Derivative oxazole

 

(57) Abstract:

Usage: in medicine as inhibitors of the aggregation of blood platelets. The essence of the invention: derivatives of oxazole F.-ly (1), given in the text description. table 1.

The invention relates to heterocyclic carbon compounds having drug and pivotdata properties, and to obtain and use them. In particular, the invention is associated with derivatives oxazole, which are inhibitors of the aggregation of blood platelets.

Aldous and others (D. L. Aldous et al.J.Org.Chem., 25, 1151 (1960) describe the chemistry of sterilisation formula

CH = CH in which R is hydrogen, para-methoxy-, ortho-hydroxy - 3,4-methylendioxy group.

Brown [1] describes the class of oxazol-2-property aliphatic monocarboxylic acids, ALLROUNDER in position 4 and/or 5 oxazoline ring formula

R1in which each of the substituents R2and R3is a member of the group consisting of unsubstituted phenyl, naftalina, thienyl and fueling radicals, substituted by substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy-, nitro - and triptorelin radicals and cu containing 2-5 carbon atoms, and amides derived gidroksamovoi acid, lower alilovic esters and lower alkanoyloxy lowest alilovic esters of them. Join US patent N 3578671 include effective in the clinic anti-inflammatory agent, usually known as oxaprozin (R2= R3= phenyl, R1= =(CH2)2COOH).

Manwell and others describe a series of derivatives of 2,3-dihydro-2-oxo-1H-imidazol[4.5-b]-rhinolining simple ester of the formula

Owhich by the way R1and R2are hydrogen, and "alk-Y" is a residue alanovoy acid and ether complex. Known compounds are cyclic AMP (amp) fosfodiesterazu inhibitory activity and are useful as inhibitors of the aggregation of blood platelets and/or as a cardiotonic funds.

Lautenslager etc. describes a number of triphenylimidazole-2-roxellanae acid formula

in which R1, R2, R3, R4, R5and R6each is H, halogen, alkyl, alkoxy group and trifluoromethyl; n is an integer of 1-10, and R7is H, alkali metal ions, alkyl or benzyl group. Compounds [2] are useful etc the equipment member of the series, in which R1-R6is hydrogen, n - 7, and R7- sodium (identifiable in the field of technology as ottimista sodium) is described as having protivoraketnoi activity and is being developed in the clinic as antihyperlipidemic tools.

Its features the invention relates to a derivative of oxazole having formulas (1)

S - (CH2)nCO2R where n is 7-8, and R represents hydrogen or lower alkyl, which are inhibitors of adenosine diphosphate and induced collagen aggregation of human plasma platelet-rich, and are intended for use as inhibitors of the aggregation of blood platelets mammals.

In accordance with the invention the compounds of formula (1) obtained by the method, including:

(a) hydrolysis of compounds of formula (2)

S - (CH2)nCO2Rain which n is 7-9 and Randis lower alkyl, to the corresponding acid, or

(b) esterification of the compounds of formula (3)

S - (CH2)nCO2H in which n is 7-9, with lower alkanol, or (C) alkylation of 4,5-diphenyl-2-(3H)-oxazolone with Br-(CH2)nCOORain Kotka and pharmaceutical properties, which make them particularly useful as inhibitors of the aggregation of blood platelets (thrombocytes).

Platelet aggregation is part of a complex physiological mechanism of formation of a blood clot in the vascular system. Thromboembolic phenomenon, i.e. the formation of blood clots, associated with hemostasis and a number of painful conditions in mammals, including thrombophlebitis, phlebothrombosis, cerebral thrombosis, coronary thrombosis, and retinal vascular thrombosis. The increase in the propensity for platelet aggregation, sometimes called adhesiveness ("tack") platelets, occurs after childbirth, surgery, such as bypass surgery coronary artery, organ transplantation, plastic surgery on vessels, implantation of artificial heart valves, not to mention the other, and in ischemic heart disease, atherosclerosis, multiple sclerosis, intracranial tumors, thromboembolism and hyperlipemia. Thus, the compounds of the invention, which have anti-platelet properties (inhibit aggregation of blood platelets), are useful for the prevention or treatment of conditions involving platelet aggregation and thrombosis, such as indicated inhibition of platelets.

