RU2042669C1 - Oxazole compounds and a method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: compounds of oxazole of the general formula (I)

where n 7-9; R hydrogen or C₁-C₄--alkyl were synthesized by reaction of complex ketoester of the formula (II)

with ammonium acetate followed by isolation of the end product or if necessary by esterification with C₁-C₄--alkanol. Synthesized compounds show inhibiting effect on aggregation of human plasma enriched with platelets induced by adenosine diphosphate or collagen. EFFECT: improved method of synthesis. 3 cl, 1 tbl

Description

 The invention relates to heterocyclic carbon compounds having medicinal and bioactive properties, to their preparation and use, in particular, the invention relates to oxazole derivatives characterized by formula (I) (see below), which are inhibitors of blood platelet aggregation.

CH CH

в которой R является водородом, пара-метокси, орто-гидрокси- и 3,4-метилендиокси-группой [1]
Известен класс оксазол-2-полиуглеродных алифатических монокарбоновых кислот, арилированных в положении 4 и/или 5 оксазольного кольца формулы

R¹ в которой каждый из заместителей R² и R³ является членом группы, состоящей из незамещенных фенильных, нафтильных, тиенильных и фурильных радикалов, замещенных заместителями, выбираемыми из группы, состоящей из галогеновых, низших алкильных, низших алкокси-, нитро- и три-фторметильных радикалов, и в которой R¹ выбирается из группы, состоящей из карбоксиалкильных и карбоксиалалкенильных радикалов, каждый из которых содержит от 2 до 5 атомов углерода, и амидов, производных гидроксамовой киcлоты, низших алкиловых сложных эфиров и низших алканоилокси-низших алкиловых эфиров из них [2] Соединения [2] включают эффективное в клинике противовоспалительное средство, известное обычно как оксапрозин (R²-R³-фенил, R¹= (СН₂)₂СООН).Known chemistry of styryloxazoles of the formula

CH CH

in which R is hydrogen, para-methoxy, ortho-hydroxy and 3,4-methylenedioxy [1]
A known class of oxazole-2-polycarbon aliphatic monocarboxylic acids arylated in position 4 and / or 5 of the oxazole ring of the formula

R ¹ in which each of the substituents R ² and R ³ is a member of the group consisting of unsubstituted phenyl, naphthyl, thienyl and furyl radicals substituted with substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro and three -fluoromethyl radicals, and in which R ¹ is selected from the group consisting of carboxyalkyl and carboxialalkenyl radicals, each of which contains from 2 to 5 carbon atoms, and amides, derivatives of hydroxamic acid, lower alkyl esters and lower alkano of their alloxy lower alkyl esters [2] Compounds [2] include a clinically effective anti-inflammatory agent commonly known as oxaprozin (R ² -R ³ phenyl, R ¹ = (CH ₂ ) ₂ COOH).

в которой R₁ и R₂ являются водородом, а Alk-Y является остатком алкановой кислоты и сложного эфира [3]
Соединения [4] имеют циклическую АМФ (аденозинмонофосфат) фосфодиэстеразную ингибирующую активность и являются полезными в качестве ингибиторов агрегации кровяных пластинок и/или в качестве кардиотонических средств.A series of derivatives of 2,3-dihydro-2-oco-1H-imidazole (4,5-b) -quinoline vinyl ether of the formula

in which R ₁ and R ₂ are hydrogen, and Alk-Y is the residue of alkanoic acid and ester [3]
Compounds [4] have cyclic AMP (adenosine monophosphate) phosphodiesterase inhibitory activity and are useful as inhibitors of blood platelet aggregation and / or as cardiotonic agents.

в которой R¹,R²,R³,R⁴,R⁵ и R⁶ каждый является Н, галогеном, алкилом, алкокси-группой и трифторметилом, n является целым числом от 1 до 10, а R⁷ является Н, ионами щелочного металла, алкильной или бензильной группой [5] Соединения являются полезными при лечении тромбоэмболической, воспалительной и/или атеросклеротической болезни у человека. Особенно предпочтительно член серий, в котором от R¹ до R⁶является водородом, n является 7, а R⁷ является натрием (идентифицируемый в области техники как октимибэт натрия), описан на обладающий противоагрегаторной активностью и разрабатывается в клинике в качестве антигиперлипидамического средства.A number of triphenylimidazol-2-yloxyalkanoic acids of the formula are known.

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each H, halogen, alkyl, alkoxy and trifluoromethyl, n is an integer from 1 to 10, and R ⁷ is H, alkaline ions metal, alkyl or benzyl group [5] The compounds are useful in the treatment of thromboembolic, inflammatory and / or atherosclerotic disease in humans. Particularly preferred is a member of a series in which R ¹ to R ⁶ is hydrogen, n is 7, and R ⁷ is sodium (identified in the art as sodium octimibet), has been described to have anti-aggregatory activity and is being developed in the clinic as an antihyperlipidic agent.

