Derivatives substituted benzoylbenzoate - or 2 - oxazolidinone acid or their pharmacologically acceptable salts and method of production thereof

 

(57) Abstract:

Usage: in medicine, in as matter-of leukotriene antagonists and inhibitors of lipoxygenase. The essence of the invention: derivatives of substituted benzoyl-, biphenyl -, or 2-oxazolidinone acid f-ly I: A (CH2)nO - B, where A group f-ly I, where X Is N or C(R3)-; or-S-, provided that when X is C(R3)-, Z or lower alkyl, n is 1 or 2, b - group, f-l II, III, IV, V, where R4, R5, R6, R7m have the respective meanings or their salts. Connection f-ly I receive the interaction of compounds f-ly HO2-B connection f-crystals of A(CH2)n-X, where X is tsepliaeva group. Structure f-l II, III, IV, V (see drawing). 2 C. and 8 C.p. f-crystals, 1 Il. , 6 PL.

The invention relates to new derivatives substituted benzoylbenzene-, biphenyl - 2-oxazolidinone acid, which has inhibitory activity against lipoxygenase, phospholipase A2and which are leukotriene antagonists; derivatives, which are suitable for use as anti-inflammatory, antiallergic agents, as well as protectors.

Now firmly established that the metabolism of arachidonic acid (AA) genasi leads to the formation of prostaglandins and thromboxanes. It is known that prostaglandins are formed from endoperoxides GG2and PGH2in the process of arachidonic acid metabolism caused by cyclooxygenase. These endoperoxide are also precursors of thromboxanes (Tx/A2and IN2. Tha2this vasoconstrictor), a vasoconstrictor agent, stimulating the aggregation of platelets. In the normal state vasoconstrictor properties and ability to induce aggregation of platelets by thromboxanes balanced by another product that is formed from endoperoxides in cyclooxygenase cycle, prostacyclin (PGI2), which represents vasodilator (vasodilator agent), with the ability to suppress (inhibit) the aggregation of platelets. In case of reduction of prostacyclin synthesis and/or increased activity of platelets observed thrombosis and vasoconstriction (narrowing of blood vessels. The role of prostanoids in hemostasis and thrombosis is discussed in P. I. Gryglewski, CRC Crit. Rev. Biochem. 7, 291 (1980) and I. B. Smith, Am.I.Pathol 99, 743 (1980). It is known that cyclooxygenase metabolites are directly involved in the response to inflammation (see Higgs and other Aiossa Peeac, 16, 287-299, 1984). This is manifested through their vasodilator activity, their participation in avelini edema. Finally, various aspects of cell-mediated immunity associated with cyclooxygenase products.

Another direction (cycle) AA metabolism includes the enzymes lipoxygenase and leads to the formation of several oxidized products, called leukotrienes. The latter denote LT nomenclature system, and the most important products lipoxygenase cycle metabolism of AA to leukotrienes are IN4WITH4and D4. It was found that the substance, indicating a slow-acting component of anaphylaxis (SRS-A) is a mixture of leukotrienes, LTC4and LTD4as the primary product and containing various amounts of other leukotriene metabolites (Bach, etc. I. Immunology 215, 115-118, 1980, Biochem. Biophys. Res, Commun. 93, 1121-1126, 1980).

The value of these leukotrienes, confirmed by a large number of facts, is that these leukotrienes are involved in inflammatory reactions, exhibit chemotactic activity, stimulate lysosomal secretion (secretion) of the enzyme and act as an important factor in the immediate allergic reaction. It is established that LTC4and LTD4it is an effective bronchoconstrictor human bronchi (see Dahlen and other Nature 288, 484-48 Am. Rev. Resp. Dis. 126, 449, 1982), they are also potent factors sosudorasshiratmi in the skin (see Bisgaard and other Prostaglandins 23, 797, 1982) and is responsible for the formation of blisters and sudden exacerbation of the disease (Camp and other Br. I. Pharmacol. 80, 497, 1983). Ones leukotrien, LTB4this potent chemotactic factor for leukocytes (see A. W. Ford-Hutchinson, I. Roy Soc. Med. 74, 831-833, 1981), stimulating the accumulation of cells and affecting the vascular smooth muscle (see Bray, Br. Med. Bull. 39, 249, 1983). The activity of leukotrienes as mediators of inflammation and Allergy broadly confirmed by the data review Bailey and Casey Ann. Reports. Med. Chem. 19, 87, 1986).

The phospholipase a2(LAF2this enzyme, which determines the speed of the process cycle arachidonic acid, because he is responsible for the hydrolysis of ester bonds of AA from phospholipids in the C-2 position of membrane. As a result of this hydrolysis produces two products (1)-free arachidonic acid (AA), which becomes available for further metabolism or cyclooxygenase direction or lipoxygenase direction, and (2) lysophospholipid. The action on the LAF2alkylamidopropylamine initiated education trombozitarnoe be noted, that, apparently, anti-inflammatory steroids inhibit eicosanoid synthesis due to the fact that induce protein synthesis, inhibition LAF2denoted as macrocortin or lipomodulin (see Flower and other Nature, London, 278, 456, 1979 and Hirata, etc. Proc. Nat. Acad. Sci. USA, 77, 2533, 1980).

As the initial stage, leading to the subsequent conversion of AA in various eicosanoids in cyclooxygenase and lipoxygenase directions, allocation of AA from membrane phospholipids catalyzed LAF2that is a stage that determines the course of various physiological manifestations associated with the activity of eicosanoids and/or TAF. As FLF2as it was found necessary to aggregate platelets (Pickett and others Biochem. I. 160, 405, 1976), contraction of the cardiac muscle excitation (Geisler and others Pharm. Res. Commun. 9, 117, 1977), as well as the synthesis of prostaglandins (Vogt. Adv. Prostagl. Thromb. Res. 3, 89, 1978), the inhibition LAF2associated with a therapeutic effect on the physiological effects of the TAF or products cyclooxygenase and/or lipoxygenase metabolism of AA.

There is also evidence that the products cyclooxygenase (lipoxygenase) metabolism play Klucevsek, microorganisms, etc.,) or intracellular (ischemia, viruses, and so on) agents, and in the protection of cells against such destruction. Thus, on the one hand, prostaglandins are chitosamine action in respect of the gastric mucosa (see Robert, Gastroenterology, 77, 761-767, 1979), and this action of prostaglandins, especially the E series is considered as an important factor in the treatment of gastrointestinal ulcers (see Isselbacher, Drugs 33, (Mgr.) 38-46, 1987). On the other hand, ex vivo experiments show that the fabric of the gastric mucosa of rats pre-treated with ethyl alcohol, is able to generate LTC4and that is the production of LTC4quantitatively associated with the severity of the destruction caused by ethanol (see Lange and other Naunyn Schmiedeberg Arch. Pharmacol. Suppl. 330, P 27, 1985). It was also shown that LTC4can induce constriction of both venous and arteriolar vessels in the submucosa of rats (see Whittle, IUPHAR, 9th Int. Cong. of Pharm. S 30-2, London, England, 1984). This is very important because the lesion mucous membrane, caused by ethyl alcohol, may be multifactorial in nature, for example, may be associated with stasis of blood flow in the stomach, contributing a significant share to the development of hemorrhagic necrotic processes affected (burnt tissue) (see Guth and d is crazii pepsin, and reducing transcluding potential (Pendleton and others, Eur. J. Pharmacol. 125, 297-99, 1986). In this connection we should mention significant, recently established fact, inhibitors of 5-lipoxygenase and some antagonists of leukotrienes protect gastric mucosa from damage caused by oral or parenteral introduction of the most anti-inflammatory drugs non-steroidal nature (see Rainsford, Agentsand Actions, 21, 316-319, 1987). Platelet activating factor have also been implicated as a mediator, gastrointestinal damage, and recently it was found that inhibitors of 5-lipoxygenase inhibit induced TAF, lesions of the gastric mucosa (Gastroenterology, 96, A55, A, 1989). Thus a significant part of the evidence indicates the involvement products lipoxygenase activity in the development of pathological symptoms associated with lesions of the gastric mucosa, such as those caused by the action of ethyl alcohol and taking anti-inflammatory drugs non-steroidal nature. Compounds that inhibit the biological action of leukotrienes and TAF and/or control the biosynthesis of these substances, for example, by inhibiting 5-lipoxygenase, are considered as substances predstavlaete and SRS, and lipoxygenase as enzyme, causing the metabolism of AA to leukotrienes indicates that the rational selection of drug therapy to prevent, suppress or improve the symptoms of allergies, anaphylaxis, asthma and inflammation, as well as gastric protectors should be based either on the block allocation mediators mediators such States, or on the counter their influence. Compounds that inhibit the biological action of leukotrienes and SRS and/or control the biosynthesis of these substances, for example, by inhibiting the LAF2participating in the allocation of arachidonic acid from the phospholipids of the membrane, or by inhibiting lipoxygenase, are considered as the substance of value as drugs used in the treatment of allergic bronchial asthma, allergic rhinitis, as well as other intermediate allergic reactions, and also in ensuring cytotoxity stomach.

