RU2030408C1 - Oxazole derivatives - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: derivatives of oxazole of the formula (I) given in description text. EFFECT: improved method of synthesis. 1 tbl

Description

 The invention relates to heterocyclic carbon compounds having medicinal and bioactive properties, and to their preparation and use. In particular, the invention binds to oxazole derivatives, which are inhibitors of platelet aggregation.

CH = CH

, в которой R является водородом, пара-метокси-, орто-гидрокси- и 3,4-метилендиокси-группой.Eldouse et al. (DLAldous et al. J. Org. Chem. 25, 1151 (1960) describe the chemistry of styryloxazoles of the formula

CH = CH

in which R is hydrogen, a para-methoxy, ortho-hydroxy and 3,4-methylenedioxy group.

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 трифторметильных радикалов и в которой R¹ выбирается из группы, состоящей из карбоксиалкильных и карбоксиалкенильных радикалов, каждый из которых содержит 2-5 атомов углерода, а амидов, производных гидроксановой кислоты, низших алкиловых сложных эфиров и низших алканоилокси-низших алкиловых сложных эфиров из них. Соединения патента США N 3578671 включают эффективное в клинике противовоспалительное средство, известное обычно как оксапрозин (R² = R³ = фенил, R¹ = =(CH₂)₂COOH).Brown [1] describes a class of oxazole-2-hemi-carbon aliphatic monocarboxylic acids arylated at 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 trifluoromethyl radicals and in which R ¹ is selected from the group consisting of carboxyalkyl and carboxyalkenyl radicals, each of which contains 2-5 carbon atoms, and amides, derivatives of hydroxanoic acid, lower alkyl esters and lower alkanoyloxy-n higher alkyl esters thereof. The compounds of US Pat. No. 3,578,671 include a clinically effective anti-inflammatory agent, commonly known as oxaprozin (R ² = R ³ = phenyl, R ¹ = (CH ₂ ) ₂ COOH).

_O в которой между прочим R₁ и R₂ являются водородом, а "alk-Y" является остатком алкановой кислоты и сложного эфира. Известные соединения имеют циклическую АМФ (аденозинмонофосфат) фосфодиэстеразную ингибирующую активность и являются полезными в качестве ингибиторов агрегации кровяных пластинок и/или в качестве кардиотонических средств.Minwell et al. Describe a series of 2,3-dihydro-2-oxo-1H-imidazole derivatives of [4.5-c] -quinolinyl ether of the formula

_O in which, by the way, R ₁ and R ₂ are hydrogen, and "alk-Y" is a residue of alkanoic acid and an ester. Known compounds 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 1-10, а R⁷ является Н, ионами щелочного металла, алкильной или бензильной группой. Соединения [2] являются полезными при лечении тромбоэмболической, воспалительной и/или атеросклеротической болезни у человека. Особенно предпочтительный член серий, в котором R¹-R⁶ является водородом, n - 7, а R⁷ - натрием (идентифицируемый в области техники как октимибат натрия) описан как обладающий противоагрегаторной активностью и разрабатывается в клинике в качестве антигиперлипидемического средства.Lautenschlager et al. Describe a series of triphenylimidazol-2-yloxyalkanoic acids of the formula

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 of 1-10, and R ⁷ is H, alkali metal ions, an alkyl or benzyl group. Compounds [2] are useful in the treatment of thromboembolic, inflammatory and / or atherosclerotic disease in humans. A particularly preferred member of the series in which R ¹ -R ⁶ is hydrogen, n is 7, and R ⁷ is sodium (identified in the art as sodium octimibate) is described as having anti-aggregator activity and is being developed in the clinic as an antihyperlipidemic agent.

S - (CH₂)_nCO₂R где n составляет 7-8, а R представляет собой водород или низший алкил, которые являются ингибиторами аденозин-дифосфата и индуцированной коллагеном агрегации человеческой плазмы, обогащенной тромбоцитами, и предназначены для использования в качестве ингибиторов агрегации кровяных пластинок млекопитающих.In its features, the invention relates to oxazole derivatives having the formulas (1)

S - (CH ₂ ) _n CO ₂ R where n is 7-8 and R is hydrogen or lower alkyl, which are inhibitors of adenosine diphosphate and collagen-induced platelet-rich human plasma aggregation, and are intended to be used as aggregation inhibitors mammalian blood platelets.

