Compounds containing condensed bicyclic nucleus intermediate compounds, methods for their preparation and pharmaceutical composition for inhibiting the turning of the enzyme and angiotensin neutral endopeptidase

 

(57) Abstract:

Compounds containing condensed bicyclic core of formula I, where A represents a residue of formula (a) or (b), X represents O or S; R1and R12is hydrogen, C1-5-alkyl, phenyl-(lower)alkylen, naphthyl-(lower)alkylene, C3-7-cycloalkyl-(lower)alkylene, thienyl-(lower)alkylene, or R1and R12taken together with the carbon atom to which they are attached, close C5- C6-cycloalkyl ring; R2is hydrogen or C = O, R3and R7is hydrogen or lower alkyl; R6is lower alkyl; m and r = 0 or 1; Y is CH2or O; n = 1 or 2, or their pharmaceutically acceptable salts are inhibitors of double action, possessing the ability to inhibit the conversion of the enzyme and angiotensin neutral endopeptidase.

< / BR>
9 C. and 4 h.p. f-crystals, 1 table.

The invention relates to new compounds containing condensed bicyclic core, which are used as angiotensin inhibitors of the conversion of the enzyme. Some of these compounds possess inhibitory activity against neutral endopeptidase. This invention also relates to pharmaceutical is of such compositions. This invention also relates to a method for producing such novel compounds, novel intermediates and methods of producing such intermediates.

New condensed bicyclic inhibitors of this invention include compounds of formula I

< / BR>
and their pharmaceutically acceptable salts:

where

A represents A

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

< / BR>
X represents O or S(O)t;

R1and R12independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, substituted alkyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, cycloalkylation-, aryl-alkylene, substituted aryl-alkylene, and heteroaryl-alkylene or R1and R12taken together with the carbon atom to which they are attached, form cycloalkyl ring or condensed benzocyclobutene ring;

R2represents hydrogen, or R11-S-;

R3, R5and R7independently selected from hydrogen, alkyl, substituted alkyl, aryl-(CH2)p-, substituted aryl-CH2)p- heteroaryl-(CH2)p-,

< / BR>
and

< / BR>
R4represents alkyl, cycloalkyl-(CH2)p-, substituted alkyl, rietvlei alkyl, substituted alkyl, cycloalkyl-(CH2)p-, aryl-(CH2)p-, substituted aryl-(CH2)p- or heteroaryl-(CH2)p;

R8represents hydrogen, lower alkyl, cycloalkyl or phenyl;

R9represents hydrogen, lower alkyl, lower alkoxy or phenyl;

R10represents lower alkyl or aryl-(CH2)p-;

R11represents hydrogen, alkyl, substituted alkyl, cycloalkyl-(CH2)p-, aryl-(CH2)p-, substituted aryl-(CH2)p- heteroaryl-(CH2)p- or-S-R11forms a symmetrical disulfide wherein R11is

< / BR>
m is 0 or 1;

Y is CH2, S(O)tor O, provided that Y represents S(O)tor O only if m is 1;

n is 1 or 2;

p is 0 or an integer from 1 to 6;

q is 0 or an integer from 1 to 3;

r is 0 or 1; and

t is 0, 1 or-1.

The term "alkyl" refers to a radical with unbranched or branched chain containing up to 7 carbon atoms. The term "lower alkyl" refers to a radical with unbranched or branched chain containing up to 4 carbon atoms, and is a preferred sub-group for a term of Ala is d 1 - 7 carbon atoms, where one or more, preferably one, two or three hydrogen atoms replaced by a hydroxy, amino, cyano, halogen, triptorelin, -NH(lower alkyl), -N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy group.

The terms "lower alkoxy" and "lower alkylthio" refers to such lower alkyl groups are as defined above, attached to the oxygen atom or sulfur.

The term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms with cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl being preferred.

The term "alkenyl" refers to the radical with unbranched and branched chain with 3 to 7 carbon atoms containing one or two double bonds. Preferably "alkeneamine" groups represent a radical with unbranched chain with 3 to 5 carbon atoms containing one double bond.

The term "substituted alkenyl" refers to such radicals with unbranched or branched chain with 3 to 7 carbon atoms containing one or two double bonds, where the hydrogen is substituted by hydroxy, amino, halide, triptorelin, cyano, -NH(lower alkyl), -N(lower alkyl)2nor is extensive or branched chain, containing up to 7 carbon atoms, i.e.,- CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, etc.

The term "aryl" refers to phenyl, 1-naphthyl and 2-naphthyl. The term "substituted aryl" refers to phenyl, 1-naphthyl and 2-naphthyl containing a Deputy selected from lower alkyl, lower alkoxy, lower alkylthio, halogen, hydroxy, trifloromethyl, amino, -NH(lower alkyl) or-N(lower alkyl)2and di - or tri-substituted phenyl, 1-naphthyl or 2-naphthyl, where these substituents selected from methyl, methoxy, methylthio, halogen, hydroxy and amino.

The term "heteroaryl" refers to an unsaturated ring with 5 or 6 carbon atoms containing one or two atoms O and S and/or 1 to 4 nitrogen atom, provided that the total number of heteroatoms in the ring is 4 or less. Heteroaryl ring is attached using the available carbon atom or nitrogen atom. Preferred heteroaryl groups include 2-, 3 - or 4-pyridyl, 4-imidazolyl, 4-thiazolyl, 2 - and 3-thienyl, and 2 - and 3-furyl. The term "heteroaryl" also includes bicyclic ring, where the 5 - or 6-membered ring containing atoms O, S and N, as defined above, it is condensed with benzene or pyridinium ring. Prearalie ring may be optionally substituted on available carbon atom by lower alkyl, halogen, hydroxy, benzyl or cyclohexylmethyl. In addition, if a mono - or bicyclic core has N atom, this N atom may also be replaced by N-protecting group, such as

< / BR>
< / BR>
2,4-dinitrophenyl, lower alkyl, benzyl or benzhydryl.

The compounds of formula I, where A represents the

< / BR>
X represents O or S, and

Y is CH2, O or S, can be obtained by the reaction of a combination of compounds with allmerica side chain of the formula II

< / BR>
with connection to a condensed bicyclic ring of formula III

< / BR>
with the product of formula IV

< / BR>
where

R3represents hydrogen or an acid protecting group, such as methyl, ethyl, t-butyl or benzyl.

The above reaction can be carried out in an organic solvent such as methylene chloride and in the presence of the agent combinations, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, benzotriazol-1-yloxytris(dimethylamino)-phosphodiesterase, or carbonyldiimidazole. Or allergopharma acid of formula II can be converted into an activated form to the reaction mixture, such as an acid chloride, mixed anhydride, simfy product of formula I, where R2is hydrogen and R3represents hydrogen, a method is known in the literature. For example, if R6represents methyl and R3represents ethyl, treatment of a methanol solution of sodium hydroxide followed by treatment with an aqueous solution of the acid gives the products, where R2and R3represent hydrogen.

The product of formula I, where R2represents hydrogen, can be allerban acylhalides formula V

< / BR>
where

halogen is F, Cl or Br,

or allerban anhydride of formula VI

< / BR>
with the production of other products of the formula I, where R2is

< / BR>
The products of formula I, where R2is-S-R11and R11represents alkyl, substituted alkyl, cycloalkyl-(CH2)p-, aryl-(CH2)p-, substituted aryl-(CH2)p- or heteroaryl-(CH2)p- can be obtained by the interaction of the products of formula I, where R2represents hydrogen, with sulfonyl compound of formula VII

H3C-SO2-S-R11< / BR>
in an aqueous alcohol solvent, to obtain the desired products. The compounds of formula VII are known in the literature or can be obtained by known methods is obtained by the interaction of the product of formula I, where R2represents hydrogen, with a compound of formula VII, where R11is triphenylmethyl or triallelic, with the subsequent removal triphenylethylene or trialkylsilyl group in acidic conditions.

Symmetrical disulfide products of formula I can be obtained by direct oxidation of the product of formula I, where R2represents hydrogen, iodine according to known methods, for example see Ondetti and others, U.S. patent 4105776.

Connection with side killerkarrit formula II, where R12represents hydrogen, described in the literature (see , for example, Ondetti and other U.S. patent 4105776 and 4339600, Haslanger and other U.S. patent 4801609, Delaney and other U.S. patent 4722810 and so on).

Connection with side killerkarrit formula II, where R1and R12both other than hydrogen, and r is 0, can be obtained by the interaction of the substituted carboxylic acid of formula VIII

< / BR>
with bis///(4-methoxy)phenyl/metilsulfate in the presence of sitedisability with obtaining the compounds of formula IX

< / BR>
Treatment of compounds of formula IX in a strong acid, such as triftormetilfullerenov acid removes methoxybenzyl protecting group and subsequent acylation with acylhalides formula V or anhydride f the th carboxylic acid of formula VIII can interact with lifedisabilities and grey, giving a mercaptan of the formula X

< / BR>
Mercaptan of the formula X can then be allerban acylhalides formula V or anhydride of the formula VI, giving the compound of formula II, where R1and R12both other than hydrogen, and r is 0.

Connection with side allmarkets.ru formula II, where R1and R12both other than hydrogen, and r is 1, can be obtained by the interaction of the substituted carboxylic acid of formula XI

< / BR>
with para-toluensulfonate in pyridine to obtain a lactam of the formula XII

< / BR>
Treatment of the lactam of formula XII susitikimui formula XIII

< / BR>
in the presence of dimethylformamide gives the desired connection with allmernational chain of the formula II, where R1and R12both other than hydrogen, and r is 1.

The compounds of formula I, where A is

X represents O or S and Y is CH2, O or S, can be obtained by the reaction of a combination of an acid of formula XIV

< / BR>
where

R7is acid protecting group,

connection with condensed bicyclic nucleus of the formula III in the presence of the agent of the combination, as defined above, to obtain the product of formula XV

< / BR>
Or acid of the formula XIV can be converted is Warshawsky and other in European patent application 534396 and 534492.

The compounds of formula I, where A represents the

< / BR>
X represents O or S and Y is CH2, O or S, can be obtained by the interaction of a keto acid or ester of formula XVI

< / BR>
connection with condensed bicyclic nucleus of the formula III in terms of recovery product of the formula XVII

< / BR>
The keto acid and esters of formula XVI described in the literature (see, for example, Ruyle U.S. patent 4584294 and Parsons and other U.S. patent 4873235).