It is now established that some new derivatives of benzoylbenzene-, biphenyl - 2-oxazolidinone acid inhibit LAF2and lipoxygenase and counteract the effect of foods lipoxygenase nah, antiallergic and cytotoxity funds. The invention provides new compounds of the following formula: A/CH2/nO-B, in which this phenoxyethyl, phenoxyphenyl or a group of the formula

in which X is-N - or R3Z it = = N, N , , -S - or-0-

R1is hydrogen, lower alkyl or phenyl;

R2is hydrogen or lower alkyl; or R1and R2combined together, form a benzene ring; R3is hydrogen or lower alkyl;

n is 1-2; this

< / BR>
(CH2)mCOOR5or (CH2)mCOOR5< / BR>
in which R4and R5each, independently of one another, represents hydrogen or lower alkyl; R6this halogen or nitro group; R7this is R8or-COOR5R8this is lower alkyl; m is 0-3; and pharmacologically acceptable salts of these compounds.

The term "lower alkyl" refers to groups containing 1-6 carbon atoms in the chain. The term "halogen" refers to fluorine, chlorine or bromine.

Group And covers, interalio, 5 - or 6-membered unsaturated nitrogen-, sulfur - or oxygen-containing mono - or benzododecinium heterocycles, possibly substituted lower alkyl or phenyl. Under the previous apredator, pyridyl, pyrazinyl, pyrimidinyl, benzofuranyl, benzothiazol, benzothiazolyl, indolyl, benzoxazolyl, chinoline, benzimidazolyl, honokalani, hintline, etc., the Most preferred chinoline, benzothiazolyl and benzimidazolyl.

Compounds of the invention can form pharmaceutically acceptable salts with pharmacologically acceptable organic and inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, Mamonova, amber, methansulfonate, sulfonic acid, acetic, propionic, tartaric, citric, malic, lactic, almond, cinnamic, palmitic, taconova acid and benzosulfimide. Compounds which are carboxylic acids capable of forming alkali metal salts and carboxylates of alkali-earth metals, as well as the carboxylates pharmacologically acceptable cations derived from ammonia or primary amines. The latter include, but are not limited to these examples, ammonium ion, a mono-, di -, and ammonium, mono-, di - and triethylammonium, benzyldimethylamine, cyclohexylamine, benzylamine, dibenzylamine, piperidinylidene, 1,4-dimethylpiperazine, 1-n-butylpiperazine, 2-methylpiperidine, 1-ethyl-2-methylpiperidine, mono-, di - and triethanolammonium, ethyldimethylamine, n-butylanthraquinone, Tris(hydroxymethyl)methylammonium, phenyleneethynylene etc.

Compounds of the invention can be obtained according to the following reaction schemes. When it is necessary to obtain the connection formula

A(CH2)nO reaction is subjected to 4-methoxybenzonitrile with 3-bromolla, then the compound obtained bromilow in Eilenriede and receive the intermediate compound 3-bromomethyl-4-methoxy benzophenone.

< / BR>
The obtained bromo derivatives are then subjected to reaction with sodium cyanide, resulting in a receive intermediate product cyanoderivatives, which is hydrolized in the presence of a base and get a carboxylic acid, which will Demetriou and get hydroxycarbonate acid

< / BR>
CH3O< / BR>
< / BR>
< / BR>
The obtained intermediate product hydroxycarbonate acid is transformed into methyl ester when interacting with methyl alcohol in the presence of para-toluenesulfonic acid, then treated with a compound corresponding alkyl halide in which the value is determined by inhibiting ester may be hydrolyzed by conventional methods, the result is the desired product in the form of the free carboxylic acid.

Compounds of the invention of formula

A(CH2)nO R6this is the nitro-group, and R7this is C-R8can be obtained as follows, for example, 4-bromo-3-nitroacetophenone start to react with 4-iodoanisole in the presence of copper bronze, as a result of this reaction receive the intermediate methoxyestradiol biphenyl, which then Demetriou aluminum bromide and get hydroxyprogesterone connection. Then it will start to react with a compound corresponding haloalkyl And which is As defined above, Hal is halogen and get the final desired product.

< / BR>
< / BR>
Compounds in which R6it is a halogen and R7this CHCOOR6can be obtained according to the method that uses a 4-methoxyphenylacetamide intermediate compound obtained in the previous diagram. 4-Acetyl-4-methoxy-2-nitrobiphenyl intermediate product in the previous diagram restore chloride divalent tin and receive an intermediate product of amino, in which then the amino group is substituted by halogen. For example, the amino group may be substituted with fluorine cher wodnego when interacting with sodium nitrite in the presence of tetrafluoroboric acid. The resulting acetylgalactosamine then converted into the corresponding carboxylic acid by demethylation of methyl hydrogen and receive the 2-fluorescent-4-hydroxy-1,1-biphenyl-4-acetic acid

< / BR>
The last intermediate connection carboxylic acid etherification with methanol in the presence of para-toluenesulfonic acid, the resulting product then communicates with the appropriate connection haloalkyl And in which As defined above, and Hal is halogen, the result is the desired product in the form of methyl ester

< / BR>
The resulting ester can be hydrolyzed with traditional ways of obtaining the desired product in the form of a carboxylic acid.

Compounds of the invention of formula

(CH2)mCOOR5or (CH2)mCOOR5< / BR>
can be obtained as follows. In reaction run benzaldehyde and 4-methoxybenzaldehyde and receive a 4-methoxybenzoyl, which is then converted into polosukhina by reaction with succinic anhydride. Polosukhina then run into the reaction with urea and acetic acid, and receive the intermediate product 4-(4-methoxyphenyl)-5-phenyl-2-oxalylamino acid

< / BR>
The last intermediate progeny product, which is then subjected to reaction with the corresponding connection alkyl halide And in which As defined above, Hal is halogen, and get the desired end product in the form of methyl ester

CH2COOH

The resulting ester can be hydrolyzed with traditional ways of obtaining the desired end product in the form of a carboxylic acid.

Relevant source materials used in the reaction schemes above, are commercially available or can be synthesized according to methods well known to specialists in this field. For example, the intermediate compound 2-bromomethylphenyl can be obtained in accordance with the following reaction scheme

< / BR>
Benzododecinium heterocyclic compounds used in the above sequence of reactions, can also be commercially available or can be obtained by known methods. For example, derivatives such as 1-methyl-2-chloromethylbenzene, 2-chloromethylthiazole and 2-chloromethylbenzene can be obtained in accordance with the following reaction scheme:

R R

where X is-0 - or NCH3. The reaction is preferably carried out at a controlled low temperaturesalinity to inhibit the activity of the enzyme LAF2as well as the enzyme lipoxygenase and mitigate mediators, resulting from enzymatic metabolism, suitable for use in the treatment of diseases, the conductors of which are oxidation products of arachidonic acid. Thus, the compounds of the invention indicated for the treatment of diseases such as rheumatoid arthritis, inflammation of the digestive tract, osteoarthritis, tendinitis, bursitis, psoriasis (and related skin inflammation) and similar diseases, including inflammatory processes. In addition, because of their ability to resist LTC4, LTD4and LTE4who are the deputies of SRS-A, they are useful in the processes of inhibition of symptoms induced by these leukotrienes. Therefore, the compounds of the invention indicated for the prevention and treatment of pathological States which are caused by LTC4, LTD4and LTE4such as allergic rhinitis, allergic bronchial asthma and other caused by leukotrienes, naso-bronchial obstructive diseases of the respiratory tract, as well as other intermediate allergic reactions such as allergic conjunctivitis. These TMI.

Compounds of the invention are cytoprotective funds and are considered as a tool, especially useful for joint reception with traditional anti-inflammatory drugs non-steroidal nature, causing as a result of their main side effects painful irritation of the gastrointestinal tract. Chitosamine action of these compounds significantly reduces gastroenterogie the effects of traditional anti-inflammatory drugs. This protective action is based not only on the ability of the compounds of the invention to inhibit the biological action of leukotrienes and/or control the biosynthesis of these substances by inhibiting lipoxygenase, but also on the effect of the bypass, which turns off lipoxygenase oxidation of arachidonic acid and switches to cyclooxygenase cycle of conversion of arachidonic acid, leading to increased formation of cytoprotective prostaglandins. Such biological effects make compounds of the invention are particularly useful in the treatment of diseases such as erosive esophagitis, inflammation of the digestive tract and induced gemologistonly means (NSAID), hepatic ischemia, damage to or necrosis of the liver tissue, pancreas, kidneys, myocardium, caused by the action of toxic substances; destruction of the liver parenchyma caused by hepatoxins, such as carbon tetrachloride and D-galactosamine; renal ischemia; diseases caused by destruction (hepatic damage; bile salt pancreatitis or gastrointestinal disorder; the collapse of the cells; caused by injury or stress; and renal failure caused by glycerin.

When the compounds of the invention are used in the treatment of allergic respiratory diseases, as anti-inflammatory agents and/or cytoprotective means, then it can be included in the final oral forms such as tablets, capsules, etc. Connection, you can enter by themselves or together with suitable carriers (fillers), such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethylcellulose, a wax with a low melting temperature, cocoa butter, etc., Solvents, perfumes, solubilizing means, lubricant, suspendresume means, connecting means for disintegration of tablets, etc. means Mohsen cases, the proportion of active ingredient in these compositions, both in liquid and in solid, must be at least this amount in order to show the desired activity upon oral administration. Compounds of the invention can be administered by parenteral, in these cases, they are used in the form of sterile solutions containing other dissolved substances, for example, in enough salt or glucose, in order to introduce the solution was isotonic. For administration by inhalation or insufflation (blowing) data connections can put into compositions in the form of an aqueous or partially aqueous solutions, such that then can be used in the form of aerosols.

The dosage requirements vary depending on the specific formulations, routes of administration paparata, the severity of the disease (symptoms) and a specific subject, which will be subjected to treatment. Treatment generally should be started with small doses that are lower than the optimal dose of this compound. Then to increase the dosage to achieve optimal under the circumstances of the effect. As a rule, the compounds of the invention are most preferably administered in a concentration that will generally give effective results without causing undesirable (bad) or is here, this dose may be divided into appropriate curiosi that are entered in the appropriate time of day.