Pharmacological properties of the considered compounds can be demonstrated by conventional in vitro and in vivo biological tests, such as the following.

Inhibition of aggregation of human platelets in vitro.

Aggregometer (a device for measuring aggregation) was used according to the method of born (C. V. R. J. Born Physil (London), 1962, 162, 67-68), which modified the Mustard and others (Mustard J. F. et al. J. Lab. Clin Med., 1964, 64, 548-599) to evaluate the in vitro activity of various compounds on inhibition of adenosine diphosphate (ADP).

The hand of a volunteer donor is cleaned with 70% ethyl alcohol. Sterilized syringe with a volume of 20 ml and needle were used to select 20 ml of blood. The blood was immediately added to the tube for testing, containing 3.8% sodium citrate to prevent clotting of blood (1 CH citrate at 9 o'clock the blood).

Platelet-rich plasma (OTP) was separated by centrifugation for 10 min at a speed of 1000 rpm (140 XA) of citrate (3.8 per cent) human blood. All glassware used to obtain the OTP, were treated with silicone. ADP at a final concentration of 0.5 μg/ml or 0.05 ml of the collagen suspension obtained according to the method described by Evans the Oia were dissolved in dimethyl sulfoxide (DMSO), to 5 μl added to platelet-rich plasma, would give the desired concentration for testing. Control tests with filler were carried out and compared with the aggregation induced in platelet-rich plasma containing concentrations of the tested compounds. Were obtained response curves for the dose, the calculated values of the inhibitory concentration (IC50) and the percentage of inhibition at 32 µg/ml In this test, the value of the IC50for dipyridamole useful in the clinic anti-platelet funds is 512 µg/ml against ADP. The results of the inhibition of aggregation of human platelets in vitro and test results for the compounds of examples 1-4 are presented in the table.

In vivo inhibition of thrombosis induced by laser in vivo.

Method of thrombosis induced by the laser, is a modification of the method developed by Sanders and others (Sanders, A. G. et al, Brit. J. Exp.pathol, 1954, 35, 331) and Grant and others (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, J. S. et al) in the book of Platelets and Thrombosis (publishers Scriabin and sherry, Baltimore, Wagon Park Press, S. 247-262, 1974 in platelets and Thrombosis, A. Scziabine and S. Sherry, eds Baltimore, Univ Park Press.

2) obtained for 10 trials of each rabbit was used as the control value. The test compound was administered orally and posledujuwie tests were carried out at selected periods of time. Pharmacological activity was evaluated by comparing pre - and Paleozoic medium zones of blood clots.

In the above bilateral model, thrombosis, the compound of example 6 shows 53% inhibition of thrombosis in oral dose of 10 mg/kg, 38% inhibition at the dose of 3 mg/kg and 23% inhibition at the dose of 1 mg/kg of live weight.

The dosage used in therapeutic methods of the invention varies with the change of the form of the introduction of specifically selected compounds tested subjectional and 0.05-10 mg/kg of body weight parenterally (for the most part characterized as subcutaneous, intramuscular and intravenous injection). It is assumed that the effective uniform dose for humans varies in the range of 1-100 mg, preferably 0.5 to 20 mg, administered one to three times a day. In accordance with accepted clinical practice, the effective dose can be determined by introducing the compounds of formula (1) at a dose much lower doses of compounds, which should be effective, and then increase the dosage with minor increases up until not achieved the desired effect.

