Aryl - or heteroaromatic tetrahydronaphthalen-, chroman-, thiochroman - and 1,2,3,4-tetrahydrocannabinolic acids exhibiting retinopathy biological activity

 

(57) Abstract:

Describes new compounds of General formula (1) in which X is S, O; X is [C(R1)2]nwhere n means an integer from 0 to 2; R1means independently H or alkyl with the number of carbon atoms from 1 to 6; R2means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6; R3means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6; and m means an integer from 0 to 2; o is an integer from 0 to 4; R denotes an integer from 0 to 2; r is an integer from 0 to 2, provided that when Z denotes O, the sum of p, at least, means 1, and r, at least, means 1 and (W)pis not a single alkyl group; Y represents phenyl or pyridyloxy group, which possibly have as a substituent one or two groups R2; W means the Deputy selected from the group consisting of F, Br, Cl, J, C1-6of alkyl, fluoro-substituted C1-6of alkyl, NO2N3HE CO2OCH3; L is -(C=Z)-NH - or HN-(C=Z); Z denotes O or S; And means (CH2)qwhere q means 0-5; means COOH or its pharmaceutically acceptable salt, COOR8, R8means alkyl group . C. and 27 C.p. f-crystals, 2 tab.

The invention relates to new compounds with retinopathy biological activity. More specifically, this invention relates to Amida, educated aryl - or heteroarylboronic, tetrahydronaphthalen-, chroman-, thiochroman - and 1,2,3,4-tetrahydropirancarboxylic acids, in which at least one aromatic or heteroaromatic amide fragments contains electron Deputy. The compounds are agonists of RAR receptors retinoids.

Compounds with retinopathy activity, are well known in the art and described in numerous U.S. patents and other countries and scientific publications. It is well known and accepted technique that retinopathy activity is used to treat partial withdrawal symptoms and conditions of numerous diseases in animals of the class Mammalia, including humans. In other words, the conventional technique in that the pharmaceutical composition containing retinopathy compound or compounds as an active ingredient is useful as a regulator of cell proliferation and cell differentiation, and particularly as agents for treating diseases, is ktera, psoriasis, ichthyosis and other keratinization and hyperproliferative skin diseases, eczema, diffuse neurodermatitis, disease Daria, zoster Wilson, to prevent and changes in glucocorticoid disorders (steroid atrophy), as a local antibacterial agents and antivignetting funds for the skin and for the treatment and changes the ravages of age and light on the skin. Retinoid compounds are also used for the prevention and treatment of cancer and precancerous conditions, including precancerous and malignant hyperproliferative diseases such as cancer of the breast, skin, prostate, neck, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasia, dysplasia, neoplasia, leukoplakia and papillomas of the mucous membranes, and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used for the treatment of eye diseases, including, without limitation, the proliferative vitreoretinopathy (PVR), retinal detachment, Sjogren syndrome (xeroderma) and other types of Corporatio (changes of the cornea), as well as for treatment and prevention of various cardiovascular diseases, the Oia postangioplasty of restenosis and as an agent to increase the level of tissue plasminogen activator (TPA) in the bloodstream. Other applications of retinoid compounds include the prevention and treatment of conditions and diseases associated (linked) with the human papilloma virus (HPV, HPV), including warts and genital warts, various inflammatory diseases, such as pneumosclerosis, REIT, colitis, Crohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and seizure (cob), improper pituitary function, including insufficient production of growth hormone (STH), modulation of apoptosis, including both the induction of apoptosis and inhibition of activated apoptosis of T-cells, for hair regrowth, including combination therapy of these compounds and other agents such as MinoxidilR(Minoxidil), (treatment) of diseases associated with the immune system, including the use of these compounds as immunosuppressants and Immunostimulants, modulation of transplants and to facilitate wound healing, including modulation of haloze.

U.S. patents NN 4,740,519 (Shroot et al.), 4,826,969 (Maignan et al.), 4,326,055 (Loeliger et al. ), 5,130,335 (Chandraratna et al.), 5,324,840 (Chandraratna), 5,344,959 (Chandraratna), 5,130,335 (Chandraratna et al.), published European Application (EA) NN 0170105 (Shudo), 0176034 A (Wuest et al. ), 0350846 A (Klaus et al.). N. DE 3715955 A1 (Klaus et al.), DE 3602473 A1 (Wuest et al.) and article J. Amer. Acad. Derm. 15: 756-764 (1986) (Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo et al.), J. Med. Chem. 1988 31, 2182-2192 (Kagechicka et al.), Chemistry and Biology of Synthetic Retinoids CRC Press Inc. 1990 p. 334-335, 354 (Dawson et al.) describe or affect connections that contain tetrahydronaphthalene fragment and have retinopathy or related biological activity. In U.S. Patent N 4,391,731 (Boller et al.) describes derivatives of naphthalene for use in liquid crystal compositions.

In the U.S. Patents NN 4,980,369; 5,006,550; 5,015,658; 5,045,551; 5,089,509; 5,134,159; 5,162,546; 5,234,926; 5,248,777; 5,264,578; 5,272,156; 5,278,318; 5,324,744; 5,346,895; 5,346,915; 5,348,972; 5,348,975; 5,380,877; 5,399,561; 5,407,937 (owned by the same applicant as this application) and are shown in the patents and publications, describes derivatives chromane, thiochroman and 1,2,3,4-tetrahydroquinoline with retinopathy activity. Further, several applications simultaneously, all paperwork, and recently issued patents owned by the applicant of this application, aimed at obtaining additional connections with retinopathy activity.

Well-known currently is that in mammals (and other organisms) there are two main types Retz types have subtypes; collection RAR subtypes indicated RAR, RARand RARand , in RXR the subtypes are the following: RXR, RXRand RXR. It was also found in the technique that the distribution of the two main types of receptors for retinoids and several subtypes is not homogeneous in the different tissues and organs of mammals. Accordingly, among the compounds with agoniston activity against receptors for retinoids, specificity or selectivity with respect to one of the main types or families and even specificity or selectivity with respect to one or more subtypes within the family of receptors is considered desirable pharmacological properties.

This invention provides compounds with retinopathy biological activity, and specifically compounds that are associated with one or more RAR receptor subtypes retinoids.

This invention covers compounds of Formula 1

< / BR>
where X is S, O, NR', where R' is H or alkyl containing from 1 to 6 carbon atoms or;

X is [C(R1)2]nwhere n means an integer between 0 and 2;

R1means independently H or alkyl with a number of ATO 1 to 6;

R3means independently hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;

m means an integer from 0 to 2;

o is an integer from 0 to 4;

p is an integer from 0 to 2;

r is an integer from 0 to 2, provided that when Z denotes O, the sum of p and r is at least equal to 1;

Y represents phenyl or naftalina group, or heteroaryl selected from the group consisting of pyridyl, teinila, furil, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, and these phenyl, naftalina and heteroaryl groups, if possible, have as a substituent one or two groups R2;

W means the Deputy selected from the group consisting of F, Br, Cl, I, C1-6of alkyl, fluoro-substituted C1-6of alkyl, NO2N3, OH, OCH2OCH3OC1-10of alkyl, tetrazol, CN, SO2C1-6of alkyl, SO2C1-6-fluoro-substituted alkyl, SO-C1-6of alkyl, CO-C1-6of alkyl, COOR8, phenyl, phenyl itself substituted with a W group other than with phenyl or substituted phenyl;

L is -(C=Z)-NH - or-NH-(C=Z)-;

Z denotes O or S;

A means (CH2)qwhere q denotes from 0 to 5, lower branched Aldo 6 carbon atoms and 1 or 2 double bonds; quinil containing from 2 to 6 carbon atoms and 1 or 2 triple bond;

B means COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2OH, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10 or trimethylsilyloxy, where the alkyl group contains from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 or cycloalkyl group with the number of carbon atoms from 5 to 10, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5.

In the second aspect of this invention relates to the use of compounds of Formula 1 for the treatment of skin diseases, including, without limitation, Starkey keratinization and hyperproliferative skin diseases, eczema, diffuse neurodermatitis, disease Daria, zoster Wilson, to prevent and changes in glucocorticoid disorders (steroid atrophy), as a local antibacterial agents and antivignetting funds for the skin and for the treatment and changes the ravages of age and light on the skin. Connections are also used for the prevention and treatment of cancer and precancerous conditions, including precancerous and malignant hyperproliferative diseases such as cancer of the breast, skin, prostate, neck, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasia, dysplasia, neoplasia, leukoplakia and papillomas of the mucous membranes, and in the treatment of Kaposi's sarcoma. In addition, these compounds can be used for the treatment of eye diseases, including, without limitation, the proliferative vitreoretinopathy (PVR), retinal detachment, Sjogren syndrome (xeroderma) and other types of Corporatio (changes of the cornea), as well as for treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism, for example, dyslipidemia, for predator plasminogen (TPA) in the bloodstream. Other applications of the compounds according to this invention include the prevention and treatment of conditions and diseases associated (linked) with the human papilloma virus (HPV, HPV), including warts and genital warts, various inflammatory diseases, such as pneumosclerosis, REIT, colitis, Crohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and seizure (cob), improper pituitary function, including insufficient production of growth hormone (STH), modulation of apoptosis, including both the induction of apoptosis and inhibition of activated apoptosis of T-cells, for hair regrowth, including combination therapy of these compounds and other agents such as MinoxidilR(Minoxidil), (treatment) of diseases associated with the immune system, including the use of these compounds as immunosuppressants and Immunostimulants, modulation of transplants and to facilitate wound healing, including modulation of haloze.

This invention also relates to pharmaceutical preparations containing the compound of Formula 1 in a mixture with a pharmaceutically acceptable carrier.

In another aspect of this izobretena acid or acceptor water, the compounds of Formula 2 with a compound of Formula 3 or the compounds of Formula 2a with a compound of Formula 3a, where X1means OH, halogen or other group that makes the group-COX1capable of forming amide and where the values of the other characters given in the description of Formula 1.

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H2N-Y(W)r-A-B

Formula 3

< / BR>
X1OC-Y(W)r-A-B

Formula 3a

Further, this invention relates to such reactions of compounds of Formula 1, which causes the transformation of the B-group in that the reaction product continues to conform to the Formula 1.

General definitions of terms used in embodiments of the invention

The term alkyl refers to and covers any and all groups which are known as normal alkyl, branched alkyl and cycloalkyl. The term of alkenyl means and covers normal alkeneamine, branched alkeneamine and cycloalkenyl group having one or more unsaturated bonds. Similarly, the term quinil means and covers normal alkyline and branched alkyline group containing one or more triple bonds.

Lower alkyl means the above broad definition of the alkyl group, the soda is laroda for branched and cycloalkyl groups. Lower alkenyl is defined similarly as containing from 2 to 6 carbon atoms in the case of normal alkenyl groups and from 3 to 6 carbon atoms for the branched lower and cycloalkenyl groups. Lowest alkinyl similarly defined as containing from 2 to 6 carbon atoms for normal lower etkinlik groups and from 4 to 6 carbon atoms for the branched lower etkinlik groups.

The term "complex ester (ester)" as it is used here, refers to and encompasses any compound falling under this term in classical organic chemistry. It includes esters of organic and inorganic acids. In case B in the Formula 1 denotes-COOH, this term covers the products derived from the interaction of this functional group with alcohols or tiospirone, preferably with aliphatic alcohols containing from 1 to 6 carbon atoms. If the ester is formed from compounds where B denotes-CH2OH, this term covers compounds, formed from organic acids capable of esters including phosphorous-containing and sulfur-containing acids, or compounds of formula-CH2OCOR11where R11means any substituted or nezamedin what about the number of carbon atoms in the aliphatic fragments from 1 to 6.

If this application is not specified otherwise, the preferred esters derived from saturated aliphatic alcohols or acids with the number of carbon atoms ten or less, or the cyclic or saturated aliphatic cyclic alcohols and acids with the number of carbon atoms from 5 to 10. Particularly preferred aliphatic esters are those formed from lower alkyl acids and alcohols. Preferred phenyl or lower alkyl phenyl ethers.

Amides make sense, classically corresponds to this term in organic chemistry. In this case, it includes the unsubstituted amides and all aliphatic and aromatic mono - and disubstituted amides. If this application is not specified otherwise, the preferred inorganic salts are mono - and disubstituted amides formed from saturated aliphatic radicals containing ten or less carbon atoms, or the cyclic or saturated alifaticheskii-cyclic radicals containing from 5 to 10 carbon atoms. Particularly preferred inorganic salts are those formed from substituted and unsubstituted lower alkylamines followed. Preferred mono - and disubstituted amides formed from substituted and unsubstituted phenyl - or nicely formula CK, where K means (-OR)2. Here R is lower alkyl. Also, K may mean-OR7O-, where R7means lower alkyl containing from 2 to 5 carbon atoms, a linear or branched.

