users, 1H, NH);13C NMR (DMSO-d6) δ 22,49, 31,20, 42,79, 47,13, 51,58, 117,78, 119,59, 122,10, 122,97, 127,08, 129,02, 130,20, 130,39, 132,07, 135,60, 138,99, 142,40, 143,83, 165,25, 167,92, 170,99, 172,86; LC-MS: MH+=444; analytical calculated for C24H21N5O4+ 1,5 H2O: C, 61,27; H, 5,14; N, 14,89; found: C, 61,03; H, is 4.93; N, 14,75.

5.52. N-[2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-morpholine-4-ylbenzene

A mixture of 4-morpholine-4-eventing acid (0,22 g, 1.1 mmol) and CBI (0,19 g, 1.2 mmol) in DMF (4 ml) was stirred at 40°C for 2 hours To the suspension was added a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (0.40 g, 1.1 mmol) and the mixture was stirred at 40°C for 2 hours To the reaction mixture were added water (20 ml) and the mixture was stirred at room temperature for 30 minutes, the Suspension was filtered and the precipitate washed with water (20 ml), ethyl acetate (20 ml) and water (20 ml) to give the product as a white solid (370 mg, yield 74%). HPLC: Waters Xterra C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient of 5%-95% for 5 min, CH3CN/0.1% of NH4OOCH, 1,10 min (96,5%); TPL: 275-277°C;1H NMR (DMSO-d6) δ 2,00 (d, J=5,1 Hz, 1H, CHH), of 2.38 (m, 1H, CHH), 2,54-of 2.66 (m, 1H, CHH), 2,81-a 3.01 (m, 1H, CHH), 3,15 of 3.28 (m, 4H, CH2CH2), the 3.65-of 3.80 (m, 4H, CH2CH2), 4,30 (d, J=17,4 Hz, 1H, CHH), of 4.44 (d, J=17.6 Hz, 1H, CHH), 4,56 (d, J=5,9 Hz, 2H, CH2 ), 5,10 (DD, J=5,1, 13,2 Hz, 1H, NCH), 6,98 (d, J=9.1 Hz, 2H, Ar), was 7.45 (d, J=7.9 Hz, 1H, Ar), 7,51 (s, 1H, Ar), to 7.68 (d, J=7.9 Hz, 1H, Ar), 7,81 (d, J=8,9 Hz, 2H, Ar), 8,88 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,46, 31,15, 42,54, 47,07, 47,33, 51,53, 65,86, 113,40, 121,96, 122,86, 123,72, 126,99, 128,50, 130,24, 142,31, 144,38, 152,95, 165,87, 167,91, 170,96, 172,83; LC-MS: MH+=463; analytical calculated for C25H26N4O5+ 0,6 H2O: C, 63,44; H, 5,79; N, 11,84; found: C, 63,19; H, 5,42; N, 12,09.

5.53. 2-Amino-2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ndimethylacetamide hydrochloride

Step 1: To a stirred solution of N-Boc-(4'-chlorophenyl)glycine (1,16 g, 4,10 mmol) in DMF (20 ml) was added to the OED (0,69 g, 4.30 mmol). The reaction mixture was heated to 40°C for 2 h and Then was added 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione hydrochloride (1.50 g, 4,10 mmol). After 3.5 h at 40°C was added water (70 ml). The precipitated solid was separated by filtration, washed with water (3×20 ml) and dried in vacuum to obtain tert-butyl-1-(4-chlorophenyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methylamino)-2-oxoethylidene in a solid white color (1.77 g, yield 80%). The crude product was used in the next stage without additional purification.

Stage 2: To a stirred solution of tert-butyl 1-(4-chlorophenyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methylamino)-2-which of coeternity (0.84 g, 1.50 mmol) in EtOAc (35 ml) was added a dilute solution of HCl (2n. in simple ether, 30 ml). After 3 days the precipitate was separated by filtration, washed with diethyl ether (3×10 ml) and dried in vacuum. The solid was dissolved in water (100 ml) and was extracted with EtOAc (2×50 ml). The aqueous phase was concentrated and the residue triturated with simple ether for 1 h, the Product was separated by filtration and dried in vacuum to obtain the product in a solid white color (0.65 g, yield 88%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, gradient, CH3CN/0.1% of H3PO4: 10/90-90/10 for 10 min, 90/10 (5 min), 4,91 min (for 98.00%); TPL: 255-257°C;1H NMR (DMSO-d6) δ 1.93 and-of 2.09 (m, 1H, CHH), 2,39 (arcs, J=4,4, 13.1 Hz, 1H, CHH), 2,54-2,69 (m, 1H, CHH), 2,82-3,03 (m, 1H, CHH), 4,24 (d, J=17,4 Hz, 1H, CHH), 4,30-of 4.54 (m, 3H, CH2, CHH), 5,02-5,19 (m, 2H, CH, CH), 7,22-7,41 (m, 2H, Ar), 7,47-7,71 (m, 5H, Ar), 9,35 (t, J=5,9 Hz, 1H, NH), 10,99 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,48, 31,20, 42,26, 47,03, 51,59, 54,80, 121,89, 121,96, 122,85, 126,97, 128,80, 129,81, 130,49, 133,02, 133,99, 142,27, 142,70, 167,22, 167,82, 170,98, 172,85; LC-MS: MH+=441/443; analytical calculated for C22H22N4O4Cl2+ 0,6 H2O: C, 54,13; H, 4,79; N, 11,48; found: C, 53,89; H, 4,82; N, 11,60.

