Condensed heterocyclic compounds and inhibitors of squalene synthetase

 

(57) Abstract:

Condensed heterocyclic compounds of the formula I, where R1is hydrogen, C1-7-alkyl, optionally substituted by oxopropoxy; R'2is phenyl, substituted by halogen or lower alkoxygroup, X'-C1-4-alkylen, replaced by carboxyla, alkoxycarbonyl, hydroxyl, terazol-5-yl, carbarnoyl, substituted lower alkyl, tetrazol-5-yl, carboxyla, or lower alkoxycarbonyl; ring And benzene ring is substituted by halogen, or thienyl, replaced by halogen; ring J1to 7-membered heterocyclic ring containing not more than three heteroatoms in the ring; D, To represent C or N; Z1- C, O, N or S(O)q; q = 0, 1, 2; ring J is not necessarily contains in addition to R1, R'2and X' is oxo or tiocsserial, well inhibit squalene-synthetase. 2 C. and 20 C.p. f-crystals, 4 PL.

The invention relates to a condensed heterocyclic compounds or their salts and inhibitors of squalene synthetase containing these compounds as an effective component.

Hypercholesterolemia, high blood pressure and Smoking are known as the three major risk factors that cause coronary heart disease, ima important control over the concentration of cholesterol in the blood.

Among the pharmaceutical compositions intended to reduce the content of cholesterol in the blood, it is necessary to pay attention to those that control the biosynthesis of cholesterol, in addition to those that inhibit its absorption by binding bile acids, including, among others, such as cholestyramine, colestipol /disclosed, for example, in U.S. patent 4027009/, and those that inhibit intestinal absorption of cholesterol by inhibiting acylcoenzyme A cholesterol-acyl-transferase /AST/ including metaname /disclosed in the French patent N 1476569/. As pharmaceutical drugs to control cholesterol biosynthesis for medical use proposed: lovastatin /U.S. patent 4231938/ simvastatin /U.S. patent 4444784/ pravastatin /U.S. patent 4346227/ etc. that are able to inhibit in particular 3-hydroxy-3-methyl-glutaryl-coenzyme /HMG-CoA/-reductase. However, the inhibition of HMG-CoA reductase is also inhibition not only of cholesterol biosynthesis and biosynthesis of some other components, such as ubiquinone, dolichol and heme A, which is essential for living organisms, and therefore, undesirable side effects can be dangerous.

Squalene synthesis predstavlyaeti is an enzyme, providing catalyzed by squalene reductive dimerization of two molecules farnesylpyrophosphate acid.

On the other hand, compounds that, as expected, are inhibitors of cholesterol biosynthesis by inhibiting squalene synthetase, are disclosed in Journal of Medicinal Chemistry. Vol. 51, N 10, pp. 1869-1871, 1988, in Japanese published without examination, applications N H1-213288/1989/ JPA H1/1989/ - 213288/ JPA H2/1990/-101088, JPA H2/1990/-235820, JPA H2 /1990-235821, JPA H3/1991/-20226, JPA H3/1991/-68591, JPA H3/1991/-148288 and in U.S. patent 5019390, 5135935, WO9215579, WO9309155 and WO9313096.

There are various compounds that demonstrate protivopolozennuju activity due to inhibition of the synthesis of squalene /JPA H4/1992/-279589, EP/475706, EP-494622, EP-503520, etc./.

Links to derivatives of 2-oxo-2,3,4,5-tetrahydro-1H-[1] -benzazepine are available in J. Med. Chem., 14, 849 /1971/, Chem. Pharm. Bull, 38, 3331/1990/, J. Chem. Soc. PERKIN TPANS. 1, 353/1991/ and in J. Med. Chem. 14, 40/1971/.

Links to derivatives of 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine are available in J. Prakt. Chem. 36, 5/1967/, Arch. Pharm. 300, 299/1967/ and in U.S. patent 3463774.

2,3-Dihydro-2-oxo-1H-1,4-benzodiazepine derivatives, whose 3-position is an alkyl group, substituted complex ether, carboxylic acid or carbamoyl, and in position 5 - is aryl group, disclosed in J. Het, 9, 134/1970/.

Links to derivatives of 2-oxo-2,3,5,6-tetrahydro-1H-4,1 - benzoxazocin disclosed in Chem. Pharm. Bull, 34/1/, 140/1986/.

Links to derivatives of 2,4-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine are in "Heterocyclic Compounds" ed. by R. Yan Cryer Friday, September /1991/ John Wiley and Sous, Inc. pp 289-313.

Links to derivatives of 2-oxo-1,2-dihydro-3H-1,3,4, -benzotriazepine available in Japanese open patent layout N S 45-11148/1970/ JPB'S 45/1970/-11148/.

Links to derivatives of 2-oxo-1,2,4,5-tetradehydro-3H-1,3-benzodiazepine are J. Chem. Soc. Perkin. Trans. 1/12/, 1331/1976/ and in the French patent N 2528838.

Ubiquinone, dolichol and heme A, as it was known, synthesized from farnesylpyrophosphate scheme of the biosynthesis of cholesterol. Therefore, in order to avoid side effects due to the loss of these compounds, it is desirable to inhibit enzyme systems of the following farnesylpyrophosphate, especially squalene-synthetase, in the scheme of the biosynthesis of cholesterol.

Given the above, the inventors undertook a thorough research and found that the condensed cyclic compound is perfectly inhibit squalene-synthetase, which was the subject of invention.

More specifically, the present invention is proposed:

/1/. Connect the PPU;

R'2represents an optionally substituted phenyl group or optionally substituted aromatic heterocyclic ring group;

X'4is Deputy containing optionally esterified carboxyl group, optionally substituted karbamoilnuyu group, optionally substituted hydroxyl group, optionally substituted by an amino group, or optionally substituted heterocyclic radical containing protontherapy hydrogen;

ring A is optionally substituted benzene ring or optionally substituted aromatic heterocyclic ring;

ring J1is 7-membered heterocyclic ring containing not more than three components ring heteroatoms;

D represents C or N;

Z1represents C, N, S(O)q(q = 0, 1 or 2), or 0;

K is C or N;

ring J1optional has, in addition to R1, R'2and X', the other substituents, provided that the condensed ring composed of ring A and J1that is not 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring, 2-oxo/2,3-dihydro or 2,3,4,5-tetrahydro/-1H-1,4-benzodiazepine ring or 2,4-dioxy-2,3,4,5-te is represented by the General formula (I'

< / BR>
where R1represents hydrogen or optionally substituted hydrocarbon group;

R'2represents an optionally substituted phenyl group or optionally substituted aromatic heterocyclic ring group;

X' represents a Deputy containing optionally esterified carboxyl group, optionally substituted carbomoyl group, optionally substituted hydroxyl group, optionally substituted by an amino group, or optionally substituted heterocyclic radical containing protontherapy hydrogen;

ring A is optionally substituted benzene ring or optionally substituted aromatic heterocyclic ring;

ring J2is 7-membered heterocyclic ring;

Z2is S(O)q(q = 0, 1 or 2), C or O;

K is C or N;

G represents O or S, provided that the condensed ring composed of ring A and J2that is not 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring or its salt.

/3/. Inhibitor of squalene synthetase containing the compound of formula I"

< / BR>
where R1represents hydrogen or NeoMaster the second group, optionally substituted phenyl group, or an optionally substituted group of aromatic heterocyclic ring;

X' represents a Deputy containing optionally esterified carboxyl group, optionally substituted carbomoyl group, optionally substituted hydroxyl group, optionally substituted by an amino group or optionally substituted heterocyclic radical containing protontherapy hydrogen;

ring A is optionally substituted benzene ring or optionally substituted aromatic heterocyclic ring;

ring J' is 7 - or 8-membered heterocyclic ring containing not more than three components ring heteroatoms;

D represents C or N;

moreover, the ring J' is optional, in addition to R1, R2and X', the additional substituents, provided that the condensed ring A and J' are not 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring,

or its pharmaceutically acceptable salt.

/4/. The inhibitor on p. /3/, where the compound represented by formula (I"'

< / BR>
where R1represents hydrogen or optionally substituted hydrocarbon group;

Rthe group or optionally substituted aromatic heterocyclic group;

X1represents a bond or a divalent atomic chain;

Y represents an optionally esterified carboxyl group, optionally substituted carbomoyl group, optionally substituted hydroxyl group, optionally substituted by an amino group, or optionally substituted heterocyclic radical containing protontherapy hydrogen;

ring A is optionally substituted benzene ring or optionally substituted aromatic heterocyclic ring;

Z3is =N-, -N(R7)- /R7represents H, alkyl or acyl group/; -S-, -S,/O/, S/O2/-, -CH2- or-O-;

G4represents O or S;

the symbol denoted by a double bond when Z3is =N-, or a simple link, if Z3is not = N-, provided that if Z3represents-O-, and ring A is optionally substituted benzene ring G is S,

or its pharmaceutically acceptable salt.

Further, in the present invention, a method of obtaining new compounds represented by formula I or their salts.

In formulas I, I', I", I"' as the hydrocarbon group in viraginity type aliphatic chains, alicyclic hydrocarbon groups and aryl groups, and so on, with the most preferred hydrocarbon groups such as aliphatic chains.

As aliphatic hydrocarbon groups, chain type, you can specify, for example, branched or unbranched aliphatic hydrocarbon groups as alkyl groups, alkeline group, alkyline group, and so on, with the most preferred alkyl groups. As alkyl groups you can specify, for example, C1-7-alkyl groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, and so on , and among them such preferred C3-5is an alkyl group, as n-propyl, isopropyl, isobutyl, neopentyl and so on, with the most preferred isobutyl and neopentyl. As mentioned alkyl groups you can specify, for example, C2-6-alkeline groups as 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-BU is l, 5-hexenyl and so on, and among them the most preferred vinyl, allyl, Isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl etc. as mentioned alkyl groups you can specify, for example, C2-6-alkinyl as ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and so on, with the most preferred ethinyl, 1-PROPYNYL, 2-PROPYNYL.

Examples of the alicyclic hydrocarbon groups include saturated or unsaturated alicyclic hydrocarbon groups such as cycloalkyl group, cycloalkenyl group, cycloalkenyl group, etc. as specified cycloalkyl groups preferred C3-9-cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cycloneii and so on, with the most preferred C3-6-cycloalkyl groups, such as cyclopropyl, cyclobutyl, cycloheptyl, cyclohexyl, etc. as cycloalkenyl groups you can specify, for example 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobutene-1-yl, -cyclotene-1-yl, etc. Mo-1-yl, 2,5-cyclohexadiene-1-yl, etc.

Examples of aryl groups in the above hydrocarbon groups are monocyclic or condensed polycyclic aromatic hydrocarbon group, for example phenyl, naphthyl, antril, tenantry, acenaphthylene and so on, and among them the most preferred phenyl, 1-naphthyl, 2-naphthyl, etc.

As the substituents in "optionally substituted hydrocarbon group" represented by R1you can specify optional substituted cycloalkyl group or cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted amino, optionally substituted hydroxyl group, optionally substituted tirinya groups, halides (for example, fluorine, chlorine, bromine, iodine/ the carbonyl group, and so on, and the hydrocarbon group represented by R1, optionally substituted by 1-5 /preferably 1-3/ of these substituents at any possible position. As the aryl groups in the above optionally substituted aryl groups, you can specify phenyl, naphthyl, antril, tenantry, Azatutyan and so on, and among them, phenyl, 1-naphthyl and 2 - naphthyl are preferred. As Vice-specified optionally substituted aryl, ora, chlorine, bromine, iodine/, C1-3is an alkyl group (for example, methyl, ethyl, propyl and so on/ and the aryl may be arbitrarily substituted with one or two of them. As cycloalkyl groups mentioned "optionally substituted cycloalkyl groups, you can specify C3-7cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc., the Type and number of substituents in the above optional replaced cycloalkyl groups are almost the same as in the case of the above-mentioned aryl groups. As cycloalkyl groups mentioned optionally substituted cycloalkenyl groups can be specified, along with other such C3-6-cycloalkenyl group, as cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl etc., Types and number of the substituents at the above optional replaced cycloalkenyl groups are almost the same as in the case of the above-mentioned optionally substituted aryl groups. As the heterocyclic groups mentioned optionally substituted heterocyclic groups, you can specify an aromatic heterocyclic group containing as a constituent of a cyclic system of atoms at least one heteroatom, select the factual heterocyclic group/. As the aromatic heterocyclic groups you can specify an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl and so on/ and condensed aromatic heterocyclic groups, for example, benzofuranyl, isobenzofuranyl, benzo[b] thienyl, indolyl, isoindolyl, 1H-indazole, benzimidazole, benzoxazolyl, 1,2-benzisoxazole, benzothiazolyl, 1,2-benzothiazolyl, 1H-benzotriazolyl, hinely, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthyridine, purinol, pteridinyl, carbazolyl - carboline - carboline - carbolines, acridines, phenoxazines, phenothiazines, phenazines, phenoxathiin, thianthrene, phenetidines, phenanthrolines, indolizine, Pirro[1,2-b] pyridazinyl, pyrazolo[1,5-b]pyridyl, imidazo[1,2-a] pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-b]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]peritonitis and so on/ and, among them, preferred furyl, Tien the x groups include oxiranyl, azetidinol, oxetanyl, titanyl, pyrrolidinyl, tetrahydrofuryl, tylenol, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholine, piperazinil etc., as deputies have mentioned substituted heterocyclic groups, you can specify C1-3is an alkyl group (for example, methyl, ethyl, propyl, etc./. Examples of substituents of the above optionally substituted amino groups, optionally substituted hydroxyl groups and optionally substituted by hydroxyl groups and optionally substituted tylnej groups include lower /C1-3/alkyl /for example, methyl, ethyl, propyl, etc./. And, if the hydrocarbon group in the optionally substituted hydrocarbon groups represented by R1are alicyclic hydrocarbon groups or aryl groups, they may contain as substituents C1-3is an alkyl group (for example, methyl, ethyl, propyl and so on/.

Further examples R1include optionally substituted C1-6-acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, dimethylacetal, trimethylacetyl and so on, These acyl groups can contain from one to five respective substituents in lubimoe I, I', I" and I" as the substituents in "optionally substituted phenyl group" represented by R2and R'2you can specify a halogen (for example, fluorine, chlorine, bromine, iodine/, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted hydroxyl group, nitro, cyano, etc., and the phenyl group may be preferably substituted by 1-3 /preferably 1-2/ of these substituents at any possible position. As the lower alkyl can be, for example, enter1-4is an alkyl group, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. and especially methyl and ethyl are preferred. As the lower alkoxy, you can specify C1-4-alkoxygroup, including methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and so on, and particularly preferred methoxy, ethoxy. As Vice-mentioned optionally substituted lower alkyl group or optionally substituted lower alkoxygroup, you can specify the atoms of Halogens (for example, fluorine, chlorine, bromine, iodine and so on/ and from one to five of them can be optionally substituted in any possible position. As Vice-mentioned Neil, ethyl, propyl, isopropyl, butyl, tert-butyl, etc./, C3-6-cycloalkyl group /cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc./, aryl groups (for example, phenyl, 1-naphthyl, 2-naphthyl, etc./, kalkilya group /for example, benzyl, phenetyl and so on/. These substituents may form a ring together with adjacent substituents, such rings, as

< / BR>
These rings can be substituted by lower /C1-3/alkyl/ /for example, stands, ethyl, propylene, isopropyl and so on/ and so forth as the aromatic heterocyclic group "optionally substituted aromatic heterocyclic group" represented by R2or R'2you can specify an aromatic heterocyclic group described for R1and the most preferable among them furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, imidazolyl etc. as substituents of the indicated aromatic heterocyclic groups you can specify C1-3is an alkyl group (for example, methyl, ethyl, propyl and so on/.

In formulas I and I' as alkyl group "optionally substituted alkyl group" represented by R2you can specify C1-6lower alkyl groups (for example, Texel etc./, and, among them, the most preferred C1-4is an alkyl group, including methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. As Vice-mentioned optionally substituted alkyl groups, you can specify the halides (for example, fluorine, chlorine, bromine, iodine/, C1-4-low alkoxygroup /for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tributoxy and so on/.

Among the above groups represented by R2or R'2preferably optional substituted phenyl group, preferably substituted phenyl group, and most preferred phenyl groups substituted by halogen, lower alkoxy, etc.

In the above formulae I, I' and I" as a substituent containing an optionally esterified carboxyl group represented by X', you can specify optional esterified carboxyl group, and the substituents that contain optionally esterified carboxyl group, etc. These necessarily esterified carboxyl groups are almost the same as in the case of the following optionally esterified carboxyl groups represented by y

As a Deputy, soderzhashchimisya groups and substituents, containing optionally substituted karbamoilnuyu group, etc., the Above optional replaced carbamoyl group practical are the same as in the case of the following optionally substituted carbamoyl groups represented by y

As the "substituent containing an optionally substituted hydroxyl group" represented by X', you can specify optional substituted hydroxyl group and Deputy from optionally substituted hydroxyl group, etc. These optional substituted hydroxyl group are almost the same as in the case of the following optionally substituted hydroxyl groups represented by y

As the "substituent containing an optionally substituted an amino group" represented by X', you can specify optional substituted amino and the substituents containing an optionally substituted amino group, etc., These optional substituted amino group are almost the same as in the case of the following optionally substituted amino groups represented by y

As the "substituent containing an optionally substituted heterocyclic radical containing protontherapy hydrogen, prestegard and Deputy, containing optionally substituted heterocyclic radical containing protontherapy hydrogen, etc., These optional substituted heterocyclic radicals, are almost the same as in the case in the following optionally substituted heterocyclic radicals represented by y

Examples of X' include groups represented by the formula /a/:

< / BR>
where X represents a bond or the divalent or trivalent atomic chain;

Y represents an optionally esterified carboxyl group, optionally substituted carbomoyl group, optionally substituted hydroxyl group, optionally substituted by an amino group or optionally substituted heterocyclic radical containing protontherapy hydrogen;

the symbol represents a single or double bond.

In the formula /a/ as the "divalent atomic chain" represented by X, you can specify, preferably, any of the divalent chain containing 1 to 7 atoms, preferably 1 to 4, representing a non-branched chain, or they may have a side chain.

For example, you can specify a chain of the formula

< / BR>
where m and n independently represent 0, 1, 2 or 3;< the-NHCONH-, where R4and R5represent H, optionally substituted alkyl group, optionally substituted aracelio group or optionally substituted phenyl group; and R3represents H, a lower alkyl group, aracelio group or acyl group.

As the alkyl group "optionally substituted lower alkyl group" represented by R4and R5you can specify C1-6is unbranched or branched lower alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and so on /.

As Vice-mentioned optionally substituted lower alkyl groups, you can specify an aromatic heterocyclic group (for example, furyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl etc. /, optionally substituted by an amino group, optionally substituted hydroxyl group, optionally substituted Tilney group, optionally esterified carboxyl group, the atoms of Halogens (for example, fluorine, chlorine, bromine, iodine, etc., as Vice-mentioned optionally substituted amino group, optionally substituted hydroxyl group and neobyazatelnoe similar. Examples of these optionally esterified carboxyl group include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, 1-mattoxicator and so on, preferably methoxycarbonyl, etoxycarbonyl and propoxycarbonyl.

As Uralkalij group "optionally substituted Uralkalij group" represented by R4and R5you can specify benzyl, naphthylmethyl, phenylpropyl, phenylbutyl etc., as Vice-mentioned optionally substituted Uralkalij groups you can specify the atoms of Halogens (for example, fluorine, chlorine, bromine, iodine/, C1-3-alkoxygroup /for example, methoxy, ethoxy, propoxy/, galaxygoo group, amino group, carboxyl group, a sulfhydryl group, and so on

As substituents of "optionally substituted phenyl group" represented by R4and R5you can specify the atoms of Halogens (for example, fluorine, chlorine, bromine, iodine/, C1-3-alkoxy (for example, methoxy, ethoxy, propoxy etc.,/, C1-3alkyl /for example, methyl, ethyl, propyl, etc./,

provided that R4may differ in each chain.

And, as each "lower alkyl group" and "Uralkaliy group" represented by R3you can specify CUppy /for example, benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl and so on/.

As the "acyl group" represented by R3you can specify the lowest alcoholnye group /for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl etc./ lowest alkenone group /for example, acryloyl, methacryloyl, crotonoyl, isocrotonic etc./, cycloalkylcarbonyl group /for example, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl etc./ lowest alkanesulfonyl group /for example, mesyl, econsultancy, propanesulfonyl etc./, aroline group /for example, benzoyl, paratrooper, 1-naphtol, 2-naphtol etc./ aryl/lower/alcoholnye group /for example, phenylacetyl, phenylpropionyl, hydrotropes, phenylbutyric etc. / aryl/lower/alkenone group /for example, cynnamoyl, Acropol etc./, arenesulfonyl group /for example, benzazolyl, para-toluensulfonyl and so on/.

In addition, as X, you can specify a carbon chain containing the double bond or-L-C/OH/- /where L represents a bond or branched or unbranched alkylenes chain/. When they say "carbon chain containing the double bond", preferably, it is preferably 1-4, and they don't have to have a side chain. Although the double bond of the specified carbon chain may be either unbranched part and/or a branched side chain, preferably so that it was in the unbranched part of the chain. The number of double bonds in the specified carbon chain is not limited because it makes sense, and preferably, it is 1-2.

