Derivatives benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or hiv activity, the method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it, the method of treating mammals infected with hiv

 

(57) Abstract:

Describes the new derivatives benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone formula I, where R1-R6X and Y are specified in paragraph 1 of the claims values, and their pharmaceutically acceptable acid salt additive. Data heterocyclic compounds may constitute the active principle of the pharmaceutical composition having inhibitory cell adhesion or HIV activity. In addition, these compounds can be used for inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it, such as inflammatory diseases and for the treatment of humans and animals infected with HIV. 4 C. and 11 C.p. f-crystals, 2 PL.

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treatment mlekopitayushchie is enesa inflammation. The process of adhesion precedes transendothelial migration of leukocytes into the surrounding tissue and subsequent tissue damage. From compounds able to inhibit this initial adhesive interaction, expect efficiency in the treatment of inflammatory diseases, such as, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis. Other indications include, for example, respiratory distress syndrome in adults injured in connection with re-perfusion, ischemia, ulcerative colitis, vasculitis, atherosclerosis, inflammatory bowel disease and metastasis of tumors.

The adhesion receptors can be divided into three main families: the selectins, the immunoglobulin superfamily and integrins (see Nature, 346:426 (1990)). Members of all three classes promote leukocyte adhesion during inflammation (Rel. reviews, see Thrombosis and Hemostasis, 65(3); 223 (1991); Clinical and Experimental Allergy, 20:619 (1990); Transplantation, 48:727 (1989); Biochemical Pharm., 40(8):1683 (1990)). Molecule-1 leukocyte adhesion to the endothelium (hereinafter E-selectin) is a family member serving as selectin glycoprotein that promotes intercellular adhesion. In the literature there is information about the maximum expression of E-selectin on endothelial cells after 4 h after stimulation is iatory inflammation as for example, lipopolysaccharides (see Pro. Nat. Acad. Sci., 84: 9238 (1987)).

Molecule-1 intercellular adhesion (hereinafter ICAM-1) is a member of the superfamily of immunoglobulins. Maximum expression observed after 12-24 h after stimulation. There is information about the fact that after 4 h after stimulation of endothelial cells mediated inflammation and E-selectin, and ICAM-1 are located on the cell surface (see J. Clin. Invest., 52:1746 (1988); J. Immun., 137:1893 (1986); Blood, 78:2721 (1991)).

Benzothiophen, benzofuran and indoltiazepinone, oxazepine and diazepinone of the present invention inhibit the adhesion of neutrophils to endothelial cells and umbilical vein man, stimulated by tumor necrosis factor under test in vitro.

The present invention also relates to new diazepinones, oxazepines and diazepinones to treat infected with human immunodeficiency virus (HIV) patients by inhibiting the activation of HIV, which is latent in the infected persons.

Pathogenesis of human immunodeficiency virus (HIV) is a complex and still not fully revealed. The life cycle of the virus is theoretically divided into afferent and efferent components. The binding, fusion, reverse transcription, and finally, the integration of the second cycle of HIV responsible for primary HIV infection of the individual, then usually there is a flash of viremia with clinical symptoms or without them.

We developed a variety of therapeutic strategies to interfere in afferent events (see, for example, N. Mitsuya and S. Broder, Inhibition of the In Vitro Infectivity and Cytopathic Effect on Human T-lymphotropic Virus Type III/lymphadenopathy Virus-associated Virus (HTLV-III/LAV) by 2',3'-Dideoxynucleosides, Proc. Natl. Sci. (USA), 83:1911-1915 (1986)).

While the different stages of the afferent component allows effective therapeutic intervention, it has become increasingly clear that intervention only in this period is not enough. After HIV infection and disease progression in afferent stage the individual is experiencing a prolonged period of clinical latency, which can last for several years, and the individual is healthy. At this point is reached a low or zero level of viremia and viral replication in peripheral blood cells. Later, however, the disease eventually progresses to life-threatening immunosuppression (AIDS), treatment of which is not known. These later events are clinical manifestations of efferent stages of HIV infection.

Efferent component of the HIV life cycle includes events, n is necessary for the progression of HIV-infected cells from asymptomatic, not expressing HIV-symptomatic stage to manifesting HIV stage, referred to as activation. Currently efferent component and cellular basis of activation are not completely elucidated. Despite this, the development of new therapeutic agents and strategies and their application during the clinically asymptomatic period in order to combat the progression to AIDS may give some hope to the intended number (one million) are infected but clinically latent individuals.

With regard to the foregoing, the first object of the invention are derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone formula I

< / BR>
where

R1, R2, R3and R4independently of one another denote hydrogen, hydroxyl, lower alkyl, lower alkoxy,

R5and R6independently of one another denote hydrogen or lower alkyl,

X is a group S(O)nor NH,

Y is oxygen, a group S(O)nor NH,

n is 0, 1 or 2,

provided that

1) if X is the NH group, Y represents a group NH, R1means hydrogen and R3is hydrogen, R2does not mean methyl,

2) if X is the NH group, Y represents a group NH, R1, R3and R41, R3and R4does not mean hydrogen, or its pharmaceutically acceptable acid additive salt.

The second object of the invention is a pharmaceutical composition having inhibitory cell adhesion or HIV activity, containing the active principle and a pharmaceutically acceptable carrier containing a therapeutically effective amount of the compound of the above formula I and a pharmaceutically acceptable carrier.

The third object of the invention is a method for the inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it, which is that includes the introduction of a therapeutically effective amount of the proposed pharmaceutical composition in the form of a dosage unit. A preferred variant of this method is that the treatment is subjected to inflammatory disease.

