Derivatives 4,1-benzoxazepine

 

(57) Abstract:

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts. Also disclosed two specific soy is t to be used for hyperlipidemia and arteriosclerosis. 3 S. and 3 C.p. f-crystals, 4 PL.

The invention relates to a derivative of 4.1-benzoxazepin-2, or their salts, which are useful for inhibiting stvalentines and fungus growth, and to their use.

Hypercholesterolemia, high blood pressure and Smoking are the three main known factors that cause coronary heart disease. Adequate control of concentration of cholesterol in the blood is extremely important for prevention or treatment, in addition to coronary disease and coronary sclerosis.

As pharmaceutical compositions for lowering blood cholesterol, attention was drawn to a composition for the control of the biosynthesis of cholesterol along with those that inhibit its absorption by binding bile acids, including, among others, cholesterol, colestipol (described, for example, in U.S. patent N 4027009) and those that inhibit intestinal absorption of cholesterol by inhibiting acetophenone A cholesterol acyltransferase (AST), including melinamide (described in the French patent N 1476569). As pharmaceutical drugs to control cholesterol biosynthesis for medical use are lovastatin (described in the HN to inhibit especially 3-hydroxy-3-methylglutarylcoenzyme (HMG-CoA) reductase. However, the inhibition of HMG-CoA reductase is inhibited not only the biosynthesis of cholesterol, but also the biosynthesis of some other components, such as ubiquinone, dolichol and heme A, which are necessary for a living organism, so there is a risk of the result of unwanted side effects. Stvalentines is an enzyme involved in the fixed stage of de Novo cholesterol biosynthetic pathway. This enzyme catalyzes reductive dimerization of two molecules of gamesinteractive in the form squalene.

On the other hand, the compounds proposed as inhibitors of the biosynthesis of cholesterol in the inhibition stvalentines described in JPA HI (1989) - 213288, JPA H2 (1990) - 101088, JPA H2 (1990) - 235820, JPA H2 (1990) - 235821, JPA H3 (1991) - 20226, JPA H3 (1991) - 63591, JPA H3 (1991) - 48288, U.S. patent N 5019390, Journal of Medicinal Chemistry, 51 (10), PP 1369-1871 (1988), U.S. patent N 5135935 and WO 9215579.

Also, compounds proposed as inhibitors of the growth of fungi in the inhibition stvalentines described in JPA H4 (1992) - 279589, EP 475706-A, EP 494622-A and EP 503520.

Among the derivatives of 4.1-benzoxazepine derivatives 4,1-benzoxazepin-2-it, in which the 2-position substituted keto-group, those in which one of the hydrogen atoms in the 3-p is ubiquinone, dolichol and hem And synthesized from farnesylpyrophosphate the path of the biosynthesis of cholesterol. Therefore, in order to avoid side effects due to the lack of these substances, it is desirable to ingibiruet enzymes after farnesylpyrophosphate, especially stvalentines, in the pathway of biosynthesis of cholesterol.

After intensive research with the above viewpoint, the present inventors have found that derivatives of 4.1-benzoxazepin-2-it has excellent inhibiting stvalentines action and antifungal activity, and developed the present invention.

Therefore, the present invention provides:

(1) Derivative 4,1-benzoxazepin-2-it General formula (I)

< / BR>
in which R1lower alkyl, substituted by at least one optionally substituted hydroxyl group;

R2and R3independently from each other mean: (i) hydrogen, (ii) lower alkyl, (iii) phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of 1) halogen atoms, 2) the lower C1-C4alkali, 3) lower C1-C4alkoxygroup, 4) a hydroxy-group, where group 2) is not substituted or is substituted by 1-3 halogen atoms, group 4) is not substituted or is substituted by the replacement of the La on the phenyl group may together form a ring, or (iv) pyridyl;

X is a bond or linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n denote, independently of one another, 0, 1, 2 or 3, E is a bond or an oxygen atom, a sulfur atom, sulfoxide, sulfon, - NR5-, -NHCO-, -CONR7- or-NHCONH-, where R5is hydrogen, lower alkyl, methylsulphonyl, 4-methylbenzenesulfonyl or acyl, R6and R7independently from each other mean (i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group containing a heterocyclic group selected from the group consisting of 1) indolyl, 2) a hydroxy-group, 3) possibly esterified carboxypropyl and 4) phenyl, (iii) benzyl; (iv) phenyl;

Y represents optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted or a nitrogen-containing heterocyclic group; and

ring A is not substituted or is substituted by 1-3 substituents selected from the group consisting of 1) halogen atoms, 2) the lower C1-C4alkali and 3) lower C1-C4alkoxygroup; in which group 2) is not substituted or is substituted by 1-3 halogen atoms, and these substituents may form Kalah R1represents a lower alkyl group substituted with one hydroxyl group which may be substituted;

R2, R3is a hydrogen atom or phenyl group, substituted C1-C4alkoxygroup, and R2and R3are the same or different;

X represents a methylene group;

Y - carnemolla group which may be substituted; ring A represents benzene ring, substituted by a halogen atom.

Among these derivatives 4,1-benzoxazepine and their salts are preferred compounds of formula

< / BR>
where R1represents a lower alkyl group which is substituted by a hydroxyl group or a hydroxyl group, a substituted acetyl group;

Ra- C4-C4alkoxygroup;

Y - carnemolla group which may be substituted for CH3SO2or piperidino-carbonyl group which may be substituted;

Z represents a halogen atom; and their salts;

as well as the compounds of formula

< / BR>
where R1represents C1-C7alkyl group which is substituted by a hydroxyl group or a hydroxyl group, a substituted acetyl group;

Y represents carbamoyl hydroximino group and/or a group-CH2-COORb(where Rbis a hydrogen atom, methyl group or ethyl group), and their salts.

Of particular interest are:

(3R, 5S)-N-methylsulphonyl-7-chloro-5-(2,3-acid)-1- (3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-ndimethylacetamide formula

< / BR>
and its salts,

and N-[(3R, 5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3 - acid)2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine - 4-acetic acid formula:

< / BR>
and its salts.

As the salts of compound (I) can be mentioned pharmaceutically acceptable salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluensulfonate, methanesulfonate, etc. , metal salts such as sodium salt, potassium salt, calcium salt, aluminum salt, etc., and basic salts such as triethylamine salt, guanidine salt, ammonium salt, hydrazine powered salt, quinine salt, Tikhonova salt, etc.

The method of obtaining derivatives 4,1-benzoxazepine represented by the formula (I)

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where each symbol has the meaning as defined above, or a pharmaceutical is where W means

where R8- halogen (for example fluorine, chlorine, bromine and iodine) or a group-OSO3CH3and other symbols have the meanings specified above.

