Derivatives of azetidinone and their pharmaceutically acceptable salts and pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

 

(57) Abstract:

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity. 2 s and 5 C.p. f-crystals, 2 PL.

The invention relates to new-lactams, possessing biological activity, in particular derivatives of azetidinone and their pharmaceutically acceptable salts of azetidinone, as well as pharmaceutical compositions with anti-atherosclerotic or hypocholesterolemic activity.

Known-lactams that can be used as hypocholesterolemic funds (see application WO 94/14433, class A 61 K 31/395, 07.07.1994 year).

The objective of the invention is to expand the Arsenal of derivatives-lactam, i.e., 2-azetidinone, which have cholesterol-lowering activity.

The problem is solved proposed derivatives azetidinone General formula (I)

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where Ar1is phenyl, unsubstituted or someonesomeone lower alkyl, group-OR2or-O(CO)R2where R2means a hydrogen atom or lower alkyl,

Ar3is phenyl, unsubstituted or substituted with halogen,

X and Y independently of one another denote-CH2-,

R - group OR3where R3means a hydrogen atom or lower alkyl,

R1is a hydrogen atom, or

R and R1together mean an oxygen atom, a carbonyl group (=O),

q = 0 or 1,

r = 0, 1, or 2,

m and n independently of one another are 0, 1, 2, 3, 4, or 5 with the proviso that m + n + q = 2, 3, 4 or 5.

In the first group of preferred derivatives of azetidinone formula (I) include compounds in which Ar1is phenyl, unsubstituted or substituted with halogen or thienyl;

Ar2is phenyl, substituted by hydroxyl, and

Ar3is phenyl, substituted by fluorine.

The second group preferred derivatives of azetidinone formula (I) include compounds in which q = 0, X and Y mean every-CH2- and m + n = 2, 3, or 4.

In a third preferred group of derivatives of azetidinone formula (I) include compounds in which q = 1, X and Y mean every-CH2-, m + n = 1, 2, or 3, R is a group-OR3where R3is a hydrogen atom, or R and R1together, the oxygen atom CA group, including

TRANS-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio] -1-(4 - forfinal)-2-azetidinone;

TRANS-4-(4-methoxyphenyl)-1-phenyl-3-[(2 phenylethyl)thio]-2-azetidinone;

CIS-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)thio]-2-azetidinone;

TRANS-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)sulfonyl-1-(4 - forfinal)] -2-azetidinone:

CIS-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)sulfinil]-1-(4 - forfinal)-2-azetidinone;

TRANS-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfinil] - 2-azetidinone;

CIS-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfinil]- 2-azetidinone;

TRANS-4-[4-keto-3-[(2-phenylethyl)sulfinil] -1-(4-forfinal)-2 - azetidine]-phenylacetate;

CIS-4-[4-keto-3-[(2-phenylethyl)sulfinil] -1-(4-forfinal)-2 - azetidine] -phenylacetate;

(+/-)-TRANS-4-(methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfonyl]-2-azetidinone;

TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(4 - forfinal)-ethyl]thio]-2-azetidinone;

TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-hydroxy-2- (4-forfinal)ethyl]thio]-2-azetidinone;

(3R, 4R) 4-(4-hydroxyphenyl)-1 -(4-forfinal)-3-[[2-keto-2- (4-forfinal)-ethyl]Sul-vinyl]-2-azetidinone;

4(R)-(4-hydroxyphenyl)-1-(4-forfinal)-3(R)-[[2(R)-hydroxy - 2-(4-forfinal)ethyl]-sulfinil]-2-azetidinone;

4(R)-(4-hydroxyphenyl)-1-(4-forfinal)-3(R)-[[2(S)-hydrox the l)-ethyl]thio]-2-azetidinone;

(3R,4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto - 2-(3-thienyl)-ethyl]thio]-2-azetidinone;

(3R,4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto - 2-(3-pyridinyl)ethyl]-thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2 - keto-2-(4-pyridi-nil)ethyl]-thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto - 2-(2-pyridi-nil)ethyl]-thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2 - hydroxy-2-(3-thienyl)ethyl]-thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2 - hydroxy-2-(4-pyridinyl)-ethyl]thio]-2-azetidinone;

(3S, 4R) CIS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2- (4-forfinal)ethyl]-thio]-2-azetidinone:

(3S, 4R) CIS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2 - hydroxy-2-(4-forfinal)-ethyl]thio]-2-azetidinone.

Some compounds according to the invention are acids (for example, compounds which contain carboxyl group). Such compounds can form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are salts of sodium, potassium, calcium, aluminum, silver and gold. This includes salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines followed, hydroxyalkyl, following ways.

Method A:

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The compounds of formula I in which r = 0, R3means a protected hydroxyl group (options such protected hydroxyl groups are shown in table 1), and the other variables have the above significance, i.e. the compounds of formula Ia can be obtained in accordance with this scheme of reactions resulting from the interaction of carboxylic acids of the formula II with Eminem formula III in the presence of such a base as triethylamine, and an appropriate dehydrating agent, such as dichlorohydrin of dimethylamide phosphoric acid. To obtain tizaidine formula Ia formed when the substance is treated with acid, such as hydrofluoric acid. If a protected hydroxyl group, R3means CNS group, or benzyloxy, such a protective group does not need removal to obtain the compounds of formula I, however, other protective groups can be removed in order to obtain compounds of the formula I, in which R denotes a hydroxyl group, using conventional techniques.

Compounds in which R is a hydroxyl group can be converted into well-known methods in other prisutstvie a suitable base, such as sodium hydride.

