Derivative oxazole or their pharmaceutically acceptable cationic salt, or an acid additive salt

 

(57) Abstract:

Optically pure thiazolidinedione alcohols and ethers and synthetic intermediate for obtaining the aforementioned alcohols and ethers. These compounds have use as hypoglycemic and hypocholesterolemic agents. 3 S. and 12 C.p. f-crystals, 5 Il.

This invention relates to certain compounds of formulas I, II and IV, described below, are useful as hypoglycemic and hypocholesterolemic agents, and methods of their use and pharmaceutical compositions containing them.

Despite previously opened insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfanilamide (for example, hlorpropamid, tolbutamide, acetohexamide, tolazamide) and biguanides (for example, phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than successful. The use of insulin needed for about 10% of diabetic patients for whom synthetic hypoglycemic is not effective (diabetes type I, insulinozawisimy diabetes mellitus), requires multiple daily doses, usually by Semenyako the second dose of insulin causes hypoglycemia with effects ranging from weak anomalies in the content of glucose in the blood to coma or even death. Treatment of non-insulin dependent diabetes mellitus (diabetes type II) usually consists of a combination of diet, exercise, oral agents, such as sulfanilamide, and in more severe cases, insulin. However, clinically suitable hypoglycemic agents unfortunately fraught other toxic manifestations, which limit their application. In any case, individual review where one of these agents may not provide the desired action, the other may succeed. The continuous need for hypoglycemic agents, which would be less harmful or would bring success where others do not exert the desired action obvious.

In addition, it is known that in the United States and Western Europe to death cause of atherosclerosis, a disease of the arteries. The sequence of pathologies, leading to atherosclerosis and heart failure, has been described in detail Ross and Glomset. New England Journal of Medicine. p. 295, 369 377 (1976).

The initial stage in this sequence is the formation of "fatty layers in the carotid, coronary and cerebral arteries and in the aorta. These lesions yellow color due to the presence of lipid otagai. Cholesterol and cholesterol ester are mainly the lipid. In addition, as a postulate accepted that a large part of the cholesterol found in strips of fat, is a consequence of the absorption of the plasma. These fatty layer, in turn, lead to the development of fibrous plaques", which consists of accumulated internal smooth muscle cells, overloaded with lipid and surrounded by special lipid tissue, collagen, elastin and proteoglycans. Cells together with the intercellular substance of a tissue form a fibrous capsule, which includes deep deposits of broken cells and a special lipid tissue. Lipid is a largely free and esterified cholesterol. The fibrous plaque is formed slowly and probably eventually becomes hardened due to the deposition of lime salts and necrotic, developing to become "complicated lesions", which explains the blockage of arteries and the tendency to thrombosis walls and spasm of the arterial muscles, which is characterized by the onset of atherosclerosis.

Epidemiological basis has firmly established hyperlipidemia as a primary risk factor in the induction of cardiovascular samanie to decrease the levels of plasma cholesterol and low specific gravity of urine cholesterol, in particular, as an essential step in preventing the COURT. It is now known that the upper limit of "normal state" is significantly lower than estimated before. As a result, it is now clear that large groups of the population in the West have a high risk for development or progression of COURT due to this factor. Individuals who have independent risk factors in addition to hyperlipidemia, are of a particularly high degree of risk. Such independent risk factors include glucose intolerance, high blood pressure hypertrophic left ventricle and belonging to the male sex. Cardiovascular disease is especially common among diabetic patients, at least in part, due to the existence of numerous independent risk factors. Successful treatment of hyperlipidemia in the General population and in subjects with diabetic disease, in particular, is therefore extremely important in medicine.

The first step in the recommended therapeutic regimens when hyperlipidemia is a dietary intervention. Although one diet causes an appropriate response in some individuals, many other sohranyaemye have on this high potential benefits for large numbers of individuals at high risk of COURT. In addition, particularly preferably successful treatment as hyperlipidemia and hyperglycemia associated with diabetes status, simple therapeutic agent.

In addition to hypoglycemic agents named above reported various other compounds with this type of activity, as discussed in the overview of the Blank [Burger''s Medical Chemistry, Fourth Edition, Part II, John Wiley and Sons, n. y.(1979), p.p.1057 1080] Sehnur, U.S. Patent 4.367.234 reveals hypoglycemic oxazolidinedione formula

< / BR>
in which the phenyl ring is usually mono - or multiply substituted in the ortho/meta positions. It is noteworthy that with the exception of 4-forefeel analogue perezapisannaya derivatives are either inactive or have low hypoglycemic activity.

Schnur, U.S. Patent 4.342,771 discloses oxazolidinedione hypoglycemic agents formulas

< / BR>
in which Y is hydrogen or alkoxy, Y' is hydrogen or alkyl, and Y is hydrogen or halogen.