Examples of the carbon chains containing the specified double bond include Metin, vinile, propylen, Butyrin, butadienyl, methylpropenyl, ethylpropane, popypropylene, methylbutadiene, ethylbutanol, propylbetaine, methylbutadiene, ethylbutylamine, propylbetaine, penttinen, hexarelin, heptenyl, hexadienyl and heptadienyl, preferably Metin, vinile, propylen, bouteillan and butadiene. In cases where the specified carbon chain is trivalent, it is bound to a carbon atom on ring Y1, Y2or Y' in any possible position of the double bond.

Examples of branched or unbranched alkilinity chain" represented by L include branched or non-branched C1-6-alkylene chain, more specifically, such two is teletilt, propylethylene, mutilation, methyltyramine and metallisation and, preferably, such C1-3as methylene, ethylene, trimethylene and propylene.

Among the above examples of the groups represented by X', the group's formulas /b/

-X1- Y

where X1represents a bond or a divalent atomic chain;

Y represents an optionally esterified carboxyl group, optionally substituted carbomoyl group, optionally substituted hydroxyl group, optionally substituted by an amino group, or optionally substituted heterocyclic radical containing protontherapy hydrogen, are preferred.

In the formula b "divalent atomic chain" represented by X1almost the same as in the case of the above-mentioned divalent atomic chain, presents X.

In formulas a and b as the "divalent atomic chain" represented by X or X1more preferably it is possible to specify a branched or unbranched alkylene chain in which the number of carbon atoms constituting an unbranched chain is 1-7 /preferably 1-4/. Examples of these alkilinity chains include Dogville, utilitiles, ethylethylene, propylethylene, mutilation, methyltyramine and metallisation, and preferably, C1-4such as methylene, ethylene, trimethylene and propylene.

In formulas a and b as the "optionally esterified carboxyl group" represented by Y, you can specify the lowest alkoxycarbonyl /for example, methoxycarbonyl/, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, second-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol etc./ aryloxyalkyl /for example, phenoxycarbonyl, 1-mattoxicator, benzyloxycarbonyl and so on/. Among them, preferred carboxyl group, methoxycarbonyl and etoxycarbonyl. Examples of substituents of "optionally substituted carboloy group" represented by Y include optional zameshannyj lowest /C1-6/alkyl /for example, methyl, ethyl, n/a propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl etc. /, optionally substituted C3-6-cycloalkyl group /for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc./, optionally substituted aryl group (for example, phenyl, 1-naphthyl, 2-n which these substituents can be independently substituted. As substituents on the specified optionally substituted lower /C1-6/alkyl and optionally substituted C3-6-cycloalkyl group, you can specify a carboxyl group optionally esterified with a lower /C1-5/alkyl /for example, stands, ethyl, propylene, isopropyl, bootrom, tert-bootrom, Pentium, isopentyl, neopentyl etc./, an aromatic heterocyclic group (for example, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl etc./, amino group, hydroxyl group, phenyl group and so forth, and from one of the three substituents may be independently substituted.

As Vice-mentioned optionally substituted aryl groups and optionally substituted Uralkalij groups, you can specify the atoms of Halogens (for example, fluorine, chlorine, bromine, iodine/, carboxyl group, optionally esterified lowest /C1-4/alkyl /stands, ethyl, propylene, isopropyl, bootrom, tert-bootrom and so on/. And two of the substituents on the nitrogen atom may form a cyclic amino group together with a nitrogen atom. Examples of such cyclic amino groups include 1-azetidine, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and so on.

1-4/alkyl /for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.,/, C3-6-cycloalkyl group /for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc./, optionally substituted aryl group (for example, phenyl, 1-naphthyl, 2-naphthyl, etc./, optionally substituted kalkilya group /for example, benzyl. phenethyl and so on /. As Vice-mentioned optionally substituted aryl groups and optionally substituted Uralkalij groups you can specify the atoms of Halogens (for example, chlorine, fluorine, bromine, iodine/, carboxyl group, optionally tarifitsirovana lower C1-4the alkyl /for example, stands, ethyl, propylene, isopropyl, bootrom, tert-bootrom and so on/ and so forth

Examples of substituents of "optionally substituted amino group" represented by Y include lower /C1-4-alkyl /for example, methyl, ethyl, propyl, isopropyl, butyl tert-butyl, etc./, C3-6-cycloalkyl group /for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc./, optionally substituted aryl group (for example, phenyl, 1-naphthyl, 2-naphthyl, etc./, optionally substituted kalkilya group /for example, benzyl, phenetyl and so on/. As Vice-mentioned optionally substituted'or, bromine, iodine/, carboxyl group, optionally esterified lowest /C1-4the alkyl /for example, stands, ethyl, propylene, isopropyl, bootrom, tert-bootrom and so on/. Two substituent on the nitrogen atom can form together with the nitrogen atom a cyclic amino group. Examples of cyclic amino groups include 1-azetidine, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinil etc.

As heterocyclic radicals optionally substituted heterocyclic radical containing protontherapy hydrogen", represented by Y, you can specify a 5-7-membered /preferably 5-membered/ monocyclic heterocyclic radical containing at least one heteroatom selected from the group consisting of N, S and O, more preferably N-containing heterocyclic radical. The most preferred tetrazol-5-yl and groups of the formula

< / BR>
where i denotes-O - or-S-; designates /especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl/.

Specified heterocyclic radical may be protected optionally substituted lower alkyl /preferably, C1-4by alkyl, acyl, etc. as optional is benzyl, para-nitrobenzyl etc., Examples of these atilov include low/C2-5/alkanoyl, benzoyl, etc.

Among the above groups represented by X', the preferred alkyl group is substituted by an optionally esterified carboxyl group or alkyl group substituted by optionally substituted heterocyclic radical containing protontherapy hydrogen.

In formulas I, I', I" and I"' as the aromatic heterocyclic ring represented by ring A, you can specify the aromatic and heterocyclic groups, described in detail in relation to R1. Among them, preferred groups of the formula

< / BR>
As substituents of "optionally substituted benzene ring" and "optionally substituted aromatic heterocyclic group", you can specify a halogen (for example, fluorine, chlorine, bromine, iodine/, C1-4optionally substituted lower alkyl group (for example, methyl, ethyl, propyl, butyl, tert-butyl, etc. /, C1-4optionally substituted lower alkoxygroup /methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc./, nitro, ceanography, etc. Ring A may have 1 to 3 of these substituents, preferably 1-2. These substituents together necessarily substituted lower alkyl groups or optionally substituted lower alkoxygroup you can specify the atoms of Halogens /for example, fluorine, chlorine, bromine, iodine and so on, which may have 1-3 substituent in arbitrary positions. For rings A preferred those which are substituted by a methoxy group or a chlorine atom, and particularly preferred are those which are substituted by chlorine atoms.

In the formula /I/ as heterocyclic rings 7-membered heterocyclic ring containing not more than three components ring heteroatoms" represented by ring J1you can specify saturated or unsaturated 7-membered heterocyclic ring containing, as atoms constituting the heterocyclic ring, at least one heteroatom selected from O, S(O)q(q = 0, 1 or 2) and N, provided that the number of heteroatoms among the atoms constituting the cyclic system /atoms of the ring/ the specified heterocyclic ring does not exceed three.

Ring J1besides the groups represented by R2, R'2and X' may optionally have one or two appropriate substituent at any possible position. As these substituents, if they are linked to the nitrogen atom of the ring J1/ Z1is N /, you can specify C1-6branched or unbranched alkyl group (for example, methyl, ethyl, n-the AK C1-4acyl group (for example, formyl, acetyl, propionyl, butteroil and so on/. The specified alkyl or specified acyl can have from one to five atoms of Halogens (for example, fluorine, chlorine, bromine, iodine/. And if the Deputy is connected with the carbon atom or ring J1you can specify oxo, thioxo and optionally substituted hydroxyl group, optionally substituted by an amino group, etc. These optional substituted hydroxyl group of the optionally substituted amino group is almost the same as the "optionally substituted hydroxyl group" and "optionally substituted amino group" represented by y

Ring J1preferably, substituted by oxo or thiooxo, in addition to the groups R1, R'2and X', in any possible position.

D as an atom constituting the cyclic ring /atom ring/, preferably, is C. K, as constituting a ring atom, preferably, is C.

As the condensed ring composed of ring A and J1you can specify

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
As formula I preferred formula I'.

In the formula I' as 7-membered heterocyclic rings, Presto atoms, the components of the circular ring at least one heteroatom selected from O, S(O)q(q = 0, 1 or 2) and N

Z2as a constituent of a ring atom, preferably represented by S(O)q(q = 0, 1 or 2). K, as a constituent of the ring atoms, preferably presented With.

In the formula I', G preferably represents O.

In addition, as the formula I', formula

< / BR>
where R1, X', ring A, Z2and G have almost the previously indicated meanings;

ring B represents a substituted phenyl group, provided that, if Z2represented by-O-, and ring A is optionally substituted benzene ring, G, is preferably S.

Examples of the substituents of "substituted phenyl group" represented by ring B, almost the same as in the case of the above-mentioned substituents of "optionally substituted phenyl group" represented by R'2.

In the formula I" as heterocyclic rings, 7 - or 8-membered heterocyclic ring containing not more than three components ring heteroatoms" represented by ring J', you can specify a saturated or unsaturated 7 - or 8-membered heterocyclic library from O, S(O)q(q = 0, 1, 2) and N, provided that the number of heteroatoms among the atoms constituting the cyclic system /atoms of the ring/ the specified heterocyclic ring is not more than three.

Ring J' may optionally have, besides the groups represented by R1, R5and X' is one or two relevant Deputy in suitable positions. As these substituents, if they are linked to a nitrogen atom in the ring J', you can specify C1-6branched or unbranched alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl etc./ such acyl groups, as C1-4-acyl group (for example, formyl, acetyl, propionyl, butteroil and so on/. The specified alkyl or specified acyl may contain from one to five halogen atoms (for example, fluorine, chlorine, bromine, iodine/. And if this Deputy is connected with the carbon atom or ring J', you can specify oxo, thioxo, optionally substituted hydroxyl group, optionally substituted by an amino group, etc. Specified optionally substituted hydroxyl group of the optionally substituted amino group is almost the same as the "optionally substituted hidrogeno substituted by oxo or thiooxo, in addition to the groups R1, R2and X' in any possible position.

As the condensed ring composed of ring A and ring J', you can specify the following:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
D as a constituent of the ring atoms is preferably C.

The formula I preferred in the form of formula I"'

Z3preferably, a is S(O)q(q = 0, 1, or 2)

G preferably represents O.

In the formula I' as the alkyl groups represented by R7you can specify C1-6branched or unbranched lower alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl etc./, which may optionally be substituted by 1-5 atoms of Halogens (for example, fluorine, chlorine, bromine, iodine/.

As the acyl groups represented by R7you can specify C1-4acyl group (for example, formyl, acetyl, propionyl, butteroil etc./, which may be optionally substituted by 1-5 atoms of Halogens (for example, fluorine, chlorine, bromine, iodine/.

In the present invention specifically disclosed the following connections:

3,5-CIS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2, neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-propyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-isobutyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester;

3,5-TRANS-7-chloro-5-/2-methoxyphenyl/-2-oxo-1-propyl-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester;

3,5-TRANS-7-chloro-5-/2-methoxyphenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester;

3,5-TRANS-7-chloro-5-/2-methoxyphenyl/-1-isobutyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-isobutyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-methoxyphenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-methoxyphenyl/-1-isobutyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

/3R/-7-chloro-5-/2-chlorophenyl/-2,3-dihydro-1-isobutyl-2-oxo-1H - 1,4-benzodiazepin-3-acetic acid methyl ester;

/3R/-7-chloro-5-/2-chlorophenyl/-2,3-1-isobutyl - 2-oxo-1H-1,4-benzodiazepin-3-acetic acid;

/3S/-7-chloro-5-/2-chlorophenyl/-2,3-dihydro-1-isobutyl - 2-oxo-1H-1,4-benzodiazepin-3-acetic acid methyl ester;

/3S/-7-chloro-5-/2-chlorophenyl/-2,3-dihydro-1-isobutyl - 2-oxo-1H-1,4-benzodiazepin-3-acetic acid;

/N-/3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepin-3-acetyl/glycine methyl ester;

/N-/3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepin-3-acetyl/glycine;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-3-dimethylaminocarbonylmethyl - 1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-besnoitiosis,

7-chloro-5-/2-chlorophenyl/-1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H- [1]-benzazepin-3-acetic acid ethyl ester;

7-chloro-5-/2-chlorophenyl/-1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H- [1]-benzazepin-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-1,2,3,5-tetrahydro - 2-thioxo-4,1-benzazepin-3-acetic acid ethyl ester;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-1,2,3,5-tetrahydro - 2-thioxo-4,1-benzazepin-3-acetic acid;

7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester;

3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester;

3,5-CIS-7-chloro-5-/2-methoxyphenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester;

3,5-TRANS-7-chloro-5-/2-methoxyphenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid;

3,5-CIS-7-chloro-5-/2-methoxyphenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid;

3,5-TRANS-7-chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester;

3,5-CIS-7-chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester;

3,5-TRANS-7-chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo - 1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid;

3,5-CIS-7-chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo - 1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2,3-acid/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2,4-acid/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2,3-acid/-1-isobutyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2,4-dimethoxy is oxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/4-hydroxy-2-methoxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/3-hydroxy-2-methoxyphenyl/-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/4-hydroxy-2-methoxyphenyl/-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/3-ethoxy-2-methoxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/4-ethoxy-2-methoxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/3-ethoxy-2-methoxyphenyl/-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/4-ethoxy-2-methoxyphenyl/-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chloro-2-methoxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chloro-4-methoxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chloro-3-methoxyphenyl/-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chloro-4-methoxyphenyl/-1 - isobutyl-2-one-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chloro-4-hydroxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chloro-3-hydroxyphenyl/-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid;

3,5-TRANS-7-chloro-5-/2-chloro-4-hydroxyphenyl/-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, etc.

As salts of the compound 1, 1', 1" and 1"' you can specify a pharmaceutically acceptable salt, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate and so on; such organic salts, such as acetate, tartrate, citrate, fumarate, maleate, toluensulfonate, methanesulfonate, and so on ; such metal salts as sodium salt, potassium salt, calcium salt, aluminum salt, and so on, and such salts of the bases, as salts of triethylamine, guardina, ammonium, hydrazine, quinine, cinnoline etc.

The method of obtaining the compounds of the present invention is as follows:

The compound of formula Ia

< / BR>
where Y' represents an optionally esterified carboxyl group whose values were defined for Y;

other symbols have the above meanings, can be obtained in the following ways (methods A and B, see the end of the description), where t is halogen, and other symbols have the above values.

Obtaining the compounds of formula Ia-1 from compounds of formula II in method A, the compounds of formula Ia-3 from compounds of formula II' in method B, can be conducted in a solvent, for example in that the solvent of the ether type, such as diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on, in such alcoholic solvent like methanol, ethanol, propanol, butanol, and so on; in acetone, dimethylformamide, dimethyl sulfoxide and acetic acid, and, if necessary, in the presence of acid /hydrochloric, Hydrobromic, idiscovered, sulfuric, phosphoric, methansulfonate, toluenesulfonic acid/. Relative to one mole of the compound represented by formula II or II', the compound represented by formula III are usually used in amounts of from 1 to 10 moles, preferably about 1-2 moles. The temperature range is 0-200oC, preferably from about 50 to 100oC. the reaction Time is usually from 1 to 24 hours, preferably from about 1 to 3 hours

The method of obtaining the compounds of formula Ia-2 from compounds of formula Ia-4 in method B can be maintained in such a solvent, such as diethyl EFL. in dimethylformamide or dimethylsulfoxide, optionally in the presence of a base (for example, sodium hydride, lithium hydride and so on/. Relative to one mole of the compound represented by formula Ia-4, the compound represented by formula V, is used usually in an amount of from 1 to 10 moles, preferably about 1-2 moles. The reaction temperature is a value from 0 to 200oC, preferably from about 20 to 100oC. the reaction Time is from 1 to 24 hours, preferably from about 1 to 5 hours

Obtaining the compounds of formula Ia-2 from compounds of formula Ia-1 in method A and obtaining compounds Ia-4 from the compounds of formula Ia-3 in method B can be conducted in a solvent, for example in water or such ethereal solvent like diethyl ether, tetrahydrofuran, dioxin, and so on; in such hydrocarbon solvents as benzene, toluene, hexane, heptane and so on; in this alcoholic solvent like methanol, ethanol, propanol, butanol, and so on, in acetone or dimethylformamide, and, if necessary, in the presence of a base (for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, hydride, sodium hydride, potassium hydroxide, sodium hydroxide, barium hydroxide and so on/. Relative to one mole of soybean is in the range from 1 to 10 moles, preferably, from about 1 to 2 moles. The reaction temperature in the range from 0 to 100oC, preferably from about 25 to 50oC. the reaction Time is usually from 1 to 24 hours, preferably from about 3 to 10 hours

Obtaining the compounds of formula Ia-1 from compounds of formula Ia-2 in method B can be maintained in such a solvent, such as water or in a solvent such as diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on, in such alcoholic solvent like methanol, ethanol, propanol, butanol, and so on, in acetone or dimethylformamide, and, depending on necessity, in the presence of a base (for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, barium hydroxide, etc.,/. The reaction temperature may be in the range from 0 to 100 preferably from about 20 to 50oC. the reaction Time is usually 1 to 24 hours, preferably 3-10 hours

The compounds of formula Ib

< / BR>
where all the symbols have the above values,

you can obtain the following methods C and D (see the end of the description), where R is such aminosidine group="ptx2">

In methods C and D obtain the compounds of formula VIII from the compounds of formula VI or the compounds of formula VIII' and the compound of formula VI' can be conducted in a solvent, for example in an ether solvent such as diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on, and in this haloesters solvent as dichloromethane, chloroform and so on, in acetonitrile or dimethylformamide, using a concentrating agent as diethylthiophosphate, dicyclohexylcarbodiimide and so on, and, if necessary, in the presence of a base (for example, triethylamine, 4-dimethylaminopyridine, N-methylpiperidine and so on/. In relation to pray one of the compounds represented by formula VI or formula VI', the compound represented by formula VII, is usually used in an amount of from 1 to 5 moles, preferably from about 1 to about 1.5 mole. The reaction temperature falls in the interval from 0 to 100oC, preferably from about 20 to 50oC. the reaction Time is from 1 to 24 hours, preferably from about 2 to about 5 hours In this case, when using a condensing agent, for one mol of the compounds of formula VI or formula VI', it is used usually in an amount of from 1 to 5 moles, predpochtitel is soedineniya formula Ib-3 from compounds of formula VIII' in the way that D can be maintained, for example, in such an ethereal solvent like diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent like benzene, toluene, hexane and so on, in such alcoholic solvent like methanol, ethanol, propanol, butanol, etc., in acetone, dimethylformamide, acetonitrile, haloesters solvent such as dichloromethane, chloroform and so on, by methods known reg se, for example, if R represents carbobenzoxy, catalyst recovery using palladium, platinum or similar, as a catalyst, whereas, if R is tert-butoxycarbonyl, subjecting the compound obtained by removing aminosidine group R, dissolution, or suspensioni in acid /for example, hydrochloric, banowati, triperoxonane/ for catalytic reduction, for example, in such an ethereal solvent like diethyl ether, tetrahydrofuran, dioxane and so on, such a hydrocarbon solvent like benzene, toluene, hexane, heptane, etc. such alcoholic solvent like methanol, ethanol, propanol, butanol, and so on, dimethylformamide, acetonitrile and, if necessary, in the presence of an acid such as hydrochloric, banowati, acetic, propionic, methansulfonate, colorswitch is about 30 to 70oC. the reaction Time is usually from 1 to 24 hours, preferably from 3 to 10 PM

Obtaining compounds Ib-1 from compounds of formula Ib-3 in method D can be done in much the same way as obtaining the compounds of formula Ia-2 from compounds of formula Ia-4 in method B to obtain a compound represented by formula Ia, as described previously. And obtaining the compounds represented by formula Ib-2 from the compound represented by formula Ib-1 in method C, and the compounds of formula Ib-2 from the compound represented by formula Ib-1 in method D, can be done in much the same way as the method of obtaining the compounds of formula Ia-1 from compounds of formula Ia-2 in method D to obtain the compounds represented by formula Ia, as described earlier.

The compound of formula Ic

< / BR>
where the symbols have the above meanings, can be obtained in the following ways:

< / BR>
< / BR>
where all the symbols have the above values.

