5-substituted isoindoline compounds

FIELD: chemistry.

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

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

27 cl, 81 ex, 1 tbl

 

This application claims priority based on provisional application U.S. 60/841365, filed August 30, 2006; 60/925513 filed April 20, 2007, and 60/937782 filed June 28, 2007, which in their entirety are included in the description by reference.

1. The scope of the invention

This invention relates to 5-substituted isoindolines connections. Also disclosed are pharmaceutical compositions containing the connections, and methods of treatment, prevention and control for various disorders.

2. Background of the invention

2.1 Pathobiology cancer and other diseases

Cancer in the first place, is characterized by an increase in the number of abnormal cells derived from a given normal tissue, invasion of these abnormal cells to surrounding tissues or transfer of malignant cells in the lymph or blood system to peripheral lymph nodes and remote departments (metastasis). Clinical data and molecular biological studies indicate that cancer is a multistage process and begins with a slight preneoplastic changes, which, under certain conditions, progress to neoplasia. Neoplastic damage can develop cloning and develop increasing capacity for invasion, growth, metastasis and heterogeneity, especially in the conditions under which which the neoplastic cells escape the control of the host's immune system. Roitt, I., Brostoff, J. and Kale, D.,Immunology, 17.1-17.12 (3rded., St. Louis, Mo., 1993).

There is a huge variety of types of cancer, which have been described in the medical literature. Examples include lung cancer, rectum, anus, prostate, breast, brain and intestines. The incidence of cancer continues to increase with the General aging of the population, with the emergence of new types of cancer and with increased exposure of the population of cancer (for example, people infected with AIDS, or excessively exposed to solar radiation). However, the possibility of choice for the treatment of cancer is limited. For example, in the case of various types of blood cancer (eg, multiple myeloma) available only a few choices, especially if conventional chemotherapy does not lead to success, and bone marrow transplantation is not a choice. Therefore there is an urgent need for new methods and compositions that can be used to treat patients suffering from cancer.

Many cancers are associated with the formation of new blood vessels, a process known as angiogenesis. Several mechanisms have been identied that are involved in induced cancer angiogenesis. The most immediate of these mechanisms is the secretion by cancer cells cytokines with angiogenetic properties. Examples of such cytokines are acidic and OS is the ESD of the fibroblast growth factors (a,b-FGF), angiogenin, growth factor vascular endothelial (VEGF) and TNF-α. Alternative cancer cells can release angiogenesis peptides through the production of proteases and subsequent destruction vneshneekono matrix when some cytokines accumulate (for example, b-FGF). Angiogenesis can also be caused indirectly through the recruitment of inflammatory cells (especially macrophages) and then release them angiogenesis cytokines (such as TNF-α, b-FGF).

Many other diseases and disorders associated with undesirable angiogenesis or they are characterized. For example, the increased and uncontrolled angiogenesis is involved in the following number of diseases and medical conditions, not limited to: ocular neovascular disease, choroidal neovascular diseases, neovascular diseases of the retina, rubios (neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases and autoimmune diseases. Examples of such diseases and conditions include, without limitation, diabetic retinopathy, retinopathy of prematurity, graft rejection of corneal neovascular glaucoma, retrolental fibroplasia, arthritis and the proliferative vitreoretinopathy.

Accordingly, compounds the Oia, which can regulate angiogenesis or inhibit the production of certain cytokines, including TNF-α, may be useful for the treatment and prevention of various diseases and conditions.

2.2 Methods of cancer treatment

Modern cancer treatment may include surgery, chemotherapy, hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998,Medicinevol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). More recently, cancer treatment may also include biological therapy and immunotherapy. All of these approaches have significant drawbacks for the patient. Surgery may be contraindicated for health reasons or may be unacceptable to the patient. In addition, surgery may not completely remove neoplastic tissue. Radiation therapy is only effective if the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy also can often have serious side effects. Hormonal therapy is rarely performed by a single agent. Despite the fact that hormone therapy can be effective, it is often used to prevent or delay recurrence of cancer after other treatments had removed most of the cancer cells. Biological is the cue types of therapy and immunotherapy are few and can give side effects, such as rashes and swelling, symptoms, flu-like, including fever, chills and fatigue, problems with the digestive tract or allergic reactions.

With regard to chemotherapy, there are a number of chemotherapeutic agents suitable for the treatment of cancer. Most anti-cancer chemotherapeutic agents act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of deoxyribonucleotide trifosfatnogo predecessors to prevent DNA replication and subsequent cell division (Gillmanet al., Goodman and Gillman's:The Pharmacological Basis of Therapeutics, E. Tenth (McGraw Hill, New York).

Despite the availability of various chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale,Medicinevol. 3, Rubenstein and Federman, eds., Chapter 12, Section 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous side effects, including severe nausea, bone marrow depression, and immune suppression. In addition, even with the introduction of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to chemotherapeutic agents. Indeed, these cells are resistant to specific chemotherapeutic agents used in accordance with the treatment Protocol, the ACCS are resistant to other drugs, even if these agents act by a mechanism different from that used medicines for this treatment. This phenomenon is called pleiotropically or multidrug resistance. Due to drug resistance of many types of cancer are definitely immune to standard treatment protocols chemotherapeutic agents or become.

Other diseases or conditions associated with undesirable angiogenesis or characterized them, are also difficult to treat. However, there were proposed some compounds, such as Protamine, hepain and steroids that are useful for the treatment of some specific diseases. Tayloret al.,Nature297:307 (1982); Folkmanet al.,Science221:719 (1983); U.S. patent No. 5001116 and 4994443.

Still there is an urgent need for effective methods of treatment, prevention and control for cancer and other diseases and conditions, especially for conditions that are unresponsive to conventional treatments such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or eliminating toxicity and/or side effects associated with conventional therapies.

3. Brief description of the invention

The invention, in particular, the direction is about 5-substituted isoindoline compounds and their pharmaceutically acceptable salts, the solvate (e.g., hydrates), prodrugs and stereoisomers.

The invention also encompasses methods of treatment and management for various diseases and disorders. The methods include the introduction of the patient for such treatment or management of disease a therapeutically effective amount of the compounds of this invention or its pharmaceutically acceptable salt, MES, stereoisomer, or prodrug.

The invention also encompasses methods of prevention of various diseases and disorders, which include introduction to prevention patient prophylactically effective amount of the compounds of this invention or its pharmaceutically acceptable salt, MES, stereoisomer, or prodrug.

The invention also encompasses pharmaceutical compositions, discrete dosage form containing a unit dose, dose regimens and kits that include the connection according to this invention or its pharmaceutically acceptable salt, MES, hydrate, stereoisomer, clathrate, or prodrug.

4. Detailed description of the invention

In one embodiment of the invention comprises 5-substituted isoindoline compounds and their pharmaceutically acceptable salt, solvate, stereoisomers, and prodrugs.

In another embodiment of this invention ovative the t treatments, control flow and prevention of various diseases and disorders which include the introduction of the patient for such treatment or prevention a therapeutically or prophylactically effective amount of the compounds of this invention or its pharmaceutically acceptable salt, MES, stereoisomer, or prodrug. Examples of the diseases and disorders listed in the description.

In private embodiments of the compounds of this invention or their pharmaceutically acceptable salt, solvate, stereoisomer or prodrug used in combination with another drug ("second active agent") or treatment. Second active agents include small molecules and large molecules (e.g. proteins and antibodies), examples of which are presented in the description, as well as stem cells. Methods, or therapies, that can be used in combination with the introduction of the compounds of this invention include, without limitation, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy and other non-drug therapies are currently used for the treatment, prevention and control for various disorders disclosed in the description.

This invention also encompasses pharmaceutical compositions (e.g., dosage form containing a unit of the eskers), which can be used in the methods disclosed in the description. Particular pharmaceutical compositions include a compound of this invention or its pharmaceutically acceptable salt, MES, stereoisomer or prodrug and an optional second active agent.

4.1. Connection

In one embodiment, the invention encompasses the compounds of formula (I):

and their pharmaceutically acceptable salt, solvate, stereoisomers and prodrugs, in which:

n is 0 or 1;

X is CH2, C=O or C=S;

R1is:

(a) -(CH2)mR3or - (CH2)mR3where

m is 0, 1, 2 or 3; and

R3represents a 5-10 membered aryl or heteroaryl, optionally substituted by one or more Halogens;

b) -C=YR4where

Y represents O or S; and

R4is:

(C1-C10)alkyl, (C1-C10)alkoxy;

(C0-C10)alkyl-(5-10-membered heteroaryl or heterocycle), a specified heteroaryl or a heterocycle optionally substituted by one or more substituents from (C1-C6)alkyl, halogen, oxo, (C1-C6)alkoxy, or-Z-(C1-C6)alkyl, where Z is S or SO2and where specified (C1-C6)alkyl may be optionally substituted by one or several is likemy Halogens;

(C0-C10)alkyl-(5-10 membered aryl), specified by aryl optionally substituted by one or more substituents from halogen; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; or-Z-(C1-C6)alkyl, where Z is S or SO2and where specified (C1-C6)alkyl may be optionally substituted by one or more halogen; or

(C1-C6)alkyl-CO-O-R12where R12represents H or (C1-C6)alkyl; or

C) -C=ZNHR6where

Z represents O or S; and

R6is:

(C1-C10)alkyl, (C1-C10)alkoxy;

5-10-membered aryl or heteroaryl, optionally replaced by one or more substituents from halogen; cyano; (C1-C6)alkylenedioxy; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; (C1-C6)alkylthio, which is itself optionally substituted by one or more halogen; and

R2represents H or (C1-C6)alkyl.

In a particular embodiment, the invention encompasses compounds is ormula (II):

and their pharmaceutically acceptable salt, solvate, stereoisomers and prodrugs, in which:

n is 0 or 1;

X is CH2or C=O;

R7represents -(CH2)mR9where m is 0, 1, 2 or 3; and R9represents a 5-10 membered aryl or heteroaryl, optionally substituted by one or more halogen; and

R8represents H or (C1-C6)alkyl.

In one embodiment X is C=O. In another embodiment X is CH2.

In one embodiment n is 0. In another embodiment n is 1.

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

In one embodiment R9represents 5-to 10-membered aryl. In some particular embodiments, R9represents phenyl, optionally substituted by one or more Halogens.

In one embodiment R9represents a 5-10 membered heteroaryl. In some particular embodiments, R9is furyl or benzofuran.

In one embodiment R8represents N. In another embodiment R8is (C1-C6)alkyl. In some particular embodiments, R8represents methyl.

All combinations of the above embodiments covered by the invention.

Examples include them, but without limitation, the above compounds or their pharmaceutically acceptable salt, solvate (e.g., hydrates), prodrugs or stereoisomers, are:

In another embodiment, the invention encompasses the compounds of formula (III):

,

and their pharmaceutically acceptable salt, solvate, stereoisomers and prodrugs, in which:

X is CH2or C=O;

Y represents O or S;

R10is:

(C1-C10)alkyl, (C1-C10)alkoxy;

(C0-C10)alkyl-(5-10-membered heteroaryl or heterocycle), a specified heteroaryl or a heterocycle optionally substituted by one or more substituents from (C1-C6)alkyl, halogen, oxo, (C1-C6)alkoxy, or-Z-(C1-C6)alkyl, where Z is S or SO2and where specified (C1-C6)alkyl may be optionally substituted by one or more Halogens;

(C0-C10)alkyl-(5-10 membered aryl), specified by aryl optionally substituted by one or more substituents from halogen; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; or-Z-(C1-C6)is Lila, where Z is S or SO2and where specified (C1-C6)alkyl may be optionally substituted by one or more halogen; or

(C1-C6)alkyl-CO-O-R12where R12represents H or (C1-C6)alkyl; and

R11represents H or (C1-C6)alkyl.

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

In one embodiment, Y is O. In another embodiment Y represents S.

In one embodiment R10is (C1-C10)alkyl. In some particular embodiments, R10is (C5-C10)alkyl. In some particular embodiments, R10represents pentyl or hexyl.

In one embodiment R10is (C1-C10)alkoxy. In some particular embodiments, R10is (C5-C10)alkoxy. In some particular embodiments, R10is pentyloxy or hexyloxy.

In one embodiment R10represents a 5-10 membered heteroaryl. In some particular embodiments, R10is thiophenyl or furyl.

In one embodiment R10represents a 5-10 membered aryl, optionally substituted by one or more Halogens. In some particular embodiments, R10represents phenyl, optionally substituted by one or a number of the mi Halogens.

In one embodiment R10represents a 5-10 membered aryl or heteroaryl, optionally substituted (C1-C6)alkyl or (C1-C6)alkoxy, which are optionally substituted by one or more Halogens. In some particular embodiments, R10represents phenyl, substituted (C1-C3)alkyl or (C1-C6)alkoxy, substituted by one or more Halogens. In some particular embodiments, R10represents phenyl, substituted with stands or methoxy, substituted 1, 2 or 3 Halogens.

In one embodiment R10represents aryl or heteroaryl, substituted-S-(C1-C6)alkyl, where the specified alkyl itself optionally substituted by one or more Halogens. In another embodiment R10represents aryl or heteroaryl, substituted-SO2-(C1-C6)alkyl, where the specified alkyl itself optionally substituted by one or more Halogens.

In one embodiment R10is (C1-C6)alkyl-CO-O-R12where R12is (C1-C6)alkyl. In a particular embodiment, R10represents butyl-CO-O-tBu.

In one embodiment R10is (C1-C6)alkyl-CO-O-R12where R12represents N. In a particular embodiment, R10represents butyl-COOH.

In one waples the NII R 11represents N. In another embodiment R11is (C1-C6)alkyl. In some particular embodiments, R11represents methyl.

All combinations of the above embodiments covered by the invention.

Examples include, but without limitation, the above compounds or their pharmaceutically acceptable salt, solvate (e.g., hydrates), prodrugs or stereoisomers, are:

In another embodiment, the invention encompasses the compounds of formula (IV):

,

and their pharmaceutically acceptable salt, solvate, stereoisomers and prodrugs, in which:

X is CH2or C=O;

Y represents O or S;

R13is:

(C1-C10)alkyl, (C1-C10)alkoxy;

5-10-membered aryl or heteroaryl, optionally substituted by one or more substituents from halogen, cyano, (C1-C6)alkylenedioxy; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; (C1-C6)alkylthio, which is itself optionally substituted by one or more g is loginame; and

R14represents H or (C1-C6)alkyl.

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

In one embodiment, Y is O. In another embodiment Y represents S.

In one embodiment R13is (C1-C10)alkyl. In some particular embodiments, R13is (C1-C6)alkyl. In some particular embodiments, R13represents propyl, butyl of pentyl or hexyl.

In one embodiment R13is (C1-C10)alkoxy.

In one embodiment R13represents a 5-10 membered aryl or heteroaryl, optionally substituted by cyano. In some particular embodiments, R13represents phenyl, optionally substituted by cyano.

In one embodiment R13represents a 5-10 membered aryl or heteroaryl, optionally substituted (C1-C6)alkylenedioxy. In some particular embodiments, R13represents phenyl, optionally substituted, methylendioxy.

In one embodiment R13represents a 5-10 membered aryl or heteroaryl, optionally substituted by one or more Halogens. In some particular embodiments, R13represents phenyl, optionally substituted by one or more Halogens.

In one embodiment R13represents a 5-10 membered aryl and the and heteroaryl, optionally substituted C1-C6)alkyl or (C1-C6)alkoxy, which are optionally substituted by one or more Halogens. In some particular embodiments, R13represents phenyl, optionally substituted by stands or methoxy, which are themselves optionally substituted by 1, 2 or 3 Halogens.

In one embodiment R13represents a 5-10 membered aryl or heteroaryl, optionally substituted (C1-C6)alkylthio, which is itself optionally substituted by one or more Halogens.

In one embodiment R14represents N. In another embodiment R14is (C1-C6)alkyl. In some particular embodiments, R14represents methyl.

All combinations of the above embodiments covered by the invention.

Examples include, but without limitation, the above compounds or their pharmaceutically acceptable salt, solvate (e.g., hydrates), prodrugs or stereoisomers, are:

Used herein, the term "pharmaceutically acceptable salt", unless otherwise specified, refers to salts derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable non-toxic acids include inorganic organicheskoi acid, such as, without limitation, acetic acid, alginic, Anthranilic, benzolsulfonat, benzoic, camphorsulfonic, lemon, econsultancy, formic, fumaric, Turova, gluconic, glutamina, glukhareva, galacturonic, goldirova, Hydrobromic, hydrochloric, setinova, lactic, maleic, malic, almond, methansulfonate, Mukanova, nitrogen, Panova, Pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric, p-toluensulfonate and the like. Suitable are Hydrobromic, hydrochloric, phosphoric and sulphuric acid.

Used herein, the term "MES"if not stated otherwise, denotes a compound according to this invention or its salt, which further includes a stoichiometric or non-stoichiometric amount of solvent bound non-covalent intermolecular forces. If water is the solvent, the MES is a hydrate.

Used herein, the term "prodrug", if not stated otherwise, denotes a derivative of a compound that is capable of either hydrolyzed, oxidize, or otherwise react in biological conditions (in vitroorin vivowith the establishment of the connection. Examples of prodrugs include, but without limitation, compounds that sod is rat biologically hydrolyzable fragments, such as biologically hydrolyzable amide, biologically hydrolyzable ester, biologically hydrolyzable urethane, biologically hydrolyzable carbonate, biologically hydrolyzable weenie and biologically hydrolyzable phosphate analogues. Other examples of prodrugs include compounds that contain fragments-NO, -NO2, -ONO, or-ONO2. Prodrugs can typically be obtained using well known methods such as described inBurger''s Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5thed., 1995) andDesign of Prodrugs(H. Bundgaard ed., Elsevier, New York, 1985).

Used herein, the terms "biologically hydrolyzable carbamate", "biologically hydrolyzable carbonate", "biologically hydrolyzable of wreid" and "biologically hydrolyzable phosphate", if not stated otherwise, denote, respectively, carbamate, carbonate, wreid and phosphate compounds that are: 1) do not affect the biological activity of compounds, but can improve such preferential connection propertiesin vivoas absorption, duration of action and time prior to the commencement of the action, or 2) is biologically inactive but becomesin vivoin biologically active compound. Examples of biologically hydrolyzable carbamates include, but without limitation, lower alkylamines followed, substituted Ethylenediamine, aminoxy the lots, hydroxylamine, heterocyclic and heteroaromatic amines and polyetheramines.

Used herein, the term "stereoisomer", unless otherwise stated, covers all enantiomeric/stereoisomeric pure and enantiomerically/stereoisomers enriched compounds according to this invention.

Used herein, the term "stereoisomer clean, if not stated otherwise, denotes a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of this compound. For example, stereoisomers pure composition of a compound having one chiral center must be free of the opposite enantiomer of the compound. Stereoisomers pure composition of a compound with two chiral center must be free of other diastereomers of the compounds. Usually stereoisomers pure compound contains more than 80% by weight of one stereoisomer of the compound and less than 20% by weight of other stereoisomers of the compound, more preferably more than 90% by weight of one stereoisomer of the compound and less than 10% by weight of other stereoisomers of the compound, even more preferably more than 95% by weight of one stereoisomer of the compound and less than 5% by weight of other stereoisomers of the compound, and most preferably more than 97% by weight of one stereoisomer of the compound and less than 3% of p is the weight of the other stereoisomers of the compound.

Used herein, the term "stereoisomer enriched, if not stated otherwise, denotes a composition that contains more than about 55% by weight of one stereoisomer of the compound, more than about 60% by weight of one stereoisomer of the compound, preferably more than about 70% by weight of one stereoisomer of the compound, more preferably more than about 80% by weight of one stereoisomer of the compound.

Used herein, the term "enantiomerically pure", if not stated otherwise, denotes stereoisomers pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to stereoisomers enriched composition of the compound having one chiral center.

Used herein, the term "alkyl", unless otherwise specified, refers to a saturated hydrocarbon with a normal or branched chain, having indicated to him the number of carbon atoms. Representatives of saturated Akilov with normal chains include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; while saturated alkali branched chain include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-etylhexyl, 3-etylhexyl, 4-etylhexyl, 5-methylhexan, 2,3-dimethylbutyl and under the items. The term "alkyl" also encompasses cycloalkyl.

Used herein, the term "cycloalkyl", if not stated otherwise, denotes the type of alkyl containing from 3 to 15 carbon atoms, without alteration or resonance of double bonds between carbon atoms. It can contain from 1 to 4 rings. Examples of unsubstituted cycloalkyl include, but without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and substituted. Cycloalkyl may be substituted by one or more substituents as defined below.

Used herein, the term "alkoxy", unless otherwise specified, refers to-O-(alkyl), where alkyl is defined in the description. Examples of alkoxy include, but without limitation, -och3, -Och2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3and(CH2)5CH3.

Used herein, the term "aryl", if not stated otherwise, denotes a carbocyclic aromatic ring containing from 5 to 14 atoms in the ring. All atoms in the carbocyclic ring aromatic groups are carbon atoms. Aryl ring structure include compounds having one or more ring structures such as mono-, bi - or tricyclic compounds, as well as benzododecinium carbocyclic fragments, such as 5,6,7,8-tetrahydronaphthyl and the like. Representatives who ate aryl groups include phenyl, anthracene, fluorene, indenyl, azulene, phenanthrene and naphthyl.

Used herein, the term "heteroaryl", if not stated otherwise, denotes an aromatic ring containing from 5 to 14 atoms in the ring, among which at least one (e.g. one, two, or three) is a heteroatom (such as nitrogen, oxygen or sulfur). Heteroaryl ring structure include compounds having one or more ring structures such as mono-, bi - or tricyclic compounds, as well as condensed heterocyclic fragments. Examples of heteroaryl include, but without limitation, triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, thiazolyl, benzothiophene, benzisoxazole, benzisothiazole, chinoline, ethenolysis, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolin, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnoline, phthalazine, hintline, benzothiazolyl, honokalani, acridines, pyrimidyl, oxazolyl, benzo[1,3]dioxol and 2,3-dihydrobenzo[1,4]dioxin.

Used herein, the term "heterocycle", if not stated otherwise, denotes a monocyclic or polycyclic ring containing carbon atoms and hydrogen, optionally having 1 or 2-multiple bonds, and atoms of the ring sod is rat, at least one heteroatom, in particular from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Heterocyclic ring structures include, without limitation, mono-, bi - or tricyclic compounds. Particular cases of heterocycles are monocyclic or bicyclic. Representatives of heterocycles include morpholinyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, piperazinil, hydantoinyl, valerolactam, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridine, tetrahydropyrimidines, tetrahydrothiophene and tetrahydrothiopyran. The heterocyclic ring can be unsubstituted or substituted.

Used herein, the term "heteroseksualci", unless otherwise specified, refers to cycloalkyl group in which at least one of the carbon atoms in the ring is replaced by a heteroatom (such as O, S or N).

It should be noted that if there is a discrepancy between the depicted structure and the name given to this structure, the depicted structure is more important. In addition, if the stereochemistry of a structure or part of structure is not specified, for example, bold or dashed lines, the structure or part of a structure is considered as encompassing all stereoisomers.

4.2 Methods of treatment, prevention, and control over sabol is of

The invention encompasses methods of treatment, prevention and/or management for various diseases using the compounds of this invention or its pharmaceutically acceptable salt, MES, stereoisomer, or prodrug.

Examples of diseases or disorders include, but without limitation, cancer, disorders associated with angiogenesis, pain, including complex regional pain syndrome (CRPS), macular degeneration (MD) and related syndromes, skin diseases, pulmonary diseases, disorders caused by asbestos, parasitic diseases, disorders, immunocompromised, CNS disorders, CNS damage, atherosclerosis and related disorders, sleep disorders and related disorders, hemoglobinopathy and related disorders (such as anemia), disorders associated with TNFα, and other various diseases and disorders.

Used herein, the terms "treat" and "treatment", if not stated otherwise, relate to the elimination or improvement of the disease or disorder, or one or more symptoms associated with a disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder occurring due to the introduction of one or more prophylactic or therapeutic Agay is tov to the patient, having such disease or disorder.

Used herein, the terms "prevent", "preventing" and "prevention", if not stated otherwise, relate to the prevention of the beginning, re-emergence or spread of disease or disorder or one or more of its symptoms.

Used herein, the terms "control flow" and "flow control", unless otherwise stated, refer to preventing or slowing the progression, spread or worsening of the disease or disorder or one or more of its symptoms. Often the beneficial effects of prophylactic or therapeutic agent, which is achieved in the patient, does not lead to a cure of the disease or disorder.

Used herein, the expression "therapeutically effective amount" of a compound, unless otherwise specified, defines a quantity sufficient to provide a therapeutic effect in the treatment or management of a disease or disorder or to delay the manifestation or minimize one or more symptoms associated with a disease or disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent alone or in combination with other therapies, that provides a therapeutic effect ol the treatment or management of a disease or disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances therapeutic efficacy of another therapeutic agent.

Used herein, the phrase "prophylactically effective amount" of a compound, unless otherwise specified, defines a quantity sufficient to prevent a disease or disorder or to prevent its recurrence. Prophylactically effective amount of a compound means an amount of therapeutic agent alone or in combination with other agents, which provides a prophylactic effect in preventing the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

In one embodiment of the compounds presented in the description, are used for treatment, prevention and/or management for cancer or precancerous conditions. As disclosed in the description, without limitation to any particular theory, and unless otherwise indicated, it was found that some compounds presented in the description, exhibit antiproliferative effects the and various cancer cells, this new-found methods, as specified in the description, and known from the prior art. Examples of cancer cells include, but without limitation, Namalwa, HN 5q (oral carcinoma), HT-1080 (fibrosarcoma), SK-MES-1 (5q, light), U87MG (glioblastoma, astrocytoma), T98G (mutant p53, glioblastoma), SH-SY5Y (neuroblastoma), SK-N-MC (neuroblastoma), PC-3 (prostate), MCF-7 (breast), T-47D (breast), SF-268 (CNS), HCT-116 (direct intestine), 786-O (renal), AN (kidney), SN12C (renal), TK-10 (renal), CCRF-CEM (leukemia), HL-60 (leukemia), C (leukemia), A (light), Nord 92 (lung), NCI-H1650 (lung), NCI-H522 (light), GRANTA-519 (lymphoma epithelial cells), REC-1 (lymphoma epithelial cells), Malme-3M (melanoma), MDA-MB-435 (melanoma), SK-MEL-28 (melanoma), M14 (melanoma), SK-MEL-2 (melanoma), U266B1 (multiple myeloma), KARPAS-1106P (nahodkinskuju lymphoma), KARPAS-422 (nahodkinskuju lymphoma), OCI-LY-19 (nahodkinskuju lymphoma), WSU-DLCL2 (nahodkinskuju lymphoma).

Examples of cancerous and precancerous conditions include, but without limitation, described in U.S. patent No. 6281230 and 5635517 issued to Muller with al., in various patent publications Zeldis in the United States, including the publication 2004/A, published on 4 November 2004 (treatment of myelodysplastic syndrome), 2004/A published February 12, 2004 (treatment of various types of cancer) and 2004/0087546, published may 6, 2004 (treatment of myeloproliferative diseases). Examples also include disclosed in PCT/US04/14004 filed with the Oh on may 5, 2004. All of these sources are included in this description in their entirety by reference.

Examples of cancer include, but without limitation, various types of skin cancer such as melanoma, lymph node, breast, cervix, uterus, gastrointestinal tract, lung, ovaries, prostate, rectum, anus, mouth, brain, head and neck, throat, testicles, kidneys, pancreas, bone, spleen, liver, bladder, larynx, nasal passages, and cancers associated with AIDS. The compounds are particularly useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemia, for example, lymphoblastic, myelogenous, lymphocytic and miliitary leukemia. Compounds according to the invention can be applied for the treatment, prevention and control for both primary and metastatic tumors.

Other specific types of cancer include, but without limitation, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple metastases in the brain, multiform glioblastoma, glioblastoma, brain stem glioma, a malignant brain tumor with a poor prognosis malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine R is K, rectal adenocarcinoma, colorectal cancer, Duke C, and D, unresectable colorectal carcinoma, metastatic carcinoma of the liver cells, Kaposi's sarcoma, acute carotino myeloblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, nahodkinskuju lymphoma, cutaneous T-cell lymphoma, cutaneous b-cell lymphoma, diffuse lymphoma fat In cells, undeveloped follicular lymphoma, metastatic melanoma (localized melanoma, including, but without limitation, ocular melanoma), malignant mesothelioma, malignant pleural efrusy mesotheliomalocate syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, sarcoma of soft fabrics, scleroderma, cutaneous vasculitis, histocytes Langerhans cells, leiomyosarcoma, progressive bone fibrodysplasia, prostate cancer, not amenable to hormonal therapy, surgery soft tissue sarcoma with a high risk of inoperable carcinoma of the liver cells, macroglobulinemia Waldenstrom, indolent myeloma, painless myeloma, cancer of the fallopian tubes, prostate cancer, independent of androgens, non-metastatic prostate cancer stage IV, dependent on androgens, prostate cancer resistant to chemotherapy, papillary thyroid carcinoma, follicular thyroid carcinoma is, medullary thyroid carcinoma and leiomyoma. In the private embodiment cancer immune or resistant to chemotherapy or radiation.

In a particular embodiment, the invention encompasses methods of treatment, prevention or control over various forms of leukemia, such as chronic lymphocytic leukemia, chronic malacitana leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia, including leukemia who have relapsed, resistant or resistant, as described in patent publication U.S. No. 2006/0030594 published February 9, 2006, which is incorporated in its entirety by reference.

The term "leukemia" refers to malignant neoplasms in hematopoietic tissues. Leukemia includes, but without limitation, chronic lymphocytic leukemia, chronic miliitary leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute myeloblastic leukemia. Leukemia can have a relapse, to be immune or resistant to conventional therapy. The term "having a relapse" refers to a situation in which the patient entered before that, in remission leukemia after therapy, bone marrow see the return of the leukaemic cells and reduction of normal blood cells. Term is n "immune or resistant" refers to the circumstances, in which patients, even after intensive treatment, have residual leukemic cells in the bone marrow.

In another private embodiment, the invention encompasses methods of treatment, prevention, and control over various lymphomas, including nahodkinskuju lymphoma (NHL). The term "lymphoma" refers to a heterogeneous group of neoplasms 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, but without limitation, lymphoma epithelial cells, MCL, sredneperesechennoy lymphocytic lymphoma, intermediate lymphocytic lymphoma, ILL, diffuse subdifferentiable lymphocytic lymphoma, PDL, centrocytes lymphoma, diffuse lymphocytic lymphoma with malorazmernyj cells, DSCCL, follicular lymphoma, and any type of lymphoma epithelial cells, which can be observed under a microscope (nodular, diffuse, plasticheskuyu and lymphoma cover the area.

Examples of diseases and disorders associated with undesirable angiogenesis or characterized by them include, but without limitation, inflammatory diseases, autoimmune diseases, viral diseases, geneticists the e disease, allergic diseases, bacterial diseases, ocular neovascular disease, choroidal neovascular diseases, neovascular diseases of the retina and robes (neovascularization of the angle). Examples of diseases and disorders associated with undesirable angiogenesis or characterized by them include, but are not limited to, endometriosis, Crohn's disease, heart failure, advanced heart failure, kidney damage, groove toxins, toxic shock syndrome, osteoarthritis, replication of retroviruses, exhaustion, meningitis, fibrosis caused by silica, fibrosis caused by asbestos, veterinary disorder, hypercalcemia associated with malignancy, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, anemia and immune syndrome deletion 5q.

Examples of pain include, but without limitation, described in patent publication U.S. 2005/0203142, published September 15, 2005, which is incorporated into the description by reference. Examples of pain include, but without limitation, malignant pain, neuropathic pain, mixed nociceptive and neuropathic pain, pain in the internal organs, migraine, headache and postoperative pain.