Schnur, U.S. Patent 4.617,312 discloses hypoglycemic preparations of thiazolidinediones of the formula

< / BR>
where Rcis lower alkyl, XaIs F, Cl or Br, and Yais hydrogen, chlorine, lower alkyl or lower alkoxy. It is noteworthy that compounds require ortho-samesearch USA 4.340.605 disclose hypoglycemic compounds of formula

< / BR>
where Recommunication or lower alkylene and Rdis arbitrarily substituted five - or six-membered geterotsiklicheskikh group, including one or two hetero-atoms selected from N, O and S, L1and L2each can be defined as hydrogen. Based on the absence of hypoglycemic and plasma triglyceridemia the activity of certain non-terrestrial analogues suggested that a separate part of the structural formula, including the simple oxygen ether, is a valuable feature for useful activity in this series of compounds

Sohda and other Chem. Pharm.Bull. Japan, Vol.30, p.p. 3580 3600 (1982).

Eggler and other U.S. Patent 4.703,052, reveals hypoglycemic preparations of thiazolidinediones of the formula

< / BR>
where the dotted line represents an arbitrary relationship, Rf-H, methyl or ethyl, XbIS O, S, SO, SO2CH2, CO, CHON or NRk,

Rk-H or acyl group, and numerous definitions of Rg,

Rhand Rjcontain Rg, Rhand Rias hydrogen or methyl,

and Rjas arbitrary substituted phenyl, benzyl, phenethyl or styrene.

Clark and other international Patent Publication N WO 89/08651, reveals hypoglycemic thiazolide-CH=CH-, -N=CH-, -CH=N - or,

is CH2, CHOH, CO, -C=NOR or-CH=CH

X is S, O, NR, -CH=N - or-N=CH-,

Y is CH or N,

Z represents hydrogen, (C1-C7alkyl or (C3-C7) cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl or phenyl mono - or disubstituted with the same or different groups which are (C1-C3) alkyl, trifloromethyl, (C1-C3) alkoxy, fluorescent, chloro or bromo;

Z' represents hydrogen or (C1-C3) alkyl;

R and R1each independently hydrogen or methyl, and n is 1, 2 or 3.

Summary of invention.

The purpose of this invention is to provide optically pure forms of alcohol, which is a pre-existing links previously was found only in its racemic form. The invention provides each alcohol in the form substantially free of its corresponding enantiomer.

This invention is directed to (1S)-5- [4-(3-/5-methyl-2-phenyl-4-oxazolyl)-1-hydroxypropyl)benzyl] thiazolidin-2,4-dione (1), where the compound is substantially free of its corresponding IR enantiomer.

< / BR>
The invention also covers the named enantiomer 1R, (1R)-5-[4-(3-(5-methyl-2-phenyl-4-oxazolyl)estoodeeva 1S enantiomer.

< / BR>
In addition, within the scope of the invention are the compounds of formula IV,

< / BR>
where Y CHOR (racemic), (and substantially free of its corresponding R isomer)

or (and substantially free of its corresponding S enantiomer);

R represents a C1-C4) alkyl, (C7-C9) phenylalkyl, phenyl or alkoxyalkyl formula (CH2)nO(CH2)mCH3;

n is 2, 3 or 4,

m is 0, 1, 2, 3, or 4.

The invention also encompasses the pharmaceutically acceptable cationic salts and pharmaceutically acceptable acid additive salts of the compounds of the preceding two paragraphs.

Assume that the expression "pharmaceutically acceptable cationic salts" can be defined, but is not limited to such salts as the alkali metal salts (e.g. sodium or potassium), salts of alkaline earth metals (e.g. calcium or magnesium), aluminum salts, ammonium salts and salts with organic amines such as benzathine (N,N'-dibenziletilendiaminom) Colin, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylpenicillin) diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propandiol) and protein. Especially preferred is mimie acid additive salt" is defined but is not limited to such salts as hydrochloric, Hydrobromic, sulfuric, acid sulphate, phosphate, acid phosphate (secondary) acid phosphate (primary) acetic acid, succinic acid, citric acid, methansulfonate acid (mesilate) and toluensulfonate acid (tosylate) of salt.

Additionally, this invention encompasses pharmaceutical compositions for use in the treatment of hyperglycemic mammal or hypercholesterinemia mammal that include lowering the concentration of glucose in the blood amount or lowering the cholesterol content in the blood of a number of compounds of formulas I, II and VI, and pharmaceutically-acceptable carrier. Further, the invention provides a method of reducing the amount of blood glucose in hyperglycemic mammal which includes the appointment of the said mammal an effective amount of reducing glucose in the blood of the compounds of formula I, II, and IV, and a method of lowering blood cholesterol in hypercholesterinemia mammal, which includes the appointment of a named mammal reduces blood cholesterol amounts of compounds of formulas I, II and IV.

Also data intermediate compounds are substantially free of their corresponding enantiomer.

Additional intermediate compounds that are included in the scope of the present invention, are compounds of the formula V.

< / BR>
where Z Is Br or

< / BR>
and called intermediate compound essentially free of its corresponding enantiomer.

All of the information described here is easily obtained according to the reaction sequence depicted in scheme 1 and described below.