(CH₂)_nCO₂R (I) в которых R и n определяются ниже, которые являются ингибиторами аденозин-дифосфатом и коллагеном индуцированной агрегации человеческой плазмы, обогащенной тромбоцитами, и являются особенно полезными в качестве ингибиторов агрегации кровяных пластинок млекопитающих.The present invention relates to derivatives of oxazole having the formula

(CH ₂ ) _n CO ₂ R (I) in which R and n are defined below, which are inhibitors of adenosine diphosphate and collagen induced aggregation of human plasma enriched in platelets, and are especially useful as inhibitors of aggregation of mammalian blood platelets.

 Another embodiment of the invention relates to alkali metal salts of carboxylic acids of the formula (I) (R is hydrogen). Another embodiment of the invention relates to pharmaceutical compositions consisting of a compound of formula (I) mixed with at least one pharmaceutically acceptable excipient. An additional embodiment of the invention relates to a method of inhibiting platelet aggregation in mammals, which comprises administering to the mammal (if necessary such treatment) a therapeutically effective amount of a compound of formula (I) or an alkali metal salt thereof, wherein R is hydrogen.

(CH₂)_nCO₂R в которой n является 7-9, а R является водородом или низшим алкилом; или R является водородом, солью щелочного металла его.The present invention relates to platelet aggregation inhibitors in mammals having the formula

(CH ₂ ) _n CO ₂ R in which n is 7-9 and R is hydrogen or lower alkyl; or R is hydrogen, a salt of an alkali metal thereof.

 Used in the description of the limitations of the formula (I) are defined as follows.

 The term “lower alkyl” refers to a branched or unbranched saturated hydrocarbon chain containing from 1 to 4 carbon atoms, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and tertiary butyl.

 The sign Ph represents phenyl.

 The term “alkali metal salts” embraces alkali metals and most preferably sodium and potassium.

(II), в которой n является 7-9, а R является водородом или низшим алкилом с ацетатом аммония, и в случае необходимости целевой продукт, где R низший алкил, подвергают гидролизу до соответствующей кислоты или целевой продукт, где R водород, подвергают этерификации низшим спиртом с получением целевого продукта, где R низший алкил.According to the invention, the compounds characterized by the formula (I) as defined above are prepared by a process comprising the reaction of a keto ester of formula II

(II) in which n is 7-9 and R is hydrogen or lower alkyl with ammonium acetate and, if necessary, the target product, where R is lower alkyl, is hydrolyzed to the corresponding acid or the target product, where R is hydrogen, is esterified lower alcohol to obtain the desired product, where R is lower alkyl.

 The diagram illustrates the above method.

Образование оксазольного цикла обычно осуществляется обработкой сложного кетоэфира избытком ацетата аммония в уксусной кислоте при температуре кипения с обратным холодильником. Сложные кетоэфиры (IIа,b,с) получаются этерификацией бензоина соответствующим образом замещенной карбоновой кислотой. Например, сложный кетоэфир (IIа) получается реакцией сочетания бензоина (IV) и сложного полуэфира дикарбоновой кислоты НООС(СН₂)_nСООR^а, где n является 7-9, а R^а является низшим алкилом, используя 1,3-дициклогексилкарбодиимид в присутствии каталитического количества 4-диметиламинопиридина, согласно методике Вассермана и др. (Н.Н.Wasserman et al. Тetrahedron 37, 4059-4064, 1981). Очистка не требуется и сложный кетоэфир (IIа) обрабатывается избытком ацетата аммония в уксусной кислоте при температуре кипения с обратным холодильником с получением при этом оксазола (Iа). Гидролиз сложноэфирной функциональности водной гидроокисью дает соответствующую кислоту (Ib).

The formation of the oxazole cycle is usually carried out by treating the keto ester with an excess of ammonium acetate in acetic acid at the boiling temperature under reflux. Ketoesters (IIa, b, c) are obtained by the esterification of benzoin with an appropriately substituted carboxylic acid. For example, a keto ester (IIa) is obtained by the reaction of a combination of benzoin (IV) and a half-ester of a dicarboxylic acid HOOC (CH ₂ ) _n COOR ^a , where n is 7-9 and R ^a is lower alkyl using 1,3-dicyclohexylcarbodiimide in the presence of a catalytic amount of 4-dimethylaminopyridine according to the method of Wasserman et al. (N.N. Wasserman et al. Tetrahedron 37, 4059-4064, 1981). Purification is not required and the keto ester (IIa) is treated with an excess of ammonium acetate in acetic acid at reflux temperature to give oxazole (Ia). Hydrolysis of the ester functionality with aqueous hydroxide gives the corresponding acid (Ib).

 Alternatively, oxazole (Ib) can be obtained by treating the ester keto ester (IIc), where n is 6-8, ammonium acetate and acetic acid to obtain an oxazolbromide intermediate (V, n = 6-8). Treatment of this intermediate with a three-fold excess of malonic acid dimethyl ester and potassium tert-butoxide in tetrahydrofuran (THF) at reflux temperature in the presence of a catalytic amount of 18-crown ether-6 gives methyl ester (III), which is saponified to diacid (III) and thermally decarboxylates to give (Ib). The esterification (Ib) is usually carried out by heating the acid (Ib) in lower alkanol in the presence of concentrated sulfuric acid.