Examples of nociceptive pain include, but are not limited to, pain associated with chemical or t is recoskie burns, the skin cuts, bruises of the skin, osteoarthritis, rheumatoid arthritis, tendonitis and myofascial pain.

Examples of neuropathic pain include, but without limitation, CRPS type 1 CRPS type 2, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, simpaticeskii-maintained pain syndrome, causalgia, bone atrophy of the city called Torun, algoneurodystrophy syndrome shoulder arms (shoulder hand), post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, pain associated with cancer, phantom pain in extremity, fibromyalgia, chronic fatigue syndrome, pain caused by damage to the spine, Central pain after stroke, radiculopathy, diabetic neuropathy, pain after stroke, syphilis neuropathy and other painful neuropathic conditions, in particular induced by drugs, such as vincristine and walked.

Used herein, the term "complex regional pain syndrome, CRPS and syndromes related to CRPS, if not stated otherwise, denotes a chronic pain disorder characterized by one or more of the following: pain, spontaneous or caused by anything, including allodynia (painful response to a stimulus that is not normally painful) and hyperalgesia (excessive response to a stimulus, to the which usually is moderately painful); pain, disproportionate to the calling event (e.g., years of severe pain after stretching of the ligaments in the ankle)regional pain that is not limited to a single peripheral nerve cluster, and independent violation (for example, rash, changes in blood flow and rash)associated with trophic skin changes (abnormal growth of hair and nails and skin ulceration).

Examples of macular degeneration (MD) and related syndromes include, but without limitation, described in patent publication U.S. No. 2004/0091455, published may 13, 2004, which is incorporated into the description by reference. Specific examples include, but without limitation, atrophic (dry) MD, exudative (wet) MD, age-related maculopathy (ARM), the choroidal neovascularization (CNVM), the detachment of the pigment epithelium of the retina (PED) and atrophy of the retinal pigment epithelial (RPE).

Examples of skin diseases include, but without limitation, described in patent publication U.S. No. 2005/A, published on September 29, 2005, which is incorporated into the description by reference. Specific examples include, but are not limited to, keratoses and related symptoms, diseases or disorders of the skin, characterized by excessive growth of the epidermis, acne and wrinkles.

Used herein, the term "keratosis", unless otherwise specified, refers to any porage the human epidermis, marked by the presence of defined overgrowth of the Horny layer, including, but without limitation, actinic keratosis, seborrheic keratosis, keratoakantoma, follicular keratosis (illness Derier), inverted follicular keratosis, palmoplantar keratoderma (RSC, Palmar and plantar keratosis), Polyarny keratosis and keratosis similar to plaster. The term "actinic keratosis" also refers to senile keratosis, senile wart, flat senile wart, 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: rough appearance, scaly erythematous nodules, plaques, spicules and hselkovymi bulges on the affected surfaces (e.g., face, hands, ears, neck, legs and chest), the formation of keratin called skin callus, hyperkeratosis, telangiectasias, elastosis, pigmented bumps, acanthosis, parakeratosis, diskeratoz, papillomatosis, hyperpigmentation of basal cells, cell cellular atypia, metonymy figures, abnormal intercellular adhesion, dense inflammatory infiltrates and a slight predominance of this form may cell carcinoma.

Examples to the author of diseases or disorders, characterized by excessive growth of the epidermis include, but without limiting, diseases or disorders marked by excessive growth of the epidermis, including, but without limitation, infection is associated with virus papillomas, ARSENICAL keratosis, signs of Leser-Trelat, the warty discreta (WD), pochobradsky hair (TS), the changing erythrokeratodermia (EKV), serum ichthyosis (ichthyosis Arlekino), pillows on the finger joints, skin melanocytoma, parakeets, psoriasis, this form may cell carcinoma, combined and reticulated papillomatosis (CRP), acrochordon, skin keratinization, Cowden's disease is (the syndrome of multiple hamartomas), black papulosis dermatosis (DPN), a syndrome of epidermal nevus (ENS), normal ichthyosis, molluscum contagiosum, knotted the prurigo and black acanthosis (AN).

Examples of pulmonary disorders include, but without limitation, described in the publication US 2005/0239842A1, published October 27, 2005, which is incorporated into the description by reference. Examples include pulmonary hypertension and related disorders. Examples of pulmonary hypertension and related disorders include, but without limitation, primary pulmonary hypertension (PPH), secondary pulmonary hypertension (SPH), family PPH, sporadic PPH, precapillary pulmonary hypertension, pulmonary arterial hypertension (RAS), hypertension is agonoy artery, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy (TRA), plexogenic pulmonary arteriopathy, functional classes of pulmonary hypertension I through IV or pulmonary hypertension associated or secondary dysfunction occurs when the left ventricle, the disease of the mitral valve, tightening pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, disease with obstruction of the pulmonary veins, collagen vascular disease, congenital heart disease, viral infection, exposure to drugs and toxins, such as fenfluramine, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, respiratory disorders during sleep, upset with alveolar hypoventilation is often, chronic exposure to high altitude, pulmonary disease of the newborn, alveolar-capillary dysplasia, a disease sickle cell, other coagulation disorders, chronic thromboembolism, disease of connective tissue, lupus, including systemic and cutaneous lupus, schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis.

Examples of disorders associated with asbestos include, but without limitation, as described in the application US No. 2005/0100529, filed may 12, 2005 is Yes, which is included in the description by reference. Specific examples include, but without limitation, asbestos mesothelioma, malignant pleural effusion, benign pericardial effusion, pleural plaques, pleural calcification, diffuse pleural thickening, round atelectasis, fibrous mass and lung cancer.

Examples of parasitic diseases include, but without limitation, as described in the application US No. 11/271963, filed November 14, 2005, which is incorporated into the description by reference. Parasitic diseases include diseases and disorders caused by intracellular parasites of man, such as, but without limitation,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 ssp.andO. volvulus. Also covered and other diseases and disorders caused by the intracellular parasite species other than human, such as, but without limitation,Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia spp.andTheileria ssp. Specific examples include, but without limitation, malaria, babesiosis, trypanosomes, Leishmania, toxoplasmosis, encephalitis, keratitis, amebiasis, Giardia, cryptosporidiosis, isosporiasis, ciclosporin, microsporidiosis, ascariasis, trichuris, Ancylostoma is h, strongiloidoz, toxascaris, trainees, lymphatic filariasis, onchocerciasis, filariasis, schistosomiasis, and dermatitis caused by Schistosoma animals.

Examples of immunodeficiency disorders include, but without limitation, as described in the application US No. 11/271963, filed November 30, 2005. Specific examples include, but without limitation, the deficit adenozindezaminazy, the lack of antibodies with normal or elevated Ig, ataxia-telangiectasia syndrome bare lymphocyte, normal variable immune deficiency, deficit Ig with Hyper IgM, destruction of Ig heavy chain, IgA deficiency, immunodeficiency with thymoma, reticular dysgenesis syndrome Nizalova, selective deficiency of IgG subclass, transient children gipogammaglobulinemia, syndrome Wiskott-Aldrich, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but without limitation, described in the publication US No. 2005/A, published June 30, 2005, which is incorporated into the description by reference. Specific examples include, but without limitation, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and other neuroimmune disorders, such as Tourette syndrome, delirium or impairment of consciousness that occur in a short period of time, or amnestic destroy the creation, or partial memory corruption, which can occur in the absence of other injuries of the Central nervous system.

Examples of Central nervous system disorders include, but without limitation, as described in the application US No. 11/284403, filed November 18, 2005, which is incorporated into the description by reference. Specific examples include, but without limitation, destruction/damage the Central nervous system and related syndromes, including, but without limitation, primary brain damage, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal damage, head injury, brain concussion syndrome after brain concussion, contusion or rupture of the spinal subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, full SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI, the syndrome Central cord syndrome brown-Sequard syndrome external cord syndrome of cerebral cone, cauda equina syndrome, neurogenic shock, spinal shock, alternating levels of consciousness, headache, motion sickness, vomiting, memory loss, dizziness, diplopia, blurred vision, emotional lability, sleep disturbances, irritability, inability to concentrate, anxiety, behavior disorders, deficits in cognitive ability and fit.

Friend the e diseases or disorders include, but without limitation, viral, genetic, allergic, and autoimmune diseases. Specific examples include, but without limitation, HIV, hepatitis, respiratory distress syndrome of adults, diseases of bone resorption, chronic inflammatory pulmonary disease, dermatitis, bubble fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, postischemic reperfusion injury, meningitis, psoriasis, vibrationthe disease, cachexia, disease graft versus host disease, graft rejection, autoimmune disease, rheumatoid spondylitis, Crohn's disease, ulcerative colitis, inflammatory disease of the stomach, multiple sclerosis, systemic lupus eritematoso, ENL in leprosy, radiation injury, cancer, asthma or gipertoksicheskaya alveolar defeat.

Examples of atherosclerosis and related conditions include, but without limitation, described in the publication US No. 2002/0054899, published may 9, 2002, which is incorporated into the description by reference. Specific examples include, but without limitation, all forms of conditions, including atherosclerosis, including restenosis after vascular intervention such as angioplasty, stenting, atherectomy and transplantation. The invention covers all forms of vascular interventions, including p is owtime in diseases of the cardiovascular and renal systems, such as, but without limitation, renal angioplasty, subcutaneous coronary intervention (PCI), subcutaneous transluminal coronary angioplasty (PTCA), subcutaneous transluminal angioplasty of the carotid artery (the MOUTH), coronary bypass surgery, angioplasty with stent implantation, peripheral subcutaneous transluminal intervention in the iliac, femoral or popliteal arteries, and surgery with the use of impregnated synthetic grafts. The next table contains the list of the major systemic arteries, which may require treatment, all of them covered by the invention:

ArteryProvides blood supply to the part of body
AxillaryThe shoulder and the armpit
ShoulderThe upper part of the hand
BrachiocephalicHead, neck & hand
AbdominalDivides into the left gastric, splenic and hepatic artery
Common carotidNeck
Overall what I iliac Divided into external and internal iliac artery
CoronaryHeart
Deep femoralHip
FingerFingers
Rear footLeg
Outside sleepyThe neck and the outer region of head
External iliacThe femoral artery
HipHip
StomachStomach
HepaticLiver, gall bladder, pancreas and duodenum
The inferior mesentericThe descending part of the rectum, anus and the wall of the renal pelvis
The internal carotidNeck and internal head
Internal iliacThe anus, bladder, outdoor sex on the Ghana gluteal muscle, uterus and vagina
The left gastricThe esophagus and stomach
The middle sacralThe sacrum
OvarianOvaries
Palmar archHand
PeronealThe rear part of the lower leg
PoplitealKnee
Hind tibiaThe rear part of the lower leg
PulmonaryLight
BeamForearm
RenalKidney
SplenicThe stomach, pancreas and spleen
SubclavianShoulder
Superior mesentericPancreas, small intestine, ascending and transverse colon
Testicular Testicles
ElbowForearm

Examples of sleep disorders and related syndromes include, but without limitation, described in the publication US No. 2005/A, published October 6, 2005, which is incorporated into the description by reference. Specific examples include, but without limitation, snoring, sleep apnea, insomnia, narcolepsy, tired leg syndrome, nightmares, sleepwalking, food consumption in sleep and sleep disorders associated with chronic neurological or inflammatory conditions. Chronic neurological or inflammatory condition include, but without limitation, complex regional pain syndrome, chronic pain in the lower spinal Department, musculoskeletal pain, arthritis, radiculopathy, pain associated with cancer, fibromyalgia, chronic fatigue syndrome, pain in the internal organs, pain in the bladder, chronic pancreatitis, neuropathy (diabetic, herpetic, traumatic or inflammatory and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, bradykinesia, muscle rigidity, parkinsonii tremor, parkinsonism gait, stiffness, depression, long-term violations the Oia memory syndrome Rubinstein-Taybi (RTS), dementia, unstable body position, hypokinetic disorders, sinucleanse disorders, multiple system atrophy, degeneration and black striped body, olivopontocerebellar atrophy syndrome Shay-Draeger, a disease of motor neurons with parkinsonism features, dementia Levi, Tau pathological disorders, progressive supranuclear paralysis, corticobasal degeneration, temporary dementia anterior brain amyloid pathological disturbances and cognitive abilities of an average degree, Alzheimer's disease with parkinsonism, Wilson disease, a disease of Hallervorden-Space disease Chediak-Hagashi, ataxia spinal cord SCA-3, parkinsonism with X-linked dystonia, prion disease, hyperkinetic disorders, chorea, ballism, dystonic types of tremor, amyotrophic lateral sclerosis (ALS), trauma to the Central nervous system and myoclonus.

Examples of hemoglobinopathy and related disorders include, but without limitation, described in the publication US No. 2005/A, published June 30, 2005, which is incorporated into the description by reference. Specific examples include, but without limitation, hemoglobinopathies, sickle cell anemia and other disorders associated with the differentiation of CD34+cell.

Examples castroist is, associated with TNFα include, but without limitation, described in WO 98/03502 and WO 98/54170, both documents are included in their entirety by reference. Specific examples include, but without limitation, the groove toxins or toxic shock syndrome, cachexia, respiratory distress syndrome of adults, diseases of bone resorption, such as arthritis, hypercalcemia, graft versus host disease, cerebral malaria, inflammation, tumor growth, chronic pulmonary inflammatory disease, reperfusion injury, myocardial infarction, stroke, circulatory shock, rheumatoid arthritis, Crohn's disease, HIV infection and AIDS, other disorders, such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions, septic shock, sepsis, endotoxic shock, the disease is graft versus host disease, wasting, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythronotos, ENL in leprosy, HIV, AIDS and associated infections in AIDS, disorders associated with the camp, such as septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congenital heart disease, vibrationthe disease, cachexia, rejection of the graft is the oncogenic or cancerous condition, asthma, autoimmune disease, radiation injury and gipertoksicheskaya alveolar lesions, viral infections such as caused by herpes viruses, viral conjunctivitis, or atopic dermatitis.

In other embodiments, the invention also covers various immunological applications of the compounds of the present invention, in particular as vaccine adjuvants, particularly as adjuvants for cancer vaccines, as disclosed in provisional application U.S. No. 60/712823, filed September 1, 2005, which is included in the description in its entirety by reference. This aspect of the invention also relates to uses of the compounds of this invention 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.

Doses of the compounds of this invention or its pharmaceutically acceptable salt, MES, stereoisomer or prodrug vary depending on factors such as: specific indications for treatment, prevention or management of disease, the age and condition of the patient and the amount of the second active agent, if used. Usually the connection according to this invention or farmacevtichesky acceptable salt, MES, a stereoisomer or prodrug can be used in an amount of from about 0.1 mg to about 500 mg per day, and can be introduced in a conventional manner (for example, the same number entered every day during the treatment, prevention or control of disease), cyclic (for example, one week introduction, one week without injection) or in amounts that increase or decrease in the treatment, prevention or management of disease.

In other embodiments, the dose can 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 10 mg to about 25 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20 mg

4.3 Second active agents

The connection according to this invention or its pharmaceutically acceptable salt, MES, stereoisomer or prodrug can be combined with other pharmacologically active compounds ("second active agents") in methods and compositions of the invention. It is assumed that certain combinations may act synergistically in the treatment of some types of diseases or disorders and conditions and symptoms, related the data with such diseases or disorders. The connection according to this invention or its pharmaceutically acceptable salt, MES, stereoisomer or prodrug can also help reduce the side effects associated with the second active agents, and Vice versa.

In the methods and compositions of the invention can be used one or more second active ingredients or agents. Second active agents can be large molecules (e.g. proteins) or small molecules (e.g., synthetic inorganic, ORGANOMETALLIC or organic molecules).

Examples of active agents with large molecules include, but without limitation, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Particular examples of active agents are anti-CD40 monoclonal antibodies (such as, for example, SGN-40), inhibitors discontinuties (such as, for example, SAHA and lunar abyss 824), inhibitors of protein-90 cardiac shock (such as, for example, 17-AAG), inhibitors of receptor kinase insulin-like growth factor-1, inhibitors of receptor kinases vascular endothelial growth factor (such as, for example, RTK), inhibitors of receptor insulin growth factor inhibitors acyltransferase lysophosphatidic acid, inhibitors of IkB kinase inhibitors RMR, EGFR inhibitors (such as for example, gefitinib and erlotinib HCL), an is the body to HER-2 (such as, for example, trastuzumab (Herceptin®) and pertuzumab (Omnitarg™), antibodies to VEGFR (such as, for example, bevacizumab (Avastin™), VEGFR inhibitors (such as, for example, specific inhibitors of the kinase flk-1, SU5416 and ptk787/zk222584), inhibitors RK (such as, for example, wortmannin), inhibitors of C-Met (such as, for example, RNA-665752), monoclonal antibodies (such as, for example, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab (Panorex®) and G250) and the antibody anti-TNFα. Examples of active agents with small molecules include, but without limitation, anti-cancer agents with small molecules and antibiotics (eg, clarithromycin).

Private second active compounds that can be combined with the compounds of this invention vary depending on the specific indications for treatment, prevention or management of disease.

For example, for the treatment, prevention or management for cancer the second active agent includes, but without limitation, semaxanib, cyclosporin, etanercept, doxycycline, bortezomib, acivicin, aclarubicin, hydrochloride Hakodate, Cronin, adozelesin, aldesleukin, altretamin, ambomycin, acetate ametantrone, amsacrine, anastrozole, astromicin, asparaginase, aspirin, azacytidine, asettaa, azotomycin, batimastat, benzodepa, bikalutamid, hydrochloride bisantrene, dimesylate bisnafide, bizelesin, sulfate, bleomycin is a, breiner sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustin, hydrochloride karubitina, carzelesin, Cedeira, celecoxib, chlorambucil, cirolemycin, cisplatin, cladribine, mesilate of krishnalila, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, decompletion, deazaguanine, mesilate of deazaguanine, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, citrate droloxifene, propionate dromostanolone, deatomizer, edatrexate, eflornithine hydrochloride, elsamitrucin, angloplats, enpromate, epirubicin, epirubicin hydrochloride, arbolada, hydrochloride zorubicin, estramustin estramustine phosphate sodium, etanidazole, etoposide, etoposide phosphate, atopen, hydrochloride fadrozole, fazarabine, phenetidine, floxuridine, phosphate fludarabine, fluorouracil, ferocity, fashion, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, hydrochloride idarubicin, ifosfamide, ilmofosine, iproplatin, irinotecan, irinotecan hydrochloride, acetate lanreotide, letrozole, acetate leuprolide, hydrochloride liarozole, lometrexol sodium, lomustin, hydrochloride losoxantrone, masoprocol, maytansine, hydrochloride mechlorethamine, acetate megestrol, acetate melengestrol, melphalan, menogaril, mercaptopurine, meet exit, methotrexate sodium, Matorin, maturetube, maintain, miacalcin, mitotropin, mitogillin, mitomycin, mitomycin, mitosis, mitotane, mitoxantrone hydrochloride, mycophenolate acid, nocodazole, nogalamycin, ormaplatin, oxysure, paclitaxel, pegaspargase, polymycin, pentamycin sulphate peplomycin, perforated, pipobroman, piposulfan, hydrochloride piroxantrone, plicamycin, plomelin, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ibuprin, safingol, hydrochloride of safingol, semustine, contrast, spartacat sodium, sparsomycin, hydrochloride spirogermanium, spiramycin, spiroplatin streptonigrin, streptozocin, alienor, telecomuting, tecogen sodium, Taxotere, tegafur, hydrochloride Alexandrina], teniposide, teraxion, testolactone, timipre, tioguanin, thiotepa, tianfuan, tirapazamine, toremifene citrate, acetate trestolone, phosphate triciribine, trimetrexate, glucuronate of trimetrexate, triptorelin, hydrochloride tubulosa, uracil mustard gas, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine sulphate vindesine, sulfate wikepedia sulphate singleseat, sulfate villarosa, vinorelbine tartrate, sulfate veneroidea, sulfate ventricina, vorozole, triplatin, zinostatin hydrochlorid zorubicin.

Other second agents include, but without limitation, 20-EPI-1,25-dihydroxy-vitamin D3, 5-itinerarary, abiraterone, aclarubicin, allfusion, Adelina, adozelesin, aldeslakin antagonists ALL-TK, altretamin, ambamustine, amidax, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, Andrographolide, inhibitors of angiogenesis, antagonist D, antagonist G, entrelacs, anti-dorkalicious morphogenetic protein-1; antiandrogen, antiestrogen, antineoplaston, antisense oligonucleotides, glycinate aphidicolin, gene modulators of apoptosis, regulators of apoptosis, apurinovaya acid, Ara-CDP-DL-PTBA, argininosuccinate, isolagen, atamestane, adrimycin, achinstein 1, achinstein 2, achinstein 3, azasetron, anatoxin, asteroid derived baccatin III, balana, batimastat antagonists BCR/ABL, benzocaine, benzoyltartaric, beta-lactam derivatives, beta-alamin, butaclamol In, Betulinol acid, an inhibitor of bFGF, bikalutamid, bisantrene, besuseradminclient, benefit, bestanden And bizelesin, bruflat, bropirimine, budotitane, sulfoximine of buthionine, calcipotriol, calphostin With derivatives camptothecin, capecitabine carboxamid-amino-triazole, carboxamidates, CaRest M3, CARN 700 inhibitors derived from cartilage, carzelesin inhibitors caseinline (ICOS), castanospermine, cecropin B, headquarters is relics, chlorins, sulphonamide of chlorphenoxamine, cicaprost, CIS-porphyrin, cladribine, analogues clomiphene, clotrimazole, colimycin And, colimycin In, combretastatin A4 analog combretastatin, congelin, kambezidis 816, Kristol, cryptophycin 8, derivatives cryptophycin And, korazin And, cyclopentanedione, cyclopean, cephamycin, octopopit citarabina cytolytic factor, cytostatin, galiximab, decitabine, dehydrodidemnin, deslorelin, dexamethasone, Taxifolin, dexrazoxane, dexverapamil, diazinon, didemnin In, detox, diethylmercury, dihydro-5-azacytidine, dihydroxy-9, dioxazine, diphenylpyraline, docetaxel, docosanol, dolasetron, doxifluridine, doxorubicin, droloxifene, dronabinol, duocarmycin SA, ebselen, elastin, edelfosine, edrecolomab, eflornithine, elements, Amateur, epirubicin, peristeri, analog estramustine, estrogen agonists, estrogen antagonists, etanidazole, phosphate etoposide, exemestane, fadrozole, fazarabine, phenetidine, filgrastim, finasteride, flavopiridol, fileselection, fluasterone, fludarabine, hydrochloride fortunemagazine, furfenorex, formestane, fostriecin, fotemustine, texaphyrin gadolinium, gallium nitrate, Galitsin, ganirelix inhibitors gelatinase, gemcitabine, inhibitors of glutathione, HaSulam, heregulin, hexamethyleneimine, hypericin, ibandronate acid, and orubicin, idoxifene, Idamante, ilmofosine, ilomastat, imatinib (Gleevec®), imiqimod, immunostimulating peptides, an inhibitor of the receptor for insulin-like growth factor 1, interferon agonists, interferons, interleukins, iobenguane, iododeoxyuridine, 4-ipomeanol, isoplast, irsogladine, isomerases, isohemagglutinins In, fusetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, lanemile, lenograstim, sulfate lentinan, leptostachys, letrozole, factor inhibiting leukemia, alpha leucocytes interferon, leuprolide+estrogen+progesterone, leiprorelina, levamisole, liarozole, similar linear polyamine, lipophilic disaccharide glycosides of the peptide, lipophilic compounds of platinum, lissoclinum 7, lobaplatin, lubricin, lometrexol, lonidamine, losoxantrone, doxorubin, lurtotecan, texaphyrin lutetium, lisofylline, lytic peptides, maytansine, sandostatin And, marimastat, masoprocol, maspin inhibitors matrilysin, inhibitors metalloprotease matrix, menogaril, monbaron, peterlin, methionines, metoclopramide, an inhibitor of MIF, mifepristone, miltefosin, Miramistin, mitoguazone, mitolactol, analogs of mitomycin, mitonafide, mycotoxicosis fibroblastic growth factor-saporin, mitoxantrone, Maarten, molgramostim, Erbitux, human chorionic gonadotropin, complex monophosphorylated A+cell wall of myobacteria, m is Picanol, mustard gas as an anti-cancer agent, megaproxy In extracts of cell walls of myobacteria, mylapore, N-azetidinone, N-substituted benzamide, nafarelin, Agresti, naloxone+pentazocine, nipawin, naftaplin, nartograstim, nedaplatin, nemorubicin, Nejdanov acid, nilutamide, nizamettin, modulators of nitric oxide, nitroxide antioxidants, nitrolon, oblimersen (Genasense®), O6-benzylguanine, octreotide, okizeme, oligonucleotides, onapristone, ondansetron, oracin, the inductor oral cytokine, ormaplatin, osaterone, oxaliplatin, exonomics, paclitaxel, analogs of paclitaxel, derivatives of paclitaxel, palamin, palmitoylated, pamidronovu acid, panaxytriol, promifin, pyrabactin, pallidin, pegaspargase, peltatin, pentosan polysulphate sodium, pentostatin, petrosal, perflubron, perforated, parallelly alcohol, fansinating, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, Platin And, Platin, inhibitor plasminogen activator, a platinum complex compounds of platinum, the platinum complex-triamine, porfimer sodium, porfiromycin, prednisone, propyl bis-acridan, prostaglandin J2, proteasome inhibitors, immunomodulator on the basis of protein A, an inhibitor of protein kinase C, microalgal, inhibitors patientinitiated inhibitors is wrinkleresistant, the purpurin, pyrazoloacridine, pyridylsulfonyl conjugate hemoglobin-polyoxyethylene antagonists raf, raltitrexed, ramosetron, inhibitors of ras-farnesyltransferase, ras inhibitors, the inhibitor of the ras-GAP, demetilirovanny reallity, etidronate rhenium 186 Re, rhizoxin, ribozymes, retinamide RII, rohitukine, romantic, roquinimex, rubiginous B1, robaxin, safingol, saintaubin, SarCNU, sarcophyton And sargramostim, mimetics Sdi 1, semustine, inhibitor 1 - derived senescene, sense oligonucleotides, inhibitors of signal transmission, sizofiran, sobuzoxane, borocaptate sodium, sodium phenylacetate, solvera connecting somatomedin protein, Shermin, sportsbuy acid, spicamycin D, spiramycin, splenopathy, spongistatin 1, squalamine, stipend inhibitors stromelysin, solifenacin, antagonist overactive vasoactive intestinal peptide, supradicto, suramin, swainsonine, tallimustine, methodid tamoxifen, tautomycin, tazarotene, tecogen sodium, tegafur, tellurophene, telomerase inhibitors], teniposide, tetrachlorodecaoxide, tetrasomy, teleblaster, thiocoraline, thrombopoetin, mimetic of thrombopoetin, thymalfasin, the agonist of the receptor of thymopoietin, timorian, thyroid stimulating hormone, adipocere atenololo, tirapazamine, bichloride of titanocene, topsentin, toremifene, inhibitor broadcast, tretinoin, trace roridin, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostin inhibitors UBC, ubenimex, inhibiting the growth of urogenital factor obtained from sine, antagonists of the receptor for urokinase, vapreotide, variolin In, valarezo, vermin, Verdins, verteporfin, vinorelbine, Wincanton, vitaxin, vorozole, thanateros, triplatin, salaskar and stimulator of zinostatin.

Private second active agents include, but without limitation, 2-methoxyestradiol, teamstation, substances that cause apoptosis in multiple myeloma cells (such as, for example, TRAIL), statins, semaxanib, cyclosporin, etanercept, doxycycline, bortezomib, oblimersen (Genasense®), Remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, Tykerb® (lapatinib), methotrexate, Arisa®, Taxol, Taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, pamidronate, biaxin, busulfan, prednisone, a bisphosphonate, arsenic trioxide, VIOC the truths doxorubicin (Doxil®), ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac and etoposide.

Similarly, examples of private second agent corresponding to the indications for treatment, prevention or management for various diseases, can be found in the following references, which are included in their entirety: U.S. patent No. 6281230 and 5635517, application U.S. No. 10/441649, 10/483213, 10/411656, 10/693794, 10/699154 and 10/981189 and provisional application U.S. No. 60/554923, 60/565172, 60/626975, 60/630599, 60/631870 and 60/533862.

Examples of second active agents that may be used for the treatment, prevention and/or management of pain include, but without limitation, the common therapeutic agents used for the treatment or prevention of pain, such as antidepressants, anticonvulsants, antihypertensive, anxiolytic drugs, blockers, calcium channel, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatory agents, inhibitors SOH-2, immunomodulating agents, agonists or antagonists, alpha-adrenergic receptor, immunosuppressants, corticosteroids, hyperbaric oxygen, ketamine, other anesthetic agents, NMDA antagonists, and other therapeutic agents, who, for example, can be found inPhysician''s Desk Reference2003. Specific examples include, but without limitation is to be placed, acetate salicylic acid (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, habitantes (Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®), valpovo acid (Depakene®), morphine sulfate, hydromorphone, prednisone, griseofulvin, pentony, alendronate, difengidramin, guanethidine, Ketorolac (Acular®), thyrocalcitonin, dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamerol®), amitriptyline (Elavil®), imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (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 second active agents that may be used for the treatment, prevention and/or management of MD and related syndromes include, but without limitation, a steroid, a light acoustical, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone-derived neurotrophic factor, a regulator of neovascularization, an antibody anti-VEGF, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or antiangiogenic compound, or a combination of both. Private ABT the market include, but without limitation, verteporfin purlytin, angiostatin steroid, rhuFab, interferon-2α, pentoxifylline, adipocere tin, motexafin lutetium, 9-fluoro-11,21-dihydroxy-16,17-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 (see U.S. patent No. 6218369 and 6015803), genistein, genistin, 6'-O-Mal, genistin, 6'-O-AC genistin, daidzein, daidzin, 6'-O-Mal daidzin, 6'-O-AC daidzin, glycitein, glycitin, 6'-O-Mal of glycitin, biochanin And, formononetin (U.S. patent No. 6001368), ndimethylacetamide triamcinolone, dexamethasone (U.S. patent No. 5770589), thalidomide, glutathione (U.S. patent No. 5632984), basic fibroblast growth factor (bFGF), transforming growth factor b (TGF-b), neurotrophic growth factor, derived from the brain (BDNF), an activator factor 2 plasminogen (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and RETISERT implant (Bausch & Lomb). All of the above sources are included in the description in their entirety by reference.

Examples of second active agents that may be used for the treatment, prevention and/or control for skin diseases include, but without limitation, keratolytics, retinoids, α-hydroxy acids, antibiotics, collagen, botulinum toxin, interferon, steroids and immunomodulating agents. Specific examples include, but shall without limitation, 5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lactic acid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics, collagen, botulinum toxin, interferon, interferon, corticosteroids, transretinoic acid and collagen, such as collagen from human placenta, collagen placenta of animals, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast and Isolagen.

Examples of second active agents that may be used for the treatment, prevention and/or management for pulmonary hypertension and related disorders include, but are not limited to, anticoagulants, diuretics, cardiac glycosides, blockers, calcium channel, vasodilators, analogues of prostacyclin, endothelin antagonists, phosphodiesterase inhibitors (e.g., inhibitors of PDE V)inhibitors endopeptidase, agents that reduce the level of lipids, inhibitors of thromboxane and other known therapeutic agents that lower pressure in the pulmonary artery. Specific examples include, but without limitation, warfarin (Coumadin®), a diuretic, cardiac glycoside, digoxin oxygen, diltiazem, nifedipine, a vasodilator, such as prostacyclin (for example, prostaglandin 12 (PG 12), epoprostenol (EPO, Floran®), treprostinil (Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine, prostacyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlv®), irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine, iloprost, beraprost and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment, prevention and/or management for disorders related to asbestos include, but are not limited to, anthracycline, platinum, alkylating agent, oblimersen (Genasense®), this drug called cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, docetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, pamidronate biaxin, busulfan, prednisone, a bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment, prevention and/or control over parasitic diseases include, but are not limited to, 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 (in the example, stillbourne sodium), gamma-interferon, Itraconazole, the combination of the dead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide, spiramycin, IgG (serology), trimethoprim and sulfamethoxazole.

