RU2170732C2 - Derivatives of 4,1-benzoxazepine - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy. SUBSTANCE: invention relates to novel derivatives of 4,1-benzoxazepine-2-one of the formula (I)

where R¹ is lower alkyl substituted at least with one optionally substituted hydroxyl group; R² and R³ mean independently each of other hydrogen atom or phenyl that is substituted with 1-3 substitutes taken among the group including lower C₁-C₄- alkoxy-groups; X means a bond, methylene group or binding group with chain length 1-7 atoms taken among the group including -(CH₂)_m-E-(CHR₆)_n- where m and n mean independently each of other 1 or 2; E is a bond or oxygen atom, -NR₅-, -CONR₇- where R₅ means methylsulfonyl-group; R₆ and R₇ mean independently each of other: (i) hydrogen atom; (ii) unsubstituted lower alkyl or lower alkyl substituted with substitutes taken among the group including piperidine, indolyl and possibly esterified carboxy-groups; (iii) benzyl; Y means optionally substituted carbamoyl and/or substitutes at N-atom of carbamoyl group taken in common they form a ring that can be substituted, or tetrazolyl, or piperidine, and ring A is substituted with 1-3 substituted taken among the group including halogen atoms, or their salts. Invention relates to also two particular compounds. Compounds show inhibitory effect on activity of squalene synthetase and antifungal effects. Invention can be used in treatment of patients with hyperlipemia and arteriosclerosis. EFFECT: new compounds indicated above, valuable medicinal properties. 6 cl, 8 tbl, 22 ex

Description

 The invention relates to derivatives of 4,1-benzoxazepin-2-one or their salts, which are useful for inhibiting squalene synthetase and fungal growth, and to their use.

 Hypercholesterolemia, high blood pressure, and smoking are the three main known factors that cause ischemic diseases. Adequate control of blood cholesterol concentration is crucial for the prevention or treatment of coronary sclerosis, in addition to coronary disease.

 As pharmaceutical compositions for lowering blood cholesterol, attention was paid to compositions for controlling cholesterol biosynthesis along with those that inhibit its absorption by binding of bile acid, including, among others, cholesterol, colestipol (described, for example, in US patent N 4027009 ), and those that suppress intestinal absorption of cholesterol by inhibiting the enzyme A, the cholesterol acyltransferase (ACAT), including melinamide (described in French patent N 1476569). As pharmaceuticals for controlling cholesterol biosynthesis for medical use, lovastatin (described in US Pat. No. 4,231,938), simvastatin (described in US Pat. No. 4,444,784), pravastatin (US Pat. No. 4,346,227), etc., which are capable of inhibiting especially 3 -oxy-3-methylglutaryl coenzyme (HMG-CoA) reductase. However, when inhibiting HMG-CoA reductase, not only cholesterol biosynthesis is inhibited, 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 unwanted side effects resulting from it. Squalene synthetase is an enzyme involved in a fixed stage of the newly biosynthetic cholesterol pathway. This enzyme catalyzes the reductive dimerization of two famezylpyrophosphate molecules into squalene.

 On the other hand, the compounds proposed as inhibitors of cholesterol biosynthesis in the inhibition of squalene synthetase are 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 No. 5,019,390, Journal of Medicinal Chemistry, 51 (10), pp. 1369-1871 (1988), U.S. Patent N 5135935 and WO 9215579.

 Also, the compounds proposed as fungal growth inhibitors for the inhibition of squalene synthetase are described in JPA H4 (1992) - 279589, EP 475706-A, EP 494622-A and EP 503520-A.

 Among the derivatives of 4,1-benzoxazepine, derivatives of 4,1-benzoxazepin-2-one in which the 2-position is substituted by a keto group, those in which one of the hydrogen atoms in the 3-position is substituted by another substituent are described in JPA 557 (1982 ) - 345765 and in Chem. Pharm. Bull., 34, 140 (1986).

 It is known that ubiquinone, dolichol and heme A are synthesized from farnesyl pyrophosphate along the pathway of cholesterol biosynthesis. Therefore, in order to avoid side effects due to the absence of these substances, it is desirable to inhibit enzymes after farnesyl pyrophosphate, especially squalene synthetase, in the pathway of cholesterol biosynthesis.

 After intensive studies from the above point of view, the present inventors have found that the derivatives of 4,1-benzoxazepin-2-one have an excellent squalene synthetase inhibitory effect and antifungal action, and developed the present invention.

в которой R¹ - низший алкил, замещенный по крайней мере одной необязательно замещенной гидроксильной группой;
R² и R³ независимо друг от друга означают: (i) водород, (ii) низший алкил, (iii) фенил, который не замещен или замещен 1-3 заместителями, выбранными из группы, содержащей 1) атомы галогенов, 2) низшие C₁-C₄ алкилы, 3) низшие C₁-C₄ алкоксигруппы, 4) гидроксигруппу, где группа 2) не замещена или замещена 1-3 атомами галогенов, группа 4) не замещена или замещена заместителями, выбранными из группы, содержащей низшие C₁-C₄ алкилы и бензил; и два соседних заместителя на фенильной группе могут вместе образовывать кольцо, или (iv) пиридил;
X - связь или связывающая группа с длиной цепи 1-7 атомов, выбранная из группы, содержащей -(CH₂)_m-E-(CHR₆)_n-, где m и n обозначают, независимо друг от друга, 0, 1, 2 или 3, E - связь или атом кислорода, атом серы, сульфоксид, сульфон, - NR₅-, -NHCO-, -CONR₇- или -NHCONH-, где R₅ - водород, низший алкил, метилсульфонил, 4-метилбензолсульфонил или ацил, R₆ и R₇ независимо друг от друга означают (i) водород, (ii) низший алкил, который не замещен или замещен заместителями, выбранными из группы, содержащей гетероциклическую группу, выбранную из группы, содержащей 1) индолил, 2) гидроксигруппу, 3) возможно этерифицированные карбоксигруппы и 4) фенил, (iii) бензил; (iv) фенил;
Y представляет необязательно замещенный карбамоил и/или заместители на атоме N карбамоила, взятые вместе, образуют кольцо, которое может быть замещено, или азотсодержащую гетероциклическую группу; и
кольцо A не замещено или замещено 1-3 заместителями, выбранными из группы, содержащей 1) атомы галогенов, 2) низшие C₁-C₄ алкилы и 3) низшие C₁-C₄ алкоксигруппы; в которой группа 2) не замещена или замещена 1-3 атомами галогена, и эти заместители могут образовывать кольцо с каждым из соседних заместителей или их соли.Therefore, the present invention provides:
(1) Derivatives of 4,1-benzoxazepin-2-one of the general formula (I)

in which R ¹ is lower alkyl substituted by at least one optionally substituted hydroxyl group;
R ² and R ³ independently from each other mean: (i) hydrogen, (ii) lower alkyl, (iii) phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of 1) halogen atoms, 2) lower C ₁ -C ₄ alkyls, 3) lower C ₁ -C ₄ alkoxy groups, 4) hydroxy group, where group 2) is unsubstituted or substituted by 1-3 halogen atoms, group 4) is unsubstituted or substituted by substituents selected from the group consisting of lower C ₁ -C ₄ alkyls and benzyl; and two adjacent substituents on the phenyl group may together form a ring, or (iv) pyridyl;
X is a bond or a linking group with a chain length of 1-7 atoms selected from the group consisting of - (CH ₂ ) _m -E- (CHR ₆ ) _n -, where m and n are, independently of each other, 0, 1, 2 or 3, E is a bond or an oxygen atom, a sulfur atom, sulfoxide, sulfone, - NR ₅ -, -NHCO-, -CONR ₇ - or -NHCONH-, where R ₅ is hydrogen, lower alkyl, methylsulfonyl, 4-methylbenzenesulfonyl or acyl, R ₆ and R ₇ independently of one another mean (i) hydrogen, (ii) lower alkyl, which is unsubstituted or substituted by substituents selected from the group consisting of a heterocyclic group selected from the group consisting of 1) indolyl, 2) hydrox and a group, 3) optionally esterified carboxy groups and 4) phenyl, (iii) benzyl; (iv) phenyl;
Y represents an optionally substituted carbamoyl and / or substituents on the carbamoyl N atom, taken together, form a ring which may be substituted, or a nitrogen-containing heterocyclic group; and
ring A is unsubstituted or substituted by 1-3 substituents selected from the group consisting of 1) halogen atoms, 2) lower C ₁ -C ₄ alkyls and 3) lower C ₁ -C ₄ alkoxy groups; in which group 2) is unsubstituted or substituted by 1-3 halogen atoms, and these substituents can form a ring with each of the adjacent substituents or their salts.

Preferably, in the compounds of formula I and their salts, R ¹ represents a lower alkyl group substituted with one hydroxyl group which may be substituted;
R ² , R ³ is a hydrogen atom or a phenyl group substituted with a C ₁ -C ₄ alkoxy group, wherein R ² and R ³ are the same or different;
X represents a methylene group;
Y is a carbamoyl group which may be substituted; ring A represents a benzene ring substituted by a halogen atom.

