Benzoxazepin derivatives, their production method, medicine based on them, and their application

FIELD: chemistry, pharmacology.

SUBSTANCE: compound of formula [I]: is described, where the ring A represents halogen substituted benzene ring; the ring B represents benzene ring substituted with two lower, 1 to 4 carbon atoms, alcoxy-groups; the ring C represents benzene ring or five-member aromatic heterocyclic ring, that may be optionally substituted with substitute as follows: carboxyl group, C1-4-alkyl group, C2-7-alkanoiloxy-C1-6-alkyl group, phenyl-C1-4-alkyl group, phenyl group, optionally substituted with carboxyl group, or oxo-group; R1 represents C1-6-alkyl group, optionally substituted with hydroxyl group, that optionally substituted with C2-20-alkanoil or C1-7-alkyl group; X1a represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X1b represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X2 represents bound, -O- or -S- ; X3 represents bound or group, formed by one hydrogen atom elimination from either straight or branched chain C1-7-alkyl, or C2-6-alkenyl group, that optionally substituted with hydroxyl or oxo-group; and Y represents optionally etherified carboxyl group; or its salt. Benzoxazepin derivatives production method, medicine based on them, and their application are also described.

EFFECT: novel compounds have high lipids-decreasing effect and are helpful as hyperlipidemia prevention and treatment medicine.

20 cl, 168 ex

 

The present invention relates to a new derived benzoxazepine having squalene synthase inhibitory activity, cholesterinspiegel activity and triglyceridemia activity, which is useful for the prevention or treatment of hyperlipidemia and related diseases.

An abnormal increase in the concentration of serum lipids called hyperlipidemia or hyperlipemia. The serum lipids include cholesterol (ester cholesterol, free cholesterol, phospholipid (lecithin, sphingomyelin, and the like), triglycerides (neutral lipid), free fatty acid, other sterols, and the like, and in particular clinical problem is the increase in cholesterol and triglyceride (COMMON DISEASE SERIES No. 19, hyperlipemia, Haruo Nakamura ed., published on October 10, 1991, by Nankodo).

Examples of drugs to reduce cholesterol in the blood include medicines that capture bile acid and inhibit its absorption, such as cholestyramine and colestipol (for example, US 4027009), and drugs that inhibit allgovernment And-cholesterol-acyltransferase (ACAT) and inhibit the absorption of cholesterol in the intestine, such as melinamide. In addition, as drug use drugs, which inhibit the biosynthesis of cholesterol, is as lovastatin (disclosed in US 4231938), simvastatin (disclosed in US 4444784) and pravastatin (disclosed in US 4346227), which inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase.

In addition, as drug use, reduce the content of triglycerides derived fibrin acid, such as clofibrate (UK patent No. 860303), fenofibrate (German patent No. 2250327) and the like.

On the other hand, as compounds that affect the biosynthesis of cholesterol by inhibiting squalene synthase, discloses compounds in non-patent publications, such as Journal of Medicinal Chemistry, 1988, vol.31, p.1869-1871; Expert Opinion on Therapeutic Patents, 1998, vol.8, p.521-530; Bioorganic Medicinal Chemistry, 2002, vol.10, p.385-400; Bioorganic Medicinal Chemistry, 2002, vol.10, p.401-412; Chemical & Pharmaceutical Bulletin, 2002, vol.50, p.53-58; Chemical & Pharmaceutical Bulletin, 2002, vol.50, p.59-65; Journal of Medicinal Chemistry, 2002, vol.45, p.4571-4580; and patent publications such as JP-A 1-213288, JP-A 2-101088, JP-A 2-235820, JP-A 2-235821, JP-A 3-20226, JP-A 3-68591, JP-A 3-148288, JP-A 9-087260, US 5135935, US 5726306, US 5698691, EP 0645377, WO 92/15579, WO 93/09115, WO 95/021834, WO 97/10224, WO 2001/98282 and US 6537987.

Disclosure of the invention

Appropriate regulation of the concentration of serum lipids is very important for the prevention or treatment of various diseases associated with atherosclerosis, including coronary heart disease and cerebral infarction. Also, consider that hypertriglyceridemia causes pancreaticogastrostomy. Because, when the inhibitor of HMG-COA-reductase inhibits HMG-CoA-reductase, has a place, in addition to inhibition of cholesterol biosynthesis, inhibition of the biosynthesis of other components required for a living organism, such as ubiquinone, dolichol and heme A, then there harmful side effects. In addition, due to toxic effects on the liver prohibited the simultaneous use of funds, reduce triglycerides, and connections Statesboro type. On the other hand, squalene synthase is an enzyme involved in the biosynthesis of cholesterol on the main stage. This enzyme catalyzes reductive dimerization of two molecules of farnesylpyrophosphate with the formation of squalene.

Under these circumstances, the present invention is to obtain a connection that would have been more secure had a stronger lepidophyma activity, such as inhibitory activity against squalene-synthase (holesterinoponizhayuschim activity) and triglyceridemia activity, and therefore it was useful as a drug for the prophylaxis or treatment of hyperlipidemia.

In the framework of the present invention conducted intensive studies, and as a result first synthesized 4,1-benzoxazepin different chemical structure, with special replace the ü in position 3, it is shown that the specified connection unexpectedly has excellent pharmacological effects such as the effect of reducing the lipid content, based on its unique chemical structure provides a high level of delivery if transfer to the target organ and has a wide margin of safety, which led to the creation of the present invention.

Thus, in accordance with the present invention include:

(1) a compound represented by the formula [I]:

where ring a and ring In each represents an optionally substituted benzene ring, the ring represents an optional optionally substituted aromatic ring, R1represents a lower alkyl group, optionally substituted by an optionally substituted hydroxyl group, X1Arepresents a bond or optionally substituted lower alkylene, R1brepresents a bond or optionally substituted lower alkylene, X2represents a bond, -O - or-S-, X3represents a bond or optionally substituted divalent hydrocarbon group, and Y represents an optionally esterified or amidinophenoxy carboxyl group, or its salt;

(2) the compound according to item (1), where X1bthe submitted is a bond and Y is an optionally esterified carboxyl group;

(3) the compound according to item (1), where ring a is a benzene ring, substituted atom(s) halogen;

(4) the compound according to item (1), where the ring is a benzene ring, substituted lower(lowest) alkoxygroup(groups);

(5) the compound according to item (1), where the ring is an optionally additionally substituted monocyclic aromatic heterocyclic ring;

(6) the compound according to item (1), where the ring C represents an optionally additionally substituted benzene ring;

(7) the compound according to item (1), where the ring C represents an optionally additionally substituted aromatic ring, containing no hydrogen atom, which can be deprotonated;

(8) the compound according to item (1), where X1arepresents a C1-3alkylen;

(9) the compound according to item (1), where X2represents a bond;

(10) the compound according to item (1), where X3represents a C1-4alkylen;

(11) the compound according to item (1), where the formula [I] represents the formula [Ia]:

where appropriate symbols such as defined in paragraph (1);

(12) 3-(2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,3-thiazol-5-yl)propionic acid, 3-(2-{2-[(3R,5S)-7-PI is R-5-(2,3-acid)1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)propionic acid or its salt;

(13) 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)propionic acid, 2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid or its salt;

(14) 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid, 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid, 5-(3-{[(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-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid or its salt;

(15) a prodrug of the compound according to item (1);

(16) a drug containing the compound according to item (1) or its prodrug;

(17) a drug that contains a combination of compounds according to paragraph (1) or its prodrug and cholesterinspiegel funds;

(18) the drug according to item (16) or (17), which is an inhibitor of squalene synthase;

(19) the drug according to item (16) or (17), which is triglyceridemia tool;

(20) the drug according to item (16) or (17), which is lepidosiren what redston;

(21) the drug according to item (16) or (17), which is an agent for the prophylaxis or treatment of hyperlipidemia;

(22) the drug according to item (16) or (17), which is a means for lowering the level of the complex high-density lipoprotein-cholesterol;

(23) a method of obtaining a compound represented by the formula [I']:

where the ring' is an optional optionally substituted aromatic heterocyclic ring, and other symbols such as defined above in paragraph (1)or its salts, including the interaction of the compounds represented by the formula:

where Z1represents a functional group involved in the reaction of formation of aromatic heterocyclic rings, and other characters such as defined above in paragraph (1)or its salt with a compound represented by the formula:

where Z2represents a functional group involved in the reaction of formation of aromatic heterocyclic rings, and other characters such as defined above in paragraph (1)or its salt;

(24) a method of inhibiting squalene synthase in a mammal, comprising an introduction to the specified mammal an effective amount of the connect is tion under paragraph (1) or its prodrug;

(25) a method of reducing triglycerides in a mammal, comprising an introduction to the specified mammal an effective amount of the compound according to item (1) or its prodrug;

(26) a method of decreasing the level of lipid in a mammal, comprising an introduction to the specified mammal an effective amount of the compound according to item (1) or its prodrug;

(27) a method for preventing or treating hyperlipidemia in a mammal, comprising an introduction to the specified mammal an effective amount of the compound according to item (1) or its prodrug;

(28) a method of increasing the level of complex high-density lipoprotein - cholesterol in a mammal, comprising an introduction to the specified mammal an effective amount of the compound according to item (1) or its prodrug;

(29) the use of the compounds according to paragraph (1) or its prodrug to obtain an inhibitor of squalene synthase;

(30) the use of the compounds according to paragraph (1) or its prodrug to get triglyceridemia funds;

(31) the use of the compounds according to paragraph (1) or its prodrug to get lepidosirenidae funds;

(32) the use of the compounds according to paragraph (1) or its prodrug to obtain funds for the prophylaxis or treatment of hyperlipidemia;

(33) the use of the compounds according to paragraph (1) or its prodrug for medium spans the VA to increase the level of complex high-density lipoprotein - cholesterol; and the like.

Detailed description of the invention

Deputy "optionally substituted benzene ring"represented by ring A, includes halogen (e.g. fluorine, chlorine, bromine, iodine), optionally substituted lower alkyl group containing 1-4 carbon atoms (e.g. methyl, ethyl, propyl, butyl, tert-butyl etc), optionally substituted lower alkoxygroup containing 1-4 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc), a hydroxyl group, a nitro-group and cyano. The ring And may contain 1-3, preferably 1-2 specified substituent. Adjacent substituents of the indicated substituents may together form a ring. Deputy optionally substituted lower alkyl groups containing 1-4 carbon atoms, or optionally substituted lower alkoxygroup containing 1-4 carbon atoms, include halogen (e.g. fluorine, chlorine, bromine, iodine), with optional substitutable positions may be 1-3 substituent. Ring a is preferably a benzene ring substituted by halogen atoms, etc., more preferably a benzene ring substituted by a chlorine atom. Ring And preferably is a benzene ring represented by the formula:

where W is a at the m halogen (for example, fluorine, chlorine, bromine, iodine), preferably W represents a chlorine atom.

Deputy "optionally substituted benzene ring"represented by ring B, includes the same number of the same groups as for the above substituent of the "optionally substituted benzene ring"represented by ring A. Ring is preferably a benzene ring, substituted lower alkoxygroup containing 1-4 carbon atoms and, incidentally, is preferably a benzene ring represented by the formula:

where R2Aand R2bindependently represent a hydrogen atom or a lower alkyl group containing 1-4 carbon atoms (e.g. methyl, ethyl, propyl, butyl, etc.), and particularly preferably R2Aand R2bboth represent a methyl group.

Aromatic ring optionally additionally substituted aromatic ring"represented by ring includes an aromatic hydrocarbon ring and an aromatic heterocyclic ring. The aromatic hydrocarbon ring include, for example, benzene ring, naphthalene ring and the like, and preferably is a benzene ring. Aromatic heterocyclic ring or an aromatic heterocyclic ring "optional additional is but substituted aromatic heterocyclic ring", represented by the ring C'), include, for example, aromatic heterocyclic ring containing at least one (preferably 1-4, more preferably 1-2) 1-3 (preferably 1 or 2 kinds) of heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, as ring atoms.

The aromatic heterocyclic ring include 5 - or 6-membered aromatic monocyclic heterocyclic rings such as furan, thiophene, pyrrole, oxazole, isoxazol, thiazole, isothiazol, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazin, triazine and the like; 8-12-membered condensed aromatic heterocyclic group, such as benzofuran, isobenzofuran, benzo[b]thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, benzopyran, 1,2-benzothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, hinzelin, cinoxacin, phthalazine, naphthiridine, purine, pteridine, carbazole, α-carbolin, β-carbolin, γ-carbolin, acridine, phenoxazin, phenothiazines, fenesin, phenoxathiin, tianren, phenanthridine, phenanthroline, indolizine, pyrrolo[1,2-b]pyridazine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,5-a]p is ridin, imidazo[1,2-b]pyridazin, imidazo[1,2-a]pyrimidine, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazine and the like (preferably a heterocyclic ring in which the specified 5-6-membered monocyclic aromatic heterocyclic ring condensed with a benzene ring or a heterocyclic ring, in which the same or different two of the above 5-6-membered monocyclic aromatic heterocyclic rings are condensed, and more preferably a heterocyclic ring in which the above 5-6-membered monocyclic aromatic heterocyclic ring condensed with the benzene ring ring) and the like.

The ring is preferably monocyclic aromatic heterocyclic ring, a benzene ring or the like and, among others, preferred is a 5-membered monocyclic aromatic heterocyclic ring such as pyrazole, imidazole, thiazole, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole or the like.

Although the ring may be an aromatic ring containing a hydrogen atom which can be deprotonated, or aromatic ring containing no hydrogen atom, which can be deprotonated, but preferred is an aromatic ring not containing a hydrogen atom which can be d is protonated. Aromatic ring not containing a hydrogen atom which can be deprotonated, includes in addition to the aromatic ring, initially containing no hydrogen atom, which can be deprotonated (for example, benzene ring, a thiazole, oxazole, isoxazol, 1,2,4-oxadiazole, 1,3,4-oxadiazole and so on), aromatic ring, in which the hydrogen atom, which can be deprotonated is substituted (for example, pyrrole, pyrazole, imidazole, etc., the hydrogen atom which nitrogen atom constituting the ring is substituted or associated with X1Aand/or X1bthrough constituting a ring nitrogen atom).

Deputy, which may have an aromatic ring optionally additionally substituted aromatic ring"represented by ring C includes (i) carboxyl group optionally esterified with an optionally halogenated1-6alkyl group or an optionally halogenated6-10aryl-C1-4alkyl group (for example, stands, ethyl, propylene, isopropyl, bootrom, tert-bootrom, phenyl, benzyl, etc.), (ii) the group of phosphoric acid, optionally mono - or disubstituted with optional halogenated1-6alkyl group (for example, stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl, n-Pentium, isopentyl, neopentyl is m, the hexyl and so on) or With2-7alkanoyloxy-C1-6the alkyl, such as acetoxymethyl and pivaloyloxymethyl, (iii) a sulfonic acid group, (iv) sulfonamidnuyu group, optionally substituted by optionally halogenated1-6alkyl group or an optionally halogenated6-10aryl-C1-4alkyl group (for example, stands, ethyl, propylene, isopropyl, bootrom, tert-bootrom, benzyl, etc.), (v) hydroxyl group and a sulfhydryl group which may be optionally substituted by optionally halogenated1-3alkyl group (for example, stands, ethyl, propylene, etc.), (vi) karbamoilnuyu group, (vii) phenyl group, optionally substituted by 1-5 substituents [e.g., hydroxyl group, chlorine, fluorine, aminosulfonyl group, amino group, optionally substituted C1-3alkyl group (for example, stands, ethyl, propylene and so forth] and is not necessarily associated with the aromatic ring is O or S, (viii) an amino group, optionally mono - or disubstituted by optionally halogenated1-3alkyl group (for example, stands, ethyl, propylene, etc.), (ix) cyclic amino group, optionally substituted With 1-31-3the alkyl (for example, stands, ethyl and so on), benzyl, phenyl and the like (for example, 5-6-membered cyclic amine which the group optionally containing in addition to the nitrogen atom an oxygen atom or a sulfur atom as atom forming part of a ring, such as a cyclic amino group produced by removing one hydrogen atom from a cyclic amine such as piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazin, 1,2,3,4-tetrahydroisoquinoline or phthalimide), (x) 5-6-membered aromatic heterocyclic group containing 1-4 heteroatoms selected from N, O and S, and optionally associated with the aromatic ring via O or S (for example, pyridyl, imidazolyl, indolyl, tetrazolyl etc.), (xi) a halogen atom (e.g. chlorine, fluorine, bromine, iodine, etc.), (xii)1-4alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.)1-4alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc) or With1-4allylthiourea (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio and so on), each of which may be substituted by the Deputy selected from a halogen atom, a C1-4alkoxygroup,1-4allylthiourea, carboxyl and phenyl, (xiii)5-7cycloalkyl group (for example, cyclopentyl, cyclohexyl, cycloheptyl etc.) and (xiv) optionally halogenated1-7Alcano is hydroxy (e.g., formyloxy, acetoxy, propionyloxy, butyryloxy, tert-butoxycarbonylamino, isobutyryloxy, valeriote, pivaloyloxy etc). "Optional optionally substituted aromatic ring may be substituted by 1-6, preferably 1-3 above mentioned substituents at substitutable positions. Two of these substituents may together form With3-6alkylen,3-6alkylene,3-6alkylenedioxy or the like. For example, when two adjacent substituent in the phenyl group are linked together, they form With4alkylen, tetrahydronaphthalene group.

The lower alkyl group "lower alkyl group optionally substituted by an optionally substituted hydroxyl group"represented by the symbol R1includes, for example, With1-6alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl and the like. Of these is preferred With3-6alkyl group, and more preferable From4-5an alkyl group. Incidentally, it is preferable branched C4-5alkyl group such as isobutyl, neopentyl or the like.

Deputy, which may contain lower alkyl group "lower alkyl group optionally substituted by an optionally substituted hydroxyl GRU who sing", represented by the symbol R1includes hydroxyl group, optionally substituted C2-20alkanoyl or1-7the alkyl. Specified Deputy includes, for example, hydroxyl group, atomic charges (acetoxy), propionyloxy, tert-butoxycarbonylamino, palmitoleic, dimethylaminoethoxy, 2-aminopropionic and the like. The lower alkyl group may be substituted by 1-3 mentioned substituents at substitutable positions.

Examples R1include 1-propyl, 1-isopropyl, 1-isobutyl, 1-neopentyl, 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2-acetoxymethyl-2-methylpropyl, [1-(hydroxymethyl)cyclobutyl]methyl, and the like. Of them, preferred is 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2-acetoxymethyl-2-methylpropyl and the like.

Lowest alkylen "optionally substituted lower alkylene"represented by X1Aincludes, for example, With1-6alkylene, such as methylene dimetilan, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. Of them, preferred is an unbranched1-4alkylene, such as methylene dimetilan, three is the ethene, tetramethylene or the like, and more preferred is an unbranched1-3alkylen.

Deputy, which may contain low alkylen "optionally substituted lower alkylene"represented by X1Aincludes the same groups described above as examples for the substituent, which may contain an aromatic ring optionally additionally substituted aromatic ring"represented by ring, oxoprop and the like. "Lower alkylene" may be substituted by 1-6, preferably 1-3 mentioned substituents at substitutable positions.

X1Arepresents preferably a bond or unbranched1-3alkylene and particularly preferably methylene.

Lowest alkylen "optionally substituted lower alkylene"represented by X1bincludes the same groups described above as examples of the lower alkylene "optionally substituted lower alkylene"represented by X1A. Deputy, which may contain low alkylen "optionally substituted lower alkylene"represented by X1bincludes the same number of the same groups, as indicated as an example for the Deputy, which may contain low alkylen "optionally substituted lower alkylene"presented sup> 1A.

X1brepresents preferably a bond or unbranched1-3alkylene and particularly preferably a bond.

X2represents preferably a link.

"Divalent hydrocarbon group" of the "optionally substituted divalent hydrocarbon group"represented by X3includes a group formed by removing one hydrogen atom from a hydrocarbon group. The hydrocarbon group includes C1-7unbranched or branched alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, neopentyl, hexyl, heptyl), C3-7cycloalkyl group (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl etc), unbranched or branched C2-6alkenylphenol group (for example, vinyl, allyl, Isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.), C6-10aryl group (e.g. phenyl, naphthyl), C7-14arylalkyl groups is (for example, benzyl, phenethyl, naphthylmethyl) and the like.

Deputy, which may contain "divalent hydrocarbon group" of the "optionally substituted divalent hydrocarbon group"represented by X3includes the same group as the above as the examples of substituent which may contain lower alkylene "optionally substituted lower alkylene", represented by the symbol X1Anot necessarily halogenated1-6alkylidene (for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene etc), vinyliden, cyclohexylidene, benzylidene and the like. "Divalent hydrocarbon group" may be substituted by 1-6, preferably 1-3 mentioned substituents at substitutable positions.

"Divalent hydrocarbon group" of the "optionally substituted divalent hydrocarbon group"represented by X3includes (1) unbranched or branched alkylene, in which the number of carbon atoms in the unbranched part of the chain equals 1-7, preferably 1-4) (for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, propylene, utilitiles, ethylethylene, propylethylene, mutilation, methyltyramine, metallisation etc.), (2) the carbon chain containing the double bond, with the number of carbon atom is in, the components of the unbranched part of the chain equal to 2-7 (preferably 2-4) (for example, vinile, propylen, butylen, butadienyl, methylpropenyl, ethylpropane, popypropylene, methylbutadiene, ethylbutanol, propylbetaine, methylbutadiene, ethylbutylamine, propylbetaine, penttinen, hexarelin, heptenyl, pentadienyl, hexadienyl, heptadienyl etc.), (3) phenylene (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, etc.) and (4) of the divalent group in which a phenylene and alkylene and/or albaniles combined with each other (for example, -CH2-C6H4-, -CH2CH2-C6H4-, -CH2-C6H4-CH2and so on).

X3represents preferably1-4alkylene, such as methylene, ethylene, trimethylene, tetramethylene or the like, vinile, propylen, phenylene or the like.

"Optionally esterified or adaderana carboxyl group"represented by the symbol Y, includes carboxyl, lower alkoxycarbonyl containing 2-7 carbon atoms (e.g., methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, second-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol etc.)7-14aryloxyalkyl (for example, phenoxycarbonyl, 1-naphthoxy bonil), With8-12Uralelectromed (for example, benzyloxycarbonyl etc), carbarnoyl, N-C1-6allylcarbamate, N,N-dis1-6allylcarbamate, N-C8-12aralkylamines, N,N-dis8-12aralkylamines, 1-pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinomethyl and the like. Of them Y is preferably carboxyl, methoxycarbonyl, etoxycarbonyl or the like, and particularly preferably carboxyl.

The compound represented by the formula [I]includes particularly preferably 3-(2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,3-thiazol-5-yl)propionic acid, 3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)propionic acid, 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)propionic acid, 2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid, 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid, 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin the-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid, 5-(3-{[(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-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid and the like.

The compound represented by the formula [I]may be in free form or in the form of pharmacologically acceptable salts, and both forms are included in the scope of the present invention. When the compound represented by formula (I)has an acidic group such as carboxyl group, etc., it can form a salt with inorganic bases (e.g. alkali metal such as sodium, potassium, etc., alkaline earth metal such as calcium, magnesium, etc., transition metal, such as zinc, iron, copper, etc), or organic bases (e.g. organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanol-amine, diethanolamine, triethanolamine, Tris(hydroxymethyl)methylamine, dicyclohexylamine N,N'-dibenziletilendiaminom and tert-butylamine, cosóate amino acids such as arginine, lysine, ornithine and the like).

When the compound represented by formula (I) according to the present invention has a coreómain group, such as amino group or the like, it can form a salt with inorganic or organic acids (e.g. hydrochloric acid, nitric sour is Oh, sulfuric acid, phosphoric acid, carbonic acid, duopoloy acid, formic acid, acetic acid, propionic acid, triperoxonane acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid, etc.) and acidic amino acids such as aspartic acid or glutamic acid.

The compound represented by the formula [I]or its salt has asymmetric carbon atoms at position 3 and position 5 and may be a mixture of stereoisomers. The isomers can be separated by known methods. Preferred is TRANS-form, in which the substituents in position 3 and position 5 is directed in the opposite direction from each other relative to the plane 7-membered ring, and particularly preferred is a compound having an absolute configuration represented by the formula [Ia]. In addition, the compound represented by the formula [I]or its salt can be a racemic form or optically active form, and optically active form can be separated from the racemic forms of the known methods of optical separation.

The prodrug of the compound represented by the formula [I]or the th Sol refers to the connection, which is transformed into a compound represented by the formula [I]or its salt with the chemical interaction with the enzyme or acid of the gastric juice under physiological conditions in vivo, i.e. the compound which is converted to the compound represented by the formula [I]or its salt as a result of enzymatic oxidation, recovery, hydrolysis or the like, or the compound which is converted to the compound represented by the formula [I]or its salt by hydrolysis with acid gastric juice or the like. The prodrug of the compound represented by the formula [I]or its salt includes, when the compound represented by the formula [I]or its salt contains amino group, the compound, the amino group of which allyawan, alkylated or phosphorylated (for example, a compound represented by the formula [I]or its salt, an amino group which eikozanoidov, alanalanalana, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofurfurylamine, pyrrolidinedione, pivaloyloxymethyl or tert-Butlerova and so on); when the compound represented by the formula [I], or its salt contains hydroxyl group, the compound, hydroxyl group which allyawan, alkylated, phosphorylated or Borisovna (for example, a connection, a hydroxyl group cat is cerned azetilirovanna, palmitoylation, propanolamine, pihlajasaari, succinylcholine, omarileaman, alanalanalana or dimethylaminoethylacrylate etc); and, when the compound represented by the formula [I]or its salt of the carboxyl group, the compound, the carboxyl group which etherification or liderovna (for example, a connection, a carboxyl group which utilitarian, phenylacetylamino, karboksimetilcelljuloza, dimethylaminoethylacrylate, pivaloyloxymethyl, ethoxycarbonylmethylene, ftalodinitrilov, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methylethylamine, cyclohexyloxycarbonyloxy or methylaminopropane etc). These prodrugs can be obtained is known per se from compounds represented by the formula [I]or its salt.

The prodrug of the compound represented by the formula [I]or its salt may be a compound that is transformed into a compound represented by the formula [I]or its salt under physiological conditions, as described in Development of Pharmaceutical Products, vol. 7, Molecular Design, 163-198, Hirokawa Shoten (1990).

The compound represented by the formula [I]or its salt can be aqueous or anhydrous.

The compound represented by the formula [I]or its salt can be observed isotope (for example,3 H,14C,35S125I and so on).

The compound represented by the formula [I]or its salt can be obtained, for example, by the engagement of the connection represented by the formula [II]:

where symbols such as defined above, or its derivative with a compound represented by the formula:

where symbols such as defined above, or its salt is known per se (for example, "Comprehensive Heterocyclic Chemistry", ed. by A.R.Katritzky and C.W.Rees, vol.4-6, Pergamon Press, Oxford, 1984), or education then aromatic heterocyclic ring cyclization reaction.

The combination of functional groups involved in the response of the education aromatic heterocyclic ring"represented by the symbol Z1and Z2includes, for example:

(1) one is a carboxyl group, and the other 2 - aminoalkanoic group,

(2) one is a carboxyl group, and the other hydrazide,

(3) one is thiocarbamoyl group, and the other alkanoyloxy group substituted by a halogen atom in position 2, and

(4) one is a N-hydroxyamides, and the other is a carboxylic acid halide, or the like.

The method of obtaining the compound represented by the formula [I'], includes the process And about the ECC and the like, where the source material is used as a compound represented by the formula [II'], or a subclass thereof.

Method And

Method In

where Z1Ais hydroxyimino or sulfur atom, Z2Arepresents a methylene group or aminogroup and Z2brepresents a halogen atom or a lower alkyl group in which the carbon atom adjacent to a carbonyl group substituted by one halogen atom.

In the first stage, the method of obtaining the compound represented by the formula [IV]of the compounds represented by the formula [II'], or its derivative and a compound represented by the formula [III]includes, for example, a process comprising the condensation of a compound represented by the formula [II']and compounds represented by formula [III], using the well-known dehydratation-condensing agent in the presence of both compounds at the same time, the method including activating the carboxylic acid compounds represented by the formula [II'], a well-known activation method, and then its interaction with the connection, represented by the formula [III], and the method including the interaction derived compounds represented by the formula [II'], with the compound represented by the second formula [III].

Dehydratation-condensing agent includes, for example, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, hexaflurophosphate 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium, and the like.

The method of activating the carboxylic acid includes, for example, the way of transformation of a carboxylic acid anhydride of the acid using chloroformiate, pivaloyloxy or the like, the conversion of carboxylic acid to the acid chloride acid using oxalicacid, thionyl chloride or the like, the esterification of carboxylic acid 1-hydroxybenzotriazole using dehydratation-condensing agent or the like, and the like.

The way the interaction is derived compounds represented by the formula [II'], with the compound represented by the formula [III]includes heating the ester derivative of the compound represented by the formula [II'], in the presence of compounds represented by formula [III].

The compound represented by the formula [III]can be obtained, for example, in accordance with the publication Convenient Syntheses of δ-Aminolevulinic Acid, Ayelet Nudelman and Abraham Nodelman, Synthesis 1999, No. 4, pp568-570.

In stage 2 of the method of obtaining the compound represented by the formula [I], compounds represented by the formula [IV]includes processing what eaction of Lesson (Lawesson) or phosphorus oxychloride (POCl 3).

In stage 3, the method of obtaining the compound represented by the formula [V], of the compounds represented by the formula [II'], or its derivative includes, for example:

1) obtaining the compound represented by the formula [V], using as the intermediate compounds represented by the formula [VIII]:

obtained from compound represented by the formula [II'], commonly known method of amidation;

2) obtaining the compound represented by the formula [V], using as the intermediate compounds represented by the formula [IX]:

where X1A'represents an optionally substituted lower alkylene, obtained by the reaction of recovery carboxylic acid or its derivative, of the compounds represented by the formula [II'], or its derivative;

3) obtaining the compound represented by the formula [V], using as the intermediate compounds represented by the formula [X]:

obtained well-known reaction recovery carboxylic acid or its derivative of the compound represented by the formula [II'], or its derivative, or a well-known oxidation reaction of the alcohol of the compound represented by the formula [I];

or something.

The way amidation includes condensation with ammonia or 1-hydroxybenzotriazole (HOBt·NH3) using dehydration-condensing agent, and obtaining the amide represented by the formula [XI]:

where L1represents a protective group for the amino group, followed by removal of the protective group for amino group.

The reduction of carboxylic acid or its derivative involves the reaction of recovery of carboxylic acid or carboxylic acid derivative using a reducing agent such as sociallyengaged, diisobutylaluminium, borohydride sodium or the like.

Roccia oxidation of the alcohol includes, for example, processing a complex of sulfur trioxide and pyridine or oxalylamino in dimethyl sulfide, oxidation using an oxidant, such as chlorproma pyridinium or reagent dessa-Martin, etc. and the like.

The method of obtaining the compound represented by the formula [V], of the compounds represented by formula [VIII], includes, for example, processing anhydride, such as anhydride triftormetilfullerenov acid, processing dehydratation-condensing agent such as carbonyldiimidazole, in the presence of allylbromide and the like.

The method of obtaining the compounds is of, represented by the formula [V], of the compounds represented by the formula [IX], includes, for example, converting a hydroxyl group in the substituted group, followed by treatment with cyanide, the reaction Mitsunobu in the presence of cyanide, such as acetonecyanohydrin (processing derivatives of azodicarboxylic acid, such as 1,1'-(azodicarbon)dipiperidino, and an organic compound of phosphorus, such as tri-n-butylphosphine or triphenylphosphine, and the like.

The method of obtaining the compound represented by the formula [V], of the compounds represented by the formula [X], includes, for example, communication using an oxidant such as iodine in aqueous ammonia, the Wittig reaction using a complex ester of phosphoric acid, containing in its molecule a cyano, such as diethyl ether complex cyanomethylphosphonate acid, followed by hydrogenation reaction, and the like.

In stage 4, the method of obtaining the compound represented by the formula [VI]of the compounds represented by the formula [V], includes, for example, treatment of compounds represented by formula [V], complex diethyl ether dithiophosphoric acid or the like, processing hydroxylammonium in the presence of alkali, such as sodium bicarbonate.

Furthermore, the method of obtaining the compound represented by the formula [VI], including the AET, for example, the processing method of the connection represented by the formula [VIII], sulfureous agent such as pentasulfide of Diaspora and the like.

At stage 5, the method of obtaining the compound represented by the formula [I], compounds represented by the formula [VI], and compounds represented by the formula [VII], includes, for example, heating the compounds represented by the formula [VI]in the presence of compounds represented by formula [VII], and the like.

Among the compounds represented by formula [VII], a compound represented by the formula [XII]:

where Z3represents a lower alkyl group, in which it is substituted by a halogen atom at the carbon atom adjacent to the carbonyl group can be obtained, for example, the implementation of the method, or the like.

Way

where Z4represents a halogen atom.

At stage 6, the method of obtaining the compound represented by the formula [XII], of the compounds represented by formula [XIII], includes, for example, interaction with diazomethane or trimethylsilyldiazomethane in a solution of Hydrobromic acid in acetic acid, and the like.

In each reaction of the production method of compound [I] or its salt in each reaction of the synthesis of the starting compounds described to enter the, when the original connection has amino group, carboxyl group or a hydroxy-group as a substituent, such Deputy may be protected by a protective group commonly used in the chemistry of peptides, or the like. Upon completion of the reaction, if necessary, the protective group can be removed to obtain the desired connection.

The protective group for the amino group includes, for example, formyl, C1-6alkylsulphonyl (for example, acetyl, ethylcarboxyl etc), phenylcarbinol,1-6allyloxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl etc), vinyloxycarbonyl,7-10aralkylamines (for example, benzylcarbamoyl etc), trityl, phthaloyl, N,N-dimethylaminomethylene and the like, each of which may be optionally substituted. As Deputy for use halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.)1-6alkylsulphonyl (for example, methylcarbamoyl, ethylcarboxyl, butylcarbamoyl etc), the nitro-group or the like, and the number of substituents is about 1-3.

The protective group for carboxyl group includes, for example, With1-6alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl etc), phenyl, trityl, silyl and the like, each of which may be optionally substituted. As a Deputy used a halogen atom (the example fluorine, chlorine, bromine, iodine and so on), formyl, C1-6alkylsulphonyl (for example, acetyl, ethylcarboxyl, butylcarbamoyl etc), the nitro-group or the like, and the number of substituents is about 1-3.

The protective group for the hydroxy-group includes, for example, With1-6alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl etc), phenyl, C7-10aralkyl (e.g., benzyl etc), formyl, C1-6alkylsulphonyl (for example, acetyl, ethylcarboxyl etc), vinyloxycarbonyl, benzoyl,7-10aralkylamines (for example, benzylcarbamoyl etc), pyranyl, furanyl, silyl and the like, each of which may be optionally substituted. As a Deputy used a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.)1-6alkyl (e.g. methyl, ethyl, n-propyl, etc.), phenyl, C7-10aralkyl (e.g., benzyl etc), the nitro-group or the like, and the number of substituents is about 1 to 4.

The method of removal of the protective group can be both known and similar way. For example, use the method that contains treatment with an acid, a base, restoration, ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium, palladium acetate or the like.

In addition, in each reaction of the method of obtaining the compounds is of [I] or its salt in each synthesis reaction starting materials, described above, can be used widely known solvent.

Widely known solvent includes, for example, ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and 1,4-dioxane; esters such as ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene and toluene; an aromatic heterocyclic compounds such as pyridine and lutidine; amides such as N,N-dimethylformamide and N-organic; halides such as chloroform and methylene chloride; alcohols, such as methanol, ethanol, 2-propanol and 2,2-dimethylethanol; hydrocarbon compounds such as hexane, heptane and petroleum ether; carboxylic acids such as formic acid and acetic acid; water and the like.

The solvent used in the reaction may be a single solvent or a mixture of 2-6 solvents.

The reaction can also be carried out in the presence of a base such as amines, such as triethylamine, N,N-Diisopropylamine, pyridine or N-methylmorpholine, sodium hydroxide, potassium carbonate or the like.

The reaction can also be carried out in the presence of acid, such as hydrochloric acid, sulfuric acid, acetic acid or the like.

The compound represented by the formula [I]or its salt obtained by the methods described above can be provided which are cleaned or traditional partitioning methods, such as recrystallization, distillation, chromatography or the like. When obtained in the manner described above, the compound represented by the formula [I] of the present invention, is a free compound, it can be converted into salt known per se method or equivalent method (for example, neutralization, and so on). On the contrary, when the connection get in the form of a salt, it can be converted into the free compound or another salt known in itself, or its equivalent way. When the compound obtained is a racemic form, it can be divided into d-form and l-form of the traditional optical methods division.

Starting compound represented by the formula [I]or its salt can also be in the form of salts, such salts of the compounds represented by the formula [I], but the type of salt is not particularly limited, if only she had not violated the response.

The compound represented by the formula [II]or its derivative can be obtained, for example, by the method described in EPA567026, WO95/21834 (PCT application is based on application No. 6-15531 patent Japan), EPA645377 (application based on application No. 6-229159 patent Japan), EPA645378 (application based on application No. 6-229160 patent Japan) or JP-A 9-136880 or similar method.

Since the compound represented by formula (I)or its salt or prodrug (hereinafter sometimes the " just as the compound (I), including its salt and prodrug) viscotoxin and has inhibitory activity against squalene-synthase, LDL cholesterinspiegel activity, triglyceridemia activity, lepidophyma activity, non-HDL cholesterinspiegel activity and HDL cholesterinspiegel activity, it is useful as a safe drug for the prevention or treatment of hyperlipemia, such as hypercholesterolemia, hypertriglyceridemia or hyposplenia in a mammal (e.g. mouse, rat, rabbit, dog, cat, cattle, pig, monkey, human and the like), and is also useful as a safe drug for the prophylaxis or treatment of metabolic syndrome. In addition, the compound is useful as a safe drug for the prophylaxis or treatment of renal diseases such as nephritis or nephropathy, arteriosclerosis, coronary artery disease, myocardial infarction, angina, heart failure, aneurysm, cerebral arteriosclerosis, cerebral apoplexy, transient ischemic stroke, cerebral infarction, peripheral arteriosclerosis, intermittent claudication, thrombosis, hypertension, osteoporosis, diabetes (e.g., type-dependent insulin resistance, and the like), diabetic complications (such as the er, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic angiopathy, and the like), pancreatic disorders or restenosis after percutaneous intraluminal coronary angioplasty (RTSA) or stent placement.

Further purpose of the present invention is described in more detail.

The compound (I) has a high triglyceridemia activity and cholesterinspiegel activity, as well as excellent biological properties and are particularly suitable for the treatment or prevention of hyperlipemia, particularly hypertriglyceridemia, hyperlipoproteinemias and hypercholesterolemia, as well as the resulting metabolic syndrome and atherosclerotic paragenesia vessels and secondary diseases, such as coronary artery disease, heart attack, angina, heart attack, brain, cerebral ischemia, intermittent claudication, peripheral arteriosclerosis, gangrene and the like.

For the treatment of these diseases the compound (I) can be used separately or in combination with other medicinal components such as lepidosirenidae tool, cholesterinspiegel tool, a means to increase the level of HDL, or an inhibitor of cholesterol intake (by simultaneous administration or administration with some inter the ALOM). In this case, these compounds are preferably administered in the form of oral medications (including tablets, disintegrating in the mouth) or, if necessary, they can be entered as rectal preparations in the form of a suppository. In this case, the possible components for the combined applications include, for example, an agonist of PPARαsuch as fibrates [e.g., Clofibrate, Bezafibrate, Gemfibrozil, Fenofibrate, Wy-1463, GW9578, and the like], and cholesterinspiegel tool, such as nicotinic acid and its derivatives and analogues [e.g., Acipimox and probucol], a resin that binds bile acids [e.g., Cholestyramine, Colestipol and the like], a compound that inhibits the absorption of cholesterol [for example, Ezetimibe, Sitosterol, Neomycin, and the like], a connection that inhibits the biosynthesis of cholesterol [for example, an inhibitor of HMG-CoA reductase inhibitor such as Lovastatin, Simvastatin, pravastatin, Atorvastatin, ZD-4522 (Rosuvastatin), Itavastatin and the like], an inhibitor of squalene-epoxidase [for example, NB-598 and its counterpart, and the like] or the agent that increases the level of HDL due to inhibition of protein that carry the cholesterol ester [for example, JTT-705, CP-529-414 and the like]. In addition, possible combination with an inhibitor of acyl-Coenzyme A-cholesterol-acyltransferase (ACAT; ASAT) (for example, melinamide and so on) is whether the means regressing rich lipid plaques (for example, compounds described in WO 02/06264, WO 03/059900 etc). It is also possible to combination with means for decreasing the amount of fat in the body, such as an inhibitor of pancreatic lipase (e.g., orlistat and so on).

Another possible component for the combined application includes the inhibitor occidentalis-lanosterol-cyclase activity, for example derived decalin, derived Azadegan and derivative Indiana.

In particular, in combination with an inhibitor of HMG-CoA reductase inhibitor, can reduce myalgia and miles, which are also side effects of the inhibitor of HMG-CoA-reductase. In addition, this combination not only has lepidophyma activity, but also effective against osteoporosis and Alzheimer's disease and may improve the prognosis of coronary heart disease (apoplexy of the brain, heart attack, or the like).

In addition, the compound of formula (I) are applicable for the treatment of diseases associated with hyperchylomicronemia, such as acute pancreatitis. As for the mechanism of pancreatitis, it is considered that the chylomicrons cause microembolization in the blood capillary of the pancreas or because of hyperchylomicronemia increases the production of free fatty acid in the decomposition of triglycerides by pancreatic lipase, which leads to increased IU the spas irritation free fatty acid and to the development of pancreatitis. Thus, since the compound of the formula (I) according to the present invention has triglyceridemia activity, it can treat pancreatitis and can be used to treat pancreatitis alone or in combination with the known method of treatment. For the treatment of this disease, the compound (I) can be administered orally or topically and can be used separately or in combination with known active connection. Examples of components that can be combined in this case, include Aprotinin (Trasilol), gabexate (FOY), nafamostat (Pusan), citicoline (St. Nicholas), ulinastatin (Miracle) and the like for antifermentny treatment. In addition to relieving pain using an anticholinergic drug, a non-narcotic analgesic or drug.

Another significant example of the application of compound (I) is used for the treatment of secondary hyperlipidemia. For disease, including diabetes, hyperthyroidism, nephrotic syndrome or chronic renal insufficiency, and the like, begins to develop hyperlipidemia. In many cases, hyperlipidemia exacerbates these diseases, there forms a vicious circle. Thanks to its lepidophyma activity of compound (I) is also applicable to the treatment of the above diseases or prevent R is Suite, and in this case it may be administered separately or in combination with the following medicines:

medicines for the treatment of diabetes mellitus: Kinetic, Panfil, Humulin, Euglucon, Glypican, Daonil, Novolin, Monotard, insulin, Glucobay, Damelin, Ristinen, ballkan, Damelin S, illini; amplifiers insulin sensitivity (thiazolidinone and nationaleconomy PPAR agonists: pioglitazone, Avandia, KRP-297, TAK-559, MCC-555, etc., isoxazolidinone drugs: JTT-501, etc.), biguanide medicines (for example, mitiglinide etc), drugs that promote insulin secretion (for example, funds for the basis of sulfonylurea and so on), inhibitors α-glucosidase (for example, voglibose etc), β3agonists (e.g., TAK-677 etc), insulin, etc.;

medicines for the treatment of hypothyroidism: dried thyroid gland (Thyroid), levothyroxine sodium (Tradin S), liotironin-sodium (Teronen, Tianamen);

medicines for the treatment of nephrotic syndrome: prednisolone (Predomin), succinate prednisolone-sodium (Predomin), succinate methylprednisolone-sodium (solu-Medrol), betamethasone (Landeron);

means for anticoagulant therapy: dipyridamole (Persantin), diasappeared (Comedian) and the like;

medicinal medium spans the VA for treatment of chronic renal failure, diuretic [for example, furosemide (Lasix), bumetanide (Lunation), azosemide (Diart) etc.], ACE inhibitors (e.g. enalapril maleate (Renewal) etc.), antagonists of angiotensin II receptor [e.g., candesartan cilexetil (Blopress), losartan-potassium (Noloten), valsartan (Diovan), irbesartan etc.] antagonists of CA (mangiron)), blockers αreceptors, and the like.

In combination with these drugs, the compound (I) may preferably be administered orally.

Since hyperlipidemia aggravates atherosclerosis and causes hypertension, compound (I) is applicable for the treatment or prevention of hypertension, and in this case, the compound (I) may be introduced separately or in combination with other medicines listed below. Examples of possible combinations in this case include antagonists of angiotensin II [e.g., losartan-potassium (Nu-Lotan), candesartan cilexetil (Blopress) and the like], ACE inhibitors [e.g., enalapril maleate (Renewal), lisinopril (Zestril, Lunges), deeplinked (Adecal), captopril, and the like], a calcium antagonist [e.g., amlodipine besilate (amlodin, norvasc), manydimensional (Callot) and the like], hypotensive diuretics, blockers αreceptor blockers βreceptors and the like.

Another important indication is for the compound (I) is osteoporosis, accompanied by the increase of cholesterol in the blood. Thanks to its high lepidophyma activity of compound (I) can be used to treat or prevent osteoporosis, accompanied by the increase of cholesterol in the blood, and in this case, the compound (I) can be entered separately or in combination with other medicines listed below. Examples of possible combinations in this case include sex hormones and related drugs [e.g., estrogen, ipriflavon (Austen), raloxifene, asteron, tibolone, and the like], an inhibitor of bone resorption, such as calcitonin, vitamin D [e.g., alfacalcidol, calcitriol, and the like], bisphosphonates (eg, etidronate, clodronate and the like) and the like, a means of accelerating bone formation, such as a compound of fluorine, PTH (PTH) and the like.