Another preparation method (Ib) involves the esterification of benzoin (IV) with a three-fold excess of HOOC (CH ₂ ) _n COOH dicarboxylic acid, where n is 7-9, in the presence of a slight excess of 1,3-dicyclohexylcarbodiimide and a catalytic amount of 4-dimethylaminopyridine in methylene chloride, to get the keto ester (IIb). Treatment of the crude keto ester (IIb) with ammonium acetate under standard conditions gives oxazole acid (Ib), which is separated from the reaction by-products using column chromatography.

 The alkali metal salts of the carboxylic acids of formula (I) are usually obtained by dissolving the acid in methanol together with the molar equivalent of an alkaline base, such as sodium methoxide, and precipitating the salt into a precipitate or removing the solvent.

 As stated above, the compounds of formula (I) have pharmacological properties that make them particularly useful as inhibitors of aggregation of blood platelets (platelets).

 Platelet aggregation is considered part of the complex physiological mechanism of thrombus formation in the vascular system. A thromboembolic phenomenon, i.e., the formation of blood clots, is associated with hemostasis and a number of disease states in mammals, including thrombophlebitis, phlebothrombosis, cerebral thrombosis, coronary thrombosis and retinal vascular thrombosis. An increase in the tendency to platelet aggregation, sometimes called platelet adhesion (“adherence”), is observed after childbirth, surgical operations such as coronary artery bypass surgery, organ transplantation, vascular plastic surgery, implantation of artificial heart valves, with coronary heart disease, atherosclerosis, multiple sclerosis, intracranial tumors, thromboembolism and hyperlipemia (A. Porlawski et al. Artherosclerosis Research, 8, 721, 1968). Thus, compounds of the invention that have antithrombogenic properties (inhibit platelet aggregation) are useful in the prevention or treatment of conditions including platelet aggregation and thrombosis, such as mentioned above. It is also believed that the compounds in question have antimetastatic potential due to their platelet inhibition properties.

 The pharmacological properties of the compounds of interest can be demonstrated by routine in vitro and in vivo biological tests.

 In vitro inhibition of human platelet aggregation.

 Aggregometer (device for measuring aggregation) is used according to the Born method (GVRBorn. J.Physiol. (London), 1962, 162, 67-68), which was modified by Mustard et al. (Mustard VF et al. J. Lab.Clin. Med. 1964, 64, 548-599) to evaluate the in vitro activity of various compounds with respect to inhibition of adenosine disphosphate (ADP) and collagen-induced platelet aggregation. The hand of a volunteer donor is cleaned with 70% ethanol. A sterilized 20 ml syringe and a needle are used to draw 20 ml of blood. Blood is immediately added to the test tube containing 3.8% sodium citrate to prevent blood coagulation (I part citrate in 9 parts of blood).

Platelet-rich plasma (OTP) was isolated by centrifugation for 10 min at a speed of 100 rpm from citrated (3.8%) human blood. All glass products used to obtain OTP are treated with silicone. ADP at a final concentration of 0.5 μg / ml or 0.05 ml of a collagen suspension prepared according to the method described by Evans et al. (Evans G. et al. J. Exp. Med. 1968, 128, 877-894) use to induce aggregation. The various test compounds are dissolved in dimethyl sulfoxide (DMSO) so that 5 μl added to platelet rich plasma gives the desired concentration for the test. Carry out control tests with filler and compare with aggregation induced in platelet-rich plasma containing various concentrations of test compounds. Dose response curves are obtained, Inhibitory Concentration values (IC ₅₀ ) are calculated, and the percent inhibition is noted at 32 μg / ml. In this test, the IC ₅₀ values for dipyridamole, a useful antithrombogenic agent in the clinic, are 512 μg / ml against ADP and 245 μg / ml against collagen. The results are presented in the table for various compounds of formula I and II and related prototype compounds.

 Obviously, the acids of formula (I) (examples 2 and 4) are active, while short-chain acids [2] are essentially inactive against ADP-induced human platelet aggregation. As for the esters (examples 1 and 3) corresponding to examples 2 and 4, they are relatively weak in vitro antiplatelet agents, but they are suitable as prodrugs in vivo, where they are easily hydrolyzed to active acids.

 In vivo inhibition of thrombosis induced by laser.

 The laser-induced thrombosis method is a modification of the technique developed by Sanders et al. (Sanders A.G. et al. B Brit.J. Exp.Pathol, 1954, 35, 311) and Grant et al. (Grant L. et al b.Proc.Sos. Exp. Viol. Med. 1965, 119, 1126).

 This method is described in detail by Fleming et al. (Fleming g.S. et al. Platelets and Thrombosis. Publishers Scriabin and Sherry, Baltimore, Universal Park Press, 1974, p. 247-262).