где R¹ представляет низшую алкильную группу, которая замещена гидроксильной группой или гидроксильной группой, замещенной ацетильной группой;
R_a - C₄-C₄ алкоксигруппа;
Y - карбамоильная группа, которая может быть замещена CH₃SO₂, или пиперидино-карбонильная группа, которая может быть замещена;
Z представляет атом галогена; и их соли;
а также соединения формулы

где R¹ представляет C₁-C₇ алкильную группу, которая замещена гидроксильной группой или гидроксильной группой, замещенной ацетильной группой;
Y представляет карбамоильную группу, которая может быть замещена CH₃SO₂ или пиперидино-карбонильную группу, которая замещена гидроксильной группой и/или группой -CH₂-COOR_b (где R_b - атом водорода, метильная группа или этильная группа), и их соли.Among these derivatives of 4,1-benzoxazepine and their salts, preferred compounds of the formula

where R ¹ represents a lower alkyl group which is substituted by a hydroxyl group or a hydroxyl group substituted by an acetyl group;
R _a is a C ₄ -C ₄ alkoxy group;
Y is a carbamoyl group which may be substituted with CH ₃ SO ₂ , or a piperidino-carbonyl group which may be substituted;
Z represents a halogen atom; and their salts;
as well as compounds of the formula

where R ¹ represents a C ₁ -C ₇ alkyl group which is substituted by a hydroxyl group or a hydroxyl group substituted by an acetyl group;
Y represents a carbamoyl group which may be substituted by CH ₃ SO ₂ or a piperidino-carbonyl group which is substituted by a hydroxyl group and / or a group —CH ₂ —COOR _b (where R _b is a hydrogen atom, methyl group or ethyl group), and salt.

и его соли,
и N-[(3R, 5S)-1-(3-ацетокси-2,2-диметилпропил)-7-хлор-5-(2,3- диметоксифенил)2-оксо-1,2,3,5-тетрагидро-4,1-бензоксазепин-3-ацетил] пиперидин- 4-уксусная кислота формулы:

и ее соли.Of particular interest are:
(3R, 5S) -N-methylsulfonyl-7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5- tetrahydro-4,1-benzoxazepine-3-acetamide of the formula

and its salts,
and N - [(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) 2-oxo-1,2,3,5-tetrahydro -4,1-benzoxazepine-3-acetyl] piperidine-4-acetic acid of the formula:

and its salts.

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

где каждый из символов имеет значения, определенные выше, или их фармацевтически приемлемых солей, заключающийся в реакции циклизации соединения, представленного формулой:

где W означает

где R₈ - галоген (например фтор, хлор, бром и йод) или группа -OSO₃CH₃, а другие символы имеют значения, указанные выше.A method of obtaining derivatives of 4,1-benzoxazepine represented by formula (I)

where each of the symbols has the meanings defined above, or their pharmaceutically acceptable salts, consisting in the cyclization reaction of the compounds represented by the formula:

where w means

where R ₈ is halogen (e.g. fluorine, chlorine, bromine and iodine) or the group —OSO ₃ CH ₃ , and other symbols have the meanings indicated above.

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

 The specified compound (I) can be administered to a person orally or non-orally. Orally administered compositions may be in solid or liquid form, more particularly in the form of tablets (including sugar-coated tablets and film-coated tablets), syrups, emulsions, suspensions, or the like. These compositions can be prepared by methods known in general and contain carriers or excipients commonly used for pharmaceutical preparations, for example, carriers or excipients such as lactose, starch, sucrose or magnesium stearate, in the manufacture of tablets.

 Examples of compositions for non-oral administration are injectable preparations and suppositories, and injections include hypodermic injections, intradermal injections, intramuscular injections. These injectable preparations may be prepared by methods generally known in the art, more specifically, by suspending or emulsifying a compound of the present invention in sterile water or oil commonly used for the preparation of injectable compositions. Aqueous liquids used for the preparation of injectable preparations include physiological saline and isotonic saline and, if necessary, a suitable suspending agent, such as sodium carboxymethyl cellulose, nonionic surfactant or the like, can also be used. Sesame oil, soybean oil, etc. can be used as oil. and benzyl benzoate, benzyl alcohol and the like. can be used as a solubilizer. Thus prepared preparations for injection are usually poured into appropriate ampoules.

 The compound of formula (I) or a salt thereof can be safely used with low toxicity. Although the daily dose varies depending on the condition and weight of the patient, the type of compound, route of administration and other factors, for example, in the case of administration of a compound of the present invention for the treatment of hypercholesterolemia, the daily oral dose for an adult is about 1-500 mg, preferably about 10 -200 mg. No toxicity was observed at all in this interval.

 The compounds of formula (I) as squalene synthetase inhibitors are effectively used in mammals, for example humans, in a therapeutically effective amount, which is usually provided by an oral daily dose for an adult of from about 1 to about 500 mg, preferably about 10-200 mg. In case of non-oral administration (for example, by injection or suppository), the therapeutically effective amount of the daily dose is from about 0.1 to about 100 mg, preferably about 1-20 mg.

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

 In the case of the administration of a compound of the present invention, 2-5 mg / kg as a unit dose for antifungal treatment is usually used to treat fungal infections.

 The compounds of formula (I) for antifungal treatment are effectively applied to a mammal, for example a human, in a therapeutically effective amount, which is usually provided by an oral daily dose for an adult of from about 0.1 to about 100 mg, preferably about 1-50 mg. For non-oral use, such as injections or suppositories, the therapeutically effective daily dose is about 0.1-100 mg, preferably about 1-50 mg.

 In the following description, two types of racemic diastereoisomers are obtained depending on the type of compounds which are obtained due to the presence of an asymmetric carbon atom in the 3rd and 5th positions. Isomers in which the substituents in the 3rd and 5th positions are oriented in the same direction with respect to the plane of the 7-membered ring are called cis-isomers, while those in which the substituents in the 3rd and 5th positions are oriented in opposite directions to each other are called trans-isomers.

BEST MODE FOR CARRYING OUT THE INVENTION
The following working examples, examples of compositions and experimental examples are provided only to illustrate the present invention in more detail and should not be construed as limiting the invention.

К раствору (3R,5S)-7-хлор-5-(2,3-диметоксифенил)-1- неопентил-2-оксо-1,2,3,5-тетрагидро-4,1-бензоксазепин-3-уксусной кислоты (0,5 г) и 0,25 г гидрохлорида сложного метилового сложного эфира пиперидин-4-карбоновой кислоты в диметилформамиде (10 мл) добавляют при комнатной температуре диэтилцианофосфонат (0,28 г) и триэтиламин (0,38 мл) и смесь перемешивают в течение 1 ч. К смеси добавляют воду (100 мл) и этилацетат (100 мл). Органический слой промывают 1н. HCl и насыщенным водным раствором бикарбоната натрия, после чего сушат водным сульфатом магния. Растворитель отгоняют и остаток очищают с помощью колоночной хроматографии на силикагеле (элюенты:гексан: этилацетат = 1:1) (об/об) с получением 0,62 г бесцветного кристаллического продукта, т.пл. 124-126^oC.[Examples]
Reference Example 1
N - [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine methyl ester 3-acetyl] piperidine-4-carboxylic acid

To a solution of (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) and 0.25 g of piperidine-4-carboxylic acid methyl ester hydrochloride in dimethylformamide (10 ml) were added diethyl cyanophosphonate (0.28 g) and triethylamine (0.38 ml) at room temperature and the mixture was stirred within 1 h. Water (100 ml) and ethyl acetate (100 ml) were added to the mixture. The organic layer was washed with 1N. HCl and a saturated aqueous solution of sodium bicarbonate, after which it is dried with aqueous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (eluents: hexane: ethyl acetate = 1: 1) (v / v) to obtain 0.62 g of a colorless crystalline product, mp. 124-126 ^o C.

Elemental analysis for C ₃₁ H ₃₉ ClN ₂ O ₇ • 0.3H ₂ O:
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 mainly described in Example 1.

Соединение N 2-38,
Y

,
т. пл. (^oC) 150-151.

Compound N 2-38,
Y

,
t. pl. ( ^o C) 150-151.

Соединение (0,5 г), полученное, как описано в Ссылочном примере 1, растворяют в смеси 1н. водного раствора гидроксида натрия (4 мл), метанола (10 мл) и тетрагидрофурана (5 мл). Раствор перемешивают в течение 1 ч при комнатной температуре, а затем добавляют 1н. HCl (50 мл) и этилацетат (100 мл). Органический слой промывают водой и сушат безводным сульфатом магния. Растворитель удаляют и остаток перекристаллизовывают из гексана-диэтилового эфира с получением 0,47 г бесцветных кристаллов, т.пл. 145-147^oC.Reference Example 2
N - [(3R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl ] piperidine-4-carboxylic acid

The compound (0.5 g) obtained as described in Reference Example 1 was dissolved in a 1N mixture. an aqueous solution of sodium hydroxide (4 ml), methanol (10 ml) and tetrahydrofuran (5 ml). The solution was stirred for 1 h at room temperature, and then 1N was added. HCl (50 ml) and ethyl acetate (100 ml). The organic layer was washed with water and dried with anhydrous magnesium sulfate. The solvent is removed and the residue is recrystallized from hexane-diethyl ether to obtain 0.47 g of colorless crystals, so pl. 145-147 ^o C.