As noted above, the compound represented by formula (I) of the present invention has the ability to inhibit schalensitze and antifungal activity. In addition, the compounds of the present invention is able to inhibit other enzymes in the pathway of biosynthesis of cholesterol. Essentially we can say that the compound of formula (I) of the present invention inhibits the biosynthesis of cholesterol, it is useful for the prophylaxis or treatment of hypercholesterolemia or coronary sclerosis in mammals (e.g. mice, rats, rabbits, dogs, cats, cows, pigs and people) and, in addition, for the prevention or treatment of fungal infections.

The specified compound (I) can be administered to the person orally or nearline. Enter the oral composition may be in solid or liquid form, more specifically, in the form of tablets (including covered sugar pills and tablets, film-coated), syrups, emulsions, suspensions or so on, These compositions can be prepared there are generally ways and contain carriers or excipient, usually used is whether stearate, in the manufacture of tablets.

Examples of not oral compositions for injection are injections and suppositories, and injections include hypodermic injection, intradermal injection, intramuscular injection. These injectables can be prepared generally known methods, more specifically, by suspension or emulsion of the compound of the present invention in sterile water or oil, usually used for preparation of compositions for injection. The aqueous liquid used to prepare drugs for injection include physiological saline and an isotonic solution and, if necessary, suitable suspendisse agent, such as natrocarbonatite-cellulose, non-ionic surfactant or so forth, can also be used. As oil can lead sesame oil, soybean oil, etc., and benzyl benzoate, benzyl alcohol, etc. can be used as a solubilizer. Thus prepared the drugs for injection is usually poured into appropriate capsules.

The compound of formula (I) or its salt can be safely used with low toxicity. Although a daily dose waruiru the beam injection compounds of the present invention for the treatment of hypercholesterolemia, daily oral dose for an adult is about 1-500 mg, preferably about 10-200 mg In this interval was not observed toxicity.

The compounds of formula (I) as inhibitors stvalentines effectively applied to a mammal, such as man, in therapeutically effective amount, which is usually provided oral daily dose for an adult human of from about 1 to about 500 mg, preferably about 10-200 mg if not oral use (for example in the form of injections or suppositories) a therapeutically effective amount is a daily dose is from about 0.1 to about 100 mg, preferably about 1-20 mg

Compounds of the present invention also show a wide range of antifungal activity, as determined by the methods of dilution in broth or on agar.

In the case of the introduction of the compounds of the present invention for the treatment of fungal infections usually apply 2-5 mg/kg as a single dose of antifungal treatment.

The compounds of formula (I) with antifungal treatment effectively applied to a mammal, such as man, in therapeutically effective the ome 100 mg, preferably about 1-50 mg When not oral use, such as injections or suppositories, a therapeutically effective daily dose is about 0.1-100 mg, preferably about 1-50 mg.

In the following description receive two types of racemic diastereoisomers depending on the type of connections that get due to the presence of asymmetric carbon atom at the 3-m and 5-m positions. Isomers in which the substituents in the 3-m and 5-m positions are oriented in the same direction with respect to the plane of the 7-membered ring, called CIS-isomers, whereas those in which the substituents in the 3-m and 5-m positions are oriented in opposite directions, are called TRANS-isomers.

The best option of carrying out the invention

The following working examples, examples of compositions and experimental examples are provided merely to further illustrate the present invention and should not be construed as limiting the invention.

[Example]

Reference example 1

Methyl ester of N-[(3R,5S)-7-chloro-5-(2,3 - acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetyl]piperidine-4-carboxylic acid

< / BR>
To a solution of the 5 g of the hydrochloride complex of ester methyl piperidine-4-carboxylic acid in dimethylformamide (10 ml) is added at room temperature diethylthiophosphate (0.28 g) and triethylamine (0,38 ml) and the mixture stirred for 1 h To the mixture is added water (100 ml) and ethyl acetate (100 ml). The organic layer was washed with 1N. HCl and saturated aqueous sodium bicarbonate, then dried aqueous magnesium sulfate. The solvent is distilled off and the residue is purified by column chromatography on silica gel (eluent:hexane: ethyl acetate = 1:1) (V/V) with the receipt of 0.62 g of a colorless crystalline product, so pl. 124-126oC.

Elemental analysis for C31H39ClN2O70,3 H2O:

Calculated: C 62,84; H 6,74; N 4,73

Found: C 62,78; H 6,69; N 4,72.

Reference example 1

The following compound was obtained by the method basically described in Example 1.

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The compound N 2-38,

Y

so pl. (oC) 150-151.

Reference example 2

N-[(3R, 5S)-7-Chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetyl]piperidine-4-carboxylic acid

< / BR>
The compound (0.5 g), obtained as described in Referential example 1 was dissolved in a mixture of 1H. an aqueous solution of sodium hydroxide (4 ml), methanol (10 ml) and tetrahydrofuran (5 ml). The solution is stirred for 1 h at room temperature, and then add 1N. HCl (50 ml) and ethyl acetate (100 ml). The organic layer is washed with water and dried without obtaining to 0.47 g of colorless crystals, so pl. 145-147oC.

Elemental analysis for C30H37ClN2O70,3 H2ABOUT:

Calculated: C 62,29; H 6,55; N 4,84

Found: C 62,20; H Of 6.65; N Of 4.83.

Reference example 3

N-Toluensulfonyl-(3R, 5S)-7-chloro-5-(2,3-acid)-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetylated

< / BR>
To a solution of (3R,5S)-7-chloro-5-(2,3-acid)-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (0.5 g) and p-toluensulfonate (0,22 g) in dichloromethane was added 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide (0.27 g) and dimethylaminopyridine (20 mg). The mixture is stirred for 3 h at room temperature and concentrate under reduced pressure. The concentrate was dissolved in ethyl acetate (100 ml). The solution is washed with water and dried, and the solvent is then distilled off. The residue is purified by column chromatography on silica gel (eluent: dichloromethane: methanol: water = 200: 10: 1 (V/V) to obtain 0.6 g of colorless crystals, so pl. 110-113oC.

Elemental analysis for C31H55ClN2O7S H2O:

Calculated: C 58,81; H of 5.89; N 4,42

Found: C 58,73; H 5,73; N 4,62.

Reference example 4 (3R, 5S)-N-phosphonomethyl-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-is 1, in dichloromethane (5 ml), add trimethylsilylpropyne (0,38 g). The mixture is stirred over night at room temperature and add ethyl acetate. This mixture is washed with 0.5 N. aqueous sodium hydroxide solution, saturated aqueous ammonium chloride and water, and then dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from a mixture of ethanol and diethyl ether (1:10) to obtain the 0,41 g of colorless crystals, so pl. 152-155oC.

Elemental analysis for C25H32ClH2O7P 1,7 H2O:

Calculated: C 51,28; H 6,09; N 4,78

Found: C 51,20; H 6,11; N 4,77.

