Azaindole-indole derivatives, methods for preparing and using

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaindole-indole derivatives and pharmaceutically acceptable salts thereof of general formula: Y=Z (G), wherein Y means a group of azaindole of formula (Yl) Z means a group of indole of formula (Z1) or (Z2) wherein the values "=", R, R1, R1', R2, R3, R4, R2', R3, R4', R5' are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit cycline-dependent kinase that enables using them in a pharmaceutical composition.

6 cl, 3 dwg, 9 tbl, 8 ex

 

The technical field

The present invention relates to one group derived azaindole-indole completely new structure. The molecular structure of these derivatives is characterized by the fact that they are bound by azaindole with a bimolecular indoles in various positions, forming large π-conjugated heterocyclic systems. These derivatives through various mechanisms prevent disorders of growth and cell proliferation. The present invention also includes methods of making the derivatives, including pharmaceutical compositions described derivatives and their use.

Prior art

The present patent for an invention is a patent following the following patents:

1) "Specific indole compounds, method of their production and use in the treatment and prevention of cancer and other diseases", CN 02138518, 1A, published 04.05.2005);

2) "Emulsion for use in the insoluble drugs and method of its manufacture", CN 200410052816, 5A, priority 14.07.2004);

3) the Method of manufacture of derivatives of N(1)-hydrocarbon-3' oxime-indirubin (I) and their medical use, CN 200510094482.2 And published 01.08.2007;

4) "the Dispersion agent for the manufacture of insoluble drugs", CN 200610038112.1 And priority 17.01.2006.

Monomeric compounds of plants Lider who are among the drugs in the fight against cancer, as for example, Camptothecin isolated from Camptotheca pointed, and Paclitaxel obtained from Golovchatoi, which are the two well-known drugs.

Modern pharmaceutical research, traditional herbal medicines showed that contained in Indigo Naturalis derivatives vendola - indirubin (1, indirubin, 2',3-dindal, Magenta color) is particularly effective for the treatment of chronic myeloid leukemia (CML) they are characterized by fast action, a small amount, less side effect, low cost, etc. Subsequently carried out a structural processing and extensive scientific study of the biological activity of the compounds of vendola containing Indigo Naturalis [including Indigo (2), 2,2'-dindal, blue; sondigo (3), 3,3'-dindal, brown], it was observed that N-1-methyl-sondigo have a better therapeutic effect than indirubin, and low toxicity.

Further research showed that the pharmacodynamic mechanism of indirubin and its derivatives inhibit the spread of tumors by inhibiting cyclin-dependent kinases called cyclin-kinase (CSKA).

The family of cyclin-dependent kinase (CSK) is a typical kinase serine/threonine, and signal what Halekulani cell growth, acting mainly on the different phases of the cell cycle process cell cycle is divided into four phases G1, S, G2 and M), which allows the cells to grow and proliferate (DNA replication and segregation of chromosomes), peace (cells broke away from the cycle of separation that enters the resting phase of growth and division, known as the G0 phase) or enter into apoptosis. CSC also have regulatory functions of nerves and thymus. CZK differ from other kinases, they play the role of catalyst and regulator only when relevant cyclename and education complex complex dimer. In human cells, there are at least nine members of the family CZK (CZK 1~9) and 11 tsiklonov (A~J). Various CZK combined with a variety of cyclename or their paradigalla: CZK associated with cyclename a and B1-B3; CZK associated with cyclename A, D1-D3, and E; CSC, CSC and CSC contact cyclename D1-D3; CSC also associated mainly with pk35; CZK associated with cyclin H; CZK associated with cyclin K, associated with D.

According to the results of biomedical research of the Nobel prize in 2001, "the Relationship of cell proliferation and cancer, almost all tumor cells have different anomalies cell cyclina kinase[1-2]cancer cells take long phases S, G2 and M, and unlimited proliferous. For example, more than 85% of the pain is s breast cancer with an abnormal cyclin E / CSC / 6 [3]. Using deterrence of cyclin-dependent kinases can effectively block cell proliferation (but not kill cells), thereby or to promote cellular differentiation and maturation, or to promote apoptosis; allowing you to achieve the effect of treatment of various tumors. There is reason to believe that the cellular cyclin kinase as an inhibitor, is a new type of anticancer drug with a wide spectrum of action. In addition, these drugs inhibit the proliferation of cells, but do not kill cells, they are characterized by high selectivity, good efficiency and low toxicity.

Studies have shown that cyclin-dependent kinase as an inhibitor can effectively restrain breast cancer, colon cancer, prostate cancer, brain cancer and other cancers. More significant is that they inhibit cell proliferation, these compounds also have good exposure to the inhibition of cell hormonesensitive prostate cancer (PC-3, DU-145), the number of cells resistant to hormonal therapy and chemotherapy late metastatic cancers of the prostate. Thus, the search of the inhibitor of cyclin-dependent kinases has become a new rational strategy for research and development of new anticancer drugs[4-6].

Up to the present time and about 10 species monomolecular according to the chemical structure of the inhibitors and/or control agents CZK paid attention and studied, this is mainly inhibitors CZK aimed at the region of Asia-Pacific[7]. Used in clinical treatment of indirubin and N-1-methyl-sondigo are one of these kinds of[8-9]. In addition, two compounds has entered a period of clinical research: UCN-01 and flavopiridol developed by the National cancer Institute (NCI) of the U.S.[10].

In summary, the compounds of vendola type of indirubin are important inhibitor CSC, low side effects, but this type of connection do not dissolve in water and fat, which prevents their use in clinical treatment. In recent years, many foreign research institutions and pharmaceutical companies have conducted extensive structural changes of compounds of this type, however, the effectiveness of the compounds of vendola type of indirubin against tumors is still far from satisfactory.

In short, this area is urgently needed to develop new inhibitors with excellent ability of inhibiting the activity of cyclin-dependent kinase (CSK).

Disclosure of inventions

The purpose of the present invention is the creation of derivative azaindole-indole as an inhibitor CZK; these compounds should have high inhibitory activity, well to dissolve the input and other benefits.

Another objective of the present invention is to provide methods of making these compounds, their pharmaceutical compositions and their use.

According to the first invention, offers the derivatives of azaindole-indole and its pharmaceutically acceptable salts, according to the formula

,

where Y represents the group azaindole by the formula (Y1) or (Y2);

Z represents a group of indole by the formula (Z1) or (Z2);

"=" means a double bond located at the 3-position of the group azaindole Y and between the 2'- and 3'-positions of the group of the indole-Z;

in the above formulas, Y1, Y2, Z1 and Z2, R1and R1'independently represent H or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: With1~C6alkyl, aryl, aralkyl, acyl, aroyl, glycosyl or Biosil, protected acyl, glikozidom or biosrom; this is described substituents selected from: halogen, hydroxyl, C1-C3alkyl, nitro or amino;

R2, R3, R4, R2', R3', R4'and R5'independently represent H, halogen, hydroxyl, sulfhydryl or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: C1~sub> 4alkyl, nitro, amino, amido, amide, C1~C4alkoxy, methylthio, phenyl, phenoxy, aryl, aralkyl, trifluoromethyl, acyl, aroyl, sulfonic group, sulfamoyl, isocyanate or alkyl-isocyanate, while described substituents selected from: halogen, hydroxyl, C1-C3alkyl, nitro or amino;

R is oxygen, sulfur, selenium or the group NR6or NOR6in which R6represents H, or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: With1~C6-alkyl direct connection or branched connection, aryl, aralkyl,3~C6alicyclic group, acyl, aroyl, sulfonyl or phosphoryl; this is described substituents selected from: halogen, hydroxyl, C1-C3alkyl, nitro or amino.

Another best example described compounds shown in formulas (I), (II), (III) or (IV)in which formula (I) is a derivative of 5-atindimubona, formula (II) derivatives of 5-azizeenho, formula (III) derivatives of 7-atindimubona, and formula (IV) derivatives of 7-azizeenho;

where R, R1, R2, R3, R4, R1', R2', R3', R4'and R5'denote, as above.

In another Optim is flax example, R1and R1'independently represent H, C1~C6alkyl, aryl, aralkyl, acyl, aroyl, glycosyl protected alkyl or glikozidom;

R2, R3, R4, R2', R3', R4'and R5'independently represent H, halogen, hydroxyl, sulfhydryl,1~C4alkyl, amino, amido, amide, C1~C4alkoxy, methylthio, phenyl, phenoxy, aryl, aralkyl, trifluoromethyl, acyl, aroyl, sulfonic group or isocyanate;

the above glycoside is arabinose, xylose, ribose, mannose or glucose;

R is oxygen, sulfur, selenium or the group NR6or NOR6in which R6represents H, C1~C6-alkyl direct connection or branched connection, aryl, aralkyl,3~C6alicyclic group, acyl, aroyl, sulfonyl or phosphoryl.

Another best example described compounds are selected from the following groups: derivatives of 5-atindimubona; (table 1: compound 1-59), derivatives of 5-azizeenho (table 2: connections 60-89), derivatives of 7-atindimubona (table 3: connection 92-150) and derivatives 7-azizeenho (table 4: connection 151-180).

Another best example of the above-mentioned pharmaceutically acceptable salts include salts formed with inorganic acids or organic acids, inorganic acid which you include the following: hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid; organic acids include formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonate (1, 5), Asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, butylcarbamoyl acid, diethyloxalate acid, malonic acid, succinic acid, fumaric acid, Emelyanova acid, hexandiol acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionate acid, piknova acid, ascorbic acid, nicotinic acid, isonicotinamide acid, econsultancy acid, paratoluenesulfonyl acid, citric acid and amino acid.

Secondly, in the present invention is provided a Pharmaceutical composition comprising: (a) compounds or their pharmaceutically acceptable salts, according to claim 1 of the formula; (b) pharmaceutically acceptable carriers.

In another optimal sample form perform the following composition: solution for injection in small, medium and large scale, powder for injection, emulsion injection, tablets, pills, capsules, ointments, creams, plasters, liniments, powders, aerosols, implants, drops, suppositories, ointments, various types of nano-medicines; or l is bosomy.

Another best example is described pharmaceutical compositions can be used separately as Monomeric funds or in combination with other drugs (for example, joint use in surgery, the use of in combination with one or more drugs European medicine or herbal medicines Chinese medicine, or in combination with radiation therapy and gene therapy, or sharing in combination with bio-regulators).

Thirdly, the present invention presents a method of manufacturing a pharmaceutical composition, which includes the following steps: (a) mixing the compounds or their pharmaceutically acceptable salts according to claim 1 and (b) pharmaceutically acceptable carriers, thereby forming a pharmaceutical composition.

Fourthly, the present invention is provided the use of compounds or their pharmaceutically acceptable salts for the treatment of the following diseases: diseases caused by deviation from the norm of cyclin-dependent kinases, disorders of growth and proliferation of cells, or insulin resistance.

Another best example is described diseases include malignant cancers, psoriasis, viral skin diseases, HIV, degeneration and disorder, and other diseases of the nervous system and diabetes 2 t the PA.

Fifthly, the present invention is provided a composition, which contains compounds or their pharmaceutically acceptable salts according to formula IG as an inhibitor of cyclin-dependent kinases.

Another best example is described compositions are compositions of pharmaceutical products (containing media that are acceptable for pharmaceutical products), the composition of foods (containing carriers acceptable to the food and cosmetic composition containing media suitable for cosmetics).

Sixthly, the present invention provided methods of internal and external inhibition of cyclin-dependent kinase mammalian animals, or treatment of diseases caused by excessive activity of cyclin-dependent kinases, including measures of the introduction of objects requiring treatment, the compounds of formula IG, or pharmaceutically acceptable salts, or pharmaceutical compositions containing the compounds of formula IG, or a pharmaceutically acceptable salt.

In another optimal example describes diseases caused by too high activity of cyclin-dependent kinases, include: malignant tumors, psoriasis, viral skin diseases, HIV, neurodegeneration, disorder and other diseases of the nervous system.

Brief description of drawings

Figure 2 shows the degree of inhibition of the derivative 5 - and 7-atindimubona and derived 5 - and 7-azizeenho about the growth of androgen-independent cancer cells DU145 human prostate. Using different concentrations of compounds№№107, 108, 112, 115, treated cancer cells DU145 logarithmic growth period of a man's prostate for 72 hours to measure the rate of cell growth by MTT method.

Figure 3 shows the inhibition of the derivative 5 - and 7-atindimubona and 5 - and 7-azizeenho CZK androgen-independent cancer cells DU145 human prostate; with compounds No. 124, 126 different concentrations treated cancer cells DU145 logarithmic growth period of a man's prostate for 24 hours, take the total protein of the cells, measured by the method of "Western blot" phosphorus-2Thr160, P27 and cyclin-D1, taking β-Actin as an internal standard.

The best option of carrying out the invention

Inventor after extensive and in-depth research first created one group derived azaindole-indole as inhibitors CZK; these compounds are formed by azaindole in connection with indole-parabolically in different positions, they formed large π-conjugated heterocyclic systems. Tests showed that this group derived azaindole-indol can through a variety of mechanisms to implement the biological is aktivnosti, to inhibit cell growth and proliferation, to inhibit cyclin-dependent kinases, inductivity endogenous inhibitors of cyclin-kinase (ICK), as well as to restore the signal conversion insulin and other functions, thereby curing various diseases caused by disorder of cell growth, including cancer, psoriasis, viral skin diseases, HIV and neurodegeneration, a disorder of the nervous system, also type 2 diabetes caused by insulin resistance.