The fourth object of the invention is a method of treating mammals, i.e., a person or animal infected with HIV, which is that includes the introduction of a therapeutically effective amount of the proposed pharmaceutical composition in the form of a plunger e is 2">

Pharmaceutically acceptable acid additive salts of compounds of formula I include salts of inorganic acids, such as, for example, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, uudistoodetena acid, hydrofluoric acid, phosphoric acid, and salts of non-toxic organic acids such as, for example, aliphatic mono - and dicarboxylic acids, phenyl-substituted alcancarao acid, oxyalkylene acid, alkalicarbonate acids, aromatic acids, aliphatic and aromatic sulfonic acids. As examples of such salts can be called sulfate, persulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, secondary phosphate, primary phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, triptorelin, propionate, kaprilat, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, bansilalpet, toluensulfonate, phenyl acetate, citrate, lactate, maleate, tartrate, methanesulfonate. In addition, it is possible to use salts of amino acids such as arginate and the like and gluconate, galacturonic, N-munya salt of the above basic compounds obtained by contacting the free base with a sufficient amount of the desired acid to obtain the salt in the standard manner. The free base can be release by contacting the salt with a base and the release of free bases in a standard way. Free base slightly differ from their respective salt on some physical properties, such as solubility in polar solvents, but otherwise the biological properties of the salts are equivalent to the corresponding free base.

Some of the compounds of this invention may exist in resolutiony forms, and solvated forms, including hydrogenated forms. In General, the solvated forms, including hydrogenated forms are equivalent nonsolvated forms and all these forms are encompassed by the present invention.

Preferred compounds of formula I are those in which R1, R3and R4mean hydrogen.

In addition, preferred compounds of formula I are further those, in which R1, R3and R4mean hydrogen, R2means hydrogen or lower alkoxy, X stands for a group S(O)nor NH, Y represents oxygen or a group S(O)nand n means 0, 1 or 2.

In particular, preferred compounds of green-5(4H)-he 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f] -1,4-diazepin-5(4H)-one-1-oxide, 3,4-dihydro-9-methoxy-6-methyl-2H-1,4-oxazepine[6,7-b] -indol-5(6H) -, 2,3-dihydro-1H-benzothieno-[3,2-e] -1,4-diazepin-5-he 2,3-dihydro-9-methoxy-1H-benzothieno-[2,3-f] -1,4-oxazepan-5-he, 2,3-dihydro-9-methoxy-6-oxide-1H-benzothieno-[2,3-f]oxazepine-5-he, 2,3-dihydro-9-methoxy-2-methyl-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he.

When determining the indications for inhibitor of cell adhesion or inhibitor of the activation of HIV doctor will take into account, of course, among other things, the appropriate status of the patient, the severity of the condition, as well as age, gender, weight, etc.

To achieve therapeutic effect desired amount of the compounds of formula I or its pharmacologically acceptable acid additive salt, of course, varies depending on the compound, route of administration funds, treatment of the patient, a specific disorder, or a corresponding disease. A preferred variant of the invention encompasses a method of treatment of persons suffering from inflammatory diseases, such as, for example arthritis or swelling, including giving connections in effective anti-inflammatory amount. A suitable dose of a compound of formula I or it is Radney from any of the above conditions, is 0.1 μg to 500 mg of the compound per 1 kg of body weight. In the case of a system giving the dose may be 0.5 to 500 mg of the compound per 1 kg of body weight, preferably 0.5 to 50 mg/kg body weight of the patient two or three times a day. In the case of local application, for example on the skin or in the eyes, a suitable dose may be 0.1 ng to 100 μg of the compound per 1 kg, usually about 0.1 mg/kg

In the case of oral delivery of compounds for the treatment or prophylaxis of arthritis or inflammation caused by any reason, a suitable dose of a compound of formula I or its physiologically acceptable acid salt additive may be the same as in the previous paragraph, but preferably using 1 to 10 mg of the compound per 1 kg, and more preferably 1 to 5 mg/kg of body weight of the patient, for example 1 to 2 mg/kg

Needless to say, a person skilled in the art (doctor or veterinarian) will determine and prescribe the effective amount of the compound to prevent or stop the progression of the respective state. The physician or veterinarian can do that at the beginning of treatment gives a relatively low dose, then increase the dose to achieve maximum response.

The active principle can, preferaly I or its pharmaceutically acceptable acid additive salt and a pharmaceutically acceptable carrier. Such compositions are an additional object of the present invention.

For use in the field of veterinary medicine and medicine of the composition of this invention contain the active principle together with a pharmaceutically acceptable carrier and optionally other (other) therapeutic(s) ingredient(s). The carrier(s) need(s) to be acceptable(and)" in the sense that he(s) has(have) to be compatible(and) with the other ingredients of the compositions and harmless(and) for the patient.

Songs include preparations suitable for oral, pulmonary, ocular, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular, local, or nasal transbukkalno introduction. Such compositions include known drugs for a long or extended action.

The composition can be produced in the form of the drug, including dosing unit. You can get them any known in the pharmaceutical field method. These methods can reach the stage of contact of the active agent with a carrier, representing at least one auxiliary substance. Typically, the compositions are obtained by uniform and homogeneous contact of academia product in the desired drug.

Suitable for oral application, the preparations according to the invention may be in the form of discrete units, such as, for example, a capsule, a starch capsule, tablet, pellet, containing a predetermined amount of the active agent; as a powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion of the type oil in water, emulsion water in oil. The active principle may also be in the form of a bolus, electuary or paste.

The suitability of the compounds of the present invention as inhibitors of leukocyte adhesion to vascular endothelium and, therefore, suitability for treatment-related inflammation diseases or conditions can be determined on the basis of their effectiveness in various standard tests.

Below is a description of the progress tests and test results.

The test expression of a molecule-1 intercellular adhesion and E-selectin in endothelial cells of the umbilical vein of a person.

Cell culture.