The compound of formula X from compound IX, obtained by the method disclosed in J. Med. Chem. 27,1508 /1984/, J. Med. Chem, 14, 851, /1971/, you can get practically on the way to obtain the compounds of formula Ia-2 from compounds of formula Ia-4 in method B to obtain a compound represented by formula Ia. P is the firn solvent, as diethyl ether, tetrahydrofuran, dioxane and so on , a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on, dimethylformamide or dimethylsulfoxide, in the presence of sodium hydride, lithium hydride, sitedisability etc., Relative to one mole of the compounds of formula X, the compounds of formula XI are usually used as from 1 to 5 moles, preferably from about 1 to 2 moles. The temperature of the reaction is -78oC to 50oC, preferably from -78oC and 0oC. the reaction Time is usually from 1 to 24 hours, preferably from 3 to 10 hours Obtaining the compounds of formula Ic-2 from compounds of formula Ic-1 are almost the same as obtaining the compounds represented by formula Ia-2 in method B.

The compound of formula Ib

< / BR>
where the symbols have the above meanings, can be obtained by methods E, F and G (see the end of the description).

Compounds XIII of VI', XV XIV of the way E or compounds XVI of VI, XVII II in method F, can be obtained by using per se acylation reaction.

The acylation can be conducted in such a volatile solvent like diethyl ether, tetrahydrofuran, dioxane and so on, in such halide solvent, like dichloromethane, dichloroethane, chloroform, four is mamide, dimethyl sulfoxide, etc. and, if necessary, in the presence of water and base /for example, organic bases such as 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine etc., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc./. On one mol of the compounds of formula IV', XIV, VI or II are usually used from 1 to 10 moles of the acid chloride or methanesulfonamido, preferably, from 1 to 3 moles. The reaction temperature is usually in the range from -50 to 100oC, preferably from about 0o50oC. the reaction Time is usually from about 5 to 10 hours

Compound XIII' from compound XIII in method E, VI of VI' and II-II' in method F can be conducted in a solvent, for example ether solvent like diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on, in such alcoholic solvent like methanol, ethanol, propanol, etc., acetone, dimethylformamide, etc. and, if necessary, in the presence of a base (for example, sodium bicarbonate, of potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc./. On one mol of compound toctitle, from 1 to 2 moles. Temperature range of responses from 0 to 100oC, preferably from about 20 to 50oC. the reaction Time is usually from 1 to 24 hours, preferably from about 3 to 10 hours

Connection Id-I their XV in method E, II' VI' and the reduction of carbonyl groups VVII from XVI in method F can be maintained by processing the complex metalhydride /for example, sociallyengaged, natroalunite, nutritionallybalanced, detribalized etc./ proton solvent /methanol, ethanol, propanol, butanol and so on/ or in an aprotic solvent (for example, ethyl ether, tetrahydrofuran, dioxane and so on/. On one mol of the compounds of formula XV, VI or XVI of such complex metalhydride usually used in amounts in the range of from 0.3 to 5 moles, preferably from 0.5 to 2 moles. The reaction temperature is usually in the range of from -20 to 100oC, preferably from about 20 to 50oC.

The cyclization of Id-2 from compounds of formula XVII in method F lead in a solvent, for example, in the ether solvent such as diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on, in such alcoholic solvent like methanol, ethanol, propanecarboxylate sodium, of potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc./. On one mol of the compounds of formula XVII these grounds are usually used in quantities of from one to 5 moles, preferably from about 1 to 2 moles. The reaction temperature is the interval from -20 to 100oC. the Reaction usually occurs within 1 to 20 hours, preferably from about 2 to 5 hours

The reaction of obtaining compound XIII XIV of' in the way E can lead to alcohol represented by formula IV, and optionally in the presence of such inorganic acids as hydrochloric Hydrobromic, sulfuric, and so on, or such organic acids as toluensulfonate, methanesulfonate and so on, the reaction Temperature is usually in the range of from -20 to 100oC, preferably from about 20 to 50oC. the reaction Time is usually 10-100 hours, preferably 10-48 hours

Connection Id-4 Id-1 in method E, and the connection Id-4 Id-2 way F can be obtained in much the same way as compound Ia-1 Ia-2 in method B for the synthesis of compounds represented by formula Ia.

Compounds represented by Id-3 and Id-5 in method G, you can get known per se methods.

The compound of formula Id'

< / BR>
where the symbols have okanye earlier values.

The solvent can be any solvent which does not disturb the reaction, for example, acetone, dioxane, dichloromethane, dichloroethane, chloroform, etc. and as the oxidizing agent can be used permanganate, chromic acid, Nickel peroxide, etc., To one mol of compound Ik' use from 0.5 to 20 molar equivalents of oxidizing agent, preferably from 1 to 3 molar equivalents. The reaction temperature is usually from 0 to 100oC, preferably from 15 to 50oC. the reaction Time is from 0.5 to 5 hours, preferably from about 1 to 2 hours

The compounds of formula Ie

< / BR>
can be obtained in the following way:

or

< / BR>
< / BR>
< / BR>
where the symbols have the above values.

The compound of formula XXIII of the compounds of formula VI or formula XXII can be obtained by using one mol of the compounds of formula VI or formula XXII, usually from 1 to 10 moles, preferably 1-2 moles, of the compounds of formula XXIV in a solvent, for example, ether solvent such as diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent like benzene, toluene, hexane or heptane; an alcohol solvent as methanol, ethanol, propanol, butanol, and so on; or tocompetition from about 50 to 100oC. the reaction Time is from 1 to 48 hours, preferably from about 10 to 24 hours

The compound of formula Ie from compounds of formula XXIII can be obtained by using one mol of the compounds of formula XXIII, usually 1 to 10 moles, preferably 1-2 mol Carboniferous agent, including triphosgene, 1,1'-carbonyldiimidazole, 4-nitrophenyl, chloroformate or so on, in such a solvent which does not disturb the reaction, for example, in such an ethereal solvent like diethyl ether, tetrahydrofuran or dioxane; hydrocarbon solvents as benzene, toluene, hexane or heptane; an alcohol solvent as methanol, ethanol, propanol or butanol; in such a solvent as dimethylformamide or dimethylsulfoxide. The reaction temperature is usually in the range from 0 to 200oC, preferably from about 50 to 100oC. the reaction Time is 0.5 to 24 hours, preferably from about 1 to 5 hours

The compound of formula If

< / BR>
where the symbols have the above values,

can be obtained in the following way (see the end of the description),

where the symbols have the above values.

The compound of the formula XXVII compound of formula XXV and XXVI) can be obtained using one mol of the compounds of formula XXV from 1 dooi XXVI, in this ethereal solvent, as dimethylamide, ethyl ether, tetrahydrofuran, dioxane, etc. in the presence of sodium hydride, lithium hydride, alkylate or so on, the reaction Temperature is in the range from -78 to 100oC, preferably from about -20 to 30oC. the reaction Time is from 0.1 to 5 hours, preferably from about 0.5 to 2 hours

The compound of formula XXVIII of the compounds of formula XXVII can be obtained by processing the complex metalhydride /for example, sociallyengaged, natroalunite, detribalized, literalized etc. / in a solvent, for example, in proton solvent /methanol, ethanol, propanol, butanol and so on/ or in an aprotic solvent (for example, ethyl ether, tetrahydrofuran, dioxane and so on/. This set of metalhydride usually used for one mole of the compound of formula XXVII, in the amount of from 0.3 to 5 molar equivalents, preferably from about 0.5 to 2 molar equivalents. The reaction temperature is in the range of from -20 to 100oC, preferably from about 0 to 20oC. the reaction Time is usually from 0.5 to 10 hours, and preferably from 1 to 5 o'clock

The compound of formula XXIX can be obtained by oxidizing the compound of formula XXVIII. As the solvent, m is, is using, for example, dimethyl sulfoxide and oxalicacid, or pyridine and sulfur trioxide, for example, in a solvent such as dioxane, tetrahydrofuran, dichloromethane, dichloroethane, chloroform or so on, In this case, one mole of the compound represented by formula XXVIII, oxidizing agent used is from 0.5 to 20 molar equivalents, preferably from 1 to 3 molar equivalents. The reaction time is from 0.1 to 10 hours, preferably from about 0.2 to 2 hours, the reaction Temperature is from -78 to 50oC, preferably from -78 to 20oC. If necessary, the reaction can be conducted in the presence of a base (for example, 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine and so on/.

The compound represented by the formula XXX can be obtained by subjecting the compound represented by the formula XXIX and the compound represented by the formula XXXV, restorative aminating. For example, one mole of the compound represented by the formula XXIX, using from 0.5 to 10 molar equivalents, preferably from 0.5 to 1.5 molar equivalents of compounds of formula XXXV and from 0.3 to 5 molar equivalents, preferably from 0.5 to 1.5 molar equivalents of complex metalhydride /for example, nutribase, tetrahydrofuran, dioxane and so on; in a hydrocarbon solvent such as benzene, toluene, hexane, heptane and so on; or in an alcohol solvent such as methanol, ethanol, propanol, etc. the reaction Temperature is in the range of values from 0 to 100oC, preferably from about 30 to 60oC. the reaction Time is usually 1 to 24 hours, preferably from about 3 to 10 hours

The compound of formula XXXI can be obtained through the interaction of the compounds of formula XXX with triperoxonane anhydride or chloride triperoxonane acid. The reaction can be conducted using one mol of the compounds of formula XXX, from 0.5 to 3 molar equivalents, preferably 1-2 molar equivalents, triperoxonane anhydride or chloride triperoxonane acid, in this ethereal solvent like diethyl ether, tetrahydrofuran, dioxane and so on; such hydrocarbon solvents as benzene, toluene, hexane, heptane and so on; such halide solvent, like dichloromethane, dichloroethane, chloroform, and so on ; or dimethylformamide, at a temperature in the range from 0 to 100oC, preferably from about 20 to 50oWith, for from about 5 minutes to about 5 hours, preferably from about 0.1 to 1 o'clock This reaction can be conducted, if necessary, in pristine, tetramethylaniline, and so on, or sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate and so on/.

The compound of formula XXXII can be obtained by catalytic hydrogenation of compounds of formula XXXI using as a catalyst of palladium on charcoal, in an alcohol solvent such as methanol, ethanol, propanol, butanol, and so on; in dimethylformamide, acetonitrile, ethyl ether complex acetic acid, etc., the hydrogen Pressure is from 1 to 100 atmospheres, preferably 1 to 10 atmospheres, the reaction temperature from 0 to 200oC, preferably from about 20 to 50oC.

The compound of formula XXXIII can be obtained by the interaction of the compounds of formula XXXII and halogenated hydrocarbon groups; or in the reaction of reductive amination of the aldehyde or ketone groups. The conditions for getting it almost the same as the conditions for obtaining compounds of Ia-2 Ia-4 in method B in the case of obtaining the compound represented by the above formula Ia, or conditions of obtaining XXX from XXIV in the case of obtaining the compounds of formula If.

The compound of formula XXXIV can be obtained by hydrolysis of compounds of formula XXXIII in this alcoholic solvent like methanol, atii such acids, as hydrochloric, sulfuric, phosphoric, etc. the reaction Temperature is between 0 and 100oC, preferably from 30 to 70oC, and the reaction time is 1-48 hours, preferably from about 10 to 20 hours

The compound of formula If-1 of XXXIV, you can get practically the same as in the production method of the Ie-2 XXIII in the case of obtaining the compounds of formula Ie. A compound of formula If-2 If-1 can be obtained in much the same way as receiving Ia-1 Ia-2 in method B to obtain the compounds of formula Ia.

The compound of formula Ig

< / BR>
where the symbols have the above values,

can be obtained in the following way:

< / BR>
< / BR>
< / BR>
where the symbols have the above values.

The compound of formula XXXVI can get almost as well as get a connection Ia-2 Ia-4 in method B in the case of obtaining the compound represented by formula Ia, or by reductive amination, which is almost the same with getting XXIX XXX from in the case of obtaining the compounds of formula If.

The compound of formula XXXVII can be obtained by the interaction of the compounds of formula XXXVI with malonaldehyde, for example in such a volatile solvent like diethyl ether, tetrahydrofuran, dioxane and so on, so kusnoy acid, acetonitrile, water, etc., To one mol of compound XXXVI malonaldehyde used in an amount of from 1 to 10 molar equivalents, preferably from about 1 to 2 molar equivalents. The reaction temperature falls in the range from -20 to 100oC, preferably from 0 to 70oC, and the reaction time is 0.5 to 24 hours, preferably from about 1 to 3 hours

The compound of formula Ig-1 can be obtained by the interaction of the compounds of formula XXXVII with a compound of formula XXXVIII in the presence of, for example, sodium hydride, alkylate and so on, for example, in a solvent such as dimethylformamide, acetonitrile, diethyl ether, tetrahydrofuran, dioxane and so on, on one mol of the compounds of formula XXXVII use from 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents of compounds of formula XXXVIII and from 0.5 to 3 molar equivalents, preferably from 1 to 1.5 molar equivalents of sodium hydride or alkylate. The reaction temperature is from -20 to 100oC, preferably from 0 to 30oC, and the reaction time from 0.5 to 24 hours, preferably from about 1 to 3 hours

The compound of formula Ih

< / BR>
where the symbols have the above values,

can be obtained in the following way:

< / BR>
< / BR>
< / BR>

The compound of formula XXXX XXXXI, Ih-1 and h-2, you can get practically the same as in method G to obtain the compounds of formula Id.

The compound of formula Ii

< / BR>
where the symbols have the above values,

can be obtained by the reaction of compounds of formula ij

< / BR>
where the symbols have the above values,

with diphenylphosphorylacetate in a solvent in the presence of base, followed by treatment of the reaction product of the acid in the solvent. The solvent can be used for the reaction of compounds of formula Ij and diphenylphosphinite any solvent which does not interfere with the course of the reaction, and as an example, you can specify such halide solvent, like dichloromethane, dichloroethane, chloroform, and so on, such an ethereal solvent like diethyl ether, tetrahydrofuran, dioxane and so on, dimethylformamide, etc. as the substrate that can be used, you must specify the triethylamine, 4-dimethylaminopyridine, triethylenediamine, TETRAMETHYLBUTYL the IDA, preferably, from 1.5 to 3 molar equivalents. The reaction temperature is the interval from -20 to 50oC, preferably from about 0 to 20oC. the reaction Time is from 0.5 to 5 hours, preferably about 1-2 o'clock

In the case of processing the received product acid as solvent use water, dioxane, dimethylformamide and so on, and the acid can be used such mineral acids as sulfuric, hydrochloric, nitric, Hydrobromic acid, etc., the reaction Temperature is the range from about 50 to 100oC. the reaction Time is from 0.5 to 5 hours, preferably about 1-2 o'clock

The compound of formula Ik

< / BR>
where the symbols have the above values,

can be obtained by restoring the compound of the formula Im

< / BR>
where m' = 1, 2, or 3;

other symbols have the above values.

For example, the connection Ik can be obtained by treating compound Im complex metalhydride /for example, sociallyengaged, natroalunite, sodium borohydride, etc./ proton solvent /methanol, ethanol, propanol, butanol, etc./ or aprotic solvent (for example, ethyl ether, tetrahydrofuran, dioxane and so on/. On Odie is bivalents complex metalhydride. The reaction temperature falls in the range from -20 to 100oC, preferably from about 0 to 20oC. the reaction Time is usually from 0.5 to 10 hours, preferably from about 1 to 3 hours

The compound of formula Ik can also be obtained by transforming the amine portion of the compounds of formula Ii in a hydroxyl group. For example, the connection Ik can be obtained by adding sodium nitrite to the compound Ii in a solvent in the presence of acid, then treating the thus obtained azide in a solvent in the presence of a base. To obtain diazocompounds, on one mole of the compound of formula Ii is used from 0.5 to 3 molar equivalents, preferably from 1 to 1.5 molar equivalents of sodium nitrite in a solvent, for example in water, in aqueous dioxane or aqueous dimethylformamide. The acid can be any acid, unless it does not interfere with the reaction such as acetic acid, sulfuric acid, etc., the reaction Temperature falls in the range from -20 to 20oC, preferably from 0 to 5oC, and the reaction time is from 5 to 60 minutes, preferably from about 10 to 30 minutes

The compound of formula XXXXII

< / BR>
where Q' is halogen /chlorine, bromine, iodine/;

other characters have mentioned previously the AK in the case of obtaining the compounds of formula Ik of the compounds of formula Ii, as a result of interaction of the compounds of formula Ii with sodium nitrite in hydrochloric acid /reaction diazotization/, Hydrobromic acid or idiscovered acid, followed by heating the resulting product. The reaction temperature in the range from 20 to 200oC; preferably from 50 to 100oC. the reaction Time is from 5 minutes to 2 hours, preferably from about 15 to 30 minutes

The connection formulas In

< / BR>
where Y" is among the values specified for Y, esterified carboxyl group, possibly substituted carbomoyl group, hydroxyl group, hydrogen, halogen /chlorine, bromine, iodine/;

other symbols have the above values,

can be obtained by condensation of compounds of formula Ij and the compounds of formula XXXXIII

< / BR>
where the symbols have the above values.

The compound of formula Ij and the compound of formula XXXXIII condense in the presence of a condensing agent in a solvent, and optionally in the presence of a base. Examples of the used solvents can serve as hydrocarbon solvents such as benzene, toluene, hexane, heptane and so on, such halide solvents, such as dichloromethane, dichloroethane, chloroform, chetyrekh is home to the thrill, dimethylformamide, etc. Examples of bases include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine and so on, as a condensing agent, you must specify the agents used in the synthesis of peptides, for example, dicyclohexylcarbodiimide, diethylthiophosphate, 1-ethyl-3-/3-dimethylaminopropyl/carbodiimide, etc. On one mol of the compounds of formula /Ij/ use from 0.5 to 2 molar equivalents, preferably 1 to 1.2 molar equivalents of the compounds of formula XXXXIII, and from 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents of a condensing agent. The reaction temperature is from 0 to 100oC, preferably from 2 to 50oC. the reaction Time is from 0.5 to 24 h, preferably about 1-5 hours

The compound of formula Io

< / BR>
where the symbols have the above values,

you can get in the interaction of the compounds of formula Ij with diphenylphosphorylacetate in a solvent in the presence of a base followed by reaction of the resulting product with a compound of formula XXXXIII in the solvent. For the reaction of compounds of formula Ij with diphenylphosphorylacetate can be used any solvent which does not interfere with the reaction, and examples of such restoratively, as ether, tetrahydrofuran, dioxane, etc. or dimethylformamide. As a possible reason, you can specify triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine. On one mol of the compounds of formula Ij is used from 1 to 10 molar equivalents, preferably from 1.5 to 3 molar equivalents dimethylacetanilide. The reaction temperature from -20 to 50oC, preferably from 0 to 20oC. the reaction Time is from 0.5 to 5 hours, preferably from about 1 to 2 hours

Examples of solvents that can be used in the reaction of thus obtained product with a compound of formula XXXXIII include halide solvents, such as dichloromethane, dichloroethane, chloroform, etc. such ethereal solvents, such as ether, tetrahydrofuran, dioxane and so on, acetonitrile, dimethylformamide, etc. If necessary, use the base as a basis, you can specify such organic bases like triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, etc. On one mol of the compounds of formula Ij using 0.5 to 3 molar equivalents, preferably from 1 to 1.5 molar equivalents of the compounds of formula XXXXIII. The reaction temperature from 0 to 150oC, predpochtitelnye formula Ip

< / BR>
where the symbols have the above values,

can be obtained by condensing the compound of formula Ii with a compound of formula XXXXIV

< / BR>
where the symbols have the above values.

This reaction can be conducted similarly as in the method of obtaining the compounds of formula In.

The compound of formula Iq

< / BR>
where E' represents an oxygen atom or-NH - groups defined previously for E';

other symbols have the above values,

can be obtained by the reaction of compounds of formula Ii and compounds represented by the formula Ik with a compound of formula XXXXV

< / BR>
where the symbols have the above values.

More specifically, the compound of formula Ii or the compound of formula Ik is subjected to interaction with the compound of the formula XXXXV in a solvent such as an alcohol solvent, like methanol, ethanol, propanol, butanol, and so on, this ethereal solvent like diethyl ether, tetrahydrofuran, dioxane and so on , in dimethylformamide, etc. in the presence of a base, for example, inorganic bases such as sodium bicarbonate, potassium carbonate and so on, such organic bases like triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetr to 1.5 molar equivalents of the compounds of formula XXV, and on one mol of the compounds of formula Ii or the compound of formula Ik is used from 1 to 5 molar equivalents, preferably 1-2 molar equivalent of base. The reaction temperature from 0 to 200oC, preferably from 20 to 100oC. the reaction Time is 0.5 to 24 hours, preferably from about 1 to 3 hours

The compound of formula Ir

< / BR>
where the symbols have the above values,

can be obtained by the reaction of compounds of formula XXXXII with the compound of the formula XXXXVI

< / BR>
where the symbols have the above values.

Examples of possible solvents include aprotic solvents, such as ethyl ether, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, etc. and , if necessary, inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and so on, such organic bases like triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine etc., sodium hydride, cesium fluoride, etc., To one mol of the compounds of formula XXXXII use from 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents of the compounds of formula XXXXVI. The reaction temperature from 0 to 20oC, preferably from 20 to the e formula Is

< / BR>
where the symbols have the above values,

you can get gidrolizu compound of the formula It

< / BR>
where Y represents esterified carboxyl group among the groups defined for Y.