S - (CH₂)_nCO₂R^a в которой n составляет 7-9, а R^а является низшим алкилом, до соответствующей кислоты, или
(б) этерификацию соединения формулы (3)

S - (CH₂)_nCO₂H в которой n составляет 7-9, с помощью низшего алканола, или (в) алкилирование 4,5-дифенил-2-(3Н)-оксазолтиона с помощью Br-(CH₂)nCOOR^a в котором n является 7-8, а R^а является низшим алкилом.In accordance with the invention, the compounds of formula (1) are obtained by a process comprising:
(a) hydrolysis of a compound of formula (2)

S - (CH ₂ ) _n CO ₂ R ^a in which n is 7-9 and R ^a is lower alkyl, to the corresponding acid, or
(b) the esterification of the compounds of formula (3)

S - (CH ₂ ) _n CO ₂ H in which n is 7-9 using lower alkanol, or (c) alkylation of 4,5-diphenyl-2- (3H) -oxazolethione with Br- (CH ₂ ) nCOOR ^a in which n is 7-8, and R ^a is lower alkyl.

 The compounds of formula (1) have pharmacological and pharmaceutical properties that make them particularly useful as inhibitors of platelet aggregation (platelets).

 Platelet aggregation is considered part of the complex physiological mechanism of thrombus formation in the vascular system. Thromboembolic event, i.e. the formation of blood clots is associated with hemostasis and a number of painful conditions 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, not to mention others, and with coronary heart disease, atherosclerosis, multiple sclerosis, intracranial tumors, thromboembolism and hyperlipemia. 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 subject compounds can be demonstrated by routine in vitro and in vivo biological tests, for example the following.

 Inhibition of human platelet aggregation in vitro.

 Aggregometer (device for measuring aggregation) was used according to the Born method (CVRBorn J.Physiol (London), 1962, 162, 67-68), which was modified by Mustard et al. (Mustard JFet al. J. Lab. Clin Med. , 1964, 64, 548-599) to evaluate in vitro the activity of various compounds with respect to inhibition of adenosine diphosphate (ADP).

 The hand of a volunteer donor is cleaned with 70% ethanol. A sterilized 20 ml syringe and a needle were used to draw 20 ml of blood. Blood was immediately added to the test tube containing 3.8% sodium citrate to prevent blood coagulation (1 part citrate per 9 parts blood).

Platelet-rich plasma (OTP) was isolated by centrifugation for 10 min at a speed of 1000 rpm (140 xg) from citrated (3.8%) human blood. All glass products used to obtain OTP were 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) was used to induce aggregation. Various test compounds were dissolved in dimethyl sulfoxide (DMSO) so that 5 μl added to platelet-rich plasma would give the desired concentration for the test. Control tests with filler were carried out and compared with aggregation induced in platelet-rich plasma containing concentrations of test compounds. Dose response curves were obtained, inhibitory concentration values (IC ₅₀ ) were calculated, and percent inhibition was noted at 32 μg / ml. In this test, the IC ₅₀ values for dipyridamole, a clinically useful antithrombogenic agent, are 512 μg / ml against ADP. The results of inhibition of human platelet aggregation in vitro and the test results for the compounds of examples 1-4 are presented in the table.

 In vivo inhibition of thrombosis induced by in vivo laser.

 The laser-induced thrombosis method is a modification of the technique developed by Sanders et al. (Sanders, AG et al in Brit. J. Exp.pathol, 1954, 35, 331) and Grant et al. (Grant, L., et al. in Proc. Soc. Exp. Biol. Med, 1965, 119, 1123). A detailed description of this method is described by Fleming and others (Fleming, JS et al) in the book Platelets and Thrombosis (publishers Scriabin and Sherry, Baltimore, Universal Park Press, pp. 247-262, 1974 in platelets and Thrombosis, A. Scziabine and S .Sherry, eds Baltimore, Univ Park Press.

Lucite's auditory chambers were chronically implanted by an adult English lop-eared rabbit. Animals were placed in a quiet lying position in the supination position. Localized microvascular damage was 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 caused the formation of a small thrombus 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 using a micrometer eyepiece. The average area of blood clots (μM ² ) obtained for 10 tests of each rabbit was used as a control value. The test compound was administered orally and post-dose tests were performed at selected time periods. Pharmacological activity was evaluated by comparing the pre- and post-dose middle zones of blood clots.