5.54. 2-Amino-5-chloro-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]benzamide

DIPEA (1,46 ml of 8.12 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)shall piperidin-2,6-dione of methanesulfonate (1.0 g, a 2.71 mmol) and 5-chlorinator anhydride 3 (0,535 g, a 2.71 mmol) in acetonitrile (10 ml) under nitrogen atmosphere. The reaction mixture was heated to boiling under reflux for 14 h, at this time LC-MS showed completion of the reaction. To the suspension was added water and the precipitate was collected by filtration, washed with additional water and dried in vacuum to obtain the product as a white solid (860 mg, yield 74%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 6,30 min (98.7 per cent); TPL: 242-244°C;1H NMR (DMSO-d6) δ 1,79-of 2.16 (m, 1H, CHH), 2,29 is 2.46 (m, 1H, CHH), 2,60 (d, J=16.6 Hz, 1H, CHH), 2,74-is 3.08 (m, 1H, CHH), 4,08-4,69 (m, 4H, CH2CH2), 5,11 (DD, J=4,9, 13,2 Hz, 1H, CH), 6,60 (s, 2H, NH2), was 6.73 (d, J=8.7 Hz, 1H, Ar), 7,18 (DD, J=2,4, 8,8 Hz, 1H, Ar), 7,46 (d, J=7.9 Hz, 1H, Ar), 7,53 (s, 1H, Ar), to 7.59-7,76 (m, 2H, Ar), 9,01 (t, J=5.8 Hz, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 31,20, 42,44, 47,12, 51,56, 114,81, 117,71, 118,12, 122,07, 122,91, 127,07, 127,33, 130,35, 131,60, 142,38, 143,92, 148,78, 167,67, 167,92, 170,98, 172,85; LC-MS: MH+=427, 429; analytical calculated for C21H19ClN4O4+ 0,2H2O: C, 58,73; H, 4,32; N, of 13.05; found: C, 58,68; H, 4.26 deaths; N, 12,80.

5.55. Isoindoline connection

Isoindoline compounds presented above were obtained according to Scheme 2.

Scheme 2

Stage 1: Added DIPEA (2.0 mmol, 2 EQ.) to a stirred mixture of 3-(5-aminomethyl the-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione of methansulfonate 3 (0.26 g, 1.0 mmol) and the corresponding nitrophenylacetylene 4 (1.1 mmol) in acetonitrile (10 ml) under nitrogen atmosphere. The mixture was stirred at room temperature for 12 hours was Added 1N. a solution of HCl (10 ml) and the precipitate was filtered, washed with additional water and dried to obtain substituted 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(2-nitrophenyl)thiourea 5.

Stage 2: To a stirred mixture of this intermediate compound 5 (1.0 mmol) in EtOH (10 ml) was added a solution of sodium dithionate (1,74 g, 10 mmol) in water (10 ml). The mixture was heated to 60°C for 1 h, the Reaction mixture was concentrated to dryness to obtain compound 6, which was used directly in the next stage without additional purification.

Stage 3: Connection 6 suspended in DMF and added EDCI (EDCI, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, to 0.19 g, 1.0 mmol). The mixture was stirred overnight and the reaction mixture was suppressed by adding acetic acid (2 ml). The crude product was purified using preparative HPLC, to obtain compound 7.

5.56. Isoindoline connection

Following the techniques presented in sections 5.34-5.35, received 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(2-hydroxy-4,5-dimetilfenil)urea, using as initial substance 4,5-dimethyl-2-NITROPHENOL.

General method A: With the feature corresponding to the original carboxylic acid (2.0 mmol) and CBI (0.32 g, 2.0 mmol) in DMF (30 ml) was stirred for 2 hours at 40°C and then added 3-(5-(aminomethyl)-1-occaisonaly-2-yl)piperidine-2,6-dione methanesulfonate (0.74 g, 2.0 mmol) and continued to stir for 24 hours. The mixture was evaporated under vacuum and the residue was purified preparative HPLC.

Using General method A, were obtained the following compounds:

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(3-(morpholinomethyl)phenyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(4-methyl-3-(morpholinomethyl)phenyl)ndimethylacetamide;

2-(4-chloro-3-(morpholinomethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(3-(2-morpholinoethyl)phenyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(4-methyl-3-(2-morpholinoethyl)phenyl)ndimethylacetamide;

2-(4-chloro-3-(2-morpholinoethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ndimethylacetamide;

N-((2-(2,6-voxopop ridin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(4-(morpholinomethyl)phenyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(3-methyl-4-(morpholinomethyl)phenyl)ndimethylacetamide;

2-(3-chloro-4-(morpholinomethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(4-(2-morpholinoethyl)phenyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(3-methyl-4-(2-morpholinoethyl)phenyl)ndimethylacetamide;

2-(3-chloro-4-(2-morpholinoethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(4-(2-morpholinoethoxy)phenyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(3-methyl-4-(2-morpholinoethoxy)phenyl)ndimethylacetamide;

2-(3-chloro-4-(2-morpholinoethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(3-(2-morpholinoethoxy)FeNi is)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-2-(4-methyl-3-(2-morpholinoethoxy)phenyl)ndimethylacetamide;

2-(4-chloro-3-(2-morpholinoethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)ndimethylacetamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-(morpholinomethyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-methyl-4-(morpholinomethyl)benzamide;

3-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-(morpholinomethyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-(2-morpholinoethyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-methyl-4-(2-morpholinoethyl)benzamide;

3-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-(2-morpholinoethyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(morpholinomethyl)benzamide;

N-((2-(2,6-doxopater the DIN-3-yl)-1-occaisonaly-5-yl)methyl)-3-((4-methylpiperazin-1-yl)methyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-methyl-3-(morpholinomethyl)benzamide;

4-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(morpholinomethyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(2-morpholinoethyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-methyl-3-(2-morpholinoethyl)benzamide;

4-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(2-morpholinoethyl)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-(2-morpholinoethoxy)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-methyl-4-(2-morpholinoethoxy)benzamide;

3-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-(2-morpholinoethoxy)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(2-morpholinoethoxy)benzamide;

N-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-4-methyl-3-(2-morpholinoethoxy)benzamide and

4-chloro-N-((2-(2,6-dioxopiperidin-3-the l)-1-occaisonaly-5-yl)methyl)-3-(2-morpholinoethoxy)benzamide.