Lucite's auditory chambers are chronically implanted in adult English fold rabbits. The animals are brought to a quiet lying position in the supination position. Localized microvascular damage is caused by focusing a single beam of a ruby laser through a microscope into the cavity (lumen) of a vessel with a diameter of 10-60 μm. This causes the formation of a small blood clot consisting of platelets collected around the core of one or two damaged red blood cells. The area of blood clots was determined as a result of two perpendicular measurements made by using the eyepiece of a micrometer. The average area of blood clots (μm ² ) obtained for 10 tests of each rabbit is used as a control value. The test compound is administered orally and post-dose tests are carried out at selected time periods. Pharmacological activity is assessed by comparing the pre-and post-dose middle zones of blood clots.

 In the biolaser model of thrombosis below, the compound of Example 5.4 exhibits 53% inhibition of thrombosis at an oral dose of 10 mg / kg, 38% inhibition at a dose of 3 mg / kg and 23% inhibition at a dose of 1 mg / kg live weight.

 The dosage used in the therapeutic methods of the invention currently under consideration varies with the form of administration, the particular compound selected, the test subject and the desired effect. Suitable effective dosages for animals range from 0.1 to 50 mg / kg of live weight orally and from 0.05 to 10 mg / kg of live weight parenterally (for the most part characterized as subcutaneous, intramuscular and intravenous injection). It is contemplated that an effective unit dose for humans varies from 1 to 100 mg, and preferably from 0.5 to 20 mg, when administered from one to three times a day. In accordance with generally accepted clinical practice, an effective dose can be determined by administering a compound of formula (I) at a dosage significantly lower than the dose of the compound that is to be effective, and then increasing the dosage with slight increases to achieve the desired effect.

 When carrying out the therapeutic methods described herein, the active ingredient of the formula (I) or the alkali metal salts of the carboxylic acids of the formula (I) are preferably administered together with a pharmaceutically acceptable carrier, such compositions form part of the invention. Suitable dosage forms for oral use are tablets, dispersible powders, granules, capsules, syrups and elixirs. Examples of parenteral dosage forms are solutions, suspensions, dispersions, emulsions, and the like. Compositions for oral use may contain one or more conventional adjuvants, such as sweeteners, flavoring agents, coloring agents and preservatives. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, including inert diluents such as calcium carbonate, sodium carbonate, lactose and talc; granulating and disintegrating agents such as starch and alginic acid; binders such as starch, gelatin and acacia, and lubricants such as magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated according to known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a long-lasting effect over an extended period of time. Similarly, the suspension, syrups and elixirs may contain the active ingredient in admixture with any conventional excipients used to prepare compositions such as suspending agents, for example methyl cellulose, tragacanth and sodium alginate, wetting agents, for example lecithin, polyoxyethylene stearate; preservatives, such as parahydroxybenzoic acid ethyl ester. Capsules may contain the active ingredient alone or mixed together with an inert solid diluent such as calcium carbonate, calcium phosphate and kaolin. Injectable compositions are formulated, as is known in the art, and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above.

 The invention is illustrated by the following examples.

In the examples, all temperatures are presented in degrees centigrade. Melting points are recorded on a Thomas-Hoover instrument for capillary determination of the melting point and are uncorrected. Proton magnetic resonance spectra ( ¹ H-NMR) were recorded on a Brucker AM 300, Brucker WM 360 or Varian Gemini spectrometer. All spectra are defined in CDL ₃ or DMSO-d ₆ , unless otherwise indicated, and chemical shifts are reported in units of delta shifted to a weak field from the internal standard tetramethylsilane (TMS), and the interaction constants between protons are reported in hertz (Hz). The types of cleavage are denoted as follows: with a singlet, a doublet, a triplet, a quartet, a m multiplet, a broadened peak and a doublet doublet.

(CH₂)₈CO₂CH₃
Смесь 4,5-дифенил-2-оксазолнонановой кислоты (800 мг, 2 ммоля), метанола (20 мл) и концентрированной серной кислоты (2 капли) нагревают до кипения с обратным холодильником. По истечении 2 ч, растворитель выпаривают и остаток делят на части между водой и СН₂Сl₂. Органическую фазу отделяют, промывают насыщенным раствором NаНСО₃, высушивают над сульфатом натрия и концентрируют под вакуумом, чтобы получить в остатке масло. Хроматография на колонке с силикагелем при использовании смеси гексанов и диэтилового эфира (4:1) в качестве элюента, дает метиловый эфир, 4,5-дифенил-2-окса- золнонановой кислоты (800 мг, 96%).PRI me R 1. 4,5-Diphenyl-2-oxazolonanoic acid methyl ester

(CH ₂ ) ₈ CO ₂ CH ₃
A mixture of 4,5-diphenyl-2-oxazolonanoic acid (800 mg, 2 mmol), methanol (20 ml) and concentrated sulfuric acid (2 drops) was heated to reflux. After 2 hours, the solvent was evaporated and the residue was partitioned between water and CH ₂ Cl ₂ . The organic phase is separated, washed with saturated NaHCO ₃ solution, dried over sodium sulfate and concentrated in vacuo to give an oil residue. Chromatography on a silica gel column using a mixture of hexanes and diethyl ether (4: 1) as an eluent gives methyl ether, 4,5-diphenyl-2-oxazolonanoic acid (800 mg, 96%).