Reference example 5

(3R, 5S)-7-chloro-5-(2,3-acid)-1-neopentyl-1,2,3,5 - tetrahydro-3-(1H(or 3H)-tetrazol-5-yl)-methyl-4,1-benzoxazepin-2-he

< / BR>
(1) Dimethylformamidine a solution of (3R,5S)-7-chloro-5-(2,3 - acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid (2.0 g), ammonium chloride (1.2 g) and triethylamine (1.0 ml) cooled in an ice bath. To the solution add diethylthiophosphate of 0.85 g) and triethylamine (0.5 ml). The mixture is stirred for another 20 min, add ice water and extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous magnesium sulfate.

Rastvoriteli)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-ndimethylacetamide in the form of colorless crystals, so pl. 170-172oC.

(2) Compound (3.2 g) obtained in stage (1), and thionyl chloride (1.8 ml) suspended in toluene (40 ml). The resulting suspension is stirred for 1 h at 110 - 120oC. the Solvent is removed. To the residue is added ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic layer is dried with anhydrous sodium sulfate and then the solvent is distilled off. The residue is purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 3: 1) (V/V) to obtain 1.7 g (3R,5S)-7 - chloro-5-(2,3-acid)-1-neopentyl-1,2,3,5-tetrahydro-3 - cyanomethyl-4,1-benzoxazepin-2-it is in the form of colorless crystals, so pl. 193-194oC.

(3) To a solution of compound (1.7 g) obtained in stage (2) in toluene (20 ml), add trimethylsilane (0.45 g) and oxide dibutyrate (IV) (30 mg). The mixture is stirred for 24 h at 110 - 120oC. the Reaction mixture was concentrated, add diethyl ether (20 ml) and then washed with an aqueous solution of sodium hydroxide. The aqueous layer was acidified with 1N. HCl and extracted with ethyl acetate. The organic layer is washed with water and then dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from dichloromethane-hexane to obtain be,5H2ABOUT:

Calculated: C 58,24; H 5,91; N 14,15

Found: C 58,43; H 6,18; N 13,76.

Working example 1

(3R, 5S)-7-Chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)- 1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepin-2-he

< / BR>
(1) To a solution of (3)-4-chloro-2-[ - -hydroxy-[2,3 - acid)methyl] aniline (2.0 g) and sodium bicarbonate (0,86 g) in ethyl acetate (20 ml) added dropwise a solution of complex monoethylene ether chloride dimethylmaleic acid (1.3 g) in ethyl acetate (20 ml). The mixture is stirred for 3 hours under ice cooling. To the solution was added water (30 ml) and the organic layer is dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is purified by column chromatography on silica gel with getting complicated ethyl ester (S)-2-[N-(2-(2,3-dimethoxy-hydroxybenzyl)-4 - chlorophenyl] carbarnoyl] -2,2-dimethyloctane acid (2,92 g) as a colorless oily compound.

1H-NMR (CDCl3) : to 1.22 (3H, t, J=7.4 Hz), of 1.37 (3H, s) of 1.42 (3H, s), of 3.84 (3H, s) to 3.89 (3H, s), 4,05-4,19 (3H, m), 6,01 (1H, s), is 6.61 (1H, d, J= 1,8, 7,4 Hz), 6.90 to-7,05 (3H, m), 7,28 (1H, d, J=3,0, 8,8 Hz), 8,07 (1H, d, J=8,4 Hz), 9,49 (1H, Shir).

(2) To a solution of compound (2.83 g) obtained in stage (1) in tetrahydrofuran (30 ml) are added, while cooling with ice, alumoweld litestar sodium hydroxide (13 ml) and water (50 ml), and then any insoluble matter is filtered off. The filtrate is extracted with ethyl acetate. The extract is washed with water and dried, whereupon the solvent is distilled off. The residue is purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 1:1 (V/V) to give (S)-[5-chloro-2-(2,2-dimethyl-3-hydroxypropyl) AMINOPHENYL](2,3-acid)methanol (0.88 g) as a colorless oily compound.

1H-NMR (CDCl3) : of 0.91 (3H, s) of 0.93 (3H, s), 2,95 (2H, s), 3,37 (2H, s), 3,83 (3H, s), 3,88 (3H, s), of 5.99 (1H, s), 6,63 (1H, d, J=8,8 Hz), 6,77 (1H, DD, J= 1,6 and 7.6 Hz), make 6.90 (1H, DD, J=1,6 and 7.6 Hz), 7,03 (1H, d, J=2,6 Hz), 7,03 (1H, t, J=7,6 Hz), 7,13 (1H, d, J=2,6, 6,8 Hz).

(3) To a solution of compound (0.88 g) obtained in (2) in ethyl acetate (10 ml), add sodium bicarbonate (0.39 g). To the mixture add a solution of complex monoecious ester of fumaric acid chloride (0.45 g) in ethyl acetate (10 ml) and stirred for 30 min at room temperature. The reaction mixture is washed with water and dried, and the solvent is then distilled off. The residue is dissolved in ethanol (10 ml), to which is added potassium carbonate (0,70 g). The resulting mixture is stirred over night at room temperature. To the reaction mixture are added ethyl acetate (50 ml) and then washed with water and dried. The solvent distillate-5-(2,3-acid)-1-(2,2 - dimethyl-3-hydroxypropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3 - acetic acid (0,57 g) as colorless crystals, so pl. 188-190oC.

(4) the Compound (0.5 g) obtained in stage (3), dissolved in a mixture of tetrahydrofuran (5 ml) and ethanol (3 ml). To the solution was added 1N. an aqueous solution of sodium hydroxide (1 ml) and then stirred for 20 min at 60oC. To the reaction mixture are added water (50 ml) followed by extraction with ethyl acetate. The extract is dried and the solvent is distilled off. The residue is recrystallized from ethyl acetate-hexane to obtain (3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2 - dimethoxypropane)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin - 3-acetic acid (0.33 g) as colourless crystals, so pl. 199-202oC.

(5) To a solution of compound (2 g) obtained in stage (4), and 3-aminopropionitrile (0,29 g) in dimethylformamide (20 ml) at room temperature, add diethylthiophosphate (0.75 g) and triethylamine (0.51 g). The mixture is stirred for 30 min, and then add complex ethyl ester acetic acid (100 ml). The mixture is washed with water and dried. The solvent is distilled off and the residue is recrystallized from hexane to obtain 3-[[(3R,5S)-7-chloro-2,3-acid)-1-(3 - hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetyl]amino]propionitrile (2.25 g) as colourless crystals, so pl. 118-121ml). To the solution add dimethylaminopyridine (0.1 g) and the mixture stirred for 30 min at room temperature. The solvent is distilled off and the residue is dissolved in ethyl acetate (100 ml). The solution was washed with 1N. HCl and water and then dried with anhydrous magnesium sulfate. The solvent is distilled off and get 3-[(3R,5S)-1-(3-atomic charges-2,2-dimethylpropyl)-7-chloro-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin - 3-acetyl] aminopropionitrile (2.2 g) as a colorless amorphous solid product.