 In the above biolaser model, thrombosis, the compound of Example 6 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 of live weight.

 The dosage used in the therapeutic methods of the invention varies with a change in the form of administration, the particular compound selected, the test subject and the desired effect. Suitable effective doses for animals vary between 0.1-50 mg / kg body weight orally and 0.05-10 mg / kg body weight parenterally (for the most part characterized as subcutaneous, intramuscular and intravenous injection). It is contemplated that an effective unit dose for humans varies between 1-100 mg, and preferably 0.5-20 mg, 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 (1) at a dosage of a significantly lower dose of the compound, which should be effective, and then increasing the dosage with slight increases until the desired effect is achieved.

 When carrying out the considered therapeutic methods, the active ingredient of the formula (1) or alkali metal salts of carboxylic acids of the formula (1) are preferably administered together with a pharmaceutically acceptable carrier. 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 to provide the composition with a suitable pharmaceutical elegance. 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 a mixture with any conventional excipients used to prepare compositions such as suspending agents (e.g. methyl cellulose, tragacanth and sodium alginate), wetting agents (e.g. lecithin, polyoxyethylene stearate) and preservatives agents such as para-hydroxybenzoic acid ethyl ester. Capsules may contain the active ingredient alone or 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.

In the following examples, all temperatures are presented in degrees centigrade. Melting points were recorded on a Thomas-Hoover instrument for capillary determination of the melting point and are uncorrected. Proton magnetic resonance spectra ( ^I H-NMR) were recorded on a Brucker AM 300 spectrometer, a Bruker WM 360 or Varian Gemini spectrometer. All spectra were determined 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 indicated as follows: s, singlet; d doublet; T. triplet; sq. quartet; m. multiplet; ear. broadened peak and dd. doublet of a doublet.

S - (CH₂)₇CO₂CH₃
Гидрид натрия (0,71 г 60%-ной дисперсии, 18 ммолей) добавляют к перемешиваемому раствору 4,5-дифенил-2-(3Н)-ок- сазолтиона (4,05 г, 16 ммолей) в диметилформамиде (50 мл), содержащемуся в атмосфере азота. Смесь перемешивают при комнатной температуре в течение 15 мин, чтобы получить суспензию, и по каплям добавляют раствор метилового эфира 8-бромоктановой кислоты (3,83 г, 16 ммолей) в ДМФА (10 мл). После завершения добавления реакционную смесь перемешивают при температуре окружающей среды в течение 2,5 ч и при 50^оС в течение 30 мин. Реакционную смесь разбавляют диэтиловым эфиром и водой и перемешивают. Органический слой отделяют, высушивают (MgSO₄) и концентрируют, чтобы в остатке получить масло, которое хроматографируют на колонке с силикагелью. Элюирование с помощью смеси гексанов и диэтилового эфира (сначала 2:1, затем 1:1 и наконец 1:2) дает метиловый эфир 8-[(4,5-дифенил-2-оксазолил)-тио] -октановой кислоты (4,40 г, 67,2%) в виде частичного гидрата.Example 1. 8 - [(4,5-Diphenyl-2-oxazolyl) thio] octanoic acid methyl ester

S - (CH ₂ ) ₇ CO ₂ CH ₃
Sodium hydride (0.71 g of a 60% dispersion, 18 mmol) is added to a stirred solution of 4,5-diphenyl-2- (3H) -oxazolethione (4.05 g, 16 mmol) in dimethylformamide (50 ml) contained in an atmosphere of nitrogen. The mixture was stirred at room temperature for 15 minutes to obtain a suspension, and a solution of 8-bromoctanoic acid methyl ester (3.83 g, 16 mmol) in DMF (10 ml) was added dropwise. After complete addition, the reaction mixture was stirred at ambient temperature for 2.5 hours and ^at 50 ° C for 30 min. The reaction mixture was diluted with diethyl ether and water and stirred. The organic layer was separated, dried (MgSO ₄ ) and concentrated, so that an oil was obtained in the residue, which was chromatographed on a silica gel column. Elution with a mixture of hexanes and diethyl ether (first 2: 1, then 1: 1 and finally 1: 2) gives 8 - [(4,5-diphenyl-2-oxazolyl) thio] octanoic acid methyl ester (4, 40 g, 67.2%) as a partial hydrate.

