RU2037481C1 - Derivatives of substituted benzoylbenzene-, biphenyl or 2-oxazolealkanoic acid or their pharmacologically acceptable salts, and a method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: products: derivatives of substituted benzoyl-, biphenyl- or 2-oxazolealkanoic acid of the formula (I) A(CH₂)_nO-B where A a group of the formula (I) where X-N- or C(R³)-

- or -S- at condition that when C(R³)-- Z

or lower alkyl then n 1-2; B a group of the formulas II, III, IV, V where R⁴, R⁵, R⁶, R⁷, m have corresponding meanings, or their salts. Compounds of the formula (I) were synthesized by interaction of compound of the formula HO₂-B with compound of the formula A(CH₂)_n-X where X splitting off group. Synthesized compounds were used in medicine as leucotriene antagonists and lipoxygenase inhibitors. EFFECT: improved method of synthesis. 11 cl, 6 tbl

Description

The invention relates to new derivatives of substituted benzoylbenzene-, biphenyl- and 2-oxazolalkanoic acids, which have an inhibitory effect on lipoxygenase, phospholipase A ₂ and which are antagonists of leukotrienes; derivatives that are suitable for use as anti-inflammatory, anti-allergic agents, as well as as cytoprotectors.

It has now been firmly established that the metabolism of arachidonic acid (AA) in mammals occurs in two different ways. Metabolism of arachidonic acid by cyclooxygenase enzymes leads to the formation of prostaglandins and thromboxanes. It is known that prostaglandins are formed from the endoperoxides PGG ₂ and PGH ₂ during the metabolism of arachidonic acid caused by cyclooxygenase. These endoperoxides are also precursors of thromboxanes (T _x / A ₂ and B _2. TxA ₂ is a vasoconstrictor), a vasoconstrictor that stimulates platelet aggregation. In the normal state, the vasoconstrictor properties and the ability to cause platelet aggregation by thromboxanes are balanced by another product formed from endoperoxides in the cyclooxygenase cycle, prostacyclin (PGI ₂ ), which is a vasodilator (vasodilator) with the ability to suppress (inhibit) platelet aggregation. In the case of a decrease in prostacyclin synthesis and / or an increase in platelet activity, thrombosis and narrowing of blood vessels are observed. The role of prostanoids in hemostasis and thrombosis is reviewed by PIGryglewski, CRC Crit. Rev. Biochem. 7, 291 (1980); and IBSmith, Am. I. Pathol 99, 743 (1980). Cyclooxygenase metabolites are known to be directly involved in the response to inflammation (see Higgs et al. AaoCca Peeac, 16, 287-299, 1984). This is manifested through their vasodilating activity, their participation in increasing vascular permeability for peptide mediators of pain and febrile arousal, and participation in the formation of edema. Finally, various aspects of cell-mediated immunity are associated with cyclooxygenase products.

Another direction (cycle) of AA metabolism involves lipoxygenase enzymes and leads to the formation of a number of oxidized products called leukotrienes. The latter are denoted by the LT nomenclature system, and most of the important products of the lipoxygenase cycle of AA metabolism are the leukotrienes B ₄ , C ₄ and D ₄ . The slow-acting component of anaphylaxis (SRS-A) has been found to be a mixture of leukotrienes, with LTC ₄ and LTD ₄ as primary products and containing various amounts of other leukotriene metabolites (Bach et al. I. Immunology 215, 115- 118, 1980, Biochem. Biophys. Res, Commun. 93, 1121-1126, 1980).

The importance of these leukotrienes, confirmed by a large number of facts, is that these leukotrienes participate in inflammatory reactions, exhibit chemotactic activity, stimulate lysosomal secretion of the enzyme and act as an important factor in the immediate allergic reaction. LTC ₄ and LTD _{4 have been found to} be effective human bronchial bronchoconstrictors (see Dahlen et al. Nature 288, 484-486, 1980 and Piper, Int. Arc. Appl. Immunol. 76, app. 1, 43, 1985, which stimulate in vitro secretion of mucus from the respiratory tract (Maron et al. Am. Rev. Resp. Dis. 126, 449, 1982), they are also potent vasodilators in the skin (see Bisgaard et al. Prostaglandins 23, 797, 1982) and are responsible for blistering and sudden exacerbation of the disease (Samr et al. Br. I. Pharmacol. 80, 497, 1983). Non-peptide leukotriene, LTB ₄ , is a potent chemotactic factor for leukocytes (see AW Ford Hutchinson, I. Roy S oc. Med. 74, 831-833, 1981), which stimulates cell accumulation and affects the vessels of smooth muscles (see Bray, Br. Med. Bull. 39, 249, 1983). The activity of leukotrienes as mediators of inflammatory processes and allergies is widely confirmed data from a review by Bailey and Casey Ann. Reports. Med. Chem. 19, 87, 1986).

Phospholipase A ₂ (PLA ₂ ) is an enzyme that determines the rate of the arachidonic acid cycle, since it is responsible for hydrolysis of the ester linkage of AA with phospholipids at the C-2 position of the membrane. As a result of this hydrolysis reaction, two products are formed: (1) free arachidonic acid (AA), which becomes available for subsequent metabolism either in the cyclooxygenase direction or in the lipoxygenase direction, and (2) -lysophospholipid. When PLA _{2 is} exposed to alkylarachidonoylglycerophosphatidylcholine, the formation of a platelet-activating factor (TAF) is initiated; TAF is a pro-pathogen of inflammation (see Wedmore et al. Br. I. Phapmacol. 74, 916-917, 1981). In this regard, it should be noted that anti-inflammatory steroids seem to inhibit eicosanoid synthesis by inducing the synthesis of a protein that inhibits PLA ₂ , referred to as macrocortin or lipomodulin (see Flower et al. Nature, London, 278, 456, 1979 and Hirata et al. Proc. Nat. Acad. Sci. USA, 77, 2533, 1980).

As the initial stage leading to the subsequent conversion of AA to various eicosanoids as a result of cyclooxygenase and lipoxygenase directions, the isolation of AA from membrane phospholipids catalyzed by PLA ₂ is a stage that determines the course of various physiological manifestations associated with the activity of eicosanoids and / or TAF. Since FLF ₂ was found to be necessary for platelet aggregation (Pickett et al. Biochem. I. 160, 405, 1976), cardiac muscle contraction and arousal (Geisler et al. Pharm. Res. Commun. 9, 117, 1977 ), as well as the synthesis of prostaglandins (Vogt. Adv. Prostagl. Thromb. Res. 3, 89, 1978), the inhibition of PLA _{2 is} associated with a therapeutic effect on physiological manifestations caused by TAF or products of AA cyclooxygenase and / or lipoxygenase metabolism.

There is also evidence that the products of cyclooxygenase (lipoxygenase) metabolism play a key role both in the pathogenesis of destruction of the gastric mucosa caused as extracellular (contents of the stomach and intestines, microorganisms, etc.) or intracellular (ischemia, viruses, etc.). ) agents, and in protecting cells against such destruction. Thus, on the one hand, prostaglandins exhibit a cytoprotective effect against 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, (adj.) 38-46, 1987). On the other hand, ex vivo experiments show that the tissue of the gastric mucosa of rats pre-treated with ethanol is capable of generating LTC ₄ , and that this production of LTC _{4 is} quantitatively associated with the severity of destruction caused by ethanol (see Lange et al. Naunyn Schmiedeberg Arch Pharmacol. Suppl. 330, P 27, 1985). It has also been shown that LTC ₄ can induce narrowing of both the venous and arteriolar vessels of the submucosa in rats (see Whittle, IUPHAR, 9th Int. Cong. Of Pharm. S 30-2, London, England, 1984). This is very important because damage to the mucosa caused by ethanol can be multifactorial, for example, it can be associated with stasis of blood flow in the stomach, which contributes a significant share to the development of hemorrhagic necrotic processes of the affected (burnt tissue) (see Guth et al. Gastroenterology 87, 1083-1090, 1984). Moreover, in anesthetized cats, exogenous LTD ₄ causes both an increase in pepsin secretion and a decrease in trans-gastric potential (Pendleton et al. Eur. J. Pharmacol. 125, 297-99, 1986). In this regard, it is worth mentioning a significant, recently established fact, 5-lipoxygenase inhibitors and some leukotriene antagonists protect the gastric mucosa from damage caused by oral or parenteral administration of most non-steroidal anti-inflammatory drugs (see Rainsford, Agentsand Actions, 21, 316-319, 1987 ) Platelet activating factor is also involved, as a mediator, in gastrointestinal injuries, and it has recently been found that 5-lipoxygenase inhibitors inhibit TAF-induced gastric mucosa lesions (Gastroenterology, 96, A55, A434, 1989). Thus, a significant part of the evidence indicates the involvement of lipoxygenase activity products in the development of pathological signs associated with damage to the gastric mucosa, such as, for example, those caused by the action of ethyl alcohol and the use of non-steroidal anti-inflammatory drugs. Compounds that inhibit the biological effect of leukotrienes and TAFs and / or control the biosynthesis of these substances, for example, by inhibiting 5-lipoxygenase, are regarded as substances of value as cytoprotective agents.

Accordingly, the biological activity of leukotrienes and SRS, and lipoxygenase, as an enzyme that causes the metabolism of AA in leukotrienes, indicates that a rational choice of drug therapy in order to prevent, suppress or improve symptoms of allergies, anaphylaxis, asthma and inflammatory processes, as well as gastric cytoprotectors, should be based either on blocking the allocation of mediators mediators of such conditions, or on counteracting their influence. Compounds that inhibit the biological effect of leukotrienes and SRS and / or control the biosynthesis of these substances, for example, by inhibiting PLA ₂ , which is involved in the isolation of arachidonic acid from membrane phospholipids, or by inhibiting lipoxygenase, are considered as substances of value as drugs used in treatment of allergic bronchial asthma, allergic rhinitis, as well as other intermediate allergic reactions, as well as ensuring gastric cytoprotection.