Endothelial cells of the umbilical vein of a person (supplied by the firm "Clonetics") in flasks T-25 cultured for 1 to 3 days at a temperature of 37oC in atmosphere containing 5% diaminetetraacetic acid (hereinafter ETUC), within 5 - 10 seconds After desantirovaniya wash solution add 10 ml of trypsin solution and EDUC cells and stirred for 2 to 4 minutes, flipping rubber band on the wall of the flask. Then the contents of the flask are served in the centrifuge tube with a capacity of 50 ml containing 40 ml of medium. The environment is an endothelial basal medium (supplied by the firm "Clonetics") containing 2 mg/l hydrocortisone, 0.05 mg/l epidermal growth factor, 12 mg/l extract, bovine brain, and 6% heat-inactivated fetal calf serum (supplied by the firm "Hanlon"). Cells are centrifuged at 15oC for 10 - 15 min, the supernatant removed and the cells resuspended in fresh medium. Cells obtained in this way are again processed, then sown in a plate with 96 cups.

Stimulation by the cytokine.

5 days after reaching confluence, the cells are stimulated by tumor necrosis factor (supplied by the firm "Gensym") to obtain a final concentration of medium equal to 140 u/ml, and incubated at 37oC for 4 h Later the medium is removed from the incubator and stored for analysis of the production of the chemokine. The cells three times washed with phosphate-containing the cups superstarcase 10% formalin for 15 minutes Then the cells washed three times modified by way of Dulbecco medium Needle (hereinafter referred to environment DMEM) (supplied by company "Flexible"), containing 2% bovine serum albumin, and stored in the refrigerator during the night.

Enzyme-linked immunosorbent assay.

Mouse monoclonal anti-human molecule-1 intercellular adhesion (supplied by company R & D Systems, cat. N BBA-4) or mouse monoclonal anti-human E-selectin (firm R & D Systems, cat. N BBA-2) dissolved in an environment of DMEM containing 2% bovine serum albumin. These molecule-1 or E-selectin at a concentration of 0.5 μg/ml is added to each plate and incubated at 37oC for 2 hours Monocultures 4 times washed with environment DMEM containing 2% bovine serum albumin. Add diluted in the ratio 1:3000 conjugated peroxidase released from sheep protivorechivy immunoglobulin G (supplied by the firm "Keppel") and incubated at 37oC for one hour. Cells washed four times with medium, DMEM. Then to a fixed cells add a coloring reagent and incubated for 15 min at room temperature. The reaction is stopped by adding 2%-aqueous solution of oxalic acid. The absorption is 414 nm for the devices is dimethyl sulfoxide at a concentration of 30 mmol, and dilute with medium to achieve the final concentration. Cells are added dissolved in the compound for 30 minutes before stimulation with tumor necrosis factor. The absorbance of unstimulated cells is subtracted from the absorbance values stimulated by tumor necrosis factor cells to determine the percentage inhibition. Percent inhibition is determined by comparing the absorbance handled only by a native connection cells (control experiment) with cells treated with the investigational compound. The values of KT50determined using linear regression analysis.

The method of determining the inhibition of adhesion of human neutrophils to stimulated tumor necrosis factor endothelial cells of the umbilical vein of a person.

Cell culture.

Endothelial cells of the umbilical vein of the second passage (supplied by the firm "Clonetics Corporation, San Diego, CA, CC-2617) sown in plates with 96 cups (supplied by the company Corning glass werks", Corning, NY) density of approximately 5103cells on the plate and grown to confluence in complete endothelial basal medium (EBM, MCDB, the company supplied Clonetics) containing 10 ng/ml epidermal growth factor, 1 μg/ml hydrocortisone, 0.4% of extractable vysielanie cells, cultures add 0.2 ml of complete endothelial basal medium on the Cup.

The manufacturer of the tested compounds.

Compound transferred to the mother solution volume of 10 ml, the concentration of which is 1.0 mmol. First connection solubilizer in 0.1 ml of dimethyl sulfone, and then added to 9.9 ml of complete endothelial basal medium. Then compound in a single phase is diluted to achieve a concentration of 66.6 μm. Operations solubilization and dilution is carried out in polystyrene containers.

Stimulation of endothelial cells of the umbilical vein of a person.

Recombinant human tumor necrosis factor (supplied by the firm "Gensym, Boston, Massachusetts, code of TNF-H) receiving at a concentration equal to 400 IU/ml in complete endothelial basal medium. The mother liquor of tumor necrosis factor consists of 20000 IU/ml phosphate-containing buffer saline (PBS, supplied by the firm "Flexible", Grand island, NY) and 0.1% bovine serum albumin. It stored at -70oC. the Endothelial cells of the umbilical vein of a person once washed with 0.2 ml of warm incomplete endothelial basal medium, then stimulifecorporate 37oC for 4 hours This operation is carried out by adding 0.1 ml of tumor necrosis factor, taken at a concentration of 400 u/ml, and 0.1 ml (66,6 μm) of the test compounds. Substances added slowly to prevent rupture of the monolayer of endothelial cells. Each connection experience in six cups. In addition, each plate to control the experience with restimulating cells and experience with cells stimulated by tumor necrosis factor without processing the test connection.

Staining of neutrophils.

An hour before the addition of neutrophils to endothelial cells and neutrophils at a concentration of 5106/ml are tagging 5 µm calcein-AM (supplied by the firm "Molecular Sample", Eugene, Oregon) in balanced salt solution Hanks, containing 0,45% albumin bovine serum, at 37 ° oC for 30 minutes Uterine calcein get at a concentration of 5 mmol in anhydrous dimethyl sulfoxide, dried and stored at -20oC. After incubation, the cells washed twice with cold balanced salt solution Hanks and resuspended to a final concentration equal to 1106cells/ml in complete endothelial basal medium.

Adding what about adding neutrophils to endothelial monolayer cell plate is treated with 0.2 ml of warm incomplete endothelial basal medium for removal of tumor necrosis factor and test connection. To each of the processing Cup slowly add neutrophils (1105cells) and incubated at 37oC for 30 minutes Then the plates are washed twice with 0.2 ml of warm incomplete endothelial basal medium, then add 0.1 ml of medium for scanning the plate.

Determination of relative fluorescence.

The relative fluorescence determined using a system Millipore Cytofluor 300 (excitation = 480, emission = 530, sensitivity = 4).