Or a connection to a condensed bicyclic nucleus of formula III may interact with triptolemos formula XVIII

< / BR>
giving the product of formula XVII.

The compounds of formula I, where A represents the

< / BR>
X represents O or S and Y is CH2, O or S, can be obtained by the reaction of a combination of phosphoshikimate formula XIX

< / BR>
where

R5represents lower alkyl or benzyl,

connection with condensed bicyclic nucleus of formula III, to obtain the product of formula XX

< / BR>
Preferably R3in the compound of formula III represents lower alkyl or benzyl. R3and R5acid protecting group can then be removed, for example, hidri"ptx2">

Phosphorochloridate formula XIX are known in the literature (see, for example, Karanewsky et U.S. patent 4432971 and 4432972 and Karanewsky U.S. patent 4460579).

The products of formula I, where X or Y or both are S-(O)tand t is 1 or 2, can be obtained by oxidation of compounds of formula IV, XV, XVII or XX-known oxidizing agents such as meta-chlorbenzene acid, peracetic acid, monoperoxyphthalic acid, hexahydrate salt of magnesium, etc. by Controlling the amount of oxidizing agent and the reaction time receive the products, where t is 1 or 2.

The products of formula I in ethereal form, where R5or R7is

< / BR>
can be obtained by treating the corresponding compounds of formula I, where R5or R7is hydrogen and R3is acid protecting group, the compound of the formula XXI

< / BR>
where

L represents a removable group, such as chlorine, bromine or tolilsulfonil,

with the subsequent removal of the acid protecting group, R3.

The ester products of formula I, where R3is

< / BR>
can be obtained by treating the corresponding compounds of formula I, where R3is hydrogen and R2represents a connection is obtained according to the following methods, which are also part of this invention. For example, if Y represents CH2then N-protected amino acid of formula XXII

< / BR>
can be subjected to reaction combination with ether amino acids of formula XXIII

< / BR>
with the receipt of the dipeptide of formula XXIV

< / BR>
where

P1is aminoamides group, such as benzyloxycarbonyl or t-butyloxycarbonyl, or a group which together with the N-atom forms a protecting group, such as phthalimido;

P2represents hydroxy or mercaptothiadiazole group;

R3is easily removable ether protecting group.

Preferred P2protecting groups, if X represents S, are acyl groups such as acetyl or benzoline, especially acetyl. Preferred P2protecting groups, if X represents O, are acyl groups, tetrahydropyranyl, employed silyl group and tritely, especially triphenylmethyl and 1,1-dimethyltrimethylene. This reaction mix is conducted preferably in the presence of the agent combinations, such as benzotriazol-1-yloxytris-(dimethylamino)fosfodiesterasa, ethyl-3-(3-dimethylamino)propellerpowered or IU which mediate the compounds of formula XXIV, for example, by treatment with sodium methoxide in methanol, if P2is acetyl or benzoyl, or by treatment with an acid such as p-toluensulfonate acid in methanol, if P2represents acetyl, benzoyl, trityl, tetrahydropyranyl, or 1,1-dimethyltrimethylene. The resulting product is then subjected to cyclization reaction catalyzed by acid, preferably by treatment in a strong acid, such as triperoxonane acid, para-toluensulfonate acid or commercially available polystyrenesulfonate polymer type ion-exchange resin, such as Amberlite 15. This cyclization reaction can be performed in aprotonin a solvent such as methylene chloride or chloroform, to obtain the intermediate compounds of formula XXV

< / BR>
The compounds of formula XXIV, after removal of the P2protecting group and cyclization reaction, where X is O can be converted into the corresponding compounds where X is S. This can be done in various ways. For example, the compound of formula XXIV, after removal of the P2group, can be treated with triphenylphosphine, diisopropylcarbodiimide and teoksessa acid. The resulting thioacetate then obrabecim the sleigh above cyclization reaction.

In another method, the compound of formula XXIV, after removal of the P2the group treated by known methods, obtaining the compound of formula XXVI

< / BR>
where

L represents a group to delete, such as methanesulfonate, pair-toluensulfonate, iodine or bromine. For example, treatment of compounds of formula XXIV, after removal of the P2protecting groups methanesulfonamido, gives compound of formula XXVI, where L is methansulfonate.

The compound of formula XXVI is then treated with capitialism, receiving the appropriate thioacetate. Treatment with sodium methoxide in methanol gives the corresponding mercaptan, which can then be subjected to the cyclization reaction described above.

Or the compound of formula XXIV, where X is O, can be directly converted into an intermediate compound of formula XXV treatment in a strong acid, such as triperoxonane acid, para-toluensulfonate acid or commercially available polystyrenesulfonate polymer type ion-exchange resin, such as Amberlite 15, in an appropriate solvent, such as methylene chloride or chloroform.

N-Protecting group is then removed from the compounds of formula XXV, abucay attributively or palladium on coal and ammonium salt of formic acid or hydrogen, if P1is benzyloxycarbonyl, or by treatment with hydrochloric acid in dioxane or other strong acid, if P1is t-butoxycarbonyl, receiving the compound of formula III with a condensed bicyclic core.

In another way, if Y is CH2N-protected amino acid of formula XXII can be subjected to reaction combination with the ether hydroxyamino acid of formula XXVII

< / BR>
with the receipt of the dipeptide of formula XXVIII

< / BR>
where

P1and P2have the meanings as defined above.

This reaction mix is preferably carried out in the presence of the agent combinations, such as methanesulfonylaminoethyl or ethyl-3-(dimethylamino)carbodiimide.

Gidroksosoedinenii XXVIII is then oxidised to the aldehyde of formula XXIX

< / BR>
treatment oxalylamino/dimethylsulfoxide followed by treatment of the tertiary amine in aprotonin a solvent such as methylene chloride. The aldehyde of formula XXIX is then treated, as described above, to remove the P2protecting groups and then subjected to cyclization reaction catalyzed by the acid, as described above, giving an intermediate compound of formula XXV.


< / BR>
where

P3represents an N-protecting group. For example, R3and N-atom can form phtalimide balance. N-protected L-hydroxyisoleucine formula XXX is then treated for the introduction of P3acid protecting group methyliodide in the presence of a base or treated with a strong acid in methanol, where R3represents methyl. This ester is then oxidised to produce the aldehyde of formula XXXI

< / BR>
The aldehyde of formula XXXI is then treated with ortho-formic ester of formula XXXII

< / BR>
in the presence as catalyst of a strong acid and the corresponding alcohol, i.e., OH-alkyl, where alkyl is the same as alkyl in the ortho-formic ether of the formula XXXII, receiving the compound of formula XXXIII

< / BR>
Removing the N-protecting group, R3for example, the processing hydrazinehydrate, if R3and N-atom form phtalimide balance, gives a starting material of formula XXIII, where m is equal to 1.

Starting material of formula XXIII, where m is 0, can be obtained by protecting the N-atom - benzylguanine with obtaining the compounds of formula XXXIV

< / BR>
where

P3represents an N-protecting group such as t-butyloxycarbonyl, or where P3is m process for the introduction of R3acid protecting group, as described above, obtaining XXXV

< / BR>
By hydrolysis, if R3represents lower alkyl, remove the benzyl ester group of compound XXXV obtaining XXXVI

< / BR>
Selective reduction of compound XXXVI, for example, by treatment with atention, ethyl-3-(3-dimethylamino) - propyl carbodiimide and dimethylaminopyridine with subsequent processing triethylsilanol, palladium on coal and acetonitrile gives the aldehyde of formula XXXVII

< / BR>
The aldehyde of formula XXXVII is then treated with ortho-ester of formic acid, as described above, and the N-protecting group P3delete, as described above, to obtain the educt of the formula XXIII, where m is equal to 0.

Hydroxysteroid ether amino acids of the parent substance of the formula XXVII can be obtained by the interaction of a solution of Diethylenetriamine with a suspension of sodium hydride with stirring, followed by reaction with haloalkylthio formula XXXVIII

< / BR>
where the halogen is Br, I or Cl,

obtaining the compounds of formula XXXIX

< / BR>
A solution of diethyl ether of formula XXXIX is treated with sodium hydroxide and heated and then is acidified and heated again getting hydroxynicotinate formula XL
they gidrolizuut enzyme with obtaining hydroxynicotinate formula XLI

< / BR>
Hydroxyquinolinato formula XLI is then converted into the ester of formula XXVII in the usual way. For example, hydroxyquinolinato formula XLI can be processed by trimethylsilylpropyne in methanol to obtain cleaners containing hydrochloride salt of methyl ester compounds of formula XXVII.

Educt of formula XXII can be obtained in the following way. If X represents O, hydroxy - amino acid of formula XLII

< / BR>
subject interaction for the introduction of P1and P2protecting groups. For example, treatment of the acid of formula XLII N-carbenoxolone in the presence of sodium carbonate followed by treatment with chlorotriphenylmethane and triethylamine gives the educt of formula XXII, where X is O, R1together with the N atom forms phthalimido and P2is trityl. Or treatment of the acid of formula XLII N-(benzyloxycarbonyloxy)succinimide in an aqueous solution of sodium carbonate and acetone followed by treatment of t-butyldimethylsilyloxy or allermuir agent of the formula V or VI gives the educt of formula XXII, where X represents O, P1is benzyloxycarbonyl and P2is t-butyldimethylsilyl or acyl group such as acetyl.

Ednam sulfuric acid solution to obtain a mercaptan of the formula XLIII

< / BR>
The mercaptan of formula XLIII is then treated for the introduction of P2protecting groups. For example, treatment of the mercaptan of formula XLIII with acetic anhydride gives the educt of formula XXII, where X is S, n is 1, P2is acetyl and P1is benzyloxycarbonyl.

If X is S and n is 2, L-methionine can be protected on the N-atom. For example, the reaction with benzylchloride or N-(benzyloxycarbonyloxy)succinimide gives N-[(phenylmethoxy)carbonyl]-L-methionine, which is then atrificial processing alcohol, alkyl-OH, in the presence as catalyst of an acid, such as p-toluensulfonate acid. Processing oxidizing agent such as N-chlorosuccinimide in aqueous solution gives the sulfoxide of formula XLIV

< / BR>
Sulfoxide of formula XLIV is then treated with acid anhydride such as acetic anhydride, to obtain the compounds of formula XLV

< / BR>
Treatment with alkali metal hydroxide, with the subsequent removal of formaldehyde, for example, processing regenerating agent such as sodium borohydride, followed by treatment with acid anhydride such as acetic anhydride, yields the starting material of formula XXII, where X is S, n is 2, R
< / BR>
giving dipeptide of formula XLVII

< / BR>
where

P1and P2have the meanings as defined previously;

R3is acid protecting group.