Elemental analysis for C ₃₀ H ₃₇ ClN ₂ O ₇ • 0.3H ₂ O:
Calculated: C 62.29; H 6.55; N 4.84
Found: C, 62.20; H 6.65; N, 4.83.

К раствору (3R,5S)-7-хлор-5-(2,3-диметоксифенил)-1- неопентил-2-оксо-1,2,3,5-тетрагидро-4,1-бензоксазепин-3-уксусной кислоты (0,5 г) и п-толуолсульфонамида (0,22 г) в дихлорметане добавляют 1-этил-3-(3'-диметиламинопропил) карбодиимид (0,27 г) и диметиламинопиридин (20 мг). Смесь перемешивают в течение 3 ч при комнатной температуре и концентрируют при пониженном давлении. Концентрат растворяют в этилацетате (100 мл). Раствор промывают водой и сушат, а затем растворитель отгоняют. Остаток очищают с помощью колоночной хроматографии на силикагеле (элюенты: дихлорметан: метанол: вода = 200: 10: 1 (об/об) с получением 0,6 г бесцветных кристаллов, т.пл. 110-113^oC.Reference Example 3
N-Toluenesulfonyl- (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- acetylamide

To a solution of (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) and p-toluenesulfonamide (0.22 g) in dichloromethane add 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide (0.27 g) and dimethylaminopyridine (20 mg). The mixture was stirred for 3 hours at room temperature and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (100 ml). The solution was washed with water and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluents: dichloromethane: methanol: water = 200: 10: 1 (v / v) to obtain 0.6 g of colorless crystals, mp 110-113 ^° C.

Elemental analysis for C ₃₁ H ₅₅ ClN ₂ O ₇ S • H ₂ O:
Calculated: C 58.81; H 5.89; N, 4.42
Found: C, 58.73; H 5.73; N 4.62.

К раствору соединения (1,0 г), полученного, как описано в Ссылочном примере 1, в дихлорметане (5 мл), добавляют триметилсилилбромид (0,38 г). Смесь перемешивают в течение ночи при комнатной температуре и добавляют этилацетат. Эту смесь промывают 0,5 н. водным раствором гидроксида натрия, насыщенным водным раствором хлорида аммония и воды, а затем сушат безводным сульфатом натрия. Растворитель отгоняют и остаток перекристаллизовывают из смеси этанола и диэтилового эфира (1:10) с получением 0,41 г бесцветных кристаллов, т.пл. 152-155^oC.Reference Example 4 (3R, 5S) -N-phosphonomethyl-7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine -3-acetamide

To a solution of the compound (1.0 g) obtained as described in Reference Example 1 in dichloromethane (5 ml), trimethylsilyl bromide (0.38 g) was added. The mixture was stirred overnight at room temperature and ethyl acetate was added. This mixture is washed with 0.5 N. an aqueous solution of sodium hydroxide, a saturated aqueous solution of 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 0.41 g of colorless crystals, so pl. 152-155 ^o C.

Elemental analysis for C ₂₅ H ₃₂ ClH ₂ O ₇ P • 1.7H ₂ O:
Calculated: C 51.28; H 6.09; N 4.78
Found: C, 51.20; H 6.11; N, 4.77.

(1) Диметилформамидный раствор (3R,5S)-7-хлор-5-(2,3- диметоксифенил)-1-неопентил-2-оксо-1,2,3,5-тетрагидро-4,1- бензоксазепин-3-уксусной кислоты (2,0 г), хлорида аммония (1,2 г) и триэтиламина (1,0 мл) охлаждают в ледяной бане. К раствору добавляют диэтилцианофосфонат (0,85 г) и триэтиламин (0,5 мл). Смесь перемешивают еще 20 мин, добавляют воду со льдом и экстрагируют этилацетатом. Органический слой промывают водой и сушат безводным сульфатом магния.Reference Example 5
(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-1,2,3,5-tetrahydro-3- (1H (or 3H) -tetrazol-5-yl) - methyl 4,1-benzoxazepin-2-one

(1) Dimethylformamide solution (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3 -acetic acid (2.0 g), ammonium chloride (1.2 g) and triethylamine (1.0 ml) are cooled in an ice bath. Diethyl cyanophosphonate (0.85 g) and triethylamine (0.5 ml) were added to the solution. The mixture was stirred for another 20 minutes, ice water was added and extracted with ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate.

The solvent is distilled off and the residue is recrystallized from diethyl ether to obtain 1.0 g of (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2,3,5- tetrahydro-4,1-benzoxazepine-3-acetamide in the form of colorless crystals, so pl. 170-172 ^o C.

(2) The compound (3.2 g) obtained in stage (1) and thionyl chloride (1.8 ml) are suspended in toluene (40 ml). The resulting suspension was stirred for 1 hour at 110-120 ^° C. The solvent was removed. Ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml) were added to the residue. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluents: hexane: ethyl acetate = 3: 1) (v / v) to obtain 1.7 g (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) - 1-neopentyl-1,2,3,5-tetrahydro-3-cyanomethyl-4,1-benzoxazepin-2-one in the form of colorless crystals, mp. 193-194 ^o C.

(3) To a solution of the compound (1.7 g) obtained in step (2) in toluene (20 ml), trimethylsilyl azide (0.45 g) and dibutyltin (IV) oxide (30 mg) were added. The mixture was stirred for 24 hours at 110-120 ^° C. The reaction mixture was concentrated, diethyl ether (20 ml) was added and then washed with an aqueous solution of sodium hydroxide. The aqueous layer is acidified with 1N. HCl and extracted with ethyl acetate. The organic layer was 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 colorless crystals, so pl. 148-150 ^o C.

Elemental analysis for C ₂₄ H ₃₈ ClN ₅ O ₄ • 0.5H ₂ O:
Calculated: C 58.24; H 5.91; N, 14.15
Found: C, 58.43; H 6.18; N, 13.76.

(1) К раствору (3)-4-хлор-2-[ α- -гидрокси-[2,3- диметоксифенил)метил] анилина (2,0 г) и бикарбоната натрия (0,86 г) в этилацетате (20 мл) по каплям добавляют раствор сложного моноэтилового эфира хлорида диметилмалоновой кислоты (1,3 г) в этилацетате (20 мл). Смесь перемешивают в течение 3 ч при охлаждении льдом. К раствору добавляют воду (30 мл) и органический слой сушат безводным сульфатом натрия. Растворитель отгоняют и остаток очищают с помощью колоночной хроматографии на силикагеле с получением сложного этилового эфира (S)-2-[N-(2-(2,3-диметокси -α- гидроксибензил)-4- хлорфенил] карбамоил] -2,2-диметилуксусной кислоты (2,92 г) в виде бесцветного маслянистого соединения.Working example 1
(3R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -1,2,3,5-tetrahydro-3- [1H- ( or 3H) -tetrazol-5-yl] methyl-4,1-benzoxazepin-2-one

(1) To a solution of (3) -4-chloro-2- [α--hydroxy- [2,3-dimethoxyphenyl) methyl] aniline (2.0 g) and sodium bicarbonate (0.86 g) in ethyl acetate (20 ml) a solution of dimethylmalonic acid chloride monoethyl ester (1.3 g) in ethyl acetate (20 ml) was added dropwise. The mixture was stirred for 3 hours while cooling with ice. Water (30 ml) was added to the solution, and the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain (S) -2- [N- (2- (2,3-dimethoxy-α-hydroxybenzyl) -4-chlorophenyl] carbamoyl] -2,2 ethyl ester -dimethylacetic acid (2.92 g) as a colorless oily compound.

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.4 Hz), 1.37 (3H, s), 1.42 (3H, s), 3.84 (3H, s), 3.89 (3H, s), 4.05-4.19 (3H, m), 6.01 (1H, s), 6.61 (1H, d, J = 1.8, 7, 4 Hz), 6.90-7.05 (3H, m), 7.28 (1H, d, J = 3.0, 8.8 Hz), 8.07 (1H, d, J = 8.4 Hz), 9.49 (1H, broad).

 (2) To a solution of the compound (2.83 g) obtained in step (1) in tetrahydrofuran (30 ml), lithium aluminum hydride (0.5 g) was added under ice-cooling. The mixture was stirred for 3 hours at room temperature. 1N was added to the reaction mixture. an aqueous solution of sodium hydroxide (13 ml) and water (50 ml), and then insoluble matter is filtered off. The filtrate was extracted with ethyl acetate. The extract was washed with water and dried, after which the solvent was distilled off. The residue was purified by silica gel column chromatography (eluents: hexane: ethyl acetate = 1: 1 (v / v) to obtain (S) - [5-chloro-2- (2,2-dimethyl-3-hydroxypropyl) aminophenyl] ( 2,3-dimethoxyphenyl) methanol (0.88 g) as a colorless oily compound.

¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, s), 0.93 (3H, s), 2.95 (2H, s), 3.37 (2H, s), 3.83 ( 3H, s), 3.88 (3H, s), 5.99 (1H, s), 6.63 (1H, d, J = 8.8 Hz), 6.77 (1H, dd, J = 1 6, 7.6 Hz), 6.90 (1H, dd, J = 1.6, 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 the compound (0.88 g) obtained in (2) in ethyl acetate (10 ml), sodium bicarbonate (0.39 g) was added. To the mixture was added a solution of fumaric acid chloride monoethyl ester (0.45 g) in ethyl acetate (10 ml) and stirred for 30 minutes at room temperature. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was dissolved in ethanol (10 ml), to which potassium carbonate (0.70 g) was added. The resulting mixture was stirred overnight at room temperature. Ethyl acetate (50 ml) was added to the reaction mixture, and then washed with water and dried. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-hexane to obtain (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethyl-3-hydroxypropyl) -2- ethyl ester oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.57 g) as colorless crystals, mp. 188-190 ^o C.