More specifically, the compound of the formula It hydrolyzing in a solvent such as water, methanol, ethanol, propanol, butanol, etc., in the presence of hydroxide of alkali metal such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc./ or sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, or in the presence of a mineral acid /nitric, hydrochloric, Hydrobromic, folic acid, sulfuric acid, etc. / or triperoxonane acid at a temperature of from 10 to 150oC, preferably from 10 to 50oC. the reaction Time varies depending on temperature, and is usually from 1 to 24 h, preferably from 2 to 10 o'clock

The compound of formula Iu

< / BR>
where Y represents optionally substituted carbomoyl group among the groups mentioned for Y;

other symbols have the above values,

can be obtained by condensation of compounds of formula Iv

< / BR>
where the symbols have the listed ranea" defined for Y". The reaction can be conducted in almost the same conditions as in the case of obtaining the compound represented by formula 3 In.

The compound of formula Iw

< / BR>
where R8is the Deputy of the "optionally substituted hydroxyl group", defined for Y;

other symbols have the above values,

you can get almost the same way as in the method of obtaining the compounds of formula Iq of the compounds of formula Ix

< / BR>
where the symbols have the above values,

and the compounds of formula XXXXVII

HO-R8< / BR>
where the symbols have the above values.

The compound of formula Iy

< / BR>
where R9is optionally substituted by an amino group as defined for Y;

other symbols have the above values,

you can get almost the same way as the compound of formula Iq of the compounds of formula XXXXVIII

H-R9< / BR>
where the symbols have the above values,

and the compounds of formula Ix.

The compound of formula Iz

< / BR>
where the symbols have the above meanings, can be obtained by the interaction of the compounds of formula I

< / BR>
where the symbols have the above values,

meta is hydrofuran, dioxane and so on, such a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on, such halide solvent as dichloromethane, chloroform, etc., acetonitrile, dimethylformamide, etc., To 1 mol of the compound I use is usually from 1 to 5 moles, preferably 1 to 1.5 moles of metallocarboranes acid. The reaction temperature is in the range from 0 to 100oC, preferably from 0 to 30oC. the reaction Time is from 1 to 10 hours, preferably from about 1 to 2 hours

The compound of the formula I

< / BR>
where the symbols have the above values,

can be obtained by using as starting material the compound of formula Iz or formula I , almost the same as in the case of obtaining the compounds of formula Iz of the compounds of formula I.

The compound of the formula I

< / BR>
where the symbols have the above values,

can be obtained by restoring the connection of the formula I

< / BR>
where the symbols have the previous values,

in a solvent, e.g. in water, then alcohol solvent as methanol, ethanol, propanol, etc. in this ethereal solvent like diethyl ether, tetrahydrofuran, dioxane and so on, in such a hydrocarbon solvent, like dichloromethane, chloroform sodium, etc. On 1 mol of the compounds of formula I used is from 0.2 to 5 molar equivalents, preferably from about 0.3 to 1 molar equivalent of a reducing agent. The reaction temperature from 0 to 100oC, preferably from 20 to 50oC. the reaction Time is from 0.5 to 10 hours, preferably from about 1 to 3 hours

The connection formulas

< / BR>
where the symbols have the above values,

you can get as a result of interaction of the compounds of formula I

< / BR>
where the symbols have the above values,

with a reagent of Lawesson or pentasulfide phosphorus in a solvent such as an alcohol solvent, like methanol, ethanol, propanol, etc. in this ethereal solvent like diethyl ether, tetrahydrofuran, dioxane and so on, such a hydrocarbon solvent like benzene, toluene, hexane, heptane and so on , such halide solvent as dichloromethane, chloroform, etc., hexamethylphosphoramide, dimethyl sulfoxide, etc., To 1 mol of the compounds of formula I used is from 1 to 10 molar equivalents, preferably from 1 to 3 molar equivalents of the reagent Lowassa or pentasulfide phosphorus. The reaction temperature from 0 to 150oC, preferably from about 50 to 100oC. the reaction Time is from one to 24 h, p the e values

you can get as a result of interaction of the compounds of formula I with the compound of the formula XXXXIX

R7-Q',

where the symbols have the above values,

almost in the same conditions as in the case of obtaining compound XIII in method E, VI, II in method F in the compounds represented by formula Id.

At that time, as compounds represented by the General formulas I, I', I" and I"' of the present invention have an inhibitory effect on squalene-synthetase or antifungal activity, among the compounds of the present invention are compounds capable of inhibiting other enzymes in the scheme of the biosynthesis of cholesterol. If so, the connection represented by the formulas I, I', I" and I"' should inhibit the biosynthesis of cholesterol, which is necessary for the prevention or treatment of hypercholesterinemia or coronary sclerosis in mammals /for example, mice, rats, rabbits, dogs, cats, cows, pigs and people/ and also for the prophylaxis or treatment of fungal infections.

These compounds can enter people oral or parenteral. Compositions for oral administration can be in solid or liquid form, more specifically, in the form of tablets /including tablets with sugar coating and These compositions can be obtained known per se methods, and they contain carriers or excipients that are commonly used in pharmaceutical preparations, such carriers or excipients as lactose, starch, sucrose or stearate to obtain tablets.

Compositions for non-oral administration presents solutions for injection and suppositories, and injectable preparations include injections through the skin, subcutaneous and intramuscular. These injections can be obtained known per se methods, more specifically, due to the suspension or emulsification of the compounds of the present invention in sterile water and the oils that are commonly used to obtain a composition for injection. Water liquid intended for use in the preparation of solutions for injection include physiological solution and isotonic solution, and, if necessary, suitable suspendisse agent, such as sodium carboxymethyl cellulose, non-ionic surface active agent or similar as oils, you can specify sesame oil, soybean oil and so on, and along with this you can use benzyl benzoate, benzyl alcohol, etc. as agents contributing to the dissolution. Thus prepared preparado low toxicity and safe to use. Although the daily dosage depends on the condition and weight of the body of the proposed patient, the type of connection, the method of administration, and so on, in the case of the introduction of the compounds of the present invention for therapy of hypercholesterinemia, the daily dose for oral administration for adults is from about 1 to 500 mg, preferably from about 10 to 200 mg. within these limits, the toxicity is not observed.

An effective daily dose of the compounds I, I', I" and I"' with the introduction of mammals /for example, for adults as an inhibitor of squalene synthetase, is from about 1 to 500 mg, preferably from about 10 to 200 mg in the case of oral administration, whereas in the case of non-oral administration of /for example, in the form of injections, suppositories, etc./, this interval is from about 0.1 to 100 mg, preferably from about 1 to 50 mg.

In addition, compound I, I', I" and I"' demonstrate a wide spectrum of antibacterial activity, which is defined in ways dilution broth or agar.

An effective daily dose for adults compounds I, I', I" and I"' for combating fungi with the introduction of mammals /for example, people, etc./ make up from about 0.1 to 100 mg, preferably from about 1 to 50 mg in the case of oral administration, while in the 100 mg, preferably, from 1 to 50 mg.

In the present invention abbreviations of amino acids are given in accordance with the nomenclature of the IUPAC-IUB, or given trivial names. For example, Tryp: tryptophan, Ser: serine, Asp: aspartic acid, Glu: glutamina acid, Gly: glycine, Leu: leucine, Ala: alanine, Me: methyl, Et: ethyl, and Ph: phenyl. In cases where amino acids have optical isomers, they are L-isomers, unless otherwise indicated.

The following examples, examples of the compositions and test examples are intended merely for purposes of illustration of the invention and in no way are limiting.

In the following descriptions, the stereoisomers obtained depending on the types of compounds if groups X' and R2or R2related to saturated carbon atoms. Those isomers in which the group X' and R2or R2' are oriented in the direction of the plane of the rings J1I , J2or J', called CIS-isomers, whereas those in which the groups X' and R2or R2' are oriented in the opposite direction to each other, are called TRANS-isomers.

Example 1. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl complex is si conc. hydrochloric acid /60 ml/ and acetic acid /60 ml/, and the resulting solution was stirred for 3 h at 100oC. the Reaction mixture is cooled, and to it was added 100 ml of 3 N. aqueous sodium hydroxide solution. The resulting mixture was extracted with dichlorocarbanilide by tetrahydrofuran, 10% volume/volume/. The extract obtained was washed with a saturated aqueous solution of ameriglide, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is dissolved in dimethylformamide containing 3% xylene /the volume of/the amount of/ and the resulting solution was heated overnight at boiling under reflux. The solvent is distilled off. To the residue add methanol /50 ml and concentrated sulfuric acid /0.5 ml/. The resulting mixture is boiled for 3 hours under reflux. The solvent is distilled off. The residue is dissolved in dichloromethane, the resulting solution was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from a mixture of dichloromethane/petroleum ether, to obtain 5.6 g of colorless crystals, so pl. 200-205oC.

Elemental analysis for C18H15Cl2NO33H2O:

Calculated: C 53,82; H 3,91; N 3,49

Found: C 53,78; H 4,0 slots methyl ester

< / BR>
5-Chloro /2-chlorophenyl/-3-/neopentylene/benzyl alcohol /6.5 g/ and diablocody acid /2.85 g/ treated by the method of example 1. The obtained residue is recrystallized from a mixture of dichloromethane/petroleum ether, to obtain 2,31 g of colorless crystals. So melting 153-156oC.

Elemental analysis for C23H25Cl2NO3S:

Calculated: C 59,23; H 5,40; S 6,87; 3,00 N

Found: C 58,99; H 5,32; S TO 6.80; N WAS 2.76

Example 3. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
The residue obtained by concentrating the mother liquor obtained after elimination of the CIS isomer by filtration after recrystallization in example 2, is dissolved in 30 ml of methanol. To this solution was added potassium carbonate /0.87 g/, and the resulting mixture stirred for 3 h at room temperature. The reaction mixture was concentrated, dissolved in dichloromethane. The resulting solution was washed with water, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel /eluent hexane; ethyl ester of acetic acid 3:1 /the volume of/the amount of/ to obtain a solid product, cat. melting 133-136oC.

Elemental analysis: for C23H25Cl2NO3S:

Calculated: C 59,23; H of 5.40; N 3,00; S 6,87

Found: C 59,36; H and 5.30; N 2,84; S 6,86

Example 4. 3,5-TRANS-7-Chloro-/2-chlorophenyl/-1-propyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
A solution of ester methyl 3,5-TRANS-7-chloro-/2-chlorophenyl/- 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid /0.5 g/ obtained in example 1 in 5 ml of dimethylformamide is cooled to 0oC. To this solution was added sodium hydride /36 mg/, and the resulting mixture stirred for 5 min at 0oC. To this solution was added to 0.19 g of 1-bromopropane, and the resulting mixture stirred for 3 h at room temperature. To the reaction mixture, water is added, and extracted with dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is purified on a chromatographic column with silica gel /hexane: ethyl ester of acetic acid = 3: 1 /the volume of/the volume of/ as eluent to obtain 0.56 g of colorless oily compound.

IRmaxcm-1: 1740, 1670

1H NMR /CDCl3

Example 5. In much the same way as in example 4, to obtain the following compounds (see table. 1 in the end of the description).

Example 6. 7-Chloro-5-/2-methoxyphenyl/-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
2-Amino-5-chloro -- /2-methoxyphenyl/benzyl alcohol /1 g/ and diablocody acid /0.6 g/ handle almost by the method of example 1, and the gain of 1.34 g of a pale yellow amorphous substance IRmax/KBr/ cm-1: 1740, 1680

1H NMR /CDCl3/ : 2,394 - 2,535 /1H, m, 3,031 - 3,187 /1H, m/; 3,64, 3,691 /6H, each s/, 3,792 - 3,925 /1H, m, 5,512, 6,237 /1H/, 6,744 - 6,783 /7H, m/.

Example 7. 3,5-TRANS-7-Chloro-5-/2-methoxyphenyl/-2-oxo-1-propyl - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
7-Chloro-5-/2-methoxyphenyl/-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepine-3-acetic acid methyl ester /0.5 g/, obtained in example 6, is treated according to the method of example 4, resulting in a gain of 0.17 g of colorless crystals, So melting 81 - 107oC.

Elemental analysis for C22H24ClNO4S O 3H2O:

Calculated: C 60,14; H 5,64; N 3,19.

Found: C 59,97; the ENT -- /2-methoxyphenyl/benzyl alcohol treated according to the method of examples 2 and 3 to obtain the following compounds, are given in table. 2.

Example 9. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid

< / BR>
To a mixture of 2 ml of water and 4 ml of methanol is added 3,5-TRANS - 7-chloro-5-/2-chlorophenyl/-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepine-3-acetic acid methyl ester /0.15 g/, obtained in example 3, and the potassium carbonate /0.07 g/. The resulting mixture was heated to 60oC for 2 hours boiling under reflux, add 50 ml of water. The solution is acidified with 1N. HCl, extracted with dichloromethane. The extract obtained was washed with a saturated aqueous solution of ameriglide, dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is recrystallized from a mixture of dichloromethane/petroleum ether to obtain 0.12 g of colorless crystals. So melting 269 - 271oC.

Elemental analysis for C22H23Cl2NO3S:

Calculated: C 58,41; H 5,12; N 3,10; S 7,09

Found: C 58,39; H 5,19; N 2,84; S 6,78

Example 10. Almost by the method of example 9 receive connection table. 3 (see the end of the description).

Example 11. /3R/-7-Chloro-5-/2-chlorophenyl/-2,3-dihydro-2-oxo - 1H-1,4-benzodiazepine-3-acetic acid methyl ester

< / BR>
/1/, /3R/-3-B IS.

In 50 ml of dichloromethane was dissolved N-benzyloxycarbonyl-D-asparginase acid beta-methyl ester /4.3 g/. The resulting solution was cooled to 0oC add 1.6 g N-methylmorpholine and 2.2 g of isobutylacetate. The resulting mixture was stirred for 10 min at room temperature, add a solution of 2-amino-2', 5-dichlorobenzophenone /4.1 g/ 20 ml dichloromethane. The resulting mixture is heated for 20 minutes under reflux. The reaction mixture is stirred for 2 days at room temperature, add 100 ml of dichloromethane. The mixture is washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate and saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from a mixture of hexane/ethyl acetate/ 3 : 1 /the volume of/the amount of/ before getting to 3.73 g of pale yellow crystals.

So melting 160 - 162oC.

/2/,/3R/-7-Chloro-5-/2-chlorophenyl/-2,3-dihydro-2-oxo-1H - 1,4-benzodiazepine-3-acetic acid methyl ester.

To a solution of the compound obtained in /1/ /3,76/g/ 60 ml of methanol is added 10% Pd/C /0.5 g/ and a concentrated HCl /0,59 ml/. The resulting mixture is subjected to catalytic reset is the headed the remainder is dissolved in a mixed solvent /dichloromethane : tetrahydrofuran = 9 : 1/ /100 ml. The resulting solution was washed with aqueous sodium bicarbonate solution and a saturated aqueous saline solution, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is dissolved in dimethylformamide /20 ml/ add acetic acid /1 ml and stirred for 2 h at 60oC. To the reaction mixture are added 50 ml of ethyl acetate, stirred for 2 h at 60oC. To the reaction mixture are added 50 ml of ethyl acetate, washed with 5% aqueous solution of acid potassium sulfate, saturated aqueous sodium bicarbonate and saturated aqueous salt solution. The solvent is then distilled off and the residue is recrystallized from ethyl acetate to obtain 2,97 g of colorless crystals. So melting 168 - 170oC.

Elemental analysis for C18H14Cl2N2O3O 75H2O:

Calculated: C 55,33; H 4,00; N 7,17

Found: C 54,92; H of 3.60; N 7,21

Example 12. /3R/-1-Isobutyl-7-chloro-5-/2-chlorophenyl/-2,3 - dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester

< / BR>
/3R/-7-Chloro-5-/2-chlorophenyl/-2,3-dihydro-2-oxo-1H-1,4 - benzodiazepine-3-acetic acid methyl ester /0.5 g/, obtained in example 11 and Isopropylamine /0,23 g/ handle almost by the method of example 4 to
1H-NMR /CDCl3/ : 0,795 /3H, d, J = 6,4 Hz/, 0,882 /3H, d, J = 6,6 Hz/, 1,759 /1H, m/ 3,220 /1H, DD, J = 7,0, 16,8 Hz/, 3,438 /1H, DD, J = 7,4, 16,8 Hz/, 3,528 /1H, q, J = 4,8, 14,2 Hz/, 3,723 /3H/, 4,167 /1H, t, J = 7,1 Hz/, 4,332 /1H, DD, J = 10,0, 14,2 Hz/, 7,078 /1H, d, J = 2,4 Hz/ 7,371 - 7,532 /6H, m/.

Example 13. /3R/-1-Isobutyl-7/chloro-5-/2-chlorophenyl/- 2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid

< / BR>
/3R/-1-Isobutyl-7-chloro-5-/2-chlorophenyl/-2,3-dihydro-2-oxo-1H - 1,4-benzodiazepine-3-acetic acid methyl ester /0,23 g/, obtained in example 12, handle practically by the method of example 9 to obtain 0.11 g of colorless crystals. So melting 175 - 178oC.

Elemental analysis for C21H20Cl2N2O3O 2H2< / BR>
Calculated: C 59,65; H a 4.86; N 6,62

Found: C 59,54; H 4,96; N 6,62

Example 14. /3R, 5S/-1-Isobutyl-7-chloro-5-/2-chlorophenyl/-2,3,4,5 - tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid

< / BR>
In a mixed solvent /methane : water = 6 : 1/ /0.7 ml/ dissolve /3R/-1-isobutyl-7-chloro-5-/2-chlorophenyl/-2,3-dihydro - 2-oxo-1H-1,4-benzodiazepine-3-acetic acid /30 mg, obtained in example 13. To this solution was added sodium borohydride /10 mg/. The reaction mixture is stirred for two hours at room temperature, add dichloromethane /50 ml/ and water /50 ml/. Water t. The solvent is removed and the residue is recrystallized from a mixture of dichloromethane/petroleum ether to obtain 17 mg of colorless crystals. So melting 184 - 188oC.

Elemental analysis for C21H22Cl2N2O3H2O:

Calculated: C 57,41; H 5,50; N 6,38

Found: C 57,56; H 5,16; N 6,40

Example 15. /3S/-7-Chloro-5-/2-chlorophenyl/-2,3-dihydro-2-oxo-1H - 1,4-benzodiazepine-3-acetic acid methyl ester

< / BR>
N-Benzyloxycarbonyl-L-asparginase acid beta-methyl ester is processed according to the method of example 11 to obtain recrystallizes solid product.

IRmaxKBr/ cm-1: 1740, 1690, 1610

1H-NMR /CDCl3/ : 3,218 /1H, DD, J = 6,8, 17,0 Hz/, 3,447 /1H, DD, J = 7,4, 17,0 Hz/, 3,756 /3H/, 4,234 /1H, t, J = 7,1 Hz/, 7,069-7,130, 7,353-7,486 /7H, m/.

Example 16. /3S/-1-Isobutyl-7-chloro-5-/2-chlorophenyl/2,3-dihydro-2 - oxo-1H-1,4-benzodiazepine-3-acetic acid methyl ester

< / BR>
/3S/-7-Chloro-5-/2-chlorophenyl/-2,3-dihydro-2-oxo-1H-1,4 - benzodiazepine-3-acetic acid methyl ester obtained in example 15, is treated according to the method of example 4 to obtain blignault oily compounds

IRmax/net/ cm-1: 1740, 1680, 1610.

1H-NMR /CDCl33H, with/, 4,166 /1H, t, J = 7,1 Hz/, 4,332 /1H, DD, J = 10,0 14,2 Hz/, 7,077 /1H, d, J = 2,4 Hz/, 7,370-7,530 /6H, m/.

Example 17. /3S/-7-Chloro-5-/2-chlorophenyl/-2,3-dihydro-1-isobutyl - 2-oxo-1H-1,4-benzodiazepine-3-acetic acid

< / BR>
/3S/-1-Isobutyl-7-chloro-5-/2-chlorophenyl/2,3-dihydro-2-oxo-1H - 1,4-benzodiazepine-3-acetic acid methyl ester is treated almost by the method of example 9 to obtain a colorless solid connections. So melting 171-179oC.

Elemental analysis for C21H20Cl2N4O3:

Calculated: C 60,15; H to 4.81; N 6,68

Found: C 60,41; H 4,89; N 6,85

Example 18. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzodiazepine-3-acetic acid methyl complex ester S-oxide

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzodiazepine-3-acetic acid methyl ether complex /1 g/ obtained in example 3 in 10 ml of dichloromethane add 0,37 g metallocarboranes acid, stirred for 10 min at room temperature. To the reaction mixture are added 50 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated aqueous salt dissolve armedangels until receipt of 0.59 g of colorless crystals. So melting 166-169oC.

Elemental analysis for C23H25Cl2NO4S I7H2O:

Calculated: C 53,85; H 5,58; N 2,73

Found: C 53,70; H 5,27; N 2,36

Example 19. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl complex ester S-oxide

< / BR>
3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl complex ester S-oxide /0.5 g/ obtained in example 18, the handle almost to the method of example 9 to obtain 0,38 g of colorless crystals. So melting 230-235oC.