Analysis for C ₂₅ H ₂₉ NO ₃ :
Calculated, C 76.70; H 7.47; N, 3.58.

 Found, C 76.61; H 7.84; N, 3.94.

¹ H-NMR (CDL ₃ ) δ: 1.20 to 1.50 (8H, m), 1.64 (2H, quintet, J = 7 Hz), 1.87 (2H, quintet, J = 7 Hz ), 2.32 (2H, t, J = 7.5 Hz), 2.87 (2H, t, J = 7.5 Hz), 3.67 (3H, s), from 7.20 to 7, 50 (6H, m) and from 7.70 to 7.80 (4H, m).

(CH₂)₈CO₂H
2-[7-(4,5-Дифенил-1-оксазолил)-гептил] -пропандикарбоновую кислоту (4,50 г, 10 ммолей) нагревают с перемешиванием при 150^оС. После 2 ч колбу охлаждают и остаток растирают в порошок с помощью смеси гексана и диэтилового эфира (1:1), чтобы получить белое твердое вещество. Кристаллизация из водного изопропилового спирта дает 4,5-дифенил-2-оксазолнонановую кислоту (3,15 г, 87%), температура плавления 83-85^оС.PRI me R 2. 4,5-Diphenyl-2-oxazolonanoic acid

(CH ₂ ) ₈ CO ₂ H
2- [7- (4,5-Diphenyl-1-oxazolyl) -heptyl] propanedioic acid (4.50 g, 10 mmol) was heated with stirring at 150 ^C. After 2 hours the flask was cooled and the residue triturated with using a mixture of hexane and diethyl ether (1: 1) to obtain a white solid. Crystallization from aqueous isopropyl alcohol gives 4,5-diphenyl-2-oksazolnonanovuyu acid (3.15 g, 87%), melting point 83-85 ° ^C.

Analysis for C ₂₄ H ₂₇ NO ₃ :
Calculated, C 76.37; H, 7.22; N 3.72.

 Found, C 76.37; H, 7.21; N, 3.66.

¹ H-NMR (DMSO-d ₆ ) δ: 1.10 to 1.40 (8H, m), 1.46 (2H, m), 1.71 (2H, m), 2.15 (2H, t, J = 7 Hz), 2.76 (2H, t, J = 7 Hz), from 7.20 to 7.45 (6H, m), from 7.45 to 7.65 (4H, m), 11.99 (1H, broad s).

(CH₂)₇CO₂CH₃
Смесь бензоина (6,00 г, 28 ммолей), монометилового эфира азелаиновой кислоты (7,17 г, 92%-ный чистоты, 32 ммолей), 1,3-дициклогексилкарбодиимида (7,00 г, 34 ммолей), 4-диметиламино-пиридина (каталитическое количество) и хлористого метилена (120 мл) перемешивают при комнатной температуре. После 16 ч смесь фильтруют и растворитель выпаривают. К остатку добавляют ацетат аммония (10,90 г, 141 ммолей) и уксусную кислоту (150 мл) и смесь нагревают при кипячении с обратным холодильником в течение 65 мин до того, как ее охлаждают и разбавляют водой. Смесь экстрагируют диэтиловым эфиром, объединенные экстракты высушивают над сульфатом натрия и концентрируют под вакуумом. Остаточное масло хроматографируют на колонке с силикагелью, используя смесь гексанов и диэтилового эфира (7:3) в качестве элюента, чтобы получить метиловый эфир 4,5-дифенил-2-оксазолоктановой кислоты 8,34 г, 77% в виде масла.PRI me R 3. Methyl ester of 4,5-diphenyl-2-oxazolactanoic acid

(CH ₂ ) ₇ CO ₂ CH ₃
A mixture of benzoin (6.00 g, 28 mmol), azelaic acid monomethyl ester (7.17 g, 92% pure, 32 mmol), 1,3-dicyclohexylcarbodiimide (7.00 g, 34 mmol), 4-dimethylamino -pyridine (catalytic amount) and methylene chloride (120 ml) was stirred at room temperature. After 16 hours, the mixture was filtered and the solvent was evaporated. Ammonium acetate (10.90 g, 141 mmol) and acetic acid (150 ml) were added to the residue, and the mixture was heated under reflux for 65 minutes before being cooled and diluted with water. The mixture was extracted with diethyl ether, the combined extracts were dried over sodium sulfate and concentrated in vacuo. The residual oil is chromatographed on a silica gel column using a mixture of hexanes and diethyl ether (7: 3) as an eluent to give 4,5-diphenyl-2-oxazolactanoic acid methyl ester 8.34 g, 77% as an oil.