Compounds of the present invention

Used in this article, the term "compounds of the present invention or derivatives azaindole-indole" may be used interchangeably, they refer to compounds or pharmaceutically acceptable salts shown in the General formula IG.

Specifically, in the present invention implemented significant structural transformation connection indirubin, sondigo, increased solubility and bioavailability, enhanced the effect of drug therapy, low dose of the drug, reduced adverse reactions drug. Compared with the parent nuclei existing connections of indirubin, sondigo, maternal nuclei of the compounds of the present invention formed large π-conjugated heterocyclic systems, thereby, improved the solubility of the compounds of the present invention in the ode.

One group of optimal compounds shown in General formula (I), General formula (II), General formula (III) and General formula (IV), among them in the General formula (I) derivatives of 5-atindimubona, in the General formula (II) derivatives of 5-azizeenho, in the General formula (III) derivatives of 7-atindimubona, in the General formula (IV) derivatives of 7-azizeenho.

R1and R1'independently represent H or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: With1~C6alkyl, aryl, aralkyl, acyl, aroyl, glucosyl or Biosil, protected acyl, glikozidom or biosrom; this is described substituents selected from: halogen, hydroxyl, C1-C3alkyl, nitro or amino;

R2, R3, R4, R2', R3', R4'and R5' independently represent H, halogen, hydroxyl, sulfhydryl or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: C1~C4alkyl, nitro, amino, amido, amide, C1~C4alkoxy, methylthio, phenyl, phenoxy, aryl, aralkyl, trifluoromethyl, acyl, aroyl, sulfonic group, sulfamoyl, isocyanate or alkyl-isocyanate, while described substituents selected from: halogen, hydro the forces, With1-C3alkyl, nitro or amino;

R is oxygen, sulfur, selenium or the group NR6or NOR6in which R6represents H, or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: C1~C6-alkyl direct connection or branched connection, aryl, aralkyl,3~C6alicyclic group, acyl, aroyl, sulfonyl or phosphoryl; this is described substituents selected from: halogen, hydroxyl, C1-C3alkyl, nitro or amino.

In the above General formulas (I), (II), (III) and (IV) there are more good connections, in particular: R1and R1'independently represent H, C1~C6alkyl, aryl, aralkyl, acyl, aroyl, glycosyl protected alkyl or glikozidom;

R2, R3, R4, R2', R3', R4'and R5'independently represent H, halogen, hydroxyl, sulfhydryl, C1~C4alkyl, amino, amido, amide, C1~C4alkoxy, methylthio, phenyl, phenoxy, aryl, aralkyl, trifluoromethyl, acyl, aroyl, sulfonic group or isocyanate;

the above glycoside is arabinose, xylose, ribose, mannose or glucose;

R is oxygen, sulfur, selenium or the group NR6or NOR6in which R6represents H, C1~C6-alkyl direct connection or razvetvlenno the communication aryl, aralkyl,3~C6alicyclic group, acyl, aroyl, sulfonyl or phosphoryl.

The preferred species of the compounds are derivatives of azaindole-indole, prepared in example implementations, namely in the following table:

The connection numbertype
1-59derivatives of 5-atindimubona
60-89derivatives of 5-azizeenho
92-150derivatives of 7-atindimubona
151-180Derivatives of 7-azizeenho

Pharmaceutically acceptable salt

In the present invention also includes compounds of the present invention and their pharmaceutically acceptable salts formed with inorganic or organic acids. Inorganic acids include: hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid. Organic acids include formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonate (1, 5), Asiatic acid, oxalic acid, tartaric acid, lactic sour is a, salicylic acid, benzoic acid, butylcarbamoyl acid, diethyloxalate acid, malonic acid, succinic acid, fumaric acid, Emelyanova acid, hexandiol acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionate acid, piknova acid, ascorbic acid, nicotinic acid, isonicotinamide acid, econsultancy acid, paratoluenesulfonyl acid, citric acid and amino acid.

In the present invention improved physical and chemical properties described salts, increased permeability of cells, the ability of access to the cells, thereby increased the effectiveness of the medicine.

The activity of the compounds of the present invention

Compounds of the present invention and their salts are inhibitors of cyclin-dependent kinases, and they can indoctrinate endogenous inhibitors of cyclin-dependent kinases, thereby constraining growth and cell proliferation, promote apoptosis of tumor cells. Compounds of the present invention and their salts by restoring the signal conversion increase insulin sensitivity of peripheral tissues to use insulin, reducing the effect of insulin resistance. Thus, specified in the present invention compounds and their salts can be used to prepare the ke of drugs for the treatment of diseases, deviation from the norm of cyclin-dependent kinases, disorders of growth and proliferation of cells, or insulin resistance. These diseases include cancer, psoriasis, viral skin diseases, HIV, and neurodegeneration, a disorder of the nervous system and diabetes mellitus type 2.

To facilitate understanding of the present invention the inventor provided a description of the mechanism of action of the compounds of the present invention. It should be understood, however, that the scope of protection of the present invention is not limited to the mechanism described.

In the present invention, for example asuindasun, in fact, is the product of the binding molecules azaindole with a molecule of indole 3.2' position; for example, azizeenho, it is a product of adhesion molecules azaindole with one molecule of indole in the 3,3'-positions. Replacement of the nitrogen atom of one of the carbon atoms of the benzene ring allows to obtain the following four types of isomers:

Purine (a specific example below) represents one inhibitor CZK of 10 known types of chemical structures, as well as the inhibitor CZK[7]in the first studies. From the point of view of structure, azaindole and Purina have many similarities, they have a 6-membered aromatic heterocycles and 5-clonegall.

The results of the tests of the present invention have shown that the compounds of the present invention have similar activity inhibitor CZK.

Non-insulin dependent diabetes mellitus (type 2 diabetes) is one of the major diseases in the world, dangerous to human health and leading to its death, its mechanism of pathogenesis is insulin resistance. Studies have shown that derivatives of indirubin affect the activity of components of the PI3K (phosphoinositide-3-kinase) signaling pathway of insulin by activation of the protein kinase) and inhibition (target of rapamycin in mammals), restore the signal conversion to insulin, thus increasing the sensitivity of peripheral tissues to insulin, reducing the effect of insulin resistance.

Thus, derivatives of the present invention have an effect against tumors, psoriasis, viral skin diseases, HIV, neurodegeneration, nervous system disorders, and diabetes mellitus type 2.

Compositions and methods of use

The present invention also provides pharmaceutical compositions containing compounds of the present invention. The described compositions can be used to inhibit the asset is barb CSC, inductively ICC, recovery, conversion of the signal of insulin. The composition of the present invention may be a pharmaceutical combination containing pharmaceutically acceptable carriers), a combination of health products (containing pharmaceutically acceptable carriers, combination foods (containing acceptable for food storage media) and beauty combination (containing acceptable for cosmetic carriers).

Preferably, if the composition of this invention is a pharmaceutical composition comprising a compound of the present invention or their pharmaceutically acceptable salts), and a number of pharmaceutically acceptable carriers or excipients.

Completion form pharmaceutical compositions of the present invention is not limited, they can be in any clinically acceptable manner. Form perform the following composition: solution for injection in small, medium and large scale, powder for injection, emulsion injection, tablets, pills, capsules, ointments, creams, plasters, liniments, powders, aerosols, implants, drops, suppositories, ointments, various kinds nonrecurring funds; from the corresponding liposomes mainly made of the above-mentioned injection. As a rule, different dosage forms should be responsible methods of making Leka is STV.

Preferably, if the medicinal composition of this invention made in the form of injections, liquid funds, hard assets. Such solid dosage combinations can be made using conventional methods. Drug combination, for example, injection, liquid preparations, solid preparations must be made under conditions of sterilization or appropriate treatment.

In another optimal example, in the present invention provided to the injection of the compound (or pharmaceutically acceptable salts) of the present invention, i.e. emulsion, sub-micro-emulsions, nano-emulsions prepared using surfactants and/or solvent and/or oil components and/or other auxiliary materials.

In another optimal example, in the present invention provided a solid dispersion agent compounds (or pharmaceutically acceptable salts) of the present invention, i.e. the products are high concentrations dispersed in a water-soluble, nevadacalifornia, enteric inert carriers generated in the dispersion system in the form of a solid body, and by traditional manufacturing methods: capsules, tablets, pills, ointments, suppositories and injection equipment, etc. as a result of this connection not only maintain the high degree of dispersion, but stably stored.

Methods of administration of drugs

When using combinations of drugs injected safe and effective amount of the compounds of the present invention in mammals; the so-called safe and effective amount, usually is at least about 1 mg/day, and in most cases not more than 10 mg/kg of body weight. And the best dose of about 1 mg/day or about 3 mg/kg of body weight. Of course, the specific dose is determined depending on ways of introduction of the drug and the health status of the patient and other factors, these questions must be within the skills of experienced physicians.

Compounds (or pharmaceutically acceptable salts) of the present invention can be used separately as Monomeric funds or in combination with other drugs. The selected combined use include: joint use with a surgical operation, use in combination with one or more drugs of European medicine, in combination with herbal medicines Chinese medicine, in combination with radiation therapy and gene therapy, in combination with bio-regulators.

Methods of administration of the pharmaceutical compositions of the present invention is not limited to the specific terms, including: oral administration, injection,intratumoral introduction, implants introduction, intraoral introduction, anal, introduction, monopsonized introduction, internal and external attachment.

In the optimal injection include: intravenous injection, intramuscular injection, subcutaneous injection, intracavitary injection.

The manufacturing methods

The compound of the present invention described in the General formula IG can be prepared in accordance with the process according to the following formula, and taking into account the known synthetic methods in the field of this technology. In General, the following preparation process, all reactions should be carried out at a temperature of -10° to a temperature of recirculated air, usually at room temperature (about 25°) to a temperature of recirculation. Better, if the temperature of the reaction at a temperature of 5-100°, even better at temperatures of 20-80°. Reaction time, usually without special restrictions, usually 1 minute to 24 hours, better 1-20 hours. Solvents, as a rule, should be polar, such as water, master file preparation, alcohols (e.g. methanol, ethanol, isopropanol and so on). In the synthesis of chemical compounds can be used physico-chemical methods such as 1H NMR spectroscopy (1H-NMR), mass spectrometry (MS) and elemental analysis for structural identification.

1. Intermediate and target compounds 5-atindimubona (of the General formula (I)

(1) Synthesis of intermediate: 1-hydrocarbon-5-azaindole-2,3-dione (A):

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2, glycosyl, protected acyl, etc..

Take 5-azaindole with hydrocarbon in the N-1 position, and then as a result of oxidation with CrO3and CH3COOH receive the product (S): 1-hydrocarbon-5-azaindole-2,3-dione[11].

(2) Synthesis of intermediate compounds: derivatives of 1-acetyl-3-hydroxyindole (In)

Where R3'=H, Cl, Br, F, CH3The co3, SCH3, Ph, etc.

The product (V) obtained as follows: take of substituted derivatives of 2-aminobenzoic acid with Chloroacetic acid as a substitute, produce acylation and ring closure in the presence of acetic anhydride and sodium acetate, and restore.

(3) Synthesis of the target compounds: derivatives of 5-atindimubona (I)

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2, glycosyl, protected acyl, etc.; R3'=H, Cl, Br, F, CH3The co3, SCH3and Ph etc.

1-hydrocarbon-5-azaindole-2,3-dione and 1-acetyl-3-hydroxyindole or 5-halogenated-1-acetyl-3-hydroxyindole heated under acidic conditions, irrigating matched with the public N 2get derivatives of 1-hydrocarbon-5-atindimubona (I).

(4) Synthesis of the target compounds: derivatives of 3'-oximino-5-atindimubona

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2, glycosyl, protected acyl, etc.; R3'=H, Cl, Br, F, CH3The co3, SCH3, Ph, etc.

(5) Synthesis of the target compounds: 5-asuindasun-3'-oxime ether, etc.

Where R=CH3ON, EtON, R1=CH3With2H5n-C3H7n-C4H9Ph-CH2etc., R3'=H, Cl, Br and F, and so on.

2. The target connection 5-azizeenho (General formula II)

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2, glycosyl, protected acyl, etc., R3'=H, Cl, Br, F, HE, and co3etc.

Derivatives of 1-hydrocarbon-5'-substituted 5-azizeenho (II) are obtained by reaction of 1-hydrocarbon-5-azaindole-2,3-dione (A) with 5-substituted 2-hydroxyindole in alkaline conditions.

3. Intermediate and target compounds 7-atindimubona (General formula III)

(1) Synthesis of intermediate: 1-hydrocarbon-7-Azaindole-2,3-dione (S):

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2likoil, protected by acyl, etc.

Take 7-azaindole with the alkyl group in the N-1 position, and then as a result of oxidation with CrO3and CH3COOH[11]receive the product (S): 1-hydrocarbon-7-azaindole-2,3-dione (III).

(2) Synthesis of the target compounds: 7-atindimubona (III)

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2, glycosyl, protected acyl, etc.; R3'=H, Cl, Br, F, CH3and co3, SCH3and Ph etc.