Elemental analysis for C22H23Cl2NO4S:

Calculated: C 56,41; H of 4.95; N, 2,99

Found: C 56,36; H 5,04; N 3.04 FROM

Example 20. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-L-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ether complex S-dioxide

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin acetic acid methyl ether complex /0.3 g/, obtained in example 3 in 10 ml of dichloromethane added 0.25 g of metallocarboranes acid and the resulting mixture stirred for 2 h at room temperature, and then store the CLASS="ptx2">

Elemental analysis: for C23H25Cl2NO5S:

Calculated: C 46,14; H is 5.06; N 2,81

Found: C 46,22; H 5,16; N 2,69

Example 21. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid S-dioxide

< / BR>
3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid /0.3 g/, obtained in example 9, process, almost by way of example 18 and example 20 to obtain 0.14 g of colorless crystals. So melting 245-249oC.

Elemental analysis for C22H23Cl2NO5S O2H2O:

Calculated: C EUR 54.15; H a 4.83; N 2,87

Found: C 54,08; H a 4.83; N 2,65

Example 22. N/3,5-TRANS/-1-Neopentyl-7-chloro-5-/2-chlorophenyl/-2 - oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl/glycine methyl ester

< / BR>
In 2 ml of dichloromethane was dissolved 3,5-TRANS-7-chloro-5-/2 - chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine - 3-acetic acid /0.1 g/, obtained in example 9, and the hydrochloride of the methyl complex ester of glycine /31 mg/. At 0oC to this solution was added 54 mg diethylthiophosphate and 49 mg of triethylamine. The resulting mixture was stirred for 30 min at room temperature. To the reaction mixture 5 is a thief, followed by drying over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from a mixture of dichloromethane/petroleum ether to obtain 99 mg of colorless crystals. So melting point 188-189oC.

Elemental analysis for C25H28Cl2N2O4S:

Calculated: C 57,36; H 5,39; N 5,35

Found: C 57,36; H 5,39; N 5,19

Example 23. N/3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2 - oxo-1-2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl/glycine

< / BR>
The compound obtained in example 22 /50 mg/ hydrolized according to the method of example 9 to obtain 35 mg of colorless crystals, So melting 229 - 230oC.

Elemental analysis for C24H26Cl2N2O4SO3H2O:

Calculated: C 55,99; H to 5.21; N, 5,44

Found: C 55,98; H 5,09; N OF 5.29

Example 24. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-3 - dimethylaminocarbonylmethyl-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzothiazepin

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid /1 g/ obtained in example 9, and dimethylaminohydrolase /0.2 g/ 20 ml dichloromethane add diethylthiophosphate /375 mg/ triethylamine /558 g/. The resulting mixture was stirred for 30 min at the room for the m sodium bicarbonate and aqueous salt solution, the solvent is then distilled off. The residue is recrystallized from a mixture of dichloromethane/petroleum ether to obtain 0,98 g of colorless crystals. T. melting point 190 - 193oC.

Elemental analysis for C24H28Cl2N2O2S:

Calculated: C 60,12; H of 5.89; N OF 5.84

Found: C 59,99; H 5,88; N OF 5.92

Example 25. 7-Chloro-5-/2-chlorophenyl/-1-isobutyl-2-oxo-2,3,4,5 - tetrahydro-1H-[1]-Betaseron-3-acetic acid ethyl ester

< / BR>
By the way, opened in J. Med. Chem. 27, 1508 /1984/, J. Med. Chem. 14, 851 /1971/ synthesize intermediate compounds.

/1/. 3-/Etoxycarbonyl/-4-/2-chlorophenyl/-4-phenyl-3-butenova acid, oily connection

IRmax/net/ cm-1: 1730, 1715, 1705

/2/. 4-/2-Chlorophenyl/-4-phenylalkanoic acid ethyl ester, oily connection

IRmax/net/ cm-1: 1730.

1H NMR /CDCl3/ : 1,23/3H, t, J = 7,1 Hz/, 2,2 - 2,5 /4H, m, 4,10/2H, q, J = 7,1 Hz/, 4,45 - 4,6 /1H, m, 7,0 - 7,4 /9H, m/,

/3/. 4-/2-Chlorophenyl/-4-fenilalanina acid.

T. melting 133 - 135oC.

Elemental analysis for C16H15ClO2:

Calculated: C 69,95; H 5,50

Found: C 70,10; H 5,42

/4/. 4-/2-Chlorophenyl/-1-tetralone, oily connection

IRmax/net/ cm /5/ 4-/2-chlorophenyl/-1-tetralone. T. melting point 114 - 115oC.

/6/ 5-/2-chlorophenyl/-2,3,4,5-tetrahydro-1H-/1/benzazepin-2-he

T. melting 226 - 227oC

Elemental analysis for C16H14ClNO:

Calculated: C 70,72; H 5,19; N 5,15

Found: C is 70.94; H 5,20; N 5,20

/7/. 5-/2-Chlorophenyl/-1-isobutyl-2,3,4,5-tetrahydro-1H-[1] - benzazepin-2-it.

To a solution of 5-/2-chlorophenyl/-2,3,4,5-tetrahydro-1H-[1]- benzazepin-2-it /2.8 g/ and isobutyramide /2,24 ml/ 20 ml of dimethylformamide added sodium hydride /0,82 g, 60% oil/ at 0oC. the resulting mixture was stirred at room temperature for 4 h, the solvent is distilled off and the residue is purified on a chromatographic column with silica gel to obtain 2,98 g of colorless crystals. T. melting 139 - 140oC

Elemental analysis for C20H22ClNO:

Calculated: C 73,27; H 6,76; N 4,27

Found: C 73,08; H 6,69; N 4,36

/8/. 7-Chloro-5-/2-chlorophenyl/-1-isobutyl-2,3,4,5-tetrahydro-1H- [1]-benzazepin-2-he

A solution of 5-/2-chlorophenyl/-1-isobutyl-2,3,4,5-tetrahydro-1H-[1]- benzazepin-2-it /2.7 g/ and N-chlorosuccinimide /1,65 g/ 10 ml of dimethylformamide is stirred for 7 h at 70oC. To the reaction mixture was added 100 ml of ethyl ether complex of acetic acid, washed with diluted hydrochloric Ki is. actuarial removed, and the residue is recrystallized from a mixture of hexane/ethyl ester of acetic acid to obtain 2,39 g of colorless crystals. T. melting point 152 - 154oC.

/9/. 7-Chloro-5-/2-chlorophenyl/-1-isobutyl-2-oxo-2,3,4,5 - tetrahydro-1H-[1] -benzazepin-3-acetic acid ethyl ester.

To 5 ml of tetrahydrofuran, add 0.25 ml of Isopropylamine, and the resulting mixture is cooled to -15oC add was 1.58 M hexane solution of n-utility /1,14/ ml, and the mixture was stirred for 45 min at -15oC. To the reaction mixture is added 7-chloro - 5-/2-chlorophenyl/-2,3,4,5-tetrahydro-1H-[1] -benzazepin-2-it /0.5 g/ dissolved 5 ml of tetrahydrofuran, stirred for 15 min at 0oC.

The reaction mixture was cooled to -78oC add ethyl ester Vodokanal acid /0.25 ml/. The resulting mixture was stirred for 15 min at -78oC, then for one hour at 0oC. To the reaction mixture is added 1N. hydrochloric acid /50 ml, extracted with ethyl ester of acetic acid. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate. The solvent is distilled off, the residue is purified on a chromatographic column with silica gel H NMR /CDCl3/ : 0,5 - 1,15 /6H, m/, 1,15 - 1,4 /3H, m/, 1,7 - 3,1 /5H, m/, 3,1 - 3,9 /2H, m/ 4,0 - 4,1 /2H, m, 4,4 - 4,8 /1H, m, 6,4 - 7,6 /7H, m/.

SIMS /m/ / : 449 /MH+/ (chemically induced MC)

Example 26. 7-Chloro-5-/2-chlorophenyl/-1-isobutyl-2-oxo-2,3,4,5 - tetrahydro-1H-[1]-benzazepin-3-acetic acid

< / BR>
The compound of example 25 /90 mg/ handle almost by the method of example 9 to obtain 50 mg of colorless crystals.

T. melting point 165 - 171oC.

Elemental analysis for C22H23Cl2NO3:

Calculated: C 62,86; H 5,51; N 3,33

Found: C 62,77; H 5,61; N 3,29

Example 27. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-1,2,3,4 - tetrahydro-2-thioxo-4,1-benzoxazepin-3-acetic acid ethyl ester

< / BR>
A solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo - 1,2,3,4-tetrahydro-4,1-benzoxazepin-3-acetic acid ethyl ether complex /1.0 g/ and reagent Lawesson /1.3 g/ toluene /15 ml/ heated for 8 hours under reflux. The insoluble part is filtered, the resulting filtrate is concentrated under reduced pressure. The concentrate is purified on a chromatographic column with silica gel to obtain 0.68 g of yellow crystals. T. melting 200 - 201oC.

Elemental analysis for C24H27Cl2
< / BR>
The compound of example 27 /0.4 g) is treated almost by the method of example 9 to obtain 0.1 g of yellow crystals.

T. melting 248 - 249oC.

Elemental analysis: for C22H23Cl2NO3S:

Calculated: C 58,41; H 5,12; N 3,10

Found: C 58,48; H 5,33; N 3,01

Example 29. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1,2,4,5-tetrahydro-2-thioxo-4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepine-3-acetic acid ethyl ester /1.0 g/ obtained in example 1, is treated by the method of example 27 to obtain 0.95 g of yellow crystals. T. melting 194 - 197oC.

Elemental analysis for C18H15Cl2NO2S2:

Calculated: C 52,43; H to 3.67; N 3,40

Found: C 52,41; H 3,53; N 3,10

Example 30. 7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester

< / BR>
/1/. 5-Chloro-3-/2-chlorbenzoyl/-2-neopentylene.

In a mixed solvent of 200 ml of methanol and 100 ml of acetic acid was dissolved 2-amino-5-chloro-3-/2-chlorbenzoyl/thiophene/10,89 g/. To the resulting solution was added 8,69 ml evalulead /8,69 ml/ and molecular sieves 3 /0,5 Gia /of 2.51 g/ 10 ml of methanol, and the resulting mixture was stirred for 2.5 h at room temperature. The solvent is distilled off. The organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel to obtain 4,85 g of pale yellow crystals. T. melting 74 - 76oC.

Elemental analysis for C16H17Cl2NOS:

Calculated: C 56,14; H 5,01; N 4.09 TO

Found: C 56,18; H 5,17; N 3,89

/2/. 3-/N-/5-Chloro-3-/2-chlorbenzoyl/-2-thienyl/-N-neopentyl-carbarnoyl/acrylic acid ethyl ester.

To a solution of 5-chloro-3-/2-chlorbenzoyl/-2-neopentylene-thiophene /4,85 g/, triethylamine /of 5.92 ml/ in a small number of dimethylaminopyridine in dimethylformamide /60 ml/ added dropwise a solution of monoethanol ester of fumaric acid chloride /4,60 g/ 20 ml of dimethylformamide. The reaction mixture was stirred at room temperature overnight, poured into water, extracted with ethyl ester of acetic acid. The extract obtained was washed with 1M aqueous solution of acid potassium sulfate and a saturated aqueous saline solution, dried over anhydrous magnesium sulfate. The solvent is distilled off. The remainder of acidifier acetic acid to obtain 4.3 g of colorless crystals. T. melting 79 - 81oC.

Elemental analysis for C22H23NO4S O5H2O:

Calculated: C 55,35; H 5,07; N 2,93

Found: C 55,25; H a 4.83; N 3,00

/3/. 3-/5-Chloro-3-hydroxy-2-Chlorobenzyl/-2-thienyl/-N - neopentylene /acrylic acid ester.

To a solution of 3-/N-/5-chloro-3-/2-chlorbenzoyl/-2-thienyl/-N - neopentylene/acrylic acid complex of ethyl ether /2,37 g/ and heptahydrate of trichloride cesium /2,98 g/ 100 ml methanol gradually add 303 mg of sodium borohydride at room temperature. The resulting mixture was stirred for 20 min at room temperature, acetone is added and then the solvent is distilled off. To the obtained residue, add 1M acid potassium sulfate and ester of acetic acid. The organic layer was washed with a saturated aqueous saline solution, dried over magnesium sulfate. The solvent is distilled off and the obtained residue is purified on a chromatographic column with silica gel to obtain non-crystalline solids /2,47 g/.

1H-NMR /CDCl3/ : 0,91, 1,00 /9H/, 1,20 - 1,35 /3H, m/ 2,50 - 2,59 //1H, m, 2,90 - 4,28 /4H, m/ 5,95, 6,05 /1H/, 6,52 - 7,60 /7H, m/.

/4/ 7-chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl with the sludge acid ethyl ether complex /2,37 g/ 50 ml of ethanol is added 700 mg of potassium carbonate. The resulting mixture was stirred for 8 h at room temperature. The reaction mixture was poured into water, which is extracted with ethyl ether acetic acid. The extract obtained was washed with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate. The solvent is distilled off. The residue is purified on a chromatographic column with silica gel to obtain a pale yellow oily compound /1.73 g/.

1H NMR /CDCl3| : 0,99, 1,02 /9H, each c/, 1,26, 1,28 /3H, each so /, 2,60 - 3,09 /3H, m/ 4,08 - 4,25 /2H, m/, to 4.38, 4,57 /1H, each d/, 4,67, 4,92 /1H, each DD/, by 5.87, 6.42 per /1H, each c/, 6,06, 6,51/1H, each c/, 7,20 - 7,66 /4H, m/.

Example 31. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-thieno[2,3-e]benzoxazepin-3-acetic acid

< / BR>
The compound obtained in example 30 /1.64 g/, is dissolved in a mixed solvent of 30 ml of methanol and 30 ml of tetrahydrofuran. To the solution was added potassium carbonate, stirred for 2 h at 60oC. the Reaction mixture was acidified with 1N. hydrochloric acid, then poured into water, extracted with ethyl ester of acetic acid. The organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel disloca to obtain 68 mg of colorless crystals.

T. melting 202 - 204oC.

Elemental analysis for C20H21Cl2NO4S:

Calculated: C 54,30; H 4,78; N 3,17

Found: C 54,20; H to 4.62; N 3,16

Example 32. 3,5-TRANS-7-Chloro-5-/2-methoxyphenyl/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e] oxazepine-3-acetic acid ethyl ester and 3,5 - CIS-7-chloro-5-/2-methoxyphenyl/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e] oxazepine-3 - acetic acid ethyl ester

< / BR>
< / BR>
According to the method of example 30 receive these connections:

/1/. 5-Chloro-3-/2-methoxybenzoyl/-2-neopentanoate

T. melting 117 - 118oC.

Elemental analysis for C17H20ClNO2S:

Calculated: C 60,43; H 5,97; N 4,15

Found: C 60,15; H of 5.92; N 4,10

/2/. 3-/N-/5-Chloro-3-/2-methoxybenzoyl/-2-thienyl-N - neopentylene/acrylic acid ethyl ester, oily connection

1H NMR /CDCl3/ : 0,96/9H,, 1,26/3H, t, J = 7.2 Hz/, 3,57 /1H, d, J = 13,7 Hz/, to 3.73 /3H/, 3,74/1H, d, J = 13,7 Hz/, 4,18/2H, square, J = 7,2 Hz/, 6,75/1H/, for 6.81/1H, d, J = 15.3 Hz/, 6,90? 7.04 baby mortality /2H, m, 7,12 /1H, d, J = 15.3 Hz/, 7,31 - 7,51 /2H, m/,

/3/ 3-/N-/5-/chloro-3-/-hydroxy-2-methoxybenzyl/-2-thienyl/-N - neopentylene/acrylic acid ester, oily connection

1H NMR /CDCl3/ : 0,91/9H,s/, 1,00/9H, each c/-7-chloro-5-/2-methoxyphenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-thieno[2,3-e] oxazepine-3-acetic acid ethyl ester

T. melting point 148 - 150oC

Elemental analysis for C23H28ClNO5S:

Calculated: C 59,28; H the 6.06; N 3,01

Found: C 59,17; H 5,95; N 2,90

3,5-CIS-7-Chloro-5-/2-methoxyphenyl/-1-neopentyl/-2-oxo-1,2,3,5 - tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester.

1H NMR /CDCl3/ : 0,97 /9H,, 1,26 /3H, t, J = 7,1 Hz/, 2,81 /1H, DD, J = 8,1, 17,0 Hz/, 2,96/1H,d, J=14,2 Hz/, 3,01/IH,DD, J=5,8, of 17.0 Hz, 3,89 /3H/, 4,10-4,23 /2H, m/ 4,54 /1H, d, J = 14,2 Hz/, 4,90 /1H, DD, J = 5,7, 8,1 Hz/, 6.42 per /1H/, 6,56 /1H/, 6,88-6,97 /2H, m, 7,22-7,32 /1H, m, 7,35-7,41 /1H, m/.

Example 33. 3,5-CIS-7-Chloro-5-/2-methoxyphenyl/-1-neopentyl/-2 - oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid

< / BR>
TRANS-form ethyl ether complex /0.51 g/ obtained in example 32, is treated according to the method of example 31 to obtain 0.18 g of colorless crystals.

So melting point 220-222oC.

Elemental analysis for C21H24ClNO5S:

Calculated: C 57,59; H 5,52; N 3,20

Found: C 57,54; H 5,58; N 3,18

Example 34. 3,5-CIS-7-Chloro-5-/2-methoxyphenyl/-1-neopentyl/-2 - oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid

< / BR>
CIS-form ethyl ether complex of example 32 /0.28 g/ treated by the method of example 31 to obtain 0.16 g of colorless crystals. So plvl the 3,20

Found: C 57,36; H 5,42; N 3,11

Example 35. 3,5-TRANS-7-Chloro-1-isobutyl-5-/2-methoxyphenyl/-2 - oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e] oxazepine/2/acetic acid ethyl ester and 3,5-CIS-7-chloro-1-isobutyl-5-/2-methoxyphenyl/- 2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e] oxazepine-3-acetic acid ethyl ester

< / BR>
< / BR>
These connections receive according to the method of example 30.

/1/. 5-Chloro-2-isobutylamino-3-/2-methoxybenzoyl/thiophene

So melting 83-84oC.

Elemental analysis for C16H18ClNO2S:

Calculated: C 59,34; H ceiling of 5.60; N 4,33

Found: C 59,41; H 5,63; N 4,30

/2/. 3-/N-/5-Chloro-3-/2-methoxybenzoyl/-2-thienyl/-N - isobutylbarbituric/acrylic acid ethyl ester in the form of oily compounds

1H NMR /CDCl3/ : 0,92 /6H, Shir/, 1,28 /3H, t, J = 7,1 Hz/, 1,89-2,12 /1H, m, 3,12-3,27 /1H, m/ 3,75 /3H/, 3,80-4,00 /1H, m, 4,20 /2H, q, J = 7,1 Hz/, 6,76-7,54 /7H, m/.

/3/. 3-/N-/5-chloro-3-/ - hydroxy-2-methoxybenzyl/-2-thienyl/-N - isobutylbarbituric/acrylic acid ethyl ester in the form of oily compounds

1H NMR /CDCl3/ : 0,80-1,00 /6H, m/, 1,19-1,32 /3H, m/, 1,88-2,16 /1H, m, 2,69-3,24 /2H, m, 3,74, with 3.79 /3H, each s/, a 3.87-4.26 deaths /3H, m/, 5,80 of 5.99 /1H, m, of 6.49-of 7.64 /7H, m/.

/4/. 3,5-TRANS-7-Chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo - 1,2,3,5-tetrahydro-4,1-th analysis for C22H26ClNO5S:

Calculated: C 58,46; H 5,80; N 3,10

Found: C 58,23; H 5,72; N 3,03

3,5-CIS-7-Chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo - 1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid ethyl ester as an oily compound.

1H NMR /CDCl3/ : 0,96 /6H, d, J = 6,6 Hz/, 1,27 /3H, t, J = 7,1 Hz/, 2,05-2,24 /1H, m, 2,81 /1H, DD, J = 8,1, 17,0 Hz/, 3,00 /1H, DD, J = 5,6, 17,0 Hz/, 3,09 /1H, DD, J = 5,3, a 14.1 Hz/, 3,88 /3H,, 4,17 /2H, q, J = 7,1 Hz/, or 4.31 /1H, DD, J = 9,3, a 14.1 Hz/, 4,89 /1H, DD, J = 5,6, 8,1 Hz/, 6,41 /1H/, 6,48 /1H/, 6,86-of 6.96 /2H, m, 7,20-7,34 /2H, m/.

Example 36. 3,5-TRANS-7-Chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo - 1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid

< / BR>
TRANS-form of ester /0,68 g/ obtained in example 35, treated by the method of example 31 to obtain 0,22 g of colorless crystals. So the melting point of 183-185oC.

Elemental analysis for C20H22ClNO5S:

Calculated: C 56,67; H 5,23; N 3,30

Found: C 56,40; H 5,18; N 3,29

Example 37. 3,5-CIS-7-Chloro-1-isobutyl-5-/2-methoxyphenyl/-2-oxo - 1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic acid

< / BR>
CIS-form of ester of example 35 /0,59 g/ treated by the method of example 31 to obtain 0.27 g of colorless solid. So melting point 144-146oC.