(4) The compound (0.5 g) obtained in step (3) is dissolved in a mixture of tetrahydrofuran (5 ml) and ethanol (3 ml). 1N was added to the solution. an aqueous solution of sodium hydroxide (1 ml), and then stirred for 20 minutes at 60 ^° C. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was recrystallized from ethyl acetate-hexane to give (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethoxypropyl) -2-oxo-1,2, 3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.33 g) as colorless crystals, mp. 199-202 ^o C.

(5) To a solution of the compound (2 g) obtained in step (4) and 3-aminopropionitrile (0.29 g) in dimethylformamide (20 ml), diethyl cyanophosphonate (0.75 g) and triethylamine ( 0.51 g). The mixture was stirred for 30 minutes and then ethyl acetate (100 ml) was added. The mixture is washed with water and dried. The solvent is distilled off and the residue is recrystallized from hexane to give 3 - [[(3R, 5S) -7-chloro (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1 , 2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl] amino] propionitrile (2.25 g) as colorless crystals, mp. 118-121 ^o C.

 (6) The compound (2 g) obtained in step (5) and acetic anhydride (0.39 g) are dissolved in pyridine (20 ml). Dimethylaminopyridine (0.1 g) was added to the solution, and the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with 1N. HCl and water, and then dried with anhydrous magnesium sulfate. The solvent was distilled off to obtain 3 - [(3R, 5S) -1- (3-acetyloxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3 , 5-tetrahydro-4,1-benzoxazepine-3-acetyl] aminopropionitrile (2.2 g) as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.01 (3H, s), 2.03 (3H, s), 2.55-2.71 (2H, m), 2.92 (1H, d, J = 8.0, 14.4 Hz), 3.41-3.59 (3H, m), 3.62 (3H, s), 3.72 (1H, d, J = 11.2 Hz), 3.86 (1H, d, J = 11.2 Hz), 3.90 (3H, s), 4.33 (1H, dd, J = 5.0, 8.0 Hz), 4.56 (1H, d, J = 14.2 Hz), 6.26 (1H, s), 6.50-6.60 (1H, br.), 6.64 (1H, s) 6.97-7.38 (5H, m).

(7) A solution of the compound (2.2 g) obtained in step (6), triphenylphosphine (2.0 g), diethyl azidocarboxylate (0.87 g) and triethylsilyl azide (1.3 g) in tetrahydrofuran (10 ml) is stirred in for 2 hours at 60 ^° C. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluents: hexane: ethyl acetate = 1: 1 (v / v)) to obtain (3R, 5S) -7-chloro-3- [1- (2-cyanoethyl) -1H-tetrazole -5-yl] methyl-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethyl-3-hydroxypropyl) -1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one in the form of a colorless oily compound. This compound was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml) and 1N was added. aqueous sodium hydroxide solution (8 ml). The mixture was stirred for one hour at 60 ^° C. Water (50 ml) was added to the reaction mixture, acidified with 1N. HCl and extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was recrystallized from ethyl acetate-hexane to give 0.96 g of colorless crystals, mp. 158-160 ^o C.

Elemental analysis for C ₂₄ H ₂₈ HClN ₃ O ₅ :
Calculated: C 57.43; H 5.62; N 13.95
Found: C, 57.55; H 5.58; N 13.75.

Working example 2
The compound obtained as described in Example 1- (4) is subjected to a reaction according to the procedure generally described in Reference Example 1, and the compounds shown in Table 1 are obtained.

Working example 3
The compound obtained as described in Example 2 is reacted according to the procedure essentially described in Reference Example 2 to give the compounds shown in Table 2.

Используя соединение, полученное, как описано в Рабочем примере 1 (4) (0,4 г), и метансульфонамид (0,1 г), проводят реакцию по методике, в основном описанной в Рабочем примере 14, и получают 0,075 г бесцветного кристаллического продукта, т.пл. 221-223^oC.Working example 4
(3R, 5S) -N-Methylsulfonyl-7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethoxypropyl) -2-oxo-1,2,3,5- tetrahydro-4,1-benzoxazepine-3-acetamide

Using the compound obtained as described in Working Example 1 (4) (0.4 g) and methanesulfonamide (0.1 g), the reaction is carried out according to the procedure mainly described in Working Example 14, and 0.075 g of a colorless crystalline product is obtained. , mp 221-223 ^o C.

Elemental analysis for C ₂₅ H ₃₁ ClN ₂ O ₅ S:
Calculated: C 54.10; H 5.63; N 5.05
Found: C, 54.30; H 5.69; N, 4.87.

(1) К раствору оксалилхлорида (2,2 мл) в дихлорметане (120 мл) при -78^oC по каплям добавляют раствор диметилсульфоксида (2,4 мл) в дихлорметане (20 мл). Смесь перемешивают при -78^oC в течение 10 мин, а затем добавляют раствор 5-(гидроксиметил)-2,2,5-триметил-1,3-диоксана (2 г) в дихлорметане (40 мл). Смесь перемешивают при -78^oC еще 15 мин. К этому раствору добавляют триэтиламин (13,2 мл). Смесь нагревают вплоть до 0^oC и добавляют насыщенный водный раствор хлорида аммония (40 мл). Органический слой промывают водой и сушат безводным сульфатом натрия с последующей отгонкой растворителя. Остаток очищают с помощью колоночной хроматографии на силикагеле [элюенты: гексан: этилацетат (3: 1)] с получением 2 г альдегида в виде бесцветного маслянистого соединения. К метаноловому раствору этого альдегида (2 г) добавляют (S)-4-хлор-2-[ α- гидрокси-(2,3- диметоксифенил)метил]анилин (3,3 г) и уксусную кислоту (0,75 г). Смесь перемешивают при комнатной температуре в течение 10 мин, а затем добавляют цианоборогидрид натрия (0,8 г). Смесь перемешивают в течение ночи при 60^oC, добавляют воду и экстрагируют этилацетатом. Экстракт последовательно промывают водным 1 н раствором гидроксида натрия и водой, после чего сушат безводным сульфатом натрия. Растворитель отгоняют и остаток очищают с помощью колоночной хроматографии на силикагеле [элюенты: гексан-этилацетат (2:1)], в результате чего получают 3,7 г (S)-[2-(2,2,5-триметил-1,3-диоксан-5-илметил)-амино-5-хлорфенил] (2,3- диметоксифенил)метанола в виде бесцветного маслянистого соединения.Working example 5
(3R, 5S) -N-Methylsulfonyl-7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl) -2-oxo-1,2,3, 5-tetrahydro-4,1-benzoxazepine-3-acetamide

(1) A solution of dimethyl sulfoxide (2.4 ml) in dichloromethane (20 ml) was added dropwise to a solution of oxalyl chloride (2.2 ml) in dichloromethane (120 ml) at -78 ^° C. The mixture was stirred at -78 ^° C for 10 minutes, and then a solution of 5- (hydroxymethyl) -2,2,5-trimethyl-1,3-dioxane (2 g) in dichloromethane (40 ml) was added. The mixture was stirred at -78 ^° C for another 15 minutes. Triethylamine (13.2 ml) was added to this solution. The mixture was heated to 0 ^° C. and a saturated aqueous solution of ammonium chloride (40 ml) was added. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue was purified by silica gel column chromatography [eluents: hexane: ethyl acetate (3: 1)] to obtain 2 g of the aldehyde as a colorless oily compound. To the methanol solution of this aldehyde (2 g) is added (S) -4-chloro-2- [α-hydroxy- (2,3-dimethoxyphenyl) methyl] aniline (3.3 g) and acetic acid (0.75 g) . The mixture was stirred at room temperature for 10 minutes, and then sodium cyanoborohydride (0.8 g) was added. The mixture was stirred overnight at 60 ^° C., water was added and extracted with ethyl acetate. The extract was washed successively with an aqueous 1 N sodium hydroxide solution and water, after which it was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography [eluents: hexane-ethyl acetate (2: 1)], whereby 3.7 g of (S) - [2- (2,2,5-trimethyl-1, 3-dioxan-5-ylmethyl) amino-5-chlorophenyl] (2,3-dimethoxyphenyl) methanol as a colorless oily compound.

¹ H-NMR (CDCl ₃ ) δ, 81 (3H, s), 1.38-1.45 (6H, m), 3.22 (2H, s), 3.30-3.40 (1H, broad), 3.60 (4H, s), 3.83 (3H, s), 3.89 (3H, s), 4.90-5.00 (4H, broad), 5.97 (1H c), 6.71-7.27 (6H, m).