1H-NMR (CDCl3) : of 0.95 (3H, s) a 1.01 (3H, s) 2,03 (3H, s), 2,55-a 2.71 (2H, m), 2,92 (1H, d, J=8,0, 14.4 Hz), 3,41 - 3,59 (3H, m), 3,62 (3H, s), and 3.72 (1H, d, J=11.2 Hz), 3,86 (1H, d, J=11.2 Hz), 3,90 (3H, s) to 4.33 (1H, DD, J= 5.0 and 8.0 Hz), 4,56 (1H, d, J=14,2 Hz), of 6.26 (1H, s), 6,50-6,60 (1H, W), only 6.64 (1H, s), 6,97-7,38 (5H, m).

(7) a Solution of the compound (2.2 g) obtained in stage (6), triphenylphosphine (2.0 g), diethylazodicarboxylate (0.87 g) and triethylsilane (1.3 g) in tetrahydrofuran (10 ml) is stirred, for 2 h at 60oC. the Reaction mixture was concentrated under reduced pressure. The concentrate is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1 (V/V)) and obtain (3R,5S)-7-chloro-3-[1- (2-cyanoethyl)-1H-tetrazol-5-yl]methyl-5-(2,3-acid)-1- (2,2-dimethyl-3-hydroxypropyl)-1,2,3,5-tetrahydro-4,1 - benzac is tetrahydrofuran (10 ml) and add 1N. an aqueous solution of sodium hydroxide (8 ml). The mixture is stirred for one hour at 60oC. To the reaction mixture are added water (50 ml), acidified with 1N. HCl and extracted with ethyl acetate. The extract is dried and the solvent is distilled off. The residue is recrystallized from ethyl acetate-hexane to obtain 0.96 g of colorless crystals, so pl. 158-160oC.

Elemental analysis for C24H28HClN3O5:

Calculated: C 57,43; H 5,62; N 13,95

Found: C 57,55; H 5,58; N Of 13.75.

Working example 2

The compound obtained as described in Example 1-(4), is subjected to reaction according to the method basically described in Reference example 1, and receive connections listed in Table 1.

Working example 3

The compound obtained as described in Example 2 is subjected to reaction according to the method basically described in Reference example 2, and receive connections are presented in Table 2.

Working example 4

(3R, 5S)-N-Methylsulphonyl-7-chloro-5-(2,3-acid)-1- (3-hydroxy-2,2-dimethoxypropane)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-ndimethylacetamide

< / BR>
Using the compound obtained as described in Working example 1 (4) (0.4 g), and methanesulfonamide (0.1 g), conducting the reaction according to the method, mainly described the>Elemental analysis for C25H31ClN2O5S:

Calculated: C 54,10; H 5,63; N OF 5.05

Found: C 54,30; H 5,69; N 4,87.

Working example 5

(3R, 5S)-N-Methylsulphonyl-7-chloro-5-(2,3-acid)-1-(3 - hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-ndimethylacetamide

< / BR>
(1) To a solution of oxalicacid (2.2 ml) in dichloromethane (120 ml) at -78oC added dropwise a solution of DMSO (2.4 ml) in dichloromethane (20 ml). The mixture was stirred at -78oC for 10 min, and then add a solution of 5-(hydroxymethyl)-2,2,5-trimethyl-1,3-dioxane (2 g) in dichloromethane (40 ml). The mixture was stirred at -78oC for another 15 minutes To this solution is added triethylamine (13,2 ml). The mixture is heated until the 0oC and add saturated aqueous solution of ammonium chloride (40 ml). The organic layer is washed with water and dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue is purified by column chromatography on silica gel [eluent: hexane: ethyl acetate (3: 1)] to obtain 2 g of the aldehyde as a colorless oily compound. To a methanol solution of this aldehyde (2 g) added (S)-4-chloro-2 - [hydroxy-(2,3 - acid)methyl]aniline (3.3 g) and acetic acid (0.75 g). The mixture is ü stirred over night at 60oC, add water and extracted with ethyl acetate. The extract is successively washed with aqueous 1 n sodium hydroxide solution and water, then dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is purified by column chromatography on silica gel [eluent: hexane-ethyl acetate (2:1)], resulting in a gain of 3.7 g (S)-[2-(2,2,5-trimethyl-1,3-dioxane-5-ylmethyl)-amino-5-chlorophenyl] (2,3 - acid)methanol as a colorless oily compound.

1H-NMR (CDCl3) ,81 (3H, s), 1,38-of 1.45 (6H, m), up 3.22 (2H, s), 3,30 is 3.40 (1H, Shir. ), of 3.60 (4H, s), 3,83 (3H, s) to 3.89 (3H, s), 4,90-5,00 (4H, W), 5,97 (1H, s) of 6.71-7,27 (6H, m).

(2) To a solution of compound obtained in stage (1) (3.7 g) in ethyl acetate (40 ml), add sodium bicarbonate (1.78 g). To the mixture at 0oC add complex monotropy ester of fumaric acid chloride (1,41 g). The mixture is stirred at room temperature for 30 minutes To the solution add water. The organic layer is washed with water and then dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue (5.2 g) was dissolved in ethanol (100 ml) and add potassium carbonate (1.1 g). The mixture is stirred over night at room temperature. To the reaction mixture, water is added, followed EXT is try using column chromatography on silica gel [eluent:hexane-ethyl acetate (2:1) - the ethyl acetate] to obtain 2.65 g of complex ethyl ester (3R,5S)-7-chloro-1-(2,2,5 - trimethyl-1,3-dioxane-5-ylmethyl)-5-(2,3-acid)-2 - oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (A) and 1.12 g of complex ethyl ester (3R,5S)-7-chloro-1-(3 - hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-acid) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (B), each of which represents a colorless amorphous solid product.

A:1H-NMR (CDCl3) : of 0.95 (3H, s) of 1.24 (3H, t, J=7.0 Hz), of 1.36 and 1.39 in (each 3H, s), 2,77 (1H, DD, J=5,8, and 16.4 Hz), totaling 3.04 (1H, DD, J=7,8, and 16.4 Hz), 3,29 (1H, d, J=and 12.2 Hz), 3,40 (1H, d, J=12,2 Hz) to 3.58 (3H, s), 3,68 (2H, s), the 3.89 (3H, s), 4,07-4,19 (3H, m), and 4.40 (1H, d, J=5,8, and 7.8 Hz), 4,48 (1H, d, J=14,2 Hz), 6,16 (1H, s), 6,63 (1H, d, J=1,8 Hz), 6,95 was 7.45 (6H, m).

IN:1H-NMR (CDCl3) : of 0.62 (3H, s), 1,25 (3H, t, J=7.0 Hz), 2,78 (1H, DD, J=5,2, 16,6 Hz), of 3.07 (1H, DD, J=8,2, 16,6 Hz), 3,39-of 3.80 (4H, m), of 3.60 (3H, s) to 3.89 (3H, s), of 4.13 (2H, DQC., J=1,8, 7,0 Hz), 4,20-to 4.28 (1H, m) to 4.41 (1H, DD, J=5,2, 18.2 Hz), is 4.85 (1H, d, J=14.6 Hz), 6,12 (1H, s), 6,63 (1H, s), 6.89 in-7,39 (6H, m).