Examples of second active agents that may be used for the treatment, prevention and/or control over immunodeficiency disorders include, but are not limited to, antibiotics (therapeutic or prophylactic), such as, but not limited to, ampicillin, clarithromycin, tetracycline, penicillin, cephalosporins, streptomycin, kanamycin, and erythromycin, antiviral agents, such as, but not limited to, amantadine, rimantadine, acyclovir, and ribavirin, immunoglobulin, plasma, medicines, improving immunology, such as, but without limitation, levamisole and isoprinosine, biological agents, such as but without limitation, gamma-globulin, transfer factor, interleukins, and interferons; hormones such as, but without limitation, thymic and another immunologic agents such as, but without limitation, stimulatory In cells (e.g., BAFF/BlyS), cytokines (such as IL-2, IL-4 and IL-5), growth factors (such as TGF-α), antibodies (e.g., anti-CD40, or IgM), oligonucleotides containing neetilirovannye CpG-motifs and vaccines (e.g.viral or tumor peptide vaccines).

Examples of second active agents to the that can be used to treat, prevention and/or management for disorders of the CNS include, but without limitation, agonist or antagonist of dopamine, such as, but not limited to, levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline, mesilate of pentalpha, cabergoline, pramipexole hydrochloride, ropinerole, amantadine hydrochloride, hydrochloride selegilina, carbidopa, mesilate of pergolid, Sinemet CR and Symmetrel, MAO inhibitor, such as, but without limitation, iproniazid, clorgyline, phenelzine and isocarboxazid, inhibitor of COMT, such as, but without limitation, tolkapon and entacapone, a cholinesterase inhibitor, such as, but without limitation, the salicylate of physostigmine, physostigmine sulfate, physostigmine bromide, the bromide neostigmine, methyl sulfate of neostigmine, chloride amrinone, chloride of hidroponia, taken, pralidoxime, obidoxime, trimedoxime, diacetylenes, andriani, pyridostigmine and demerary, anti-inflammatory agent, such as, but without limitation, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, salt gold, Rho-D immune globulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetilsalic the sludge acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamovaya acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, thiomalate gold-sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone or betamethasone and other glucocorticoids, antiemetic agent, such as, but without limitation, 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, oxipurinol, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, triterpenoid, thioproperazine, tropisetron, and mixtures thereof.

Examples of second active agents that may be used for the treatment, prevention and/or management for CNS damage and related syndromes include, but without limitation, immunomodulating agents, immunosuppressant, antihypertensive agents, protelos aronie means, fibrinolytic agents, agents against plaque formation, antipsychotic agents, antidepressants, benzodiazepines, buspirone, amantadine and other known or conventional agents used in patients with damage to the CNS damage and related syndromes. Specific examples include, but are not limited to, steroids (e.g., glucocorticoids, such as, but without limitation, methylprednisolone, dexamethasone and betamethasone), anti-inflammatory agent, including, but without limitation, 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 mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamico acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, thiomalate gold-sodium, auranofin, methotrexate, colchicine, allopurinol, probesets is d, sulfinpirazon and benzbromarone, an analogue of camp, including, but without limitation, db-cAMP, the agent, including methylphenidate medication that includes l-threo-methylphenidate, d-threo-methylphenidate, dl-threo-methylphenidate, l-Erythro-methylphenidate, d-Erythro-methylphenidate, dl-Erythro-methylphenidate, and mixtures thereof, diuretic agent, such as, but without limitation, mannitol, furosemide, glycerol and urea.

Examples of second active agents that may be used for the treatment, prevention and/or management of sleep disorders and related syndromes include, but without limitation, a tricyclic antidepressant agent, a selective inhibitor of serotonin reuptake, anti-epileptic agent (gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam, topiramate), protivoaritmicheskih the agent, the agent that blocks the sodium channel, selective inhibitor of inflammatory mediator, an opioid agent, a second immunomodulatory compound, combined agent, and other known or conventional agents used in the treatment of sleep. Specific examples include, but without limitation, Neurontin, oxycontin, morphine, topiramate, amitriptyline, nortriptyline, carbamazepine, levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline, mesilate of pentalpha, cabergoline, the dihydrochloride prompex the La, ropinerole, amantadine hydrochloride, hydrochloride selegilina, carbidopa, mesilate of pergolid, Sinemet CR, Symmetrel, iproniazid, clorgyline, phenelzine, isocarboxazid, tolkapon, entacapone, salicylate of physostigmine, physostigmine sulfate, physostigmine bromide, the bromide neostigmine, methyl sulfate of neostigmine, chloride amrinone, chloride of hidroponia, taken, pralidoxime, obidoxime, trimedoxime, 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, Rho-D immune globulin, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamovaya acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, thiomalate gold-sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon, benzbromarone, betametha what he 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, oxipurinol, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, triterpenoid, thioproperazine, tropisetron, and mixtures thereof.

Examples of second active agents that may be used for the treatment, prevention and/or control over hemoglobinopathy and related disorders include, but are not limited to, interleukins, such as IL-2 (including recombinant IL-II("rIL2") andcanarypoxIL-2), IL-10, IL-12 and IL-18; interferons, such as interferon Alfa-2A, interferon alpha-2b, interferon Alfa-n1, interferon Alfa-n3, interferon beta-1A and interferon gamma-1b and G-CSF, hydroxyurea, butyrate or derivatives butyrate, nitric oxide, HEMOXIN™ (NIPRISAN™, see U.S. patent No. 5800819), antagonists channel Gardos, such as clotrimazole and derivatives triarylmethane, Deferoxamine, a protein and a blood transfusion or blood products, such as Hemospan™ or Hemospan PS™ (Sangart).

Introduction to a patient compounds according to this invention, its pharmaceutically acceptable salt, MES, stereoisomer, and prodrug and the WTO is s active agents can be carried out simultaneously or sequentially in the same or different routes of administration. The suitability of the used specific route of administration for private active agent will depend on the active agent (e.g., whether it can be administered orally without decomposition before we get into the bloodstream) and the disease to be treated. The preferred route of administration of the second active agents or ingredients of the invention known to the average person skilled in the art. See, for example,Physician''s Desk Reference, 1755-1760 (56thed., 2002).

In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously, once or twice a day, in the amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, from about 50 to about 200 mg. of a Specific amount of the second active agent will depend on a private agent, the type of disease to be treated or control, severity and stage of the disease, the quantities of the compounds of the invention and any additional active agents choose simultaneously injected to the patient.

As discussed in any part of the description, the invention encompasses a method of reducing, eliminating and/or preventing adverse and unwanted effects associated with conventional treatment, including, but without limitation, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. Compounds according to the invention and other active ingredients can be administered to the patient before, during or after the manifestation of side effects associated with conventional treatment.

4.4 Cyclic therapy

In some embodiments, prophylactic or therapeutic agents according to the invention is administered to a patient in a loop. Cyclic therapy involves the introduction of the active agent over a period of time followed by a rest period, 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.

Further, in a particular embodiment of the invention the compound according to the invention is administered daily in a single dose or divided doses in a cycle of four to six weeks with a rest period of from about one week to two weeks. The invention further allows to increase the frequency, number and duration of dosing cycles. Thus, other private embodiment of the invention encompasses the introduction of the compounds according to the invention in greater than normal, the number of cycles when it is entered separately. In a particular embodiment of the invention the compound according to the invention is administered in a greater number of cycles than usual causing toxicity, ogran the sustained dose, the patient to which the second active ingredient is introduced.

In one embodiment the compound of the invention administered daily and continuously for three or four weeks at a dosage from about 0.1 mg to about 500 mg per day followed by a break in one or two weeks. In other embodiments, the dosage 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, from about 1 mg to about 20 mg followed by a break.

In one embodiment of the invention the compound according to the invention and a second active ingredient is administered orally with the introduction of the compounds according to the invention for 30-60 minutes until the second active ingredient in the cycle from four to six weeks. In another embodiment of the invention the combination of the compounds according to the invention and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycle.

Typically, the number of cycles during which the patient receives the combined treatment, will be from about one to about 24 cycles, more typically from about two to about 16 cycles, and even more typically from about four to about three cycles.

4.5 Pharmaceutical compositions and dosage forms

The pharmaceutical compositions can be used to obtain a discrete unit dosage forms. Pharmaceutical compositions and dosage forms of the invention contain a compound of the invention or its pharmaceutically acceptable salt, MES, stereoisomer, and prodrug. Pharmaceutical compositions and dosage forms of the invention may further contain one excipient or more.

Pharmaceutical compositions and dosage forms of the invention may also contain one or more additional active ingredients. Examples of optional or additional active ingredients listed above in section 4.3.

Edinennye dosage forms according to the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g. subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial), local (e.g., eye drops or other ophthalmic preparations), transdermal or percutaneous introduction into the patient. Examples of dosage forms include, but without limitation, tablets, oblong tablets, capsules, such as soft elastic gelatin capsules, sachets, tablets, lozenges, dispersion, suppositories, powders, aerosols (e.g., nasal DSS and or inhalers), gels; liquid dosage forms suitable for oral or mucosal injection to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, emulsions oil-in-water or a liquid emulsion of 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 application, and sterile solids (e.g., crystalline or amorphous solids)that can be recovered liquid dosage forms suitable for parenteral administration to a patient.

The composition, appearance, and type of dosage forms of the invention typically will depend on their application. For example, dosage forms used to treat acute forms of the disease, can contain large quantities of one or more active ingredients than contains a dosage form used to treat chronic forms of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more active ingredients than contains oral dosage form used to treat the same disease. This and other aspects, in which private dosage forms covered by the invention, differ from each other, with clarity, Acevi who are specialist in this field. See, for example,Remington's Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are well known to the expert in the field of pharmacy, as non-limiting examples of suitable excipients are listed in the description. The suitability of a particular excipient for inclusion in a pharmaceutical composition or dosage form depends on a number of factors well known in this field, including, but without limitation, the way in which dosage form will enter the patient. For example, oral dosage forms such as tablets may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on individual active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by certain excipients, such as lactose, or if they are subjected to water. The active ingredients, which contain primary or secondary amines, are particularly susceptible to such accelerated decomposition. Therefore, this invention encompasses pharmaceutical compositions and dosage forms that contain little lactose or other mono - or disaccharides, if any, to wdtout. Used herein, the expression "does not contain lactose" means that the amount of lactose, if it is present, it is not enough to significantly increase the speed of razrusheniya active ingredient.

Does not contain lactose compositions according to the invention may include excipients that are well known in this area and are listed, for example, inU.S. Pharmacopeia(USP) 25-NF20 (2002). In General, do not contain lactose compositions include the active ingredients, a binder/filler, and a lubricating substance in pharmaceutically compatible and pharmaceutically acceptable amounts. The preferred does not contain lactose dosage forms include active ingredients, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

The invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the destruction of some compounds. For example, the addition of water (for example, 5%) is widely acceptable in the pharmaceutical field as a means of simulating long-term storage to determine characteristics such as shelf life or stability of the drug over time. See, for example, Jens T. Carstensen,Drug Stability: Principles & Practice, 2ndEd., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat is the W accelerate the degradation of some compounds. Thus, the effect of water on the drug can be of great importance, because with moisture and/or humidity are often faced during production, processing, packaging, storage, transportation and use of drugs.

Anhydrous pharmaceutical compositions and dosage forms according to the invention can be obtained using anhydrous or containing little moisture ingredients in small presence of moisture or low humidity. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient which contains a primary or secondary amine, preferably is anhydrous, assuming significant contact with moisture and/or humidity during manufacturing, packaging and/or storage.

Anhydrous pharmaceutical compositions should be prepared and stored in such a way so as to maintain the anhydrous nature. Accordingly, anhydrous compositions are preferably packaged using materials known as protects from the action of water, so that they could be included in the appropriate sets. Examples of suitable packaging include, but without limitation, hermetically sealed foils, plastics, containers containing the unit doses (e.g., ampoule), blister packaging and in bands.

The invention further chemicals which encompasses pharmaceutical compositions and dosage forms, which contain one or more compounds, which reduces the degree of decomposition of the active ingredient. Such compounds, which in the description referred to as "stabilizers"include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the number and specific types of active ingredients in dosage forms may vary depending on such factors as, but without limitation, the way in which they should be administered to the patient. However, typical dosage forms of the invention contain a compound of the invention in an amount of from about 0.10 to about 500 mg Typical dosage forms of the invention contain a compound of the invention in an amount of about 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

Typical dosage forms contain a second active ingredient in an amount of from 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, from about 50 to about 200 mg. of Course, the specific amount of the second active agent will depend on the specific agent used, the type being treated or control over cancer, the amounts of(a) the compounds according to the invention and any optional active agents, parallel input patient.

4.5.1 Oral dozorova the forms

The pharmaceutical compositions according to the invention suitable for oral administration may be presented as discrete dosage forms, such as, but without limitation, tablets (e.g., lozenges), oblong tablets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined quantity of active ingredients and can be prepared in pharmaceutical methods, well known to the person skilled in the art. See, in General,Remington's Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA (1990).

Typical oral dosage forms according to the invention receive by combining the active ingredients in the original mixture with at least one excipient in accordance with conventional pharmaceutical methods of preparation. Excipients can have a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but without limitation, water, glycols, oils, alcohols, flavoring, preservatives and dyes. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules and oblong tablets)include, but are without the ograniczenia, starches, sugars, microcrystalline cellulose, diluents, for granulating agents, lubricants, binders and dezintegriruetsja agents.

Due to their easy introduction of tablets and capsules represent the most advantageous oral form containing a unit dose, in their case, use solid excipients. If desired, tablets may be coated using standard aqueous or nonaqueous techniques. Such dosage forms can be obtained by any of the methods of pharmacy. In General, pharmaceutical compositions and dosage forms will receive a uniform and thorough mixing of the active ingredients with liquid carriers, finely ground solid carriers or both, and then shaping the product into desired look, if you want.

For example, tablets can be obtained by pressing or molding. Molded tablets can be obtained by compressing in a suitable machine the active ingredient in a free flowing form such as powder or granules, optionally mixed with excipients. Molded tablets can be obtained by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of excipients that can be used in the dosage forms according to the invention, include, but without limitation, the binder is, fillers, disintegrant and grease. Binders suitable for use in pharmaceutical compositions and dosage forms include, but without limitation, corn starch, potato starch, other starches, gelatin, natural and synthetic resins, such as gum, sodium alginate, alginic acid, other alginates, powdered tragant, guar gum, cellulose and its derivatives (for example, ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hypromellose (e.g., №№ 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. Private binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or containing little moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.

Examples of fillers suitable for use in pharmaceutical compositions and dosage forms disclosed in the description, include, but are not limited to, talc, calcium carbonate (e.g. the measures granules or powder), microcrystalline cellulose, powdered cellulose, dextrine, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. Binder or filler in pharmaceutical compositions according to the invention are usually present in an amount of from about 50 to about 99 weight percent by weight of the pharmaceutical composition or dosage form.

Disintegrant used in the compositions of the invention to obtain tablets, which collapse under the influence of the aquatic environment. Tablets that contain too much disintegrant, may deteriorate during storage, while containing too little may not be destroyed with the desired speed in the desired conditions. Thus, for solid oral dosage forms according to the invention, use enough disintegrant, which is not too big, not too small to cause damage by changing the release of the active ingredients. The amount of disintegrant varies based on the type of drug, and can easily be determined by an ordinary specialist in the field. Typical pharmaceutical compositions include from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 deprimere 5 mass percent of disintegrant.

Disintegrant, which can be used in pharmaceutical compositions and dosage forms according to the invention, include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium crosscarmellose, crosspovidone, potassium polacrilin, sodium starch glycolate, starch from potato and tapioca starches, other starches, pregelatinized starch, clay, other algini, other cellulose resins, and mixtures thereof.

Lubricant, which can be used in pharmaceutical compositions and dosage forms according to the invention, include, but without limitation, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulphate, talc, gidrirovannoe vegetable oil (e.g. oil groundnut oil from cotton seeds, sunflower oil, sesame oil, olive oil, corn oil and oil from soybeans), zinc stearate, etiloleat, tillaart, agar and mixtures thereof. Additional lubricants include, for example, selody silica gel (AEROSIL200, produced by W. R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. E. what if any are used, lubricants are used in amounts of less than about 1 weight percent of the pharmaceutical compositions or dosage forms in which they are administered.

Solid oral dosage form according to the invention include the compound of the invention, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

4.5.2 Dosage forms with controlled release

The active ingredients of the invention can be introduced by means of controlled-release or devices for delivery, which are well known to the ordinary person skilled in the art. Examples include, but without limitation, described in U.S. patent No. 3845770, 3916899, 3536809, and 3598123 4008719, 5674533, 5059595, 5591767, 5120548, 5073543, 5639473, 5354556 and 5733566, each of which is included in the description by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hypromellose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to obtain the desired release profile in varying proportions. Suitable drugs with controlled what Svobodnye, known specialist in this area, including those disclosed in the description, can be readily selected for use with the active ingredients according to the invention. The invention thus encompasses a unit dosage forms suitable for oral administration such as, but without limitation, tablets, capsules, gelatin capsules and oblong tablets, which are adapted for controlled release.

All pharmaceutical products with controlled release have a common goal of improving drug therapy compared to attainable their competitors with uncontrolled release. Ideally, the use of optimally designed drug controlled release in medical treatment is characterized by the minimum of the drug substance used for the treatment or management for the state in minimum time. Advantages of the compositions of controlled release include improved activity of the drug, reduced frequency of administration and increased compatibility of the patient. In addition, the composition of controlled release can be used to affect the start time of the action or other characteristics, such as the level of medication in the blood, and thus, can affect the appearance (e.g., undesirable) side effects.

p> Most of the drugs controlled release developed for the initial release amount of the drug (active ingredient), which immediately produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body the drug must be released from the dosage form at a rate that shall reimburse the amount of the drug is metabolized and removed from the body. Controlled release of the active ingredient can be stimulated by various conditions, including, but without limitation, pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.5.3 Parenteral dosage forms

Parenteral dosage forms can be administered to the patients in various ways, including, but without limitation, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since their introduction usually bypasses the natural protection of the patient from foreign substances, parenteral dosage forms are preferably sterile or suitable for sterilization PE the ed by the introduction of the patient. Examples of parenteral dosage forms include, but without limitation, ready-made solutions for injection, dry products, ready for dissolution or suspension in a pharmaceutically acceptable carrier for injection, prepared suspension for injection and emulsions.

Suitable carrier materials that can be used for parenteral dosage forms according to the invention, are well known to the person skilled in the art. Examples include, but without limitation, water for injection according to the USP, water media, such as, but not limited to, sodium chloride injection, ringer's solution for injection, dextrose injection, dextrose and sodium chloride injection, ringer's solution with lactate for injection, miscible with water media, such as, but without limitation, ethyl alcohol, polyethylene glycol and polypropylenglycol, and non-aqueous media such as, but without limitation, corn oil, cotton seed oil groundnut, sesame oil, etiloleat, and isopropylmyristate the benzyl benzoate.

Compounds that increase the solubility of one or more active ingredients disclosed in the description may also be entered in parenteral dosage forms according to the invention. For example, cyclodextrin and its derivatives can be used to improve dissolve the spine of immunomodulatory compounds of the invention and its derivatives. See, for example, U.S. patent No. 5134127, which is included in the description by reference.

4.5.4 Dosage forms for local use and for mucous membranes

Dosage forms for local use and for mucous membranes according to the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops and other eye drugs or other forms known to the person skilled in the art. See, for example,Remington's Pharmaceutical Sciences, 16thand 18thed., Mack Publishing, Easton PA (1980 &1990) andIntroduction to Pharmaceutical Dosage Forms, 4thed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for the treatment of mucosal tissues in the mouth, can be obtained as a liquid for rinsing the mouth or oral gels.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to produce dosage forms for local use and for mucous membranes covered by this invention, well-known specialist in the field of pharmaceutics 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 without limitation, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropylmyristate, from repellet, mineral oil and mixtures thereof to form solutions, emulsions or gels that are non-toxic and pharmaceutically acceptable. If desired, the wetting or humectants can also be added to pharmaceutical compositions, and dosage forms. Examples of such optional ingredients are well known in this field. See, for example,Remington's Pharmaceutical Sciences, 16thand 18thed., 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 ingredients. Similarly, the polarity of the solvent carrier, its ionic strength or toychest can be adjusted to improve delivery. Compounds such as stearates, can be added to the pharmaceutical compositions or dosage forms to favorably change the hydrophilicity and lipophilicity of one or more ingredients, thus, to improve delivery. In this respect, the stearates can serve as a lipid carrier for drugs, as emulsifying agent or surfactant, and as an agent that improves the delivery or enhance penetration. Different salt, hydrate or solvate of the active ingredients can be used to further control the properties of the obtained composition.

4.6 Sets

In one waples the research Institute of the active ingredients of the invention are preferably not administered to the patient simultaneously or one and the same route of administration. Therefore, this invention encompasses kits that are using the practicing physician can simplify administration to the patient of appropriate amounts of active ingredients.

Set according to the invention includes a dosage form of the compounds of the invention. Sets covered by the invention, further may include additional active ingredients such as oblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, Taxotere, IFN, inhibitor SOH-2, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-CIS-retinova acid or a pharmacologically active mutant or derivative, or combinations thereof. Examples of additional active ingredients include, but without limitation, disclosed in the description (see, for example, section 4.3).

Kits according to the invention further may include devices that are used for the introduction of active ingredients. Examples of such devices include, but are not limited to, syringes, tanks droppers, patches and inhalers.

Kits according to the invention further may include cells or blood for transplantation, as well as pharmaceutically acceptable carriers that may be used for introducing one or more active ingredients. For example, if the active ingredient is presented in solid form, to ora must be reconstituted for parenteral administration, the kit may contain a sealed container with a suitable carrier in which the active ingredient can be dissolved with the formation of not containing solid particles of a sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but without limitation, water for injection according to the USP, water media, such as, but not limited to, sodium chloride injection, ringer's solution for injection, dextrose injection, dextrose and sodium chloride injection, ringer's solution with lactate for injection, miscible with water media, such as, but without limitation, ethyl alcohol, polyethylene glycol and polypropylenglycol, and non-aqueous media such as, but without limitation, corn oil, cotton seed oil groundnut, sesame oil, etiloleat isopropylmyristate and benzyl benzoate.

5. Examples

Some embodiments of the invention are illustrated by the following non-limiting examples.

5.1 5-{[(Benzofuran-2-ylmethyl)-amino]-methyl}-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione

To a mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol) in CH2Cl2(20 ml) add diisopropylethylamine (of 0.52 ml, 3.0 mmol), 2-benzofurazanyl (of 0.36 ml, 3.0 IMO the b) and glacial acetic acid (0.17 ml, 3.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. Add triacetoxyborohydride sodium (1.27 g, 6.0 mmol) and the mixture is left overnight under stirring at room temperature. Add water (20 ml)to quench the reaction and the mixture extracted with CH2Cl2(2×50 ml). The organic layer was washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml) and dried (MgSO4), and evaporated in vacuum. The remainder chromatographic using a gradient of ethyl acetate : hexane, elwira of 0.38 g of the product at the ratio of ethyl acetate : hexane 83:17 to 30%yield. So pl. 133-135º, Waters Xterra RP18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of HCO2(NH4), 5,11 min (98,22%);1H NMR (DMSO-d6) δ 2,04 is 2.10 (m, 1H), 2,50 2.63 in (m, 2H), 2,84-2,96 (m, 1H), 3,20 (user, 1H), 3,85 (s, 2H), 3,94 (s, 2H), 5,14 (DD, J=12,6 Hz, 5.1 Hz, 1H), 6.73 x (s, 1H), 7,17-7,27 (m, 2H), of 7.48-7,58 (m, 2H), to 7.84 (t, J=7.8 Hz, 2H,), to 7.93 (s, 1H), 11,12 (s, 1H);

13C NMR (DMSO-d6) δ 22,0, 30,9, 45,0, 48,9, 51,5, 103,6, 110,8, 120,7, 122,6, 123,2, 123,6, 128,2, 129,6, 131,4, 134,1, 148,8, 154,1, 157,3, 167,1, 167,2, 169,8, 172,7.

Analysis: Calculated for C23H19N3O5: C, 66,18; H, 4,59; N, 10,07. Found: C, 66,02; H, 4,27; N, 9,94.

5.2 5-Benzylamino-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione

Stage 1: a Mixture of dimethyl-4-nitrophthalic (15.0 g, 62,7 mmol) and 10% Pd-C (1.5 g) in ethyl acetate (100 ml), left overnight to hydrogenation at 50 psi. The reaction mixture is filtered is via celite, and the filter is additionally washed with ethyl acetate (50 ml). The solvent is evaporated and the residue is stirred in hexano. Filtered the solid phase, optionally washed with hexane and dried, obtaining 12,77 g of dimethyl 4-amino-phthalic acid as a pale orange solid with a yield of 97%.1H NMR (DMSO-d6) δ 3,71 (s, 3H), of 3.75 (s, 3H), 6,17 (s, 2H), 6,58-of 6.65 (m, 2H), EUR 7.57 (d, J=8,4 Hz, 1H).

Stage 2: a Mixture of dimethyl 4-amino-phthalic acid (0.84 g, 4.0 mmol), benzaldehyde (0,81 ml, 8.0 mmol) and acetic acid (1,37 ml of 24.0 mmol) in CH2Cl2(40 ml) was stirred at room temperature for 10 minutes. Add triacetoxyborohydride sodium (2,54 g, 12,0 mmol) and the mixture is left overnight under stirring. The reaction mixture was diluted with CH2Cl2(20 ml), washed with water (2×100 ml), saturated sodium bicarbonate solution (1×100 ml) and saturated salt solution (1×100 ml) and dried (MgSO4), and evaporated in vacuum. The oil obtained chromatographic using a gradient of ethyl acetate : hexane, elwira product with a ratio of ethyl acetate : hexane 20:80, 1.1 g of dimethyl ester of 4-benzylamino-phthalic acid with a yield of 93%.1H NMR (DMSO-d6) δ 3,70 (s, 3H), 3,74 (s, 3H), 4,36 (d, J=6.0 Hz, 2H), 6,57-6,69 (m, 2H), 7,22-7,39 (m, 6H), 7,60 (d, J=8,4 Hz, 1H).

Stage 3: a Mixture of dimethyl 4-benzylamino-phthalic acid (1,11 g, 3,71 mmol) and 3n sodium hydroxide (50 is l) in ethanol (100 ml) is refluxed for one hour. The reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is dissolved in water (100 ml), washed with CH2Cl2(2×100 ml) and acidified (HCl), the resulting mixture was extracted with ethyl acetate (2×100 ml). The combined organic extracts washed with water (2×100 ml) and dried (MgSO4), and evaporated in vacuum. The obtained solid was stirred in ether for 2 hours. The solid is filtered off and dried, obtaining 0.50 g 4-benzylamino-phthalic acid with a yield of 74%.1H NMR (DMSO-d6) δ of 4.35 (d, J=5.7 Hz, 2H), 6,59-6,62 (m, 2H), 7,10-7,34 (m, 6H), 7,54-EUR 7.57 (m, 1H), 12,48 (user, 2H).

Stage 4: a Mixture of 4-benzylamino-phthalic acid (to 0.47 g, 1.7 mmol) and hydrochloriderat-α-aminoglutethimide (0,29 g, 1.7 mmol) in pyridine (10 ml) and left overnight at boiling under reflux. The reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is distributed between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase is extracted with ethyl acetate (100 ml). The combined organic phases are washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), and the solvent is removed in vacuum. The remainder chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl22:98. The thus obtained solid substance is stirred for 30 minutes at JFK and the re and filtered, additionally washed with ether and dried, obtaining of 0.49 g of product as yellow solid with a yield of 78%. So pl. 239-241°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 9,15 (95,32%).1H NMR(DMSO-d6) δ 1,94 is 2.01 (m, 1H), 2,43 at 2.59 (m, 2H), 2,81-of 2.93 (m, 1H), 4,46 (d, J=6.0 Hz, 2H), 5,02 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 6.89 in (DD, J=8,4 Hz, J=1.8 Hz, 1H), of 6.96 (d, J=1.5 Hz, 1H), 7.23 percent-7,33 (m, 1H), 7,35 (d, J=4,2 Hz, 4H), 7,56 (d, J=8,4 Hz, 1H), 7,71 (t, J=5.7 Hz, 1H), 11,06 (s, 1H);13C NMR (DMSO-d6) δ 22,2, 30,9, 45,9, 48,6, 105,7, 115,9, 116,5, 125,0, 127,0, 127,1, 128,5, 134,0, 138,6, 154,2, 167,1, 167,6, 170,1, 172,8. Analysis: Calculated for C20H17N3O4+0,1 h2O: C, 65,78; H, 4.75 V; N, 11,51. Found: C, 65,49; H, 4,71; N: Of 11.45.

5.3 2-(2,6-Dioxo-piperidine-3-yl)-5-[(furan-2-yl-methyl)amino]-isoindole-1,3-dione

Stage 1: a Mixture of dimethyl 4-amino-phthalic acid (0.84 g, 4.0 mmol), 2-furaldehyde (0,66 ml, 8.0 mmol) and acetic acid (1,37 ml of 24.0 mmol) in CH2Cl2(40 ml) is stirred for 10 minutes at room temperature. Add triacetoxyborohydride sodium (2,54 g, 12,0 mmol) and the mixture is left overnight under stirring. The reaction mixture was diluted with CH2Cl2(20 ml), washed with water (2×100 ml), saturated sodium bicarbonate solution (100 ml) and saturated salt solution (100 ml) and dried (MgSO4), and evaporated in vacuum. The oil obtained chromatographic using a gradient of ethyl acetate : g is Xana, elwira product with a ratio of ethyl acetate : hexane 40:60, 1,11 g of dimethyl 4-[(furan-2-ylmethyl)amino]-phthalic acid with a yield of 96%.1H NMR (DMSO-d6) δ 3,71 (s, 3H), 3,76 (s, 3H), 4,34 (d, J=5.7 Hz, 2H), 6,27-6,40 (m, 2H), 6,62-of 6.78 (m, 2H), 7,18 (t, J=5.7 Hz, 1H), to 7.59-to 7.64 (m, 2H).

Stage 2: a Mixture of dimethyl 4-[(furan-2-ylmethyl)amino]-phthalic acid (1,11 g of 3.84 mmol) and 3n sodium hydroxide (50 ml) in ethanol (100 ml) is refluxed for one hour. The reaction mixture is cooled to room temperature, and the solvent is removed in vacuum. The residue is dissolved in water (100 ml), washed with CH2Cl2(2×100 ml) and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2×100 ml)and the organic phase washed with water (2×100 ml) and dried (MgSO4), and evaporated. The obtained solid was stirred in ether for 2 hours. The solid is filtered off and dried, obtaining of 0.44 g of 4-[(furan-2-ylmethyl)amino]-phthalic acid with a yield of 44%.1H NMR (DMSO-d6) δ 4,33 (d, J=5,1 Hz, 2H), of 6.31 (d, J=3.0 Hz, 1H), to 6.39 (DD, J=3.0 Hz, 1.8 Hz, 1H), 6,65-of 6.71 (m, 2H), 7,00 (t, J=5.7 Hz, 1H), EUR 7.57-of 7.60 (m, 2H), 12,51 (user, 2H).