5.57. 3-[5-(6-Chloro-4-oxo-4H-hinzelin-3-ylmethyl)-1-oxo-1,3-dihydroindol-2-yl]piperidine-2,6-dione

2-Amino-5-chloro-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]benzamide (250 mg, 0,586 mmol) was suspiciously in triethylorthoformate (3 ml) and the mixture was heated to 85°C over night. Was added in the reaction of formic acid (100 l) and the mixture was heated for 1 h To the reaction was added water, obtaining a white precipitate. The precipitate was filtered, washed with additional water and dried in a vacuum drying Cabinet with obtaining the product in a solid white color (140 mg, yield 55%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CΗ3CN/0.1% of H3PO4, 7,20 min (97,9%); TPL: 308-310°C;1H NMR (DMSO-d6) δ 1,90-of 2.08 (m, 1H, CHH), 2,37 (arcs, J=4,3, 13,2 Hz, 1H, CHH), 2,59 (d, J=17.6 Hz, 1H, CHH), 2,78-3,03 (m, 1H, CHH), 4,23-of 4.35 (m, 1H, NCHH), to 4.38-4,51 (m, 1H, NCHH), 5,10 (DD, J=5.0 and 13.1 Hz, 1H, NCH), 5,33 (s, 2H, NCH2), 7,52 (d, J=7.7 Hz, 1H, Ar), to 7.59 (s, 1H, Ar), to 7.67-7,80 (m, 2H, Ar), 7,88 (DD, J=2.5 and 8.7 Hz, 1H, Ar), of 8.09 (d, J=2.3 Hz, 1H, Ar), 8,66 (s, 1H, NCHN), 10,98 (s, 1H, CONH);13C NMR (DMSO-d6) δ 22,45, 31,17, 47,13, 49,20, 51,59, 122,68, 122,91, 123,23, 125,11, 127,56, 129,59, 131,14, 131,50, 134,59, 140,45, 142,59, 146,68, 148,47, 159,20, 167,63, 170,92, 172,82; LC-MS: MH+=437, 439; analytical calculated for C22H17C1N4O4+ 0,4 H2O: C, to 59.51; H, Android 4.04; N, Br12.62; 7,98, Cl; found: C, 59,29; H, 3,66; N, KZT 12.39; 7,82, Cl.

5.58. 6-Chloro-3-[2-(2,6-dioxopiperidin-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-1H-hinzelin-2,4-dione

To a suspension of 2-amino-5-chloro-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]benzamide (250 mg, 0,586 mmol) in acetonitrile (5 ml) was added DIPEA (0,204 ml, 1,171 mmol), followed by phosgene (of 0.62 ml, 1,171 mmol). The reaction mixture was heated to 60°C. After 4 h was added additional phosgene (0,31 ml) and continued stirring for 1 h, after which LC-MS showed completion of the reaction. The reaction suspension was suppressed using dilute HCl, a white precipitate was collected by filtration and washed with additional water and richly Et2O. the Precipitate was dried in a vacuum drying Cabinet with obtaining the product in a solid white color (185 mg, yield 84%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CΗ3CN/0.1% of H3PO4, 7,97 min (97,6%); TPL: 358-360°C;1H NMR (DMSO-d6) δ 1,88-2,07 (m, 1H, CHH), 2,24 at 2.45 (m, 1H, CHH), 2,53 of 2.68 (m, 1H, CHH), 2,79-a 3.01 (m, 1H, CHH), 4,17 is 4.36 (m, 1H, CHH), 4,36-of 4.54 (m, 1H, CHH), 5,09 (DD, J=4,9, 13,2 Hz, 1H, CH), 5,19 (s, 2H, PhCH2), from 7.24 (d, J=8.7 Hz, 1H, Ar), 7,47 (d, J=7.9 Hz, 1H, Ar), 7,54 (s, 1H, Ar), to 7.68 (d, J=7.7 Hz, 1H, Ar), 7,74 (DD, J=2,4, 8,8 Hz, 1H, Ar), 7,89 (d, J=2.3 Hz, 1H, Ar), 10,98 (s, 1H, NH), 11,72 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,46, 31,18, 43,50, 47,12, 51,58, 115,11, 117,49, 122,29, 122,96, 126,37, 126,54, 127,29, 130,65, 135,04, 138,38, 141,17, 142,39, 149,90, 161,08, 167,79, 170,94, 172,83, LC-MS: MH=453, 455; analytical calculated for C22H17C1N4O5+ 0,3 H2O: C, 57,66; H, a 3.87; N, 12,23; Cl, 7,74; found C, 57,60; H, 3,90; N, Of $ 11.97; Cl, 7,72.

5.59. 4-Chloro-3-methylphenylene ether [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]carbamino acid

To a solution of paranitrophenylphosphate (1000 mg, 0.5 mmol) in CH3CN (5 ml) was added dropwise a solution of CH3CN (5 ml) of 4-chloro-m-cresol (from 71.3 mg, 0.5 mmol) and DIPEA (of 0.24 ml, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes was Added a salt of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione with methanesulfonic acid (from 0.37 g, 1 mmol) followed by addition of DIPEA (of 0.24 ml, 1.5 mmol). The mixture was stirred over night at ambient temperature. The mixture is then filtered. The obtained residue was purified on a column of silica gel, elwira using methanol and methylene chloride, to obtain 4-chloro-3-methylphenylene ether [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]carbamino acid in a solid white color (30 mg, yield 14%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 50/50, CH3CN/0.1% of H3PO4, tR=3.0V min (97%); TPL225-227°C;1H NMR (DMSO-d6) δ 1,91-of 2.08 (m, 1H, CHH), 2,32 (s, 3H, CH3), is 2.40 (DD, J=4,3, to 12.8 Hz, 1H, CHH), 2,63 (users, 1H, CHH), 2,83-to 3.02 (m, 1H, CHH), 4,22-4,56 (m, 4H, CH2CH2), 5,12 (DD, J=5,1, 13,2 Hz, 1H, NCH), 7,01 (DD, J=2,3, and 8.7 Hz, 1H, Ar), 7,17 (d, J=2.3 Hz, 1H, Ar), 740 (d, J=8.7 Hz, 1H, Ar), 7,46 (d, J=7,4 Hz, 1H, Ar), 7,55 (s, 1H, Ar), 7,72 (d, J=7.9 Hz, 1H, Ar), of 8.47 (t, J=6.0 Hz, 1H, NH), 10,99 (s, 1H, NH).13C NMR (DMSO-d6) δ 19,52, 22,49, 31,20, 44,04, 47,15, 51,59, 121,03, 122,04, 123,04, 124,43, 127,01, 129,33, 130,58, 136,54, 142,45, 143,35, 145,35, 149,62, 154,43, 167,87, 170,99, 172,86; LC-MS: 442; analytical calculated for C22H20ClN3O6C, 59,80; H, 4,56; N, of 9.51; found: C, 59,74; H, of 4.45; N, 9,58.