в которой Х это -N- или

R³ Z это

=

= N

,

N

,

, -S- или -0-
R¹ это водород, низший алкил или фенил;
R² это водород или низший алкил; или R¹ и R², объединенные вместе, образуют бензольное кольцо; R³ это водород или низший алкил;
n равно 1-2; В это

(CH₂)_mCOOR⁵ или

(CH₂)_mCOOR⁵
в которых R⁴ и R⁵ каждый, независимо друг от друга, представляет водород или низший алкил; R⁶ это галоид или нитро-группа; R⁷ это -

-R⁸ или -

COOR⁵ R⁸ это низший алкил; m равно 0-3; и фармакологически приемлемые соли этих соединений.It has now been found that some new derivatives of benzoylbenzene-, biphenyl- and 2-oxazolalkanoic acid inhibit PLA ₂ and lipoxygenase and counteract the effects of products of the lipoxygenase direction of AA metabolism; therefore, these compounds are suitable for use as anti-inflammatory, anti-allergic and cytotoxic agents. The invention provides new compounds of the following formula: A / CH ₂ / _n OB, wherein A is phenoxyethyl, phenoxyphenyl or a group of the formula

in which X is -N- or

R ³ Z is

=

= N

,

N

,

, -S- or -0-
R ¹ is hydrogen, lower alkyl or phenyl;
R ² is hydrogen or lower alkyl; or R ¹ and R ² combined together form a benzene ring; R ³ is hydrogen or lower alkyl;
n is 1-2; In it

(CH ₂ ) _m COOR ⁵ or

(CH ₂ ) _m COOR ⁵
in which R ⁴ and R ⁵ each independently of one another is hydrogen or lower alkyl; R ⁶ is a halogen or nitro group; R ⁷ is -

-R ⁸ or -

COOR ⁵ R ⁸ 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 A encompasses, interalio, 5- or 6-membered unsaturated nitrogen, sulfur, or oxygen containing mono- or benzocondensed heterocycles, optionally substituted with lower alkyl or phenyl. The following heterocyclic groups fall under the previous definition: furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl, benzoxazolyl, quinolinyl, benzimidazolinyl, etc. Quinolinyl, benzothiazolyl and benzimidazolyl are most preferred.

 The compounds of the invention can form pharmacologically acceptable salts with pharmacologically acceptable organic and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic acid, sulfonic acid, propanoic acid, sulfonic acid, propanoic acid tartaric, citric, malic, lactic, almond, cinnamon, palmitic, itaconic acid and benzenesulfonic acid. Compounds that are carboxylic acids are capable of forming alkali metal salts and alkaline earth metal carboxylates, as well as carboxylates of pharmacologically acceptable cations derived from ammonia or basic amines. The latter include, but are not limited to, ammonium ion, mono-, di- and trimethylammonium, mono-, di- and triethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, 1-isopropylpiperidinium, morpholinium, pyrrole, pyrrole -methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyldiethylammonium, (hydroxymethyl) methylammonium, fe nylmonoethanolammonium and the like

реакции подвергают 4-метоксибензонитрил с 3-бромтолуолом, затем полученное соединение бромируют в этиленбромиде и получают промежуточное соединение 3-бромометил-4-метокси бензофенон.Compounds of the invention can be prepared according to the following reaction schemes. When it is necessary to obtain a compound of the formula
A (CH ₂ ) _n O

4-methoxybenzonitrile with 3-bromotoluene is reacted, then the resulting compound is brominated in ethylene bromide to give the intermediate 3-bromomethyl-4-methoxy benzophenone.

Полученное бромпроизводное затем подвергают реакции с цианидом натрия, в результате чего получают промежуточный продукт цианопроизводное, которое гидролизуют в присутствии основания и получают карбоновую кислоту, которую деметилируют и получают гидроксикарбоновую кислоту

^CH3^O

Полученный промежуточный продукт гидроксикарбоновую кислоту превращают в метиловый эфир при взаимодействии с метиловым спиртом в присутствии пара-толуолсульфокислоты, затем обрабатывают соединением соответствующего галоидного алкила, в котором значение А определено и Hal это галоид, в результате получают требуемый продукт в виде метилового эфира

Полученный метиловый эфир может быть гидролизован традиционными способами, в результате получают нужный продукт в виде свободной карбоновой кислоты.

The resulting bromine derivative is then reacted with sodium cyanide, whereby an intermediate product is obtained which is hydrolyzed in the presence of a base to produce a carboxylic acid which is demethylated and hydroxycarboxylic acid is obtained

^CH 3 ^O

The resulting intermediate hydroxycarboxylic acid is converted to methyl ether by reaction with methyl alcohol in the presence of para-toluenesulfonic acid, then treated with a compound of the corresponding alkyl halide, in which A is defined and Hal is a halide, as a result, the desired product is obtained in the form of methyl ether

The resulting methyl ester can be hydrolyzed by conventional methods, resulting in the desired product in the form of a free carboxylic acid.

R⁶ это нитрогруппа и R⁷ это -C-R⁸, могут быть получены следующим образом, например, 4-бромо-3-нитроацетофенон запускают в реакцию с 4-иоданизолом в присутствии медной бронзы, в результате этой реакции получают промежуточный метоксисодержащий бифенил, который затем диметилируют бромидом алюминия и получают гидроксипромежуточное соединение. Последнее затем запускают в реакцию с соединением соответствующего галоидалкилa А, в котором значение А определено выше, Hal это галоид и, в результате, получают конечный требуемый продукт.Compounds of the invention of the formula
A (CH ₂ ) _n O

R ⁶ is a nitro group and R ⁷ is —CR ⁸ , can be prepared as follows, for example, 4-bromo-3-nitroacetophenone is reacted with 4-iodoanisole in the presence of copper bronze, this reaction gives an intermediate methoxy-containing biphenyl, which then dimethylated with aluminum bromide to give a hydroxy intermediate compound. The latter is then reacted with a compound of the corresponding haloalkyl A, in which A is defined above, Hal is a halogen and, as a result, the final desired product is obtained.

Соединения, в которых R⁶ это галоид и R⁷ это CHCOOR⁶, могут быть получены по способу, в котором используется 4-метоксибифенилсодержащее промежуточное соединение, полученное в предыдущей схеме. 4-Ацетил-4-метокси-2-нитробифенил промежуточный продукт предыдущей схемы восстанавливают хлоридом двухвалентного олова и получают промежуточный продукт аминопроизводное, в котором затем аминогруппу замещают на галоид. Например, аминогруппа может быть замещена на фтор через стадию получения переходного промежуточного продукта диазонийфторобората, который получают из аминопроизводного при взаимодействии с нитритом натрия в присутствии тетрафтороборной кислоты. Полученный ацетилфторометоксибифенил затем превращают в соответствующую карбоновую кислоту посредством деметилирования бромистым водородом и получают в результате 2-фторо-4-гидрокси-1,1-бифенил-4-уксусную кислоту

Последнее промежуточное соединение карбоновой кислоты этерифицируют метанолом в присутствии пара-толуолсульфокислоты, полученный продукт затем взаимодействует с соответствующим соединением галоидалкила А, в котором А определен выше, а Hal это галоид, в результате получают требуемый продукт в виде метилового эфира

Полученный эфир может быть гидролизован традиционными способами с получением нужного продукта в виде карбоновой кислоты.

Compounds in which R ⁶ is halogen and R ⁷ is CHCOOR ⁶ can be prepared by a process that uses the 4-methoxybiphenyl-containing intermediate obtained in the previous scheme. The 4-acetyl-4-methoxy-2-nitrobiphenyl intermediate of the previous scheme is reduced with stannous chloride to give the amino derivative, in which the amino group is then replaced by a halogen. For example, an amino group can be replaced by fluorine through the step of preparing a transition intermediate of diazonium fluoroborate, which is obtained from an amino derivative by reacting with sodium nitrite in the presence of tetrafluoroboric acid. The resulting acetyl fluoromethoxybiphenyl is then converted to the corresponding carboxylic acid by demethylation with hydrogen bromide to give 2-fluoro-4-hydroxy-1,1-biphenyl-4-acetic acid

The last carboxylic acid intermediate is esterified with methanol in the presence of p-toluenesulfonic acid, the resulting product is then reacted with the corresponding haloalkyl compound A, in which A is defined above, and Hal is a halogen, and the desired product is obtained in the form of methyl ester

The resulting ether can be hydrolyzed by conventional methods to obtain the desired product in the form of a carboxylic acid.

(CH₂)_mCOOR⁵ или

(CH₂)_mCOOR⁵
могут быть получены следующим образом. В реакцию запускают бензальдегид и 4-метоксибензальдегид и получают 4-метоксибензоин, который затем превращают в полусукцинат по реакции с янтарным ангидридом. Полусукцинат затем запускают в реакцию с мочевиной и уксусной кислотой и получают промежуточный продукт 4-(4-метоксифенил)-5-фенил-2-оксзолпропионовую кислоту

Последний промежуточный продукт деметилируют бромистым водородом и этерифицируют метанолом, получают гидрокси метиловый эфир промежуточный продукт, который затем подвергают реакции с соответствующим соединением галоидного алкила А, в котором А определен выше, Hal это галоид, и получают требуемый конечный продукт в виде метилового эфира

CH₂COOH
Полученный эфир может быть гидролизован традиционными способами с получением требуемого конечного продукта в виде карбоновой кислоты.Compounds of the invention of the formula

(CH ₂ ) _m COOR ⁵ or

(CH ₂ ) _m COOR ⁵
can be obtained as follows. Benzaldehyde and 4-methoxybenzaldehyde are reacted to give 4-methoxybenzoin, which is then converted to hemisuccinate by reaction with succinic anhydride. The hemi succinate is then reacted with urea and acetic acid to give the intermediate 4- (4-methoxyphenyl) -5-phenyl-2-oxzolpropionic acid

The last intermediate product is demethylated with hydrogen bromide and esterified with methanol, an intermediate product is obtained, which is then reacted with the corresponding compound of alkyl halide A, in which A is defined above, Hal is a halide, and the desired end product is obtained in the form of methyl ether

CH ₂ COOH
The resulting ester can be hydrolyzed by conventional methods to give the desired end product as a carboxylic acid.

Бензоконденсированные гетероциклические соединения, использованные в приведенных последовательностях реакций, также могут быть коммерчески доступны или могут быть получены известными способами. Например, такие производные, как 1-метил-2-хлорметилбензимидазол, 2-хлорометилбензтиазол и 2-хлорметилбензоксазол могут быть получены в соответствии со следующей реакционной схемой:
R

R

где Х это -0- или NCH₃. Реакцию предпочтительно проводить при контролируемой низкой температуре в органическом растворителе, таком как метиленхлорид.The corresponding starting materials used in the reaction schemes of the foregoing are commercially available or can be synthesized according to methods well known to those skilled in the art. For example, the intermediate 2-bromomethylquinoline can be obtained in accordance with the following reaction scheme

Benzocondensed heterocyclic compounds used in the above reaction sequences may also be commercially available or may be prepared by known methods. For example, derivatives such as 1-methyl-2-chloromethylbenzimidazole, 2-chloromethylbenzothiazole and 2-chloromethylbenzoxazole can be prepared according to the following reaction scheme:
R

R

where X is -0- or NCH ₃ . The reaction is preferably carried out at a controlled low temperature in an organic solvent such as methylene chloride.