The

Example 38. 3,5-TRANS-7-Chloro-5-/2,3-acid/-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
5-chloro /2,3-acid/-2-/neopentylene/benzyl alcohol /1.0 g/ and diablocody acid /0,41 g/ treated by the method of example 1 to obtain 0,38 g of colorless crystals. So melting 193-196oC.

Elemental analysis for C25H30ClNO5SO3H2O:

Calculated: C 60,36; H 6,20; N 2,86

Found: C 60,43; H 6,21; N 2,75

Example 39. 3,5-TRANS-7-Chloro-5-/2,3-acid/-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-luxusni acid

< / BR>
3,5-TRANS-7-Chloro-5-/2-acid/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester obtained in example 38 /10 g/ treated by the method of example 9 to obtain 7.7 g of colorless crystals. So melting 263-277oC.

Elemental analysis for C24H28ClNO5S:

Calculated: C 60,31; H 5,91; N 2,93

Found: C 60,03; H 5,86; N 2,84

Example 40. N-//3R,5S/-7-Chloro-5-/2,3-acid/-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl - /-L-Lazenby methyl ester and N-//3S,5R/-7-Chloro-5-/2,3-acid/-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-beans-7-chloro-5-/2.3-acid/-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid /7,1 g/ L-Lazenby methyl ester /2.7 g/. To the solution add diethylthiophosphate /3.6 g/ and triethylamine /3.5 g/. The resulting mixture was stirred for 30 min at room temperature, washed with 5% HCl, saturated aqueous sodium bicarbonate and saturated aqueous solution of salt. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel, using as eluent a mixture of hexane: ethyl ester of acetic acid = 4:1, to obtain 4,13 g N-//3R, 5S/-7-chloro-5/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepin-3-acetic/-L-leucine methyl ether complex of the first fraction in the form of colorless crystals. So melting point 121-123oC.

()2D2-235,2o/C=0,39, MeOH/

1H-NMR /CDCl3/ : 0,932 /6H, t, J = 6.2 Hz/, 0,989 /9H, s/, 1,49 - 1,67 /3H, m/ 2,322 /1H, DD, J = 3,2, 14, 2 Hz/, 2,97 /1H, DD, J = 10,6, 14,2 Hz/, 3,187 /1G, d, J = 14,0 Hz/, 3,696 /3H/, 3.715 /3H/, 3,779 /1H, DD, J = 3.2, and a 10.6 Hz/, 3,889 /3H/, 4,420 /1H, d, J = 14,0 Hz/, 4,47 - 4,59 /1H, m, 6,05 - 6,10 /1H, Shir./, 6,270 /1H/, 6,814 - 7,400 /6H, m/.

From the second fraction receive 4.15 g N-//3S, 5R/-7-chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1_ benzothiazepin-3-acetyl - /-L-leucine methyl ether complex in the form of a non-crystalline solid product.

()2D2, 178,6o/C = 0,47, MeOH/

= 13,8 Hz/, 3,69 - of 3.78 (7H, m/ 3,890 /3H/, of 4.44 - 4,54 /2H, m/ 6,281 /1H/, 6,37 - 6,41 /1H, Shir/, 6,801 - 7,396 /6H, m/.

Example 41. /3R, 5S/-7-Chloro-5-/2,3-dimethoxyphenyl/2-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzothiazepine-3-acetic acid methyl ester

< / BR>
To a solution of N-//3R, 5S/-7-chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepin-3-acetyl - /-L-leucine methyl ether complex /4,13 g/ obtained in example 40, in 100 ml of methanol are added 50 ml of concentrated HCl, and the resulting mixture heated for 24 h under reflux. The reaction mixture is extracted with dichloromethane, and the extract obtained is dried over anhydrous sodium sulfate, then the solvent is distilled off. The residue is purified on a chromatographic column with silica gel/eluent: acetic acid: ethyl ether = 3:1 volume/volume. The obtained solid product is recrystallized from a mixed solvent /dichloromethylsilane ether to obtain 2,87 g of colorless crystals. So melting point 170-171oC.

Example 42. /3S, 5R/-7-Chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1/ benzothiazepin-3-acetic acid methyl ester

< / BR>
N-//3S, 5R/-7-Chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzothiazepin-3-acetyl - /-L-Le is Holocene 2.70 g of colorless crystals. So melting point 168-170oC.

Example 43. /3R, 5S/-7-Chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid

< / BR>
/3R, 5S/-7-Chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester /2.6 g/ obtained in example 4 is treated by the method of example 9 to obtain 1.98 g of colorless crystals. So melting 263-271oC.

()2d2-303,5o= 0,92, MeOH/

Elemental analysis for C24H28ClNO5S:

Calculated: C 60,31; H 5,90; N 2,93

Found: C 60,09; H between 6.08; N, 2,99

Example 44. /3S, 5R/-7-Chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid

< / BR>
/3S, 5R/-7-Chloro-5-/2,3-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester /2.5 g/ obtained in example 42, process, almost by the method of example 9 to obtain 1.88 g of colorless crystals. So melting 261-270oC.

()2D2+290,2o/c = 0,61, MeOH/

Elemental analysis for C24H28ClNO5S:

Calculated: C 60,31; H 5,90; N 2,93

Found: C 60,13; H of 5.89; N 2,97

Example 45. 3,5-TRANS-Chloro-5-/2,4-dimethoxyphenyl -- 2,4-acid/-2-/neopentylene/benzyl alcohol /38,9 g/ and diablocody acid /16,1 g/ treated by the method of example 1 to obtain a 32.5 g of colorless crystals. So melting point 190-191oC.

Elemental analysis for C25H30ClNO5S:

Calculated: C 61,03; H x 6.15; N 2,85

Found: C 60,95; H 6,12; N 2,75

Example 46. 3,5-TRANS-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid

< / BR>
3,5-TRANS-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester /27 g/ obtained in example 45, treated by the method of example 9 to obtain to 26.6 g of colorless crystals. So melting 157-160oC.

Elemental analysis for C24H28ClNO5S:

Calculated: C 60,31; H 5,91; N 2,93

Found: C 60,57; H of 5.83; N 2,66

Example 47. N-//3S, 5R/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepin-3-acetyl - /-L-alanine tert-butyl ester and N-//3R, 5S/-7-chloro-5-/2,4-acid/-4-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepin-3-acetyl - /-L-alanine tert-butyl ester

< / BR>
< / BR>
3,5-TRANS-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid /15 g/ L-alanine tert-butyl ester /hydrochloride/ /6,0 g/ treated by the method of example 40 to obtain of 6.31 g N/3S, 5R/-7-chloro-5-/2,4-acid/the crystalline solid product from the first fraction.

1H-NMR (CDCl3/ : 0,975 /9H, s/, 1,322 /3H, d, J = 7,0 Hz/, 1,463 /9H, s/, 2,300 /1H, DD, J = 3,8,, 14.6 Hz/, 2,993 /1H, DD, J = 10,0,, 14.6 Hz/, 3,205 /1H, d, J = 13,8 Hz/, 3,663 /3H/, 3,713 /1H, DD, J = 3,8, 10,0 Hz/, 3,858 /3H/, 4,358 /1H, square, J = 7,0 Hz/ 4,471 /1H, d, J = 13,8 Hz/, 6,243 /1H/, 6,471 /1H, d, J = 2.4 Hz/, 6,606 /1H, d, J = 2,4, 8,4 Hz/, 6,836 /1H, d, J = 1,8 Hz/, UAH 7,264 /2H, m/ 7,624 /1H, d, J = 8.6 Hz/,

From the second fraction get to $ 7.91 g N//3R, 5S/-7-chloro-5-/2,4-acid/-1-/neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepin-3-acetyl - /-L-alanine tert-butyl ether complex in the form of a non-crystalline solid product.

1H NMR /CDCl3/ : 0,968 /9H, s/, 1,338 /3H, d, J = 7,0 Hz/, 1,440 /9H, s/, 2,332 /1H, DD, J = 3,6, and 15.2 Hz/, 2,937 /1H, DD, J = 10,4, 15.2 Hz/, 3,186 /1H, d, J = 13,8 Hz/, 3,660 /3H/, 3,781 /1H, DD, J = 3,6, 10,4 Hz/, 4,369 /1H, kV, J = 7,0 Hz/, 4,447 /1H, d, J = 13,8 Hz/, 6,240 /1H/, 6,470 /1H, d, J = 2,4 Hz/, 6,603 /1H, DD, J = 2,4, 8.6 Hz/, 6,841 /1H/, UAH 7,264 /2H, m/ 7,629 /1H, d, J = 8.6 Hz/.

Example 48. /3S, 5R/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
N-//3S, 5R/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepin-3-acetyl - /-L-alanine tert-butyl ester /of 6.31 g/ obtained in example 47, process, almost by way of example 41 to obtain colorless crystals. So melting point 187-188oC.


< / BR>
N-//3R, 5S/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl - /-L-alanine tert-butyl ester /to $ 7.91 g/ obtained in example 47, treated by the method of example 41 to obtain the 3.89 g of colorless crystals. So melting point 188-190oC.

Example 50. /3S, 5R/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzothiazepine-3-acetic acid

< / BR>
/3S, 5R/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester /3.5 g/ obtained in example 48, treated by the method of example 9 to obtain 3,22 g of colorless crystals. So melting 147-151oC.

()2D2+255,9o/C=0,35, MeOH/

Elementary analysis for C24H28ClNO5S:

Calculated: C 60,31; H 5,91; N 2,93

Found: C 60,58; H of 5.82; N 2,79

Example 51. /3R, 5S/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid

< / BR>
/3R, 5S/-7-Chloro-5-/2,4-acid/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester /3,37 g/ obtained in example 49, treated by the method of example 9 to obtain 3.28 g of colorless crystals. So melting point 148 24
H28ClNO5S:

Calculated: C 60,31; H 5,91; N 2,93

Found: C 60,32; H of 5.83; N 2,87

Example 52. 7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-3H-1,3-benzodiazepine-3-acetic acid methyl ester

< / BR>
/1/. - /5/Chloro-2-nitrophenyl/-2-chlorophenylalanine acid methyl ester

A solution of sodium hydride /3.4 g/, 2-chlorophenylalanine acid methyl ether complex /28,3 g/ and 4-chloro-1,2-dinitrobenzene /27 g/ 100 ml of dimethylformamide is stirred for one hour at 0oC. the Reaction mixture was added to dilute hydrochloric acid /300 ml, extracted with ethyl ester of acetic acid. The extract was washed with a saturated aqueous saline solution, dried over anhydrous sodium sulfate, and the solvent is distilled off. The remaining oily product was then purified through column chromatography with silica gel /eluent: hexane: ethyl ester of acetic acid = 10:1, volume/volume, recrystallized from hexane to obtain 26,3 g of yellow crystals. So melting 96-97oC.

Elementary analysis for C15H11Cl2NO4:

Calculated: C 52,96; H 3,26; N 4,12

Found: C 53,04; H 3,34; N 4,06

/2/. 2-/2-Nitro-5-chlorophenyl/-2-/2-chlorophenyl/ethanol.

The mix - /5-chloro-2-nitrophenylamino for 4 h at room temperature. This solution is added to 20% aqueous solution of acetic acid /50 ml/ extracted with ethyl ester of acetic acid. The extract obtained was washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The remaining oily compound purified through column chromatography with silica gel until receipt of 11.0 g of oily compound.

1H NMR /CDCl3/ : 1,90 /1H, Shir/, 4,15-4,33 /2H, m/ 5,270 /1H, t, J = 6.2 Hz/, 7,20-7,40 /6H, m/ 7,867 /1H, d, J = 8,4 Hz/

/3/. - /5-Chloro-2-nitrophenyl/-2-chlorophenylacetyl

A solution of dimethyl sulfoxide /6,7 ml/ 30 ml dichloromethane are added to a solution of oxalicacid /6.2 oz/ 300 ml dichloromethane at -78oC. the resulting mixture was stirred for further 10 min at -78oC. To this solution add a solution of 2-/2-nitro-5-chlorpheniramine /11,04 g/ 100 ml dichloromethane at -78oC and the resulting mixture is stirred for further 15 min at -78oC.

To the reaction mixture add 37 ml of triethylamine is heated to 0oC, add saturated aqueous solution of ammonium chloride /124 ml/. The organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The remaining oily compound purified through column chromatography with silica gel /eluent:Huck isH NMR /CDCl3/ : 6,299 /1H/, 6,836 /1H, d, J = 2.2 Hz/, 7,14 - 7,65 /5H, m/ 8,096 /1H, d, J = 88 Hz/, 9,887 /1H, s/.

/4/ N-/2-/2-chlorophenyl/-2-/2-nitro-5-chlorophenyl/ethyl/glycine methyl ester

To a solution - /5-chloro-2-nitrophenyl/-2-chlorophenylalanine /1.68 g/ 15 ml of methanol, add the hydrochloride of the methyl complex ester of glycine /0,69 g/ and 0.45 g of sodium acetate. The resulting mixture was stirred for 30 min at room temperature, add 0.35 g of cyanoborohydride sodium. To this mixture is added hydrogen chloride for 5 minutes the resulting solution was stirred for 3 h at 50oadd 1H. an aqueous solution of sodium hydroxide /50 ml) and extracted with dichloromethane. The extract obtained was washed with water, then the solvent is distilled off. The remaining oily product was then purified through column chromatography with silica gel /eluent hexane:ethyl ester of acetic acid = 3:1 vol/vol/ to obtain 1.1 g of oily compound.

1H NMR /CDCl3/ : 3,200 /2H, DD, J = 6,8, and 12.2 Hz/, 3,366 /1H, DD, J = 7,6, and 12.2 Hz/, 3,482 /2H,/, 3,731 /3H/, 5,255 /1H, t, J = 7.2 Hz/, 7,22-7,44 /6H, m/ 7,846 /1H, d, J = 8.6 Hz/.

/5/. N-/2-/2-Chlorophenyl/-2-/2-nitro-5-chlorophenyl/ethyl/N-TRIFLUOROACETYL/glycine methyl ester.

To a solution of N-/2-/2-chlorophenyl/-2-/2-nitro-5-chlorophenyl/etrangere, and the resulting mixture stirred for 10 min at room temperature. The resulting solution was washed with 1N. aqueous solution of hydrochloride of sodium and saturated aqueous saline solution, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel /eluent hexane:ethyl ester of acetic acid = 5:1 volume/volume to obtain 5,95 g of oily compound.

1H NMR /CDCl3/ : 3,786 /3H/, 4,138 /1H, DD, J = 7,0, 14,0 Hz/, 4,215 /2H,/, 4,434 /1H, DD, J = 8,8, 14,0 Hz/, 5,473 /1H, DD, J = 7,0, 8,8 Hz/, 7,27 - 7,52 /6H, m/, 7.874 inches /1H, d, J = 8,4 Hz/.

/6/ N-/2-/2-amino-5-chlorophenyl/-2-/2-chlorophenyl/ethyl/-N-/TRIFLUOROACETYL/glycine methyl ester

To a solution of N-/2-/2-chlorophenyl/-2-/2-nitro-5-chlorophenyl/ethyl/-N- /TRIFLUOROACETYL/glycine methyl ether complex /1 g/ in ethyl ether acetic acid /20 ml/ add 10% Pd/C catalyst /100 mg/. The resulting mixture is subjected to catalytic recovery at room temperature and atmospheric pressure. After completion of the reaction the catalyst is removed, and the solvent is distilled off. The residue is purified on a chromatographic column with silica gel /elwira a mixture of hexane:ethyl ester of acetic acid = 4:1 volume/volume to obtain 0.39 g of oily compound.

/7/ N-/2-/5-chloro-2-neopentylene/-2-/2-chlorophenyl/ ethyl/-N-/triptorelin methyl ester.

To a solution of N-/2-/2-amino-5-chlorophenyl/-2-/2-chlorophenyl/ethyl/- N-/TRIFLUOROACETYL/glycine methyl ether complex /0.39 g/ 5 ml of methanol, add 0.05 ml of acetic acid and 78 mg of evalulead. The resulting mixture was stirred for 30 min at room temperature, added 57 mg of cyanoborohydride sodium. The resulting mixture is stirred for one hour at room temperature, then add 50 ml of dichloromethane. This solution was washed with 1N. aqueous solution of sodium borohydride, then water, and then the solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent hexane : ethyl ester of acetic acid = 5 : 1 volume/volume to obtain 0.27 g of oily compound.

1H-NMR /CDCl3/ : 0,851 /9H,, 2,65 - 2,83 /2H, m/ 3,316/1/4 x 1H, d, J = 17,4 Hz/, 3,51 - 3,60 /1H, m/ 3,702/1/4 x 3H, s/, 3,748/3/4 x 3H, s/, 3,873 /1H, DD, J = 9,8, and 13.4 Hz/, 4,055/3/4 x 1H, J = 17,9 Hz/, 4,274 /1H, DD, J = 5,8, a 13.4 Hz/, 4,72 - 4,86 /1H, m, 6,53 - 6,60 /1H, m, 7,11 - 7,40 /6H, m/.

/8/ N-/2-/5-chloro-2-neopentylene/-2-/2-chlorophenyl/ ethyl/glycine methyl ester

To a solution of N-/2-/5-chloro-2-neopentylene/-2- /2-chlorophenyl/ethyl/-N-/Thrifty /0.6 ml/ heated under reflux for one day. To this reaction mixture was added 1 N. aqueous sodium hydroxide solution /8 ml, and extracted with dichloromethane. The extract obtained was washed with water, the solvent is distilled off, resulting in a gain of 72 mg of oily compounds.

1H-NMR /CDCl3/ : 0,823 /9H, s/, 2,659 /1H, d,/, J = 11.2 Hz/, 2,769 /1H, d, J = 11.2 Hz/, 3,029 /1H, DD, J = 5,2, and 11.8 Hz/, 3,279 /1H, DD, J = 8,4, and 11.8 Hz/, 3,427 /1H, d, J = 17.6 Hz/, 3,528 /1H, d, J = 17.6 Hz/, 3,741 /3H/, 4,563 /1H, DD, J = 5,2, 8,4 Hz/, 6,538 /1H, d, J = 8,8 Hz/, 6,99 - 7,42 /6H, m/.

/9/ 7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-3H-1,3-benzodiazepine-3-acetic acid methyl ester.

To a solution of N-/2-/5-chloro-2-neopentylene/-2- /2-chlorophenyl/ethyl/glycine methyl ester /0,47 g/ and 0.21 g of triethylamine in 5 ml of toluene added triphosgene /0.14 g/. The resulting mixture was heated for 5 h at 70oC. To the reaction mixture are added 50 ml of dichloromethane, washed with 1N. hydrochloric acid and water, then the solvent is distilled off. The residue is recrystallized from hexane to obtain 0,30 g of colorless crystals. So melting 142 - 148oC.

1H-NMR /CDCl3/ : 0,940 /9H, s/, 3,492 /1H, d, J = 14,4 Hz/, 3,639 /1H, d, J = 17,2 Hz/, 3,715 /3H/, 3,976 /2H, d, J = 8.6 Hz/, 4,038 /1H, d, J = 17,2 Hz/, 4,308 /1H, d, J = 14,4 Hz/, 5,317 /1H, d, J = 8.6 Hz/, 6,645 /1H, d, J = 1,8 Hz/, 7,14 - 7,50 /6H, m/.

< / BR>
7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-3H-1,3-benzodiazepine-3-acetic acid methyl ester /0,30 g/ treated by the method of example 9 to obtain 0.21 g of colorless crystals.

So melting 228 - 231oC.

Elemental analysis for C22H24Cl2N2O3:

Calculated: C 60,70; H 5,56; N TO 6.43

Found: C 60,37; H 5,49; N 6,15

Example 54. 3,6-TRANS-8-Chloro-6-/2-chlorophenyl/-1-neopentyl - 2-oxo-2,3,5,6-tetrahydro-1H-4,1-benzoxazin-3-acetic acid ethyl ester

< / BR>
/1/. 2-/2-Amino-5-chlorophenyl/-2-/2-chlorophenyl/ethanol.

To a solution of 2-/2-nitro-5-chlorophenyl/-2-/2-chlorophenyl/ethanol /7,0 g/ obtained in example 52-/2/ in 70 ml of ethanol is added 3.4 g of hydrazine hydrate is added and the Raney Nickel /0.1 g/. The resulting mixture was stirred for 30 minutes at room temperature. The catalyst was removed, the solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent hexane : ethyl ester of acetic acid = 2 : 1 volume/volume to obtain 4.44 g of oily compound.

1H-NMR /CDCl3/ : 4,107 /2H, d, J = 6,6 Hz/, 4,587 /1H, t, J = 6,6 Hz/, 6,597 /1H, d, J = 8,4 Hz/, 7,01 - 7,43 /6H, m/.

/2/ 2-/5-chloro-2-neopentylene/-2-/2-chlorophenyl/ethanol

To a solution of hidehide. The resulting mixture was stirred for 30 min at room temperature. To the solution was added 1.5 g of cyano sodium borohydride, and the mixture is stirred for another hour at room temperature. Then the reaction mixture is treated according to the method of example 52-/7/ to obtain 5.5 g of oily compound.