5.60. 1-[1-(3,4-Dichlorophenyl)ethyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

Stir a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione of methansulfonate (of 0.37 g, 1.00 mmol) and CBI (0.18 g, 1.10 mmol) in N,N-dimethylformamide (10 ml) was heated to 40°C in nitrogen atmosphere overnight. Then added 1-(3,4-dichlorophenyl)ethylamine (0,19 g, 1.00 mmol) and the mixture was heated at 40°C during the night. Was added water (60 ml), the precipitate was filtered, washed with water (30 ml) and was purified preparative HPLC (gradient of CH3CN/H2O: 10/90 for 5 min, up to 100/0 for 10 min, 100/0 for 5 min). The solvent was evaporated and the residue triturated in a simple ether (20 ml) for 1 h the Product was then isolated by filtration and dried in vacuum to obtain 1-[1-(3,4-dichlorophenyl)ethyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea as solid white (0,084 g, yield 17%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm,1 ml/min, 240 nm, gradient, CH3CN/0.1% of H3PO4: 10/90-90/10 for 10 min, 90/10 (5 min), to 8.57 min (96,68%); TPL: 200-202°C;1H NMR (DMSO-d6) δ of 1.32 (d, J=7,0 Hz, 3H, CH3), a 1.88-2.13 in (m, 1H, CHH), 2,28-2,47 (m, 1H, CHH), 2,55-2,70 (m, 1H, CHH), 2,79 totaling 3.04 (m, 1H, CHH), 4,18-4,55 (m, 4H, CH2CH2), 4,74 (Queen, J=7,0 Hz, 1H, CH), 5,11 (DD, J=4,9, 13,2 Hz, 1H, CH), 6,51 (s, 1H, NH), of 6.66 (d, J=7.9 Hz, 1H, NH), 7,20-7,46 (m, 3H, Ar), of 7.48 to 7.62 (m, 2H, Ar), the 7.65 (d, J=7.7 Hz, 1H, Ar), 10,99 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 22,80, 31,20, 42,86, 47,07, 48,18, 51,55, 121,61, 122,81, 126,28, 126,70, 127,78, 128,79, 130,14, 130,38, 130,77, 142,26, 145,29, 147,41, 157,20, 167,95, 170,98, 172,85; LC-MS: MH=489, 491; analytical calculated for C23H22N4O4C12+ 0,9 H2O: C, 54,64, H, 4,75, N, 11,08; found: C, 54,27, H, 4,66, N, 10,98.

5.61. 1-(3-Chloro-4-(2-(2-methoxyethoxy)ethoxy)phenyl-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea

3-(5-Aminomethyl-1-oxo-1,3-dihydroindol-2-yl)piperidine-2,6-dione methanesulfonate (1,11 g, 3.0 mmol) and 1,1'-carbonyldiimidazole (535 mg, 3.3 mmol) suspended in dry DMF (20 ml) and the mixture was stirred at room temperature for 24 hours Under stirring part of the reaction mixture (6,7 ml, ~1 mmol) was transferred into a tube containing 3-chloro-4-(2-(2-methoxyethoxy)ethoxy)aniline hydrochloride (310 mg, 1.1 mmol). The resulting mixture was stirred at room temperature overnight and the reaction was monitored using LC-MS. After 48 CV the reaction mixture was made optional 3-chloro-4-(2-(2-methoxyethoxy)ethoxy)aniline hydrochloride (56 mg, 0.2 mmol) and stirring continued for an additional 24 h the Reaction mixture was acidified with 1 N. HCl was added with stirring the water until the formation of sludge. The precipitate was collected by filtration, dried by suction, and then was dissolved in DMF and purified using preparative HPLC (C-18 to obtain 1-(3-chloro-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea in a solid white color (390 mg, yield 72%). HPLC: Waters Symmetry C18, 5 μm, of 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, of 5.40 min (99.8 per cent); TPL: 188-190°C;1H NMR (DMSO-d6) δ 1,92 is 2.10 (m, 1H, CHH), 2,29-2,47 (m, 1H, CHH), 2,60 (DD, J=2.2, while the 15.4 Hz, 1H, CHH), 2,82-a 3.01 (m, 1H, CHH), of 3.25 (s, 3H, CH3), of 3.46 (DD, J=3,7, and 5.6 Hz, 2H, CH2), 3,61 (DD, J=3,8, 5.7 Hz, 2H, CH2), to 3.73 (d, J=4,7 Hz, 2H, CH2), 4.09 to (t, J=4.9 Hz, 2H, CH2), 4,24-4,55 (m, 4H, CH2CH2), 5,11 (DD, J=5,1, 13,2 Hz, 1H, CH), 6,77 (t, J=5,9 Hz, 1H, NH),? 7.04 baby mortality (d, J=9.1 Hz, 1H, Ar), 7,19 (DD, J=2.5 and 9.0 Hz, 1H, Ar), 7,38-7,49 (m, 1H, Ar), 7,51 (s, 1H, Ar), to 7.64 (d, J=2.6 Hz, 1H, Ar), 7,69 (d, J=7.7 Hz, 1H, Ar), 8,65 (s, 1H, NH), 10,98 (s, 1H, NH);13C NMR (DMSO-d6) δ 22,51, 31,20, 42,80, 47,12, 51,56, 58,05, 68,80, 68,85, 69,84, 71,29, 114,66, 117,58, 119,49, 121,24, 121,88, 122,91, 126,89, 130,29, 134,53, 142,38, 144,84, 148,40, 155,25, 167,95, 171,01, 172,86; LC-MS: MH=545, 547; analytical calculated for C26H29ClN4O7+ 0,4 H2O: C, 56,55; H, 5,44; N, 10,15, found: C, 56,64; H, of 5.34; N, 10,15.