This reaction mix is preferably carried out in the presence of the agent combinations, such as benzotriazol-1-yloxytris(dimethylamino)fosfodiesterasa or ethyl-3-(3-dimethylamino)propyl carbodiimide.

P2protecting group can be selectively removed from the intermediate compounds of formula XLVII, for example, by treatment with sodium methoxide in methanol, if P2represents an acyl group such as acetyl or benzoyl, and treatment with an acid such as p-toluensulfonate acid in methanol, if P2is trityl, tetrahydropyranyl, or zatrudnieniu silyl group. The resulting product is then subjected to cyclization reaction catalyzed by the acid, as described above, to obtain the intermediate compound of formula XLVIII

< / BR>
The intermediate compound of formula XLVIII, where X is S and n is 2, can be obtained by obrabotka hydroxy derivative in mercaptan, as described above, with subsequent cyclization reaction catalyzed by acid.

N-Protecting group is then removed from the compounds of formula XLVIII, for example by treatment with hydrazinehydrate, if P1together with N-atom form phthalimido group, or processing attributively or palladium on coal and ammonium salt of formic acid or hydrogen when P1is benzyloxycarbonyl, giving the compounds of formula III with a condensed core.

Starting material of formula XLVI, where Y is O, can be obtained by the interaction of the N-phthalimido protected ester of the amino acids of formula XLIX

< / BR>
with allyltrichlorosilane in the presence triftormetilfullerenov acid to obtain the compounds of formula L

< / BR>
Treatment of compounds of formula L with ozone in methanol, then with dimethyl sulfide followed by treatment of ortho-formate of formula XXXII in the presence of p-toluensulfonate acid gives a secure connection formula LI

< / BR>
Removing the N-protecting group, for example, by treatment with hydrazinehydrate, gives a starting material of formula XLVI, where Y represents O.

Starting material of formula XLVI, where Y is S, can be obtained by the interaction cysteine the potassium obtaining ether amino acids of formula LIV

< / BR>
The compounds of formula I contain three asymmetric centre in condensed bicyclic parts of the structure with possible additional centers in the side chain. Because optically pure form a condensed bicyclic products is preferred that all such forms are within the scope of this invention. The above methods can utilize racemates, enantiomers or diastereomers as starting materials. If you get diastereomers connection, they can be separated by conventional chromatographic or fractional crystallization. Preferably, the hydrogen attached to the main bridge to the carbon atom in the orientation shown below

< / BR>
The compounds of formula I, where R3, R5and/or R7represent hydrogen, can be allocated in the form of pharmaceutically acceptable salts. Appropriate salts for this purpose are alkali metal salts, such as sodium and potassium, salts of alkaline earth metals such as calcium and magnesium salts derived from amino acids such as arginine, lysine, etc., and salts derived from amines, such as alkylamines followed, such as t-butylamine, t-amylamine etc., substituted alkylamines followed, nab is different trialkylamines and Quaternary ammonium salts. These salts can be obtained by the interaction of the acid form of the compound with base, providing the desired ion in a medium in which the precipitated salt, or in the aquatic environment, followed by lyophilization.

The preferred compounds of this invention are those compounds where

A represents A

< / BR>
R2represents hydrogen, or R11-S-; R3represents hydrogen or lower alkyl with 1-4 carbon atoms; r is 0 or 1; R11is lower alkyl with 1-4 carbon atoms; R1represents aryl-CH2-, substituted aryl-CH2-; heteroaryl-CH2-; cycloalkyl-CH2- where cycloalkyl contains 3 to 7 carbon atoms, or an unbranched or branched alkyl chain with 1 to 7 carbon atoms and R12represents hydrogen; or R1and R12taken together with the carbon atom to which they are attached, give cycloalkyl ring with 5-7 carbon atoms; R6is lower alkyl with 1-4 carbon atoms or phenyl; n is 1 or 2; m is 0 or 2; X represents O or S and Y is CH2, O or S, provided that Y represents O or S only when m is 1.

Most preferred are compounds given above, where R2predstavljaet benzyl, cyclopropylmethyl, or unbranched or branched alkyl chain with 3-5 carbon atoms, especially benzyl; R12is hydrogen; n is 1 or 2; m is 0 or 1; X represents O or S and Y is CH2, O or S, provided that Y represents O or S only when m is 1.

The single most preferred compound is /4S/4 (r*), 7 , 10a / //-octahydro-4-/(2-mercapto-1-oxo-3-phenylpropyl)amino/-5-oxo-7H - pyrido[2,1-b]-/1,3/diazepin-7-carboxylic acid, i.e. the compound of the formula

< / BR>
The compounds of formula I, where A represents the

< / BR>
are inhibitors of double action, possessing the ability to inhibit the conversion of the enzyme and angiotensin neutral endopeptidase. The compounds of formula I, where A represents the

< / BR>
are selective inhibitors, which are able to inhibit the conversion of the enzyme angiotensin. Thus, the compounds of formula I, including pharmaceutically acceptable salts, are useful in the treatment of physiological conditions in which the inhibitors of the converting enzyme angiotensin been shown as useful. Such conditions include painful condition characterized by impaired pressure ¡heart failure, glaucoma and renal diseases such as renal failure, diabetic neutropenia, and kidney failure (renal his or her subsequent treatment with cyclosporine or other immunosuppressants. Other States in which the inhibitors of the converting enzyme angiotensin, as reported, are useful include cirrhosis of the liver, inhibition of progression of atherosclerosis, prevention or treatment of hypertensive or diabetic retinopathy, improvement of cardiac dysfunction and subsequent disruption of the cardiac activity and the prevention of restenosis after plastic surgery on the blood vessels. The dual action inhibitors are also useful in the treatment of physiological conditions in which, as shown, will be useful inhibitors of neutral endopeptidase. Such conditions include cardiovascular disease, in particular hypertension, hyperaldosteronism, kidney disease, glaucoma, as well as the weakening of acute and chronic pain. Thus, the compounds of formula I are useful for reducing blood pressure, and inhibitors of formula I double steps are also useful for this purpose due to their diuresis and natriuresis properties. Ing the>The compounds of formula I, including pharmaceutically acceptable salts can be introduced for these purposes in quantities similar to those used previously for inhibitors of the converting enzyme angiotensin. For example, the compounds of formula I can be administered to the mammal, for example a person, a dose from about 0.1 mg to about 100 mg per kg of body weight per day, preferably from about 0.5 mg to about 25 mg per kg of body weight per day. The compounds of formula I preferably are introduced orally, but parenteral routes, such as subcutaneously, intramuscularly and intravenously, can also be used as can be used and the local route of administration. The daily dose can be entered at once or may be divided into 2 to 4 dose during the day.

Inhibitors of formula I can be introduced in combination with an ANF 99 - 126 person. This combination will contain the inhibitor of formula I is from about 1 to about 100 mg per 1 kg of body weight and ANF 99-126 man from about 0.001 to about 0.1 mg per 1 kg of body weight.

Inhibitors of formula I can be introduced in combination with other types of pharmaceutically active compounds. For example, diuretic, calcium channel blockers, activators of potassium channels, reducing any other pharmaceutically acceptable ingredients can be included in the composition for the above-described pharmaceutical use. Appropriate compositions for oral administration include tablets, capsules and elixirs, and related compositions for parenteral administration include sterile solutions or suspensions. The appropriate composition for the treatment of glaucoma include local compositions, such as solutions, ointments and solids, as described in U.S. patent 4442089. From about 10 to 500 mg of the active ingredient is included together with a physiologically acceptable binder, carrier, filler, preservative, stabilizer, an aromatic substance, etc., in the form of a unit dose, as noted, for an acceptable pharmaceutical practice.

The following examples illustrate the invention. Temperatures are given in degrees. Thin-layer chromatography was performed on silica gel unless otherwise stated.

Example 1

/4S/ 4 (R*), 7 10a //-octahydro-4-//2 - mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido/2,1-b//1,3/ oxazepine-7-carboxylic acid

a) (S)-2-phthalimido-4-hydroxybutanoic acid salt of triethylamine

A solution of L-homoserine (3.0 g, 25.2 mmole) and sodium carbonate (2,670 g, 25.2 mmole) in water (60 ml) was treated with N-carbenoxolone (5,570 g, 25.4 mmole). After stirring at room temperature for whether the brine, was dried (sodium sulfate) and filtered into a solution of triethylamine (4.0 ml) in methylene chloride (40 ml). The cloudy solution was concentrated and triturated with ethyl acetate and ethyl ether to obtain 5,11 g mentioned in the title compounds as white solids: I. pl. 142 - 144oC, TLC (5% acetic acid in ethyl acetate) Rf= 0.36;

[]D= is 6.2o(c = 0.8 chloroform).

Data analysis for C18H26N2O5:

Calculated, %: C 61,70; N. OF 7.48; N 7,99

Found, %: C 61,45; N 7,47; N 7,84

b) (S)-2-phthalimido-4-/triphenylmethane/butane acid, salt of triethylamine

The homogeneous solution of the product of stage (a) (1,890 g, 5.4 mmole) in chloroform (20 ml) was treated with triethylamine (80 μl) followed by treatment of the solid chlorotriphenylmethane (1,590 g, 5,70 mmole). After stirring at room temperature for 2.5 hours the solution was separated between ethyl acetate and 0.1 N hydrochloric acid (150 ml). The organic layer was washed with water and brine, then dried (sodium sulfate) and filtered into a solution of triethylamine (1.0 ml) in methylene chloride (30 ml). The solution was concentrated until the oil was again dissolved in a small amount of methylene chloride and ethyl acetate and triturated with ethyl acetate to until the solution does not pomot the tion, washed with ethyl acetate and ethyl ether, and dried in vacuum to obtain 2,538 g mentioned in the title compounds as white solids: I. pl. 165 - 170oC (Razlog.) TLC (10% methanol in chloroform) Rf= 0,23;

[]D= +7,0o(c = 1,2, chloroform).

c) (S)-2-phthalimido-6-hydroxyhexanoic acid

A solution of (+)-L--hydroxyisoleucine (obtained according to the method Bodanszky and others , J. Med. Chem. 1978, 21, 1030-1035) (1,030 g, 7.0 mmole) and sodium carbonate (745 mg, 7.0 mmole) in water (12 ml) was treated with N-carbenoxolone (1,495 g, 7.0 mmole) and the mixture was stirred at room temperature for 2 hours. The solution was filtered, cooled to 0oC and acidified using 6 N hydrochloric acid to obtain a white precipitate. The solid is collected by filtration and dried in vacuum at 80oC for 1 hour to obtain 1,297 g specified in the connection name: so pl. 162 - 163oC; []D= -35,7o(c = 1,3, methanol).

d) (S)-2-phthalimido-6,6-dimethoxycinnamic acid, methyl ester

The crude product from stage (c) (3,752 g, 13.5 mmole) and cesium carbonate (at 2,178 g, 6.7 mmole) in dimethylformamide (44 ml) was treated with methyliodide (3.0 ml, at 6.84 g, 48,2 mmole). After stirring at room temperature for 2 hours the mixture was diluted % saturated sodium bicarbonate solution and brine, then was dried (sodium sulfate), filtered and removed from the intermediate ester as a colourless oil (3,825 g). The oil was homogeneous according to TLC (1:1 - acetone:hexane) Rf= 0,37.