1-hydrocarbon-7-azaindole-2,3-dione and 1-acetyl-3-hydroxyindole or 5-halogenated-1-acetyl-3-hydroxyindole heated under acidic conditions, irrigating, respectively, N2get derivatives of 1-hydrocarbon-7-atindimubona (III).

(3) Synthesis of the target compounds: 3'-oxime-7-atindimubona.

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2; glycosyl, protected acyl, etc.; R3'=H, Cl, Br, F, CH3and co3, SCH3and Ph etc.

(4) Synthesis of the target compounds: 7-asuindasun-3'-oxime ether, etc.

Where R=CH3ON, EtON, R1=CH3With2H5n-C3H7n-C4H9Ph-CH2etc., R3'=H, Cl, Br, etc.

4. The target connection: 7-azizeenho (General formula (IV)

Where R1=CH3With2H5n-C3H7n-C4H9Ph-CH2, glycosyl, protected acyl, etc.; R3'=H, Cl, Br, F, HE, and co3etc.

Derivatives of 1-hydrocarbon-5'-substituted 7-azizeenho (IV) are obtained by reaction of 1-hydrocarbon-7-azaindole-2,3-dione (C) With 5-substituted 2-hydroxyindole in alkaline conditions.

The main advantages of this invention are:

1) the Present invention completely changed the atomic structure of the molecules of the parent nucleus of indirubin, sondigo, thus forming a class of compounds with a completely new structure, and improved electrical properties of the original molecule. Given that the pyridine soluble in water, and the benzene is almost insoluble in water, the present invention has improved the solubility of the proposed compounds in water, thus increasing bioavailability.

2) Compounds of the present invention relates to inhibitors of cyclin-dependent kinases, they Inuktitut endogenous inhibitors of cyclin-kinase, thereby preventing growth and proliferation of cells, promoting apoptosis of tumor cells.

3) Compounds of the present invention due to the recovery of signal conversion make insulin in peripheral tissues sensitive to insulin and reduce the role of insulin resistance.

4) the Connection of this image is to be placed have improved physicochemical properties and increased permeability of the cells, they can easily enter into the cells, thereby increasing the efficacy of a drug.

Specific examples of implementation

The invention is further illustrated by the detailed description of examples of its implementation. These examples only serve to illustrate the invention, they do not limit its essence, the specific options. In the experimental methods used in the following examples, all procedures are performed under standard conditions or according to the manufacturer's instructions and all parts, percentages and fractions are listed by weight, unless expressly indicated otherwise.

Example 1. Preparation of compounds

The melting temperature derivatives of 5 - or 7-atindimubona and 5 - or 7-sondigo obtained in this example implementation, was measured by measurement of the melting temperature Mel-TEMP without calibration. Mass spectrum (MS) was determined using a mass spectrometer HP1100LC/MSD.

Thin-layer chromatography plate (TLC) were made of silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd.) and 0.8% solution of CMC-Na in distilled water; the components were mixed, activated for 1 hour at a temperature of 100-110°, then kept in the dryer and brought under ultraviolet light (wavelength 254 nm and 365 nm). The chromatographic column was Packed with silica gel (200-300 mesh or 100-200 mesh) (Qingdao Haiyang Chemical Co., Ltd) using the dry method. In rodny 1H-NMR (1H-NMR) were determined using nuclear magnetic resonance apparatus of the type Bruck AV-300, the internal standard TMS. Elemental analysis was carried out using the equipment Elementar'ario EL III.

The reagents were commercially available chemically pure and analytically pure products varieties. Unless otherwise indicated, reagents were used directly without additional processing.

Example 1-1. Preparation of intermediate compounds

(1) 1-methyl-5-azaindole-2,3-dione

1-methyl-5 azaindole (2.0 g, 15 mmol) is dissolved in 70 ml of Asón, in advance suspension 3.2 g CrO3in 20 ml of water, poured into the above solution of acetic acid, conduct the reaction for 0.5 hour at room temperature, the mixture is diluted with water, extracted 3 times with chloroform; the organic matter dissolved in chloroform, the organic phases are integrated and are washed with water, dehydrated composition is enriched. Get orange intermediate compound 1-methyl-5-azaindole-2,3-dione (1.5 g, yield 62%; other 140-142°C).

2) 2-(N-carboxymethylamino)-5-chlorobenzoic acid

2-amino-5-chlorbenzene acid (2.0 g, 11.6 mmol) was dissolved in 15 ml of 2 mol/l Na2CO3; Chloroacetic acid (0.69 g, 7.3 mmol) was dissolved in 7.5 ml of 2 mol/l Na2CO3the last solution slowly drops added to the previous solution. Then the mixture was stirred at 80°C for 20 hours, cooled to room temperature, was added 50 ml of ether and 8 ml of 2 mol/l hydrochloric acid. Separated organic phase was dried with MgSO4. After concentration was obtained a light brown solid. After purification column chromatography on silica gel (ethyl acetate/methanol, by volume 1/1) received a white solid (2-(N-carboxymethylamino)-5-chlorbenzene acid) (1.58 g, yield 59%; other: 182-183°C).

(3) 1-acetyl-5-chloro-3-acetoxymethyl

2-(N-carboxymethylamino)-5-chlorbenzene acid (1.20 g, 5.2 mmol) and anhydrous sodium acetate (0.6 g, 7.3 mmol) was dissolved in 8 ml of acetic anhydride. After stirring for 5 hours at 60°C. the reaction mixture was cooled to room temperature, and sodium acetate was filtered. After concentration in the concentrated filtrate was added 100 ml of ethyl acetate to dissolve, was added 100 ml of water and 20 ml saturated sodium bicarbonate, separated organic layers. Organic matter in the water layer was extracted with ethyl acetate (50 ml × 2). The combined organic phases were washed with saturated sodium bicarbonate (100 ml × 2), dried and evaporated to obtain a white body (1-acetyl-5-chloro-3-acetoxyethyl) (0.84 g, yield: 64%).

(4) 1-acetyl-5-chloro-3-carboxyla

1-acetyl-5-chloro-3-acetoxymethyl (1.0 g, 3.97 mmol) were mixed in 20 ml of water and sodium sulfite (1.0 g, 7.94 mmol), the mixture was heated at 80°C for 3 hours, cooled to room temperature, was extracted with what ethyl acetate (100 ml × 2). The combined organic phase was dried. After concentration, the obtained white needle-like solid (1-acetyl-5-chloro-3-carboxybenzoyl) (0.84 g, yield 66%; other: 186-188°C).

(5) 1-methyl-7-azaindole 2,3-dione

1-methyl-7-azaindole (2 g, 15 mmol) was dissolved in 70 ml of acetic acid was suspensively 3.2 g CrO3in 20 ml of water. The reaction mixture was stirred for 0.5 h at room temperature and was diluted with water. The mixture was extracted with trichloromethane three times. The combined organic phase was washed with water, dried and evaporated. Was obtained orange intermediate compound (1-methyl-7-azaindole-2,3-dione) (1.73 g, yield: 71.3 per cent; other: 162-163°C).

(6) 2-(N-carboxymethylamino)-5-bromobenzoic acid

2-amino-5-bromobenzoic acid (2 g, 9 mmol) was dissolved in 15 ml of 2 mol/l Na2CO3; Chloroacetic acid (0.69 g, 7.3 mmol) was dissolved in 7.5 ml of 2 mol/l Na2CO3.

Then, after stirring for 20 hours at a temperature of 80°C, the reaction mixture was cooled to room temperature. 50 ml of ether and 8 ml of 2 mol of hydrochloric acid was added to the mixture. The organic phase was separated and dried with MgSO4. After evaporation there was obtained a light brown solid.

After purification column chromatography on silica gel (ethyl acetate/methanol, the volume on the volume 1/1) received a white solid (2-(N-carboxymethyl) - Rev. min)-5-brabantia acid) (1.55 g, yield: 60%,; etc.: 178-180°C).

(7) 1-acetyl-5-bromo-3-acetoxymethyl

2-(N-carboxymethylamino)-5-bromobenzoic acid (0.84 g, 3.4 mmol) and anhydrous sodium acetate (0.6 g, 7.3 mmol) was dissolved in 8 ml of acetic anhydride. After stirring for 5 hours at 60°C. the reaction mixture was cooled to room temperature, and sodium acetate was filtered. After concentration in the concentrated filtrate was added 100 ml of ethyl acetate to dissolve, was added 100 ml of water and 20 ml saturated sodium bicarbonate, separated organic layers. Organic matter in the water layer was extracted with ethyl acetate (50 ml × 2). The combined organic phases were washed with saturated sodium bicarbonate (100 ml × 2), dried and evaporated to obtain a white body (1-acetyl-5-bromo-3-acetoxyethyl) (1.3 g, yield: 25.4 per cent).

(8) 1-acetyl-5-bromo-3-carboxyla

1-acetyl-5-bromo-3-acetoxymethyl (1.0 g, 3.38 mmol) and sodium sulfite (1.0 g, 7.94 mmol) were mixed in 20 ml of water. After heating at 80°C for 3 hours the reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 ml × 2). The combined organic phase was dried. After concentration, the obtained white needle-like solid (1-acetyl-5-bromo-3-carboxybenzoyl) (0.7 g, yield 82%; other: 180-182°C).

Example 1-2. The synthesis of the target compounds

(1) 1-methyl-5-asuindasun (2)

To 1-methyl-5-azaindole-2,3-dione (0.2 g, 1.23 mmol) was added 1-acetyl-3-hydroxyindole (0.21 g, 1.2 mmol), 20 ml of water and 0.02 g paratoluenesulfonyl acid. The reaction mixture was stirred and boiled under nitrogen atmosphere for 1 hour to obtain a purple-red solution. After cooling, the mixture was extracted with trichloromethane, washed with water and evaporated. Got a purple solid. After purification column chromatography on silica gel (trichlormethane/petroleum ether, by volume, 3/1) it was recrystallization with ethyl acetate, got red needle-like crystals of 1-methyl-5-asuindasun (2) (0.15 g, yield 44%; other: 114-116°C).

ESI-MS: 278.1 [M+H]+C16H11N3O2(277.2);

1H NMR (AV-300, CDCl3, ppm) δ: 3.48 (s, 3H, -CH3), 7.08 (m, 1H, 5'-H), 7.09 (m, 1H, 6'-H), 7.16 (dd, 1H, J=7.6 Hz, 4'-H), 7.76 (d, J=7.6 Hz, 1H, 7'-H), 8.10 (s, 1H, 4-H), 8.26 (dd, J=5.5 Hz; 1H. 6-H), 9.10 (dd, J=5.5 Hz, 1H, 7-H), 10.4 (bs, 1H, N-H);

Similarly for C16H11N3O2: C, 69.31 H, 3.97 N, 15.16;

Obtained: C, 69.15 H, 4.09 N, 15.29.

(2) 1-benzyl-5'-chloro-5-asuindasun (19)

Used the same method as (1), 1-benzyl-5-azaindole-2,3-dione and 1-acetyl-5-chloro-3-hydroxyindole in number, as in (1), and 0.02 g paratroop-sulfonic acid was dissolved in 20 ml of water. The reaction mixture was stirred and boiled under nitrogen atmosphere for 1 hour to obtain a purple-red solution. After cooling, the mixture extra is believed by trichlormethane, washed with water and evaporated. Received a purple solid. After purification column chromatography on silica gel (trichlormethane/petroleum ether, by volume, 3/1) it was recrystallization with ethyl acetate, got red needle-like crystals of 1-benzyl-5'-chloro-5-asuindasun (19) (0.18 g, yield 39%; other: 110-112°C).

ESI-MS: 389 [M+H]+C22H14ClN3O2(387.9);

1H NMR (AV-300, CDCl3, ppm) δ: 5.21 (s, 2H, N-CH2), 10.44 (s, 1H, N-H), 6.91~9.02 (m, 11H, Ar-Hs);

Similarly for C22H14ClN3O2: C, 68.13 H, 3.64 N, 10.83;

Obtained: C, 68.42 N, 3.59 N,at 10.89.

(3) 1-butyl-5-asuindasun-3'-oxime (40)

Was dissolved 1-butyl-5-asuindasun (0.4 g, 1.25 mmol, obtained by the method (1)) in 12 ml of methanol, adding 6 ml of anhydrous pyridine and 0.15 g of hydroxylamine hydrochloride (2.2 mmol).

The reaction mixture was stirred and boiled for 1 hour, cooled and concentrated to remove most of the solvent. The residue was dumped in 100 ml of crushed ice, intensive stirring, then filtered, and the obtained orange solid. After purification column chromatography on silica gel (trichlormethane/petroleum ether, by volume, 3/1) received orange crystalline powder of 1-butyl-5'-5-asuindasun-3'-oxime (40) (0.32 g, yield 90%; other: 250-252°C).

ESI-MS: 335.1 [M+H]+C19H18N4O2(334.3);

1N NR (AV-300, D6-DMSO, ppm) δ: 0.91 (t, 3H, -CH3), 1.3l (m, 2H, -CH2), 2.28 (m, 2H, -CH2), 3.28 (m, 2H, N-CH2), 7.10~8.81 (m, 7H, Ar-Hs), 11.71 (s, 1H, N-H), 13.70 (s, 1H, N-OH);

Similarly for C19H18N4O2: C, 68.25 H 5.43 N,16.76;

Obtained: C, 68.33 H, 5.56 N, 16.66.