5.62. Testing

5.62.1 Testing inhib the simulation α in MCP To

Received menagerie cells of peripheral blood (MCPC, PBMC) from normal donors by centrifugation in a density gradient on Ficoll Hypaque (Pharmacia, Piscataway, new Jersey, USA). Cells were cultured in RPMI 1640 (Life Technologies, Grand island, new York, USA), supported by 10% AB+ human serum (Gemini Bio-products, woodland, CA, USA), 2 mm L-glutamine, 100 U/ml penicillin and 100 µg/ml streptomycin (Life Technologies).

MCPC (2×105cells) were sown in 96-well flat-bottomed plates to the cultivation of tissues Costar (Corning, NY, USA) in three repetitions. Cells stimulated with LPS (from Salmonella abortus equi, Sigma, catalog number L-1887,St. Louis, Missouri, USA) at 1 ng/ml at the end in the absence or presence of compounds. The proposed compounds were dissolved in DMSO (Sigma) and implement the additional dilution in culture medium immediately before use. The final concentration of DMSO in all samples was 0.25 per cent. Compounds were added to the cells one hour prior to stimulation with LPS. Cells then were incubated for 18-20 hours at 37°C in 5% CO2and supernatant then collected, diluted in culture medium and conducted quantitative determination of the levels of TNF-α using ELISA method (Endogen, Boston, mA, USA). The value of the IC50calculated using non-linear regression, sigmoidal dependence to the a-effect, seeking top to 100% and below 0%, giving a variable slope (GraphPad Prism v3.02).

5.62.2. The production of IL-2 and MIP-3α T-cells

Was Abagnale MCPC adhesive monocytes, placing 1×108MCPC in 10 ml complete medium (RPMI 1640, supported by 10% thermoinactivation fetal bovine serum, 2 mm L-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin) on 10-cm Petri dish in an incubator at 37°C, 5% CO230-60 minutes Cups washed with medium to separate all loose MCPC. T cells were purified by negative selection using the following mixture of antibodies (Pharmingen) and microspheres Dynabead (Dynal) for each 1×108unattached MCPC: 0.3 ml microspheres with sheep antibodies against mouse IgG, 15 μl of anti-CD16, 15 μl of anti-CD33, 15 μl of anti-CD56, 0,23 ml of microspheres with antibodies against CD19, 0,23 ml of microspheres with antibodies against HLA class II and 56 μl of anti-CD14 beads. The cells and the mixture of microspheres/antibodies rotated, turning upside down, for 30-60 min at 4°C. Purified T cells were separated from the microspheres using a Dynal magnet. Typical output is approximately 50% of T cells, the purity of 87-95% CD3+that is estimated by flow cytometry.

Covered 96-well flat-bottomed plates to the cultivation of tissues anti-CD3 antibody OKT3 at 5 µg/ml in the FSB, 100 µl per well, incubated at 37°C for 3-6 h, and then washed 4 times full environment 100 m is l/well directly before addition of T cells. Compounds were diluted up to 20 times at the end in round-bottom 96-well pad. Final concentration of approximately 10 μm, approximately 0,00064 μm. 10 mm of the original solution proposed compounds were diluted 1:50 in full for the first 20-fold dilution to 200 μm in 2% DMSO and serially diluted 1:5 in 2% DMSO. Was added to each connection when 10 μl to 200 μl cultures to a final concentration of DMSO of 0.1%. Cultures were incubated at 37°C, 5% CO2within 2-3 days and supernatant analyzed to determine IL-2 and MIP-3α (macrophage protein inflammation 3α) using ELISA method (R&D Systems). The levels of IL-2 and MIP-3α were normalized to the quantity, producyruemogo in the presence of a number of proposed connections, and hoped IC50using non-linear regression, sigmoidal dose-effect tending from top to 100% and below 0%, giving a variable slope (GraphPad Prism v3.02).

5.62.3. Testing cell proliferation

Cell line Namalwa, MUTZ-5 and UT-7 was obtained from the data Bank Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig, Germany). The cell line KG-I were obtained from the American type culture collection (Manassas, VA, USA). Cell proliferation, as indicated by the embedding3H-thymidine was determined in all cell lines as follows.

Cells were sown in the medium in 96-well tablets at 6000 cells on UNCW. The cells were pre-treated with compounds at approximately 100, 10, 1, 0,1, 0,01, 0,001, 0,0001 and 0 μm in final concentration of DMSO approximately 0.25% three times at 37°C in a humid chamber at 5% CO2within 72 hours Then to each well was added one microcurie3H-thymidine (Amersham) and the cells were incubated again at 37°C in a humid chamber at 5% CO2within 6 hours the Cells were collected on a filter tablets UniFilter GF/C (Perkin Elmer) using the collector cells (Tomtec) and tablets were left to dry over night. Added Microscint 20 (Packard) (25 ál/well) and the tablets were analyzed device TopCount NXT (Packard). Each well was read within one minute. The percentage of inhibition of cell proliferation was calculated by calculating the average of three repetitions, and normalized to DMSO control (0% inhibition). Each compound was tested for each cell line in three separate experiments. The final value of the IC50calculated using non-linear regression, sigmoidal dose-effect tending from top to 100% and below 0%, giving a variable slope (GraphPad Prism v3.02).

5.62.4. Immunoprecipitation and Western blot turns

The Namalwa cells were treated with DMSO or number of connections for 1 h, then stimulated with 10 U/ml Epo (R&D Systems) for 30 minutes Got lysates of cells and either the wasp is actulaly immunoprecipitation using antibodies to Epo receptor, either immediately shared with LTO-PAG electrophoresis. Immunoblot probed with antibodies to Akt, phospho-Akt (Ser473 or Thr308), phospho-Gab1 (Y627), Gab1, IRS2, actin and IRF-I and analyzed for the device to obtain images of the Storm 860, using the software ImageQuant (Molecular Dynamics).

5.62.5. Analysis of the cell cycle

Cells were treated with DMSO or the number of connections during the night. Was carried out by staining propidium iodide to determine the cell cycle, using CycleTEST PLUS (Becton Dickinson) according to the manufacturer's Protocol. After staining, the cells were analyzed in a flow cytometer FACSCalibur using the software ModFit LT (Becton Dickinson).