 Analysis.

 Calculated,%: C 69.46; H 6.70; N, 3.33.

C ₂₄ H ₂₇ NO ₃ S , ₃ 0.3 H ₂ O.

 Found,%: C 69.48; H 6.88; N, 3.15.

1 ^H-NMR (CDC ₃ ) δ: 1.26-2.33 (10H, m); 2.30 (2H, t); 3.24 (2H, t); 3.66 (3H, s); 7.31 (6H, m) and 7.60 (4H, m).

S - (CH₂)₇CO₂H
Метиловый эфир 8-[(4,5-дифенил-2-оксазолил)-тио]-октановой кислоты (2,0 г, 4,9 ммоль) растворяют в метаноле (30 мл). Добавляют раствор моногидрата гидроокиси лития (0,41 г, 9,8 ммоль) в воде (8 мл) и смесь нагревают при кипячении с обратным холодильником 1 ч. После охлаждения до комнатной температуры метанол удаляют под вакуумом, остаток разбавляют водой и подкисляют примерно до рН 2, используя разбавленный раствор соляной кислоты. Смесь экстрагируют этилацетатом, объединенные экстракты высушивают над MgSO₄ и концентрируют. Остаток хроматографируют на колонке с силикагелью, используя смесь CH₂Cl₂/MeOH (95/5) в качестве элюента, чтобы получить 8-[(4,5-дифенил-2-оксазолил)-тио]-октановую кислоту (1,70 г, 88%).PRI me R 2. 8 - [(4,5-Diphenyl-2-oxazolyl) thio] octanoic acid

S - (CH ₂ ) ₇ CO ₂ H
8 - [(4,5-Diphenyl-2-oxazolyl) thio] octanoic acid methyl ester (2.0 g, 4.9 mmol) was dissolved in methanol (30 ml). A solution of lithium hydroxide monohydrate (0.41 g, 9.8 mmol) in water (8 ml) was added and the mixture was heated under reflux for 1 h. After cooling to room temperature, methanol was removed in vacuo, the residue was diluted with water and acidified to about pH 2 using a dilute hydrochloric acid solution. The mixture was extracted with ethyl acetate, the combined extracts were dried over MgSO ₄ and concentrated. The residue was chromatographed on a silica gel column using CH ₂ Cl ₂ / MeOH (95/5) as an eluent to give 8 - [(4,5-diphenyl-2-oxazolyl) thio] octanoic acid (1.70 g, 88%).

 Analysis.

 Calculated,%: C 68.59; H 6.46; N, 3.48.

C ₂₃ H ₂₅ NO ₃ S , ₄ 0.4 H ₂ O.

 Found,%: C 68.84; H 6.57; N, 3.23.

I _H-NMR (CDC ₃ ) δ: 1.27-1.80 (10H, m); 2.26 (2H, t); 3.18 (2H, t); 7.26 (6H, m) and 7.48 (4H, m).

 Example 3. Methyl ester of [3 - [[(4,5-diphenyl-2-oxazolyl) thio] methyl] phenoxy] acetic acid.

S - CH

OCH₂CO₂CH₃
4,5-Дифенил-2-(3Н)-оксазолтион (5,7 г, 22,8 ммоль) растворяют в ДМФА (100 мл). Гидрид натрия (1,0 г, 60%-ной дисперсии, 25 ммоль) добавляют и смесь перемешивают в атмосфере азота 30 мин. Прозрачный раствор охлаждают до 0^оС и раствор метилового эфира 3-(бромметил)-фенокси-уксусной кислоты (6,5 г, 25 ммоль) в ДМФА (10 мл) добавляют по каплям. По завершении добавления суспензию перемешивают при 0^оС в течение 1 ч, а затем при комнатной температуре в течение 2 ч. Реакционную смесь разбавляют этиловым эфиром и водой (каждые по 200 мл) и перемешивают. Органический слой отделяют, промывают водой (2 х 20 мл), высушивают (MgSO₄) и концентрируют под вакуумом. Сырое вещество очищают флеш-хроматографией на силикагеле, используя смесь гексана и диэтилового эфира (2:1) в качестве элюента, чтобы получить метиловый эфир [3-[[(4,5-дифенил-2-оксазолил)-тио]-метил]-фенокси] -уксусной кислоты (1,5 г, 13%) в виде масла.