Calculations.

The test is considered valid if the stimulation of cells with tumor necrosis factor leads to a 300% increase increase adhesion of neutrophils compared with restimulating cells. The results are shown as percent inhibition stimulated by tumor necrosis factor adhesion.

< / BR>
Some compounds according to the invention was tested in concentrations of 33.3, 10,0, 3.3 and 1.0 µmol for determining average values of KT50that was determined using linear regression analysis.

The test results of the compounds according to the invention are given in table. 1.

It was found that the compounds according to the invention, in particular the compounds of formula III, the brake is therefore are suitable for the treatment of AIDS.

Attempts to understand the viral and cellular basis of clinical asymptomatic period show that HIV is a resting or exprimarea the provirus in the population is chronically infected cells. Specific type of HIV virus, HIV-1, were subjected to a series of different tests, as a result of which it became clear that the virus is reposing or nexperience the provirus in the population is chronically infected T-lymphocytes. However, in the framework of these tests does not set out the details of nuclear and biochemical mechanisms, which are the basis of latent viral status. For detailed information, see Bednarik and other Mechanisms of HIV-1 Latency in the journal Aids, N 6, S. 3-16, 1992

Until recently it was assumed that during clinical asymptomatic period of HIV is by a stationary or exprimidos all populations chronically infected cells. Due to observations of low or absent levels of viraemia and virus replication in peripheral Gemalto was assumed that HIV is not active during clinical asymptomatic period. However, it was found that this latent state at the time the ge of disease, in the journal Nature, No. 362, C. 355-358, 1993).

During clinical latent state there is a dichotomy between the degree of viral load and viral replication in peripheral Gemalto in relation to lymphatic organs. On the basis of these observations, it was found that peripheral gamecity not accurately reflect the present stage of the disease the HIV virus, in particular at the beginning of the clinical course of HIV infection. Actually, the disease of the HIV virus is active and growing, even if the activity measured in the peripheral Gemalto viral indicators, low and the patient is in clinical hidden state.

Inevitably the stage of the disease develops starting from clinically asymptomatic latent period to the expression and active symptomatic period. According to Butera and others (see Aids, N 6, S. 994, 1992) have been developed in different cellular models, which upon treatment with cytokines can experimenatl HIV-1. Therefore, at the stage of microbiological latent state of HIV-1 begins to replicate only after receipt of the extracellular signal. This signal can be caused not only by the interaction of soluble cytokine to the receptor, but metrication radiation or thermal shock. In addition, extracellular signal may be caused by autocrine or paracrine manner, so that the activated HIV-1 virus, the cell can continue to eksponiruetsya and simultaneously activate adjacent latent cell.

It is assumed that additional factors are involved in the activation of the HIV virus. It was found that the use of 12-0-tetradecanoylphorbol-13-acetate leads to a decrease in the number of receptors CD4 and viral gene expression in HIV infected cells (see Hamamoto and others in the journal Biochem. Biophys. Res. Commun., N 164, S. 339-344, 1989). Interestingly, Hamamoto also investigated the effect of highly active inhibitors of protein kinase C, such as, for example, staurosporine, H-7, UCN-01, caused by 12-0-tetradecanoylphorbol-13-acetate reduction in the number of CD4 receptors and increased expression of HIV. It is found that staurosporine is an effective inhibitor as a reduction in the number of CD4 receptor, and expression of the HIV virus.

Cell path for transmitting an activation signal from the plasma membrane to the virus that leads to expression of HIV-1, less well-known. Recently, at the Symposium National Cooperative Discovery Grant (NCDDG)/AIDS, held from 3 - 7 November 1991, P. Fiorino, S. T. Butera, T. M. folks, and R. F. Chinati tell the tion of the HIV virus. A test system includes a cell line OM-10.1, i.e. unique chronically infected promyelocytic clone, which stores the level of the receptor of CD4+ to activation of HIV-1 by tumor necrosis factor. The expression of the receptor CD4 (+) on the surface of cells, and reverse transcriptase activity is used to determine the expression of the virus.

Alternative to determine the expression of the HIV virus can be applied and the activity of the protease. Cells OM-10.1 retain the level of the receptor of CD4+ to activate the virus and respond to the induction of tumor necrosis factor. Therefore, these cultures are used for easy and quick studies of the pharmacological properties of compounds for their ability to prevent the reduction in the number of receptor CD4 (+) on the cell surface and expression of the HIV virus.

Investigated a number of compounds exhibiting antiviral activity against acute or chronically infected cells by testing their ability to inhibit the expression of the HIV virus in the cells of the OM-10.1. In addition, we examined the number of compounds that interact with biochemical pathways that may adversely affect the reactivation. The results were shown on the poster, predstavnostnih compounds Nikoleishvili inhibitors activation of HIV-1 consider 3'-fluoro-3'-deoxythymidine, interferon Y and desferrioxamine.

Covered by formula I compound 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f] -1,4-diazepin-5(4H)-he is at a concentration of 0.21 μm shows 50% inhibition in the cells of the OM-10.1 (see tab. 1).

The proposed compounds exhibit activity in a standard in vivo studies, which measure the ability of substances to prevent flow into neutrophils, and therefore their usefulness for the treatment of inflammation. In one experiment rats-males-type Wistar weighing 220 - 245 g not fed for 16 - 18 hours They give intravenous buffer (a mixture of ethanol and saline in a ratio equal to 1:1) or the proposed connection in the buffer. Rats poorly anaesthetize diethyl ether, they are given an intravenous injection of a solution of 2.5 mg of bovine serum albumin in saline solution. Immediately after intravenous injection of a small incision between the ribs and using a suitable needle into the pleural cavity is injected solution 0.2 ml isolated from rabbit immunoglobulin G antialbumin bovine serum in phosphate-containing salt solution (concentration: 10 mg/ml saline).