The solution oxalicacid at -78oC (1,37 ml, 2.00 g, 15.7 mmole) in dry methylene chloride (58 ml) was treated dropwise with a solution of dry dimethylsulfoxide (2,24 ml, 2,47 g of 31.6 mmole) in methylene chloride (2 ml). After 10 minutes, was added to the solution of the above alcohol-ether mixture (3,825 g, 13.1 mmole) in metilenhloride (10 ml). Then after 15 minutes was added triethylamine (8.0 ml) and the mixture was stirred at -78oC for 5 minutes, then was heated to 0oC. the Mixture was diluted with ethyl acetate/ethyl ether and successively washed with 1 N hydrochloric acid, water and brine, then dried (sodium sulfate), filtered and removed to obtain the crude desired aldehyde. The oil was homogeneous according to TLC (1:1 acetone:hexane) Rf= 1,48.

The solution of the above aldehyde in methanol (17 ml) and methylene chloride (17 ml) was treated trimethylamin ether of ortho-formic acid (1.7 ml) followed by treatment of the monohydrate p-toluensulfonate acid (180 mg). The mixture was stirred at room temperature for 1.5 chavali water and brine, then was dried (sodium sulfate), filtered and removed. The residue was subjected to flash chromatography (Merck silica gel, 1: 1 ethyl acetate:hexane) and cleaned fraction of the product by crystallization from a mixture of ethyl acetate/hexane, obtaining analytically pure indicated in the name of the product (3,452 g, the first selection and 215 mg of the second selection) in the form of white needle-shaped substances: I. pl. 69-70oC, TLC (1:1 ethyl acetate:hexane) Rf= 0,35; []D= -27,4o(c = 1.5, chloroform).

Data analysis for C17H21NO6:

Calculated, %: C 60,89; N. OF 6.31; N 4,18

Found, %: C 60,80; N 6,32; N 4,16.

e) /S/-/R*R*//-2//2 phthalimido-4-/triphenylmethane/- 1-oxobutyl/amino/-6,6-dimethoxycinnamic acid, methyl ester

The crude product from part (d) (2,540 g, EUR 7.57 mmole) in methanol (18 ml) was treated with hydrazinoacetate (378 μl, 390 mg, 7,80 mmole). The mixture became homogeneous within 10 minutes. After stirring at room temperature for 3 days, the resulting slurry was filtered, removed, mixed with methylene chloride, was filtered and was again removed, obtaining the crude amine intermediate as a colorless oil. At the same time, the salt solution of triethylamine product from part (b) (4,622 g, 7,80 mmole) in methylene chloride (50 ml) at 0ooC and 2 hours at room temperature, the solution was separated between ethyl ether and water. The organic layer was washed with 50% saturated sodium bicarbonate solution and brine, then dried (sodium sulfate), filtered and removed. The residue was subjected to flash chromatographicaliy (Merck silica gel, 6:4 ethyl acetate:hexane) to give 3,580 g net mentioned in the title compound as a white foam. TLC (6:4 ethyl acetate:hexane) Rf= 0,32; []D= +26,2o(c = 0.6, chloroform).

f) /S-/R*, R*//-2//2 phthalimido-4-hydroxy-1-oxo - butyl/amino/-6,6-dimethoxycinnamic acid, methyl ester

A solution of the product from part (e) (5,420 g, 8.0 mmole) in methanol (60 ml) was treated with monohydrate p-toluensulfonate acid (520 mg). After stirring at room temperature for 1.5 hours the mixture was separated between ethyl acetate and dilute sodium bicarbonate solution. The phases were separated and the aqueous layer was again extracted with ethyl acetate. The collected organic extracts were washed with brine, dried (sodium sulfate), filtered and removed. The residue was subjected to flash chromatographicaliy (of Merck silica compound is of oducti in the form of a colorless oil. TLC (7:3 ethyl acetate:hexane) Rf= 0,26; []D= +18,7o(c = 1,3, chloroform).

g) /4S - 4,7,10 a //-Octahydro-4-phthalimido-5-oxo-7H-pyrido[2,1-b] - /1,3/oxazepine-7-carboxylic acid, methyl ester

A solution of the product from part (f) (2.10 g, of 4.95 mmole) in methylene chloride (100 ml) was treated with Amberlite15 ion - exchange resin (240 mg, pre sequentially washed with 6N hydrochloric acid, water, tetrahydrofuran, then with methylene chloride). After stirring at room temperature for 2.5 hours the solution was filtered, removed and subjected to flash chromatographicaliy (Merck silica gel, 6:4 ethyl acetate:hexane, followed by 100% ethyl acetate) to give 1.40 g mentioned in the title product as a white foam.

h) /S/-2-/Acetylthio/benzoylpropionate acid

The solution of nitrite (10.3 g, 280 mmol) was added to a solution of D-phenylalanine (30.0 g, 181 mmole) and potassium bromide (73,5 g) in sulfuric acid (2,5 N, 365 ml) for 1 hour, maintaining at the same time the reaction temperature at 0oC. the Mixture was additionally stirred for 1 hour at 0oC and then for 1 hour at room temperature. The reaction solution was extracted with ether, the ether was back extracted with water and the ether layer was dried over sulkily: so the TRC. 141oC (0.55 mm Hg); []D= + 14,4o(c = 2,4, chloroform).

The mixture teoksessa acid (7 ml, 97,9 mmole) and potassium hydroxide (5,48 g, 97,9 mmole) in acetonitrile (of 180.5 ml) was stirred in argon atmosphere at room temperature for 1 and 3/4 hours. The mixture was cooled in a bath of ice and a solution of /R/-2-bromo-3-benzoylpropionic acid (20.4 g, 89 mmole) in acetonitrile (20 ml) was added within 10 minutes. The reaction mixture was stirred in argon atmosphere at room temperature for 5 hours, filtered and the acetonitrile was removed in vacuum. The oily residue was again dissolved in ethyl acetate and washed with a 10% solution of potassium bisulfate and water. The ethyl acetate was removed in vacuum, obtaining a 19.6 g of the crude product. The crude product was cleaned by receiving his dicyclohexylamine salt, using isopropyl ether as a solvent for crystallization. Analytically pure sample of /S/-2-/acetylthio/benzoylpropionic acid, dicyclohexylamine salt was obtained by recrystallization from ethyl acetate: so pl. 146 - 147oC; []D= - 39,6oC (c = 1,39, chloroform).

Data analysis for C11H12O3S C12H23N:

Calculated, %: C 68,11; N TO 8.70; N 3,45, S TO $ 7.91

Found, %: C 67,93; N 8,71; N 3,3 is m potassium bisulfate and ethyl acetate, receiving /S/-2-/acetylthio/benzoylpropionate acid; []D= -70,1oC (c= 1,91, chloroform).

Data analysis for C11H12O3S:

Calculated, %: C 58,91; N 5,39; S 14,30

Found, %: C 58,73; N 5,41; S 14,53.

i/ Methyl ether /4S/4 /R*/, 7 10a //-octahydro-4-//2-/acetylthio/-1-oxo-3-phenylpropyl/amino/-5-oxo-7H- [2,1-b] /1,3/oxazepine-7-carboxylic acid

The product from part (g) (620 mg, 166 mmole) in methanol (10 ml) was treated with hydrazinoacetate (85 μl, 88 mg, 1.75 mmole) and the solution was stirred at room temperature for 44 hours. The mixture was filtered and the solid washed with methanol. The filtrate was removed, triturated with methylene chloride, again filtered and removed, obtaining the crude amine in the form of a cloudy oil (400 mg).

A cold solution (0oC) /S/-2-/acetylthio/benzoylpropionic acid (410 mg, to 1.83 mmole) and triethylamine (250 μl, 182 mg of 1.80 mmole) in methylene chloride (10 ml) was treated with the above amine (in the form of a solution in 8 ml of methyl chloride), followed by processing benzotriazol-1-yloxytris/dimethylamine/phosphodiesterases (808 mg and 1.83 mmole). Transparent, almost colorless solution was stirred at 0oC for 40 minutes and then at room temperature for 2 is part of a 50% solution of saturated sodium bicarbonate and brine, then was dried (sodium sulfate), filtered and removed. The residue was subjected to flash chromatographicaliy (Merck silica gel 60-70% ethyl acetate in hexane) to give 602 mg of pure, mentioned in the title product as a white foam: TLC (6:4 ethyl acetate:hexane) Rf= 0.27.

j) /4S/4/R*/, 7, 10a/- octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/oxazepine-7-carboxylic acid

A solution of the product from part (i) if 0oC (590 mg, 1,32 mmole) in methanol (10 ml, obeskislorozhennuju propulsiveness argon) was treated with 1 N sodium hydroxide solution (7 ml, obeskislorozhennuju propulsiveness argon). After stirring for 15 minutes the solution was heated to room temperature and continued stirring in an argon atmosphere additional 4.5 hours. The mixture was acidified with 5% potassium bisulfate, was diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, then dried (sodium sulfate), filtered and concentrated to approximately 3 ml of the Residue was mixed with ethyl acetate and a small amount of hexane and the resulting solid was collected by filtration and dried in vacuum, obtaining 413 mg specified in the product name: so pl. of 180.5oC (decomposed.). TLC (2% who Olonka (6.0 x 150 mm); elute 40% A:90% water - 10% methanol - 0.2% of phosphonic acid and 60% B:10% water - 90% methanol - 0.2% of phosphonic acid; flow rate 1.5 ml/min with detection at 220 nm; t = 6.73 x min (95,7%).