Following the possible use of compound (I) is used for the inhibition of thrombus formation. Because the level of triglycerides in the blood and factor VII, which is involved in blood coagulation, positively correlated, and the absorption of fatty acids ω-3 reduces the level of triglycerides and inhibits coagulation, hypertriglyceridemia accelerates the formation of blood clots. In addition, since VLDL gipolipidemicheskoe patient is elinee increases the secretion of an inhibitor of plasminogen activation of endothelial cells of blood vessels, than VLDL entity normalny level of lipids in the blood, it is considered that the triglyceride (hereinafter referred to as TG (TG)) reduces fibrinolytic capacity. Therefore, by his triglyceridemia activity of compound (I) are suitable for the prevention or treatment of thrombosis. In this case, the connection can be used, preferably by oral administration alone or in combination with known drugs listed below.

Medicines that prevent blood clots: inhibitors of blood coagulation [e.g., heparin sodium, heparin calcium, warfarin calcium (Warfarin), etc.], thrombolytic drugs [e.g., urokinase], medicines against platelet aggregation [e.g., aspirin, sulfinpirazon (Anturan), dipyridamole (Persantin), ticlopidine (Panaldine), Cilostazol (Pletal), clopidogrel etc].

Further, the compound (I) has a high activity in raising the level of complex high-density lipoprotein - cholesterol and viscotoxin. Therefore, these compounds and their salts can be safely used as, for example, means for the prevention or treatment of primary lipoprotein low or high density-cholesterolemia, diseases of Tangle (Tangier) or the like, as well as tools for preventive care is IKI or treatment of myocardial infarction, atherosclerotic disease, hyperlipidemia, mixed lipid disorders, diabetes, diabetic complications or the like and can be used for prevention or treatment of arteriosclerosis, hyperlipemia, hypertension, diabetes, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, arrhythmia, diseases of the peripheral blood vessels, thrombosis, pancreatic disorders, ischemic heart disease, cerebral ischemia, myocardial syndrome, heart failure, valve disease of heart or Alzheimer's disease in mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, cattle, horse, sheep, monkey, human etc). In addition, compound (I) is suitable for the treatment and prevention of hipolite, diseases of Tangle and coronary heart disease, which often develops in a patient with diabetes after menopause. Further, the compound (I) are particularly suitable for the treatment and prevention of hyperlipemia, particularly hypertriglyceridemia, hyperlipoproteinemias and hypercholesterolemia, as well as caused by atherosclerotic vascular lesions and their secondary diseases, such as coronary vessels, cerebral ischemia, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis,intermittent claudication, gangrene and the like.

A significant example of another application of the compound (I) is the prevention or treatment of Alzheimer's disease. Risk factor for Alzheimer's disease is known to increase cholesterol levels in the blood. Due to its high activity in improving the content of the complex high-density lipoprotein - cholesterol and the lipid-lowering, the compound (I) can be used for prevention or treatment of Alzheimer's disease, and for this purpose it may be introduced separately or in combination with the following medicines. In this case, the possible combination includes a combination with acetylcholinesterase inhibitor (e.g., such as Aricept, Exelon and the like), an inhibitor of the production or secretion of amyloid β (e.g., inhibitor γor β-secretase, such as JT-52, LY-374973 and the like or SIB-1848, and the like), an inhibitor of coagulation amyloid β (e.g., such as PTI-00703, BETABLOC (AN-1792), and the like) and the like.

Further, since the compound (I) has activity in reducing blood glucose and is active in reducing blood glucose in rats with diabetes type diabetes fat, it improves insulin resistance. With regard to its biological properties, it is especially useful for Professor the prevention or treatment of hyperglycemia, and are caused by secondary diseases, such as complications observed in the stage of diabetic nephropathy and renal failure, disease of the circulatory system, such as anemia, abnormal metabolism in the bones, vomiting, nausea, lack of appetite and diarrhea, neurosis, such as neuropathy, diabetic neuropathy, diabetic retinopathy, diabetic angiopathy, as well as insulin resistance and are caused by diseases such as hypertension and impaired toleratethe to glucose, and a secondary disease, such as heart disease, heart failure, ischemic heart disease, cerebral ischemia, intermittent claudication and gangrene.

For treatment of the above diseases, the tool of the present invention to improve the content of the complex high-density lipoprotein - cholesterol can be used separately for the prevention or treatment or in combination with other means to reduce the level of glucose in the blood or antihypertensive agents. In this case, these compounds are preferably administered in the form preparations for oral administration (including disintegrating in the mouth tablets). Alternatively, they may optionally be introduced in the form of preparations for rectal injection in the form of a suppository. Possible to combine components include (1) preparation of insulin (e.g., the forehead is aceski insulin and the like), (2) means on the basis of sulfonylureas (e.g. glibenclamide, gliclazide, glimepiride and the like), (3) inhibitor α-glucosidase (e.g., voglibose, acarbose and the like), (4) amplifier insulin sensitivity (e.g., pioglitazone, rosiglitazone and the like), (5) inhibitor alsoreported (for example, Epalrestat, Corestat and the like), an inhibitor of glycation (for example, aminoguanidine, and the like).

It is also possible to combination with treatment for gynecological diseases (treatment for climacteric disorders (conjugated estrogen, estradiol, testosterone enanthate and estradiol valerate, and the like), treatment for breast cancer (tamoxifen citrate and the like), a treatment for endometriosis and hysteromyoma (leiprorelina acetate, danazol, and the like) and the like, or a combination of such drugs with treatment for diabetes.

In addition, possible combination with anti-hypertensive agent, and examples of antihypertensives include (1) diuretic (eg, furosemide, spironolactone, and the like), (2) an inhibitor of sympathetic nerve (e.g., atenolol, and the like), (3) receptor antagonist of angiotensin II (e.g., losartan, candesartan cilexetil, valsartan, irbesartan, olmesartan and the like), (4) in hibitor angiotensin I-converting enzyme (for example, enalapril maleate, deeplinked and the like), (5) calcium antagonist (e.g., nifedipine, manydimensional, amlodipine besilate and the like) and the like.

In addition, it is possible to combination drug for the treatment of chronic heart failure, examples of which include (1) blocker β-receptor, (2) ACE inhibitor [e.g., enalapril maleate (renewal), lisinopril (lunges, zestril etc.)], (3) receptor antagonist of angiotensin II [e.g., candesartan cilexetil (blopress), valsartan, losartan, etc.)], (4) aldosterone antagonist (spironolactone, eplerenone), (5) the endothelin antagonist, (6) the inhibitor of the Na-H exchange, (7) an inhibitor of Na-Ca exchange, (8) MCC-135, and the like.

The compound (I) has a high activity in protecting skeletal muscles. That is, the compound (I) exhibits a therapeutic or prophylactic effect against the state of leaf tissue becoming necrotic or softening of skeletal muscle caused by different factors, such as ischemia, stress, excessive exercise, trauma (hematoma, krovotechenie of skeletal muscle, electric shock, burns, malignant hyperthermia, malignant syndrome, metabolic myopathy, inflammatory myopathy, muscular dystrophy, infection, intoxication, metabolic and hyperthermia. In particular, the compound (I) protects the skeletal muscle is the violations in the cell as a result of the above factors. In addition, compound (I) exhibits a therapeutic or prophylactic effect against myalgia caused by cytotoxicity of other drugs (for example, inhibitors of HMG-COA reductase inhibitor, cyclosporine, fibrate medicines etc), and then acute necrosis of skeletal muscles in severe cases, etc.

In particular, the compound (I) exhibits a high therapeutic or prophylactic effect against myalgia caused by inhibitor of HMG-COA reductase inhibitor, and then serious acute necrosis of skeletal muscle and inhibits the decrease in the content of geranylgeranylpyrophosphate in the muscle cell, called inhibitor of HMG-COA reductase inhibitor (e.g., atorvastatin, lovastatin, simvastatin, pravastatin, rosuvastatin, itavastatin, fluvastatin, tseriwastatina, pitavastatin etc).

The compound (I) exhibits high activity in protecting skeletal muscles and low toxicity. Therefore, the tool of the present invention can safely be applied to, for example, as a means for the prevention or treatment of acute necrosis of skeletal muscles, mioglobinurii associated with acute necrosis of skeletal muscles, or myalgia in a mammal (e.g. mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, human etc).

The compound (I) exhibits high activity in the increase of the content of oubain is on and the prophylactic or therapeutic effect, as well as inhibitory effect against the development of organ dysfunction and the extinction of their functions and therefore useful as a tool for prevention or treatment and for inhibiting the development of disease based on the specified pharmacological activity. In this case, the organ dysfunction includes hypofunction of various organs and its complications and, incidentally, it is preferable ischemic organ dysfunction. That is, the compound of the present invention can prevent the death of cells caused by ischemia or the like, and can protect the function of cells and body and therefore it can also be used as a means to maintain the functions of the body, means for protection of the body, an inhibitor of cell death of an organ or the like. In particular, the compound of the present invention can prevent or treat hypofunction of the heart (including damage to the heart muscle), hypofunction of the brain and the hypofunction of the pancreas as a result of various factors (in particular, based on ischemia) and the extinction of the function of each organ and may hinder progress toward death.

In addition, organ dysfunction may be a specified dysfunction resulting from diseases such as arteriosclerotic diseases (heart attack, angina, heart attack head what about the brain, bleeding in the brain and so on), including ischemic heart disease, or may represent a dysfunction of organs that occur during or after surgery, or organ transplantation. In addition, the tool according to the present invention is applicable also for inhibition of progression, to improve prediction and prevention of secondary development and relapse of disease (in particular, ischemic diseases, such as ischemic heart disease or heart attack brain), which are the cause of the above organs dysfunction.

In this description, the bodies include, for example, brain, liver, kidney, heart, spleen, pancreas, eyes (retina) and nervous tissue (Central nervous tissue, peripheral nervous tissue, etc.); preferably the peripheral nerve tissue and, above all, preferred are the heart and nervous tissue.

The presence of as activity in the inhibition of squalene synthase and activity in the increase of the content of ubiquinone allows the use of a tool for prediction of coronary disease or the like for the brain, heart, kidneys, nervous tissue, pancreas or the like. For example, in the case of the brain (nervous tissue), it becomes possible inhibition of progress to coma, maintaining consciousness or the extension of life is and can be used to treat Parkinson's disease or Alzheimer's disease, resulting from neurodegenerative diseases of the Central nervous system. In addition, treatment is possible numbness of the hands and feet, violations or lack of perception, pain, disturbance of sensitivity to heat, sores or nervous hyporeflexia result in peripheral neuropathy. If the heart becomes possible treatment of heart failure or arrhythmia or prolongation of life. In the case of kidney becomes possible inhibition of progress to dialysis or kidney transplantation or life extension.

The compound of the present invention shows high activity in the increase of the content of ubiquinone, as well as preventive or therapeutic effect against the development of organ dysfunction or extinction of their functions and low toxicity. Therefore, the connection of the present invention can safely be applied to, for example, as a means for prevention or treatment of heart attack, arteriosclerotic diseases, hyperlipemia, heart attack, brain hemorrhage in the brain, neurodegenerative diseases or diabetes or diabetic complications, as well as means for prevention or treatment and for inhibiting the progression of organ dysfunction or extinction of their functions.

The compound (I) can be used to treat or profilaktualisierung, hyperlipemia, mixed lipid disorders, diabetes, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, arrhythmia, peripheral vascular disease, thrombosis, pancreatic disorders, coronary heart disease, CHD (coronary heart disease), cerebral ischemia, heart attack, effects of a heart attack heart disease heart valve or Alzheimer's disease. In addition, compound (I) can be used for prevention or treatment of heart attack, brain, krovoisliania in the brain, pollakiuria, incontinence or worsened bladder emptying due to neuropathy, Parkinson's disease, based on neurodegenerative disease and cerebral vascular dementia in addition to heart failure and renal failure. The compound (I) is applicable also for retaining the death caused by these diseases, or prolong life.

In addition, as it became known, ubiquinone activates UCP (unbound protein). Therefore, the compound (I) is applicable for the prevention or treatment of obesity and is suitable for prevention or treatment associated with obesity, impaired glucose tolerance, diabetes, insulin resistance, hypertension, hyperlipemia or the like.

Pascalc the compound (I) possesses activity in the inhibition of squalene synthase and originalvalue activity in addition to activity in improving lipid metabolism, such as holesterinoponizhayuschim activity, triglyceridemia activity and activity in raising the level of complex high-density lipoprotein-cholesterol (HDL), it can usefully be used to prevent or treat organ dysfunction or fading function of organs, incidentally, organ dysfunction or fading functions of organs resulting from diseases such as arteriosclerotic disease (heart attack, angina, heart attack, brain hemorrhage in the brain and so on), including coronary heart disease. In addition, since the compound (I) has originalvalue activity in addition to lepidophyma activity, it may, for example, to treat ischemic heart disease, to prevent or to treat more severe heart failure and to slow the progression of heart failure to death, and therefore it is very useful compared to lepidosiren means not having originalvalue activity. In addition, in relation to other organs such as the brain, kidney and nervous tissue, the compound (I)possessing in addition to lepidophyma activity originalvalue activity, is excellent from the viewpoint of the ability to prevent or to treat in addition to organ dysfunction fading options and organs or tissues and also has the effect of prolonging life.

When using compounds (I) for the prevention or treatment of the above various diseases it can be used in combination with biologics (e.g., antibodies, vaccine preparations and so on). In accordance with another variant of the compound (I) can be used in combination therapy, in combination with genetic therapy. Antibodies and vaccine preparations include vaccine preparations aimed at angiotensin II, vaccine preparations aimed at SETR, antibodies to SERT, antibodies to TNF-α and antibodies aimed at another cytokine, amyloid-β vaccine drugs and vaccines 1 diabetes-type (DIAPEP-277 of Peptor Company, etc), as well as antibodies or vaccine agents that target cytokines, renin-angiotensin enzymes and their products, antibodies or vaccine agents that target enzymes or proteins involved in lipidil metabolism in the blood, antibodies or vaccine-related enzymes or proteins involved in coagulation or fibrinogenolysis in the blood, and antibodies or vaccine agents that target proteins involved in glucose metabolism or development of resistance to insulin. Genetic therapy includes therapeutic activities using genes associated with cytokine, renin-angiotenzinovymi enzymes and their products, therapeutic activities used in the of DNA trap (DNA decoy), such as NFkB trap, therapeutic activities using antisense agent, a therapeutic activities using the genes related to enzymes or proteins involved in lipid metabolism in the blood (for example, genes associated with metabolism, release or absorption of cholesterol, triglyceride, HDL-cholesterol or phospholipid blood), therapeutic activities using the genes related to enzymes or proteins (for example, growth factors such as HGF, VEGF, and so on)involved in vascularization therapy occlusion of peripheral vessels, therapeutic activities using genes associated with proteins involved in glucose metabolism or development of resistance to insulin, and antisense agent for cytokine, such as TNF. In accordance with another variant of the compound (I) can be used in combination with a method of updating various organs, such as the renewal of the heart, updating the kidneys, the update of the pancreas or revascularization, or vascularization therapy using transplantation of bone marrow cells (mononuclear cell bone marrow, stem cell, bone marrow etc).

When combining the compound (I) with other drugs for use in relation to the above mentioned line is the result of the diseases these active components can be entered as a single tool, obtained by combining them into one product.

The compounds of formula (I) can be applied orally or neironalna by injection, intravenous drip infusion, inhalation, rectal injection or local introduction and you can use them as they are or in the form of pharmaceutical compositions (e.g., powders, granules, tablets, pills, capsules, injectable solutions, syrups, emulsions, elixirs, suspensions, solutions and so on). Then there is at least one compound (I) can be used individually or in a mixture with pharmaceutically acceptable carrier (excipient, filler, additive and/or diluent).

As a drug of the present invention the compound (I), which is the active component can be introduced in the form of loose powder, but it is usually administered in form, is made in the traditional way, in a suitable manner using a suitable number of conventional pharmaceutical carrier, such as a filler (e.g. calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, starch, crystalline cellulose, talc, granulated sugar, porous substances, etc.), binders (for example, dextrin, gums, alcoholicbeverage starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose is s, pullulan etc), baking powder (for example, potassium carboxymethylcellulose, sodium croscarmelose, crosspovidone, nitrosamines hydroxypropylcellulose, partially αstarch and so on), lubricants (e.g. magnesium stearate, calcium stearate, talc, starch, sodium benzoate and so on), the coloring matter (for example, resin, dye, burnt sugar, half iron oxide, titanium dioxide, Riboflavin), corriente (for example, podslushivaet, flavoring and so on), stabilizer (for example, sodium sulfate, etc.) and preservative (for example, parabens, sorbic acid etc). The drug of the present invention, including the above substance typically contains the compound (I) in an amount effective for the treatment and prevention of disease. The content of the compounds of formula (I) in the medicinal product according to the present invention is usually 0.1-100% of the total mass of the preparation. The drug of the present invention may contain as an active component of the medicinal components other than the compound (I), and these components are not particularly limited, but would have achieved the purpose of the invention, and they can be used in appropriate combination ratio. Specific examples of dosage forms include tablets (including tablets with sugar p is a covering and tablets film-coated), pills, capsules, granules, powders, syrups, emulsions, suspensions, injectable solutions, injectable solutions, extended actions, pharmaceutical forms for inhalation and ointments. These drugs made in the traditional way (for example, a method described in the Pharmacopoeia of Japan).

In particular, the tablet can be produced by granulating the compound (I) individually or in a homogeneous mixture of the compound (I) and filler, binder, baking powder or other suitable additives suitable way with the subsequent addition of lubricants or the like and then pressing the obtained granules, direct compaction of the compound (I) individually or in a homogeneous mixture of the compound (I) and filler, binder, baking powder or other suitable additives; or pressing of the granules obtained in advance, separately or in a homogeneous mixture of them and suitable additives. This tablet can optionally contain a dye, corrigent or the like. This tablet can also be covered with a suitable coating agent. The preparation for injection can be produced by dissolving, suspendirovanie or emulsification of a certain amount of compound (I) in water for injection, saline solution, ringer's solution or the like in the case in the underwater solvent or in a traditional vegetable oil or the like in the case of a non-aqueous solvent with a number formed of injection solution, or a certain amount of attachment the compound (I) in the vessel for injection and then the closing of the specified container.

Carrier for oral drug includes substances that are traditionally used in the manufacture of medicines, such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose, etc. Media for injection solution comprises distilled water, saline solution, glucose solution for infusion. In addition, can be appropriately introduced other additives used for conventional drug.

The medicinal substance according to the present invention can also be used in the form of the drug for prolonged action. The preparation of the prolonged action may be a microcapsule (for example, a microcapsule in the form of a microsphere, microparticle, and so on), when it is produced by the method of "drying-in-water (method M/method To/M/, and so on), a phase separation method, a method of drying by atomization or an equivalent method, or the product obtained manufacture of microcapsules or pharmaceutical compositions in the form of spheres, needles, pills, film or paste as a starting material in the form of various dosage forms. Dosage form includes injecting the drug (for example, a drug for injection or implant for implantation intramuscularly, subcutaneously, in the body and so on; II andstc the mucosal remedy for nasal cavity, rectum, uterus etc, etc), and oral medication (for example, hard capsule, soft capsule, granule, powder, suspension etc).

When the preparation of the prolonged action is an injectable solution, injectable solution of the extended action is produced by dispersion of microcapsules in the dispersing agent (for example, surfactants such as Tween 80, HCO-60, etc.; polysaccharides, such as carboxymethylcellulose, Argent sodium, sodium hyaluronate, etc.; protointerface, polyethylene glycol, etc.), preservatives (for example, methylparaben, propyl paraben, etc.), isotonic agents (e.g. sodium chloride, mannitol, sorbitol, glucose etc), local anesthetics (e.g., xylocaine the hydrochloride, chlorobutanol etc), etc. with obtaining aqueous suspension or dispersion of microcapsules in vegetable oil (e.g. sesame oil, corn oil etc) and mix it with phospholipids (such as lecithin, and so on) or triglycerides of medium chain fatty acids (e.g., Miglyol 812 and so on) to obtain an oil suspension.

When the preparation of the prolonged action is a microcapsule, the average diameter of the particles is from about 1 to about 300 microns, preferably from about 1 to about 150 microns, more preferably from about 2 to about 00 microns.

When the microcapsule is made in the form of sterile drug, there is a method containing sterilized at all stages of manufacture, the method containing the sterilized using gamma radiation, the method containing the addition of an antiseptic, etc. but the method is not particularly limited.

The drug of the present invention can be manufactured in the form of the drug to the traditional method. Such a drug can usually be produced by blending and mixing the active component with an additive such as an excipient, diluent or carrier. "Parenteral" introduction when used in this description includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection and infusion. The preparation for injection, for example a sterile aqueous or oily suspension for injection, can be fabricated using a suitable dispersing agent or wetting agent and a suitable suspending agent method known in the art. A sterile preparation for injection can be a sterile injectable solution or suspension in a diluent or solvent, which traveler is non-toxic and can be entered(a) parenterally, for example an aqueous solution. Acceptable carrier or solvent, which can be used on the includes water, the ringer's solution and isotonic sodium chloride solution. As solvent or suspending agent, you can usually use a sterile non-volatile oil. For this you can use any non-volatile oil or fatty acid, and natural, synthetic or semi-synthetic mono-, di - or triglycerides.

Suppositories for rectal injection can be produced by mixing the drug with a suitable non-irritating additives, for example additives, solid at normal temperature and liquid at a temperature in the intestinal tract, which melts in the rectum and release the drug, such as cocoa butter or polyethylene glycol.

Examples of solid dosage forms for oral administration include the above powders, granules, tablets, pills, capsules, etc. Specified dosage form can be produced by mixing and/or mixing of the compounds as active component at least one additive such as sucrose, lactose, cellulose sugar, mannitol (D-mannitol), ▫ maltitol, dextran, starches (e.g. corn starch), microcrystalline cellulose, agar, alginates, chitina, chitosans, pectins, tragacantha gum, Arabic gum, gelatin, collagens, casein, albumin and synthetic or semi-synthetic polymers or glycerides. The decree is installed dosage forms can contain other useful additives, which include an inert diluent, lubricating substance, such as stearic acid and magnesium stearate, preservatives such as parabens and sorbic acid, antioxidant, such as ascorbic acid, α-tocopherol and cysteine, baking powder (for example, sodium croscarmelose), binder (e.g., hydroxypropylcellulose), thickening agent, a buffer, podslushivaet, flavoring substance and flavor. Tablets and pills can also be equipped with intersolubility coating. Solutions for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions. They may contain an inert diluent, which is usually used in this field, for example water, and additives, if necessary. These solutions for oral administration can be produced by the conventional method, for example by mixing the compounds as active ingredient and an inert diluent and, if necessary, other additives.

Oral preparation can contain, depending on the dosage form is about 0.01 to 99 wt.%, preferably 0.1 to 90 wt.%, usually about 0.5-50 wt.% the proposed compounds as the active component.

The dose for a particular patient is determined depending on age, weight, General physical condition, sex, diet, time of administration, the FPIC of the BA introduction, the rate of excretion, combination of drugs and the extent of symptoms of the patient to be treated, or taking into account these and other factors.

The compound of the present invention has a squalene synthase inhibitory activity, cholesterinspiegel activity and triglyceridemia activity shows high selectivity in the transition to the target organ and has a wide margin of safety. Therefore, the connection according to the present invention is applicable for the prevention or treatment of hyperlipemia as lepidosirenidae tool, and are also suitable for the prevention or treatment of arteriosclerosis.

Drug containing the compound (I) of the present invention, viscotoxin and can be used without danger. Daily dose medications varies depending on the condition and weight of the patient, type of connection, as a way of introduction, etc. for Example, using drugs as a means for prevention or treatment of hyperlipemia daily dose for an adult (body weight about 60 kg) is about 1-500 mg, preferably about 10-200 mg of the active ingredient [compound (I)] in the case of oral medication and about 0.1-100 mg, preferably about 1-50 mg, usually about 1-20 mg of the active component in the case of parenteral drug. In these pre is Elah toxicity was not observed.

The following examples, examples of the preparation and experimental examples illustrate the present invention in more detail but do not limit it.

Range1H NMR was determined using a spectrometer Varian Gemini-type 200 (200 MHz) or type 300 (300 MHz) using tetramethylsilane as an internal standard. All values δ shown in ppm (ppm). The digital value specified for the mixed solvent, means the ratio of the concentrations of the respective solvents by volume, unless otherwise specified,% means % by weight unless otherwise stated. The ratio of the eluting solvents for chromatography on silica gel is the volume ratio, unless otherwise noted. Room temperature (normal temperature) when used in this specification means a temperature in the range from about 20°With up to about 30°C.

The corresponding symbols in the examples have the following meanings:

AC: acetyl, Pr: n-propyl, Me: methyl, Bu: n-butyl, Et: ethyl,iPr: isopropyl, Et2A: diethyl ether, DMF (DMF)N,N-dimethylformamide, DMSO (DMSO: dimethylsulfoxide, THF (THF: tetrahydrofuran, s (C): singlet, d (l): doublet, t (t): triplet, q (kV): Quartet, dd (DD: double doublet, dt (dt): double triplet, m (m): multiplet, br (W): broad, J: a permanent connection.

Example 1

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl the l)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid

(1) Carbonyldiimidazole (10.2 g, 63.1 mmol) was added to a suspension of 2-(tert-butoxycarbonylamino)acetic acid (10 g, to 57.1 mmol) in THF (100 ml) and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added magnesium chloride (5.4 g, to 57.1 mmol) and monoethylamine potassium (9.7 g, to 57.1 mmol) and the mixture was stirred at 60°C for 1 hour. The mixture was filtered to remove insoluble substances. The filtrate was diluted with ethyl acetate (200 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (2:1)] to obtain ethyl 4-(tert-butoxycarbonylamino)-3-oxobutanoate (11.9 g, to 48.5 mmol, 85%) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), to 1.45 (2H, s), a 3.87 (2H, s), of 3.96 (3H, s), is 4.21 (2H, q, J=7.2 Hz), was 7.08 (1H, d, J=8.7 Hz), 7,39 (9H, s)to 3.49 (2H, s), 4,14 (2H, d, J=5.8 Hz), is 4.21 (2H, q, J=7,4 Hz), 5,15-5,24 (1H, Shir).

(2) 4 HCl solution in ethyl acetate (50 ml) was added to a solution of ethyl 4-(tert-butoxycarbonylamino)-3-oxobutanoate (11 g, with 44.8 mmol)obtained in example 1-(1)in acetic acid (6 ml) and the mixture was stirred at room temperature in the course is the development of 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was led from ethyl acetate to obtain hydrochloride of ethyl 4-amino-3-oxobutanoate (7.9 g, to 43.5 mmol, 97%) as a colorless powder.

1H-NMR (CD3OD) δ: of 1.27 (3H, t, J=7.2 Hz), of 3.69 (2H, s)4,124 (2H, s), 4,20 (2H, q, J=7.2 Hz).

(3) Pivaloate (0.51 g, to 4.23 mmol) was added to a solution of 2-[(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-yl]acetic acid (2 g, of 3.85 mmol) and triethylamine (0,41 g, 4.04 mmol) in acetonitrile (15 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. To the reaction solution were added hydrochloride ethyl 4-amino-3-oxobutanoate (0.84 g, to 4.62 mmol, obtained in examples 1-(2), when 0°C and then added dropwise a solution of triethylamine (0,58 g, 5,77 mmol) in acetonitrile (2 ml).

After stirring at room temperature for 30 minutes the reaction solution was diluted with ethyl acetate (50 ml), washed with 1 N. hydrochloric acid, 5% aqueous solution of potassium hydrosulfate, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:3)] to obtain ethyl 4-(2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}amino)-3-oxobutanoate (1.8 g, a 2.75 mmol, 71%) as colorless powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)a 1.01 (3H, s)of 1.28 (3H, t, J=7.0 Hz), 2,03 (3H, s), a 2.71 (1H, DD, J=5,6, or 14.8 Hz), and 2.79 (1H, DD, J=7,4, 14,8 Hz), of 3.48 (2H, s), of 3.54 (1H, d, J=14,2 Hz), 3,62 (3H, s), 3,71 (1H, d, J=to 11.4 Hz), 3,86 (1H, d, J=11.4 in Hz)to 3.89 (3H, s), 4,14-of 4.25 (4H, m), 4,37 (1H, DD, J=5,6, and 7.4 Hz), 4,55 (1H, d, J=14,2 Hz), of 6.26 (1H, s), 6,58-6,62 (1H, Shir), 6,63 (1H, s), of 6.96-7,33 (5H, m).

(4) a Solution of ethyl 4-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}amino)-3-oxobutanoate (0.5 g, 0,773 mmol)obtained in example 1-(3), and reagent Lesson (0,46 g of 1.16 mmol) in THF (5 ml) was stirred at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:1)] to obtain ethyl (2-{[(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-yl]methyl}-1,3-thiazol-5-yl)acetate (0,41 g, 0,635 mmol, 82%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.03 (3H, s)of 1.28 (3H, t, J=7.2 Hz), 2,03 (3H, s), 3,44 (1H, DD, J=7,2, 15,0 Hz), 3,55 (1H, DD, J=6,9, 15,0 Hz)to 3.58 (1H, d, J=14.4 Hz), 3,62 (3H, s), of 3.73 (1H, d, J=10,8 Hz), 3,80 (2H, s), 3,85 (1H, d, J=10,8 Hz)to 3.89 (3H, s), 4,20 (2H, q, J=7.2 Hz), 4,33 (1H, DD, J=6,9, 7,2 Hz), of 4.57 (1H, d, J=14.4 Hz), of 6.31 (1H, s), 6,60 (1H, t, J=2.1 Hz), of 6.96-7,34 (5H, m), the 7.43 (1H, s).

(5) a Mixture of ethyl (2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxy who yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetate (0.3 g, 0,465 mmol)obtained in example 1-(4), 1 N. aqueous sodium hydroxide solution (1 ml) and ethanol (3 ml) was stirred at 60°C for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and then extracted with ethyl acetate (50 ml) twice. The extract is washed with saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol-hexane (1:5) to give (2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid (0,23 g, 0.400 mmol, 86%) as Besenova prismatic crystal.

TPL: 219-222°C (Razlog.) (EtOH-hexane).

[α]D22-209,2° (c = 0,34, MeOH).

IK νmax(KBr) cm-1: 3500-2400, 1724, 1658.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 3,19 (1H, d, J=12.3 Hz), 3,38 (1H, d, J=14.4 Hz), of 3.46 (1H, DD, J=7,2, 15,0 Hz)and 3.59 (1H, DD, J=6,0, 15,0 Hz), 3,61 (3H, s)to 3.64 (1H, d, J=12.3 Hz), 3,82 (2H, s), 3,88 (3H, s), 4,35 (1H, DD, J=6,0, 7,2 Hz), 4,47 (1H, d, J=14.4 Hz), of 6.20 (1H, s), to 6.58 (1H, d, J=1,8 Hz), of 6.96 and 7.36 (5H, m), of 7.48 (1H, s).

Anal. calculated for C28H31N2O7ClS: C, 58,48; H, 5,43; N, 4,87.

Found: C, 58,32; H, And 5.30; N, 4,68.

Example 2

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-methyl-1,3-thiazol-5-yl)acetic who Isleta

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,641 (3H, s)of 1.05 (3H, s)to 2.29 (3H, s)3,18 (1H, d, J=12.3 Hz), 3,37 (1H, d, J=13,8 Hz), 3,42 (1H, DD, J=6,9, 15,0 Hz), of 3.54 (1H, DD, J=5,4, 15,0 Hz), 3,61 (3H, s)to 3.64 (1H, d, J=12.3 Hz), to 3.73 (2H, s), 3,88 (3H, s), the 4.29 (1H, DD, J=5,4 and 6.9 Hz), 4,47 (1H, d, J=13,8 Hz), to 6.19 (1H, s), to 6.57 (1H, d, J=2.1 Hz), of 6.96-to 7.35 (5H, m).

Example 3

2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-2-methylpropionate acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.67 (3H, s), was 1.04 (3H, s), of 1.65 (6H, s)and 3.15 (1H, d, J=11,6 Hz)to 3.41 (1H, DD, J=7,2, 14,8 Hz)to 3.41 (1H, DD, J=14.4 Hz), of 3.54 (1H, DD, J=6,2, 14,8 Hz), 3,61 (3H, s), 3,62 (1H, d, J=11,6 Hz), 3,89 (3H, s), 4,34 (1H, DD, J=6,2, 7,2 Hz), 4,48 (1H, d, J=14.4 Hz), of 6.20 (1H, s), 6,55 (1H, s), of 6.96 and 7.36 (5H, m), 7,46 (1H, s).

Example 4

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-ethyl-1,3-thiazol-5-yl)acetic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s)of 1.18 (3H, t, J=7.5 Hz), 2.63 in (2H, q, J=7.5 Hz), 3,18 (1H, d, J=12.0 Hz), 3,37 (1H, d, J=14.4 Hz), 3,43 (1H, DD, J=7,2, 15,0 Hz), of 3.54 (1H, DD, J=6,0, 15,0 who C), 3,61 (3H, s)to 3.64 (1H, d, J=12.0 Hz), 3,74 (2H, s), 3,88 (3H, s), or 4.31 (1H, DD, J=6,0, 7,2 Hz), 4,47 (1H, d, J=14.4 Hz), to 6.19 (1H, s), to 6.57 (1H, d, J=1,8gts), 6,95 and 7.36 (5H, m).

Example 5

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)propionic acid

(1) Carbonyldiimidazole (9.7 g, 60 mmol) was added to a solution of monoethylamine acid (7,3 g, 50 mmol) in THF (70 ml) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added magnesium chloride (4.8 g, 50 mmol) and monoethylamine potassium (8.5 g, 50 mmol) and the mixture was stirred at 60°C for 1 hour. The mixture was filtered to remove insoluble substances and the filtrate was concentrated under reduced pressure. The residue was diluted with water, acidified and then extracted with ethyl acetate (70 ml) twice. The extracts were washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:1)] to obtain diethyl-3-oxohexanoate (8,9 g, 41.2 mmol, 82%) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.26 (3H, t, J=7.2 Hz), of 1.29 (3H, t, J=7.2 Hz), 2,61 (2H, t, J=6.6 Hz), 2,87 (2H, t, J=6.6 Hz), 3,50 (97/100 x 2H, s), 4,14 (2H, q, J=7.2 Hz), is 4.21 (2H, q, J=7.2 Hz), 5,02 (3/100 x 1H, C.

(2) a Solution of sodium nitrite (3,3 g, 48 mmol) in water (40 ml) was added dropwise to a solution of diethyl 3-oxohexanoate (8.7 g, 40,2 mmol)obtained in example 5-(1)in acetic acid (20 ml) under cooling with ice. Then added water (60 ml) and the mixture was stirred over night. The reaction solution was extracted with ethyl acetate (50 ml) twice. The extracts were washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [developing solution: hexane-ethyl acetate (2:1)] to obtain diethyl 2-hydroxyimino-3-oxohexanoate (9.3 g, of 37.9 mmol, 94%) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.4 Hz), of 1.35 (3H, t, J=7.4 Hz), 2,68 (2H, t, J=6.6 Hz), 3,17 (2H, t, J=6.6 Hz), 4,17 (2H, q, J=7.4 Hz), to 4.38 (2H, q, J=7,4 Hz).

(3) Zinc powder (18.7 g, 0,286 mol) was added to a solution of diethyl 2-hydroxyimino-3-oxohexanoate (9 g, to 36.7 mmol)obtained in example 5-(2), and acetic anhydride (26 g, 0,220 mol) in acetic acid (120 ml) at room temperature and the mixture was stirred for 24 hours. The mixture was filtered to remove insoluble substances and the insoluble matter was washed with ethyl acetate (50 ml). The filtrate and the washing solution were combined and then concentrated under reduced Yes is the process to obtain diethyl 2-acetylamino-3-oxohexanoate (9.0 g, to 32.9 mmol, 90%) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.25 (3H, t, J=7.2 Hz), of 1.33 (3H, t, J=7.2 Hz), of 2.08 (3H, s), 2,62-to 2.67 (2H, m), 2,95 (1H, dt, J=18,6, and 6.6 Hz), 3,11 (1H, dt, J=18,6, and 6.6 Hz), of 4.12 (2H, q, J=7.2 Hz), the 4.29 (2H, q, J=7,2 Hz), and 5.30 (1H, d, J=6.6 Hz), of 6.68 (1H, d, J=6,6 Hz).

(4) Diethyl 2-acetylamino-3-oxohexanoate (8.8 g, to 32.2 mmol)obtained in example 5-(3)was added to 4 N. the solution of HCl in ethyl acetate (90 ml) and the mixture is boiled under reflux for 4 hours. The reaction solution was concentrated under reduced pressure and the residue was led from a mixture of ethyl acetate-ether to obtain the hydrochloride of 5-amino-4-oxopentanoic acid (4.4 g, to 26.3 mmol, 82%) as Besenova needle crystal.

1H-NMR (CD3OD) δ: to 2.65 (2H, t, J=7.0 Hz), of 2.81 (2H, t, J=7.0 Hz), was 4.02 (2H, s).

(5) Pivaloate (0.51 g, to 4.23 mmol) was added to a solution of 2-[(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-yl]acetic acid (2 g, of 3.85 mmol) and triethylamine (0,41 g, 4.04 mmol) in acetonitrile (15 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. To the reaction solution at 0°C was added the hydrochloride 5-amino-4-oxopentanoic acid (0,77 g, to 4.62 mmol)obtained in example 5-(4), and then was added dropwise a solution of triethylamine (0,58 g, 5,77 mmol) in acetonitrile (2 ml).

After stirring at room temperature for 30 minutes the reaction is ionic solution was diluted with ethyl acetate (50 ml), washed with 1 N. hydrochloric acid and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in DMF (30 ml), was added potassium carbonate (0.65 g, 4,69 mmol) and methyliodide (0,67 g, 4,69 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (100 ml), washed with water, 5% aqueous solution of potassium hydrosulfate, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:3)] to obtain methyl 5-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}amino)-4-oxopentanoate (1.2 g, of 1.85 mmol, 44%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s)2,03 (3H, s), 2,60 was 2.76 (5H, m), with 2.93 (1H, DD, J=7,0,, 14.6 Hz), 3,53 (1H, d, J=14.4 Hz), 3,61 (3H, s), 3,68 (3H, s), 3,71 (1H, d, J=12.0 Hz), 3,86 (1H, d, J=12.0 Hz), the 3.89 (3H, s), 4,17 (2H, d, J=4.6 Hz), to 4.38 (1H, DD, J=6,8, 7,0 Hz), 4,55 (1H, d, J=14.4 Hz), of 6.26 (1H, s), to 6.58 (1H, t, J=4.6 Hz), 6,63 (1H, s), of 6.96-to 7.32 (5H, m).

(6) Methods similar to the methods of examples 1-(4)-(5)was obtained 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)propionic acid.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,68 (2H, t, J=7.0 Hz), 3,11 (2H, t, J=7.0 Hz), 3,17 (1H, d, J=11.8 Hz), 3,38 (1H, d, J=14,2 Hz), 3,42 (1H, DD, J=7,0, to 15.4 Hz), 3,57 (1H, DD, J=5,8, to 15.4 Hz), 3,62 (3H, C)to 3.64 (1H, d, J=11.8 Hz), with 3.89 (3H, s), 4,34 (1H, DD, J=5,8, 7,0 Hz), 4,48 (1H, d, J=14,2 Hz), of 6.20 (1H, s), to 6.58 (1H, s), 6,97-7,37 (6H, m).

Example 6

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)butane acid

In a manner similar to the method of example 5 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s)a 1.96 (2H, quintet, J=7.0 Hz), is 2.41 (2H, t, J=7.0 Hz), of 2.86 (2H, t, J=7.0 Hz), 3,17 (1H, d, J=11.8 Hz), 3,38 (1H, d, J=14.4 Hz), 3,43 (1H, DD, J=7,0, 15,0 Hz), 3,57 (1H, DD, J=5,8, 15,0 Hz), 3,62 (3H, s)to 3.64 (1H, d, J=11.8 Hz), with 3.89 (3H, s), 4,35 (1H, DD, J=5,8, 7,0 Hz), 4,48 (1H, d, J=14.4 Hz), of 6.20 (1H, s), to 6.58 (1H, d, J=1,8 Hz), of 6.96-7,38 (6H, m).

Example 7

2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s)to 3.34 (1H, d, J=13.5 Hz), of 3.46 (1H, DD, J=7,2, 15,0 Hz), 3,57 (1H, DD, J=6,0, 15,0 Hz), 3,62 (3H, s), a-3.84 (2H, s), 3,88 (3H, s)to 4.33 (1H, DD, J=6,0, 7,2 Hz), 4,50 (1H, d, J=13.5 Hz), of 6.31 (1H, s), 6,56 (1H, d, J=2.1 Hz), 6.90 to-7,00 (1H, m), 7,10-7,20 (2H, m), 7,26 (1H, d, J=8.7 Hz), 7,30 (1H, d, J=2,1, to 8.7 Hz),7,47 (1H, s).

Example 8

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 1,33-of 1.55 (2H, m), 1,76-of 1.94 (3H, m), 1,96-2,12 (1H, m), 3,41-of 3.78 (9H, m), 3,83 (2H, s), a 3.87 (3H, s), 4,34 (1H, DD, J=6,0, 6.9 Hz), 4,58 (1H, d, J=14.4 Hz), between 6.08 (1H, s), to 6.57 (1H, d, J=2.1 Hz), to 6.95 (1H, DD, J=1,8, 7,8 Hz), 7,07-to 7.18 (2H, m), 7,33-7,42 (2H, m), of 7.48 (1H, s).

Example 9

3-{2-[((3R,5S)-7-chloro-5-(2,3-acid)-1-{[1-(hydroxymethyl)cyclobutyl]methyl}-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl]-1,3-thiazol-5-yl}propionic acid

In a manner similar to the method of example 5 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 1,34-of 1.55 (2H, m), 1.77 in-1,95 (3H, m), 1,98-2,10 (1H, m), 2,68 (2H, t, J=7.5 Hz), 3,11 (2H, t, J=7.5 Hz), 3,42 (1H, DD, J=6,9, 15,0 Hz), 3,50-3,82 (7H, m)to 3.89 (3H, s), 4,34 (1H, t, J=6,41 Hz), 4,58 (1H, d, J=14,32 Hz)6,09 (1H, s), to 6.58 (1H, d, J=2.1 Hz), 6,98 (1H, DD, J=1,8, 8.1 Hz), to 7.09 (1H, DD, J=1.5 and 7.8 Hz), 7,17 (1H, t, J=8.1 Hz), 7,35-the 7.43 (3H, m).

Example 10

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δas 0.96 (3H, t, J=7.5 Hz), 1,57-of 1.81 (2H, m), 3,43-3,63 (6H, m), a-3.84 (2H, s), a 3.87 (3H, s), 4,30-to 4.52 (2H, m), 6,11 (1H, s), 6,60 (1H, d, J=1,8 Hz), 6,91 and 7.36 (5H, m), 7,49 (1H, s).

Example 11

(2-{[(3R,5S)-7-chloro-5-(2,3-dimethoxy who yl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: to 0.92 (3H, d, J=6.4 Hz), a 1.01 (3H, d, J=6.8 Hz), 1,95-of 2.08 (1H, m), 3,32-3,62 (6H, m), 3,82 (2H, s), a 3.87 (3H, s), or 4.31-and 4.40 (2H, m), 6,21 (1H, s), 6,59 (1H, d, J=2.3 Hz), 6,92-to 7.35 (5H, m), 7,49 (1H, s).

Example 12

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-ethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 1.26 (3H, t, J=7.2 Hz), 3.43 points-of 3.64 (6H, m), a-3.84 (2H, s), a 3.87 (3H, s)to 4.33 (1H, t, J=6.0 Hz), 4,49-to 4.62 (1H, m), between 6.08 (1H, s), 6,60 (1H, d, J=1,8 Hz), 6,91 and 7.36 (5H, m), of 7.48 (1H, s).

Example 13

(4-Benzyl-2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s)and 3.15 (1H, d, J=11.7 Hz), 3,32 (1H, d, J=14.4 Hz), to 3.41 (1H, DD, J=7,5, of 14.7 Hz), 3,53 (1H, DD, J=6,3, of 14.7 Hz), of 3.60 (3H, s), 3,62 (1H, d, J=11.7 Hz), 3,76 (2H, s), a 3.87 (3H, s), of 4.00 (2H, s), 4,32-to 4.38 (1H, m), 4,42 (1H, d, J=14.4 Hz), 6,17 (1H, s), 6,55 (1H, d, J=2.4 Hz), to 6.95 (1H, DD, J=2,1, 7,2 Hz), 7,02-7,30 (8H, m), 7,32 (1H, DD, J=2,4, and 8.7 Hz)

Example 14

3-(2-{[(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-yl]methyl}-1,3-thiazol-5-yl)propionic acid

To a solution of 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)propionic acid (0.5 g, 0,849 mmol)obtained in example 5 in THF (10 ml), was added pyridine (0,34 ml, 4,24 mol) at room temperature and then was added dropwise acetylchloride (of 0.18 ml, 2.55 mmol). The mixture was stirred for 2.5 hours. After adding water (5 ml) and the mixture was stirred at room temperature for 19 hours and the reaction solution was extracted with ethyl acetate. The organic layer is washed with 1 N. hydrochloric acid, water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-(2-{[(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-yl]methyl}-1,3-thiazol-5-yl)propionic acid (0.5 g, 0,792 mmol, 93%) as colorless powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.23 (3H, s)2,02 (3H, s), 2,68 (2H, t, J=7.5 Hz), 3,10 (2H, t, J=7.5 Hz), 3,42 (1H, DD, J=7,2, 15,0 Hz), 3,53 (1H, d, J=14.1 Hz), of 3.54 (1H, DD, J=6,3, 15,0 Hz), 3,61 (3H, s), of 3.73 (1H, d, J=11,1 Hz), 3,85 (1H, d, J=11,1 Hz), 3,88 (3H, s), 4,32 (1H, DD, J=6,3, 7,2 Hz), 4,56 (1H, d, J=14.1 Hz), of 6.29 (1H, s), 6,59 (1H, d, J=2.1 Hz), of 6.96 (1H, DD, J=2,1, 7,8 Hz), 7,06-7,26 (2H, m), 7,27 (1H, d, J=8.7 Hz), 7,31 (1H, DD, J=2,1, to 8.7 Hz), 7,35 (1H, s).