Then the incision is closed with clamp stainless steel size 9 mm After 4 h of rats killed using carbon dioxide ustore. Coming out of the pleural cavity stream buffer is subjected to analysis. Leukocytes (> 90% neutrophils) will count counter company "Coulter". The volume of effluent stream buffer is measured by the method of cultivation with application of the dye (see, C. Carter, and others in the journal J. Pharm. Pharmacol., N 34, S. 66-67, 1982). Animals given the proposed connection, compared with animals given only the buffer. The statistical significance of the activity of the tested compounds was determined by t-experience by the Student.

The results of this analysis, which is subjected to the compound of example 1 are given in table. 2.

In another experience in vivo mice-females-type Balb/c mice are placed in cages in groups of seven. During the experiment mice had free access to food and water. They give oral media (0.5% solution hydroxypropylmethylcellulose containing 0.2% Tween 80) or the proposed compound dissolved or suspended in the specified media. One hour after oral feeding of anaesthetize mice by inhalation of diethyl ether and injected intraperitoneally with 1.0 ml of 3% of thioglycollate in saline solution. After 2 h after injection of thioglycollate mice killed using carbon dioxide and injicerade. The peritoneal cavity is massaged and cut, and the resulting liquid is collected in centrifuge tubes with a capacity of 15 ml From each mouse take aliquot sample and using counter company "Coulter" (model ZBi, supplied by the firm "Coulter Instrument", , Hialeah, pc. Florida, USA) to calculate the total number of cells in each aliquot sample. Take another aliquot of the sample with the purpose of its examination under a microscope with subsequent staining with a modified dye company "Wright". Using hematological analysis to determine the percentage of neutrophils, leaked in the peritoneal cavity.

In this experiment, the compound of example 1 exhibits the following inhibition of the influx of neutrophils: 26,1% at a concentration of 10 mg/kg, 31,9% at a concentration of 30 mg/kg and respectively to 34.3% at a concentration of 100 mg/kg

The proposed connection can be achieved in the following ways:

According to the first method as the original compounds used 3-hydroxy-, 3-thiol-3-aminobenzo[b] thiophene-benzofuran - or indole-2-carboxylate 1 (scheme 1). Esters of 3-hydroxy-benzo[b]thiophene-2 receive according to the method described by Connor and others in the journal J. Med. Chem., N 35, S. 958, 1992 3-dibenzo[b]thiophene-2-carboxylate get usamade in the presence of a base, such as 1,8-diazabicyclo[5.4.0] -undec-7-ene, in the environment of a solvent, such as N, N'-dimethylformamide or tetrahydrofuran. 3 aminobenzo[b]thiophene-2-carboxylate get well-known method, described by Beckom in the journal J. Org. Chem. N 37, 3224 S., 1972, 3-hydroxyindole-2-carboxylate get by known methods described, for example, Unangst and others in the journal J. Heterocyclic Chem., N 24, 811 S., 1987, and Moyer and others in the journal J. Org. Chem., N 51, 5106 S., 1986, 3-tienda-2-carboxylate get by known methods described, for example, Unangst and others in the journal J. Heterocyclic Chem., N 24, S. 811, 1987; Atkinson and others in the journal Synthesis, page 480, 1988; Nagaratnam and others in the journal Indian J. Chem., N 20B, S. 672, 1981 3-aminoindole-2-carboxylate get by known methods, described S. C. Simakova and others in the Chemical-pharmaceutical journal, No. 17, S. 1183, 1983

Scheme 1 illustrates the conversion of compounds 1 to the proposed connection. Esters are subjected to interaction with derivative substituted by halogen acetonitrile, such as bromoacetonitrile, in the presence of a base, such as tert-butyl potassium, tetrahydrofuran, acetonitrile or dimethyl sulfoxide at temperatures of 0 - 80oC. Get esters 2. Nitrile restore to the proper pericycle is the hydrogenation of esters of 2 cobalt catalyst of Raney type in the environment of the solvent, such as tetrahydrofuran, in the presence of a base, such as triethylamine, at elevated temperatures and under pressure. In such conditions esters 2 are transformed directly to the lactam 4. In the case of pre-allocating the intermediate product 3 cyclist to lactam 4 in basic conditions, preferably in the presence of sodium methylate in methanol, or in acidic conditions, preferably in the presence of polyphosphoric acid at elevated temperatures.

In the synthesis of some of the proposed connections necessary or desirable to transfer reactive group as a hydroxyl, amino or carboxyl, derivatives, protecting them from unwanted side reactions. The protective group is removed from hydroxyl, amino group, or carboxyl standard methods. Conventional chemical group capable of protecting reactive groups as hydroxyl, amino and carboxyl, as well as methods of their introduction in the molecule and subsequent removal described by green and WATCOM source Protective Groups in Organic Synthesis, published by John Wiley and Sanz, Inc., New York, 1991

So, for example, 3-amino, 3-hydroxy - or 3-tional, benzothiophen or benzofuran (compound 1 in scheme 1) can be saintil or benzyloxycarbonyl. When carrying out the reaction in the above-mentioned conditions are the connection 5. By removing the protective group in compound 5 the well-known ways, such as applying triperoxonane acid or aqueous acid in the case of tert-butoxycarbonyl, or hydrogenolysis in the case of benzyloxycarbonyl obtain compound 3, which cyclist by the above method. Another way to obtain compound 3 is the interaction of compounds 1 with ethylenimine in the environment of an alcoholic solvent (see Nagarajan and others in the journal Indian J. Chem., N 20B, S. 672, 1981).

The second common method of obtaining compounds 4 (see scheme 2) is the interaction of the corresponding 3-halogenated derivatives of 6 with Ethylenediamine and copper oxide in the environment of a solvent, such as pyridine, in the presence of a base such as potassium carbonate, to obtain compounds 3, where Y represents the group NH (see S. M. Hiermit and others in the journal Proc. Nat. Acad. Sci., India, N 60, S. 367, 1990). The interaction of 3-halogenated derivatives of 2-aminoethanol in the environment of a solvent, such as dimethylformamide, in the presence of a base, such as diazabicyclo obtain compound 3, where Y represents sulfur. The interaction of 3-halogen derivatives with nitroethanol in the environment of a solvent, such as those. sleduyushim restoration of the nitro groups to amine obtain compound 3, where Y is oxygen. In some cases, compound 3 are not allocated, but directly to make connections 4.