(4) 1-butyl-5-asuindasun-3'-monooxime O-methyl (53)

1-butyl-5-asuindasun-3'-oxime (1.5 g, 4.5 mmol) was added to 50 ml of 5% potassium hydroxide in anhydrous ethanol, dissolved in warm temperature, and filtered. To the filtrate was added 5 drops ml SN with constant stirring. When the reaction was allocated the heat was obtained a dark red precipitate. After stirring for 0.5 hours the precipitate was filtered and washed with water to obtain a neutral solution, dried and got dark red crude product, which was recrystallization acetone, got dark red crystals of 1-butyl-5-asuindasun-3'-monooxime O-methyl (53) (1.20 g, yield 77%; other: 209-211°C).

ESI-MS: 349.1 [M+H]+C20H20N4O (348.2);

1H-NMR (AV-300, D6-DMSO, ppm) δ: 0.98 (t, 3H, -CH3), 1.46 (m, 2H, -CH2), 2.08 (m, 2H, -CH2), 3.86 (m, 2H, N-CH2), 4.16 (s, 3H, O-CH3), 7.10~9.19 (m, 7H, Ar-Hs), 10.86 (bs, 1H, N-H);

Similarly for C20H20N4O2: C, 68.95 H, 5.79, N, 16.08

Obtained: C, 68.81 N, 5.62 N, 15.85.

(5) 1-isopropyl-5-azizeenho (73)

1-Isopropyl-5 isoindol-2,3-dione (0.4 g, 2.1 mmol) and 2-hydroxyindole (0.28 g, 2.1 mmol) was added in 10 ml of e is anola, adjust the pH to 9 using 1 mol/l NaOH, the reaction was performed at 70°C for two hours and got a brown body. After cooling, was filtered, washed with water and ethanol were dried in vacuo, resulted in a red-brown solid 1-isopropyl-5-azizeenho (73) (0.44 g, yield 66%; other: 128~130°C).

ESI-MS: 306.1 [M+H]+, 304.2 [M-N]-C18H15N3O2(305.3);

1H NMR (AV-300, D6-DMSO, ppm) δ: 1.52 (d, 6N, -CH(CH3)2), 4.81 (m, 1H, -CH(CH3)2), 6.86-9.32 (m, 7H, Ar-Hs), 10.96 (bs, 1H, N-H);

Similarly for C18H15N3O2: C, 70.81 H 4.95 N, 13.76

Obtained: C, 70.62 H, 5.10 N, 13.58.

(6) 1-methyl-7-asuindasun (93)

To 1-methyl-7-azaindole 2,3-dione (0.2 g, 1.23 mmol) was added 1-acetyl-3-hydroxyindole (0.21 g, 1.2 mmol), 20 ml of water and 0.02 g paratoluenesulfonyl acid. The reaction mixture was recycled with nitrogen under stirring for 1 hour, received a purple-red solution. After cooling, the solution was extracted with chloroform, washed with water, concentrated, received a purple body. After purification column chromatography on silica gel (trichlormethane/petroleum ether, by volume, 3/1) was recrystallization with ethyl acetate, got red needle-like crystals of 1-methyl-7-asuindasun (93) (0.14 g, yield 41,1%; other: 116~118°C).

ESI-MS: 278.1 [M+H]+C16H11N3O2(277.2);

1 H NMR (AV-300, CDCl3, ppm) δ: 3.59 (s, 3H, -CH3), 7.08 (m, 1H, 5'-H), 7.09 (m, 1H, 6'-H), 7.16 (dd, 1H, J=7.6 Hz, 4-H), 7.58 (m, 1H, 5-H), 7.76 (d, J=7.6 Hz, 1H, 7'-H), 8.21 (dd, J=5.5 Hz, 1H, 4-H), 9.13 (dd, J=5.5 Hz, 1H, 6-H), 10.4 (bs, 1H, N-H);

Similarly for C16H11N3O2: C, 69.31 H, 3.97 N, 15.16;

Obtained: C, 69.05 N, 4.18 N, 15.34.

(7) 1-benzyl-5'-bromo-7-asuindasun (109)

By the same method as in (6), 1-benzyl-7-azaindole 2,3-dione and 1-acetyl-5-bromo-3-hydroxyindole in number, as in (6), was added 20 ml of water and 0.02 g paratoluenesulfonyl acid. The reaction mixture was recycled with nitrogen under stirring for 1 hour, received a purple-red solution. After cooling, the solution was extracted with chloroform, washed with water, concentrated, received a purple body. After purification column chromatography on silica gel (trichlormethane/petroleum ether, by volume, 3/1) was recrystallization with ethyl acetate, got red needle-like crystals of 1-benzyl-5'-bromo-7-asuindasun (109) (0.14 g, yield 27%; other: 112~114°C).

ESI-MS: 433 [M+H]+C22H14BrN3O2(432.2);

1H NMR (AV-300, CDCl3, ppm) δ: 5.24 (s, 2H, N-CH2), 10.44 (s, 1H, N-H), 6.91~9.0 (m, 11N, Ar-Hs);

Similarly for C22H14BrN3O2: C, 61.13 (H, 3.26 N, 9.72;

Obtained: C, 60.72 N, 3.57 N, 9.38.

(8) 1-butyl-7-asuindasun-3'-oxime (131)

1-butyl-7-asuindasun (0.4 g, 1.25 mmol, obtained by the method of (6)) was dissolved in 12 ml of methanol, adding 6 mbazwana pyridine and 0.15 g of hydroxylamine hydrochloride (2.2 mmol). The reaction mixture was heated and recycled within 1 hour, cooled, concentrated to remove most of the solvent, the residues were dumped in 100 ml of crushed ice, intensive stirring, was filtered, the result has been an orange body. After purification column chromatography on silica gel (trichlormethane/petroleum ether, by volume, 3/1) was recrystallization with ethyl acetate, the obtained orange solid 1-butyl-7-asuindasun-3'-oxime (131) (0.31 g, yield 87,7%; other: 254~256°C).

ESI-MS: 335.1 [M+H]+C19H18N4O2(334.3);

1H NMR (AV-300, D6-DMSO, ppm) δ: 0.92 (t, 3H, -CH3), 1.31 (m, 2H, -CH2), 2.28 (m, 2H, -CH2), 3.32 (m, 2H, N-CH2), 7.03~8.81 (m, 7H, Ar-Hs), 11.7 (s, 1H, N-H), 13.7 (s, 1H, N-OH);

Similarly for C19H18N4O2: C, 68.25 N, 5.43 N, 16.76;

Obtained: C, 68.09 H, 5.60 N, 16.58.

(9) 1-butyl-7-asuindasun-3'-monooxime O-methyl ether (144)

1-butyl-7-asuindasun-3'-oxime (1.5 g, 4.5 mmol) was added to 50 ml of 5% potassium hydroxide in anhydrous ethanol, dissolved in warm temperature, and filtered. To the filtrate was added 5 drops ml SN with constant stirring. When the reaction was allocated the heat was obtained a dark red precipitate. After stirring for 0.5 hours the precipitate was filtered and washed with water to obtain a neutral solution, dried and got dark red crude product, which re who was kristallizirovany acetone, got dark red crystals of 1-butyl-7-asuindasun-3'-monooxime O-methyl (144) (1.26 g, yield 80.5 per cent; other: 212-214°C).

ESI-MS: 349.1 [M+H]+C20H20N4O (348.2);

1H-NMR (AV-300, D6-DMSO, ppm) δ: 0.98 (t, 3H, -CH3), 1.46 (m, 2H, -CH2), 2.08 (m, 2H, -CH2), 3.88 (m, 2H, N-CH2), 4.16 (s, 3H, O-CH3), 7.06~9.19 (m, 7H, Ar-Hs), 10.86 (bs, 1H, N-H);

Similarly for C20H20N4O2: C, 68.95 H, 5.79, N, 16.08

Received: From, at 68.79 H, 5.59 N, 15.88.

(10) 1-isopropyl-7-azizeenho (164)

1-isopropyl-7 azaindole-2,3-dione (0.4 g, 2.1 mmol) and 2-hydroxyindole (0.28 g, 2.1 mmol) was added in 10 ml of ethanol, adjust the pH to 9 using 1 mol/l NaOH, the reaction was performed at 70°C for two hours and got a brown body. After cooling, was filtered, washed with water and ethanol were dried in vacuo, resulted in a red-brown solid 1-isopropyl-7-azizeenho (164) (0.42 g, yield of 63.2%; other: 132~134°C).

ESI-MS: 306.1 [M+H]+, 304.2 [M-N]-C18H15N3O2(305.3);

1H NMR (AV-300, D6-DMSO, ppm) δ: 1.51 (d, 6N, -CH(CH3)2), 4.78 (m, 1H, -CH(CH3)2), 6.86-9.3 (m, 7H, Ar-Hs), 10.99 (bs, 1H, N-H);

Similarly for C18H15N3O2: C, 70.81 H 4.95 N, 13.76

Obtained: C, 70.53 N, 5.04 N, 13.52.

In accordance with the above-mentioned method has prepared the 59 compounds 5-atindimubona (1), also synthesized derivatives of 5-atindimubona 2, 19, 40 and 53. Their structures are presented in table 1, all the structures of these new compounds were confirmed by IR-spectrometry, ultraviolet spectrometry (UV/VIS), mass spectrometry (ESI-MS), NMR (1H-NMR) and elemental analysis.

In formula 1, R2~R4, R1', R2', R4'and R5'accordingly represents N, and the rest, see table 1:

Table 1
The structure of the compounds 5-atindimubona (I)
No.R1R3'R
1234
1NNAbout
2CH3HAbout
3CH3OHAbout
4CH3Och3About
5CH3SCH3About
6C2H5HAbout
7i-C3H7HAbout
8n-C4H9HAbout
9CH2-PhHAbout
10CH3BrAbout
11CH3ClAbout

Continuation of table 1
1234
12C2H5BrO
13ClO
14i-C3H7BrO
15i-C3H7ClO
16n-C4H9BrO
17n-C4H9ClO
18CH2-PhBrO
19CH2-PhClO
20CH2-PhFO
21Triacetyl ribosylHO
22PhCOOCH3S
23CH3CH2CO OCH3S
24CH3BrN-OH
25CH3ClN-OH
26CH3PhN-OH
27CH3SCH3N-OH
28C2H5BrN-OH
29C2H5ClN-OH
30i-C3H7BrN-OH
31i-C3H7ClN-OH
32n-C4H9BrN-OH
33n-C4H9C N-OH
34CH2-PhBrN-OH
35CH2-PhClN-OH
36CH2-PhFN-OH
37CH3HN-OH
38C2H5HN-OH

Continuation of table 1
1234
39i-C3H7HN-OH
40n-C4H9HN-OH
41CH2-PhHN-OH
42ribosylHN-OH
43GlycosylHN-OH
44CH3HN-OCH3
45CH3BrN-OCH3
46CH3ClN-OCH3
47C2H5HN-OCH3
48C2H5BrN-OCH3
49C2H5ClN-OCH3
50i-C3H7HN-OCH3
51i-C3H7BrN-OCH
52i-C3H7ClN-OCH3
53n-C4H9HN-OCH3
54n-C4H9BrN-OCH3
55n-C4H9ClN-OCH3
56CH2-PhHN-OCH3
57CH2-PhFN-OCH3
58CH2-PhBrN-OCH3
59CH2-PhClN-OCH3

In accordance with the method of preparation of 1-Isopropyl-5-azizeenho (73) of all synthesized 30 compounds 5-azizeenho (73), their structure is presented in table 2. The structures of these new compounds, p is doriden IR-spectrometry, ultraviolet spectrometry (UV/VIS), mass spectrometry (ESI-MS), NMR (1H-NMR) and elemental analysis.

In formula II, R2~R4, R2', R4'and R5', respectively, are N, the remaining see table 2:

Table 2
The structure of the compounds 5-azizeenho (II)
No.R1R1'R3'
1234
60CH3HH
61CH3HBr
62CH3HCl
63CH3HF
64CH3CH3HE/td>
65CH3CH2COHOch3
66PhCOHOch3
67Triacetyl ribosylHN
68C2H5HN
69With2H5C2H5Br
70C2H5HCl
71C2H5HF
72C2H5C2H5HE
73i-C3H7HN
74i-C3H7 HBr
75i-C3H7HCl
76i-C3H7HF
77i-C3H7i-C3H7HE
78n-C4H9HN

Continuation of table 2
1234
79n-C4H9HBr
80n-C4H9HCl
81n-C4H9n-C4H9OH
82n-C4H9 HF
83n-C4H9n-C4H9OCH3
84CH2-PhHH
85CH2-PhHBr
86CH2-PhCH2-PhCl
87CH2-PhHF
88CH2-PhCH2-PhOH
89ribosylHH

In accordance with the above methods of preparation of derivatives of 7-atindimubona 93, 109, 131, and 144 only synthesized 59 compounds of type 7-atindimubona (III), their structures are presented in table 3. The structures of these new compounds were confirmed by IR-spectrometry, ultraviolet spectrometry (UV/VIS), mass spectrometry (ESI-MS), NMR (1H-NMR) and elemental is the analysis.