(3) To an ethanol solution of the compound (A) obtained in stage (2) (2.25 g), add 1N. an aqueous solution of sodium hydroxide (4.0 ml). The mixture was stirred at 60oC for 1 h, and then water is added, followed by neutralization by addition of 1N. HCl. The reaction mixture was extracted with ethyl acetate. Extin-5-ylmethyl)-5-(2,3-acid)-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetic acid as a colorless amorphous solid product.

1H-NMR (CDCl3) : of 0.95 (3H, s) of 1.35 and 1.39 in (each 3H, s) 2,84 (1H, DD, J=7,8, and 16.4 Hz), is 3.08 (1H, DD, J=7,8, and 16.4 Hz), or 3.28 (1H, d, J=12,2 Hz) to 3.41 (1H, d, J=12,2 Hz) to 3.58 (3H, s), of 3.69 (2H,s) to 3.89 (3H, s) to 4.16 (1H, d, J= a 13.8 Hz), 4,35 (1H, DD, J=5,4, and 7.8 Hz), 4,89 (1H, d, J=13,8 Hz), 6,16 (1H, s), of 6.65 (1H, d, J=2.0 Hz), of 6.96-7,47 (5H, m).

(4) To a solution of compound obtained in stage (3) (0.15 g) in dimethylformamide (2 ml) add methanesulfonamide (29 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg) and dimethylaminopyridine (10 mg). The mixture is stirred over night at room temperature, and then to this mixture is added ethyl acetate (50 ml). The mixture is washed, and then dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is dissolved in acetone (2 ml). To the solution add monohydrate p-toluensulfonate acid (0.1 g). The mixture is stirred over night at room temperature and to this mixture is added ethyl acetate (50 ml). The mixture is washed with water, dried with anhydrous sodium sulfate, and the solvent is distilled off. The residue is washed with a mixture of ethyl ether and hexane (1:1) and filtered to obtain 40 mg of a colorless amorphous solid product.

1H-NMR (CDCl3) : 0,63 (3H, s), 2,85 of 2.92 (2H, m), or 3.28 (3H, s), 3.25 to 3,70 (5H, m) and 3.59 (3H, s) to 3.89 (3H, s), 4,43 (1H, t, J=6,1 Hz), 4,78 (1H, d, J=14,2 Hz), 8,16 (1H, s), to 6.67 (1H, s), 6,95-7,40 (6H, m).drank)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin - 3-acetyl] piperidine-4-ndimethylacetamide

< / BR>
Using the compound (0.5 g), obtained as described in Working example 3-1, and methanesulfonamide (0.1 g), conducting the reaction according to the method basically described in Reference example 3, resulting in receive 90 mg of colorless crystals, so pl. 175-180oC.

Elemental analysis for C32H42ClN3O9S1:

Calculated: C, 56,50; H, to 6.22; N, 6,18

Found: C, 56,70; H, 6,50; N, 5,90.

Working example 7

(3R, 5S)-N-bis(Ethoxy)faustinelli-7-chloro-5-(2,3-acid)-1- (3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin - 3-ndimethylacetamide

< / BR>
Using the compound (1.0 g), obtained as described in Working example 1-(4), and diethylaminoethylamine (0,38 g), conducting the reaction according to the method basically described in Reference example 1, resulting in a gain of 1.24 g of colorless crystals, so pl. 138-140oC.

Elemental analysis for C29H40ClN2O9P:

Calculated: C, 55,55; H, to 6.43; N, 4,47

Found: C, 55,25; H, 6,47; N, Of 4.44.

Working example 8

(3R, 5S)-N-Phosphonomethyl-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2 - dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ndimethylacetamide

< / BR>
Compound (0.3 g), obtained as described in Working example 7, the evaluation of the CSO solid connections.

1H-NMR (CD3OD) : 0,94 (3H, s) of 0.93 (3H, s), 2,75-2,82 (2H, m), 3,20 (1H, d, J=11,4 Hz), 3,40-3,70 (3H, s) to 3.58 (3H, s) to 3.89 (3H, s), 4,35-to 4.46 (2H, m), 6,18 (1H, s), 6,53 (1H, d, J=2.2 Hz), 7,08-to 7.61 (5H, m).

Working example 9

N-[(3R, 5S)-7-Chloro-1-(2,2,5-trimethyl-1,3-dioxane-5-ylmethyl-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-acetic acid complex ethyl ester,

< / BR>
Using the compound (2.0 g), obtained as described in Working example 5-(3), and hydrochloride complex of ethyl ether piperidine-4-acetic acid (0.7 g), conducting the reaction according to the method basically described in Reference example 1, resulting in a gain of 2.4 g of colorless amorphous solid product.

HNMR (CDCl3,) as 0.96 (3H, s), 1,25 (3H, t, J=7.2 Hz), of 1.36 and 1.39 in (each 3H, s), 1,65-to 1.82 (4H, m), 1,95-of 2.08 (1H, m), 2,18-of 2.26 (2H, m), 2.49 USD 2.63 in (1H, m), 2,73 (1H, DL, J=4,8, to 15.8 Hz), 2,92-of 3.06 (1H, m), of 3.12 (1H, DD, J=8,2, to 15.8 Hz), and 3.31 (1H, d, J=12.0 Hz), 3,10 (1H, d, J=12.0 Hz), to 3.58 (3H, s), the 3.65 (1H, d, J=11.8 Hz), to 3.73 (1H, d, J=11.8 Hz), with 3.89 (3H, s), 3,94-to 3.99 (1H, m), 4.04 the-4,18 (3H, m), 4,46-4,56 (3H, m), 6,16 (1H, s), 6,60-6,62 (1H, m), 6,95-7,46 (5H, m).

Working example 10

N-[(3R, 5S)-7-Chloro-1-(3-hydroxy-2-hydroxymethyl-2-methyl-propyl)-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-acetic acid complex ethyl ester

< / BR>
To a solution of soedinenii acid (35 mg) and water (2 ml). The mixture was stirred at 50oC for 6 hours To the reaction mixture are added ethyl acetate (50 ml). The mixture was washed with 1N. aqueous solution of sodium hydroxide and water, and then dried with anhydrous sodium sulfate. The solvent is distilled with the receipt of 1.62 g of a colorless amorphous solid product.

1H-NMR (CDCl3) : of 0.62 (3H, s), and 1.00 to 1.34 (2H, m) of 1.26 (3H, t, J=7.4 Hz), 1.70 to is 1.81 (2H, m), 1,95-of 2.08 (1H, m), 2,19-of 2.28 (2H, m), of 2.51-2,78 (2H, m), 3,01-is 3.08 (1H, m), 3,17 (1H, DD, J=9,0, 15.2 Hz), 3,40-3,74 (5H, m), of 3.60 (3H, s) to 3.89 (3H, s), 3,89-of 3.94 (1H, m), 4,13 (2H, square, J=7,4 Hz), 4,48-of 4.54 (2H, m), a 4.83 (1H, d, J=14.6 Hz), 6,13 (1H, s), is 6.61 (1H, d, J=1,8 Hz), 6,97-7,44 (5H, m).