1H-NMR /CDCl3/ : 0,813 /9H, s/, 2,654 /1H, d, J = 11,4 Hz/, 2,766 /1H, d, J = 11,4 Hz/, 4,11 - 4,15 /2H, m/ 4,590 /1H, t, J = 6.3 Hz/, 6,549 /1H, d, J = 8.6 Hz/, 7,01 - 7,44 /6H, m/.

/3/ a 3/N-/2-/1-/2-chlorophenyl/-2-hydroxyethyl/-4-chlorophenyl/- N-neopentylene/acrylic acid ethyl ester.

To 300 ml of dichloromethane is added 2-/5-chloro-2-neopentyl-AMINOPHENYL/-2-/-chlorophenyl/ethanol/5,5/-sodium bicarbonate /1.7 g/. To the resulting mixture add monotropy ester chloride fumaric acid /2,6 g/, stirred for one hour at room temperature. To the reaction mixture was added 100 ml of dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off, the residue is purified on a chromatographic column with silica gel /eluent : ethyl ester of acetic acid = 5 : 1 vol/vol/ to obtain 6,9 in the form of oily compounds.

1H-NMR /CDCl3/ : 0,679 /1/29H,/, 0,941 /1/29H,/, 1,210 /1/23H, t, J = 7.2 Hz/, 1,249 of 15.2 Hz/, 6,167 /1/2, d, J = 15.2 Hz/, 6,69 - 7,81 /8H, m/.

/4/. 8-Chloro-6-/2-chlorophenyl/-1-neopentyl-2-oxo-2,3,5,6 - tetrahydro-1H-4,1-benzoxazin-3-acetic acid ethyl ester.

To 70 ml of dichloromethane added 3-/N-/2-/1-/2-chlorophenyl/- 2-hydroxyethyl/-4-chlorophenyl/-N-neopentylene/acrylic acid ethyl ether complex /6.8 g/, 18-crown-6 /of 3.78 g/ and potassium carbonate. The resulting mixture was stirred for 3 days at room temperature. The insoluble part is filtered off, the solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent hexane : ethyl ester of acetic acid = 5 : 1 vol/vol/ to obtain 1.64 g noncrystalline solid product.

1H NMR /CDCl3/ : 1,028 /9H, s/, there were 1,227 /3H, t, J = 7.2 Hz/, 2,740 /1H, DD, J = 6,61, and 17.2 Hz/, 2,974 /1H, DD, J = 7,8, and 17.2 Hz/, 3,716 /1H, d, J = 13,4 Hz/, 3,94 - 4,14 /5H, m/ 4,417 /1H, DD, J = 1,4, and 11.4 Hz/, 4,671 /1H, DD, J = 1,4, 8,8 Hz/, 7,014 /1H, d, J = 2.2 Hz/, of 7.23 - 7,43 /6H, m/.

Example 55. 3,6-TRANS-8-Chloro-6-/2-chlorophenyl/-1-neopentyl-2 - oxo-2,3,5,6-tetrahydro-1H-4,1-benzoxazin-3-acetic acid

< / BR>
3,6-TRANS-8-Chloro-6-/2-chlorophenyl/-1-neopentyl-2 - oxo-2,3,5,6-tetrahydro-1H-4,1-benzoxazin-3-acetic acid ethyl ester /1.2 g/ obtained in example 54, treated by the method of example 9 to the floor/SUB>Cl2NO4H2O:

Calculated: C 58,98; H of 5.81; N, 2,99

Found: C 58,82; H 5,43; N 2,97

Example 56. 7-Chloro-5-/2-chlorophenyl/-1-neopentyl-1,2-dihydro-2-oxo - 3H-1,3,4-benzotriazepine-3-acetic acid ethyl ester

< / BR>
/1/. 5-Chloro-2-neopentylene-2-chlortrimaton.

To a solution of 2-amino-2', 5-dichlorobenzophenone /10 g/ 50 ml of methanol add jalaldeen /3.4 g/ 5 ml of acetic acid. The resulting mixture was stirred 30 min at 0oC. To this solution add cyanoborohydride sodium /3.1 g/, and the resulting mixture is stirred for one day at 60oC. the Solution is concentrated, add dichloromethane /100 ml. The resulting mixture was washed with water and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified on a chromatographic column with silica gel /eluent hexane: ethyl ester of acetic acid = 20:1 volume/volume to obtain 6.3 g of solid compound yellow. To a solution of this compound /0.5 g/ 5 ml of toluene, add 0.3 g of reagent Lawesson, and the resulting mixture heated for two hours under reflux. To the reaction mixture are added ethyl ester acetic acid /50 ml washed with water, and then dried over anhydrous sodium sulfate. Rastan-2',5-dichlorobenzotrifluoride

To a solution of 5-chloro-2-neopentylene-2-chlortrimaton /0,54 g/ 7 ml ethanol add hydrochloride hydrazinoacetate /0.11 g/. The resulting mixture was stirred for one day at 70oC. To the reaction mixture are added 50 ml of dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent hexane : ethyl ester of acetic acid = 15 : 1 volume/volume/ to obtain 0.16 g of oily product.

1H NMR /CDCl3/ : 0,95 /9H, s/, 1,273 /3H, t, J = 7.2 Hz/, 2,964 /2H, d, J = 5.8 Hz/, 4,04 /4,27/4H, m/ 5,969 /1H, t, J = 5.8 Hz/, 6,681 /1H, d, J = 9,0 Hz/, 6,879 /1H, d, J = 2,6 Hz/, 7,15 - 7,50 /5H, m/.

/3/. 7-Chloro-5-/2-chlorophenyl/-1-neopentyl-1,2-dihydro-2-oxo-3H-1,2,4-benzotriazin-3-acetic acid ethyl ester.

To a solution of 2-neopentylene-2', 5 - dichloropentafluoropropane /0.16 g/ and 90 mg of triethylamine in 2 ml of toluene added 54 mg of triphosgene. The resulting mixture is stirred for one hour at 70oC add ethyl ester acetic acid /50 ml/. The resulting mixture was washed with water, dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent hexane : DCl3/ : 0,883 /9H, s/, 1,238 /3H, t, J = 7,0 Hz/, 3,376 /1H, d, J = 14,0 Hz/, 4,184 /2H, q, J = 7,0 Hz/, 4,319 /1H, d, J = 16,8 Hz/, 4,363 /1H, d, J = 14,0 Hz/, 4,484 /1H, d, J = 16,8 Hz/, 6,857 /1H, d, J = 2,6 Hz/, 7,20 - 7,50 /6H, m/.

Example 57. 7-Chloro-5-/2-chlorophenyl/-1-neopentyl-1,2-dihydro - 2-oxo-3H-1,3,4-benzotriazepine-3-acetic acid

< / BR>
To a solution of 7-chloro-5-/2-chlorophenyl/-1-neopentyl-1,2-dihydro - 2-oxo-3H-1,3,4-benzotriazepine-3-acetic acid ethyl ester obtained in example 56 /0.16 g/ 3 ml ethanol add 1H. an aqueous solution of sodium hydroxide /0.3 ml/. The resulting mixture was stirred for 4 h at room temperature. To the reaction mixture 50 ml of water, acidified with 1 N. HCl, then the solution is concentrated. To the obtained concentrate, add 50 ml of dichloromethane, washed with water, then the solvent is distilled off. The residue is recrystallized from a mixture of dichloromethane-petroleum ether to obtain 91 mg of colorless crystals. So melting 181 - 183oC.

Elemental analysis for C21H21Cl2N3O3:

Calculated: C 58,07; H to 4.87; N 9,67

Found: C 57,90; H 5,13; N 9,46

Example 58. 3,5-TRANS-7-Chloro-5-/2,4-acid/-1-neopentyl - 3-/tetrazol-5-yl/methyl-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-he

< / BR>
/1/. 3-/3,5/TRANS-7-Chloro-5-/2,4-acid/-1-neopentyl - 2-oxo-1,2,3,5-tetr is/-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid, obtained in example 46 /1 g/ and 150 mg of 3-aminopropionitrile /150 mg/ 10 ml dichloromethane added 340 mg diethylthiophosphate and 320 mg of triethylamine. The resulting mixture was stirred for 10 min at room temperature. To the reaction mixture was added 100 ml of dichloromethane, washed with 1 N. aqueous solution of NaOH and water, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from hexane to obtain 1.07 g of colorless crystals.

So melting 93 - 103oC.

Elemental analysis for C27H32ClN3O4S:

Calculated: C 61,18; H between 6.08; N 7,93

Found: C 61,41; H 6,11; N 7,84

/2/. 3-/3,5/TRANS-7-Chloro-3-/2-cyanoethyl/tetrazol-5-yl/methyl-5- /2,4-acid/-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-it.

3-/3,5/TRANS-7-Chloro-5-/2,4-acid/-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetylamino/propionitrile /0.1 g/, triphenylphosphine /99 mg/ diethylazodicarboxylate /66 mg/ and trimethylsilylmethyl /44 mg/ 2 ml of tetrahydrofuran is stirred for one day at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting concentrate is purified on a chromatographic column with silica gel /eluent hexane : ethyl ester of uksosn the l3/ : 0,938 /9H,, 2,96 - 3,16 /4H, m/, 3,17 - 3,52 /1H, m/ 3,667 /3H/, 3,867 /3H,, 3,92 - 3,99 /1H, m, 4,16 - 4,28 /1H, m, 4,73 - 4,81 /2H, m/ 6,290 /1H, m, of 6.49 - 7,65 /6H, m/.

/3/ 3,5-TRANS-7-chloro-5-/2,4-acid/-1-neopentyl-3 - tetrazol-5-yl/methyl-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-he

In a mixed solvent consisting of 1 ml of methanol and 1 ml of tetrahydrofuran, added 59 mg of 3,5-TRANS-7-chloro-3-/1-/2 - cyanoethyl/tetrazol-5-yl/methyl-5-/2,4-acid/-2-neopentyl - 1,2,3,5-tetrahydro-4,1-benzothiazepin-2-it. To this solution add 1 N. aqueous sodium hydroxide solution /of 0.11 ml, stirred for 6 h at room temperature.

To the reaction mixture add water /50 ml/. The solution is acidified, extracted with dichloromethane. The extract obtained was washed with a saturated aqueous solution of ameriglide, dried over anhydrous sodium sulfate. The solvent is distilled off, the residue is recrystallized from dichloromethane to obtain 26 mg of colorless crystals. So melting 168 - 173oC.

Elemental analysis for C24H28ClN5O3S:

Calculated: C 57,42; H 5,62; N 13,95

Found: C 57,28; H 5,22; N AT 13.84

Example 59. /3R, 5R/-7-Chloro-5-/2,3-acid/-1-neopentyl-3- /tetrazol-5-yl/methyl-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-he

< / BR>
Using /3R, example 58 get:

/1/. /3R, 5S/-7-chloro-5-/2,3-acid/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetylamino/-propionitrile.

1H-NMR /CDCl3/ : 0,991 /9H, s/, 2,335 /1H, DD, J = 3,8, 14,8 Hz/, of 2.54 2.63 in /2H, m/ 2,938 /1H, DD, J = 10,6, 14,8 Hz/, 3,27 /1H, d, J = 13,6 Hz/, 3,39 - 3,50 /2H, m/ 3,720 /3H/, 3,778 /1H, DD, J = 3,8, to 10.6 Hz/, 3,892 /3H/, 4,455 /1H, d, J = 13,6 Hz/, 6,279 /1H/, the 6.0 - 6,66 /1H, Shir/, 6,821 /1H, d, J = 1,8 Hz/, 6,981 /1H, DD, J = 1,4, 8,0 Hz/, 7,16 - 7,39 /4H, m/.

/2/ the /3R, 5S/-7-Chloro-3-/1-/2-cyanoethyl/tetrazol-5-yl/methyl-5 - diazepin-2-it.

1H-NMR /CDCl3/ : 0,962 /9H, s/, 2,97 - 3,17 /4H, m/ 3,473 /1H, DD, J = 10,6, 14.6 Hz/, 3,729 /3H/, 3,902 /3H/, was 4.02 /1H, DD. J = 3,6, to 10.6 Hz/, 4,306 /1H, d, J = 14,0 Hz/, 4,74 - 4,81 /2H, m/ 6,333 /1H/, 6,84 - to 7.77 /6H, m/.

/3/. /3R,3S/-7-Chloro-5-/2,3-acid/-1-neopentyl-3- /tetrazol-5-yl/methyl-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-it. So melting 139 - 144oC.

Elemental analysis for C24H28ClN5O3S:

Calculated: C 57,42; H 5,62; N 13,95

Found: C 57,55; H 5,76; N 13,78

Example 61. /3R,3S/-7-Chloro-5-/2-chlorophenyl/-3-/2-hydroxyethyl/-1 - neopentyl-1,2,3,5-tetrahydro-4,1-benzothiazepin

< / BR>
To 20 ml of tetrahydrofuran, add /3R,3S/-7-chloro-/-2-chlorophenyl/-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid /2 g/, and sociallyengaged /0.4 g/.

The resulting mixture is heated for the hydrated filtrate is concentrated and purified through column chromatography with silica gel /eluent hexane : ethyl ester of acetic acid = 2:1 vol/vol/ to obtain 1.65 g of the non-crystalline solid product.

1H NMR /CDCl3/ : 0,963 /9H,, 1,69 - 1,83 /2H, m, 2,45 /1H, Shir/, 2,563 /1H, d, J = 14.6 Hz/, 3,09 /1H, d, J = 10,6 Hz/, 3,72 - 3,84 /4H, m/ 3,96 - 4,14 /1H, m/ 6,344 /1H, d, J = 2,4 Hz/, 6,596 /1H/, 7,05 - 7,71 /6H, m/.

Example 62. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-3- /tetrazol-5-yl/-methylaminomethyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzothiazepin

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl - oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid in dimethylformamide /0.2 g/ from example 9 and aminoacetonitrile /0.12 g/ add diethylthiophosphate /0.12 g/ and triethylamine /0,14 ml/. The resulting mixture was stirred for 40 min at 0oC. To the reaction mixture is added a mixture of ice water and extracted with ethyl ester of acetic acid. The extract obtained was washed with water, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from hexane to obtain 0,19 g of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl-3- /cyanomethylphosphonate/-2-oxo-1,2,3,5-tetrahydro-4,1 - benzothiazepine. So melting 233 - 234oC. To a solution of 0.2 mixture is stirred for 24 hours at a temperature in the range from 110 to 120oC. the Reaction mixture was concentrated, add 20 ml of ethyl ether, washed with diluted aqueous sodium hydroxide solution. The aqueous layer was acidified with 1 N. HCl, and extracted with ethyl ester of acetic acid. The organic layer is washed with water, and then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from a mixture of dichloromethane-hexane to obtain 0.21 g of colorless crystals. So melting 264 - 265oC.

Elemental analysis for C24H26Cl2N6O20.8 H2:

Calculated: C 53,31; H 5,00; N 15,54

Found: C 53,58; H 5,14; N 15,33

Example 63. 7-Chloro-5-/2-chlorophenyl/-2,4-dioxo-1-neopentyl - 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid ethyl ester

< / BR>
/1/. 2',5-dichloro-2-pointillistically.

To 50 ml of an ethanol solution of 2-amino-2',5-dichlorophenylamino /2,35 g/ add jalaldeen /1,21 ml/ acetic acid and /0,67 g/. The resulting mixture is stirred for one hour at room temperature. To the reaction mixture add cyanoborohydride sodium /0.97 g/ and stirred over night. The reaction mixture was concentrated, add ethyl ester of acetic acid /100 ml. The resulting mixture was washed with water, and dried over what silicagel /eluent hexane : toluene = 5:1 vol/vol/ to obtain 1.7 g of oily compound.

1H NMR /CDCl3/ : 0,89 /9H, s/, 2,86 /2H, d, J = 5,2 Hz/, 4,08 /1H, Shir/, 5,66 /1H, Shir/, 6,5 - 6,85 /3H, m/, 7,0 - 7,2 /3H, m/, 7,34 /1H, d, J = 8.0 a, 1,6 Hz/.

/2/. 7-Chloro-5-/2-chlorophenyl/-2,4-dioxo-1-neopentyl-2,3,4,5 - tetrahydro-1H-1,5-benzodiazepine.

To 25 ml of solution in tetrahydrofuran, 2',5-dichloro-2-neopentyl - aminodiphenylamine /3.7 g/ added dropwise 5 ml tetraphenylboron solution malonylurea /of 1.33 ml/ at 0oC. the mixture is stirred for one hour at room temperature, then for 2 h at 60oC. the Reaction mixture was concentrated, add ethyl ester of acetic acid /100 ml. The resulting mixture was washed with water, dried over anhydrous sodium sulfate, the solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent hexane : ethyl ester of acetic acid = 2:1 vol/vol/ to obtain 1.20 g of colorless crystals. So melting 245 - 246oC.

Elemental analysis for C20H20Cl2N2O2:

Calculated: C 61,39; H 5,15; N 7,16

Found: C 61,10; H 5,04; N 6,99

/3/. 7-Chloro-5-/2-chlorophenyl/-2,4-dioxo-1-neopentyl-2,3,4,5 - tetrahydro-1H-1,5-benzodiazepine-3-acetic acid ethyl ester.

To a solution of 7-Chloro-5-/2-chlorophenyl/-2,4-dioxo-1-neopentyl-2,3,4,5 - tetrahydro-1H-1,5-Beria /60% oil, 40 mg/, and the resulting mixture stirred for 30 min at room temperature. To the reaction mixture is added sodium hydride /40 mg 3/ and ethyl ester of Chloroacetic acid /0,11/ ml, is stirred for 3 hours Then add ethyl ester acetic acid /50 ml, washed with water. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel, eluent hexane : ethyl ester of acetic acid = 4:1 vol/vol/ to obtain 0.25 g of colorless crystals. So melting 152 - 153oC.

Elemental analysis for C24H26Cl2N2O4:

Calculated: C 60,38; H 5,49; N BY 5.87

Found: C 60,22; H 5,61; N 6,05

Example 64. 7-Chloro-5-/2-chlorophenyl/-2,4-dioxo-1-neopentyl - 1,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid

< / BR>
7-Chloro-5-/2-chlorophenyl/-2,4-dioxo-1-neopentyl - 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid ethyl ester /0.2 g/ obtained in example 63, treated by the method of example 57 to obtain 0.18 g of colorless crystals. So melting 282 - 285oC.

Elemental analysis for C22H22Cl2N2O4:

Calculated: C 58,81; H 4,94; N 6,23

Found: C 58,71; H 5,15; N 6,21

Example 65. /3R,5S/-7-Chloro-5-/2,4-acid/-1-neopentyl-2 - oxo-1,2,3 ENT-5-/2,4-acid/-1-neopentyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzodiazepine-3-acetic acid /1,275 g/, obtained in example 51. To this solution add 1 N. aqueous sodium hydroxide solution /to 2.57 ml/, then all this focus. The obtained concentrate was washed with ethyl ether acetic acid to obtain 1.23 g of colorless crystals, which are not melt below 300oC.

()2D4-267,7o= 0,64, MeOH/

Elemental analysis for C24H27ClNO5SNa O7H2O:

Calculated: C 56,24; H 5,58; N 2,73

Found: C 56,16; H 5,80; N 2,81

Example 66. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1,2,3,5-tetrahydro - 4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-2-oxo-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl complex ether /0.5 g/ 5 ml dichloromethane added tetrabutylammonium /0.96 g/. The resulting mixture was refluxed for 7 hours, the Solvent is distilled off. To the residue add 1 N. HCl /8 ml, and the resulting mixture is refluxed for 10 minutes the Solution is neutralized 1H. aqueous NaOH solution, extracted with dichloromethane. The obtained extract is dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel /eluent hexane: the>

1H NMR /CDCL3/ : 2,97 /1H, DD, J = 5,8, 16.0 Hz/, 3,20 /1H, DD, J = 8,0, 16.0 Hz/, 3,26 /1H, DD, J = 2,4, and 13.4 Hz/, 3,35 - 3,42 /1H, m, 3,61 /1H, DD, J = 4,8, and 13.4 Hz/, 3,68 /3H</, 5,96 /1H/, 6,55 /1H, d, J = 2.2 Hz/, 6,83 /1H, d, J = 8,2 Hz/, 7,03 /1H, DD, J = 2,4, 8,2 Hz/, 7,28 - 7,56 /4H, m/.

Example 67. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid ethyl ester

< / BR>
/1/. 5-Chloro-2-/2,4-dimethoxybenzyl-- /2-chlorophenyl/-benzyl alcohol.

2-Amino-5-chloro -- /2-chlorophenyl/benzyl alcohol /20 g/ and 2,4-dimethoxybenzaldehyde /12.5g/ treated by the method of example 30 to obtain 33 g of oily compound.