The compounds of the invention, due to their ability to inhibit the activity of the enzyme FLA ₂ , as well as the enzyme lipoxygenase, and to counteract mediators resulting from enzymatic metabolism, are suitable for use in the treatment of diseases that are mediated by arachidonic acid oxidation products. Thus, the compounds of the invention are indicated in the treatment of diseases such as rheumatoid arthritis, inflammation of the digestive tract, osteoarthritis, tendonitis, bursitis, psoriasis (and related skin inflammations) and similar diseases, including inflammatory processes. In addition, due to their ability to counteract LTC ₄ , LTD ₄ and LTE ₄ , which are substituents of SRS-A, they are useful in the inhibition of symptoms induced by these leukotrienes. Therefore, the compounds of the invention are indicated for the prevention and treatment of those painful conditions caused by LTC ₄ , LTD ₄ and LTE ₄ , for example, allergic rhinitis, allergic bronchial asthma and others, provoked by leukotrienes, naso-bronchial obstructive airways diseases, as well as other intermediate allergic reactions, such as allergic conjunctivitis. These compounds are especially valuable as drugs for the prevention and treatment of allergic bronchial asthma.

 The compounds of the invention are cytoprotective agents and are considered to be particularly useful for co-administration with traditional anti-inflammatory drugs of a non-steroidal nature, causing painful gastrointestinal irritation due to their main side effect. The cytoprotective effect of these compounds significantly reduces the gastro-irritating effect of traditional anti-inflammatory drugs. This protective effect is based not only on the ability of the compounds of the invention to inhibit the biological effect of leukotrienes and / or to control the biosynthesis of these substances by inhibiting lipoxygenase, but also on the bypass effect, which turns off the lipoxygenase oxidation of arachidonic acid and switches to the cyclooxygenase conversion cycle of arachidonic acid, which leads to to increase the formation of cytoprotective prostanglandins. Such biological effects make the compounds of the invention particularly useful in the treatment of diseases such as erosive esophagitis, inflammation of the digestive tract and induced hemorrhagic lesions, such as those caused by alcohol and non-steroidal anti-inflammatory drugs (NSAIDs), hepatic ischemia, damage or necrosis of liver tissue, pancreas glands, kidneys, myocardium caused by the action of a toxic substance; destruction of the liver parenchyma caused by hepatoxins such as carbon tetrachloride and D-galactosoamine; renal ischemia; diseases caused by destruction (liver damage; bile salt pancreatitis or stomach upset; cell breakdown; caused by trauma or stress; and renal failure caused by glycerin.

 When the compounds of the invention are used in the treatment of allergic diseases of the respiratory tract, as anti-inflammatory drugs and / or cytoprotective agents, they can be included in oral release forms, such as tablets, capsules, and the like. The compounds can be administered alone or in combination with suitable carriers (excipients) such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax cocoa butter and the like Thinners, perfumes, solubilizing agents, lubricants, suspending agents, binders, tablet disintegrating agents and the like. funds can be used in graduation form. Compounds can be encapsulated with or without other carriers. In all cases, the proportion of the active ingredient in the named compositions, both in liquid and in solid, should be at least in such a quantity as to exert the desired oral activity. The compounds of the invention can also be administered parenterally, in these cases they are used in the form of sterile solutions containing other dissolved substances, for example, a sufficient amount of salt or glucose, so that the injected solution is isotonic. For administration by inhalation or insufflation (insufflation), these compounds can be formulated as aqueous or partially aqueous solutions, such that can then be used in the form of aerosols.

 Dosage requirements vary depending on the particular formulations used, the route of administration of pieparat, the severity of the disease (symptoms), and the particular subject to be treated. As a rule, treatment should be started with small doses less than the optimal dose of this compound. Then the dosage is increased to achieve the optimum effect under the circumstances. In general, it is most desirable to administer the compounds of the invention in a concentration that will usually give an effective result without causing undesirable (harmful) or destructive side effects, and they can be administered in a single dose or, if necessary, this dose may be divided into suitable sub-doses that are administered at the appropriate time of day.

The action of the compounds of the invention as PLA ₂ and lipoxygenase inhibitors, leukotriene antagonists, as well as anti-inflammatory drugs and potential gastro irritants can be demonstrated by standard pharmacological methods, which will be more fully described in the examples.

These pharmacological procedures, interalia, determine the specificity of the action of the compounds of the invention as PLA ₂ inhibitors measured by the ability of these compounds to inhibit the synthesis of LTB ₄ and PGE _{2 of} glycogen-excised rat polymorphonuclear leukocytes, as well as their ability to inhibit the release of arachidonic acid, carried out using PLA ₂ , a source which is a person. Pharmacological studies further demonstrate the ability of the compounds of the invention to inhibit in vivo lipoxygenase and cyclooxygenase directions of conversion (metabolism) of arachidonic acid.

 The examples illustrate the methods of preparation and pharmacological study of the compounds of the invention.

PRI me R 1. 1- [2-nitro-4 ^' - (2-quinolinylmethoxy) - [1,1 ^I' -biphenyl] -4-yl-ethanone.

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

A stirred 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 a nitrogen atmosphere, placed in an oil bath heated to 80 ^about C. The temperature was slowly raised to 110 ^about C, then the mixture was kept 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 washings were evaporated, and the remaining dark brown thick oil was passed through flash chromatography (Merck 60 silica gel pre-impregnated with dichloromethane, elution was carried out using 9: 1 hexane-ethyl acetate mixture to remove impurities, and to isolate the main product mixture of 8: 2 hexane-ethyl acetate) to afford 16.2 g (32% yield) of the title compound (yellow solid, m.p. 124-126 ° ^C).

NMR (CDCl ₃ , 400 MHz): δ 2.67 (C, 3H, COCH ₃ ), 3.85 (s, 3H, OCH ₃ ), 6.97 (d, 2H, J 8.74 Hz, ArH) 2.27 (d, 2H, J 8.74 Hz, ArH), 7.56 (d, 1H, J 8 Hz, ArH), 8.15 (d, 1H, J 8 Hz, ArH), 8, 34 (s, 1H, ArH). MS / EI, m / z /: 271 / M ⁺ /.

B. 4-Acetyl-4 ^{'-hydroxy-2-nitrobiphenyl.}

To a stirred solution of aluminum bromide AlBr ₃ (12.6 g, 47.4 mmol) in benzene (45 ml) was added dropwise a solution of methyl ether (5 g, 18.45 mmol) of the substance of step A in benzene (12 ml) under nitrogen atmosphere. ) within 30 minutes The resulting solution was stirred at room temperature for 3.5 hours (TLC, 8: 2 hexane-ethyl acetate). The mixture was cooled in an ice bath, and the resulting complex was destroyed by adding dropwise 6 N HCl (about 37 ml). The organic layer is separated and the aqueous phase is re-extracted with ether (3x), the combined extracts are concentrated to a small volume and extracted again with 2.5 g of NaOH (2x50 ml + 1x10 ml). The alkaline extracts are cooled and acidified with concentrated HCl (to pH 2). The solid was collected and dried (4.27 g, 90%). It is used in the next step without further purification.

NMR (CDCl ₃ , 400 MHz): δ 2.67 (s, 3H, COCH ₃ ), 5.03 (broadening, 1H, OH), 6.91 (d, 2H, J 8.56 Hz, ArH), 7.23 (d, 2H, J 8.57 Hz, ArH), 7.55 (d, 1H, J 7.9 Hz, ArH), 8.15 (d, 1H, J 8.1 Hz, ArH) 8.34 (s, 1H, ArH).

MS (EI, m (s): 257 (6.p. M ⁺ ).

C. 1- [2-nitro-4 ^' - [2-quinolinyl) -1,1 ^' -biphenyl-4-yl] ethanone.

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 for 15 minutes. 2-Chloromethylquinoline (3.34 g, 18.83 mmol), free, freshly prepared from the hydrochloride salt, is added and the mixture is refluxed for 10 hours (TLC, 7: 3 hexane-ethyl acetate). A 10% excess of potassium carbonate, 18-crown-6 and chloromethylquinoline was added, boiling was continued for another 4 hours. The solvent was distilled off, and the residue was diluted with water and extracted with ethyl acetate (3x). The extracts are washed and dried over anhydrous magnesium sulfate. The residue was flash chromatographed (Merck 60 silica gel pre-impregnated with dichloromethane and eluted to increase polarity with 7: 3, 1: 1 and 1: 3 mixtures of hexane-ethyl acetate and then with pure ethyl acetate). Flash chromatography afforded 2.59 g of a pure product of the title compound. Recrystallization from toluene gave a yellow solid with mp. 160-162 ^{° C} (2.05 g, 30%).

NMR (CDCl ₃ , 400 MHz): δ 2.66 (s, 3H, COOH ₃ ), 5.43 (s, 2H, OCH ₂ Ar), 7.10 (d, 2H, J 8.7 Hz, ArH ), 7.27 (d, 2H, J 8.7 Hz, ArH), 7.56 (m, 2H, ArH), 7.68 (d, 1H, J 8.49 Hz, ArH), 7.75 (dt, 1H, ArH), 7.84 (d, 1H, J 8.1 Hz, ArH), 8.09 (d, 1H, J 8.5 Hz, ArH), 8.14 (dd, 1H, ArH), 8.22 (d, 1H, J 8.49 Hz, ArH), 8.34 (s, 1H, ArH). MS (EI, m (s): 398 (M ⁺ ), 256,158,142.

Analysis for C ₂₄ H ₁₈ N ₂ O ₄
Calculated, C 72.35; H, 4.55. N, 7.03.

 Found, C, 71.96; H 4.75; N, 6.80.

PRI me R 2. 2-fluoro-4 '- (2-quinolinylmethoxy) - [1,1 ^' -biphenyl] -4-acetic acid.

A. 4-Acetyl-4 ^' -methoxy-2-aminobiphenyl.

To a stirred warm solution of stannous chloride (49.4 g, 218.9 mmol) in a mixture of concentrated HCl (72 ml) and ethanol (99 ml) was added the nitro derivative of Example 1 A (10.7 g, 39.5 mmol). The resulting yellow solution was refluxed for 3.5 hours (TLC, 1: 1 hexane-ethyl acetate). Ethyl alcohol was removed and the residue was poured into a mixture of 50% NaOH (360 ml) and ice. The resulting solid was extracted (dichloromethane, 3x), the extracts washed with water and dried over anhydrous sodium sulfate. Removal of the solvent gave a yellow solid (9.31 g, 97.8%), mp. 152-154 ^about S.