The effect of the compounds of the invention as inhibitors LAF2and lipoxygenase, leukotriene antagonists, as well as funds that have anti-inflammatory action and have a potential effect on gastroenteritis gastric irritants, may be demonstrated by standard methods pharmacology, which will be more fully described in the examples.

These pharmacological treatments, interalia, determine the specificity of action of the compounds of the invention as inhibitors LAF2measured by the ability of these compounds to inhibit the synthesis of LTB4and PGE2glikogensintetazy polymorphisim by leukocytes of rats, as well as their ability to inhibit the secretion of arachidonic acid, which is implemented through LAF2whose source is human. Pharmacological studies additionally demonstrate the ability of the compounds of the invention to inhibit in vivo lipoxygenase and cyclooxygenase direction of transformation (metabolism) of arachidonic acid.

The examples illustrate the methods of obtaining and farm the XI)-[1,1I'-biphenyl]-4-yl-Etalon.

A. 4-Acetyl-4'-methoxy-2-nitrobiphenyl.

Stir a mixture of 4-iodoanisole (43,65 g, 0,187 mol), 4-bromo-3-nitroacetophenone (40.6 g, 0,116 mol) and copper powder (copper bronze, 36 g, 0,567 mol) stored in an atmosphere of nitrogen, was placed in an oil bath heated to 80aboutC. the Temperature is slowly raised to 110aboutC, then the mixture was stirred at this temperature for 5 days (TLC, 8:2 hexane-ethyl acetate). After cooling, the mixture was dissolved in dichloromethane and filtered through a pad of celite. The filtrate and the washing water was evaporated, and the remaining thick oil dark brown missed via flash chromatography (silicagel Merck 60, pre-soaked in dichloromethane, elution was performed using a mixture of 9:1 hexane-etelaat, to remove impurities, and to highlight the main product mixture 8:2 hexane-ethyl acetate), was obtained 16.2 g (32% yield) of the titled compound (solid yellow color, so pl. 124-126aboutC).

NMR (DCl3, 400 MHz): To 2.67 (S, 3H, PINES3), 3,85 (s, 3H, och3), 6,97 (d, 2H, J a total of 8.74 Hz, AGN), and 2.27 (d, 2H, J a total of 8.74 Hz, ArH), 7,56 (d, 1H, J 8 Hz, ArH), of 8.15 (d, 1H, J 8 Hz, ArH), to 8.34 (s, 1H, ArH). MS/EI, m/z:271/M+/.

Century 4-Acetyl-4'what) in benzene (45 ml) dropwise under nitrogen atmosphere add a solution of methyl ester (5 g, of 18.45 mmol) of the substance stage And in benzene (12 ml) for 30 minutes the resulting solution was stirred at room temperature for 3.5 h (TLC, 8: 2 hexane-ethyl acetate). The mixture is cooled in an ice bath, and the resulting complex is destroyed by adding dropwise 6 N. HCl (approximately 37 ml). Separate the organic layer and the aqueous phase extravert ether (3x), the combined extracts are concentrated to a small volume and extracted again with 2.5 g of NaOH (g ml + 1x10 ml). Alkaline extracts are cooled and acidified with concentrated HCl (to pH 2). The solid is collected and dried (4,27 g, 90%). It is used in the next stage without further purification.

NMR (CDCl3, 400 MHz): to 2.67 (s, 3H, PINES3), 5,03 (broadening, 1H, HE), 6,91 (d, 2H, J 8,56 Hz, ArH), of 7.23 (d, 2H, J to 8.57 Hz, ArH), at 7.55 (d, 1H, J 7.9 Hz, ArH), of 8.15 (d, 1H, J 8.1 Hz, ArH), to 8.34 (s, 1H, ArH).

MS (EI, m(z): 257(6.R. M+).

C. 1-[2-nitro-4'-[2-chinoline)-1,1'-biphenyl-4-yl]alanon.

A mixture of phenol (4.4 g, 17,12 mmol) obtained in stage B, powdered potassium carbonate (2.37 g, 17,12 mmol), 18-crown-6 ether (0,453 g, 1,71 mmol) and acetonitrile (38 ml) was stirred at room temperature under nitrogen atmosphere for 15 minutes 2-Chlormethine (3,34 g, 18,83 mmol), free, freshly prepared from chlorite is(TLC, 7: 3 hexane-ethyl acetate). Add a 10% excess of potassium carbonate and 18-crown-6 and chloromethylene, continue boiling for 4 hours the Solvent is distilled, and the residue diluted with water and extracted with ethyl acetate (3x). The extracts are washed and dried over anhydrous magnesium sulfate. The residue is subjected to flash chromatographicaliy (silicagel Merck 60 pre-saturated dichloromethane and Polyany for increasing polarity mixtures of 7: 3, 1: 1 and 1:3 hexane-ethyl acetate, and then pure ethyl acetate). After flash chromatography got 2,59 g of pure product named connection. After recrystallization from toluene got a solid yellow color with so pl. 160-162about(2,05 g, 30%).

NMR (CDCl3, 400 MHz): to 2.66 (s, 3H, COOH3), 5,43 (s, 2H, och2Ar), 7,10 (d, 2H, J 8.7 Hz, ArH), 7,27 (d, 2H, J 8.7 Hz, ArH), 7,56 (m, 2H, ArH), to 7.68 (d, 1H, J 8,49 Hz, ArH), of 7.75 (dt, 1H, ArH), to 7.84 (d, 1H, J 8.1 Hz, ArH), of 8.09 (d, 1H, J 8.5 Hz, ArH), to 8.14 (DD, 1H, ArH), by 8.22 (d, 1H, J 8,49 Hz, ArH), to 8.34 (s, 1H, ArH). MS (EI, m(z): 398(M+), 256,158,142.

Analysis in C24H18N2ABOUT4< / BR>
Designed, 72,35; N 4,55. N 7,03.

Found, 71,96; N. Of 4.75; N 6,80.

P R I m m e R 2. 2-fluorescent-4'-(2-hyalinella)-[1,1'-biphenyl]-4-acetic acid.

A. 4-Acetyl-4'-meal) in a mixture of concentrated HCl (72 ml) and ethanol (99 ml) was added dropwise within 45 min nitro-derivatives of example 1 And (10.7 g, to 39.5 mmol). The resulting yellow solution is heated under reflux for 3.5 h (TLC, 1:1 hexane-ethyl acetate). Ethyl alcohol is removed, and the residue poured into a mixture of 50% NaOH (360 ml) and ice. The resulting solid product is extracted (dichloromethane, 3), the extracts washed with water and dried over anhydrous sodium sulfate. After removal of the solvent receive solid yellow (9,31 g, 97.8 per cent), so pl. 152-154aboutC.

NMR (CDCl3, 400 MHz): at 2.59 (s, 3H, PINES3), of 3.80 (s, 3H, och3), 6,97 (d, 2H, J 8.7 Hz, ArH), of 7.23 (d, 1H, J 7.4 Hz, ArH), 7,40 (d, 2H, J 8.7 Hz, ArH), of 7.48 (d, 1H, J 7,3 Hz, ArH), 7,49 (s, 1H, ArH). MS (EI, m/z:(M-CH3)+, 226, (M-CH3)+, 198 (M-PINES3)+, 83.

Century 4-Acetyl-4'-methoxy-2-ferometer.

To stir cooled ice mixture of aniline (9.2 grams, of 38.2 mmol) in tetrahydrofuran (26 ml), water (9.8 ml) and HBF4(49% and 35.1 ml) is added slowly a solution of sodium nitrite (2,82 g, 48,85 mmol) in water (5 ml). In the process of adding the outside temperature is maintained below the 5aboutC. the Mixture is then additionally stirred for 20 min at 0-5aboutC. Formed of diezani the fluoroborate is filtered off and washed with 10% solution of HBF4and 10% solution of methanol in ether and dry the camping heated under reflux for 2.5 h (TLC, 1:1 hexane-ethyl acetate, UV). The xylene is removed, and the residue is extracted with ethyl acetate (3x) and ether. The combined extracts are washed with 10% sodium carbonate solution, vymalivayut and dried over anhydrous magnesium sulfate. Removal of the solvent leads to the formation of oil of amber (6,03 g) which is purified by means of flash chromatography (silicagel Merck 60, preliminary impregnation dichloromethane, elution with a mixture of 95:5 hexane-ethyl acetate). The named compound was obtained in a solid yellow color in the number of 3,12-of 4.75 g (33-51% depending on experience); so pl. 100-101aboutC.

NMR (CDCl3, 400 MHz): 2,62 (s, 3H, PINES3), 3,86 (s, 3H, och3), of 7.00 (d, 2H, J a 8.9 Hz, ArH), 7,50-7,80 (m, 5H, ArH).

MS (EI/m(C): 244(M)+, 229(b.p. M-CH3)+.

C. 2-Fluorescent-4'-methoxy-[1,1'-biphenyl]-4-acetic acid.

A mixture of sulfur (0,468 g, 14.6 mmol), research (to 2.57 ml) and the ketone obtained in stage A (3,95 g, 16.2 mmol) is heated for 17 h under reflux (TLC, the acid-treated layer of silica gel, 8:2 hexane-ethyl acetate). When cooled add glacial acetic acid (9,9 ml), sulfuric acid (1.6 ml) and water (4 ml) and continue to reflux in techenie volume and extracted with 10% sodium carbonate solution. Alkaline extracts carefully acidified in the cold, was added concentrated HCl (to pH 2). Acid, the title of which is given in the header, extracted with ether (3x), and the extracts washed and dried over anhydrous magnesium sulfate. After removal of the solvent receive solid brown with a reddish tint color (2.37 g, 56.3% of so pl. 140-142aboutC).