5.62.6. Assessment of apoptosis

Cells were treated with DMSO or number of connections for various periods of time, then washed with annexin V proryvnym buffer (BD Biosciences). Cells were incubated with annexin V binding protein and propidium iodide (BD Biosciences) for 10 min, the Samples were analyzed using flow cytometry.

5.62.7. Luciferase test

The Namalwa cells were transfusional 4 µg design AP1-luciferase (Stratagene) at 1×106cells and 3 µl of the preparation of Lipofectamine 2000 (Invitrogen)following the manufacturer's instructions. Six hours after transfection cells were treated with DMSO or the number of featur is imago connection. The luciferase activity was analyzed using a luciferase lyse buffer and substrate (Promega), and was measured using a luminometer (Turner Designs).

5.62.8. Antiproliferative drug test

Day 1:Cells were planted in 96-well plate at 50 μl/well in 10% FSB RPMI (without glutamine, without penicillin and streptomycin) at night. Used the following cells:

Cells of colorectal cancer: Colo 205 3200 cells/well; the positive control irinotecan

Cancer cells pancreas: BXPC-3 1200 cells/well; the positive control gemcitabine

Cancer cells of the prostate: PC3 1200 cells/well; the positive control docetaxel

The breast cancer cells: MDA-MB-231 2400 cells/well; the positive control paclitaxel.

Day 2: Performed a serial dilution of compounds from 0.00001 μm to about 10 μm (or 0,000001~1 μm) at 50 μl/well (2×) and added to the tablets in two iterations with the positive control. Then the plates were incubated at 37°C for 72 hours.

Day 5: The results were detected by the method of CellTiter Glo. In the tablets was added 100 μl/well reagent CellTiter Glo and incubated for 10 minutes at room temperature, and then analyzed in the apparatus for reading tablets Top Count. The value of the IC50for each connection, usually determined on the basis of the results of two or more separate experiments.

<> 5.63. Inhibition α

Properties of some of the proposed compounds in the inhibition α assessed using methods substantially similar to the procedures described in Section 6.62.1 above. Test compounds include 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-pyridin-4-ylmethylene)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-hydroxymethylene)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methyl-2Η-pyrazole-3-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-Mei-1-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[4-(4-methyl-4Η-[1,2,4]triazole-3-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methylthiazole-4-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(1-methyl-1Η-pyrazole-3-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(morpholinomethyl)phenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea; 1-(3-amino-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(3-phenoxyphenyl)urea; 1-((2-(2,6-dioxode uridin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea; N-(4-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]ureido}phenyl)ndimethylacetamide; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-were)urea; 1-[3-(1H-benzimidazole-2-yl)-4-chlorophenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-(4-tert-butylcyclohexyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methylcyclohexyl)urea; 1-(6-chloropyridin-3-yl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-[4-(2,4-differenl)thiazol-2-yl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea and 3-{5-[3-(3-chloro-4-were)freedomites]-1-oxo-1,3-dihydroindol-2-yl}-2,6-dioxopiperidin-1-ymetray ether of 2,2-dimethylpropionic acid. Were determined the values of the IC50for all tested compounds, which were in the range of about 0.2 to 300 nm.

5.64. Antiproliferative effect on cells Νamalwa

Antiproliferative action of some of the proposed compounds were evaluated using the cell line Νamalwa, following the procedures essentially similar to those described in Section 5.62.3 above. Test compounds include 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-pyridin-4-ylmethylene)urine is inu; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-hydroxymethylene)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methyl-2Η-pyrazole-3-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-Mei-1-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methylthiazole-4-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(1-methyl-1Η-pyrazole-3-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(morpholinomethyl)phenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea; 1-(3-amino-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(3-phenoxyphenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]urea; 1-(4-tert-butylcyclohexyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methylcyclohexyl)urea and 3-{5-[3-(3-chloro-4-were)freedomites]-1-oxo-1,3-dihydroindol-2-yl}-6-dioxopiperidin-1-ymetray ether of 2,2-dimethylpropionic acid. Were determined the values of the IC50for all tested compounds, which were in the range of about 0.02 to 40 nm.

5.65. Antiproliferative effect on PC3 cells

Antiproliferative action of some of the proposed compounds were evaluated using the cell line PC3, following the procedures essentially similar to those described in Section 5.62.8 above. Test compounds include 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-pyridin-4-ylmethylene)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methyl-2Η-pyrazole-3-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methylthiazole-4-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(1-methyl-1Η-pyrazole-3-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(morpholinomethyl)phenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea; 1-(3-amino-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(3-phenoxyphenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-methylphe who yl)urea; 1-[3-(1Η-benzimidazole-2-yl)-4-chlorophenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-(4-tert-butylcyclohexyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methylcyclohexyl)urea; 1-(6-chloropyridin-3-yl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1Η-isoindole-5-ylmethyl]urea; 1-[4-(2,4-differenl)thiazol-2-yl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 3-{5-[3-(3-chloro-4-were)freedomites]-1-oxo-1,3-dihydroindol-2-yl}-2,6-dioxopiperidin-1-ymetray ether of 2,2-dimethylpropionic acid and 1-[1-(3,4-dichlorophenyl)ethyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea. Were determined the values of the IC50for all tested compounds, which were in the range of about 0.001 to 0,74 ám.

5.66. Antiproliferative effect on cells BxPC3

Antiproliferative action of some of the proposed compounds were evaluated using the cell line BxPC3, following the procedures essentially similar to those described in Section 5.62.8 above. Test compounds include 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-pyridin-4-ylmethylene)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methyl-2Η-p is razol-3-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methylthiazole-4-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(1-methyl-1Η-pyrazole-3-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(morpholinomethyl)phenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea; 1-(3-amino-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(3-phenoxyphenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-were)urea; 1-[3-(1Η-benzimidazole-2-yl)-4-chlorophenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-(4-tert-butylcyclohexyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methylcyclohexyl)urea; 1-[4-(2,4-differenl)thiazol-2-yl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1Η-isoindole-5-ylmethyl]urea; 3-{5-[3-(3-chloro-4-were)freedomites]-1-oxo-1,3-dihydroindol-2-yl}-2,6-dioxopiperidin-1-ymetray ether of 2,2-dimethylpropionic acid and 1-[1-(3,4-dichlorophenyl)ethyl]-3-[2-(2,6-dioxopiperidin the-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea. Were determined the values of the IC50for all tested compounds, which were in the range of about 0.01 to 0.94 μm.