In the third General method of obtaining compound 4 also use 3-halogenated derivatives of 6 (see scheme 3), which is subjected to interaction with the primary amine containing-position suitable protected amino group, hydroxyl or thiol group. Receive the intermediate product 7. By removing the protective group and subsequent cyclization receive connections 4. In a similar way interaction 3-hydroxyl-3-thiol -, or 3-amino-derivative with an amine having the suitable position of the deleted group. The resulting intermediate products 8 cyclist with getting connections 4.

Compounds 4, where X is sulfur and Y is oxygen or the group NR, can be converted to the corresponding sulfoxidov and/or sulfones 9 using an oxidising agent such as chlormadinone acid, or oxaziridine, and the degree of oxidation depends on the reaction conditions (scheme 4). Similar oxidation of compounds 4, where Y represents sulfur, get either the sulfoxide or sulfon 10.

The conditions of the reactions solusinya compounds of the present invention.

Example 1

2,3-dihydro-9-methoxy[1]benzothieno[2,3-f]-1,4-diazepin-5(4H)-he

To 500 mg (1,95 mmol) with a room temperature solution of methyl 3-chloro-5-methoxy-benzo[b] thiophene-2-carboxylate, obtained in the result of the interaction of known 3-chloro-5-methoxy-benzo[b]thiophene-2-carbonylchloride with methanol (see J. Med. Chem., 35:958 (1992)) in 20 ml of dimethylformamide add first 885 mg (7,79 mmol) of 2-aminoethanethiol in the form of hydrochloride, and then of 2.33 ml (15,58 mmol) of diazabicyclo. The reaction mixture was stirred at room temperature for 1.5 h, then heated to 70oC. the Mixture is diluted with ethyl acetate and washed with aqueous hydrochloric acid, water and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuum. The crude product is recrystallized from a mixture of hexane and ethyl acetate to obtain 2,3-dihydro-9-methoxy[1] benzothieno[2,3-f]-1,4-diazepin-5(4H)-she yield 74%. Etc., 209 - of 209.5oC.

Example 2

2,3-dihydro-[1]benzothieno[2,3-f]-1,4-oxazepine-5(4H)-he

A mixture of 405 mg (1,64 mmol) of a compound methyl ester 3-(cyanoethoxy)benzo[b]thiophene-2-carboxylic acid (see J. Hetero. Chem., 12: 1037 (1975)), 0,5 ml of triethylamine and 0.50 g of Raney cobalt in 50 ml of tetrahydrofuran is heated at 100oC in the atmosphere 84,372 kg/using as a first eluent mixture of hexane and ethyl acetate in the ratio of 1: 1 and then ethyl acetate receive 2,3-dihydro-[1]benzothieno[2,3-f]-1,4-oxazepine-5(4H)-it is with the release of 55%. T. p. 244 - 245oC.

Example 3

2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f]-1,4-diazepin-5(4H)-one-1-oxide

A mixture of 200 mg (0.75 mmol) of 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f]-1,4-diazepin-5(4H)-she and 116 mg (0.75 mmol) NaBO3-4H2O in 18 ml of acetic acid was stirred at room temperature overnight. The reaction mixture is filtered, then the filtrate add 60 ml of water. By filtering the receive 2,3-dihydro-9-methoxy-[1] benzothieno[2,3-f]-1,4-diazepin-5(4H)-one-1-oxide with the release of 69%. Etc., 215 - 216oC (decomp.).

Example 4

3,4-dihydro-9-methoxy-6-methyl-2H-1,4-oxazepine[6,7-b]-indol-5(6H)-he

A. Methyl-3-(cyanoethoxy)-5-methoxy-1-methyl-1H-indole-2-carboxylate

A suspension of 3.2 g (29 mmol) of potassium tert-butylate in 60 ml of dimethylsulfoxide is treated with portions of 5.6 g (24 mmol) of methyl-3-hydroxy-5-methoxy-1-methyl-1H-indole-2-carboxylate (see Unangst etc., J. Heterocyclic Chem., 24: 811 (1987)). The mixture is stirred for 15 min, then added dropwise 4.8 ml (5.7 g, 76 mmol) chloroacetonitrile. The mixture is heated at 80oC for 90 min, cooled and served in 800 g of ice and water. The precipitated solid is filtered, washed with 10% solution of methanol in water and recrystallized from aqueous acetonitrile to obtain 3.9 g (60%) of product. the-2-carboxylate and 0.40 ml (0.29 grams, 2.9 mmol) of triethylamine in 35 ml of tetrahydrofuran in an autoclave treated with 0.40 g of Raney cobalt as a catalyst. In the autoclave create high pressure hydrogen applications (41,4829 kg/cm2) and heated at 80oC for 10 h, the Reaction mixture is cooled, filtered and the filtrate evaporated. The oily residue is dissolved in 50 ml of methanol, after which the solution is added to 0.80 g (15 mmol) of sodium methylate. The mixture is heated under reflux for 3 h, cooled and evaporated. The residue is partitioned between 75 ml of ethyl acetate and 150 ml of brine. The aqueous layer was extracted several times with fresh ethyl acetate. The combined organic layers washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual crude product is purified by flash chromatography on silica gel. Alualu carry a 5% solution of methanol in dichloromethane to obtain 0.18 g (33%) of product. A sample, recrystallized from a mixture of ethyl acetate and hexane, has, etc., 184 - 186oC.