In formula III, R2, R4, R1', R2', R4'and R5'respectively is N, the others see Table 3:

The structure of the compounds 7-atindimubona (III)

PhCO
Table 3
No.R1R3R3'R
12345
92NNNO
93CH3NNO
94CH3CH3HEO
95CH3CH3Och3O
96CH3 CH3SCH3O
97C2H5NHO
98i-C3H7NHO
99n-C4H9NHO
100CH2-PhNHO
101CH3NBrO
102CH3NClO
103C2H5NBrO
104C2H5HCl O
105i-C3H7NBrO
106i-C3H7HClO
107n-C4H9NBrO
108n-C4H9NClO
109CH2-PhNBrO
110CH2-PhNClO
111CH2-PhNHCH3FO
112Triacetyl ribosylCH3NO
113CH3Och3S
114CH3CH2COFOch3S
115CH3NBrN-OH
116CH3NClN-OH
117CH3CF3PhN-OH

N-OH H
Continuation of table 3
12345
118CH3CH3SCH3N-OH
119C2H5HBr
120C2H5HClN-OH
121i-C3H7HBrN-OH
122i-C3H7HClN-OH
123n-C4H9HBrN-OH
124n-C4H9HClN-OH
125CH2-PhHBrN-OH
126CH2-PhHClN-OH
127CH2-PhHFN-OH
128 CH3HHN-OH
129C2H5HHN-OH
130i-C3H7HHN-OH
131n-C4H9HHN-OH
132CH2-PhHHN-OH
133ribosylCH3HN-OH
134glucosylCH3HN-OH
135CH3HHN-OCH3
136CH3H BrN-OCH3
137CH3HClN-OCH3
138C2H5HHN-OCH3
139C2H5HBrN-OCH3
140C2H5HClN-OCH3
141i-C3H7HHN-OCH3
142i-C3H7HBrN-OCH3
143i-C3H7HClN-OCH3
144n-C4H9HN-OCH3

Continuation of table 3
12345
145n-C4H9HBrN-OCH3
146n-C4H9HClN-OCH3
147CH2-PhHNN-OCH3
148CH2-PhHFN-OCH3
149CH2-PhHBrN-OCH3
150CH2-PhHClN-OCH3

In the CE is provided with the above methods of preparation of 1-isopropyl-7-azeiteiro (164) of all synthesized 30 compounds 7 azizeenho (IV), their structures are presented in table 4. The structures of these new compounds were confirmed by IR spectrometry, ultraviolet spectrometry (UV/VIS), mass spectrometry (ESI-MS), NMR (1H-NMR) and elemental analysis.

In formula IV, R2, R4, R2', R4'and R5'respectively N, other, see table 4.

Table 4
Structures of compounds 7 azaindole (IV)
No.R1R1'R3R3'
12345
151CH3NNN
152CH3HNBr
153CH3HHC
154CH3HHF
155CH3CH3CH3HE

Continuation of table 4
12345
156CH3CH2COHFOch3
157PhCOHCH3Och3
158Triacetyl ribosylHCH3N
159C2H5HNN
160C2H 5C2H5NBr
161C2H5HNCl
162C2H5HNF
163C2H5C2H5CF3HE
164i-C3H7HNH
165i-C3H7HNBr
166i-C3H7HNCl
167i-C3H7HOch3F
168i-C3/sub> H7i-C3H7NHE
169n-C4H9HNH
170n-C4H9HNBr
171n-C4H9HHCl
172n-C4H9n-C4H9SCH3HE
173n-C4H9HHF
174n-C4H9n-C4H9Och3Och3
175CH2-PhHHN
176CH2-PhHHBr
177CH2-PhCH2-PhSCH3Cl
178CH2-PhHOch3F
179CH2-PhCH2-PhHHE
180ribosylHCH3N

Example 2. Test the antitumor activity (1)

1. Materials and devices

(i) Cell line: androgen-independent cancer cells DU145 prostate purchased from the United States, American Type Culture Collection.

(ii) reagents RPM1 1640 Medium (USA GIBCOBRL), calf serum (Hangzhou bio-engineering company Sizzilin), MTT (Sigma), HEPES (LTD Shanghai biotech company Liju-Dongfeng), L-glutamine (imported from Japan), dimethyl sulfoxide (DMSO, analytical reagent).

Test samples: selected 20 of the new compounds 5-Azai drubin and 5 azizeenho (own production), 38 of the new compounds 7-asuindasun and 7 azizeenho (own production).

Reference substance: 1-ethyl-indirubin (90), 1-ethyl-indirubin-3'-oxime (91), (own production, patterns are identified, treated with retinoic acid).

(iii) Preparation of reagents

A. the Environment of cell culture: 10.4 g of 1640 medium powders, 2.1 g of sodium bicarbonate, 0.3 g of glutamine, 5.95 g of HEPES, 100,000 units of penicillin and 100,000 units of streptomycin were added to 1000 ml of double distilled water. The mixture was sterilized by filtration using a microporous membrane filter, after the packing was stored at -20°C. Before use the medium was added inactivated calf serum.

B. calf Serum was inactivated in a water bath at 56°C for 30 minutes, after packaging were stored at -20°C.

C. MTT: dissolved in 5 mg/ml PBS, and kept in a dark place at 4°C, valid for two weeks.

D. PBS: 8.00 g of sodium chloride, 0.20 g of potassium chloride, 3.4 g dvenadcatiletnego disodium hydrogen phosphate, 0.20 g of decalage hydrogen phosphate was dissolved in water bath at 37°C in double distilled water, packaged in 1000 ml container, after filling wounded at 4°C.

That is Made solutions in dimethyl sulfoxide 58 test samples, substances (90 and 91) and processed retinoin the th acid and kept at -20°C.

(iv) Main devices:

CO2incubator (type GB16, the German company Heraeus): Table for cleaning (SW-CJ-1F, LTD Suzhou air technology Anti); horizontal centrifuge (type LXJ-II, Shanghai Medical instrument factory No. 3); immunoassay analyzer (BIO RAD Model 550, USA); inverted biological microscope (XSZ-D2, Chongqing optical instrumentalna factory); a device for rapid mixing (type SK-1, LTD Changzhou Elektroprivreda company Guohua); thermostatic electric tank (type DK-8D, the Shanghai plant medical thermostatic equipment); flow cytometer (FACSCalibur, American companies B-D); platform vibrator (type 752-A, the Shanghai factory of medical analytical instruments); electronic scale (type BS110S, the German company Sartorius).

2. Methods.

(i) Culturing cells

DU145 cells grafted in RPM11640 medium with 10% fetal serum of calves, put in an incubator with 5% CO2, 37°C, transferred every 2-3 days during the experiment, take the cells in the logarithmic phase.

(ii) the Experimental group

In the experiments take the cells in the logarithmic phase, create a cell suspension, after uniform mixing determine cell viability Trifanova blue staining, the number of viable cells should b the th more than 98%. The cell suspension is divided equally into several groups: 1: blank control group (cell suspension); 2: experimental group (cell suspension + medicine).

(iii) by the MTT Method determines the values of the IC50(half the amount of inhibition)

Prepare backup solution with dimethyl sulfoxide concentration of 20 mmol (experiment carried out within 4 hours). The experiments are carried out under sterile conditions, in a working solution on the basis of RPMI1640 medium with 10% fetal serum of calves, prepare the working solution tested drug concentration of 80 µm, the concentration of the drug is gradually increased in 2 times (1,25-20 Microm).

Selected DU145 cells in the logarithmic phase, centrifuged, counted and prepared suspension density of 2.5×104/ml of medium RPMI1460 containing 10%serum of the calves. The suspension was inoculated in a plate with 96 holes, each hole of 5000 cells/200 ml, were cultured for 24 hours at 37°C in 5% environment CO2. Then at the above concentrations were inoculated in 6 groups (including the control group), each group created 8 bottom holes. After excretion within 72 hours, the viability of cells was measured by MTT colorimetry. The value of absorption (A) was measured with wavelength detection at 540 nm, the wavelength link is at 630 nm. Calculate in accordance with the following formula the degree of inhibition:

The ratio of inhibition (I) was calculated by the following equation, where T is the magnitude of the absorbance of the experimental groups, and - the value of the absorbance of the pure control group:

I=(1-T/C)×100%.

In accordance with the concentration curve of inhibition calculated the regression equation to get the 50%and 90%inhibition concentration (IC50and IC90µm). The results are presented in table 5 and table 6 and Figure 2.

Table 5
Derivatives of 5-atindimubona and 5-isindicative: IC50and IC90inhibiting the growth of cancer cells DU145
No.IC50(µM)IC90(µM)No.IC50(µM)IC90(µM)
7>100not tested386.422.0
811.539.0 6348.0>100
912.085.0678.044.0
128.828.07117.087.0
159.048.0759.729.0
186.623.57816.051.0
251.712.27914.577.0
284.514.082>100>100
292.26.8
30 3.37.0907.231.0
313.711.5914.221.8
357.320.0Tretinoin>50

td align="left"> 7.1
Table 6
Derivatives of 7-atindimubona and azithomycin: IC50and IC90inhibiting the growth of cancer cells DU145
No.IC50(µM)IC90(µM)No.IC50(µm)IC90(µm)
9540.0>1001267.119.0
98>100not tested1282.7
9911.587.01293.812.0
1009.531.51307.0517.0
10111.560.013116.080.0
1028.018.015443.0>100
10310.032.215810.549.0
1048.545.016014.061.0
1058.128.516114.045.0
10618.5 100.016217.589.0
10714.026.01649.0519.0
10811.042.01658.328.0
1097.024.016610.031.5
1117.434.016914.047.0
1166.916.017015.090.0
1194.012.01719.046.0
1205.461.0173>100&t; 100
1213.129.0
1228.025.0907.030.0
1233.75.0914.122.0
1241.812.0Tretinoin>50
Note: in the table of the molecular structure of the control of substances 90 and 91 the following:

3. Discussion

(i) From the results of the MTT test is easy to see that the vast majority of derivatives of 5-or 7-atindimubona and 5 - or 7-saisonmieten has strong antitumor activity, inhibiting effects against the growth of tumor cells is much stronger than in the processing of retinoic acid as induced differentiated agent cells. Even more important is that tableuse most derivatives of 5 - or 7-atindimubona and 5 - or 7-saisonmieten have a good inhibiting effects for androgen-independent prostate cancer cells DU-145, with that in current clinical practice still had nothing to fight;

(ii) many of derivatives of 5 - or 7-atindimubona and 5 - or 7-azizeenho have the value of the IC50close or less IC50control substances (90 and 91), and composition 91 is a well - known inhibitor of CDKs[13].Patterns of connections 38, 129 very similar to the 91, the difference between them lies only in the types of atoms on the 5 or 7 position. Also suggested that the new synthesized compositions of the present invention may have a similar mechanism of inhibiting the growth of tumor cells;

(iii) 3'-oxymorphine and 5'-halogenated or 7-aziendasantanna derivatives show higher inhibitory effect on the growth of tumor cells, especially the connection 25, 30, 116, 121 and 124, and the connection 30, 121 and 124 have better security.

Example 3. Test anti-tumor activity (2)

1. Tumor cells: cancer cells human liver 7701 QGY, HepG-2, cancer cells of the human lung A, cells of chronic myeloid leukemia person C, cells human leukemia CEM cells melanoma mouse KIll.

2. Using the methods described in example 2, was determined biological activity of new synthesized derivatives of 5 - or 7-atindimubona and 5 - or 7-azizeenho (20 compounds) on the activity of inhibiting the growth of various tumor cells is K. The test results with the 50% inhibitory concentration (IC50microns) are presented in table 7.

Table 7
Inhibiting concentration (IC50microns) derivatives of 5 - or 7-atindimubona and 5 - or 7-azizeenho inhibiting the growth of tumor cells
Cancer cells IC50(µM)7701QGYHepG-2ACSEMKIII
1234567
9523.950.135.28.19.015.6
9912.429.318.46.77.110.1
10115.028.8 21.67.812.023.0
10239.541.522.89.57.018.2
10528.018.019.620.410.214.0
10628.018.019.620.410.214.0
10910.021.215.812.59.018.6
11128.517.024.315.211.015.1
11611.120.512.58.25.6 6.3
11913.58.18.57.99.08.1

4.2
Continuation of table 7
1234567
12114.916.018.111.511.36.0
12611.216.39.65.18.114.2
1287.612.610.07.710.53.6
1297.413.014.13.47.0
15436.029.312.419.09.812.0
15844.018.022.32.812.08.3
16025.431.129.110.210.815.0
16433.129.023.318.612.79.1
17028.025.019.510.38.518.5
17613.720.613.24.17.48.3

The results of these tests on the antitumor activity with imetelstat about that the derivatives of 5 - or 7-atindimubona and 5 - or 7-azizeenho have diverse biological activity of inhibiting the growth of tumor cells, thus opened a new direction for the study of antitumor compounds of indirubin, provided the material base for the development of new antitumor drugs.