The compounds of formula Ia, in which q = 1, and R and R1together form a carbonyl oxygen atom (=O) can be converted into the corresponding compounds in which R1means a hydrogen atom, a R is a hydroxyl group, a reductive reagent as borohydride sodium.

To obtain the appropriate sulfinyl compounds, i.e. compounds of the formula I in which r = 1 and the remaining radicals and indices have the above values (i.e. compounds of formula IB) tizaidine formula Ia with a protected hydroxyl group act one equivalent of oxidant such as nakilat, for example m-chlormadinone acid or metaperiodate sodium:

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To obtain the appropriate sulfanilic compounds, i.e. compounds of the formula I, in which r is 2 and the remaining variables have the above values (i.e. compounds of formula Ib) tizaidine formula Ia with a protected hydroxyl group are two equivalents of the above oxidizing agent

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In the compounds IB and IB protective group in the substituent R11if necessary, can be charged with obtaining compounds of formula I.


where L denotes a leaving group such as bromine atom or iodine.

Using the described method And reactions obtained by the method B, the compounds of formula Ia can be converted into sulfanilimide and sulfonylurea compounds, and compounds in which R and R1form a carbonyl oxygen atom (= O) can be converted into a compound where R means a hydrogen atom and R1means a hydroxyl group, and compounds in which R is a hydroxyl group can be converted into compounds in which R means alkoxyl.

The way IN

The compounds of formula I, where the index r = 0 and the remaining radicals and the indices are above a certain value, can be obtained by enantioselective method according to the following scheme:

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Auxiliary reagent CHLOROSILANES oxazolidinone of the formula VII is reacted with a mercaptan of the formula VI, variables, radicals motoroladroid. The resulting compound of formula VIII is treated with titanium tetrachloride in the presence of such grounds, as diisopropylethylamine (base Gunga), and injected into the reaction with Eminem formula III, then decomposing the reaction mixture with acid, for example acetic acid. The resulting compound of formula IX cyclist by the reaction with such similitudes reagent as bis(trimethylsilyl)ndimethylacetamide (BSA) and therefore fluoride catalyst, as tetrabutylammonium fluoride (TBAF). The cyclization product is divided into CIS - and TRANS-isomers of formula Iك and Ia using the usual methods of selection, such as flash chromatography.

Compounds of formula Iك and Ia can be converted into the corresponding sulfinyl and sulfonylurea compounds by reactions with nagkakamali as described above, or with such a reagent, as (R) or (S)(10-camphorsulfonic)- oxaziridine. For example, the compound of formula Iك can be converted into the corresponding sulfinyl connection S and If the scheme:

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Before the separation of CIS - and TRANS-isomers or after it, as it is more convenient, in the compounds of formula Iك and Ia remove the protective group in the radical R3if the connection R means IT, this group can be functionalized so,cataloguing, they are known for specializing in this area sintetica or synthesized by known methods.

Reactive groups not involved in the above-described transformations can be protected during the reaction the usual protective groups which can be removed after the reaction by standard techniques. Table 1 shows some typical protective groups.

As mentioned above, the compounds according to the invention possess hypocholesterolemic activity and therefore they can be an active ingredient of pharmaceutical compositions with anti-atherosclerotic and hypocholesterolemic activity. This pharmaceutical composition, which in addition to an effective amount of the active substance contains more pharmaceutically acceptable carrier is a further object of the invention.

The proposed pharmaceutical composition may also contain inhibitors of the biosynthesis of cholesterol in an effective amount.

As an inhibitor of cholesterol biosynthesis include, for example, inhibitors of HMG CoA reductase inhibitor such as lovastatin, pravastatin, fluvastatin, simvastatin and Cl-981; synthetase inhibitors hydroxide the Teal-2,4-undecadienal acid); inhibitors bio-synthesis of squalene, for example, squarestate 1; and inhibitors of squalene-epoxidase, for example, NB-598 (hydrochloride (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-inyl)-3-[(3,3'-Bethoven-5-yl)methoxy] benzene-methanamine), and other inhibitors of cholesterol biosynthesis, such as DMP-565. Preferred inhibitors of HMG CoA reductase inhibitor is lovastatin, pravastatin and simvastatin.

The activity in vivo of the compounds of the formula I is confirmed by the following experience:

Hypolipidemic effective beginning in the experience in vivo in hyperlipidemics hamsters

Hamsters are divided into groups of six animals and give them food with controlled cholesterol (PurinaChow # 5001, the cholesterol content of 0.5%) for seven days. The amount of feed consumed is fixed for determining the receipt of cholesterol on the background of the action of the investigated compounds. Animals receive a dose issleduemykh connection once a day, simultaneously with the beginning of the feed above feed. Oral dosage is 0.2 ml of vegetable oil in its pure form (for control group experimental animals) or solution (or suspension) of the studied compounds in vegetable oil. All animals in painful or in poor physical condition usanee hammer their beheading. Blood is taken in a vacuum receiving tubes containing ethylenediaminetetraacetate (EDTA), for analysis of plasma lipids, and liver extract resection for analysis of lipids in tissues. Analysis of lipids is carried out according to published methods (Schnitzer-Polokoff, R. And et , Al. Biochem. Physiolog., 99A, 4 (1991), pp. 665-670). These experiments are given in percent reduction in lipid content compared to control.

The results of the experiment are summarized in table 2.

The experimental data represent the percentage change (i.e. the percentage reduction in the content of cholesterol esters) in relation to the control. This implies that negative numbers reflect a positive effect of reducing the level of lipids.