Scheme 1 is shown in Fig. 1, 2, 3.

p-bromoacetophenone subjected to interaction with hydrodam sodium and diethylcarbamoyl in tetrahydrofuran with the purpose of obtaining-keeeper, which is further subjected to interaction with sodium hydride and 5-methyl-2-phenyl-4-oxazolyl chloride in tetrahydrofuran and subsequent hydrolysis and decarboxylation heated to boiling under reflux a solution of acetic acid and hydrochloric acid to obtain a ketone of formula VI

< / BR>
This ketone is transformed into its S and R alcohol products recovery, using one of two different methods. So, the reduction of the ketone (VI) with sodium borohydride at 0oC in a solution of tetrahydrofuran and ethanol from about 20 minutes to 8 hours gives a racemic alcohol, which is a cm who Aut individual optically pure components reactions with chiral isocyanate. Called chiral isocyanate is selected for its ability to give diastereoisomer, which are easily distinguishable in some physical ways. Thus, (R)-(-)-1-(naphthyl)utilitzant undergoes interaction with the racemic alcohol is heated to boiling under reflux the toluene for 17 hours.

Pay an additional amount of isocyanate in order to bring the reaction to completion, and then heated to boiling under reflux continued for 24 hours. The reaction gives two diastereomeric carbamate configurations RR and RS.

Various physical properties of these diastereomers lead to one, the RR isomer selectively kristalltherme from a solution containing equal amounts of the two compounds. The solution used in this particular case, is a system of diethyl ether/hexane (1/2). The solid material obtained from this crystallization is recrystallized from ethyl acetate for further purification of (RR)-diastereoisomer.

The manifold stages of crystallization in recrystallization now mainly contain (RS)-diastereoisomer. Removal of solvent and purification of the composition on silica gel, eluruumis a mixture of hexane/diethyl ether (1/2) results in the tov turn back into alcohols by the reaction of these carbamates with trichlorosilane and triethylamine in benzene. Each of the thus obtained alcohol exists in the form of an individual enantiomer is essentially free of its corresponding enantiomer.

The second method of obtaining these alcohols is cooking them in optically pure form directly from the ketone precursor via stereoselective recovery process, thus eliminating the need for chiral separation process. This stereoselective recovery is achieved using boranova reducing agent such as borane methyl sulfide complex, catecholborane or borane tetrahydrofuran in the presence of an appropriate chiral oxazaborolidine catalyst in a cyclic ether solvent such as dioxane or tetrahydrofuran. The choice of the stereochemistry of the catalyst directly influences the stereochemical configuration of the derived alcohol. Thus, the choice of catalyst R-configuration leads to alcohol's configuration, the choice of catalyst's configuration leads to an alcohol R configuration. In particular, the preferred system for obtaining the S-alcohol is the reaction of a ketone of formula VI with borane methyl sulfide complex in the presence of (R)-tetrahydro-1 - methyl-3,3-given; predpochtitelnei system to obtain alcohol is the reaction of a ketone of formula VI with barometer sulfide complex in tetrahydrofuran in the presence of (S)-tetrahydro-1-methyl-3,3 diphenyl,-1H, 3H-pyrrolo [1,2-C][1,3,2]oxanabol.

These alcohols are then processed to thiazolidindiones alcohols and esters as shown in scheme 1. All reactions described below, is successful with both R and S configurations of the alcohol of formula III.

The alcohol of formula III is subjected to interaction with t-butyldimethylsilyloxy and imidazole in dimethylformamide at room temperature overnight to obtain O-protected alcohol. Bromide protected so the alcohol component is transformed into the aldehyde, using a well-known conditions n-butylamine at -78oC, low-temperature quenching of the anion with dry dimethylformamide and standard water treatment. Under standard water treatment decreases the dilution of the reaction mixture with water and extraction of the resulting aqueous solution with a sufficient quantity of an organic solvent, usually two or three portions, in order to remove any organic compounds from aqueous solution. An organic solvent, usually this is from commercially available 2,4-thiazolidinedione, using conventional methods of heating to boiling under reflux of ethanol and piperidine kataliz order to obtain the product of olefinic condensation. Produced thus olefin hydronaut by introducing hydrogen into a closed reaction vessel containing the olefin, the reaction-inert solvent and a catalyst. The pressure inside the reaction vessel can be varied from 15 to 50 f/DM2(PSi) 1,054-3,515 kg/cm2. The hydrogenation will take place under these conditions is approximately 2 to 48 hours. The preferred catalyst is palladium due to its resistance to sulfur poisoning, and palladium deposited on an inert carrier such as carbon. Under the "inertial reaction solvent" refers to a solvent that will not degrade or otherwise interfere with the reaction. Reaction inert solvents for reactions of this type include ethanol, methanol or tetrahydrofuran, but are not limited to these solvents. The preferred solvent is tetrahydrofuran.

The protective group is removed using a 3.5% aqueous perchloric acid in tetrahydrofuran at room temperature for approximately 12 hours. The end result is the enantiomeric alcohol was selected after as mentioned alcohols were obtained in optically pure form.

Optically pure alcohols of formula III are also useful as intermediate compounds in the preparation of the ether derivatives of the formula IV. Thus, the interaction of alcohol each formula III with an appropriate base and alkyl, alkoxyalkyl, phenyl or aralkyl a halide of the formula RX, in a reaction inert solvent at a temperature in the range of 0oC to the boiling point of this solvent is preferably from 2 to 48 hours.