Stage 3: a Mixture of 4-[(furan-2-ylmethyl)amino]-phthalic acid (of 0.43 g, 1.7 mmol) and hydrochloriderat-α-aminoglutethimide (0.27 g, 1.7 mmol) in pyridine (10 ml) and left overnight at boiling under reflux. The reaction mixture is cooled to room temperature, and the solvent is removed in in the cosmology vacuum. The residue is distributed between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase is extracted with ethyl acetate (100 ml). The combined organic phases are washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), and the solvent is removed in vacuum. The remainder chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl24:96. The obtained solid is left overnight under stirring in the air. The solid is filtered, optionally washed with ether and dried. Purified preparative HPLC using isocratic elution with a mixture of acetonitrile-water, elwira product with a ratio of acetonitrile-water 45:55 and getting 0.24 g of the product as a yellow solid with a yield of 41%. So pl. 143-145°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 4,96 (96,16%).1H NMR(DMSO-d6) δ 1,96-2,03 (m, 1H), 2,44-2,60 (m, 2H), 2,82-to 2.94 (m, 1H), of 4.44 (d, J=5.7 Hz, 2H), to 5.03 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 6,35-6.42 per (m, 2H), 6,94-7,07 (m, 2H), 7,53-to 7.61 (m, 3H), 11,06 (s, 1H);13C NMR (DMSO-d6) δ 22,2, 30,9, 39,3, 48,6, 105,7, 107,5, 110,4, 116,0, 116,8, 124,9, 134,0, 142,5, 151,8, 154,0, 167,1, 167,6, 170,1, 172,8. Analysis: Calculated for C18H15N3O5+0,1 h2O: C, 60,88; H, OR 4.31; N, 11,83. Found: C, 60,58; H, A 3.87; N: 11,59.

5.4 5-(3-Chloro-benzylamino)-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione

Stage 1: a Mixture of DIMET the gross ester 4-amino-phthalic acid (0.84 g, 4.0 mmol), 3-chloro-benzaldehyde (of 0.91 ml, 8.0 mmol) and acetic acid (1,37 ml of 24.0 mmol) in CH2Cl2(40 ml) is stirred for 10 minutes at room temperature. Add triacetoxyborohydride sodium (2,54 g, 12,0 mmol) and the mixture is left overnight under stirring. The reaction mass was diluted with CH2Cl2(20 ml), washed with water (2×100 ml), saturated sodium bicarbonate solution (100 ml) and saturated salt solution (100 ml) and dried (MgSO4), and evaporated. The oil obtained chromatographic using a gradient of ethyl acetate : hexane, elwira product with a ratio of ethyl acetate : hexane 35:65, 1.10 g of dimethyl ester of 4-(3-chloro-benzylamino)-phthalic acid with a yield of 82%.1H NMR (DMSO-d6) δ 3,71 (s, 3H), of 3.75 (s, 3H), 4,39 (d, J=6.0 Hz, 2H), 6,66-6,70 (m, 2H), 7,28-7,39 (m, 5H), to 7.61 (d, J=9.0 Hz, 1H).

Stage 2: a Mixture of dimethyl 4-(3-chloro-benzylamino)-phthalic acid (1.10 g, 3,30 mmol) and 3n sodium hydroxide (50 ml) in ethanol (100 ml) is refluxed for one hour. The reaction mixture is cooled to room temperature, and the solvent is removed in vacuum. The residue is dissolved in water (100 ml), washed with CH2Cl2(2×100 ml) and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2×100 ml)and the organic phase washed with water (2×100 ml), dried (MgSO4) and evaporated, receiving of 1.00 g of 4-(3-chloro-benzylamino)-phthalic acid with a yield of 99%.1H NMR (who MCO-d 6) δ 4,37 (d, J=5.7 Hz, 2H), 6,59-6,62 (m, 2H), 7,18 (t, J=6.0 Hz, 1H), 7,28-7,39 (m, 4H), 7,56-to 7.61 (m, 1H), 12,51 (user, 2H).

Stage 3: a Mixture of 4-(3-chloro-benzylamino)-phthalic acid (0.97 g, 3.2 mmol) and hydrochloriderat-α-aminoglutethimide (0.52 g, 3.2 mmol) in pyridine (20 ml) and left overnight at boiling under reflux. The reaction mixture is cooled to room temperature, and the solvent is removed in vacuum. The residue is distributed between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase is extracted with ethyl acetate (100 ml). The combined organic phases are washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), and the solvent is removed in vacuum. The remainder chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl25:95. The obtained solid is left overnight with stirring in methanol (5 ml). The solid is filtered, optionally washed with methanol and dried, obtaining 0.96 g of product as a yellow solid with a yield of 76%. So pl. 250-252°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 6,46 (99,41%).1H NMR (DMSO-d6) δ 1,95-2,03 (m, 1H), 2,42 at 2.59 (m, 2H), 2,81-of 2.93 (m, 1H), 4,49 (d, J=6.0 Hz, 2H), 5,02 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 6,88-6,98 (m, 2H), 7,30-7,42 (m, 4H), 7,58 (d, J=8,4 Hz, 1H), 7,72 (t, J=6.0 Hz, 1H), 11,06 (s, 1H);13C NMR (DMSO-d6) δ 22,1, 30,9, 45,2, 48,6, 105,7, 116,0, 116,8, 125,1, 125,7, 126,9, 127,0, 130,, 133,2, 134,1, 141,5, 154,0, 167,0, 167,5, 170,1, 172,8. Analysis: Calculated for C20H16N3O4Cl+0,15H2O: C, 59,98; H, 4,10; N, 10,49. Found: C, 59,61; H, A-3.84; N, 10,36.

5.5 5-[(Benzofuran-2-ylmethyl)-amino]-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione

Stage 1: a Mixture of dimethyl 4-amino-phthalic acid (0.84 g, 4.0 mmol), 2-benzotrichloride (0,83 ml, 8.0 mmol) and acetic acid (1,37 ml of 24.0 mmol) in CH2Cl2(40 ml) is stirred for 10 minutes at room temperature. Add triacetoxyborohydride sodium (2,54 g, 12,0 mmol) and the mixture is left overnight under stirring. The reaction mass was diluted with CH2Cl2(20 ml), washed with water (2×100 ml), saturated sodium bicarbonate solution (100 ml) and saturated salt solution (100 ml) and dried (MgSO4), and evaporated. The oil obtained chromatographic using a gradient of ethyl acetate : hexane, elwira product with a ratio of ethyl acetate : hexane 25:75, 0,89 g of dimethyl 4-[(benzofuran-2-ylmethyl)-amino]-phthalic acid with a yield of 65%.1H NMR (DMSO-d6) δ 3,71 (s, 3H), 3,76 (s, 3H), 4,56 (d, J=5.7 Hz, 2H), 6,76-6,83 (m, 3H), 7,20-7,29 (m, 2H), 7,35 (t, J=6.0 Hz, 1H), 7,51-the 7.65 (m, 3H).

Stage 2: a Mixture of dimethyl 4-[(benzofuran-2-ylmethyl)-amino]-phthalic acid (0,89 g, 3,30 mmol) and 3n sodium hydroxide (50 ml) in ethanol (100 ml) is refluxed for one hour. The reaction mixture Oh adut to room temperature, and the solvent is removed in vacuum. The residue is dissolved in water (100 ml), washed with CH2Cl2(2×100 ml) and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2×100 ml)and the combined organic layers washed with water (2×100 ml), dried (MgSO4) and evaporated, getting to 0.80 g of 4-[(benzofuran-2-ylmethyl)-amino]-phthalic acid with a yield of 98%.1H NMR (DMSO-d6) δ of 4.54 (d, J=4.5 Hz, 2H), of 6.71-6,77 (m, 3H), 7.18 in-7,29 (m, 3H), 7,51-to 7.61 (m, 3H), to 12.52 (user, 2H).

Stage 3: a Mixture of 4-[(benzofuran-2-ylmethyl)-amino]-phthalic acid (0,80 g, 2.6 mmol) and hydrochloriderat-α-aminoglutethimide (0,42 g, 2.6 mmol) in pyridine (20 ml) and left overnight at boiling under reflux. The reaction mixture is cooled to room temperature, and the solvent is removed in vacuum. The residue is distributed between ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The aqueous phase is extracted with ethyl acetate (100 ml). The combined organic phases are washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), and the solvent is removed in vacuum. The remainder chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl25:95. The appropriate fractions are collected and processed coal for discoloration (1.5 g), filtered through celite and evaporated, receiving of 0.68 g of the product as yellow solid with a yield of 66%. So pl. 259-261°C. HPLC, Water Symmetry C-18, of 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 5,14 (a 99.16%).1H NMR (DMSO-d6) δ 1,95 for 2.01 (m, 1H), 2,43-2,60 (m, 2H), 2,81-of 2.93 (m, 1H), 4,66 (d, J=6.0 Hz, 2H), to 5.03 (DD, J=12.9 Hz, J=5.4 Hz, 1H), for 6.81 (s, 1H), 7,01 (DD, J=8,4 Hz, J=2.1 Hz, 1H), 7,12 (d, J=1.8 Hz, 1H), 7.18 in-7,29 (m, 2H), 7,52-to 7.61 (m, 3H), 7,72 (t, J=5.7 Hz, 1H), 11,06 (s, 1H);13C NMR (DMSO-d6) δ 22,2, 30,9, 48,6, 104,0, 105,8, 110,9, 116,1, 117,1, 120,9, 122,8, 124,0, 125,0, 127,9, 134,0, 153,9, 154,2, 155,1, 167,1, 167,5, 170,1, 172,8. Analysis: Calculated for C22H17N3O5+0,1 h2O: C, 65,21; H, TO 4.28; N, 10,37. Found: C, 65,07; H, The 4.29; N, 10,32.

5.6 2-(4-Chloro-phenyl)-N-[2-(2,6-dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-ndimethylacetamide

A mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-dione (0.40 g, 1,29 mmol), 4-chlorophenylacetyl (0,19 ml, 1,29 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 2 days. Add an additional 4-chlorophenylacetyl (0.04 ml) and the reaction mixture is stirred for 2 hours. The solid is filtered off, washed with additional acetonitrile and water, receiving of 0.13 g of product with a yield of 24%. So pl. 264-266°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 3,23 (98,97%).1H NMR (DMSO-d6) δ 1,96-2,03 (m, 1H), 2,32 is 2.46 (m, 1H), 2,53-2,63 (m, 1H), 2,86 are 2.98 (m, 1H), 3,51 (s, 2H), 4,25 is 4.45 (m, 4H), 5,1 1 (DD, J=13,2 Hz, J=5,1 Hz, 1H), 7,29-7,42 (m, 6H), to 7.67 (d, J=7.8 Hz, 1H),8,67 (t, J=6.0 Hz, 1H), 10,99 (s, 1H);13C NMR (DMSO-d6) δ 22,5, 31,2, 41,5, 42,2, 47,1, 51,6, 122,0, 122,9, 127,0, 128,1, 130,4, 130,9, 131,1, 135,3, 142,3, 143,7, 167,9, 169,9, 171,0, 172,9. Analysis: Calculated for C22H20N3O4Cl+0,2H2O: C, 61,53; H, 4,79; N, 9,78. Found: C, 61,52; H, Of 4.44; N, 9,40.

5.7 N-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-cryptomaterial

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol), 4-cryptomaterial (0,70 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol) in DMF (20 ml) is stirred under nitrogen atmosphere at room temperature for 1 hour. The mixture is distributed between ethyl acetate (75 ml) and water (75 ml)and the aqueous phase extracted with ethyl acetate (75 ml). The combined organic layers washed with water (3×100 ml) and evaporated. The remainder chromatographic in ethyl acetate, obtaining 1.1 g of product with a yield of 75%. So pl. 200-202°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 4,85 (97,90%).1H NMR (DMSO-d6) δ 2,02 is 2.10 (m, 1H), 2,46-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,66 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), of 7.48-7,51 (m, 2H), 7,81-to $ 7.91 (m, 3H), 8,02-with 8.05 (m, 2H), 9,34 (t, J=6.0 Hz, 1H), 11,13 (, 1H);13C NMR (DMSO-d6) δ
22,0, 30,9, 42,7, 48,9, 119,9 (kV, J=255), 120,7, 122,0, 123,5, 129,6, 129,8, 131,6, 133,0, 133,4, 147,3, 150,4, 165,2, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C22H16F3N3O6: C, 55,58; H, 3,39; N, 8,84. N is Geno: C, 55,38; H, 3,18; N, 8,69.

5.8 N-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-methyl-benzamide

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-(trifluoromethyl)-benzoyl chloride (0.45 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue is dissolved in ethyl acetate (100 ml). The organic phase is washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The remainder chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl25:95. The obtained solid is left overnight under stirring in ether, filtered and dried, obtaining 0.66 g of product with a yield of 48%. So pl. 168-170°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 8,49 (95,33%).1H NMR (DMSO-d6) δ 2,02-of 2.09 (m, 1H), 2,46-2,63 (m, 2H), 2,84-2,96 (m, 1H), and 4.68 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 7,71-to 8.12 (m, 7H), 9,46 (t, J=6.0 Hz, 1H), 11,13 (s, 1H);13C NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 122,0, 123,6, 123,9 (kV, J=270,8 Hz), and 125.4 (q, J=3.75 Hz), 128,2, 129, 9mm, 131,3 (kV, J=31,5 Hz), 131,6, 133,5, 137,7, 147,2, 165,3, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C22H16N3O5F3: C, 57,52; H, 3,51 ; N, 9,15. Found: C, 5,27; H, AT 3.35; N, 9,00.

5.9 [2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-amide thiophene-2-carboxylic acid

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 2-thiophenecarbonitrile (of 0.32 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in CH2Cl2(20 ml) was stirred at room temperature for 2 days. The organic phase is washed with dilute aqueous HCl (2×50 ml) and water (2×50 ml), dried (MgSO4) and evaporated in vacuo. The remainder chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl23:97. The obtained solid was stirred in ethyl acetate for 1 hour, filtered and receive 0,69 g of product with a yield of 58%. So pl. 219-221°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, of 5.84 (95,85%).1H NMR (DMSO-d6) δ 1,99-of 2.09 (m, 1H), 2,46-2,63 (m, 2H), 2,83-2,95 (m, 1H), to 4.62 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,18 (DD, J=5,1 Hz, J=3.6 Hz, 1H), 7,79-to 7.84 (m, 4H), to $ 7.91 (d, J=7.8 Hz, 1H), 9,23 (t, J=6.0 Hz, 1H), 11,13 (s, 1H);13C NMR (DMSO-d6) δ 22,0, 30,9, 42,4, 49,0, 121,9, 123,6, 128,0, 128,4, 129,8, 131,2, 131,6, 133,4, 139,3, 147,4, 161,4, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C19H15N3O5S: C, 57,42; H, OF 3.80; N, 10,57. Found: C, 57,49; H, 3,42; N, 10,28.

5.10 [2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-amide Huck is anovas acid

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), hexanophenone (of 0.42 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature, and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (150 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The residue left overnight under stirring in ether (20 ml). The obtained solid is filtered and evaporated in vacuum, obtaining 0.71 g of product with a yield of 61%. So pl. 178-180°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 8,83 (98,70%).1H NMR (DMSO-d6) δ 0,86 (t, J=6.6 Hz, 3H), of 1.27 and 1.33 (m, 4H), 1,48 is 1.58 (m, 2H), 2,02-of 2.09 (m, 1H), 2,16 (t, J=7.5 Hz, 2H), 2,46-2,63 (m, 2H), 2,83-2,96 (m, 1H), 4,43 (d, J=6.0 Hz, 2H), 5,14 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,72-of 7.90 (m, 3H), 8,51 (t, J=6.0 Hz, 1H), 11,13 (s, 1H);13C1H NMR (DMSO-d6) δ 13,8, 21,8, 22,0, 24,9, 30,9, 30,9, 35,2, 41,8, 49,0, 121,8, 123,5, 129,7, 131,6, 133,3, 147,8, 167,0, 167,1, 169,8, 172,5, 172,7. Analysis: Calculated for C20H23N3O5: C, 62,33; H, OF 6.02; N, 10,90. Found: C, 62,20; H, Of 5.99; N, 10,84.

5.11 [2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-amide heptane acid

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), leptanilloides ones (0.46 ml, 3.0 mmol) and diisopropylethylamine (1,05 ml of 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The residue is purified preparative HPLC using isocratic elution with a mixture of acetonitrile:water, 45:65, receiving of 0.60 g of product with a yield of 50%. So pl. 141-143°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 3,99 (98,05%).1H NMR (DMSO-d6) δ is 0.84 (t, J=6.6 Hz, 3H), 1,24-of 1.30 (m, 6H), 1,48-and 1.54 (m, 2H), 2,02-of 2.09 (m, 1H), 2,16 (t, J=7.2 Hz, 3H), of 2.51 2.63 in (m, 2H), 2,83-2,96 (m, 1H), 4,43 (d, J=6.0 Hz, 2H), 5,14 (DD, J=5,4, 12.9 Hz, 1H), 7,72-7,89 (m, 3H), and 8.50 (t, J=6.0 Hz, 1H), 11,12 (s, 1H);13C NMR (DMSO-d6) δ 13,9, 22,0, 25,2, 28,3, 30,9, 31,0, 35,3, 41,8, 49,0, 121,8, 123,4, 129,7, 131,6, 133,3, 147,8, 167,0, 167,1, 169,8, 172,5, 172,7. Analysis: Calculated for C21H25N3O5+0,1 h2O: C, 62,86; H, 6,33; N, 10,47. Found: C, 62,54; H, 6,21; N, 10,38.

5.12 Tert-butyl ester 5-{[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-carbarnoyl}-pentanol acid

Stage 1: To the solution of nanometrology ester of adipic acid (4.8 g, 30 mmol) in DMF (30 ml) is added CDI (4.9 g, 30 mmol) and the resulting mixture was stirred in nitrogen atmosphere at 40°C. for 1 hour. Add tert-butanol (4.4 g, 60 mmol) and DBU (4.6 g, 30 mmol) is carried out stirring at 40°C. for 70 hours. The mixture is then poured into ether (100 ml) and this mixture is washed with 10% aq. SPLA (100 ml), 10% aq. To2CO3(100 ml) and water (3×100 ml), dried (MgSO4) and evaporated, receiving of 5.1 g of tert-butyl methyl ether hexadecanoic acid with a yield of 78%.1H NMR (CDCl3) δ of 1.44 (s, 9H), 1,59-to 1.67 (m, 4H), 2.21 are of 2.26 (m, 2H), to 3.67 (s, 3H).

Stage 2: lithium Hydroxide (0,53 g, 22 mmol) are added to a solution of tert-butyl methyl ether hexadecanoic acid (4.8 g, 22 mmol) in a mixture of methanol:water 3:1 (80 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture is evaporated in vacuum. The residue is partitioned between water (60 ml) and methylene chloride (75 ml)and the aqueous phase is washed with methylene chloride (3×75 ml) and evaporated, obtaining 4.0 g of lithium salt of mono-tert-butyl ether hexadecanoic acid.1H NMR (D2O) δ 1,45 (s, 9H), 1,54 is 1.58 (m, 4H), 2,15-of 2.20 (m, 2H), 2,25-of 2.34 (m, 2H).

Stage 3: DBU (1.9 g, 12.3 mmol) is added to a stirred suspension of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (2.5 g, 7.7 mmol) in acetonitrile (75 ml), which leads to the formation of a transparent solution. The mixture is stirred at room temperature for 10 minutes and then add the lithium salt of mono-tert-butyl ether hexadecanoic acid (1.9 g, 9.2 mmol) and HOBt (1.2 g, 9.2 mmol) followed by addition of EDC (2.2 g, 11.6 mmol). The mixture is stirred in an atmosphere of N2 1 hour and add DMF (20 ml). After stirring for an additional 16 hours the mixture is evaporated in vacuum. The residue is distributed between ethyl acetate (100 ml) and water (100 ml), the aqueous phase is extracted with ethyl acetate (2×100 ml). The combined organic layers washed with water (3×100 ml) and evaporated. The remainder chromatographic on silica, elwira with ethyl acetate, obtaining 2.1 g of product with a yield of 58%. So pl. 108-110°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 35/65 CH3CN/0.1% of H3PO4, to 7.64 (to 96.65%).1H NMR (DMSO-d6) δ to 1.38 (s, 9H), 1,45-1,55 (m, 4H), 2,02-of 2.08 (m, 1H), 2,15-of 2.21 (m, 4H), 2,46-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,43 (d, J=5.8 Hz, 2H), 5,14 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,72-7,76 (m, 2H), 7,87 (d, J=7.5 Hz,, 1H), 8,51 (t, J=5.8 Hz, 1H), 11,12 (s, 1H);13C NMR (DMSO-d6) δ 22,0, 24,2, 24,6, 27,7, 30,9, 34,5, 34,9, 41,9, 49,0, 79,4, 121,9, 123,4, 129,7, 131,6, 133,3, 147,8, 167,0, 167,1, 169,8, 172,1, 172,2, 172,8. Analysis: Calculated for C24H29N3O7+0,2H2O: C, 60,67; H, 6,24; N, 8,84. Found: C, 60,60; H, 6,16; N, 8,65.

5.13 5-{[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]carbarnoyl}-pentane acid

A solution of tert-butyl ester 5-{[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]carbarnoyl}-pentanol acid (0,85 g, 1.8 mmol) in formic acid (25 ml) was stirred at room temperature for 90 minutes. The mixture is evaporated in vacuo and the residue triturated in a mixture of ether/this is latitat and filtered, getting 0.66 g with a yield of 88%. So pl. 144-146°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% of H3PO4, 4,15 (95,81%).1H NMR (DMSO-d6) δ 1,44-to 1.59 (m, 4H), 2,02-of 2.09 (m, 1H), 2,16-of 2.24 (m, 4H), 2,46-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,43 (d, J=6.0 Hz, 2H), 5,14 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,72-to 7.77 (m, 2H), 7,87 (d, J=7.8 Hz, 1H), 8,51 (t, J=6.0 Hz, 1H), 11,12 (s, 1H), 12,00 (s, 1H);13C NMR (DMSO-d6) δ 22,0, 24,1, 24,7, 30,9, 33,3, 34,9, 41,9, 48,9, 121,9, 123,5, 129,7, 131,6, 133,3, 147,8, 167,0, 167,1, 169,8, 172,2, 172,7, 174,3. Analysis: Calculated for C20H21N3O7+0,2H2O: C, 57,33; H, 5,13; N, THERE IS A 10.03. Found: C, 57,33; H, 4,89; N, 9,81.

5.14 [2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-amide 6-(2-oxo-oxazolidin-3-yl)-hexanoic acid

Stage 1: a Mixture of 2-oxazolidinone (1,74 g, 20.0 mmol), ethyl-6-Bromhexine (4,46 g, 20.0 mmol) and sodium hydride (0,80 g of 60% dispersion, 20 mmol) in acetonitrile (10 ml) is heated to 160°C. in a microwave reactor for 15 minutes. The mixture is cooled and the solvent is removed under reduced pressure. The crude product ethyl ester 6-(2-oxo-oxazolidin-3-yl)-hexanoic acid is used directly in the next stage.

Stage 2: lithium Hydroxide (0,48 g, 20 mmol) is added to the crude product from step 1 in a mixture of methanol-water (30 ml) and the resulting mixture was stirred at room temperature for 70 hours. The mixture is evaporated in vacuum. The residue is dissolved in water (75 m is), washed with methylene chloride (3×75 ml) and acidified (HCl). The resulting mixture was extracted with methylene chloride (6×50 ml)and the combined extracts dried (MgSO4) and evaporated, obtaining 2.0 g of 6-(2-oxo-oxazolidin-3-yl)-hexanoic acid with a total yield of 49% in two stages.1H NMR (CDCl3) δ 1,36-of 1.44 (m, 2H), 1,51-of 1.74 (m, 4H), of 2.38 (t, J=7.4 Hz, 2H), or 3.28 (t, J=7.2 Hz, 2H), of 3.56 (t, J=8.0 Hz, 2H), 4,33 (t, J=8.0 Hz, 2H).

Stage 3:DBU (1.2 g, 8.1 mmol) is added to a stirred suspension of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol) in acetonitrile (35 ml), which leads to the formation of a transparent solution. The mixture is stirred at room temperature for 10 minutes, then add 6-(2-oxo-oxazolidin-3-yl)-hexanoic acid (2.0 g, 10 mmol) and HOBt (0.5 g, 3.7 mmol) followed by addition of EDC (0,89 g, 4.7 mmol). After stirring for an additional 16 hours the mixture is evaporated in vacuum. The residue is distributed between ethyl acetate (50 ml) and water (100 ml)and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic layers evaporated. The remainder chromatographic on silica using a gradient of methylene chloride-methanol, elwira and 0.61 g of product with a ratio of methylene chloride-methanol 93:7 with the release of 42%. So pl. 178-180°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 25/75 CH3CN/0.1% of H3PO4, 3,36 (98,33%).1H NMR (DMSO-d6) δ 1.26 in-1,8 (m, 2H), 1,43-to 1.61 (m, 4H), 2,04-of 2.08 (m, lH), to 2.18 (t, J=7.4 Hz, 2H), 2,46-2,63 (m, 2H), 2,83-2,96 (m, 1H), 3,12 (t, J=7,1 Hz, 2H), 3,49 (t, J=8.0 Hz, 2H), 4,42 (t, J=8.0 Hz, 2H), 4,43 (d, J=5.8 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,72-to 7.77 (m, 2H), 7,89 (d, J=7.8 Hz, 1H), 8,51 (t, J=5.8 Hz, 1H), 11,12 (s, 1H);13C NMR (DMSO-d6) δ 22,0, 24,8, 25,7, 26,4, 30,9, 35,1, 41,9, 43,3, 43,8, 49,0, 61,5, 121,8, 123,5, 129,7, 131,6, 133,3, 147,8, 157,8, 167,0, 167,1, 169,8, 172,4, 172,7. Analysis: Calculated for C23H26N4O7+0,3H2O: C, 58,05; H, 5,63; N, 11,77. Found: C, 58,05; H, 5,42; N, Are 11.62.

5.15 Hexyl ester [2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-carbamino acid

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol), vexillifera (0.51 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol) in THF (35 ml) was stirred at 40°C. in a nitrogen atmosphere for 3 hours. The mixture is cooled and diluted with ethyl acetate (100 ml), washed with water (3×100 ml) and evaporated. The remainder chromatographic using a gradient of methylene chloride-methanol, elwira product with a ratio of methylene chloride-methanol 19:1. This substance is further purified preparative HPLC using isocratic elution with a mixture of acetonitrile-water 50-50, and obtain 0.40 g in the form of a white solid with a yield of 31%. So PL. 111-113°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4that 5,08 (99,11%).1H NMR (DMSO-d6) δ 1,11-of 1.57 (m, 11N), 2,02-,07 (m, 1H), 2,46-2,63 (m, 2H), 2,84-2,96 (m, 1H), 3,97 (t, J=8,3 Hz, 2H), 4,35 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,72-to 7.77 (m, 2H), 7,84-of 7.90 (m, 2H), 11,13 (s, 1H);13C NMR (DMSO-d6) δ 13,8, 22,0, 25,0, 28,6, 30,8, 30,9, 43,5, 49,0, 64,0, 121,6, 123,5, 129,8, 131,6, 133,2, 147,9, 156,6, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C21H15N3O6: C, 60,71; H, 6,07; N, 10,11. Found: C, 60,49; H, 6,13; N, To 9.91.

5.16 4-Chloro-N-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-benzamide

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.4 g, 1.18 mmol), 4-chlorobenzylchloride (0.15 ml, 1.18 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and is evaporated in vacuum, obtaining of 0.49 g of product with a yield of 94%. So pl. 163-165°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 3,38 (98,94%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,53-2,60 (m, 2H), 2.63 in-a 2.71 (m, 1H), to 4.62 (d, J=6.0 Hz, 2H), 7,56-to 7.59 (m, 2H), to 7.77-7,83 (m, 3H), of 7.90-7,94 (m, 2H), of 9.30 (t, J=5.7 Hz, 1H), 11,02 (s, 1H);13C NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,6, 58,7, 121,6, 123,2, 128,5, 129,2, 129,6, 131,4, 132,6, 133,4, 136,3, 147,2, 165,4, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C22H18N3O5Cl: C, 60,08; H, 4,12; N, And 9.5. Found: C, 59,70; H, Of 3.94; N, 9,43.

5.17 N-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-triptoreline-benzamid

A mixture of the hydrochloride of 5-aminomethyl-2-((3S)-3-methyl-2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.4 g, 1.18 mmol), 4-(triptoreline)of benzoyl chloride (0,19 ml, 1.18 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The residue is stirred in ether (20 ml). The solid is filtered, receiving at 0.42 g of product with a yield of 72%. So pl. 161-163°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 5,58 (97,42%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,49-2,60 (m, 2H), 2,63-of 2.72 (m, 1H), 4,63 (d, J=6.0 Hz, 2H), of 7.48-7,51 (m, 2H), 7,78-to 7.84 (m, 3H), 8,00-with 8.05 (m, 2H), 9,34 (t, J=5.7 Hz, 1H), 11,02 (s, 1H);13C NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,6, 58,7, 119,9 (kV, J=255), 120,7, 121,6, 123,2, 125,0, 129,6, 131,4, 133,0, 133,4, 147,2, 150,4, 165,2, 167,7, 167,8, 172,1, 172,2. Analysis: Calculated for C23H18N3O6F3: C, 56,45; H, 3,71; N, 8,59. Found: C, 56,16; H, 3,39; N, 8,45.

5.18 [2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-hexanoic acid amide

The mixture is of hydrochloride 5-aminomethyl-2-((3S)-3-methyl-2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.40 g, 1.2 mmol), hexanophenone (0.17 ml, 1.2 mmol) and N,N-diisopropylethylamine (of 0.41 ml, 2.4 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The obtained solid is left overnight under stirring in ether, filtered and dried, obtaining 0.36 g of product with a yield of 77%. So pl. 154-156°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 4,51 (97,79%).1H NMR (DMSO-d6) δ of 0.85 (t, J=6.9 Hz, 3H), 1,19-of 1.32 (m, 4H), 1,48-of 1.57 (m, 2H), 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,15 (t, J=7.5 Hz, 2H), 2,53-2,60 (m, 2H), 2,63-of 2.72 (m, 1H), to 4.41 (d, J=6.0 Hz, 2H), 7.68 per-7,81 (m, 3H), 8,49 (t, J=6.0 Hz, 1H), 11,02 (s, 1H);13C NMR (DMSO-d6) δ 13,8, 21,0, 21,8, 24,9, 28,6, 29,1, 30,9, 35,2, 41,8, 58,7, 121,4, 123,1, 129,5, 131,3, 133,2, 147,7, 167,7, 167,9, 172,1, 172,2, 172,4. Analysis: Calculated for C21H25N3O5: C, 63,15; H, OF 6.31; N, 10,52. Found: C, 63,06; H, 6,14; N, 10,48.