Example 15

2-{[(3R,5S)-7-chloro-5-(2,3-acid)1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-methyl-1,3-thiazole-5-carboxylic acid

(1) DMF (0.01 ml) was added to a solution of 2-[(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-yl]acetic acid (3 g, of 6.49 mmol) and thionyl chloride (2.3 g, a 19.5 mmol) in THF (10 ml). The reaction solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was dissolved in THF (10 ml) and added dropwise to a solution of hydrogen sulfide in pyridine (30 ml). The reaction solution was stirred at 0°C for 1 hour and then was diluted to 2.5 M sulfuric acid. The product was extracted with ethyl acetate (50 ml), washed with saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure to obtain [(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]thio-S-acetic acid (6,53 g) as colorless powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s)2,03 (3H, s), 3,11 (1H, DD, J=6,2, and 16.4 Hz), to 3.33 (1H, DD, J=7,0, and 16.4 Hz), 3,54 (1H, d, J=14,0 Hz), 3,61 (3H, s), and 3.72 (1H, d, J=11,4 Hz), 3,85 (1H, d, J=11,4 Hz), 3,89 (3H, s), 4,37 (1H, DD, J=6,2, 7,0 Hz), 4,56 (1H, d, J=14,0 Hz), and 6.25 (1H, s), only 6.64 (1H, d, J=1,8 Hz), of 6.96-to 7.35 (5H, m).

(2) a Solution of [(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]thio-S-acetic acid (1 g, of 1.87 mmol), polucen the th in example 15-(1), triethylamine (0,41 g, 4.04 mmol) and methyl 2-chloroacetoacetate (0.31 g, of 2.06 mmol) in ether (10 ml) was boiled under reflux for 2 hours. After adding to the reaction solution of water the mixture was extracted with ethyl acetate (50 ml), washed with saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (2:1)] to obtain methyl 2-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}thio)-3-oxobutanoate (0.9 g, 1.38 mmol, 74%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s)2,02 (3H, s)to 2.18 (3H, s), 3,14-3,26 (2H, m), 3,53 (1H, d, J=14.4 Hz), 3,61 (3H, s), and 3.72 (1H, d, J=12.0 Hz), 3,74 (9/10 x 3H, s), 3,78 (1/10 x 3H, s), 3,85 (1H, d, J=12.0 Hz), with 3.89 (3H, s), 4,43 (1H, t, J=6.4 Hz), of 4.54 (1H, d, J=14.4 Hz), 5,50 (1/10 x 3H, s), of 6.26 (1H, s), 6,62 (1H, d, J =1,8 Hz), of 6.96-to 7.35 (5H, m).

(3) Solution of methyl 2-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}thio)-3-oxobutanoate (0.8 g, of 1.23 mmol)obtained in example 15-(2), and ammonium acetate (0.33 g, 4,32 mmol) in acetic acid (5 ml) was heated under reflux for 1 hour. The reaction solution was diluted with ethyl acetate (50 ml), washed with saturated aqueous solution of hydrocarbo the ATA sodium and saturated aqueous sodium chloride, was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:2)]to obtain methyl 2-{[(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-yl]methyl}-4-methyl-1,3-thiazole-5-carboxylate (0,62 g, 0,982 mmol, 80%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.03 (3H, s)2,03 (3H, s)to 2.65 (3H, s)3,421 (1H, DD, J=7,0, 14,8 Hz), 3,53 (1H, d, J=14,0 Hz), of 3.56 (1H, DD, J=6,0, 14,8 Hz), 3,62 (3H, s), and 3.72 (1H, d, J=11,4 Hz), 3,86 (3H, s),3,86 (1H, d, J=11.4 in Hz)to 3.89 (3H, s), or 4.31 (1H, DD, J=6,0, 7,0 Hz), 4,56 (1H, d, J=14,0 Hz), 6,30 (1H, s), is 6.61 (1H, d, J=2.2 Hz), of 6.96-7,37 (5H, m).

(4) a Mixture of methyl 2-{[(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-yl]methyl}-4-methyl-1,3-thiazole-5-carboxylate (0.4 g, 0,634 mmol)obtained in example 15-(3), 1 N. aqueous sodium hydroxide solution (2 ml) and ethanol (4 ml) was stirred at 60°C for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and then extracted with ethyl acetate (50 ml) twice. The extracts were washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol-hexane (1:1) to give 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dim is ylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-methyl-1,3-thiazole-5-carboxylic acid (0.15 g, 0,261 mmol, 41%) as Besenova prismatic crystal.

1H-NMR (CDCl3) δ: 0,66 (3H, s), was 1.04 (3H, s)to 2.65 (3H, s), and 3.16 (1H, d, J=12.0 Hz), 3,40 (1H, d, J=14.1 Hz), 3,43 (1H, DD, J=6,9, 14.4 Hz), 3,55 (1H, DD, J=5,7, a 14.1 Hz), 3,62 (1H, d, J=12.0 Hz), 3,62 (3H, s), 3,90 (3H, s),4,32 (1H, DD, J=5,7 and 6.9 Hz), 4,47 (1H, d, J=14.1 Hz), 6,21 (1H, s), 6,59 (1H, s), 6,99-7,38 (5H, m).

Example 16

2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-5-carboxylic acid

(1) To a solution of 2-[(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-yl]acetic acid (10 g, 19.2 mmol) in DMF (100 ml) was added 1-hydroxy-1H-benzothiazolinone salt (4.1 g, 26.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimides (5,16 g, 26.9 mmol). After stirring the mixture at room temperature for 13 hours was added water (50 ml) and the mixture was diluted with ethyl acetate (350 ml). The organic layer is washed with 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-[(3R,5S)-3-(2-amino-2-oxoethyl)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropyl acetate (10.0 g) as a colourless then the Cabinet.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)a 1.01 (3H, s)2,03 (3H, s), 2,68 (1H, DD, J=5,7, of 14.7 Hz), 2,87 (1H, DD, J=7,5, of 14.7 Hz), 3,54 (1H, d, J=13,8 Hz), 3,61 (3H, s), of 3.73 (1H, d, J=11,1 Hz), 3,86 (1H, d, J=11,1 Hz), 3,89 (3H, s), 4,39 (1H, DD, J=5,7, 7.5 Hz), 4,56 (1H, d, J=13,8 Hz), 5,46 (1H, Shir), 5,95 (1H, Shir), of 6.26 (1H, s), only 6.64 (1H, d, J=2.4 Hz), 6,91-7,01 (1H, m), 7,15-7,24 (2H, m), 7,31 (1H, d, J=8,4 Hz), 7,35 (1H, DD, J=2,4, 8,4 Hz).

(2) a Solution of 3-[(3R,5S)-3-(2-amino-2-oxoethyl)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (10.8 g, to 20.8 mmol)obtained in example 16-(1), and reagent Lesson (10,1 g of 24.8 mmol) in THF (100 ml) was boiled under reflux for 1 hour under stirring. Allowing to stand for cooling to room temperature, was added a saturated aqueous solution of sodium bicarbonate (20 ml) and the mixture was stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (800 ml), washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:1)] to obtain 3-[(3R,5S)-3-(2-amino-2-tixati)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropyl acetate (5,14 g) as a white crystal.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)a 1.01 (3H, s)2,03 (3H, s), is 3.08 (1H, DD, J=5,4, and 13.5 Hz), and 3.31 (1H, DD, J=7,5, 3.5 Hz), 3,55 (1H, d, J=14.1 Hz), 3,55 (1H, d, J=14.1 Hz), 3,61 (3H, s), and 3.72 (1H, d, J=11,4 Hz), 3,86 (1H, d, J=11.4 in Hz)to 3.89 (3H, s), 4,46 (1H, DD, J=5,4, 7.5 Hz), a 4.53 (1H, d, J=14.1 Hz), of 6.26 (1H, s), of 6.65 (1H, d, J=2.4 Hz), 6,91-7,01 (1H, m), 7,15-7,24 (2H, m), 7,31 (1H, d, J=8.7 Hz), was 7.36 (1H, DD, J=2,4, and 8.7 Hz), 7,49 (1H, Shir), to 7.64 (1H, Shir).

(3) Acetic acid (0,13 ml, 2.34 mmol) was added to a suspension of the potassium salt of ethyl 2-chloro-3-oxopropionate (0,42 g, 2,24 mmol) in isopropanol (10 ml) and the mixture was stirred for 30 minutes. To the mixture was added 3-[(3R,5S)-3-(2-amino-2-tixati)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (1.0 g, of 1.87 mmol)obtained in example 16-(2), and the mixture is boiled under reflux for 30 hours with stirring. Allowing to stand for cooling, to the reaction solution was added water (5 ml) followed by extraction with ethyl acetate (200 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (7:3-65:35)] to obtain ethyl 2-{[(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-yl]methyl}-1,3-thiazole-5-carboxylate (0.6 g) as colorless non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H), of 1.31 (3H, t, J=7.2 Hz), 2,03 (3H, s), 2,82 (1H, DD, J=5,7, is 16.8 Hz), of 2.92 (1H, DD, J=7,5, is 16.8 Hz), 3,54 (1H, d, J=14.1 Hz), 3,62 (3H, s), and 3.72 (1H, d, J=11,1 Hz), 3,85 (1H, d, J=11,1 Hz), a 3.87 (3H, s), of 4.12 (2H,, kV, J=7,2 Hz), 4,19 (1H, DD, J=5,7, 7.5 Hz), of 4.57 (1H, d, J=14.1 Hz), 6,28 (1H, s), 6,53-6,55 (1H, m), 6.89 in-7,40 (5H, m), to 8.70 (1H, s).

(4) potassium Carbonate (0.26 g, at 1.91 mmol) was added to a solution of ethyl 2-{[(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-yl]methyl}-1,3-thiazole-5-carboxylate (0.6 g, 0.95 mmol)obtained in example 16-(3), in methanol (6 ml) and the mixture was stirred at room temperature for 2 hours. Was added to the reaction solution, water (3 ml) followed by extraction with ethyl acetate (80 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (67:33-3:2)] to obtain methyl 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl-1,3-thiazole-5-carboxylate (0.3 g) as colorless non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 3,07-is 3.21 (1H, m)to 3.38 (1H, d, J=14.1 Hz), to 3.58-3,70 (1H, m), 3,61 (3H, s), of 3.73 (2H, d, J=6.6 Hz), 3,85 (3H, s), 3,88 (3H, s), 4,48 (1H, d, J=14.1 Hz), a 4.53 (1H, t, J=6.6 Hz), 6,17 (1H, s), 6,52-6,55 (1H, m), 6.90 to-7,10 (2H, m), 7,07-7,20 (1H, m), 7,2-7,40 (2H, m)8,71 (1H, s).

(5) a Mixture of methyl 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl-1,3-thiazole-5-carboxylate (0.3 g, 0.52 mmol)obtained in example 16-(4), 1 N. aqueous sodium hydroxide solution (1 ml) and ethanol (5 ml) was stirred at room temperature for 8 hours. After the mixture was acidified using 1 N. hydrochloric acid (1.2 ml), thereto was added ethyl acetate (70 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained crystal was washed with hexane to obtain 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-5-carboxylic acid (0,19 g) as a white crystal.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s), 3,19 (1H, d, J=12.3 Hz), 3,40 (1H, d, J=14.1 Hz), to 3.58-of 3.78 (3H, m), 3,61 (3H, s), a 3.87 (3H, s), 4,47 (1H, d, J=14.1 Hz), of 4.57 (1H, t, J=6.0 Hz), 6,18 (1H, s), 6,56 (1H, s), 6.90 to-7,01 (2H, m), 7,12 (1H, t, J=7.8 Hz), 7,30-7,40 (2H, m), 8,76 (1H, s).

Example 17

2-{[(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-yl]methyl}-1,3-thiazole-5-carboxylic acid

After adding pyridine (0.9 ml, 8,91 mol) to a solution of 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydrox the -2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-5-acetic acid (1.0 g, 1.78 mmol)obtained in example 16, in THF(10 ml) at room temperature, acetylchloride (0,38 ml, to 5.35 mmol) was added dropwise and the mixture was stirred for 1 hour. Added pyridine (0.3 ml, 3,71 mmol) and then acetylchloride (0.1 ml, of 1.41 mmol) and the mixture was still stirred for 30 minutes. After adding water (5 ml) and the mixture was stirred at room temperature for 19 hours and the reaction solution was extracted with ethyl acetate. The organic layer is washed with 1 N. hydrochloric acid, water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2-{[(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-yl]methyl}-1,3-thiazole-5-carboxylic acid (0,76 g) as pale-brown non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s)2,03 (3H, s), 3,42-3,63 (3H, m), 3,63 (3H, s), of 3.73 (1H, d, J=11,1 Hz), 3,70-are 3.90 (1H, m), 3,85 (1H, d, J=11,1 Hz)to 3.89 (3H, s)4,55 (1H, d, J=14.1 Hz), 4,50-4,60 (1H, m)of 6.29 (1H, s), 6,63 (1H, d, J=2.7 Hz), 6,98 (1H, DD, J=1.5 and 8.1 Hz), was 7.08 (1H, DD, J=1.5 and 8.1 Hz), 7,17 (1H, t, J=8.1 Hz), 7,29 (1H, d, J=9.0 Hz), 7,34 (1H, DD, J=2,7, 9,0 Hz), 8,76 (1H, s).

Example 18

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxypropionic acid

(1) 11'-Carbonyldiimidazole (0.24 g, for 1.49 mol) was added to a solution of 2-{[(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-yl]methyl}-1,3-thiazole-5-carboxylic acid (0.75 g, 1,24 mmol)obtained in example 17, in THF (10 ml) at room temperature and the mixture was stirred for 1 hour. Added monoethylamine-potassium (0,23 g, 1.37 mmol) and magnesium chloride (0,13 g, 1.37 mmol) and the mixture was stirred at 55°C for 1 hour. Allowing the mixture to stand for cooling, was added 1 N. hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (67:33-1:1)] to obtain ethyl 3-(2-{[(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-yl]methyl}-1,3-thiazol-5-yl)-3-oxopropionate (0,59 g, 0.88 mmol, 71%) as a colorless non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.03 (3H, s)of 1.26 (3H, t, J=7.5 Hz), 2,03 (3H, s), of 3.54 (1H, d, J=14.1 Hz), to 3.58-of 3.80 (2H, m), of 3.60 (3H, s), of 3.73 (1H, d, J=10,8 Hz), a-3.84 (1H, d, J=10,8 Hz), a 3.87 (3H, s), 3,93 (1H, d, J=15,9 Hz), 4,00 (1H, d, J=15,9 Hz), of 4.12 (2H, q, J=7.5 Hz), 4,50 (1H, t, J=6.6 Hz), of 4.54 (1H, d, J=14.1 Hz), 6,28 (1H, s), 6,56 (1H, s), 6.89 in-7,00 (2H, m), 7,10 (1H, t, J=7,8 G is), 7,30-7,34 (2H, m), a total of 8.74 (1H, s).

(2) a Suspension of ethyl 3-(2-{[(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-yl]methyl}-1,3-thiazol-5-yl)-3-oxopropionate (0,59 g, 0.88 mmol)obtained in example 18-(1)in ethanol (20 ml) was cooled to -20°C and added to it borohydride sodium (36 mg, 0.96 mmol). After stirring for 2 hours was added a saturated aqueous solution of ammonium chloride (5 ml) and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (55:45-35:65)] to obtain ethyl 3-(2-{[(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-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxypropionate (0,49 g) as colorless powder.

1H-NMR (CDCl3) δ: to 0.92 (3H, s)to 0.97 (3H, s)of 1.26 (3H, t, J=7.2 Hz), 2,04 (3H, s), 2,77 (1H, DD, J=5,1, or 15.9 Hz), to 2.94 (1H, DD, J=9,0, or 15.9 Hz), 3,05-is 3.21 (2H, m), 3,42 (1H, d, J=14.1 Hz), 3,62 (3H, s), 3,66 (1H, d, J=11.7 Hz), 3,82 (1H, d, J=11.7 Hz), with 3.89 (3H, s), of 4.12 (2H, q, J=7.2 Hz), 4,42 (1H, d, J=14.1 Hz), 4,30-to 4.52 (1H, m), 4,62-4,71 (1H, m), 5,62-5,80 (1H, m), of 6.26 (1H, s), 6,62 (1H, d, J=2.1 Hz), 6,98 (1H, DD, J=2,4, 7,2 Hz), 7,10-7,26 (3H, m), 7,30 (1H, DD, J=2,1, to 8.7 Hz), 8,55 (1H, s).

(3) a Mixture of ethyl 3-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl is)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxypropionate (0.06 g, 0.09 mmol)obtained in example 18-(2), 1 N. aqueous sodium hydroxide solution (0.5 ml) and ethanol (1 ml) was stirred at room temperature for 2 hours. The mixture was acidified using 1 N. hydrochloric acid (0.6 ml) and added to it in ethyl acetate (40 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained crystal was washed with hexane to obtain 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxypropionic acid (0.05 g) as a white crystal.

1H-NMR (CDCl3) δ: 0,66 (3H, s), and 1.00 (3H, s), 2,73 (1H, DD, J=5,1, 16.2 Hz), of 2.81 (1H, DD, J=8,4, 16.2 Hz), 3,14 (1H, d, J=12.0 Hz), 3,19 (1H, DD, J=5,4, 14.1 Hz), to 3.36 (1H, d, J=14.1 Hz), 3,48 (1H, DD, J=7,8, 14.1 Hz), of 3.60 (1H, d, J=12.0 Hz), 3,61 (3H, s)to 3.89 (3H, s)to 4.41 (1H, d, J=14.1 Hz), 4,50 (1H, DD, J=5,4, and 7.8 Hz), 5,64 (1H, DD, J=5,1, 8,4 Hz), 6,18 (1H, s), 6,56 (1H, d, J=2.1 Hz), 6,95-7,03 (2H, m), 7,16 (1H, t, J=7.8 Hz), 7,29 (1H, d, J=9.0 Hz), 7,35 (1H, DD, J=2,1, 9.0 Hz), 8,59 (1H, s).

Example 19

(2E)-3-(2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acrylic acid

(1) Triethylamine (of 0.11 ml, 0.77 mmol) and methanesulfonamide (0.05 ml, of 0.68 mmol) was added to a solution of ethyl 3-(2-{[(3R,5S)-1-(3-acetoxy-2,2-di is ethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxypropionate (0.4 g, 0.59 mmol)obtained in example 18-(2), in THF (5 ml) under ice cooling and the mixture was stirred for 1 hour. To the resulting mixture was further added triethylamine (of 0.11 ml, 0.77 mmol) and methanesulfonamide (0.05 ml, of 0.68 mmol) and the mixture was stirred for 1 hour. Then added DBU (0,12 ml, 0.77 mmol) and the mixture was stirred for 1 hour. Then added water (10 ml) and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (63:37-52:48)] to obtain ethyl (2E)-3-(2-{[(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-yl]methyl}-1,3-thiazol-5-yl)acrylate (0.05 g) as a colourless non-crystalline powder.

1H-NMR (CDCl3) δas 0.96 (3H, s)of 1.05 (3H, s), 1,25 (3H, t, J=7.2 Hz), 2,04 (3H, s), 3,40 (2H, d, J=6.0 Hz), 3,54 (1H, d, J=14,0 Hz), 3,61 (3H, s), of 3.73 (1H, d, J=11,0 Hz), 3,86 (1H, d, J=11.0 in Hz), a 3.87 (3H, s), 4,19 (2H, q, J=7.2 Hz), 4,37 (1H, t, J=6.6 Hz), of 4.57 (1H, d, J=14,0 Hz), 6,18 (1H, d, J=15,4 Hz), 6,28 (1H, s), is 6.54 (1H, s), to 6.88 (1H, DD, J=1,4, and 7.6 Hz), 6,92 (1H, DD, J=1,4, and 7.6 Hz), 7,05 (1H, t, J=7,6 Hz), 7.23 percent-7,38 (2H, m), 7,92 (1H, d, J=15,4 Hz), 8,63 (1H, s).

(2) a Mixture of ethyl (2E)-3-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro the -4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acrylate (0.34 g, 0.52 mmol)obtained in example 19-(1), 1 N. aqueous sodium hydroxide solution (1.5 ml) and ethanol (7 ml) was stirred at 40°C for 1 hour. Allowing to stand for cooling, the mixture was acidified using 1 N. hydrochloric acid (1.7 ml) was added ethyl acetate (160 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained crystal was washed with hexane to obtain (2E)-3-(2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acrylic acid (0.28 g) as a pale yellow crystal.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.06 (3H, s), 3,19 (1H, d, J=11.7 Hz), 3,37 (1H, d, J=13,8 Hz), 3,39 is-3.45 (2H, m), 3,61 (3H, s)to 3.67 (1H, d, J=11.7 Hz), 3,86 (3H, s), to 4.38 (1H, t, J=7.2 Hz), 4,46 (1H, t, J=13,8 Hz), 6,16 (1H, d, J=15.6 Hz), 6,16 (1H, s), 6,53 (1H, d, J=2.1 Hz), to 6.88 (1H, DD, J=1.5 and 8.1 Hz), 6,93 (1H, DD, J=1.5 and 8.1 Hz), was 7.08 (1H, t, J=8.1 Hz), 7,29 (1H, d, J=8.7 Hz), 7,33 (1H, DD, J=2,1, to 8.7 Hz), 8,02 (1H, d, J=15.6 Hz), 8,66 (1H, s).

Example 20

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-thiazol-4-yl)propionic acid

(1) Pivaloate (0.51 g, to 4.23 mmol) was added to a solution of 2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-b is socksipy-3-yl]acetic acid (2 g, of 3.85 mmol) and triethylamine (0,41 g, 4.04 mmol) in acetonitrile (15 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. To the reaction solution at 0°C was added the hydrochloride of methyl (4S)-4-amino-5-oxohexanoate (0,83 g, 4,24 mmol) and then was added dropwise a solution of triethylamine (0,58 g, 5,77 mmol) in acetonitrile (2 ml).

After stirring at room temperature for 30 minutes the reaction solution was diluted with ethyl acetate (50 ml), washed with 1 N. hydrochloric acid, 5% aqueous solution of potassium hydrosulfate, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:2)] to obtain methyl (4S)-4-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}amino)-5-oxohexanoate (1.85 g, 2,80 mmol, 73%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s)of 1.78-1.90 (1H, m), 2,03 (3H, s), of 2.23 (3H, s), 2,25-to 2.42 (3H, m), 2,70 (1H, DD, J=5,4, 14.4 Hz), 2,89 (1H, DD, J=7,8, 14.4 Hz), 3,54 (1H, d, J=14.1 Hz), 3,61 (3H, s), 3,67 (3H, s), and 3.72 (1H, d, J=11,1 Hz), 3,85 (1H, d, J=11,1 Hz)to 3.89 (3H, s), 4,36 (1H, DD, J=5,4, and 7.8 Hz), of 4.54 (1H, d, J=14.1 Hz), 4,56 with 4.65 (1H, m), and 6.25 (1H, s), 6,60-only 6.64 (1H, Shir), only 6.64 (1H, s), 6,97-to 7.32 (5H, m).

(2) a Solution of methyl (4S)4-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}amino)-5-oxohexanoate (0.51 g, 0,773 mol)obtained in example 20-(1), and reagent Lesson (0.40 g, 1.00 mmol) in THF (5 ml) was stirred at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:1)] to obtain methyl 3-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-thiazol-4-yl)propionate (0.31 g, 0,470 mmol, 61%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.03 (3H, s)2,03 (3H, s), of 2.34 (3H, s)of 2.64 (2H, t, J=7.4 Hz), 2,87(2H, t, J=7.4 Hz), to 3.34 (1H, DD, J=6,8, or 15.0 Hz), 3,50 (1H, DD, J=6,2, 15,0 Hz), 3,53 (1H, d, J=14,2 Hz), 3,62 (3H, s), 3,63 (3H, s), and 3.72 (1H, d, J=11,0 Hz), 3,85 (1H, d, J=11.0 in Hz)to 3.89 (3H, s), 4,27 (1H, DD, J=6,2, 6,8 Hz), 4,56 (1H, d, J=14,2 Hz), of 6.29 (1H, s), 6,60 (1H, d, J=1,8 Hz), 6,95 and 7.36 (5H, m).

(3) a Mixture of methyl 3-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-thiazol-4-yl)propionate (0.2 g, 0,303 mmol)obtained in example 20-(2), 1 N. aqueous sodium hydroxide solution (1 ml) and ethanol (2 ml) was stirred at 60°C for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and extracted with ethyl acetate (50 ml) twice. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and then concentrated the ri reduced pressure to obtain 3-((2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-thiazol-4-yl)propionic acid (0.18 g, 0,298 mmol, 98%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), of 2.33 (3H, s), 2,66-of 2.72 (2H, m), 2,83-2,89 (2H, m), and 3.16 (1H, d, J=11.8 Hz), 3,37 (1H, DD, J=6,2, to 15.4 Hz), 3,42 (1H, d, J=14.6 Hz)and 3.59 (1H, DD, J=6,6, to 15.4 Hz), 3,62 (3H with), 3,63 (1H, d, J=11.8 Hz), 3,90 (3H, s), 4,30 (1H, DD, J=6,2, and 6.6 Hz), 4,46 (1H, d, J=14.6 Hz), of 6.20 (1H, s), 6,60 (1H, d, J=1.4 Hz), 6,97-7,39 (5H, m).

Example 21

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-4-yl)acetic acid

In a manner similar to the method of example 16, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s), 3,17 (1H, d, J=11,9 Hz)to 3.41 (1H, d, J=14,5 Hz), 3,48 (1H, DD, J=6,5, to 15.4 Hz), 3,60-3,71 (5H, m), 3,80 (2H, s), 3,90 (3H, s), 4,35 (1H, t, J=6.5 Hz), 4,46 (1H, d, J=14,5 Hz), 6,21 (1H, s), 6,60 (1H, s), 7,00 (1H, DD, J=2.1 a, 7,7 Hz), 7,05 (1H, s), 7,11-7,22 (2H, m), 7,33-7,40 (2H, m).

Example 22

2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-4-carboxylic acid

(1) a Solution of 3-[(3R,5S)-3-(2-amino-2-oxoethyl)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (3.0 g, 5,61 mmol)obtained in example 16-(2), and ethyl 3-bromo-2-oxopropionate (0,79 ml, 6,28 mmol) in ethanol (30 ml) was boiled with reflux for 2 hours under stirring. After vystaveni the cooling to the reaction solution were added water (15 ml) followed by extraction with ethyl acetate (300 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:2-1:1)] to obtain ethyl 2-{[(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-yl]methyl}-1,3-thiazole-4-carboxylate (1.1 g) as a colorless non-crystalline powder from the first elyuirovaniya fraction and ethyl 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-4-carboxylate (2.0 g) as colorless powder from the second elyuirovaniya faction.

First allerona fraction

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.03 (3H, s)to 1.37 (3H, t, J=7.0 Hz), 2,03 (3H, s), 3,41-3,62 (3H, m), 3,61 (3H, s), and 3.72 (1H, d, J=11.0 in Hz)of 3.96 (1H, d, J=11.0 in Hz)to 3.89 (3H, s), 4,27-and 4.40 (1H, m), 4,39 (2H, kV, J=7,0 Hz), 4,55 (1H, d, J=14,0 Hz), of 6.31 (1H, s), 6,59 (1H, d, J=1,8 Hz), 6,98 (1H, DD, J=2.0 a, 7,8 Hz), was 7.08 (1H, DD, J=2.0 a, 7,8 Hz), 7,17 (1H, t, J=7.8 Hz), 7.23 percent-7,40 (2H, m), of 8.09 (1H, s).

Second allerona fraction

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)to 1.38 (3H, t, J=7,0 Hz), and 3.16 (1H, t, J=11.8 Hz), 3,37 (1H, d, J=25 14.4 Hz), 3,45-and 3.72 (3H, m), 3,62 (3H, s)to 3.89 (3H, s), 4,05-to 4.15 (1H, m), 4,35 (1H, t, J=7,0 Hz), 4,39 (2H, q, J7,0 Hz), 4,47 (1H, d, J=14.4 Hz), 6,21 (1H, s), 6,56 (1H, d, J=2.2 Hz), of 6.99 (1H, DD, J=1,8, 8.0 Hz), 7,07 (1H, DD, J=1,8, 8.0 Hz), 7,18 (1H, t, J=8.0 Hz), 7,29 (1H, d, J=8,4 Hz), 7,35 (1H, DD, J=2,2, 8,4 Hz), of 8.09 (1H with).

(2) a Mixture of ethyl 2-{[(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-yl]methyl}-1,3-thiazole-4-carboxylate (0.34 g, 0.52 mmol) and ethyl 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-4-carboxylate (2.0 g, 3,40 mmol)obtained in example 22-(1), 1 N. aqueous sodium hydroxide solution (14,0 ml) and ethanol (60 ml) was stirred at room temperature for 5 hours. The mixture was acidified using 1 N. hydrochloric acid (14,5 ml) was added thereto ethyl acetate (380 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. To the obtained residue was added diethyl ether (30 ml), 1 N. aqueous sodium hydroxide solution (14 ml) and water (100 ml). The aqueous layer was washed with diethyl ether (50 ml) and then acidified 1 N. hydrochloric acid (14,5 ml) and was added ethyl acetate (380 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-Ki-the Roxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-4-carboxylic acid (2.9 g) as a pale-yellow non-crystalline powder.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)3,18 (1H, d, J=12.0 Hz), 3,38 (1H, d, J=13,8 Hz), of 3.54 (1H, DD, J=7,2, of 14.7 Hz), 3,56-3,68 (1H, m), 3,62 (3H, s)to 3.89 (3H, s), 4,34 (1H, DD, J=5,7, 7,2 Hz), 4,46 (1H, d, J=13,8 Hz), 6,21 (1H, s), to 6.57 (1H, d, J=2.1 Hz), 6,98 (1H, DD, J=1.5 and 8.1 Hz), 7,06 (1H, DD, J=1.5 and 8.1 Hz), 7,17 (1H, t, J=8.1 Hz), 7,29 (1H, d, J=8.7 Hz), 7,35 (1H, DD, J=2,1, to 8.7 Hz), 8,18 (1H, s).

Example 23

2-{[(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-yl]methyl}-1,3-thiazole-4-carboxylic acid

In a manner similar to the method of example 17, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.03 (3H, s)2,03 (3H, s), 3,45-3,66 (3H, m), 3,61 (3H, s), and 3.72 (1H, d, J=10,8 Hz), 3,85 (1H, d, J=10,8 Hz)to 3.89 (3H, s), 4,32 (1H, DD, J=5,7, 7,2 Hz), 4,55 (1H, d, J=13,8 Hz), of 6.31 (1H, s), 6,60 (1H, d, J=2.4 Hz), 6,98 (1H, DD, J=1.5 and 7.8 Hz), 7,06 (1H, DD, J=1.5 and 7.8 Hz), 7,10-7,20 (1H, m), 7,27 (1H, d, J=9.0 Hz), 7,32 (1H, DD, J=2,4, and 9.0 Hz), 8,18 (1H, s).

Example 24

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-4-yl)-3-hydroxypropionic acid

In a manner similar to the method of example 18, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s), 2,78 totaling 3.04 (2H, m), and 3.16 (1H, d, J=11,4 Hz), 3,39 (1H, d, J=14.1 Hz), 3,40-3,70 (3H, m), 3,61 (3H, s)to 3.89 (3H, s), or 4.31 (1H, t, J=6.6 Hz), 4,46 (1H, d, J=14.1 Hz), 5,11-to 5.21 (1H, m), of 6.20 (1H, s), 6,59 (1H, s), of 6.96-7,02 (1H, m), 7,08-7,20 3H, m), 7,29-7,41 (2H, m).

Example 25

(2E)-3-{2-[((3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl]-1,3-thiazol-4-yl}acrylic acid

In a manner similar to the method of example 19 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.06 (3H, s)3,18 (1H, d, J=12.0 Hz), to 3.41 (1H, d, J=13,8 Hz), 3,49 (1H, DD, J=6,6, 15.3 Hz), to 3.58-3,70 (2H, m), 3,63 (3H, s), 3,90 (3H, s), and 4.40 (1H, t, J=6.6 Hz), 4,48 (1H, d, J=to 13.8 Hz), 6,23 (1H, s), 6,60 (1H, d, J=2.4 Hz), 6,62 (1H, d, J=15.3 Hz), 7,00 (1H, DD, J=2,4, 7,2 Hz), 7,13-7,21 (2H, m), 7,30-7,41 (3H, m), a 7.62 (1H, d, J=15.3 Hz).

Example 26

4-[((3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl]-2-methyl-1,3-thiazole-5-carboxylic acid

(1) Carbonyldiimidazole (3.7 g) was added to a suspension of 2-[(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-yl]acetic acid (10 g) in THF (100 ml) and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added magnesium chloride (2.2 g) and monoethylamine potassium (4.0 g) and the mixture was stirred at 60°C for 1 hour. The reaction solution was diluted with ethyl acetate (200 ml), washed with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated podnimetsia sodium chloride, was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl 4-{[(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-yl]}-3-oxobutanoate (10.2 g) as a white crystal.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)a 1.01 (3H, s)of 1.27 (3H, s)2,02 (3H, s), 2,96 (1H, DD, J=5,0, and 17.2 Hz), with 3.27 (1H, DD, J=7,8, of 17.0 Hz), 3,42 is 3.57 (3H, m), 3,61 (3H, s), 3,69-3,82 (2H, m)to 3.89 (3H, s), 4,18 (2H, q, J=7.4 Hz), to 4.41-of 4.57 (2H, m), 6,24 (1H, s), 6,63 (1H, s), 6,95-7,02 (1H, m), 7,15-7,20 (2H, m), 7,33-7,34 (4H, m).

(2) Sulfurylchloride (0,23 ml) was added to a solution of ethyl 4-{[(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-yl]}-3-oxobutanoate (1.5 g)obtained in example 26-(1)in dichloromethane (30 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and was extracted with chloroform. The organic layer was concentrated under reduced pressure. To the residue was added thioacetamide (0.21 g) and ethanol (30 ml) and the mixture is boiled under reflux during the night. The reaction solution was concentrated and the residue was purified column chromatography on silica gel to obtain ethyl 4-[((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-yl)methyl]-2-methyl-1,3-thiazole-5-carbox elata (0,80 g) in the form Besenova amorphous crystal.

1H-NMR (CD3OD) δ: of 0.93 (3H, s)of 1.23 (3H, s)of 1.27 (3H, t, J=7.2 Hz), 2,03 (3H, s)of 2.64 (3H, s), 3,51 is 3.57 (1H, m), of 3.60 (3H, s), 3,67-of 3.85 (4H, m), a 3.87 (3H, s)to 4.23 (2H, q, J=7.2 Hz), 4,37-of 4.44 (2H, m), of 6.26 (1H, s), 6,53 (1H, s), 6.87 in-6,99 (2H, m), 7,05-7,10 (1H, m), 7,16-to 7.18 (1H, m), 7,32-7,37 (2H, m).

(3) a Mixture of ethyl 4-[((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-yl)methyl]-2-methyl-1,3-thiazole-5-carboxylate (0.7 g)obtained in example 26-(2), 2 N. aqueous sodium hydroxide solution (2 ml) and ethanol (10 ml) was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and extracted with chloroform (50 ml) twice. The extract is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 4-[((3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl]-2-methyl-1,3-thiazole-5-carboxylic acid (0,19 g) as a white crystal.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), was 1.04 (3H, s)of 1.12 (3H, s)to 1.14 (3H, s), 2,62 (3H, s), 3,12-and 3.16 (1H, m), 3,35 is 3.40 (1H, m), 3,53 (3H, s), 3,62-3,68 (3H, m), a 3.87 (3H, s), to 4.41-4,50 (2H, m), 6,16 (1H, s), 6,53 (1H, s), 6,93-6,97 (2H, m), 7,09-7,14 (1H, m), 7,26-7,33(2H, m).

Example 27

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-be who oxazepan-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid calcium salt

(1) phosphorus Oxychloride (0.35 g, of 2.33 mmol) was added to a solution of ethyl 4-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}amino)-3-oxobutanoate (1 g, 1.55 mmol)obtained in example 1-(3), in DMF (3 ml) and the mixture was stirred at 70°C for 1 hour. The reaction solution was cooled in an ice bath was added a saturated aqueous solution of sodium bicarbonate (50 ml). The product was extracted with ethyl acetate (50 ml) twice, washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:2)] to obtain ethyl (2-{[(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-yl]methyl}-1,3-oxazol-5-yl)acetate (0,57 g, 0,906 mmol, 58%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.03 (3H, s)of 1.26 (3H, t, J=7.4 Hz), 2,03 (3H, s), 3,24 (1H, DD, J=7,4, to 15.8 Hz), to 3.36 (1H, DD, J=6,6, to 15.8 Hz), 3,54 (1H, d, J=14,0 Hz), 3,61 (3H, s), 3,68 (2H, s), of 3.73 (1H, d, J=to 11.4 Hz), 3,85 (1H, d, J=11.4 in Hz)to 3.89 (3H, s), 4,18 (2H, q, J=7.4 Hz), of 4.44 (1H, DD, J=6,6, 7,4 Hz), 4,58 (1H, d, J=14,0 Hz), 6,30 (1H, s), 6,60 (1H, s), 6,85 (1H, s), 6,94-7,33 (5H, m).

(2) a Mixture of ethyl (2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-t is trihydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetate (0,47 g, 0,747 mmol)obtained in example 27-(1), 1 N. aqueous sodium hydroxide solution (2 mmol) and ethanol (5 ml) was stirred at 60°C for 30 minutes. The resulting mixture was washed with water (5 ml), acidified and extracted with ethyl acetate (50 ml) twice. The extract is washed with saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure to obtain (2-{[(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-yl]methyl}-1,3-oxazol-5-yl)acetic acid (0,42 g). The obtained product was dissolved in ethanol (6 ml) and to the solution was added 1 N. aqueous sodium hydroxide solution (0.75 ml). The mixture was then concentrated under reduced pressure. The residue was dissolved in water (2 ml) and the solution was added calcium chloride (42 mg, 0,378 mmol) in water (0.5 ml). The obtained precipitation was filtered to obtain the calcium salt of (2-{[(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-yl]methyl}-1,3-oxazol-5-yl)acetic acid (0.29 grams, 0,247 mmol, 66%) as a colorless powder.

1H-NMR (CDCl3-D3OD (1:2)) δ: 0,81 (3H, s)to 0.97 (3H, s), 3,19 (1H, d, J=11.8 Hz), 3,22-3,29 (2H, m), 3,50 (1H, d, J=11.8 Hz), 3,55 (2H, s), of 3.60 (3H, s), 3,62 (1H, d, J=13,4 Hz), 3,90 (3H, s), 4,40-4,47 (2H, m), 6,21 (1H, s), 6,55 (1H, d, J=2.6 Hz), 6,78 (1H, s), 7,02-7,37 (5H, m).

Example 28

(2-{[(3R,5S)-7-chloro-5-(2,3-dim is toxigenic)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-methyl-1,3-oxazol-5-yl)acetic acid calcium salt

In a manner similar to the method of example 27, has been specified in the header of the connection.

1H-NMR (CDCl3-D3OD (1:2)) δ: or 0.83 (3H, s)of 0.95 (3H, s), is 2.05 (3H, s), 3,18-3,26 (3H, m), 3,44-3,68 (4H, m)and 3.59 (3H, s)to 3.89 (3H, s), to 4.38-to 4.46 (2H, m), of 6.20 (1H, s) 6,53 (1H, d, J=2.2 Hz), 7,02-to 7.59 (5H, m).

Example 29

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)propionic acid

(1) in a Manner similar to the method of example 27-(1)was obtained methyl 3-(2-{[(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-yl]methyl}-1,3-oxazol-5-yl)propionate.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.03 (3H, s)2,03 (3H, s)of 2.64 (2H, t, J=7.4 Hz), 2,96 (2H, t, J=7.4 Hz), 3,21 (1H, DD, J=7,0, to 15.4 Hz), to 3.33 (1H, DD, J=6,6, to 15.4 Hz), 3,54 (1H, d, J=14,2 Hz), 3,61 (3H, s), 3,69 (3H, s), of 3.73 (1H, d, J=11,0 Hz), 3,85 (1H, d, J=11.0 in Hz)to 3.89 (3H, s)to 4.41 (1H, DD, J=6,6, 7,0 Hz), 4,58 (1H, d, J=14,2 Hz), 6,30 (1H, s), 6,60 (1H, s), of 6.65 (1H, s), 6,95-7,33 (5H, m).

(2) a Mixture of methyl 3-(2-{[(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-yl]methyl}-1,3-oxazol-5-yl)propionate (0.11 g, 0,175 mmol)obtained in example 29-(1), 1 N. aqueous sodium hydroxide solution (0.5 ml) and ethanol (2 ml) was stirred at 60°C for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified, and then the extras who were garofali with ethyl acetate (50 ml) twice. The product was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by recrystallization from a mixture of ethanol-hexane (1:1) to obtain 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)propionic acid (50 mg, 0,0873 mmol, 50%) as a colorless powder.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)to 2.67 (2H, t, J=7.0 Hz), 2,95 (2H, t, J=7,0 Hz), and 3.16 (1H, d, J=12,8 Hz), up 3.22 (1H, DD, J=7,0, to 15.8 Hz), 3,37 (1H, DD, J=6,6, to 15.8 Hz), 3,39 (1H, d, J=15,4 Hz), 3,62 (3H, C), 3,63 (1H, d, J=12,8 Hz)to 3.89 (3H, s), of 4.44 (1H, DD, J=6,6, 7,0 Hz), 4,48 (1H, d, J=15,4 Hz), to 6.19 (1H, s), 6,59 (1H, s), of 6.68 (1H, s), of 6.96 and 7.36 (5H, m).

Example 30

4-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)butane acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), was 1.04 (3H, s), of 1.95 (2H, quintet, J=7.4 Hz), of 2.38 (2H, t, J=7.4 Hz), 2,69 (2H, t, J=7.4 Hz), and 3.16 (1H, d, J=and 12.2 Hz), 3,21 (1H, DD, J=6,6, 15.6 Hz), to 3.38 (1H, DD, J=7,0, 15.6 Hz), 3,40 (1H, d, J=15,0 Hz), 3,61 (3H, s), 3,63 (1H, d, J=and 12.2 Hz), 3,89 5 (3H, s), 4,42-to 4.52 (2H, m), to 6.19 (1H, s), to 6.58 (1H, s), of 6.66 (1H, s), 6,95 and 7.36 (5H, m).

Example 31

2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzac is azepin-3-yl]methyl}-1,3-oxazol-5-yl)-2-methylpropionate acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), 1,037 (3H, s), and 1.56 (6H, s), 3,17 (1H, d, J=11,6 Hz)at 3.25 (1H, DD, J=7,0, to 15.8 Hz), to 3.38 (3H, DD, J=6,6, to 15.8 Hz), 3,39 (1H, d, J=14,0 Hz), 3,61 (3H, s), 3,62 (1H, d, J=11,6 Hz), 3,88 (3H, 20)to 4.41 (1H, DD, J=6,6, 7,0 Hz), 4,47 (1H, d, J=14,0 Hz), 6,18 (1H, s), to 6.57 (1H, s), to 6.80 (1H, s), 6,95-7,53 (5H, m).

Example 32

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-ethyl-1,3-oxazol-5-yl)acetic acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), was 1.04 (3H, s)of 1.16 (3H, t, J=7,6 Hz), 2,43 (2H, q, J=7,6 Hz), 3,17 (1H, d, J=12.0 Hz), 3,26-3,30 (2H, m)to 3.38 (1H, d, J=14.4 Hz), 15 of 3.60 (3H, s), 3,62 (2H, s), 3,62 (1H, d, J=12.0 Hz), a 3.87 (3H, s), 4,39-4,50 (2H, m), 6,17 (1H, s), to 6.57 (1H, d, J=1.4 Hz), 6,93-7,39 (5H, m).

Example 33

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s), with 3.27 (1H, DD, J=7,2, the 15.6 Hz), the 3.35 (1H, DD, J=6,0, the 15.6 Hz), to 3.36 (1H, d, J=13,8 Hz), 3,61 (3H, s), 3,71 (2H, s), a 3.87 (3H, s), of 4.44 (1H, DD, J=6,0, 7,2 Hz), 4,50 (1H, d, J=13,8 Hz), of 6.29 (1H, s), 6,56 (1H, s), to 6.88 (1H, s)6,94 (1H, DD, J=1.5 and 7.8 Hz) 7,03 (1H, DD, J=0,9, and 7.8 Hz), 7,13 (1H, t, J=7.8 Hz), 7,26-7,34 (2H, m).

Example 34

2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: to 0.92 (3H, d, J=6.6 Hz), and 1.00 (3H, d, J=6.9 Hz), 1,95-of 2.09 (1H, m), 3,32-to 3.41 (3H, m), of 3.57 (3H, s), of 3.69 (2H, s), a 3.87 (3H, s), 4,37 (1H, t, J=7,8, or 13.8 Hz), 4,46 (1H, t, J=6.3 Hz), to 6.19 (1H, ), 6,60 (1H, d, J=1,8 Hz), make 6.90 (1H, s), 6,92 and 7.36 (5H, m).