Analysis for C ₂₄ H ₂₇ NO ₃ :
Calculated, C 76.37; H, 7.22; N 3.72.

 Found, C, 76.25; H 7.28; N, 4.05.

¹ H-NMR (CDL ₃ ) δ: 1.10 to 1.35 (6H, m), 1.45 (2H, quintet, J = 7 Hz), 1.67 (2H, quintet, J = 7 Hz ), 2.12 (2H, t, J = 7.5 Hz), 2.66 (2H, t, J = 7.5 Hz), 3.47 (3H, s), from 7.05 to 7, 25 (6H, m) and from 7.35 to 7.55 (4H, m).

(CH₂)₇CO₂H
Смесь метилового эфира, 4,5-дифенил-2-оксазолоктановой кислоты (7,00 г, 18,5 ммолей), 5N раствора гидроокиси натрия (7,42 мл), воды (100 мл) и метанола (20 мл) нагревают на паровой бане в течение 45 мин. После перемешивания в течение 75 мин при комнатной температуре смесь разбавляют водой (150 мл), нагревают на паровой бане в течение 10 мин, а затем оставляют перемешиваться в течение ночи при комнатной температуре. Смесь нагревают до кипения с обратным холодильником в течение 1 ч, охлаждают, подкисляют с помощью 2N раствора соляной кислоты и экстрагируют с помощью СН₂Сl₂. Объединенные экстракты высушивают над сульфатом натрия и концентрируют под вакуумом, чтобы получить масло, которое кристаллизуется. Перекристаллизация из смеси диэтилового эфира СН₂Сl₂ и гексанов дает 4,5дифенил-2-оксазолоктановую кислоту (5,25 г, 77%), температура плавления 70-73^оС.PRI me R 4. 4,5-Diphenyl-2-oxazolactanoic acid

(CH ₂ ) ₇ CO ₂ H
A mixture of methyl ether, 4,5-diphenyl-2-oxazolactanoic acid (7.00 g, 18.5 mmol), 5N sodium hydroxide solution (7.42 ml), water (100 ml) and methanol (20 ml) is heated steam bath for 45 min. After stirring for 75 minutes at room temperature, the mixture was diluted with water (150 ml), heated in a steam bath for 10 minutes, and then allowed to stir overnight at room temperature. The mixture was heated to boiling under reflux for 1 h, cooled, acidified with 2N hydrochloric acid and extracted with CH ₂ Cl ₂ . The combined extracts are dried over sodium sulfate and concentrated in vacuo to give an oil that crystallizes. Recrystallization from diethyl ether-CH ₂ Cl ₂ and hexanes afforded 4,5difenil-2-oksazoloktanovuyu acid (5.25 g, 77%), melting point 70-73 ° ^C.

Analysis for C ₂₃ H ₂₅ NO ₃ .

 Calculated, C 76.01; H 6.94; N, 3.86.

 Found, C 75.87; H 6.94; N, 4.16.

¹ H-NMR (CDL ₃ ) δ: 1.20 to 1.45 (6H, m), 1.54 (2H, quintet, J = 7 Hz), 1.75 (2H, quintet, J = 7 Hz ), 2.23 (2H, t, J = 7.5 Hz), 2.76 (2H, t, J = 7.5 Hz), from 7.10 to 7.35 (6H, m), from 7 , 40 to 7.60 (4H, m) and 11.74 (1H, br.s.).

 PRI me R 5. Obtaining intermediate schemes.

Смесь бензоина (10 г, 47 ммолей), 8-бромоктановой кислоты (11,57 г, 52 ммолей), 1,2-дициклогексилкарбодиимида (11,66 г, 57 ммолей), 4-диметиламинопиридина (каталитическое количество) и хлористого метилена (250 мл) перемешивают при комнатной температуре в атмосфере азота. После 17 ч смесь фильтруют и концентрируют, чтобы получить в остатке масло, которое хроматографируют на колонке с силикагелем. Элюирование с помощью смеси гексанов и диэтилового эфира (9:1) дает 2-оксо-1,2-дифенилэтиловый эфир 8-бромоктановой кислоты (18,43 г, 93%). 1 г образца повторно хроматографируют, получая аналитически чистое вещество, температура плавления 58-62^оС.5.1. 8-Bromoctanoic acid 2-oxo-1,2-diphenylethyl ester

A mixture of benzoin (10 g, 47 mmol), 8-bromoctanoic acid (11.57 g, 52 mmol), 1,2-dicyclohexylcarbodiimide (11.66 g, 57 mmol), 4-dimethylaminopyridine (catalytic amount) and methylene chloride ( 250 ml) was stirred at room temperature in a nitrogen atmosphere. After 17 hours, the mixture was filtered and concentrated to give an oil that was chromatographed on a silica gel column. Elution with a mixture of hexanes and diethyl ether (9: 1) gave 2-oxo-1,2-diphenylethyl ether of 8-bromoctanoic acid (18.43 g, 93%). 1 g of the sample is rechromatographed, obtaining analytically pure substance, melting point 58-62 ^about C.