In the case of racemic compounds of formula I, as well as active diastereomers or enantiomers of the compounds of formula I, their introduction in doses of 0.1-25 mg/kg accompanied by the decline of esters of cholesterol in the region from -21 to -97% and lowering the level of cholesterol in serum from -57% to 0%. The connection preferably show a decrease in the level of esters of cholesterol in the range of -21 dBm -97% at a dosage of from 0.1 to 3 mg/kg, and more preferably reducing esters of cholesterol in the range of soedineniya example No. 5 and lovastatin as an inhibitor of the biosynthesis of cholesterol in the individual and joint applications. Animals were given commercially available food under the name Purina Chow N 5006 containing maltodextrin, to which was added either the compound of example No. 5 in a dose of 0.01 mg/kg/day, or lovastatin at a dose of 5 mg/kg/day, or the compound of example No. 5 and lovastatin in the dose. The experiments were conducted within 14 days, the blood was taken before the start of the experiments and in the 3rd, 11th and 14th day. With 10 µl of plasma were taken to determine her total cholesterol, which was applied 1 ml of 0.15 M Tris - buffer, pH 7.0, containing 0.1% p-chlorophenol, of 0.13 u/ml cholesterol oxidase, of 0.13 IU/ml hydrolases esters of cholesterol, and 2.4 u/ml peroxidase and 0.015% 4-aminoantipyrine. Analyses were performed at 37oC for 10 minutes

When giving compounds of example No. 5 total cholesterol in blood plasma compared to control almost not decreased, when the country lovastatin was observed a decrease of approximately 10%, whereas joint dacha compound of example No. 5 and lovastatin reduce total cholesterol in plasma was about 30% compared to control.

Daily hypocholesterolemic the dose of a compound of formula I is from about 0.1 to about 30 mg/kg of body weight per day, preferably about 5 to about 1000 mg of the drug per day as a single dose or divided into 2 to 4 doses. However, the exact dose determined by the supervising Clinician and is dependent on the effectiveness of the introduced compound, the age, weight, condition and response of the patient.

For combinations in the framework of the present invention, when azetidinone with sulfur-containing Deputy administered in combination with inhibitors of the biosynthesis of cholesterol, a typical daily dose of the inhibitor of the biosynthesis of cholesterol is from 0.1 to 80 mg/kg weight of the mammal per day, and it is administered in one or in several stages, usually once or twice a day: for example, in the case of inhibitors of the reductase of hydroxyacylglutathione And from about 10 to about 40 mg per dose is administered once or twice a day, which amounts to a total daily dose of about 10-80 mg / day, other inhibitors of the biosynthesis of cholesterol of about 1-1000 mg per dose for receiving one or two times a day, which amounts to a total daily dose from about 1 mg to about 2000 mg per day. The exact dose of each component of the input combination is determined by the supervising Clinician and is dependent on the effectiveness of the introduced compound, the age, weight, condition and response of the patient.

If the components of the combination is administered separately, the number of doses taken in each day companero admission should be less frequent.

Since the present invention relates to reducing the level of cholesterol in plasma by treatment with a combination of active ingredients and these active ingredients may be administered separately, the invention also relates to the combination of separated pharmaceutical compositions in one package. That is, this set is considered as the merging of two separate parts: the pharmaceutical composition of an inhibitor of the biosynthesis of cholesterol and pharmaceutical compositions of azetidinone with sulfur-containing substituent in inhibiting its absorption. The kit preferably includes instructions for receiving the individual components. This combined form is especially preferred in cases where the individual components have to be taken in different dosage forms (e.g., oral and parenteral) or when dosages are taken at different intervals.

Obtaining derivatives of azetidinone formula (I) is illustrated by the following examples.

Encountered the concept of CIS and TRANS are relative orientation in positions 3 and 4 of azetidinone, unless nothing else. The index "J" refers to the constant spin-spin interaction is Inon. Spectra circular dichroism was determined in methanol solution.

Example 1

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The first stage. In 1.2 l of toluene is refluxed connected through a trap Dean-stark mixture of 128 ml of 4-foronline and 290 g of 4-tert. -butyldimethylchlorosilane. After 24 hours, evaporated in vacuo and dissolve the residue in 0.2 l of hot hexane. The solution is cooled to -20oC and separated fallen Imin filtering, receive 378 g (94% of theory), so pl. 51,4 - 52,2oC.

The second phase. To a mixture of 0.55 g phenylethenocytosines acid (obtained in two stages: a) the interaction of fenilatilamina with ethyl ether bromoxynil acid and b) saponification of the water-alcohol solution of sodium hydroxide) obtained in the first stage imine and 1.2 ml of triethylamine in 20 ml of methylene chloride at a temperature of 0oC add dichlorohydrin dimethylaminopropanol acid. Left under stirring overnight, allowing the reaction mass to warm to room temperature. To the mixture are added ethyl acetate and 10% sodium bicarbonate solution. Washed with water, dried over magnesium sulfate and evaporated organic layer, and then purify the residue using flash chromatography on silica gel with a mixture of hexane and ethyl the chiral phase (Chiralcet OD), eluent: hexane/isopropanol (66:1), selecting the second peak.

The third stage. To a solution of 215 mg obtained in the second stage of the substance in 21 ml of acetonitrile at 0oC add 2.5 ml of 48% hydrofluoric acid and left under stirring overnight, allowing the reaction mass to warm to room temperature. To the reaction mass add sulphuric ether and cold water, washed the organic layer with 10% sodium bicarbonate solution and water. The organic layer is dried over magnesium sulfate and concentrated. The product emit flash chromatography on silica gel, elwira with a mixture of hexane with ethyl acetate (5:1). The target compound 1 obtained as a colorless solid (0.16 g, 96% of theory).