Example 35

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (3H, t, J=7.5 Hz), 1.56 to of 1.84 (2H, m), 3,23-of 3.54 (3H, m), of 3.56 (3H, s), of 3.69 (2H, s), 3,86 (3H, s), 4,40-to 4.52 (2H, m)6,09 (1H, s), 6,60 (1H, d, J=2.1 Hz), make 6.90 (1H, s), 6,93-7,37 (5H, m).

Example 36

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-ethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 1.25 (3H, t, J=7.2 Hz), or 3.28 (1H, DD, J=7,2, the 15.6 Hz), 3,39 (1H, DD, J=7,2, the 15.6 Hz), 3,50-3,66 (4H, m), of 3.69 (2H, s), 3,86 (3H, s), of 4.45 (1H, t, J=6.3 Hz), 4,48-to 4.62 (1H, m), the 6.06 (1H, s), 6,61 (1, d, J=1,8 Hz), make 6.90 (1H, s), 6,92-7,37 (5H, m).

Example 37

(4-Benzyl-2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s)and 3.15 (1H, d, J=12,6 Hz), 3,26 (2H, DD, J=4,5, 7,2 Hz), 3,35 (1H, d, J=14.4 Hz), 3,51 (2H, d, J=1,8 Hz)and 3.59 (3H, s), 3,60 (1H, d, J=12,6 Hz), with 3.79 (2H, s), 3,86 (3H, C)to 4.41 (1H, t, J=7.2 Hz), 4,43 (1H, d, J=14.4 Hz), x 6.15 (1H, s), 6,55 (1H, d, J=2.1 Hz), 6,93 (1H, DD, J=1.5 and 8.1 Hz), 6,98 (1H, DD, J=1.5 and 8.1 Hz), was 7.08 (1H, t, J=8.1 Hz), 7,13-7,26 (5H, m), 7,28 (1H, d, J=9.0 Hz), 7,34 (1H, DD, J=2,1, 9,0 Hz).

Example 38

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-oxazol-4-yl)propionic acid

(1) phosphorus Oxychloride (0.35 g, of 2.33 mmol) was added to a solution of methyl (4S)-4-({2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}amino)-5-oxohexanoate (1 g, 1.55 mmol)obtained in example 20-(1)in DMF (3 ml) and the mixture was stirred at 80°C for 1 hour. The reaction solution was cooled in an ice bath was added a saturated aqueous solution of sodium bicarbonate (50 ml). The product was extracted with ethyl acetate (50 ml) twice, about ivali water and saturated aqueous sodium chloride, was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:1)] to obtain methyl 3-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-oxazol-4-yl)propionate (0,83 g, 1,29 mmol, 83%) in the form of colorless powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.03 (3H, s)2,03 (3H, s), 2,22 (3H, s), 2.57 m-2,62 (2H, m), 2,66-a 2.71 (2H, m), 3,19 (1H, DD, J=7,2, the 15.6 Hz)at 3.25 (1H, DD, J=6,0, the 15.6 Hz), 3,54 (1H, d, J=13,8 Hz), 3,61 (3H, s), 3,64 (3H, s), 3,74 (1H, d, J=11,1 Hz), a-3.84 (1H, d, J=11,1 Hz)to 3.89 (3H, s), 4,36 (1H, DD, J=6,0, 7,2 Hz), of 4.57 (1H, d, J=13,8 Hz), of 6.29 (1H, s), 6,59 (1H, d, J=1,8 Hz), 6,95-7,34 (5H, m).

(2) a Mixture of methyl 3-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-oxazol-4-yl)propionate (0,67 g, 1.04 mmol)obtained in example 38-(1), 1 N. aqueous sodium hydroxide solution (2.5 ml) and ethanol (7 ml) was stirred at 60°C for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and then extracted with ethyl acetate (50 ml) twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure to obtain 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-Tetra is Idro-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-oxazol-4-yl)propionic acid (0,47 g, 0,801 mmol, 77%) as a colorless powder.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,22 (3H, s), 2,62-of 2.72 (4H, m), 3,12-3,19 (2H, m), 3,67-of 3.46 (2H, m), 3,62 (3H, s), 3,63 (1H, d, J=12.3 Hz), with 3.89 (3H, s), 4,39-4,48 (2H, m), to 6.19 (1H, s), 6,60 (1H, d, J=2.1 Hz), 6,98-7,47 (5H, m).

Example 39

3-[((3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl]pyrazole-4-carboxylic acid

(1) N,N-dimethylformaldehyde (0,41 ml) was added to a solution of ethyl 4-[((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-yl)]-3-oxobutanoate (1.5 g)obtained in example 26-(1)in toluene (30 ml) and the mixture is boiled under reflux during the night. After concentrating the reaction solution to the residue was added ethanol (30 ml) and hydrazine hydrate (0.14 g) and the mixture is boiled under reflux for 3 hours. The reaction solution was concentrated and the residue was purified column chromatography on silica gel to obtain ethyl 3-[((3R,5S)-7-chloro-5-(2,3-acid)-1-(3-acetoxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl]pyrazole-4-carboxylate (0,90 g) as a brown oil.

1H-NMR (CD3OD) δ: of 0.95 (3H, s)of 1.02 (3H, s)of 1.26 (3H, t, J=7.4 Hz), 2,03 (3H, s), 3,47-3,55 (2H, m), 3,62 (3H, s), 3,71-3,88 (2H, m)to 3.89 (3H, s), 4,08-to 4.15 (2H, m), is 4.21 (2H, q, J=7.4 Hz), of 4.54 (1H, d, J=14.1 Hz), 6,27 (1H), of 6.61 (1H, s), of 6.96-6,99 (1H, m), 7,10-7,33 (4H, m), 7,87(1H, s).

(2) a Mixture of ethyl 3-[((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-yl)]methyl]pyrazole-4-carboxylate (1.0 g)obtained in example 39-(1), 2 N. of a saturated aqueous sodium hydrogen carbonate solution (3.3 ml) and ethanol (20 ml) was stirred at 80°C during the night. The resulting mixture was diluted with water (50 ml), acidified and then extracted with chloroform (50 ml) twice. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with 3-[((3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl]pyrazole-4-carboxylic acid (0.18 g) as a white crystal.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.06 (3H, s)3,18 (1H, d, J=11.7 Hz), 3,37 (1H, d, J=15,0 Hz), 3,56-3,61 (3H, m), 3,63 (3H, s)to 3.89 (3H, s), 4,14 (1H, t, J=6.9 Hz), 4,49 (1H, d, J=14.4 Hz), to 6.19 (1H, s), 6,60 (1H, d, J=10 and 2.4 Hz), 6,97-7,00 (1H, m), 7,08-7,10 (1H, m), 7,16 and 7.36 (5H, m), 7,94 (1H, s).

Example 40

1-(3-carboxypropyl)-3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid

(1) potassium Carbonate (of 0.741 g) was added to a solution of ethyl-5{[(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-yl]methyl}-1H-pyrazole-4-carboxylate (3.00 g), obtained in example 39-(1), and ethyl 4-bromobutyrate (0,794 ml) in DMF (30 ml) and the mixture was stirred over night. The reaction solution was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl 3-{[(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-yl]methyl}-1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-4-carboxylate (0,98 g) from the first elyuirovaniya fraction and ethyl 5-({(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-yl}methyl)-1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-4-carboxylate (1.78 g) of the second elyuirovaniya faction.

(2) To a solution of ethyl 3-{[(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-yl]methyl}-1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-4-carboxylate (0.8 g)obtained in example 40-(1)in ethanol (8 ml) was added 1 N. aqueous sodium hydroxide solution (4 ml) and the mixture was stirred over night. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with ethyl acetate. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then koncentrira is whether under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the title compound (157 mg).

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.03 (3H, s), 2,10-of 2.21 (2H, m), 2,28-of 2.38 (2H, m), and 3.16 (1H, d, J=12.1 Hz), 3,28 is-3.45 (2H, m), 3,52 at 3.69 (5H, m), 3,86 (3H, s), of 4.13 (2H, t, J=6.22 per Hz), to 4.41-to 4.52 (2H, m), 6,17 (1H, C)6,56 (1H, d, J=2,07 Hz)6,94 (1H, DD, J=1,9, 7.9 Hz), 7,05-7,17 (2H, m), 7,30-7,40 (2H, m), a 7.85 (1H, s).

Example 41

1-(3-carboxypropyl)-5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid

1 N. Aqueous sodium hydroxide solution (4 ml) was added to a solution of ethyl 5-({(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-yl}methyl)-1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-4-carboxylate (0.75 g)obtained in example 40-(1)in ethanol (20 ml) and the mixture was stirred for 2 days. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with ethyl acetate. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the title compound (590 mg).

1H-NMR (CDCl3) δ: 0,76 (3H, s)of 0.87 (3H, s), 1,83 is 1.96 (2H, m), and 2.14 (2H, t, J=7,3 Hz), 3,03-320 (2H, m), 3,23-of 3.43 (2H, m), 3,50 (3H, s), 3,68 (1H, d, J=14.1 Hz), 3,83 (3H, s), 4,07-of 4.25 (3H, m), 4,35 (1H, d, J=14.1 Hz), of 4.57 (1H, s), 6,10 (1H, s), of 6.26 (1H, d, J=2.6 Hz), 6,59 (1H, d, J=3.3, which is 5.9 Hz), 7,09-to 7.18 (2H, m)to 7.50 (1H, DD, J=2.5 and 8.7 Hz), of 7.70 (1H, d, J=8,Hz), to 7.77 (1H, s).

Example 42

1-(carboxymethyl)-3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid

In a manner similar to the method of example 40, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: 0,76 (3H, s), is 0.84 (3H, s), 3.00 and-is 3.21 (2H, m), 3,22 is 3.57 (5H, m), the 3.65 (1H, d, J=14,0 Hz), 3,82 (3H, s), 4,23-and 4.40 (2H, m), 4,50 (2H, s), the 6.06 (1H, s), of 6.31 (1H, d, J=2.5 Hz), of 6.96 (1H, d, J=7,0 Hz), 7,05-7,22 (2H, m), 7,49 (1H, DD, J=2,1, to 8.7 Hz), to 7.68 (1H, d, J=8,9 Hz), to 7.99 (1H, s).

Example 43

1-(carboxymethyl)-5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid

In a manner similar to the method of example 41, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: of 0.75 (3H, s)of 0.87 (3H, s), 3,03-3,20 (2H, m), 3,24-to 3.41 (2H, m), 3,51 (3H, s), 3,66 (1H, d, J=14.1 Hz), of 3.84 (3H, s), 4,10-4,18 (1H, m)to 4.33 (1H, d, J=14.1 Hz), 4,51-4,60 (1H, m)to 5.00 (2H, s), 6,11 (1H, s), 6,28 (1H, d, J=2.6 Hz), 6,72 (1H, DD, J=2.0 a, 7,3 Hz), 7,11-7,22 (2H, m)to 7.50 (1H, DD, J=2.5 and 8.7 Hz), 7,69 (1H, d, J=8,9 Hz), to 7.77 (1H, s).

Example 44

2-[5-({(3R,5S)-1-[3-(atomic charges)-2,2-dimethylpropyl]-7-chloro-5-(2,3-acid)2-the CSR-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl}methyl)-4-(etoxycarbonyl)-1H-pyrazole-1-yl]benzoic acid

1,1-Dimethoxy-N,N-dimethylethanamine (0,598 ml) was added to a solution of ethyl 4-[(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-yl]-3-oxobutanoate (2 g) in toluene (20 ml) and the mixture is boiled under reflux during the night. After the mixture was concentrated under reduced pressure, to the residue was added ethanol (20 ml) and 2-hydrazinophenyl acid (0,567 g) and the mixture is boiled under reflux for 3 hours. After concentration under reduced pressure the residue was purified column chromatography on silica gel with obtaining specified in the connection header (0,83 g).

1H-NMR (DMSO-d6) δ: 0,83-0,87 (6H, m), is 1.11 (3H, t, J=7,1 Hz), 1,89 (3H, s), 3,18-and 3.31 (2H, m), of 3.45 (3H, s), 3,56-3,71 (3H, m), 3,83 (3H, s), 3,99-4,16 (3H, m), 4.26 deaths (1H, d, J=14,3 Hz), 6,00 (1H, s), and 6.25 (1H, d, J=2.3 Hz), to 6.67 (1H, DD, J=1,4, and 7.3 Hz), 7,09-7,21 (2H, m), 7,38 was 7.45 (1H, m), 7,46-to 7.64 (4H, m), 7,83 (1H, d, J=8.1 Hz), of 7.97 (1H, s).

Example 45

3-(5-{[(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-yl]methyl}-4-(etoxycarbonyl)-1H-pyrazole-1-yl)benzoic acid

In a manner similar to the method of example 44, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: of 0.85 (3H, s)of 0.87 (3H, s), 1.04 million-1,11 (3H, m)to 1.87 (3H, s), 3,28-to 3.38 (1H, m), of 3.45 (3H, s), 3.46 in of 3.75 (4H, m), 3,82 (3H, s), 4,10 (3H, m), 432 (1H, d, J=14,3 Hz), 6,01 (1H, s), of 6.20 (1H, d, J=2.5 Hz), 6,46 (1H, DD, J=2,6, and 6.6 Hz), 7,07-to 7.15 (2H, m), 7,47-to 7.59 (2H, m), 7,68 (1H, d, J=8,9 Hz), 7,73-7,79 (1H, m), 7,93-7,98 (1H, m), 8,02 (1H, t, J=1,8 Hz), 8,10 (1H, s).

Example 46

4-(5-{[(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-yl]methyl}-4-(etoxycarbonyl)-1H-pyrazole-1-yl)benzoic acid

In a manner similar to the method of example 44, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: 0,86 (s, 6H), 1,10 (3H, t, J=7,1 Hz)to 1.87 (3H, s)to 3.38 (1H, d, J=4.0 Hz), 3,44 (3H, s), 3,53-3,74 (4H, m), 3,82 (3H, s), a 4.03-to 4.15 (3H, m), 4,32 (1H, d, J=14,3 Hz), of 5.99 (1H, s), from 6.22 (1H, d, J=2.5 Hz), 6,46 (1H, DD, J=2,1, 7,0 Hz), 7,09-7,19 (2H, m), 7,46 (1H, DD, J=8,7, 2,5 Hz), 7,58-of 7.69 (3H, m), 7,94 (2H, d, J=8.5 Hz), 8,11 (1H, s).

Example 47

1-(2-carboxyphenyl)-5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid

1 N. Aqueous sodium hydroxide solution (3.4 ml) was added to a solution of 2-(5-{[(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-yl]methyl}-4-(etoxycarbonyl)-1H-pyrazole-1-yl)benzoic acid (0.5 g)obtained in example 44, in ethanol (5 ml) and the mixture was stirred over night. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with ethyl acetate. Receiving the hydrated extract was washed with a saturated aqueous solution of sodium chloride, was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the title compound (0.28 g).

1H-NMR (DMSO-d6) δ: 0,70 (3H, s)of 0.79 (3H, s), 2,96-of 3.12 (2H, m), 3,22-3,37 (2H, m), of 3.46 (3H, s), of 3.56 (1H, d, J=14,0 Hz), 3,83 (3H, s), is 4.21 (1H, d, J=14,0 Hz), 4,50 (1H, t, J=5,2 Hz), 5,95 (1H, s), 6,24 (1H, d, J=2.5 Hz), 6,69 (1H, DD, J=1,6, 7,4 Hz), 7,08-of 7.23 (2H, m), of 7.36-7,42 (1H, m), 7,44-7,58 (4H, m), 7,76-a 7.85 (1H, m), to $ 7.91 (1H, s).

Example 48

1-(3-carboxyphenyl)-5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid

In a manner similar to the method of example 47, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: 0,70 (3H, s)0,81 (3H, s), 2,98-3,14 (2H, m), of 3.46 (3H, s), 3,48-3,66 (2H, m), 3,82 (3H, s), 4,20 (1H, DD, J=3,9, and 9.6 Hz), 4,28 (1H, d, J=14.1 Hz), 5,96 (1H, s), to 6.19 (1H, d, J=2.5 Hz), 6,46 (1H, DD, J=2,5, 6,7 Hz), 7,10 (2H, m), 7,43-the 7.65 (4H, m), 7,71 for 7.78 (1H, m), 7,94 (1H, d, J=7.9 Hz), 8,02-of 8.06 (2H, m).

Example 49

1-(4-carboxyphenyl)-5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid

In a manner similar to the method of example 47, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: 0,70 (3H, s)to 0.80 (3H, s), 2,97-3,13 (2H, m), 3,4 (3H, C)3,56-3,70 (2H, m), 3,82 (3H, s)4,07 (1H, DD, J=3,9, 9.8 Hz), 4,23-4,32 (1H, m), 4,51 (1H, t, J=4.9 Hz), to 5.93 (1H, s), of 6.20 (1H, d, J=2.5 Hz), 6,47 (1H, DD, J=1,8, 7,1 Hz), 7,07-7,20 (2H, m), 7,41 (1H, DD, J=2.5 and 8.7 Hz), 7,54-to 7.64 (3H, m), 7,92 (2H, d, J=8.7 Hz), of 8.06 (1H, s).

Example 50

1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-5-carboxylic acid

(1) [(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-yl]acetic acid (10 g, 19.2 mmol) was dissolved in THF (80 ml) and to the solution was added dropwise under ice cooling, N-methylmorpholine (2.2 ml, of 23.1 mmol) and ethyl chlorocarbonate (2,54 ml of 23.1 mmol). After stirring at the same temperature for 1 hour the mixture was cooled to -30°C and added to it borohydrate sodium (2,18 g, 58,0 mmol). Then slowly added dropwise MeOH (80 ml) and the mixture was stirred for 1 hour. At the same temperature was added to a mixture of saturated aqueous solution of ammonium chloride and the mixture was extracted with AcOEt (480 ml). The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (2:3)] to obtain (3R,5S)-1-(3-what zatoki-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ethanol (9.3 g) in the form Besenova crystal.

1H-NMR (DMSO-d6) δ: of 0.95 (3H, s)of 1.03 (3H, s)2,03 (3H, s), 2.05 is-is 2.30 (2H, m), 3,57 (1H, d, J=13,8 Hz), 3,63 (3H, s), 3,70-3,93 (7H, m), 4,10 (1H, t, J=6.2 Hz), 4,55 (1H, d, J=13,8 Hz), 6,28 (1H, s), only 6.64 (1H, d, J=2.2 Hz), 6,93-7,05 (1H, m), 7,15-of 7.23 (2H, m), 7,31 (1H, s), 7,31 (1H, DD, J=2,2, 8,8 Hz).

(2) In nitrogen atmosphere n-tributylphosphine (0,74 ml, 2,96 mmol) and 1,1'-azodicarbonamide (0.75 g, 2,96 mmol) was added to a solution of (3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ethanol (1.0 g, to 1.98 mmol)obtained in example 50-(1), methyl 1H-pyrazole-5-carboxylate (0.25 g, to 1.98 mmol) and toluene (20 ml) and the mixture was stirred at room temperature for 8 hours. After addition of hexane (10 ml) and the mixture was stirred for 30 minutes and then filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (70:30-65:35)] to obtain methyl 1-{2-[(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-yl]ethyl}-1H-pyrazole-5-carboxylate (0,81 g) as a colourless non-crystalline powder from the first elyuirovaniya faction and methyl 1-{2-[(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-yl]ethyl}-1H-pyrazole-3-carboxylate (0.17 g) in the form best is to maintain the powder from the second elyuirovaniya faction.

First allerona fraction

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s)2,02 (3H, s), 2,30-to 2.41 (2H, m), 3,50 (1H, d, J=14.1 Hz), of 3.60 (3H, s), of 3.73 (1H, d, J=11.4 in Hz)of 3.77 (1H, t, J=6.6 Hz), 3,82 (3H, s), a-3.84 (1H, d, J=11,4 Hz), 3,88 (3H, s)4,55 (1H, d, J=14.1 Hz), the 4.65-4.75 in (2H, m), 6,24 (1H, s), 6,60 (1H, d, J=2.4 Hz), 6,74 (1H, d, J=2.1 Hz), 6,97 (1H, DD, J=1.5 and 8.1 Hz), 7,10-7,27 (3H, m), 7,30 (1H, DD, J=2,4, and 8.4 Hz), 7,35 (1H, d, J=2.1 Hz).

Second allerona fraction

1H-NMR (CDCl3) δ: of 0.94 (3H, s)a 1.01 (3H, s)2,02 (3H, s), 2,30 at 2.45 (2H, m), 3,50 (1H, d, J=14.1 Hz), 3,61 (3H, s), 3,71 (1H, d, J=11,1 Hz), of 3.78 (1H, t, J=6.9 Hz), a-3.84 (1H, d, J=11,1 Hz)to 3.89 (6H, s), 4,28-4,50 (2H, m), 4,51 (1H, d, J=14.1 Hz), 6,24 (1H, s), 6,62 (1H, d, J=2.4 Hz), of 6.71 (1H, d, J=2.4 Hz), 6,95-7,02 (1H, m), 7.18 in-7,22 (2H, m), 7,26 (1H, d, J=8.7 Hz), 7,32 (1H, DD, J=2,4, and 8.7 Hz), 7,37 (1H, d, J=2,4 Hz).

(3) a Mixture of methyl 1-{2-[(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-yl]ethyl}-1H-pyrazole-5-carboxylate (0,72 g at 1.17 mmol)obtained in example 50-(2), 1 N. aqueous sodium hydroxide solution (4.0 ml) and ethanol (14 ml) was stirred at room temperature for 3 hours. The mixture was acidified using 1 N. hydrochloric acid (5.0 ml) was added ethyl acetate (150 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained crystal was recrystallized from a mixture of ethyl acetate-hexane to obtain 1-{2-[(3R,5S)-7-chloro-5-(2,3-acid-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-5-carboxylic acid (0,63 g) in the form Besenova crystal.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 2,28-of 2.50 (2H, m), and 3.16 (1H, d, J=12.3 Hz), 3,35 (1H, d, J=14.4 Hz), of 3.60 (3H, s), 3,62 (1H, d, J=12.3 Hz), with 3.79 (1H, t, J=6.6 Hz), 3,88 (3H, s), 4,43 (1H, d, J=14,4 Hz),4,59-to 4.81 (2H, m), 6,12 (1H, s), to 6.58 (1H, d, J=2.1 Hz), at 6.84 (1H, d, J=2.1 Hz), 6,97 (1H, DD, J=1.5 and 7.8 Hz), 7,20 (1H, t, J=7.8 Hz), 7,21-7,29 (2H, m), 7,32 (1H, DD, J=2,1, to 8.7 Hz), 7,40 (1H, d, J=and 2.1 Hz).

Example 51

1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-3-carboxylic acid

A mixture of methyl 1-{2-[(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-yl]ethyl}-1H-pyrazole-3-carboxylate (0.17 g, 0.28 mmol)obtained in example 50-(2), 1 N. aqueous sodium hydroxide solution (1.0 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours. Then added 1 N. aqueous sodium hydroxide solution (1.5 ml) and the mixture was stirred for 3 hours. The mixture was acidified using 1 N. hydrochloric acid (2.8 ml), after which was added ethyl acetate (80 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained crystal was recrystallized from a mixture of ethyl acetate-hexane to obtain 1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahed the o-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-3-carboxylic acid (0.12 g) in the form Besenova crystal.

1H-NMR (CDCl3) δ: 0,63 (3H, s)of 1.05 (3H, s), 2,30-of 2.50 (2H, m)and 3.15 (1H, d, J=11,1 Hz)to 3.36 (1H, d, J=14.4 Hz), 3,60 (1H, d, J=11,1 Hz), 3,61 (3H, s), 3,82 (1H, t, J=6.6 Hz), 3,90 (3H, s), 4,30-4,50 (3H, m), x 6.15 (1H, s), is 6.61 (1H, s), 6.75 in-6,87 (1H, m), 7,15-to 7.50 (5H, m).

Example 52

(2E)-3-(1-{2-[(3R,5S)-7-chloro-5-(2,3-acid-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)ethyl]-1H-pyrazole-5-yl}acrylic acid

In a manner similar to the method of example 19 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s)of 1.26 (3H, t, J=7.0 Hz), 2,29 at 2.45 (2H, m)and 3.15 (1H, d, J=11.8 Hz), to 3.36 (1H, d, J=14,2 Hz)to 3.64 (1H, d, J=11.8 Hz), to 3.36 (1H, d, J=14,2 Hz)to 3.64 (1H, d, J=11.8 Hz)as the 3.65 (3H, s), 3,85 (1H, t, J=6.2 Hz), 3,90 (3H, s), 4,21-and 4.40 (2H, m), of 4.44 (1H, d, J=14,2 Hz), x 6.15 (1H, s), 6,32 (1H, d, J=16.0 Hz), 6,41 (1H, d, J=2.2 Hz), 6,60 (1H, d, J=1,8 Hz), 6,95-7,10 (1H, m), 7,16-7,30 (2H, m), 7,26-7,41 (3H, m), of 7.64 (1H, d, J=16.0 Hz).

Example 53

1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-imidazole-5-carboxylic acid

In a manner similar to the method of example 50, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 2,29-to 2.40 (2H, m)and 3.15 (1H, d, J=12.0 Hz), to 3.36 (1H, d, J=14.1 Hz), 3,60 (1H, d, J=12.0 Hz), 3,61 (3H, s), 3,85 (1H, t, J=7.5 Hz), with 3.89 (3H, s), of 4.44 (1H, d, J=14,1 Hz), 6,14 (1H, s), is 6.61 (1H, d, J=2.1 Hz), 6,98-7,02 (1H, m), 7,13-7,26 (2H, m), 7,28 (1H, d, J=8.7 Hz), 7,34 (1H, DD, J=2,1, to 8.7 Hz), to 7.64 (1H, s), and 7.7 (1H, C).

Example 54

1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrrole-2-carboxylic acid

In a manner similar to the method of example 50, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 2.21 are 2,39 (2H, m), 3,14 (1H, d, J=11.4 in Hz), the 3.35 (1H, d, J=14.4 Hz), 3,61 (1H, d, J=11,4 Hz), 3,61 (3H, in), 3.75 (1H, t, J=6.9 Hz), with 3.89 (3H, s), 4,30-br4.61 (2H, m), of 4.44 (1H, d, J=14.4 Hz), 6,05-6,10 (1H, m), 6,13 (1H, s), 6,60 (1H, d, J=2.1 Hz), for 6.81-6.90 to (1H, m), 6,94-7,03 (2H, m), 7,15-7,30 (3H, m), 7,32 (1H, DD, J=2.1 a, 8,7 Hz).

Example 55

(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3,4-oxadiazol-2-yl)acetic acid

(1) Pivaloate (2.8 ml) was added to a solution of 2-[(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-yl]acetic acid (10 g) and triethylamine (3.2 ml) in THF (100 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. To the reaction solution at 0°C was added ethyl 3-hydrazino-3-oxopropionate (3.5 g) and then was added dropwise a triethylamine (3.2 ml). The mixture was stirred at room temperature for 2 hours and the reaction solution was diluted with ethyl acetate (50 ml). The obtained extract was washed with 1 N. hydrochloric acid is th, 5% aqueous solution of potassium hydrosulfate, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl 3-(2-{[(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-yl]acetyl}hydrazino)-3-oxopropionate (2.5 g) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.94 (3H, s), and 1.00 (3H, s), 1,25 (3H, t, J=7.2 Hz), 2,02 (3H, s), 2,70-2,77 (1H, m), 2,92-of 3.00 (1H, m), 3,39 (2H, s), 3,53 (1H, d, J=14,2 Hz), of 3.60 (3H, s), 3,69-a 3.87 (2H, m), 3,88 (3H, s), 4,19 (2H, q, J=7.2 Hz), 4,22-4,39 (1H, m), of 4.54 (1H, d, J=14.4 Hz), and 6.25 (1H, s), 6,63 (1H, d, J=1,8 Hz), of 6.96-of 6.99 (1H, s), 7,15-7,24 (2H, m), 7,28-to 7.35(2H, m).

(2) phosphorus Oxychloride (0.8 ml) was added to a solution of ethyl 3-(2-{[(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-yl]acetyl}hydrazino)-3-oxopropionate (3.7 g)obtained in example 55-(1)in DMF (50 ml) and the mixture is boiled under reflux throughout the night. The reaction solution was concentrated under reduced pressure, poured into aqueous potassium carbonate solution and extracted with ethyl acetate. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The remainder of the imali column chromatography on silica gel to obtain ethyl 5-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-1,3,4-oxadiazol-2-yl)acetate (1.2 g) as a yellow oil.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s)of 1.26 (3H, t, J=6.9 Hz), 2,03 (3H, s), 3,31 is 3.57 (3H, m), 3,61 (3H, s), 3.75 to a 3.87 (2H, m), 3,88 (3H, s), 3,91 (2H, s)to 4.17 (2H, q, J=6.9 Hz), 4,46-of 4.57 (2H, m), 6.30-in (1H, s), is 6.61 (1H, d, J=2.1 Hz), 6,95-6,98 (1H, m), 7,05-7,19 (2H, m), 7,33-7,34(2H, m).

(3) a Mixture of ethyl 5-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-1,3,4-oxadiazol-2-yl)acetate (1.1 g)obtained in example 55-(2), 1 N. aqueous sodium hydroxide solution (9,35 ml) and methanol (20 ml) was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and extracted with chloroform (50 ml) twice. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain (5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3,4-oxadiazol-2-yl)acetic acid (0,19 g) as a white crystal.

1H-NMR (DMSO-d6) δ: 0,63 (3H, s)to 0.92 (3H, s), 3,12-and 3.16(2H, m), 3,38-3,44 (2H, m), of 3.56 (3H, s), 3,61-with 3.79 (2H, m), 3,85 (3H, s), 4,24-4,50 (3H, m), 6,14 (1H, s), 6,55 (1H, s), 6,92-to 6.95 (1H, m), 7,12-7,17 (2H, m,), 7,31-7,37(2H, m).

Example 56

(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl-1,3,4-thiadiazole-2-yl)acetic acid

(1) Solution of ethyl 3-(2-{[(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-yl]acetyl}hydrazino))-3-oxopropionate (1.0 g)obtained in example 55-(1), and reagent Lesson (0.96 g) in THF (50 ml) was stirred at 80°C for 1 hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl 2-(5-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-1,3,4-thiadiazole-2-yl)acetate (0.8 g) as a white amorphous crystal.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s), of 1.30 (3H, t, J=7.0 Hz), 2,03 (3H, s), 3,51-to 3.58 (1H, m), 3,62 (3H, s), 3,66-a 3.87 (4H, m)to 3.89 (3H, s), 4,11-4,16 (2H, m), are 4.24 (2H, q, J=7.0 Hz), 4,35 (1H, t, J=6,4 Hz), 4,55 (1H, d, J=14,3 Hz), 6,32 (1H, s), is 6.61 (1H, d, J=1.9 Hz), of 6.99 (1H, DD, J=2,3, 7.5 Hz), 7,17-7,20 (2H, m).

(2) a Mixture of ethyl 2-(5-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-1,3,4-thiadiazole-2-yl)acetate (0.9 g)obtained in example 56-(1), 1 N. of a saturated aqueous solution of sodium hydroxide (8.0 ml) and methanol (20 ml) was stirred when the room is the temperature value within 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and extracted with chloroform (50 ml) twice. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 2-(5-{[(3R,5S)-1-(3-hydroxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]methyl}-1,3,4-thiadiazole-2-yl)acetic acid (0,19 g) as a white crystal.

1H-NMR (DMSO-d6) δ: 0,76 (3H, s), is 0.84 (3H, s), 3,06-3,18 (2H, m), 3,35-to 3.49 (2H, m), 3,52 (3H, s), 3,66-3,71 (1H, m), of 3.78 (2H, s), of 3.84 (3H, s), 4.26 deaths is 4.35 (2H, m), 6,14 (1H, s)6,38 (1H, d, J= 2.3 Hz), 7,06-7,22 (3H, m), 7,51-of 7.55 (1H, m), 7,71 (1H, d, J= 9.0 Hz).

Example 57

3-(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxyl-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3,4-thiadiazole-2-yl)propionic acid

(1) Pivaloate (2.8 ml) was added to a solution of 2-[(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-yl]acetic acid (10 g) and triethylamine (3.2 ml) in THF (100 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. To the reaction solution at 0°C was added ethyl 4-hydrazino-4-oxobutanoate (3.7 g) and then was added dropwise a triethylamine (3.2 ml). After stirring PR the room temperature for 2 hours, the reaction solution was diluted with ethyl acetate (50 ml). The obtained diluted solution was washed with 1 N. hydrochloric acid, 5% aqueous solution of potassium hydrosulfate, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl 4-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}hydrazino)-4-oxobutanoate (3.6 g) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.95 (3H, s), and 1.00 (3H, s), 1,25 (3H, t, J=7.2 Hz), 2,03 (3H, s)to 2.54 (3H, t, J=6.4 Hz), 2,66 is 2.75 (3H, m), 2,89-of 2.97 (1H, m), of 3.54 (1H, d, J=14,3 Hz), 3,61 (3H, s), 3,69-3,88 (2H, m)to 3.89 (3H with), is 4.15 (2H, q, J=7.2 Hz), 4,33-to 4.38 (1H, m), of 4.54 (1H, d, J=a 13.9 Hz), of 6.26 (1H, s), only 6.64 (1H, d, J=1.9 Hz), 6,97-7,00 (1H, s), 7,16-of 7.23 (2H, m), to 7.32 and 7.36 (2H, m), 8,11 (1H, sird), 8,31 (1H, sird).

(2) a Solution of ethyl 4-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}hydrazino)-4-oxobutanoate (1.0 g)obtained in example 57-(1), and reagent Lesson (0,92 g) in THF (50 ml) was stirred at 80°C within 1 hour. The reaction solution was poured into water and then extracted with ethyl acetate. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure is. The residue was purified column chromatography on silica gel to obtain ethyl 3-(5-{[(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-yl]methyl}-1,3,4-thiadiazole-2-yl)propionate (0.7 g) as a white powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s)of 1.29 (3H, t, J=7.2 Hz), 2,03 (3H, s), 2,85 (2H, t, J=7.4 Hz), 3,37 (3H, t, J=7.4 Hz), 3,48-3,55 (2H, m), 3,62 (3H, s), 3,65-a 3.87 (2H, m), 3,90 (3H, s)to 4.15 (2H, kV, J=7,2 Hz), 4,35 (1H, t, J=6.4 Hz), of 4.54 (1H, d, J=14,3 Hz), of 6.31 (1H, s), is 6.61 (1H, d, J=2.3 Hz), 6,98-7,01 (1H, m), 7,13-of 7.23 (2H, m), 7,28-to 7.35(2H, m).

(3) a Mixture of ethyl 3-(5-{[(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-yl]methyl}-1,3,4-thiadiazole-2-yl)propionate (0.7 g)obtained in example 57-(2), 1 N. aqueous sodium hydroxide solution (8.0 ml) and methanol (20 ml) was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (50 ml), acidified and extracted with chloroform (50 ml) twice. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with 3-(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxyl-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3,4-thiadiazole-2-yl)propionic acid (0,19 g) as a white crystal.

1H-NMR (DMSO-d6) δ: 0,78 (3H, s)to 0.88 (3H, s)of 2.75 (3H, t, J=7.0 Hz), is 3.08-3,20 (2H, m) 3,26 (3H, t, J=7.0 Hz), 3,49-to 3.52 (1H, m), 3,53 (3H, s), 3,67-3,81 (1H, m), 3,85 (3H, s), 4,27-4,37 (2H, m), 4,58 (1H, Sirs), 6,16 (1H, s)6,40 (1H, d, J=2.6 Hz), 7,02-7,05 (1H, m), 7,14-7,26 (2H, m), 7,54 (1H, DD, J=2,6, and 8.7 Hz), 7,72 (1H, d, J=8.7 Hz).

Example 58

(3-{[(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-yl]methyl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl)acetic acid

(1) Triethylamine (10.0 ml, 0,0717 mol) was added to a suspension of hydroxylaminopurine (to 4.98 g, 0,0717 mol) in DMSO and the mixture was stirred for 30 minutes. The reaction solution was filtered and to the filtrate was added 3-[(3R,5S)-7-chloro-3-(lanmeter)-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (7,18 g, 0,0143 mol). The mixture was stirred at 80°C for 18 hours. The reaction solution was extracted with ethyl acetate, washed sequentially 1 N. aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-[(3R,5S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (7.9 g) in the form areconsidering amorphous substance.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s)2,03 (3H, s), 2,59 (1H, is d, J=6,1, 14.4 Hz), 2,72 is 2.80 (1H, m), 3,50-3,66 (4H, m), and 3.72 (1H, d, J=11,0 Hz), 3,82-3,88 (1H, m)to 3.89 (3H, s), 4,05-4,16 (1H, m), of 4.54 (1H, d, J=14,2 Hz), 4,94 (2H, s), and 6.25 (1H, s), 6,62 (1H, d, J=2.2 Hz), 6,95-7,01 (1H, m), 7,15-of 7.23 (2H, m), 7,28-to 7.35 (2H, m).

(2) CDI (1,34 g, 8,24 mmol) and DBU (1.23 ml, 8,24 mmol) was added to a solution of 3-[(3R,5S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (4.0 g, 7,49 mmol)obtained in example 58-(1)in THF (40 ml) and the mixture was stirred at room temperature for 20 hours. The reaction solution was extracted with ethyl acetate, washed sequentially 1 N. aqueous solution of hydrochloric acid and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:2-2:3)] to obtain 3-[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-3-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (2,53 g) in the form Besenova amorphous substance.

1H-NMR (CDCl3) δ: 0,97 (3H, s), and 1.00 (3H, s), is 2.05 (3H, s), a 3.01 (1H, DD, J=4,0, 15,0 Hz), 3,11 (1H, DD, J=6,9, 15,0 Hz), 3,53 (1H, d, J=14,2 Hz), the 3.65 (3H, s), 3,68 (1H, d, J=11.2 Hz), with 3.89 (3H, s), 3,95 (1H, d, J=11.2 Hz), 4,20 (1H, DD, J=4.2, and the 6.8 Hz), 4,58 (1H, d, J=14,2 Hz), 6,24 (1H, s), to 6.67 (1H, d, J=2.4 Hz), 7,00 (1H, DD, J=1,7, 8.1 Hz), 7,10-7,22 (2H, m), 7,29-7,40 (2H, m).

(3) sodium Hydride (46 mg of 1.16 mmol) was added to a solution of 3-[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-3-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (0.6 g, 0,893 mmol)obtained in example 58-(2), in DMF under ice cooling and the mixture was stirred for 30 minutes. To the reaction solution was added tert-butylbromide and the mixture was stirred for 1.5 hours under ice cooling and then at room temperature for 30 minutes. After the reaction solution was added 1 N. hydrochloric acid, the mixture was extracted with ethyl acetate, washed successively with water and saturated aqueous sodium chloride and then dried over magnesium sulfate. After concentration under reduced pressure the residue was purified column chromatography on silica gel (manifesting solvent: hexane-ethyl acetate (3:1-2:1)) to obtain tert-butyl (3-{[(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-yl}methyl)-5-oxo-1,2,4-oxadiazol-4(5H)-ilaclama (0,43 g).

1H-NMR (CDCl3) δ: of 0.95 (3H, s)a 1.01 (3H, s)of 1.47 (9H, s)2,03 (3H, s), 2,94-to 3.09 (2H, m), 3,55 (1H, d, J=14,2 Hz), 3,61 (3H, s), 3,71 (1H, d, J=11.2 Hz), 3,85 (1H, d, J=11.0 in Hz)to 3.89 (3H, s), 4,34-4,39 (3H, m), 4,51 (1H, d, J=14,2 Hz), 6,28 (1H, s), 6,63 (1H, d, J=2.2 Hz), 6,97-7,06 (2H, m), 7,19 (1H, t, J=7.9 Hz), 7,29-7,39 (2H, m).

(4) Triperoxonane acid (5 ml) was added to tert-butyl (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-yl}methyl)-5-oxo-1,2,4-oxadiazol-4(5H)-racette (0,42 g, 0,616 mmol)obtained when the ore 58-(3), under ice cooling and the mixture was stirred for 30 minutes and then at room temperature for 50 minutes. The reaction solution was concentrated under reduced pressure to obtain [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-yl]methyl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]acetic acid (0.40 g).

1H-NMR (CDCl3) δas 0.96 (3H, s), and 0.98 (3H, s), is 2.05 (3H, s), 3,05-is 3.08 (2H, m), of 3.54 (1H, d, J=14,2 Hz), 3,62 (3H, s), of 3.73 (1H, d, J=11,0 Hz), 3,85-of 3.95 (4H, m), 4,34 (1H, t, J=11,0 Hz), 4,47-of 4.54 (3H, m), 6,27 (1H with), 6,62 (1H, d, J=2.2 Hz), 6,98-7,39 (6H, m).

Example 59

[3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]acetic acid

1 N. Aqueous sodium hydroxide solution (1,21 ml of 1.21 mmol) was added to a mixture of (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-yl]methyl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl)acetic acid (0.25 g, 0,405 mmol)obtained in example 58, in a mixture of ethanol-THF (1:1) (3 ml) and the mixture was stirred for 2 hours. The reaction solution was acidified using 1 N. hydrochloric acid (1.5 ml), was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride and then dried over magnesium sulfate. After concentration under igenom pressure the residue was purified preparative HPLC to obtain [3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]acetic acid (0.16 g).

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)to 3.09 (2H, d, J= 7,4 Hz), 3,24 (1H, d, J=12.1 Hz), 3,42 (1H, d, J=14.6 Hz), to 3.58-the 3.65 (4H, m), a 3.87-are 3.90 (4H, m), 4,34 (1H, t, J=6,7 Hz)to 4.41 (1H, d, J=14.6 Hz), 4,46 (2H, s), 6,16 (1H, s), is 6.61 (1H, d, J=2.2 Hz), 7,00 (2H, d, J= 8,3 Hz), 7,16-the 7.43 (3H, m)

Example 60

3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)propionic acid

The triethylamine (of 0.44 ml, 3,18 mmol) and ethyl 4-chloro-4-oxybutyrate (0,29 ml of 2.06 mmol) was added dropwise to a solution of 3-[(3R,5S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (1.0 g, of 1.87 mmol)obtained in example 58-(1)in THF (10 ml) under ice cooling and the mixture was stirred at room temperature for 24 hours. After concentrating the reaction solution under reduced pressure was added water (10 ml) and the mixture is boiled under reflux for 22 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After concentration under reduced pressure the residue was dissolved in ethanol (10 ml) and to the solution was added 2 N. aqueous sodium hydroxide solution (3,74 ml of 7.48 mmol). Then the mixture was stirred for 2 hours. The reaction rastv the ture was diluted with water and then was extracted with diethyl ether. The extract was acidified 6 N. hydrochloric acid, was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. After dissolution of the residue in ethanol to the solution was added activated charcoal and the mixture was stirred for 10 minutes. Was filtered insoluble materials and the filtrate was concentrated under reduced pressure to obtain 3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)propionic acid (0.66 g).

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 2,89 (2H, d, J=7,2 Hz), 3,12-of 3.27 (4H, m), 3,34-of 3.43 (2H, m), to 3.58-to 3.67 (4H, m)to 3.89 (3H, s), 4,39-to 4.52 (2H, m), to 6.19 (1H, s), 6,60 (1H, d, J=1.5 Hz), of 6.96-7,40 (5H, m).

Example 61

2-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)acetic acid

In a manner similar to the method of example 60, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 3,17-3,44 (4H, m), 3,60-to 3.67 (4H, m), 3,88 (3H, s)to 3.99 (2H, s), 4,43-4,50 (2H, m), 6,18 (1H, s), 6,60 (1H, d, J=1.5 Hz), of 6.96-7,41 (4H, m).

Example 62

3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-1,2,4-t is eazol-5-carboxylic acid

Itmean (0.2 ml) was added to a solution of 3-[(3R,5S)-3-(2-amino-2-tixati)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (2 g)obtained in example 16-(2), in acetone (20 ml) and the mixture was stirred over night. After concentration under reduced pressure, to the residue was added butanol (20 ml) and ethyl hydrazino(oxo)acetate (MX 0.317 g) and the mixture is boiled under reflux for 2 hours. After concentration under reduced pressure, to the residue was added ethanol (20 ml) and 1 N. aqueous sodium hydroxide solution (4 ml) and the mixture was stirred over night. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with ethyl acetate. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the title compound (0.32 g).

1H-NMR (CDCl3) δ: 0,76 (3H, s)0,86 (3H, s), 3,05-up 3.22 (3H, m), 3,51 (3H, s)to 3.67 (1H, d, J=14.1 Hz), 3,83 (3H, s), 4,25 was 4.42 (2H, m), 4,56 (1H, s), 6,11 (1H, s), 6.35mm (1H, d, J=2,5Hz), is 6.78 (1H, s), 7,10-to 7.18 (2H, m), 7,55 (1H, DD, J=2,5, and 8.9 Hz), 7,72 (1H, d, J=8,9 Hz).

Example 63

(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-1,2,4-triaz is l-5-yl)acetic acid

In a manner similar to the method of example 62, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.75 (3H, s)0,86 (3H, s), 3.04 from-3,19 (4H, m), 3,50 (3H, s), 3,65-and 3.72 (3H, m), 3,83 (3H, s), 4,28-and 4.40 (2H, m), 6,10 (1H, s)6,34 (1H, d, J=2,4 Hz), 6,86 (1H, DD, J=2,3, 7,0 Hz), 7,09-7,20 (1H, m), 7,55 (1H, DD, J=2,4, and 8.9 Hz), 7,71 (1H, d, J=8,9 Hz).