5.19 Hexyl ether {2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl}-carbamino acid

A mixture of the hydrochloride of 5-aminomethyl-2-((3S)-3-methyl-2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.40 g, 1.18 mmol), vexillifera (0,19 g, 1.18 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in acetonitrile (20 ml) was stirred at whom atoi temperature for 1 hour. The reaction mixture was concentrated, and the residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and is evaporated in vacuum, obtaining 0.45 g of product with a yield of 88%. So pl. 95-97°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 6,94 (97,26%).1H NMR (DMSO-d6) δ 0,78 is 0.86 (m, 3H), 1,09-of 1.26 (m, 6H), 1,52-and 1.54 (m, 2H), 1,89 (s, 3H), 1,99-of 2.08 (m, 1H), 2,54 at 2.59 (m, 2H), 2,64-of 2.72 (m, 1H), 3.96 points (t, J=6.6 Hz, 2H), 4,33 (d, J=6.0 Hz, 2H), 7,70-7,87 (m, 4H), 11,02 (s, 1H);13C NMR (DMSO-d6) δ 13,8, 21,0, 22,0, 25,0, 28,6, 29,1, 30,9, 43,5, 58,7, 64,0, 121,3, 123,1, 129,6, 131,4, 133,1, 147,7, 156,6, 167,7, 167,8, 172,1, 172,2. Analysis: Calculated for C22H27N3O6: C, 61,53; H, 6,34; N, 9,78. Found: C, 61,73; H, 6,33; N, 9,58.

5.20 3,4-Dichloro-N-[2-(2,6-dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]benzamide

A mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro - isoindole-2-yl)-piperidine-2,6-dione (0.50 g, 1.6 mmol), 3,4-dichlorobenzotrifluoride (0.34 g, 1.6 mmol) and tea (0.32 g, 3.2 mmol) in THF (25 ml) is heated to 40°C. with stirring in an atmosphere of N22.5 hours. The mixture is filtered, the filtered solid is loaded onto a column of silica gel, colorout washed, using a gradient of methylene chloride-methanol. The elute product with a ratio of methylene chloride-methanol 93:7, 0,42 g, yield 58%. So pl. 260-262°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H 3PO4, 3,36 (99,65%).1H NMR (DMSO-d6) δ 1,96-2,03 (m, 1H), 2,31 is 2.43 (m, 1H), 2,56-2,62 (m, 1H), 2,85-of 2.97 (m, 1H), 4,30 (d, J=17,4 Hz, 1H), of 4.44 (d, J=17,4 Hz, 1H), 4,59 (d, J=6.0 Hz, 2H), 5,11 (DD, J=a 13.4 Hz, J=5.0 Hz, 1H), 7,45-of 7.55 (m, 2H), of 7.70 (d, J=7,8, 1H), 7,78 (d, J=8,4 Hz, 1H), 7,88 (DD, J=8,4 Hz, J=1.8 Hz, 1H), 8,14 (d, J=2.1 Hz, 1H), was 9.33 (t, J=6.0 Hz, 1H), 10,98 (s, 1H);13C NMR (DMSO-d6) δ 22,5, 31,2, 42,9, 47,1, 51,6, 122,2, 123,0, 127,2, 127,6, 129,2, 130,4, 130,7, 131,3, 134,1, 134,4, 142,4, 143,4, 164,0, 167,9, 171,0, 172,8. Analysis: Calculated for C21H17Cl2N3O4+0,25H2O: C, 55,95; H, 3,91; N, TO 9.32. Found: C, 55,98; H, 3,55; N, To 9.32.

5.21 N-[2-(2,6-dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-triptoreline-benzamid

A mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro - isoindole-2-yl)-piperidine-2,6-dione (0.40 g, 1,29 mmol), 4-(triptoreline)of benzoyl chloride (0,20 ml, 1,29 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The solid is filtered, optionally washed with acetonitrile (20 ml) and dried, obtaining 0,41 g of product with a yield of 68%. So pl. 133-135°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 5,44 (of 99.98%).1H NMR (DMSO-d6) δ
1,98 is 2.01 (m, 1H), 2,27 at 2.45 (m, 1H), 2.57 m-2,62 (m, 1H), 2,85-of 2.97 (m, 1H), 4,30 (d, J=17,1 Hz, 1H), 4,45 (d, J=17,4 Hz, 1H), 4,60 (d, J=5.7 Hz, 2H), 5,11 (DD, J=13.5 Hz, J=5,1 Hz, 1H), 7,46-of 7.55 (m, 4H), 7,70 (d, J=7.8 Hz, 1H), 8,04 (d, J=8.7 Hz, 2H), 9,27 (t, J=5.7 Hz, 1H), 10,98 (s, 1H);1 C NMR (DMSO-d6) δ 22,5, 31,2, 42,8, 47,1, 51,6, 119,9 (kV, J=Hz 255,8), 120,7, 122,1, 122,9, 127,1, 129,6, 130,4, 133,2, 142,4, 143,7, 150,3, 165,1, 167,9, 171,0, 172,8. Analysis: Calculated for C22H18N3O5F3+0,15H2O: C, 56,94; H, OF 3.97; N, 9,05. Found: C, 56,54; H, 3,63; N, 8,95.

5.22 [2-(2,6-Dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]amide, furan-2-carboxylic acid

A mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro - isoindole-2-yl)-piperidine-2,6-dione (0.40 g, 1,29 mmol), 2-frailcare (0,13 ml, 1,29 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the solid is optionally washed with acetonitrile (20 ml) and dried, obtaining 0.33 g of product with a yield of 71%. So pl. 338-340°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% of H3PO4, 5,65 (96,68%).1H NMR (DMSO-d6) δ 1,97 is 2.10 (m, 1H), 2,19 at 2.45 (m, 1H), 2,50-2,62 (m, 1H), 2,73-3,03 (m, 1H), 4,30 (d, J=17,1 Hz, 1H), of 4.44 (d, J=17,4 Hz, 1H), 4,53 (d, J=5.7 Hz, 2H), 5,10 (DD, J=13,2 Hz, J=5,1 Hz, 1H), 6,64-to 8.20 (m, 6H), 9,04 (t, J=6.0 Hz, 1H), 10,98 (s, 1H);13C NMR (DMSO-d6) δ 22,5, 31,2, 42,0, 47,1, 51,6, 111,9, 113,6, 122,1, 122,9, 127,1, 130,4, 142,4, 143,7, 145,1, 147,7, 157,8, 167,9, 171,0, 172,8. Analysis: Calculated for C19H17N3O5+0,1 h2O: C, 61,82; H, 4,70; N, 11,38. Found: C, 61,45; H, To 4.46; N, 11,37.

5.23 [2-(2,6-Dioxo-piperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]hexanoic amide CIS is the notes

A mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro - isoindole-2-yl)-piperidine-2,6-dione (0.40 g, 1,29 mmol), hexanophenone (of 0.18 ml, 1,29 mmol) and diisopropylethylamine (0,41 ml, is 2.37 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The solid is filtered and optionally washed with acetonitrile, to obtain 0.26 g of product with a yield of 55%. So pl. 206-208°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 5,30 (98,77%).1H NMR (DMSO-d6) δ 0,86 (t, J=6.6 Hz, 3H), 1,25-of 1.29 (m, 4H), 1,48 is 1.58 (m, 2H), 1,98 is 2.01 (m, 1H), and 2.14 (t, J=7.2 Hz, 2H), 2,33-to 2.42 (m, 1H), 2.57 m) 2.63 in (m, 1H), 2,86 are 2.98 (m, 1H), 4,27-4,47 (m, 4H), 5,11 (DD, J=13,2 Hz, J=4,8 Hz, 1H), 7,37 was 7.45 (m, 2H), 7,68 (d, J=7.8 Hz, 1H), 8,40 (t, J=5.4 Hz, 1H), 10,98 (s, 1H);13C NMR (DMSO-d6) δ 13,8, 21,8, 22,5, 24,9, 30,9, 31,2, 35,3, 42,0, 47,1, 51,6, 122,0, 122,9, 127,0, 130,3, 142,3, 144,1, 167,9, 171,0, 172,2, 172,8. Analysis: Calculated for C20H25N3O4+0,1 h2O: C, 64,36; H, FOR 6.81; N, OF 11.26. Found: C, 64,16; H, To 6.80; N, 11,17.

5.24 [2-(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]amide pyridine-2-carboxylic acid

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione of 0.85 g, 2.5 mmol), hydrochloride of ptolemaida (0.45 g, 2.5 mmol) and triethylamine (from 0.76 g, 7.5 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 13 hours. Rea is operating, the mixture is filtered. The filtrate was concentrated in vacuo and the residue is dissolved in ethyl acetate (100 ml). The organic phase is washed with 4n aqueous HCl (150 ml) and neutralized with sodium bicarbonate. The solids are filtered, washed with water (200 ml) and dried, obtaining the product as a white solid (0,47 g, 46%). So pl. 365-367°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 6,59 (96,15%).1H NMR (DMSO-d6) δ of 1.88 (s, 3H), 2,01-2,07 (m, 1H), 2,54-to 2.74 (m, 3H), with 4.64 (d, J=6.3 Hz, 2H), to 7.61-the 7.65 (m, 1H), 7,79-7,83 (m, 3H), 7,98-of 8.06 (m, 2H), 8,68 (d, J=4,8 Hz, 1H), being 9.61 (t, J=6.3 Hz, 1H), br11.01 (s, 1H);13C NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,3, 58,7, 121,8, 122,0, 123,1, 126,7, 129,6, 131,3, 133,5, 137,8, 147,3, 148,5, 149,7, 164,2, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C21H18N4O5+0,3H2O: C, 61,25; H, 4,55; N, 13,61. Found: C, 60,88; H, 4,22; N, 13,33.

5.25 N-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-cryptomelane

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione of 0.85 g, 2.5 mmol), 4-(trifluoromethyl)benzoyl chloride (0,52 ml, 2.5 mmol) and triethylamine (0.51 g, 5.0 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 13 hours. The reaction mixture is filtered. The filtrate is concentrated and the resulting yellow residue chromatographic on silica gel using a gradient of methanol-methylene chloride elwira product when the ratio of methanol-methylene chloride 3:97, get the product as a white solid (0,94 g, yield 80%). So pl. 188-190°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 3,82 (99,33%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,53-of 2.72 (m, 3H)and 4.65 (d, J=6.0 Hz, 2H), 7,79-8,11 (m, 7H), 9,46 (t, J=6.0 Hz, 1H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,6, 29,1, 42,7, 58,8, 121,7, 123,2, 123,9 (kV, J=271 Hz), output reached 125.5 (q, J=3.8 Hz), 128,2, 129,7, 131,3 (kV, J=31,5 Hz), 131,4, 133,5, 137,7, 147,0, 165,3, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C23H18N3O5F3: C, 58,35; H, A 3.83; N, 8,88. Found: C, 58,05; H, To 3.64; N, 8,65.

5.26 N-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-isonicotinamide

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione of 0.85 g, 2.5 mmol), hydrochloride of isonicotinohydrazide (0.45 ml, 2.5 mmol) and triethylamine (from 0.76 g, 7.5 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the resulting yellow residue chromatographic on silica gel using a gradient of methanol-methylene chloride, elwira product when the ratio of methanol-methylene chloride 5:95. The product is stirred in water (20 ml) for 15 hours. The obtained solid is filtered and optionally washed with water (20 ml). The solid is then stirred in methanol (20 ml) for two days, filtered and is washed with additional methanol (20 ml), receiving the product as a white solid (0,23 g, yield 23%). So pl. 186-188°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 25/75 CH3CN/H2O, 3,06 (97,62%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,53 was 2.76 (m, 3H)and 4.65 (d, J=5.7 Hz, 2H), 7,79-to 7.84 (m, 5H), 8,76 (d, J=6.0 Hz, 2H), 9,51 (t, J=6.0 Hz, 1H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,6, 58,8, 121,2, 121,7, 123,2, 129,7, 131,4, 133,5, 140,9, 146,8, 150,3, 164,9, 167,7, 167,8, 172,1, 172,2. Analysis: Calculated for C21H18N4O5+0,2H2O: C, 61,52; H, TO 4.52; N, 13,66. Found: C, 61,28; H. 4,36; N, 13,55.

5.27 4-Fluoro-N-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-benzamide

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione of 0.85 g, 2.5 mmol), 4-tormentilla (and 0.40 ml, 2.5 mmol) and triethylamine (0.51 g, 5.0 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 2 hours. The reaction mixture is filtered. The filtrate was concentrated in vacuo, and the residue chromatographic on silica gel using a gradient of methanol-methylene chloride, elwira product when the ratio of methanol-methylene chloride 5:95. Combined fractions are concentrated and the resulting solid was stirred in ether for 2 hours. The suspension is filtered and the solid is optionally washed with ether, receiving the product as a white solid (0,41 g, yield 38%). So pl. 31-233°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 3,90 (96,87%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-to 2.06 (m, 1H), 2,54 is 2.75 (m, 3H), to 4.62 (d, J=5.7 Hz, 2H), 7,30 and 7.36 (m, 2H), to 7.77-7,83 (m, 3H), 7,95-to 7.99 (m, 2H), 9,24 (t, J=6.0 Hz, 1H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,6, 58,7, 115,3 (d, J=21 Hz), 121,6, 123,2, 129,6, 129,9 (d, J=8,3 Hz), 130,4 (d, J=3.0 Hz), 131,4, 133,4, 147,3, 164,0 (d, J=247 Hz), 165,3, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C22H18N3O5F: C, 62,41; H, THE 4.29; N, 9,92. Found: C, 62,46; H, 4,12; N, 9,88.

5.28 N-[2-(3S)-(3-methyl-2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-6-trifluoromethyl nicotinamide

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.65 g, 1.9 mmol), 6-(trifluoromethyl)nicotinanilide (and 0.40 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate (100 ml) and washed with 4n HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The remainder chromatographic on silica gel (ethyl acetate), obtaining of 0.58 g of product with a yield of 65% in the form of a white solid. So pl. 358-360°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 5,10 (99,34%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2.00 in of 2.08 (m, 1H), 2,55-of 2.72 (m, 3H), 4,69 (d, J=6.0 Hz, 2H), and 7.8 (s, 3H), 8,08 (d, J=8,1 Hz, 1H), 8,51 (DD, J=8,1 Hz and 1.8 Hz, 1H), of 9.21 (d, J=1.2 Hz, 1H), being 9.61 (t, J=6.0 Hz, 1H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,6, 29,1, 42,7, 58,8, 120,7 (kV, J=3.0 Hz), 121,4 (kV, J=273 Hz), 121,8, 123,2, 129,8, 131,4, 132,6, 133,5, 137,5, 146,6, 148,2 (kV, J=33,8 Hz), 149,0, 163,9, 167,7, 167,8, 172,1, 172,2. Analysis: Calculated for C22H17N4O5F3+0,1 h2O: C, 55,49; H, TO 3.64; N, 11,77. Found: C, 55,11; H, 3,35; N, 11,64.

5.29 3,4-Dichloro-N-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-benzamide

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.65 g, 1.9 mmol), 3,4-dichlorobenzotrifluoride (and 0.40 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue is dissolved in ethyl acetate (100 ml) and washed with 4n HCl (2×150 ml), water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The solid is left overnight under stirring in ether and then filtered. Solid chromatographic on silica gel using a gradient of ethyl acetate : hexane, elwira product with a ratio of the ethyl acetate-hexane 90:10. The combined fraction was concentrated in vacuo and the resulting solid was stirred in ether for 2 hours. The suspension is filtered and the solid is optionally washed with ether, receiving the product as a white solid (0.54 g, yield 60%). So pl. 162-164°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 4,89 (98,63%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 1,99-of 2.08 (m, 1H), 2,55 is 2.75 (m, 3H), 4,63 (d, J=6.0 Hz, 2H), 7,78-7,89 (m, 5H), 8,13 (d, J=2.1 Hz, 1H), 9,39 (t, J=6.0 Hz, 1H), br11.01 (s, 1H);

13C NMR (DMSO-d6) δ 21,0, 28,6, 29,1, 42,7, 58,8, 121,7, 123,2, 127,6, 129,2, 129,7, 130,8, 131,3, 131,4, 133,5, 134,2, 134,3, 146,9, 164,2, 167,7, 167,8, 172,1, 172,2. Analysis: Calculated for C22H17N3O5Cl2: C, 55,71; H, 3,61; N, 8,86. Found: C, 55,34; H, 3,66; N, 8,67.

5.30 [2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-amide thiophene-2-carboxylic acid

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione of 0.85 g, 2.5 mmol), 2-thiophenecarbonitrile (and 0.37 ml, 2.5 mmol) and triethylamine (0.51 g, 5.0 mmol) in anhydrous acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue chromatographic on silica gel using a gradient of methanol-methylene chloride, elwira product when the ratio of methanol-methylene chloride 5:95. The solvent was concentrated in vacuo and the resulting solid is dissolved in DMF (4 ml) and the mixture is heated to 95°C for 1 hour. Then added dropwise water (5 ml) and the mixture is allowed to cool to room temperature and left overnight under stirring. Obtained the Uspenskiy filtered and optionally washed with water, receiving the product as a white solid (0,62 g, yield 60%). So pl. 222-224°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 6,67 (96,69%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,53-by 2.73 (m, 3H), 4,60 (d, J=6.0 Hz, 2H), 7,16-7,19 (m, 1H), 7,76-to 7.84 (m, 5H), which 9.22 (t, J=6.0 Hz, 1H), br11.01 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,4, 58,7, 121,6, 123,2, 128,0, 128,4, 129,6, 131,1, 131,4, 133,4, 139,3, 147,3, 161,3, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C20H17N3O5S: C, 58,39; H, 4,16; N, OF 10.21. Found: C, 58,55; H, 3,98; N, 10,06.

5.31 2-(4-Chlorophenyl)-N-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-ndimethylacetamide

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.65 g, 1.9 mmol), 4-chlorophenylacetyl (0,36 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. To the reaction mixture add an additional 4-chlorophenylacetyl (0,36 ml, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol) and continue stirring for additional 3 hours. The reaction mixture is filtered and the filtrate concentrated. The residue is dissolved in ethyl acetate (100 ml) and washed with 4n HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and concentrated in vacuo. The remainder chromatographic on silica gel using a gradient of methanol-CH2Cl2, elwira cont the CT with a ratio of methanol-CH 2Cl25:95, receiving of 0.60 g of the product as a white solid with a yield of 69%. So pl. 156-158°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 6,09 (95,59%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,53 was 2.76 (m, 3H), 4,42 (d, J=6.0 Hz, 2H), 7,28-7,44 (m, 4H), 7.68 per-7,80 (m, 3H), 8,73 (t, J=6.0 Hz, 1H), 11,03 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,6, 29,1, 41,4, 42,1, 58,8, 121,5, 123,1, 128,2, 129,6, 130,9, 131,2, 131,4, 133,3, 135,1, 147,3, 167,7, 167,8, 170,1, 172,1, 172,2. Analysis: Calculated for C22H17N4O5F3+0,10H2O+0,15EtOAc: C, 60,45; H, 4,60; N, 8,96. Found: C, 60,37; H, 4,21; N, 8,56.

5.32 [2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-amide isoquinoline-3-carboxylic acid

Hydrate 3-ethinlestradiol acid (0.33 g, 1.9 mmol) dissolved in DMF (20 ml) and added CDI (0.34 g, 2.1 mmol). The mixture is stirred at 40°C. for 1 hour. Then add the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.65 g, 1.9 mmol) and triethylamine (0.39 g, 3.8 mmol)and the reaction mixture stirred at 40°C for an additional 90 minutes. The mixture is cooled to room temperature and left overnight under stirring. Add water (30 ml) and the precipitated solid. The precipitated solid substance produce by filtration, optionally washed with water and dried, obtaining 0.66 g of product with a yield of 76%. So pl. 259-261°C. ASH, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 3,24 (the 97.97%).1H NMR (DMSO-d6) δ of 1.88 (s, 3H), 2,01-2,07 (m, 1H), 2,53-to 2.74 (m, 3H), 4,71 (d, J=6.3 Hz, 2H), 7,80-a 7.92 (m, 5H), 8,19-of 8.28 (m, 2H), 8,58 (s, 1H), 9,42 (s, 1H), 9,75 (t, J=6.3 Hz, 1H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,4, 58,7, 120,0, 121,8, 123,1, 127,8, 128,0, 129,2, 129,3, 129,6, 131,4, 133,6, 135,3, 143,5, 147,5, 151,6, 164,5, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C22H20N4O5+0,20H2O: C, 65,27; H, TO 4.47%; N, 12,18. Found: C, 64,98; H, 4,33; N, 12,18.

5.33 N-((2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-isoindoline-5-yl)methyl)-4-(triptoreline)benzamid

Thea added to stir the mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol) and 4-(triptoreline)of benzoyl chloride (0.75 g, 3.1 mmol) in acetonitrile (30 ml), the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 ml) and ethyl acetate (100 ml). The organic phase is separated and concentrated in vacuo. The remainder chromatographic on silica gel using a gradient hexane-ethyl acetate, elwira 1.2 g of the product when the content of ethyl acetate 60-70%, with a yield of 76% in the form of a white solid. So pl. 171-173°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 4,72 (97,94%).1H NMR (DMSO-d6) δ 2,02 is 2.10 (m, 1H), 2,46-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,66 (d, J=5.8 Hz, 2H), 5,15 (DD, J=12,8 Hz, J=5 Hz, 1H), 7,81-a 7.92 (m, 5H), 8,00-8,03 (m, 2H), 9,41 (t, J=5.8 Hz, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 122,0, 123,6, 126,4, 128,7, 129,5 (kV, J=306 Hz), 129,9, 131,6, 133,5, 135,9, 136,5, 147,2, 165,5, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C22H16N3O5F3S: C, 53,77; H, OR 3.28; N, 8,55. Found: C, 53,55; H, 3,14; N, Of 8.37.

5.34 N-((2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-isoindoline-5-yl)methyl)-4-(1,1,2,2-tetrafluoroethoxy)benzamide

A mixture of 4-(1,1,2,2-tetrafluoroethoxy)benzoic acid (0.73 g, 3.1 mmol) and CDI (0.55 g, 3.4 mmol) in DMF (20 ml) was stirred at 40°C. for 2 hours, and then add the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol). After 2 hours the mixture is cooled to room temperature, poured into ethyl acetate (100 ml)and then washed with NaHCO3(3×75 ml) and then concentrated. The remainder chromatographic on silica gel (ethyl acetate), obtaining 0,79 g of the product as a white solid in 51%yield. So pl. 148-150°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 4,72 (98,94%).1H NMR (DMSO-d6) δ 1,99 is 2.10 (m, 1H), 2,48-2,63 (m, 2H), 2,84-2,96 (m, 1H), 4,66 (d, J=5.8 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 6,85 (TT, J=51,9, J=3,1, 1H), 7,42 (d, J=8.7 Hz, 2H), 7,81-a 7.92 (m, 3H), 8,00-of 8.04 (m, 2H), to 9.32 (t, J=5.8 Hz, 1H), 11,13 (s, 1H);1H NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 107,7 (TT, J=247, J=40), 116,4 (TT, J=269, J=27), 121,2, 122,0, 123,5, 129,5, 129,8, 131,6, 132,5, 133,4, 147,4, 150,3, 165,4, 167,0, 167,1, 169,8, 172,7. Analysis: Bycicle what about C 23H17N3O6F4: C, 54,44; H, TO 3.38; N, 8,28. Found: C, 54,24; H, Or 3.28; N, 8,15.

5.35 4-Bromo-N-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-benzamide

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol), 4-bromobenzonitrile (0.68 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol) in acetonitrile (20 ml) is stirred for 3 hours at room temperature. The reaction mixture is filtered and the filtrate concentrated. The remainder chromatographic on silica gel (ethyl acetate)to give 1.2 g of product as a white solid with a yield of 83%. So pl. 166-168°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 6,07 (the 97.97%).1H NMR (DMSO-d6) δ 2,02 is 2.10 (m, 1H), 2,46-2,63 (m, 2H), 2,83-2,95 (m, 1H), with 4.64 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 7,69-7,74 (m, 2H), 7,80-to $ 7.91 (m, 5H), of 9.30 (t, J=6.0 Hz, 1H), 11,12 (s, 1H);13H NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 122,0, 123,5, 125,2, 129,4, 129,8, 131,4, 131,6, 133,0, 133,5, 147,4, 165,5, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C21H16N3O5Br: C, 53,63; H, 3.43 Points; N, 8,94; Br, 16,99. Found: C, 53,61; H, 3,14; N, 8,84; Br, Ls 16.80.

5.36 N-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-ethyl-benzamide

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1,00 g, 3.1 mmol), 4-ethylbenzylamine (0.52 g, 3.1 mmol)and triethylamine (0,63 g, 6.2 mmol) in acetonitrile (20 ml) is stirred for 3 hours at room temperature. The reaction suspension was filtered and the solid phase, optionally washed with acetonitrile. The solid is then stirred in water for 2 hours, filtered and dried, obtaining 0.51 g of product. The filtrate from the reaction mixture concentrated. The remainder chromatographic on silica gel (ethyl acetate). Combined fractions are concentrated and the resulting solid is left overnight under stirring in ether, filtered and dried, obtaining of 0.59 g of the product with a total yield of 85%. The product is a white solid. So pl. 191-193°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 6,56 (99,32%).1H NMR (DMSO-d6) δ of 1.20 (t, J=5.7 Hz, 3H), 2,02 is 2.10 (m, 1H), 2,47-2,70 (m, 2H), 2,83-2,95 (m, 1H), with 4.64 (d, J=5.7 Hz, 2H), 5,16 (DD, J=12.9 Hz, J=5,1 Hz, 1H), 7,33 (d, J=8.1 Hz, 2H), 7,79-to $ 7.91 (m, 5H), 9,15 (t, J=6.0 Hz, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 15,3, 22,0, 28,0, 30,9, 42,5, 49,0, 121,9, 123,5, 127,3, 127,7, 129,8, 131,4, 131,6, 133,4, 147,5, 147,7, 166,3, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C23H21N3O5: C, 65,86; H, OF 5.05; N, 10,02. Found: C, 65,73; H, A 4.86; N, To 9.91.

5.37 N-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-ethoxy-benzamide

4-Ethoxybenzoyl acid (0.51 g, 3.1 mmol) dissolved in DMF (20 ml) and added CDI (0.55 g, 3.4 mmol). The mixture is stirred at 40°C. for 1 hour. Then to ablaut hydrochloride 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1,00 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol) and the reaction mixture was stirred at 40°C. additional 90 minutes. The mixture is then cooled to room temperature and left overnight under stirring. Then add water (30 ml) and the precipitated solid. Solid allocate filtration, optionally washed with water and the resulting solid chromatographic on silica gel (ethyl acetate)to give 0.21 g of product with a yield of 16% in the form of a white solid. So pl. 213-215°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, of 3.77 (99,35%).1H NMR (DMSO-d6) δ of 1.34 (t, J=6.9 Hz, 3H), 2,02-of 2.09 (m, 1H), 2,46-2,62 (m, 2H), 2,83-2,95 (m, 1H), 4,06 is 4.13 (m, 2H), to 4.62 (d, J=6.0 Hz, 2H), 5,14 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 6,98-7,03 (m, 2H), 7,79-to $ 7.91 (m, 5H), 9,07 (t, J=5.7 Hz, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 14,5, 22,0, 30,9, 42,5, 49,0, 63,3, 114,0, 121,9, 123,5, 125,9, 129,1, 129,7, 131,6, 133,4, 147,9, 161,0, 165,9, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C23H21N3O6: C, 63,44; H, A 4.86; N, 9,65. Found: C, 63,41 ; H, Was 4.76; N, 9,41.

5.38 N-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-methanesulfonyl-benzamide

4-(Methylsulphonyl)benzoic acid (0,62 g, 3.1 mmol) dissolved in DMF (20 ml) and added CDI (0.55 g, 3.4 mmol). The mixture is stirred at 40°C. for 1 hour. Add hydrochloride 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol) and Treaty the amine (0,63 g, 6.2 mmol) and the reaction mixture was stirred at 40°C. additional 90 minutes. The mixture is cooled to room temperature and left overnight under stirring. The reaction mixture was concentrated and the residue chromatographic on silica gel (ethyl acetate), obtaining 0,83 g of product with a yield of 57% in the form of a white solid. So pl. 241 to 243°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 3,48 (98,80%).1H NMR (DMSO-d6) δ 2,03-of 2.08 (m, 1H), 2.49 USD 2.63 in (m, 2H), and 2.83-2.91 in (m, 1H), 3.27 to (s, 3H), and 4.68 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 7,82-a 7.92 (m, 3H), 8,04-8,07 (m, 2H), 8,12-of 8.15 (m, 2H), 9,49 (t, J=5.7 Hz, 1H), 1 1,12 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,8, 43,3, 49,0, 122,0, 123,6, 127,1, 128,3, 129,9, 131,6, 133,5, 138,3, 143,1, 147,1, 165,2, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C22H19N3O7S: C, 56,28; H, 4,08; N, 8,95. Found: C, 56,13; H, 3,90; N, A Total Of 8.74.

5.39 N-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-iodine-benzamid

4-Identify acid (0,77 g, 3.1 mmol) dissolved in DMF (20 ml) and added CDI (0.55 g, 3.4 mmol). The mixture is stirred at 40°C. for 1 hour. Add hydrochloride 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol)and the reaction mixture stirred at 40°C. additional 90 minutes. The mixture is cooled to room temperature and left overnight under stirring. The reaction mixture will contentresult and the rest chromatographic on silica gel (ethyl acetate) to obtain a solid substance, which left overnight under stirring in ether, filtered and dried, obtaining of 1.33 g of product with a yield of 83% in the form of a white solid. So pl. 163-165°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 3,27 (97,68%).1H NMR (DMSO-d6) δ 2,03-of 2.09 (m, 1H), 2,46-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,63 (d, J=6.0 Hz, 2H), 5,14 (DD, J=12.9 Hz, J=5.4 Hz, 1H), to 7.67-to $ 7.91 (m, 7H), 9,29 (t, J=5.7 Hz, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,6, 49,0, 99,1, 122,0, 123,5, 129,2, 129,8, 131,6, 133,3, 133,5, 137,3, 147,4, 165,8, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C21H16N3O5I: C, 48,76; H, 3,12; N, 8,12. Found: C, 48,64; H, 2,77; N, A 7.85.

5.40 N-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-methylsulfanyl-benzamide

4-(Methylthio)benzoic acid (0.52 g, 3.1 mmol) dissolved in DMF (20 ml) and added CDI (0.55 g, 3.4 mmol). The mixture is stirred at 40°C. for 1 hour. Add hydrochloride 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol) and the reaction mixture was stirred at 40°C. additional 90 minutes. The mixture is cooled to room temperature and left overnight under stirring. The reaction mixture was concentrated and the residue chromatographic on silica gel (ethyl acetate)to give 0.75 g of product with a yield of 56% in the form of a white solid. So pl. 187-189°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min,240 nm, 40/60 CH3CN/0.1% of H3PO4, br4.61 (95,58%).1H NMR (DMSO-d6) δ 2,03 is 2.10 (m, 1H), 2,46-2,63 (m, 2H), 2,52 (s, 3H), 2,83-2,95 (m, 1H), 4,63 (d, J=6.0 Hz, 2H), 5,14 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 7,35 (d, J=8,4 Hz, 2H), 7,80-to $ 7.91 (m, 5H), 9,18 (t, J=6.0 Hz, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 14,1, 22,0, 30,9, 42,6, 49,0, 121,9, 123,5, 124,9, 127,7, 129,8, 129,9, 131,6, 133,4, 142,8, 147,7, 165,9, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C22H19N3O5S+0,1 h2O: C, 60,15; H, TO 4.41; N, TO 9.57. Found: C, 59,98; H, 4,32; N, Being 9.61.