R in the compound RX is a (C1-C4) alkyl, (C7-C9) aralkyl, phenyl or alkoxyalkyl formula-(CH2)nO (CH2)mCH3where n is 2, 3 or 4 and m is 0,1,2,3, or 4. X part is chloro, bromo or iodo. Reaction inert solvent for reactions of this type include, but are not limited to, diethyl ether, dioxan, dimethoxyethane, tetrahydrofuran and dimethylformamide. The preferred solvent is tetrahydrofuran, while the preferred base is sodium hydride. Preferred alkyl halides are methyl iodide, ethyl and benzyl bromide.

The ester obtained as described in the previous of paragenesis formulas 1 and 2. So, bromo component of the ester of formula III is subjected to interaction with n-butyllithium and dimethylformamide in tetrahydrofuran to obtain the aldehyde, which is subjected to interaction with 2,4-thiazolidinedione and catalytic piperidine in ethanol, receiving the condensation product in the form of the olefin. This olefin restore in the presence of palladium on carbon in tetrahydrofuran, receiving the specified end product of formula IV. Specific details of the reactions used to obtain these esters are similar to the details described in the previous paragraphs regarding the preparation of the alcohols of formulas I and II.

These compounds of formulas I, II and IV are used as gipoglikemicheskie or hypocholesterolemic agents for mammals. Compounds of formulas I and II additional metabolites are their corresponding ketones in vivo (in a living organism). Men mainly formed S-form of alcohol. The activity required for the first of these clinical applications, is determined by testing on a hypoglycemic effect on the s/s mice as follows.

Mouse in age from five to eight weeks C57 BL/CJ-s/s (obtained from the Jackson laboratory a, Bartlarbor, Maine) were planted n the s weighed and selected for processing 25 Microlitre blood using ocular bleed before any further processing to filter the blood. The blood sample was immediately diluted 1 to 5 with saline containing 2.5 mg/ml of sodium fluoride and 2% sodium heparin, and kept on ice for metabolic analyses. Then the animals daily for five days had injected a drug (5 to 50 mg/kg), positive control (50 mg/kg) of ciglitazone, U.S. Patent, 4467902, Sohda and other Chem. Pharm. Bull. vol. 32. p.p. 4460 - 4465, 1984), or binders. All drugs were administered in a binder substance, consisting of about 25. from methylcellulose. On day 5 animals were again weighed and the blood was collected (by ocular) to determine the levels of blood metabolites. Freshly harvested samples were centrifuged for two minutes at 10,000 xg (rpm) at room temperature. The supernatant was analyzed for glucose, for example, using ABA 200 Bichromatic Analyzer, using the A-gent glucose UV system reagents toxicomanes method (modification of the method of Richterich and Dauwalder, Schweigeriche Mediginische Woshenschrift, 101, 860) (1971), using 20, 60 and 100 mg/ml standards. The plasma glucose was then calculated by the equation Plasma glucose (mg/DL) sample volume x 5 x 1,67 8,35 x sample volume, where 5 is the dilution factor and 1.67 - regulation of plasma hematocrit (total hematocrit is 40%). A registered trademark of Abbot Laboratories, Diagnostics Division, 820 Mission Street, SO, Pasadena, California, 91030.


Studies such as those described below, demonstrate that the compounds of formula (I) carry out the reduction of levels of serum cholesterol in mammals.

Used female mice (line C 57 Br/Cd (J) obtained from the Jackson laboratory a, Bar Harbor, Maine, at the age of 8 to 12 weeks, after 2 4 weeks of acclimatization with free access to water and standard laboratory food. Animals were randomly allocated into three groups of 6 to 7 animals. All three groups were transferred to a diet containing 0.75 percent cholesterol, 31% sucrose, 15.5% starch, 20% casein, 17% of cellulose, and 4.5% corn oil, 5% coconut oil, 0.25% of halyevoy acid, 4% salt and 2% vitamin allowing to feed ad. lib (needs to choose) within 18 days, and every day gave medicine 9 11 o'clock a. m. (before noon) in the last 5 days by oral administration, control group with 5 mg/kg binder (0.1% aqueous methyl cellulose) and the test groups with the target connection when dosage all night, starting at 5 p.m. (after noon). The next morning the test groups were administered the fifth and final dose of the compounds and, three hours later, animals were killed by decapitation. Blood from the main artery of the body was collected and allowed to clot, and serum was analyzed enzymatically using the Abbott VP automatic analyzer, HDL cholesterol LDL and VIDL cholesterol, and total cholesterol. Regardless of the assessment on the basis of LDL + VLDL levels of cholesterol, total cholesterol or the ratio of LDL + VLDL/HDL, the compounds of this invention in most cases show a favorable result in the reduction of cholesterol levels. The presented compounds of formulae (I, II and IV) may be clinically assigned mammals, including humans, either oral or parenteral. Preferably the introduction oral route, which is more appropriate and avoids pain and irritation injection. However, in circumstances where the patient is unable to swallow medication, or absorption following oral application weakened by disease or other anomalies, it is necessary that the medication is administered parenterally. In both ways, the dosage is in the range from about 0.10 to 50 mg/kg body weight of the subject is Asami. However, the optimal dosage for an individual subject in need of treatment will be determined by the person responsible for treatment, usually initially assigned smaller doses and then produces an increase on this to determine the most appropriate dose. It will vary in accordance with the specific applicable connection and the subject to be treated.