Example 64

3-[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-yl}methyl)-5-hydroxy-1H-pyrazole-1-yl]benzoic acid

To a solution of ethyl 4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]}-3-oxobutanoate (2 g)obtained in example 26-(1)in ethanol (20 ml) was added 3-hydrazinophenyl acid (0,567 g) and the mixture is boiled under reflux during the night. After concentration under reduced pressure the residue was purified column chromatography on silica gel with obtaining specified in the title compound (1.9 g).

1H-NMR (DMSO-d6) δ: to 0.92 (6H, s)to 1.99 (3H, s), 2,79-of 3.07 (2H, m), 3,52 (3H, s), 3,61-of 3.80 (3H, m), 3,85 (3H, s), 4,19 (1H, t, J=6.5 Hz), 4,36 (1H, d, J=14,3 Hz), 5,42 (1H, s), 6,13 (1H, s), to 6.39 (1H, d, J=2,4 Hz), 7,10-7,24 (3H, m), of 7.48-to 7.59 (2H, m), of 7.75 (2H, t, J=9.0 Hz), 7,95 (1H, d, J=7.9 Hz), of 8.28 (1H, s).

Example 65

3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]meth is l}-5-hydroxy-1H-pyrazole-1-yl)benzoic acid

1 N. Aqueous sodium hydroxide solution (3.4 ml) was added to a solution of 3-[3-({(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-yl]methyl}-5-hydroxy-1H-pyrazole-1-yl)benzoic acid (0.9 g)obtained in example 64, in ethanol (4.5 ml) and the mixture was stirred over night. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with ethyl acetate. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the connection header (0,586 g).

1H-NMR (DMSO-d6) δ: 0,78 (3H, s)0,86 (3H, s), 2,78-3,24 (4H, m), 3,53 (3H, s), of 3.69 (1H, d, J=14.1 Hz), 3,85 (3H, s), 4,18 (1H, t, J=6.5 Hz), 4,32 (1H, d, J=14.1 Hz), 4,56 (1H, t, J=4.9 Hz), 5,42 (1H, s), 6,12 (1H, s), to 6.39 (1H, d, J=2.4 Hz), 7,07-7,26 (3H, m), 7,47-of 7.60 (2H, m), to 7.67-7,81 (2H, m), 7,95 (1H, d, J=8.1 Hz), 8,29 (1H, s).

Example 66

4-[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-yl}methyl)-5-hydroxy-1H-pyrazole-1-yl]benzoic acid

In a manner similar to the method of example 64, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: to 0.92 (3H, s)of 0.93 (3H, s)to 1.99 (3H, s), 2,80 was 3.05 (2H, m), 3,52(3H, C), 3,61-3,81 (3H, m), 3,85 (3H, s), 4,17 (1H, t, J=6.4 Hz), 4,36 (1H, d, J=14.1 Hz), 5,43 (1H, s), 6,13 (1H, s), 7,10-of 7.23 (3H, m), 7,54 (1H, DD, J=2,2, 8.6 Hz), of 7.75 (d, J=8,8 Hz), to 7.84 (2H, d, J=8,8 Hz), to 7.99 (d, J=8.6 Hz), 8,32 (1H, s).

Example 67

4-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-hydroxy-1H-pyrazole-1-yl)benzoic acid

In a manner similar to the method of example 65, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: 0,78 (3H, s)of 0.87 (3H, s), 2,80-of 3.25 (4H, m), 3,53 (3H, s), of 3.69 (1H, d, J=14.1 Hz), 3,85 (3H, s)to 4.16 (1H, t, J=6.5 Hz), 4,32 (1H, d, J=14.1 Hz), 4,56 (1H, t, J=4,8 Hz), 5,43 (1H, s), 6,12 (1H, s),to 6.39 (1H, d, J=2.4 Hz), 7,09-7,24 (3H, m), 7,53 (1H, DD, J=2,4, 8.6 Hz), 7,72 (1H, d, J=8,8 Hz), the 7.85 (2H, d, J=8,8 Hz), 7,94-of 8.04 (2H, m).

Example 68

(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-ethoxy-1H-pyrazole-1-yl)acetic acid

(1) Pyridine (0.3 ml) was added to a solution of ethyl 4-[(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-yl]-3-oxobutanoate (2 g)obtained in example 26-(1), and hydrochloride of acylhydrazines (0.577 g) in ethanol (20 ml) and the mixture is boiled under reflux for 3 hours. After concentrating the mixture under reduced pressure, the residue was purified column chromatography on forces is the Kagel to obtain ethyl (3-{[(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-yl]methyl}-5-ethoxy-1H-pyrazole-1-yl)acetate (0,62 g) from the first elyuirovaniya fraction and ethyl [3-({(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-yl}methyl)-5-hydroxy-1H-pyrazole-1-yl]acetate (1.2 g) from the second elyuirovaniya faction.

(2) 1 N. Aqueous sodium hydroxide solution (3.3 ml) was added to a solution of ethyl (3-{[(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-yl]methyl}-5-ethoxy-1H-pyrazole-1-yl)acetate (0.45 g)obtained in example 68-(1)in ethanol (4,5 ml) and the mixture was stirred over night. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with chloroform. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the connection header (0,38 g).

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s)of 1.40 (3H, t, J=7.0 Hz), to 3.02 (1H, DD, J=6,3, 14,8 Hz), 3,11-3,26 (2H, m), 3,37 (1H, d, J=14,3 Hz), 3,57-3,70 (4H, m)to 3.89 (3H, s), 4,05-to 4.23 (3H, m), of 4.45 (1H, d, J=of 14.3 Hz), 4,63 (2H, s)5,49 (1H, s), 6,17 (1H, s), to 6.58 (1H, d, J=1,8 Hz), 6,98 (1H, DD, J=2,4, 7,1 Hz), 7,11-of 7.23 (2H, m), 7,25-7,39 (3H, m).

Example 69

(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-hydroxy-1H-pyrazole-1-yl)acetic acid

1 N. Aqueous sodium hydroxide solution (0.5 ml) was added to a solution of ethyl [3-({(3R,5S)-1-[3-(atomic charges)-2,2-dimethylpropyl]-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-1-benzoxazepin-3-yl}methyl)-5-hydroxy-1H-pyrazole-1-yl]acetate (0.1 g), obtained in example 68-(1)in ethanol (1 ml) and the mixture was stirred over night. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with a mixture of chloroform-methanol. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the connection header (0,042 g).

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.03 (3H, s), 2,84 was 3.05 (2H, m), 3,11-of 3.23 (2H, m), 3,32-3,44 (2H, m), 3,62 (3H, s)to 3.89 (3H, s), 4.26 deaths (1H, t, J=6.5 Hz), 4,34-of 4.49 (2H, m), 4.53-in-4,63 (1H, m), 6,16 (1H, s), 6,62 (1H, d, J=2.0 Hz), of 6.96? 7.04 baby mortality (1H, m), 7,08-of 7.25 (3H, m), 7,30-the 7.43 (3H, m).

Example 70

[5-(carboxymethoxy)-3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1H-pyrazole-1-yl]acetic acid

Methylbromide (0,459 g) and potassium carbonate (0,441 g) was added to a solution of ethyl [3-({(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-yl}methyl)-5-hydroxy-1H-pyrazole-1-yl]acetate (0.5 g)obtained in example 68-(1)in acetonitrile (5 ml) and the mixture was stirred over night. The reaction solution was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over sulfate mage the Oia and then concentrated under reduced pressure. To the obtained residue were added ethanol (5 ml) and 1 N. aqueous sodium hydroxide solution (2,78 ml) and the mixture was stirred over night. The reaction solution was neutralized 1 N. hydrochloric acid and was extracted with chloroform. The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the connection header (0,116 g).

1H-NMR (DMSO-d6) δ: 0,76 (3H, s)of 0.85 (3H, s), and 2.83 (2H, m), of 3.12 (2H, m), 3,51 (3H, s), the 3.65 (1H, m), of 3.84 (3H, s)to 4.01 (1H, m), 4,32 (1H, d, J=14.1 Hz), 4,58 (2H, s), of 4.66 (2H, s), vs. 5.47 (1H, s)6,09 (1H, ), 6.35mm (1H, d, J=2.4 Hz), 7,12 (3H, m), 7,51 (1H, DD, J=2.5 a, 8,8 Hz), to 7.67 (1H, d, J=8,8 Hz).

Example 71

(2E)-3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acrylic acid

(1) Oxalicacid (10 ml) was added to a solution of (2E)-4-(bromophenyl)-4-oxo-2-butenova acid (24.5 g) in a mixture of THF (200 ml) and DMF (3 drops) and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (120 ml). The resulting solution was added dropwise to a mixed solvent of a solution of 3-({4-chloro-2-[(S)-(2,3-acid)(hydroxyl)m is Teal]phenyl}amino)-2,2-dimethyl-1-propanol (24.5 g) in ethyl acetate (300 ml) and 1 N. an aqueous solution of sodium hydroxide (130 ml) under ice cooling and the mixture was stirred at 0°C for 1 hour. The organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in ethanol (240 ml)was added DBU (11 ml) and the mixture was stirred at room temperature overnight. Was gradually added to the reaction solution, water (60 ml) and the mixture was stirred for 1 hour. Was filtered phase precipitate crystals and washed them mixed solution of ethanol/water = 2/1 to obtain (3R,5S)-3-[2-(4-bromophenyl)-2-oxoethyl]-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-she (24.5 g).

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s), 3,14 (1H, d, J=12.0 Hz), 3,32 (1H, DD, J=4.5 Hz, to 17.4 Hz), 3,42 (1H, d, J=14.4 Hz), 3,62 (3H, s)to 3.64 (1H, m), 3,81 (1H, m), 3,90 (3H, s), 4,48 (1H, d, J=12.0 Hz), br4.61 (1H, q, J=4, 2 Hz), to 6.19 (1H, s), 6,63 (1H, s), of 6.99 (1H, DD, J=2,4 Hz, 7.5 Hz), to 7.15 (2H, m), 7,41 (2H, m), to 7.61 (2H, d, J=8,4 Hz), to 7.84 (2H, d, J=8,4 Hz).

(2) of palladium Acetate (338 mg), triphenylphosphine (788 mg), acrylate (2.2 ml) and triethylamine (3.3 ml) was added to a solution of (3R,5S)-3-[2-(4-bromophenyl)-2-oxoethyl]-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-she (6.0 g)obtained in example 71-(1), VDMA (60 ml) and the mixture was heated at 100° C for 20 hours under nitrogen atmosphere. Was added to the reaction solution of 1 N. hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl (2E)-3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2,-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acrylate (3.1 g).

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)of 1.35 (3H, t, J=7.2 Hz), 3,14 (1H, m)to 3.36 (1H, m), of 3.43 (1H, m), 3,63 (3H, s)to 3.64 (1H, m), 3,81(1H, m), 3,90 (3H, s), 4,48 (1H, d, J=13,2 Hz), br4.61 (1H, q, J=3.6 Hz), of 6.20 (1H, s), 6,53 (1H, d, J=16.5 Hz), only 6.64 (1H, m), of 6.99 (1H, m), 7,16 (2H, m), 7,41 (2H, m), 7,60 (2H, d, J=8,4 Hz), to 7.68 (1H, d, J=16.5 Hz), 7,98 (2H, d, J=8,4 Hz).

(3) 2 N. Aqueous sodium hydroxide solution (25 ml) was added to a solution of ethyl (2E)-3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acrylate (3.1 g)obtained in example 71-(2), in a mixture of THF (100 ml) and ethanol (100 ml) and the mixture was stirred at room temperature for 10 hours. After concentrating the reaction solution under reduced pressure the residue was dissolved in water and washed with ether. The aqueous layer was acidified using 1 N. hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, su is or over magnesium sulfate and then concentrated under reduced pressure to obtain (2E)-3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acrylic acid (1.1 g).

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s)and 3.15 (1H, d, J=12.0 Hz), to 3.36 (1H, DD, J=3,9 Hz, and 17.1 Hz), 3,43 (1H, d, J=15,0 Hz), 3,62 (3H, s), 3,66 (1H, m), 3,82 (1H, t, J=9,3 Hz)to 3.89 (3H, s), 4,48 (1H, d, J=14.4 Hz), to 4.62 (1H, q, J=3,9 Hz), to 6.19 (1H, s), of 6.52 (1H, d, J=15,9 Hz), 6,63 (1H, s), 6,98 (1H, m), to 7.15 (2H, m), 7,40 (2H, m), a 7.62 (2H, d, J=8,4 Hz), to 7.77 (1H, d, J=15,9 Hz), to 7.99 (2H, d, J=8,4 Hz).

Example 72

3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid

(1) the Raney Nickel was added to a solution of ethyl (2E)-3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acrylate (6.2 g)obtained in example 71-(2), in a mixture of THF (100 ml) and ethanol (50 ml) and the mixture was stirred at room temperature overnight in a hydrogen atmosphere. The catalyst was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain ethyl 3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionate (6.6 g) as a crude crystal, which was used in the next stage without purification.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s)of 1.24 (3H, t, J=7.4 Hz), 2.63 in (2H, t, J=8,4 Hz)of 3.00 (2H, t, J=8,4 Hz), 3,13 (1H, m)to 3.33 (1H, m), 3,42 (1H, d, J=14.6 Hz), 3,62 (3H, in), 3.75 (2H, m)to 3.89 (3H, C)is 4.21 (1H, m), 4,4 (1H, d, J=14.6 Hz), to 4.62 (1H, q, J=4, 2 Hz), to 6.19 (1H, s), 6,63 (1H, m), 6,98 (1H, t, J=5.0 Hz), 7,18 (2H, m), 7,29 (2H, d, J=8.0 Hz), 7,40 (2H, m), of 7.90 (2H, d, J=8.0 Hz).

(2) 2 N. Aqueous sodium hydroxide solution (15 ml) was added to a solution of ethyl 3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionate (3.5 g)obtained in example 72-(1)in a mixture of THF (50 ml) and ethanol (50 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in water and then washed with ether. The aqueous layer was acidified using 1 N. hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid (2.2 g).

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 2,70 (2H, t, J=7.8 Hz), a 3.01 (2H, t, J=7,8 Hz)and 3.15 (1H, d, J=12.0 Hz), to 3.33 (1H, DD, J=4.5 Hz, to 17.4 Hz), 3,42 (1H, d, J=17,4 Hz), 3,62 (3H, s), 3,66 (1H, m), 3,82 (1H, t, J=15 and 8.7 Hz), with 3.89 (3H, s), 4,48 (1H, d, J=14.4 Hz), to 4.62 (1H, q, J=4, 2 Hz), to 6.19 (1H, s), 6,63 (1H, m), of 6.99 (1H, t, J=5,1 Hz), 7,18 (2H, d, J=5,1 Hz), 7,30 (2H, d, J=8.1 Hz), 7,40 (2H, m), to $ 7.91 (2H, d, J=8,1 Hz).

Example 73

(2E)-3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazin the Jn-3-yl]acetyl}phenyl)acrylic acid

In a manner similar to the method of example 71, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), and 3.31 (1H, DD, J=17,1, 4,8 Hz)to 3.41 (1H, d, J=14.1 Hz), 3,63 (3H, s), 3,80 (1H, t, J=9.0 Hz), 3,90 (3H, s), 4,51 (1H, d, J=14.1 Hz), of 4.67 (1H, DD, J=8,4, 4,8 Hz), of 6.31 (1H, s), 6,52 (1H, d, J=16.2 Hz), 6,63 (1H, m), 6,98 (1H, t, J=4,8 Hz), 7,16 (2H, d, J=4.5 Hz), 7,37 (2H, m), to 7.61 (2H, d, J=8.1 Hz), 7,76 (1H, d, J=16.2 Hz), 8,01 (2H, d, J=8,1 Hz).

Example 74

(2E)-3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acrylic acid

In a manner similar to the method of example 71, has been specified in the header of the connection.

1H-NMR (CDCl3) δas 0.96 (9H, s), 3,37 (1H, m), 3,42 (1H, d, J=14.1 Hz), to 3.64 (3H, s), 3,82 (1H, t, J=8.1 Hz), with 3.89 (3H, s)to 4.52 (1H, d, J=14.1 Hz), of 4.67 (1H, DD, J=7,8, and 4.5 Hz), 6,32 (1H, s), of 6.50 (1H, d, J=16,2 Hz), only 6.64 (1H, m), 6,98 (1H, m), 7,13 (2H, m), of 7.36 (2H, m), 7,49 (1H, t, J=7.5 Hz), 7,72 (1H, d, J=7.8 Hz), 7,79 (1H, d, J=16.2 Hz), 8,01 (1H, d, J=7.5 Hz), 8,17 (1H, s).

Example 75

(2E)-3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acrylic acid

In a manner similar to the method of example 71, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s), and 3.16 (1H, d, J=12.0 Hz), 3,39 (1H, m), 3,44 (1H, d, J=14.4 Hz), 3,63 (3H, s), 3,66 (1H, m), 3,82(1H, m), 3,90 (3H, s), 4,49 (1H, d, J=14,4 Hz), 64 (1H, kV, J=4.5 Hz), of 6.20 (1H, s), of 6.52 (1H, d, J=15,9 Hz), of 6.65 (1H, s), 7,00 (lH,m), 7,19 (2H, m), 7,42 (2H, m), 7,51 (1H, t, J=7.5 Hz), 7,76 (1H, m), 7,79 (1H, d, J=15,9 Hz), 8,01 (1H, d, J=7.5 Hz), 8,14 (1H, s).

Example 76

3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid

In a manner similar to the method of example 72, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s)to 2.67 (2H, t, J=7.5 Hz), 2,99 (2H, t, J=7.5 Hz), and 3.31 (1H, DD, J=17,4 Hz and 4.5 Hz), 3,40 (1H, d, J=13,8 Hz), 3,81 (1H, m)to 3.89 (3H, s), 4,50 (1H, d, J=13,8 Hz)and 4.65 (1H, q, J=4,8 Hz), of 6.31 (1H, s), 6,63 (1H, m), 6,97 (1H, m), to 7.15 (2H, m), 7,28 (2H, d, J=8.1 Hz), 7,37 (2H, m), 7,92 (2H, d, J=8,1 Hz).

Example 77

3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid

In a manner similar to the method of example 72, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.03 (3H, s)to 2.65 (2H, t, J=7.5 Hz), 2,98 (2H, t, J=7.5 Hz), 3,19 (1H, d, J=12.0 Hz), 3,37 (1H, DD, J=4,2 Hz, is 16.8 Hz), 3,44 (1H, d, J=17,4 Hz), 3,62 (3H, s), 3,66 (1H, m), 3,86 (1H, t, J=9.6 Hz), 3,88 (3H, s), 4,47 (1H, d, J=12.0 Hz), 4,63 (1H, q, J=4.5 Hz), to 6.19 (1H, s), only 6.64 (1H, m), 6,98 (1H, m), 7,18 (2H, m), 7,41 (4H, m), 7,78 (2H, m).

Example 78

3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid

In a manner similar to the method of example 72, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s)to 2.66 (2H, t, J=7.5 Hz), 2,98 (2H, t, J=7.5 Hz), to 3.34 (1H, DD, J=17,1 Hz, 4.8 Hz), 3,40 (1H, d, J=14.1 Hz), 3,63 (3H, s), the 3.65 (1H, m), of 3.78 (1H, t, J=7.8 Hz), 3,88 (3H, s)to 4.52 (1H, d, J=14.1 Hz)and 4.65 (1H, q, J=3,9 Hz), of 6.31 (1H, s), 6,63 (1H, m), 6,98 (1H, m), 7,17 (2H, m), 7,38 (4H, m), 7,83 (2H, m).

Example 79

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid

In a manner similar to the method of example 72, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s), was 1.04 (3H, s)to 2.66 (2H, m), is 3.08 (2H, m), 3,20 (1H, d, J=12.0 Hz), and 3.31 (1H, DD, J=4.5 Hz, and 17.7 Hz), of 3.45 (1H, d, J=17,4 Hz), 3,61 (3H, s), 3,63 (1H, m), of 3.77 (1H, m), a 3.87 (3H, s), 4,47 (1H, d, J=12.0 Hz), 4,63 (1H, q, J=4, 2 Hz), 6,18 (1H, s), of 6.65 (1H, m), 6,98 (1H, m), 7,18 (2H, m), 7,29 (2H, m), 7,38 (3H, m), 7,80 (1H, d, J=8,1 Hz).

Example 80

4-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)butane acid

In a manner similar to the method of example 72, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s)a 1.96 (2H, m)to 2.35 (2H, t, J=6.9 Hz), a 2.71 (2H, t, J=7.8 Hz), and 3.16 (1H, d, J=12.0 Hz), to 3.34 (1H, DD, J=4.5 Hz, to 17.4 Hz), 3,42 (1H, d, J=14.1 Hz), 3,61 (3H, s), 3,63 (1H, m), 3,81 (1H, t, J=8.7 Hz), 3,88 (3H, s), 4,48 (1H, d, J=14.1 Hz), to 4.62 (1H, q, J=3,9 Hz), 6,18 (1H, s), 6,62 (1H, m), 6,97 (1H, m), 7,17 (2H, m), 7,29 (2H, m), 7,39 (2H, m), 7,89 (2H, d, J=8,1 Hz).

Example 81

3-(4-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}phenyl)propionic acid

(1) acetylchloride (0.4 ml) was added to a solution of ethyl 3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionate (3.0 g)obtained in example 72-(1)in a mixture of THF (50 ml) and pyridine (0.8 ml) and the mixture was stirred at room temperature for 2 hours. Was added to the reaction solution with water followed by extraction with ethyl acetate. The obtained organic layer was washed successively with diluted hydrochloric acid, saturated aqueous NaHCO3and water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain ethyl 3-(4-{[(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-yl]acetyl}phenyl)propionate (2.7 g) in the form of oil.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s)of 1.26 (3H, t, J=7.2 Hz), 2,04 (3H, s), 2,62 (2H, t, J=7.8 Hz), 2,99 (2H, t, J=7.8 Hz), 3,30 (1H, DD, J=4,8, to 17.4 Hz), 3,60 (1H, m), 3,61 (3H, s), 3,76 (2H, m), 3,89 (3H, s), 4,11 (2H, q, J=7.2 Hz), 4,56 (1H, d, J=14.4 Hz), to 4.62 (1H, q, J=4,8 Hz), 6,28 (1H, s), of 6.65 (1H, m), 6,97 (1H, m), 7,16 (2H, is), 7,26 (2H, m), of 7.36 (2H, m), 7,89 (2H, d, J=8,4 Hz).

(2) Borohydride sodium (40 mg) and methanol (2 ml) was sequentially added to a solution of ethyl 3-(4-{[(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-yl]acetyl}phenyl)propionate (0.2 g)obtained in example 81-(1)in THF (5 ml) and the mixture was stirred at room temperature for 30 minutes. After addition of 1 N. hydrochloric acid, the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed successively with diluted hydrochloric acid and water, dried over magnesium sulfate and then concentrated under reduced pressure. After dissolving the obtained residue in THF (5 ml) and ethanol (5 ml) to the resulting solution were added 2 N. aqueous sodium hydroxide solution (2.5 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with diluted hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-(4-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}phenyl)propionic acid (83 mg) in powder form.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H,s), of 2.27 (2H, m)of 2.64 (2H, m), with 2.93 (2H, m), and 3.16 (1H, d, J=12.0 Hz), 3,37 (1H, d, J=14.1 Hz), 3,61 (2H, m), 3,63 (3H, s), 3,90 (3H, s), 4,14 (1H, m), 4,47 (1H, d, J=14.1 Hz), a 4.83 (1H, m), 6,18 (1H, s), 6,64 (1H, m), 7,00 (1H, m)and 7.1 to 7.4 (8H, m).

Example 82

3-(4-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}phenyl)propionic acid

Thionyl chloride (0.2 ml) was added to a solution of ethyl 3-(4-{[(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-yl]acetyl}phenyl)propionate (1.2 g)obtained in example 81-(1)in a mixture of dichloromethane (30 ml) and pyridine (0.5 ml) and the mixture was stirred at room temperature within 1 hour. After adding dilute hydrochloric acid, the reaction solution was extracted with dichloromethane. The organic layer was washed successively with diluted hydrochloric acid, saturated aqueous NaHCO3and water, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in acetic acid (10 ml)was added to a solution of zinc powder (2.5 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture through Celite and the filtrate was concentrated under reduced pressure. To the obtained residue was added a saturated aqueous solution of NaHCO3and see what camping was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel. The resulting oil was dissolved in THF (10 ml) and ethanol (10 ml), to the solution was added 2 N. aqueous solution of NaOH (5.0 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with diluted hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-(4-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}phenyl)propionic acid (115 mg) in powder form.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,19 (2H, m), 2.63 in (2H, m), 2,90 (2H, m)and 3.15 (1H, d, J=11.7 Hz), 3,37 (1H, d, J=14.1 Hz), 3,62 (4H, m), 3,63 (3H, s), 3,81 (2H, m), 3,90 (3H, s), of 4.45 (1H, d, J=14.1 Hz), 6,18 (1H, s), only 6.64 (1H, m), 7,00 (1H, m)and 7.1 to 7.4 (8H, m).

Example 83

4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}benzoic acid

The palladium acetate (655 mg), 1,1'-bis(diphenylphosphino)ferrocene (1.6 g) and triethylamine (4.0 ml) was added to a solution of (3R,5S)-3-[2-(4-bromophenyl)-2-oxoethyl]-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimetyl the filing)-1,5-dihydro-4,1-benzoxazepin-2-(3H)-she (6.0 g), obtained in example 71-(1)in a mixture of DMF (60 ml) and methanol (30 ml) and the mixture was heated at 60°C for 20 hours in an atmosphere of carbon monoxide. After addition of 1 N. hydrochloric acid, the reaction solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel and the obtained oil was dissolved in a mixture of THF (100 ml) and ethanol (100 ml). To the resulting solution were added 2 N. aqueous solution of NaOH (25 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with diluted hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}benzoic acid (1.7 g).

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s), and 3.16 (1H, d, J=11.7 Hz), 3,39 (1H, DD, J=3,9 Hz, and 17.7 Hz), 3,43 (1H, d, J=13,8 Hz), 3,62 (3H, s), the 3.65 (1H, m), 3,85 (1H, t, J=7.8 Hz), with 3.89 (3H, s), 4,49 (1H, d, J=14.4 Hz), 4,63 (1H, q, J=4.5 Hz), to 6.19 (1H, s), 6,63 (1H, m), 6,98 (1H, m), 7,16 (2H, m), 7,41 (2H, m),? 7.04 baby mortality (2H, d, J=8,4 Hz), 8,17 (2H, d, J=8,4 Hz).

Example 84

3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-then it is carbonated the ro-4,1-benzoxazepin-3-yl]acetyl}benzoic acid

In a manner similar to the method of example 83, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.06 (3H, s), 3,17 (1H, d, J=11.7 Hz), 3,42 (1H, m), 3,63 (3H, s)to 3.67 (1H, m), 3,90 (3H, s), 3,93 (1H, m), 4,50 (1H, d, J=14,7 Hz), of 4.66 (1H, q, J=4.5 Hz), 6,21 (1H, s), 6,65 (1H, m), 7,00 (1H, m), 7,19 (2H, m), 7,42 (2H, m), to 7.59 (1H, t, J=7.8 Hz), to 8.20 (1H, m), 8,30 (1H, m), 8,71 (1H, m).

Example 85

(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenoxy)acetic acid

(1) in a Manner similar to the method of example 71-(1)was synthesized (3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-1,5-dihydro-4,1-benzoxazepin-2(3H)-he, using (2E)-4-(acetoxyphenyl)-4-oxo-2-butenova acid as the starting material.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s), 3,17 (1H, m), or 3.28 (1H, DD, J=4.5 Hz, is 16.8 Hz), 3,43 (1H, d, J=14.1 Hz), 3,61 (3H, s), the 3.65 (1H, m), with 3.79 (1H, m)to 3.89 (3H, s), 4,47 (1H, d, J=14.1 Hz), to 4.62 (1H, m), 6,18 (1H, s), 6,62 (1H, m), at 6.84 (2H, d, J=8.7 Hz), 6,97 (1H, t, J=4.5 Hz), 7,17 (2H, m), 7,39 (2H, m), 7,87 (2H, d, J=8.7 Hz).

(2) K2CO3(0.5 g) and ethylbromoacetate (0,22 ml) was added to a solution of (3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-1,5-dihydro-4,1-benzoxazepin-2(3H)-she (1.0 g)obtained in example 85-(1)in DMF (20 ml) and the mixture was stirred at room is temperature in for 2 hours. After addition of 1 N. hydrochloric acid, the reaction solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. After dissolving the obtained residue in a mixture of THF (10 ml) and ethanol (10 ml) to the resulting solution were added 2 N. aqueous NaOH solution (5 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with diluted hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain (4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenoxy)acetic acid (0,82 g) in powder form.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 3,20 (1H, d, J=12.0 Hz), and 3.31 (1H, DD, J=3,9 Hz, and 17.1 Hz), 3,42 (1H, d, J=15,0 Hz), 3,62 (3H, s), 3,66 (1H, m), 3,81 (1H, m), 3,90 (3H, s), 4,46 (1H, d, J=14,7 Hz), br4.61 (1H, m), 4,71 (2H, s), 6,17 (1H, s), 6,63 (1H, m)6,94 (2H, d, J=9.0 Hz), 7,00 (1H, m), 7,17 (2H, m), 7,40 (2H, m), 7,95 (2H, d, J=9.0 Hz).

Example 86

(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acetic acid

(1) in a Manner similar to the method of example 71-(1)was synthesized ethyl (4-{[(3R,5S)-7-chloro-5-(2,3-shall methoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acetate using (2E)-4-[4-(2-ethoxy-2-oxoethyl)phenyl]-4-oxo-2-butenova acid as the starting material.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s), 1,25 (3H, t, J=7.2 Hz), 3,14 (1H, m)to 3.35 (1H, m), 3,43 (1H, d, J=15.3 Hz), the 3.65 (3H, s), the 3.65 (3H, m), 3,81 (1H, m), 3,90 (3H, s)to 4.15 (2H, q, J=7.2 Hz), 4,49 (1H, d, J=15.3 Hz), 4,63 (1H, m), of 6.20 (1H, s), only 6.64 (1H, m), of 6.99 (1H, m), 7,18 (2H, m), 7,40 (4H, m), of 7.90 (2H, m).

(2) 2 N. Aqueous solution of NaOH (30 ml) was added to a solution of ethyl (4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acetate (7,1 g)obtained in example 86-(1)in a mixture of THF (50 ml) and ethanol (100 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with diluted hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain (4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acetic acid (4.8 g).

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), and 3.16 (1H, d, J=11.7 Hz), to 3.34 (1H, DD, J=4,2 Hz, to 17.4 Hz), 3,42 (1H, d, J=14.1 Hz), 3,62 (3H, s), the 3.65 (1H, m), of 3.69 (2H, s), 3,81 (1H, m)to 3.89 (3H, s), 4,47 (1H, d, J=14.1 Hz), to 4.62 (1H, m), 6,18 (1H, s), only 6.64 (1H, m), of 6.99 (1H, m), 7,17 (2H, m), 7,45 (4H, m), 7,89 (2H, m).

Example 87

2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl is)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-3-francebuy acid

Ethyl 4-[(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-yl]-3-oxobutanoate (1.2 g) was dissolved in toluene (5 ml) and then to the resulting solution was added DBU (0.3 ml). After then adding 40% aqueous solution of chloroacetaldehyde (0.4 ml) under ice cooling and the mixture was stirred at room temperature for 1 hour. After adding water, the reaction solution was extracted with toluene. The obtained organic layer was concentrated under reduced pressure. The obtained residue was dissolved in toluene (20 ml), was added a catalytic amount of p-toluensulfonate acid and the mixture was heated at 100°C for 2 hours. The reaction solution was concentrated and then purified on a column of silica gel. The obtained residue was dissolved in a mixture of THF (5 ml) and methanol (20 ml), was added 2 N. aqueous NaOH solution (5 ml) and the mixture was stirred at room temperature overnight. The reaction solution was acidified with diluted hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-3-furancarboxylic (26 mg).

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.06 (3H, s), and 3.16 (1H, d, J=11.7 Hz), 3,40 (1H, d, J=14,7 Hz), 3,57 (3H, m), of 3.60 (3H, s), a 3.87 (3H, s), the 4.29 (1H, m), 4,50 (1H, d, J=14,7 Hz), 6,17 (1H, s), 6,53 (1H, s)6,70 (1H, m), of 6.99 (1H, d, J=8,4 Hz), to 6.95 (1H, d, J=9.3 Hz), 7,12 (1H, t, J=8.1 Hz), 7,31 (3H, m).

Example 88

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-4-yl)propionic acid

(1) 10% Pd on carbon (47 mg) was added to a solution of ethyl (2E)-3-(2-{[(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-yl]methyl}-1,3-thiazol-4-yl)acrylate (0,47 g to 0.72 mmol)obtained in example 19-(1)in THF (5 ml) under nitrogen atmosphere and then was injected hydrogen. The mixture was stirred at room temperature for 48 hours and then at 40°C for 12 hours. The catalyst was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (73:27-65:35)] to obtain ethyl 3-(2-{[(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-yl]methyl}-1,3-thiazol-4-yl)propionate (0,38 g of 0.58 mmol, 81%) as a colorless oil.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.03 (3H, s)to 1.21 (3H, t, J=7.2 Hz), 2,03 (3H, s)to 2.67 (2H, t, J=7.5 Hz), to 3.02 (2H, t, J=7.5 Hz), 3.45 points (1, DD, J=7,2, 15,0 Hz), 3,54 (1H, d, J=14.4 Hz), of 3.56 (1H, DD, J=5,7, or 15.0 Hz), 3,62 (3H, s), of 3.73 (1H, d, J=11,1 Hz), 3,85 (1H, d, J=11,1 Hz)to 3.89 (3H, s), 4,11 (2H, q, J=7.2 Hz), the 4.29 (1H, DD, J=5,7, 7,2 Hz), 4,56 (1H, d, J=14.4 Hz), of 6.31 (1H, s), 6,60 (1H, d, J=2.4 Hz), PC 6.82 (1H, s), 6,98 (1H, DD, J=2,4, 7,2 Hz), 7,10-7,20 (2H, m), 7,28 (1H, d, J=8,4 Hz), 7,33 (1H, DD, J=2,4, 8,4 Hz).

(2) a Mixture of ethyl 3-(2-{[(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-yl]methyl}-1,3-thiazol-4-yl)propionate (0.35 g, of 0.53 mmol)obtained in example 88-(1), 1 N. aqueous sodium hydroxide solution (3.0 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours. The mixture was acidified using 1 N. aqueous hydrochloric acid (3.5 ml) was added ethyl acetate (80 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-4-yl)propionic acid (0.3 g, 0.51 mmol, 96%) as a colorless non-crystalline powder.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s), 2,69 is 2.80 (2H, m), to 3.02 (2H, t, J=7,2 Hz), and 3.16 (1H, d, J=12.0 Hz), to 3.41 (1H, d, J=14,7 Hz), 3,48 (1H, DD, J=6,6, 15.3 Hz), 3,59-3,70 (2H, m), 3,62 (3H, s), 3,90 (3H, ), to 4.33 (1H, t, J=6.6 Hz), 4,47 (1H, d, J=14,7 Hz), 6,21 (1H, s), 6,59 (1H, d, J=2.7 Hz), 6.89 in (1H, s), 7,00 (1H, DD, J=2,4, and 7.8 Hz), 7,10-7,22 (2H, m), 7,38-8,01 (2H, m).

Example 89

[2-{[3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-(2-phenylethyl)-1,3-thiazol-5-yl]acetic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,81 of 2.92 (4H, m), 3,17 (1H, d, J=11.4 in Hz)to 3.36 (1H, d, J=14.4 Hz), 3,40-3,70 (3H, m), of 3.46 (2H, s), 3,61 (1H, d, J=11.7 Hz), a 3.87 (3H, s), 4,34 (1H, t, J=6.9 Hz), 4,47 (1H, d, J=14.4 Hz), of 6.20 (1H, s), to 6.58 (1H, d, J=2.4 Hz), 6.90 to-7,06 (3H, m), 7,09-7,38 (7H, m).

Example 90

[2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-(2-phenylethyl)-1,3-oxazol-5-yl]acetic acid

In a manner similar to the method of example 27, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), was 1.04 (3H, s), 2,68 (2H, t, J=7.5 Hz), 2,87 (2H, t, J=7.5 Hz), and 3.16 (1H, d, J=12.0 Hz), 3,20-of 3.42 (3H, m)to 3.36 (2H, s), 3,61 (3H, s), 3,62 (1H, d, J=12.0 Hz), a 3.87 (3H, s), 4,40-4,51 (2H, m), 6,18 (1H, s), 6,59 (1H, d, J=2.1 Hz), to 6.95 (1H, DD, J=1,8, 8.1 Hz), 7,02-7,29 (8H, m), 7,37 (1H, DD, J=2,1, 8,4 Hz).

Example 91

1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-4-carboxylic acid

In a manner similar to the method of example 50, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,29-of 2.50 (2H, m)and 3.15 (1H, d, J=12.3 Hz), to 3.36 (1H, d, J=13,8 Hz)3,607 (1H, d, J=12.3 Hz), 3,61 (3H, s), of 3.78 (1H, t, J=7.5 Hz), with 3.89 (3H, s), 4,25-4,43 (2H, m), of 4.45 (1H, d, J=13,8 Hz), x 6.15 (1H, s), 661 (1H, d, J=2.4 Hz), 7,00 (1H, DD, J=2,4, 7,2 Hz), 7,15-7,26 (2H, m), 7,28 (1H, d, J=8,4 Hz), 7,34 (1H, DD, J=2,4, and 8.4 Hz), the 7.85 (1H, s), 7,88 (1H, s).

Example 92

3-(1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-5-yl)propionic acid

In a manner similar to the method of example 88, using 1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-5-carboxylic acid obtained in example 50, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 2,20 is 2.43 (2H, m), 2,69 (2H, t, J=8.1 Hz), 2,87 are 2.98 (2H, m)and 3.15 (1H, d, J=12.3 Hz), 3,35 (1H, d, J=14.1 Hz), 3,605 (3H, s)3,613 (1H, d, J=12.3 Hz), 3,88 (1H, t, J=6.3 Hz), with 3.89 (3H, s), 4,20-4,30 (2H, m)to 4.41 (1H, d, J=14.1 Hz), 5,97 (1H, d, J=1,8 Hz), 6,13 (1H, s), is 6.61 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=2,1, 7,8 Hz), 7,17-7,40 (5H, m).

Example 93

3-(1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-4-yl)propionic acid

In a manner similar to the method of example 92, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 2,23-to 2.40 (2H, m)of 2.50 (2H, t, J=7.2 Hz), a 2.71 (2H, t, J=7,2 Hz)and 3.15 (1H, d, J=11.7 Hz), 3,35 (1H, d, J=14.4 Hz), 3,607 (1H, d, J=11.7 Hz), 3,61 (3H, s), and 3.72 (1H, t, J=6.6 Hz), 3,90 (3H, s), 4,18-4,37 (2H, m), 4,42 (1H, d, J=14.4 Hz), 6,14 (1H, s), is 6.61 (1H, d, J=2,1 Hz), of 6.96-7.03 is (1H, m), 7,15-7,30 (5H, m), 7,35 (1H, DD, J=2.1 a, 8,7 Hz).

Example 94

1-{2-[(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-yl]ethyl}-1H-pyrazole-4-carboxylic acid

In a manner similar to the method of example 14 had been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s)2,03 (3H, s), 2,30-of 2.50 (2H, m), 3,52 (1H, d, J=14.1 Hz), 3,62 (3H, s), and 3.72 (1H, d, J=10,8 Hz), of 3.77 (1H, DD, J=5,4, 7,2 Hz), 3,86 (1H, d, J=10,8 Hz), 3,90 (3H, s), 4,25-4,43 (2H, m), 4,56 (1H, d, J=14.1 Hz), of 6.26 (1H, s), only 6.64 (1H, d, J=2.7 Hz), 6,97-7,05 (1H, m), 7,17-of 7.25 (2H, m), 7,26 (1H, d, J=9.0 Hz), 7,33 (1H, DD, J=2.7, and 9.0 Hz), 7,86 (1H, s), of 7.90 (1H, s).

Example 95

3-(1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-4-yl)-3-hydroxypropionic acid

In a manner similar to the method of example 18, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 2,28-to 2.40 (2H, m), 2,63 is 2.80 (2H, m)and 3.15 (1H, d, J=12.0 Hz), 3,35 (1H, d, J=14.1 Hz), 3,55-3,62 (1H, m), 3,61 (3H, s), 3,76-3,82 (1H, m), 3,90 (3H, s), 4,19-of 4.44 (3H, m)5,00-5,09 (1H, m), 6,13 (1H, s), 6,62 (1H, d, J=2.1 Hz), 6,98-7,02 (1H, m), 7,19-7,22 (6H, m).

Example 96

3-(1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-5-yl)-3-hydroxypropionic acid

In a manner similar to the method of example 18, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,62 (3/2H, s)0,63 (3/2H, s)1,02 (3/2H, s)1,03 (3/2H, s), 2,20-2,40 (1H, m), 2.21 are 2,43 (1H, m), 2,79-3,03 (2H, m), 3,148 (1/2H, d, J=12.0 Hz), 3,158 (1/2H, d, J=12.0 Hz), and 3.31 (1/2H, d, J=14.1 Hz), 3,35 (1/2H, d, J=14.1 Hz), 3,50-3,63 (1H, m), 3,59 (3/2H, s), 3,60 (3/2H, s), 3,88 (3H, s), 3,91-a 4.03 (1H, m), 4,20-4,51 (3H, m), 5,18 is 5.28 (1H, m)6,09 (1/2H, s), 6,11 (1/2H, C)6,139 (1/2H, s)6,144 (1/SN, C), is 6.61 (1H, d, J=1,8 Hz), of 6.96-7,01 (1H, m), 7,15-7,40 (5H, m).

Example 97

(2E)-3-(1-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1H-pyrazole-4-yl)acrylic acid

In a manner similar to the method of example 19 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,29-2,49 (2H, m)and 3.15 (1H, d, J=12.3 Hz), to 3.36 (1H, d, J=13.5 Hz), 3,61 (1H, d, J=12.3 Hz), 3,62 (3H, s), 3,80 (1H, DD, J=5,4, 7,2 Hz), 3,90 (3H, s), 4,28-and 4.40 (2H, m,), to 4.46 (1H, d, J=13.5 Hz), 6,09 (1H, d, J=15,9 Hz), 6,16 (1H, s), 6,62 (1H, d, J=2.4 Hz), 7,03 (1H, DD, J=2,1, 7,2 Hz), 7.18 in-7,24 (2H, m), 7,29 (1H, d, J=8,4 Hz), was 7.36 (1H, DD, J=2,4, and 8.4 Hz), 7,55 (1H, s), EUR 7.57 (1H, d, J=15,9 Hz), a 7.62 (1H, s).

Example 98

4-(5-{[(3R,5S)-7-chloro-5-(2,3-acid-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)-1,3,4-thiadiazole-2-yl]butane acid

In a manner similar to the method of example 56, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, what), of 1.05 (3H, s), of 2.15 (2H, quintet, J=7.2 Hz), 2.49 USD (2H, t, J=7,2 Hz), and 3.16 (2H, t, J=7.2 Hz), of 3.10-3.20 (1H, m)to 3.38 (1H, d, J=13,8 Hz), 3,53 (1H, DD, J=6,6, 15.3 Hz), to 3.58-3,70 (2H, m), 3,62 (3H, s), 4,39 (1H, t, J=6.6 Hz), of 4.45 (1H, d, J=13,8 Hz), of 6.20 (1H, s), 6,59 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=1,8, 8.1 Hz), 7,12 (1H, DD, J=1,8, 8,2 Hz), 7,19 (1H, t, J=8.1 Hz), 7,32 (1H, d, J=8,4 Hz), was 7.36 (1H, DD, J=2,1, 8,4 Hz).

Example 99

2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylpropionate acid

(1) Concentrated sulfuric acid (0.1 ml) was added to a solution of (2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid (7.5 g, 13,0 mmol)obtained in example 1 in ethanol (75 ml) and the mixture was heated with reverse refrigerator for 24 hours under stirring. Allowing to stand for cooling to room temperature, the mixture was concentrated under reduced pressure and to the residue was added ethyl acetate (400 ml). The organic layer was washed saturated aqueous sodium carbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in DMF (70 ml). To the solution was added imidazole (1.06 g, 15.7 mmol) and tert-butyldimethylchlorosilane (2,36 g, 15.7 mmol) and the mixture peremeci the Ali for 14 hours. After adding water (50 ml), the reaction solution was extracted with ethyl acetate (350 ml) and the organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:1)] to obtain ethyl (2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetate (7,97 g, 11,1 mmol, 85%) as pale-yellow non-crystalline powder.

1H-NMR (CDCl3) δ: 0,09 (3H, s)of 0.11 (3H, s)to 0.96 (3H, s), and 0.98 (9H, s), 1,10 (3H, s)of 1.39 (3H, t, J=6.9 Hz), 3,29 (1H, d, J=9.9 Hz), 3,34 (1H, d, J=9.9 Hz), 3,55 (1H, DD, J=7,2, 15,0 Hz)to 3.67 (1H, DD, J=6,0, 15,0 Hz), and 3.72 (3H, s), of 3.78 (1H, d, J=13,8 Hz)to 3.89 (2H, s)to 3.99 (3H, s), 4,30 (2H, q, J=6.9 Hz), 4,43 (1H, DD, J=6,0, 7,2 Hz), 4,50 (1H, d, J=13,8 Hz), 6,38 (1H, s), 6,65 of 6.68 (1H, m), 7,07 (1H, DD, J=the 2.4 and 6.9 Hz), 7,20-7,31 (2H, m), of 7.36-7,40 (2H, m), 7,52-rate of 7.54 (1H, m).