Example 5

2,3-dihydro-1H-benzothieno-[3,2-e]-1,4-diazepin-5-he

Hydrochloride difficult methyl ester 3-(2-aminoethylamino)benzo[b]thiophene-2-carboxylic acid

A solution of 1.00 g (5,62 mmol) of 2-(4,5-dihydro-1H-imidazol-2-yl)bentolila (what holodilniki within 90 minutes The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated to dryness, and the residue is dissolved in hot chloroform. After a few hours the precipitate is collected and dried. The mother solution allows to obtain a second output of the crystals as hydrochloride difficult methyl ester 3-(2-aminoethylamino)benzo[b]thiophene-2-carboxylic acid. Total yield: 61%. Etc., 219 - 220oC.

2,3-dihydro-1H-benzothieno-[3,2-e]-1,4-diazepin-5-he

A solution of 339 mg (1.18 mmol) of the hydrochloride difficult methyl ester 3-(2-aminoethylamino)benzo[b] thiophene-2-carboxylic acid and fresh of sodium methylate (out of 134 mg (2.48 mmol) of sodium in 5 ml of methanol is heated under reflux for 18 hours the Mixture is cooled, neutralized with 25 ml 1 n hydrochloric acid and cooled to 0oC for one hour. The resulting yellow crystalline product is filtered and dried in vacuum at 60oC for several hours to obtain 2,3-dihydro-1H-benzothieno-[3,2-e]-1,4-diazepin-5-it. Yield: 64%. In the gradient column chromatography using as eluent first 2% solution of methanol in ethyl acetate and then 5% aqueous solution of methanol in ethyl acetate to obtain analytically pure 2,3-digiteo-[3,2-f]-1,4-oxazepan-5-he

Methyl ester of 3-cyanoethoxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid

To have a room temperature to a solution of 1.00 g (4.2 mmol) of methyl-3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (see Connor and others, J. Med. Chem., 25:959 (1992)) in 20 ml of dimethyl sulfoxide add 494 mg (to 4.41 mmol) of potassium tert-butylate, and then 878 μl (12,58 mmol) bromoacetonitrile. The mixture is stirred at room temperature for 1.5 h, after which she served in the ethyl acetate and 1 n hydrochloric acid. The organic layer is first washed with 1 n hydrochloric acid, then with several portions of brine, then dried over magnesium sulfate. In the filtration, removal of solvent in vacuo and recrystallization of the residue from a mixture of ethyl acetate and hexane receive 413 mg of the product. An additional output in the amount of 112 mg can be obtained from the mother liquor. So on 159,5 - 160oC.

2,3-dihydro-9-methoxy-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he

A solution of 2.5 g (9.0 mmol) of a compound methyl ester 3-cyanoethoxy-5-methoxy-benzo[b]-thiophene-2-carboxylic acid in 50 ml of tetrahydrofuran is heated to intense boiling. Quickly add 9.0 ml (90,2 mmol) brandibelle, continue heating for 25 min and add tetrahydrofuran to mommas cooled to 0oC and carefully add 50 ml of 6 n hydrochloric acid. Hydrogen gas is released and the temperature of the reaction mixture increases. The precipitate is collected by filtration, washed with water and dried in vacuum over night.

2.3 g (8.2 mmol) of solid substances is served in a fresh solution of sodium methylate (from 1.9 grams (82,0 mmol) of sodium in 40 ml of methanol. The reaction mixture is heated to 50oC for 2 h, then heated under reflux for 2 hours After cooling to room temperature the precipitate is collected and washed first with cold methanol, and then with cold diethyl ether. The solid is dried in vacuum over night to yield 1.18 g (52%) of product. An analytical sample of 2,3-dihydro-9-methoxy-1H-benzothieno-[2,3-f] -1,4-oxazepan-5-she will receive as a result of recrystallization from a mixture of ethyl acetate and hexane. Etc., 264 - 265oC.

Example 7

2,3-dihydro-9-methoxy-6-oxide-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he

To a suspension of 1.00 g (4.0 mmol) of 2,3-dihydro-9-methoxy-1H-benzothieno-[2,3-f] -1,4-oxazepan-5-it in 100 ml of warm methanol added first to 8.0 ml (80 mmol) of 30% hydrogen peroxide, and then 445 mg (4,01 mmol) of selenium dioxide. The reaction mixture was stirred at room temperary the mixture is cooled to -40oC and the precipitate collected by filtration. The residue is subjected to gradient column chromatography using as eluent 5% methanol in ethyl acetate with a gradual increase in the concentration of methanol to obtain its mixture with ethyl acetate in the ratio of 1:1. Get 338 mg of product. An analytical sample of 2,3-dihydro-9-methoxy-6-oxide-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-it is obtained by recrystallization from a mixture of methanol and ethyl acetate. Etc., 273 - 274oC.

Example 8

2,3-dihydro-9-methoxy-2-methyl-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he

Methyl ester 3-(1-cyanoethoxy)-5-methoxy-benzo(b]-thiophene-2-carboxylic acid

To have a room temperature to a solution of 1.00 g (4.2 mmol) of methyl-3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (see Connor and others, J. Med. Chem. , 35: 958 (1992)) in 20 ml of dimethyl sulfoxide added first, 494 mg (to 4.41 mmol) tert-butyl sodium, and then 1.1 ml (12.6 mmol) of 2-chloropropionitrile. The mixture is stirred at room temperature for 1.5 h, then heated to 82oC for 3 hours the Reaction mixture is poured into ethyl acetate and 1 n hydrochloric acid. The organic layer is first washed with 1 n hydrochloric acid, then with several portions of brine, and then drying the and from a mixture of ethyl acetate and hexane receive 853 mg of product. T. p. 127 - 129oC.