The compounds may be used in pharmaceutical preparations containing the compound or its pharmaceutically acceptable salt of the acid, in combination with a pharmaceutically-acceptable carrier or diluent.

Suitable pharmaceutically-acceptable carriers include inert solid fillers or solvents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described above. Thus, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. Pharmaceutical colpetty and the like. For parenteral administration the compounds can be combined with sterile aqueous or organic media to obtain injectable solutions or suspensions. For example, can be used solutions in Kungaeva or peanut oil, aqueous propylene glycol and the like, as well as aqueous solutions of water-soluble pharmaceutically acceptable additional acid salts of the compounds. Injectable solutions prepared in this way can then be applied intravenously, intraperitoneally, subcutaneously or intramuscularly, preferably intramuscular use for men.

The invention is illustrated by the subsequent examples. However, it should be clear that the invention is not limited to the specific details of these examples. All reactions are carried out in an inert atmosphere, such as nitrogen, unless otherwise noted. Abbreviations THF and DMF, where used, are tetrahydrofuran and dimethylformamide, respectively. It is assumed that such solvents containing a relatively small amount of water, satisfy ensure that the water does not interfere with the course of these reactions. The nomenclature used here is based on Rigandy and Klesney, the IUPAC No (5,2 g, 0.21 mol) is suspended in dry ethyl ether and cooled to 0oC. was Added diethyl carbonate (17,7 g of 0.15 mol) and the contents were stirred for ten minutes, while adding dropwise p-bromoacetophenone (19,9 g of 0.1 mol) in diethyl ether (50 ml) and ethanol (0.2 ml) initiated the reaction. The addition was continued for twenty minutes, the solution was heated to boiling under reflux for three hours, cooled to room temperature and poured into a cooled 10% aqueous hydrochloric acid (250 ml). The aqueous solution was twice extracted with diethyl ether (750 ml) and the combined extracts were washed successively with water (250 ml), a solution of salt (250 ml) and dried (MgSO4). The solvent was distilled under reduced pressure and the residue was purified on silica gel, elwira a mixture of hexane/ethyl acetate (4,1) with 20.2 g (74%) named in the title compound in the form of oil. PMR (60MH2, ClDCl3): .1,1(t, 3H) x 3.9(S, 2H), 4,1(q, 2H), 4,1(q, 2H), 7,55(d, J 7H, 2H), of 7.75(d, J 2H2, 2H).

Here and hereinafter in the PMR spectra (1H NMR) d doublet, S - singlet, t triplet, m, multiplet, q Quartet, d d double Duplet, b - broadened signal.

Example 2

4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]bromobenzoyl

Sodium hydride (1.3 g, 55 mmol) was dissolved in THF (75 ml) and added dropwise to the suspension over 30 minutes. The resulting solution was stirred an additional 30 minutes after this time added in portions over 5 minutes solid 5-methyl-2-phenyl-4-oxazolyl methyl chloride (10.0 g, 48 mmol). The reaction mixture was heated to boiling under reflux for 48 hours, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in acetic acid (120 ml) and concentrated HCl (30 ml), and heated to boiling under reflux for five hours. The reaction mixture was cooled to room temperature and poured into ice water (300 ml). The aqueous solution was extracted twice with ethyl acetate (500 ml) and the organic extracts combined and washed with salt solution (250 ml), dried (MgSO4) and concentrated under reduced pressure. Purification on silica gel, blueroom a mixture of hexane/ethyl acetate (4/1), led to a crude solid product, which was further purified by recrystallization from hexane to obtain named the title compound (11.5 g, 65%) as white crystals with So pl. 80 81oC. PMR (60 MH2, CDCl3); d 2,2 (S, 3H), and 2.8(t, 2H), 3,2(t, 2H), 7,2 - 8,0 (t, 9H).

Example 3

(S)-4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-hydroxypropyl]bramasol

Named in the title of the previous example is sieves (10 g, pre-dried in high vacuum at 150oC, over night). After standing overnight, the solution decantation with Sith and it was determined the water content 0,0092% (analyses, Karl Fischer). Added (R)-Tetrahydro-1 - methyl-3,3-diphenyl-1H, 3H-pyrrolo[1,2-c] [1,3,2] occasional (748 mg, 2.7 mmole) at ambient temperature and the solution was treated with borane methyl sulfide complex (2M in THF, 76 ml. 152 mmole) added dropwise over 75 minutes. The reaction mixture was stirred another 15 minutes, cooled to 0oC and put out the reaction by adding dropwise a cold methanol (280 ml). The solution after quenching was stirred 18 hours at ambient temperature. The solvent was distilled under reduced pressure and the residue was dissolved in methylene chloride (200 ml) and washed successively aqueous phosphate buffer with pH 4 (200 ml) and dried (MgSO4). The organic layer was overtaken at atmospheric pressure to a residual volume of 100 ml, was added hexane and continued distillation until the distillate temperature 62oC. Removed the heat source and the residue was led and was granulated for 16 hours. White solid product was collected by vacuum filtration and dried in high vacuum for poll-2-phenyl-4-oxazolyl)-hydroxypropyl]bromobenzoyl