The mass spectrum with surface ionization 394 (M+H) 256 (100%).

Elemental analysis: calculated %: C 69,41, H 5,19, N 3,52.

C23H20NO2SF0,25H2O. Found %: C 69,42, H 5,26, N 3,45.

[]2D5+44,8o(1.25 mg/ml in methanol).

1H NMR in deuterium chloroform: 2,95 (m, 4H), 3,93 (D., J=2.4 Hz, 1H), 4,67 (D. , J= 2.4 Hz, 1H), 5,06 (S., 1H), 6,85 (D., 1H), 6,92 (DD. 2H), 7,15-7,3 (9H).

Method B

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The first stage. The solution 9,76 ml chloroacetanilide in 110 ml of methylene chloride at a temperature of 0o

The second phase. To a solution of 6.0 g obtained in the first stage product and 5.1 ml of triethylamine in 0.1 l of methylene chloride add femalecelebrity. At room temperature, stirred for 16 hours, then add about 50 g of silica gel and evaporated in vacuum. The residue is purified flash chromatography on silica gel, elwira a mixture of ethyl acetate/hexane (1:4). Receive a colorless solid substance, the output 7,81 g (92%), which can be recrystallized from a mixture of ethyl acetate/hexane (1:4).

The third stage. To a solution of titanium tetrachloride in 200 ml of methylene chloride (obtained by diluting 75 ml of 1N solution of titanium tetrachloride in methylene chloride) was added with stirring 7.5 ml of tetraisopropoxide titanium, maintaining the temperature at 0oC. After 15 minutes, add to 34.1 g obtained in the second stage of the matter and after another 5 minutes add 66 g obtained in the first stage of the method And imine. The reaction mass is then cooled to -40oC, incubated 20 minutes and DOS to a temperature of -70oC and add 250 ml of isopropyl alcohol. Gradually over 6 hours heated the reaction mass to room temperature, then add 500 ml of 0.1 n hydrochloric acid and sulphuric ether. Washed the organic layer with water, dried over magnesium sulfate, evaporated and purified the residue by crystallization from methanol. Get colorless solid, yield of 30.9 g (46% of theory).

The fourth stage. A solution of 10 g obtained in the third stage of the product in 0.5 l of toluene is heated to 90oC and add 7,4 ml N,O - bis(trimethylsilyl)ndimethylacetamide. After 1 hour, the reaction mass is then cooled to 45oC and add to 0.47 g of tetrabutylammonium fluoride. In the next 18 hours continue stirring at 45oC, from time to time, adding more bis(tri-methylsilyl)-ndimethylacetamide (3 molar equivalent). When the total reaction time is 24 hours, add 150 ml of methanol and stirred at room temperature for 1 hour. The reaction mass is evaporated in vacuum and purified flash chromatography on silica gel, elwira TRANS-isomer. Continuing the elution with a mixture of hexane/ethyl acetate (5:1) to obtain CIS-isomer.

The fifth stage. Separately treated with the solutions obtained in the fourth stage of TRANS - and CIS-isomers in ucaut respectively TRANS - and CIS-azetidinone 1 and 1a.

1a: Mass spectrum with chemical ionization 394 (M+H, 100%.

Elemental analysis: calculated for C23H20NO2SF%: C 70,21, H 5,13, N Of 3.56, S 8,15; found: C 70,33, H 5,43, N 3,71, S 8,20.

1H NMR in deuterium chloroform: 2,78 (m, 4H), to 4.52 (D., J=5 Hz, 1H), 5,23 (D., J=5 Hz, 1H), 6,82 of 7.3 (13H).

When using 4-methoxybenzylideneamino described in the third and fourth stages of method B in example 1 operations receive the following

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1B: Elemental analysis: calculated for C24H23NO2S%: C 74,01, H 5,95, N 3,6, S by 8.22; found: C 74,19, H, 6,0, N Of 3.73, S 8,03.

[] 232 nm = +3,4104, [] 248 nm = -3,07104.

1H NMR in deuterium chloroform: 2,95 (m, 4H), 3,82 (C., 3H), 3,95 (D., J= 2.2 Hz, 1H), 4.72 in (D., J=2.2 Hz, 1H), 6,9-7,3 (14H).

The mass spectrum with surface ionization: 390(M+H), 252 (100%).

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1H NMR in deuterium chloroform: 2,78 (m, 4H), 3,8 (C., 3H), 4.53-in (DV, J=5.5 Hz, 1H), 5,27 (D., J=5.5 Hz, 1H), 6,9-7,3 (14H).

Example 2

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A solution of 2.3 g obtained in example 1 compound 1 and 1.48 g of (1s)-(+)-(10-camphorsulfonic)oxaziridine in 40 ml of tetrahydrofuran is refluxed. After 14 hours the reaction mass is evaporated and purify the residue using flash chromatography on silica gel by elution of the first diastereoisomer 2a mixture of methylNO3SF%: C 67,47, H 4,92, N 3,42;

found: C 67,12, H 5,02, N 3,43.

[] 219 nm = -5,49104, [] 254 nm = +5,2 104< / BR>
[]2D5+214,4o(1.25 mg/ml in methanol).

1H NMR in deuterium chloroform: 3.15 in (m, 3H), 3,92 (m, 2H), 5.25-inch (D., J= 2.5 Hz, 1H), 6,0 (W., 1H), 6.8 OR 6.9 (4H), 7,15-TO 7.35 (8H).