2,3-dihydro-9-methoxy-2-methyl-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he

A solution of 400 mg (1.37 mmol) of a compound methyl ester 3-(1-cyanoethoxy)-5-methoxybenzo[b] -thiophene-2-carboxylic acid in 10 ml of tetrahydrofuran is heated to intense boiling. Was added dropwise to 1.4 ml (13.7 mmol) of brandibelle and heating continued for 20 min with the addition of tetrahydrofuran to the point of evaporation. The reaction mixture is cooled to room temperature and carefully add 7.5 ml of 6 n hydrochloric acid. After 5 min the reaction mixture was cooled to 0oC and add 68,5 ml of 1 n sodium hydroxide, and then the ethyl acetate. The layers separated, and the organic phase is washed first with a mixture of brine and water in the ratio 1:1, then additional brine. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is subjected to gradient column chromatography using as eluent a mixture of methanol, hexane and chloroform in the ratio 5:25:70, then a mixture of methanol and chloroform in a ratio of 10:90, and then a mixture of methanol and chloroform in the ratio of 30:70, resulting in a gain of 135 mg of product. An analytical sample of 2,3-dihydro-9-methoxy-2-methyl-1H - benzothieno-[2,3-f] -1,4-oxazepan-5-the ia according to the invention can be easily recycled with standard diluents and carriers for convenient oral or parenteral giving people and animals for the treatment of diseases such as, for example, inflammation, in particular arthritis, and the like. The following examples illustrate how to obtain a typical pharmaceutical compositions.

Example 9

Receive capsules with a capacity of 250 mg

250 mg of 2,3-dihydro-9-isopropoxy-7-chloro-1H-benzothieno-[2,3-f] -1,4-oxazepine-5-it is mixed with 150 mg of lactose and 150 mg of corn starch to obtain a homogeneous mixture. The mixture is poured into gelatin capsules, which give orally in the amount of 1 - 3 per day for the treatment of arthritis.

Example 10

Composition for oral suspension

Ingredient - Number

2,3-dihydro-8-ethyl-10-trifluoromethyl-6-oxide-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he - 500 mg

The solution of sorbitol (70%) - 40 ml

Sodium benzoate 150 mg

Saccharin 10 mg

The cherry flavor 50 mg

Distilled water - 100 ml

The solution of sorbitol served in 40 ml of distilled water, and oxazepine suspended. To the mixture add saccharin, sodium benzoate and fragrance and dissolve. The volume was adjusted to 100 ml by adding distilled water. Each ml of syrup contains 5 mg of oxazepine. This composition for oral villas is ideally suited for the treatment of inflammation in the area of Pediatrics.

Example 11

Obtaining solutions daraut of 20.0 g of 2,3-dihydro-7-dimethylamino-1H-benzothieno-[3,2-e] -1,4-diazepin-5-it. The pH of a solution of hydrochloric acid was adjusted to 5.5, and the volume adjusted to 1000 ml by adding distilled water. The composition is sterilized, bottled in vials with a capacity of 5.0 ml, each containing 2.0 ml of the composition (which represents 40 mg active diazepinone) and sealed in a nitrogen atmosphere. The composition intravenously give patients suffering from inflammation or AIDS.

Example 12

Getting cream for local application

500 mg of 2,3-dihydro-7-ethoxy-benzopyrano-[2,3-f]-1,4-oxazepan-5-it is mixed with 15 g of cetyl alcohol, 1 g of lauryl sodium, 40 g of liquid silicone stamps D. C. 200 (trade product of the company "Dow Corning Co., Midland, Mich.), 43 g of sterile water, 0.25 g of methylparaben and 0.15 g propyl paraben. The mixture is heated to approximately 75oC with constant stirring, then cooled to room temperature at which the mixture hardens. The drug is applied to the skin surface of a patient suffering from inflammation.

1. Derivatives benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone formula I

< / BR>
where R1, R2, R3and R4independently of one another denote hydrogen, hydroxyl, halogen, lower alkyl - group S(O)nor NH,

Y is oxygen, a group S(O)nor NH,

n is 0, 1 or 2,

provided that

1) if X is NH, Y is NH, R1is hydrogen and R3is hydrogen, R2does not mean methyl,

2) if X is NH, Y is NH, R1, R3and R4is hydrogen, R2does not mean methoxy or ethoxy, and

3) if X is NH, Y is sulfur, at least one of the radicals R1, R3and R4does not mean hydrogen,

or their pharmaceutically acceptable acid additive salt.

2. Derivatives benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone under item 1, where R1, R3and R4mean hydrogen.

3. Derivatives benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone on p. 2, where R2means hydrogen or lower alkoxy, X stands for a group S(O)nor NH, Y represents oxygen or a group S(O)nand n means 0, 1 or 2.

4. Derived indoltiazepinone under item 3, which represents a 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f]-1,4-diazepin-5(4H)-he.

5. Derived oxazepine under item 3, which represents a 2,3-dihydro-[1] benzothieno[2,3-f]-1,4-oxazepine-5(4H)-he.

6. Derived indoltiazepinone on p. 3, oxazepine on p. 3, represents 3,4-dihydro-9-methoxy-6-methyl-2H-1,4-oxazepine[6,7-b]-indole-5(6N)-he.

8. Derived diazepinone under item 3, which represents a 2,3-dihydro-1H-benzothieno[3,2-e]-1,4-diazepin-5-he.

9. Derived oxazepine under item 3, which represents a 2,3-dihydro-9-methoxy-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he.

10. Derived oxazepine under item 3, which represents a 2,3-dihydro-9-methoxy-6-oxide-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he.

11. Derived oxazepine under item 3, which represents a 2,3-dihydro-9-methoxy-2-methyl-1H-benzothieno-[2,3-f]-1,4-oxazepan-5-he.

12. Pharmaceutical composition having inhibitory cell adhesion or HIV activity, containing the active principle and a pharmaceutically acceptable carrier, characterized in that the active agent it includes a therapeutically effective amount of the compounds under item 1.

13. The method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it, characterized in that it includes the introduction of a therapeutically effective amount of the pharmaceutical composition under item 12 in the form of dosage units.

14. The method according to p. 13, characterized in that the treatment is subjected buchet introduction therapeutically effective amount of the pharmaceutical composition under item 12 in the form of a dosage unit.

 

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