Example 4. Inhibiting effects CDKs

Reagents: Sources of test compounds are the same as in Example 2. Unless otherwise indicated, all other chemical reagents were purchased in the U.S. from Sigma. Polyacrylamide gel electrophoresis of proteins (SDS-PAGE), SDS, electrophoresis buffer, buffer solution for transmission of proteins, nitrocellulose membrane, etc. acquired by the American company American Bio-Rad Life Science Company. Set to test the Western blot (Western bolt) and films has acquired the U.S. company American GE Company. Phospho-CDK2Thr160antibody, p27 antibody inhibitor of endogenous cilincing, antibodies CyclinD1 and β-Actin were purchased, respectively, in the American Cell Signaling Inc., DAKO and Santa Cruz Biochemical Technology Company.

Tumor cells and their cultivation: same as in example 2.

The method of Western blot tested Phospho-CDK2, P27, and cyclin D1:

Spent processing androgen-independent prostate cancer cells human DU145, in accordance with the concentration, as shown in Figure 3, using derivatives of 5 - or 7-atindimubona 5 - yl) - Rev. 7 azizeenho No. 124 and No. 126 within 24 hours. Collected cells were washed in accordance with the methods described in the literatures[14], proteins were extracted, took the required amount. Took 50 mg of protein was performed SDS-polyacrylamide gel electrophoresis. After electrophoresis proteins were transferred to nitrocellulose membranes using specific antibody Phospho-CDK2, P27 antibody inhibitor of endogenous cilincing and CyclinDl antibody test conducted Western blot, the antibody β-Actin was chosen as an internal standard, ECI film recorded the test results.

The results and discussion.

According to the test connection indirubin have the function of inhibiting CDKs cancer cells. The above examples 2 and 3 showed that derivatives of 5 - or 7-atindimubona and 5 - or 7-azizeenho of the present invention have a strong function of inhibiting cell growth. To better explain what these connections by regulating the activity cilincing perform the function of inhibiting the growth of cells, used the method of Western blot using specific antibody fosfaurilirovannogo Cdc2 protein and other important antibodies proteins P27 and cyclin D1p27 regulation of the cell cycle; observed the influence of activities representative compounds No. 124 and No. 126 of the present invention on the expression of the protein P27 and cyclin D1.

As shown in Figure 3, after treatment with compounds which is 124 and No. 126 within 24 hours of CDK2 activity (phosphorylation) in androgen-independent cancer cells of human prostate DU145 decreased significantly At the same time the expression of the protein cyclin D1 also declined significantly. On the contrary, in the same experimental conditions, the influence of endogenous inhibitors of cyclin-kinase in the expression of P27 was significantly increased. As a result of changes in these signaling proteins, cell growth is inhibited. Derivative 5 - or 7-atindimubona and 5 - or 7-azizeenho Inuktitut expression of P27 may be, by activating the path of the AhR receptor[15].

Example 5. Study of solid dispersants

Example 5-1.

The connection 110 in examples 1-25 mg
The polyethylene glycol 40050 mg

Process technology: polyethylene glycol 400 at 50°C was melted, adding connections 110 in examples 1-2 were mixed to uniformity, with stirring, at the same time held the cold vulcanization with ice, dried in a desiccator for 24 hours, then in accordance with conventional methods have produced pills or capsules.

Example 5-2.

The connection 18 in examples 1-25 mg
Polyethylene glycol 600050 mg
Lactose: microcrystallin the mini-cellulose = 10:1 1 g

Process technology: took the connection 18 in examples 1-2 was dissolved moderate alkaline solution of ethanol, adding polyethylene glycol 6000, melted at 50°C; stirring to uniformity, add auxiliary materials (lactose/microcrystalline cellulose = 10/1), stirring until the state semi-dry powder, was placed in a 60°C oven for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 5-3.

The connection 18 in examples 1-25 mg
Polyvinylpyrrolidone K-2550 mg
Lactose/microcrystalline cellulose = 10/11 g

Process technology: took the connection 18 in examples 1-2, poured in moderate alkaline ethanol solution, stirring until dissolved, adding polyvinylpyrrolidone K-25, was stirred to dissolve the added ancillary materials (lactose/microcrystalline cellulose = 10/1), mixing to uniformity, were placed in a 60°C oven for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 5-4.

The connection 31 in examples 1-2
5 mg
Polyoxyethylene (35) castor oil350 mg
Lactose/microcrystalline cellulose = 1/41 g

Process technology: Took the connection 31 in examples 1-2 was dissolved in chloroform appropriate number of added polyoxyethylene (35) castor oil, stirring to dissolve the added ancillary materials (lactose/microcrystalline cellulose = 1/4), stirring until smooth. The mixture was heated in 80°C water bath to evaporate trichlormethane, dried in a 60°C oven for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 5-5.

The connection 116 in examples 1-25 mg
Poloxamer 188100 mg
Microcrystalline cellulose1 g

Process technology: took the connection 116 in examples 1-2 was dissolved in an appropriate alkaline solution of ethanol, was added poloxamer 188, stirred to dissolve, added auxiliary materials (microcrystalline Zell is concerned), was stirred to uniformity, was placed in a 60°C drying for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 5-6.

Composition 18 in examples 1-25 mg
Poloxamer 188100 mg
Polyethylene glycol 600050 mg
Lactose/microcrystalline cellulose = 10/11 g

Process technology: took the connection 18 in examples 1-2 was dissolved in moderate alkaline solution of ethanol, was added poloxamer 188 and polyethylene glycol 6000, was stirred to dissolve the added ancillary materials (lactose/microcrystalline cellulose = 10/1), mixing to uniformity, were placed in a 60°C oven for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 5-7.

Compound 119 in examples 1-25 mg
Polyvinylpyrrolidone K-2550 mg
Poloxamer 18850 mg
Polyethylene glycol 600050 mg
Lactose1 g

Process technology: compound 119 in examples 1-2 was dissolved in moderate alkaline ethanol, adding poloxamer 188, polyethylene glycol 6000 and polyvinylpyrrolidone K-25, stirring to dissolve the added ancillary materials were placed in a 60°C oven for 24 hours, then in accordance with conventional methods produced tablets or capsules.

Example 5-8.

The connection 18 in examples 1-25 mg
Polyvinylpyrrolidone K-2550 mg
Poloxamer 188100 mg
Polyethylene glycol 6000100 mg
Lactose/microcrystalline cellulose = 10/11 g

Process: Take the connection 18 in examples 1-2, were placed in a moderate amount of alkaline ethanol solution was added poloxamer 188, polyethylene glycol 6000 and polyvinylpyrrolidone K-25, stirring to dissolve the added ancillary materials (lactose/microcrystalline cellulose = 10/1), stirring until rawname the spine, and placed in a 60°C oven for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 5-9.

The connection 29 in examples 1-25 mg
Polyoxyethylene (40) castor oil750 mg
Polyethylene glycol 400050 mg

Process technology: compound 29 in examples 1-2 was dissolved in polyoxyethylene (40) hydrogenated castor oil/ethanol, adding polyethylene glycol 4000, was heated to 50°C., stirring to dissolve, provided the solvents were utverjdali ice bags, were placed in a 60°C oven for 24 hours, in accordance with conventional methods produced granules or capsules.

Example 5-10.

Compound 121 in examples 1-25 mg
Polyoxyethylene (40) castor oil350 mg
Polyvinylpyrrolidone K-2550 mg
Lactose/microcrystalline cellulose = 7/31 g

Process technology: took link is 121 in examples 1-2, dissolved his polyoxyethylene (40) hydrogenated castor oil/ethanol, was added polyvinylpyrrolidone K-25, stirring to dissolve the added ancillary materials (lactose/microcrystalline cellulose = 7/3), mixing to uniformity, frozen, and dried at a temperature of -50°C for 24 hours, in accordance with conventional methods produced tablets or granules.

Example 5-11.

The connection 18 in examples 1-25 mg
Polyoxyethylene (40) castor oil350 mg
Polyvinylpyrrolidone K-2550 mg
Sodium dodecyl sulfate10 mg
Lactose/microcrystalline cellulose = 10/11 g

Process technology: dissolved in an appropriate volume of an ethanol solution of polyoxyethylene (40) castor oil and sodium dodecyl sulphate, after complete dissolution of the added compound 18 in examples 1-2, stirring until dissolved, was added polyvinylpyrrolidone K-25, mixing to dissolve the added ancillary materials (lactose/ microcrystalline whole is ulosa = 10/1), mixing to uniformity, and were placed in a 60°C oven for 24 hours, in accordance with conventional methods have produced pills.

Example 5-12.

The connection 18 in examples 1-25 mg
Polyoxyethylene (40) castor oil350 mg
Polyvinylpyrrolidone 1750 mg
Lactose/microcrystalline cellulose = 10/11 g

Process technology: Took the connection 18 in examples 1-2 was dissolved his polyoxyethylene (40) hydrogenated castor oil/ethanol, was added polyvinylpyrrolidone R17, stirring to dissolve the added ancillary materials (lactose/microcrystalline cellulose = 10/1), mixing to uniformity, were placed in a 60°C oven for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 5-13.

Connection 34 in examples 1-25 mg
The polyethylene glycol succinate vitamin E350 mg
Polyvinylene Idan K-90 50 mg
Lactose/microcrystalline cellulose = 5/51 g

Process technology: took the connection 34 in examples 1-2, dissolved it in a polyethylene glycol succinate vitamin E/ethanol, adding polyvinylpyrrolidone K-90, stirring to dissolve the added ancillary materials (lactose/microcrystalline cellulose = 5:5), mixing to uniformity, and were placed in a 60°C oven for 24 hours, in accordance with conventional methods produced tablets or capsules.

Example 6. Studies on the solubility of the solid dispersion preparations.

Devices: RCZ-5A Intelligent detector percent solubility, production, Tianjin University Precision Instruments Factory; UV1900 Ultraviolet spectrophotometer, production Shanghai Yayan Electronic Science And Technology Co., Ltd.

Test method for solubility: tested in accordance with test method for solubility (the third way) "Chinese Pharmacopeia)), 2005. According to this method, tested at a speed of 100 rpm and a temperature of 37±0.5°C, 100 ml of an aqueous solution of 1% sodium dodecyl sulfate ultrasonic degassing. Samples were taken after 45 minutes, immediately filtered through a 0.8 Μm film, the filtrate was diluted. The light absorption was measured using UV1900, calculated the percentage of soluble the tee.

Results and discussion:

In the above examples, we studied the percentage solubility of the solid dispersion preparations. The results are presented in table 8.

Table 8
Comparison of solubility of the solid dispersion preparations
Examples of implementationThe percentage solubility (%)
The connection 18 in examples 1-24
5-227
5-340
5-615
5-856
5-1171
5-1292

From the above table it can be seen that the solid dispersion preparations, which are made from the compounds of the present invention has overcome the disadvantages of these compounds, consisting in poor hydrophilicity and complexity to create relevant products. The result is a significant increase in the solubility of the compounds can be obtained useful the courthouse square. Due to the use of solid dispersion preparations with joint substrates under the interaction of more than one carrier, the compounds of the present invention have better solubility than one media, the solubility of the respective solid dispersion preparations will be much better.

Example 7. Studies on injection

Example 7-1.

Connection 18 in Examples 1-210 mg
Triglycerides of medium chain400 mg
Lecithin200 mg
Glycerol225 mg
Poloxamer 188200 mg

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 18 in examples 1-2, were introduced in dimethyl sulfoxide was heated at low temperature to dissolve, adding triglycerides of medium chain. The mixture was heated at a low temperature, stirred, mixed evenly.

Aqueous phase: glycerol, poloxamer 188, adding water for injection, was heated at a low temperature under vigorous stirring, slowly pour in oil the s phase and continued stirring for 3 minutes. Evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-2.

The connection 25 in examples 1-210 mg
The oleic acid monoglycerides500 mg
Phospholipids300 mg
Glycerol225 mg
Poloxamer 188200 mg

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 25 in examples 1-2, were heated at a low temperature, was dissolved in an appropriate amount of dimethyl sulfoxide, adding monoglycerides of oleic acid, was heated to dissolve, and then attached to the phospholipids, was heated at a low temperature, mixed evenly.

Aqueous phase: glycerol, poloxamer 188, adding water for injection, was heated with vigorous stirring, gradually on balali in the oil phase and continued stirring for 3 minutes. Evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-3.

The connection 34 in examples 1-216 mg
Albumin human 20%1 ml

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 34 in examples 1-2, were heated and dissolved at a low temperature in a mixture of tetrahydrofuran and methylene chloride.

Aqueous phase: aqueous solution of human albumin was poured into the oil phase, conducted ultrasonic treatment for 1 min, evaporated in a vacuum rotary evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-4.

The connection 122 in examples 1-210 mg
The polyethylene glycol 400100 mg
Lecithin50 mg
Hydroxypropyl-β-cyclodextrin200 mg

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 122 in examples 1-2 was dissolved in an alkaline solution of ethanol, adding lecithin and polyethylene glycol 400 were mixed to dissolve.

Aqueous phase: hydroxypropyl-β-cyclodextrin was dissolved in a solution of 70% ethanol was poured into the oil phase by adding appropriate amount of water for injection, stirred to uniformity, evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-5.

The connection 110 in examples 1-210 mg
Poloxamer 188200 mg
Lecithin30 mg
Hydroxypropyl-β-cyclodextrin300 mg
0.9% sodium chloride10 ml

Process technology: all the following processes are performed in a sterile room.