When conducting the considered therapeutic methods active ingredient of formula (1) or alkali metal salts of carboxylic acids of the formula (1) preferably introduced together with a pharmaceutically acceptable carrier. Suitable dosage forms for oral administration are tablets, dispersible powders, granules, capsules, syrups and elixirs. Examples of parenteral dosage forms are solutions, suspensions, dispersions, emulsions, etc., Compositions for oral use may contain one or more conventional Adjuntas, such as sweeteners, substances imparting taste and aroma, pigments and canned in order to reap the active ingredient in a mixture with conventional pharmaceutically acceptable excipients, including inert diluents such as calcium carbonate, sodium carbonate, lactose and talc; granulating and dezintegriruetsja tools, such as starch and alginic acid; binders, such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a long lasting effect over an extended period of time. Similarly, suspensions, syrups and elixirs may contain the active ingredient in a mixture with any of the common fillers used for obtaining such compositions, as suspendresume means (for example, methylcellulose, tragakant and sodium alginate), wetting agents (e.g. lecithin, polyoxyethylenated) and preservatives, such as ethyl ester of para-hydroxybenzoic acid. Capsules may contain the active ingredient alone or together with an inert solid diluent such as calcium carbonate, calcium phosphate and kaolin. Injectisome composition are prepared, as is known in the art and mo is e or similar with the above.

In the following examples, all temperatures are presented in degrees centigrade scale. The melting points were recorded on the instrument Thomas-Hoover capillary determine the melting point and are uncorrected. Proton nuclear magnetic resonance spectrum (IH-NMR) were recorded on a spectrometer Bruker AM 300, Bruker WM 360 or Varian Gemini. All spectra were determined in Cl3or DMSO-d6unless otherwise noted, and chemical shifts are reported in units of Delta shifted in a weak field from the internal standard tetramethylsilane (TMS), and constant interaction between the protons are reported in Hertz (Hz). Types of cleavage are indicated as follows: s, singlet; D. doublet; T. triplet; sq Quartet; m, multiplet; ush. broadened peak and DD. the doublet of doublet.

P R I m e R 1. Methyl ester of 8-[(4,5-diphenyl-2-oxazolyl)-thio]-octanoic acid

S - (CH2)7CO2CH3< / BR>
Sodium hydride (0.71 g of 60% dispersion, 18 mmol) is added to a stirred solution of 4,5-diphenyl-2-(3H)-OK - stationa (of 4.05 g, 16 mmol) in dimethylformamide (50 ml) contained in a nitrogen atmosphere. The mixture is stirred at room temperature for 15 min to obtain a suspension, and C adding the reaction mixture was stirred at ambient temperature for 2.5 h and at 50aboutC for 30 minutes, the Reaction mixture was diluted with diethyl ether and water and mix. The organic layer is separated, dried (MgSO4) and concentrate to a residue to obtain the oil, which chromatographic on the column with silicagel. Elution using a mixture of hexanol and diethyl ether (first, 2:1, then 1:1 and finally 1:2) gives the methyl ester of 8-[(4,5-diphenyl-2-oxazolyl)-thio] -octanoic acid (4,40 g, 67.2 per cent) as a partial hydrate.

Analysis.

Calculated,%: C 69,46; H 6,70; N 3,33.

C24H27NO3S0,3 H2O.

Found,%: C 69,48; H 6,88; N 3,15.

IH-NMR(l3) : 1,26-2,33 (10H, m); 2,30 (2H, t); 3,24 (2H, t); 3,66 (3H, s); 7,31 (6N, m) and 7.60 (4H, m).

P R I m m e R 2. 8-[(4,5-Diphenyl-2-oxazolyl)-thio]-octanoic acid

S - (CH2)7CO2H

Methyl ester of 8-[(4,5-diphenyl-2-oxazolyl)-thio]-octanoic acid (2.0 g, 4.9 mmol) dissolved in methanol (30 ml). Add a solution of the monohydrate of lithium hydroxide (0,41 g, 9.8 mmol) in water (8 ml) and the mixture heated to boiling under reflux 1 h After cooling to room temperature, the methanol is removed under vacuum, the residue diluted with water and acidified to approximately pH 2 using diluted hydrochloric Balance chromatographic on the column with silicagel, using a mixture of CH2Cl2/MeOH (95/5) as eluent, to obtain 8-[(4,5-diphenyl-2-oxazolyl)-thio]-octanoic acid (1.70 g, 88%).