The mass spectrum with chemical ionization 410 (M+H).

Then elute the diastereoisomer 2B and crystallized the diastereoisomer 2B of isopropyl alcohol. Obtain 1.48 g (62%) of colorless solid.

Elemental analysis: calculated for C23H20NO3SF%: C 67,47, H 4,92, N 3,42;

found: C 67,28, H 4,89, N 3,45.

[] 233 nm = +5,56104, [] 251 nm = -2,79 104.

[]2D5-16o(1.25 mg/ml in methanol).

1H NMR in deuterochloroform: 3,1-3,14 (m, 4h), 4.2V (D., J=2 Hz, 1H), 5,39 (D., J=2 Hz, 1H), 6,7 (D., 2H), 6,95 (m, 2H), 7,15 - to 7.35 (8H).

The mass spectrum with chemical ionization 410 (M+H).

Applying the technique of the method according to example 2 obtained in example 1, compound 1a receive the following connections:

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2B: Elemental analysis: calculated for C23H20NO3SF%: C 67,47 H to 4.92, N 3,42 S 7,83; found: C 67,21, H, 5,0, N, 3,5, S of 7.48.

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2G: Elemental analysis: calculated for C23H20NO3SF%: C 67,47, H 4.92 in, is milenaria at 0oC handle m-chlormadinone acid (0.16 g) at -78oC. After 2 hours, add dilute sodium bisulfite and heated the reaction mass to room temperature. Add ethyl acetate and sequentially washed organic layer with 10% sodium bicarbonate solution and saturated sodium chloride solution, then dried over magnesium sulfate and evaporated in vacuum. The residue is purified by HPLC on silica gel, elwira a mixture of ethyl acetate/hexane (1:2) junction 3A, exit 0,185 g, and 3b, the output of 0.10 g

3A: Elemental analysis: calculated for C24H23NO3S%: C 71,09, H 5,72, N 3,45;

found: C 70,87, H 5,55, N 3,52.

[] 220 nm = -5,36104, [] 257 nm = +5,46104.

1H NMR in deuterium chloroform: 3.15 in (m, 3H), 3,8 (C., 3H), at 3.9 (m, 1H), 3,94 (D., J=2.5 Hz, 1H), 5,33 (D., J=2.5 Hz, 1H), 6,9-to 7.35 (14H).

3b: Elemental analysis: calculated for C24H23NO3S%: C 71,09, H 5,72, N 3,45, S 7,83; found: C 70,90, H 5,72, N 3,55.

[] 220 nm = -4,8103, [] 233 nm = +7,44104, [] 250 nm = -4,0104.

1H NMR in deuterium chloroform: 3,18 (m, 4H), 3,8 (C., 3H), 4,12 (D., J=2 Hz, 1H), 5,5 (D., J=2 Hz, 1H), 6,9-to 7.35 (14H).

Applying the technique of the method according to example 3 compound 1B receive the following connections:

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3b: Elemental analysis: caters is chloroforme: 2,85 (m, 1H), 2.95 and (m, 1H), 3,12 (m, 1H), 3,62 (m , 1H), 3,8 (C., 3H), 4,4 (D., J=5.6 Hz, 1H), 5,35 (D., J=5.6 Hz, 1H), 6,9-to 7.35 (14H).

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3D: Elemental analysis: calculated for C24H23NO3S0,2 H2O in %: C 70,46, H 5,77, N 3,42; found: C 70,32, H 5,78, N 3.46 in.

1H NMR in deuterium chloroform: 3,17 (m, 3H), 3,4 (m, 1H), 3,83 (C., 3H), 4,69 (D., J=5,2 Hz, 1H), 5,55 (D., J=5,2 Hz, 1H), 6,95 to 7.4 (14H).

[]2D5-136o(in methanol);

Example 4

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To 60 mg of compound 2B in 5 ml of methylene chloride added to 0.025 ml of triethylamine and 0.017 ml of acetic anhydride. After 2 hours the reaction mass is evaporated and purify the residue using flash chromatography on silica gel, elwira a mixture of ethyl acetate/hexane (1:1). Get a white solid.

Elemental analysis: calculated for C25H22NO4SF%: C 66,5, H 4,91, N, 3,1, S, 7,1; found: C 66,28, H 5,10, N 3,29, S 6,99.

Applying the above production method of compound 4 on the original products 2C and 2D are respectively:

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4A: Elemental analysis: calculated for C25H22NO4SF%: C 66,5, H 4,91, N, 3,1, S, 7,1; found: C collected 66.36, H 5,13, N 3,23, S 7,02.

1H NMR in deuterium chloroform: 2,32 (C., 3H), of 2.92 (m, 2H), 3,14 (m, 1H), 3,7 (m, 1H) 4,42 (D., J=5.7 Hz, 1H), 5,38 (D., J=5.7 Hz, 1H), 7,0 (m, 2H), 7,12-to 7.35 (9H), 7,44 (D., 2H).

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1H NMR in tataroglu is 5

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The first stage. To a mixture of 13 ml of 4-methoxybenzylamine and 10 ml of ethyl-2-mercapto-acetate in 0.2 l of methylene chloride under nitrogen atmosphere was added 14 ml of triethyl-amine. After 48 hours, dilute the reaction mass 0.5 l of sulphuric ether and successively washed the organic phase with 0.3 n hydrochloric acid (three times) and 10% sodium bicarbonate. After drying and evaporation of the organic layer obtain 22 g of oil. A portion of the oil (5 g) dissolved in 75 ml of tetrahydrofuran and 75 ml of water and add 1 g of lithium hydroxide. After stirring for 72 hours, add 0.15 l of water and extracted with 0.2 l of hexane. The aqueous phase is acidified with 1 n hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. Get 4,25 g (96%) solid yellow color.