Data analysis for C20H28N2O4S 0.12 ethyl acetate:

Calculated, %: 58,05; N 6,24; N 6,95; S OF 7.96

Found, %: C 58,23; N 6,34; N 6,83; S 7,81.

Example 2

/3R /3/S*/, 6, 9a//- hexahydro-3-//2-mercapto-1-oxo-3-phenylpropyl/amino/-4-oxo-2H, 6H-pyrido [21-b]/1,3-thiazin-6-carboxylic acid

a) N-//phenylmethoxy/carbonyl/-L-cysteine

A solution of N, N'-bis//phenylmethoxy/carbonyl/-L-cysteine (4,658 g, 9,16 mmole) in methanol (35 ml) was treated with 2N sulfuric acid solution (23 ml), followed by processing portions of zinc dust (2,442 g of 37.3 mmole). The mixture was heated at 70oC for 1.5 hours, filtered while the solution is still warm and concentrated on a rotary evaporator. The remaining solution was extracted with ethyl ether and the ether extract washed with water and brine and dried (sodium sulfate), filtered and removed. The residue (oil) was dissolved in carbon tetrachloride, cooled to 0oC and introduced the seed to slow sediment. The solid is collected by filtration and washed with cold four is rigid 4% acetic acid in ethyl acetate), receiving additional product after crystallization (246 mg). The total yield of product 2,894, TLC (5% acetic acid in ethyl acetate) Rf= 0,58.

b) S-Acetyl-N-//phenylmethoxy/carbonyl/-L-cysteine

The homogeneous solution of the product from part (a) (2.70 g, 10.6 mmole) in water (30 ml, obeskislorozhennuju propulsiveness argon) containing potassium bicarbonate (2,140 g, with 21.4 mmole) was treated with acetic anhydride (8.0 ml, 8,66 g, 84,8 mmole). After 10 minutes at room temperature the mixture was acidified with 10% hydrochloric acid and was extracted with ethyl ether. The ether extract was washed twice with water and brine and dried (sodium sulfate), filtered and removed, getting the oil. The residue was subjected to azeotropic rectification three times with toluene and twice with a mixture of ethyl ether/hexane, after which the oil crystallized. The residue is triturated with a mixture of ethyl ether/hexane and the solid was collected by filtration, getting 2,19 g of pure indicated in the product name. TLC (5% acetic acid in ethyl acetate) Rf= 0,56.

c) Methyl ester of /S/-2-//N-phenylmethoxy/carbonyl-S-acetyl-L-cysteinyl/amino/-6,6 - dimethoxycinnamic acid

A slurry of methyl ether /S/-2-phthalimido-6,6-dimethoxy-hexanoic acid (obtained as described in example 1 (d homogeneous within 10 minutes. After stirring at room temperature for 67 hours, the resulting slurry was filtered, removed, mixed with methylene chloride, was filtered and was again removed, obtaining the crude amine intermediate as a colourless oil.

At the same time, part of the slurry of the product from part (b) (1,185 g, 3,98 mmole) in methylene chloride (14 ml) was treated with triethylamine (555 μl, 403 mg, 3,98 mmole). Then the homogeneous solution was cooled to 0oC, was treated with the above amine in the form of a solution in methylene chloride (7 ml), then treated benzotriazol-1-yloxytris/dimethylamine/phosphonium-hexaphosphate (1,762 g, 3,98 mmole). The mixture was stirred at 0oC for 2.5 hours, then at room temperature for 45 minutes. The solvent was removed and the residue was separated between ethyl acetate and water. The organic layer was washed with 50% saturated sodium bicarbonate solution and brine, then dried (sodium sulfate), filtered and removed. The residue was subjected to flash chromatographicaliy (Merck silica gel, 65: 35 ethyl acetate:hexane) to give to 1.15 g of pure indicated in the name of the product as a white foam. TLC (75:25 ethyl acetate:hexane) Rf= 0,42.

Data analysis for C22H32N2O8S:

Calculated, %: C 54,53; N 6,66; N 5,78; S 6,Neil/amino/-4-oxo-2H, 6H-pyrido [2,1-b] /1,3/-thiazin-6-carboxylic acid

Obeskislorozhennuju solution (prorokowanie argon) of product from part (c) (1,040 g of 2.15 mmole) in methanol (12 ml) at 0oC was treated with sodium methoxide (25 wt. % in methanol, 490 μl, 463 mg, and 2.14 mmole). After 20 minutes the mixture was marked with a saturated solution of ammonium chloride, diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine and dried (sodium sulfate), filtered and removed. The residue was again dissolved in methylene chloride (200 ml) and stirred at room temperature with Amberlite- ion exchange resin 820 mg, pre-washed sequentially 6N hydrochloric acid, water, tetrahydrofuran, then with methylene chloride. After 3 hours the solution was filtered, removed and subjected to flash chromatographicaliy (Merck silica gel, 65:35 ethyl acetate:hexane), getting 757 mg specified in the name of the product as a colourless oil. TLC (75:25 ethyl acetate:hexane/Rf= 0.58.

e/ Methyl ether /3R /3, 6, 9a//- -hexahydro-3-amino-4-oxo-2H, 6H-pyrido [2,1-b]/1,3/thiazin-6-carboxylic acid

A solution of the product from part (d) (752 mg, 1.99 mmole) in dry methylene chloride (15 ml) was treated at room temperature with attributively (620 m is ω 10% hydrochloric acid and was extracted with ethyl ether. The layers were separated and the ether layer was extracted again with water. The collected aqueous layers were podlachian (pH 13) with a 10% solution of sodium hydroxide and was extracted twice with methylene chloride. Collected methylenechloride extracts (sodium sulfate) filtered and removed, getting 290 mg of the crude indicated in the name of the product as a colourless oil. TCL (10% methanol in methylene chloride) Rf= 0,38.

f) Methyl ether /3R /3/ S*/6 9a//- hexahydro-3-//2-/acetylthio/1-oxo-3-phenylpropyl/amino/-4-oxo-2H, 6H-pyrido [2,1-b] -/1,3/thiazin-6-carboxylic acid

A cold solution (0oC) /S/-2-acetylthio/benzoylpropionic acid (294 mg, 1,31 mmole) and triethylamine (180 μl, 131 mg of 1.29 mmole) in methylene chloride (8 ml) was treated with the product from part (e) (287 mg, of 1.17 mmole) in solution in 6 ml of methylene chloride. Then add benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (575 mg, of 1.30 mmole). Transparent, almost colorless solution was stirred at 0oC for 1 hour and then at room temperature for 1 hour. The solvent was removed on a rotary evaporator and the residue was separated between ethyl acetate and a 5% solution of potassium bisulfate. The organic layer was sequentially washed with water, 50% saturated solution b is chromatographicaliy (Merck silica gel; 1: 1 - etelaat:hexane) to give 412 mg of pure indicated in the name of the product as a white foam. TL (1:1 ethyl acetate:hexane) Rf= 0,27; -107,0oC (C = 0.6, chloroform).

g) /3R-/3/ S*,/6 9a//- hexahydro-3-//-2-mercapto-1-oxo-3-phenylpropyl/amino/-4-oxo-2H, 6H-pyrido[2,1-b]-/1,3/thiazin-6-carboxylic acid

A solution of the product from part (f) at 0oC (406 mg, of 0.90 mmole) in methanol (5 ml, obeskislorozhennaja propulsiveness argon) was treated with 1 N sodium hydroxide solution (5 ml, obeskislorozhennuju propulsiveness argon). After stirring for 1 hour the solution was heated to room temperature and stirring in an argon atmosphere continued additional 1.25 hours. The mixture was acidified with 5% solution of potassium bisulfate, was diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, then dried (sodium sulfate), filtered and removed. The residue was twice subjected to flash chromatographicaliy (Merck silica gel, 2% acetic acid in ethyl acetate).

Fraction of the product was controlled according to HPLC. The desired fractions were collected, removed and was twice subjected to the azeotropic distillation with ethyl acetate. The residue was placed in a small amount of ethyl acetate and triturated with hexane. R is ukta in the form of a solid white foam. TLC (2% acetic acid in ethyl acetate) Rf= 0,46; []D= -57,0oC (=0,4, chloroform).

Data HPLC (gel permeation chromatography) : YMC S-3 ODS column (150 mm 6,0); allerona 40% A:90% water-10 methanol -0,2% phosphoric acid and 60% B : 10% water - 90% methanol - 0.2% of phosphoric acid; flow rate 1.5 ml/min, detection at 220 nm; tR= 8,33 min (95,0%).

Data analysis for C18H22N2O4S20.2 ethyl acetate:

Calculated, %: C 54,79; N 5,77; N 6,80; S 15,56

Found, %: 54,59; N 6,04; N 6,59; S 15,16.

Example 3

/4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H - pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid

a) Methyl ether /S-/R*, R*//-2-//2-phthalimido-4-/acetylthio/-1-oxobutyl/amino-6,6 - dimethoxycinnamic acid

A cold solution (0oC) triphenylphosphine (to 1.143 g, 4,36 mmole) in tetrahydrofuran (20 ml) was treated with diisopropylperoxydicarbonate (860 μl, 883 mg, 4,37 mmole). Within 5 minutes there appeared a white slurry. After 30 minutes the solution was added methyl ether /S-/R*, R*/-2-//2-phthalimido-4-hydroxy-1-oxobutyl/amino/-6,6 - dimethoxycinnamic acid (obtained as described in example 1 (f), 928 mg, 2,19 mmole) in tetrahydrofuran (8 ml) with PEFC is the 1.25 hour then was divided between 50% saturated solution of sodium bicarbonate and ethyl acetate. An ethyl acetate extract was washed with brine, dried (sodium sulfate), filtered and removed. The residue was again dissolved in ethyl acetate and treated with a small amount of hexane to precipitate triphenylphosphine. The mixture was filtered and the filtrate was subjected to flash chromatographicaliy (Merck silica gel, 65:35 ethyl acetate:hexane) to give 894 mg specified in the name of the product as a colourless oil. TLC (75:25 ethyl acetate:hexane) Rf= 0,43.

b) Methyl ether /4S/4, 7, 10a//- octahydro-4-phthalimido-5-oxo-7H-pyrido[2,1-b]/1,3/diazepin - 7-carboxylic acid

Obeskislorozhennuju (propulsiveness argon product from part (a) (814 mg, 1.65 mmole) in methanol (15 ml) at 0oC was treated with sodium methoxide (25 wt. % in methanol, of 1.05 ml, 4.6 mmole). After 5 minutes, the mixture was suppressed by a saturated solution of ammonium chloride, diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, then dried (sodium sulfate), filtered and removed. The residue was again dissolved in methylene chloride (180 ml) and stirred at room temperature ionoobmennoi resin Amberlite15 (285 mg, pre praetor was filtered, was removed and subjected to flash chromatographicaliy (Merck silica gel, 1:1 ethyl acetate:hexane) to give 314 mg specified in the title product as a white foam. Rubbing foam with ethyl acetate gave specified in the title product as a white solid. So pl. = 147 - 148oC. TLC (75: 25 ethyl acetate: hexane) Rf= 0,56; []D= -143,2o(C = 0.6, chloroform).

c) Methyl ether /4S/4/R*/, 7, 10a//- octahydro-4-//2-/acetylthio/-1-oxo-3-phenylpropyl /amino/-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

The product from part (b) (280 mg, 0.72 mmole) in methanol (8 ml) was treated with hydrazinoacetate (42 μl, to 43.3 mg, 0,86 mmole) and the solution was stirred at room temperature for 67 hours. The mixture was filtered and the solid washed with methanol. The filtrate was removed, triturated with methylene chloride, again filtered and removed, obtaining the crude amine as a yellow oil (about 205 mg).