5.67. Antiproliferative effect on cells MDAMB321

Antiproliferative action of some of the proposed compounds were evaluated using the cell line MDAMB321, following the procedures essentially similar to those described in Section 5.62.8 above. Test compounds include 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-pyridin-4-ylmethylene)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methyl-2Η-pyrazole-3-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methylthiazole-4-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(1-methyl-1Η-pyrazole-3-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(morpholinomethyl)phenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea; 1-(3-amino-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(3-phenoxyphenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(3-what ethyl-[1,2,4]oxadiazol-5-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-were)urea; 1-[3-(1Η-benzimidazole-2-yl)-4-chlorophenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-(4-tert-butylcyclohexyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methylcyclohexyl)urea; 1-(6-chloropyridin-3-yl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1Η-isoindole-5-ylmethyl]urea; 1-[4-(2,4-differenl)thiazol-2-yl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 3-{5-[3-(3-chloro-4-were)freedomites]-1-oxo-1,3-dihydroindol-2-yl}-2,6-dioxopiperidin-1-ymetray ether of 2,2-dimethylpropionic acid and 1-[1-(3,4-dichlorophenyl)ethyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea. Were determined the values of the IC50for all tested compounds, which were in the range of about 0.4 to 380 nm.

5.68. Antiproliferative effect on cells Colo205

Antiproliferative action of some of the proposed compounds were evaluated using the cell line Colo205, following the procedures essentially similar to those described in Section 5.62.8 above. Test compounds include 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-pyridin-4-iletilebilecegi; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methyl-2Η-pyrazole-3-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(2-methylthiazole-4-yl)phenyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(1-methyl-1Η-pyrazole-3-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-(morpholinomethyl)phenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-methyl-3-nitrophenyl)urea; 1-(3-amino-4-were)-3-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(3-phenoxyphenyl)urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(4-nitrophenyl)urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]urea; 1-((2-(2,6-dioxopiperidin-3-yl)-1-occaisonaly-5-yl)methyl)-3-(3-hydroxy-4-were)urea; 1-[3-(1Η-benzimidazole-2-yl)-4-chlorophenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-(4-tert-butylcyclohexyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methylcyclohexyl)urea; 1-(6-chloropyridin-3-yl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-IsoIn the ol-5-ylmethyl]urea; 1-[4-(2,4-differenl)thiazol-2-yl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea; 3-{5-[3-(3-chloro-4-were)freedomites]-1-oxo-1,3-dihydroindol-2-yl}-2,6-dioxopiperidin-1-ymetray 2,2-dimethylpropionic acid and 1-[1-(3,4-dichlorophenyl)ethyl]-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea. Were determined the values of the IC50for all tested compounds, which were in the range of about 0.15 to 130 nm.

The foregoing examples are presented in order to the average person skilled in the art to provide a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of the disclosed invention. Modifications which are obvious to experts in the art, are included in the scope the following claims. All publications, patents and patent applications cited herein, incorporated by reference in their entirety, as if each such publication, patent or patent application is specifically and individually would be included in the present description by reference.

1. The compound of Formula I:

or its pharmaceutically acceptable salt, or stereoisomer, where
X represents CH2;
Y represents the Oh Oh cyanamide (N-C≡N), or amido (NH);
m represents the integer 0 or 1;
R1represents hydrogen or C1-6alkyl;
R2represents hydrogen, C1-10alkyl, C0-6alkyl-(5-10-membered heteroaryl, including one, two or three heteroatoms independently selected from O, S or N), C0-6alkyl-(6-membered heterocyclyl, which is morpholinyl or piperazinil), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21or - (CH2-Z)-(6-membered heteroaryl, which represents a pyridinyl), where each heteroaryl and heterocyclyl optionally substituted by one or more C1-6alkilani;
R3represents hydrogen, halogen, -NO2C0-6alkyl-OH, C0-4alkyl-NH2or21;
R21represents phenyl, pyridinyl, piperidinyl or-CO(CH2R22;
R22represents-NH2or piperazinil; and
Z represents O;
provided that when R1represents hydrogen, then R2is not hydrogen or C1-10by alkyl;
provided that when R3is a halogen, then R2represents a C0-6alkyl-(5-6-membered heterocyclyl).

2. The compound according to claim 1, where R1represents hydrogen or methyl.

3. The compound according to claim 1 or 2, where R2represents the waters of the genus, acetamido, hydroxy, hydroxymethyl, 2-methyl-1H-imidazol-1-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-(methylpiperazin-1-yl)methyl, 2-methyl-2H-pyrazole-3-yl, 1-methyl-1H-pyrazole-3-yl, 2-methylthiazole-4-yl, 4-methyl-4H-1,2,4-triazole-3-yl, morpholinomethyl, (pyridin-4-yl)methyl, (pyridin-4-yloxy)methyl, phenoxy, pyridine-2-yloxy, piperidine-4-yloxy, 2-aminoacetate or 2-piperazine-1-RECETOX.

4. The compound according to any one of claims 1 to 2, where R3represents hydrogen, amino, acetamido, hydroxy, nitro, aminomethyl, hydroxymethyl, (pyridine-4-yloxy)methyl, phenoxy, pyridine-2-yloxy, piperidine-4-yloxy, 2-aminoacetate or 2-piperazine-1-RECETOX.

5. The compound according to claim 3, where R3represents hydrogen, amino, acetamido, hydroxy, nitro, aminomethyl, hydroxymethyl, (pyridine-4-yloxy)methyl, phenoxy, pyridine-2-yloxy, piperidine-4-yloxy, 2-aminoacetate or 2-piperazine-1-RECETOX.

6. The compound according to claim 1, which is:


















or its pharmaceutically acceptable salt, or stereoisomer.