The second phase. At a temperature of 0oC to a mixture of 1 g obtained in the first stage product and 1.55 g obtained in the first stage of example 1 by the method And imine in 40 ml of methylene chloride is added to 0.56 ml dimethylaminopropylamine. The mixture is heated to room temperature and stirred for 16 hours. The reaction mass is diluted with 100 ml of sulphuric ether and successively washed with 1 n hydrochloric acid, 10% bicarbonate natraul the resulting residue using flash chromatography on silica gel with hexane/ethyl acetate (20:1). Obtain 0.75 g (30%) of oil.

The third stage. To a solution of 0.2 g obtained in the second stage product in 5 ml of triperoxonane acid at a temperature of 0oC add 121 mg of the acetate of mercury. After 15 minutes, add water and sulphuric ether, washed, dried and evaporated organic layer. The residue is purified using flash chromatography on silica gel with hexane/ethyl acetate (10:1). Obtain 0.15 g of oil.

The fourth stage. To a mixture of 0.15 g obtained in the third stage of the product and 0.06 ml of triethylamine in 5 ml of methylene chloride under nitrogen atmosphere was added 86 mg of 2-bromo-4'-fortetienne. After 5 hours the reaction mass is diluted with ethyl ether and washed successively 1N hydrochloric acid, 10% sodium bicarbonate and a saturated solution of sodium chloride. The organic layer is dried, evaporated and purify the residue using flash chromatography on silica gel with hexane/ethyl acetate (9:1). The resulting oil is separated by HPLC on a column with a chiral sorbent (Chirlacel AS), elwira a mixture of hexane/isopropyl alcohol (85:15) enantiomer 5(1)

([] 228 nm = -3,77103, [] 244 nm = +3,34103and then enantiomer 5(2)

([] 228 nm = +3,65103, [] 244 nm = -3,24103).

The fifth stage. When processing enantiomer 5(2) forestwide is a matter for C23H17NO3SF2%: C 64,93, H is 4.03, N 3,29, S 7,52; found: C 64,87, H 4,39, N 3,31, S 7,25.

Example 6

< / BR>
The first stage. To a solution of 0.4 g obtained in the fourth stage of example 5 enantiomer 5(2) in 20 ml of methanol was added 28 mg of sodium borohydride. After 2 hours, add sulphuric ether and water, the organic layers dried and evaporated, when cleaning the residue using flash chromatography with a mixture of ethyl acetate/hexane (1:6) elute the diastereomers 6(1) and 6(2).

The second phase. Obtained in the first stage, the diastereomers 6(1) and 6(2) separately treated with hydrofluoric acid by analogy with the third stage of example 1, method A. Receive 6(a) and 6(b).

6A: 1H NMR in deuterium chloroform: 2,85 (DD., J=6,12 Hz, 1H), 3.04 from (DD., J= 3.12 Hz, 1H), 4,06 (D., J=2.4 Hz, 1H), 4,7 (D., J=2.4 Hz, 1H), 4,9 (D., J= 3,9 Hz, 1H), 6,85-to 7.35 (12H).

6b: 1H NMR in deuterium chloroform: a 3.01 (m, 2H), 3,97 (D., J=2.2 Hz, 1H), 4,7 (D., J=2.2 Hz, 1H), 4.92 in (D., J=4,8 Hz, 1H), 6,85 and 7.36 (12H).

Example 7

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The first stage. Obtained according to example 6 of the first stage of the diastereoisomer 6(1) is treated with m-chlormadinone acid analogously to example 3. The reaction products purified by HPLC on silica gel, elwira a mixture of ethyl acetate/hexane (1:2). Get diastereoisomers 7(1) and 7(2).

The second phase. Polucen RETA stage of example 1, method A. Get 7a and 7b.

1H NMR in deuterium chloroform with 10% watermethanol: 7a: 3,35 (D., 1H, in), 3.75 (DD. , 1H), 4,22 (S., 1H), 5,20 (m, 2H), 6,80 (D., 2H), 6,9 (m, 2H),? 7.04 baby mortality (m , 2H), 7,24 (m, 4H), 7,38 (m, 2H). 7b: to 3.02 (DD., 1H), 3,26 (m, 1H), 4,21 (D., J=2.1 Hz, 1H), 5,14 (DD., 1H), 5,41 (D., J=2.1 Hz, 1H), 6,78 (D., 2H), 6,9 (m, 2H), 6,98 (m, 2H), 7,18 (m, 4H), 7,28 (m, 2H).

Melting point: 7a: 207-211oC; 7b: 110oC (decomp.).

Similarly, the methods of the first and second stages of the diastereoisomer 6(2) obtained in the first stage of example 6, get 7th and g

1H NMR in deuterium chloroform with 10% watermethanol:

7b: 3,12 (DD., 1H), 3,30 (m, 1H), 4,45 (D., J=2.2 Hz, 1H), 5,04 (DD., 1H), 5,39 (D., J=2.2 Hz, 1H), 6,78 (D., 2H), to 6.88 (m, 2H), 6,94 (m, 2H), 7,20 (m, 6H).

7G: 3,10 (DD., 1H), and 3.72 (m, 1H), 4,07 (D., J=2.5 Hz, 1H), 5,09 (DD., J= 2.3 Hz, 1H), 5,17 (D., J=2.5 Hz, 1H), 6,78 (D., 2h), 6,85 (m, 2H), 6,98 (m, 2H), 7,18 (m, 4H), 7,30 (m, 2H).