A cold solution (0oC) /S/-2-acetylthio/benzodiapines acid (178 mg, of 0.79 mmole) and triethylamine (111 μl, 80 mg of 0.80 mmole) in methylene chloride (3 ml) was treated with the above amine (in the form of a solution in 7 ml of methylene chloride), followed by processing benzotriazol-1-yloxytris/dimethylamine/phosphodiesterases (353 mgtow. The solvent was removed and the residue was separated between ethyl acetate and a 5% solution of potassium bisulfate. The organic layer was sequentially washed with water, 50% saturated sodium bicarbonate solution and brine and then dried (sodium sulfate), filtered and removed. The residue was subjected to flash chromatographicaliy (Merck silica gel, 1:1 ethyl acetate:hexane) to give 272 mg of pure indicated in the name of the product as a white foam.

d) /4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5 - oxo-7H-pyrido[2,1-b] /1,3/-thiazepine-7-carboxylic acid

A solution of the product from part (c) (227 mg, of 0.49 mmole) in methanol (5 ml, obeskislorozhennuju propulsiveness argon) was treated at room temperature 1 N solution of sodium hydroxide (8 ml, obeskislorozhennuju propulsiveness argon). After stirring for 1 hour the mixture was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine and then dried (sodium sulfate), filtered and concentrated. The obtained solid was mixed with ethyl acetate and collected by filtration. The filtrate was subjected to flash chromatographicaliy (Merck silica gel, 1% acetic acid in ethyl acetate) and W is the substance. The solid is collected, receiving a total number of 150 mg specified in the product name, so pl. 216 - 217oC (decomposition) TLC (2% acetic acid in ethyl acetate) Rf= 0,56; []D= = -72,6oC (c = 0,28, dimethylformamide).

HPLC YMC S-3 ODS column (150 mm 6,0) : elute 40% A: 90% water - 10% methanol - 0.2% of phosphoric acid and 60% B : 10% water - 90% methanol and 0.2% phosphoric acid, flow rate 1.5 ml/min, detection at 220 nm, tR= 9,48 min (97,4%).

Data analysis for C19H24N2O4S20.14 ethyl acetate:

Calculated, %: C 55,82; N. OF 6.02; N 6,66; S 15,24

Found, %: C 55,53; N 6,01; N 6,63; S 14,91.

Example 4

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxopyrrolo [2,1-b]/1,3/oxazepine-7-carboxylic acid

a) /S/-2-phthalimido-5-oxo-5-/phenylmethoxy/pentane acid

To a solution-benzyl-L-glutamate (17,49 g, 73,70 mmole) in water (180 ml) of sodium carbonate (7,81 g, 73,70 mmole) and dioxane (120 ml) was added N-carbenoxolone (16,50 g, 75,27 mmole, of 1.02 EQ). After stirring at room temperature for 4.5 hours, the reaction mixture was acidified using 6 N hydrochloric acid (30 ml) and was extracted with ethyl acetate (2 400 ml). United an ethyl acetate extracts were washed with 50% brine (200 scienoe oil (41,4 g). To a solution of the crude residue in ethyl acetate (100 ml) was added dicyclohexylamine (14 ml). After being in the fridge over night ethyl ether was removed on a rotary evaporator and the oily residue was led from a mixture of ethyl acetate/hexane. The precipitate was collected by filtration, washed with hexane and dried in vacuum, obtaining 21,21 g specified in the product name in the form dicyclohexylamine salt. The suspension of this dicyclohexylamine salt in ethyl acetate (200 ml), washed with 5% solution of sodium bisulfate (350 ml), brine (50 ml) and dried over magnesium sulfate, filtered and concentrated, gaining 13.5 g mentioned in the title product as a white foam. TLC (3% acetic acid in 9:1 ethyl acetate:heptane) Rf= 0,30.

b) Ethyl ester of /S/-2-phthalimido-5-oxo-5-/phenylmethoxy/- pentanol acid

To a solution of the product from part (a) (13.22 g, 36,0 mmole) and cesium carbonate (5,86 g, 18,0 mmole) in dimethylformamide (100 ml) was added itmean (8.1 ml of 129.6 mmole, 3.6 EQ.). The yellow solution was stirred for 2.5 hours and then was divided between ethyl acetate (300 ml) and water (250 ml). An ethyl acetate extract washed with 5% sodium bicarbonate solution and brine, dried on magnesium sulfate, filtered and concentrated the sue ethyl acetate/hexane. The desired fractions were combined and concentrated, obtaining 10.0 g specified in the product name. TLC (1:1 ethyl acetate:hexane) Rf= 0,45.

c) Methyl ester of /S/-2-phthalimido-4-/carboxy/butane acid

To a solution of the product from part (b) (10.0 g, 26,22 mmole) in ethyl acetate (115 ml) was added 20% palladium hydroxide on carbon as catalyst (1,90 g) and the resulting suspension was stirred in hydrogen atmosphere (balloon) for 2.5 hours. The mixture was filtered, intensively washed with ethyl acetate, concentrated and dried in vacuum to yield 7,29 g of the crude indicated in the product name in the form of a white solid substance, so pl. 137 - 138oC. TLC (10 % methanol/methylene chloride) Rf= 0.43.

d) Methyl ester of /S/-2-phthalimido-5-oxo-5-/ethylthio/-pentanol acid

To a solution of the product from part (c) (7,27 g 24,95 mmole) in methylene chloride (125 ml) at 0oC in argon atmosphere was added ethanthiol (to 4.81 ml, 64,92 mmole, 2.6 equiv.) 4-dimethyl-aminopyridine (609 mg, 4.99 mmole, 0.2 EQ.) and ethyl-3-/3-di-methylamino/ propellerpowered cleaners containing hydrochloride salt (5,27 g, 27,47 mmole, 1.1 EQ.). After stirring at 0oC for 2 hours and at room temperature for 1 hour the reaction mixture was concentrated, diluted with ethyl acetate (Ali and dried in vacuum to yield 8,30 g specified in the product name in the form of crude oil. TLC (1:1, ethyl acetate:hexane) Rf= 0,47.

e) Methyl ether /S/-2-phthalimido-5-oxopentanoic acid

A suspension of the product from part (d) (8,30 g, 24,75 mmole) and 10% palladium on coal (1.24 g) in acetonitrile (150 ml) in an argon atmosphere was treated dropwise with triethylsilane (to $ 7.91 ml, a 49.5 mmole, 2 EQ.). After stirring at room temperature for 45 minutes, the mixture was filtered, concentrated and dried in vacuum. The crude residue was cleaned chromatography on a column (525 cm) with silica gel, elwira 25% mixture of ethyl acetate/hexane (4 l), followed by elution with 35% mixture of ethyl acetate/hexane (2 l). The desired fractions were combined, getting the ceiling of 5.60 g specified in the product name. TLC (1:1 ethyl acetate:hexane) Rf= 0,32.

f) Methyl ether /S/-2-phthalimido-5,5-dimethoxyphenol acid

A solution of the product from part (e) (ceiling of 5.60 g, 20,34 mmole) in methanol (60 ml) and methylene chloride (40 ml) was treated trimethylamin ether of ortho-formic acid (3.8 ml, 34,59 mmole, 1.7 EQ.) and monohydrate n-toluensulfonate acid (280 mg). After stirring at room temperature for 1.5 hours the reaction was suppressed 2 ml saturated sodium bicarbonate solution, concentrated and separated between ethyl acetate (400 ml) and water (100 ml). An ethyl acetate Oia, was filtered and concentrated to crude oil. The crude residue was cleaned chromatography on a column of 520 cm silica gel, elwira 30% mixture of ethyl acetate/hexane (2 l). The desired fractions were combined, concentrated and dried in vacuum, obtaining 6,20 specified in the product name. TLC (1:1 ethyl acetate/hexane) Rf= 0,40.