Working example 11

N-[(3R, 5S)-7-Chloro-1-(3-hydroxy-2-hydroxymethyl-2-methyl-propyl)-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-acetic acid

< / BR>
To an ethanol solution of the compound obtained as described in Working example 10, type 1H. an aqueous solution of sodium hydroxide. The reaction mixture was stirred at 60oC for 2 hours. To the reaction mixture are added water (100 ml) and ethyl acetate (50 ml) and then acidified with 1N. HCl. The organic layer is washed with water and dried with anhydrous sodium sulfate. The solvent is distilled with the receipt of 0.94 g of a colorless amorphous solid product.

1H-NMR (CDCl3, is), 3,91-4,00 (1H, m), 4,48-of 4.54 (2H, m), 4,78 (1H, d, J=15.2 Hz), 6,12 (1H, s), is 6.61 (1H, s), 6,97-7,39 (5H, m).

Working example 12

N-[(3R, 5S)-1-(3-Acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-acetic acid complex ethyl ester

< / BR>
To a solution of the compound obtained as described in Working example 10, (0.5 g) in pyridine (5 ml), add acetic anhydride (0.20 g) and dimethylaminopyridine (10 mg). The mixture is stirred at room temperature for 30 minutes To the reaction mixture are added ethyl acetate (50 ml). The mixture was washed with 1N. HCl and water, and then dried, followed by distillation of the solvent. The residue is purified by column chromatography on silica gel (eluent: ethyl acetate) and obtain 0.50 g of colorless amorphous solid product.

1H-NMR (CDCl3) : of 1.02 (3H, s), 1,00-1,40 (2H, m), 1.25 and 1.26 in (total 3H, each t, J=7.2 Hz), 1,60-1,80 (2H, m), 1,92-2,05 (1H, m), from 2.00 (3H, s) 2,03 (3H, s), 2,16-of 2.26 (2H, m), 2,46-to 2.65 (1H, m), 2,67-2,77 (1H, m), 2,99-3,19 (2H, m) of 3.60 (3H, s), 3,64-4,19 (6H, m) to 3.89 (3H, s), of 4.44-of 4.54 (2H, m), of 4.67 (1H, d, J=14.6 Hz), 6,23 (1H, s), of 6.65 (1H, s), of 6.96-7,34 (5H, m).

Working example 13

N-[(3R, 5S)-1-(3-Acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-uxua method mostly described in Working example 12, resulting in a gain of 0.28 g of a colorless amorphous solid product.

1H-NMR (CDCl3) : 0,95-of 1.36 (2H, m) of 1.03 (3H, s), 1,71 of-1.83 (2H, m), 1.93 and-2,07 (1H, m), from 2.00 (3H, m), is 2.05 (3H, s), 2,23 is 2.33 (2H, m), 2,48-2,63 (1H, m), 2,65-2,78 (1H, m), 3.00 and-3,18 (2H, m), of 3.60 (3H, s), 3,65-4,14 (6H, m) to 3.89 (3H, s), 4,46-4,56 (2H, m), of 4.66 (1H, d, J=14,8 Hz), 6,24 (1H, s), only 6.64 (1H, s), of 6.96-7,34 (5H, m).

Working example 14

(3R,5S)-N-Methylsulphonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7 - chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin - 3-ndimethylacetamide

< / BR>
Using the compound obtained as described in Working example 5 (0.1 g), acetic anhydride (39 mg) and dimethylaminopyridine (5 mg), conducting the reaction according to the method basically described in Working example 12, resulting in a gain of 70 mg of a colorless amorphous solid product.

1H-NMR (CDCl3) : 1,00 (3H, s), from 2.00 and 2.02 (each 3H, s), 2,85 (1H, DD, J=5,4, to 15.4 Hz), 2,98 (1H, DD, J=7,2, to 15.4 Hz), 3,26 (3H, s), 3,61 (3H, s), 3,70 (1H, d, J=14,2 Hz), a-3.84 (1H, d, J=11.4 in Hz) to 3.89 (3H, s), 3,94-3,99 (2H, m), 4,11 (1H, d, J=11.4 in Hz), and 4.40 (1H, d, J=6.2 Hz), 4,46 (1H, d, J=14,2 Hz), 6,28 (1H, s), 6,69 (1H, d, J=1.6 Hz), 6,97-the 7.43 (5H, m).

Working example 15

N-[(3R, 5S)-1-(3-Acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-uksosn is 2-1, (0.5 g), conducting the reaction according to the method basically described in Working example 12, resulting in a gain of 0.35 g of a colorless amorphous solid product.

1H-NMR (CDCl3) : 0,93 (3H, s) of 1.02 (3H, s) of 1.26 (3H, t), represented 2.02 (3H, s), 3,61 (3H, s) to 3.89 (3H, s), 4,14 (2H, square), and 4.5 (3H, m), of 6.26 (1H, s), 6,62 (1H, s), of 6.9 to 7.4 (5H, m).

Working example 16

N-[(3R, 5S)-1-(3-Acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-acetic acid

< / BR>
Using the connection (0,37 g), obtained as described in Working example 3-1, carry out reaction according to the method basically described in Working example 12, resulting in a gain of 0.35 mg of a colorless crystalline product, so pl. 194 - 196oC.

Elemental analysis for C32H41ClN2O9:

Calculated: C, 61,4, H, 6,41; N, 4,34

Found: C, 61,23; H, 6,18; N, 4,39.

Working example 17

N-[(3R, 5S)-7-Chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -4 - hydroxypiperidine-4-acetic acid methyl ester

< / BR>
(1) To a solution of complex ethyl ester (3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-stirred for 1 h at 60oC. To the reaction mixture, water is added, neutralized 1H. HCl and subjected to extraction with ethyl acetate. The solution of the extract is dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from a mixture of ethyl acetate and hexane, resulting in a gain of 0.38 g of (3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl-5-(2,3 - acid)-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetic acid, so pl. 208-210oC.

(2) Using the compound obtained in (1), (0.25 g), and hydrochloride of ester methyl 4-hydroxypiperidine-4 - acetic acid (0,105 g), conducting the reaction according to the method basically described in Reference example 1, resulting in a gain 0.125 g of colorless amorphous solid product.

1H-NMR (CDCl3) : 1,35-of 1.84 (6H, m), 2,47 (2H, d), 2,65-to 2.85 (1H, m), 2.95 and of 3.28 (2H, m), 3,35-of 3.78 (7H, m), 3,62 (3H, s), of 3.73 (3H, s), 3,90 (3H, s), 4,22-and 4.40 (2H, m) to 4.52 (1H, DD), 4,84 (1H, DD), 6,13 (1H, d), 6,62 (1H, m), 6,95-the 7.43 (5H, m).