Melting point: 7b: 98oC (decomp.); 7G: 106,5oC (decomp.).

Example 8

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To a solution 0,185 g racemic product obtained in the second stage of example 1 by the method And, in 20 ml of methylene chloride was added m-chlormadinone acid. After 3 hours, add the sodium bisulfite and sodium bicarbonate and stirred for 10 minutes, then extracted with ethyl acetate. The organic fraction purified using flash chromatographed 0.15 g (76%).

Elemental analysis: calculated for C24H23NO4S%: C 68,39, H 5,5, N 3,32;

found: C 68,12, H 5,49, N 3,37.

The mass spectrum with ionization by electronic impact 421 (M+).

1H NMR: 3,2 (m, 2H), 3,55 (m, 2H), 3,80 (C., 3H), 4,23 (D., J=2.4 Hz, 1H), of 5.53 (D., J=2.4 Hz, 1H), 6,9 (D., 2H), and 7.1 (m, 1H), 7,28 (11H).

Example 9

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The first stage. Enantiomer 5(2) obtained in the fourth stage of example 5 is treated by analogy with example 3. The reaction product is purified using flash chromatography elwira a mixture of ethyl acetate/hexane (1:3) diastereoisomer 9(1) and the diastereoisomer 9(2).

The second phase. Obtained in the first stage, the diastereomers 9(1) and 9(2) is treated with hydrofluoric acid by analogy with the third stage of example 1, method A. Receive 9a and 96.

9a: So pl. 112,5-117oC.

1H NMR in deuterium chloroform: 4,39 (D., J=2.4 Hz, 1H), 4,93 (D., J=16 Hz, 1H), 5.25-inch (D. , J= 16 Hz, 1H), 5,32 (D., J=2.4 Hz, 1H), 5,55 (sh.with. 1H), 6,85-to 6.95 (m, 4H), to 6.88 (m, 2H), 7.18 in-7,30 (m, 6H), 8,05-of 8.09 (m, 2H).

9b: So pl. 188-195oC.

1H NMR in deuterium chloroform with 5% watermethanol: 4,39 (D., J=2.1 Hz, 1H), 4,46 (D., J=15 Hz, 1H), 4,62 (D., J=15 Hz, 1H), 5,42 (doctor J=2.1 Hz, 1H), 6.75 in (D., 2H), 6,9 (D. D., 2H), 7,08-7,20 (m, 6H), of 7.90 (m, 2H).

Example 10

< / BR>
The first stage. Repeat the synthesis of example 1, method B, one hundred>/P>The second phase. Obtained in the first stage of the TRANS-isomer is treated with acetate of mercury. Get the product of the third stage of example 5 in optically pure form.

The third stage. By analogy with the fourth and fifth stages of example 5 interaction obtained in the second stage of the product with 1'-bromo-2-acetyl-thiophene get the target product in the form of a solid substance with so pl. 148-150oC.

Example 11

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Repeat the operation of example 10, using the third stage, 1'-bromo-3-acetylthiophene. Get the target compound in the form of a solid substance with so pl. 176-178oC. Elemental analysis: calculated for C21H16NO3S2F%: C 61,01, H 3,90, N 3,39, S 15,48; found: C 61,33, H 4,12, N 3,51, 's shed 15.37.

Example 12

< / BR>
Repeat the operation of example 10, using the third stage, 1'-bromo-3-acetylpyridine. Get the target compound in the form of a solid substance with so pl. 74-90oC. Mass spectrum with ionization fast atom bombardment 409(M+H).

Example 13

< / BR>
Repeat the operation of example 10, using the third stage, 1'-bromo-4-acetylpyridine. Get the target compound in the form of a solid substance with so pl. 65-69oC. Elemental analysis: calculated for C22H17N2SF%: C 64,69, H 4,20,in the third stage, 1'-bromo-2-acetylpyridine. Get the target compound in the form of a solid substance with so pl. 59-64oC.

Example 15

< / BR>
Obtained in example 11 compound in methanol is treated with sodium borohydride receive a mixture of diastereomers in the form of a solid substance with so pl. 65-70oC.

Elemental analysis: calculated for C21H18NO3S2F%: C 60,71, H 4,37, N 3,37, S 15,4; found: C 60,67, H 4,48, 3,40 N, S $ 15.87 with.

Example 16

< / BR>
Obtained according to example 12 compound in methanol is treated with sodium borohydride at a temperature of 0oC. After 30 minutes, poured into a mixture of methylene chloride and water, separate the solution in methylene chloride and purified the product by flash chromatography on silica gel, elwira a mixture of methylene chloride/methanol (95:5). Get the target compound in the form of a solid substance with so pl. 85-90oC.

Example 17

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By analogy with example 16 obtained in example 13 compound synthesized target product with so pl. 95-98oC

Elemental analysis: calculated for C22H19N2O3SF%: C 64,38, H 4,67, N 6,82, S 7,81; found: C 64,09, H 4,95, 6,67 N, S 8,06.

Example 18

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The first stage. Obtained in the first stage of example 10 CIS-isomer is treated by analogy with the second stage of PI connection stage by analogy with the fourth and fifth stages of the example 5. Get the target product in the form of a solid substance with so pl. 180-185oC.

Elemental analysis: calculated for C23H17NO2SF2%: C 64,93, H is 4.03, N 3,29, 's rate of 7.54; found: C 65,13, H 4,16, N 3,43, S 7,70.