1H NMR /CDCL3/ : 3,75 /3H/, 3,76 /3H/, 4,23 /2H,/, 6,10 /1H/, 6,35 - 6,44 /2H, m/ 6,63 /1H, d, J = 8,8 Hz/, 6,88 /1H, d, J = 2,6 Hz/, 7,03 - 7,12 /2H, m, 7,24 - 7,45 /4H, m/,

/2/ 3-/N-/4-chloro-2-/2-chloro-hydroxybenzyl/phenyl/-N-/2,4 - dimethoxybenzyl/carbamoylation acid complex ethyl ester 5-chloro-2-/2,4-dimethoxyaniline -- /2-chlorophenyl/benzyl alcohol /33 g/ and monotropy ester of fumaric acid chloride /12.8 g/ treated by the method of example 30 to obtain 48,9 g of oily compound.

1H NMR /CDCl3/ : 1,18 - 1,35 /3H, m/, of 3.46 /3H,, 3,78 /3H/, 3,82 - 3,83 /2H, each s/, 3,94 - 4,34 /2H, m/, with 4.64 /1/2 1H, d, J = 14,2 Hz/, 5,48 /1/2 1H, J = 14,2 Hz/, 6,02 - 8,00 /12H, m/.

/3/ 3,5-Tran ester.

To a solution of compound /48,9 g/ obtained in /2/ in 500 ml of ethanol, added 12.4 g of potassium carbonate. The resulting mixture is stirred over night at room temperature. The solvent is distilled off. To the residue is added 200 ml of dichloromethane, washed with water, dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from a mixed solvent consisting of dichloromethane and hexane to obtain to 41.4 g of colorless crystals.

So melting 135 - 136oC.

/4/. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-3-acetic acid ethyl ester.

The compound obtained in the /3/ /5 g/, 10 g of potassium persulfate and secondary acidic potassium phosphate /3,3 g/ is added to a mixed solvent consisting of 80 ml of acetonitrile and 40 ml of water is refluxed for 2 hours To the reaction mixture, water is added, extracted with ethyl acetate. The obtained extract is dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent hexane : ethyl ester of acetic acid = 3:1 volume/volume of/ before getting to 1.83 g of colorless crystals. So melting 132 - 137oC.

/5/. 3,5-t is>The compound obtained in /4/ /1.8 g/, processed by the method of example 66 to obtain 0,69 g of colorless oily product

1H NMR /CDCl3/ : 1,14 /3H, t, J = 7.2 Hz/, 2,54 /1H, DD, J = 6,6, 15,0 Hz/, 2,73 /1H, DD, J = 7,4, 15,0 Hz/, 3,29 - 3,32 /2H, m, 4,05 /2H, q, J = 7.2 Hz/, 4,20 - 4,32 /1H, m, 6,33 /1H/, 6,4 /1H, d, J = 2,4 Hz/, 6,72 /1H, d, J = 8,4 Hz/,? 7.04 baby mortality - 7,43 /5H, m/.

Example 68. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-propyl - 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ether complex /0.1 g/ obtained in example 66, 2 ml of methanol, add Propionaldehyde /76 mg/ day and 24 mg of acetic acid. The resulting mixture was stirred for 30 min at room temperature. To the reaction mixture add cyanoborohydride sodium /25 mg/, stirred for one hour at room temperature. To the reaction mixture are added 50 ml of dichloromethane, washed with water, dried over anhydrous sodium sulfate. The solvent is distilled off, resulting in a gain of 0.13 g of colorless oily product.

1H NMR /CDCl3/ : 0,99 /3H, t, J = 7,4 Hz/, 1,46 - 1,63 /2H, m, was 2.76 - 3,05 /5H, m/, 3,24 - of 3.46 /2H, m/ 3,68 /3H/, to 6.43 /1H/, 6,53 /1H, d, J = 2,4 Hz/, 7,05 - 7,42 /5H, m/ 7,73 - to 7.77 /1H, m/.


< / BR>
3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid ethyl ester /0.1 g/ obtained in example 67, treated by the method of example 68 to obtain a colorless oily product /0.06 g/.

1H NMR /CDCl3/ : 0,98 /2H, t, J = 7.2 Hz/, 1,19 / 3H, t, J = 7.2 Hz/, 1,57 - 1,74 /2H, m, 2,53 /1H, DD, J = 5,8, 15,0 Hz/, 2,74 /1H, DD, J = 7,6, 15,0 Hz/, 2,92 - 3,06 /2H, m, 3,27 - 3,47 /2H, m, 4,10 /2H, DQC J = 1,4, 7,2 Hz/, 4,17 - 4,25 /1H, m/ 6,39 /1H, d, J = 2,4 Hz/, to 6.43 /1H/, 6,90 /1H, d, J = 8.6 Hz/, 7,14 /1H, DD, J = 2,6, 8.6 Hz/, 7,28 - 7,63 /4H, m/.

Example 70. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-propyl-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid hydrochloride

< / BR>
To a solution of 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-propyl-1,2,3,5 - tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ether complex /0,13 g/ obtained in example 68, 1 ml dioxane, add 6 N. HCl /1 ml, and the resulting mixture is refluxed for 30 minutes, the Solvent is distilled off and the residue is recrystallized from a mixture of ethanol-hexane to obtain 57 mg of colorless crystals. So melting 165 - 168oC.

Elemental analysis for C20H21Cl2NO2SO3H2O:

Calculated: C 53,12; H 5,04; N 3,10

Found: C 53,21; H to 5.03; N 3,34

Example 71. 3,5-TRANS-7-Chloro-5-/2-chlorphen the l-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetic acid ethyl ester /0.15 g/, obtained in example 69, treated by the method of example 70 to obtain 50 mg of colorless crystals. So melting 105 - 112oC.

Elemental analysis for C20H21Cl2NO3HClO6H2O:

Calculated: C 54,40; H and 5.30; N 3,17

Found: C 54,33; H lower than the 5.37; N 3,17

Example 72. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-propionyl 1,2,3,5-tetrahydro-4,4-benzothiazepin-3-acetic acid methyl ester

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/- 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ether complex /100 mg, obtained in example 66, 2 ml dichloromethane added sodium bicarbonate /59 mg/. To the resulting mixture add propionate /60 mg. The resulting mixture was stirred for 2 h at room temperature and add 50 ml of dichloromethane. The resulting mixture was washed with water, the solvent is distilled off. The residue is recrystallized from a mixture of ethyl ether-petroleum ether to obtain 90 mg of colorless crystals.

So melting 191 - 194oC.

1H NMR /CDCl3/ : 1,14 /3H, t, J = 7.2 Hz/, 2,07 - 2,33 /2H, m, 2,83 /1H, DD, J = 7,6, 16,8 Hz/, 3,02 /1H, DD, J = 7,2, 16,8 Hz/, 3,24 /1H, DD, J = 3,0, to 13.6 Hz/, 3,32 - 3,44 /1H, m/ 3,68 /3H/, 4,85 /1H, DD, J = 5,0, to 13.6 Hz/, 6,00 /1H, with/, 6,60 /1H, d, J = 2.2 Hz/, 7,11 - 7,63 /6H, m/.

Example 73. 3,5-t is

< / BR>
3,5-TRANS-7-Chloro-5-/2-chlorophenyl/- 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid ethyl ester /100 mg, obtained in example 67, treated by the method of example 72 to obtain 70 mg of oily product.

1H NMR /CDCl3/ : 1,07 /3H, t, J = 7,0 Hz/, 1,16 /3H, t, J = 7,4 Hz/, 2,14 - 2,52 /2H, m/ 2,61 /1H, DD, J = 5,4, to 15.4 Hz/, 2,88 /1H, DD, J = 9,2, to 15.4 Hz/ at 3.25 /1H, DD, J = 3.2, and to 13.6 Hz/, 3,85 - 4,16 /2H, m, 4,24 - 4,40 /1H, m, 4,56 /1H, DD, J = 6,0, to 13.6 Hz/, 6,29 /1H/, 6,50 /1H, d, J = 2.2 Hz/, 7,16 - 7,68 /6H, m/.

Example 74. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-propionyl 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-propionyl 1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic acid methyl ester /90 mg, obtained in example 72, in 2 ml of dioxane was added 1 ml of 2 n HCl. The resulting mixture was refluxed for 2 h, add 50 ml of dichloromethane. The resulting mixture was washed with water, the solvent is distilled off. The residue is recrystallized from a mixture of ethyl ether-hexane to obtain 52 mg of colorless crystals.

So melting 230 - 232oC.

Elemental analysis for C20H19Cl2NO3S:

Calculated: C 56,61; H 4,51; N 3,30

Found: C, 56.26 vertical; H 4,65; N 3,51

Example 75. 3,5-TRANS-7-Chloro-5-/enil/-1-propionyl 1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetic acid ethyl ester /70 mg/, obtained in example 73, treated by the method of example 74 to obtain 43 mg of colorless crystals.

So melting 187 - 190oC.

Elemental analysis for C20H19Cl2NO4:

Calculated: C 58,84; H 4,69; N 3,43

Found: C 58,75; H of 4.67; N 3,59

Example 76. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetic acid tert-butyl ester

< / BR>
/1/. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid tert-butyl ether.

To a solution of 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl-2-oxo - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid /2 g/ 20 ml dichloromethane was added 1 ml of isobutene and concentrated sulfuric acid /0.05 mg/. The resulting mixture was left to stand for 24 h in a sealed reactor. The solution is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is purified on a chromatographic column with silica gel /hexane : ethyl ester of acetic acid = 5:1 vol/vol/ to obtain a rate of 1.67 g of colorless crystals. So melting 145 - 147oC.

/2/. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-uksusno /1/, add tetrabutylammonium /1,57 g/. The resulting mixture is treated according to the method of example 66 to obtain 0.52 g of colorless oily product.

1H NMR /CDCl3/ : 0,95 /9H,, 1,44 /9H, s/, 2,33 /1H, DD, J = 5,0, to 15.4 Hz/, 2,55 /1H, DD, J = 7,8, or 15.4 Hz/, 2,56 /1H, d, J = 13,2 Hz/, 3,09 / 1H, DD, J = 1,8, 11.2 Hz/, 3,63 - 3,78 /2H, m, 4,12 - 4.26 deaths /1H, m, 6,32 /1H/, 6,59 /1H, with/, 7,11 - 7,76 /6H, m/.

Example 77. 3,5-TRANS-7-Chloro-5-/2-chlorophenyl/-1-neopentyl - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

< / BR>
To a solution of 3,5-TRANS-7-chloro-5-/2-chlorophenyl/-1-neopentyl - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid tert-butyl ether /0.5 g/ obtained in example 76, in 5 ml of dioxane is added 2 N. aqueous solution of hydrogen chloride /1 ml/. The resulting mixture is refluxed for 3 hours, the Reaction mixture is neutralized 1 N. NaOH, add 100 mg of dichloromethane, washed with water. The solvent is distilled off. The residue is purified on a chromatographic column with silica gel /eluent dichloromethane-methanol = 0:1: 0,1 vol/vol/ to obtain 85 mg of colorless crystals.

So melting 195 - 208oC.

Elemental analysis for C22H25Cl2NO32H2O:

Calculated: C 62,04; H 6,01; N 3,29

Found: C 62,14; H 6,01; N 3,42

Assessment active solutions of the enzymes, as shown later in the experimental examples 1 and 2.

More specifically, a solution of the enzyme /protein 0.8 µg/ prepared in experimental examples 1 and 2, are added to a solution /total volume of 50 μl/ containing 5 μm [1-3H]farnesylated /specific activity 25 µci/ mol, 1 mm NADPH, 5 mm MgCl2, 6 mm glutathione, 100 mm buffer solution of potassium phosphate /pH 7,4/ and drug test /which is used in the form of an aqueous solution or a solution in DMSO, and the reaction allowed to proceed at 37oC for 45 minutes To this reaction mixture is added 150 μl of a mixture of chloroform : methanol /1:2/, the reaction mixture is suspended, add 50 ál of chloroform and 50 μl of 3 N. aqueous sodium hydroxide solution. 50 μl chloroformate layer /lower layer containing the reaction mixture, consisting mainly of squalene, and 3 ml of liquid scintillator based on toluene, mix, and determine the radioactivity of the mixture using a scintillation counter. The activity of inhibiting squalene synthetase expressing the concentration inhibiting 50% of the radioactivity in CHLOROFORMATES layer /IC50molar concentration /M//.

Experimental example 1. Getting the rat enzyme.

Male cu is left solution ice, homogenized in 15 ml ice-cold buffer /100 mm potassium phosphate /pH 7,4/, 15 mm nicotinamide, 2 mm MgCl2/, then centrifuged for 20 min /4oC/ at 10,000 rpm the Supernatant layer was separated, and the centrifugation continue for 90 min /4oC/ 105000/min the precipitate is suspended in 100 mm ice phosphate buffer /pH 7,4/, which is again centrifuged for 90 min /4oC/ 105000/min the precipitate /microsome fraction/ suspended in ice-cold 100 mm califorina buffer /pH 7,4/ 40 mg/ml concentration of protein was determined using the ICA set for analysis of protein Pias Co. Ltd./. This suspension is used as the enzyme solution.

Experimental example 2. Obtaining the human enzyme.

Cells human liver HepG2 /about 1 109cells obtained by incubation in Dulbecco-modified medium Needle /37oC in the presence of 5% CO2/, suspended in 10 ml ice-cold buffer /100 mm califofnia buffer /pH 7,4/, 30 mm nicotinamide and 2.5 mm MgCl2/. Cells are crushed, processing ultrasound /twice for 30 seconds. This get microsome fraction according to the method experimentally is the suspension and used as enzyme solution. The results are shown in table. 4 (see the end of the description).

Examples of the compositions.

Agent, inhibiting squalene-synthetase containing as an effective component the compound represented by formula I, I', I", I"' of the present invention, or its salt, in those cases when it is used as a therapeutic agent, hypercholesterinemia can be prepared, for example, in accordance with the following recipes:

1. Capsules mg:

/1/ Connection examples 10 - 8 - 10

/2/ Lactose - 90

/3/ Microcrystalline cellulose - 70

/4/ Stearate - 10

One capsule - 180 mg.

/1/, /2/ and /3/ and a half /4/ mixed, the resulting mixture granularit to it add the rest /4/. The resulting mixture is filled into gelatin capsules.

2. Tablets mg

/1/ Connection example 10-8 - 10

/2/ Lactose - 35

/3/ Corn starch - 150

/4/ Microcrystalline cellulose - 30

/5/ Stearate - 5

One tablet - 230 mg.

/1/, /2/ and /3/ and 2 / 3 /4/ and 1/2 /5/ mixed, the resulting mixture granularit add the rest of /4/ and /5/. The resulting mixture granularit add the rest of /4/ and /5/. The resulting mixture is pressed and get pills.

3. Pray alcohol - 20

One ampoule 130 mg.

/1/, /2/ and /3/ are dissolved in distilled water for injection to obtain the full volume of 2 ml, placed in a vial, which is sealed. All manipulations produced in sterile conditions.

4. Capsules mg:

/1/ the Compound of example 9 - 10

/2/ Lactose - 90

/3/ Microcrystalline cellulose - 70

/4/ Stearate - 10

One capsule - 180 mg.

/1/, /2/ and /3/ and 1/2 /4/ mixed, the resulting mixture granularit add the rest /4/. The resulting mixture was filled in a gelatin capsule.

5. Tablets mg

/1/ the Compound of example 9 - 10

/2/ Lactose - 35

/3/ Corn starch - 150

/4/ Microcrystalline cellulose - 30

/5/ Stearate - 5

One tablet - 230 mg

/1/, /2/ and /3/ and 2 / 3 /4/ and 1/2 /5/ mixed, the resulting mixture granularit add the rest of /4/ and /5/. The resulting mixture was pressed into a tablet.

6. Preparations for injection, mg:

/1/ Sodium salt of the compound of example 9 - 10

/2/ Inositol - 100

/3/ Benzyl alcohol - 20

One ampoule 130 mg

/1/, /2/ and /3/ are dissolved in distilled water for injection to obtain the full volume of 2 ml, placed in a vial, the vial sealed. All manipulations carried out in a wiped the/SUB> represents hydrogen or C1-7is an alkyl group, optionally substituted by oxopropoxy;

R'2represents a phenyl group substituted by halogen or lower alkoxygroup; X' is C1-4-alkylene, substituted carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, tetrazol-5-yl, carbamoyl group, substituted lower alkyl, optionally substituted tetrazol-5-yl, a carboxyl group or a lower alkoxycarbonyl;

ring a represents benzene ring, substituted by halogen, or thienyl substituted by halogen;

ring J1to 7-membered heterocyclic ring containing not more than three heteroatoms in the ring;

D represents C or N;

Z1- C, O, N, or S(O)q(where q = 0, 1 or 2);

K - s or N;

ring J1optional contains in addition to R1, R'2and X' such additional Deputy as oxo or thioxo-, provided that the condensed ring composed of ring a and J1that is not 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring or 2-oxo-2,3-dihydro-1H-1,4-benzodiazepine ring,

or their salt.

2. Connection on p. 1, formula I'

< / BR>
or its salt,

where R1predstavit phenyl group, substituted by halogen or lower alkoxygroup;

X' - C1-4-alkylene, substituted carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, tetrazol-5-yl, carbamoyl group, substituted lower alkyl, optionally substituted tetrazol-5-yl, a carboxyl group or a lower alkoxycarbonyl;

ring And benzene ring is substituted by halogen, or thienyl substituted by halogen;

ring J2to 7-membered heterocyclic ring;

Z2- S(O)q(where q = 0, 1 or 2), or;

K is C or N;

G is O or S, provided that the condensed ring composed of ring a and J2that is not 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring.

3. The compound or its salt under item 1 or 2, where R1- C1-7is an alkyl group, optionally substituted by exography.

4. The compound or its salt according to p. 3, where R1- C1-7is an alkyl group.

5. The compound or its salt under item 1 or 2, where X' - C1-4-alkylene, substituted carboxyl group or a lower alkoxycarbonyl group.

6. The compound or its salt under item 1 or 2, where X' - C1-4-alkylene, substituted tetrazol-5-yl.

7. Connection elem ring J1is oxo or thioxo-.

9. The compound or its salt under item 1, where the condensed ring composed of ring a and J1represents a

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10. The compound or its salt according to p. 2, where Z2- S(O)q(where q = 0, 1 or 2).

11. The compound or its salt according to p. 2, where K is C.

12. Inhibitor of squalene synthetase, characterized in that it contains a compound or its salt under item 1.

13. Inhibitor under item 12, wherein R1represents C1-7is an alkyl group, optionally substituted by exography.

14. Inhibitor under item 13, wherein R1represents C1-7is an alkyl group.

15. Inhibitor under item 12, wherein R2represents a substituted phenyl group.

16. Inhibitor under item 12, wherein X' represents a C1-4-alkylene, substituted carboxyl group or a lower alkoxycarbonyl group.

17. Inhibitor under item 12, wherein X' represents a C1-4-alkylene, substituted tetrazol-5-yl.

18. Inhibitor under item 12, characterized in that a represents thienyl

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19. Inhibitor under item 12, characterized in that the stage is the action scene themes that the condensed ring composed of ring a and J1is

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21. Inhibitor under item 12, characterized in that the compound represented by formula (I"'

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where R1represents hydrogen or C1-7is an alkyl group, optionally substituted by oxopropoxy;

R'2represents a phenyl group substituted with halogen or lower alkoxycarbonyl group;

X1- C1-4-alkylen;

Y represents a carboxyl group, a lower alkoxycarbonyl group, hydroxyl group, tetrazol-5-yl, karbamoilnuyu group, substituted lower alkyl, optionally substituted tetrazol-5-yl, a carboxyl group or a lower alkoxycarbonyl;

ring And benzene ring, substituted with halogen, or thienyl, substituted with halogen;

Z3is =N-, -NH-, -S-, -S(O)-, -S(O)2-, -CH2- or-O-;

G is O or S;

the symbol represents a double bond when Z3is =N-, and a simple link, when there is =N-, provided that when Z3represents-O -, and ring a represents benzene ring, substituted with halogen, G is S;

or its pharmaceutically acceptable salt.

22. Indiacom:

24.09.93 - R1represents hydrogen or C1-7is an alkyl group; R'2represents a phenyl group substituted with halogen or lower alkoxycarbonyl group; X' is C1-4-alkylene, substituted carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group; carbamoyl group, substituted lower alkyl, optionally substituted carboxyl group or a lower alkoxycarbonyl; ring And benzene ring, substituted with halogen; D is C; Z1Is o or S; K is C; the ring J1not necessarily having, in addition, R1, R'2or X', such additional Deputy as oxo or thioxo-, or salt.

29.09.93 - X' - C1-4-alkylen; ring a - thienyl, substituted with halogen; Z1- N, SO, SO2C.

 

Same patents:

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

The invention relates to androidiani carboxanilides, compositions based on them and the way to deal with arteriotomy and can be used in agriculture

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

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where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

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The invention relates to methods for new nitrogen-containing compounds of General formula I

Rwhere R1is hydroxy, lower alkanoyloxy, OCOT1Y2where: Y1, Y2is hydrogen, lower alkyl when X = CH2; R2group of the formula

ororor< / BR>
ororwhere n' is 0,1,2,3; n = 2,1,0, where: Y3Y4is hydrogen, lower alkyl, Y5- phenyl-lower alkoxy, hydrogen, lower alkoxy when X is - S R2group

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds

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