7. The compound of Formula II:

or its pharmaceutically acceptable salt, or stereoisomer, where
X represents CH2;
m is 1;
R4represents a C3-6cycloalkyl, 6-membered heterocyclyl, including one heteroatom selected from N or O, 5-10-membered heteroaryl comprising one or two heteroatoms, independently selected from S and N, or C3-4alkyl-NR41R42; where cycloalkyl, heterocyclyl and heteroaryl, each optionally substituted by one or more halogen, C1-6alkilani, -CO-NR43R44C1-4alkyl-phenyl, where phenyl may optionally be substituted by one or more halogen; and
R41, R42, R43, R44and R45each independently represents hydrogen or C1-6alkyl.

8. The connection according to claim 7, where R4represents a 3-(N,N-diethylamino)propyl, 4-tert-butylcyclohexyl, CIS-4-tert-butylcyclohexyl, TRANS-4-tert-butylcyclohexyl, 4-methylcyclohexyl, CIS-4-methylcyclohexyl, TRANS-4-methylcyclohexyl, 1-benzylpiperidine-4-yl, 4-methyltetrahydro-2H-Piran-4-yl, piperidine-4-yl, 4-phenylcyclohexyl, CIS-4-fenell logical or TRANS-4-phenylcyclohexyl.

9. The connection according to claim 7, which is:





or its pharmaceutically acceptable salt, or stereoisomer.

10. The compound of Formula III:

or its pharmaceutically acceptable salt, or stereoisomer, where
X represents CH2;
m is an integer 1;
R5and R6each, independently represents halogen or C1-6alkyl, oxo;
R7represents-COR71;
R71represents a C1-10alkyl or piperidinyl where piperidinyl may optionally be substituted one-COOR74;
R74represents a C1-10alkyl.

11. The connection of claim 10, where R5represents fluorine or chlorine.

12. The compound of claim 10 or 11, where R6represents fluorine or chlorine.

13. The connection of claim 10, which is:



or its pharmaceutically acceptable salt, or stereoisomer.

14. The compound of Formula IV:

or its pharmaceutically acceptable salt, or stereoisomer, where
X represents CH2;
n represents the eloe the number 0 or 1;
R8represents hydrogen or halogen; and
R9represents hydrogen, amino imidazolyl or morpholinyl;
provided that when m is 0, R9is not hydrogen.

15. The connection 14, where n is equal to 1.

16. The connection 14, which is:


or its pharmaceutically acceptable salt, or stereoisomer.

17. The compound of the following formula:



or its pharmaceutically acceptable salt, or stereoisomer.

18. Pharmaceutical composition for controlling angiogenesis or inhibition of production α containing compound according to any one of claims 1 to 17 and one or more pharmaceutically acceptable excipients or carriers.

19. The pharmaceutical composition according p, where the composition is prepared for administration as a single dose.

20. Pharmaceutical compositions for p, where the composition is made up in the form of dosage forms for oral, parenteral or intravenous injection.

21. The pharmaceutical composition according to claim 19, where the composition is made up in the form of dosage forms for oral, parenteral or intravenous injection.

22. The pharmaceutical composition according p where lcars the governmental form for oral administration is a tablet or capsule.

23. A method of treating or preventing diseases or disorders, which includes an introduction to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 17, where the disease or disorder is a cancer, disorders associated with angiogenesis, pain, macular degeneration or related syndromes, skin diseases, pulmonary disorders caused by asbestos disease (asbestosis), parasitic diseases, immunodeficiency States, disorders of the Central nervous system, CNS injury, atherosclerosis or related disorders, sleep disorders or related disorders, hemoglobinopathy or related disorders or associated with α disorders.

24. The method according to item 23, where the disease is cancer.

25. The method according to paragraph 24, where the cancer is a cancer of the blood or solid cancer.

26. The method according to item 23, where the compound is administered orally or parenterally.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 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: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula its stereoisomers, including R and S isomers, wherein: 'A' represents N; Y and Y' represent O; '---' is absent; R1 and R2 are identical or different, and independently represent hydrogen or C1-12 alkyl; R3 represents hydrogen; R4 represents heteroaryl which can be optionally substituted in any acceptable position by one or more substitutes Ra; Z represents -(CH2)n-heteroaryl which can be optionally substituted in any acceptable position by one or more substitutes Ra; T, U, V and W are identical or different, and independently represent hydrogen or halogen; Ra is independently specified in hydrogen, halogen, C1-12 alkyl, C1-12 haloalkyl, -C(=Y)OR7, -(CH2)nYR7, each of which can be optionally substituted in any acceptable position by halogen; R7 represents hydrogen or C1-12 alkyl; m represents 1; m′ represents 0; n represents 1; wherein: the above heteroaryl is specified in 1,2,3-triazolyl, pyridinyl, 1-oxypyridinyl (pyridinyl-N-oxide), pyrazinyl, isoxazolyl, imidazo[1,2-α]pyrimidinyl, imidazo[1,2-α]pyrazinyl. The compounds of the given invention are applicable to prevent, relieve and/or treat bacterial infections in an individual. The bacterial infection is caused by the drug-resistant species Staphylococcus, Streptococcus, Enterococcus, Bacterioides, Clostridia, H. influenza, Moraxella, acid-resistant species like Mycobacterium tuberculosis, as well as linezolid-resistant species Staphylococcus and Enterococcus.

EFFECT: phenyloxazolidinone compounds as antimicrobial agents.

12 cl, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel indole and benzomorpholine derivatives of a formula (I) or its pharmaceutically acceptable salt, where R1 represents C1-6-alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 represents halogeno; R3 represents hydrogen; n equals 2, X represents -CH2CH2-O or -CH=CH-; Y represents -O- or -CR4(OH)-; R4 represents hydrogen or C1-3 alkyl. Invention also relates to a pharmaceutical composition based on formula (I) compound and a method of treatment or prevention of the said pathological states.

EFFECT: obtained are novel compounds, which are positive allosteric modulators of matabotropic subtype 2 receptors (mGluR2), which are useful for treatment or prevention of neurological and psychiatric disorders, associated with glutamate dysfunction, and diseases, involving metabotropic subtype 2 receptors GluR2.

22 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

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