(g) methyl ether /S/-2-amino-5,5-dimethoxyphenol acid

A solution of the product from part (f) (6,16 g, MT 19: 18 mmole) in methanol /125 ml/ processed by hydrazinoacetate (0,98 ml, 20,14 mmole, of 1.05 EQ.). After stirring at room temperature for 6 days and the resulting slurry was filtered, concentrated, triturated in methylene chloride, filtered, concentrated and dried in vacuum to obtain 3.57 g specified in the product name in the form of a turbid oil. TLC (10% methanol in methylene chloride) Rf= 0,41.

h) Methyl ether /S -/R*, R*//-2-//2-phthalimido-4- /triphenylmethane/-1-oxobutyl/amino-5,5-dimethoxyphenol acid

The solution triethylamine salt /S/-2-phthalimido-4-/triphenylmethane/ butane acid, obtained as described in example 1 (b), (are 11.62 g, 19,60 mmole, 1.05 of EQ. ) in methylene chloride (100 ml) at 0oC worked benzotriazol-1-yloxytris/dimethylamine/phosphonium was treated with a solution of the product from part (g) (3.57 g, 18,67 mmole) in methylene chloride (50 ml). After 10 minutes of reaction at 0oC and 2 hours at room temperature, the solution was separated between ethyl acetate (300 ml) and water (100 ml). An ethyl acetate layer was washed with 50% saturated sodium bicarbonate solution (100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated. The residue was cleaned chromatography on a column of 525 cm silica gel, elwira a mixture of 1:1 ethyl acetate/hexane, obtaining 8,58 g specified in the product name. TLC (1:1 ethyl acetate/hexane) Rf= 0,20.

i) Methyl ether /S-/R*, R*//-2-//2-phthalimido-4 - hydroxy-1-oxobutyl/amino/-5,5-dimethoxyphenol acid

A solution of the product from part (h) (8,58 g, 12,91 mmole) in methanol (100 ml) was treated with monohydrate n-toluensulfonate acid (850 mg). After stirring at room temperature for 3.5 hours, the mixture was separated between ethyl acetate (200 ml) and 10% saturated sodium bicarbonate solution (100 ml). The phases were separated and the aqueous layer was extracted again with ethyl acetate (100 ml). United an ethyl acetate extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was cleaned chromatography on a column of 520 cm silica gel, elwira 8:2 mixture of ethyl which was interaval and dried in vacuum, getting to 4.33 g specified in the connection name. TLC (8:2 ethyl acetate:hexane) Rf= 0,21.

j) Methyl ether /4S/4, 7, 9a/- octahydro-4-phthalimido-5-oxopyrrolo [2.1-b] /1,3/oxazepine-7-carboxylic acid

A solution of the product from part (i) (1.89 g, 4,48 mmole) in methylene chloride (90 ml) was treated with ion exchange resins - Amberlit15 (400 mg, pre sequentially washed with 6 N hydrochloric acid, water, tetrahydrofuran and methylene chloride). After stirring at room temperature for 3 hours the solution was filtered, concentrated and subjected to flash chromatographicaliy in column 5 of 15 cm silica gel, elwira mix 6:4 ethyl acetate/hexane, getting 1.51 g mentioned in the title product as a white foam. TLC (8:2 ethyl acetate - hexane) Rf= 0,32.

k) Methyl ether /4S/4, 7, 9a/- -4-amino-octahydro-5-oxopyrrolo [2,1 - b] /1,3/oxazepine-7-carboxylic acid

The product from part (j) (764 g, 2.13 mmole) in methanol (15 ml) was treated with hydrazinoacetate (109 μl, of 2.24 mmole, of 1.05 equiv.) and the solution was stirred at room temperature for 4 days. The mixture was filtered and the solid washed with methanol. The filtrate was concentrated, triturated in methylene chloride, was again filtered and concentrated. Estate fractions were combined and concentrated to obtain 451 mg specified in the product name in the form of oil. TLC (10% methanol in methylene chloride) Rf= 0,18.

l) Methyl ether /4S/4/R*/, 7, 9a//- octahydro-4-//2-/acetylthio/-1-oxo-3 - phenylpropyl/amino/-5-oxopyrrolo [2,1-b]/1,3/-oxazepine-7-carboxylic acid

Suspension dicyclohexylamine salt /S/-2-acetylthio-3 - benzoylpropionic acid obtained as described in example 1 (h), 870 mg, and 2.14 mmole, 1,14 EQ. / ethyl acetate (70 ml), washed with 5% solution of potassium bisulfate (520 ml), 50% brine (20 ml) and brine (20 ml), dried (anhydrous sodium sulfate). Filtered, concentrated and dried in vacuum over night, receiving /S/-2-/acetylthio/benzoylpropionate acid.

This free acid was dissolved in dry methylene chloride (10 ml), cooled to 0oC (ice bath salt) and treated with triethylamine (298 μl, and 2.14 mmole) followed by treatment with a solution of the product from part (k) (430 mg, of 1.88 mmole) in methylene chloride (10 ml) and benzotriazol-1-yloxytris/-dimethylamine/ phosphodiesterases (947 mg, and 2.14 mmole, to 1.14 EQ.). The resulting solution was stirred at 0oC for 50 minutes and then at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate (150 ml), washed with 0.5 N hydrochloric acid (50 ml), water (50 ml), saturated solution beaten dry. The crude product was adsorbing on celite (CeliteR) and was chromatographically on a column of silica gel (5 to 10 cm), elwira 60% mixture of ethyl acetate/hexane (3 l). The desired fractions were combined and concentrated, getting 779 mg of pure indicated in the product name. TLC (6:4 ethyl acetate:hexane) Rf= 0,17.

m/ /4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5 - oxopyrrolo[2,1-b]/1,3/oxazepine-7-carboxylic acid

A solution of the product from part (1) (754 mg, of 1.74 mmole) in methanol (15 ml) was purged with argon for 30 minutes, cooled to 0oC (ice bath salt), then was treated dropwise previously purged (argon, 30 minutes) solution of 1.0 N sodium hydroxide (12 ml), continuing prorokowanie argon for an additional time of reaction. The reaction mixture was stirred at 0oC for 3 hours, acidified at 0oC 5% solution of potassium bisulfate to pH 1, then extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with 50% brine (100 ml), brine (100 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum, obtaining a white foam. The residue was cleaned chromatography on a column of 2.5 to 15 cm silica gel, e is chloroform and dried in vacuum overnight at 50oC over pjatiokisi phosphorus, getting listed in title product as a white foam, so pl. 88 - 92oC []D= (c = 1.0, methanol). TLC (1% acetic acid in ethyl acetate) Rf= 0,24.

1H-NMR: 400 MHz; CDCl3: 1,80 - 2,31 (m s, 7H), 3,10 (m, 1H), 3, 27 (m, 1H), 3,63 (m, 1H), 4,0 (m, 1H), 4,20 (m, 1H), 4,49 (m, 1H), and 4.75 (m, 1H), 5,23 (m, 1H), 7,19 - 7,30 (m's, 5H), 7,52 (d, 1H, J = 6 Hz).

13C-NMR: 100 MHz; CDCl3: 26,4, 32,0, 32,6, 41,2, 44,2, 53,0, 59,4, 70,6, 89,47, 126,9, 128,4, 129,3, 137,4, 171,2, 171,6, 174,8.

Data analysis for C18H22N2O5S 0,85 H2O

Calculated, %: C 54,91; N 6,07; N 7,12; S 8,14

Found, %: C 54,85; N. Of 5.68; N 7,18; S 8,14.

HPLC: tR= 13,5 min (96,7%, UV 220): YMCS - 3ODS (C-18) 6,0 150 mm 30% B: A to 100% B:A 25 min linear gradient /A = 90% water/methanol and 0.2% phosphoric acid, B = 90% methanol/water + 0.2% of phosphoric acid/flow rate 1.5 ml/min

Example 5

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5 - oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid

a) Methyl ether/S-/R*, R*//-2-//2-phthalimido-4- /acetylthio/-1-oxobutyl/amino/-5,5-dimethoxyphenol acid

A solution of triphenylphosphine (1.26 g, 4,79 mmole) at 0oC in dry tetrahydrofuran (15 ml) was treated aminobutiramida azodicarboxylate (943 μl, 4,79 mmole). The obtained white chlorimide-4 - hydroxy-1-oxobutyl/amino/-5,5-dimethoxyphenol acid (obtained as described in example 4 (i), 1.35 g, 3,20 mmole) in dry tetrahydrofuran (15 ml) followed by treatment of the weak thioglucose acid (343 μl, 4,79 mmole). The mixture was stirred at 0oC for 1.5 hours and then was divided between ethyl acetate (150 ml) and 50% sodium bicarbonate solution (100 ml). An ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, concentrated, absorbed on celite and dried in vacuum. The crude substance was cleaned chromatography on a column of 2.5 to 15 cm silica gel, elwira 1:1 mixture of ethyl acetate:hexane (1 l) and 6:4 ethyl acetate:hexane (1 liter). The desired fractions were combined, concentrated and dried in vacuum, obtaining 1.35 g specified in the product name in the form of oil. TLC (8:2 ethyl acetate : hexane) Rf= 0,42.

b) Methyl ether /S-/R*, R*//-2-//2-phthalimido-4 - mercapto-1-oxobutyl/amino/-5,5-dimethoxyphenol acid

Obeskislorozhennuju (propulsiveness argon) solution of the product from part (a) (1,33 g, was 2.76 mmole) in methanol (25 ml) at 0oC was treated with sodium methoxide (25 wt. % in methanol), of 1.52 ml, 6,63 mmole, 2.4 equiv./. After 3 minutes, the mixture was marked with a saturated solution of ammonium chloride (3 ml), diluted with water and extracted with ethyl acetate (100 ml). An ethyl acetate extract was washed with water (50 ml) and RAA column 5 of 15 cm silica gel, elwira 1:1 (3 l), followed by elution 8:2 /2 l/ mixture of ethyl acetate:hexane. The fractions containing the desired product were combined, concentrated, getting 853 mg specified in the connection name in the form of oil. TLC (8:2 ethyl acetate:hexane) Rf= 0,43.

c) Methyl ether /4S/4, 7, 9a//- octahydro-4-phthalimido-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

A solution of the product from part (b) (847 mg, of 1.93 mmole) in methylene chloride (20 ml) was treated with ion exchange resins - Amberlit15 (700 mg, pre sequentially washed with 6 N hydrochloric acid, water, tetrahydrofuran and methylene chloride). After stirring at room temperature for 17 hours, the solution was filtered, concentrated and subjected to flash chromatographicaliy on a column of 2.5 to 15 cm silica gel, elwira a mixture of 1:1 ethyl acetate: hexane, getting 691 mg specified in the title product as a white foam. TLC (8:2 ethyl acetate:hexane) Rf= 0,48.

d) Methyl ether /4S/4, 7, 9a//- 4-amino-octahydro-5-oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid

The product from part (c) (899 mg, 2,40 mmole) in methanol (17 ml) was treated with hydrazinoacetate (122 μl, 2,52 mmole, of 1.05 equiv.) and the solution was stirred at room temperature for 3 days. The mixture the virgin soil was filtered, concentrated and dried in vacuum, obtaining 572 mg specified in the product name in the form of a turbid oil. TLC (10% methanol in methylene chloride) Rf= 0,13.

e) Methyl ether /4S/4/R*/, 7, 9a/- octahydro-4-//2-/acetylthio/-1-oxo-3 - phenylpropyl/amino/-5-oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid

Suspension dicyclohexylamine salt /S/-2-/acetylthio/- benzoylpropionic acid (obtained as described in example 1 (h), (1,045 g of 2.58 mmole, 1.1 EQ.) in ethyl acetate (100 ml), washed with 5% solution of potassium bisulfate (5 25 ml), 50% brine (25 ml) and brine (25 ml), dried (anhydrous sodium sulfate), filtered, concentrated and dried in vacuum for 1 hour, receiving /S/-2-/acetylthio/-benzoylpropionate acid.