NMR (CDCl ₃ , 400 MHz): δ 2.59 (s, 3H, COCH ₃ ), 3.80 (s, 3H, OCH ₃ ), 6.97 (d, 2H, J 8.7 Hz, ArH) , 7.23 (d, 1H, J 7.4 Hz, ArH), 7.40 (d, 2H, J 8.7 Hz, ArH), 7.48 (d, 1H, J 7.3 Hz, ArH ), 7.49 (s, 1H, ArH). MS (EI, m / z / :( M-CH ₃ ) ⁺ , 226, (M-CH ₃ ) ⁺ , 198 (M-COSH ₃ ) ⁺ , 83.

B. 4-Acetyl-4 ^' -methoxy-2-ftorobifenil.

To a stirred ice-cooled mixture of aniline (9.2 g, 38.2 mmol) in tetrahydrofuran (26 ml), water (9.8 ml) and HBF ₄ (49% 35.1 ml), sodium nitrite solution is slowly added (2, 82 g, 48.85 mmol) in water (5 ml). During the addition, the outside temperature is kept below 5 ° ^C. The mixture was then stirred for an additional 20 minutes at 0-5 ° ^C. The resulting diazonium fluoroborate is filtered off and washed with 10% aqueous HBF ₄ and 10% methanol in ether and dried in a vacuum. The salt is decomposed under heating at 70 ° ^C in xylene (95 ml). After decomposition ceased, the mixture was refluxed for another 2.5 hours (TLC, 1: 1 hexane-ethyl acetate, UV). Xylene is removed and the residue is extracted with ethyl acetate (3x) and ether. The combined extracts were washed with 10% sodium carbonate solution, salted out and dried over anhydrous magnesium sulfate. Removal of the solvent leads to the formation of an amber-colored oil (6.03 g), which is purified by flash chromatography (silica gel of the Merck 60 brand, pre-impregnated with dichloromethane, eluting with 95: 5 hexane-ethyl acetate). The title compound was obtained in the form of a yellow solid in an amount of 3.12-4.75 g (33-51%, depending on the experience); so pl. 100-101 ^about C.

NMR (CDCl ₃ , 400 MHz): δ 2.62 (s, 3H, COCH ₃ ), 3.86 (s, 3H, OCH ₃ ), 7.00 (d, 2H, J 8.9 Hz, ArH) 7.50-7.80 (m, 5H, ArH).

MS (EI / m (s): 244 (M) ⁺ , 229 (bp M-CH ₃ ) ⁺ .

C. 2-Fluoro-4 ^' -methoxy- [1,1 &^apos; -biphenyl] -4-acetic acid.

A mixture of sulfur (0.468 g, 14.6 mmol), morpholine (2.57 ml) and the ketone obtained in stage A (3.95 g, 16.2 mmol) is heated for 17 hours under reflux (TLC, treated with acid silica gel layer, 8: 2 hexane-ethyl acetate). Under cooling, glacial acetic acid (9.9 ml), sulfuric acid (1.6 ml) and water (4 ml) were added and heating was continued under reflux for 30 hours. Water was then added and the mixture was extracted with ether (3x). The combined extracts are concentrated to a small volume and extracted with 10% sodium carbonate solution. The alkaline extracts were carefully acidified in the cold, and concentrated HCl was added (to pH 2). The acid, the title of which is given in the title, is extracted with ether (3x), and the extracts are washed and dried over anhydrous magnesium sulfate. After removal of the solvent a solid was obtained a tan to brown color (2.37 g, 56.3%, m.p. 140-142 ° ^C).

NMR (CDCl ₃ , 400 MHz): δ 3.68 (s, 2H, CH ₂ COO), 3.85 (s, 3H, OCH ₃ ), 6.96-7.50 (m, 7H, ArH). MS (EI / m (s): 260 (M) ⁺ , 215 (b, p. M-COOH) ⁺ .

D. 2-Fluoro-4 ^' -hydroxy- [1,1 &^apos; -biphenyl] -4-acetic acid.

To a solution of methyl ester (1.31 g, 5.04 mmol) of step C in glacial acetic acid (17 ml) was added dropwise a 48% solution of HBr in acetic acid (25 ml), and the mixture was heated under reflux for 4.5 h (TLC, 7: 3 hexane-ethyl acetate). A little water was added and the mixture was extracted with ether (3x). The extracts were washed, dried over anhydrous magnesium sulfate. Removal of the solvent gave the title compound as a brownish-reddish substance (1.13 g, 92%), mp. 208-210 ^about C.

NMR (DMCO-d ₆ , 400 MHz): δ 3.61 (s, 2H, CH ₂ COO), 6.83 (d, 2H, J 8.64 Hz, ArH), 7.1-7.42 ( m, 5H, ArH), 9.61 (s, 1H, COOH). MS (CI m (s): (M) ⁺ 246, 201 (M-COOH) ⁺ .

E. 2-Fluoro-4 ^{'-hydroxy [1,1'} -biphenyl] -4-acetic acid methyl ester.

A solution of the acid from step D (1.1 g, 4.47 mmol) in methyl alcohol (10 ml) containing p-toluenesulfonic acid. H ₂ O (0.159 g) was heated under reflux for 1.5 h (TLC, acid-treated silica gel layer, 7: 3 hexane-ethyl acetate). The solvent was removed, the residue was dissolved in ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solid was brown-reddish color (1.16 g, m.p. 115-118 ^{° C,} quantitative yield) was used in the next step without further purification.

NMR (CDCl ₃ , 400 MHz): δ 3.65 (s. 2H, CH ₂ COO), 3.73 (s, 3H, COOCH ₃ ), 6.88 (d, 2H, J 8.8 Hz, ArH ), 7.10 (m, 2H, ArH), 7.32-7.44 (m, 3H, ArH).

MS (EI, m (s): 260 (M) ⁺ , 201 (bp M-COOSN ₃ ) ⁺ .

F. 2-Fluoro-4 ^' - (2-quinolinylmethoxy) - [1,1 ^' -biphenyl] -4-acetic acid methyl ester.

A mixture of phenol from step E (1.16 g, 4.46 mmol), powdered anhydrous potassium carbonate (0.616 g, 4.46 mmol), 18-crown-6 (0.118 g, 0.445 mmol) and acetonitrile was stirred at room temperature in nitrogen atmosphere for 15 minutes Then, 2-chloromethylquinoline (0.871 g, 4.9 mmol) was added to it in the form of a free base freshly prepared from hydrochloride salt, and the mixture was placed in an oil bath heated to 65 ^° C for 5 hours. A 10% excess of carbonate was added. potassium, 18-crown-6 and chloromethylquinoline, and heating was continued for another 6 hours (TLC, 19: 1 dichloromethane-methanol or 7: 3 hexane-ethyl acetate). The solvent was removed and the residue was diluted with water and extracted (3x) with ethyl acetate. The extracts were washed and dried over anhydrous magnesium sulfate. After removal, a yellowish-brown solid is obtained, which is purified by flash chromatography (silica gel Merck 60, pre-treated with dichloromethane, eluting with 7: 3 hexane-ethyl acetate). The compound thus obtained (1.55 g, 87%) was recrystallized from methanol. Received a solid product almost white with so pl. 99-101 ^about S.

NMR (CDCl ₃ , 400 MHz): δ 3.64 (s, 2H, CH ₂ COO), 3.72 (s, 3H, COOCH ₃ ), 5.43 (s, 2H, OCH ₂ Ar), 7, 1 (M, 4H, ArH), 7.35 (t, 1H, ArH), 7.47 (d, 2H, ArH), 7.55 (t, 1H, ArH), 7.69 (d, 1H, ArH), 7.74 (t, 1H, ArH), 7.84 (d, 1H, ArH), 8.09 (d, 1H, ArH), 8.20 (d, 1H, ArH) = MS (EI , m (s): 401 M ⁺ , 142, 114.

Analysis for C ₂₅ H ₂₀ FNO ₃ .

 Calculated, C 74.80; H 5.02; N, 3.49.

 Found, C, 74.68; H 4.65; N, 3.49.

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

A solution of the ester (1.69 g, 4.21 mmol) of step F in dry tetrahydrofuran (20 ml) was treated under nitrogen, dropwise adding 1N. LiOH (12.6 ml), and the mixture was stirred at room temperature for 3 hours (TLC, 19: 1 dichloromethane-methanol or 1: 1 hexane-ethyl acetate). The solvent was removed and the residue was treated with water and neutralized with 10% acetic acid to a pH of 6.5. The acid was extracted with ethyl acetate (large volume needed) and the extracts were dried over anhydrous magnesium sulfate and then evaporated to give a nearly white solid (1.65 g, quantitative yield, m.p. 190-193 ^C. (decomp.) Recrystallized from ethyl acetate and received a white solid (1.3 g, 80% yield, mp 195-196 ^about With decomp.). The sample for analysis was dried in vacuum at 40 ^about C.

NMR (DMCO-d ₆ , 400 MHz): δ 3.62 (s, 2H, CH ₂ COO), 5.41 (s, 2H, CH ₂ OAr), 7.15 (m, 4H, ArH), 7 41 (t, 1H, J 8 Hz, ArH), 7.48 (d, 2H, ArH), 7.61 (t, 1H, ArH), 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 ( ⁺ PAB, m (s): 388 (M) ⁺ .

Analysis for C ₂₄ H ₁₈ FNO ₃ .

 Calculated, C 74.41; H 4.68; N, 3.62.

 Found, C, 74.28; H 4.48; N, 3.69.

 PRI me R 3. 3- [4- (2-Quinolinylmethoxy (benzoyl) benzene acetic acid.

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

Into a three-necked flask equipped with a refrigerator, a mechanical stirrer and a dropping funnel, 1.925 g (79.19 mmol) of magnesium shavings and ether in an amount sufficient to cover the shavings were charged in a stream of nitrogen. A few drops of a solution of bromotoluene (15.79 g, 92.28 mmol) in ether (40 ml) were added together with an iodine crystal to initiate the reaction. Then the remaining solution was added dropwise, and the mixture was heated under reflux until the magnesium chips were completely dissolved. After cooling, a solution of 4-methoxybenzonitrile (10 g, 75.1 mmol) dried in vacuo over P ₂ O ₅ ) was added in one portion.

The mixture was heated for 2 hours (TLC, lack of starting reagents), cooled (ice bath) and slowly treated with cold water (130 ml), then diluted with H ₂ SO ₄ (1: 1 v / v 25 ml). Decomposition of the complex is completed by heating the mixture under reflux for 4 hours (control by TLC, 8: 2 ether-ethyl acetate). Then stirring was continued overnight at room temperature, the layer was separated and extracted with ether (3x). The extracts were washed with 5% NaHCO ₃ solution, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (amber-colored oil, 13.93 g) was purified by flash chromatography (Merck silica gel 60, eluting with 8: 2 petroleum ether-ethyl acetate) to give the title compound as a light yellow oil colors (12.5 g, 73.5% yield).