Pharmaceutically acceptable salt can be prepared from any of the compounds of this invention containing a functional group capable of forming such salt, for example an acid group. Pharmaceutically acceptable salt refers to any salt which retains the activity of the parent compound and does not produce any harmful or adverse effects on the entity to which it is introduced and the conditions in which it is introduced. Pharmaceutically acceptable salts may be organic or inorganic bases. Salt may be a mono - or polyvalent ion. Of particular interest are the inorganic ions of sodium, potassium, calcium and magnesium. Organic salts can be obtained from amines, especially ammonium salts of amines such as mono-, di - and trialkylamines or ethanolamines. Salt can also give caffeine, tromethamine and the like molecule. When the basicity of the nitrogen atom is sufficient for the formation of adducts with acid, they can be obtained from any of Soli represent such which form inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. You can also use any of a number of simple organic acids, such as mono-, di - or tricarboxylic acid.

Some compounds in this invention may have TRANS and CIS (E and Z) isomers. In addition, the compounds of this invention can contain one or more chiral centers and therefore may exist in the form of enantiomers and diastereomers. This invention intends to cover all such isomers themselves, as well as a mixture of CIS - and TRANS-isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers).

As for the symbol Y in Formula 1, the preferred compounds for this invention are those in which Y represents phenyl, pyridyl, 2-thiazolyl, thienyl or furyl, and more preferred phenyl. As for the substituents in the groups Y (phenyl) and Y (pyridyl), preferred are compounds in which the phenyl group is 1,4 (para)-provisions has as substituents L and A-B groups, and in which the 2,5-positions of pyridine rings are available in as Vice-L and A-B groups. (Substitution of 2.5-prooty"). In preferred compounds according to this invention there is no possible substitute for R2in the Y-group.

As for the amide or carbamoyl functions "L", linking the two cyclic portion of the molecule, L preferably denotes-CZ-NH-; in other words preferred in this invention are the amide or carbamoyl compounds in which the carbonyl (CO) or thiocarbonyl (CS) group linked to the remainder of the condensed cycle.

Relative to the symbol X in Formula 1 have to say that preferred for this invention are those compounds in which X is [C(R1)2]nand n is 1, and those in which X represents O or S (derived chromane and thiochroman).

The group R1represents preferably H or CH3. Group R2represents preferably hydrogen.

A-B-group of preferred compounds are (CH2)n-COOH or - (CH2)n-COOR8where the value of n and R8given above. Even more preferably, when n is zero and R8means lower alkyl, or n means zero, and B means COOH or its pharmaceutically acceptable salt.

the traveler is in the compounds according to this invention or in the aromatic portion of the condensed cyclic system, or as a substituent in the aryl or heteroaryl group y Preferably, when W is the group is the group Y or in the group Y, and the aromatic fragment of condensed heterocyclic systems. When the group Z means S (thioamides), W-group need not be present in the compounds according to this invention, although however, it is preferable to have at least one W group. In the aryl or heteroaryl of Y-fragment group W is preferably located in a position adjacent to the group A-B; it is preferable, when the group A-B is in the para-position of the phenyl ring relative to the "amide" fragment, and hence W-group is preferably the meta-position relative to the amide fragment. When W is the group is also present in the aromatic portion of the condensed heterocyclic system, it is in position 8 cores chromane or thiochroman, the group Z=C-NH preferably occupies position 2 and W-group is in position 3 or 4. Preferred groups W are F, NO2, Br, I, CF3N3and OH. Having as substituents one or two fluorine atoms in the group Y is particularly preferred. When the Y group is which preferably represents a COOH or COOR8.

The most preferred compounds of this invention are shown in table 1, related to compounds of Formula 4 and Formula 5.

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< / BR>
Methods of administration of the compounds according to this invention

Compounds according to this invention it is possible to enter systemically or topically, depending on such considerations as the condition being treated, the need for specific local treatment, number of medications, which must be entered, and a variety of other reasons.

In the treatment of dermatosis usually prefer to appoint a local medication, although in some cases, for example, in the treatment of tectonic acne or psoriasis can be applied oral introduction. You can use any conventional form for topical administration, such as solution, suspension, gel, ointment and the like. Drugs (with recipes) for local use are well described in the literature (technology) pharmaceuticals, for example in the book Remington Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. As preparations for local use, these compounds can be introduced in the form of a powder or spray solution, especially in the form of an aerosol. If the drug must enter systems suitable for oral administration. For intravenous or intraperitoneal administration of the compounds can be prepared in the form of a solution or suspension, which can be applied by injection. In some cases, you can use these connections in the form of a suppository or in the form of long-acting drugs for subcutaneous or intramuscular injection.

In preparations for topical use, you can add other medications for such additional purposes as the treatment of dry skin; protect from light; other medications for the treatment of dermatoses; medications to prevent infection, reduce irritation, inflammation and the like.

For the treatment of dermatoses or any other indications known or to be discovered that they are sensitive to the action of compounds that are similar to retinova acid, is affected by the introduction of a therapeutically effective dose of one or more compounds according to this invention. Therapeutic (dose) concentration is a concentration that causes improve a specific condition, or slows down its deterioration (distribution). In some special cases, the connection can potentially be used prophylactically for predose to change depending on condition, and in some cases it can vary depending on the severity exposed to the treatment condition and sensitivity of the patient to treatment. Accordingly, there is no single, in all cases, applied concentration (dose), but requires a change (modification), depending on the specific disease, the treatment is carried out. Such doses are detected during a routine experiment. However, one can expect, for example, that in the treatment of acne or similar skin diseases, the drug containing from 0.01 to 1.0 milligram per milliliter of the compound is therapeutically effective in all cases. It can be expected that in General (system) application number from 0.01 to 5 mg per kg of body weight per day will have a therapeutic effect in the treatment of many diseases with the use of these substances.

The study retinopathy biological activity

Retinopathy activity of the compounds according to this invention can be installed by analysis, which measures the ability of compounds to bind to receptor sites of retinoids. As noted in the introductory part of this patent application, in mammals (and other organisms) there are two main types of receptors retinova acid (RAR and RXR). Inside the which in various tissues and organs of mammals is not homogeneous. Selective binding of only one or two subtypes of the family of receptors for retinoids can lead to useful pharmacological properties due to changes in the distribution of subtypes in some tissues or organs of a mammal. In the above-stated reasons, the binding of any or all of retinoids receptors, as well as specific or selective activity of a family of receptors or are selective or specific activity of any of the subtypes of receptors are considered desirable pharmacological properties.

In light of the foregoing known analytical methods (testing) determine agoniston compounds in the receptor subtypes RAR, RAR, RAR, RXR, RXRand RXR. For example, analysis of the TRANS-activation of the chimeric receptor, which checks the subtypes of receptors RAR, RAR, RARand RXRagoniston activity and which is based on work published by Feigner P. L. and Holm M. (1989) Focus, 11 2, described in detail in U.S. Patent N 5,455,265.

Analysis of the development of calorizator and analysis (reaction) binding of the ligand, which measure (detect) the ability of the compounds according to this invention svjazyvaites is. 30-33 and 37-41), published on 24 June 1993, a description of the analysis of the binding of the ligand is shown below.

ANALYSIS (REACTION) OF THE LIGAND BINDING

All tests (experiments) on the binding definition perform similarly. All six types of receptors derived from type receptor (RAR and RXR , , ), expressed by Baculovirus (baculovirus). The starting solutions of all compounds are prepared as 10 mm solution in ethanol and diluted in a series conducted DMSO:ethanol = 1:1. Buffers for analysis in the case of all six receptors contain the following: 8% glycerol, 120 mm KCl, 8 mm Tris, 5 mm CHAPS, 4 mm DTT and 0.24 mm PMSF, pH 7.4 at room temperature.

All analyses of the binding of the receptor (receptor binding) are the same. The final volume in the analysis of 250 μl and contains, depending on the analyzed receptor, from 20 to 40 µg of protein extract, 5 nm [3H]-all-TRANS-retinova acid or 10 nm [3H]-9-CIS-retinova acid and varying in the interval from 0 to 10-5M concentrations of competing ligands. Tests conducted in 96-well pad. Temperature control is carried out at 4oC to achieve equilibrium. Nonspecific binding is defined as such a binding that remains is astationary add 50 ál of 6.25% of hydroxyapatite in the appropriate aqueous buffer solution. Aqueous buffer solution contains 100 mm KCl, 10 mm Tris and or 5 mm CHAPS (RXR , , ), or 0.5% Triton X-100 (RAR ,,). The mixture is shaken and thermostatic for 10 minutes at 4oC, centrifuged and the supernatant separated. Hydroxyapatite even thrice washed with an appropriate aqueous buffer solution. The complex receptor-ligand adsorb hydroxyapetite. The number of complex receptor-ligand determined in the sediment of hydroxyapatite using a liquid scintillation counter.

After correction for nonspecific binding determine the value of the IC50. The value of the IC50represents the concentration of the competing ligand that is required to reduce specific binding by 50%. The value of the IC50determine graphically on the logistic curve. Values of Kddetermine, using the equation of Cheng-Prusova values for IC50concentrations of labeled ligand and Kdlabeled ligand. The results of binding assays ligand expressed in the values of Kd. (See Cheng et al. Biochemical Pharmacology, Vol. 22 pp 3099-3108, specially introduced in this description by reference).

Table 2 shows the results of the analysis (response) binding of the ligand to some of the examples soedinenii her examples of compounds according to this invention associated with the RAR receptors are specific or selective.

TESTED CANCER CELL LINES

MATERIALS AND METHODS

Hormones

All TRANS-retinova acid (t-RA) (Sigma Chemicals Co., St. Louis, MO) and stored at -70oC. Before each experiment, the compound dissolved in 100% ethanol (concentration 1 mm) and diluted in culture medium immediately before use. All experiments carried out at the dim light. Control tests were carried out using the same concentration of ethanol in experimental plates (dies), and this concentration of solvent in any test had no effect.

Cells and cell culture

All cell lines, RPMI 8226, ME-180 and AML-193, was received from the American Collection of Cell Cultures (ATCC, Rockville, MD). RPMI 8226 is a line of blood-forming (hematopoietic) cells obtained from the peripheral blood of the patient multiple myeloma (a disease of Calera). Cells similar to lymphoblastoid cells other cell lines of human lymphocytes and secrete type lungs (polypeptide) chain immunoglobulin. Cells RPMI 8226 grown in RPMI medium (Gibco), supplemented with 10% fetal calf serum (ETS), glutamine and antibiotics. Cells incubated in the form of suspendirovanie 1 × 105/ml twice a week.

ME-180 is a cell line squamous cell (epidermoid) human cancer derived from neck. The tumor was vysokointensivnogo carcinoma squamous cells with irregular clusters of cells without prominent keratinization. Cell ME-180 were grown and maintained in the environment McCoy (McCoy) 5a (Gibco), supplemented with 10% ETS, glutamine and antibiotics. Cells kept in monolayer cultures grown at 37oC in a humidified atmosphere of 5% CO2in the air. Cells were diluted to a concentration of 1 × 105/ml twice a week.

Line AML-193 was obtained from blast cells classified as cell M5 acute monocytic leukemia. To obtain this cell line was required growth factor, granulocyte colony-stimulating factor (GM-CSF), a growth factor necessary for its continuous (long) proliferation in a nutrient medium a specific chemical composition. Cells were grown and stored in modified according Iscove (Iscove) environment Dulbecco, supplemented with 10% ETS, glutamine and antibiotics with 5 μg/ml insulin (Sigma Chemical Co.) and 2 ng/ml rh GM-CSF (R & D systems). Cells were diluted to a concentration of 3 × 105/ml twice a week.

Vluyn isotope thymidine, was developed based on the techniques described Shrivastav et al. Cells RPMI-8226 placed in a 96-hole (hole bottom) plate (Costar) at a density of 1,000 cells/well. In appropriate wells add subjects retinoid compounds to the final concentrations indicated to a final volume of 150 ál/well. Tablets thermostatic 96 hours at 37oC in a humidified atmosphere of 5% CO2in the air. Then to each well was added 1 MX [5-3H] -thymidine (Amersham, U. K., specific activity 43 Ci/mmol) in 25 μl of culture medium and cells thermostatic 6 o'clock the Next culture process as described below.

Cell ME-180, collected using trypsin, placed in 96-well plates with flat-bottomed wells (dies) (Costar) at a density of 2,000 cells/well. Culture is treated as described above for RPMI 8226 with the following exceptions. After incubation with thymidine supernatant carefully separated and the cells washed with a 0.5 mm solution of thymidine in phosphate buffer-saline solution. Cell ME-180 quickly treated with 50 μl of 2.5% trypsin to remove cells from the tablet.