Named in the title of the example 2 compound (5.0 g, 13 mmol) was dissolved in THF (75 ml) and added dropwise during 20 minutes to a suspension of sodium borohydride (513 mg, 13 mmol) in 75 ml of ethanol at 0oC and the reaction mixture was stirred for 3 hours at 0oC. the Reaction mixture was poured into ice water (500 ml) and was extracted twice with diethyl ether (700 ml). The organic extracts were combined and washed with water (250 ml) salt solution (250 ml) and dried (MgSO4). The solvent was removed under reduced pressure and the residue was recrystallize from hexane to obtain 4.4 g (92%) of racemic named in the title compounds

So pl. 82 83oC. PMR (60 MH2, CDCl3); d 2.0 (m, 2H), 2,2(S, 3H), 2,5 (t, J 6H2, 2H), 4,6 (m, 1H), 4,7 (broadened S, 1H, hydroxyl proton), and 7.1 to 7.5 (m, 7H), 7.8 to 8.0 (m, 2H).

Example 5

(RR)-4-[3-[5-methyl-2-phenyl-4-oxazolyl)-1-(1-naphthyl) ethylenedicarboxylic)propyl]bromobenzoyl.

Named in the title of the example 4 compound (1,8, 5 mmol) was treated with (R)-(-)-1-(naphthyl)utilitarianism (1.0 g, 5 mmole) in toluene (100 ml) and the resulting solution was heated to boiling under reflux for 17 hours. Added an additional 1 g of the isocyanate and heated to boiling under reflux was continued by the diethyl ether/hexane (1/2) to obtain 1.1 g (37%) of solid product. Recrystallization from ethyl acetate resulted in 570 mg (20%) of pure more polar compounds named in the title with So pl. 185 186oC. (C 0,03, DMSO).

Example 6

(RS)-4-[3-(5-methyl-2-phenyl-4-oxazolyl)-3-(1-naphthyl)ethylenedicarboxylic] cut bromobenzoyl

The mother liquor from the stages of crystallization and recrystallization of the previous example was concentrated under reduced pressure and purified on silica gel, elwira a mixture of hexane/diethyl ether (1/2) to obtain 630 mg (22%) of pure less polar diastereoisomer. So pl. 120 125oC []D- 39,55 (C 0,31, MDSO).

Example 7

(S)-4-[3-(5-methyl-2-phenyl-4 - oxazolyl)-1-hydroxypropyl]bromobenzoyl

Named in the title of example 6 compound (1.56 g, 2.7 mmole) was dissolved in benzene (65 ml) was treated with trichlorosilane (1,4 ml) and triethylamine (1.9 mg) and the resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water (250 mg) and ethyl acetate (250 ml) and stirred for ten minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (250 ml). The organic extracts were combined, washed with saturated aqueous sodium bicarbonate (100 ml), water (100 ml) salt solution (100 ml) and dried (MgSO4). Solvents udachu pure S-alcohol resin (820 mg). The PMR spectrum showed that it is a racemic mixture.

Example 8

(S)-4-[1-(t-butyldimethylsilyloxy)-3-(5-methl-2-phenyl)-4 - oxazolyl)propyl]bromobenzoyl

Named in the title of example 7 compound (769 ml, 2.0 mmole) T-butyldimethylsilyloxy (377 mg, 2.5 mmole) and imidazole (340 mg, 5.0 mmole) were combined in DMF (10 ml) and stirred at room temperature for 24 hours. The reaction mixture was diluted with water (100 ml) and was extracted with ethyl acetate (CH ml). The organic layers were combined, washed with water (100 ml), saturated aqueous sodium bicarbonate (100 ml) salt solution (100 ml) and dried (MgSO4). The solvent was removed under reduced pressure to obtain named in the title compound in the form of resin (860 mg, 85%). PMR (60 MH2, CDCl3) 0,5 (d, 6N), 1,0 (s, N), of 2.0 to 2.7 (m, 4H), 2,3 (s, 3H), 4,8 (t, J 5H2, J H), and 7.1 to 7.6 (m, 7H), 7,9 8,1 (m, 2H).

Example 9

(S)-4-[1-(t-butyldimethylsilyloxy)-3-(5-methyl-2-phenyl-4-oxazolyl) propyl]benzaldehyde.

n-Utility (1.6 M in hexane, 1.3 ml) was added over ten minutes to named in the title of example 8, the compound (780 mg, 1.6 mmole) in THF (60 ml). The reaction mixture was stirred at 78oC for an additional 50 minutes and added dry DMF (152 mg, 2.0 mmole). The reaction mixture was stirred additional 1.5 hours at 784). The solvent was removed under reduced pressure and the residue was purified on silica gel, elwira a mixture of hexane/diethyl ether (4/1), to obtain named in the title aldehyde (650 mg, 93%). PMR (60 MH2, CDCl3), d 0,5 (d, 6N), 1,0 (S, N), of 2.0 to 2.7 (m,4H), 2,3 (S, 3H), 4,9 (dd, J 6Z, 12Z, 1), 7,2 8,0 (m, N), OR 10.1 (S, 1H).

Example 10

(S)-5-[4(1-t-butyldimethylsiloxy)-3-(5-methyl-2-phenyl-4-oxazolyl)drank)phenylmethylene]thiazolidine-2,4-dione.