Example 19

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Obtained in the first stage of example 18 compound is treated with sodium borohydride in analogy to example 16, and then act on the reaction product of hydrofluoric acid by analogy with the third stage of example 1 according to the method of A. Get the target connection with so pl. 95-105oC.

The proposed pharmaceutical composition is illustrated by the following examples of some specific drugs (see below).

In each composition, the term "active principle" means a compound of formula I.

Method of cooking

Mix ingredients N 1 and N 2 in a suitable mixer for 10-15 minutes. Add ingredient # 3 and granularit mixture. The wet granules wipe, if necessary, through a grid with large cells (e.g., 0.25 inches, 0,63 cm). The wet granules are dried and, if necessary, sieved and then mixed with ingredient # 4 and mix for 10-15 minutes. Add ingredient # 5 and mix for 1-3 minutes. The mixture is pressed the Ute ingredients N 1, N 2 and N 3 in a suitable mixer for 10-15 minutes. Add ingredient # 4 and mix for 1-3 minutes. Mixture designed to fill the capsules of hard gelatin, which consists of two parts, a device for capsulating.

Optionally, in the above preparations, you can include another inhibitor of the biosynthesis of cholesterol in the right quantity.

1. Derivatives of azetidinone General formula (I)

< / BR>
where Ar1is phenyl, unsubstituted or substituted with halogen, or a 5 - or 6-membered heteroaromatic radical containing nitrogen or sulfur;

Ar2is phenyl, substituted lower alkyl, a group-OR2or-O(CO)R2where R2is a hydrogen atom or lower alkyl;

Ar3is phenyl, unsubstituted or substituted with halogen;

X and Y independently of one another denote-CH2-;

R - group OR3where R3is a hydrogen atom or lower alkyl;

R1is a hydrogen atom or R or R1together, the oxygen atom of the carbonyl group (=O),

q = 0 or 1;

r is 0, 1 or 2,

m and n independently of one another are 0, 1, 2, 3, 4, or 5 with the proviso that m + n + q = 2, 3, 4 or 5,

and their pharmaceutically acceptable salts.

2. Derivatives of azetidinone fo the config by hydroxyl, and Ar3is phenyl, substituted by fluorine.

3. Derivatives of azetidinone formula (I) under item 1 or 2, where q = 0, X and Y mean every-CH2- and m + n = 2, 3, or 4.

4. Derivatives of azetidinone formula (I) under item 1 or 2, where q = 1, X and Y mean every-CH2-, m + n = 2 or 3, R is a group-OR3where R3is a hydrogen atom, or R and R1together, the oxygen atom of the carbonyl group (=O).

5. Derivatives of azetidinone formula (I) under item 1, selected from the group including

TRANS-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio] -1-(4-forfinal)-2-azetidinone;

TRANS-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)thio]-2-azetidinone;

CIS-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)thio]-2-azetidinone;

TRANS-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)sulfinil] -1-(4-forfinal)-2-azetidinone;

CIS-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)sulfinil] -1-(4-forfinal)-2-azetidinone;

TRANS-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfinil] -2-azetidinone;

CIS-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfinil]-2-azetidinone;

TRANS-4-[4-keto-3-[(2-phenylethyl)sulfinil]-1-(4-forfinal)-2-azetidine] -phenylacetate;

CIS-4-[4-keto-3-[(2-phenylethyl)sulfinil] -1-(4-forfinal)-2-azetidine] -phenylacetate;

(+/-)-TRANS-4-(methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfon TRANS-4-[4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-hydroxy-2-(4-forfinal)ethyl]thio]-2-azetidinone;

(3R, 4R) 4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(4-forfinal)-ethyl]sulfinil]-2-azetidinone;

4(R)-(4-hydroxyphenyl)-1-(4-forfinal)-3(R)-[[2(R)-hydroxy-2-(4-forfinal)ethyl]sulfinil]-2-azetidinone;

4(R)-(4-hydroxyphenyl)-1-(4-forfinal)-3(R)-[[2(S)-hydroxy-2-(4-forfinal)ethyl]sulfinil]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(2-thienyl)-ethyl]thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(3-thienyl)-ethyl]thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(3-pyridinyl)ethyl]thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(4-pyridinyl)ethyl]thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(2-pyridinyl)ethyl]thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-hydroxy-2-(3-thienyl)ethyl]thio]-2-azetidinone;

(3R, 4R) TRANS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-hydroxy-2-(4-pyridinyl)ethyl]thio]-2-azetidinone;

(3S, 4R) CIS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-keto-2-(4-fluoro-phenyl)ethyl]thio]-2-azetidinone;

(3S, 4R) CIS-4-(4-hydroxyphenyl)-1-(4-forfinal)-3-[[2-hydroxy-2-(4-fluoro-phenyl)ethyl]thio]-2-azetidinone.

6. Pharmaceutical composition with anti-atherosclerotic or hypohalous the Ki acceptable carrier, characterized in that, as a derivative of azetidinone contains compounds of General formula (I) according to any one of paragraphs.1 - 5 or its pharmaceutically acceptable salt in an effective amount.

7. The pharmaceutical composition according to p. 6, characterized in that it further comprises an inhibitor of the biosynthesis of cholesterol in an effective amount.

Priority points and features:

18.11.94 on PP.1, 2, 5 to 7, where Ar1is phenyl, unsubstituted or substituted with halogen; PP.3 and 4;

05.06.95 on PP.1, 5 - 7, where Ar1- 5 - or 6-membered heteroaromatic radical containing nitrogen or sulfur.

 

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