S - CH

OCH ₂ CO ₂ CH ₃
4,5-Diphenyl-2- (3H) -oxazolethione (5.7 g, 22.8 mmol) was dissolved in DMF (100 ml). Sodium hydride (1.0 g, 60% dispersion, 25 mmol) was added and the mixture was stirred under nitrogen for 30 minutes. The clear solution was cooled ^to 0 ° C and a solution of methyl 3- (bromomethyl) -phenoxy-acetic acid ethyl ester (6.5 g, 25 mmol) in DMF (10 ml) was added dropwise. Upon completion of the addition, the suspension was stirred at 0 ° ^C. for 1 hour, and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl ether and water (200 ml each) and stirred. The organic layer was separated, washed with water (2 x 20 ml), dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a mixture of hexane and diethyl ether (2: 1) as an eluent to give [3 - [[(4,5-diphenyl-2-oxazolyl) thio] methyl] methyl ester] α-phenoxy] -acetic acid (1.5 g, 13%) as an oil.

 Analysis.

 Calculated,%: C 68.75; H 4.69; N, 3.62.

C ₂₅ H ₂₁ NO ₄ Si.

 Found,%: C 68.39; H 4.65; N, 3.58.

1 _H-NMR (CDC ₃ ) δ: 3.75 (3H, s); 4.40 (2H, s); 4.56 (2H, s); 6.78 (1H, doublet of doublets, I = 8 Hz, I '= 2.5 Hz) and 6.98-7.92 (13H, m).

 PRI me R 4. [3 - [[(4,5-Diphenyl-2-oxazolyl) thio] methyl] phenoxy] acetic acid.

S - CH

OCH₂CO₂CH
Метиловый эфир [3-[[(4,5-дифенил-2-оксазолил)-тио]-метил]-фенокси]-уксусной кислоты (1,1 г, 2,6 ммоль) растворяют в метаноле (25 мл). Добавляют моногидрат гидроокиси лития (0,22 г, 5,1 ммоль), за которым следует добавление по каплям воды (5 мл). Эту смесь нагревают при кипячении с обратным холодильником в течение 30 мин, охлаждают до комнатной температуры и концентрируют под вакуумом. Остаток растворяют в воде (15 мл) и подкисляют примерно до рН 2. Смесь экстрагируют хлористым метиленом (25 мл), объединенные экстракты высушивают над MgSO₄ и концентрируют под вакуумом. Остаток очищают с помощью хроматографии на колонке с силикагелью, используя смесь CH₂Cl₂ и MeOH (95: 5) в качестве элюента, чтобы получить [3-[[(4,5-дифенил-2-оксазолил)-тио] -метил] фенокси]-уксусную кислоту (0,6 г, 56,4%), т.пл. 136-137^оС.

S - CH

OCH ₂ CO ₂ CH
[3 - [[(4,5-Diphenyl-2-oxazolyl) thio] methyl] phenoxy] acetic acid methyl ester (1.1 g, 2.6 mmol) was dissolved in methanol (25 ml). Lithium hydroxide monohydrate (0.22 g, 5.1 mmol) was added, followed by dropwise addition of water (5 ml). This mixture was heated under reflux for 30 minutes, cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and acidified to about pH 2. The mixture was extracted with methylene chloride (25 ml), the combined extracts were dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of CH ₂ Cl ₂ and MeOH (95: 5) as an eluent to obtain [3 - [[(4,5-diphenyl-2-oxazolyl) thio] methyl ] phenoxy] -acetic acid (0.6 g, 56.4%), mp. 136-137 ^about S.

 Analysis.

 Calculated,%: C 69.05; H 4.59; N, 3.36.

C ₂₄ H ₁₉ NO ₄ S.

 Found,%: C 68.83; H 4.64; N, 3.35.

1 _H-NMR (CDC ₃ ) δ: 4.41 (2H, s); 4.61 (2H); 6.82 (1H, doublet of doublets, I = 8.2 Hz, I '= 2 Hz) and 7.03-7.64 (1H, m).

Claims (1)

Oxazole derivatives of the general formula

where n = 7 - 9;
R is hydrogen or lower alkyl.

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