Working example 18

N-[(3R,5S)-7-Chloro-1-(3-hydroxy-2-hydroxymethyl-2-methyl-propyl)-1,2,3,5 - tetrahydro-5-(2,3-acid)-3-(1H (or 3H)-tetrazol-5-yl) -methyl-4,1-benzoxazepin-2-he

< / BR>
(1) To a solution of the compound (0.5 g), obtained as described in Working example 5-(3), ammonium chloride (0.25 g) and triethylamine (0.17 g) in digitiform the round for 30 min, and then add ethyl acetate (50 ml). The mixture is washed with water and then dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue is purified by column chromatography on silica gel (eluent: ethyl acetate) and obtain 0.52 g of amide compound as amorphous solid.

(2) To a solution of dimethylformamide (41 mg) in acetonitrile (1.5 ml) add oxalicacid (65 mg) at 0oC. the Mixture is stirred for 10 minutes, then add a solution of the compound obtained in stage (1) (0.25 g) in acetonitrile (1.5 ml) and pyridine (82 mg). The mixture was stirred at 0oC for 10 minutes To the reaction mixture are added ethyl acetate (50 ml). The mixture is washed with water and dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue is purified by column chromatography on silica gel [eluent: hexane: ethyl acetate (2:1)] to obtain 0.31 g of nitrile compounds.

(3) Solution of the compound obtained in stage (2), (1.0 g) in toluene (15 ml) is subjected to reaction according to the method basically described in Reference example 5-(3), using trimethylsilane (0,43 g) and nitric oxide dibutyrate (IV) (45 mg), resulting in getting (3R,5R)-7-chloro-1-(2,2,5 - trimethyl-1,3-dioxane-5-ylmethyl)-5-(2,3-demeton the th product.

(4) To a solution of compound obtained in stage (3) (1.0 g) in acetone (10 ml) add monohydrate p-toluensulfonate acid (50 mg) and water (1 ml). The mixture was stirred at 60oC during the night. To the reaction mixture are added water (50 ml) followed by extraction with ethyl acetate. The organic layer is dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is purified by column chromatography on silica gel (eluent: ethyl acetate-methanol (20:1) to give 0.87 g of colorless amorphous solid product.

1H-NMR (CDCl3) : is 0.69 (3H, s), of 3.45 (1H, DD, J=4,4, 14.4 Hz), 3,56 of 3.75 (5H, m), 3,62 (3H, s), 3,90 (3H, s), the 4.29 (1H, DD, J=4,4, 8,8 Hz), 4,63 (1H, d, J=15.2 Hz), 6,18 (1H, s), to 6.67 (1H, d, J=2.2 Hz), 7,05-the 7.43 (5H, m).

Working example 19

(3R, 5S)-1-(3-Acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-1,2,3,5 - tetrahydro-5-(2,3-acid)-3-(1H (or 3H)-tetrazol-5-yl)-4,1 - benzoxazepin-2-he

< / BR>
To a solution of the compound obtained as described in Working example 18, (0,77 g) in pyridine (7 ml) is added acetic anhydride (0,335 g) and dimethylaminopyridine (40 mg). The mixture is stirred at room temperature for 30 min, and then added ethyl acetate (50 ml). The mixture was washed with 1N. HCl and water, and then dried with anhydrous sodium sulfate, followed by distillation of the solution is on the product.

1H-NMR (CDCl3) : and 0.98 (3H, s), 2,03, 2,04 (each 3H, s), 3,40 (1H, DD, J= 5,1, to 15.8 Hz), 3,55-to 3.67 (2H, m), the 3.65 (3H, s), 3,82-3,91 (2H, m) to 3.89 (3H, s), Android 4.04 (1H, d, J=11,6 HZ), 4,18 (1H, d, J=11.2 Hz), 4,30 (1H, DD, J= 5,2, and 6.6 Hz), of 4.66 (1H, d, J=14.6 Hz), 6,27 (1H, s), 6,69 (1H, d, J=2.2 Hz), 6,95-7,42 (5H, m).

Working example 20

(3R, 5S)-N-[2-(Pyrrolidin-1-yl)ethyl] -7 - chloro-1-(3-hydroxy-2-hydroxymethyl-3-methylpropyl)-5-(2,3-acid)- 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ndimethylacetamide

< / BR>
(1) To a solution of the compound obtained as described in Working example 5-(3), (0.5 g), and diethylthiophosphate (54 mg) in dimethylformamide (1.5 ml) was added 1-(2-amino-ethyl) pyrrolidine (0.16 g). The mixture is stirred at room temperature for 30 min, and then added ethyl acetate (50 ml). The mixture is washed with water and dried, followed by distillation of the solvent. The residue is purified by column chromatography on silica gel [eluent:ethyl acetate-methanol-triethylamine (10: 1: 0,1) to obtain (3R,5S)-N-[2-(pyridin-1-yl)ethyl] -7-chloro-1-(2,2,5 - trimethyl-1,3-dioxane-5-ylmethyl)-5-(2,3-acid)-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-ndimethylacetamide (0,19 g) as a colorless amorphous solid product.

(2) To a solution of compound obtained in stage (1) (0,19 g) in tetrahydrofuran (2 ml) is added concentrated HCl (1 ml). Polucen is by adding 1N. NaOH. The resulting material is extracted with ethyl acetate, washed with water and dried, whereupon the solvent is distilled off. The residue is purified by column chromatography on silica gel (eluent: ethyl acetate-methanol-triethylamine (2: 1: 0,1)) and obtain 97 mg of a colorless amorphous solid product.

1H-NMR (CDCl3) : of 0.62 (3H, s), 1,75-1,80 (4H, m), 2,50-2,72 (7H, m), 2,87 (1H, DD, J=7,0, of 14.2 Hz), 3,31 is 3.76 (7H, m) and 3.59 (3H, s) to 3.89 (3H, s), of 4.45 (1H, t, J=6.4 Hz), 4.82 (1H, d, J=15,0 Hz), 6,12 (1H, s), 6,35-6,50 (1H, W), 6,62 (1H, s), 6,99-7,37 (5H, m).

Working example 21 (3R,5S)-N-Methylsulphonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3 - acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ndimethylacetamide

< / BR>
The compound obtained as described in Working example 19 (1.2 g), is subjected to reaction according to the method basically described in Working example 19, resulting in a gain of 1.01 g of colorless crystalline product, so pl. 108-112oC.

Elemental analysis for C27H32ClN2O9S:1,5 H2O:

Calculated: C, 51,96; H, of 5.81; N, 4,49

Found: C, 52,01; H, Of 5.82; N, 4,30.

Working example 22

(3R, 5S)-1-(3-Acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3 - acid)-1,2,3,5-tetrahydro-3-[1H(or 3H) tetrazol-5-yl] methyl-4,1-benzoxazepin-2-he

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The connection is received, the 9, resulting in a gain on 25 mg of a colorless amorphous solid product.