5.41 N-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-4-ethylsulfanyl-benzamid

4-(Ethylthio)benzoic acid (0.56 g, 3.1 mmol) dissolved in DMF (20 ml) and added CDI (0.55 g, 3.4 mmol). The mixture is stirred at 40°C. for 1 hour. Add hydrochloride 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1,00 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol) and the reaction mixture was stirred at 40°C. additional 90 minutes. The mixture is cooled to room temperature and left overnight under stirring. The reaction mixture was concentrated and the residue chromatographic on silica gel using a gradient of ethyl acetate : hexane, elwira product with a ratio of the ethyl acetate-hexane 80:20, obtaining 1.1 g of product with a yield of 81% in the form of a white solid. So pl. 175-177°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 6,93 (99,44%).1H NMR (DMSO-d6) ∆ 1,2 (t, J=7.5 Hz, 3H), 2,02-of 2.09 (m, 1H), 2,47-2,63 (m, 2H), 2,83-2,95 (m, 1H), 3,06 (kV, J=7.5 Hz, 2H), 4,63 (d, J=5.7 Hz, 2H), 5,14 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,37-7,39 (m, 2H), 7,80-to $ 7.91 (m, 5H), 9,18 (t, J=6,0 Hz, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 13,9, 22,0, 25,2, 30,9, 42,6, 49,0, 121,9, 123,5, 126,3, 127,8, 129,8, 130,4, 131,6, 133,4, 141,2, 147,6, 165,9, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C23H21N3O5S: C, 61,19; H, 4,69; N, 9,31. Found: C, 60,80; H, 4,34; N, Of 9.21.

5.42 N-((2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-isoindoline-5-yl)methyl)-2-(4-(triptoreline)phenyl)ndimethylacetamide

A mixture of 4-(triptoreline)phenylacetic acid (0.73 g, 3.1 mmol) and CDI (0.55 g, 3.4 mmol) in DMF (20 ml) was stirred at 40°C. for 2 hours, and then add the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol). After 2 hours the mixture is cooled to room temperature, poured into ethyl acetate (100 ml) and washed with NaHCO3(3×75 ml) and concentrated. The remainder chromatographic on silica gel (ethyl acetate)to give 1.2 g of product with a yield of 77% as a white solid. So pl. 140-142°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, a 3.87 (98,06%).1H NMR (DMSO-d6) δ 2,02-of 2.09 (m, 1H), 2,47-2,63 (m, 2H), 2,84-2,96 (m, 1H), 3,62 (s, 2H), 4,46 (d, J=5.8 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,45 (d, J=8,4 Hz, 2H), 7,65-to 7.77 (m, 4H), 7,87 (d, J=7.5 Hz, 1H), 8,82 (t, J=5.8 Hz, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 21,2, 30,1, 40,9, 41,3, 48,2, 119,9, 120,0, 121,1, 122,6, 128,8 (kV, J=306 Hz), 129,0, 1299, 130,8, 132,5, 135,3, 139,2, 146,5, 166,1, 166,2, 167,0, 171,9. Analysis: Calculated for C23H18N3O5F3S: C, 54,65; H AND 3.59; N, 8,31. Found: C, 54,45; H, To 3.73; N, 7,93.

5.43 Tert-butyl-N-((2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-isoindoline-5-yl)methyl)-benzamide

Thea added to the mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol) and 4-(tert-butyl)benzoyl chloride (0,61 g, 3.1 mmol) in acetonitrile (35 ml) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 ml) and ethyl acetate (100 ml) and the organic phase is separated and concentrated. The remainder chromatographic on silica gel using a gradient hexane-ethyl acetate, elwira 1.1 g of the product when the content of ethyl acetate 80-90%, with a yield of 80% in the form of a white solid. So pl. 164-166°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 4.26 deaths (99,57%).1H NMR (DMSO-d6) δ of 1.30 (s, 9H), 2,01-of 2.09 (m, 1H), 2,46-2,63 (m, 2H), 2,84-2,96 (m, 1H)and 4.65 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,49-7,52 (m, 2H), 7,79-to $ 7.91 (m, 5H), 9,16 (t, J=6.0 Hz, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 34,6, 42,5, 49,0, 121,9, 123,5, 125,1, 127,1, 129,7, 131,1, 131,6, 133,3, 147,8, 154,3, 166,3, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C25H25N3O5+0,25H2O: C, 66,43; H, 5,69; N, 9 : 30 A.M. Found: C, 66,49; H, 5,62; N, 8,96.

5.44 5-Bromo-N-[[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-ISO the valleys-5-yl]methyl]-picolinate

A mixture of 5-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 ml) is stirred under nitrogen atmosphere at 40°C. for 2 hours. Then add the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (of 0.67 g, 2.0 mmol) and the mixture is stirred at this temperature for additional 2 hours. The mixture is cooled to room temperature and the solvent is evaporated in vacuum. The residue is dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate (2×100 ml). The organic phase is evaporated. The remainder chromatographic on silica gel, using methylene chloride as the mobile phase. Get a pale red solid, this solid is triturated with 10 ml of acetonitrile for 16 hours. The solid phase is filtered and optionally washed with 7 ml of acetonitrile. The product is dried in vacuum, obtaining 0.55 g (yield 57%) as a white solid. So pl. 260-262°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 45/55 CH3CN/0.1% of H3PO4, 3,61 (RUB 96.62%).1H NMR (DMSO-d6) δ of 1.88 (s, 3H), 2.00 in of 2.08 (m, 1H), 2,49-2,62 (m, 2H), 2,65-by 2.73 (m, 1H), to 4.62 (d, J=6.3 Hz, 2H), 7,76-of 7.82 (m, 3H), of 7.97 (DD, J=8,4 Hz, J=0.6 Hz, 1H), compared to 8.26 (DD, J=8,4 Hz, J=2.3 Hz, 1H), 8,81 (DD, J=2.3 Hz, J=0.6 Hz, 1H), 9,63 (t, J=6.3 Hz, 1H), 11,00 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 29,1, 42,4, 58,7, 121,8, 123,1, 123,5, 123,9, 129,6, 131,3, 133,6, 140,5, 147,1, 148,5, 149,3, 163,5, 167,7, 167,8, 172,0, 172,1. Analysis:Calculated for C 21H17BrN4O5: C, 51,97; H, OF 3.53; N, 11,55. Found: C, 52,05; H, 3,44; N Is 11.39.

5.45 N-[[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-isoindoline-5-yl]methyl]-4-(methylsulfonyl)benzamide

A mixture of 4-(methylsulphonyl)benzoic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 ml) is stirred under nitrogen atmosphere at 40°C. for 2 hours. Then add the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (of 0.67 g, 2.0 mmol) and stirring is continued at this temperature for additional 2 hours. The mixture is cooled to room temperature and distributed between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic phase is washed with saturated aqueous sodium bicarbonate (2×100 ml) and evaporated. The remainder chromatographic on silica gel using a mixture of methylene chloride-methanol 99:1 as the mobile phase, receiving 0,30 g with a yield of 32%. The product obtained as a white solid. So pl. 165,5-167,5°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 4,08 (96,23%).1H NMR (DMSO-d6) δ is 2.09 (s, 3H), 2,22-of 2.28 (m, 1H), 2,73-2,95 (m, 3H), 3,47 (s, 3H), a 4.86 (d, J=5.7 Hz, 2H), 7,98-of 8.04 (m, 3H), of 8.25 (d, J=8.7 Hz, 2H), 8,32 (d, J=8.7 Hz, 2H), 9,58 (t, J=5.7 Hz, 1H), 11,21 (s, 1H);13With NMR (DMSO-d6) δ 23,0, 30,6, 31,1, 44,8, 45,6, 60,8, 123,7, 125,2, 129,2, 130,3, 131,7, 133,4, 135,5, 140,4, 145,2, 149,0, 167,2, 169,7, 169,9, 174,1, 174,2. Analysis is: Calculated for C 23H21N3O7S+0,3H2O: C, 56,50; H, OF 4.45; N, 8,59. Found: C, 56,61; H, Was 4.42; N, 8,30.

5.46 4-Ethyl-N-[[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-isoindoline-5-yl]methyl]benzamide

Thea (of 0.44 g, 4.4 mmol) is added to a mixture of 4-ethylbenzylamine (0.34 g, 2.0 mmol) and hydrochloride 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (of 0.67 g, 2.0 mmol) in acetonitrile (20 ml). The mixture is stirred at room temperature for 2 hours and evaporated in vacuum. The residue is partitioned between water (100 ml) and ethyl acetate (100 ml) and the organic phase is evaporated. The remainder chromatographic on silica gel using ethyl acetate as the mobile phase, receiving 0.65 g with a yield of 76%. The product obtained as a white solid. So pl. 160-162°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 45/55 CH3CN/0.1% of H3PO4, 4,20 (97,47%).1H NMR (DMSO-d6) δ 1,19 (t, J=7.7 Hz, 3H), 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,54-2,62 (m, 2H), 2,65-2,78 (m, 3H), br4.61 (d, J=6.0 Hz, 2H), 7,32 (d, J=8.1 Hz, 2H), 7,76-to 7.84 (m, 5H), 9,14 (t, J=6.0 Hz, 1H), br11.01 (s, 1H);13With NMR (DMSO-d6) δ 15,4, 21,1, 28,1, 28,6, 29,2, 42,6, 58,8, 121,6, 123,2, 127,4, 127,8, 129,6, 131,4, 131,5, 133,4, 147,6, 147,7, 166,4, 167,8, 167,9, 172,2, 172,3. Analysis: Calculated for C24H23N3O5: C 66,50; H, TO 5.35; N, RS 9.69. Found: C, To 66.30; H, 5,26; N, 9,56.

5.47 N-[[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-isoindoline-5-yl]methyl]-4-(triptoreline)-benzamide

Thea (of 0.44 g, 4.4 mmol) is added to a mixture of 4-(triptoreline)of benzoyl chloride (0,48 g, 2.0 mmol) and hydrochloride 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (of 0.67 g, 2.0 mmol) in acetonitrile (15 ml). The mixture is stirred at room temperature for 2 hours and evaporated in vacuum. The residue is partitioned between water (75 ml) and ethyl acetate (75 ml) and the organic phase washed with water (2×75 ml) and evaporated. The remainder chromatographic on silica gel using ethyl acetate as the mobile phase, receiving and 0.62 g of product with a yield of 62%. The product obtained as a white solid. So pl. 138-140°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 4,77 (96,89%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,54-2,60 (m, 2H), 2,63 is 2.75 (m, 1H), with 4.64 (d, J=6.0 Hz, 2H), 7,78-7,86 (m, 5H), 7,99-8,03 (m, 2H), 9,40 (t, J=6.0 Hz, 1H), br11.01 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 29,0, 42,7, 58,8, 121,7, 123,2, 126,5, 128,7, 129,5 (kV, J=306), 129,7, 131,4, 133,4, 135,9, 136,5, 147,0, 165,4, 167,7, 167,8, 172,1, 172,2. Analysis: Calculated for C23H18F3N3O5S: C, 54,65; H AND 3.59; N, 8,31. Found: C, 54,56; H, To 3.36; N, 8,24.

5.48 N-[[2-(2,6-Dioxo-piperidine-3-yl)-1-oxo-isoindoline-5-yl]methyl]-4-(triptoreline)-benzamide

Thea (0.65 g, 6.4 mmol) is added to a mixture of 4-(triptoreline)of benzoyl chloride (0,77 g, 3.2 mmol) and hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-di is at (1.0 g, 3.2 mmol) in DMF (25 ml). The mixture is stirred at room temperature for 1 hour and then diluted with water (40 ml) and stirred for 15 minutes. Precipitated precipitated solid is filtered and optionally washed with water (40 ml). The substance is stirred in 4% aqueous HCl (15 ml) and filtered, the solid is optionally washed with 4% aqueous HCl (15 ml) and water (15 ml). The solid is dried in vacuum, obtaining of 0.90 g of product as a cream solid color with yield 59%. So pl. 203-205°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 2,91 (96,41%).1H NMR (DMSO-d6) δ 1,96-2,03 (m, 1H), 2,31 at 2.45 (m, 1H), 2,54 2.63 in (m, 1H), 2,85 are 2.98 (m, 1H), or 4.31 (d, J=17,4 Hz, 1H), 4,45 (d, J=17,4 Hz, 1H), br4.61 (d, J=5,9 Hz, 2H), 5,11 (DD, J=13,2 Hz, J=5,1 Hz, 1H), 7,50 (d, J=7.8 Hz, 1H), 7,56 (s, 1H), of 7.70 (d, J=7.8 Hz, 1H), to 7.84 (d, J=8,1 Hz, 1H), 8,02 (d, J=8,1 Hz, 1H), 9,35 (t, J=5,9 Hz, 1H), 10,98 (s, 1H);13With NMR (DMSO-d6) δ 22,5, 31,2, 42,8, 47,1, 51,6, 122,1, 122,9, 126,3, 127,1, 128,7, 129,5 (kV, J=306), 130,4, 135,9, 136,8, 142,4, 143,6, 165,3, 167,9, 171,0, 172,8. Analysis: Calculated for C22H18F3N3O4S+0,4H2O: C, 54,52; H, 3,91; N, 8,65. Found: C, 54,51; H, 3,61; N, 8,64.

5.49 4-Ethylsulfanyl-N-[[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]methyl]benzamide

A mixture of 4-(ethylthio)benzoic acid (0.36 g, 2.0 mmol) and CDI (0.34 g, 2.1 mmol) in DMF (20 ml) stirred in an atmosphere of N2at 40°C for 2 hours. Then add hydroch Oric 5-aminomethyl-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0,67 g, 2.0 mmol) and stirring is continued at 40°C in an atmosphere of N2an additional 3 hours. The mixture is distributed between ethyl acetate (75 ml) and saturated aqueous sodium bicarbonate (100 ml), the aqueous phase is extracted with ethyl acetate (75 ml). The combined organic phases are then washed with saturated aqueous sodium bicarbonate (3×100 ml), dried (MgSO4) and evaporated. The remainder chromatographic (silica gel)using a gradient of ethyl acetate/hexane, getting to 0.92 g of product with a yield of 61% in the form of a white solid. So PL-137°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4that is 4.03 (99,73%).1H NMR (DMSO-d6) δ of 1.27 (t, 3H, J=7,3 Hz)to 1.99 (s, 3H), 2,00-2,02 (m, 1H), 2,49-to 2.65 (m, 3H), 3,06 (q, 2H, J=7,25 Hz), br4.61 (d, 2H, J=6.0 Hz), 7,38 (DD, 2H, J=6.0 Hz, J=3.0 Hz), 7,76-a 7.85 (m, 5H), 9,17 (t, 1H, J=6.0 Hz), br11.01 (s, 1H);13C NMR (DMSO-d6) δ 13,9, 21,0, 25,2, 28,5, 29,1, 42,6, 58,7, 121,6, 123,2, 126,3, 127,8, 129,6, 130,4, 131,4, 133,4, 141,2, 147,5, 165,9, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C24H23N3O5S+0,3H2O: C, 61,21; H, OF 5.05; N, 8,92. Found: C, 61,27; H, 5,13; N, 8,80.

5.50 4-Ethoxy-N-[[(2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]methyl]benzamide

A mixture of 4-(ethoxy)benzoic acid (0.33 g, 2.0 mmol) and CDI (0.34 g, 2.1 mmol) in DMF (20 ml) was stirred at 40°C in an atmosphere of N22 hours. Then add the hydrochloride of 5-aminomethyl-2-[(3S)-3-m is Teal-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0,67 g, 2.0 mmol) and stirring is continued at 40°C in an atmosphere of N2additional 2 hours. The reaction mixture is distributed between ethyl acetate (75 ml) and saturated aqueous sodium bicarbonate (100 ml). The aqueous phase is extracted with ethyl acetate (75 ml). The combined organic phases are then washed with saturated aqueous sodium bicarbonate (3×100 ml), dried (MgSO4) and evaporated. The remainder chromatographic (silica gel)using a gradient of ethyl acetate/hexane getting 0.27 g of product with a yield of 31% in the form of a white solid. So PL-165°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 5,73 (97,04%).1H NMR (DMSO-d6) δ of 1.34 (t, 3H, J=6.0 Hz), a 2.01 (s, 3H), 2,03-to 2.06 (m, 1H), 2,49-a 2.71 (m, 3H), 4.09 to (q, 2H, J=7.0 Hz), 4,60 (d, 2H, J=6.0 Hz), 7,00 (d, 2H, J=9,0), 7,75-7,87 (m, 5H), 9,06 (t, 1H, J=6.0 Hz), br11.01 (s, 1H);13With NMR (DMSO-d6) δ 14,5, 21,0, 28,5, 29,1, 42,5, 58,7, 63,3, 114,0, 121,5, 123,1, 125,9, 129,1, 129,5, 131,4, 133,3, 147,7, 161,0, 165,9, 167,7, 167,9, 172,1, 172,2. Analysis: Calculated for C24H23N3O6+0,75H2O: C, 62,26; H, 5,33; N, THE REMAINING 9.08. Found: C, 62,25; H, 5,13; N, 9,17.

5.51 N-((2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-isoindoline-5-yl)methyl)-5-(ethylthio)picolinate

Stage 1: a Mixture of 2-chloro-5-nitropyridine (25,0 g, 158 mmol) and diethylmalonate (21,9 g, 166 mmol) in DMF (150 ml) cooled to 0°C. in small portions, add sodium hydride (6.50 g of 60% dispersion in mineral is m oil 162 mmol). The mixture is stirred at 0°C for 1 hour, completing the addition. Then small portions add one equivalent of sodium hydride (6.50 g of 60% dispersion in mineral oil, 162 mmol). The reaction is quenched by addition of acetic acid (10 ml) and the mixture is evaporated to dryness. The residue left overnight for trituration with diethyl ether (150 ml), filtered, obtaining the crude dimethyl 2-(5-nitropyridine-2-yl)malonate as an orange solid.

Stage 2: the Crude product from step 1 are suspended in 250 ml of water in an ice bath and add 10h NaOH (15 ml). From a dropping funnel to add a hot solution of KMnO4(33.3 g, 210 mmol) in water (140 ml) and 10h NaOH (8 ml). Additional solid KMnO4(110 g, 690 mmol) added in several portions with 10h NaOH. Completing the addition, the mixture is heated to 95°C for 90 minutes. To the mixture add celite and filtered in the still hot through a bed of celite. The filter is washed with hot 2n NaOH (200 ml). The filtrate is cooled and the pH adjusted to 3-4 with concentrated HCl. The solid precipitate is filtered and dried, obtaining 9.4 g of 5-NITROPHENOL acid in the form of a cream solid color with the release of 35% in two stages.1H NMR (DMSO-d6) δ compared to 8.26 (DD, 1H, J=8.7 Hz, J=0.6 Hz), a total of 8.74 (DD, 1H, J=8.7 Hz, J=2.7 Hz), 9,44 (DD, 1H, J=2.7 Hz, J=0.6 Hz), 13,92 (user, 1H).

Stage 3: a Suspension of 5-NITROPHENOL acid (6.0 g, 36 mmol) in methanol HC (1.25 M) is refluxed and stirred for 16 hours. The mixture is cooled to ambient temperature. The product is filtered and optionally washed with methanol (20 ml) and dried in vacuum, obtaining 1.6 g of methyl 5-nitropyridine with the release of 94%.1H NMR (DMSO-d6) δ of 3.95 (s, 3H), 8,29 (DD, 1H, J=8,4 Hz, J=0.6 Hz), the rate of 8.75 (DD,1H,J=8,4 Hz, J=2.7 Hz), 9,46 (DD, 1H, J=2.7 Hz, J=0.6 Hz).

Stage 4: Atantis sodium (1.6 g, and 17.2 mmol) are added to a solution of methyl 5-nitropyridine (2.8 g, 16 mmol) in DMF (30 ml) and the resulting mixture was stirred at room temperature. After 3 hours add acetic acid (1 ml) and the mixture is evaporated to dryness. The residue is suspended in methanol (50 ml) and treated with 3n NaOH. The resulting mixture was stirred at room temperature for 16 hours and then evaporated. The residue is dissolved in water (100 ml), washed with ethyl acetate (2×100 ml) and acidified to pH 3-4 (conc. HCl), resulting in precipitation of the product. The precipitate is filtered, washed with water (100 ml) and dried in vacuum, obtaining 2.3 g of 5-(ethylthio)pikolinos acid with a yield of 79%.1H NMR (DMSO-d6) δ of 1.23 (t, 3H, J=7,3 Hz), 3,14 (q, 2H, J=7,3 Hz), 7,86 (DD, 1H, J=8,4 Hz, J=2.4 Hz), 7,95 (DD, 1H, J=8,4 Hz, J=0.9 Hz), to 8.57 (DD, 1H, J=2.4 Hz, J=0.9 Hz), to 13.09 (user, 1H).

Stage 5: CDI (of 0.44 g, 2.7 mmol) are added to a mixture of 5-(ethylthio)pikolinos acid (0,48 g, 2.6 mmol) and DMF (20 ml) and the resulting mixture was stirred at 40°C. for 2 hours. Then add methanesulfonate 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1,00 g, 2.6 mmol who) and stirring is continued at 40°C in an atmosphere of N 2an additional 3 hours. The mixture is distributed between ethyl acetate (75 ml) and saturated aqueous sodium bicarbonate (100 ml), the aqueous phase is extracted with ethyl acetate (75 ml). The combined organic phases are washed with saturated aqueous sodium bicarbonate (3×100 ml), dried (MgSO4) and evaporated. The remainder chromatographic (silica gel)using a gradient of ethyl acetate/hexane getting 0.65 g of product with a yield of 60% in the form of a white solid. So pl. 198-200°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 7,53 (97,70%).1H NMR (DMSO-d6) δ of 1.28 (t, 3H, J=7,3 Hz), 2,02-of 2.08 (m, 1H), 2,45-2,62 (m, 2H), 2,83-2,95 (m, 1H), 3,13 (q, 2H, J=7,3 Hz)and 4.65 (d, 2H, J=6.3 Hz), 5,14 (DD, 1H, J=12.9 Hz, J=5.4 Hz), 7,83-to 7.95 (m, 5H), 8,54 (DD, 1H, J=2,3 Hz, J=0.8 Hz), at 9.53 (t, 1H, J=6.3 Hz), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 13,8, 22,0, 25,2, 30,9, 42,3, 49,0, 122,1, 122,2, 123,5, 129,8, 131,5, 133,5, 135,4, 138,0, 146,3, 146,4, 147,5, 164,1, 167,0, 167,1, 169,8, 172,7. Analysis: Calculated for C22H20N4O5S: C, 58,40; H, TO 4.46; N, 12,38. Found: C, 58,27; H, Of 4.35; N, 12,30.

5.52 1-(2-Chloro-phenyl-)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

Stage 1: a Mixture of 4-Brattleboro anhydride (10.0 g, 44.1kHz mmol), hydrochloriderat-α-aminoglutethimide (7,25 g, to 44.0 mmol) and sodium acetate (3,61 g, to 44.0 mmol) in acetic acid (150 ml) and left overnight at boiling under reflux. P is a promotional mixture is cooled to room temperature and the solvent is evaporated in vacuum. The residue is stirred in water (170 ml) for 3 hours and the resulting solid is filtered off, optionally washed with water (80 ml) and dried in vacuum, to obtain 13.8 g of 5-bromo-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-5-dione with the release of 93%.1H NMR (DMSO-d6) δ 2,03 is 2.10 (m, 1H), 2,43-2,63 (m, 2H), 2,82-of 2.97 (m, 1H), 5,17 (DD, J=12,8 Hz, J=5.3 Hz, 1H), 7,85-7,88 (d, J=7.9 Hz, 1H), 8,10 (DD, J=7.9 Hz, J=1.7 Hz, 1H), 8,16 (d, J=1.7 Hz, 1H), of 11.15 (s, 1H);13With NMR (DMSO-d6) δ 21,9, 30,9, 49,2, 125,3, 126,4, 128,5, 130,1, 133,2, 137,6, 165,9, 166,4, 169,7, 172,7. Analysis: Calculated for C13H9N2O4Br: C, 46,32; H, 2,69; N, 8,31. Found: C, 46,23; H, 2,47; N, To 8.41.

Stage 2: DMF Tegaserod through nitrogen bubbler 1 hour and add 5-bromo-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (13,7 g, to 40.6 mmol), cyanide zinc (2.86 g, 24.4 mmol), Tris(dibenzylideneacetone)dipalladium (0.74 g, 0.80 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0,90 g, 1.6 mmol). The reaction mixture is heated to 120°C. for 3 hours, cooled to 60°C. and filtered through celite. The filter additionally washed with DMF (160 ml), and the filtrate is evaporated in vacuum. The residue is stirred in water (300 ml) for 2 days and filtered, optionally washed with water and dried in vacuum. The obtained solid is triturated with acetone (300 ml) for 1 hour and filtered, the solid is optionally washed with acetone (300 ml) and dried in vacuum. The resulting substance is boiled in methanol under reflux for 1 hour, cooled to room is temperature, filtered, optionally washed with methanol and dried, to obtain 11.1 g of 2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile with the release of 96%. So pl.>60'C.1H NMR (DMSO-d6) δ 2,03-2,12 (m, 1H), 2,43-of 2.64 (m, 2H), 2,83-of 2.97 (m, 1H), 5,22 (DD, J=12,8 Hz, J=5,2 Hz, 1H), 8,12 (d, J=7.8 Hz, 1H), scored 8.38 (DD, J=7.8 Hz, J=1.4 Hz, 1H), 8,49 (s, 1H), 11,17 (s, 1H);13With NMR (DMSO-d6) δ 21,8, 30,9, 49,3, 117,0, 117,4, 124,2, 127,3, 131,8, 134,5, 139,1, 165,6, 165,9, 169,5, 172,7. Analysis: Calculated for C14H9N3O4+0,3H2O: C, 58,26; H, 3,35; N, 14,56. Found: C, 58,01; H, A 3.01; N, 14,37.

Stage 3: a Mixture of 2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile (1,00 g of 3.53 mmol), 4n HCl (4.5 ml), 10% Pd-C (0.1 g) and coal for discoloration (0.06 g) in DMF (30 ml), left overnight to hydrogenation at 50 psi. Add water (5 ml) and the reaction mixture filtered through celite. The filter is washed with methanol (10 ml). The filtrate is concentrated and the residue is evaporated together with ethanol (2×5 ml). The obtained solid is triturated with ethanol (5 ml) for 1 hour, filtered, optionally washed with ethanol (10 ml) and dried, obtaining 0.97 g of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione as a white solid with a yield of 85%. So pl.>260°C.1H NMR (DMSO-d6) δ 2,05-2,12 (m, 1H), 2,45 2.63 in (m, 2H), 2,83 are 2.98 (m, 1H), 4,24 (s, 2H), by 5.18 (DD, J=12,6 Hz, J=5.4 Hz, 1H), of 7.96-8,03 (m, 2H), 8,11 (s, 1H), 8,73 (user, 3H), of 11.15 (s, 1H);13With NMR (DMSO-d6) is 22,0, 30,9, 41,7, 49,1, 123,6, 123,9, 131,0, 131,5, 135,4, 141,5, 166,8, 166,9, 169,8, 172,7. Analysis: Calculated for C14H14N3O4Cl+0,15H2O: C, 51,51; H, WAS 4.42; N, 12,87. Found: C, 51,16; H, And 4.40; N, 12,59.

Stage 4: a Mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 2-chlorophenylalanine (of 0.36 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (100 ml) and washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml). During this washing the precipitated solid. It is filtered and optionally washed with water. The organic phase of the filtrate is dried (MgSO4) and the solvent is removed in vacuum. The combined solid phase is stirred in ether for 3 hours and filtered, to obtain 1.2 g of product with a yield of 92%. So pl. 238-240°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 4,34 (98,10%).1H NMR (DMSO-d6) δ 1,99-of 2.08 (m, 1H), 2,50 2.63 in (m, 2H), 2,82-2,95 (m, 1H), 4,51 (d, J=5.8 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5.3 Hz, 1H), 6,94-the 7.43 (m, 3H), of 7.65 (t, J=5.8 Hz, 1H), 7,79-to 8.14 (m, 4H), 8,24 (s, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,6, 49,0, 121,1, 121,6, 121,7, 122,8, 123,6, 127,5, 129,1, 129,8, 131,7, 133,3, 136,5, 148,2, 154,9, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C21H17N4O5Cl+0,1 h2O: C, 56,98; H, 392; N 12,66. Found: C, 56,71; H, Of 4.05; N, Of 12.33.

5.53 1-(3-Chlorophenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 3-chlorophenylalanine (and 0.37 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (150 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated. The obtained solid was stirred in ether for 3 hours and filtered, obtaining 1.2 g of product with a yield of 92%. So pl. 214-216°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 4,58 (98,39%).1H NMR (DMSO-d6) δ 1,99-2,07 (m, 1H), 2,50-2,62 (m, 2H), 2,82-2,95 (m, 1H), 4,47 (d, J=5.5 Hz, 2H), 5,14 (DD, J=12,5 Hz, J=5,1 Hz, 1H), 6,93-6,98 (m, 2H), 7,22-7,28 (m, 2H), 7,66-to $ 7.91 (m, 4H), 8,96 (s, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 116,2, 117,2, 120,8, 121,7, 123,5, 129,7, 130,2, 131,6, 133,1, 133,2, 141,9, 148,5, 155,1, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C21H17N4O5Cl+0,1 h2O: C, 56,98; H, TO 3.92; N, 12,66. Found: C, 56,96; H, 3,70; N, 12,29.

5.54 1-(4-Chlorophenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]urea

<> A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-chlorophenylalanine (range 0.38 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) was stirred at 40°C for 2 days. The reaction mixture is cooled to room temperature. The solid is filtered, washed with water (20 ml), washed with ethyl acetate (20 ml) and dried, to obtain 0.64 g of product with a yield of 48%. So pl. 278-280°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 4,18 (98,85%).1H NMR (DMSO-d6) δ 2,03-2,07 (m, 1H), 2,46-2,62 (m, 2H), 2,82-2,96 (m, 1H), 4,47 (d, J=5.8 Hz, 2H), 5,14 (DD, J=12,5 Hz, J=5,2 Hz, 1H), 6,91 (t, J=5.8 Hz, 1H), 7,26 (d, J=8,8 Hz, 2H), 7,44 (d, J=8,9 Hz, 2H), to 7.77-to $ 7.91 (m, 3H), 8,89 (s, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 119,3, 121,7, 123,5, 124,7, 128,5, 129,7, 131,6, 133,2, 139,3, 148,6, 155,1, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C21H17N4O5Cl+0,3H2O: C, 56,52; H, 3,98; N, 12,55. Found: C, 56,19; H, Of 3.78; N, To 12.28.

5.55 1-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(2-methoxyphenyl)-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 2-methoxyphenylalanine (and 0.40 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature, the solvent delete the exist in a vacuum. The residue is suspended in a two-phase mixture of ethyl acetate (150 ml) and dilute aqueous HCl (150 ml). The solid is filtered and washed with water (50 ml). The obtained solid substance chromatographic using a gradient of methanol-CH2Cl2, elute the product with a ratio of methanol-CH2Cl25:95, receiving the product (0,090 g, yield 7%). So pl. 276-278°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 8,93 (98,32%).1H NMR (DMSO-d6) δ 2,02-of 2.09 (m, 1H), 2,46-2,62 (m, 2H), 2,83-2,95 (m, 1H), 3,84 (s, 3H), 4,48 (d, J=5.8 Hz, 2H), 5,15 (DD, J=12,8 Hz, J=5.3 Hz, 1H), 6,83-of 6.99 (m, 3H), 7,51 (t, J=6.0 Hz, 1H), 7,78-8,11 (m, 5H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,5, 49,0, 55,6, 110,59, 118,11, 120,4, 121,3, 121,6, 123,5, 129,1, 129,7, 131,6, 133,2, 147,4, 148,6, 155,2, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H20N4O6+1,2H2O: C, 57,69; H, IS 4.93; N, 12,23. Found: C, 57,63; H, 4,19; N, 11,84.