(2) To a solution of the compound obtained in step (1) (3.7 g) in ethyl acetate (40 ml), sodium bicarbonate (1.78 g) was added. To the mixture at 0 ^° C. was added monoethyl ester of fumaric acid chloride (1.41 g). The mixture was stirred at room temperature for 30 minutes. Water is added to the solution. The organic layer was 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 potassium carbonate (1.1 g) was added. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried with anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography [eluents: hexane-ethyl acetate (2: 1) - ethyl acetate] to obtain 2.65 g of ethyl ester (3R, 5S) -7-chloro-1- (2,2,5- trimethyl-1,3-dioxan-5-ylmethyl) -5- (2,3-dimethoxyphenyl) -2- oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (A) and 1.12 g of (3R, 5S) -7-chloro-1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl) -5- (2,3-dimethoxyphenyl) -2-oxo-1 ethyl ester, 2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (B), each of which is a colorless amorphous solid.

A: ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.24 (3H, t, J = 7.0 Hz), 1.36 and 1.39 (each 3H, s) , 2.77 (1H, dd, J = 5.8, 16.4 Hz), 3.04 (1H, dd, J = 7.8, 16.4 Hz), 3.29 (1H, d, J = 12.2 Hz), 3.40 (1H, d, J = 12.2 Hz), 3.58 (3H, s), 3.68 (2H, s), 3.89 (3H, s), 4.07-4.19 (3H, m), 4.40 (1H, d, J = 5.8, 7.8 Hz), 4.48 (1H, d, J = 14.2 Hz), 6 16 (1H, s), 6.63 (1H, d, J = 1.8 Hz), 6.95-7.45 (6H, m).

B: ¹ H-NMR (CDCl ₃ ) δ: 0.62 (3H, s), 1.25 (3H, t, J = 7.0 Hz), 2.78 (1H, dd, J = 5.2 , 16.6 Hz), 3.07 (1H, dd, J = 8.2, 16.6 Hz), 3.39-3.80 (4H, m), 3.60 (3H, s), 3 89 (3H, s), 4.13 (2H, qq, J = 1.8, 7.0 Hz), 4.20-4.28 (1H, m), 4.41 (1H, dd, J = 5.2, 18.2 Hz), 4.85 (1H, d, J = 14.6 Hz), 6.12 (1H, s), 6.63 (1H, s), 6.89 - 7.39 (6H, m).

(3) To the ethanol solution of compound (A) obtained in step (2) (2.25 g) was added 1N. aqueous sodium hydroxide solution (4.0 ml). The mixture was stirred at 60 ^° C. for 1 hour, and then water was added, followed by neutralization by adding 1N. HCl. The reaction mixture was extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain 2.3 g of (3R, 5S) -7-chloro-1- (2,2,5-trimethyl-1,3-dioxan-5-ylmethyl) -5- ( 2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.35 and 1.39 (each 3H, s), 2.84 (1H, dd, J = 7.8, 16.4 Hz), 3.08 (1H, dd, J = 7.8, 16.4 Hz), 3.28 (1H, d, J = 12.2 Hz), 3.41 (1H, d, J = 12 , 2 Hz), 3.58 (3H, s), 3.69 (2H, s), 3.89 (3H, s), 4.16 (1H, d, J = 13.8 Hz), 4, 35 (1H, dd, J = 5.4, 7.8 Hz), 4.89 (1H, d, J = 13.8 Hz), 6.16 (1H, s), 6.65 (1H, d , J = 2.0 Hz), 6.96-7.47 (5H, m).

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

¹ H-NMR (CDCl ₃ ) δ: 0.63 (3H, s), 2.85-2.92 (2H, m), 3.28 (3H, s), 3.25-3.70 (5H , m), 3.59 (3H, s), 3.89 (3H, s), 4.43 (1H, t, J = 6.1 Hz), 4.78 (1H, d, J = 14, 2 Hz), 8.16 (1H, s), 6.67 (1H, s), 6.95-7.40 (6H, m).

Используя соединение (0,5 г), полученное, как описано в Рабочем примере 3-1, и метансульфонамид (0,1 г), проводят реакцию по методике, в основном описанной в Ссылочном примере 3, в результате чего получают 90 мг бесцветных кристаллов, т.пл. 175-180^oC.Working example 6
N-Methylsulfonyl-N- [3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3, 5-tetrahydro-4,1-benzoxazepine-3-acetyl] piperidin-4-acetamide

Using the compound (0.5 g) obtained as described in Working Example 3-1 and methanesulfonamide (0.1 g), the reaction is carried out according to the procedure mainly described in Reference Example 3, whereby 90 mg of colorless crystals are obtained , mp 175-180 ^o C.

Elemental analysis for C ₃₂ H ₄₂ ClN ₃ O ₉ S ₁ :
Calculated: C, 56.50; H, 6.22; N, 6.18
Found: C, 56.70; H, 6.50; N, 5.90.

Используя соединение (1,0 г), полученное, как описано в Рабочем примере 1-(4), и диэтиламинометилфосфонат (0,38 г), проводят реакцию по методике, в основном описанной в Ссылочном примере 1, в результате чего получают 1,24 г бесцветных кристаллов, т.пл. 138-140^oC.Working example 7
(3R, 5S) -N-bis (Ethoxy) phosphinylmethyl-7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2, 3,5-tetrahydro-4,1-benzoxazepine-3-acetamide

Using the compound (1.0 g) obtained as described in Working Example 1- (4) and diethylaminomethylphosphonate (0.38 g), a reaction is carried out according to the procedure essentially described in Reference Example 1, whereby 1 is obtained. 24 g of colorless crystals, so pl. 138-140 ^o C.

Elemental analysis for C ₂₉ H ₄₀ ClN ₂ O ₉ P:
Calculated: C, 55.55; H, 6.43; N, 4.47
Found: C, 55.25; H, 6.47; N, 4.44.

Соединение (0,3 г), полученное, как описано в Рабочем примере 7, подвергают реакции, в основном по методике, описанной в Ссылочном примере 4, в результате чего получают 0,26 г аморфного твердого соединения.Working example 8
(3R, 5S) -N-Phosphonomethyl-7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3,5- tetrahydro-4,1-benzoxazepine-3-acetamide

The compound (0.3 g) obtained as described in Working Example 7 is subjected to a reaction mainly by the procedure described in Reference Example 4, whereby 0.26 g of an amorphous solid compound is obtained.

¹ H-NMR (CD ₃ OD) δ: 0.94 (3H, s), 0.93 (3H, s), 2.75-2.82 (2H, m), 3.20 (1H, d, J = 11.4 Hz), 3.40-3.70 (3H, s), 3.58 (3H, s), 3.89 (3H, s), 4.35-4.46 (2H, m ), 6.18 (1H, s), 6.53 (1H, d, J = 2.2 Hz), 7.08-7.61 (5H, m).

Используя соединение (2,0 г), полученное, как описано в Рабочем примере 5-(3), и гидрохлорид сложного этилового эфира пиперидин-4-уксусной кислоты (0,7 г), проводят реакцию по методике, в основном описанной в Ссылочном примере 1, в результате чего получают 2,4 г бесцветного аморфного твердого продукта.Working example 9
N - [(3R, 5S) -7-Chloro-1- (2,2,5-trimethyl-1,3-dioxan-5-ylmethyl-5- (2,3-dimethoxyphenyl) -2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl] piperidin-4-acetic acid ethyl ester,

Using the compound (2.0 g) obtained as described in Working Example 5- (3) and piperidin-4-acetic acid ethyl ester hydrochloride (0.7 g), the reaction is carried out according to the procedure mainly described in Reference Example 1, whereby 2.4 g of a colorless amorphous solid are obtained.

^H- NMR (CDCl ₃ ,) δ: 0.96 (3H, s), 1.25 (3H, t, J = 7.2 Hz), 1.36 and 1.39 (each 3H, s), 1 65-1.82 (4H, m), 1.95-2.08 (1H, m), 2.18-2.26 (2H, m), 2.49-2.63 (1H, m) 2.73 (1H, dl, J = 4.8, 15.8 Hz), 2.92-3.06 (1H, m), 3.12 (1H, dd, J = 8.2, 15, 8 Hz), 3.31 (1H, d, J = 12.0 Hz), 3.10 (1H, d, J = 12.0 Hz), 3.58 (3H, s), 3.65 (1H d, J = 11.8 Hz), 3.73 (1H, d, J = 11.8 Hz), 3.89 (3H, s), 3.94-3.99 (1H, m), 4 04-4.18 (3H, m), 4.46-4.56 (3H, m), 6.16 (1H, s), 6.60-6.62 (1H, m), 6.95 -7.46 (5H, m).