NMR (CDCl ₃ , 400 MHz): δ 2.4 (s, 3H, CH ₃ ), 3.9 (s, 3H, OCH ₃ ), 6.96 (d, J 8.8 Hz, 2H, ArH) 7.38 (m, 2H, ArH), 7.53 (d, J 6.9 Hz, ArH), 7.57 (s, 1H, ArH), 7.82 (d, J 8.7 Hz, 2H, ArH).

MS (EI, m (s): 226 (M) ⁺ , 135 (broad peak), 91.

B. 3-Bromomethyl- [4 ^' -methoxy] benzophenone.

A solution of benzophenone (17.5 g, 77.4 mmol) of step A in ethylene bromide (26.5 ml) containing a small amount of benzoyl peroxide was heated under reflux. A solution of bromine (12.7 g, 79.6 mmol) in ethylene bromide (15 ml) was added dropwise dropwise during 30 min during the irradiation of the mixture with a 300 W photolamp. Reflux was continued for 17 hours (TLC, 9: 1, petroleum ether-ethyl acetate, traces of the starting material were still present). The solvent was distilled off in vacuo, and the residue (brown oil) was purified by flash chromatography (silica gel, Merck 60, previously adsorbed in dichloromethane, eluting with 9: 1 ethyl ether-ethyl acetate) to give unreacted starting material (2.59 g, about 15%) and the desired product (14.36 g, 61% or 71.5% based on the selected unreacted starting material), as well as a certain amount of mixed fractions (about 5.20 g). Yellow solid melting at 58-61 ^{° C} and this material is used without further treatment in the next step.

NMR (CDCl ₃ , 400 MHz): δ 3.88 (s, 3H, OCH ₃ ), 4.52 (s, 2H, CH ₂ Br), 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 (s): 306/304/1 bromine, M ⁺ 225 135 (wide peak).

 Traces of bromine derivative at 386/384/382.

C. 3-Cyanomethyl- [4 ^' -methoxy] benzophenone.

The bromine derivative (14 g, 45.9 mmol) in step B was dissolved in dioxane (30 ml) and a solution of NaCN (7 g) in water (28.5 sludge) was added. The mixture was heated under reflux for 6 h (TLC, petroleum ether-ethyl acetate 8: 2), then passed through activated carbon, if necessary, and extracted with ether (3x). The extracts were dried over anhydrous magnesium sulfate and evaporated to dryness, resulting in a brown oil (13.44 g). The crude product was purified by flash chromatography (Merck silica gel 60 previously adsorbed in dichloromethane) eluting with 6: 4 hexane-ethyl acetate) to give the pure product (10.69 g, 92% yield) as a light yellow oil, which cures when standing. Almost colorless solid product melts at 70-71 ^about C.

NMR (CDCl ₃ , 400 MHz): δ 3.80 (s, 2H, CH ₂ CN), 3.87 (s, 3H, OCH ₃ ), 6.95 (d, J 8.6 Hz, ArH), 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 (s): 251 (M) ⁺ , 135 (broad peak).

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

The nitrile (4 g, 15.9 mmol) of step C was dissolved in a 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). During cooling, water was added to the ice bath. The solution was washed with ethyl acetate and then acidified in cold with concentrated HCl to pH 2. The acid was extracted with ethyl acetate (3x), and the extracts were dried over anhydrous magnesium sulfate, and then evaporated to dryness to give a crude product (yellow solid, 3.56 g, yield 82%), mp 138-140 ^about C.

NMR (CDCl ₃ , 400 MHz): δ 3.72 (s, 2H, CH ₂ COO), 3.88 (s, 3H, OCH ₃ ), 6.95 d, J 8.8 Hz, 2H, ArH) 7.43 (t, 1H, ArH), 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 (s): 270 (M) ⁺ , 211 (M-CH ₂ COOH) ⁺ , 135 (broad peak), 107.

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

The homogeneous mixture of the acid (8.1 g, 0.030 mmol) and pyridine Step D (13.87 g, 0.120 mmol) was stirred in a nitrogen stream under heating in an oil bath at 200-210 ^C for 7 hours (TLC, toluene-methanol 9: 1, dichloromethane-methanol 9: 1). After cooling, the mixture was dissolved in dichloromethane. The solution was extracted with 1N. NaOH solution, the extract was acidified in the cold with concentrated HCl and extracted with ethyl acetate (3x). After drying over anhydrous magnesium sulfate, the solvent was removed and the resulting crude compound, given the title, as a brownish-yellow solid (7.61 g, quantitative yield), mp. 147-149 ^about S.

NMR (DMCO-d ₆ , 400 MHz): δ 3.67 (s, 2H, CH ₂ COO), 6.88 (d, J 8.84 Hz, 2H, ArH), about 7.5 (m, 4H , ArH), 7.65 (d, J 8.8 Hz, 2H, ArH), 10.4 (s, 1H, OH), 12.3 (s, 1H, COOH).

MS (m (s): 257 (M + H) ⁺ , 217, 131, 91 (broad peak).

 F. 3- [4-Hydroxybenzoyl] phenylacetic acid methyl ester.

A mixture of acid (8.56 g, 33.4 mmol) of step E and paratoluene sulfonic acid monohydrate (1.05 g, 5.6 mmol) in methanol (70 ml) was heated for 2.5 hours 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, obtaining a brownish-reddish solid product of 8.68 g, 96.2% yield), so pl. 111-113 ^about C. This crude product was used in the next stage.

NMR (CDCl ₃ , 400 MHz): δ 3.69 (s, 2H, CH ₂ COO), 3.69 (s, 3H, COOCH ₃ ), 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), 7.64 (s, 1H, ArH), 7.74 (d, 2H, J, 8.4 Hz, ArH).

MS (m (s) 271 (M + H) ⁺ , 217.131.91 (broad peak).

 G. 3- [4- (2-Quinolinylmethoxy) benzoyl] benzoacetic acid methyl ester.

A mixture of phenol (4 g, 14.8 mmol), stage F, anhydrous powder K ₂ CO ₃ (2.05 g, 14.8 mmol) and 18-crown-6 (0.4 g, 1.48 mmol) in acetonitrile (35 ml) was stirred at room temperature under nitrogen for 15 minutes. Then, one portion was added 2-Chloromethylquinoline (2.9 g, 16.28 mmol, freshly prepared from the hydrochloride salt) and the mixture was heated in an oil bath while maintaining the temperature at 65-70 ^{° C} for 8 hours (TLC, toluene-methanol 9: 1). A 10% excess of K ₂ CO ₃ , crown ether and chloromethylquinoline was added and heating was continued for another 8 hours. Acetonitrile was distilled off and the residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give a brownish-yellow solid product (6.57 g). The crude product was purified by flash chromatography (silica gel) of the Merck 60 brand, previously adsorbed in dichloromethane, eluting with ethyl acetate 7: 3) and the title compound was obtained as a light yellow solid (5.03 g, 82.7 yield). %), mp 93-95 ^about S.

NMR (CDCl ₃ , 400 MHz): δ 3.67 (s, 5H, CH ₂ COO + OCH ₃ ), 5.45 (s, 2H, ArCH ₂ O), 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), 7.6-7.7 (m, 3H, ArH), 7.7-7.82 (m, 4H, ArH), 8.07 (d, 1H, ArH), 8, 20 (d, J 8.4 Hz, 1H, ArH).

MS (EI, m (s): 411 (M) ⁺ , 142, 121 (broad peak).

 N. 3- [4- (2-Quinolinylmethoxy (benzoyl) benzene acetic acid.

To a solution of ether (5 g, 12.16 mmol) of step G in dry tetrahydrofuran (66 ml) was added 1M LiOH (37 ml, 37 mmol), and the mixture was stirred under nitrogen at room temperature for 2.5 h (TLC, toluene methyl alcohol 9: 1). Tetrahydrofuran was evaporated and the residue was diluted with water, acidified to pH 6.5 with 10% acetic acid and extracted with ethyl acetate (3x). The extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (4.94 g, pale yellow in color) was recrystallized from ethyl acetate to give 3.65 g (75% yield) of pure title compound (white solid, m.p. 146-147 ° ^C).

NMR (DMCO-d ₆ , 400 MHz): 3.68 (s, 2H, CH ₂ COO), 5.48 (s, 2H, ArCH ₂ O), 7.22 (d, 2H, 8.8 Hz, ArH), 7.47 (m, 1H, ArH), 7.53 (m, 2H, ArH), 7.62 (m, 2H, ArH), 7.69 (d, J 8.4 Hz, 1H, ArH), 7.74-7.82 (m, 3H, ArH), 8.2 (m, 2H, g ArH), 8.43 (d, J 8.5 Hz, 1H, ArH), 12.39 (1H, COOH).

MS (EI, m (s): 397, (M) ⁺ , 380g (M-OH) ⁺ , 142.

Analysis for C ₂₅ H ₁₉ NO ₄ .

 Calculated, C 75.57; H 4.78; N, 3.53.

 Found, C, 75.22; H 4.76; N, 3.39.

PRI me R 4. 3- [4-2-Naphthalenylmethoxy (benzoyl] benzene acetic acid
A. 3- [4- (2-Naphthalenylmethoxy (benzoyl) benzene acetic acid methyl ester.

A mixture of phenol (1 g, 3.7 mmol) of Example 3 F, anhydrous powder K ₂ CO ₃ (0.48 g, 3.7 mmol), 18-crown-6 ether (0.098 g, 0.37 mmol) and acetonitrile (10 ml) was stirred under nitrogen for 15 minutes. To the mixture was added 2-Bromomethylnaphthalene (0.496 g, 4.07 mmol) was placed in an oil bath and heated for 10 hours while maintaining the temperature at 65-70 ^{° C} (TLC, dichloromethane-ethyl acetate 8: 2). A 10% excess of K ₂ CO _3, crown ether and bromomethylnaphthalene was added, and heating was continued for another 4 hours. Acetonitrile was distilled off, and the residue was dissolved in water and extracted with ethyl acetate (3x). The extracts were washed with 1M NaOH and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (1.49 g, waxy solid) was used without further processing in the next step.

NMR (CDCl ₃ , 400 MHz): δ 3.7 (s, 5H, OCH ₃ + CH ₂ COO), 5.32 (s, 2H, A CH ₂ O), 7.08 (d, J 8.7 Hz, 2H, ArH), 7.4-7.56 (m, 5H, ArH), 7.63-7.68 (m, 2H, ArH), 7.82-7.92 (m, 6H, ArH ) MS (m (s): 410 (M) ⁺ , 141 (broad peak).