Cells AML-193 is placed in 96-well plates with round bottom wells (Costar) at a density of 1,000 cells/well. In compliance the volume of 150 ál/well. Tablets thermostatic 96 h at 37oC in a humid atmosphere of 5% CO2in the air. Then to each well was added 1 MX [5-3H] -thymidine (Amersham, U. K., specific activity 43 Ci/mmol) in 25 μl of culture medium and cells thermostatic 6 o'clock

All cell lines are then treated as follows: the cellular DNA is precipitated by 10% trichloroacetic acid on a flat glass filter using advance Satanovsky harvester SKATRON cell (Skatron Instruments, Sterling VA). The radioactivity introduced into DNA, as a direct indicator of cell growth, is measured using a liquid scintillation counter. The number (quantity) represent the average disintegration per minute embedded thymidine hole triple repeat SEM.

In the above in vitro examples of cell lines Compounds 6, 8, 12, 14, and 20 in this invention cause a significant decrease in proliferation of tumor cell lines (as measured by the introduction of radioactive thymidine) in the concentration range from 10-11up to 10-6they say the test connection.

SPECIFIC VARIANTS OF THE INVENTION

Compounds according to this invention can be obtained synthetic chemical camping, as conditions specific variants of the invention may be generalized to obtain any and all compounds represented by Formula 1.

Generally speaking, the process of producing compounds according to this invention includes the amide formation through reaction of compounds of General Formula 2 with a compound of General Formula 3, or by the reaction of compounds of General Formula 2a with a compound of General Formula 3a. Thus, as noted above, the compound of Formula 2 is an acid or an activated form of the carboxylic acid associated with aromatic fragment nuclei tetrahydronaphthalene, (X is [C(R1)2]nand n is 1), dihydroindeno ([C(R1)2]nwhere n is 0), Romana (X is 0), thiochroman (X is S) or tetrahydroquinoline (X represents NR'). Carboxylic acid or its "activated form" are in the 2 or 3 position of the fragment of tetrahydronaphthalene and 6 or 7 position of the fragment chromane, thiochroman or tetrahydroquinoline. In preferred compounds according to this invention these deputies) position 2 tetrahydronaphthalene and position 6 chromane, thiochroman or tetrahydroquinoline.

The term "activated" form of carboxylic acids the ID in the reaction with the primary amine of Formula 3. In the case of "reverse amides" activated form of the carboxylic acid is a derivative (Formula 3a), which are capable of forming amide by reaction with primary amidol Formula 2a. Generally speaking, this means such derivatives of carboxylic acids, which are commonly known and used in the technique for the formation of amide bonds with amines. Examples of appropriate derivatives for these purposes are the anhydrides of the acids, bromohydrin acids, esters of carboxylic acids, in particular (especially) active esters in which the alcohol residue in ether forms a good leaving group. Currently, the most preferred reagents of Formula 2 or Formula 3a) are the acid chlorides (X is Cl). The acid chlorides of Formula 2 or Formula 3a) can be obtained by traditional methods from the corresponding esters (X means, for example, ethyl) by hydrolysis and treatment with chloride tiomila (SOCl2). The acid chlorides of Formula 2 or Formula 3a) can also be obtained directly by treatment of carboxylic acid chloride tiomila, if carboxylic acid is more affordable in the industry, or more easily obtained well-known chemical methods. The acid chlorides of Formula 2 or Formula 3a) usually react the acid acceptor, for example pyridine.

Themselves carboxylic acid of Formula 2 or Formula 3a) is also used to obtain amide, they react with an amine, a catalyst (4-dimethylaminopyridine) in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide (DCC) or more preferably the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC).

Carboxylic acids or the corresponding esters of Formula 2 are usually obtained as described in the chemical scientific and patent literature, and literary techniques to earn them, if necessary, be modified by such chemical reactions or processes that are known in the art by themselves. For example, 2,2-, 4,4 -, and/or 2,2,4,4-substituted chroman-6-carboxylic acid and chroman-7-carboxylic acid can be obtained according to the methods described in U.S. Patents NN 5,006,550; 5,314,159; 5,324,744 and 5,348,975. 2,2-, 4,4 -, and/or 2,2,4,4-substituted thiochroman-6-carboxylic acid prepared as in methods given in U.S. Patent N 5,015,658. 5,6,7,8-Tetrahydronaphthalen-2-carboxylic acid, generally speaking, receive according to the methods given in U.S. Patent N 5,130,335.

In Reaction Schemes 1 and 2 show examples of the synthesis of derivatives of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylic acid, is)-carbamoyl derivatives, the appropriate Formula 1. As shown in Reaction Scheme 1, ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylic acid (Compound A) nitrous, receiving the corresponding 3-nitrosoaniline (Compound B). The nitrogroup Connection B restore, receiving the corresponding 3-aminosidine (Connection C) described in the publication Lehmann et al. Cancer Research, 1991, 51, 4804. Ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylic acid (Compound C) bromilow, receiving the corresponding 4-bromo derivatives (Compound D), which as a result of interaction with solidities and restore using H3PO2converted into ethyl ether 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4 does not depend-2-carboxylic acid (Compound E). Saponification of Compound E leads to 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4 does not depend-2-carboxylic acid (Compound F), which is used as a reagent in accordance with Formula 2. Ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylic acid (Compound C) also diazotised and reacts with HBF4giving ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-fornatale-2-carboxylic acid (Compound G), which either by itself, leftalign (Compound H, obtained by literary technique Krause, Synthesis, 1972, 140) is a starting compound in the example depicted in Reaction Scheme 2. Connection H bromilow, receiving the corresponding bromo-derivative (Compound I), which is then protected by a hydroxyl group by treatment with methoxymethane (MOMCl), receiving 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxyethoxy-2 does not depend (Compound J). Compound J reacts with tert-butyllithium and carbon dioxide, yielding the corresponding carboxylic acid (Compound K), from which, after removal of the acid protective methoxymethyl group, get 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene-3-carboxylic acid (Compound L). Connection L bromilow getting 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-hydroxynaphthalene-3-carboxylic acid (Compound M). Compound L, Compound M are reagents in accordance with Formula 2. The hydroxy-group of Compounds M protect for further transformations using methoxyethylamine (MOMCl) in the presence of a base, getting 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-methoxyethoxyethoxy-3 - carboxylic acid (Compound N).

In Reaction Schemes 3, 4 and 5 show examples of the synthesis of derivatives of 2,2,4,4 - 4,4-substituted, hrih (amide) compounds, included in the scope of this invention. So, with regard to Reaction Scheme 3, 2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound O, see U.S. Patent N 5,006,550) bromilow bromine in acetic acid, receiving the corresponding 8-bromo derivatives (Compound P). The connection P is transformed into the acid chloride by treatment with chloride tiomila, and the resulting acid chloride used in the reaction with the amine of Formula 3, receiving carbamoyl (amide) compounds according to this invention. The acid chloride also reacts with an alcohol (methanol) in the presence of a base, giving the corresponding methyl ester 2,2,4,4-tetramethyl-8-brahaman-6-carboxylic acid (Compound R). The bromine atom in the Compound R is replaced by triptorelin group in the reaction with trifurcation sodium in the presence of a catalyst of copper iodide and 1-methyl-2-pyrrolidinone (NMP), and ester group its shades, you get a 2,2,4,4-tetramethyl-8-cryptomelane-6-carboxylic acid (Compound S). Connection S corresponds to the Formula 2 and apply by itself or as an acid chloride or other activated form to react with amines of Formula 3, giving carbamoyl (amide) compounds according to this invention. 2,2,4,4-Tetramethylchroman-6-karbonovye-6-carboxylic acid (Compound V) another reagent of Formula 2. In addition, in another example, depicted in Reaction Scheme 3, 2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound O) turn in ethyl ether and then nitrous, obtaining the ethyl ester of 2,2,4,4-tetramethyl-8-nitropropan-6-carboxylic acid (Compound W). Further, the Connection O reacts with ICl, giving 2,2,4,4-tetramethyl-8-iochroma-6-carboxylic acid (Compound X).

As shown in the example shown in Reaction Scheme 4, 2-METHYLPHENOL subjected to a series of transformations described in U.S. Patent N 5,045 getting 2,2,4,4,8-pentamethylchroman (Y Connection). Compound Y bromilow bromine in acetic acid, getting 2,2,4,4,8-pentamethyl-6-brahaman (Compound Z), which reacts with tert.-butyllithium, and then with carbon dioxide, giving 2,2,4,4,8-pentamethylchroman-6-carboxylic acid (Compound1).

In Reaction Scheme 5 shows the synthesis of 4,4-dimethyl-8-brahaman-6-carboxylic acid (Compound B1) bromirovanii 4,4-DIMETHYLPROPANE-6-carboxylic acid obtained according to the descriptions in U.S. Patent N 5,059,621. 2,2,4,4,8-Pentamethylchroman-6-carboxylic acid (Compound1) and 4,4-dimethyl-8-brahaman-6-carboxylic acid (Compound B1are the reagents of Formula 2, by themselves or compounds according to this invention.

Returning now to the reaction between the reagent of Formula 2 with an amine of Formula 3, you must specify that, in General, amines are really getting in the manner described in scientific and patent literature. More specifically, the amines of Formula 3 can be obtained as described in the scientific and patent literature or known in the literature compounds using such chemical reactions or transformations that are known to chemists organikum. In Reaction Scheme 6 shows examples of the preparation of amines of Formula 3 (where Y denotes phenyl) received from the industry of the parent compounds (Aldrich Chemical Company, or Research Plus, Inc. ). Below are examples that illustrate the use of the compounds in the synthesis of some preferred compounds according to this invention.

Thus, in accordance with Reaction Scheme 6, 3-nitro-6-methylformate (Aldrich) oxidised to transform the obtained carboxylic acid to the acid chloride, then with ethyl ether, followed by reduction of the nitro group and receive the ethyl ester of 2-fluoro-4-aminobenzoic acid (Compound C1). 3-Nitro-6-methylpropanol (Aldrich) and 3-nitro-6-methylcarbazole (Aldrich) as a result, virtually the same series of reactions give ethyl ester of 2-bromo-4-aminobenzoic acid (Compound D11) via the corresponding acid chloride. 2,3,5,6-Titrator-4-aminobenzoic acid (Aldrich) atrificial ethanol in the presence of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 4-dimethylaminopyridine in CH2Cl2getting ethyl ester 2,3,5,6-titrator-4-aminobenzoic acid (Compound G1). 2,4,6-Triptoreline acid (Aldrich) is transformed into methyl ester via the acid chloride and 4-fluorine-atom substituted by reaction with sodium azide followed by hydrogenation, to obtain methyl ester of 2,6-debtor-4-aminobenzoic acid (Compound H1). Connection C1D1E1F1and H1are amine reagents of Formula 3. Additional examples of reactants of Formula 3 are nitro-, fluorine-, chlorine-, bromine - and triptoreline derivatives aminosilane heteroarylboronic acids or their lower alkalemia esters, for example ethyl ester 2-amino-4-chloropyridin-2-carboxylic acid, ethyl ester of 5-amino-3-chloropyridin-5-carboxylic acid and 3,4-dibromo-5-aminothiophene-2-carboxylic acid. Recent examples of compounds can be obtained, respectively, by chlorination or bromirovanii 2-aminopyridine-5-carboxylic acid or its ester, 3-aminopyridine-6-carboxylic acid or the DN of the compounds of Formula 2 and Formula 3, or between the compounds of Formula 2a and Formula 3a, described above represents the currently used method of synthesis carbamoyl (amide) compounds according to this invention. Many examples of this reaction are described in detail below in the experimental part. Carbamoyl (amide) compounds according to this invention can be converted into thiocarbamoyl (thioamide) compounds according to this invention, in which, referring to Formula 1, Z means S, the reaction karamarinov (amide) compounds with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (reagent Lawesson). This reaction illustrates the Reaction Scheme 7 on two particular examples of compounds according to this invention.

In Reaction Scheme 7 one source connection, ethyl ester 4-[5',6', 7', 8'-tetrahydro-5', 5', 8',8'-tetramethylnaphthalene-2 - yl)carbarnoyl]benzoic acid (Compound I1receive by literary technique Kagechicka et al. J. Med. Chem. 1988, 31, 2182-2192. Another source connection, ethyl ester 2-fluoro-4-[5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalene-2 - yl)carbarnoyl]benzoic acid (Compound 1) are obtained in accordance with this invention.

In the Reaction Schemes 8, 9 and 10 are examples of obtaining carbamoyl (amide) compounds according to this izaberete the Nations resulting karamarinov (amide) compounds, all reactions carried out in the same flask. So, for example, as shown in Reaction Scheme 8, 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxyethoxy-naphthalene-2-carboxylic acid (Compound K) interacts with ethyl ether of 4-amino-2-fermenting acid (Compound1in CH2Cl2in the presence of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and dimethylaminopyridine (DMAP) to give ethyl ester of 2-fluoro-4-[5',6',7',8'-tetrahydro-5', 5', 8', 8'-tetramethyl-2 - methoxyethoxyethoxy-3-yl)carbarnoyl]benzoic acid (Compound K1). Methoxymethyl protection is removed in the Connection K1processing thiophenols and efratom boron TRIFLUORIDE, obtaining the ethyl ester of 2-fluoro-4-[5', 6', 7',8'-tetrahydro-5',5',8',8'-tetramethyl - 2'-hydroxynaphthalene-3-yl)carbarnoyl] benzoic acid (Compound 7). Hydroxyl group of Compound 7 is transformed into n-hexyl ester by reaction with hexyllithium in the presence of a weak base.