5.56 1-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-methoxyphenyl)-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-methoxyphenylalanine (of 0.39 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) was stirred at 40°C for 2 days. The reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (150 ml) and washed with diluted in the ne HCl (2×150 ml) and water (2×150 ml). The solvent is removed in vacuo and the resulting solid chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl25:95, get 0,57 g of product with a yield of 44%. So pl. 241 to 243°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 5,69 (98,79%).1H NMR (DMSO-d6) δ 2,04-of 2.08 (m, 1H), 2.49 USD 2.63 in (m, 2H), 2,85-2,90 (m, 1H), 3,69 (s, 3H), of 4.45 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 6.75 in (t, J=6.0 Hz, 1H), 6,80-6,84 (m, 2H), 7,29-to 7.32 (m, 2H), to 7.77-to $ 7.91 (m, 3H), 8,51 (s, 1H), 11,13 (s, 1H);1H NMR (DMSO-d6) δ 22,0, 30,9, 42,6, 49,0, 55,1, 113,8, 119,6, 121,7, 123,5, 129,6, 131,6, 133,2, 133,3, 148,9, 154,1, 155,5, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H20N4O6: C, 60,55; H, TO 4.62; N, 12,84. Found: C, 60,22; H, Of 4.35; N, Br12.62.

5.57 1-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-m-tolyl-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), m-trilinoleate (range 0.38 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The solid is filtered, optionally washed with acetonitrile (20 ml) and dried in vacuum, obtaining 0,72 g of product with a yield of 57%. So pl. 220-222°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, to 5.21 (95,95%).1H NMR (DMSO-d6) is 2,02 is 2.10 (m, 1H), 2,24 (s, 3H), 2,48-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,47 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 6,72 (d, J=7.2 Hz, 1H), 6,83 (t, J=6.0 Hz, 1H), 7,07-7,25 (m, 3H), 7,78-of 7.82 (m, 2H), of 7.90 (d, J=7.8 Hz, 1H), 8,64 (s, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 21,2, 22,0, 30,9, 42,6, 49,0, 115,0, 118,4, 121,7, 122,0, 123,5, 128,5, 129,6, 131,6, 133,2, 137,7, 140,2, 148,8, 155,3, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H20N4O5: C, 62,85; H, 4,79; N, 13,33. Found: C, 62,54; H, 4,60; N, 13,38.

5.58 1-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-p-tolyl-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), p-trilinoleate (range 0.38 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in CH2Cl2(20 ml) and left overnight under stirring at room temperature. The solid is filtered, optionally washed with CH2Cl2(20 ml). The solid phase is left overnight under stirring in methanol, refluxed for 3 hours and filtered. The filtrate is concentrated and the residue is stirred in ethyl acetate and filtered. Combine the solid phase, get 0,70 g of product with a yield of 56%. So pl. 238-240°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 4,66 (98,56%).1H NMR (DMSO-d6) δ 1,99 is 2.10 (m, 1H), of 2.21 (s, 3H), 2,47-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,46 (d, J=5.7 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 6,79 (t, J=6.0 Hz, 1H), 7,03 (d, J=8,4 Hz, 2H),7,29 (d, J=8,4 Hz, 2H), 7,78-to $ 7.91 (m, 3H), 8,59 (s, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 20,3, 22,0, 30,9, 42,6, 49,0, 117,94, 121,7, 123,5, 129,0, 129,6, 130,0, 131,6, 133,2, 137,7, 148,9, 155,3, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H20N4O5+0,1 h2O: C, 62,58; H, 4,82; N, OF 13.27. Found: C, 62,37; H, 4,55; N, 12,92.

5.59 1-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-trifloromethyl)-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-(triptoreline)phenylisocyanate (0.45 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (150 ml) and washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml). The solvent is removed in vacuo and the residue left overnight under stirring in ether (20 ml). The obtained solid phase is filtered, receive the product (1.3 g, yield 89%). So pl. 226-228°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 9,50 (98,37%).1H NMR (DMSO-d6) δ 2,02-of 2.09 (m, 1H), 2,47-2,63 (m, 2H), 2,83-2,95 (m, 1H), 4,48 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 6,93 (t, J=6.0 Hz, 1H), 7.23 percent (d, J=8,4 Hz, 2H), 7,49-rate of 7.54 (m, 2H), 7,79-to $ 7.91 (m, 3H), 8,96 (s, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,6, 49,0, 118,9, 120,16 (kV, J=254 Hz), 21,6, 121,7, 123,5, 129,7, 131,6, 133,2, 139,59, 142,1, 148,6, 155,2, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H17N4O6F3: C 53,88; H, 3,49; N, 11,42. Found: C, 53,80; H, 3,15; N, 11,25.

5.60 1-(4-Cyanophenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-cyanophenylacetic (of 0.43 g, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in CH2Cl2(20 ml) was stirred at room temperature for 2 days. The solid phase is filtered and optionally washed with CH2Cl2(20 ml). The solid is stirred in ethyl acetate for 3 hours and filtered. The residue is purified preparative HPLC using a gradient of acetonitrile-water, elwira product with a ratio of acetonitrile-water 35:65, obtain 0.56 g of product with a yield of 43%. So pl. 265-267°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 8,97 (97,25%).1H NMR (DMSO-d6) δ 2,04-of 2.08 (m, 1H), 2,50 2.63 in (m, 2H), 2,83-2,95 (m, 1H), 4,49 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,18 (t, J=5.7 Hz, 1H), 7,58-of 7.69 (m, 4H), 7,79-to $ 7.91 (m, 3H), 9,38 (s, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,6, 49,0, 102,6, 117,6, 119,4, 121,7, 123,5, 129,7, 131,6, 133,1, 133,2, 144,8, 148,3, 154,8, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H17N5O5+0,4H2O: C, 60,25; H, 4.09 TO; N 15,97. Found: C, 59,87; H, 3,70; N $ 15.87 With.

5.61 1-(4-Tre the-butyl-phenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-(tert-butyl)-phenylisocyanate (0.52 g, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (100 ml) and washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated. The solid is left overnight under stirring in ether and filtered, to obtain 0.34 g of product with a yield of 24%. So pl. 207-209°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 4,87 (95,56%).1H NMR (DMSO-d6) δ 1,24 (s, 9H), 2,02-of 2.09 (m, 1H), 2.49 USD 2.63 in (m, 2H), 2,83-2,95 (m, 1 H), 4,47 (d, J=5.7 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), 6,79 (t, J=6.0 Hz, 1H), 7,22-7,33 (m, 4H), 7,78 - to $ 7.91 (m, 3H), 8,96 (s, 1H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 31,2, 33,8, 42,6, 49,0, 117,7, 121,6, 123,5, 125,2, 129,6, 131,6, 133,2, 137,6, 143,5, 148,9, 155,3, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C25H26N4O5+0,15H2O: C, 64,55; H, 5,70; N, 12,04. Found: C, 64,17; H, 5,44; N, 11,90.

5.62 1-(3,4-Dichloro-phenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 3,4-dichlo is phenylisocyanate (0.56 g, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in pyridine (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is suspended in a two-phase mixture of CH2Cl2(150 ml) and water (150 ml) and stirred for 2 hours. The solid is filtered, optionally washed with water (50 ml) and dried. The obtained solid was stirred in methanol (200 ml) at room temperature for 1 hour, filtered and dried. This substance is refluxed in methanol (2×200 ml) for 3 hours, filtered and dried. The obtained solid substance chromatographic using a gradient of methanol-CH2Cl2(with 0.1% triethylamine), elute of 0.23 g of the product when the ratio of methanol-CH2Cl2(with 0.1% triethylamine) 7:93 to exit 16%. So pl. 290-292°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 10,50 (97,00%).1H NMR (DMSO-d6) δ 2,03-2,07 (m, 1H), 2,56-2,62 (m, 2H), 2,82-to 2.94 (m, 1H), 4,47 (d, J=5,9 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5.4 Hz, 1H), 7,05 (t, J=6,1 Hz, 1H), 7,29 (DD, J=8,8 Hz, J=2.4 Hz, 1H), 7,46 (d, J=8,8 Hz, 1H), to 7.77-to $ 7.91 (m, 4H), 9,11 (s, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 117,9, 118,9, 121,7, 122,4, 123,5, 129,7, 130,4, 130,9, 131,6, 133,3, 140,6, 148,4, 155,0, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C21H16N4O5Cl2+0,25H2O: C, 52,57; H, 3,47; N, 11,68. Found: C, 52,22; H, 3,25; N, To 11.56.

5.63 1-(3,4-D is methyl-phenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 3,4-dimethylphenylsilane (0,42 g, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) was stirred at 40°C for 2 days. The reaction mixture is cooled to room temperature. The solid is filtered, washed with water (20 ml), washed with ethyl acetate (20 ml) and dried, to obtain 1.0 g of product with a yield of 78%. So pl. 238-240°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 5,35 (98,53%).1H NMR (DMSO-d6) δ 2,03-2,07 (m, 1H), 2,12 (s, 3H), of 2.15 (s, 3H), 2,46-2,62 (m, 2H), 2,82-2,96 (m, 1H), 4,45 (d, J=5,9 Hz, 2H), 5,14 (DD, J=12,6 Hz, J=5.3 Hz, 1H), 6,77 (t, J=5,9 Hz, 1H), of 6.96 (d, J=7,0 Hz, 1H), 7,09-7,18 (m, 2H), to 7.77-to $ 7.91 (m, 3H), charged 8.52 (s, 1H), 11,12 (s, 1 H);13With NMR (DMSO-d6) δ 18,6, 19,6, 22,0, 30,9, 42,6, 49,0, 115,5, 119,3, 121,7, 123,5, 128,8, 129,5, 129,6, 131,6, 133,2, 136,1, 137,9, 148,9, 155,3, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C23H22N4O3+0,4H2O: C, 62,55; H, 5,20; N, 12,69. Found: C, 62,22; H, 5,12; N, KZT 12.39.

5.64 1-(3-Chloro-4-methyl-phenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 3-chloro-4-methyleneglutarate (of 0.41 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. D clonney the mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is stirred two-phase mixture of CH2Cl2(150 ml) and water (150 ml) and the organic solvent is removed in vacuum. The obtained solid is filtered and left overnight under stirring in methanol (100 ml) at room temperature, filtered and dried, obtaining the product as a white solid (1.2 g, yield 88%). So pl. 243-245°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 8,42 (98,48%).1H NMR (DMSO-d6) δ 2,04-of 2.09 (m, 1H), 2,24 (s, 3H), 2,47-of 2.64 (m, 2H), 2,83-2,96 (m, 1H), 4,47 (d, J=5.6 Hz, 2H), 5,16 (DD, J=12.3 Hz, J=4.9 Hz, 1H), 6,92 (t, J=5.7 Hz, 1H), 7,13-7,21 (m, 2H), 7,66-a 7.92 (m, 4H), 8,86 (s, 1H), 11,14 (s, 1H);13With NMR (DMSO-d6) δ 18,7, 22,0, 30,9, 42,7, 49,0, 116,5, 117,8, 121,7, 123,5, 127,5, 129,7, 131,0, 131,6, 133,0, 133,2, 139,5, 148,6, 155,1, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H19N4O5Cl+0,4H2O: C, 57,19; H, 4,32; N, 12,12. Found: C, 56,80; H, 4,12; N, 11,75.

5.65 1-(4-Chloro-3-methyl-phenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-chloro-3-(trifluoromethyl)phenylisocyanate (0,66 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in CH2Cl2(20 ml) was stirred at room temperature for 2 days. The solid is filtered and optionally washed with CH2Cl2(20 ml) and dried, obtaining 1.0 g p is oduct with yield 68%. So pl. 285-287°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 6,01 (95,01%).1H NMR (DMSO-d6) δ 2,02-of 2.09 (m, 1H), 2,46-2,63 (m, 2H), 2,84-to 2.94 (m, 1H), 4,49 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5.4 Hz, 1H), to 7.09 (t, J=6.0 Hz, 1H), 7,54-the 7.65 (m, 2H), 7,79-7,94 (m, 3H), of 8.06 (d, J=2.4 Hz, 1H), 9,29 (s, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 116,3 (kV, J=6.0 Hz), 122,8 (kV, J=270 Hz), 121,6, 121,7, 122,5, 123,5, 126,6 (kV, J=30 Hz), 129,7, 131,8, 131,6, 133,2, 139,9, 148,4, 155,0, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C20H16N4O5ClF3+0,2H2O: C, 51,03; H, AND 3.31; N, 10,82. Found: C, 50,68; H, 2,96; N, 10,55.

5.66 1-Benzo[1,3]dioxol-5-yl-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 3,4-(methylendioxy)phenylisocyanate (0,49 g, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in methylene chloride (20 ml) was stirred at room temperature for 1 hour. The solid is filtered and optionally washed with methylene chloride (20 ml), dried in vacuum, get 0,86 g of product with a yield of 64%. So pl. 200-202°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 3,10 (96,75%).1H NMR (DMSO-d6) δ 2,02-of 2.09 (m, 1H), 2,48-2,63 (m, 2H), 2,83-to 2.94 (m, 1H), 4,45 (d, J=6.0 Hz, 2H), 5,15 (DD, J=12,6 Hz, J=5,1 Hz, 1H), to 5.93 (s, 2H), 6,70-to 6.80 (m, 3H), 7,16 (d, J=1.8 Hz, 1H), to 7.77-to $ 7.91 (m, 3H), to 8.62 (s, 1H), 11,13 (8 1H); 13With NMR (DMSO-d6) δ 22,0, 30,9, 42,6, 49,0, 110,6, 100,6, 108,0, 110,5, 121,7, 123,5, 129,6, 131,6, 133,2, 134,7, 141,6, 147,1, 148,8, 155,4, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C22H18N4O7+0,1 h2O: C, 58,43; H, 4,06; N, KZT 12.39, Found: C, 58,20; H, Of 3.78; N, 12,21.

5.67 1-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-naphthalene-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (1.0 g, 3.1 mmol), 1-naphthylisocyanate (0.52 g, 3.1 mmol) and triethylamine (0,63 g, 6.2 mmol) in THF (35 ml) is heated to 40°C. in a nitrogen atmosphere with stirring for 21 hours. The mixture is cooled to room temperature and distributed between ethyl acetate (100 ml) and dilute aqueous HCl (100 ml) and the organic phase washed with water (2×100 ml), dried (MgSO4) and evaporated. The remainder chromatographic using a gradient of methylene chloride-methanol, elwira product with a ratio of methylene chloride-methanol 19:1. This substance is further purified preparative HPLC using isocratic elution with a mixture of acetonitrile-water 40-60, and obtain 0.3 g as a white solid (21%). So pl. 229-231°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4that was 4.76 (96,81%).1H NMR (DMSO-d6) δ 1,96-2,03 (m, 1H), 2,40-of 2.56 (m, 2H), was 2.76-2,89 (m, 1H), 4,48 (d, J=6.0 Hz, 2H), 5,09 (DD, J=12,6 Hz, J=5.4 Hz, 1H), 7,17 (t, J=6.0 Hz, 1H), was 7.36 (t, J=8.0 Hz, 1H), 7,44-rate of 7.54 (m, 3H), 7,76-7,89 (m, 5H), of 8.04 (d, J=7.8 Hz, 1H), 8,68 (s, 1H), 11,06 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 42,7, 49,0, 117,2, 121,5, 121,7, 122,5, 123,5, 125,5, 125,8, 125,9, 128,3, 129,7, 131,6, 133,2, 133,7, 134,8, 148,7, 155,8, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C25H26N4O5+0,2H2O: C, 65,27; H, TO 4.47%; N, 12,18. Found: C, 65,32; H, To 4.17; N, 12,14.

5.68 1-Butyl-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.97 g, 3.0 mmol), utilizationof (0.33 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue is dissolved in ethyl acetate (100 ml) and washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The residue is purified preparative HPLC using isocratic elution with a mixture of acetonitrile-water 35:65, receiving 0.20 g of product with a yield of 17%. So pl. 171-173°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 35/65 CH3CN/0.1% of H3PO4, 3,13 (97,37%).1H NMR (DMSO-d6) δ of 0.87 (t, J=6.9 Hz, 3H), 1,21-of 1.41 (m, 4H), 2,02 is 2.10 (m, 1H), 2,46-2,63 (m, 2H), and 2.83-2.91 in (m, 1H), 2,94 totaling 3.04 (m, 2H), 4,36 (d, J=6.0 Hz, 2H), 5,14 (DD, J=12,6 Hz, J=5.4 Hz, 1H), 6,07 (t, J=5.7 Hz, 1H), 6,51 (t, J=6.0 Hz, 1H), 7,71-7,88 (m, 3H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 13,7, 19,5, 22,0, 30,9, 32,1, 39,0, 42,7, 49,0, 121,5, 123,4, 129,5, 131,5, 133,0, 149,5, 158,, 167,0, of 167.2, 169,8, 172,7. Analysis: Calculated for C19H22N4O5: C 59,06; H, 5,74; N, 14,50. Found: C, 58,84; H, 5,73; N, 14,29.

5.69 1-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-pentyl-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), penalization (of 0.39 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in CH2Cl2(20 ml) and left overnight under stirring at room temperature. The solid is filtered, optionally washed with CH2Cl2(20 ml) and methanol (20 ml). The substance dries, yielding 0.54 g of product with a yield of 45%. So pl. 176-178°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4and 3.15 (98,59%).1H NMR (DMSO-d6) δ 0,86 (t, J=6.6 Hz, 3H), 1.18 to to 1.42 (m, 6H), 2,02 is 2.10 (m, 1H), 2,46-2,63 (m, 2H), 2,83-3,03 (m, 3H), 4,46 (d, J=6.3 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 6,07 (t, J=5.7 Hz, 1H), 6,51 (t, J=6.0 Hz, 1H), 7,71-7,88 (m, 3H), 11,12 (s, 1H);13With NMR (DMSO-d6) δ 13,9, 21,9, 22,0, 28,6, 29,6, 30,9, 39,3, 42,7, 48,9, 121,5, 123,4, 129,5, 131,5, 133,1, 149,5, 158,0, 167,0, 167,2, 169,8, 172,7. Analysis: Calculated for C20H24N4O5: C 59,99; H, 6,04; N, 13,99. Found: C, 59,65; H, Of 5.89; N, 13,86.

5.70 1-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-hexyl-urea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-IsoIn the ol-1,3-dione (0.97 g, 3.0 mmol), mexilitine (of 0.43 ml, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature. and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (150 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated. The residue is purified preparative HPLC using isocratic elution with a mixture of acetonitrile-water 55:45, getting to 0.67 g of product with a yield of 54%. So pl. 162-164°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 3,41 (99,34%).1H NMR (DMSO-d6) δ of 0.85 (t, J=6.3 Hz, 3H), 1,24-of 1.36 (m, 8H), 2,03-2,07 (m, 1H), 2,45-2,62 (m, 2H), 2,82-only 2.91 (m, 1H), 2,96-3,03 (m, 2H), 4,36 (d, J=5,9 Hz, 2H), 5,14 (DD, J=12,5 Hz, J=5.3 Hz, 1H), 6,07 (t, J=5.6 Hz, 1H), of 6.52 (t, J=6.0 Hz, 1H), 7,71-7,76 (m, 2H), 7,87 (d, J=7.7 Hz, 1H), 11,12 (s, 1 H);13With NMR (DMSO-d6) δ 13,9, 22,0, 22,1, 26,0, 29,9, 30,9, 31,0, 39,37, 42,8, 49,0, 121,6, 123,4, 129,5, 131,5, 133,1, 149,5, 158,0, 167,1, 167,2, 169,8, 172,7. Analysis: Calculated for C21H26N4O5+0,15H2O: C, 60,46; H, 6.35MM; N, 13,43. Found: C, 60,17; H, 6,23; N, 13,57.

5.71 1-(4-Chlorophenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-thiourea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), 4-chlorophenothiazine (0.51 g, 3.0 mmol) and N,N-diisopropylethylamine (1,05 is l, to 6.00 mmol) in THF (20 ml) and left overnight under stirring at 40°C. the Reaction mixture is cooled to room temperature, and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The obtained solid is left overnight under stirring in ether and filtered. The solid is purified preparative HPLC using isocratic elution with a mixture of acetonitrile-water 40:60. Thus obtained solid was stirred in ether and filtered, receiving 0.75 g of product with a yield of 55%. So pl. 239-241°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4that is 6.19 (95,49%).1H NMR (DMSO-d6) δ 2,03 is 2.10 (m, 1H), 2,46-2,63 (m, 2H), 2,84-2,96 (m, 1H), 4,91 (d, J=5.4 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,37-7,40 (m, 2H), 7,45-of 7.48 (m, 2H), 7,80-to 7.84 (m, 2H), 7,89-to $ 7.91 (m, 1H), 8,46 (s, 1H), of 9.89 (s, 1H), 11,13 (s, 1H);13With NMR (DMSO-d6) δ 22,0, 30,9, 46,8, 49,0, 121,9, 123,4, 125,1, 128,3, 128,5, 129,7, 131,4, 133,4, 138,0, 147,2, 167,0, 167,2, 169,8, 172,7, 181,2. Analysis: Calculated for C21H17N4O4SCl: C, 55,20; H, Of 3.75; N, Of 12.26. Found: C, 54,81 ; H, 3,51; N, 12,05.

5.72 1-[2-(2,6-Dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-p-tolyl-thiourea

A mixture of the hydrochloride of 5-aminomethyl-2-(2,6-dioxo-piperidine-3-yl)-isoindole-1,3-dione (0.97 g, 3.0 mmol), p-tolerization Janata (0.45 g, 3.0 mmol) and N,N-diisopropylethylamine (1,05 ml of 6.00 mmol) in THF (20 ml) is heated to 40°C and left overnight under stirring. The reaction mixture is cooled to room temperature and the solvent is removed in vacuum. The residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml). The solid is filtered. The organic layer of the two-phase filtrate is evaporated and the residue combined with a solid, which was filtered. This solid is left overnight under stirring in ether and filtered. The obtained solid was stirred in DMF (10 ml), filtered, optionally washed with DMF and water. The solid is stirred in ether and filtered, obtaining 0.31 g of product with a yield of 24%. So pl. 246-248°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 6,47 (96,05%).1H NMR (DMSO-d6) δ 2,02 is 2.10 (m, 1H), of 2.38 (s, 3H), 2,46-2,63 (m, 2H), 2,83-2,96 (m, 1H), 4,89 (d, J=5.7 Hz, 2H), 5,15 (DD, J=12.9 Hz, J=5.4 Hz, 1H), 7,12-7,26 (m, 4H), 7,79-to 7.95 (m, 3H), 8,23 (t, 1H), 9,71 (s, 1H), 11,13 (, 1H);13With NMR (DMSO-d6) δ 20,5, 22,0, 30,9, 46,9, 49,0, 121,9, 123,4, 124,1, 129,3, 129,6, 131,4, 133,4, 134,1, 136,0, 147,6, 167,0, 167,2, 169,8, 172,7, 181,1. Analysis: Calculated for C22H20N4O4S+0,1 h2O: C, 60,29; H, 4,65; N5 12,78 Found: C, 60,10; H, 4,36; N, 12,67.

5.73 1-(4-Chlorophenyl)-3-[2-(3S)-(3-methyl-2,6-dioxo-piperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

Stage 1: a Mixture of 4-Brattleboro anhydride (7,53 g, a 33.2 mmol), hydrobromide (3S)-3-amino-3-methyl-piperidine-2,6-dione (8.00 g, 44.1kHz mmol) and sodium acetate (2,72 g, a 33.2 mmol) in acetic acid (150 ml) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and the solvent is evaporated in vacuum. The residue is stirred in water (170 ml) for 3 hours and the resulting solid is filtered, optionally washed with water (80 ml) and dried, to obtain 6.3 g of 5-bromo-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione to yield 54%.1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,01-of 2.09 (m, 1H), 2,53-by 2.73 (m, 3H), 7,79 (DD, J=5.7 Hz, J=2.7 Hz, 1H), of 8.06 (m, 2H), 11,04 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 29,0, 58,9, 124,9, 125,9, 128,3, 130,0, 133,0, 137,4, 166,6, 167,2, 172,0, 172,1.

Stage 2: DMF (160 ml) Tegaserod through nitrogen bubbler 1 hour and add 5-bromo-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (of 6.31 g, 18.0 mmol), cyanide zinc (1.26 g, the 10.8 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.33 g, 0.40 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0.4 g, 0.7 mmol). The reaction mixture is heated to 120°C. for 3 hours, cooled to 60°C. and filtered through celite. The filter additionally washed with DMF (100 ml) and the filtrate is evaporated in vacuum. The residue is stirred in water (200 ml) for 2 days and filtered, optionally washed with water (50 ml) and dried. The obtained solid is triturated with acetone (50 ml) and stirred is 1 hour, and filtered and optionally washed with acetone (40 ml). Drying gives 4.7 g of 2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile with the release of 88%. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, to 5.21 (98,40%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02 is 2.10 (m, 1H), of 2.51-by 2.73 (m, 3H), 8,03 (d, J=7.8 Hz, 1H), with 8.33 (DD, J=7.8 Hz, J=1.5 Hz, 1H), 8,40 (s, 1H), 11,06 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,5, 28,9, 59,1, 116,7, 117,4, 123,8, 126,9, 131,7, 134,4, 138,8, 166,3, 166,6, 171,8, 172,2.

Stage 3: a Mixture of 2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile (4,70 g, 15.8 mmol), 4n HCl (21 ml), 10% Pd-C (1.88 g) in CH3HE (200 ml) hydronaut at 50 psi H216 hours. Add water (24 ml) and the reaction mixture filtered through celite. The advanced filter is washed with methanol (50 ml). The filtrate is concentrated and dried, obtaining 3.5 g of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione to yield 66%. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% of H3PO4, 1,00 (97,70%).1H NMR (DMSO-d6) δ 1.91 a (s, 3H), 2,03 is 2.10 (m, 1H), 2,49-2,61 (m, 2H), 2,66 is 2.75 (m, 1H), 4,23 (s, 2H), 7,89-8,03 (m, 3H), 8,68 (user, 3H), 11,04 (s, 1H);13With NMR (DMSO-d6) δ 20,9, 28,6, 29,0, 41,6, 58,9, 123,2, 123,5, 130,8, 131,4, 135,3, 141,2, 167,5, 167,6, 172,1, 172,2.

Stage 4: a Mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.51 g, 1.5 mmol), 4-chloraniline Janata (0,19 ml, 1.5 mmol) and N,N-diisopropylethylamine (of 0.52 ml, 3.0 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue is dissolved in ethyl acetate (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The remainder chromatographic using a gradient of methanol-CH2Cl2, elwira product when the ratio of methanol-CH2Cl24:96. The obtained solid is left overnight under stirring in ether, filtered and dried, to obtain 0.39 g of product with a yield of 57%. So pl. 245-247°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 45/55 CH3CN/0.1% of H3PO4that was 4.76 (99,33%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 1,99-of 2.08 (m, 1H), 2,54-2,60 (m, 2H), 2,63-of 2.72 (m, 1H), 4,45 (d, J=6.0 Hz, 2H), 6.89 in (t, J=6.0 Hz, 1H), 7,25-7,29 (m, 2H), 7,42-7,46 (m, 2H), 7,75-7,83 (m, 3H), 8,87 (s, 1H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,6, 29,1, 42,6, 58,7, 119,3, 121,3, 123,1, 124,7, 128,4, 129,5, 131,3, 133,2, 139,3, 148,4, 155,1, 167,8, 167,9, 172,1, 172,2. Analysis: Calculated for C22H19N4O5Cl: C, 58,09; H, 4,21; N, 12,32. Found: C, 57,70; H, 4,20; N, 11,99.

5.74 1-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-(4-triptoreline-phenyl)-urea

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.40 g, 1.2 mmol), 4-(triptoreline)phenylisocyanate (of 0.18 ml, 1.2 mmol and N,N-diisopropylethylamine (0,41 ml, 2.4 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue is dissolved in ethyl acetate (100 ml). The organic phase is washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The obtained solid is left overnight under stirring in ether, filtered and dried, to obtain 0.54 g of product with a yield of 90%. So pl. 168-170°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% of H3PO4, 6,04 (98,93%).1H NMR (DMSO-d6) δ 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,52-2,60 (m, 2H), 2,63-of 2.72 (m, 1H), 4,46 (d, J=6.0 Hz, 2H), 6,91 (t, J=6.0 Hz, 1H), 7,22 (d, J=8.1 Hz, 2H), of 7.48-7,53 (m, 2H). 7,75-7,83 (m, 3H), of 8.95 (s, 1H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 21,0, 28,6, 29,1, 42,6, 58,7, 118,9, 120,2 (kV, J=254 Hz), 121,3, 121,6, 123,1, 129,5, 131,4, 133,2, 139,6, 142,1, 148,4, 155,1, 167,8, 167,9, 172,1, 172,2. Analysis: Calculated for C23H19N4O6F3: C, 54,77; H, OF 3.80; N, 11.11 IS. Found: C, 54,57; H, 3,44; N, Of 10.93.

5.75 1-Hexyl-3-[2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidine-3-yl]-isoindole-1,3-dione (0.51 g, 1.5 mmol), mexilitine (to 0.22 ml, 1.5 mmol) and N,N-diisopropylethylamine (0,52 ml, 3.00 mmol) in acetonitrile (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue is dissolved in is tracedata (100 ml), washed with dilute aqueous HCl (2×150 ml) and water (2×150 ml), dried (MgSO4) and evaporated in vacuo. The obtained solid is left overnight under stirring in ether, filtered and dried, to obtain 0.5 g of product with a yield of 78%. So pl. 195-197°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 45/55 CH3CN/0.1% of H3PO4, 4,25 (98,51%).1H NMR (DMSO-d6) δ of 0.85 (t, J=6.6 Hz, 3H), 1,24-of 1.30 (m, 6H), 1.32 to to 1.38 (m, 2H), 1,89 (s, 3H), 2,02-of 2.08 (m, 1H), 2,53-2,60 (m, 2H), 2,63 was 2.76 (m, 1H), 2,99 (DD, J=12.9 Hz, J=6,6 Hz, 2H), 4,34 (d, J=6.0 Hz, 2H), 6,06 (t, J=5.7 Hz, 1H), 6,50 (t, J=6.3 Hz, 1H), 7.68 per-7,80 (m, 3H), 11,02 (s, 1H);13With NMR (DMSO-d6) δ 13,9, 21,0, 22,0, 26,0, 28,6, 29,1, 29,9, 31,0, 39,3, 42,7, 58,7, 121,2, 123,0, 129,3, 131,3, 133,0, 149,4, 158,0, 167,8, 167,9, 172,1, 172,2. Analysis: Calculated for C22H28N4O5+0,10H2O: C, 61,41; H, IS 6.61; N, 13,02. Found: C, 61,16; H, 6,66; N, 12,70.

5.76 1-(3-Chloro-4-methyl-phenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1,3-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

Stage 1: Mechanically stirred mixture of 4-bromo-2-methylbenzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 ml) ostwalt at night when heated to 80°C. the Reaction mixture is cooled to room temperature and partitioned between water (1500 ml) and the mixture hexane:ethyl acetate 4:1 (1500 ml). The organic layer is washed with water and dried (Na2SO4). The solvent is removed in vacuum, get 110 g is amylovora ester 4-bromo-2-methylbenzoic acid in the form of an oil with a yield of 100%. 1H NMR (DMSO-d6) δ of 2.51 (s, 3H), of 3.84 (s, 3H), 7,40 for 7.78 (m, 3H).