К раствору соединения, полученного, как описано в Рабочем примере 9, (2,0 г), в ацетоне (20 мл), добавляют моногидрат п-толуолсульфоновой кислоты (35 мг) и воду (2 мл). Смесь перемешивают при 50^oC в течение 6 ч. К реакционной смеси добавляют этилацетат (50 мл). Смесь промывают 1н. водным раствором гидроксида натрия и воды, а затем сушат безводным сульфатом натрия. Растворитель отгоняют с получением 1,62 г бесцветного аморфного твердого продукта.Working example 10
N - [(3R, 5S) -7-Chloro-1- (3-hydroxy-2-hydroxymethyl-2-methyl-propyl) -5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3 5-tetrahydro-4,1-benzoxazepine-3-acetyl] piperidin-4-acetic acid ethyl ester

To a solution of the compound obtained as described in Working Example 9 (2.0 g) in acetone (20 ml), p-toluenesulfonic acid monohydrate (35 mg) and water (2 ml) were added. The mixture was stirred at 50 ^° C. for 6 hours. Ethyl acetate (50 ml) was added to the reaction mixture. The mixture is washed with 1N. an aqueous solution of sodium hydroxide and water, and then dried with anhydrous sodium sulfate. The solvent was distilled off to obtain 1.62 g of a colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 0.62 (3H, s), 1.00-1.34 (2H, m), 1.26 (3H, t, J = 7.4 Hz), 1, 70-1.81 (2H, m), 1.95-2.08 (1H, m), 2.19-2.28 (2H, m), 2.51-2.78 (2H, m), 3.01-3.08 (1H, m), 3.17 (1H, dd, J = 9.0, 15.2 Hz), 3.40-3.74 (5H, m), 3.60 ( 3H, s), 3.89 (3H, s), 3.89-3.94 (1H, m), 4.13 (2H, q, J = 7.4 Hz), 4.48-4, 54 (2H, m), 4.83 (1H, d, J = 14.6 Hz), 6.13 (1H, s), 6.61 (1H, d, J = 1.8 Hz), 6, 97-7.44 (5H, m).

К этаноловому раствору соединения, полученного, как описано в Рабочем примере 10, добавляют 1н. водный раствор гидроксида натрия. Реакционную смесь перемешивают при 60^oC в течение 2 часов. К реакционной смеси добавляют воду (100 мл) и этилацетат (50 мл), а затем подкисляют 1н. HCl. Органический слой промывают водой и сушат безводным сульфатом натрия. Растворитель отгоняют с получением 0,94 г бесцветного аморфного твердого продукта.Working example 11
N - [(3R, 5S) -7-Chloro-1- (3-hydroxy-2-hydroxymethyl-2-methyl-propyl) -5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3 , 5-tetrahydro-4,1-benzoxazepine-3-acetyl] piperidine-4-acetic acid

To the ethanol solution of the compound obtained as described in Working Example 10, 1N was added. aqueous sodium hydroxide solution. The reaction mixture was stirred at 60 ^° C. for 2 hours. Water (100 ml) and ethyl acetate (50 ml) were added to the reaction mixture, and then acidified with 1N. HCl. The organic layer was washed with water and dried with anhydrous sodium sulfate. The solvent was distilled off to obtain 0.94 g of a colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 0.63 (3H, s), 1.05-1.36 (2H, m), 1.70-1.85 (2H, m), 1.92-2 05 (1H, m), 2.23-2.32 (2H, m), 2.51-2.80
(2H, m), 2.96-3.23 (2H, m), 3.44-3.70 (5H, m), 3.60 (3H, m), 3.89 (3H, s), 3.91-4.00 (1H, m), 4.48-4.54 (2H, m), 4.78 (1H, d, J = 15.2 Hz), 6.12 (1H, s) 6.61 (1H, s); 6.97-7.39 (5H, m).

К раствору соединения, полученного, как описано в Рабочем примере 10, (0,5 г), в пиридине (5 мл), добавляют уксусный ангидрид (0,20 г) и диметиламинопиридин (10 мг). Смесь перемешивают при комнатной температуре в течение 30 мин. К реакционной смеси добавляют этилацетат (50 мл). Смесь промывают 1н. HCl и водой, а затем сушат с последующей отгонкой растворителя. Остаток очищают с помощью колоночной хроматографии на силикагеле (элюент: этилацетат) и получают 0,50 г бесцветного аморфного твердого продукта.Working example 12
N - [(3R, 5S) -1- (3-Acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5 Tetrahydro-4,1-benzoxazepine-3-acetyl] piperidin-4-acetic acid ethyl ester

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

¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.00-1.40 (2H, m), 1.25 and 1.26 (total 3H, each t, J = 7, 2 Hz), 1.60-1.80 (2H, m), 1.92-2.05 (1H, m), 2.00 (3H, s), 2.03 (3H, s), 2, 16-2.26 (2H, m), 2.46-2.65 (1H, m), 2.67-2.77 (1H, m), 2.99-3.19 (2H, m), 3.60 (3H, s), 3.64-4.19 (6H, m), 3.89 (3H, s), 4.44-4.54 (2H, m), 4.67 (1H, d, J = 14.6 Hz), 6.23 (1H, s), 6.65 (1H, s), 6.96-7.34 (5H, m).

Используя соединение, полученное, как описано в Рабочем примере 11, проводят реакцию по методике, в основном описанной в Рабочем примере 12, в результате чего получают 0,28 г бесцветного аморфного твердого продукта.Working example 13
N - [(3R, 5S) -1- (3-Acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5 Tetrahydro-4,1-benzoxazepine-3-acetyl] piperidine-4-acetic acid

Using the compound obtained as described in Working Example 11, a reaction is carried out according to the procedure mainly described in Working Example 12, whereby 0.28 g of a colorless amorphous solid product is obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.36 (2H, m), 1.03 (3H, s), 1.71-1.83 (2H, m), 1.93-2 , 07 (1H, m), 2.00 (3H, m), 2.05 (3H, s), 2.23-2.33 (2H, m), 2.48-2.63 (1H, m ), 2.65-2.78 (1H, m), 3.00-3.18 (2H, m), 3.60 (3H, s), 3.65-4.14 (6H, m), 3.89 (3H, s), 4.46-4.56 (2H, m), 4.66 (1H, d, J = 14.8 Hz), 6.24 (1H, s), 6.64 (1H, s), 6.96-7.34 (5H, m).

Используя соединение, полученное, как описано в Рабочем примере 5, (0,1 г), уксусный ангидрид (39 мг) и диметиламинопиридин (5 мг), проводят реакцию по методике, в основном описанной в Рабочем примере 12, в результате чего получают 70 мг бесцветного аморфного твердого продукта.Working example 14
(3R, 5S) -N-Methylsulfonyl-1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3, 5-tetrahydro-4,1-benzoxazepine-3-acetamide

Using the compound obtained as described in Working Example 5, (0.1 g), acetic anhydride (39 mg) and dimethylaminopyridine (5 mg), the reaction is carried out according to the procedure mainly described in Working Example 12, resulting in 70 mg colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 2.00 and 2.02 (each 3H, s), 2.85 (1H, dd, J = 5.4, 15.4 Hz), 2.98 (1H, dd, J = 7.2, 15.4 Hz), 3.26 (3H, s), 3.61 (3H, s), 3.70 (1H, d, J = 14.2 Hz), 3.84 (1H, d, J = 11.4 Hz), 3.89 (3H, s), 3.94-3.99 (2H, m), 4.11 (1H d, J = 11.4 Hz), 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), 6.97-7.43 (5H, m).

Используя соединение, полученное, как описано в Рабочем примере 2-1, (0,5 г), проводят реакцию по методике, в основном описанной в Рабочем примере 12, в результате чего получают 0,35 г бесцветного аморфного твердого продукта.Working example 15
N - [(3R, 5S) -1- (3-Acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro -4,1-benzoxazepine-3-acetyl] piperidin-4-acetic acid ethyl ester

Using the compound obtained as described in Working Example 2-1, (0.5 g), a reaction is carried out according to the procedure mainly described in Working Example 12, whereby 0.35 g of a colorless amorphous solid product is obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, s), 1.02 (3H, s), 1.26 (3H, t), 2.02 (3H, s), 3.61 ( 3H, s), 3.89 (3H, s), 4.14 (2H, q), 4.5 (3H, m), 6.26 (1H, s), 6.62 (1H, s) 6.9-7.4 (5H, m).

Используя соединение (0,37 г), полученное, как описано в Рабочем примере 3-1, проводят реакцию по методике, в основном описанной в Рабочем примере 12, в результате чего получают 0,35 мг бесцветного кристаллического продукта, т. пл. 194- 196^oC.Working example 16
N - [(3R, 5S) -1- (3-Acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro -4,1-benzoxazepine-3-acetyl] piperidin-4-acetic acid

Using the compound (0.37 g) obtained as described in Working Example 3-1, the reaction is carried out according to the procedure mainly described in Working Example 12, whereby 0.35 mg of a colorless crystalline product is obtained, mp. 194 - 196 ^o C.

Elemental analysis for C ₃₂ H ₄₁ ClN ₂ O ₉ :
Calculated: C, 61.4; H, 6.41; N, 4.34
Found: C, 61.23; H, 6.18; N, 4.39.