Took the connection 110 in examples 1-2 was dissolved in an alkaline solution of ethanol, adding poloxamer 188, heated, stirring to dissolve, cooled, added 0.9% solution of sodium chloride, mixed with an appropriate amount of ethanol was added lecithin, mixing evenly, was added hydroxypropyl-β-cyclodextrin, mixing evenly, held ultrasonic treatment for 1 min, evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-6.

The connection 30 in examples 1-210 mg
Poloxamer 188200 mg
Soy lecithin 20 mg
Hydroxypropyl-β-cyclodextrin400 mg

Process technology: all the following processes are performed in a sterile room.

Took the connection 30 in examples 1-2 was dissolved in an alkaline solution of ethanol, adding soy lecithin, poloxamer 188 to dissolve, and then add the hydroxypropyl-β-cyclodextrin, water for injection and dissolved in a suitable amount of ethanol; evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-7.

The connection 18 in examples 1-210 mg
The polyethylene-glycol monolaurate200 mg
Lecithin20 mg
Hydroxypropyl-β-cyclodextrin200 mg

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 18 in examples 1-2, RA is tarali in an alkaline solution of ethanol, adding lecithin and polyethylene-glycol monolaurate, stirring to dissolve.

Aqueous phase: hydroxypropyl-β-cyclodextrin was added to the 70% solution of ethanol was poured into the oil phase, Parasiva; evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-8.

Connection 19 in examples 1-210 mg
Polyoxyethylene (40) castor oil100 mg
Lecithin50 mg
Hydroxypropyl-β-cyclodextrin200 mg

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 19 in examples 1-2 was dissolved in alkaline ethanol, adding lecithin and polyoxyethylene (40) castor oil, stirring to dissolve.

Aqueous phase: hydroxypropyl-β-cyclodextrin was dissolved in 70% ethanol, poured in the oil phase by adding a suitable quantity the quantity of water for injection, we altered uniformly evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The obtained emulsion was sterilized, filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-9.

The connection 18 in examples 1-220 mg
20% human albumin5 ml

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 18 in examples 1-2 was dissolved in a mixed solution of tetrahydrofuran and trichloroethylene at ultrasonic processing.

Aqueous phase: human albumin was dissolved in an appropriate amount of a solution of 0.1 mol/l hydrochloric acid, with vigorous stirring was poured into the oil phase, continued intensive stirring for 5 minutes to achieve uniformity. The mixture was homogenized (600 bar) and cooled water. The operation was repeated for six times. Evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

The resulting emulsion sterilize the Lee, was filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 7-10.

Connection 120 in examples 1-210 mg
Srednezapadnyj triglyceride600 mg
The polyethylene glycol succinate vitamin E200 mg
Lecithin100 mg
Poloxamer 188200 mg
Glycerin225 mg

Process technology: all the following processes are performed in a sterile room.

Oil phase: take the connection 120 in examples 1-2, after the dissolution of ethanol was added polyethylene glycol succinate vitamin E, srednezapadnyj triglyceride, poloxamer 188, heated until dissolution.

Aqueous phase: 8 ml of 2.25% solution of glycerol was poured in the oil phase were mixed by adding the solution of lecithin, subjected to ultrasonic treatment for 10 minutes, evaporated in a rotary vacuum evaporator at low temperature to remove the organic solvents.

Policenews sterilized, was filtered, laminar condition was poured into a sterile lyophilized vial, frozen, dried, corked, closed lids of aluminum to seal.

Example 8. Test the solubility

Compound 129 and 91 are very similar in structure, the difference between them is only in the type of atoms in the 7-position (see formula below)was used as solvent for checking changes the solubility of 7-atindimubona compared with indirubin.

Test method: at room temperature (20°C) were taken, respectively, compound 129 and 91, 5 mg, was added to 2 ml of the appropriate solvent after mixing was dissolved, the results are presented in table 9.

Table 9
Comparison of the solubility of the compounds 129 and control product 91
Solvent12991
deionized waterslightly solubleInsoluble
Methanolinstantslightly soluble
Ethanolslightly solubleInstant
Acetoneslightly solubleEasily soluble
Chloroformslightly solubleEasily soluble
Petroleum ether (boiling point: 60~90°C)insolubleslightly soluble

According to the results presented in the table above, you can see that the derivatives of 7-atindimubona (129) the solubility increased significantly, and solubility in fat decreased. In General, the solubility and jirorastvorimogo of indirubin not good, but processed indirubin jirorastvorimogo increased, the solubility decreased, the connection 91 is exactly the same. This change of solubility reflects the need to study derivatives of 7-atindimubona. Evaluation of the absorption of drugs in the body and choice of dosage forms will bring favorable side.

Referred to in this invention all references cited in this application as AIDS, as all the articles were separately cited as a reference. In addition, it should be understood that the donkey reading the above content in the present invention, the technical personnel in this field can make various changes or modifications these equivalent forms also fall within the scope of the constraint formula, applied to this application.

Links

[1] Lundberg AS, Weinberg RA., Control of the cell cycle and apoptosis, Eur J Cancer, 1999, 35: 531-539.

[2] Sherr CJ. Canaer cell cycles, Science, 1996, 274: 1672-1677.

[3] Keyomarsi K., Pardee AB., Redundant cyclin overexpression and amplification in breast cancer cells, Proc Natl Acad Sci USA, 1993, 90: 1112-1116.

[4] Gray N, Detivand L, Meijer L, et al., ATP-site directed inhibitors of cyclin-dependent kinases, Curr Med Chem, 1999, 6: 859-875.

[5] Malumbres M, et al., Targeting cell cycle kinases for cancer therapy, Curr Med Chem, 2007: 14(9): 969-85.

[6] Rudolph J., Inhibiting transient protein-protein interactions: lessons from the Cdc25 protein tyrosine phosphatases, Nat Rev Cancer, 2007, 7(3): 202-11.

[7] A. Huwe, R. Mazitschek, Giannis A., Small molecules as inhibitors of cyclin-dependent kinases, Angew Chem Int Ed 2003, 42: 2100-2138.

[8] JI Suzzane, Kama, Juan Liang, etc., Indigo Naturalis, see: edited by the Institute of medication at the Chinese Academy of medical Sciences. Modern research of Chinese herbal medicine (volume 1)first edition, Beijing: Joint publishing house of Beijing medical University and China medical University "Xiehe", 1995: 227-257.

[9] Nam, S., Buettner R, Turkson, J. et al., Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells, PNAS, 2005, 102(17): 5998-6003.

[10] Roy KK., Sausville EA. Early development of cyclin dependent kinase modulators, Curr Pharm Design, 2001, 7(16): 1669-1687.

[11] Doklady, Akad Nauk SSSR, 1958, 118: 302-305.

[12] Christoph M.S., Pascale H., John M. et al., Synthesis and evaluation of analogues of 10H-indolo[3,2-b]-quinoline as G-quadruplex stabilising ligands and potential inhibitors of the enzyme telomerase, Org. Biomol. Chem., 2004, 2: 981-988.

[13] Yao CIC the EN, Van Longue, van Jakoi and other training Method and medical use derivatives N (1)-alkyl-3'-oxime, indirubin(I), inventive Chinese patent CN 1329376C, 2007-8-1.

[14] Wang LG, Ossowski L., Ferrari AC, Androgen receptor level is controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line, Oncogene, 2004, 23: 5175-5184.

[15] Marie K., Marc C., Maryse L. et al., Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins, Oncogene, 2004, 23: 4400-4412.

1. Derivatives azaindole-indole and its pharmaceutically acceptable salts according to the formula

where Y stands for a group of azaindole formula (Y1) (Y2)

Z means a group of the indole of formula (Z1) or (Z2)

"=" means a double bond located at the 3-position of the group azaindole Y and between the 2'- and 3'-positions of the group of the indole-Z;
in the above formulas, Y1, Y2, Z1 and Z2, R1and R1independently denote H or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: With1-C6alkyl, aryl, aralkyl, acyl, aroyl, glucosyl or Biosil, protected acyl, glucotrol or biosrom; this is described substituents selected from the group of halogen, hydroxyl, C1-C3alkyl, nitro or amino;
R2, R3, R4, R2', R3', R4', R5'independently denote H,halogen, hydroxyl, sulfhydryl or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: C1-C4alkyl, nitro, amino, amido, amide, C1-C4alkoxy, methylthio, phenyl, phenoxy, aryl, aralkyl, trifluoromethyl, acyl, aroyl, sulfonic group, sulfamoyl, isocyanate or alkyl-isocyanate, while described substituents selected from the group of halogen, hydroxyl, C1-C3alkyl, nitro or amino;
R is oxygen, sulfur, selenium or the group NR6or NOR6in which R6means N, or the following groups which may be unsubstituted or substituted with 1 to 3 substituents: With1-C6-alkyl direct connection or branched connection, aryl, aralkyl,3-C6alicyclic group, acyl, aroyl, sulfonyl or phosphoryl; this is described substituents selected from the group of halogen, hydroxyl, C1-C3alkyl, nitro or amino.

2. Compounds or their pharmaceutically acceptable salts according to claim 1, as they are represented in the formulas (I), (II), (III) or (IV)in which formula (I) represents proizvodi 5-atindimubona, formula (II) derivatives of 5-azizeenho, formula (III) derivatives of 7-atindimubona, and formula (IV) derivatives of 7-azizeenho


where R, R1, R2, R3, R4, R1', R2', R3', R4'and R5'means, as described above.

3. Compounds or their pharmaceutically acceptable salts according to claim 1, in which R1and R1'independently mean H, C1-C6alkyl, aryl, aralkyl, acyl, aroyl, glycosyl protected alkyl or glucotrol;
R2, R3, R4, R2', R3', R4'and R5'independently denote H, halogen, hydroxyl, sulfhydryl, C1-C4alkyl, amino, amido, amide, C1-C4alkoxy, methylthio, phenyl, phenoxy, aryl, aralkyl, trifluoromethyl, acyl, aroyl, sulfonic group or isocyanate;
the above glycoside is arabinose, xylose, ribose, mannose or glucose;
R is oxygen, sulfur, selenium, or a group NR6or NOR6in which R6represents H, C1-C6-alkyl direct connection or branched connection, aryl, aralkyl,3-C6alicyclic group, acyl, aroyl, sulfonyl or phosphoryl.

4. Compounds or their pharmaceutically acceptable salts according to claim 1, in which the said compound is selected from the following: derivatives of 5-asuindasun (I) (table 1), derivatives of 5-azizeenho (II) (table 2), derivatives of 7-asuindasun (III) (table 3) and derivatives 7-azizeenho (IV) (table 4)

where R2-R4, Rsup> 1', R2', R4'and R5'mean N, and the remaining radicals are presented in table 1:
The structure of the compounds 5-atindimubona (I)
Table 1

No.R1R3R
1234
1NNO
2CH3NO
3CH3HEO
4CH3Och3O
5CH3SCH3O
6With2H5NO
7i-C3H7 NO
8n-C4H9NO
9CH2-PhNO
10CH3BrO
11CH3ClO
12With2H5BrO
13With2H5ClO
14i-C3H7BrO
15i-C4H9ClO
16n-C4H9BrO
17/td> n-C4H9ClO
18CH2-PhBrO
19CH2-PhClO
20CH2-PhFO
21Triacetyl ribosylNO
22PhCOOch3S
23CH3CH2COOch3S
24CH3BrN-OH
25CH3ClN-OH
26CH3PhN-OH
27CH3SCH3N-OH
28With2H5BrN-OH
29With2H5ClN-OH
30i-C3H7BrN-OH
31i-C3H7ClN-OH
32n-C4H9BrN-OH
33n-C4H9ClN-OH
34CH2-PhBrN-OH
35CH2-PhClN-OH
36CH2-P FN-OH
37CH3NN-OH
38With2H5NN-OH
39i-C3H7NN-OH
40n-C4H9NN-OH
41CH2-PhNN-OH
42ribosylNN-OH
43GlycosylNN-OH
44CH3NN-och3
45CH3BrN-och3
46CH3ClN-och3
47With2H5NN-och3
48With2H5BrN-och3
49With2H5ClN-och3
50i-C3H7NN-och3
51i-C3H7BrN-och3
52i-C3H7ClN-och3
53n-C4H9NN-och3
54n-C4H9BrN-och3
55n-C4H9ClN-och3
56CH2-PhNN-och3
57CH2-PhFN-och3
58CH2-PhBrN-och3
59CH2-PhClN-och3


where R2-R4, R2', R4'and R5'mean N, and the remaining radicals are presented in table 2:
The structure of the compounds 5-azizeenho (II)
Table 2
No.R1R1'R3'
1234
60CH3 NN
61CH3NBr
62CH3NCl
63CH3NF
64CH3CH3HE
65CH3CH2CONOch3
66PhCONOch3
67Triacetyl ribosylNN
68With2H5NN
69With2H5With2H5Br
With2H5NCl
71With2H5NF
72With2H5With2H5HE
73i-C3H7NN
74i-C3H7NBr
75i-C3H7NCl
76i-C3H7NF
77i-C3H7i-C3H7HE
78n-C4H7NN
79SS 4H7NBr
80n-C4H7NCl
81n-C4H7n-C4H9he
82n-C4H7NF
83n-C4H7n-C4H9Och3
84CH2-PhNN
85CH2-PhNBr
86CH2-PhCH2-PhCl
87CH2-PhNF
88CH2-PhCH -PhHE
89ribosylNN