(2) Bestremembered lithium (0.63 ml, 0.7 mmol) was added dropwise to a solution of ethyl (2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetate (0.5 g, 0.70 mmol)obtained in example 99-(1)in THF (5 ml) at -78°C in nitrogen atmosphere. After stirring at the same temperature for 1 h the sa was added dropwise benzylbromide (0,08 ml, 0.7 mmol) and the mixture was stirred at -50°C for 5 hours. After adding a saturated aqueous solution of ammonium chloride (3 ml) the mixture was extracted with ethyl acetate (60 ml) and the organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (4:1-73:27)] to obtain ethyl 2-(2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylpropionate (0.33 g, 0.41 mmol, 59%) as a colourless oil.

1H-NMR (CDCl3) δ: -0,11 (3H, s)-0,02 (3H, s)of 0.85 (3H, s)to 0.88 (9H, s), and 1.00 (3H, s), 1,15 (3/2H, t, J=6.9 Hz), 1,16 (3/2H, t, J=6.9 Hz), 3,05 (1/2H, DD, J=4,8 and 6.9 Hz), 3,10 (1/2H, DD, J=4,8, 6,9 Hz), 3,19 (1H, d, J=9.6 Hz), 3,24 (1H, d, J=9.6 Hz), 3,32 (1/2H, DD, J=3.3, which is 8.4 Hz), 3,37 (1/2H, DD, J=3.3, which is 8.4 Hz), 3,44 (1H, DD, J=7,5, 15,0 Hz), 3,53 (1H, DD, J=5,7, or 15.0 Hz), 3,62 (3H, s), 3,68 (1H, d, J=a 14.1 Hz), with 3.89 (3H, s), as 4.02-4,16 (3H, 25 m), 4,25-4,34 (1H, m)to 4.41 (1H, d, J=14.1 Hz), 6,28 (1H, s), to 6.57 (1H, s), 6,92-7,00 (1H, m), 7,08-7,33 (9H, m), 7,37 (1H, s).

(3) the Complex of boron TRIFLUORIDE and diethyl ether (0.16 ml, 1,22 mmol) was added dropwise to a solution of ethyl 2-(2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylprop the Nata (0.33 g, 0.41 mmol)obtained in example 99-(2), in acetonitrile (5 ml). After stirring at the same temperature for 1.5 hours was added water (2 ml) and the mixture was extracted with ethyl acetate (60 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:1-2:3)] to obtain ethyl 2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylpropionate (0.24 g, 0.35 mmol, 85%) as a colorless non-crystalline powder.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.06 (3H, s)of 1.16 (3H, t, J=7.2 Hz), 3.00 and-is 3.21 (2H, m), 3,29-3,50 (3H, m), 3,55 (1H, DD, J=5,7, 15.3 Hz), 3,59-3,70 (1H, m), 3,62 (3H, s)to 3.89 (3H, s), 4,00-is 4.21 (4H, m), 4,27-4,39 (1H, m), 4,49 (1H, d, J=14.4 Hz), of 6.20 (1H, s), to 6.57 (1H, d, J=1.5 Hz), 6,94-7,01 (1H, m), 7.03 is-to 7.35 (9H, m), 7,37 (1H, s).

(4) a Mixture of ethyl 2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylpropionate (0.2 g, 0.29 mmol)obtained in example 99-(3), 1 N. aqueous sodium hydroxide solution (1 ml) and ethanol (5 ml) was stirred at room temperature for 1 hour. The mixture was acidified using 1 N. hydrochloric acid (2.3 ml) and then extragere the Lee ethyl acetate (35 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylpropionic acid (0,19 g, 0.29 mmol, sec.) as Besenova non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), 1.04 million (3/2H, s)1,05 (3/2H, s), 3,06 (1H, DD, J=7,5 for 13.8 Hz), 3,18 (1H, d, J=12.0 Hz), 3,37 (1H, d, J=14,7 Hz), 3,30-3,63 (3H, m), 3,61 (3H, s), 3,63 (1H, d, J=12.0 Hz), a 3.87 (3/2H, s), 3,88 (3/2H, s), 4,05-4,17 (1H, m), 4,27-4,37 (1H, m), 4,46 (1H, d, J=14,7 Hz), to 6.19 (1H, s), 6,55-6,60 (1H, m), 6,92-7,00 (1H, m), 7,05-7,41 (10H, m).

Example 100

(2-{[(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-yl]methyl}-1,3-thiazol-5-yl)acetic acid

In a manner similar to the method of example 14 had been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s)2,02 (3H, s), 3,39-3,62 (3H, m), 3,61 (3H, s), of 3.73 (1H, d, J=10,8 Hz), 3,82 (2H, s), 3,85 (1H, d, J=10,8 Hz), 3,88 (3H, s)to 4.33 (1H, t, J=6.9 Hz), 4,56 (1H, d, J=to 13.8 Hz), 6,30 (1H, s), 6,59 (1H, d, J=2.4 Hz), of 6.96 (1H, DD, J=3,3, 6,6 Hz), 7,10-7,20 (2H, m), 7,26-7,34 (2H, m), 7,47 (1H, s).

Example 101

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid calcium is th Sol

In a manner similar to the method of example 27, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,61 (3H, s)of 0.87 (3H, s), 3.04 from-3,30 (3H, m), 3.40 in-the 3.65 (7H, m), of 3.84 (3H, s), 4,23-4,50 (2H, m), 6,13 (1H, s), 6,55 (1H, s), 6,93 (1H, d, J=8.1 Hz), 7,09-7,38 (5H, m).

Example 102

(2Z)-2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylacrylate acid

(1) Bestremembered lithium (1,33 ml of 1.46 mmol) was added dropwise to a solution of ethyl (2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetate (1.0 g, of 1.39 mmol)obtained in example 99-(1)in THF (10 ml) at -78°C in nitrogen atmosphere. After stirring at the same temperature for 1 hour was added dropwise benzaldehyde (0.15 g, of 1.39 mmol) and the mixture was stirred at -20°C for 5 hours. After adding a saturated aqueous solution of ammonium chloride (5 ml) the mixture was extracted with ethyl acetate (120 ml) and the organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent hexane-ethyl acetate (73:27-62:38)] to obtain ethyl 2-(2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxy-3-phenylpropionate (0,23 g, 0.28 mmol, 20%) as a colourless oil.

1H-NMR (CDCl3) δ: -0,11 (3H, s)-0,02 (3H, s), 0,80-of 1.35 (9H, m)of 0.87 (9H, s), 2,90 of 3.28 (3H, m), 3,30-3,74 (6H, m), 3,88 (3H, s), 4,00-4,43 (4H, m), 5,03-5,12 (1/2H, m), 5,17 (1/2H, m), 6,25 (1/2H, s), 6,27 (1/2H, s), 6,56 (1H, Shir), 6,90-7,40 (11H, m)

(2) Triethylamine (0.06 ml, 0.43 mmol) and methanesulfonamide (0,03 ml, 0.43 mmol) was added to a solution of ethyl 2-(2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxy-3-phenylpropionate (0,22 g, 0.27 mmol)obtained in example 102-(1)in THF (5 ml) under cooling with ice. After stirring at the same temperature for 1.5 hours was added dropwise DBU (0,08 ml of 0.53 mmol) and the mixture was stirred for 2 hours. After adding water (5 ml), the reaction solution was extracted with ethyl acetate (60 ml) and the organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (67:33-1:1)] to obtain ethyl (2Z)-2-(2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-5-yl)-3-phenylacrylate (0.09 g, 0.12 mmol, 44%) as a colourless necris alicebraga powder.

1H-NMR (CDCl3) δ: -0,10 (3H, s)-0,01 (3H, s)of 0.85 (3H, s)to 0.88 (9H, s), and 1.00 (3H, s)of 1.33 (3H, t, J=7.2 Hz), 3,20 (1H, d, J=9.9 Hz), 3,24 (1H, d, J=9.9 Hz), 3,50-3,59 (2H, m), 3,62 (3H, s), of 3.69 (1H, d, J=to 13.8 Hz), 3,88 (3H, s), 4,20 is 4.35 (3H, m), 4,42 (1H, d, J=13,8 Hz), of 6.29 (1H, s), to 6.57 (1H, s), to 6.95 (1H, DD, J=2,4, 7.5 Hz), 6,99-7,11 (2H, m), 7,14-7,37 (4H, m), 7,44 (1H, s), to 7.93 (1H, s).

(3) the Complex of boron TRIFLUORIDE and diethyl ether (22 μl, 0.18 mmol) was added dropwise to a solution of ethyl (2Z)-2-(2-{[(3R,5S)-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylacrylate (0.09 g, 0.12 mmol)obtained in example 102-(2), in acetonitrile (5 ml) under cooling with ice. After stirring at the same temperature for 1.5 hours was added water (2 ml) and the mixture was extracted with ethyl acetate (60 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in ethanol (3 ml), was added 1 N. aqueous sodium hydroxide solution (0.6 ml) and the mixture was stirred at room temperature for 5 hours. The reaction solution was acidified using 1 N. aqueous hydrochloric acid (1 ml) and then extracted with ethyl acetate (35 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then koncentrirane and under reduced pressure to obtain (2Z)-2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-phenylacrylate acid (0.07 g, 0.11 mmol, 85%) as pale-yellow non-crystalline powder.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.06 (3H, s)3,18 (1H, d, J=12.0 Hz), 3,39 (1H, d, J=14.4 Hz), 3,53 at 3.69 (3H, m), 3,61 (3H, s), a 3.87 (3H, s), 4,37 (1H, DD, J=5,7, 7,2 Hz), 4,49 (1H, d, J=14.4 Hz), 6,21 (1H, s), to 6.58 (1H, d, J=1,8 Hz), 6.90 to-7,00 (1H, m), 7,02-7,10 (2H, m), 7,17-7,40 (7H, m), 7,51 (1H, s), of 8.06 (1H, s).

Example 103

(2R)-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)(hydroxy)acetic acid

In a manner similar to the method of example 99, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.03 (3H, s), 3,20 (1H, d, J=12.3 Hz), 3,38 (1H, d, J=14.1 Hz), 3,48 (1H, DD, J=6,6, 15.3 Hz), 3,53-to 3.67 (2H, m), of 3.60 (3H, s), 3,88 (3H, s), 4,30-and 4.40 (1H, m), of 4.44 (1H, d, J=14.1 Hz), 5,33 (1H, s), 6,18 (1H, s), 6,59 (1H, d, J=1,8 Hz), 6,97 (1H, DD, J=1,8, 7,8 Hz), 7,09-7,21 (2H, m), 7,26-7,40 (2H, m), 7,66 (1H, s).

Example 104

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-4-yl)-3-methylbutanoate acid

In a manner similar to the method of example 16, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)of 1.39 (3H, s)of 1.41 (3H, s), 2,71 (2H, s), 3,10-is 3.21 (1H, shears), 3,43 (1H, d, J=14.4 Hz), 3,51 (1H, DD, J=6.3, in the 15.6 Hz), 3,59-3,71 (2H, m), 3,62 (3H, s)to 3.89 (3H, s), 4,32 (1H, t, J=6.3 Hz), 4,46 (1H, d, J=14.4 Hz), 6,21 (1H, s), 6,60 (1H, d, J=1,8 Hz), 6,92 (1H, s), 99 (1H, DD, J=2.7, and 7.5 Hz), 7,10-7,20 (2H, m), 7,35-7,45 (2H, m).

Example 105

(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-5-yl)acetic acid

(1) To a solution of (3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ethanol (1.0 g, to 1.98 mmol)obtained in example 50-(1), acetonecyanohydrin (0,23 ml, 2.57 mmol) and toluene (20 ml) was added n-tributylphosphine (0,74 ml, 2,96 mmol) and 1,1'-azodicarbonamide (0.75 g, 2,96 mmol) under nitrogen atmosphere and the mixture was stirred at room temperature for 3 hours. After addition of hexane (10 ml) and the mixture was stirred for 30 minutes and then filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (7:3-3:2)] to obtain 3-[(3R,5S)-7-chloro-3-(2-Tianeti)-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (0.75 g, of 1.46 mmol, 74%) as a colorless non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)2,03 (3H, s), from 2.00 to 2.35 (2H, m), to 2.57 (2H, t, J=7.5 Hz), 3,53 (1H, d, J=14.4 Hz), 3,62 (3H, s), and 3.72 (1H, d, J=11,1 Hz), 3,86 (1H, d, J=11,1 Hz), 3,90 (3H, s)to 3.99 (1H, DD, J=4,8, 7.5 Hz), of 4.57 (1H, d, J=14.4 Hz), 6,27 (1H, s), of 6.66 (1H, d, J=2.1 Hz), 7,00 (1H, is d, J=3,0, 7,2 Hz), 7,16-of 7.25 (2H, m), 7,30 (1H, d, J=8.7 Hz), was 7.36 (1H, DD, J=2.1 a, 8,7 Hz).

(2) O,O'-diethyldithiophosphate (0,20 ml of 1.17 mmol) was added to a solution of 3-[(3R,5S)-7-chloro-3-(2-Tianeti)-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (0.5 g, 0.97 mmol)obtained in example 105-(1), and 4 N. HCl (2.5 ml) and the mixture was stirred at room temperature for 16 hours. After adding water (5 ml) the mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:2-1:1)] to obtain 3-[(3R,5S)-3-(3-amino-3-tioxaprofen)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (0,38 g, 0.69 mmol, 71%) as a pale yellow crystal.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)a 1.01 (3H, s)2,03 (ZN, C), 2,20-of 2.34 (2H, m), 2.71 to to 2.94 (2H, ha), 3,52 (1H, d, J=14.1 Hz), 3,62 (3H, s), and 3.72 (1H, d, J=11,1 Hz), 3,88 (1H, d, J=11,1 Hz), 3,90 (3H, s), of 3.96 (1H, t, J=6.3 Hz), 4,56 (1H, d, J=14.1 Hz), of 6.26 (1H, s), only 6.64 (1H, d, J=2.4 Hz), 6,95? 7.04 baby mortality (1H, m), 7,15-7,24 (2H, m), 7,29 (1H, d, J=9.0 Hz), 7,35 (1H, DD, J=2,4, and 9.0 Hz), 7,30-7,40 (1H, m), of 7.48 (1H, Shir).

(3) in a Manner similar to the method of example 16 using 3-[(3R,5S)-3-(3-amino-3-tioxaprofen)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-di is ethylpropylamine, obtained in example 105-(2)has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), was 1.04 (3H, s), 2,18-to 2.42 (2H, m), 2.95 and-3,20 (3H, m), 3,37 (1H, d, J=14.4 Hz), 3,57-3,70 (1H, m), 3,61 (3H, s), 3,74 (2H, s), 3,82-to 3.99 (1H, m)to 3.89 (3H, s), 4,46 (1H, d, J=14.4 Hz), x 6.15 (1H, s), 6,59 (1H, s), 6,92-7,02 (1H, m), 7,13-of 7.23 (2H, m), 7,25-7,40 (3H, m).

Example 106

3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-5-yl)propionic acid

In a manner similar to the method of example 105, the received specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), was 1.04 (3H, s), 2,17-to 2.41 (2H, m), 2,62 (2H, t, J=7.2 Hz), 2.95 and-3,21 (5H, m)to 3.36 (1H, d, J=14.4 Hz), 3,607 (3H, s)3,612 (1H, d, J=11.7 Hz), 3,88 (3H, s), 3,84-of 3.94 (1H, m), of 4.44 (1H, d, J=14.4 Hz), 6,14 (1H, s), 6,60 (1H, d, J=1,8 Hz), 6,98 (1H, DD, J=2,4, 6.9 Hz), 7,13-7,22 (2H, m), 7,26 -7,40 (3H, m).

Example 107

2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazole-5-carboxylic acid

In a manner similar to the method of example 105, the received specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.06 (3H, s), 2,20-of 2.50 (2H, m), is 3.08-of 3.32 (2H, m), 3,17 (1H, d, J=11,4 Hz), 3,37 (1H, d, J=14.4 Hz), 3,62 (3H, s), 3,63 (1H, d, J=11.4 in Hz)to 3.89 (3H, s), of 3.95 (1H, DD, J=5,1, 7.5 Hz,), 4,48 (1H, d, J=14.4 Hz), 6,16 (1H, s), is 6.61 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=3.0 a, and 6.6 Hz), 7,13-of 7.23 (2H, m), 7,29 (1H, d, J=8.7 Hz), 7,35 (1H, DD, J=,1, to 8.7 Hz), of 8.27 (1H, s).

Example 108

2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazole-4-carboxylic acid

In a manner similar to the method of example 105, the received specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,22-of 2.50 (2H, m), 3,06-to 3.38 (2H, m), 3,17 (1H, d, J=11,4 Hz), 3,37 (1H, d, J=14.1 Hz), 3,61 (3H, s), 3,62 (1H, d, J=11.4 in Hz)to 3.89 (3H, s), of 3.95 (1H, DD, J=5,4, 7.5 Hz,), to 4.46 (1H, d, J=14.1 Hz), x 6.15 (1H, s), 6,60 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=2,4, 7.5 Hz), 7,10-of 7.23 (2H, m), 7,31 (1H, d, J=8,4 Hz), was 7.36 (1H, DD, J=2,1, 8,4 Hz), 8,10 (1H, s).

Example 109

(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)acetic acid

In a manner similar to the method of example 105, the received specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,18 at 2.45 (2H, m), 3,03-3,30 (3H, m)to 3.38 (1H, d, J=14.4 Hz), 3,617 (3H, s)3,618 (1H, d, J=11.7 Hz), of 3.77 (2H, d, J=1.2 Hz), with 3.89 (3H, s), 3,93 (1H, DD, J=5,4, 7.5 Hz,), 4,47 (1H, d, J=14.4 Hz), 6,16 (1H, s), is 6.61 (1H, d, J=2.1 Hz), to 6.95 (1H, t, J=1.2 Hz), 6,95-7,01 (1H, m), 7,16-of 7.23 (2H, m), 7,31 (1H, d, J=8,4 Hz), was 7.36 (1H, DD, J=2,1, 8,4 Hz).

Example 110

2-{2-[(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-yl]ethyl}-1,3-thiazole-5-carboxylic acid

Way is, similar to the method of example 14 had been specified in the header of the connection.

1H-NMR (CD3OD) δ: 0,98 (3H, s), 0,99 (3H, s)to 1.98 (3H, s), 1,90-of 2.23 (2H, m), 2,90-3,20 (2H, m)to 3.58 (3H, s), 3,60-to 3.92 (3H, m), a 3.87 (3H, s), of 4.45 (1H, d, J=14.1 Hz), 4.75 V-the 4.90 (1H, m), of 6.20 (1H, s), 6,51 (1H, d, J=2.1 Hz), 6,99-7,21 (3H, m), 7,35-7,45 (1H, m), 7,54 (1H, d, J=9.0 Hz), of 7.90 (1H, s).

Example 111

3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)-3-hydroxypropionic acid

In a manner similar to the method of example 18, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,18-to 2.42 (2H, m), 2,73-2,82 (1H, m), 2,82-2,96 (2H, m)3,00-up 3.22 (2H, m)and 3.15 (1H, d, J=12.0 Hz), 3,37 (1H, d, J=13,8 Hz), 3,61 (3H, s), 3,62 (1H, d, J=12.0 Hz), 3,89 (3H, s), 3,90-4,01 (1H, m), 4,47 (1H, d, J=13,8 Hz), 5,10-5,17 (1H, m), x 6.15 (1H, s), 6,60 (1H, d, J=2.1 Hz), 6,95-7,01 (1H, m), 7,07 (1H, s), 7,15-7,21 (2H, m), 7,31 (1H, d, J=8.7 Hz), was 7.36 (1H, DD, J=for 2.1, 8.7 Hz).

Example 112

(2E)-3-(2-{2-[3R,5S]-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl}ethyl)-1,3-thiazol-4-yl)acrylic acid

In a manner similar to the method of example 19 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.06 (3H, s), 2,20 is 2.43 (2H, m), 3,05-3,24 (3H, m)to 3.38 (1H, d, J=14.4 Hz), 3,62 (3H, s), 3,60 at 3.69 (1H, m), of 4.05 (1H, DD, J=5,7, 7,2 Hz), 4,47 (1H, d, J=14.4 Hz), 6,16 (1H, s), 6,59 (1H, d, J=15.3 Hz), 6,60 (1H, d, J2,4 Hz), 6,98 (1H, DD, J=2,7, and 6.6 Hz), 7,14-7,29 (3H, m), 7,32 (1H, d, J=8.7 Hz), 7,37 (1H, DD, J=2,4, and 8.4 Hz), 7,58 (1H, d, J=15.3 Hz).

Example 113

3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)propionic acid

In a manner similar to the method of example 88, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,20-to 2.42 (2H, m), 2,60-of 2.75 (2H, m), 2,90-of 3.25 (3H, m)to 3.38 (1H, d, J=14,7 Hz)3,619 (3H, s)3,624 (1H, d, J=11.7 Hz), with 3.89 (3H, s), of 3.96 (1H, DD, J=5,4 and 6.9 Hz), 4,48 (1H, d, J=14,7 Hz), 6,16 (1H, s), is 6.61 (1H, d, J=1,8 Hz), to 6.80 (1H, s), of 6.96-7.03 is (1H, m), 7,17-of 7.23 (2H, m), 7,27-7,40 (2H, m).

Example 114

3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)-3-methylbutanoate acid

In a manner similar to the method of example 16, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.06 (3H, s)to 1.38 (3H, s)of 1.39 (3H, s), 2,20-to 2.42 (2H, m)to 2.67 (1H, d, J=15,0 Hz), 3,10-to 3.35 (3H, m)to 3.41 (1H, d, J=14,7 Hz), 3,62 (3H, s), 3,63 (1H, d, J=11.7 Hz), 3,90 (3H, ), of 3.96 (1H, t, J=5,GC), 4,48 (1H, d, J=14,7 Hz), 6,16 (1H, s), is 6.61 (1H, s), make 6.90 (1H, s), 7,00 (1H, DD, J=2,1, 7,8 Hz), 7,14-7,22 (2H, m), 7,30-7,40 (2H, m).

Example 115

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,3-thiazol-4-yl)acetic acid

(1) the Solution of the complex with pyridine-sulfur trioxide (USD 5.76 g, and 36.2 mmol) in DMSO (18 ml) was added dropwise to a solution of (3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ethanol (3,66 g of 7.23 mmol)obtained in example 50-(1)in dichloromethane (70 ml). After stirring at room temperature for 1.5 hours was added water (15 ml). After extraction with dichloromethane (150 ml) the organic layer washed with 5% aqueous solution of potassium hydrosulfate, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride and then dried over magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (2:1)] and then washed with a mixture of 2-propanol-hexane to obtain 3-[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-3-(2-oxoethyl)-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (2,39 g, 4,74 mmol, 66%) as a white crystal.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s)2,03 (3H, s), 2,86 (1H, DDD, J=1,2, 5,4, and 17.7 Hz), to 3.09 (1H, DDD, J=1,2, 6,9, and 17.7 Hz), 3,55 (1H, d, J=14.4 Hz), 3,62 (3H, s), of 3.73 (1H, d, J=11,1 Hz), 3,86 (1H, d, J=Hz 11,1), the 3.89 (3H, s), 4,42 (1H, DD, J=5,4 and 6.9 Hz), 4,56 (1H, d, J=14.1 Hz), 6,28 (1H, s), of 6.66 (1H, d, J=1,8 Hz), of 6.96-7,01 (1H, m), 7,15-of 7.23 (2H, m), 7,28-7,40 (2H, m), 9,81 (1H, Shir).

(2) a Solution of 3-[(3R,5S)-7-chloro-5-(2,3-dimethoxy enyl)-2-oxo-3-(2-oxoethyl)-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (2.0 g, of 3.97 mmol)obtained in example 115-(1)in dichloromethane (25 ml) was added dropwise to a solution of tert-butyldimethylsilyloxy (0,59 g of 4.17 mmol), potassium cyanide (44 mg, of 0.68 mmol) and 18-crown-6-ether (0,42 g of 1.59 mmol) in dichloromethane (25 ml) under nitrogen atmosphere. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (41:9-3:1)] to obtain 3-[(3R,5S)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-Tianeti)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (1,96 g, 3.04 from mmol, 77%) in the form of a white crystal.

1H-NMR (CDCl3) δ: 0,04 (3H, s), 0,14 (3/2H, s)0,15 (3/2H, s)0,68 (9/2H, s)0,79 (9/2H, s), 0,95 (3/2H, s)0,96 (3/2H, s)2,03 (3H, s), 2,18 at 2.45 (2H, m), 3,52 (1H, d, J=14.1 Hz), 3,62 (3H, ), to 3.73 (1/2H, d, J=11,1 Hz), 3,74 (1/2H, d, J=11,1 Hz), 3,98-4,16 (1H, m), 4,55 (1/2H, d, J=14.1 Hz), 4,56 (1/2H, d, J=14.1 Hz), br4.61 was 4.76 (1H, m), of 6.26 (1H, s), 6,99 (1/2H, d, J=2.7 Hz), 7,01 (1/2H, d, J=2.7 Hz), 6,95-7,02 (1H, m), 7,10-7,39 (4H, m).

(3) Diphenylmethylphosphine acid (0.39 g, 1.55 mmol) was added to a solution of 3-[(3R,5S)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-Tianeti)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (0.5 g, 0.78 mmol)obtained in example 115-(2), isopropyl alcohol (10 ml) and the mixture was stirred at 60°C for 14 hours. The mixture was cooled whom to room temperature and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (41:9-3:1)] to obtain 3-[(3R,5S)-3-(3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-3-tioxaprofen)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (0,48 g, 0.71 mmol, 91%) as a white crystal.

1H-NMR (CDCl3) δ: -0,06 (3/2H, s)-0,02 (3/2H, s)0,03 (3/2H, s)0,04 (3/2H, s)0,76 (9/2H, s)0,81 (9/2H, s)0,94 (3/2H, s), 0,95 (3/2H, s)of 1.03 (3H, s)2,03 (3H, s), 2,01-of 2.20 (1H, m), 2,39-2,60 (1H, m), 3,51 (1/2H, d, J=14.1 Hz), 3,52 (1/2H, d, J=14.1 Hz), of 3.60 (3H, s), 3,69-of 3.78 (1H, m), 3,84 (1/2H, d, J=10,8 Hz), 3,85 (1/2H, d, J=10,8 Hz)to 3.89 (3H, s)4,08 (1/2H, DD, J=6,0, 10.5 Hz), 4,29 (1/2H, t, J=6.6 Hz), 4,54 (1/2H, d, J=14.1 Hz), 4,56 (1/2H, d, J=14.1 Hz), 4,63 (1/2H, t, J=6.6 Hz), 4.72 in (1/2H, DD, J=4,5, and 9.0 Hz), and 6.25 (1H, s), 6,60 is 6.67 (1H, m), 6,95-7,01 (1H, m,), 7,14-the 7.43 (5H, m).

(4) a Solution of 3-[(3R,5S)-3-(3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-3-tioxaprofen)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (0,42 g of 0.62 mmol)obtained in example 115-(3), and ethyl 4-chloro-3-oxobutanoate (84 μl, of 0.62 mmol) in ethanol (10 ml) was stirred at 80°C for 32 hours. Allowing the solution to stand for cooling, was added water (5 ml) and the mixture was extracted with ethyl acetate (130 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified is column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (41:9-3:1)] to obtain ethyl (2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}-1,3-thiazol-4-yl)acetate (0.18 g, 0.28 mmol, 45%) as a white crystal.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)of 1.26 (3H, t, J=7.2 Hz), 2,25-2,48 (1H, m), 2,50-2,70 (1H, m)and 3.15 (1H, t, J=11,1 Hz)to 3.38 (1H, d, J=14.4 Hz), 3,54-3,70 (1H, m), 3,62 (3/2H, s), 3,64 (3/2H, s), 3,74 (1H, in), 3.75 (1H, s)to 3.89 (3H, s), 3,99 (1/2H, DD, J=4.2, and to 11.1 Hz), 4,07 (1/2H, DD, J=4.2, and to 11.1 Hz), 4,10-4,30 (3H, m), 4,47 (1/2H, d, J=14.4 Hz), 4,50 (1/2H, d, J=14.4 Hz), 5,11-5,23 (1H, m), 6,18 (1/2H, s), to 6.19 (1/2H, s), 6,61 (1/2H, d, J=2.1 Hz), 6,63 (1/2H, d, J=2.1 Hz), 6,94-7,02 (1H, m), 7,095 (1/2H, s)7,103 (1/2H, s), 7,14-7,40 (4H, m).

(5) manganese Dioxide (0.2 g of 2.38 mmol) was added to a solution of ethyl (2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}-1,3-thiazol-4-yl)acetate (0.15 g, 0.24 mmol)obtained in example 115-(4), in THF (5 ml) and the mixture was stirred at 70°C for 4 days. Allowing the mixture to stand for cooling, was filtered insoluble substance by means of Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:1-2:1)] to obtain ethyl (2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,3-thiazol-4-yl)acetate (71 mg, 0.11 mmol, 48%) as a white crystal.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)of 1.29 (3H, t, J=6.9 Hz), 3,14 (1H, t, J=10.5 Hz), to 3.41 (1H, d, J=14.4 Hz), to 3.58 (1H, DD, J=4,8, and 18.3 Hz), 3,56 at 3.69 (1H, m), 3,62 (3H, s), 3,89 (H, C)3,98 (1H, DD, J=8,1, and 18.3 Hz), 4,15 (1H, DD, J=3,9, and 10.8 Hz), 4,20 (2H, q, J=6.9 Hz), 4,49 (1H, d, J=14.4 Hz), 4,60 (1H, DD, J=4,8, 8.1 Hz), 6,18 (1H, s), 6,63 (1H, s), 6,95-7,01 (1H, m), 7,15-7,22 (2H, m)that was 7.36-the 7.43 (2H, m), EUR 7.57 (1H, s).

(6) a Solution of ethyl (2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,3-thiazol-4-yl)acetate (60 mg, 0.10 mmol)obtained in example 115-(5), and potassium carbonate (26 mg, 0.20 mmol) in ethanol (3 ml) and water (0.5 ml) was boiled under reflux for 5 hours under stirring. Allowing to stand for cooling, and the mixture was acidified using 1 N. aqueous hydrochloric acid (1 ml) and was extracted with ethyl acetate (70 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained crystal was washed with a mixture of ethyl acetate-hexane and then dried under reduced pressure to obtain (2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,3-thiazol-4-yl)acetic acid (40 mg, 0.07 mmol, 70%) as a pale yellow crystal.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), and 3.16 (1H, d, J=12.0 Hz), to 3.41 (1H, d, J=14.1 Hz), of 3.54 (1H, DD, J=4,8, and 18.3 Hz), 3,61 (3H, s), 3,62 (1H, d, J=12.0 Hz), 3,88 (3H, s)to 3.99 (1H, DD, J=8,4, and 18.3 Hz), 4,47 (1H, d, J=14.1 Hz), 4,60 (1H, DD, J=4,8, and 8.4 Hz), 6,16 (1H, s), 6,62 (1H, d, J=2.7 Hz), 6,93-7,00 (1H, m), 7,10-7,20 (2H, m), 7,33-7,42 (2H, m), 7,55 (1H, s).

p> Example 116

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,3-thiazol-5-yl)propionic acid

In a manner similar to the method of example 115, received specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), was 2.76 (2H, t, J=7.2 Hz), 3,14 (1H, d, J=12.0 Hz), 3,23 (1H, t, J=7.2 Hz), to 3.41 (1H, d, J=15,0 Hz), of 3.54 (1H, DD, J=4,8 and 18.0 Hz), 3,61 (3H, s), 3,62 (1H, d, J=12.0 Hz), the 3.89 (3H, s), of 3.95 (1H, DD, J=8,4 and 18.0 Hz), 4,48 (1H, d, J=15,0 Hz), 4,58 (1H, DD, J=4,8, and 8.4 Hz), 6,17 (1H, s), 6,62 (1H, s), 6,95-7,01 (1H, m), 7,13-7,20 (2H, m), 7,38-7,42 (2H, m), 7,74 (1H, s).

Example 117

(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}-1,3-thiazol-4-yl)acetic acid

A mixture of ethyl (2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}-1,3-thiazol-4-yl)acetate (0.25 g, 0.40 mmol)obtained in example 115-(4), 1 N. aqueous sodium hydroxide solution (1 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours. The mixture was acidified using 1 N. aqueous hydrochloric acid (1.2 ml) and then extracted with ethyl acetate (35 ml). The extract obtained was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then what was koncentrirebuli under reduced pressure to obtain (2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}-1,3-thiazol-4-yl)acetic acid (0.24 g, 0.40 mmol, sec.) in the form of a colorless non-crystalline powder.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s), 2,30-2,70 (2H, m), 3,17 (1H, t, J=11.7 Hz), 3,40 (1H, d, J=14.4 Hz), 3,61 (1H, d, J=11.7 Hz), 3,63 (3H, s), with 3.79 (2H, s), 3,90 (3H, s), 4,19-4,32 (1H, m), 4,48 (1/3H, d, J=14.4 Hz), 4,50 (2/3H, d, J=14.4 Hz), 5,20-and 5.30 (1H, m), 6,18 (2/3H, s), 6,21 (1/3H, s), 6,62 (2/3H, d, J=2.4 Hz), 6,67 (1/3H, d, J=2.4 Hz), 6,98-7,03 (1H, m), 7,07 (1H, s), 7,15-of 7.23 (2H, m), 7,30-7,42 (2H, m).

Example 118

3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-1-hydroxyethyl}-1,3-thiazol-5-yl)propionic acid

In a manner similar to the method of example 117, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s), was 1.04 (3H, s), 2,13-to 2.41 (2H, m), 2,50-2,60 (1H, m), 2,61 (2H, t, J=7.5 Hz), 3,10 (2H, t, J=7.5 Hz), 3,10-3,10 (1H, m), 3,39 (1/2H, d, J=13,8 Hz), 3,40 (1/2H, d, J=13,8 Hz), 3,57-to 3.64 (1H, m), 3,62 (3H, s), 3,90 (3H, s), 4,19-4,30 (1H, m)4,466 (1/2H, d, J=13,8 Hz)4,474 (1/2H, d, J=13,8 Hz), 5,01-5,20 (1H, m), 6,17 (1/2H, s), to 6.19 (1/2H, s), 6,58-6,63 (1H, m), 6,95-7,02 (1H, m), 7,15-7,30 (2H, m), 7,31-the 7.43 (3H, m).

Example 119

(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-2-thienyl)acetic acid

DMF (1 drop) and thionyl chloride (0,42 ml, 5,77 mmol) was added dropwise to a solution of 2-[(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-luxusni acid (2.5 g, to 4.81 mmol) in THF (25 ml) at room temperature. The mixture was stirred for 4 hours and then concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (30 ml). To the solution was added dropwise ethyl 2-thiopheneacetic (0,69 ml of 4.57 mmol) and tin chloride (1,24 ml, 10.6 mmol) under cooling with ice. The mixture was heated to room temperature and was stirred for 13 hours. The reaction solution was poured into ice water and was extracted with dichloromethane (170 ml). The organic layer was washed 1 N. aqueous hydrochloric acid, water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (1:1-3:7)] to obtain ethyl (5-{[(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-yl]acetyl}-2-thienyl)acetate as a mixture with impurities. The resulting mixture was dissolved in ethanol (7 ml) and water (1 ml), was added potassium carbonate (86 mg, 0,63 mmol) and the mixture is then boiled under reflux for 2 hours under stirring. Allowing the mixture to stand for cooling, it is acidified 1 N. aqueous hydrochloric acid (1.5 ml) and then extracted with ethyl acetate (35 ml). The organic layer was washed n is sasenum aqueous solution of sodium chloride, was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified preparative liquid chromatography [manifesting solvent: water-acetonitrile (9:1 to 5:95)] to obtain (5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-2-thienyl)acetic acid (52 mg, 0.09 mmol, 2% (stage 2)in the form of pale-yellow non-crystalline powder.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 3,19 (1H, d, J=11.7 Hz), or 3.28 (1H, DD, J=4,5, a 16.8 Hz), to 3.41 (1H, d, J=14.1 Hz), 3,61 (3H, s)to 3.64 (1H, d, J=11.7 Hz), 3,70 (1H, DD, J=8,1, is 16.8 Hz), with 3.89 (5H, s), 4,45 (1H, d, J=14.1 Hz), 4,58 (1H, DD, J=4,5, 8.1 Hz), 6,17 (1H, s), 6,62 (1H, s), 6,95-7,10 (2H, m), 7,11-7,20 (2H, m), 7,35-7,41 (2H, m), 7,66 (1H, d, J=3.6 Hz).

Example 120

4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-5-carboxylic acid

In a manner similar to the method of example 26, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s)and 3.15 (1H, d, J=12.0 Hz), 3,40 (1H, d, J=14.4 Hz), of 3.60 (3H, s), the 3.65 (1H, d, J=12.0 Hz in), 3.75 (2H, DD, J=1,5, and 6.6 Hz), 3,88 (3H, s), 4,48 (1H, d, J=14.4 Hz), 4,55 (1H, t, J=6.6 Hz), 6,18 (1H, s), 6,55 (1H, s), of 6.96 (2H, DD, J=2,7, and 7.8 Hz), 7,13 (1H, t, J=7.8 Hz), 7,32-7,40 (2H, m), 8,71 (1H, s).

Example 121

(2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin the-3-yl]propyl}-1,3-thiazol-5-yl)acetic acid

(1) Ethyl(diethoxyphosphoryl)acetate (4,76 ml, 24 mmol) was added dropwise to a suspension of sodium hydride (0.88 g, 22 mmol) in THF (108 ml) at 0°C. After stirring for 30 minutes was added 3-[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-3-(2-oxoethyl)-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (10.8 g, 20 mmol). After stirring for 1 hour, the mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl (2E)-4-[(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-yl]-2-butenoate (11,5 g, 20 mmol, 100%).

1H-NMR (CDCl3) δ: of 0.95 (3H, s) of 1.03 (3H, s) of 1.28 (3H, t, J=7,06 Hz) 2,03 (3H, s) to 2.74 (2H, m) of 3.53 (1H, d, J=14,13 Hz) 3,62 (3H, s) 3,86 (6H, m) 4,18 (2H, q, J=7,16 Hz) 4,56 (1H, d, J=14,13 Hz) 5,90 (1H, d, J=15,64 Hz) of 6.26 (1H with) only 6.64 (1H, m, J=2.26 and Hz) to 6.95 (2H, m), 7,27 (4H, m).

(2) Ethyl (2E)-4-[(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-yl]-2-butenoate (15 g) and 26.1 mmol)obtained in example 121-(1)was dissolved in methanol (150 ml), to the solution was added magnesium (3,17 g, 131 mmol) and the mixture was stirred within 3 hours. The reaction solution was diluted uh what razetto, washed with 1 N. aqueous hydrochloric acid, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (150 ml), was added 1 N. aqueous sodium hydroxide solution (52 ml) and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in water and washed with ether. The aqueous layer was acidified using 1 N. aqueous hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml), the solution was added pyridine (6,46 ml, 80 mmol) and acetylchloride (to 4.98 ml, 70 mmol) and the mixture was stirred for 1 hour. After adding water (50 ml), the reaction solution was stirred for 4 hours and then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 4-[(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-yl]butane acid (10,9 g of 19.8 mmol, 76%).

1H-NMR (CDCl3) δ: of 0.94(3H, C) of 1.02 (3H, s) of 1.56 is 2.00 (4H, m) 2,03 (3H, s) is 2.37 (2H, t, J=7,16 Hz) 3,51 (1H, d, J=14,13 Hz) 3,61 (3H, s) 3,70-to 3.92 (6H, m) 4,56 (1H, d, J=14,13 Hz) 6,24 (1H, s) 6,63 (1H, d, J=2.26 and Hz) 6,98 (1H, DD, J=7,54, and 2.26 Hz) 7,15-7,37 (4H, m).

(3) Isobutylbarbituric (0,55 ml, 4.20 mmol) was added to a solution of 4-[(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-yl]butane acid (2.0 g, 3.65 mmol), poluchennoi in example 121-(2), and triethylamine (of 0.53 ml, a 3.83 mmol) in dimethylacetamide (20 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. To the reaction solution at 0°C was added the hydrochloride 4-amino-3-oxobutanoic acid (0.71 g, 4.02 mmol)obtained in example 1-(2), and then was added dropwise pyridine (0,47 ml of 5.84 mmol).

After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate. The resulting mixture was washed with 1 N. aqueous hydrochloric acid, 5% aqueous solution of potassium hydrosulfate, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in THF (20 ml), to the solution was added a reagent Lesson (1.8 g, of 4.44 mmol) and the mixture was stirred at 70°C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated aqueous chloride is the atrium, was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in ethanol (20 ml), was added 1 N. aqueous sodium hydroxide solution (10 ml) and the mixture was stirred for 4 hours. The aqueous layer was acidified with 5% aqueous solution of potassium hydrosulfate and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the title compound (1.0 g, of 1.66 mmol, 43%).

1H-NMR (DMSO-d6) δ: 0,76 (3H, s) of 0.83 (3H, s) 1,63 is 1.86 (4H, m) 2,90 (2H, t, J=6, 78 Hz) 3,02-3,20 (2H, m) 3,51 (3H, s) to 3.64 (1 H, d, J=14,13 Hz) of 3.78-a 3.87 (m, 5H) OR 4.31 (1H, d, J=14,13 Hz) a 4.53 (1H, t, J=5,09 Hz) equal to 6.05 (1H, ) 6,38 (1f d, J=2,45 Hz) to 7.15 (2H, d, J=to $ 7.91 Hz) 7,21-7,28 (1H, m) 7,41 (1H, s) 7,51 (1H, DD, J=8,76, of 2.54 Hz) 7,66 (1H, d, J=cent to 8.85 Hz).

Example 122

3-(2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,3-thiazol-5-yl)propionic acid

In a manner similar to the method of example 121, received specified in the header of the connection.

1H-NMR (DMSO-d6) δ: of 0.75 (3H, s) of 0.83 (3H, s) 1,59-of 1.88 (4H, m) 2,48 at 2.59 (2H, m) 2,83-3,20 (6N, m) 3,51 (3H, s) to 3.64 (1H, d, J=14,13 Hz) of 3.78-3,86 (4H, m) or 4.31 (1H, d, J=14,13 Hz) a 4.53 (1H, t, J=5,09 Hz) equal to 6.05 (1H, s) 6,37 (1H, d, J=2,45 Hz) 7,11-7,28 (m, 3H) 7,51 (1H, DD, J=8,67, of 2.45 Hz) 7,66 (1H, d, J=cent to 8.85 Hz).

p> Example 123

(2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]propyl}-1,3-thiazol-4-yl)acetic acid

(1) Diethylenetriamine (3,88 ml, 24 mmol) was added dropwise to a suspension of sodium hydride (0.88 g, 22 mmol) in THF (108 ml) at 0°C. After stirring for 30 minutes was added 3-[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-3-(2-oxoethyl)-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (10.8 g, 20 mmol). After stirring for 1 hour the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (105 ml)was added magnesium (2.4 g, 100 mmol) and the mixture was stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with 1 N. aqueous hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (68 ml), was added triethylamine (3,69 ml of 26.6 mmol) and acetylchloride (1,51 ml and 21.2 mmol) and the mixture was stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous Hydra is sodium carbonate and saturated aqueous sodium chloride, was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with 3-[(3R,5S)-7-chloro-3-(3-lanprobe)-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (5.5 g, 10.4 mmol, 52%).

1H-NMR (CDCl3) δ: of 0.94 (3H, s) of 1.02 (3H, s) of 1.66-2,41 (N, m) 3,47-3,93 (10H, m) 4,56 (1H, d, J=14,13 Hz) and 6.25 (1H, s) only 6.64 (1H, d, J=2.26 and Hz) of 6.99 (1H, DD, J=7,25, 2.35 Hz) 7,14-7,39 (4H, m).

(2) 3-[(3R,5S)-7-chloro-3-(3-lanprobe)-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (5,3 g, 10 mmol)obtained in example 123-(1), was dissolved in 4 BC, the hydrochloric acid - ethyl acetate (53 ml). To the resulting solution was added O,O'-diacylhydrazines (2,01 ml, 12 mmol) and the mixture was stirred over night. The reaction solution was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 2-[(3R,5S)-3-(4-amino-4-tikabali)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-1,1-dimethylethylamine (2.8 g, equal to 4.97 mmol, 50%).

MC (ES+) [M+1] 563.

(3) 2-[(3R,5S)-3-(4-Amino-4-tikabali)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-1,1-dimethylethylamine (0,563 g, 1.0 mmol)obtained in example 123-(2), was dissolved in ethanol (10 ml). To a solution of relax is whether ethyl 4-chloro-3-oxobutanoate (0,243 ml, 1.8 mmol) and the mixture was stirred at 90°C for 2 hours. After cooling the reaction solution to room temperature, was added 1 N. aqueous sodium hydroxide solution (5 ml) and the mixture was stirred for 5 hours. The aqueous layer was acidified with 5% aqueous solution of potassium hydrosulfate and then was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the title compound (0.3 g, 0,498 mmol, 50%).

1H-NMR (DMSO-d6) δ: 0,76 (3H, s) of 0.83 (3H, s) 1,63 is 1.86 (4H, m) 2,90 (2H, t, J=6,78 Hz) 3,02-3,20 (2H, m) 3,51 (3H, s) to 3.64 (1H, d, J=14,13 Hz) of 3.78-a 3.87 (5H, m) or 4.31 (1H, d, J=14,13 Hz) a 4.53 (1H, t, J=5,09 Hz) equal to 6.05 (1H, s) 6,38 (1H, d, J=2,45 Hz) to 7.15 (2H, d, J=to $ 7.91 Hz) 7,21-7,28 (1H, m) 7,41 (1H, s) 7,51 (1H, DD, J=8,76, of 2.54 Hz) 7,66 (1H, d, J=cent to 8.85 Hz).