Stage 2: Mechanically stirred mixture of methyl ester 4-bromo-2-methylbenzoic acid (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 ml) is heated for 45 minutes at a low boil and maintained at the boil under reflux for 21 hours. The reaction mixture is cooled to room temperature, diluted with saturated aqueous solution of sodium bisulfite and concentrated in vacuo. The residue is distributed between water and the mixture hexane:ethyl acetate 1:1. The organic phase is washed with water, saturated salt solution and filtered through a bed of silica gel. The solvent is removed in vacuum, obtaining a mixture of oil/solid, which is dissolved in ether and filtered. The filtrate chromatographic on silica gel using a gradient hexane:ethyl acetate, elwira product when the ratio hexane:ethyl acetate 4:1, and obtain 102 g of methyl ester of 4-bromo-2-methyl bromide-benzoic acid with a yield of 66%.1H NMR (DMSO-d6) δ a 3.87 (s, 3H), at 4.99 (s, 2H), to 7.67-of 7.97 (m, 3H).

Stage 3: Mechanically stirred mixture of methyl ester 4-bromo-2-methyl bromide-benzoic acid (121 g, 390 mmol) and hydrochloride 3-amino-piperidine-2,6-dione (64,2 g, 390 mmol) in DMF (400 ml) dropwise treated with triethylamine (98,5 g, 980 mmol) for 75 minutes. When you are finished adding reactionuses left overnight under stirring at room temperature. The mixture sequentially quenched with acetic acid (50 ml), water (2500 ml) and a mixture of ethyl acetate:hexane 1:1 (600 ml). After stirring the mixture for 20 minutes, the solid is filtered, washed with water and leave overnight for air drying. Solid Modesto stirred in acetic acid (200 ml) and refluxed for 2 hours. The mixture is cooled to room temperature and filtered. The solid is optionally washed with acetic acid, hexane and left overnight for drying in the air, get to 25.3 g of 3-(5-bromo-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-dione as a gray solid with a yield of 20%.1H NMR (DMSO-d6) δ 1,97-2,04 (m, 1H), 2,32 is 2.46 (m, 1H), 2,56-2,63 (m, 1H), 2,85-of 2.97 (m, 1H), 4,34 (d, J=17.7 and Hz, 1H), 4,47 (d, J=17.7 and Hz, 1H), 5,11 (DD, J=13,2 Hz, J=5,1 Hz, 1H), to 7.67 (d, J=8,1 Hz, 1H), 7,72 (DD, J=8,1 Hz, J=1.5 Hz, 1H), 7,89 (d, J=0.9 Hz, 1H), 11,00 (s, 1H).

Stage 4: a Mechanically stirred mixture of 3-(5-bromo-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-dione (25,2 g, 78 mmol), bis(diphenylphosphino)ferrocene (2.0 g), Tris(dibenzylideneacetone)diplegia (2.0 g) and cyanide zinc (9.4 g, 80 mmol) in DMF (300 ml) is heated to 120°C and stirred at this temperature for 19 hours. The reaction mixture is cooled to 40°C and add an additional 9.4 g of cyanide of zinc, 2 g of bis(diphenylphosphino)ferrocene and 2 g of Tris(dibenzylideneacetone)diplodia. The mixture is stirred at 120°C for 2 hours, cooled to the room temperature and quenched with water (900 ml). The solid is filtered, optionally washed with water and leave overnight for air drying. The solid is stirred with hot acetic acid (200 ml) for 20 minutes. The solid is filtered, optionally washed with acetic acid, ethyl acetate and hexane and dried in the air, getting 30,8 g of the crude 2-(2,6-dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile as a gray solid.1H NMR (DMSO-d6) δ 1,99 e 2.06 (m, 1H), 2,35 at 2.45 (m, 1H), 2.57 m) 2.63 in (m, 1H), 2,86 are 2.98 (m, 1H), 4,42 (d, J=17.7 and Hz, 1H), 4,55 (d, J=17.7 and Hz, 1H), 5,15 (DD, J=13,2 Hz, J=5,1 Hz, 1H), to $ 7.91 (d, J=7.8 Hz, 1H), to 7.99 (DD, J=7.8 Hz, J=0.9 Hz, 1H), 8,16 (s, 1H), 11,03 (s, 1H).

Stage 5: a Mixture of 2-(2,6-dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (9,2 g, 34 mmol), 10% Pd-C (1.7 g) and concentrated HCl (5.3g) in N-organic (300 ml), left overnight to hydrogenation at 58 psi. The crude reaction mixture was filtered through celite and the catalyst washed with water. The combined filtrates concentrated in vacuo, and the product - hydrochloride 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-dione - allocate by fractional crystallization of the residue from a mixture of isopropanol-water (1.9 g, 18%).1H NMR (DMSO-d6) δ 1.85 to of 2.20 (m, 1H), 2,35 at 2.45 (m, 1H), 2,58 is 2.80 (m, 1H), 2,87-2,99 (m, 1H), 4.16 the (s, 2H), 4,35 (d, J=17.5 Hz, 1H), 4,49 (d, J=17.5 Hz, 1H), 5,13 (DD, J=13,2 Hz, J=4,8 Hz, 1H), 7,63 (d, J=7.8 Hz, 1H), 7,72 (s, 1H), 7,79 (d, J=7.8 Hz, 1H), 8,43 (user, 3H), 1,01 (s, 1H).

Stage 6: a Mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-dione (0.50 g, 1.6 mmol), 3-chloro-4-methyleneglutarate (0.27 g, 1.6 mmol) and tea (0.32 g, 3.2 mmol) in THF (25 ml) is heated to 40°C. with stirring in an atmosphere of N2. After 3 hours add an additional portion of 3-chloro-4-methyl isocyanate (0.17 g, 1.1 mmol) and continue stirring for 2 hours. The mixture is filtered and the filter washed with ethyl acetate. The solid is triturated with 10 ml of a mixture of acetone-DMF 1:1 and filtered. The filter is washed with acetone and the solid is dried in vacuum, obtaining 430 mg of product with a yield of 60%. So pl. 258-260°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 4,49 (98,75%).1H NMR (DMSO-d6) δ 1,90 is 1.96 (m, 1H), 2,16 (s, 3H), 2,25-2,39 (m, 1H), 2,50 is 2.55 (m, 1H), 2,78-only 2.91 (m, 1H), 4,24 (d, J=18,0 Hz, 1H), 4,33-to 4.41 (m, 3H), 5,04 (DD, J=13.5 Hz, J=4.5 Hz, 1H), 6.73 x (t, J=6.0 Hz, 1H),? 7.04 baby mortality-7,13 (m, 2H), was 7.36-7,44 (m, 2H), to 7.59-7,44 (m, 2H), 8,69 (s, 1H), 10,92 (s, 1H);13With NMR (DMSO-d6) δ 18,7, 22,5, 31,2, 42,8, 47,1, 51,5, 116,4, 117,6, 121,9, 122,9, 126,9, 127,4, 130,3, 131,0, 133,0, 139,6, 142,4, 144,7, 155,1, 167,9, 171,0, 172,9. Analysis: Calculated for C22H21ClN4O4: C, 59,93; H, 4,80; N, 12,71. Found: C, 59,77; H, Br4.61; N, 12,69.

5.77 1-(4-Chloro-phenyl)-3-[2-(2,6-dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-urea

A mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-dione (0.50 g, 1.6 mo is b) 4-chlorophenylalanine (0.25 g, 1.6 mmol) and tea (0.32 g, 3.2 mmol) in THF (25 ml) is heated to 40°C. with stirring in an atmosphere of N2. After 3 hours add an additional portion of 4-chlorophenylalanine (0.17 g, 1.1 mmol) and continue stirring for 2 hours. The mixture is filtered and the filter washed with ethyl acetate. The solid is purified preparative HPLC using isocratic elution with a mixture of acetonitrile-water 35:65, receiving 0,22 g of product with a yield of 32%. So pl. 270-272°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% of H3PO4, 3,28 (95,95%).1H NMR (DMSO-d6) δ 1,96 - 2,03 (m, 1H), 2,35-to 2.41 (m, 1H), 2.57 m-2,62 (m, 1H), 2,85-2,96 (m, 1H), or 4.31 (d, J=to 15.0 Hz, 1H), to 4.41-4,48 (m, 3H), 5,11 (DD, J=13.5 Hz, J=4.5 Hz, 1H), for 6.81 (t, J=6.0 Hz, 1H), 7.24 to 7,52 (m, 6H), of 7.70 (d, J=9.0 Hz, 1H), 8,81 (s, 1H), 10,99 (s, 1H);13With NMR (DMSO-d6) δ 22,5, 31,2, 42,8, 47,1, 51,5, 119,2, 121,9, 122,9, 124,6, 126,9, 128,4, 130,3, 139,4, 142,4, 144,7, 155,1, 167,9, 171,0, 172,9. Analysis: Calculated for C21H19ClN4O4+0,2H2O: C, 58,60; H, OF 4.54; N, 13,02. Found: C, 58,50; H, 4,15; N, 12,69.

5.78 1-[2-(2,6-dioxo-piperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-3-hexyl-urea

A mixture of the hydrochloride of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindole-2-yl)-piperidine-2,6-dione (0.50 g, 1.6 mmol), mexilitine (0.20 g, 1.6 mmol) and tea (0.32 g, 3.2 mmol) in THF (25 ml) is heated to 40°C. with stirring in an atmosphere of N2. After 3 hours add additional the second portion exisitant (0.20 g, 1.6 mmol) and continue stirring for 20 hours. The mixture is filtered and the filter washed with ethyl acetate and dried in vacuum, obtaining of 0.60 g of product with a yield of 92%. So pl. 234-236°C. HPLC, Waters Symmetry C-18, a 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 35/65 CH3CN/0.1% of H3PO4, 3,57 (96,04%).1H NMR (DMSO-d6) δ 0,86 (t, J=7.5 Hz, 3H), 1,25-to 1.38 (m, 8H), 1,99-2,02 (m, 1H), 2,37-to 2.41 (m, 1H), 2,56-2,62 (m, 1H), 2,87-3,03 (m, 3H), 4.26 deaths-4,32 (m, 3H), 4,43 (d, J=18,0 Hz, 1H), 5,10 (DD, J=13.5 Hz, J=4.5 Hz, 1H), 5,96 (t, J=6.0 Hz, 1H), 6,39 (t, J=6.0 Hz, 1H), 7,38 (d, J=7,5, 1H), 7,44 (s, 1H), 7,66 (d, J=6.0 Hz, 1H), 10,98 (s, 1H);13With NMR (DMSO-d6) δ 13,9, 22,1, 22,5, 26,0, 29,9, 31,0, 31,1, 39,3, 42,9, 47,0, 51,5, 121,7, 122,8, 126,8, 130,1, 142,3, 145,6, 158,0, 168,0, 171,0, 172,9. Analysis: Calculated for C21H28N4O4+0,1 h2O: C, 62,70; H, 7,07; N, 13,93. Found: C, 62,66; H, 6,89; N, 13,87.

5.79 (3'S)-3-(3'-Methoxyphenyl)-1-methyl-1-[2-(3-methyl-2',6'-dioxo-piperidine-3'-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-ylmethyl]-urea

5.79.1 Hydrochloride (3'S)-4-methylaminomethyl-2-(3'-methyl-2',6'-dioxo-piperidine-3'-yl)-isoindole-1,3-dione

Stage 1: a Solution of potassium hydroxide (1.3 g, 23,1 mmol) in water (5 ml) is added to a stirred solution of dimethyl 3-[(tert-butoxycarbonyl-methyl-amino)-methyl]phthalic acid (2.6 g, 7.7 mmol) in methanol (35 ml). The resulting solution was left overnight under stirring at room temperature. The mixture of concentrate and add water (30 ml). Recip is nnow the mixture washed with ether (30 ml). The aqueous layer was acidified with 4n HCl to pH 2. The mixture is extracted with CH2Cl2(3×40 ml) and dried. The solvent is removed, get a mixture of 3-[(tert-butoxycarbonyl-methyl-amino)-methyl]phthalic acid and its nanometrology of ester, which is used in the next stage without further purification.

Stage 2: a Mixture of 3-[(tert-butoxycarbonyl-methyl-amino)-methyl]phthalic acid (2.5 g, 7,71 mmol) and hydrobromide monohydrate (3S)-3-amino-3-methylpiperidine-2,6-dione (2.0 g, 8,48 mmol) in pyridine (40 ml) and left overnight at boiling under reflux. The mixture is cooled and concentrated. The residue is dissolved in EtOAc (100 ml) and water (50 ml). Solution in EtOAc washed with water (50 ml), 1N citric acid (50 ml), water (50 ml), feast upon. NaHCO3 (50 ml), water (50 ml) and saturated salt solution (50 ml) and dried (MgSO4). The solvent is removed and the residue purified by chromatography (SiO2CH2Cl2:EtOAc 9:1)obtain tert-butyl ether (3'S)-methyl-[2-(3'-methyl-2',6'-dioxo-piperidine-3'-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-ylmethyl]carbamino acid (0,99 g, 31%).

Stage 3: 2n HCl/ether (3 ml) is added to a stirred solution of tert-butyl methyl ether (3'S)-methyl-[2-(3'-methyl-2',6'-dioxo-piperidine-3'-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-ylmethyl]carbamino acid (0,99 g, 2.4 mmol) in methylene chloride (20 ml). The mixture is left overnight under stirring at room temperature. Add the fir (20 ml) and the mixture is filtered and dried, receive hydrochloride (3'S)-4-methylaminomethyl-2-(3'-methyl-2',6'-dioxo-piperidine-3'-yl)-isoindole-1,3-dione (0.73 g, 87%).1H NMR (DMSO-d6) δ l1,04 (s, 1H), 9,56 (s, 2H), 8,05-7,88 (m, 3H), 4,56 is 4.45 (m, 2H), 2,73 of $ 2.53 (m, 6H), 2,10-2,04 (m, 1H), 2,02 (s, 3H);13With NMR (DMSO-d6) δ 172,15, 171,96, 168,08, 167,31, 136,48, 134,68, 131,26, 130,23, 129,05, 123,59, 58,84, 54,88, 45,73, 32,42, 29,09, 28,55, 21,04.

5.79.2 (3'S)-3-(3-Methoxyphenyl)-1-methyl-1-[2-(3'-methyl-2',6'-dioxo-piperidine-3'-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-ylmethyl]-urea

To a stirred suspension of the hydrochloride (3'S)-4-(methylaminomethyl-2-(3'-methyl-2',6'-dioxo-piperidine-3'-yl)-isoindole-1,3-dione and triethylamine (0.3 g, 3.0 mmol) in THF (30 ml) is added 3-methoxyphenylalanine (0.4 g, 2.6 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue is dissolved in methylene chloride (70 ml), washed with 1N HCl (30 ml), water (2×30 ml) and saturated salt solution (30 ml) and dried (MgSO4). The solvent is removed and the residue purified by chromatography (SiO2CH2Cl2:EtOAc 9:1), receive (3'S)-3-(3-methoxyphenyl)-1-methyl-1-[2-(3'-methyl-2',6'-dioxo-piperidine-3'-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-ylmethyl]-urea (0.7 g, 74%). So pl. 166-168º.1H NMR (DMSO-d6) δ 11,03 (s, 1H), 8,46 (s, 1H), 7,83 (t, J=7.5 Hz, 1H), of 7.75 (d, J=6,6 Hz, 1H), 7,58 (d, J=7,3 Hz, 1H), 7,19-7,07 (m, 3H), 6,55-6,51 (m, 1H), to 4.98 (s, 2H), 3,70 (s, 3H), 3,03 (s, 3H), 2,72 is 2.51 (m, 3H), 2,10-2,04 (m, 1H), 1.91 a (s, 3H);13With the Mr (DMSO-d 6) δ 172,46, 172,44, 168,70, 167,99, 159,59, 155,88, 141,87, 138,74, 135,11, 132,51, 131,98, 129,20, 127,57, 121,78, 112,38, 107,68, 105,78, 59,01, 55,15, 47,67, 35,39, 29,38, 28,86, 21,31. Analysis: Calculated for C24H24N4O6: C 62,06; H, TO 5.21; N, 12,06. Found: C, 62,15; H, 5,32; N, 11,71.

5.80 Research

5.80.1 Study of inhibition of TNFα in RMBS

Menagerie cells of peripheral blood (RMS) from normal donors obtained by centrifugation on density Ficoll Hypaque (Pharmacia, Piscataway, NJ, USA). Cells were cultured in RPMI 1640 (Life Technologies, Grand Island, NY, USA), supplemented with 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).

RMS (2×105cells) triple plated in flat-bottomed 96-well plates to cell cultures Costar (Corning, NY, USA). Cells are stimulated LPS (fromSalmonella abortus equi, Sigma cat no L-1887, St. Louis, MO, USA) at a final concentration of 1 ng/ml in the absence or presence of compounds. Compounds according to the invention dissolved in DMSO (Sigma)and subsequent dilution produced in culture medium immediately before use. The final concentration of DMSO in all studies should be about 0.25%. Compounds are added to cells 1 hour before LPS stimulation. Cells are then incubated for 18-20 hours at 37°C in 5% CO2and then collect the supernatant, diluted with culture medium and examined for levels of TNFα methods the MD ELISA (Endogen, Boston, MA, USA). Calculate the IC50using non-linear regression, sigmoidal function dose-response, limiting the top 100% and down to 0%, allowing the variation of the slope (GraphPad Prism v3.02).

5.80.2 Production of IL-2 and MIP-3α T-cells

RMS released from strongly associated monocytes, placing 1×108RMS in 10 ml complete medium (RPMI 1640, supplemented with 10% fetal bovine serum, held thermal inactivation, 2 mm L-glutamine, 100 u/ml penicillin and 100 μg/ml streptomycin) at 10 cm Cup of tissue culture incubator at 37°C, 5% CO230-60 minutes. The Cup is washed with medium to remove all unbound RMS. T cells purified by negative selection using the following mixture of antibodies (Pharmingen) and Dynabead (Dynal) for each 1×108unbound RMS: 0.3 ml beads sheep IgG against mouse, and 0.15 μl of beads anti-CD16, and 0.15 μl of anti-CD33, and 0.15 μl of anti-CD56, 0,23 ál of anti-CD19, 0,23 ál beads anti-HLA class II and 56 μl of beads anti-CD14. The mixture of cells and beads/antibody mix by inversion 30-60 minutes at 4°C. Purified T cells separated from the beads using a Dynal magnet. Normal output 50% of T cells, 87-95% CD3+for cytometry in the stream.

Flat-bottomed 96-well plates to tissue culture coated with antibody anti-CD3 OCT at 5 µg/ml in PBS, 100 μl per well, incubated at 37°C for 3-6 hours and washed four times in complete medium 100 µl/well directly before you added the m T-cells. Compounds diluted to 20 times the final concentration in round-bottom 96-well tablet for tissue cultures. Final concentration is from about 10 microns to about 0,00064 μm. Concentrate 10 mm of the compounds according to the invention is diluted 1:50 for the first 20x dilution to 200 μm in 2% DMSO and serially diluted 1:5 in 2% DMSO. Connection add 10 ál 200 ál of culture, giving the final concentration of DMSO of 0.1%. The culture is incubated at 37°C, 5% CO2within 2-3 days, and the supernatant analyzed for IL-2 and MIP-3α ELISA method (R&D Systems). The levels of IL-2 and MIP-3α normalized to the amount produced in the presence of a number of compounds according to the invention, and calculate EU50using non-linear regression, sigmoidal function dose-response, limiting the top 100% and down to 0%, allowing the variation of the slope (GraphPad Prism v3.02).

5.80.3 the Study of cell proliferation

Cell lines Namalwa, MUTZ-5 and UT-7 were obtained from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig, Germany). Cell line KG-1 obtained from the American Type Culture Collection (Manassas, VA, USA). Cell proliferation according to the indications include3H-thymidine was measured in all cell lines as follows.

The cells were placed in 96-well tablets at 6000 cells per well in the environment. The cells were pre-treated with compounds at approximately 100, 10, 1, 0,1, 0,01, 0,001, 0,0001 and 0 μm in the end is concentratie DMSO approximately 0.25% in three series 72 hours at 37°C in a humidified incubator with 5% CO 2. One microcurie3H-thymidine (Amersham) was then added to each well and the cells are again incubated 6 hours at 37°C in a humidified incubator with 5% CO2. All cells were collected in filter plates UniFilter GF/C (Perkin Elmer)using the collector cells (Tomtec), and then the cells were left overnight, allowing to dry. Added Microscint 20 (Packard) (25 ál/well), and the tablets were analyzed on a TopCount NXT (Packard). Each well was counted for one minute. The percentage of inhibition of cell proliferation was calculated by averaging all three series and the regulation on the control DMSO (0% inhibition). Each compound was tested for each cell line in three separate experiments. End IC50was calculated using non-linear regression, sigmoidal function dose-response, limiting the top 100% and down to 0%, allowing the variation of the slope (GraphPad Prism v3.02).

5.80.4 Immunoassay and Western blot turns

Cells Namalwa 1 hour was treated with DMSO or compounds according to the invention, then 30 minutes and stimulated with 10 u/ml EPO (R&D Systems). Prepared cell lysates and were either immunoassay EPO receptor Ab, or immediately was separated by SDS-PAGE. Immunoblot probed Akt, phospho-Akt (Ser473 or Thr308), phospho-Gab1 (Y627), Gab1, IRS3, actin and IRF-1 Abs and analyzed on a Storm 860 Imager using the software ImageQuant (Molecular Dynamics).

5.80.5 Analysis of the cell cycle

Cells remained the Yali overnight for processing DMSO or compounds according to the invention. Did iodide staining of propecia for cell cycle using CycleTEST PLUS (Becton Dickinson) according to the manufacturer's Protocol. After staining, cells were analyzed on a flow cytometer FACSCalibur using software ModiFit LT (Becton Dickinson).

5.80.6 Analysis of apoptosis

Cells were treated with DMSO or compounds according to the invention at different points in time, then washed with washing buffer (annexin-V (BD Biosciences). Cells 10 minutes, incubated with protein binding annexin-V, and iodide of propecia (BD Biosciences). The samples were analyzed using flow cytometry.

5.80.7 Study luciferase

The Namalwa cells were transfusional 4 µg AP-1-luciferase (Stratagene) at 1×106cells and 3 ál of lipofectamine (Invitrogen) according to manufacturer's instructions. Six hours after transfection cells were treated with DMSO or compounds according to the invention. The luciferase activity was investigated using a buffer for lysis, luciferase and the substrate (Promega) and measured using a luminometer (Turner Designs).

5.81 Antiproliferative activity

In one experiment antiproliferative effect of some compounds suggested in the description, testing, using Namalwa cells, HN 5q, HT-1080, SK-MES-1 and RS-3, in accordance with the study of proliferation, which is essentially similar to that described above in 5.803. Tested compounds show values of the IC50in the range from 0.5 to 200 microns for Namalwa cells, from 0.0001 to 10 μm for cells HN 5q, from 0.01 to 20 μm for cells HT-1080, from 0.001 to 30 μm for cells SK-MES-1 and 0.005 to 10 μm for cells PC-3. These results show that the compounds proposed in the description, exhibit antiproliferative effect on various cancer cells.

In another experiment two cell lines of human glioblastoma, T98G (glioblastoma multiforme, mutant p53) and U87MG (glioblastoma-astrocytoma brain type III, wild type p53), and two cell lines of human neuroblastoma SH-SY5Y (derived from metastatic site bone marrow; trisomy of chromosome 1q; enhanced MYCN) and SK-N-MC (derived from metastatic site adorbale region; pseudodiploid with the modal number of chromosomes 46; causes tumor in Nude mice) were obtained from ATS. Data cell lines were grown concentrates the lower level were frozen in liquid nitrogen. Compounds were dissolved in DMSO to obtain a 10 mm concentrates. Cells were placed in 96-well tablets 5×103cells/100 μl medium per well. Cells were left overnight to achieve adhesion at 37°C in an incubator with 94% humidity and 5% CO2. After incubation overnight, the cells were processed in three series 100, 10, 0,1, 0,01, 0,001, 0,0001 and 0 μm promising compounds at the con who offered the concentration of DMSO of 0.1% during the treatment period of 72 hours. Cell proliferation was determined by examination of cell proliferation3H-thymidine. IC50calculated from the transformed data using non-linear regression, sigmoidal function dose-response using GraphPad Prism v4.0.

Tested compounds show values of the IC50in the range from 0.1 μm to about 1 mm for T98G cells, from 0.05 to about 150 microns to U87MG cells, from 0.0001 to 0.5 μm for cells SH-SY5Y and from 0.0001 to about 0.1 μm for cells SK-N-MC. These results show that the compounds proposed in the description, exhibit antiproliferative activity against various cancer cells.

Embodiments of the invention described above are intended to be examples only, and the person skilled in the art should know numerous equivalents to the specific compounds, materials and methods should either be able to come to him exclusively by routine experimentation. All such equivalents are considered as included in the scope of the invention and covered by the attached claims.

All patents, patent applications and publications, are linked to this description, included in their entirety. Citation or identification of any reference in this application is not an admission that such reference is available as prior art this image is to be placed. The full scope of the invention more clear with reference to the accompanying claims.

1. The compound of formula (I)

or its pharmaceutically acceptable salt, or stereoisomer, in which:
n is 0 or 1;
X represents CH2C=O;
R1is:
(a) -(CH2)mR3or-CO(CH2)mR3where
m is 0, 1; and
R3represents a 5-10 membered aryl or heteroaryl where heteroaryl means mono - or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are heteroatom selected from oxygen, nitrogen or sulfur, optionally substituted by one or more halogen; (b)=YR4where
Y represents O; and
R4is:
(C1-C10)alkyl, (C1-C10)alkoxy;
(C0-C10)alkyl-(5-10-membered heteroaryl), where heteroaryl means mono - or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are heteroatom selected from oxygen, nitrogen or sulfur, the specified heteroaryl optionally substituted by one or more substituents from halogen, oxo, or Z-(C1-C6)alkyl, where Z represents S;
(C0-C10)alkyl-(5-10 membered ar is l), specified aryl optionally substituted by one or more substituents from halogen; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; or-Z-(C1-C6)alkyl, where Z is S or SO2and where specified (C1-C6)alkyl may be optionally substituted by one or more halogen; or
(C1-C6)alkyl-CO-O-R12where R12represents H or (C1-C6)alkyl; or
C) -C=ZNHR6where
Z represents O or S; and
R6is:
(C1-C10)alkyl, (C1-C10)alkoxy;
5-10-membered aryl or heteroaryl where heteroaryl means bicyclic aromatic ring containing 9 ring atoms, of which at least one or two atoms represent oxygen; optionally replaced by one or more substituents from halogen; cyano; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; and
R2represents H or (C1-C6)alkyl.

2. The compound of formula (II)

or its pharmaceutically acceptable the salt, or a stereoisomer, in which: n is 0 or 1;
X represents CH2or C=O;
R7represents -(CH2)mR9where m is 0, 1; and R9represents a 5-10 membered aryl or heteroaryl where heteroaryl means mono - or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are heteroatom selected from oxygen, nitrogen or sulfur; optionally substituted by one or more halogen; and
R8represents H or (C1-C6)alkyl.

3. The compound according to claim 2, in which X represents C=O.

4. The compound according to claim 2, in which X represents CH2.

5. The compound according to claim 2, in which R9represents phenyl, optionally substituted by one or more Halogens.

6. The compound according to claim 2, in which R9is furyl or benzofuran.

7. The compound according to claim 2, in which the connection is
,,,
or.

8. The compound of formula (III)

or its pharmaceutically acceptable salt, or stereoisomer, in which:
X represents CH2or C=O;
Y represents O;
R10is:
(C1-C10)alkyl, (C1-C10 )alkoxy;
(C0-C10)alkyl-(5-10-membered heteroaryl), the specified heteroaryl means mono - or bicyclic aromatic ring containing from 5 to 10 ring atoms, of which at least one or two atoms are heteroatom selected from oxygen, nitrogen or sulfur; the specified heteroaryl optionally substituted by one or more substituents from halogen, oxo, or-Z-(C1-C6)alkyl, where Z is S;
(C0-C10)alkyl-(5-10 membered aryl), specified by aryl optionally substituted by one or more substituents from halogen; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; or-Z-(C1-C6)alkyl, where Z is S or SO2and where specified (C1-C6)alkyl may be optionally substituted by one or more halogen; or
(C1-C6)alkyl-CO-O-R12where R12represents H or (C1-C6)alkyl; and
R11represents H or (C1-C6)alkyl.

9. The connection of claim 8, in which X represents C=O.

10. The connection of claim 8, in which X represents CH2.

11. The connection of claim 8, in which R10represents pentyl or hexyl.

12. The connection of claim 8, in cat the rum R 10is pentyloxy or hexyloxy.

13. The connection of claim 8, in which R10is thiophenyl or furyl.

14. The connection of claim 8, in which R10represents phenyl or methyl-phenyl, optionally substituted by one or more Halogens.

15. The connection of claim 8, in which the connection is:
,,
,,
,,
,,
,,
,,
,
,,
,,
,,
,,
,,
,,
,,
,,
,,
, ,
,,
,,
,,
,,
,,
or.

16. The compound of formula (IV)

or its pharmaceutically acceptable salt or a stereoisomer, in which:
X represents CH2or C=O;
Y represents O or S;
R13is (C1-C10)alkyl;
5-10-membered aryl or heteroaryl where heteroaryl means bicyclic aromatic ring containing 9 ring atoms, of which at least one or two atoms represent oxygen; optionally substituted by one or more substituents from halogen; cyano; (C1-C6)alkoxy, itself optionally substituted by one or more halogen; (C1-C6)alkyl which is itself optionally substituted by one or more halogen; and
R14represents H or (C1-C6)alkyl.

17. The connection clause 16, in which X represents C=O.

18. The connection clause 16, in which X represents CH2.

19. The connection clause 16, in which R13represents propyl, bout the l, pentyl or hexyl.

20. The connection clause 16, in which R13represents phenyl, optionally substituted by one or more Halogens.

21. The connection clause 16, in which the connection is:
,,
,,
,,
,,
,,
or.

22. The connection clause 16, in which the connection is:
,,
,,
,,
,,
,,
,,
,,
or
.

23. Pharmaceutical composition for inhibiting TNFα, comprising a compound according to claim 1.

24. The pharmaceutical composition according to item 23 in the form of a single dosage form.

25. The pharmaceutical composition according to paragraph 24, the walking for oral or parenteral administration.

26. The pharmaceutical composition according A.25 suitable for oral administration.

27. The pharmaceutical composition according p, which is a tablet or capsule.



 

Same patents:

FIELD: medicine, pharmaceutics.

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

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

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

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

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

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

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

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

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

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

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

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

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

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

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

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

31 cl, 378 ex, 12 tbl

FIELD: medicine, pharmaceutics.

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

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

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

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

12 cl, 8 tbl, 60 ex

FIELD: chemistry.

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

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

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

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

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

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

31 cl, 378 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of the formula (I) that are characterized by the properties of M3 muscarine receptor antagonist that is applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases. In the formula (I) A is represented by the oxygen atom or the group -N(R12)-; (i) R1 is represented by C1-C6-alkyl or the hydrogen atom; and R2 is represented by the hydrogen atom or the group -R5, -Z-Y-R5, -Z-NR9R10, -Z-NR9CO-R5 or -Z-CO2H; and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; or (ii) R1 and R2 together with nitrogen to which they are bound form heterocycloalkyl ring; the mentioned ring is displaced by the group -Y-R5 or -Z-Y-R5, and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; R4 is represented by the formula group (a), (b), (c) or (d); Z is represented by C1-C16-alkylene group; Y is represented by the link or the oxygen atom; R5 is represented by C1-C6-alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or heteroC3-C6cycloalkyl group; R6 is represented by C1-C6-alkyl or the hydrogen atom; n and m equal 0; R8a and R8b are independently chosen from the group consisting of aryl, phenyl condensed with heterocycloalkyl, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl; R8c is represented by -OH or C1-C6-alkyl; R9 and R10 are represented independently by the hydrogen atom, C1-C6-alkyl, aryl, phenyl condensed with heterocycloalkyl and other components mentioned in the invention formula.

EFFECT: new compounds applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases.

10 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

Up!