Named in the title of example 9 compound (341 mg, 0,78 mmole) and 2,4-thiazolidinedione (183 mg, and 1.56 mmole) and piperidine (14 mg, 0.15 mmole) were combined in ethanol (10 ml) and was heated to boiling under reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified on silica gel, elwira a mixture of hexane/ethyl acetate/ acetic acid (16/4/1), to obtain a solid product, which was washed in hexane and has been named the title compound in the form of a white solid product (163 mg, 39%), pl. 158-160oC. PMR (300 2, CD Cl3): d -0,5 (d, 6H), 1,0 (S,9H), 2,0-2,7 (m, 4H), 2,3 (S,3H), 4,9 (m,1H), about 7.6 to 7.7 (m,7H), and 7.8 (S,1H), 8.0 a (m,2H).

Example 11

(S)-5-[4-(1-(t-butyldimethylsilyloxy)-3-(5-methyl-2-ml. 0.3 mmole) and 10% palladium on carbon (160 ml) were combined in THF (10 ml) and restored on the vibrator Parra at 50 psi and room temperature for 22 hours. The suspension was filtered through infusorial the earth and the solvent removed under reduced pressure to obtain named in the title compound in the form of resin (180 mg). PMR (300 2, CDCl3): d 0,5 (d, 6H), 1,0 (S, 9H), of 2.0-2.2 (m, 2H), 2,3 (S,3H), 2,4-2,6(m, 2H), 3,4 (d of d, 1H), 4,3 (d of d,1H), 4,7 (d of d, 1H), 7,0-to 7.3 (m, 7H), and 7.8 (m, 2H).

Example 12

Sodium salt of (S)-5-[4-(3-(5-methyl-2-phenyl-4-oxazolyl) -1-hydroxypropylmethyl]tizanidin-2,4-dione

Named in the title of example 11 compound (160 mg, 0.3 mmole) was dissolved in THF (5 ml) and treated with a 3.5% aqueous perchloric acid (3 ml). The reaction mixture was stirred at room temperature for 12 hours, diluted with ethyl acetate (25 ml), washed with water (25 ml) salt solution (25 ml) and dried (MgSO4). The solvent was removed under reduced pressure, the residue was purified on silica gel, elwira a mixture of hexane-ethyl acetate/acetic acid (66/33/1), to obtain) 115 mg of the free base in the form of a resin. The resin was dissolved in methanol (10 ml) was treated with sodium methylate (15 mg, 0.3 mmole) and stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure and ostat mg, 60%). So PL 235-240oC. PMR (300 MH2), DMSO (d6): 1,9 d (m, 2H), 2,3(S, 3H), 2,5(m, 2H), 2,7 (d of d, 1H), 3,4 (d of d, 1H) 4,1(d of d, 1H), and 4.5(m, 1H), and 5.2(d, 1H hydroxyl proton), and 7.1 (d,2H), 7,5 (m,3H), 7,9 (m,2H).

Example 13

Sodium salt of (R)-5-[4-(3-(5-methyl-2-phenyl-4-oxazolyl) -1-hydroxypropyl)benzyl]thiazolidin-2,4-dione

Named the title compound of this example is prepared mainly by the execution of successive stages described in examples 7-12, starting with the compound named in the title of example 5. So pl. 2450-250oC. PMR (300 MH2, DMSO d6) 1,9 d (m,2H), 2,3 (S,3E), 2,5 (m,2H), 2,7 (d of d,1H), 3,4 (d of d,1H), 4,1 (d of d,1H), and 4.5 (m,1H), and 5.2 (d,1H hydroxyl proton), and 7.1 (d,2H), 7,5 (m, 3H), 7,9 (m,2H).

Example 14

(S)-4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-ethoxypropan] bromobenzyl

Named in the title of example 7 compound (1.0 g, 2.7 mmole) and sodium hydride (324 ml, 6.7 mmole) was dissolved in THF (30 ml) at 0oC. the Reaction mixture was treated with ethyl-iodide (1.0 g, 6.7 mmole) and the contents were heated to boiling under reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, dissolved in water (25 ml) and was extracted twice ethyl acetate (50 ml). The organic extracts were combined, washed with water (25 ml), a solution of salt (25 ml) and dried (M the San/ethyl acetate /3/1/, having named the title compound in the form of resin (1,1, 90) PMR (300 2, CDCl3d of 1.15 (t,3H), 2,0 (m,2H), 2,3 (S,3H), 2,5 (t,2H), 3,2-3,4 (m,2H), 4.2V (d of d,1H), 7,2 (d,2H), and 7.4 (m,5H), and 7.9 (d,2H).

Example 15

The following optically pure ether derivatives are prepared by interaction of the corresponding alkyl halide (RX) with the desired optical pure alcohol specified stereokhimii, using basically the same method that is described in example 14 (Fig. 4).