Example 124

2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,3-thiazole-4-carboxylic acid

In a manner similar to the method of example 123, has been specified in the header of the connection.

1H-NMR (DMSO-d6) δ: of 0.75 (3H, s) of 0.83 (3H, s) 1,67-1,89 (4H, m) 2,94-3,19 (4H, m) 3,51 (3H, s) to 3.64 (1H, d, J=13,94 Hz) of 3.78-3,88 (4H, m) or 4.31 (1H, d, J=14,13 Hz) to 4.52 (1H, t, J=5,27 Hz) equal to 6.05 (1H, s) 6,37 (1H, d, J=2,45 Hz) 7,12-7,28 (3H, m) to 7.50 (1H, DD, J=8,76, of 2.54 Hz) 7,66 (1H, d, J=cent to 8.85 Hz).

Por the measures 125

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-methyl-1,3-thiazol-5-yl)propionic acid

In a manner similar to the method of example 1 has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), of 2.28 (3H, s)of 2.64 (2H, t, J=7,6 Hz), to 3.02 (2H, t, J=7,6 Hz), 3,31-3,44 (2H, m), 3,52 (1H, DD, J=to 15.0, 6.0 Hz), 3,63 (3H, s)to 3.89 (3H, s), 4,24-4,30 (1H, m), 4,51 (1H, d, J=13,8 Hz), of 6.31 (1H, s), to 6.57 (1H, d, J=2.1 Hz), 6,97 (1H, DD, J=6,6, and 3.2 Hz), 7,14-7,22 (2H, m), 7.24 to 7,33 (2H, m).

Example 126

2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-methyl-1,3-thiazole-5-carboxylic acid

In a manner similar to the method of example 16, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 2,68 (3H, s)to 3.36 (1H, d, J=a 13.9 Hz), 3,47 (1H, DD, J=15,0, 6.9 Hz), 3,55-3,66 (4H, m)to 3.89 (3H, s), 4,32 (1H, t, J=6.4 Hz), to 4.52 (1H, d, J=a 13.9 Hz), 6,33 (1H, s), 6,59 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=7,5, and 2.3 Hz), 7,13-of 7.23 (2H, m), 7,28-to 7.35 (2H, m).

Example 127

2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazole-4-carboxylic acid

In a manner similar to the method of example 22, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s)to 3.35 (1H, d, J=a 13.9 Hz), 3,50 at 3.69 (5H, m)to 3.89 (3H, s), 4,34(1H, t, J=6.4 Hz), 4,50 (1H, d, J=a 13.9 Hz), 6,33 (1H, s), to 6.58 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=8.0 a, and 1.4 Hz), 7,07 for 7.12 (1H, m), 7,18 (1H, t, J=7.9 Hz), 7,25-to 7.35 (2H, m), 8,19 (1H, s).

Example 128

(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-4-yl)acetic acid

In a manner similar to the method of example 16, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s)to 3.38 (1H, d, J=a 13.9 Hz), 3,48 (1H, DD, J=15,3, and 6.6 Hz), 3,60-and 3.72 (4H, m), with 3.79 (2H, s)to 3.89 (3H, s), 4,34 (1H, t, J=6.5 Hz), 4,49 (1H, d, J=a 13.9 Hz), 6,33 (1H, s), 6,60 (1H, s), of 6.99 (1H, DD, J=6,9, 2,9 Hz), 7,02 (1H, s), 7,13-of 7.23 (2H, m), 7,33 (2H, s).

Example 129

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-5-methyl-1,3-thiazol-4-yl)propionic acid

In a manner similar to the method of example 20, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 2,32 (3H, s), 2,66-by 2.73 (2H, m), 2,82-2,90 (2H, m), 3.33 and-3,44 (2H, m)to 3.58 (1H, DD, J=16,2, and 6.6 Hz), 3,63 (3H, s)to 3.89 (3H, s), 4,27 (1H, t, J=6.4 Hz), 4,49 (1H, d, J=a 13.9 Hz), of 6.31 (1H, s), 6,60 (1H, s), of 6.99 (1H, DD, J=5,8, and 3.8 Hz), 7,15-of 7.23 (2H, m), 7,31-7,39 (2H, m, J=1.9 Hz).

Example 130

2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3-5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazole-4-carboxylic acid

In a manner similar to the method of example 22, was received is specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 2,22-2,49 (2H, m), is 3.08-of 3.32 (2H, m), 3,35 (1H, d, J=a 13.9 Hz), 3,63 (3H, s), 3,90 (3H, s), of 3.94 (1H, DD, J=7,5, at 5.3 Hz), 4,50 (1H, d, J=13,8 Hz), 6,28 (1H, s), is 6.61 (1H, d, J=2.3 Hz), 6,95-7,03 (1H, m), 7,16-7,24 (2H, m), 7,25-7,37 (2H, m), 8,11 (1H, s).

Example 131

3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)propionic acid

In a manner similar to the method of example 88, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 2,18 is 2.44 (2H, m), 2,64-to 2.74 (2H, m), 2,94-3,03 (2H, m), 3.04 from-with 3.27 (2H, m)to 3.36 (1H, d, J=a 13.9 Hz), 3,63 (3H, s)to 3.89 (3H, s), of 3.94 (1H, DD, J=7,3, 5.7 Hz), to 4.52 (1H, d, J=a 13.9 Hz), 6,28 (1H, s), 6,60 (1H, d, J=2.1 Hz), to 6.80 (1H, s), of 6.99 (1H, DD, J=7,0, 2.6 Hz), 7,16 and 7.36 (4H, m).

Example 132

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-4-methyl-1,3-oxazol-5-yl)propionic acid

In a manner similar to the method of example 29, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s), is 2.05 (3H, s), 2.63 in (2H, t), is 2.88 (2H, t, J=7.4 Hz), 3,16-of 3.32 (2H, m)to 3.36 (1H, d, J=13,8 Hz), 3,62 (3H, s), 3,88 (3H, s), to 4.38 (1H, t, J=6.8 Hz), 4,51 (1H, d, J=a 13.9 Hz), 6,30 (1H, s), to 6.57 (1H, d, J=1.5 Hz), of 6.96 (1H, DD, J=8,1, 1.3 Hz), 7,03 (1H, DD, J=7,8, 1.2 Hz), 7,16 (1H, t, J=7.9 Hz), 7,27 was 7.36 (2H, m).

Example 133

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-and the]methyl}-5-methyl-1,3-oxazol-4-yl)propionic acid

In a manner similar to the method of example 38, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s), 2,22 (3H, s), 2,59-of 2.72 (4H, m), 3,17 (1H, DD, J=16,0, 6.4 Hz), 3,31 is-3.45 (2H, m), 3,63 (3H, s)to 3.89 (3H, s), and 4.40 (1H, t, J=6.8 Hz), 4,48 (1H, d, J=a 13.9 Hz), 6,30 (1H, s), 6,59 (1H, d, J=2.1 Hz), 6,97 (1H, DD, J=7,9, 1.5 Hz), was 7.08 (1H, DD, J=7,7, 1.5 Hz), 7,16 (1H, t, J=7.9 Hz), 7,32-7,42 (2H, m).

Example 134

3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)propionic acid

In a manner similar to the method of example 60, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 2,89 (2H, t, J=7.2 Hz), 3,11-of 3.27 (4H, m), 3,34-3,44 (2H, m), to 3.58-to 3.67 (4H, m)to 3.89 (3H, s), 4,39-4,51 (2H, m), to 6.19 (1H, s), 6,60 (1H, d, J=1.7 Hz), 6,98 (1H, DD, J=8,0, 1,6 Hz), 7,07 for 7.12 (1H, m), 7,18 (1H, t, J=7.9 Hz), 7,32-7,41 (2H, m).

Example 135

4-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)butane acid

In a manner similar to the method of example 60, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s)of 1.05 (3H, s), 2,08-2,19 (3H, m), 2.49 USD (2H, t, J=7.2 Hz), 2,95 (2H, t, J=7,3 Hz), 3,12 of 3.28 (2H, m), 3,34-3,44 (2H, m), 3,59-to 3.67 (4H, m)to 3.89 (3H, s), to 4.41-to 4.52 (2H, m), of 6.20 (1H, C)6,60 (1H, d, J=1.5 Hz), 6,98 (1H, DD, J=8.0 a, 1,6 Hz), to 7.09 (1H, DD, J=7,8, and 1.4 Hz), 7,17 (1H, t, J=7.9 Hz), 7,35-7,38 (2H, m).

Example 136

5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid

(1) the Hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (23,0 g, 0,120 mol) and 1H-1,2,3-benzotriazol-1-Olathe ammonium (18,26 g, 0,120 mol) was added to a solution of [(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetic acid (46,19 g, 0,100 mol) in DMF (500 ml) and the mixture was stirred for 20 hours. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride and then dried over magnesium sulfate. After concentration under reduced pressure the residue was purified column chromatography on silica gel and then recrystallized from a mixture of ethyl acetate-hexane to obtain 2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ndimethylacetamide (32,43 g) in the form of a crystal.

1H-NMR (CDCl3) δ: 0,95 (N, C), 2,65-by 2.73 (1H, m), 2,84 of 2.92 (1H, m), 3,37 (1H, d, J=13,8 Hz), 3,62 (3H, s)to 3.89 (3H, s), 4,39 (1H, DD, J=7,3, 5,9 Hz), 4,50 (1H, d, J=a 13.9 Hz), 5,27 (1H, s), 5,86 (1H, s), 6,28 (1H with), is 6.61 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=6,7, 3.1 Hz), 7.18 in-of 7.23 (2H, m), 7,31 and 7.36 (2H, m).

(2) 1-1'-Carbonylbis-1H-imidazole (9,85 g, 0,mol) and allylbromide (20.7 ml, 0,243 mol) was added to a solution of 2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]ndimethylacetamide (14.0 g, 0,0304 mol)obtained in example 136-(1)in acetonitrile (140 ml) and the mixture is boiled under reflux for 3 hours. Allowing to stand for cooling, the reaction solution was extracted with ethyl acetate, washed with 1 N. aqueous hydrochloric acid and saturated aqueous sodium chloride and then dried over magnesium sulfate. The extract was filtered through silica gel and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate-hexane to obtain [(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetonitrile (12,31 g).

1H-NMR (CDCl3) δ: 0,95 (N, C), 2,78-is 2.88 (1H, m), 2,89-2,99 (1H, m)to 3.38 (1H, d, J=a 13.9 Hz), 3,63 (3H, s), 3,90 (3H, s), is 4.21 (1H, DD, J=7,6, 5.6 Hz), 4,51 (1H, d, J=a 13.9 Hz), 6,30 (1H, s), of 6.65 (1H, d, J=2.1 Hz), 7,01 (1H, d, J=7.9 Hz), 7,19-7,41 (4H, m).

(3) Triethylamine (23,66 ml, 0,169 mol) was added dropwise to a solution of hydroxylaminopurine (11,77 g, 0,169 mol) in DMSO (150 ml) under ice cooling and the mixture was stirred for 30 minutes. Precipitation was filtered. To the filtrate was added [(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetonitrile (15.0 g, 0,0339 mol)obtained in example 136-(2), and the mixture p is remedial at 80° C for 4 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-N'-hydroxyethylamide (17.5 g) as an amorphous substance, which was used in the next reaction without purification.

1H-NMR (CDCl3) δ: 0,95 (N, C), 2,56-of 2.64 (1H, m), and 2.79 (1H, DD, J=14,4, 7,1 Hz)to 3.36 (1H, d, J=a 13.9 Hz), 3,60-the 3.65 (3H, m)to 3.89 (3H, s), 4,07-to 4.14 (1H, m), 4,50 (1H, d, J=a 13.9 Hz), to 4.98 (2H, s), 6,25-of 6.29 (1H, m), 6,60 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J-5,9, 3,9 Hz), 7,16-of 7.23 (2H, m), 7,29-to 7.35 (2H, m).

(4) Triethylamine (0,83 ml, 5,95 mmol) and methyl 6-chloro-6-oxohexanoate (0,69 g of 3.85 mmol) was added dropwise to a solution of 2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-N'-hydroxyethylamide (1,67 g, 3.5 mmol)obtained in example 136-(3), THF (15 ml) under ice cooling and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, to the residue was added water (15 ml) and the mixture is boiled under reflux for 11 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over sulfate mA the deposits. After concentration under reduced pressure the residue was purified column chromatography on silica gel to obtain methyl 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentanoate (1.04 g).

1H-NMR (CDCl3) δ: 0,95 (N, C), 1,63 is 1.91 (4H, m), a 2.36 (2H, t, J=7.2 Hz), 2,87 (2H, t, J=7.4 Hz), 3,20-of 3.42 (3H, m), 3,62 (3H, s)to 3.67 (3H, s), 3,88 (3H, s), 4,43 (1H, t, J=6.8 Hz), 4,51 (1H, d, J=a 13.9 Hz), of 6.31 (1H, s), to 6.58 (1H, s), 6,97 (1H, DD, J=8.0 a, 1,6 Hz), 7,07 (1H, DD, J=7,7, 1.5 Hz), to 7.15 (1H, t, J=7.9 Hz), 7,29-7,37 (2H, m).

(5) 2 N. Aqueous sodium hydroxide solution (2,60 ml, 5,20 mmol) was added to a solution of methyl 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentanoate (1.04 g, of 1.73 mmol)obtained in example 136-(4), in ethanol (10 ml) and the mixture was stirred for 13 hours. The reaction solution was diluted with water and then washed with diethyl ether. The extract solution was acidified using 6 N. aqueous hydrochloric acid, was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadi the evil-5-yl)pentanol acid (0,89 g).

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 1,66-of 1.93 (4H, m), 2,39 (2H, t, J=7,3 Hz), is 2.88 (2H, t, J=7.4 Hz), 3,19-to 3.41 (3H, m), 3,62 (3H, s), 3,88 (3H, s), 4,43 (1H, t, J=6.8 Hz), 4,51 (1H, d, J=a 13.9 Hz), of 6.31 (1H, s), to 6.58 (1H, d, J=1.5 Hz), of 6.96 (1H, DD, J=7,9) and 1.7 Hz), 7,07 (1H, DD, J=7,8, and 1.6 Hz), 7,14 (1H, t, J=7.8 Hz), 7,28-7,37 (2H, m).

Example 137

3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)propionic acid

In a manner similar to the method of example 136, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 2,90 (2H, t, J=7,3 Hz), and 3.16 (2H, t, J=7,3 Hz), 3,21 is 3.40 (3H, m), 3,62 (3H, s), 3,88 (3H, s), 4,42 (1H, t, J=6,7 Hz), 4,51 (1H, d, J=a 13.9 Hz), of 6.31 (1H, s), 6,59 (1H, d, J=1,5 Hz), 6,97 (1H, DD, J=8.0 a, 1,6 Hz), 7,06-7,11 (1H, m), 7,16 (1H, t, J=7.9 Hz), 7,29-7,37 (2H, m).

Example 138

4-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)butane acid

In a manner similar to the method of example 136, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 2,08-of 2.20 (2H, m), 2.49 USD (2H, t, J=7,1 Hz), 2,95 (2H, t, J=7,3 Hz), 3,19-of 3.42 (3H, m), 3,62 (3H, s), 3,88 (3H, s), of 4.44 (1H, t, J=6.8 Hz), 4,51 (1H, d, J=a 13.9 Hz), of 6.31 (1H, s), 6,59 (1H, s), 6,97 (1H, DD, J=8,0, 1.8 Hz), was 7.08 (1H, DD, J=7,8, and 1.4 Hz), 7,16 (1H, t, J=7.9 Hz), 7,30 and 7.36 (2H, m).

Example 139

3-(3-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-te is rehydro-4,1-benzoxazepin-3-yl]ethyl)-1,2,4-oxadiazol-5-yl)propionic acid

In a manner similar to the method of example 60, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,15-to 2.41 (2H, m), 2.77-to 2,98 (4H, m), 3,07-3,20 (3H, m), 3,37 (1H, d, J=14,3 Hz), 3,59-3,66 (4H, m)to 3.89 (3H, s), of 3.95 (1H, DD, J=7,7, a 5.3 Hz), 4,46 (1H, d, J=14,3 Hz), x 6.15 (1H, s), 6,60 (1H, d, J=2.3 Hz), 6,95-7,02 (1H, m), 7,17-7,22 (2H, m, J=4,1, 4,1 Hz), 7,29-7,39 (2H, m).

Example 140

3-(3-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,2,4-oxadiazol-5-yl)propionic acid

In a manner similar to the method of example 136, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s), 2,14-to 2.41 (2H, m), 2.77-to 2,98 (4H, m), 3,11 (2H, t, J=7,3 Hz)to 3.34 (1H, d, J=a 13.9 Hz), 3,63 (3H, s)to 3.89 (3H, s), 3,93 (1H, DD, J=7,9, 5,1 Hz), 4,51 (1H, d, J=13,8 Hz), 6,27 (1H, ), 6,60 (1H, d, J=2.1 Hz), 6,98 (1H, DD, J=7,0, 2.6 Hz), 7,15-7,24 (2H, m), 7,28 and 7.36 (2H, m).

Example 141

4-(3-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,2,4-oxadiazol-5-yl)butane acid

In a manner similar to the method of example 60, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s), 2,02 with 2.14 (3H, m), 2,18-to 2.42 (2H, m), of 2.45 (2H, t, J=7.2 Hz), 2.77-to 2,99 (4H, m)and 3.15 (1H, d, J=12.1 Hz), 3,37 (1H, d, J=14,3 Hz), to 3.58-3,66 (4H, m)to 3.89 (3H, s), 3.95 to (1H, DD, J=7,8, 5,4 Hz), 4,46 (1H, d, J=14,3 Hz), x 6.15 (1H, s), 6,60 (H, d, J=2.3 Hz), 6,95-7,03 (1H, m), 7,16-of 7.23 (2H, m), 7,29-7,39 (2H, m).

Example 142

3-(3-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,2,4-oxadiazol-5-yl)propionic acid

In a manner similar to the method of example 136, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s), 1.70 to 2,03 (4H, m), 2,66-2,78 (2H, m), 2,90 (2H, t, J=7,2 Hz)and 3.15 (2H, t, J=7.2 Hz), 3,34 (1H, d, J=a 13.9 Hz), 3,62 (3H, s), 3,85 (1H, DD, J=7,5, 4,8 Hz)to 3.89 (3H, s), 4,50 (1H, d, J=a 13.9 Hz), 6,24 (1H, s), 6,59 (1H, d, J=2.3 Hz), 6,98 (1H, DD, J=7,7, and 2.1 Hz), 7,15 and 7.36 (4H, m).

Example 143

(3R)-4-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)-3-methylbutanoate acid

In a manner similar to the method of example 136, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s)of 1.07 (3H, d, J=6.6 Hz), 2,33 (1H, DD, J=15,6, 7,2 Hz), 2,41-2,63 (2H, m), 2,84 (1H, DD, J=is 15.3 and 6.9 Hz), 2,96 (1H, DD, J=15,3, and 6.6 Hz), 3,21-of 3.42 (3H, m), 3,62 (3H, s), 3,88 (3H, s), 4,45 (1H, t, J=6.8 Hz), 4,51 (1H, d, J=a 13.9 Hz), of 6.31 (1H, s), to 6.58 (1H, s), of 6.96 (1H, DD, J=7,9) and 1.7 Hz), 7,06 (1H, DD, J=7,9, 1.5 Hz), 7,14 (1H, t, J=7.9 Hz), 7,29-7,37 (2H, m).

Example 144

{[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3-5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)methyl]thio}acetic acid

(1) Thioacetate to the lia (0,76 g, 5,97 mmol) was added to a solution of (3R,5S)-7-chloro-3-{[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]methyl}-5-(2,3-acid)-1-(2,2-dimethylpropyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-she (3.8 g, to 4.98 mmol), synthesized as in example 136, in DMF (30 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (4:1)] to obtain S-[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)methyl]acetate (2,45 g, 4.26 deaths mmol, 86%) as a white non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), is 2.40 (3H, s), 3,30 (2H, DD, J=6,7, and 2.4 Hz), 3,37 (1H, d, J=a 13.9 Hz), 3,62 (3H, s), 3,88 (3H, s), 4,28 (2H, s), 4,42 (1H, t, J=6.8 Hz), 4,51 (1H, d, J=13,8 Hz), 6,30 (1H, s), 6,58 (1H, d, J=1.9 Hz), 6,97 (1H, DD, J=8,1, 1.5 Hz), 7,05 (1H, DD, J=5 and 7.8, 1.0 Hz), 7,17 (1H, t, J=8.0 Hz), 7,28-7,37 (2H, m).

(2) 2 N. Aqueous sodium hydroxide solution (1,74 ml of 3.48 mmol) was added to a solution of S-[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)methyl]acetate (1.0 g, of 1.74 mmol) in methanol (10 ml) and the mixture was stirred for 1.5 hours. Re clanny the solution was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. To a solution of the residue in THF (10 ml) was added ethylbromoacetate (0,12 ml, 1.04 mmol) and potassium carbonate (0.24 g, of 1.74 mmol) and the mixture was stirred for 17 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in ethanol (10 ml), was added 2 N. aqueous sodium hydroxide solution (1,16 ml of 2.33 mmol) and the mixture was stirred for 5 hours. The reaction solution was diluted with water and then washed with diethyl ether. The extract was acidified using 1 N. aqueous hydrochloric acid, was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain {[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)methyl]thio}acetic acid (413 mg, 80%).

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 3,26 (1H, DD, J=15,7, 6,7 Hz), 3,34-3,44 (4H, m), 3,63 (3H, s)to 3.89 (3H, s), of 4.00 (2H, s), of 4.44-of 4.54 (2H, m), of 6.31 (1H, s), 6,59 (1H, s), 6,97 (1H, DD, J=8.0 a, 1,6 Hz), 7,07 (1H, DD, J=7,9, 1.5 Hz), 7,16 (1H, t, J=8.0 Hz), 7,34 (2H, d, J=1.3 Hz).

Example 145

2-{[(3-{[(3R,5S)-7-chloro-5-(2,3-Dimitar fenil)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}1,2,4-oxadiazol-5-yl)methyl]thio}-2-methylpropionate acid

In a manner similar to the method of example 144, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s), and 1.54 (3H, s), and 1.56 (3H, s), 3,20 (1H, DD, J=15,4, 6.2 Hz), 3.33 and-3,47 (2H, m), 3,63 (3H, s)to 3.89 (3H, s)to 4.01 (2H, s), of 4.44-a 4.53 (2H, m), 6,30 (1H, s), 6,60 (1H, s), 6,98 (1H, DD, J=7,8, 1.8 Hz), 7,12 (1H, DD, J=7,7, 1.7 Hz), 7,18 (1H, t, J=7.8 Hz), 7,34 (2H, d, J=0.9 Hz).

Example 146

{[1-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)-1-methylethyl]thio}acetic acid

In a manner similar to the method of example 144, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (9H, s)of 1.78 (3H, s), is 1.81 (3H, s)and 3.15 (1H, DD, J=15,8, a 5.3 Hz), 3,28-of 3.53 (4H, m)to 3.64 (3H, s)to 3.89 (3H, s), 4,47 (1H, d, J=a 13.9 Hz), a 4.53 (1H, DD, J=8,7, at 5.3 Hz), 6,30 (1H, s), 6,62 (1H with), 6,98 (1H, DD, J=7,0, 2,8 Hz), 7,13-7,22 (2H, m), of 7.36 (2H, d, J=1.3 Hz).

Example 147

{[1-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)-1-methylethyl]thio}acetic acid

In a manner similar to the method of example 144, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.67 (3H, s), was 1.04 (3H, s)of 1.78 (3H, s)to 1.79 (3H, s), 3,16-of 3.27 (2H, m), 3,35-to 3.49 (4H, m), 3,59-to 3.67 (4H, m)to 3.89 (3H, s), to 4.41-a 4.53 (2H, m), to 6.19 (1H, s), is 6.61 (1H, s), of 6.99 (1H, DD, J=7,9, 1.9 Hz), 7,11 (1H, DD, J=7,8, 1.8 Hz), 7,18 (1H, t, =7.9 Hz), 7,34-the 7.43 (2H, m).

Example 148

{[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methyl}-1,2,4-oxadiazol-5-yl)methyl]thio}acetic acid

In a manner similar to the method of example 144, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s), 3,17-of 3.32 (2H, m), 3,34-of 3.48 (4H, m), to 3.58-3,68 (4H, m)to 3.89 (3H, s), of 4.00 (2H, s), 4,42-a 4.53 (2H, m), to 6.19 (1H, s), is 6.61 (1H, d, J=1.3 Hz), 6,98 (1H, DD, J=8,1, 1,5 Hz), 7,07 (1H, DD, J=7,7, 1.5 Hz), 7,17 (1H, t, J=8.0 Hz), 7,33-7,42 (2H, m).

Example 149

2-{[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)methyl]thio}-2-methylpropionate acid

In a manner similar to the method of example 144, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s), was 1.04 (3H, s), and 1.54 (3H, s), and 1.54 (3H, s), 3,14-3,29 (2H, m), 3,34-3,47 (2H, m), 3,57-3,66 (4H, m)to 3.89 (3H, s), a 4.03 (2H, s), 4,42-to 4.52 (2H, m), to 6.19 (1H, s), 6,60 (1H, d, J=1,1 Hz), 6,98 (1H, DD, J=8,1) and 1.7 Hz), to 7.09 (1H, DD, J=7,7, 1.5 Hz), 7,17 (1H, t, J=7.9 Hz), 7,33-7,41 (2H, m).

Example 150

[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]acetic acid

(1) Methyliodide (0,65 ml, 10,48 mmol) was added to a solution of 2-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl is)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]attentioned (1.0 g, 2.10 mmol), obtained as in example 16-(2), in acetone (10 ml) and the mixture was stirred for 14 hours. After the reaction solution was concentrated under reduced pressure, to the residue was added ammonium acetate (0,81 g, 10,48 mmol) and methanol (10 ml) and the mixture is boiled under reflux for 4 hours. After adding perchloromethylmercaptan (0,23 ml, 2.1 mmol) to a solution of the residue in dichloromethane to the resulting mixture was slowly added dropwise at -10°C sodium hydroxide solution (0.375 g, 9,38 mmol) in water (3 ml). The reaction solution was stirred at -10°C for 2 hours and then at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, washed successively with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (95:5-85:15)] to obtain (3R,5S)-7-chloro-3-[(5-chloro-1,2,4-thiadiazole-3-yl)methyl]-5-(2,3-acid)-1-(2,2-dimethylpropyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-she (0,46 g, 0,857 mmol, 41%) as a white non-crystalline solid.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 3.33 and-of 3.48 (2H, m), 3,55-3,66 (4H, m)to 3.89 (2H, s), 4,50 (1H, d, J=13,8 Hz), 4,58 (1H, t, J=6,7 Hz), of 6.31 (1H, s), 6,59 (1H, d, J=1.1 Hz), 6,93? 7.04 baby mortality (2H, m), to 7.15 (1H, t, J=8.0 Hz,), 7,30-7,38 (2H, m).

1H-NMR (CDCl3) δ: of 0.95 (9H, s)of 1.26 (3H, t, J=7.2 Hz), 3,32-of 3.43 (2H, m), of 3.57 (1H, DD, J=the 15.6, 6.9 Hz), 3,63 (3H, s)to 3.89 (3H, s)to 4.01 (2H, s), 4,18 (2H, q, J=7.2 Hz), 4,50 (1H, d, J=a 13.9 Hz), 4,58 (1H, t, J=6,7 Hz), of 6.31 (1H, s), 6,59 (1H, s), of 6.96 (1H, DD, J=8,1, 1.5 Hz),? 7.04 baby mortality (1H, DD, J are 7.8 and 1.4 Hz), to 7.15 (1H, t, J=8.0 Hz), 7,34 (2H, d, J=1.3 Hz).

(3) 2 N. Aqueous sodium hydroxide solution (1,16 ml, 2.32 mmol) was added to a solution of ethyl [(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]acetate (0,48 g, 0,774 mmol), poluchennogo example 150-(2), in a mixture of ethanol (5 ml) and THF (5 ml) and the mixture was stirred for 1 hour. The reaction solution was extracted with water and then washed with diethyl ether. The aqueous layer was acidified using 1 N. aqueous hydrochloric acid, was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol-hexane to obtain [(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]acetic acid (374 mg, 0,632 mmol, 82%) as Besenova crystal.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 3,34 is-3.45 (2H, m), 3,57-3,68 (4H, m)to 3.89 (3H, s), 3,93 (2H, s), 4,49 (1H, d, J=a 13.9 Hz), 4,56 (1H, DD, J=7,2, 6.2 Hz), of 6.31 (1H, s), is 6.61 (1H, s), 6,97 (1H, DD, J=8,1, 1.5 Hz),? 7.04 baby mortality (1H, DD, J=7,7, 1.3 Hz), 7,16 (1H, t, J=7.9 Hz), 7,33-7,38 (2H, m).

Example 151

2-[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]-2-methylpropionate acid

(1) Ethyl 3-mercaptopropionate (of 0.28 ml, 2.2 mmol) and potassium carbonate (0.21 g, 1.5 mmol) was added to a solution of (3R,5S)-7-chloro-3-[(5-chloro-1,2,4-thiadiazole-3-yl)methyl]-5-(2,3-acid)-1-(2,2-dimethylpropyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-she (0.54 g, 1.0 mmol)obtained in example 150-(1)in THF (10 ml) and the mixture per Merivale at 45° C for 13.5 hours. The reaction solution was extracted with ethyl acetate, washed successively with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in ethanol, was added 2 N. aqueous sodium hydroxide solution (0,836 ml, a rate of 1.67 mmol) and the mixture was stirred for 1 hour. The reaction solution was extracted with ethyl acetate, washed successively with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. To the residue was added ethyl 2-bromo-2-methylpropionate (of 0.18 ml, 1.25 mmol), potassium carbonate (0.17 g, 1.25 mmol) and THF (10 ml) and the mixture is boiled under reflux for 14 hours. The reaction solution was extracted with ethyl acetate, washed successively with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (85:15-80:20)] to obtain ethyl 2-[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]-2-methylpropionate (0,47 g, 87%).

1H-NMR (CDCl3) δ: of 0.95 (9H, s)of 1.16 (3H, t, J=7,1 Hz)of 1.66 (3H, s), by 1.68 (3H, s), 3,35-3,44 (2H, m), 3,5 (1H, DD, J=the 15.6, 6.6 Hz), 3,62 (3H, s), 3,88 (3H, s)4,06 (2H, DDD, J=14.2 per cent and 7.1, 1.9 Hz), 4,51 (1H, d, J=a 13.9 Hz), 4,59 (1H, t, J=6.8 Hz), 6,30 (1H, s), 6,56 (1H, d, J=1.9 Hz), 6,93-7,00 (1H, m), 7,13 (1H, t, J=8.0 Hz), 7,31-7,39 (1H, m).

(2) 2 N. Aqueous sodium hydroxide solution (1.1 ml, 2,17 mmol) was added to a solution of ethyl 2-[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]-2-methylpropionate (0,47 g, 0,725 mmol)obtained in example 151-(1), in ethanol (10 ml) and the mixture was stirred for 2 hours. The reaction solution was extracted with water and then washed with diethyl ether. The aqueous layer was acidified using 1 N. aqueous hydrochloric acid, was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2-[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]2-methylpropionic acid (332 mg, 74%).

1H-NMR (CDCl3) δ: of 0.95 (9H, s)of 1.66 (3H, s), by 1.68 (3H, s), 3,34-to 3.49 (2H, m), 3,56-to 3.67 (4H, m)to 3.89 (3H, s), 4,49 (1H, d, J=a 13.9 Hz), of 4.57 (1H, t, J=6,7 Hz), of 6.31 (1H, s), to 6.58 (1H, d, J=2.1 Hz), 6,97 (2H, DD, J=7,1, 5,9 Hz), 7,14 (1H, t, J=7.9 Hz), 7,31-the 7.43 (2H, m).

Example 152

4-[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]butane acid

In a manner similar to the method of example 151, received specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.95 (9H, s), 2,03-of 2.15 (2H, m)of 2.50 (2H, t, J=7,1 Hz), 3,29 (2H, dt, J=7,0, 2.3 Hz), 3.33 and-of 3.43 (2H, m)to 3.58 (1H, DD, J=the 15.6, 6.9 Hz), 3,63 (3H, s), 3,88 (3H, s), 4,50 (1H, d, J=13,8 Hz), br4.61 (1H, t, J=6,7 Hz), of 6.31 (1H, s), to 6.58 (1H, s), of 6.96 (1H, DD, J=8,1, 1.5 Hz), 7,03 (1H, DD, J=7,9, 1.1 Hz), 7,14 (1H, t, J=7.9 Hz), 7,33 (2H, d, J=1.3 Hz).

Example 153

[(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-thiadiazole-5-yl)thio]acetic acid

In a manner similar to the method of example 150, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 3,20 (1H, d, J=11,9 Hz), the 3.35 (1H, DD, J=15,9, a 5.4 Hz), 3,42 (1H, d, J=14,3 Hz), 3,59-3,71 (5H, m)to 3.89 (3H, s)to 3.99 (2H, s), 4,46 (1H, d, J=14,3 Hz), 4,58 (1H, DD, J=7,9, and 5.5 Hz), to 6.19 (1H, s), 6,62 (1H, s), 6,98 (1H, DD, J=8.0 a, 1,6 Hz), to 7.09 (1H, DD, J=7,9, 1.5 Hz), 7,17 (1H, t, J=7.9 Hz), 7,35-7,44 (2H, m).

Example 154

5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid

(1) Triethylamine (1.2 ml, 8.5 mmol) and methyl 6-chloro-6-oxohexanoate (0,98 g, 5.5 mmol) was added dropwise to a solution of 3-[(3R,5S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate is a (2.67 g, 5.0 mmol)obtained in example 58-(1)in THF (25 ml) under ice cooling and the mixture was stirred under ice cooling for 40 minutes and then at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, was added water (25 ml) and the mixture is boiled under reflux for 18 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After concentrating the solution under reduced pressure the residue was purified column chromatography on silica gel to obtain methyl 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentanoate (1.73 g).

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.03 (3H, s), 1,65-1,90 (4 H, m)2,03 (3H, s)to 2.35 (2H, t, J=7.2 Hz), of 2.86 (2H, t, J=7,3 Hz), 3,29 (2H, DDD, J=30,5, 15,6, 6,7 Hz), 3,55 (1H, d, J=a 13.9 Hz), 3,61 (3H, s)to 3.67 (3H with), 3,74 (1H, d, J=11,1 Hz), 3,85 (1H, d, J=11,1 Hz), 3,88 (3H, s), 4,42 (1H, t, J=6,7 Hz), 4,58 (1H, d, J=14.1 Hz), 6,30 (1H, s), is 6.61 (1H, d, J=1.5 Hz), 6,97 (1H, DD, J=7,9) and 1.7 Hz), 7,07 (1H, DD, J=7,8, and 1.6 Hz), 7,14 (1H, t, J=7.9 Hz), 7,29-7,38 (2H, m).

(2) 2 N. Aqueous sodium hydroxide solution (the 5.25 ml, 10.5 mmol) was added to a solution of methyl 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentanoate (1.73 g, 2.3 mmol), obtained in example 154-(1)in ethanol (17 ml) and the mixture was stirred for 2 hours. The reaction solution was diluted with water and then washed with diethyl ether. The extract was acidified 6 N. aqueous hydrochloric acid, was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel and then recrystallized from a mixture of ethyl acetate-hexane to obtain 5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentanol acid (1.06 g).

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 1,66-of 1.93 (4H, m), 2,39 (2H, t, J=7.2 Hz), is 2.88 (2H, t, J=7.4 Hz), 3,12 of 3.28 (2H, m), 3.33 and-3,44 (2H, m), 3,57-to 3.67 (4H, m)to 3.89 (3H, s), 4,40-a 4.53 (2H, m), to 6.19 (1H, C)6,60 (1H, d, J=1.7 Hz), 6,98 1H, DD,J=8,1) and 1.7 Hz), to 7.09 (1H, DD, J=7,7, 1.5 Hz), 7,16 (1H, t, J=7.9 Hz), 7,32-7,41 (2H, m).

Example 155

4-(3-{[(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-yl]methyl}-1,2,4-oxadiazol-5-yl)butane acid

In a manner similar to the method of example 14 had been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.03 (3H, s)2,03 (3H, s), 2,07-2,19 (2H, m), 2,48 (2H, t, J=7.2 Hz), 2,95 (2H, t, J=7,3 Hz), 3,24 (1H, DD, J=15,6, 7,2 Hz), to 3.36 (1H, is d, J=the 15.6, 6.6 Hz), 3,55 (1H, d, J=14.1 Hz), 3,61 (3H, s), 3,74 (1H, d, J=11,1 Hz), 3,85 (1H, d, J=11.3 Hz), 3,88 (3H, s), 4,43 (1H, t, J=6,7 Hz), of 4.57 (1H, d, J=14.1 Hz), 6,30 (1H, s), 6,62 (1H, s), 6,97 (1H, DD, J=8.0 a, 1,6 Hz), 7,05-7,10 (1H, m), to 7.15 (1H, t, J=7.8 Hz), 7,30-7,38 (2H, m).

Example 156

5-(3-{[(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-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid

In a manner similar to the method of example 14 had been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.03 (3H, s), 1,67-to 1.77 (2H, m), 1,81 is 1.91 (2H, m), 2,03 (3H, s), 2,39 (2H, t, J=7.2 Hz), is 2.88 (2H, t, J=7.4 Hz), 3,20 of 3.28 (1H, m), 3,30-to 3.38 (1H, m), 3,55 (1H, d, J=14.1 Hz), 3,61 (3H, s), 3.72 points-of 3.77 (1H, m), 3,85 (1H, d, J=11,1 Hz), 3,88 (3H, s), 4,42 (1H, t, J=6,7 Hz), of 4.57 (1H, d, J=a 13.9 Hz), 6,30 (1H, s), is 6.61 (1H, d, J=1.7 Hz), 6,97 (1H, DD, J=7,9) and 1.7 Hz), 7,05-to 7.09 (1H, m), 7,14 (1H, t, J=7.9 Hz), 7,30-7,37 (2H, m).

Example 157

3-(3-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,2,4-oxadiazol-5-yl)propionic acid

(1) (Diethoxyphosphoryl)acetonitrile (of 5.03 g, 28.4 mmol) was added dropwise to a suspension of sodium hydride (1,14 g, 28.4 mmol) in THF (110 ml) at 0°C. After stirring for 30 minutes, to the mixture was added 3-[(3R,5S)-7-chloro-5-(2,3-acid)-2-oxo-3-(2-oxoethyl)-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (br11.01 g and 21.8 mmol)obtained in example 15-(1). After stirring for 1 hour the mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain (2E)-4-[(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-yl]-2-butenonitrile (8,15 g, 71%).

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.02 (3H, s)2,03 (3H, s), 2,64-3,10 (2H, m), 3,49 is 3.76 (5H, m), 3,81-4,00 (5H, m), 4,56 (1H, DD, J=14,1, 5,1 Hz), lower than the 5.37-of 5.48 (1H, m), of 6.26 (1 H, d, J=2.6 Hz), 6,62-to 6.80 (2H, m), of 6.96? 7.04 baby mortality (1H, m), 7,12-7,39 (4H, m).

(2) (2E)-4-[(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-yl]-2-butenonitrile (8,15 g, 12.4 mmol)obtained in example 157-(1)was dissolved in methanol (80 ml)was added magnesium (1.13 g, of 46.4 mmol) and the mixture was stirred for 19 hours. The reaction solution was diluted with ethyl acetate, washed with 1 N. aqueous hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (40 ml), was added triethylamine (5.1 ml, 36 mmol) and acetylchloride (2.0 ml, of 29.1 mmol) and the mixture was stirred for 5 hours. The reaction solution was diluted those who acetate and the organic layer was washed with water and saturated aqueous sodium chloride, was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 4-[(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-yl]butanetriol (to 3.89 g, 91%).

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s), 1,67-to 2.06 (7H, m), is 2.37 (2H, t, J=6,7 Hz), 3,52 (1H, d, J=14.1 Hz), 3,62 (3H, s), of 3.73 (1H, d, J=11,1 Hz), 3,81-3,88 (2H, m)to 3.89 (3H, s), 4,56 (1H, d, J=a 13.9 Hz), of 6.25 (1H, s), only 6.64 (1H, d, J=2.1 Hz), 7,00 (1H, DD, J=7,2, 2.3 Hz), 7,15-7,39 (4H, m).

(3) Triethylamine (5,14 ml of 36.7 mmol) was added to a solution of hydroxylaminopurine (2.55 g, to 36.7 mmol) in dimethyl sulfoxide (40 ml) and the mixture was stirred for 30 minutes. Was filtered insoluble substances. To the filtrate was added 4-[(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-yl]butanetriol (to 3.89 g of 7.35 mmol)obtained in example 157-(2), and the mixture was stirred at 80°C for 6 hours. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-[(3R,5S)-3-[4-amino-4-(hydroxyimino)butyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (4,33 g) as a crude product.

(4) by the Way, is such method of example 60, got mentioned in the title compound from 3-[(3R,5S)-3-[4-amino-4-(hydroxyimino)butyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate obtained in example 157-(3).

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 1.70 to -2,02 (4H, m), 2,66-2,78 (2H, m), 2,89 (2H, t, J=7.2 Hz), of 3.10-3.20 (3H, m)to 3.36 (1H, d, J=14,3 Hz), 3,57-3,66 (4H, m), 3,83-to 3.92 (4H, m), of 4.45 (1H, d, J=14,3 Hz), 6,12 (1H, s), 6,60 (1H, d, J=2.3 Hz), of 6.99 (1H, DD, J-6,4, and 3.4 Hz), 7,16-7,24 (2H, m), 7,30 (1H, d, J=8.7 Hz), was 7.36 (1H, DD, J=8,7, 2,4 Hz).

Example 158

4-(3-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,2,4-oxadiazol-5-yl)butane acid

In a manner similar to the method of example 157, received specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 1,71-2,02 (4H, m), 2,08-of 2.20 (2H, m), 2.49 USD (2H, t, J=7.2 Hz), is 2.74 (2H, t, J=6.4 Hz), to 2.94 (2H, t, J=7,3 Hz)and 3.15 (1H, d, J=12.1 Hz), to 3.36 (1H, d, J=14,3 Hz), 3,57-3,66 (4H, m), 3,83-to 3.92 (4 H, m), 4,46 (1 H, d, J=14,3 Hz), 6,13 (1H, s), 6,60 (1H, d, J=2.3 Hz), of 6.99 (1H, DD, J=6,8, 3.0 Hz), 7,16-7,24 (2H, m), 7,30 (1H, d, J=8.7 Hz), was 7.36 (1H, DD, J=8,7, 2,1 Hz).

Example 159

3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,2,4-oxadiazol-5-yl)propionic acid

(1) Triethylamine (of 4.05 ml of 28.9 mmol) was added to a solution of gidroxinimesoulid is (2.0 g, 5,78 mmol) in dimethyl sulfoxide (40 ml) and the mixture was stirred for 30 minutes. Was filtered insoluble substances. To the filtrate was added 3-[(3R,5S)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-Tianeti)-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (of 3.73 g, 5,78 mmol)obtained in example 115-(2) and the mixture was stirred at 80°C for 2.5 hours. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-[(3R,5S)-3-[(3Z)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-3-(hydroxyimino)propyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate in the form of a crude powder (4,07 g, 100%).

(2) Triethylamine (0.63 ml, of 4.49 mmol) and ethyl 4-chloro-4-oxobutanoate (of 0.47 ml, 3,29 mmol) was added dropwise to a solution of 3-[(3R,5S)-3-[(3Z)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-3-(hydroxyimino)propyl]-7-chloro-5-(2,3-acid)-2-oxo-2,3-dihydro-4,1-benzoxazepin-1(5H)-yl]-2,2-dimethylpropanoate (2,03 g, 2,99 mmol)obtained in example 159-(1)in THF (20 ml) under ice cooling and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was concentrated under reduced pressure, to the residue was added water (20 ml) and smesitel under reflux for 17.5 hours. After diluting the reaction solution with ethyl acetate the organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl 3-[3-(2-[(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-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1,2,4-oxadiazol-5-yl]propionate (1.65 g, 70%).

1H-NMR (CDCl3) δ: -0,07-0,11 (6N, m), 0,69-to 0.89 (9H, m), 1.04 million (3H, s), 1,09-of 1.15 (3H, m), 1,29-to 1.38 (3H, m), 2,09 with 2.14 (3H, m), 2,32-2,60 (2H, m), 2,85-2,95 (2H, m), 3,18 to be 3.29 (2H, m), 3,61 (1H, d, J=14.1 Hz), 3,68-3,72 (3H, m, J=2,4 Hz), 3,80-a 3.87 (1H, m), 3,90-4,00 (4H, m), 4,15-to 4.33 (3H, m), of 4.66 (1H, DD, J=14,0, 8,2 Hz), 5,12-of 5.29 (1H, m), 6,34 (1H, d, J=12.1 Hz), 6,72 (1H, DD, J=10,3, 2.2 Hz), 7.03 is-7,11 (1H, m), 7,22-7,44 (4H, m).

(3) the Complex of boron TRIFLUORIDE - diethyl ether (of 0.53 ml, 4,19 mmol) was added to a solution of ethyl 3-[3-(2-[(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-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1,2,4-oxadiazol-5-yl]propionate (1,65 g of 2.09 mmol)obtained in example 159-(2), in acetonitrile (20 ml) under ice cooling and the mixture was stirred for 1 hour under ice cooling. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride, sushi is whether over magnesium sulfate and then concentrated under reduced pressure. To a solution of the residue in dichloromethane (15 ml), was added triethylamine (of 0.87 ml, 6,23 ml) and then was added dropwise a solution of a complex of a sulfur trioxide - pyridine (0,83 g, 5,19 mmol) in DMSO (3.3 ml), which was prepared in advance. The mixture was stirred for 20 hours. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain ethyl 3-(3-{[(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-yl]acetyl}-1,2,4-oxadiazol-5-yl)propionate (of 1.05 g, 75%) as a crude powder.