As shown in Reaction Scheme 9, 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-methoxyethoxyethoxy-3 - carboxylic acid (Compound N) reacts with methyl ester of 4-amino-2,6-diferential acid (Compound H1in CH2Cl2in the presence of hydrochloride of 1-(3-dimethyln'-bromo-2-methoxyethoxyethoxy-3'-yl)carbarnoyl]benzoic acid (Compound M1), from which treatment, respectively, the base and acid to remove the essential metal and protective methoxymethyl group.

In Reaction Scheme 10 illustrates an example of the transformation of 2,2,4,4-tetramethyl-8-nitropropan-6-carboxylic acid (Compound V) to the corresponding acid chloride under the action of chloride of tonila followed by reaction with ethyl ester, 4-amino-2-fermenting acid (Compound C1) and hydrogenation, resulting in ethyl ether, 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-amino-6'- chromanol)carbarnoyl] benzoic acid (Compound N1). The compound N1turn into an 8-azido connection, ethyl ester 2-fluoro-4-[(2',2', 4',4'-tetramethyl-8'-azido-6'- chromanol)carbarnoyl]benzoic acid (Compound 15), the processing solidities and NaN3.

In Reaction Scheme 11 illustrates the synthesis of primary amines of Formula 2a of the acid chlorides (X1=CI) or other active derivatives of acids of Formula 2 for those cases where the primary amine of Formula 2a are not described in the literature. So, practically, in accordance with the rearrangement of kurzius, the acid chloride of Formula 2 is reacted with sodium azide in acetone, giving azide of Formula 6. Azide of Formula 6 is heated in a polar high is cozy and get the compound of Formula 2a.

In Reaction Scheme 12 shows examples of synthesis of compounds of Formula 3a in those cases when they do not get in the industry and they are not described in the literature. Thus, given by way of example 2.5-debtor-4-bromobenzoyl acid (obtained according to literature methods Sugawara et al. Kaguku Kogyo Zasshi 1970, 73, 972-979) first etherification processing ethyl alcohol and acid to obtain the corresponding ester and then carry out the reaction with butyllithium, and then with carbon dioxide, receiving monoether 2,6-differenetly acid (T1). 2,3,5,6-Debtor-4-brabantia acid (obtained by the method Reuman et al. J. Med. Chem. 1995, 38, 2531-2540) as a result of this sequence of reactions gives monoether 2,3,5,6-titrator-4-terephthalic acid. Generally speaking, this illustrates a Daisy-chain of reactions can be applied for the synthesis of all compounds of Formula 3a with modifications, easily understood by professionals in this area - in cases when their receipt is not described in the literature.

Many other reactions, are suitable for producing compounds according to this invention and for further transformation of compounds of Formula 1, included in the scope of the present invention, other compounds according to this invention, as well as what the experts in this field in the light of the present invention. In this regard, proposed the following General synthetic methodology applicable for the conversion of compounds of Formula 1 in other homologues and/or derivatives, as well as to obtain the compounds (reactants) Formulas 2 and 3 (as well as 2a and 3a).

Carboxylic acids usually atrificial boiling acid solution of the appropriate alcohol in the presence of an acidic catalyst such as hydrogen chloride or thionyl chloride. Alternatively, the carboxylic acid can condense with the appropriate alcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The ester is isolated and cleaned by appropriate methods. Acetals and ketals easily get in the way described in March, "Advabed Organic Chemistry", 2nd Edition, McGraw-Hill Book Company, p. 810). Alcohols, aldehydes and ketones can be easily protect education, respectively, esters and ethers, acetals or ketals by known methods, for example as described in McOmie, Plenum Publishing Press, 1973 and Protecting Groups. Ed. Greene, John Wiley and Sons, 1981.

Method to obtain compounds in which A denotes the (CH2)q(q means from 1 to 5), is the conversion of compounds of Formula 1 in which B means of acid or another group, homologues using well-known methods for the description of the synthetic transformations can be performed with compounds of Formula 3. Compounds according to this invention, in which A means alkenylphenol group with one or more double bonds, can be obtained, for example, by entering the desired number of double bonds in the compound of Formula 3. Generally speaking, such compounds in which A denotes an unsaturated carbon chain can be obtained by using well-known chemical sintetica scheme of the synthesis; for example, the Wittig reaction and the like, or by introducing a double bond by elimination of halogen from an alpha halogencarbonic acid, ester or aldehyde. Compounds according to this invention, in which the group A contains a triple (acetylenic) bond can be obtained by applying the corresponding intermediate aryl - or wateroriented. Such intermediates can be obtained using well known in the art reactions, for example by reaction of the corresponding ketone with strong base, such as sitedisability.

Acid and salt derivatives of the compounds of Formula 1, are easily derived from the corresponding esters. Alkaline hydrolysis using a base of an alkali metal acid gives. For example, an ester of Formula 1 can be dissolved in a polar solvent, for example a saturated alcohol (alkanol) in the atmosphere of inert gas at komnate. The solution is stirred for an extended period of time, from 15 to 20 h, cooled, acidified and the hydrolysate allocate appropriate ways. Amide (Formula 1 B means CONR9R10) can be obtained by any suitable technique known in the art, from the corresponding esters or carboxylic acids. One way of obtaining such compounds is the conversion of the acid into the acid chloride and then treatment of this compound with ammonium hydroxide (ammonia or the appropriate amine. The alcohols obtained by conversion of the corresponding acid to the acid chloride, acting chloride tiomila or other method (J. March, "Advabced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), then restore the acid chloride by detribalized (March, Ibid. pg. 1124), which gives the corresponding alcohol. Or esters can be recovered with lithium aluminum hydride at low temperatures. Alkylation of these alcohols corresponding halide alkilani under the reaction conditions Williamson (March, Ibid. pg. 357) gives the corresponding esters. These alcohols can be converted into esters by reaction with the appropriate acid in the presence of acidic catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine.

The aldehydes can be obtained from Slane (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethyl sulfoxide/oxalicacid in methylene chloride (Omura, K., Swern, D., Tetrahedron, 1978, 34, 1651).

Ketones can be obtained from the corresponding aldehyde by the action of alkyl Grignard reagent or similar with subsequent oxidation.

Acetals or ketals can be obtained from the corresponding aldehyde or ketone by the method described in March, Ibid. R. 810.

The compounds of Formula 1 in which B stands for H, can be obtained from the corresponding halide aromatic compounds, preferably those in which the halogen atom means I.

Specific examples of

Ethyl ester of 4-amino-2-fermenting acid (Compound C1)

To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7(2.74 g, 8.4 mmol) in 13.7 ml of HOAc is added slowly 6.83 ml of H2SO4. This mixture is slowly heated to 90oC for 1 h, forming a greenish heterogeneous solution. The mixture is cooled to room temperature and diluted with ethyl acetate. the pH of the solution was adjusted to 4 with NaOH (aq.). The mixture is extracted with additional ethyl acetate. The organic layer was washed with NaHCO3(saturated. ), then brine and dried over Na2SO4. After Paltrow for 1 h The excess SOCl2removed under reduced pressure and the residue is dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture is stirred at room temperature for 2 h and concentrated to dryness. Ethyl ester of 2-fluoro-4-nitrobenzoic acid obtained as a white solid after chromatography on a column using ethyl acetate/hexane (1/9). This solid is then dissolved in 10 ml of ethyl acetate and added Pd/C (50 mg). By hydrogenation using a balloon of H2turn ethyl ester 2-fluoro-4-nitrobenzoic acid indicated in the header connection. 1H NMR 7.77 (t, J = 8.4 Hz, 1H), 6.41 (DD, J1= 8.6, J2= 2.2 Hz, 1H), 6.33 (DD, J1= 13.0, J2= 2.2 Hz, 1H), 4.33 (K, J = 7.1 Hz, 2H), 4.3 (sh.s, 2H), 1.37 (t, J = 7.1 Hz, 3H).

Methyl ester of 4-amino-2,6-diferential acid (Compound H1)

Solution triterpenoids acid (150 mg, 0.85 mmol, Aldrich) in 0.5 ml SOCl2heated at boiling for 2 hours, the Reaction mixture was cooled to room temperature and the excess SOCl2removed under reduced pressure. The residue is dissolved in 1 ml of pyridine and 0.2 ml of methanol. After stirring at room temperature for 30 min the solvent is removed and the residue purified via chromatography of the oil. This oil is then dissolved in 1 ml of CH3CN and then add a solution of NaN3(100 mg, 1.54 mmol) in 0.5 ml of water. The reaction mixture is refluxed for two days. Salt is removed by filtration and the resulting solution was concentrated to oil. This oil is then dissolved in 1 ml of methanol and add a catalytic amount of Pd/C (10% weight). The reaction mixture hydronaut within 12 hours, the Catalyst was removed and the solution concentrated to oil. After chromatography on a column (ethyl acetate/hexane 1/3) emit indicated in the title compound as colorless crystals.1H NMR 6.17 (d, J = 10.44 Hz, 2H), 4.2 (sh.s, 2H), 3.87 (s, 3H).

8-Bromo-2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound P)

To a solution of 2,2,4,4-tetramethylchroman-6-carboxylic acid (200 mg, 0.85 mmol) in 0.5 ml of AcOH add Br2(0.07 ml, 1.28 mmol). The obtained dark orange solution was stirred at room temperature overnight. The excess bromine is removed under reduced pressure. Then the solution contribute in 5 ml of water and extracted with ethyl acetate (CH ml). United an ethyl acetate layers are then washed with NaHCO3(saturated.), brine and dried over MgSO4. After concentration the residue is purified by chromatography on a column (the H NMR 8.11 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 1.90 (s, 2H), 1.43 (s, 6H), 1.39 (s, 6H).

8-Iodine-2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound X)

To a solution of 2,2,4,4-tetramethylchroman-6-carboxylic acid (66 mg, 0.28 mmol) in 0.8 ml of AcOH added ICl (0.07 ml, 1.4 mmol). The obtained colored solution was stirred at room temperature overnight. Using the same methodology that was used to obtain 8-bromo-2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound P) results indicated in the title compound (107 mg) as a white solid.1H NMR 8.35 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 1.87 (s, 2H), 1.43 (s, 6H), 1.38 (s, 6H).

2,2,4,4-Tetramethyl-8-cryptomelane-6-carboxylic acid (Compound S)

A solution of 8-bromo-2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound R, 150 mg, 0.48 mmol) in 1 ml SOCl2heated at boiling for 2 hours After cooling to room temperature, the excess SOCl2removed under reduced pressure and the residue is dissolved in 1 ml of pyridine and 0.2 ml of methanol. The mixture is stirred at room temperature for 30 minutes the Solvent is removed and the residue passed through a chromatographic column (silica gel, ethyl acetate/hexane 1/10) to give the methyl ester of 8-bromo-2,2,4,4-tetramethylpyrrolidine (NMP) add NaCO2CF3(502 mg, 3.7 mmol) and CuI (350 mg, 1.84 mmol). The resulting mixture is heated to 175oC (bath temperature) for 2 hours the mixture is cooled to room temperature and bring in the icy water. The product is extracted with ethyl acetate (CH ml). The combined organic layers are then dried and concentrated to dryness. The crude substance is purified by chromatography on a column (silica gel, ethyl acetate/chloroform 1/10) to obtain the indicated in the title compound as a colourless oil (120 mg). It hydrolyzing under standard conditions with the receipt indicated in the connection header.1H NMR 8.21 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 1.92 (s, 2H), 1.41 (s, 12H).

Ethyl ester of 8-nitro-2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound W)

Ethyl ester of 2,2,4,4-tetramethylchroman-6-carboxylic acid (150 mg, 0.57 mmol) is slowly added to 0.3 ml conc. H2SO4at 0oC. To this mixture, slowly add 0.03 ml of HNO3. The reaction mixture was stirred at 0oC for 30 min and contribute in the icy water. The product is extracted with 5 ml ethyl acetate, washed with NaHCO3(saturated.), brine and dried over MgSO4. After concentration the product was then purified using chromatography on a column (ethyl acetate/GEK(s, 2H), 1.43 (s, 6H), 1.42 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H).