 B. 3- [4- (2-Naphthalenylmethoxy) benzoyl] benzene acetic acid.

The ether solution (1.29 g, 3.15 mmol) of step A was treated by dropwise adding a 1M LiOH solution, and the mixture was stirred under nitrogen overnight. The solvent was evaporated, and the residue was dissolved in water, acidified in the cold with 10% acetic acid to pH 3 and extracted with ethyl acetate (3x). The extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue (1.24 g, quantitative yield) was recrystallized by dissolving in a relatively large amount) a volume of a warm solution of ethyl acetate-dichloromethane, after which it was concentrated to half the initial volume. The precipitate was collected and dried in vacuum at 45 ^about C (0.610 g, 48.8 yield), so pl. 150-152 ^about S.

NMR (DNCO-d ₆ , 400 MHz): 3.70 (s, 2H, CH ₂ COO), 5.40 (s, 2H, A CH ₂ ), 7.20 (d, 2H, ArH), 7, 45-7.60 (m, 7H, ArH), 7.75 (d, 2H, ArH), 7.95 (m, 3H, ArH), 8.02 (s, 1H, ArH), 12.47 ( H.s. 1H, COOH).

MS ( ⁺ SAW, m (s): 397 (M + H) ⁺ , 217, 141.

Analysis for C ₂₆ H ₂₀ O ₄
Calculated, C 78.78; H, 5.09.

 Found, C, 78.12; H, 5.13.

 Example 5. 5-Phenyl-4- [4- (2-quinolinylmethoxy) phenyl] -2-oxazole propanoic acid.

 A. 4-Methoxybenzoin.

To a solution of KCN (5 g) in water (35 ml) was added 4-methoxybenzaldehyde (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 a nitrogen atmosphere for 4.5 hours, and then ethanol was distilled off in vacuo. 200 ml of water was added to the residue and then distilled off under reduced pressure (to remove unreacted benzaldehyde). The procedure was repeated twice, and the residual water was transferred into an azeotropic mixture with ethyl alcohol. The crude product (56.3 g, orange semi-solid) was purified by flash chromatography (Merck 60 silica gel previously adsorbed in dichloromethane-ethyl acetate, 8: 2 hexane-ethyl acetate elution). the result was a light yellow solid (20.1 g, 41.5%), mp 99-101 ^about S.

NMR (CDCl ₃ , 400 MHz): δ 3.82 (s, 3H, OCH ₃ ), 4.62 (br.s. 1H, OH), 5.88 (s, 1H, CHOH), 6.86 ( d, 2H, J 8.94 Hz, ArH), 7.22-7.38 (m, 5H, ArH), 7.91 (d, 2H, J 8.94 Hz, ArH), MS (EI, m (h): 243 (M + H) ⁺ , 225, 197, 137 (M-PhCO) ⁺ .

 B. 4-Methoxybenzoin hemisuccinate.

The mixture 4methoxybenzoin (20 g, 0.083 mol) and succinic anhydride (9.1 g, 0.091 mol) in toluene (6 ml) was heated for 7 hours under a nitrogen atmosphere at ¹³⁵ ° C (external temperature). The solution was poured into 0.5 N. NaHCO ₃ solution, the organic layer was separated and re-extracted with 0.5 M NaHCO ₃ . The combined extracts were washed with ether and then acidified in the cold with concentrated hydrochloric acid. The separated oil was extracted with ethyl acetate (3x), the extracts were washed with water and dried over anhydrous magnesium sulfate. The excess solvent was removed and a yellow solid was obtained (20.89 g, 73.8% yield), mp. 104-108 ^about C. This product was used in the next step without further purification.

NMR (CDCl ₃ , 400 MHz): δ 2.72-2.82 (mm, 4H, CH ₂ CH ₂ COO, 3.82 (s, 3H, OCH ₃ ), 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 (s): 342 (M) ⁺ , 135 (broad, peak).

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

A mixture of crude 4-methoxybenzoin semisuccinate (20.8 g, 0.061 mol) of step B, urea (8.7 g, 0.146 mol) and acetic acid (60 ml) was heated under reflux in a nitrogen atmosphere for 5.5 hours. cooled and poured into ice water. The separated oil was extracted with ethyl acetate (3x). The extracts were washed with water until neutral and then extracted with a saturated solution of sodium carbonate. The combined aqueous extracts were carefully acidified in the cold with concentrated hydrochloric acid HCl and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and evaporated to dryness, resulting in a yellow waxy oily substance (19.6 g). The resulting residue was purified by flash chromatography (Merck silica gel 60, eluent dichloromethane-ethyl acetate 8: 2), the result was a pale yellow solid (14.3 g, 72.7% yield), mp 100-101 ^about C.

NMR (CDCl ₃ , 400 MHz): δ 2.96 (t, 2H, CH ₂ C), 3.20 (t, 2H, CH ₂ COO), 3.83 (s, 3H, OCH ₃ ), 6, 90 (d, 2H, ArH), 7.28-7.38 (m, 3H, ArH), 7.54-7.62 (m, 4H, ArH).

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

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

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

NMR (DMCO-d ₆ , 400 MHz): δ 2.75 (t, 2H, J 7.14 Hz, CH ₂ C), 3.02 (t, 2H, J 7.1 Hz, CH ₂ COO), 6.77 (d, 2H, J 8.7 Hz, ArH), 7.35 (d, 2H, J 8.55 Hz, ArH), 7.41 (t, 3H, J 7.12 Hz, ArH) 7.50 (d, 2H, J 7 Hz, ArH); 9.64 (broad singlet, exchange interaction).

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

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

A solution of the crude acid (5 g, 16.18 mmol) of stage D in methanol (40 ml) containing a small amount of p-toluenesulfonic acid monohydrate (0.58 g) was heated under reflux for 2.5 hours. The methanol was distilled off and the residue partitioned between two phases-ethyl acetate and 20% NaCl solution. The extracts were washed, dried over anhydrous magnesium sulfate and evaporated to give a thick oil (about 4.8 g). The obtained residue was purified by flash chromatography (Merck silica gel 60 previously adsorbed in dichloromethane was eluted with a dichloromethane-ethyl acetate solution in a gradient from 90:10 to 75:25), and a white solid was obtained (3.56 g, 68% yield) ) mp 115-116 ^about S.

NMR (CDCl ₃ , 400 MHz): δ 2.92 (t, 2H, J 7.4 Hz, CH ₂ C), 3.20 (t, 2H, J 7.4 Hz, CH ₂ COO), 3, 71 (s, 3H, OCH ₃ ), 6.74 (d, 2H, J 8.59 Hz, ArH), 7.26-7.36 (m, 3H, ArH), 7.40 (d, 2H, J 8.7 Hz, ArH), 7.54 (d, 2H, J 7.56 Hz, ArH).

MS (EI, m (s): 323 (M) ⁺ , 264 (M-СООСН ₃ ) ⁺ , 105, 77 (broad peak).

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

A mixture of ether (2.46 g, 7.61 mmol) of stage F, powdered anhydrous potassium carbonate (1.05 g, 7.60 mmol), 18-crown-6 ether (0.223 g, 0.843 mmol) and acetonitrile (33 ml ) stirred at room temperature in a nitrogen atmosphere for 15 min 2-chloromethaliquinoline (free base freshly prepared from hydrochloride salt, 1.35 g, 7.60 mmol) was added to the mixture, placed in an oil bath and heated for 10 hours at 65 ^° C (after 6 hours, a 10% excess of chloromethylquinoline, 18-crown-6-ether and K ₂ CO _{3 was} added). The solvent was removed, and the residue was partitioned between the two phases with ethyl acetate and water. The extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to give a yellow solid. The crude product was purified by flash chromatography (Merck silica gel 60, eluent: toluene and then toluene-methanol 97: 5: 2.5) to give the title compound (3.5 g, quantitative yield).

NMR (CDCl ₃ , 400 MHz): δ 2.90 (t, 2H, J about 7.2 Hz, CH ₂ C), 3.16 (t 2H, J 7.2 Hz, CH ₂ COO), 3, 72 (s, 3H, OCH ₃ ), 5.41 (s. 2H, ArCH ₂ O), 7.02 (d, 2H, J 8.8 Hz, ArH), 7.29-7.36 (m, about 4H, ArH), 7.54-7.84 (m, about 6H, 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 (+ PAB, m (s): 487 (M + a) ⁺ , 465 (M + H) ⁺ .

G. 5-Phenyl-4- [4- (2-quinolinylmethoxyphenyl] -2-oxazole propanoic acid
A solution of the ether (3.4 g, 7.32 mmol) of stage F in dry tetrahydrofuran (37 ml) was treated dropwise adding a 1M solution of LiOH (21.98 ml 3 eq.) In a nitrogen atmosphere, and then stirred at room temperature in for 3 hours (TLC, dichloromethanol 97: 3 or toluene methanol 95: 5). The solvent was evaporated, the residue was dissolved in water, neutralized in the cold with a 10% solution of acetic acid to pH 5, and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to give a pale yellow solid (3.18 g, quantitative yield). The crude product was recrystallized from warm ethyl acetate (containing enough dichloromethane to obtain a clear solution) to yield a first crop of crystals (2.63 g, m.p.) 192-194 ^{° C,} dec. ) A second crop isolated by concentrating the mother liquor (0.327 g, m. Mp. 192-193 ^C, dec.). The total yield amounted to 85.8% of ISK (KBr, cm ^-1 ): 1720 (СО).

NMR (DMCO-d ₆ , 400 MHz): δ 2.76 (t, 2H, J 7 Hz, CH ₂ C), 3.03 (t, 2H, J 7 Hz, CH ₂ COO), 5.38 ( s, 2H, ArCH ₂ O), 7.11 (d, 2H, J 8.8 Hz, ArH), 7.36-7.56 (m, 7H, ArH), 7.61 (t, 1H, ArH ), 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 (s): 451 (M + H) ⁺ , 310 (broad peak).

Analysis for C ₂₈ H ₂₂ N ₂ O ₄
Calculated, C 74.65; H 4.92; N, 6.22.

 Found, C, 74.20; H 4.86; N, 6.00.

 Example 6. 4- [4- [2-Naphthalenylmethoxy] phenyl] -5-phenyl-2-oxazole propanoic acid.