Analysis.

Calculated,%: C 68,59; H 6,46; N 3,48.

C23H25NO3S0,4 H2O.

Found,%: C 68,84; H To 6.57; N 3,23.

IH-NMR(l3) : 1,27-of 1.80 (10H, m); and 2.26 (2H, t); 3,18 (2H, t); 7,26 (6N, m) and of 7.48 (4H, m).

P R I m e R 3. Methyl ester [3-[[(4,5-diphenyl-2-oxazolyl)-thio]-methyl]-phenoxy] acetic acid.

S - CHOCH2CO2CH3< / BR>
4,5-Diphenyl-2-(3H)-oxidation (5.7 g, of 22.8 mmol) dissolved in DMF (100 ml). Sodium hydride (1.0 g, 60% dispersion, 25 mmol) is added and the mixture is stirred under nitrogen atmosphere for 30 minutes a Clear solution is cooled to 0aboutC and a solution of methyl ester 3-(methyl bromide)-phenoxy-acetic acid (6.5 g, 25 mmol) in DMF (10 ml) is added dropwise. Upon completion of the addition the suspension is stirred at 0aboutC for 1 h and then at room temperature for 2 hours, the Reaction mixture was diluted with ethyl ether and water (each 200 ml) and stirred. The organic layer was separated, washed with water (2 x 20 ml), dried (MgSO4) and concentrate under vacuum. The crude substance is purified flash chromatography on forces[(4,5-diphenyl-2-oxazolyl)-thio]-methyl]-phenoxy] -acetic acid (1.5 g, 13%) in the form of butter.

Analysis.

Calculated,%: C, 68.75 Kilopascals; H 4,69; N 3,62.

C25H21NO4Si.

Found,%: C 68,39; H 4,65; N To 3.58.

IH-NMR(l3) : of 3.75 (3H, s); however, 4.40 (2H, s); 4,56 (2H, s); is 6.78 (1H, DD), I = 8 Hz, I' = 2.5 Hz) and 6,98-7,92 (13H, m).

P R I m e R 4. [3-[[(4,5-Diphenyl-2-oxazolyl)-thio]-methyl]-phenoxy]-acetic acid.

S - CHOCH2CO2CH

Methyl ester [3-[[(4,5-diphenyl-2-oxazolyl)-thio]-methyl]-phenoxy]-acetic acid (1.1 g, 2.6 mmol) dissolved in methanol (25 ml). Add the monohydrate of lithium hydroxide (0,22 g, 5.1 mmol), followed by adding dropwise water (5 ml). This mixture is heated to boiling under reflux for 30 min, cooled to room temperature and concentrate under vacuum. The residue is dissolved in water (15 ml) and acidified to about pH 2. The mixture is extracted with methylene chloride (25 ml), the combined extracts dried over MgSO4and concentrate under vacuum. The residue is purified by chromatography on a column with silicagel using a mixture of CH2Cl2and MeOH (95: 5) as eluent, to obtain [3-[[(4,5-diphenyl-2-oxazolyl)-thio] -methyl] phenoxy]-acetic acid (0.6 g, 56.4 per cent), so pl. 136-137aboutC.

Analysis.

IH-NMR(l3) : to 4.41 (2H, s); br4.61 (2H); PC 6.82 (1H, DD), I = 8,2 Hz, I' = 2 Hz) and 7,03-to 7.64 (1H, m).

DERIVATIVE OXAZOLE General formula

< / BR>
where n = 7 to 9;

R is hydrogen or lower alkyl.

 

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SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

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1 tbl, 1 ex

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EFFECT: valuable medicinal properties of drug.

5 tbl

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

22 cl, 1 tbl, 2 sch, 78 ex

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

22 cl, 1 tbl, 2 sch, 78 ex

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EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

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