NMR (CDCl3, 400 MHz): 3,68 (s, 2H, CH2Soo), 3,85 (s, 3H, och3), of 6.96-to 7.50 (m, 7H, ArH). MS (EI/m(h): 260(M)+, 215 (b,p. M-COOH)+.

D. 2-Fluorescent-4'-hydroxy-[1,1'-biphenyl]-4-acetic acid.

To a solution of methyl ester (1.31 g, 5,04 mmol) stage in glacial acetic acid (17 ml) was dropwise added a 48% solution of HBr in acetic acid (25 ml) and the mixture was heated under reflux for 4.5 hours (TLC, 7:3 hexanitrate). Added a little water, and the mixture was Proektirovanie ether (3x). The extracts were washed, dried over anhydrous magnesium sulfate. After removal of solvent received the connection specified in the form of brownish-reddish substance (1.13 g, 92%), so pl. 208-210aboutC.

NMR (DMCO-d6, 400 MHz): 3,61 (s, 2H, CH2MEO) 6,83 (d, 2H, J 8,64 Hz, ArH), 7,1-7,42 (m, 5H, ArH), being 9.61 (s, 1H, COOH). MS(CI, m(h): (M)+246, 201 (M-COOH)+.

2(Strength of 0.159 g) is heated under reflux for 1.5 h (TLC, the acid-treated layer of silica gel, hexane-ethyl acetate 7:3). The solvent was removed, the residue was dissolved in ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Solid brownish-reddish color (1,16 g, so pl. 115-118aboutC, quantitative yield) used in the next stage without further purification.

NMR (CDCl3, 400 MHz): 3,65 (C. 2H, CH2MEO) of 3.73 (s, 3H, SOON3), to 6.88 (d, 2H, J 8,8 Hz, ArH), 7,10 (m, 2H, ArH), 7,32-7,44 (m, 3H, ArH).

MS (EI, m(h): 260 (M)+, 201 (b.p. M-SOON3)+.

F. 2-Fluorescent-4'-(2 hyalinella)-[1,1'-biphenyl]-4-acetic acid methyl ester.

A mixture of phenol from stage F (1,16 g of 4.46 mmol), powdered anhydrous potassium carbonate (0,616 g of 4.46 mmol), 18-crown-6 (amount of 0.118 g, 0,445 mmol) and acetonitrile was stirred at room temperature under nitrogen atmosphere for 15 minutes Then added 2-chlormethine (0,871 g, 4.9 mmol) in the form of a free base, freshly prepared from hydrochloric salt, and the mixture was placed in an oil bath heated to 65aboutWith 5 hours Added 10%EN-methanol or 7:3 hexane-ethyl acetate). Removed the solvent and the residue was diluted with water and was Proektirovanie (3x) with ethyl acetate. The extracts washed and dried over anhydrous magnesium sulfate. After removal get solid yellowish-brownish color, which is purified using flash chromatography (silicagel Merck 60, pretreated with dichloromethane, elution 7:3 hexane-ethyl acetate). Thus obtained the specified connection (1.55 g, 87%) was recrystallized from methanol. Got a solid product is almost white with so pl. 99-101aboutC.

NMR (CDCl3, 400 MHz): to 3.64 (s, 2H, CH2Soo), and 3.72 (s, 3H, SOON3), 5,43 (s, 2H, och2Ar), and 7.1 (M, 4H, ArH), 7,35 (m, 1H, ArH), 7,47 (d, 2H, ArH), at 7.55 (t, 1H, ArH), of 7.69 (d, 1H, ArH), 7,74 (t, 1H, ArH), to 7.84 (d, 1H, ArH), of 8.09 (d, 1H, ArH), to 8.20 (d, 1H, ArH)=MS (EI, m(h): 401 M+, 142, 114.

Analysis in C25H20FNO3.

Designed With 74,80; N 5,02; N 3,49.

Found, With 74,68; N 4,65; N 3,49.

G. 2-Fluoro-4'(hyalinella)-[1,1'-biphenyl]-4-acetic acid.

A solution of ester (1,69 g is 4.21 mmol) stage F in dry tetrahydrofuran (20 ml) was treated under nitrogen atmosphere, is added dropwise adding 1N. LiOH (12,6 ml) and the mixture was stirred at room temperature for 3 h (TLC, 19:1 dichloromethane-methanol or a 1: 1 g is up to pH 6.5. Acid was Proektirovanie with ethyl acetate (requires a large amount), and the extracts were dried over anhydrous magnesium sulfate, then evaporated to obtain almost dry white balance (1.65 g, quantitative yield, so pl. 190-193aboutC (decomposition). Recrystallized from ethyl acetate and got a white solid (1.3 g, 80% yield, so pl. 195-196aboutWith decomp.). The sample was dried in vacuum at 40aboutC.

NMR (DMCO-d6, 400 MHz): 3,62 (s, 2H, CH2MEO) 5,41 (s, 2H, CH2OAr), to 7.15 (m, 4H, ArH), 7,41 (t, 1H, J 8 Hz, ArH), of 7.48 (d, 2H, ArH), to 7.61 (t, 1H, ArH), of 7.69 (d, 1H, ArH), 7,78 (dt, 1H, ArH), 8,01 (m, 2H, ArH), 8,42 (d, 1H, ArH), 12,42 (s, COOH).

MS (+The PUB, m(z): 388 (M)+.

Analysis in C24H18FNO3.

Designed With 74,41; N To 4.68; N 3,62.

Found, 74,28; N 4,48; N 3,69.

P R I m e R 3. 3-[4-(2-Hyalinella(benzoyl]benzene acetic acid.

A. 3-Methyl-[4'-methoxy]benzophenone.

In a three-neck flask equipped with a fridge, a mechanical stirrer and addition funnel, in a stream of nitrogen downloaded 1,925 g (79,19 mmol) magnesium turnings and ether in a quantity sufficient to cover the chips. Added a few drops of a solution of bromothymol (15,79 g, 92,28 mmol) in ether (40 was heated under reflux until complete dissolution of the magnesium shavings. After cooling, was added in one portion a solution of 4-methoxybenzonitrile (10 g, 75,1 mmol), dried in vacuum over P2ABOUT5).

The mixture was heated for 2 h (TLC, the lack of initial reagents), cooled (ice bath) and slowly treated with cold water (130 ml), then diluted with H2SO4(1:1 vol./about. 25 ml). The decomposition of the complex is completed by heating the mixture under reflux for 4 h (monitoring by TLC, 8: 2 ether-ethyl acetate). Then continue stirring over night at room temperature, the layer is separated and extracted with ether (3x). The extracts washed with 5% solution of NaHCO3, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (amber oil, 13,93 g) purified using flash chromatography (silicagel Merck 60, elution 8:2 petroleum ether-ethyl acetate), the result is a connection, the name of which is given in the header, in the form of oil pale yellow (12.5 g, 73,5% yield).

NMR (CDCl3, 400 MHz): 2,4 (s, 3H, CH3), a 3.9 (s, 3H, och3), of 6.96 (d, J 8,8 Hz, 2H, ArH), 7,38 (m, 2H, ArH), 7,53 (d, J 6.9 Hz, AGN), EUR 7.57 (s, 1H, ArH), of 7.82 (d, J 8.7 Hz, 2H, ArH).

MS (EI, m(C): 226(M)+, 135 (user.peak), 91.

Century 3-Bromomethyl-[4'-metoclop amount of benzoyl peroxide, heated under reflux. Dropwise within 30 min irradiation process mixture votolimpo 300 watts added a solution of bromine (12.7 g, of 79.6 mmol) in Eilenriede (15 ml). The reflux continued for 17 h (TLC, 9:1, petroleum ether-ethyl acetate, traces of starting material still present). The solvent is distilled off in vacuo, and the residue (brown oil), purified using flash chromatography (silicagel Merck 60, pre-adsorbed in dichloromethane, elution with 9:1 petroleum ether ethyl acetate), the result was unreacted starting material (2,59 g, 15%) and the desired product (14,36 g, 61% or 71.5% of the identified unreacted starting material), and some mixed fractions (approximately 5.20 g). The solid yellow product melts at 58-61aboutWith, and used this material without further processing in the next stage.

NMR (CDCl3, 400 MHz): 3,88 (s, 3H, och3), to 4.52 (s, 2H, CH2Br), of 6.96 (d, J 8,8 Hz, 2H, ArH), 7,44 (t, J 7,6 Hz, 1H, ArH), 7,58 (d, J 7.8 Hz, 1H, ArH), 7,66 (d, J 7,6 Hz, 1H, ArH), 7,76 (s, 1H, ArH), 7,81 (d, J 8,8 Hz, 1H, ArH); MS (EI, m(C): 306/304/1 bromine, M+225, 135 (user.peak).

Traces bromopropane when 386/384/382.

C. 3 dioxane (30 ml) and added a solution of NaCN (7 g) in water (28.5 Il). The mixture was heated under reflux for 6 h (TLC, petroleum ether-ethyl acetate 8:2), then pass through activated charcoal, if it was needed, and was Proektirovanie ether (3x). The extracts were dried over anhydrous magnesium sulfate and was evaporated to dryness, the obtained oil brown (13,44 g). The crude product was purified using flash chromatography (silicagel Merck 60, pre-adsorbed in dichloromethane) elution 6: 4 hexane-ethyl acetate), resulting in a net product (10,69 g, 92% yield), as a pale yellow oil which solidifies upon standing. Practically colorless solid product melts at 70-71aboutC.