Example 16

(S)-4-[(5-methyl-2-phenyl-4-oxazolyl)-1-methoxypropyl]benzaldehyde

(S)-4-[3-(5-methyl-2-phenyl-4-oxazolyl)-3-methoxypropyl] bromobenzoyl /1,1, 2.8 mmole, prepared as described in example 15 was dissolved in THF (30 ml), cooled to -78oC and treated with n-butyllithium (2.5 M in THF, 1.2 ml, 3.0 mmole) added dropwise via syringe. After addition, the reaction mixture was stirred at -78oC additional hour and treated with dry DMF (220 mg, 30 mmol). The reaction mixture was stirred at -78oC for 90 minutes and at ambient temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (200 Il) was washed with water (50 ml), 10% aqueous hydrochloric acid (50 ml), water (50 ml), salt solution (50 ml) and dried (MgSO4). The solvent was removed under reduced pressure and the CD Cl3): d 2.0 (m, 2H), 2,3 (S, 3H), 2,5 (t, 2H), 3,2 (S, 3H), 4,15 (d of d, 1H), and 7.3 (m, 3H), and 7.4 (d, 2H), and 7.8 (d, 2H), 7,9 (m, 2H), 9,9 (S, 1H).

Example 17

(S)-5-[4-(3-(5-methyl-2-phenyl-4-oxazolyl) -1-methoxypropyl)phenylmethylene]cialisin-2,4-dione

Named in the title of example 16 compound (580 mg 1.7 mmole) and piperidine (30 mg, 0,34 mmole) and 2,4-thiazolidinedione (405 mg, 3.4 mmole) were combined in standard (20 ml) and the resulting solution was heated to boiling under reflux overnight. The solvent was removed under reduced pressure and the residue was purified on silica gel, elwira a mixture of hexane/ethyl/acetate /3/1/ - plus 5% acetic acid, having named the title compound as a solid product (640 mg, 87%). So pl. 205 206oC. PMR (300 2, DMSO-d6), d 2.0 (m, 2H), 2,3 (S, 3H), 2,4 (t, 2H), 3,1 (S, 3H), 4.2V (d of d, 1H), and 7.4 (m, 5H), and 7.6 (d, 2H), and 7.7 (S, 1H), 7,9 (m, 2H).

Example 18

(S)-5-[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1 - methoxypropyl)benzyl]thiazolidin-2,4-dione

Named in the title of example 17 compound (640 mg, 1.5 mmole) was dissolved in THF (50 ml) and was first made in the presence of a sulfur-resistant 10% palladium on carbon (640 mg) on the Vibrator Parra at 50 Psi for 20 hours. The catalyst was removed by filtration through infusorial the earth and the filtrate was concentrated under reduced pressure. The residue was purified on a silica compound is purified by dissolution of the residue in 50 ml of ethyl acetate, by washing with water (25 ml), saturated aqueous sodium bicarbonate (25 ml), a solution of salt (25 ml) and dried (MgSO4), which led to a colorless resin (229 mg, 35%) TMR (300 2, CDCl3): d 2.0 (m, 2H), 2,3 (S, 3H), 2,5 (t, 2h), 3,1 (d of d, 1H), 3,2 (S, 3H), 3,5 (d of d, 1H), 4,1 (d of d, 1H), 4,4 (d of d, 1H, 7,2 (m, 4H), to 7.4 (m, 3H), 7,9 (m, 2H), 8,1 (bs, 1H, NH)

Example 19

Following ether derivative prepared mainly by the execution of successive stages described in examples 16 to 18, and since the preparation of the ether, as described in examples 14 and 15 (Fig. 5).

1. Derivative oxazole General formula I

< / BR>
where Y group CHOR where R is hydrogen, C1-C4-alkyl, C7-C9-phenylalkyl, phenyl or alkoxyalkyl formula (CH2)nO(CH2)mCH3where n is 0, 1, 2, 3 or 4; m is 2, 3 or 4, provided that when R is hydrogen, compound I is a pure 1R or 1S enantiomer is essentially free of the corresponding enantiomer, or pharmaceutically acceptable cationic salt, or an acid additive salt.

2. Connection on p. 1, where Y group

< / BR>
and essentially free of the corresponding enantiomer.

3. Connection PP.1 and 2, representing the (1S)-5-[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1 - hydroxypropyl) benzyl] thiazolidin the haunted salt, or pharmaceutically acceptable acid additive salt.

4. Connection PP.1 and 2, representing the (1R/-5-4-13-(5-methyl-2-phenyl-4-oxazolyl)-1-hydroxypropyl)benzyl) thiazolidine-2,4-dione, essentially free of 1S corresponding enantiomer, or its pharmaceutically acceptable cationic salt, or pharmaceutically acceptable acid additive salt.

5. Connection on p. 1, where Y is R-configuration, and essentially free of enantiomers, in which Y is in S-configuration.

6. Connection on p. 1, where R is methyl.

7. Connection on p. 1, where R is ethyl.

8. Connection on p. 1, where R is benzyl.

9. Connection on p. 1, where Y is in S-configuration and essentially free of enantiomers, in which Y has the R-configuration and R is methyl.

10. Oxazol formula V

< / BR>
where Z-

< / BR>
11. Connection on p. 10, where Z Br

12. Connection on p. 10, where Z

13. Connection on p. 10, where Z

14. Connection on p. 10, where Z

15. The connection formulas

< / BR>
where X -

< / BR>
and essentially free of the corresponding enantiomer.

 

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