(1) К раствору сложного этилового эфира (3R,5S)-7-хлор-1-(3-гидрокси-2-гидроксиметил-2-метилпропил)-5-(2,3- диметоксифенил)-2-оксо-1,2,3,5-тетрагидро-4,1-бензоксазепин-3-уксусной кислоты (1,0 г) в этаноле (10 мл) добавляют 1н. водный раствор гидроксида натрия. Смесь перемешивают в течение 1 ч при 60^oC. К реакционной смеси добавляют воду, нейтрализуют 1н. HCl и подвергают экстракции этилацетатом. Раствор экстракта сушат безводным сульфатом натрия. Растворитель отгоняют, а остаток перекристаллизовывают из смеси этилацетата и гексана, в результате чего получают 0,38 г (3R,5S)-7-xлop-1-(3-гидpoкcи-2-гидpoкcимeтил-2-метилпропил-5-(2,3- диметоксифенил)-2-оксо-1,2,3,5- тетрагидро-4,1-бензоксазепин-3-уксусной кислоты, т.пл. 208-210^oC.Working example 17
N - [(3R, 5S) -7-Chloro-1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5- tetrahydro-4,1-benzoxazepine-3-acetyl] -4-hydroxypiperidin-4-acetic acid methyl ester

(1) To a solution of ethyl ester (3R, 5S) -7-chloro-1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl) -5- (2,3-dimethoxyphenyl) -2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (1.0 g) in ethanol (10 ml) was added 1N. aqueous sodium hydroxide solution. The mixture was stirred for 1 h at 60 ^° C. Water was added to the reaction mixture and neutralized with 1N. HCl and subjected to extraction with ethyl acetate. The extract solution was dried with anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixture of ethyl acetate and hexane, whereby 0.38 g of (3R, 5S) -7-chlorop-1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl-5- (2, 3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid, mp 208-210 ^o C.

 (2) Using the compound obtained in (1), (0.25 g) and 4-hydroxypiperidin-4-acetic acid methyl ester hydrochloride (0.105 g), the reaction is carried out according to the procedure essentially described in Reference Example 1, resulting in 0.125 g of a colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 1.35-1.84 (6H, m), 2.47 (2H, d), 2.65-2.85 (1H, m), 2.95-3 28 (2H, m), 3.35-3.78 (7H, m), 3.62 (3H, s), 3.73 (3H, s), 3.90 (3H, s), 4, 22-4.40 (2H, m), 4.52 (1H, dd), 4.84 (1H, dd), 6.13 (1H, d), 6.62 (1H, m), 6.95 -7.43 (5H, m).

(1) К раствору соединения (0,5 г), полученного, как описано в Рабочем примере 5-(3), хлорида аммония (0,25 г) и триэтиламина (0,17 г) в диметилформамиде (5 мл) добавляют диэтилцианофосфонат (0,21 г) и триэтиламин (0,17 г). Смесь перемешивают при комнатной температуре в течение 30 мин, а затем добавляют этилацетат (50 мл). Смесь промывают водой, а затем сушат безводным сульфатом натрия с последующей отгонкой растворителя. Остаток очищают с помощью колоночной хроматографии на силикагеле (элюент: этилацетат) и получают 0,52 г амидного соединения в виде аморфного твердого вещества.Working example 18
N - [(3R, 5S) -7-Chloro-1- (3-hydroxy-2-hydroxymethyl-2-methyl-propyl) -1,2,3,5-tetrahydro-5- (2,3-dimethoxyphenyl) -3- (1H (or 3H) -tetrazol-5-yl) methyl-4,1-benzoxazepin-2-one

(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 dimethylformamide (5 ml) was added diethyl cyanophosphonate (0.21 g) and triethylamine (0.17 g). The mixture was stirred at room temperature for 30 minutes, and then ethyl acetate (50 ml) was added. The mixture was washed with water and then dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.52 g of an amide compound as an amorphous solid.

(2) To a solution of dimethylformamide (41 mg) in acetonitrile (1.5 ml) was added oxalyl chloride (65 mg) at 0 ^° C. The mixture was stirred for 10 minutes, after which a solution of the compound obtained in stage (1) (0) was added. , 25 g) in acetonitrile (1.5 ml) and pyridine (82 mg). The mixture was stirred at 0 ^° C. for 10 minutes. Ethyl acetate (50 ml) was added to the reaction mixture. The mixture was washed with water and dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue was purified by silica gel column chromatography [developing solution: hexane: ethyl acetate (2: 1)] to obtain 0.31 g of a nitrile compound.

 (3) A solution of the compound obtained in stage (2), (1.0 g) in toluene (15 ml) is subjected to the reaction according to the procedure mainly described in Reference example 5- (3), using trimethylsilyl azide (0.43 d) and dibutyltin (IV) oxide (45 mg), whereby (3R, 5R) -7-chloro-1- (2,2,5-trimethyl-1,3-dioxan-5-ylmethyl) -5 is obtained - (2,3-dimethoxyphenyl) -1,2,3,5-tetrahydro-3- (tetrazol-5-yl) methyl-4,1-benzoxazepin-2-one (1.03 g) as a colorless amorphous solid product.

(4) To a solution of the compound obtained in step (3) (1.0 g) in acetone (10 ml), p-toluenesulfonic acid monohydrate (50 mg) and water (1 ml) were added. The mixture was stirred at 60 ^° C. overnight. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol (20: 1) to obtain 0.87 g of a colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 0.69 (3H, s), 3.45 (1H, dd, J = 4.4, 14.4 Hz), 3.56-3.75 (5H, m ), 3.62 (3H, s), 3.90 (3H, s), 4.29 (1H, dd, J = 4.4, 8.8 Hz), 4.63 (1H, d, J = 15.2 Hz), 6.18 (1H, s), 6.67 (1H, d, J = 2.2 Hz), 7.05-7.43 (5H, m).

К раствору соединения, полученного, как описано в Рабочем примере 18, (0,77 г), в пиридине (7 мл) добавляют уксусный ангидрид (0,335 г) и диметиламинопиридин (40 мг). Смесь перемешивают при комнатной температуре в течение 30 мин, а затем добавляют этилацетат (50 мл). Смесь промывают 1н. HCl и водой, а затем сушат безводным сульфатом натрия с последующей отгонкой растворителя. Остаток промывают этиловым эфиром-гексаном (1:1), фильтруют и собирают 0,80 г бесцветного аморфного твердого продукта.Working example 19
(3R, 5S) -1- (3-Acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-1,2,3,5-tetrahydro-5- (2,3-dimethoxyphenyl) -3- (1H (or 3H) -tetrazol-5-yl) -4,1-benzoxazepin-2-one

To a solution of the compound obtained as described in Working Example 18 (0.77 g) in pyridine (7 ml) was added acetic anhydride (0.335 g) and dimethylaminopyridine (40 mg). The mixture was stirred at room temperature for 30 minutes, and then ethyl acetate (50 ml) was added. The mixture is washed with 1N. HCl and water, and then dried with anhydrous sodium sulfate, followed by distillation of the solvent. The residue was washed with ethyl ether-hexane (1: 1), filtered and 0.80 g of a colorless amorphous solid were collected.

¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 2.03, 2.04 (each 3H, s), 3.40 (1H, dd, J = 5.1, 15.8) Hz), 3.55-3.67 (2H, m), 3.65 (3H, s), 3.82-3.91 (2H, m), 3.89 (3H, s), 4.04 (1H, d, J = 11.6 Hz), 4.18 (1H, d, J = 11.2 Hz), 4.30 (1H, dd, J = 5.2, 6.6 Hz), 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).

(1) К раствору соединения, полученного, как описано в Рабочем примере 5-(3), (0,5 г), и диэтилцианофосфоната (54 мг) в диметилформамиде (1,5 мл) добавляют 1-(2-аминоэтил) пирролидин (0,16 г). Смесь перемешивают при комнатной температуре в течение 30 мин, а затем добавляют этилацетат (50 мл). Смесь промывают водой и сушат с последующей отгонкой растворителя. Остаток очищают с помощью колоночной хроматографии на силикагеле [элюент:этилацетат-метанол-триэтиламин (10: 1: 0,1) с получением (3R,5S)-N-[2-(пиридин-1-ил)этил] -7-хлор-1-(2,2,5- триметил-1,3-диоксан-5-илметил)-5-(2,3-диметоксифенил)-2-оксо-1,2,3,5- тетрагидро-4,1-бензоксазепин-3-ацетамида (0,19 г) в виде бесцветного аморфного твердого продукта.Working example 20
(3R, 5S) -N- [2- (Pyrrolidin-1-yl) ethyl] -7-chloro-1- (3-hydroxy-2-hydroxymethyl-3-methylpropyl) -5- (2,3-dimethoxyphenyl) - 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide

(1) To a solution of the compound obtained as described in Working Example 5- (3), (0.5 g) and diethyl cyanophosphonate (54 mg) in dimethylformamide (1.5 ml) was added 1- (2-aminoethyl) pyrrolidine (0.16 g). The mixture was stirred at room temperature for 30 minutes, and then ethyl acetate (50 ml) was added. The mixture was washed with water and dried, followed by distillation of the solvent. The residue was purified by silica gel column chromatography [developing solution: 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-dioxan-5-ylmethyl) -5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4, 1-benzoxazepine-3-acetamide (0.19 g) as a colorless amorphous solid.

(2) To a solution of the compound obtained in stage (1) (0.19 g) in tetrahydrofuran (2 ml) was added concentrated HCl (1 ml). The resulting mixture was stirred at 60 ^° C. for 30 minutes, and then water (50 ml) was added, followed by neutralization by adding 1N. NaOH. The resulting material was extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol-triethylamine (2: 1: 0.1)) to obtain 97 mg of a colorless amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 0.62 (3H, s), 1.75-1.80 (4H, m), 2.50-2.72 (7H, m), 2.87 (1H dd, J = 7.0, 14.2 Hz), 3.31-3.76 (7H, m), 3.59 (3H, s), 3.89 (3H, s), 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, broad), 6 62 (1H, s); 6.99-7.37 (5H, m).