Analysis for C ₂₂ H ₂₅ BrO ₃ .

 Calculated, C 63.32; H, 6.04.

 Found, C, 63.39; H, 5.88.

¹ H-NMR (CDL ₃ ) δ: 1.20 to 1.45 (6H, m), 1.67 (2H, quintet, J = 7 Hz), 1.82 (2H, quintet, J = 7 Hz ), 2.46 (2H, m), 3.37 (2H, t. J = 7 Hz), 6.86 (1H, s), from 7.30 to 7.55 (8H, m), 7.92 ( 2H, d, J = 7.5 Hz).

(CH₂)₇Br
Раствор 2-оксо-1,2-дифенилэтилового эфира 8-бромоктановой кислоты (16,0 г, 38 ммолей) и ацетата аммония (14,8 г, 19,2 ммолей) в уксусной кислоте (240 мл) нагревают при кипячении с обратным холодильником. После 1 ч смесь выливают в воду и экстрагируют с помощью СН₂Сl₂ трижды. Объединенные экстракты промывают водой, высушивают над сульфатом натрия и концентрируют под вакуумом, чтобы получить в остатке масло. Хроматография на колонке с силикагелью при использовании смеси гексанов и диэтилового эфира (9:1) в качестве элюента дает 2-(7-бромгептил)-4,5-дифенилоксазол (13,20 г, 86%). Образец в 1 кг повторно хроматографируют при идентичных условиях, чтобы получить аналогически чистый продукт реакции в виде масла.5.2. 2- (7-Bromheptyl) 4,4-diphenyloxazole

(CH ₂ ) ₇ Br
A solution of 8-bromoctanoic acid 2-oxo-1,2-diphenylethyl ester (16.0 g, 38 mmol) and ammonium acetate (14.8 g, 19.2 mmol) in acetic acid (240 ml) is heated under reflux a refrigerator. After 1 h, the mixture was poured into water and extracted with CH ₂ Cl ₂ three times. The combined extracts were washed with water, dried over sodium sulfate and concentrated in vacuo to give an oil residue. Chromatography on a silica gel column using a mixture of hexanes and diethyl ether (9: 1) as the eluent gives 2- (7-bromoheptyl) -4,5-diphenyloxazole (13.20 g, 86%). A 1 kg sample was rechromatographed under identical conditions to obtain a similarly pure reaction product as an oil.

Analysis for C ₂₂ H ₂₄ BrNO:
Calculated, C 66.34; H, 6.08; N, 3.52.

 Found, C, 66.36; H, 6.07; N, 7.38.

¹ H-NMR (CDL ₃ ) δ: 1.30 to 1.60 (6H, m), 1.80 to 1.95 (4H, m), 2.84 (2H, t, J = 7.5 Hz), 3.38 (2H, t, J = 7 Hz), from 7.20 to 7.40 (6H, m) and from 7.50 to 7.80 (4H, m).

(CH₂)

Смесь 2-(7-бромгептил)-4,5-дифенилоксазола (10,00 г, 25 ммолей), диметилового эфира малоновой кислоты (9,95 г, 8,60 мл, 75 ммолей), трет-бутоксида калия (8,44 г, 75 ммолей), 18-краун-6-эфира (каталитическое количество) и тетрагидрофурана (200 мл) нагревают при кипячении с обратным холодильником в атмосфере азота. После 17,5 ч смесь охлаждают, разбавляют 2N раствором соляной кислоты и экстрагируют с помощью СН₂Сl₂. Объединенные экстракты высушивают над сульфатом натрия и концентрируют под вакуумом, чтобы получить в остатке масло. Хроматография на колонке с силикагелью при использовании смеси гексанов и диэтилового эфира (9:1) в качестве элюента дает диметиловый эфир 2-[7-(4,5-дифенил-2-оксазолил)-гептил] -пропанди- карбоновой кислоты (9,47 г, 83%) в виде масла. Аналитический образец (гидратированный) получают путем повторной хроматографии образца в 3,28 г на силикагеле, используя смесь гексана и диэтилового эфира (4:1) в качестве подвижной фазы.5.3. 2- [7- (4,5-diphenyl-2-oxazolyl] heptyl) propanedicarboxylic acid dimethyl ester

(CH ₂ )

A mixture of 2- (7-bromoheptyl) -4,5-diphenyloxazole (10.00 g, 25 mmol), malonic acid dimethyl ester (9.95 g, 8.60 ml, 75 mmol), potassium tert-butoxide (8, 44 g, 75 mmol), 18-crown-6-ether (catalytic amount) and tetrahydrofuran (200 ml) are heated under reflux in a nitrogen atmosphere. After 17.5 hours, the mixture was cooled, diluted with 2N hydrochloric acid and extracted with CH ₂ Cl ₂ . The combined extracts were dried over sodium sulfate and concentrated in vacuo to give an oil residue. Chromatography on a silica gel column using a mixture of hexanes and diethyl ether (9: 1) as an eluent gives 2- [7- (4,5-diphenyl-2-oxazolyl) heptyl] propanedicarboxylic acid dimethyl ester (9, 47 g, 83%) as an oil. An analytical sample (hydrated) is obtained by re-chromatography the 3.28 g sample on silica gel using a mixture of hexane and diethyl ether (4: 1) as the mobile phase.