2-Oxo-4,4,8-trimethylpropane (Connection P1)

In a round bottom flask of 500 ml was placed NaH (1.66 g, 60% suspension in oil, 0.046 mol) and washed with dry hexane. Then add dry THF (22 ml) and then o-cresol (5 g, 0.046 mol) in 10 ml dry THF. The reaction mixture was stirred at 0oC for 30 min and then add 3,3-dimethylacrylate in 10 ml of THF. The obtained white suspension was stirred at room temperature for 12 h, and then slowly diluted with water. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, water and dried over MgSO4. After filtration and removal of solvent to obtain a yellow oil (10.44 g). This oil is then dissolved in 50 ml of dry CH2Cl2and injected by syringe into a solution of AlCl3(10.8 g, 0.069 mol) in 10 ml of CH2Cl2. The reaction mixture was stirred at room temperature for 12 hours Then carefully add ice water, the organic layer is separated, washed with NaHCO3(saturated. ), brine, water and finally dried over MgSO4. After removal of the drying agent and solvent the residue is purified by chromatography on a column (silica gel, ethyl acetate/hexane 1/9) to obtain oboes,4-Dimethyl-4-(2'-hydroxy-3'-were)pentane-2-ol (Compound R1)

To a solution of 2-oxo-4,4,8-trimethylpropane (Connection P1, 2.20 g, 11.5 mmol) in 40 ml of dry ethyl ether is added methylmagnesium (at 12.67 ml, 38 mmol, 3 M solution in THF). The reaction mixture was stirred at room temperature for 12 h, then add NH4Cl (saturated.), until all the precipitate has dissolved. The mixture is extracted with diethyl ether and the combined organic layers was separated and washed with brine, water and dried over MgSO4. After filtration and removal of solvent allocate indicated in the title compound as a tan solid (2.215 g).1H NMR 7.16 (d, J = 7.88 Hz, 1H), 7.00 (d, J = 6.72 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 5.89 (sh.s, 1H), 2.21 (s, 3H), 2.17 (s, 2H), 1.48 (s, 6H), 1.10 (s, 6H).

2,2,4,4,8-Pentamethyl-6-brahaman (Compound Z)

A solution of 2,4-dimethyl-4-(2-hydroxy-3-were)pentane-2-ol (Compound R1, 2.215 g, 9.98 mmol) in 30 ml of 15% H2SO4heated to 110oC. After cooling to room temperature the reaction mixture was extracted with diethyl ether. The organic layer was washed with NaHCO3(saturated.), brine and water. After filtration and removal of solvent the residue is passed through a column (silica gel, pure hexane) to give the desired compound in the Reaction mixture is stirred at room temperature for 12 hours The solvent is removed under reduced pressure and to the residue is added ethyl acetate, the mixture was washed with NaHCO3(saturated.), brine, water and dried over MgSO4. After filtration and removal of solvent the residue is passed through a column (silica gel, pure hexane) to give the indicated in the title compounds as white solids (2.227 g).1H NMR 7.21 (s, 1H), 7.06 (s, 1H), 2.14 (s, 3H), 1.79 (s, 2H), 1.32 (s, 6H), 1.31 (s, 6H).

2,2,4,4,8-Pentamethyl-chroman-6-carboxylic acid (Compound A1)

To a solution of 2,2,4,4,8-pentamethyl-6-brahaman (Compound Z, 1.2 g, 4.24 mmol) in 18 ml of dry THF at -78oC in argon atmosphere is added slowly 5.48 ml of tert.-BuLi (1.7 M in hexane, 9.33 mmol). The reaction mixture was stirred at -78oC for 1 h and Then passed through a solution of CO2within 1 h After the cessation of current CO2the reaction mixture was stirred additionally for 1 hour at -78oC. Then add 10% HCl. After reaching room temperature, the reaction mixture was extracted with ethyl acetate. The organic layer is then washed with brine and dried over MgSO4. After concentration the residue is purified by chromatography on a column (ethyl acetate/hexane 5/95) to give the Ref who 2H), 1.39 (s, 6H).

8-Bromo-4,4-dimethyl-chroman-6-carboxylic acid (Compound1)

Using a technique similar to the above for the synthesis of 8-bromo-2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound P), but using 4,4-dimethylaminopropanol acid (100 mg, 0.49 mmol) get marked in the title compound as a white solid.1H NMR 8.10 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 4.39 (t, J = 5.44 Hz, 2H), 1.89 (t, J = 5.4 Hz, 1H), 1.38 (s, 6H).

Ethyl ester of 2-amino-1-bromo-5,5,8,8-tetrahydro-5,5,8,8 - tetramethylnaphthalene-3-carboxylic acid (Compound D)

To a solution of ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3 - aminonaphthalene-2-carboxylic acid (Compound C, 58 mg, 0.21 mmol) in 2 ml of HOAc add Br2(0.02 ml, 0.42 mmol). The orange solution was stirred at room temperature for 2 days. Excess Br2and HOAc removed under reduced pressure and the residue passed through a column (silica gel, ethyl acetate/hexane 1/10) to obtain the indicated in the title compound as a pale orange oil (59 mg, 79.5%).1H NMR 7.90 (s, 1H), 6.41 (sh.s, 2H), 4.36 (K, J = 7.2 Hz, 2H), 1.70 (m, 4H), 1.58 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H), 1.28 (s, 6H).

Ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4 does not depend-2-carboxylic acid the (Compound D, 59 mg, 0.17 mmol) dissolved in 2 ml of EtOH at 0oC. To this solution add 1 ml triperoxonane acid and 1 ml of isoamylamine. The reaction mixture was stirred at 0oC for 30 min, then add H3PO4(0.325 ml, 3.14 mmol). The reaction mixture is brought to room temperature and stirred for 12 hours Add NaHCO3(saturated. ), the reaction mixture was extracted with ethyl acetate, dried over MgSO4, filtered and concentrated to obtain oil. The product was then purified using chromatography on a column (silica gel, ethyl acetate/hexane 1/10) to obtain the indicated in the title compounds as colorless oils.1H NMR 8.02 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 4.35 (K, J = 7.1 Hz, 2H), 1.71 (m, 4H), 1.56 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.31 (s, 6H).

Ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3 - fornatale-2-icarbonell acid (Compound G)

To a solution of ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3 - aminonaphthalene-2-carboxylic acid (Compound C, 150 mg, 0.55 mmol), cooled with ice bath, add 0.24 ml HBF4(48% solution in water) and then a solution of NaNO3(81 mg, 1.16 mmol) in 1 ml of water. The suspension is stored in the refrigerator for 3 days. The reaction mixture was sequentially washed with ethyl acetate until TLC will contentresult getting oil. The oil is dissolved in 1 ml of toluene and the mixture refluxed for 2 hours, After cooling the reaction to room temperature, the solvent evaporated and the residue passed through a column (silica gel, ethyl acetate/hexane 1/10) to obtain the marked header connection in the form of oil. 1H NMR 7.85 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 12.3 Hz, 1H), 4.38 (K, J = 7.1 Hz, 2H), 1.71 (m, 4H), 1.69 (s, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 6H).

2-Bromo-3-hydroxy-5,5,8,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (Compound I)

Using a technique similar to the above for the synthesis of 8-bromo-2,2,4,4-tetramethylchroman-6-carboxylic acid (Compound P), but using 2-hydroxy-5,5,8,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (700 mg, 3.43 mmol) and Br2(0.177 ml, 3.43 mmol) in 1.5 ml of HOAc, get marked in the title compound as a white solid (747 mg).1H NMR 7.36 (s, 1H), 6.96 (s, 2H), 5.32 (sh.s, 1H), 1.66 (s, 4H), 1.25 (s, 12H).

5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-methoxyethoxy-2 does not depend (Compound J)

To a solution of 2-bromo-3-hydroxy-5,5,8,8-tetrahydro-5,5,8,8 - tetramethylnaphthalene (Compound I, 600 mg, 2.12 mmol) and catalytic amounts Bu4NBr in 20 ml of dry CH2Cl2at 0oC add diisopropylethylamine (1.138 ml, 12.75 m the ion mixture is washed with 10% citric acid, then NaHCO3(saturated.), brine and dried over MgSO4. After filtration and removal of solvent the residue is purified by chromatography on a column (ethyl acetate/hexane 1/9) to obtain the marked header connection (772 mg) as a white solid.1H NMR 7.43 (s, 1H), 7.06 (s, 1H), 5.21 (s, 2H), 3.54 (s, 3H), 1.66 (s, 4H), 1.26 (s, 6H), 1.25 (s, 6H).

3 Methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2 - inkarbaeva acid (Compound K)

Using a technique similar to the above for the synthesis of 2,2,4,4,8-pentamethylchroman-6-carboxylic acid (Compound1), but using 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-methoxyethoxy-2-bromonaphthalene (Compound J, 722 mg, 2.21 mmol) and 2.86 ml of tert.-BuLi (4.87 mmol, 1.7 M solution in hexane) are indicated in the title compound as a white solid (143 mg).1H NMR 8.12 (s, 1H), 7.19 (s, 1H), 5.40 (s, 2H), 3.58 (s, 3H), 1.70 (s, 4H), 1.30 (s, 12H).

Ethyl ester of 2-fluoro-4-[(5,6,7,8-tetrahydro-5,5,8,8 - tetramethylnaphthalene-2-yl)carbarnoyl]benzoic acid (Compound 1)

To a solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaleneboronic acid (46 mg, 0.2 mmol) was added 1 ml of thionyl chloride. This mixture is heated at boiling for 2 hours, the Excess thionyl chloride removed by pangender-benzoic acid (Compound C1, 37 mg, 0.2 mmol) and then 0.5 ml of pyridine. The reaction mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The residue is purified by chromatography on a column (ethyl acetate/hexane (1/10) and get marked in the title compound (71.2 mg) as a white solid.1H NMR 8.06 (sh.s, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.78 (DD, J1= 2.0, J2= 12.9 Hz, 1H), 7.55 (DD, J1= 2.0, J2= 8.2 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.32 (DD, J1= 2.02, J2= 8.8 Hz, 1H), 4.38 (K, J = 7.2 Hz, 2H), 1.71 (s, 4H), 1.40 (t, J = 7.2 Hz, 3H), 1.32 (s, 6H), 1.30 (s, 6H).

Ethyl ester of 4-[3'-fluoro-5', 6',7',8'-tetrahydro-5',5',8',8'- tetramethylnaphthalene-2-yl)carbarnoyl]benzoic acid (Compound 3)

Ethyl ester 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-fornatale-2-carboxylic acid (Compound G, 75 mg, 0.27 mmol) dissolved in a mixture of 3 ml of EtOH and 1 ml NaOH (1 M in water). The reaction mixture is left to stand overnight at room temperature. The reaction is neutralized with 5% HCl. Add water (2 ml) and the mixture extracted with ethyl acetate (CH ml). The combined layers washed once with brine and dried over MgSO4. After filtration of transparent organic solution concentrated to obtain 3-fluoro-5,5,8,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-ilıca is ahydro-5',5',8',8'- tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid (Compound 1), but using the ethyl ester of 4-aminobenzoic acid (45 mg, 0.27 mmol), carboxylic acid, in turn indicated in the title compound (white solid).1H NMR 8.66 (sh.s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 12.3 Hz, 1H), 4.36 (K, J = 7.1 Hz, 2H), 1.70 (s, 4H), 1.49 (t, J = 7.1 Hz, 3H), 1.32 (s, 6H), 1.30 (s, 6H).

Ethyl ester of 2-fluoro-4-[(5', 6', 7',8'-tetrahydro-4'-bromo-5',5',8',8'- tetramethylnaphthalene-2-yl)carbamoylmethyl acid (Compound 5)

Using a technique similar to the above for the synthesis of ethyl ester of 2-fluoro-4-[(5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene - 2'-yl)carbarnoyl] benzoic acid (Compound 1), but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4 does not depend-2-carboxylic acid (Compound F) get marked in the title compound as a white solid.1H NMR 8.30 (sh.s, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.74 (DD, J1= 2.1, J2= 12.8 Hz, 1H), 7.35 (DD, J1= 2.0, J2= 8.4 Hz, 1H), 4.36 (K, J = 7.2 Hz, 2H), 1.67 (m, 4H), 1.55 (s, 6H), 1.39 (t, J = 7.2 Hz, 3H), 1.31 (s, 6H).

Ethyl ester of 2-fluoro-4-[(3'-methoxyethoxy-5',6',7',8'- tetrahydro-5', 5',8',8'-tetramethylnaphthalene-2'-yl)carbamoylmethyl acid Compound K1)

Using a technique similar to priftin-2'-yl)carbarnoyl] benzoic acid (Compound S1), but using 3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2 - icarbonell acid (Compound K, 143 mg, 0.49 mmol) and ethyl ester of 4-amino-2-fermenting acid (Compound C1, 98.5 mg, 0.54 mmol) get marked in the title compound as a white solid.1H NMR 10.1 (Sch.s, 1H), 8.20 (s, 1H), 7.93 (t, J = 8.8 Hz, 1H), 7.83 (d, J = 13.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.41 (s, 2H), 4.39 (K, J = 7.1 Hz, 2H), 3.59 (s, 3H), 1.70 (s, 4H), 1.31 (s, 12H), 1.26 (t, J = 7.1 Hz, 3H).