NMR (CDCl3, 400 MHz): of 3.80 (s, 2H, CH2CN), a 3.87 (s, 3H, och3), to 6.95 (d, J 8.6 Hz, ArH), of 7.48 (t, J 7.7 Hz, 1H, ArH), 7,54 (d, J 7,6 Hz, 1H, ArH), 7,68 (s+d, J 7,6 Hz, 2H, ArH), 7,79 (d, J 8.6 Hz, 2H, ArH).

MS (EI, m(C): 251 (M)+, 135 (user.peak).

D. 3-[4-Methoxybenzoyl]-phenylacetic acid.

Nitrile (4 g, 15.9 mmol) stage was dissolved in 40% NaOH solution (40 ml) and the solution was heated under reflux in a stream of nitrogen for 7 h (TLC, toluene-methanol 9: 1). In the process of cooling in an ice bath was added water. The solution was washed with ethyl acetate, ICTY dried over anhydrous magnesium sulfate, and then was evaporated to dryness, obtaining the crude product (solid yellow color of 3.56 g, yield 82%), so pl. 138-140aboutC.

NMR (CDCl3, 400 MHz): and 3.72 (s, 2H, CH2Soo), 3,88 (s, 3H, och3), 6,95 d, J 8,8 Hz, 2H, ArH), the 7.43 (t, 1H, ArH), of 7.48 (d, 1H, ArH), 7,65 d, 1H, ArH), 7,68 (s, 1H, ArH), 7,81 (d, J 8.6 Hz, 2H, ArH).

MS (EI, m(z): 270 (M)+, 211 (M-CH2COOH)+, 135 (user.peak), 107.

E. 3-[4-Hydroxybenzoyl]phenylacetic acid.

A homogeneous mixture of the acid (8.1 g, 0,030 mmol) stage D and pyridine (13,87 g, 0,120 mmol) was stirred in a stream of nitrogen while heating on an oil bath at 200-210aboutC for 7 h (TLC, toluene-methanol 9:1, dichloromethane-methanol 9: 1). After cooling, the mixture was dissolved in dichloromethane. The solution was Proektirovanie 1H. NaOH solution, the extract was acidified in the cold with concentrated HCl and was Proektirovanie with ethyl acetate (3x). After drying over anhydrous magnesium sulfate, the solvent was removed and received in the crude compound, which name is given in the header, in the form of a brownish-yellow solid substance (to 7.61 g, quantitative yield), so pl. 147-149aboutC.

NMR (DMCO-d6, 400 MHz): to 3.67 (s, 2H, CH2MEO) to 6.88 (d, J 8,84 Hz, 2H, ArH), about 7.5 (m, 4H, ArH), the 7.65 (d, J 8,8 Hz, 2H, ArH), of 10.4 (s, 1 is analysisnew acid methyl ester.

A mixture of acid (8,56 g, 33.4 mmol) stage E and monohydrate paratoluenesulfonyl (1,05 g, 5.6 mmol) in methanol (70 ml) was heated for 2.5 h under reflux (TLC, methanol-toluene 1:9). The methanol was evaporated, and the residue was dissolved in ethyl acetate and washed with brine. After drying over anhydrous magnesium sulfate, the solvent was removed, having a brownish-reddish solid product 8,68 g, 96,2% yield), so pl. 111-113aboutC. This crude product was used in the next stage.

NMR (CDCl3, 400 MHz): at 3.69 (s, 2H, CH2MEO) of 3.69 (s, 3H, SOON3), 6,86 (d, J 8,4 Hz, 2H, ArH), 7,41 (t, 1H, J 7,58 Hz, 1H, ArH), 7,47 (d, J 7,56 Hz, 1H, ArH), 7,62 d, J 7,4, 1H, ArH), to 7.64 (s, 1H, ArH), 7,74 (d, 2H, J and 8.4 Hz, ArH).

MS (m (C)271 ( M+ H)+,217,131,91 (user.peak).

G. 3-[4-(2-Hyalinella)benzoyl] benzooxazol acid methyl ester.

A mixture of phenol (4 g, of 14.8 mmol), stage F, powdered anhydrous K2CO3(2,05 g of 14.8 mmol) and 18-crown-6 (0.4 g, 1.48 mmol) in acetonitrile (35 ml) was stirred at room temperature under nitrogen atmosphere for 15 minutes Then one portion was added 2-chlormethine (2.9 g, 16.28 per mmol, freshly prepared from its hydrochloric salt), and the mixture was heated on an oil bath maintaining the temperature ol the of techinline and heating continued for another 8 hours Acetonitrile was distilled and the residue is divided between water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and was evaporated, the obtained brownish-yellowish solid product (6,57 g). The crude product was purified using flash chromatography (silica gel) brand Merck 60, pre-adsorbed in dichloromethane, elution-petroleum ether ethyl acetate 7:3), and has been named compound as a pale yellow solid (of 5.03 g, yield 82.7 per cent), so pl. 93-95aboutC.

NMR (CDCl3, 400 MHz): to 3.67 (s, 5H, CH2COO+CO3), the 5.45 (s, 2H, ArCH2O), was 7.08 (d, J 8,8 Hz, 2H, ArH), 7,40 (t, J 7.8 Hz, 1H, ArH), 7,46 (d, J 7.7 Hz, 1H, ArH), 7,55 (t, J 7,3 Hz, 1H, ArH), of 7.6 to 7.7 (m, 3H, ArH), 7,7-of 7.82 (m, 4H, ArH), 8,07 (d, 1H, ArH), to 8.20 (d, J 8,4 Hz, 1H, ArH).

MS (EI, m(z): 411 (M)+, 142, 121 (user.peak).

N. 3-[4-(2-Hyalinella(benzoyl]benzene acetic acid.

To a solution of the ester (5 g, 12,16 mmol) stage G in dry tetrahydrofuran (66 ml) was added 1M LiOH (37 ml, 37 mmol) and the mixture was stirred in nitrogen atmosphere at room temperature for 2.5 h (TLC, toluene methyl alcohol 9: 1). The tetrahydrofuran was evaporated and the residue was diluted with water, acidified to pH 6.5 10% acetic acid and was Proektirovanie with ethyl acetate (3x). The extracts were washed R is th color) recrystallize from ethyl acetate and got the 3.65 g (75% yield) of pure titled substance (white solid, so pl. 146-147aboutC).

NMR (DMCO-d6, 400 MHz): 3,68 (s, 2H, CH2MEO) of 5.48 (s, 2H, ArCH2O), 7,22 (d, 2H, 8,8 Hz, ArH), 7,47 (m, 1H, ArH), 7,53 (m, 2H, ArH), a 7.62 (m, 2H, ArH), of 7.69 (d, J 8,4 Hz, 1H, ArH), 7,74-of 7.82 (m, 3H, ArH), and 8.2 (m, 2H,g ArH), 8,43 (d, J 8.5 Hz, 1H, ArH), KZT 12.39 (1H, COOH).

MS (EI, m(z): 397, (M)+, 380g (M-HE)+, 142.

Analysis for C25H19NO4.

Designed With 75,57; N 4,78; N 3,53.

Found, 75,22; N Was 4.76; N 3,39.

P R I m e R 4. 3-[4-2-Naphthalenyloxy(benzoyl]benzene acetic acid

A. 3-[4-(2-Naphthalenyloxy(benzoyl] benzene acetic acid methyl ester.

A mixture of phenol (1 g, 3.7 mmol) of example 3 F, powdered anhydrous K2CO3(0,48 g, 3.7 mmol), 18-crown-6 ether (0,098 g and 0.37 mmol) and acetonitrile (10 ml) was stirred under nitrogen atmosphere for 15 minutes To the mixture was added 2-bromomelatonin (0,496 g, 4.07 mmol) was placed in an oil bath and heated for 10 h, keeping the temperature at 65-70about(TLC, dichloromethane-ethyl acetate 8:2). Added 10% excess TO2CO3,crown ether and bromomelatonin, and heating was continued for another 4 h, the Acetonitrile was distilled and the residue was dissolved in water and was Proektirovanie with ethyl acetate (3x). The extracts were washed 1M NaOH and brine, dried over was polzovali without further processing in the next stage.

NMR (CDCl3, 400 MHz): 3,7 (s, 5H, co3+ CH2Soo), 5,32 (s, 2H, CH2About), was 7.08 (d, J 8.7 Hz, 2H, ArH), 7,4-7,56 (m, 5H, ArH), 7,63-to 7.68 (m, 2H, ArH), 7,82-a 7.92 (m, 6N, ArH). MS (m(z): 410 (M)+, 141 (user.peak).

Century 3-[4-(2-Naphthalenyloxy)benzoyl]benzene acetic acid.

A solution of ester (1.29 g, a 3.15 mmol) stage And handled by adding dropwise 1M LiOH solution, and the mixture was stirred in nitrogen atmosphere overnight. The solvent was evaporated and the residue dissolved in water, docilely on cold 10% acetic acid to pH 3 and Proektirovanie with ethyl acetate (3x). The extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue (1.24 g, quantitative yield) was recrystallize by dissolution in relatively large quantities) the volume of warm solution of ethyl acetate-dichloromethane, then concentrated to half of its original volume. The precipitate was collected and dried in vacuum at 45about(0,610 g, 48.8 output), so pl. 150-152aboutC.