1H-NMR (CDCl3) δ: of 0.94 (3H, s)of 1.02 (3H, s), 1,25 (3H, t, J=7.2 Hz), 2,02 (3H, s), 2,90 (2H, t, J=7,3 Hz)at 3.25 (2H, t, J=7,3 Hz), 3,42 (1H, DD, J=17,8, a 5.4 Hz), 3,57 (1H, d, J=14,3 Hz), 3,61 (3H, s), of 3.73 (1H, d, J=11,1 Hz), 3,80-3,93 (5H, m)to 4.16 (2H, q, J=7.2 Hz), of 4.54 (1H, d, J=14.1 Hz), to 4.62 (1H, DD, J=8.0 a, 5,4 Hz), 6,28 (1H, s), of 6.65 (1H, s), 6,98 (1H, DD, J=6,4, and 3.2 Hz), 7,13-7,21 (2H, m), of 7.36 (2H, s).

(4) 2 N. Aqueous sodium hydroxide solution (2.35 ml, and 4.68 mmol) was added to a solution of ethyl 3-(3-{[(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-yl]acetyl}-1,2,4-oxadiazol-5-yl)propionate (1,05 g 1,562 mmol)obtained in example 159-(3)in ethanol (10 ml) and the mixture was stirred tip is of 30 minutes. The reaction solution was neutralized 1 N. aqueous hydrochloric acid, was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified preparative HPLC on Gilson (Gilson) to give 3-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,2,4-oxadiazol-5-yl)propionic acid (160 mg, 17%) in powder form.

1H-NMR (CDCl3) δ: 0,65 (3H, s), 1,01-of 1.07 (3H, m), 2,98 (2H, t, J=7,1 Hz), and 3.16 (1H, d, J=12.1 Hz)at 3.25 (2H, t, J=7.0 Hz), 3,37-of 3.48 (2H, m), 3,56-of 3.64 (4H, m), 3,74 (1H, d, J=19.6 Hz), 3,82-of 3.96 (5H, m), 4,43 (1H, d, J=14,3 Hz), br4.61 (1H, DD, J=8,3, 5,1 Hz), 6,16 (1H, s), 6,63 (1H, s), of 6.99 (1H, DD, J=7,2, 2.6 Hz), 7,13-of 7.23 (2H, m), 7,40 (2H, s).

Example 160

4-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-5-yl)butane acid

In a manner similar to the method of example 105, the received specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)of 1.05 (3H, s)of 1.93 (2H, quintet, J=7.5 Hz), 2,17-to 2.42 (4H, m)3,616 (2H, t, J=7.5 Hz), 3,622 (1H, d, J=12.3 Hz), 3,82-of 3.94 (1H, m)to 3.89 (3H, s), of 4.45 (1H, d, J=14.1 Hz), x 6.15 (1H, s), of 6.61 (1H, d, J=2.7 Hz), of 6.99 (1H, DD, J=2,4, 7,2 Hz), 7,15-of 7.25 (2H, m), 7,30 (1H, d, J=8.7 Hz), 7,35 (1H, DD, J=2.7, and 8.7 Hz).

Example 161

4-(2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,3-thiazol-5-yl)butane acid

In a manner similar to the method of example 122, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s), 1,75-2,05 (6H, m), 2,39 (2H, t, J=7.5 Hz), 2,84 (2H, J=7.5 Hz), 2,90-a 3.01 (2H, m)and 3.15 (1H, d, J=12.0 Hz), 3,35 (1H, d, J=14.4 Hz), 3,61 (3H, s), 3,62 (1H, d, J=12,0 Hz), 3,80-to 3.92 (1H, m)to 3.89 (3H, s), 4,46 (1H, d, J=14.4 Hz), 6,13 (1H, s), 6,60 (1H, d, J=2.4 Hz), of 6.99 (1H, DD, J=2.7, and a 7.2 Hz), 7,15-of 7.25 (2H, m), 7,30 (1H, d, J=8,4 Hz), 7,31 (1H, s), of 7.36 (1H, DD, J=the 2.4, and 8.4 Hz).

Example 162

4-(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3,4-oxadiazol-2-yl)butane acid

In a manner similar to the method of example 55, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,66 (3H, s)of 1.05 (3H, s), 2,12 (2H, quintet, J=7.2 Hz), 2.49 USD (2H, t, J=7.2 Hz), with 2.93 (2H, J=7,2 Hz), 3,17 (1H, d, J=12.3 Hz), 3,29 (1H, DD, J=6,6, or 15.9 Hz), to 3.41 (1H, d, J=14.4 Hz), 3,47 (1H, DD, J=6,6, or 15.9 Hz), 3,614 (1H, d, J=12.3 Hz), 3,615 (3H, s)to 3.89 (3H, s), 4,46 (1H, d, J=14.4 Hz), 4,51 (1H, t, J=6.6 Hz), 6,21 (1H, s), is 6.61 (1H, d, J=2.1 Hz), of 6.99 (1H, DD, J=1,8, 7,8 Hz), was 7.08 (1H, DD, J=1,8, 7,8 Hz), 7,18 (1H, t, J=7.8 Hz), 7,34-the 7.43 (2H, m).

Example 163

3-(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3,4-oxadiazol-2-yl)propionic acid

(1) Pyridine (0,067 ml, 0.83 mmol) and the anhydride triftormetilfullerenov acid (0,13 ml of 0.79 mmol) EXT is ulali to a solution of ethyl (4S)-4-(2-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl}hydrazino)-4-oxobutanoate (0.25 g, 0.38 mmol)obtained in example 57-(1)in dichloromethane (4 ml) at -10°C and the mixture was stirred for 1 hour. After further stirring at 0°C for 1 hour, was added a saturated aqueous solution of sodium bicarbonate (5 ml) and the mixture was extracted with dichloromethane (80 ml). The organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [manifesting solvent: hexane-ethyl acetate (3:2)] to obtain ethyl 3-(5-{[(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-yl]methyl}-1,3,4-oxadiazol-2-yl)propionate (0.16 g, 0.25 mmol, 66%) as a colourless non-crystalline powder.

1H-NMR (CDCl3) δ: of 0.95 (3H, s)of 1.03 (3H, s)of 1.26 (3H, t, J=7.2 Hz), 2,03 (3H, s), 2,80-2,90 (2H, m), 3,14 (2H, t, J=7.5 Hz), 3,29 (1H, DD, J=7,2, or 15.9 Hz), 3,43 (1H, DD, J=6,6, or 15.9 Hz), 3,55 (1H, d, J=14.1 Hz), 3,62 (3H, s), of 3.73 (1H, d, J=10,8 Hz), 3,85 (1H, d, J=10,8 Hz)to 3.89 (3H, s)to 4.16 (2H, q, J=7.2 Hz), 4,42-is 4.93 (1H, m), 4,55 (1H, d, J=14.1 Hz), of 6.31 (1H, s), 6,63 (1H, d, J=1,8 Hz), 6,98 (1H, DD, J=1,5, 8.1 Hz), 7,07 (1H, DD, J=1,5, 8,1), 7,18 (1H, t, J=8.1 Hz), 7,32 (1H, d, J=8,4 Hz), was 7.36 (1H, DD, J=1,8, 8,4 Hz).

(2) a Mixture of ethyl 3-(5-{[(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-yl]methyl}-1,3,4-oxadiazol-2-yl)propionate (0.1 g, 0.16 mmol), extracting the aqueous in example 163-(1), 1 N. aqueous sodium hydroxide solution (0.6 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (50 ml) and washed with diethyl ether (10 ml). The aqueous layer was acidified using 1 N. aqueous hydrochloric acid (1 ml) and then extracted with ethyl acetate (35 ml). The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3-(5-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3,4-oxadiazol-2-yl)propionic acid (67 mg, 0.12 mmol, 75%) as a white crystal.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s), 2,89 (2H, t, J=7.5 Hz), 3,14 (2H, t, J=7.5 Hz), 3,17 (1H, d, J=11.7 Hz), 3,29 (1H, DD, J=6,3, or 15.9 Hz), 3,61 (3H, s), 3,62 (1H, d, J= 11.7 Hz), with 3.89 (3H, s), 4,46 (1H, d, J=14.4 Hz), of 4.44-to 4.52 (1H, m), of 6.20 (1H, s), is 6.61 (1H, d, J=1,8 Hz), of 6.99 (1H, DD, J=1.5 and 8.1 Hz), 7,07 (1H, DD, J=1.5 and 8.1 Hz), 7,18 (1H, t, J=8.1 Hz), 7,32-7,42 (2H, m).

Example 164

3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)-3-hydroxypropionic acid

In a manner similar to the method of example 18, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s)1,1 (3/2H, C)1,04 (3/2H, s), 2,67-2,87 (2H, m), 3,10-up 3.22 (2H, m), 3,28 is 3.40 (2H, m), 3,49 (1H, DD, J=7,8, 14.1 Hz), 3,62 (3H, s), 3,59-3,68 (1H, m), 3,88 (3/2H, s), 3,89 (3/2H, s), 4,37-of 4.54 (2H, m), 5.56mm (1/2H, t, J=5.7 Hz), 5,65 (1/2H, DD, J=4,5, and 8.7 Hz), 6,18 (1H, s), 6,52 (1/2H, d, J=2.1 Hz), 6,57 (1/2H, d, J=2.1 Hz), 6,86? 7.04 baby mortality (2H, m), 7,10-7,20 (1H, m), 7,25 was 7.36 (2H, m), 8,58 (1/2H, s), 8,61 (1/2H, s).

Example 165

(2E)-3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acrylic acid

In a manner similar to the method of example 19 has been specified in the header of the connection.

1H-NMR (CDCI3) 6: 0,64 (3H, s)of 1.05 (3H, s), 3,19 (1H, d, J=12.0 Hz), 3,32-3,51 (3H, m), 3,61 (3H, s)to 3.67 (1H, d, J=12.0 Hz), a 3.87 (3H, s), 4,39 (1H, t, J=6.0 Hz), 4,47 (1H, d, J=14.4 Hz), 6,169 (1H, d, J=15.6 Hz), 6,173 (1H, s), is 6.54 (1H, d, J=1,8 Hz), 6,85-6,97 (2H, m), to 7.09 (1H, t, J=8.1 Hz), 7,26-7,37 (2H, m), 8,03 (1H, d, J=15.6 Hz), 8,67 (1H, s).

Example 166

3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)propionic acid

In a manner similar to the method of example 88, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,63 (3H, s), was 1.04 (3H, s)to 2.66 (2H, t, J=7.5 Hz), 3,10 is 3.40 (6H, m), 3,61 (3H, s), 3,66 (1H, d, J=12.0 Hz), 3,88 (3H, s), to 4.38-to 4.46 (2H, m), 6,17 (1H, s), 6,53 (1H, d, J=2.4 Hz), 6.90 to-7,00 (2H,, m), 7,13 (1H, t, J=7.8 Hz), 7,26-7,38 (2H, m), charged 8.52 (1H, s).

Example 167

4-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-timetype who yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-1,3-thiazol-5-yl)butane acid

In a manner similar to the method of example 115, received specified in the header of the connection.

1H-NMR (CDCl3) δ: 0,65 (3H, s), was 1.04 (3H, s)1,95 is 2.10 (2H, m), 2,43 (1H, t, J=7.2 Hz), of 2.97 (2H, t, J=7.2 Hz), 3,14 (1H, d, J=12.0 Hz), to 3.41 (1H, d, J=14.1 Hz), 3,55 (1H, DD, J=4,8, and 18.3 Hz), 3,61 (3H, s), 3,63 (1H, d, J=12.0 Hz), with 3.89 (3H, s), of 3.95 (1H, DD, J=8,4, and 18.3 Hz), 4,48 (1H, d, J=14.1 Hz), 4,58 (1H, DD, J=4,8, and 8.4 Hz), 6,17 (1H, s), 6,62 (1H, s), 6,95-7,00 (1H, m), 7,13-7,21 (2H, m), of 7.36-7,42 (2H, m), 7,70 (1H, s).

Example 168

3-(5-{[(3R,5S)-7-chloro-5-(2,3-dimetilfenil)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}-2-thienyl)propionic acid

In a manner similar to the method of example 119, has been specified in the header of the connection.

1H-NMR (CDCl3) δ: of 0.64 (3H, s), was 1.04 (3H, s)of 2.75 (2H, t, J=7.2 Hz), 3,09-is 3.21 (3H, m), with 3.27 (1H, DD, J=4,5, and 16.5 Hz), 3,40 (1H, d, J=14.4 Hz), to 3.58-3,74 (2H, m), 3,61 (3H, s)to 3.89 (3H, s), 4,47 (1H, d, J=14,4 Hz), 4,58 (1H, DD, J=4,5, and 8.4 Hz), 6,18 (1H, s), 6,62 (1H, s), 6.89 in (1H, d, J=3.6 Hz), 6,98 (1H, DD, J=3,0, 7,2 Hz), 7,10-7,21 (2H, m), 7,35-7,42 (2H, m), 7,63 (1H, d, J=3.6 Hz).

The tool of the present invention for the prevention or treatment of hyperlipemia can be obtained, for example, by the following formulations.

In the following formulations of components (additives)other than the active component, can be products listed in the Japanese Pharmacopoeia, the Japanese pharmaceutical Codex or the Japanese pharmaceutical accessories the x substances.

Example 1 production

Capsule

(1)(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid10 mg
(2)Lactose90 mg
(3)Microcrystalline cellulose70 mg
(4)Magnesium stearate

One capsule
10 mg

180 mg

(1), (2) and (3) and 1/2 of the component (4) are mixed and then granularit. To the resulting add the remaining part of component (4) and all enclosed in a gelatin capsule.

Example 2 production

Capsule

(1)(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid10 mg
(2)Lactose90 mg
(3)Microcrystalline cellulose70 mg
(4)Magnesium stearate

One capsule
10 mg

180 mg

(1), (2) and (3) and 1/2 of the component (4) are mixed and then granularit. To the resulting add the remaining part of component (4) and all Zack is ucaut in a gelatin capsule.

Example 3 production

Capsule

(1)3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid10 mg
(2)Lactose90 mg
(3)Microcrystalline cellulose70 mg
(4)Magnesium stearate

One capsule
10 mg

180 mg

(1), (2) and (3) and 1/2 of the component (4) are mixed and then granularit. To the resulting add the remaining part of component (4) and all enclosed in a gelatin capsule.

Example 4 production

Capsule

(1)(5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid10 mg
(2)Lactose90 mg
(3)Microcrystalline cellulose70 mg
(4)Magnesium stearate

One capsule
10 mg

180 mg

(1), (2) and (3) and 1/2 of the component (4) are mixed and then granularit. To the resulting add the rest of the components is that (4) and all enclosed in a gelatin capsule.

Example 5 production

Tablet

(1)(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid10 mg
(2)Lactose35 mg
(3)Corn starch150 mg
(4)Microcrystalline cellulose30 mg
(5)Magnesium stearate

One pill
5 mg

230 mg

(1), (2), (3), 2/3 of the component (4) and 1/2 of the component (5) are mixed and then granularit. To the pellet add the remaining part of component (4) and (5) and the mixture is pressed into a pill.

Example 6 production

Tablet

(1)(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid10 mg
(2)Lactose35 mg
(3)Corn starch150 mg
(4)Microcrystalline cellulose30 mg
(5)Magnesium stearate

One pill
5 mg

230 mg

(1), (2), (3), 2/3 of the component (4) and 1/2 of the component (5) are mixed and then granularit. To the pellet add the remaining part of component (4) and (5) and the mixture is pressed into a pill.

Example 7 production

Tablet

(1)3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid10 mg
(2)Lactose35 mg
(3)Corn starch150 mg
(4)Microcrystalline cellulose30 mg
(5)Magnesium stearate

One pill
5 mg

230 mg

(1), (2), (3), 2/3 of the component (4) and 1/2 of the component (5) are mixed and then granularit. To the pellet add the remaining part of component (4) and (5) and the mixture is pressed into a pill.

Example 8 production

Tablet

(1)((5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid10 mg
(2)Lactose35 mg
(3) Corn starch150 mg
(4)Microcrystalline cellulose30 mg
(5)Magnesium stearate

One pill
5 mg

230 mg

(1), (2), (3), 2/3 of the component (4) and 1/2 of the component (5) are mixed and then granularit. To the pellet add the remaining part of component (4) and (5) and the mixture is pressed into a pill.

Example 9 production

Injection

(1)(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid10 mg
(2)Inositol100 mg
(3)Benzyl alcohol

One ampoule
20 mg

130 mg

(1), (2) and (3) dissolved in distilled water for injection so that the total volume is 2 ml and then placed in a vial under sterile conditions. All stages performed in sterile conditions.

Example 10 production

Injection

(1)(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-thiazol-5-yl)acetic acid10 mg
(2)Inositol100 mg
(3)Benzyl alcohol

One ampoule
20 mg

130 mg

(1), (2) and (3) dissolved in distilled water for injection so that the total volume is 2 ml and then placed in a vial. All stages performed in sterile conditions.

Example 11 production

Injection

(1)3-(4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)propionic acid10 mg
(2)Inositol100 mg
(3)Benzyl alcohol

One ampoule
20 mg

130 mg

(1), (2) and (3) dissolved in distilled water for injection so that the total volume is 2 ml and then placed in a vial. All stages performed in sterile conditions.

Example 12 production

Injection

(1)(5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid10 mg
(2)Inositol100 mg
Benzyl alcohol

One ampoule
20 mg

130 mg

(1), (2) and (3) dissolved in distilled water for injection so that the total volume is 2 ml and then placed in a vial. All stages performed in sterile conditions.

Experimental example 1

Inhibitory activity against squalene-synthase

The method of determination

Inhibitory activity against squalene-synthase was determined using an enzyme solution obtained by the following method.

Enzyme solution (0.8 µg protein)obtained by the following method, was added to a solution (total 50 μl)contained 5 μm [1-3N] farnesylpyrophosphate (specific activity 25 µci/mol), 1 mm NADPH (NADP, nicotinamide adenine dinucleotide phosphate restored type), 5 mm MgCl2, 6 mm glutathione, 100 mm califofnia buffer (pH 7.4) and the test drug (added in the form of an aqueous solution or a solution in DMSO), and reaction was performed at 37°C for 45 minutes. Stopping the reaction by adding 150 μl of a mixed solution of chloroform/methanol (1:2), was added 50 μl of chloroform and 50 µl of 3 n sodium hydroxide solution. Then mixed with 50 μl of the chloroform layer (lower layer)containing the reaction product, the main component of which was squalene, with 3 ml of liquid scintillator based on toluene and metering is whether the radioactivity of the mixture liquid scintillation counter.

Inhibitory activity against squalene-synthase expressed through the concentration of the test drug required to inhibit 50% of the radioactivity incorporated in the chloroform layer (IC50the molar concentration (M)). All compounds described in the examples showed high inhibitory activity towards the synthesis of squalene with IC50equal to 1 μm or less.

Cooking the human enzyme solution

Human liver cancer HepG2 cells (approximately 1 x 109cells)obtained by growing the modified Dulbecco environment Needle containing 10% fetal serum cows (37°With, in the presence of 5% CO2), suspended in 10 ml of cooled ice buffer [100 mm califofnia buffer (pH 7.4), 30 mm nicotinamide, 2.5 mm MgCl2]was destroyed by ultrasound (30 seconds, 2 times) and then centrifuged at 10,000 x g for 20 minutes (4°). The obtained supernatant was centrifuged at 105000 x g for 90 minutes (4°). Sediment suspended in cooled ice 100 mm califorina buffer (pH 7.4) and then centrifuged at 105000 x g for 90 minutes (4°). Sediment suspended in cooled ice 100 mm califorina buffer (pH 7.4) (protein concentration of about 4 mg/ml). The resulting suspension was used as enzyme solution.

As widn is from the above results, the compound of the present invention has a high squalene synthase inhibitory activity.

Industrial applicability

Because the connection of the present invention has a squalene synthase inhibitory activity, cholesterinspiegel activity and triglyceridemia activity shows high selectivity in transmission to the target organ and has a wide margin of safety, it is useful as a means for prevention or treatment of hyperlipemia as reducing the level of lipid tool and also useful for the prevention or treatment of arteriosclerosis.

1. The compound represented by the formula [I]:

where ring a is a benzene ring substituted with halogen, and ring b is a benzene ring substituted with two lower alkoxy groups having 1-4 carbon atoms, a ring represents a benzene ring or 5-membered monocyclic aromatic heterocyclic ring, optionally substituted by a Deputy selected from the group consisting of carboxyl groups, With1-4alkyl group, a C2-7alkanoyloxy-C1-6alkyl groups, phenyl-C1-4alkyl groups, phenyl groups, optionally substituted carboxyl group, or carbonyl group, R1depict is to place a 1-6alkyl group, optionally substituted hydroxyl group, which is optionally substituted C2-20alkanoyl or1-7the alkyl, X1Ais a bond or C1-6alkylene, optionally substituted by hydroxy or oxo, X1bis a bond or C1-6alkylene, optionally substituted by hydroxy or oxo, X2represents a bond, -O - or-S-, X3represents a bond or a group formed by removing one hydrogen atom from C1-7alkyl group with straight or branched chain or2-6alkenylphenol group with a straight or branched chain, which is optionally substituted by hydroxy or oxo, and Y is an optionally esterified carboxyl group, or its salt.

2. The compound according to claim 1, where X1bis a bond and Y represents a carboxyl group.

3. The compound according to claim 1 in which the ring a is a benzene ring substituted by a chlorine atom.

4. The compound according to claim 1 in which the ring represents a benzene ring is substituted by two methoxypropane.

5. The compound according to claim 1, where X1Arepresents a C1-3alkylen.

6. The compound according to claim 1, where X2that is the link.

7. The compound according to claim 1, where X3represents a C1-4alkylen.

8. The connection p is 1, where the formula [I] represents the formula [Ia]:

where the symbols are as defined in claim 1.

9. The compound according to claim 1, which represents the

3-(2-{3-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]propyl}-1,3-thiazol-5-yl)propionic acid,

3-(2-{2-[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]ethyl}-1,3-thiazol-4-yl)propionic acid or its salt.

10. The compound according to claim 1, which represents the

3-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)propionic acid,

2-(2-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,3-oxazol-5-yl)acetic acid or its salt.

11. The compound according to claim 1, which represents the

5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid,

5-(3-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid,

5-(3-{[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxy who yl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]methyl}-1,2,4-oxadiazol-5-yl)pentane acid or its salt.

12. The compound according to claim 1, which represents the

4-{[(3R,5S)-7-chloro-5-(2,3-acid)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}phenyl)acetic acid or its salt.

13. Drug for prevention or treatment of hyperlipemia or arteriosclerosis containing compound according to claim 1.

14. Drug for prevention or treatment of hyperlipemia or arteriosclerosis, containing a combination of compounds according to claim 1 and cholesterinspiegel tools.

15. The method of obtaining the compound represented by the formula [I']:

where the ring a' represents a 5-membered monocyclic aromatic heterocyclic ring, optionally substituted by a Deputy selected from the group consisting of carboxyl groups, With1-4alkyl group, a C2-7alkanoyloxy-C1-6alkyl groups, phenyl-C1-4alkyl groups, phenyl groups, optionally substituted carboxyl group, or carbonyl group, and other symbols are as defined in claim 1, or its salt, including the interaction of the compounds represented by the formula:

or its salt with a compound represented by the formula:

or its salt is, where Z1and Z2are such that:

(1) one is a carboxyl group, and the other 2-aminoalkanoic group,

(2) one is a carboxyl group, and the other hydrazide,

(3) one is thiocarbamoyl group, and the other alkanoyloxy group substituted by a halogen atom in position 2, or

(4) one is a N-hydroxyamides and the other carboxylic acid halide, and other symbols are as defined in claim 1.

16. The use of compounds according to claim 1 to obtain an inhibitor of squalene synthase.

17. Use item 16 to obtain triglyceridemia tools.

18. Use item 16 to obtain lepidophyma tools.

19. The application of article 16, to obtain means for the prevention or treatment of hyperlipemia or arteriosclerosis.

20. Use item 16 to obtain funds to increase the level of complex high-density lipoprotein-cholesterol.



 

Same patents:

FIELD: chemistry; medicine.

SUBSTANCE: invention concerns aryl- or heteroarylcarbonylpiperazine compound of the general formula (I) , where R1 is selected out of the group including fluorene-9-on, isoxazole, cinnoline, isothiazole, isoquinoline, 9H-fluorene, 9H-xanthene and 1H-pyrazole, where linkage is implemented by any desired and possible end atom of heteroaryl or aryl radical, so that they can optionally be unsubstituted or mono- or disubstituted by substitutes: halogen, SO2-alkyl, saturated alkyl, non-saturated alkyl with one double link, halogenalkyl where alkyl part contains 1 to 20 carbon atoms, phenyl optionally mono- or disubstituted by substitutes: NO2, -OH, -NH2, halogen; R2 is O; R3 is H; R4 is phenyl substituted by one or two substitutes selected out of group: OH, halogen, alkyl, alkoxy, where alkyl part contains 1 to 20 carbon atoms; or 5, 6 or 7-atom cyclic aromatic radical including N heteroatom and substituted by alkyl containing 1 to 20 carbon atoms; m and n are 1; or its physiologically acceptable salt. The invention also concerns method of obtaining compound of the formula (I), application of compounds of the formula (I) as therapeutically effective compounds for obtaining medication for human and animal tumour treatment, medical preparations based on compound of the formula (I), method of obtaining medications and method of benignant and malignant tumour treatment. The compounds inhibit tubulin polymerisation, thus enabling their application for indicated purpose.

EFFECT: improved efficiency.

15 cl, 2 tbl, 19 ex

FIELD: chemistry.

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5 cl, 24 tbl, ex

FIELD: chemistry.

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12 cl, 5 ex, 2 tbl

FIELD: medicine; pharmacology.

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19 cl, 2 tbl, 2 dwg, 130 ex

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12 cl, 9 ex, 2 tbl

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9 cl, 8 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means -lower alkyl, -CH2-aryl, -cycloalkyl, -(CH2)3, -OC(=O)CH3, -lower alcohol, -lower alkyl-R10, -CH2COOH or -CH2CH2OCH2CH3; R2 means -lower alkyl, -CH2-aryl, -lower alcohol, -CH2C(=O)-NH2 or lower alkyl-R10 wherein at least one radical among R1 or R2 means -CH3; R3 means -COOH, -lower alkyl-COOH, -lower alcohol, -CH2OCH2, -CH2NH2, -CHNHSO2R11, -C(=O)-R12, -(CH2)nNHC(=O)-R13, -(CH2)mC(=O)N-(R15)(R16), -C(=NH)-R17 or -(CH2)n-R18; R4 means hydrogen atom (-H), -lower alkoxy group, -O-C(R7R8)C(=O)-R19, -halogen atom, -SCH3, -C=CHC(=O)-R10, -CH2CH2C(=O)-R10, -O-lower alcohol, -OCH2CH(OH)CH2N=N±N-, -OCH2CH2OCH2CH2Cl, -NHC9=O)-CH2-lower alkyl, -O(CH2)n-cycloalkyl, -O-lower alkene or 5-membered unsaturated heterocyclic ring comprising one heteroatom representing sulfur (S) or oxygen (O) atom; R5 and R6 mean independently -H, -halogen atom or -lower alkoxy group; R7 and R8 mean independently -H or -CH3; R10 means 5-6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms, such as N and O, and this group is bound with other moiety of molecule by a ring N atom; R11 means -CF3, -lower alkyl, -CH2Cl, -CH2CF3 or -R12; R12 means 5-6-membered saturated substituted or unsubstituted heterocyclic ring comprising 1 heteroatom, such as N, O and S wherein substituted ring represents heterocyclic ring substituted with -OH or -phenyl; R13 means -lower alkyl, -lower alkoxy group or -(CH2)nR14; R14 means 5-6-membered saturated or unsaturated heterocyclic ring comprising 1 and 2 heteroatoms, that are chosen from group comprising N and O; R15 means -H, -lower alkyl, -OH, -lower alkoxy group or -CH2COOCH2CH3; R17 means -lower alkoxy group, -NH2 or -N-lower alkyl; R18 means saturated or unsaturated 5-membered substituted or unsubstituted heterocyclic ring comprising from 1 to 4 heteroatoms, such as N, O and S wherein substituted ring represents heterocyclic ring that is substituted by one or two cyclic carbon atoms by =O, or it is substituted by cyclic N atom by -lower alcohol or -lower alkyl; R19 means -OH, -NHCH(CH3)2, -N(CH3)CH2-aryl, -N(CH3)-lower alkyl, 1-(aryl-(CH2)n-)-[1,4]-diazin-4-yl or 5-6-membered saturated heterocyclyl and optionally substituted with lower alkyl comprising 1 or 2 heteroatoms, such as N and O; m = 0, 1 or 2; n = 0 or 1, and their pharmaceutically acceptable salts and esters. Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to GFAT and containing the effective amount of compound of the formula (I). Invention provides expanding assortment of agents possessing inhibitory activity with respect to GFAT. Proposed compounds can be used as inhibitors of GFAT, and pharmaceutical composition possessing inhibitory activity with respect to GFAT containing above said compound of the formula (I) also.

EFFECT: valuable biochemical properties of compounds and pharmaceutical composition.

25 cl, 134 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with describing the efficient quantity of, at least, one heterocyclic compound of formula (I) or its salts, moreover, the compound of formula (I) should be chosen out of (i) the compounds of formula (III) or their salts, in which Z, Z' indicate O, X indicates S (thiazolidine dionic group), G indicates O or S; at least, one out of R2 and R3 indicates CF3, OR0 or COOR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C10-C10-alkyl, (ii) compounds (VI) or their salts: in which Z, Z' and G independently indicate O or S, at least, one out of R2 and R3 indicates hydrogen, CN, CF3, NO2, OR0, COOR0 or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, possibly substituted OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, (iii) compounds (VII) or their salts in which Z, Z' and G independently indicate O or S; R indicates saturated linear or branched C1-C10-alkyl; at least, one out of R2 and R3 indicates saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, NO2, OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl. The compounds in question reveal improved action upon stimulation of keratin fibers growth, particularly, human keratin fibers, that prevents their falling down and increases their density.

EFFECT: higher efficiency.

31 cl, 13 ex, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel indolyl-derivatives of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkyl substituted with from one to three halogen atoms; R2 means hydrogen atom, (C1-C8)-alkyl; R3 means (C1-C8)-alkoxy-group; R4 means hydrogen atom; A means oxygen atom or sulfur atom; n = 1,2 or 3. Synthesized compounds possess agonistic activity with respect to PPARα- and/or PPARγ-receptors. Also, invention relates to methods for their synthesis, a pharmaceutical composition based on thereof and their using for preparing medicinal agents, and to a method for treatment and/or prophylaxis of diseases.

EFFECT: improved method of synthesis and treatment, valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 7 sch, 17 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means substituted or unsubstituted thiazolinyl or oxazolinyl residue; each R5 and R6 means independently hydrogen atom or protective group; X means oxygen (O), sulfur atom (S) or -NR7 wherein in each case R7 means hydrogen atom or lower alkyl; RB means in each case independently hydrogen atom, (C1-C6)-alkyl, -CY3, -CHY2 or -CH2Y wherein Y means F, Br, Cl or J. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I) and possessing cytotoxic activity, and using this compound in treatment of malignant tumor with multiple drug resistance.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention concerns aryl- or heteroarylcarbonylpiperazine compound of the general formula (I) , where R1 is selected out of the group including fluorene-9-on, isoxazole, cinnoline, isothiazole, isoquinoline, 9H-fluorene, 9H-xanthene and 1H-pyrazole, where linkage is implemented by any desired and possible end atom of heteroaryl or aryl radical, so that they can optionally be unsubstituted or mono- or disubstituted by substitutes: halogen, SO2-alkyl, saturated alkyl, non-saturated alkyl with one double link, halogenalkyl where alkyl part contains 1 to 20 carbon atoms, phenyl optionally mono- or disubstituted by substitutes: NO2, -OH, -NH2, halogen; R2 is O; R3 is H; R4 is phenyl substituted by one or two substitutes selected out of group: OH, halogen, alkyl, alkoxy, where alkyl part contains 1 to 20 carbon atoms; or 5, 6 or 7-atom cyclic aromatic radical including N heteroatom and substituted by alkyl containing 1 to 20 carbon atoms; m and n are 1; or its physiologically acceptable salt. The invention also concerns method of obtaining compound of the formula (I), application of compounds of the formula (I) as therapeutically effective compounds for obtaining medication for human and animal tumour treatment, medical preparations based on compound of the formula (I), method of obtaining medications and method of benignant and malignant tumour treatment. The compounds inhibit tubulin polymerisation, thus enabling their application for indicated purpose.

EFFECT: improved efficiency.

15 cl, 2 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new nitrogen-containing heterocyclic derivatives represented by the formula (I): where symbols have the following meaning: R1 and R2 can be equal or different and denote H-, C1-C6-alkyl, C3-C14-cycloalkyl, C1-C6-alkyl-CO-, HO-CO-, C1-C6-alkyl-O-CO-, H2N-CO-, C1-C6-alkyl-HN-CO-, (C1-C6-alkyl)2N-CO-, C1-C6-alkyl-O-, C1-C6-alkyl-CO-O-, H2N-, C1-C6-alkyl-HN-, (C1-C6-alkyl)2N-, C1-C6-alkyl-CO-NH-, halogen, nitro, morpholine, pyrrolidin, imidazol or cyano; R3 and R4 can be equal or different and denote C1-C6-alkyl, C1-C6-alkyl-O-, (C1-C6-alkyl)2N- or halogen; R5 and R6 can be equal or different and denote H-, C1-C6-alkyl or halogen; R7 and R8 can be equal or different and denote H-, C1-C6-alkyl, HO-, C1-C6-alkyl-O- or halogen; R7 and R8 together can form oxo (O=); R9 denotes heterocyclic group -C1-C6-alkyl-CO-, which can be optionally substituted for at least one substitute selected out of a group b described further, where heterocyclic group is selected out of morpholine, piperazine, pyrrolidin, piperidine, thiomorpholine, azepine, diazepine, oxyazepine, decahydroquinoline, decahydroisoquinoline, hexahydroazepine or 2,5-diazabicyclo[2.2.1]heptane; R10, R11, R12 and R13 can be equal or different and denote H- or C1-C6-alkyl; group b: (1) HO, (2) C1-C6-alkyl-O-, (3) R101 R102N (where R101 and R102 can be equal or different and denote (i) H, (ii) C1-C6-alkyl), (4) halogen, (5) oxo (O=), (6) C3-C14-cycloalkyl, (7) phenyl, (8) pyrrolidine, (9) C1-C6-alkyl, which can be optionally substituted for HO, C1-C6-alkyl-O-, phenyl, C1-C6-alkyl-CO- or morpholine, (10) acyl, which can be optionally substituted for oxo (O=), where acyl is C1-C6-alkyl-CO- or heterocyclic -CO group, where heterocyclic group is imidazol, pyridine or pyrazine, (11) H2N-CO- and (12) C1-C6-alkyl-SO2; A denotes heterocycloalkyl group selected out of piperidine, pyrrolidine or hexahydroazepine; n is 0, or its pharmaceutically acceptable salts. The invention also concerns pharmaceutical composition and application of nitrogen-containing heterocyclic derivatives from each of pp. 1-11.

EFFECT: obtaining new biologically active compounds and pharmaceutical composition based on there, with inhibition effect on sodium channel activity.

16 cl, 226 ex, 32 tbl

FIELD: chemistry.

SUBSTANCE: compounds with the formula are described and its pharmaceutically acceptable salts, where Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n, p and q are as specified in the invention. The obtained compounds have the modulating activity regarding the 5-HT receptors. The pharmaceutical composition which contains the compounds with formula (I) and used in treatment of certain central nervous system diseases is also described.

EFFECT: novel compound group with useful biological properties is obtained.

10 cl, 2 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel indole derivatives with the formula , where X means S, SO, SO2; R1 means 6-membered mono-homocyclic saturated or unsaturated ring structure or 5-, 6-membered monohetercyclic saturated or unsaturated ring structure with one or two heteratoms, chosen from N, O, S, and each of the said structures is not necessarily substituted with one or more substituters, chosen from the group, consisting of halogen, CN, (1C-4C)fluoroalkyl, NO2, (1C-4C)alkyl, (1C-4C)alkoxi or (1C-4C)fluoroalkoxi; R2 means 2-nitorphenyl, 2-cyanophenyl, 2-hydroxymethylphenyl, pyridine-2-il, pyridine-2-il-N-oxide, 2-benzamide, methylic ether of the 2-benzoic acid or 2-methoxyphenyl; R3 means H, halogen or (1C-4C)alkyl; R4 means H, OH, (1C-4C) alkoxy or halogen; R5 means H, OH, (1C-4C) alkoxy, NH2 CN, halogen, (1C-4C)fluoroalkyl, NO2, hydroxy(1C-4C)alkyl, CO2H, CO2(1C-6C)alkyl, or R5 means NHR6, where R6 means (1C-6C)acyl, not necessarily substituted with one or more halogens, S(O)2(1C-4C)alkyl or S(O)2heteroaryl, not necessarily substituted with (1C-4C)alkyl or one or more halogens, where heteroaryl is the 5-membered mono-heterocyclic unsaturated ring structure with one S atom or two N atoms, or R5 means C(O)N(R8,R9), where R8 and R9 , each independently, mean H, (3C-6C)cycloalkyl or CH2R10, where R10 means H, (1C-5C)alkyl, hydroxy(1C-3C)alkyl, complex (1C-4C)alkyl ether of the carboxy(1C-4C)alkyl, (1C-3C)alkoxy(1C-3C)alkyl, (mono- or di(1C-4C)alkyl)aminomethyl, (mono- or di1C-4C)alkyl)aminocarbonyl or pyhenyl, where R8 and R9 together with N form 5- or 6-membered saturated aor unsaturated heterocyclic ring, not necessarily containing N or O as the second heteroatom, not necessarily substituted with (1C-4C)alkyl; or its saline or hydrated form.

EFFECT: allows using indoles for producing pharmaceutical agent and in method for inhibiting 5α-dihydrosterone activity.

17 cl, 7 dwg, 5 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new process of obtaining 5-[[2(R)-[l(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(8)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one compound represented by the formula 1: including: interaction of hydrochloride of compound represented by the formula 2: with compound of formula 3: in the presence of inorganic base, toluene and polar aprotic dissolvent resulting in obtaining compound represented by the formula 4: ; and cyclisation of compound of formula 4 at the temperature of 140 to 150°C resulting in production of compound of formula 1.

EFFECT: more effective and economical process of the compound production with rather high output.

12 cl, 1 ex

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means -lower alkyl, -CH2-aryl, -cycloalkyl, -(CH2)3, -OC(=O)CH3, -lower alcohol, -lower alkyl-R10, -CH2COOH or -CH2CH2OCH2CH3; R2 means -lower alkyl, -CH2-aryl, -lower alcohol, -CH2C(=O)-NH2 or lower alkyl-R10 wherein at least one radical among R1 or R2 means -CH3; R3 means -COOH, -lower alkyl-COOH, -lower alcohol, -CH2OCH2, -CH2NH2, -CHNHSO2R11, -C(=O)-R12, -(CH2)nNHC(=O)-R13, -(CH2)mC(=O)N-(R15)(R16), -C(=NH)-R17 or -(CH2)n-R18; R4 means hydrogen atom (-H), -lower alkoxy group, -O-C(R7R8)C(=O)-R19, -halogen atom, -SCH3, -C=CHC(=O)-R10, -CH2CH2C(=O)-R10, -O-lower alcohol, -OCH2CH(OH)CH2N=N±N-, -OCH2CH2OCH2CH2Cl, -NHC9=O)-CH2-lower alkyl, -O(CH2)n-cycloalkyl, -O-lower alkene or 5-membered unsaturated heterocyclic ring comprising one heteroatom representing sulfur (S) or oxygen (O) atom; R5 and R6 mean independently -H, -halogen atom or -lower alkoxy group; R7 and R8 mean independently -H or -CH3; R10 means 5-6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms, such as N and O, and this group is bound with other moiety of molecule by a ring N atom; R11 means -CF3, -lower alkyl, -CH2Cl, -CH2CF3 or -R12; R12 means 5-6-membered saturated substituted or unsubstituted heterocyclic ring comprising 1 heteroatom, such as N, O and S wherein substituted ring represents heterocyclic ring substituted with -OH or -phenyl; R13 means -lower alkyl, -lower alkoxy group or -(CH2)nR14; R14 means 5-6-membered saturated or unsaturated heterocyclic ring comprising 1 and 2 heteroatoms, that are chosen from group comprising N and O; R15 means -H, -lower alkyl, -OH, -lower alkoxy group or -CH2COOCH2CH3; R17 means -lower alkoxy group, -NH2 or -N-lower alkyl; R18 means saturated or unsaturated 5-membered substituted or unsubstituted heterocyclic ring comprising from 1 to 4 heteroatoms, such as N, O and S wherein substituted ring represents heterocyclic ring that is substituted by one or two cyclic carbon atoms by =O, or it is substituted by cyclic N atom by -lower alcohol or -lower alkyl; R19 means -OH, -NHCH(CH3)2, -N(CH3)CH2-aryl, -N(CH3)-lower alkyl, 1-(aryl-(CH2)n-)-[1,4]-diazin-4-yl or 5-6-membered saturated heterocyclyl and optionally substituted with lower alkyl comprising 1 or 2 heteroatoms, such as N and O; m = 0, 1 or 2; n = 0 or 1, and their pharmaceutically acceptable salts and esters. Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to GFAT and containing the effective amount of compound of the formula (I). Invention provides expanding assortment of agents possessing inhibitory activity with respect to GFAT. Proposed compounds can be used as inhibitors of GFAT, and pharmaceutical composition possessing inhibitory activity with respect to GFAT containing above said compound of the formula (I) also.

EFFECT: valuable biochemical properties of compounds and pharmaceutical composition.

25 cl, 134 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to phthalimido-derivatives of the general formula (I): wherein X means -N= or -CH=; R1 means -CO-NR5R6, -CHR7-(CH2)n-CO-NR5R6, -(CH2)n-NR5R6, -(CH2)n-COOR8, -(CH2)n-CN, -CHR7-(CH2)n-CF3, -(CH2)n-NH-COR9, -(CH2)n-NH-COOR8, -(CH2)n-piperidinyl, -(CH2)n-morpholinyl, -(CH2)n-tetrahydrofuranyl, -(CH2)n-thiophenyl or -(CH2)n-isoxazolyl wherein a heterocyclic ring can be substituted with (C1-C6)-alkyl; -(CH2)n-phenyl wherein phenyl ring can be substituted with halogen atom or halogen-(C1-C6)-alkyl; -(CH2)p-OR8, -(CH2)p-SR8, -(CH2)p-SO-R9 or -(CH2)n-CS-NR5R6; R2 means hydrogen atom (H), (C1-C6)-alkyl, -(CH2)p-OR10, -(CH2)p-SR or benzyl; R3 means H, (C1-C6)-alkyl; R4 means halogen atom, halogen-(C1-C6)-alkyl, cyano-, (C1-C6)-alkoxy- or halogen-(C1-C6)-alkoxy-group; Each R5 and R6 means independently of one another H, (C1-C6)-alkyl; R7 means H, -OH, (C1-C6)-alkoxy-group; R8 means H, (C1-C6)-alkyl; R9 means (C1-C6)-alkyl; R10 means H, (C1-C6)-alkyl; m = 1, 2 or 3; n = 0, 1 or 2; p = 1 or 2, and their pharmaceutically acceptable salts. Compounds of the formula (I) inhibit activity of monoamine oxidase B (MAO B) that allows their using as a drug.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 4 sch, 1 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: claim describes benzoxazepinone derivatives of formula : wherein R1 represents hydrogen, C1-C6 alkoxy, halogen or NR'R", n is 1 or 2, R', R" independently from each other represents hydrogen or C1-C6 alkyl; R2 represents hydrogen, C1-C6 alkyl -(CH2)m-C3-C7-cycloalkyl, -(CH2)m-phenyl or -(CH2)m-O-C1-C6 alkyl; m is 0.1 or 2; R3 represents C1-C6 alkyl,-(CH2)m-C(O)O-C1-C6 alkyl, C3-C7 cycloalkyl or -(CH2)m-phenyl which is unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen, trifluoromethyl, -NR'R", nitro and -SO2NH2, or represents -C3-C7 -cycloalkyl, unsubstituted or substituted by phenyl, or is -(CR′R″)o-heterocyclyl, selected from the group consisting of tetrahydropyran-4-yl, pyridin-3-yl, indol-3-yl optionally substituted by halogen or C1-C6 alkoxy group, or thiophen-2-yl, furan-2-yl, NH-pyridin-2-yl optionally substituted by nitro group or benzoimidazol-2-yl, 2-oxo-tetrahydrofuran, and benzo[1,3]dioxol-5-yl and represents -tetrahydro-naphthalen-1-yl, -CHR′-naphthalen-2-yl, -fluoren-9-yl, -(CH2)o-S-lower alkyl, -(CH2)o-S-benzyl, -(CH2)o-C(O)NH2, -(CH2)oNR′R″, -CH[C(O)NH2]-(CH2)o-phenyl, -(CH2)o-CF3, or -(CH2)o-CR′R″-CH2-NR′R″; and o is 1 or 2; or their pharmaceutically suitable acid addition salts, excluding: phenetylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, phenetylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid. The pharmaceutical on basis of the compounds of formula I aimed at the treatment of Alzheimer's disease is described.

EFFECT: production of the new compounds, benzoxazepinone derivatives having useful biological properties.

26 cl, 196 ex

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