Ethyl ester of 2-fluoro-4-[(3'-hydroxy-5',6',7',8'-tetrahydro- 5',5',8', 8'-tetramethyl-2-naphthalenyl)carbarnoyl]benzoic acid (Compound 7)

To a solution of ethyl ester of 2-fluoro-4-[(3'-methoxyethoxy-5',6',7',8'-tetrahydro-5',5',8',8'- tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid (Compound K1, 50.7 mg, 0.11 mmol) in 2 ml of CH2Cl2add thiophenol (0.061 ml, 0.55 mmol). The reaction mixture was stirred at 0oC for 2 h, then add NaHCO3(saturated.). The organic layer is separated and washed with brine, water and dried over MgSO4. After filtration and removal of solvent the residue is passed through a column (silica gel, ethyl acetate/hexane 1/3) to obtain the indicated in the title compounds as white solids (44.2 mg).1H NMR 8.61 H), 1.29 (s, 6H), 1.27 (s, 6H).

Ethyl ester of 2-fluoro-4-[(4',4-dimethyl-8'-brahaman-6'- yl)carbarnoyl]benzoic acid (Compound 9)

In a round bottom flask of 10 ml was placed 4,4-dimethyl-8-bromo-chroman-6-carboxylic acid (Compound1, 139 mg, 0.485 mmol) and added SOCl2(1 ml, large excess). The resulting solution was heated at 90oC for 2 h and cooled to room temperature. The excess SOCl2removed under reduced pressure. The residue is dissolved CH2Cl2(3 ml). Add ethyl ester of 4-amino-2-fluoro-benzoic acid (Compound C1, 90 mg, 0.49 mmol) and then pyridine (0.5 ml, large excess). The reaction mixture was stirred at room temperature overnight and then concentrated to dryness. The residue is purified by chromatography on a column (ethyl acetate/hexane (1/5) and get marked in the title compound as a white solid (190 mg).1H NMR 7.95 (t, J = 8.31 Hz, 1H), 7.88 (sh.s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.75 (DD, J1= 12.89, J2= 2.0 Hz, 1H), 7.30 (DD, J1= 8.55, J2= 2.0 Hz, 1H), 4.37 (m, 5H), 1.89 (t, J = 5.49 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.39 (s, 6H).

Ethyl ester of 2-fluoro-4-[(2', 2', 4', 4'-tetramethyl-8'-brahaman-6'- yl)carbarnoyl]benzoic acid (Compound 11)

Applying IU the benzoic acid (Compound 9), but with the use of 2,2,4,4-dimethyl-8-bromo-chroman-6-carboxylic acid (Compound P, 70 mg, 0.22 mmol) and ethyl ester of 4-amino-2-fluoro-benzoic acid (Compound C1, 38 mg, 0.22 mmol) get marked in the title compound as a white solid (80 mg, 76%).1H NMR 8.25 (W.s, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.83 (s, 2H), 7.74 (DD, J1= 2.0, J2= 13.0 Hz, 1H), 7.34 (DD, J1= 2.0, J2= 8.7 Hz, 1H), 4.37 (K, J = 7.1 Hz, 2H), 1.88 (s, 2H), 1.41 (s, 6H), 1.39 (t, J = 7.1 Hz, 3H), 1.37 (s, 6H).

Ethyl ester of 2-fluoro-4-[(2', 2', 4',4'-tetramethyl-8'- cryptomelane-6'-yl)carbarnoyl]benzoic acid (Compound 13)

Using a technique similar to the above for the synthesis of ethyl ester of 2-fluoro-4-[(4', 4'-dimethyl-8'-brahaman-6'-yl)carbarnoyl] benzoic acid (Compound 9), but with the use of 2,2,4,4-dimethyl-8-cryptomelane-6-carboxylic acid (Compound S, 57 mg, 0.19 mmol) and ethyl ester of 4-amino-2-fluoro-benzoic acid (Compound C1, 35 mg, 0.19 mmol) get marked in the title compound as a white solid.1H NMR 8.06 (d, J = 2.2 Hz, 1H), 7.99 (sh.s, 2H), 7.95 (t, J = 8.55 Hz, 1H), 7.83 (s, 2H), 7.81 (d, J = 2.2 Hz, 1H), 7.76 (DD, J1= 12.8, J2= 2.1 Hz, 1H), 7.33 (DD, J = 8.55, 1.9 Hz, 1H), 4.37 (K, J = 7.1 Hz, 2H), 1.93 (s, 2H), 1.41 (s, 12H), 1.40 (t, J = 7.1 Hz, 3H).

Ethyl ester of 2-f is a Finance 8-nitro-2,2,4,4-tetramethyl-6-romancenovel acid (Compound V) and applying a methodology similar to that shown for the synthesis of ethyl ester of 2-fluoro-4-[(4',4'-dimethyl-8'-brahaman-6'-yl)carbarnoyl]benzoic acid (Compound 9), receive the ethyl ester of 2-fluoro-4-[(2',2',4', 4'-tetramethyl-8'-nitropropan-6'-yl)carbarnoyl]benzoic acid as a white solid. This compound (50 mg, 0.12 mmol) dissolved in 2 ml of methanol. To the solution was added a catalytic amount of Pd/C and the solution is kept in the atmosphere of H2(hydrogen balloon) overnight. The catalyst was removed by filtration, the solvent evaporated and get marked in the title compound as a white solid.1H NMR 7.93 (t, J = 8.43 Hz, 1H), 7.90 (sh.s, 1H), 7.73 (DD, J = 12.9, 2.0 Hz, 1H), 7.29 (DD, J1= 8.43, 1.96 Hz, 1H), 7.23 (d, J = 2.14 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 4.35 (K, J = 7.1 Hz, 2H), 1.88 (s, 2H), 1.39 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.37 (s, 6H).

Ethyl ester of 2-fluoro-4-[(2', 2', 4', 4'-tetramethyl-8'-azithromy-6'-yl)carbarnoyl]benzoic acid (Compound 15)

To a solution of ethyl ester of 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-aminopropan-6'-yl)carbarnoyl]benzoic acid (Compound N1, 32 mg, 0.077 mmol) in 3 ml EtOH add 0.5 ml triperoxonane acid (TFA) and 0.5 ml of isoamylamine at 0oC. the Reaction mixture was stirred for 2 h, then add a solution of NaN31H NMR 8.00 (sh.s, 2H), 7.94 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 12.1 Hz, 1H), 7.64 (s, 1H), 7.31 (DD, J = 8.5, 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 4.37 (K, J = 7.1 Hz, 2H), 1.90 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.45 (s, 6H), 1.40 (s, 6H).

Methyl ester of 2,6-debtor-4-[(2', 2', 4', 4'-he tetramethyl-8'- cryptomelane-6'-yl)carbarnoyl]benzoic acid (Compound 17)

Using a technique similar to the above for the synthesis of ethyl ester of 2-fluoro-4-[(4', 4'-dimethyl-8'-brahaman-6'-yl)carbarnoyl] benzoic acid (Compound 9), but with the use of 2,2,4,4-tetramethyl-8-triftormetilfullerenov acid (Compound S, 11.2 mg, 0.037 mmol) and methyl ester of 4-amino-2,6-debtor-benzoic acid (Compound H1, 6.6 mg, 0.035 mmol) get marked in the title compound as white crystals.1H NMR 8.21 (sh. s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 7.36 (d, J = 10.20 Hz, 1H), 3.93 (s, 3H), 1.92 (s, 2H), 1.40 (s, 12H).

Ethyl ester of 2-fluoro-4-[(2', 2', 4', 4'-tetramethyl-8'-iochroma-6'- yl)carbarnoyl]benzoic acid (Compound 19)

Using a technique similar to the above for the synthesis of ethyl ester of 2-fluoro-4-[(4', 4'-dimethyl-8'-brahaman-6'-yl)carbarnoyl] benzoic acid (Compound 9), but using 2,2,4,4-tetramethyl-8-IO the imposition of the C1, 55 mg, 0.30 mmol) get marked in the title compound as a white solid.1H NMR 8.05 (sh.s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.94 (t, J = 8.4 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.75 (DD, J = 12.8, 2.1 Hz, 1H), 7.33 (DD, J = 8.8, 2.1 Hz, 1H), 4.37 (K, J = 7.1 Hz, 2H), 1.89 (s, 2H), 1.42 (s, 12H), 1.38 (s, 6H).

Ethyl ester of 2-fluoro-4-[(2', 2',4',4',8'-pentamethyl-8'- iochroma-6'-yl)carbarnoyl]benzoic acid (Compound 21)

Using a technique similar to the above for the synthesis of ethyl ester of 2-fluoro-4-[(4', 4'-dimethyl-8'-brahaman-6'-yl)carbarnoyl] benzoic acid (Compound 9), but using 2,2,4,4,8-pentamethylchroman-6-carboxylic acid (Compound1, 92 mg, 0.37 mmol) and ethyl ester of 4-amino-2-fluoro-benzoic acid (Compound C1, 75 mg, 0.41 mmol) get marked in the title compound as a white solid (100 mg). 1H NMR 8.31 (sh.s, 1H), 7.90 (t, J = 8.24 Hz, 1H), 7.76 (DD, J = 14.29, 1.7 Hz, 1H), 7.74 (s, 1H), 7.43 (s, 1H), 7.35 (DD, J = 8.67, 1.7 Hz, 1H), 4.32 (K, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.84 (s, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H), 1.34 (s, 6H).

Ethyl ester of 2-fluoro-4-[(2',2',4',4'-tetramethylchroman-6'- yl)carbarnoyl]benzoic acid (Compound 23)

Using a technique similar to the above for the synthesis of ethyl ester of 2-fluoro-4-[(4', 4'-dimethyl-8'-brahaman-6'-yl)carbarnoyl] benzoic KIS is ether 4-amino-2-fluoro-benzoic acid (Compound C1, 11.2 mg, 0.06 mmol) get marked in the title compound as a colourless oil.1H NMR 7.95 (m, 2H), 7.75 (d, J = 12.75 Hz, 1H), 7.58 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.28 (DD, J = 10.6, 1.9 Hz, 1H), 4.38 (K, J = 7.1 Hz, 2H), 1.99 (s, 2H), 1.44 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H).

Ethyl ester 4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'- naphthalenyl)thiocarbamoyl]benzoic acid (Compound 25)

To a solution of ethyl ester 4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2 - naphthalenyl)carbarnoyl]benzoic acid (Compound I1, 61 mg, 0.16 mmol) in 2 ml of anhydrous benzene add the reagent Lawesson (45 mg, 0.112 mmol). The obtained yellow solution is refluxed in an atmosphere of N2within 2 hours the Solvent is removed and the residue purified via chromatography on a column (silica gel, ethyl acetate/hexane (1/5) to obtain indicated in the title compound as a yellow solid (55 mg, 87%).1H NMR 9.04 (sh.s, 1H), 8.11 (d, J = 8.70 Hz, 2H), 7.85 (sh.s, 2H), 7.75 (sh. s, 2H), 7.55 (DD, J = 8.2, 1.9 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 4.35 (K, J = 7.1 Hz, 2H), 1.71 (s, 4H), 1.40 (t, J = 7.1 Hz, 3H), 1.30 (s, 12H).

Ethyl ester of 2-fluoro-4-[(5', 6',7',8'-tetrahydro-5',5',8',8'- tetramethyl-2'-naphthalenyl)thiocarbamoyl]benzoic acid (Compound 27)

Using a technique similar to the above for the synthesis of ethyl is using the ethyl ester of 2-fluoro-4-[(5', 6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'- naphthalenyl)carbarnoyl]benzoic acid (Compound 1, 167 mg, 0.42 mmol) in 8 ml of benzene and reagent Lawesson (220 mg, 0.544 mmol), get marked in the title compound as a pale yellow solid (127.5 mg).1H NMR 9.30 (sh.s, 1H), 8.05 (sh.s, 1H), 7.95 (t, J = 8.37 Hz, 1H), 7.77 (d, J = 1.89 Hz, 1H), 7.53 (DD, J = 8.24, 2.1 Hz, 1H), 7.49 (sh.s, 1H), 7.35 (d, J = 8.24 Hz, 1H), 4.33 (K, J = 7.1 Hz, 2H), 1.71 (s, 4H), 1.32 (s, 6H), 1.30 (s, 6H).

3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-icarbonell acid (Compound L)

To a solution of 2-bromo-3-methoxyethoxy-5,5,8,8-tetrahydro-5,5,8,8 - tetramethylnaphthalene (Compound J, 722 mg, 2.2 mmol) in 10 ml of dry THF at -78oC in argon atmosphere is added slowly 2.86 ml of tert.-BuLi (1.7 M in hexane, 4.8 mmol). The reaction mixture was stirred at -78oC for 1 h and Then passed through a solution of CO2within 1 h After the cessation of current CO2the reaction mixture was stirred additionally for 1 h at -78oC. Then add 10% HCl. After reaching room temperature the reaction mixture is left to stand overnight and then extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. After concentration the residue is purified using chromatogra substances (774 g).1H NMR 7.85 (s, 1H), 6.93 (s, 1H), 1.68 (s, 4H), 1.28 (s, 12H).