 A. 4- [4- (2-Naphthalenylmethoxy] phenyl] -5-phenyl-2-oxazole propanoic acid methyl ester.

A mixture of hydroxyether (1.5 g, 4.6 mmol) of Example 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 in a nitrogen atmosphere for 15 minutes Was added 2-Bromomethylnaphthalene (1.13 g, 5.1 mmol) and the mixture was placed in an oil bath and heated at ⁷⁰ ° C for 8-9 hours (TLC, hexane-ethyl acetate 9: 1 or dichloromethane-methanol 9: 1 ) The solvent was evaporated and the residue was dissolved in water, then extracted with ethyl acetate. The extracts were washed and dried over anhydrous magnesium sulfate. Removal of the solvent gave a brownish-yellow solid (2.17 g, quantitative yield). The sample was recrystallized from methanol (containing enough dichloromethane to obtain a clear solution), concentrated to a small volume and cooled in an ice bath. A white solid was collected and dried overnight under vacuum, mp. 134-135 ^about S.

IR (KBr, cm ^-1 ): 1740 (СО)
NMR (CDCl ₃ , 400 MHz): δ 2.89 (t, 2H, J 7.5 Hz, CH ₂ C), 3.16 (t, 2H, J 7.5 Hz, CH ₂ COO), 3, 71 (s, 3H, OCH ₃ ), 5.2 (s, 2H, A CH ₂ O), 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 (s): 464 (M + H) ⁺ , 324.

Analysis for C ₃₀ N ₂₅ NO ₄
Calculated, C 77.73; H 5.44; N, 3.02.

 Found, C, 77.44; H 5.36; N, 3.03.

 B. 4- [4- (2-Naphthalenylmethoxy) phenyl] -5-phenyl-2-oxazole propanoic acid.

A solution of ether (1.49 g, 3.21 mmol) of stage A in dry tetrahydrofuran (18 ml) containing 1 M LiOH (9.6 ml) was stirred at room temperature under nitrogen overnight (TLC, 75:25 hexane-ethyl acetate) . The solvent was evaporated, the residue was dissolved in water and acidified to pH 5 with diluted HCl. The mixture was extracted with ethyl acetate, the extracts were dried over anhydrous magnesium sulfate and evaporated, yielding 1.39 g, mp. 145-150 ^о С. To purify the obtained product, it was dissolved in hot ethyl acetate (containing enough dichlomethane to obtain a clear solution), the resulting solution was concentrated to half the initial volume, and precipitated with ether. White solid melting at 151-152 ^{° C} (1.07 g, 58%).

IR (KBr, cm ^-1 ): 1720 (СО)
NMR (DMCO-d ₆ ), 400 MHz): δ 2.78 (t, 2H, CH ₂ C), 3.03 (t, 2H, J 7 Hz, CH ₂ COO), 5.29 (s, 2H , ArCH ₂ COO), 7.10 (d, 2H, J 8.9 Hz, ArH), 7.34-7.60 (m, 10H, ArH), 7.90-8.00 (m, 4H, ArH), 12.28 (s, 1H, COOH).

Analysis for C ₂₉ H ₂₃ NO ₄ .

 Calculated, C 77.48; H 5.15; N, 3.11.

 Found, C, 76.40; H 5.16; N, 3.04.

 Example 7. 4- [4- (1-Methyl-1 H-benzimidazol-2-yl) methoxy] phenyl] -5-phenyl-2-oxazole propanoic acid.

 A. 4- [4- (1-Methyl-1 H-benzimidazol-2-yl) methoxy] phenyl] -5-2-oxazole propanoic acid methyl ester.

A mixture of ether (0.5 g, 1.55 mmol) of Example 5E, powdered anhydrous potassium carbonate (0.214 g, 1.55 mmol), 18-crown-6-ether (0.041 g, 0.155 mmol) and acetonitrile (6 ml) stirred under nitrogen at room temperature for 15 minutes Then we added 2-chloromethyl-1-methylbenzimidazole (0.307 g, 1.7 mmol) and the mixture was placed in an oil bath and heated at 65-70 ^{° C} for 4 hours (TLC, dichloromethane-ethyl acetate 9: 1, expression of iodine) . At this point, a 10% excess of K ₂ CO ₃ , 2-chloromethyl-1-methylbenzimidazole and 18-crown-6 was added and heating continued for another 10 hours. The solvent was then evaporated, the residue was dissolved in water and extracted with ethyl acetate. The extracts were washed, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue (1.64 g) was purified by flash chromatography (Merck 60 silica gel pre-adsorbed in dichloromethane containing a small amount of methanol was eluted with a 8: 2 dichloromethane-ethyl acetate mixture), resulting in 1.03 g (71.2%) yield) light yellow solid product, so pl. 142-144 ^about S.

NMR (CDCl ₃ , 400 MHz): δ 2.87 (t, 2H, J 7.1 Hz, CH ₂ C), 3.16 (t, 2H, J 7.8 Hz, CH ₂ COO), 3, 72 (s, 3H, COOCH ₃ ), 3.90 (s, 3H, CH ₃ ), 5.41 (s, 2H, ArCH ₂ COO), 7.07 (d, 2H, J 8.8 Hz, ArH ), 7.25-7.40 (m, 7H, ArH), 7.5-7.6 (m, 3H, ArH), 7.78 (d, 1H, ArH).

MS (+ CI, m (s): 468 (M + H) ⁺ , 324, 293, 147.

B. 4- [4 - [(1-Methyl-1H-benzimidazol-2-yl (methoxy] -5-phenyl-2-oxazole propanoic acid
A solution of ether (1 g, 2.14 mmol) of stage A in tetrahydrofuran (13 ml) containing 1 M LiOH (6.42 ml) was stirred under nitrogen at room temperature for 1 h (TLC, 9: 1 dichloromethane-ethanol) . The solvent was evaporated, water was added and the pH of the solution was adjusted to 6.5 by the addition of 10% acetic acid. A light yellow precipitate was collected, washed with water and dried in vacuo. Then it was redissolved in hot ethyl acetate containing methanol in an amount sufficient to obtain a clear solution), concentrated to a small volume and cooled in an ice bath, the precipitated crystals were collected and dried (0.642 g, yield 66.2%, mp 222- 224 ^C).

NMR (DMCO-d ₆ , 400 MHz): δ 2.76 (t, 2H, J 7 Hz, CH ₂ C), 3.03 (t, 2H, J 7 Hz, CH ₂ COO), 3.86 ( s, 3H, NCH ₃ ), 5.43 (s, 2H, ArCH ₂ O), 7.14-7.66 (m, 13H, ArH).

MS (CI, m (s): 454 (M + H) ⁺ , 147 (broad peak).

Analysis for C ₂₇ H ₂₃ N ₃ O ₄
Calculated, C 71.51; H, 5.11; N, 9.27.

 Found, C, 71.62; H 5.17; N, 9.40.

Example 8. 2-Fluoro-4 ^' - (2-quinolinylmethoxy [1,1 ^' -biphenyl] -4-acetic acid, 2-amino-2-hydroxymethyl-1,3-propanediol.

A solution of the compound of Example 2 (3.17 g, 8.2 mmol) and 2-amino-2-hydroxymethyl-1,3-propanediol [TRIS, 0.99 g, 8.2 mmol] in 60 ml of methanol was concentrated to a syrup . It was then diluted with ethyl acetate (250 ml) and the crystalline precipitate was collected and dried to obtain 3.18 g of the desired salt. The product is ground in a micron colloid mill to obtain a fine white powder, melting point 168-169 ^about C (yield 77.5%).

Analysis for C ₂₈ H ₂₉ FN ₂ O ₆ .

 Calculated, C 66.13; H 5.75; N, 5.51.

 Found, C, 65.75; H 5.79; N, 5.49.

 PRI me R 9. 5-Phenyl-4- [4-quinolinylmethoxy) phenyl] -2-oxazolpropionic acid, 2-amino-2-hydroxymethyl-1,3-propanediol.

To a solution of the compound of Example 5 (0.359 g, 0.796 mmol) in boiling ethanol (35 ml) was added 2-amino-2-hydroxymethyl-1,3-propanediol [TRIS, 0.0965 g, 0.796 mmol] in 0.5 ml water. After 2 hours, the mixture was frozen. The crystalline precipitate is collected and dried to obtain 0.396 g of the desired salt, melting point 170-171 ^about C.

Analysis for C ₃₂ H ₃₃ N ₃ O ₇ .

Calculated, C 67.00; H 5.75; N, 7.32;
Found, C, 66.68; H 5.77; N, 7.31.

PRI me R 10. 4 ^' - (2-Benzothiazolylmethoxy) -4-diphenylacetic acid, ethyl ether.

A. 4 ^' -hydroxy-4-diphenylacetic acid, ethyl ester.

A solution containing 4 ^{'-hydroxy-4-diphenylacetic} acid (6.7, 28.0 mmol); absolute ethanol (300 ml) and concentrated sulfuric acid (5 ml) were distilled under reflux for 2 hours. Then the reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water (200 ml) and extracted with ethyl acetate (200 ml, three times). The combined ethyl 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 a crude solid. The solid is purified by chromatography (silica gel; 30% ethyl acetate in hexane) to obtain 6.7 g (95.0%) of a white crystalline product, melting point 125-127 ^about C.

Analysis for C ₁₆ H ₁₆ O ₃ .

 Calculated, C 74.98; H, 6.29.

 Found, C, 74.62; H, 6.2.

B. 4 ^' - (2-Benzothiazolylmethoxy) -4-diphenylacetic acid, ethyl ether.

The slurry containing 4 ^' -hydroxy-4-diphenylacetic acid, ethyl ester (6.7 g, 26.0 mmol, Part A) and cesium carbonate (9.0 g, 28.0 mmol) in dimethylsulfoxide (150 ml) was stirred at room temperature. After 30 minutes, 2- (chloromethyl) benzothiazole (4.2 g, 27.0 mmol) was added and the mixture was stirred for 18 hours. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (300 ml, 3 times). The combined ethyl acetate extract was washed successively with 0.1N 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 a crude solid.

The solid is purified by chromatography (silica gel; 30% ethyl acetate in hexane) to obtain 4.0 g (39.2%) of a white crystalline product, melting point 133-134 ^about C.

Analysis for C ₂₄ H ₂₁ NO ₃ S.

 Calculated, C 71.44; H 5.25; N, 3.47.

 Found, C, 71.36; H, 5.25; N, 3.35.

PRI me R 11. 4 ^' - (Benzothiazolylmethoxy) diphenylacetic acid ethyl ether (4.0 g, 10.0 mmol), 1N. sodium hydroxide (15 ml, 15.0 mmol), methanol (200 ml) and tetrahydrofuran (200 ml) were heated under reflux for 18 hours. Then the reaction mixture was cooled, concentrated under reduced pressure, diluted with water (500 ml) and while stirring, acidified with 2N hydrochloric acid. After stirring for 2 hours, the product was collected by filtration, and after drying under vacuum, 3.8 g (99%) of a solid were obtained. Part of this material (0.5 g) was recrystallized from acetic acid, mp 208-209 ° ^C.