1H-NMR (CDCl3) : 0,97 (3H, s), 0,99 (3H, s), is 2.05 (3H, s), 3,3-3,8 (4H, m), the 3.65 (3H, s) to 3.89 (3H, s), of 4.05 (1H, d), 4,28 (1H, DD), to 4.62 (1H, d), 6,27 (1H, s), of 6.68 (1H, d), of 6.9 to 7.4 (5H, m).

Examples of tracks:

Therapeutic agent for the treatment of hyperlipemia that contains as its effective component a compound of the present invention (1) or its salt can be obtained, for example, in accordance with the following recipe:

1. Capsules mg:

(1) Compound of Example 16 - 10

(2) Lactose - 90

(3) Microcrystalline cellulose 70

(4) magnesium Stearate - 10

1 capsule - 180

Mix(1), (2), (3) and one half (4) and the mixture granularit, and then add the rest (4). The mixture is filled gelatin capsules.

2. Tablets mg

(1) Compound of Example 16 - 10

(2) Lactose - 35

(3) Corn starch - 150

(4) Microcrystalline cellulose 30

(5) magnesium Stearate - 5

1 tablet - 230

Mix(1), (2), (3), two-thirds (4) and one half (5), the mixture granularit, and then add the rest of the number of components (4) and (5). The mixture obtained is formed by pressing and get pills.

Experimental Example 1:

Activity, inhibiting stvalentines

Analytical method

Activity, the inhibitory stvalentines analyzed as described below, using solutions of the enzyme obtained by the method described below.

More specifically, a solution of enzyme (protein content of 0.8 μg), obtained by the method described below, are added to a solution (total volume 50 μl) containing 5 μm [1-3H]farnesylpyrophosphate (specific activity 25 µci/mol), 1 mm NADPH (nicotinamid-adenine-dinucleotide-phosphate restored type), 5 mm MgCl2, 6 mm glutathione, 100 mm buffer solution of potassium phosphate (pH 7,4) and the test drug (used as an aqueous solution or a solution of DMSO), and then left for 45 min at 37oC to complete the reaction. For suspension of the reaction mixture, to this reaction mixture is added 150 μl of a mixture of chloroform and methanol (1:2) followed by the addition of 50 μl of chloroform and 50 μl of 3h. hydroxide solution n the main component, and 3 ml of liquid scintillator based on toluene are mixed and determine its radioactivity using a liquid scintillation counter.

Activity, the inhibitory stvalentines, expressed as the concentration, the inhibitory 50% of the radioactivity incorporated in chloroformyl layer (IC50molar concentration (M)), as shown in Table 3.

Receiving enzyme originating from a person

Carcinoma cells human liver HepG2 (about 1 to 109cells) obtained by incubation in modified according to the method of Dulbecco environment Needle (37oC in the presence of 5% CO2) containing 10% fetal bovine serum, suspended in 10 ml ice buffer [100 mm potassium phosphate buffer (pH of 7.4), 30 mm nicotinamide, and 2.5 mm MgCl2]. These cells destroy by ultrasonic treatment (within 30 seconds, twice). Obtained after ultrasonic cell fraction is subjected to centrifugation at 10000 x g for 20 min (4oC). Then a layer of supernatant centrifuged at 105000 within 90 min (4oC). Then the residue suspended in ice 100 mm potassium phosphate buffer (pH of 7.4), and then centrifuged for 90 min (4o

As can be seen from these results, the compounds of the present invention have excellent activity, aimed at the inhibition of stvalentines.

Experimental example 2:

Analysis on the formation of cholesterol in the liver:

Cholesterol biosynthesis in rat liver were analyzed as follows, 6-week fat rat Wistar oral was administered to test the connection [Connection 4-2 (suspended in 0.5% solution of methylcellulose)], and the control group was administered orally with only a 0.5% solution of methylcellulose. After 1 h into the tail vein of rats intravenously injected sodium acetate, radiolabelled14C (supplied by Amersham) (10 µci/0.3 ml saline/rat). After 1 h, rats were killed by decapitation and 1.5 g of the first lobe of the liver was removed, and then was subjected to saponification by immersion in 3.9 ml of alkaline ethanol solution (KOH:EtOH = 1:2) for 2 h at 100oC followed by extraction, which 1, was performed three times with 5 ml each portion of petroleum ether. The extract solution was dried, and then dissolved in 3 ml of ethanol: acetone (1:1). To the resulting solution were added 2 ml of 0.5% is Ali total Sterol, and its radioactivity was measured by liquid scintillation counter. The results are presented in Table 4.

As can be seen from the above results, the compound of the present invention has excellent inhibitory action providing 80% or more inhibition of cholesterol formation.

Industrial application

Compounds of the present invention have activity of inhibiting stvalentines, activity, lower cholesterol, and activity, reduce triglyceride levels, and therefore these compounds can be used as a preventive and therapeutic agent for the treatment of hyperlipemia and as a means of reducing the concentration of lipids, and in addition, they can also be used for prevention and treatment, such as arteriosclerosis.

1. Derivatives 4,1-benzoxazepin-2-she formulas (I)

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where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group;

R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup;

(CH2)m-E-(R6)n-, where m and n = 1 or 2 independently from each other, E is a bond or oxygen atom, -NR5-, -CONR7-, where R5- methylsulphonyl, R6and R7independently of one another (i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl; (iii) benzyl;

Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine;

the ring And is substituted by 1-3 substituents selected from the group consisting of halogen atoms,

or their salts.

2. Connection on p. 1, where R1lower alkyl group substituted with one hydroxyl group which may be substituted; R2and R3is a hydrogen atom or phenyl group, substituted C1C4alkoxygroup, and R2and R3are the same or different; X is a methylene group; Y - carnemolla group which may be substituted, or piperidino-carbonyl group which may be substituted; the ring And the benzene ring, substituted by a halogen atom, or its salt.

3. Connection on p. 1 f the ilen group, substituted acetyl group;

Ra- C1-C4alkoxygroup;

Y - carnemolla group which may be substituted for CH3SO2or piperidino-carbonyl group which may be substituted;

Z is a halogen atom,

or its salt.

4. Connection on p. 1 formula

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where R1- C1-C7alkyl group which is substituted by a hydroxyl group or a hydroxyl group, a substituted acetyl group;

Y - carnemolla group which may be substituted for CH3SO2or piperidino-carbonyl group which is substituted by a hydroxyl group and/or a group-CH2Rb(where Rbis a hydrogen atom, methyl group or ethyl group),

or its salt.

5. (3R,5S)-N-Methylsulphonyl-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ndimethylacetamide formula

< / BR>
or its salt.

6. N-[(3R, 5S)-1-(3-Acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] piperidine-4-acetic acid formula

< / BR>
or its salt.

 

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where X is O,

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R1indicatesor< / BR>
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