Соединение, полученное, как описано в Рабочем примере 19, (1,2 г), подвергают реакции по методике, в основном описанной в Рабочем примере 19, в результате чего получают 1,01 г бесцветного кристаллического продукта, т.пл. 108-112^oC.Working Example 21 (3R, 5S) -N-Methylsulfonyl-1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3 5-tetrahydro-4,1-benzoxazepine-3-acetamide

The compound obtained as described in Working Example 19 (1.2 g) was subjected to a reaction according to the procedure generally described in Working Example 19, whereby 1.01 g of a colorless crystalline product was obtained, mp. 108-112 ^o C.

Elemental analysis for C ₂₇ H ₃₂ ClN ₂ O ₉ S: 1.5H ₂ O:
Calculated: C, 51.96; H, 5.81; N, 4.49
Found: C, 52.01; H, 5.82; N, 4.30.

Соединение, полученное, как описано в Рабочем примере 1. (80 мг), подвергают реакции по методике, описанной в основном в Рабочем примере 19, в результате чего получают 25 мг бесцветного аморфного твердого продукта.Working example 22
(3R, 5S) -1- (3-Acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -1,2,3,5-tetrahydro-3- [1H (or 3H) tetrazol-5-yl] methyl-4,1-benzoxazepin-2-one

The compound obtained as described in Working Example 1. (80 mg) was reacted according to the procedure described mainly in Working Example 19, whereby 25 mg of a colorless amorphous solid product was obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 0.99 (3H, s), 2.05 (3H, s), 3.3-3.8 (4H, m), 3.65 (3H, s), 3.89 (3H, s), 4.05 (1H, d), 4.28 (1H, dd), 4.62 (1H, d), 6.27 (1H c), 6.68 (1H, d), 6.9-7.4 (5H, m).

Examples of compositions:
A therapeutic agent for treating hyperlipemia containing, as its effective component, a compound of the present invention (1) or a salt thereof, can be prepared, for example, in accordance with the following formulation:
1. Capsules, mg:
(1) The compound of Example 16 to 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 is granulated, and then the remaining amount (4) is added. The resulting mixture is filled in gelatin capsules.

2. Tablets, mg:
(1) The compound of Example 16 to 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 is granulated, and then the rest of the components (4) and (5) are added. The resulting mixture is molded by compression and get tablets.

3. Injection, mg:
(1) The compound of Example 16 to 10
(2) Inositol - 100
(3) Benzyl alcohol - 20
1 ampoule - 130
Components (1), (2) and (3) are dissolved in distilled water for injection to a total volume of 2 ml, and then placed in an ampoule and this ampoule is hermetically sealed. All operations are carried out under sterile conditions.

Experimental Example 1:
Squalene Synthetase Inhibiting Activity
Analytical method
Squalene synthetase inhibitory activity was analyzed as described below using enzyme solutions prepared by the method described below.

More specifically, an enzyme solution (protein content 0.8 μg) obtained by the method described below is added to the solution (total volume 50 μl) containing 5 μM [ ^1–3 H] fernesyl pyrophosphate (specific activity 25 μCi / mol), 1 mM NADPH (reduced type nicotinamyl adenine dinucleotide phosphate), 5 mM MgCl ₂ , 6 mM glutathione, 100 mM potassium phosphate buffer solution (pH 7.4) and test drug (used as an aqueous solution or DMSO solution), and then left for 45 minutes at 37 ^° C. to undergo a reaction. To suspend the reaction mixture, 150 μl of a mixture of chloroform and methanol (1: 2) was added to this reaction mixture, followed by 50 μl of chloroform and 50 μl of 3n. sodium hydroxide solution. 50 μl of the chloroform layer (lower layer) containing the reaction mixture including squalene as the main component, and 3 ml of a toluene-based liquid scintillator are mixed and its radioactivity is determined using a liquid scintillation counter.

Squalene synthetase inhibiting activity is expressed as the concentration inhibiting 50% of the radioactivity incorporated into the chloroform layer (IC ₅₀ molar concentration (M)), as shown in Table 3.

Obtaining an enzyme derived from humans
HepG2 human liver carcinoma cells (about 1 • 10 ⁹ cells), obtained by incubation on Dulbecco's modified Eagle's medium (37 ^° C in the presence of 5% CO ₂ ) containing 10% fetal bovine serum, are suspended in 10 ml of ice-cold buffer solution [100 mm potassium phosphate buffer (pH 7.4), 30 mm nicotinamide, and 2.5 mm MgCl ₂ ]. These cells are destroyed by sonication (within 30 seconds, twice). The cell fraction obtained after sonication was centrifuged at 10,000 x g for 20 minutes (4 ^° C.). Then, the supernatant layer was centrifuged at 105,000 for 90 minutes (4 ^° C.). The precipitate was then suspended in ice-cold 100 mM potassium phosphate buffer (pH 7.4), and then centrifuged again for 90 min (4 ^° C) at 105,000. This fraction was suspended in ice-cold 100 mM potassium phosphate buffer (pH 7.4) (protein concentration of about 4 mg / ml). The resulting suspension is used as an enzyme solution.

 As can be seen from these results, the compounds of the present invention have excellent activity directed to the inhibition of squalene synthetase.

Experimental Example 2:
Analysis for the formation of cholesterol in the liver:
The cholesterol biosynthesis in rat liver was analyzed as follows, the test compound [Compound 4-2 (suspended in a 0.5% methylcellulose solution)] was orally administered to 6-week-old Wistar fat rats, and only 0.5% methylcellulose was orally administered to the control group . After 1 h, sodium acetate labeled with the radioactive isotope ¹⁴ C (supplied by Amersham) (10 μCi / 0.3 ml saline / rat) was intravenously injected into the rat tail vein. After 1 h, rats were sacrificed by decapitation and 1.5 g of the first lobe of the liver was removed, and then subjected to saponification by immersion in 3.9 ml of an alkaline ethanol solution (KOH: EtOH = 1: 2) for 2 h at 100 ^° C followed by extraction, which 1, was carried out three times with 5 ml of 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 was added 2 ml of a 0.5% solution of digitonin-ethanol. The resulting mixture was left for one hour to settle. The resulting precipitates were collected as total sterol, and its radioactivity was measured on a 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 an excellent inhibitory effect, providing 80% or more inhibition of cholesterol formation.

Industrial application
The compounds of the present invention have squalene synthetase inhibiting activity, cholesterol lowering activity and triglyceride lowering activity, and therefore these compounds can be used as prophylactic and therapeutic agents for treating hyperlipemia and as lipid lowering agents, and moreover , they can also be used for the prevention and treatment of, for example, arteriosclerosis.

Claims (6)

1. Derivatives of 4,1-benzoxazepin-2-one of the formula (I)

where R ¹ is lower alkyl substituted by at least one optionally substituted hydroxyl group;
R ² and R ³ independently from each other - hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C ₁ -C ₄ alkoxy groups;
X is a bond, a methylene group or a linking group with a chain length of 1-7 atoms, selected from the group containing - (CH ₂ ) mE- (CHR ₆ ) n-, where m and n = 1 or 2 are independently from each other, E - a bond or an oxygen atom, -NR ₅ -, -CONR ₇ -, where R ₅ is methylsulfonyl, R ₆ and R _{7 are} independently of each other (i) hydrogen, (ii) lower alkyl, which is unsubstituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxy groups; (iii) benzyl;
Y is optionally substituted carbamoyl and / or substituents on the carbamoyl N atom, taken together, form a ring that may be substituted, or tetrazolyl, or piperidine;
ring A is substituted by 1-3 substituents selected from the group consisting of halogen atoms,
or their salts. 2. The compound according to claim 1, where R ¹ is a lower alkyl group substituted with one hydroxyl group which may be substituted; R ² and R ³ are a hydrogen atom or a phenyl group substituted with a C ₁ C ₄ alkoxy group, wherein R ² and R ³ are the same or different; X methylene group; Y is a carbamoyl group which may be substituted, or a piperidino-carbonyl group which may be substituted; ring A is a benzene ring substituted by a halogen atom, or a salt thereof. 3. The compound according to claim 1 of the formula

where R ¹ is a lower alkyl group which is substituted by a hydroxyl group or a hydroxyl group substituted by an acetyl group;
R _a is a C ₁ -C ₄ alkoxy group;
Y is a carbamoyl group which may be substituted with CH ₃ SO ₂ or a piperidino-carbonyl group which may be substituted;
Z is a halogen atom,
or its salt. 4. The compound according to claim 1 of the formula

where R ¹ is a C ₁ -C ₇ alkyl group which is substituted by a hydroxyl group or a hydroxyl group substituted by an acetyl group;
Y is a carbamoyl group which may be substituted by CH ₃ SO ₂ , or a piperidino-carbonyl group which is substituted by a hydroxyl group and / or a —CH ₂ COOR _b group (where R _b is a hydrogen atom, methyl group or ethyl group),
or its salt. 5. (3R, 5S) -N-Methylsulfonyl-7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-1,2,3, 5-tetrahydro-4,1-benzoxazepine-3-acetamide of the formula

or its salt. 6. N - [(3R, 5S) -1- (3-Acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) 2-oxo-1,2,3,5- tetrahydro-4,1-benzoxazepine-3-acetyl] piperidin-4-acetic acid of the formula

or its salt.

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