Analysis for C ₂₂ H ₁₇ NO ₃ S.

 Calculated, C 70.38; H 4.56; N, 3.73.

 Found, C, 70.04; H 4.56; N 3.72.

 PRI me R 12. Compounds of 5 - and 12-hydroxyeycosatetraenoic acid.

(5-HETE and 12-HETE) and LTB ₄ are products of the oxidation of arachidonic acid in the initial stages of the lipoxygenase cycle, which have been found to be conductors of some aspects of the inflammatory and allergic response of the reaction. This is especially true for 5,12-diNETE, which is also designated as LTB ₄ (see Fordand Hitchinson, J. Roy. Soc. Med. 74, 831, 1981). Compounds that inhibit the release of arachidonic acid caused by the PLA phospholipase ₂ effectively affect the process of preventing the oxidation of arachidonic acid into various products such as leukotrienes, carried out in the lipoxygenase cycle. Accordingly, the specificity of the action of PLA ₂ inhibitors can be determined by the activity of the tested compounds in such an analysis that measures the ability of the compounds to inhibit LTB ₄ synthesis by glycogen-induced polymorphonuclear leukocytes (PMN) in the presence of an exogenous substrate.

 This analysis is carried out as follows.

Polymorphonuclear rat leukocytes (PMN) are obtained from female Wistar rats (weight 150-200 g), which was injected with a 6% glycogen solution (10 ml inside the peritoneum). Rats were sacrificed 18-24 hours after injection by CO ₂ asphyxiation, and cells isolated from the peritoneum were irrigated using saline (0.9% NaCl solution). The exudate was centrifuged, and the pelleted cells were resuspended to a concentration of 2.0 x 10 ⁷ cells / ml in HBSS containing Ca ⁺⁺ and Mg ⁺⁺ ions and 10 μM L-cysteine.

Aliquots of 1 ml volume of cell suspension was added the test drug or vehicle is then preincubated at 37 ^C for 10 min. After that, A 23187 (1 μM), [ ³ H] -AA (3.0 μMCl (ml) and unbound AA (1 μM) were added, and the samples were further incubated for another 10 minutes, the Reaction was stopped by centrifugation and cell deposition. The supernatant layers are then analyzed by HPLC using a 15 cm x 4.6 mm column with a Supelcosil Lc / Supelco / 3M / sorbent and a two solvent system with a flow rate of 1.4 m total flow.

Solvent A: 70:30 17.4 mM H ₃ PO ₄ : CH ₃ CN
Solvent B: CH ₃ CN
Gradient (the system is balanced by solvent A) (see table 1).

Changes in the percentage of solvent is described by a linear relationship
Injections: 140 L of each supernatant is injected directly into the column and metabolic products of ³ H-arachidonic acid are determined using the built-in radioactivity detector (Ramona, IN / US, Fairfield, NJ).

Standard solutions: 10 ⁴ 2.0 x 10 ⁴ dpm (decays per minute) of the eicosanoids of interest are administered as a cocktail in 90 l of ethyl alcohol.

The percentage of inhibition was determined by comparative chromatography of media stimulated with PMN treated with the drug and media of stimulated cells not subjected to drug treatment. As an internal standard, ³ N leukotriene B ₄ (LTB ₄ ) was used.

The results are presented either as a percentage of inhibition by this compound, or as IR ₅₀ .

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

Example 13. The procedure of example 12 is also used to determine the degree of inhibition by the compounds of the invention of the synthesis of arachidonic acid by the cyclooxygenase oxidation product PGE ₂ .

In this analysis, the procedure of example 12 is carried out as described. However, to determine cyclooxygenase activity, the samples are chromatographed together with authentic ( ³ H) -PGE ₂ .

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

Example 14. Compounds of the invention tested in vitro in an experiment with isolated phospholipase A ₂ to determine the ability of test compounds to inhibit the release of arachidonic acid from a substrate containing arachidonic acid under the action of the phospholipase A ₂ enzyme, the source of which can serve as a person, so other sources can be used.

 This analysis was carried out as follows. The components shown in Table 4 were added to a 15 ml polypropylene tube.

Incubate 100 l of the reaction mixture for 10 min at ³⁷ ° C in a shaking water bath. The reaction is completed by adding 2 ml of tetrahydrofuran, followed by vigorous stirring. NH ₂ columns (100 mg / ml Analytichem International) are treated with 0.5 ml of tetrahydrofuran and then with a mixture of 0.5 ml of tetrahydrofuran and water (2 ml of 0.1 ml).

The sample is loaded into the column and slowly drawn through it. The hydrolyzed arachidonic acid remaining in the column is eluted from the column with 1 ml of a mixture of tetrahydrofuran and glacial acetic acid (2%). Arachidonic acid is transferred to scintillation ampoules and quantified by β-counting. The total count of the sample is obtained by pipetting 25 μl of ³ N-arachidonate labeled E. coli directly into a scintillation vial, to which 1 ml of tetrahydrofuran is added. 10 ml of aquasol (scintillation cocktail) is added to all samples.

изменения

:
ИК₅₀ /МК/
_________________________________
ФЛА₂тромбоцитов ФЛА₂ синовиальной
человека жидкости человека
_________________________________ Лекарство: Арахидоновая кислота 8/6 3/2
Моноалид 25/2 0/14
При тестировании в этом опыте предлагаемых соединений были получены результаты, данные в табл.5.Calculations:
hydrolysis

changes

:
IR ₅₀ / MK /
_________________________________
PLA ₂ platelets PLA ₂ synovial
human fluid human
_________________________________ Medicine: Arachidonic acid 8/6 3/2
Monoalide 25/2 0/14
When testing the proposed compounds in this experiment, the results obtained in Table 5 were obtained.

 Example 15. The compounds of the invention are evaluated for their ability to inhibit the lipoxygenase and / or cyclooxygenase metabolism of arachidonic acid in vivo in mice in an experiment with peritonitis caused by enzymatic degradation of tissue. This experiment is carried out as follows.

Male mice of the DM line (age 8 weeks) are placed in six pieces in plastic boxes. Animals are injected with 1 ml inside the peritoneum or either a 1% solution of zymosan in a pyrogen-free 0.9% saline solution or saline solution (control non-stimulated version). The compounds of the invention are orally administered to animals 1 hour before zymosan injection. 20 minutes after the injection of zymosan, the animals were killed by asphyxiation in a CO ₂ atmosphere. Then, in the peritoneal cavity was treated with 2 ml of ice cold balanced salt solution Hauks (HBSS), containing no CaCl _2, MgSO ₄ ˙7H ₂ O, MgCl ₂ and ₂ O. ˙6H peritoneal lavage fluid from each mouse was taken by syringe and placed in 5 ml made of plastic, test tubes in ice and mark the volume. Sample preparation for evaluation by the ELISA method is carried out as follows: samples are centrifuged at 800 ° C for 15 min; 1 mL of supernatant is added to 8 mL ice cold methanol and kept overnight at 70 ° ^C to precipitate protein; then the samples are again centrifuged at 800 ° C for 15 minutes, then dried in a Savant Speed Vacuum Concentrator. Samples were reduced by addition of 1 ml ELISA buffer cooled with ice, and stored at ^-70 ° C until analysis. Eicosanoids (LTC ₄ and 6-keto-PGF ₁ α) are determined in accordance with standard ELISA enzyme-linked immunosorbent assay).

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

 The total number of metabolites in the washing fluid of the peritoneal cavity of the mouse is calculated and the value is determined by analyzing the deviations by comparison with the control variant (p ≅ 0.05). The effect of the drug is expressed as the percentage of deviations from control values.

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

(отрицательные величины означают потенциирование).The compound of the invention when tested in this experiment and the anti-inflammatory drug etodolac gave the following results: compound of Example 5, dose of 10 mg / kg (intraperitoneal administration (intraperitoneally), inhibition

(negative values mean potentiation).

 The results obtained indicate that the proposed compound exhibits an inhibitory effect on the lipoxygenase pathway of metabolism, but does not have an inhibitory effect on the cyclooxygenase direction.

Claims (10)

1. Derivatives of substituted benzoylbenzene-, biphenyl- or 2-oxazolalkanoic acid of the general formula I
A (CH ₂ ) _n OB,
where is a group

where X is -N- or

;
Z

or -S-, provided that when X

Z

R _{3 is} hydrogen or lower alkyl;
n 1 2;
IN

where R ₄ and R ₅ each independently of one another, hydrogen or lower alkyl;
R ₆ is a halogen or nitro group;
R ₇

R ₈ is lower alkyl;
m 0 3,
or their pharmacologically acceptable salts.  2. The compound according to claim 1, characterized in that it is 1- [2-nitro-4 '- (2-quinolinylmethoxy) - (1,1'-biphenyl) 4-yl] ethanone.  3. The compound according to claim 1, characterized in that it is 2-fluoro-4 '- [2-quinolinylmethoxy- (1,1'-biphenyl) -4] -acetic acid.  4. The compound according to claim 1, characterized in that it is 3- [4- (2-quinolinylmethoxy) benzoyl] benzeneacetic acid.  5. The compound according to claim 1, characterized in that it is 3- [4- (2-naphthalenylmethoxy) benzoyl] benzeneacetic acid.  6. The compound according to claim 1, characterized in that it is 5-phenyl-4- [4- (2-quinolinylmethoxy) phenyl] -2-oxazolepropanoic acid.  7. The compound according to claim 1, characterized in that it is 4- [4- (2-naphthalenylmethoxy) phenyl] -5-phenyl-2-oxazolepropanoic acid.  8. The compound according to claim 1, characterized in that it is 4- [4- (2-naphthalenylmethoxy) phenyl] -5-phenyl-2-oxazolpropanoic acid methyl ester.  9. The compound according to claim 1, characterized in that it is 4- [4- ((1-methyl-1-H-benzimidazol-2-yl) methoxy) phenyl] -5-phenyl -2-oxazolpropanoic acid. 10. A method of obtaining derivatives of substituted benzoylbenzene-, biphenyl- or 2-oxazolalkanoic acid of General formula I
A (CH ₂ ) _n OB,
where the values of A, n, B have the indicated values,
characterized in that carry out the reaction of interaction of the compounds of General formula
BUT,
where B has the indicated meanings,
with a compound of formula A (CH ₂ ) _n X, wherein A and n are as defined herein;
X is a leaving group,
and, if necessary, hydrolyzing the obtained product to form a compound of formula I in which R _{5 is} hydrogen or lower alkyl, and, if desired, converting the obtained compound into its pharmacologically acceptable salt.

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