4-Bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2 - inkarbaeva acid (Compound M)

3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylcarbonyl acid (Compound L, 155 mg, 0.62 mmol) dissolved in 1 ml of HOAc. To this solution add Br2(0.033 ml, 0.62 mmol). The reaction mixture is left at room temperature over night. To remove unreacted Br2passed through the reaction mixture a stream of air. The remaining solid residue was dissolved in a small amount of THF and purified by chromatography on a column (ethyl acetate/hexane 1/1) to give the desired product as a white solid.1H NMR 7.91 (s, 1H), 1.75 (m, 2H), 1.64 (m, 2H), 1.62 (s, 6H), 1.30 (s, 6H).

4-Bromo-3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8 - tetrahydronaphthalen-2-inkarbaeva acid (Compound N)

To a solution of 4-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8 - tetrahydronaphthalen-2-icarbonell acid (Compound M 233 mg, 0.71 mmol) in 6 ml of CH2Cl2add chloromethylation ether (0.162 ml, 2.1 mmol), diisopropylethylamine (0.764 ml, 4.2 mmol) and catalytic amount of tetrabutylammonium bromide. The reaction mixture is heated at 45oC Texan 1/9) to give the desired compound as a white solid (200 g). This white solid was dissolved in 20 ml EtOH. Add an aqueous solution of NaOH (0.5 ml, 1 M). The reaction mixture was stirred at room temperature overnight. EtOH is removed and to the residue add 2 ml of ethyl acetate and 3 ml of water. This mixture is slowly acidified with 10% HCl to pH 7. An ethyl acetate layer is separated and washed with brine, dried over Na2SO4. After filtering off the drying agent and removal of the solvent receive indicated in the title compound as a white solid (155 g).1H NMR 7.99 (s, 1H), 6.93 (s, 1H), 5.20 (s, 2H), 3.66 (s, 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 (s, 6H).

Ethyl ester of 2-fluoro-4-[(3'-methoxyethoxy-4'-bromo-5',6',7',8'- tetrahydro-5', 5', 8', 8'-tetramethyl-2'-naphthalenyl)carbarnoyl] benzoic acid (Compound S1)

To a solution of 4-bromo-3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8 - tetrahydronaphthalen-2-icarbonell acid (Compound N, 80 mg, 0.22 mmol) in 4 ml of CH2Cl2add DMAP (60 mg, 0.26 mmol), ethyl ester of 2-fluoro-4-aminobenzoic acid (Compound C1, 43 mg, 0.24 mmol) and EDC (50 mg, 0.26 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated to dryness. The residue is purified by chromatography on a column (ethyl acetate/hexane 1/3) to receive the J = 8.4 Hz, 1H), 7.81 (DD, J = 12.9, 1.9 Hz, 1H), 7.35 (DD, J = 8.5, 1.8 Hz, 1H), 5.20 (s, 2H), 4.39 (K, J = 7.1 Hz, 2H), 3.61 (s, 3H), 1.74 (m, 4H), 1.64 (m, 2H), 1.60 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H).

Methyl ether 2.6-debtor-4-[(3'-methoxyethoxy-4'-bromo-5', 6', 7',8'- tetrahydro-5', 5',8',8'-tetramethyl-2'-naphthalenyl)carbarnoyl]benzoic acid (Compound M1)

Using a technique similar to the above for the synthesis of ethyl ester of 2-fluoro-4-[(3'-methoxyethoxy-4'-bromo-5',6',7',8'-tetrahydro- 5',5',8',8'-tetramethyl-2'-naphthalenyl)carbarnoyl] benzoic acid (Compound S1), but using 4-bromo-3-methoxyethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2 - icarbonell acid (Compound N, 80 mg, 0.22 mmol), DMAP (60 mg, 0.26 mmol), methyl ester of 2,5-debtor-4-aminobenzoic acid (Compound H1, 52 mg, 0.24 mmol) and EDC (50 mg, 0.26 mmol) are indicated in the title compound as a clear oil.1H NMR 10.01 (sh. s, 1H), 8.11 (s, 1H), 7.42 (d, J = 10.0 Hz, 2H), 5.2 (s, 2H), 3.95 (s, 3H), 3.63 (s, 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.35 (s, 6H).

A General method of obtaining derivatives of benzoic acid by hydrolysis of the corresponding methyl and ethyl esters.

To a solution of ester (3.0 mmol) in 20 ml EtOH add 5 ml of 1 N NaOH in water. The reaction mixture was stirred at room temperature for normalny layer further washed with NaHCO3(saturated solution), brine and dried over MgSO4. After concentration of the desired carboxylic acid is isolated and, if necessary, recrystallized from ethyl acetate or acetonitrile.

2-Fluoro-4-[(5', 6', 7', 8'-tetrahydro-5',5',8',8'-tetramethyl-2'- naphthalenyl)carbarnoyl]benzoic acid (Compound 2)

1H NMR (acetone-D6) 9.86 (sh.s, 1H), 7.95 (m, 3H), 7.75 (DD, J = 7.9, 2.2 Hz, 1H), 7.62 (DD, J = 8.5, 1.6 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 1.73 (s, 4H), 1.32 (s, 6H), 1.30 (s, 6H).

4-[(3'-Fluoro-5', 6', 7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'- naphthalenyl)carbarnoyl]benzoic acid (Compound 4)

1H NMR (acetone-D6) 9.50 (sh.s, 1H), 8.04 (sh.s, 2H), 7.90 (sh.s, 2H), 7.78 (d, J = 7.81 Hz, 1H), 7.19 (d, J = 12.3 Hz, 1H), 1.72 (s, 4H), 1.30 (s, 12H).

2-Fluoro-4-[(4'-bromo-5',6',7',8'-tetrahydro-5',5',8',8'- tetramethyl-2'-naphthalenyl)carbarnoyl]benzoic acid (Compound 6)

1H NMR (acetone-D6) 9.97 (sh.s, 1H), 8.04 (d, J = 1.89 Hz, 1H), 8.01 (d, J = 1.90 Hz, 1H), 7.95 (t, J = 8.55 Hz, 1H), 7.90 (DD, J = 12.28, 2.0 Hz, 1H), 7.59 (DD, J = 8.67, 1.50 Hz, 1H), 1.76 (m, 4H), 1.58 (s, 6H), 1.35 (s, 6H).

2-Fluoro-4-[(3'-hydroxy-5', 6',7',8'-tetrahydro-5',5',8',8'- tetramethyl-2'-naphthalenyl)carbarnoyl]benzoic acid (Compound 8)

1H NMR (acetone-D6) 11.3 (sh.s, 1H), 10.2 (sh.s, 1H), 7.94 (m, 2H), 7.85 (DD, J = 11.4, 1.95 Hz, 1H), 7.53 (DD, J = 6.59, 2.08 Hz, 1H), 6.94 (s, 1H), 2.85 (sh.s, 1H), 1.70 (E 10)

1H NMR (acetone-d6) 9.87 (sh.s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.94 (t, J = 8.66 Hz, 1H), 7.91 (DD, J = 13.8, 2.0 Hz, 1H), 7.57 (DD, J = 8.6, 2.0 Hz, 1H), 4.37 (t, J = 5.44 Hz, 2H), 1.92 (t, J = 5.44 Hz, 2H), 1.40 (s, 6H).

2-Fluoro-4-[(2', 2', 4', 4'-tetramethyl-8'-brahaman-6'- yl)carbarnoyl]benzoic acid (Compound 12)

1H NMR (acetone-d6) 9.87 (sh.s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.94 (t, J = 8.54 Hz, 1H), 7.91 (DD, J = 14.0, 2.0 Hz, 1H), 7.59 (DD, J = 8.5, 2.3 Hz, 1H), 1.96 (s, 2H), 1.42 (s, 6H), 1.41 (s, 6H).

2-Fluoro-4-[(2',2',4',4'-tetramethyl-8'-cryptomelane-6'- yl)carbarnoyl]benzoic acid (Compound 14)

1H NMR (acetone-d6) 10.02 (sh.s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.92 (m, 2H), 7.56 (d, J = 7.69 Hz, 1H), 2.00 (s, 2H), 1.44 (s, 6H), 1.41 (s, 6H).

2-Fluoro-4-[(2', 2', 4',4'-tetramethyl-8'-azithromy-6'- yl)carbarnoyl]benzoic acid (Compound 16)

1H NMR 8.03 (t, J = 8.4 Hz, 1H), 7.87 (W.s, 1H), 7.79 (DD, J = 13, 2.0 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.32 (DD, J = 8.66, 1.9 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 1.91 (s, 2H), 1.45 (s, 6H), 1.41 (s, 6H).

2,6-Debtor-4-[(2', 2', 4', 4'-tetramethyl-8'-cryptomelane-6'- yl)carbarnoyl]benzoic acid (Compound 18)

1H NMR (acetone-d6) 8.30 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 10.32 Hz, 1H), 1.954 (s, 2H), 1.44 (s, 6H), 1.41 (s, 6H).

2-Fluoro-4-[(2', 2',4',4'-tetramethyl-8'-iochroma-6'- yl)carbarnoyl]benzoic acid (Soy is 12H).

2-Fluoro-4-[(2', 2', 4', 4', 8'-pentamethylchroman-6'-yl)carbarnoyl]benzoic acid (Compound 22)

1H NMR (acetone-d6) 9.77 (sh.s, 1H), 7.90 (m, 3H), 7.65 (d, J = 2.0 Hz, 1H), 7.56 (DD, J = 8.61, 2.0 Hz, 1H), 2.19 (s, 3H), 1.90 (s, 2H), 1.38 (s, 6H), 1.37 (s, 6H).

2-Fluoro-4-[(2', 2', 4', 4'-tetramethylchroman-6'-yl)carbarnoyl] benzoic acid (Compound 24)

1H NMR 7.95 (m, 2H), 7.75 (d, J = 12.75 Hz, 1H), 7.58 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.28 (DD, J = 10.6, 1.9 Hz, 1H), 1.99 (s, 2H), 1.44 (s, 6H), 1.42 (s, 6H).

4-[(5', 6', 7', 8'-Tetrahydro-5', 5', 8', 8'-tetramethyl-2'-naphthalene-2'- yl)thiocarbamoyl]benzoic acid (Compound 26)

1H NMR 9.08 (sh.s, 1H), 8.17 (d, J = 8.61 Hz, 2H), 7.95 (sh.s, 2H), 7.77 (sh. s, 1H), 7.57 (DD, J = 8.1, 2.1 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 1.72 (s, 4H), 1.32 (s, 6H), 1.31 (s, 12H).

2-Fluoro-4-[(5', 6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'- naphthalene-2'-yl)thiocarbamoyl]benzoic acid (Compound 28)

1H NMR (acetone-d6) 11.1 (sh.s, 1H), 8.27 (d, J = 13.2 Hz, 1H), 8.02 (t, J = 8.3 Hz, 1H), 7.89 (s, 1H), 7.86 (d, J = 10.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.37 Hz, 1H), 1.72 (s, 4H), 1.30 (s, 12H).

2-Fluoro-4-[(3'-hydroxy-4'-bromo-5', 6',7',8'-tetrahydro-5',5',8',8'- tetramethyl-2'-naphthalenyl)carbarnoyl]benzoic acid (Compound 34)

A solution of ethyl ester of 2-fluoro-4-[(3'-methoxyethoxy-4'-bromo-5',6',7', 8'-tetrahydro-5',5',8',8'- tetramethyl-2'-naphthalenyl)carbarnoyl]benzoic acid is peremeshivayte at room temperature overnight and acidified to pH 1 with 10% HCl. EtOH is removed and the solution was added ethyl acetate and a lot of water. The organic layer is separated and washed with NaHCO3, brine and dried over MgSO4. After filtration and concentration get 2-fluoro-4-[(3-methoxyethoxy-4'-bromo-5', 6', 7',8'-tetrahydro- 5',5',8',8'-tetramethyl-2'-naphthalenyl)carbarnoyl]benzoic acid as a white solid. Methoxymethyl group is removed by dissolving the white solid substance in 2 ml of MeOH with 3 drops of HCl (conc.). After stirring over night the reaction mixture was concentrated to dryness. The residue is distributed between ethyl acetate and water. The organic layer is separated and washed with NaHCO3, brine and dried over MgSO4. After filtration and concentration of the solid residue purified on minicrane (pipette) using ethyl acetate/hexane (1/1) to obtain the indicated in the title compound as a white solid (5.0 mg).1H NMR (acetone-d6) 10.19 (sh.s, 1H), 8.01 (s, 1H), 7.96 (t, J = 8.6 Hz, 1H), 7.76 (DD, J = 11.2, 2.0 Hz, 1H), 7.54 (DD, J = 8.8, 2.0 Hz, 1H), 1.75 (m, 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.32 (s, 6H).