where R2, R4, R1', R2', R4'and R5'mean N, and the remaining radicals are presented in table 3:
The structure of the compounds 7-atindimubona (III)
Table 3
No.R1R3R3'R
12345
92HNNO
93CH3NNO
94CH3CH3OHO
95CH3CH3Och3O
96CH3CH3SCH3O
97With2H5NNO
98i-C3H7NNO
99n-C4H9NNO
100CH2-PhNNO
101CH3NBrO
102CH3 NClO
103With2H5NBrO
104With2H5NClO
105i-C3H7NBrO
106i-C3H7NClO
107n-C4H9NBrO
108n-C4H9NClO
109CH2-PhN BrO
110CH2-PhNClO
111CH2-PhNHCH3FO
112Triacetyl ribosylCH3NO
113PhCOCH3Och3S
114CH3CH2COFOch3S
115CH3NBrN-OH
116CH3NCl N-OH
117CH3CF3PhN-OH
118CH3CF3SCH3N-OH
119With2H5NBrN-OH
120With2H5NClN-OH
121i-C3H7NBrN-OH
122i-C3H7NClN-OH
123n-C4H9NBrN-OH
124n-C4H9NClN-OH
125CH2-PhNBrN-OH
126CH2-PhNClN-OH
127CH2-PhNFN-OH
128CH3NNN-OH
129With2H5NNN-OH
130i-C3H7NNN-OH
131n-C4H9 NNN-OH
132CH2-PhNNN-OH
133ribosylCH3NN-OH
134glucosylCH3NN-OH
135CH3NNN-och3
136CH3NBrN-och3
137CH3NClN-och3
138With2H5N NN-och3
139With2H5NBrN-och3
140With2H5NClN-och3
141i-C3H7NNN-och3
142i-C3H7NBrN-och3
143i-C3H7NClN-och3
144n-C4H9NNN-och3
145n-C4H9N BrN-och3
146n-C4H9NClN-och3
147CH2-PhNNN-och3
148CH2-PhNFN-och3
149CH2-PhNBrN-och3
150CH2-PhNClN-och3


where R2, R4, R2, R4and R5mean N, and the remaining radicals are presented in table 4:
Structures of compounds 7 azaindole (IV)
Table 4
180
No. R1R1'R3R3'
12345
151CH3NNN
152CH3NNBr
153CH3NNCl
154CH3NNF
155CH3CH3CH3HE
156CH3CH2CONFOch3
157 PhCONCH3Och3
158Triacetyl ribosylNCH3N
159With2H5NNN
160With2H5With2H5NBr
161With2H5NNCl
162With2H5NNF
163With2H5With2H5CF3HE
164i-C3H7NN N
165i-C3H7NNBr
166i-C3H7NNCl
167i-C3H7NOch3F
168i-C3H7i-C3H7NHE
169n-C4H9NNN
170n-C4H9NNBr
171n-C4H9NNCl
172n-C4H9 n-C4H9SCH3he
173n-C4H9NNF
174n-C4H9n-C4H9Och3Och3
175CH2-PhNNN
176CH2-PhNNBr
177CH2-PhCH2-PhSCH3Cl
178CH2-PhNOch3F
179CH2-PhCH2-PhNHE
ribosylNCH3N

5. Compounds or their pharmaceutically acceptable salts according to claim 1, in which the aforementioned pharmaceutically acceptable salts include salts formed with inorganic acids or organic acids, inorganic acids include: hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid; organic acids include formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonate (1, 5), Asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, butylcarbamoyl acid, diethyloxalate acid, malonic acid, succinic acid, fumaric acid, Emelyanova acid, hexandiol acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionate acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, econsultancy acid, paratoluenesulfonyl acid, citric acid and amino acid.

6. The pharmaceutical composition inhibiting cyclin-dependent kinase containing compounds or their pharmaceutically reception is controlled salt according to claim 1 and pharmaceutically acceptable carriers.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of formula I or pharmaceutically acceptable salts thereof, wherein R1 represents H; R2 represents (C1-3)alkyl; R3 represents (C1-4)alkyl optionally substituted by three halogen atoms; R4 represents H; X represents O; n is equal to 1 or 2 or 3; Y is specified in OH, NR5R6 and Z, wherein Z represents a saturated 5- or 6-member heterocyclic ring containing 1 heteroatom specified in NR7, wherein the ring can be substituted by oxo(C1-3)alkyl, hydroxy(C1-3)alkyl; or wherein Z represents an aromatic 5- or 6-member heterocyclic ring containing 1-2 heretoatoms specified in N wherein the ring can be substituted by (C1-3)alkyl; R5 and R6 optionally represent H, (C3-8)cycloalkyl or (C1-6)alkyl optionally substituted 1-2 times by halogen, OH, (C1-6)alkyloxy, CONR14R15, NR14R15 or a 6-member saturated heterocyclic group containing a heteroatom specified in NR8; or R5 and R6 together with a nitrogen atom whereto attached form a 5-10-member saturated heterocyclic ring optionally additionally containing 1, 3 heteroatoms specified in NR9, with the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, CONR10R11 or NR10R11; R7 represents H; R8 represents (C1-3)alkyl; R9 represents H, (C1-3)alkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alykl, (C1-6)alkylcarbonyl, (C1-6)alkyloxycarbonyl, CONR12R13 or a 6-member heteroaryl group containing 1-2 heteroatoms specified in N; R10 and R11 optionally represent H or (C1-3)alkyl; R12 and R13 optionally represent (C1-3)alkyl; or R14 and R15 optionally represent (C1-3)alkyl. Also, the invention refers to the use of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of formula I and a pharmaceutical composition thereof.

EFFECT: there are prepared new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives effective for treating osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis and chronic pain, such as neuropathic pain .

9 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula I, wherein W and Z represent CH; Y represents CH2; wherein R1 and R2 independently represent H, halogen, CH2F, CHF2, CF3, CF2CF3, or C1-C6alkyl; R' represents H; R3 and R4 independently represent H, or C1-C3alkyl, all mentioned C1-C3alkyl groups and mentioned C1-C6alkyl groups are independently substituted by one or two groups independently substituted by one or two groups independently specified in OH, halogen, C1-C3alkyl, OC1-C3alkyl or trifluoromethyl; q=1 or 0; R5 represents C1-C6alkyl; and to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a composition, a tablet and pharmaceutical syrup having potassium channel modulation activity and containing the compound of formula I, to a method of preventing and treating diseases that are affected by the activation of potentially opened potassium channels.

EFFECT: there are prepared and described the new biologically active compounds which may be effective in the prevention or treatment of diseases or disorders that are affected by potassium channel activity.

21 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline modification of para-methoxyanilide of 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid of formula: (I) , which is obtained by crystallisation from ethyl acetate, where values of interplanar distance (d) and relative reflection intensities (Irel) are given in claim 1.

EFFECT: novel crystalline modification exhibits a high diuretic effect.

2 dwg, 9 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to complexes of lanthanides and organic ligands which are luminescent in the visible spectrum and are used in electroluminescent devices, means of protecting security paper and documents from falsification etc. Disclosed are novel luminescent coordination compounds of lanthanides of formula: where Ln is Eu3+, Tb3+, Dy3+, Sm3+, Gd3+.

EFFECT: said compounds have high luminescence intensity and considerable thermal tolerance of up to 400°C, which enables use thereof in modern production of light-emitting diodes.

4 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of formula I or pharmaceutically acceptable salts thereof, wherein R1 represents H; R2 represents (C1-3)alkyl; R3 represents (C1-4)alkyl optionally substituted by three halogen atoms; R4 represents H; X represents O; n is equal to 1 or 2 or 3; Y is specified in OH, NR5R6 and Z, wherein Z represents a saturated 5- or 6-member heterocyclic ring containing 1 heteroatom specified in NR7, wherein the ring can be substituted by oxo(C1-3)alkyl, hydroxy(C1-3)alkyl; or wherein Z represents an aromatic 5- or 6-member heterocyclic ring containing 1-2 heretoatoms specified in N wherein the ring can be substituted by (C1-3)alkyl; R5 and R6 optionally represent H, (C3-8)cycloalkyl or (C1-6)alkyl optionally substituted 1-2 times by halogen, OH, (C1-6)alkyloxy, CONR14R15, NR14R15 or a 6-member saturated heterocyclic group containing a heteroatom specified in NR8; or R5 and R6 together with a nitrogen atom whereto attached form a 5-10-member saturated heterocyclic ring optionally additionally containing 1, 3 heteroatoms specified in NR9, with the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, CONR10R11 or NR10R11; R7 represents H; R8 represents (C1-3)alkyl; R9 represents H, (C1-3)alkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alykl, (C1-6)alkylcarbonyl, (C1-6)alkyloxycarbonyl, CONR12R13 or a 6-member heteroaryl group containing 1-2 heteroatoms specified in N; R10 and R11 optionally represent H or (C1-3)alkyl; R12 and R13 optionally represent (C1-3)alkyl; or R14 and R15 optionally represent (C1-3)alkyl. Also, the invention refers to the use of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of formula I and a pharmaceutical composition thereof.

EFFECT: there are prepared new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives effective for treating osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis and chronic pain, such as neuropathic pain .

9 cl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes a crystalline hydrate of camptothecin esters, namely the crystalline hydrates of camptothecin aliphatic esters, a pharmaceutical composition containing the crystalline hydrates of camptothecin aliphatic esters for treating cancer or malignant tumours, as well as a method for treating cancer or malignant tumour.

EFFECT: what is prepared and described is the new crystalline form of the hydrate of camptothecin aliphatic ester possessing low toxicity and good absorbability in a living body.

19 cl, 5 ex, 10 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel azoindolizines or pharmaceutically acceptable salts thereof having Mek-kinase inhibitory activity in formula : ZA means CRA; RA means H or halogen; each of R1, R2 and R3 means H; W means: , each R4 and R5 means H; X1 represents -OR7; each R7 means C2-C12-hydroxyalkyl, 2,3-dihydroxypropyl, C2-C3-alkenoxyC1-C6-alkoxy, (2,2-dimethyl-[1,3]dioxalan-4-yl)-methyl or piperidinyl; X4 means: R6 means halogen or -SR16; R6 means halogen; p is equal to 1; R16 means C1-C12-alkyl.

EFFECT: invention relates to a pharmaceutical compositions containing these compounds, to a method of inhibiting the abnormal cell growth and the use of the compounds for preparing a drug preparation for inhibiting the abnormal cell growth.

9 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to pharmacology, to medication, possessing wound-healing activity. Application of hipaconitine as medication, possessing wound-healing activity is disclosed.

EFFECT: hipactonitin possesses expressed wound-healing activity.

6 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula I, wherein W and Z represent CH; Y represents CH2; wherein R1 and R2 independently represent H, halogen, CH2F, CHF2, CF3, CF2CF3, or C1-C6alkyl; R' represents H; R3 and R4 independently represent H, or C1-C3alkyl, all mentioned C1-C3alkyl groups and mentioned C1-C6alkyl groups are independently substituted by one or two groups independently substituted by one or two groups independently specified in OH, halogen, C1-C3alkyl, OC1-C3alkyl or trifluoromethyl; q=1 or 0; R5 represents C1-C6alkyl; and to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a composition, a tablet and pharmaceutical syrup having potassium channel modulation activity and containing the compound of formula I, to a method of preventing and treating diseases that are affected by the activation of potentially opened potassium channels.

EFFECT: there are prepared and described the new biologically active compounds which may be effective in the prevention or treatment of diseases or disorders that are affected by potassium channel activity.

21 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a foam formulation of an immune response modifier. The foam formulation of the immune response modifier, which contains: imiquimod; isostearic acid; a propellant; a mixture of preserving agents; sorbitan monostearate; a viscosifying agent taken in a specific ratio. A kit containing a drug preparation and an aerosol bottle. The use of the foam formulation for treating senile keratosis, basal cell skin cancer, anogenital warts, photodamaged skin, or for improving skin characteristics, cervical dysplasia, viral diseases, particularly herpes, skin metastases, skin damages caused by bites, self-healing epithelioma, for inducing interferon biosynthesis (versions).

EFFECT: above-described foam formulation of the immune response modifier is stable.

24 cl, 8 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a product of modification of sulphanilic acid, and specifically n-(1,5-dihydro-3-methyl-8-R1-8-R2-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenylsulphonic acid and salt forms thereof of general formula I: , where R1, R2 are selected from a group comprising: a hydrogen atom, methyl, a linear or branched alkyl or R1 and R2 together form a spirocycloalkyl group. Compounds of formula (I) have antibacterial activity, are more efficient with respect to both gram-negative bacteria Proteus vulgaris, Pseudomonas aeroginosa and gram-positive bacteria Staphylococcus aureus, and can be used in medicine and veterinary.

EFFECT: improved properties.

1 cl, 1 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns an agent for neutralising toxic action of tumour necrosis factor on the basis of hydrated pyrido(4,3-b)indoles of formula (1), a pharmaceutical agent on the basis thereof, and a method of treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

EFFECT: preparing the agent for treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

13 cl, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

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