NMR (DNCO-d6, 400 MHz): 3,70 (s, 2H, CH2MEO) of 5.40 (s, 2H, CH2), 7,20 (d, 2H, ArH), 7,45-of 7.60 (m, 7H, ArH), of 7.75 (d, 2H, ArH), to 7.95 (m, 3H, ArH), 8,02 (s, 1H, ArH), 12,47 (ush.with. 1H, COOH).

MS (+Surfactants, m(z): 397 (M+N)+, 217, 141.

Analysis for C26H20ABOUT4< / BR>
Designed With 78,78; N the OIC acid.

A. 4-Methoxybenzoyl.

To a solution of KCN (5 g) in water (35 ml) was added 4-methoxybenzaldehyde (to 27.2 g, 0.2 mol), benzaldehyde (21.2 g, 0.2 mol) and 95% ethanol (70 ml). The mixture was heated under reflux in nitrogen atmosphere for 4.5 h, and then was distilled in vacuum ethyl alcohol. Added 200 ml of water to the residue and then distilled under reduced pressure to remove unreacted benzaldehyde). The procedure was repeated twice, and the residual water was Perevi in azeotropic mixture with ethyl alcohol. The crude product (56,3 g, semi-solid product of orange color) was purified using flash chromatography (silicagel Merck 60, pre-adsorbed in dichloromethane-ethyl acetate elution hexane-ethyl acetate 8:2). the result was a solid light yellow (20,1 g, 41.5 percent), so pl. 99-101aboutC.

NMR (CDCl3, 400 MHz): is 3.82 (s, 3H, och3), 4,62 (ush.with. 1H, HE), 5,88 (s, 1H, NON), 6,86 (d, 2H, J to 8.94 Hz, ArH), 7,22-7,38 (m, 5H, ArH), to $ 7.91 (d, 2H, J to 8.94 Hz, ArH); MS (EI, m(C): 243 ( M+N)+, 225, 197, 137 (M-PhCO)+.

Century 4-Methoxybenzoyl polosukhina.

A mixture of 4-methoxybenzene (20 g, 0,083 mol) and succinic anhydride (9.1 g, 0,091 mol) in toluene (6 ml) was heated for 7 hours in a nitrogen atmosphere at 135aboutC (ambient temperature)B>. The combined extracts were washed with ether and then acidified in the cold with concentrated hydrochloric acid. The liberated oil was Proektirovanie with ethyl acetate (3x), the extracts washed with water and dried over anhydrous magnesium sulfate. Removed excess solvent and received solid yellow (20,89 g, 73,8% yield), so pl. 104-108aboutC. This product was used in the next stage without further purification.

NMR (CDCl3, 400 MHz): 2,72-2,82 (mm, 4H, CH2CH2Soo, is 3.82 (s, 3H, och3), 6,86 (d, 2H, J 9.1 Hz, ArH), 7,34-7,46 (m, 5H, ArH), 7,92 (d, 2H, J 9.1 Hz, ArH).

MS (EI), m(z): 342 (M)+, 135 (user,peak).

C. 4-(4-Methoxyphenyl)-5-phenyl-2-oxazol-propanoic acid.

A mixture of crude 4-methoxybenzoyl of polyacrylate (20,8 g, 0.061 mol) stage, urea (8.7 g, 0,146 mol) and acetic acid (60 ml) was heated under reflux in nitrogen atmosphere for 5.5 hours, the Mixture was cooled and poured into ice-cold water. The liberated oil was Proektirovanie with ethyl acetate (3x). The extracts are washed with water to neutrality and then Proektirovanie a saturated solution of sodium carbonate. The combined aqueous extracts were carefully acidified in the cold with concentrated hydrochloric acid HCl and preextracted received waxy, oily yellow substance (19.6 g). The obtained residue was purified using flash chromatography (silicagel Merck 60, eluent dichloromethane-ethyl acetate 8:2), the solid pale yellow (14.3 g, 72.7% yield), so pl. 100-101aboutC.

NMR (CDCl3, 400 MHz): 2,96 (t, 2H, CH2C) 3,20 (t, 2H, CH2MEO) a 3.83 (s, 3H, och3), of 6.90 (d, 2H, ArH), 7,28-7,38 (m, 3H, ArH), 7,54 to 7.62 (m, 4H, ArH).

MS (EI, m(z): 323 (M)+, 278 ( M-COOH)+, 152, 77.

D. 4-(4-Hydroxyphenyl)-5-phenyl-2-oxazol-propanoic acid.

To a solution of methoxybutanol acid (5.6 g, 17.3 mmol) stage in acetic acid (55 ml) was added 48% HBr solution (84 ml), and the mixture was heated under reflux in nitrogen atmosphere for 8 h (TLC, 1:1 hexane-ethyl acetate). After cooling, added water, and the solution was Proektirovanie with ethyl acetate (3x). The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue (brown waxy oil, a 5.25 g, 99% yield) was used in the next stage without further purification. For analytical purposes, a small sample was subjected to flash chromatographicaliy (silicagel Merck 60, eluent: dichloromethane-methanol 98-2 and 95:5).

NMR (DMCO-d6, 400 MHz): 2,75 (t, 2H, J 7,14 Hz, CH2C) to 3.02 (t, 2H, J 7,1 Hz, CH2MEO) 6,77 (d, 2H, J 8.7 Hz, ArH),x2">

MS (EI, m(z): 300(M)+, 264 (M-COOH)+, 121, 105, 77.

E. 5-Phenyl-4-[4-hydroxyphenyl] -2-oxazol-propanoic acid methyl ester.

A solution of the crude acid (5 g, 16,18 mmol) stage D in methanol (40 ml) containing a small amount of para-toluenesulfonic acid monohydrate (0,58 g) was heated under reflux for 2.5 hours, the Methanol was distilled, and the residue is divided between two phases-ethyl acetate and 20% NaCl solution. The extracts were washed, dried over anhydrous magnesium sulfate and evaporated, having a thick oil (about 4.8 g). The obtained residue was purified using flash chromatography (silicagel Merck 60, pre-adsorbed in dichloromethane, was suirable a solution of dichloromethane-ethyl acetate gradient from 90:10 to 75:25), the result obtained white solid (of 3.56 g, 68% yield) so pl. 115-116aboutC.

NMR (CDCl3, 400 MHz): 2,92 (t, 2H, J 7.4 Hz, CH2C) 3,20 (t, 2H, J 7.4 Hz, CH2Soo), 3,71 (s, 3H, och3), 6,74 (d, 2H, J 8,59 Hz, ArH), 7,26 and 7.36 (m, 3H, ArH), 7,40 (d, 2H, J 8.7 Hz, ArH), 7,54 (d, 2H, J 7,56 Hz, ArH).

MS (EI, m(z): 323 (M)+, 264 (M-SOON3)+, 105, 77 (user.peak).

F. 5-Phenyl-4-[4-(2-hyalinella)phenyl]-2-oxazole propanoic acid methyl ester.

A mixture of ether (2,ol) and acetonitrile (33 ml) was stirred at room temperature under nitrogen atmosphere for 15 min 2-chlorothiophenol (free base freshly prepared from hydrochloric salt, 1.35 g, 7,60 mmol) was added to the mixture, put it in an oil bath and heated for 10 h at 65about(Note after 6 h was added 10% excess chloromethylene, 18-crown-6-ether and K2CO3). The solvent was removed and the residue is distributed between two phases with ethyl acetate and water. The extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated, having a solid yellow color. The crude product was purified using flash chromatography (silicagel Merck 60, eluent: toluene and then the toluene-methanol 97:5:2,5), and got the connection, the name of which is given in the header (3.5 g, yield quantitative).

NMR (CDCl3, 400 MHz): 2,90 (t, 2H, J about 7.2 Hz, CH2C), and 3.16 (t, 2H, J 7.2 Hz, CH2Soo), and 3.72 (s, 3H, och3), 5,41 (C. 2H, ArCH2O) 7,02 (d, 2H, J 8,8 Hz, ArH), 7.29 trend was 7.36 (m, about 4H, ArH), 7,54-to 7.84 (m, approximately 6N, ArH), 7,83 (d, 1H, J 8.1 Hz, ArH), 8,08 (t, 1H, J 8.5 Hz, ArH), 8,19 (d, 1H, J 8.5 Hz, ArH).

MS (+PUB, m(z): 487 (M+a)+, 465 (M+N)+.

G. 5-Phenyl-4-[4-(2-chinainternational]-2-oxazole propanoic acid

A solution of ester (3.4 g, to 7.32 mmol) stage F in dry tetrahydrofuran (37 ml) was treated, dropwise adding a 1M solution of LiOH (21,98 ml, 3 EQ.) in nitrogen atmosphere, varicel has evaporated, the residue was dissolved in water, neutralized in cold 10% solution of acetic acid to pH 5 and was Proektirovanie with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated, got in the solid product is a pale yellow color (3,18 g, quantitative yield). The crude product is recrystallized from warm ethyl acetate (containing dichloromethane in a quantity sufficient to obtain a clear solution), after receiving the first batch of crystals (2,63 g, so square) 192-194aboutC, decomp. ). The second game was allocated, concentrating the mother liquor (0,327 g, so pl. 192-193aboutC, decomp. ). The total yield amounted to 85.8% of the CLAIM (KBr, cm-1): 1720 (CO).