Analysis for C ₂₇ H ₃₁ NO ₅ , 0.1 H ₂ O.

Calculated, C 71.86; H 6.97; N, 3.11; H ₂ O, 0.40.

Found, C, 71.70; H 7.26; N, 3.01; H ₂ O, 0.48.

¹ H-NMR (CDL ₃ ) δ: 1.20 to 1.50 (8H, m), 1.70 to 1.90 (4H, m), 2.80 (2H, t, J = 7.5 Hz), 3.33 (1H, t, J = 7.5 Hz), 3.68 (6H, s) from 7.20 to 7.40 (6H, m) and from 7.50 to 7.70 ( 4H, m).

(CH₂)

Смесь диметилового эфира 2-[7-(4,5-дифенил-2-оксазолил]-гептил)-пропандикар- боновой кислоты (6,00 г, 13 ммолей), 5N раствора гидроокиси натрия (13,4 мл), воды (120 мл) и метанола (20 мл) перемешивают при комнатной температуре. После 10 мин смесь нагревают при кипячении с обратным холодильником в течение 1 ч до того, как добавляют воду (80 мл) и 5N раствор NаОН (13 мл). После дополнительных 3 ч кипячения с обратным холодильником смесь охлаждают, подкисляют 2N раствором НСl и экстрагируют диэтиловым эфиром. Объединенные экстракты высушивают над сульфатом натрия и растворитель выпаривают, чтобы получить в остатке белое твердое вещество, 2-[7-(4,5-дифенил-2-оксазолил)-гептил] -пропандикарбоновую кислоту (5,65 г, 100%). Аналитический образец получают перекристаллизацией 1,15 г вещества из смеси СН₂Сl₂, диэтилового эфира в гексане, чтобы получить чистый продукт реакции (1,05 г), температура плавления 115-117^оС.5.4. 2- [7- (4,5-diphenyl-2-oxazolyl) heptyl] propanedicarboxylic acid

(CH ₂ )

A mixture of 2- [7- (4,5-diphenyl-2-oxazolyl] heptyl) propanedicarboxylic acid dimethyl ether (6.00 g, 13 mmol), 5N sodium hydroxide solution (13.4 ml), water ( 120 ml) and methanol (20 ml) are stirred at room temperature. After 10 minutes, the mixture was heated under reflux for 1 hour before water (80 ml) and 5N NaOH solution (13 ml) were added. After an additional 3 hours at reflux, the mixture was cooled, acidified with 2N HCl and extracted with diethyl ether. The combined extracts were dried over sodium sulfate and the solvent was evaporated to give a white solid, 2- [7- (4,5-diphenyl-2-oxazolyl) heptyl] propanedicarboxylic acid (5.65 g, 100%). An analytical sample was obtained by recrystallization of 1.15 g of substance from a mixture of CH ₂ Cl _2, diethyl ether in hexane to give pure product (1.05 g), melting point 115-117 ° ^C.

Analysis for C ₂₅ H ₂₇ NO ₅ .

 Calculated, C 71.25; H, 6.46; N, 3.33.

 Found, C, 71.03; H, 6.49; N, 3.27.

¹ H-NMR (DMSO-d ₆ ) δ: 1.10 to 1.45 (8H, m), 1.60 to 1.85 (4H, m), 2.78 (2H, t, J = 7.5 Hz), 3.18 (1H, t, J7.5 Hz), from 7.25 to 7.50 (6H, m), from 7.50 to 7.60 (4H, m) and 12, 64 (2H, broad s).

Claims (2)

1. Oxazole compounds of the general formula I

where n = 7-9;
R is hydrogen or C ₁ -C ₄ alkyl,
possessing an inhibitory effect on adenosine-induced diphosphate or collagen aggregation of human plasma enriched in platelets. 2. A method of obtaining compounds of oxazole of General formula I

where n is 7-9;
R is hydrogen or C ₁ -C ₄ alkyl,
characterized in that the keto ester of General formula II

where n and R have the indicated meanings,
subjected to interaction with ammonium acetate, followed by isolation of the target product and, if necessary, the obtained compound of General formula I, where R C ₁ -C ₄ alkyl, is subjected to hydrolysis to obtain the target product of General formula I, where R is hydrogen, or the obtained compound of General formula I, where R is hydrogen, is esterified with C ₁ -C ₄ alkanol to obtain the desired product of the general formula I, where R is C ₁ -C ₄ alkyl.

Images