2,6-Debtor-4-[(3'-hydroxy-4'-bromo-5', 6', 7', 8'-tetrahydro- 5',5',8', 8'-tetramethyl-2'-naphthalenyl)carbarnoyl]benzoic acid (Compound 36)

Using a technique similar to the above for the synthesis of 2-fluoro what s 34) get marked in the title compound as a white solid.1H NMR (acetone-d6) 10.23 (W. s, 1H), 8.01 (s, 1H), 7.52 (d, J = 10.2 Hz, 2H), 4.8 (sh.s, 1H), 1.75 (m, 2H), 1.65 (m, 2H), 1.60 (s, 6H), 1.31 (s, 6H).

2,6-Debtor-4-[(5', 6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'- naphthalenyl)carbarnoyl]benzoic acid (Compound 38)

To 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaleneboronic acid (43 mg, 0.19 mmol) was added 1 ml of thionyl chloride. This mixture is refluxed for 2 hours. The excess thionyl chloride is removed under reduced pressure and the residue is dissolved in 2 ml of CH2Cl2. To this solution was added methyl ether 4-amino-2,6-diferential acid (Compound H1, 7 mg, 0.2 mmol) and then 0.5 ml of pyridine. The reaction mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The residue is purified by chromatography on a column (ethyl acetate/hexane (1/5) and receive a methyl ester of the desired product as a colorless oil. 1H NMR 8.11 (d, J = 1.9 Hz, 1H), 8.05 (sh.s, 1H), 7.86 (DD, J = 6.2, 2.2 Hz, 1H), 7.41 (m, 3H), 3.93 1.69 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H). It is a colourless oil, hydrolized to the desired product using NaOH/H2O/EtOH according to the General method. 1H NMR (acetone-d6) 9.74 (sh.s, 1H), 7.95 (s, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 3H), 1.71 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H).

the lots (Compound 29)

Using a technique similar to the above for the synthesis of Compounds 1, but using Compound F and Compound1receive the desired product as a white solid.1H NMR 9.24 (sh.s, 1H), 9.23 (d, J = 1.8 Hz, 1H), 7.92 (DD, J = 8.4, 2.4 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.58 (s, 6H), 1.33 (s, 6H).

2-Nitro-4-[(4'-bromo-5',6',7',8'-tetrahydro-5',5',8',8'- tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid (Compound 30)

1H NMR 10.16 (sh.s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.09 (DD, J = 8.6, 2.1 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 1.75 (m, 2H), 1.65 (m, 2H), 1.57 (s, 6H), 1.34 (s, 6H).

Values of Kdto:

Connection 2: Kdfor RAR, RAR, RARaccordingly: 326; > 1K; >1K

Connection 3: Kdfor RAR, RAR, RARaccordingly: 2868; >10K; >10K

Compound 4: Kdfor RAR, RAR, RARaccordingly: 33; 2481; 5691

Compound 7: (Kdfor RAR, RAR, RARaccordingly: 44; >1K; >1K

All tables and figures are at the end of the description.

1. The compound of formula 1

< / BR>
where X is S, O;

X is [C(R1)2]nwhere n means an integer from 0 to 2;

R1means the scrap of carbon atoms from 1 to 6;

R3means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6;

m means an integer from 0 to 2;

means an integer from 0 to 4;

p is an integer from 0 to 2;

r is an integer from 0 to 2, provided that when Z denotes O, the sum of p, at least, means 1, and r, at least, means 1 and (W)pis not a single alkyl group;

Y represents phenyl or pyridyloxy group, which possibly have as a substituent one or two groups R2;

W means the Deputy selected from the group consisting of F, Br, Cl, J, C1-6of alkyl, fluoro-substituted C1-6of alkyl, NO2N3, OH, OCH2OCH3;

L is -(C=Z)-NH - or HN-(C=Z)-;

Z denotes O or S;

A means (CH2)q, where q = 0 to 5;

B means COOH or its pharmaceutically acceptable salt, COOR8, R8means alkyl group with carbon atoms of 1 to 10.

2. Connection on p. 1, in which Y represents phenyl.

3. Connection on p. 2, in which the phenyl group is 1,4 - positions as Vice-groups L and A-B.

4. Connection on p. 1, in which Y represents pyridyl.

5. Connection on p. 4, in which Y soda is[C(R1)2]nand n = 1.

7. Connection on p. 1, in which X stands for o

8. Connection on p. 1, in which X is S.

9. Connection on p. 1, in which A-B stands for (CH2)q-COOH or its pharmaceutically acceptable salt, (CH2)q-COOR8.

10. Connection on p. 1, in which the Deputy W in the group Y is selected from the group consisting of F, NO2, Br, J, CF3N3and OH.

11. Connection on p. 1, in which the Deputy W in a condensed cycle is selected from the group consisting of F, NO2, Br, J, CF3N3and OH.

12. Connection on p. 1, in which Z signifies O.

13. The connection formulas

< / BR>
where R1means independently H or alkyl with the number of carbon atoms from 1 to 6;

R2means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6;

R3means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6;

o is an integer from 0 to 4;

W1, W2, W3and W4each independently selected from the group consisting of H, F, Br, Cl, J, CF3, NO2N3, OH, OCH2OCH3and C1- C6of alkyl, provided that when Z denotes O, at least one of the groups W1appoints O or S;

A means (CH2)qwhere q = 0-5;

B means COOH or its pharmaceutically acceptable salt, COOR8,

R8means alkyl group with carbon atoms of 1 to 10.

14. Connection on p. 13, in which q = 0.

15. Connection on p. 14, in which R1means CH3, R2means H and R3means H.

16. Connection on p. 15 in which Z signifies O.

17. Connection on p. 16, in which B means COOR8.

18. Connection on p. 17, which is:

ethyl ester of 2-fluoro-4-[(5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

ethyl ester of 4-[(3'-fluoro-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(4'-bromo-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(3'-hydroxy-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(3'-hydroxy-4'-bromo-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2,6-debtor-4-[(3'-hydroxy-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-the Talin-2'-yl)carbarnoyl]benzoic acid.

19. Connection on p. 16, in which B denotes COOH or its pharmaceutically acceptable salt.

20. Connection on p. 19, which is:

2-fluoro-4-[(5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

4-[(3'-fluoro-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

2-fluoro-4-[4'-bromo-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

2-fluoro-4-[(3'-hydroxy-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

2-fluoro-4-[(3'-hydroxy-4'-bromo-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid;

2,6-debtor-4-[(3 hydroxy-5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid; or

ether 2,6-debtor-4[(5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)carbarnoyl]benzoic acid.

21. Connection on p. 15 in which Z signifies S.

22. Connection on p. 21, which is:

ethyl ester 4-[(5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)thiocarbamoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)thiocarbamoyl]benzo

2-fluoro-4-[(5', 6', 7', 8'-tetrahydro-5', 5', 8', 8'-tetramethylnaphthalene-2'-yl)thiocarbamoyl]benzoic acid.

23. The connection formulas

< / BR>
where R1means independently H or alkyl with the number of carbon atoms from 1 to 6;

R2means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6;

W1, W2, W3and W4each Deputy is independently selected from the group consisting of H, F, Br, Cl, I, CF3, NO2N3, OH, OCH2OCH3OC1-10the alkyl and C1- C6of alkyl, provided that when Z denotes O, then at least one of the groups W1, W2, W3and W4- groups is not H, and with the additional proviso that, when Z denotes O and X is O, then W2doesn't mean Cl;

X represents O or S;

Z denotes O or S;

A means (CH2)qwhere q is 0 to 5; and

B means COOH or its pharmaceutically acceptable salt, COOR8,

R8means alkyl group with carbon atoms of 1 to 10.

24. Connection on p. 23, in which A means (CH2)qand q = 0, and where B denotes COOH or its pharmaceutically acceptable salt, COOR8.

25. Connection on p. 24, in which R1means NASA. Connection on p. 26, in which B means COOR8.

28. Connection on p. 27, which is:

ethyl ester of 2-fluoro-4-[(2', 2', -4', 4'-tetramethyl-8'-brahaman-6'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(2', 2', -4', 4'-tetramethyl-8 cryptomelane-6'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(2', 2', -4', 4'-tetramethyl-8'-azithromy-6'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2,6-debtor-4-[(2', 2', -4', 4'-tetramethyl-8 cryptomelane-6'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(2', 2', -4', 4'-tetramethyl-8 iochroma-6'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(2', 2', -4', 4',8'-pentamethylchroman-6'-yl)carbarnoyl]benzoic acid;

ethyl ester of 2-fluoro-4-[(2', 2', -4', 4'-tetramethylchroman-6'-yl)carbarnoyl]benzoic acid; or

ethyl ester of 2-fluoro-4-[(8'-bromo-4', 4'-DIMETHYLPROPANE-6'-yl)carbarnoyl] benzoic acid.

29. Connection on p. 26, in which B denotes COOH or its pharmaceutically acceptable salt.

30. Connection on p. 29, which is:

2-fluoro-4-[(2', 2', -4', 4'-tetramethyl-8'-brahaman-6'-yl)carbarnoyl]benzoic acid;

2-fluoro-4-[(2', 2', -4', 4'-tetramethyl-8'-cryptomelane-6'-yl)carbarnoyl]benzoic acid(2', 2', -4', 4'-tetramethyl-8'-cryptomelane-6'-yl)carbarnoyl]benzoic acid;

2-fluoro-4-[(2', 2', -4', 4'-tetramethyl-8'-iochroma-6'-yl)carbarnoyl]benzoic acid;

2-fluoro-4-[(2', 2', -4', 4', 8'-pentamethylchroman-6'-yl)carbarnoyl]benzoic acid;

2-fluoro-4-[(2', 2', -4', 4'-tetramethylchroman-6'-yl)carbarnoyl]benzoic acid; or

2-fluoro-4-[(8'-bromo-4', 4'-DIMETHYLPROPANE-6'-yl)carbarnoyl] benzoic acid.

 

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The invention relates to new heterocyclic condensed to benzoylpyridine General formula I, where R1and R2denote independently from each other H or A; X denotes CR4R5; C=Z or O, Y represents CR6R7Z denotes O or CH2, R4, R5, R6or R7denote independently from each other H, A, HE or OA, or R5and R6or R7and R8indicate link together, with each molecule may receive a maximum of only one such bond, or R4and R5indicate together O-(CH2)2-O or O-(CH2)3-O, or R8and R9denote independently from each other H or A; And denotes alkyl with 1 to 6 C-atoms; n represents 0 or 1, and their physiologically acceptable salts

The invention relates to non-steroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds
The invention relates to medicine, namely to methods for treating incurable forms of cancer

The invention relates to a derivative of oxazolidin-2-it General formula (I):

< / BR>
where X is O,

Y denotesor

< / BR>
R1indicatesor< / BR>
R2and R3each, independently of one another, denotes H, A or benzyl;

A denotes alkyl with 1-6 C-atoms;

D denotes amidinopropane, aminomethyl, aminohydrocinnamic, 5-methyl-1,2,4-oxadiazolidine-3-yl or guanidinate;

r and s independently of one another denote 0, 1, 2, 3 or 4;

however, if necessary, free amino - or amidinopropane can be protected partially or fully protective for the amino function groups, as well as their enantiomers, diastereomers and physiologically acceptable salts

The invention relates to medicine and is a method of prevention and/or treatment of autoimmune diseases, including the introduction of an effective amount of pharmaceutically acceptable salt or complex of magnesium

New peptides // 2162855

The invention relates to medicine, namely to radiopharmaceutical drugs containing a radionuclide samarium-153, and may be used for the treatment of metastases of malignant tumors in the bones and rheumatoid arthritis

The invention relates to a recombinant adenovirus expression vectors, characterized by partial or complete deletion of the DNA fragment of adenovirus encoding the protein IX, and containing the gene of a foreign protein, or a functional fragment or mutant form

The invention relates to medicine, in particular to cancer, and for the treatment of cancer and prevention of its metastases
The invention relates to medicine, namely to pharmaceutical compositions for removal of benign growths on the skin and mucous membranes (papillomas, warts, nevi, warts, cutaneous cysts, xantom, atheroma, angiomas, keloid scars, as well as cervical erosion), and methods of obtaining such funds

The invention relates to pharmaceutical industry and can be used in medical institutions and in the home as a remedy to stop bleeding during surgical interventions, as well as in industrial and domestic injuries
Remedy // 2161503
The invention relates to medicine and relates to means for treating diseases, extreme inflammation, pus and necrotic tissue, and also accompanied by changes in the structure of tissues

The invention relates to the field of medicine and for the connection of rationale, malonic dialdehyde acid and any factor affecting the intracellular content of rationale or malonic dialdehyde acid as a drug to modulate the phenomenon of programmed cell death (apoptosis)
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