NMR (DMCO-d6, 400 MHz): was 2.76 (t, 2H, J 7 Hz, CH2C) 3,03 (t, 2H, J 7 Hz, CH2MEO) 5,38 (s, 2H, ArCH2O), 7,11 (d, 2H, J 8,8 Hz, ArH), was 7.36-7,56 (m, 7H, ArH), to 7.61 (t, 1H, ArH), of 7.69 (d, 1H, J 8.5 Hz, ArH), 7,78 (t, 1H, ArH), 8,00 (t, J 7.9 Hz, 2H, ArH), 8,42 (d, 1H, J 8.5 Hz, ArH).

MS (EI or C/I m(z): 451 (M+N)+, 310 (user.peak).

Analysis for C28H22N2O4< / BR>
Designed With 74,65; N To 4.92; N 6,22.

Found, 74,20; N A 4.86; N 6,00.

P R I m e R 6. 4-[4-[2-Naphthalenyloxy]phenyl]-5-phenyl-2-oxazole propanoic acid.

A. 4-[4-(2-Naphthalenyloxy]the FEA 5E, powdered anhydrous potassium carbonate (0,636 g, 4.6 mmol), 18-crown-6 ether (0,123 g, 0.46 mmol) and acetonitrile (18 ml) was stirred at room temperature under nitrogen atmosphere for 15 minutes was Added 2-bromomelatonin (1.13 g, 5.1 mmol) and the mixture was placed in an oil bath and heated at 70aboutC for 8-9 hours (TLC, hexane-ethyl acetate 9:1 dichloromethane-methanol 9:1). The solvent was evaporated, and the residue was dissolved in water, was Proektirovanie then with ethyl acetate. The extracts washed and dried over anhydrous magnesium sulfate. After removal of solvent received brownish-yellowish substance solid (2.17 g, quantitative yield). The sample was recrystallize from methanol (containing dichloromethane in a quantity sufficient to obtain a clear solution), concentrating to a small volume and cooled in an ice bath. White solid product was collected and dried overnight under vacuum conditions, so pl. 134-135aboutC.

X (KBr, cm-1): 1740 (CO)

NMR (CDCl3, 400 MHz): 2,89 (t, 2H, J 7.5 Hz, CH2C), and 3.16 (t, 2H, J 7.5 Hz, CH2Soo), 3,71 (s, 3H, och3), and 5.2 (s, 2H, CH2O) to 7.00 (d, J 8.6 Hz, ArH), 7,25-7,35 (m, 3H, ArH), 7,46-7,58 (m, 7H, ArH), 7,8-7,9 (m, 4H, ArH).

MS (CI, m(z): 464 (M+N)+, 324.

Analysis for C30is elinimate)phenyl]-5-phenyl-2-oxazole propanoic acid.

A solution of ester (1,49 g is 3.21 mmol) stage And in dry tetrahydrofuran (18 ml) containing 1M LiOH (9.6 ml) was stirred at room temperature under nitrogen atmosphere overnight (TLC, 75:25 hexanitrate). The solvent was evaporated, the residue dissolved in water and acidified to pH 5 with diluted HCl. The mixture was Proektirovanie with ethyl acetate, the extracts dried over anhydrous magnesium sulfate and evaporated, receiving 1.39 g, so pl. 145-150aboutC. For purification the product was dissolved in hot ethyl acetate (containing diclomelan in sufficient quantity to obtain a clear solution), the resulting solution was concentrated to half the original volume and besieged ether. Solid white melts at 151-152about(1.07 g, 58%).

X (KBr, cm-1): 1720 (CO)

NMR (DMCO-d6), 400 MHz): 2,78 (t, 2H, CH2C) 3,03 (t, 2H, J 7 Hz, CH2MEO) of 5.29 (s, 2H, ArCH2COO), 7,10 (d, 2H, J a 8.9 Hz, ArH), 7,34-of 7.60 (m, 10H, ArH), of 7.90-of 8.00 (m, 4H, ArH), to 12.28 (s, 1H, COOH).

Analysis for C29H23NO4.

Designed With 77,48; H 5,15; N 3,11.

Found, 76,40; H 5,16; N 3.04 From.

P R I m e R 7. 4-[4-(1-Methyl-1 H-benzimidazole-2-yl)methoxy]phenyl]-5-phenyl-2 - oxazole propanoic acid.

A. 4-[4-(1-Methyl-1 H-benzimidazole-2-yl)met scoobysnack anhydrous potassium carbonate (0,214 g, 1.55 mmol), 18-crown-6-ether level (0.041 g, 0,155 mmol) and acetonitrile (6 ml) was stirred under nitrogen atmosphere at room temperature for 15 minutes Then added 2-chloromethyl-1-methylbenzimidazole (0,307 g, 1.7 mmol) and the mixture was placed in an oil bath and heated at 65-70aboutC for 4 h (TLC, dichloromethane-ethyl acetate 9:1, the manifestation of iodine). At this point added 10% excess TO2CO3, 2-chloromethyl-1-methylbenzimidazole and 18-crown-6 and continued heating for another 10 hours the Solvent was then evaporated, the residue dissolved in water and was Proektirovanie with ethyl acetate. The extracts were washed, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue (1.64 g) was purified using flash chromatography (silicagel Merck 60, pre-adsorbed in dichloromethane containing a small amount of methanol was Polyanovo a mixture of dichloromethane-ethyl acetate 8:2), received in the result of 1.03 g (71,2% yield) of light yellow solid product, so pl. 142-144aboutC.

NMR (CDCl3, 400 MHz): 2,87 (t, 2H, J 7,1 Hz, CH2C), and 3.16 (t, 2H, J 7.8 Hz, CH2Soo), and 3.72 (s, 3H, SOON3), 3,90 (s, 3H, N3), 5,41 (s, 2H, ArCH2COO), 7,07 (d, 2H, J 8,8 Hz, ArH), 7,25-7,40 (m, 7H, ArH), 7.5 to about 7.6 (m, 3H, ArH), 7,78 (d, 1H, ArH).

MS (+CI, m(z): 468 (M+N)+, 324, 293, 147.

NMR (DMCO-d6, 400 MHz): was 2.76 (t, 2H, J 7 Hz, CH2C) 3,03 (t, 2H, J 7 Hz, CH2Soo), 3,86 (s, 3H, NCH3), 5,43 (s, 2H, ArCH2O), 7,14-7,66 (m, 13H, ArH).

MS (CI, m(z): 454 (M+N)+, 147 (user.peak).

Analysis for C27H23N3O4< / BR>
Designed With 71,51; N 5,11; N 9,27.

Found, With 71,62; N. Of 5.17; N 9,40.

P R I m e R 8. 2-Fluoro-4'-(2 hyalinella[1,1'-biphenyl]-4-acetic acid, 2-amino-2-hydroxymethyl-1,3-propandiol.

A solution of the compound from example 2 (3,17 g, 8.2 mmol) and 2-amino-2-hydroxymethyl-1,3-propane diol [TRIS, 0,99 g, 8.2 mmol] in 60 ml of methanol, concentrated to a syrup. Then diluted etiect on micron colloidal mill to obtain a fine white powder, melting point 168-169about(Output 77,5%).

Analysis in C28H29FN2O6.

Designed With 66,13; N. Of 5.75; N 5,51.

Found, 65,75; N 5,79; N 5,49.

P R I m e R 9. 5-Phenyl-4-[4-hyalinella)phenyl]-2-oxazolepropionic acid, 2-amino-2-hydroxymethyl-1,3-propandiol.

Into a solution of the compound from example 5 (0,359 g coefficient was 0.796 mmol) in boiling ethanol (35 ml) is added 2-amino-2-hydroxymethyl-1,3-propane diol [TRIS, 0,0965 g coefficient was 0.796 mmol] in 0.5 ml of water. After 2 h the mixture is frozen. The crystalline precipitate is collected and dried to obtain 0,396 g of the desired salt, melting point 170-171aboutC.

Analysis in C32H33N3ABOUT7.

Designed WITH 67,00; N. OF 5.75; N 7,32;

Found, 66,68; N 5,77; N 7,31.

P R I m e R 10. 4'-(2 Benzothiazolylthio)-4-diphenylhexane acid, ethyl ester.

A. 4'-Hydroxy-4-diphenylhexane acid, ethyl ester.

A solution containing 4'-hydroxy-4-diphenyloxazole acid (6,7, 28,0 mmol), absolute ethanol (300 ml) and concentrated sulfuric acid (5 ml) is distilled under reflux for 2 hours Then the reaction mixture is cooled to room temperature, concentrate under the acetate extract was washed with 1N. sodium hydroxide (200 ml), water (200 ml) and brine (200 ml), dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 6.9 g of crude solid. The solid is purified by chromatography (silica gel; 30% ethyl acetate in hexane) to obtain 6.7 g (95,0%) of white crystalline product, melting point 125-127aboutC.

Analysis in C16H16ABOUT3.

Designed With 74,98; N 6,29.

Found, With 74,62; N. 6,2.

Century 4'-(2 Benzothiazolylthio)-4-diphenylhexane acid, ethyl ester.

A slurry containing 4'-hydroxy-4-diphenyloxazole acid, ethyl ester (6.7 g, 26.0 mmol, part a) and cesium carbonate (9.0 g, of 28.0 mmol) in dimethylsulfoxide (150 ml) was stirred at room temperature. After 30 minutes add 2-(chloromethyl)benzothiazole (4,2 g of 27.0 mmol) and the mixture is stirred for 18 hours, the Reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (300 ml, 3 times). Combined an ethyl acetate extract is washed successively with 0.1 N. sodium hydroxide (200 ml), water (200 ml) and brine (200 ml), dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 8.0 g of the crude solid fuel is Holocene 4.0 g (39,2%) of white crystalline product, melting point 133-134aboutC.

Analysis in C24H21NO3S.

Designed With 71,44; N A 5.25; N 3,47.

Found, 71,36, N. A 5.25; N 3,35.

P R I m e R 11. 4'(Benzothiazolinone)diphenylarsine acid ethyl ester (4.0 g, 10.0 mmol), 1H. sodium hydroxide (15 ml, 15.0 mmol), methanol (200 ml) and tetrahydrofuran (200 ml) was heated under reflux for 18 hours Then the reaction mixture was cooled, concentrated under reduced pressure, diluted with water (500 ml) and stirring was acidified using 2n.the hydrochloric acid. After stirring for 2 h the product was collected by filtration and after drying under vacuum was obtained 3.8 g (99%) solids. Part of this material (0.5 g) recrystallization of acetic acid, melting point 208-209aboutC.

Analysis in C22H17NO3S.

Designed With 70,38; N 4,56; N To 3.73.

Found, With 70,04; N 4,56; N 3,72.

P R I m e R 12. Connection 5 - and 12-hydroxyeicosatetraenoic acid.

(5-NET and 12-NET) and LTB4this oxidation products of arachidonic acid in the initial stages lipoxygenase cycle, which, as shown, are agents of some aspects volacano as LTB4(see Fordand Hitchinson, J. Roy. Soc. Med. 74, 831, 1981). Compounds that inhibit due to phospholipase LAF2the allocation of arachidonic acid, thus effectively influence the process of preventing the oxidation of arachidonic acid in various products type leukotriene carried out in lipoxygenase cycle. Accordingly, the specificity of action of inhibitors LAF2can be determined by activity of the tested compounds in this analysis, which measures the ability of compounds to inhibit the synthesis of LTB4glikogensintetazy polymorphisim by leukocytes (PMA) in the presence of exogenou substrate.

This analysis is carried out as follows.

Polymorphically leukocytes of rats (PMA) is obtained from females of Wistar rats (weighing 150-200 g), which was made by injection of a 6% aqueous solution of glycogen (10 ml into the peritoneum). Rats were killed after 18-24 h after injection by asphyxia CO2and isolated from peritoneal cells were irrigated using a physiological solution (0.9% NaCl). The bleed and have exudate was centrifuged, and the precipitated cells resuspendable to the concentration of that component 2.0 x 107cells/ml in HBSS containing ions of CA++and Mg++and 10 μm of L-cysteine.

Solvent A: 70:30 17.4 mm H3RHO4:CH3SP

Solvent B: CH3CN

The gradient system balance solvent A) (see tab.1).

Changes in the percentage content of solvent is described by the linear dependence of

Injection: 140 l of each supernatant is injected directly into the column and the products of metabolism3H-arachidonic acid is determined using the built-in system with a radioactivity detector (Ramona, IN/US, Fairfield, NJ).

Standard solutions: 1042.0 x 104dpm (disintegrations per minute) eicosanoids interest, impose a cocktail in 90 l of ethanol.

The percentage of inhibition was determined by comparative chromatography was carried out environments stackstone processing. As internal standard used3N leukotrien4(LTB4).

The results are presented either as the percentage of inhibition data connection, either as IR50.

The tested compounds of the invention in this analysis showed the following results (see tab.2).

P R I m e p 13. The procedure of example 12 is also used to determine the degree of inhibition by the compounds of the invention synthesis of arachidonic acid product cyclooxygenase oxidation PGE2.

In this analysis the procedure of example 12 was carried out as described. However, to determine cyclooxygenase activity samples chromatographic together with authentic (3N)-PGE2.

The results are processed as in example 8, are presented in table.3.

P R I m e R 14. Compounds of the invention tested in vitro in experiments with isolated phospholipase a2to determine the ability of test compounds to inhibit the secretion of arachidonic acid from the substrate containing arachidonic acid by the enzyme phospholipase A2which source can serve as a person, and can be used other bavili components, presented in table.4.

Incubate 100 ál of the reaction mixture for 10 min at 37aboutWith a shake in a water bath. The reaction is completed by adding 2 ml of tetrahydrofuran, followed by vigorous stirring. NH2columns (100 mg/ml Analytichem International) treated with 0.5 ml of tetrahydrofuran, and then a mixture of 0.5 ml of tetrahydrofuran and water (2 ml 0.1 ml).

The sample is loaded into the column and slowly stretch through it. Hydrolyzed arachidonic acid remaining in the column, eluted from the column with 1 ml of a mixture of tetrahydrofuran and glacial acetic acid (2%). Arachidonic acid is transferred into scintillation vials and conduct quantitative determination method of counting. The total score of the sample is obtained by making a pipette 25 ál3N-arachidonate labeled E. coli directly into scintillation vials to which was added 1 ml of tetrahydrofuran. For all samples, add 10 ml of Aquasol (scintillation cocktail).

Calculations:

hydrolysis

changes :

IR50/MK/

_________________________________

LAF2platelets LAF2synovial

human fluid of humans

_________________________________ Medicine: Arachidonic acid 8/6 3/2

in table.5.

P R I m e R 15. Compounds of the invention are evaluated for their ability to ingibiruet lipoxygenase and/or ziklooksigenazny way of arachidonic acid metabolism in vivo in mice experience with peritonitis caused by enzymatic disintegration of tissue. This experience is carried out as follows.

Male mice of diabetes (age 8 weeks) put six pieces in a plastic box. Animals injected at 1 ml into the peritoneum or 1% solution of shimotani in 0,9% saline, or saline (control destimoney option). Compounds of the invention give the animals orally 1 h before the injection of zymosan. After 20 min after injection zymosan animals put to death by asphyxia in the atmosphere of CO2. Then in peritonealnuu cavity is treated with 2 ml ice balanced salt solution Hauks (HBSS), containing CaCl2, MgSO47H2O, and MgCl26H2O. Peritonealnuu wash fluid from each mouse take a syringe and placed into a 5 ml made of plastic test tubes for testing in ice and note the volume. Preparation of samples for evaluation by the method of ELISA, as follows: the samples are centrifuged at 800q in mortgage
For deposition of the protein; then the samples are centrifuged again at 800q for 15 min, then dried in a speed vacuum concentrator Savant. The samples restored by adding 1 ml of ELISA buffer, ice and stored at -70aboutWith up to analysis. The definition of eicosanoids (LTC4and 6-keto-PGF1) is carried out in accordance with standard procedures ELISA enzyme-linked immunosorbent assay).

Compounds that are tested by oral administration, suspended in 0.5% Tween 80. Compounds that are tested by intraperitoneal injection, suspended in 0.5% solution of methylcellulose in 0.9% saline solution.

The total number of metabolites in the wash fluid peritoneal cavity of the mouse count and determine the value by analysis of variance comparison with the control variant (p 0.05). The action of the drug expressed as percentage deviations from control values.

The activity of standard drugs shown in the table.6.

The compound of the invention when tested in this experiment and anti-inflammatory agent etodolac gave the following results: compound of example 5, the dose of 10 mg/kg (oral administration of the peritoneum (intrastate testify, the proposed connection shows inhibitory activity against lipoxygenase path of metabolism, but has no inhibitory effect on cyclooxygenase direction.

1. Derivatives substituted benzoylbenzene-, biphenyl -, or 2-oxazolidinone acid of General formula I

A(CH2)nO B,

where A group

< / BR>
where X Is N or ;

Z or-S-, provided that when X Z

R3hydrogen or lower alkyl;

n 1 2;

IN

< / BR>
< / BR>
< / BR>
where R4and R5each, independently of one another, hydrogen or lower alkyl;

R6this halogen or nitro-group;

R7< / BR>
R8this is lower alkyl;

m 0 3,

or their pharmacologically acceptable salts.

2. Connection on p. 1, characterized in that it is composed of 1-[2-nitro-4'-(2-hyalinella)-(1,1'-biphenyl)4-yl]alanon.

3. Connection on p. 1, characterized in that it is a 2-fluorescent-4'-[2-hyalinella-(1,1'-biphenyl)-4]-acetic acid.

4. Connection on p. 1, characterized in that it is a 3-[4-(2-hyalinella)benzoyl]benzooxazol acid.

5. Connection on p. 1, characterized in that it is a 3-[4-(2-naphthalenyloxy)benzo is-(2-hyalinella)-phenyl]-2-oxazolepropionic acid.

7. Connection on p. 1, characterized in that it is a 4-[4-(2-naphthalenyloxy)phenyl]-5-phenyl-2-oxazolepropionic acid.

8. Connection on p. 1, characterized in that it is a methyl ester of 4-[4-(2-naphthalenyloxy)phenyl]-5-phenyl-2-oxazolepropionic acid.

9. Connection on p. 1, characterized in that it is a 4-[4-( (1-methyl-1 - H-benzimidazole-2-yl)-methoxy)phenyl] -5 - phenyl-2 - oxazolepropionic acid.

10. The method of obtaining derivatives substituted benzoylbenzene-, biphenyl -, or 2-oxazolidinone acid of General formula I

A(CH2)nO B,

where the values of A, n, B are the specified values,

characterized in that carry out the reaction of interaction of the compounds of General formula

BUT,

where has the specified values,

with the compound of the formula A(CH2)nX, where A and n have the above meanings;

X tsepliaeva group,

and, if necessary, carry out the hydrolysis of the resulting product with the formation of the compounds of formula I in which R5hydrogen or lower alkyl, and, if desired, convert the compound obtained into its pharmaceutically acceptable salt.

 

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The invention relates to medicine, in particular to pharmacology and Hematology

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

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