This free acid was dissolved in dry methylene chloride (10 ml), cooled to 0oC (ice bath salt) and treated with triethylamine (360 μl, of 2.58 mmole), benzotriazol-1-yloxytris/ dimethylamine/phosphodiesterases (1,141 g of 2.58 mmole) and then a solution of the product from part (d) (572 mg, of 2.34 mmole) in methylene chloride (10 ml). The resulting solution was stirred at 0oC for 30 minutes and then at room temperature for 2.5 hours. The reaction mixture was concentrated, diluted I (50 ml), water (50 ml) and brine (50 ml), dried (anhydrous magnesium sulfate), filtered and evaporated to dryness. The crude product was adsorbing on celite and subjected to chromatographicaliy in column (5 10 cm) with silica gel, elwira 25% (5 l), 30% (2 l) and 40% (2 l) a mixture of ethyl acetate/hexane. Mixed fractions were combined and re-chromatographically, elwira with the same gradient. The desired fractions were combined and concentrated, obtaining 490 mg of pure indicated in the product name. TLC (1:1 ethyl acetate:hexane) Rf= 0,16.

f) /4S/4/R*/, 7, 9a//- Octahydro-4-//-2-mercapto-1-oxo-3-phenylpropyl/amino/-5 - oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (e) (490 mg, of 1.09 mmol) in methanol:tetrahydrofuran (8 ml : 4 ml) was purged with argon for 30 minutes, cooled to 0oC (ice bath salt) and then was treated dropwise previously purged (argon, 30 minutes) solution of 1.0 N sodium hydroxide (10 ml), propulsive argon throughout the addition and reaction. The reaction mixture was stirred at 0oC for 3 hours, acidified at 0oC 5% solution of potassium bisulfate to pH 2 and then extracted with ethyl acetate (375 ml). The combined organic extracts were washed brine the foam (489 mg). The residue was cleaned chromatography on a column (2.5 to 15 cm) with silica gel, elwira a mixture of ethyl acetate:heptane 9:1 (400 ml) and 0.5% acetic acid in 9:1 mixture of ethyl acetate:heptane (1 l). The desired fractions were concentrated, was removed with a mixture of methylene chloride/heptane and dried in vacuum, obtaining 428 mg of the product. Pure substance was recrystallized from a mixture of ethyl acetate/methanol/hexane. The crystals were collected by filtration, intensively washed with ethyl ether and dried in vacuum overnight at 40oC over pjatiokisi phosphorus, getting 305 mg specified in the name of the product as white crystals, so pl. 206 - 208oC []D= -96,3o(c = 1.0 in methanol). TLC (5% acetic acid in 9:1 mixture of ethyl acetate:heptane) Rf= 0,29.

1H-NMR: 400 Hz; CDCl3w/2 drops CD3OD: 1,94 (m, 1H), 2,02 (d, 1H, J = 9 Hz), of 2.08 (m, 1H), 2,20 - 2, 55 (m's, 4H), 2.95 and (m, 1H), is 3.08 (m, 1H), 3,23 (m, 1H), 3.27 to (m, 1H) and 3.59 (m, 1H), 4,54 (t, 1H, J = 7,3 Hz), 4,60 (m, 1H), 5,23 (m, 1H), 7,18 - 7,34 (m's, 5H), 7,63 (d, 1H, J = 6 Hz).

13C - NMR: 100 MHz; CDCl3w/2 drops CD3OD: 27,6, 31,1, 32,1, 32,9, 41,1, 44,0, 52,8, 60,4, 62,2, 126,77, 128,3, 129,0, 137,4, 170,2, 171,4, 172,6.

Data analysis for C18H22N2O4S20,08 H2O:

Calculated, %: C 54,60; N 5,64; N 7,07; S 16,19

Found, %: C 54,65; N 5,54; N 7,02; S 15,80.

HPLC: tR= 13,0 min (98,8%, UV 220): YMC S-3 ODS (C-othonoi acid) flow rate 1.5 ml/min

Example 6

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

The product of example 5 was prepared as follows:

a/N-//Phenylmethoxy/carbonyl/-L-homoserine

N/Benzyloxycarbonyloxy/succinimide /23,57 g, 94,58 mmole/ added to a solution of L-homoserine (10,24 g, 85,98 mmole) and sodium bicarbonate (of 7.95 g, 94,58 mmole, 1.1 EQ.). In a mixture of water (100 ml) and acetone (100 ml). The mixture was stirred at room temperature overnight. The acetone was removed under reduced pressure (rotary evaporator) and the aqueous solution was washed with methylene chloride (275 ml). Then the aqueous layer was acidified to pH 2 by addition of 6 N hydrochloric acid and was extracted with ethyl acetate (225 ml). United an ethyl acetate layers were washed with water (2100 ml) and brine, dried over sodium sulfate, filtered, concentrated and dried in vacuum, obtaining 19,54 g mentioned in the title product as a white solid. TLC (ethyl acetate: n-butanol:acetic acid: water 2:1:1:1) Rf= 0,74.

b) N-//Phenylmethoxy/carbonyl/-O-/triphenylmethyl-L-homoserine

To a suspension of the product from part (a) (19,54 g, 77,04 mmole) in chloroform (250 ml) was added triethylamine (12,35 ml, 88,59 mmole, 1.15 EQ.). Homogene the century The reaction mixture was concentrated under reduced pressure (rotary evaporator), was divided between ethyl acetate (400 ml) and 5% solution of potassium bisulfate (200 ml). An ethyl acetate layer washed with 5% solution of potassium bisulfate (200 ml), water (2200 ml), and brine (200 ml), dried over sodium sulfate, filtered and concentrated, getting to 45.4 g of substance. The residue was chromatographically on a column of 10 to 30 cm silica gel, elwira mix 6:4 ethyl acetate:hexane (2 l) followed by elution with 1% acetic acid in a mixture of 8:2 ethyl acetate:hexane, getting 8,76 Mr. clean is specified in the product name.

c) Methyl ester of /S/-2-amino-5,5-dimethoxyphenol acid

Methyl ether /S/-2-phthalimido-5,5-dimethoxyphenol acid (obtained as described in example 4 (f), 3,35 g 10,43 mmole) in methanol (70 ml) was treated with hydrazinoacetate (531 μl, 10,95 mmole, of 1.05 equiv.) and the solution was stirred at room temperature for 6 days. The mixture was filtered and the solid washed with methanol. The filtrate was concentrated, triturated with methylene chloride, was again filtered, concentrated and dried in vacuum, obtaining 1,89 g specified in the product name in the form of a turbid oil. TLC (10% methanol in methylene chloride) Rf= 0,39.

d) Noted oxopentanoic acid

A solution of the product from part (b) (5,28, 10,65 mmole, 1.1 EQ.) in dry methylene chloride (50 ml) was treated at 0oC triethylamine (1,48 ml, 10,65 mmole) followed by treatment of the product from part (C) (1.85 g, 9.68 mmole) in dry methylene chloride (30 ml) benzotriazol-1-yloxytris/dimethylamine/phosphodiesterases (4.71 g, 10,65 mmole, 1.1 EQ.). The mixture was switched for 1 hour at 0oC and then were switched at room temperature for 2 hours. The reaction mixture was separated between ethyl acetate (300 ml) and water (150 ml). An ethyl acetate layer was washed with 50% saturated sodium bicarbonate solution (200 ml) and brine (2200 ml), dried over magnesium sulfate, filtered, concentrated, adsorbing on celite and cleaned on a column of 720 cm silica gel, elwira 40% mixture of ethyl acetate/hexane (3 l) followed by elution with 50% (2 l) a mixture of ethyl acetate/hexane, getting 4,84 g specified in the product name. TLC (ethyl acetate/hexane 1:1) Rf= 0,22.

e) Methyl ether /S-/R*, R*//-2-//2-///phenylmethoxy/carbonyl/amino/-4-hydroxy-1-oxobutyl/amino/-5,5-dimethoxyphenol acid

A solution of the product from part (d) (4,80 g, 7,18 mmole) in methanol (70 ml) was treated with monohydrate p-toluensulfonate acid (300 mg). After peremeshivaniem sodium bicarbonate (200 ml). The phases were separated and the aqueous layer was again extracted with ethyl acetate (100 ml). United an ethyl acetate extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was cleaned chromatography on a column of 520 cm silica gel, elwira 7:3 (1 l), 8:2 (1 l) a mixture of ethyl acetate:hexane, followed by elution with 10% methanol in ethyl acetate (2 liters). The desired fractions were combined, concentrated and dried in vacuum, obtaining of 2.92 g specified in the product name. TLC (ethyl acetate:hexane 8:2) Rf= 0,09.

f) Methyl ether /S-/R*, R*//-2-//2-///phenylmethoxy/carbonyl/amino-4-/acetylthio/-1-oxobutyl/ amino-5,5-dimethoxyphenol acid

A solution of triphenylphosphine (of 3.06 g, 11,65 mmole, 1.7 EQ.) in dry tetrahydrofuran (40 ml) at 0oC were treated with diisopropylcarbodiimide (to 2.29 ml, 11,65 mmole). The obtained white slurry was stirred for 30 minutes and then treated with a solution of the product from part (e) (2,92 g, 6,85 mmole) in dry tetrahydrofuran followed by treatment of the weak thioglucose acid (833 μl, 11,65 mmole). The mixture was stirred at 0oC for 2 hours and then was divided between ethyl acetate (300 ml) and 50% sodium bicarbonate solution (200 ml). An ethyl acetate layer was washed R is. The crude substance was cleaned chromatography on a column of 520 cm silica gel, elwira a mixture of ethyl acetate:hexane 1:1 (3 l). The desired fractions were combined, concentrated and dried in vacuum, obtaining 2.58 g specified in the product name in the form of svargaloka solid product. TLC (ethyl acetate:hexane, 8:2) Rf= 0,40.

(g) Methyl ether /S-/R*, R*//-2-//2-///phenylmethoxy/carbonyl/amino/-4-mercapto-1-oxobutyl/amino/-5,5 - dimethoxyphenol acid

Obeskislorozhennuju (propulsiveness argon) solution of the product from part (f) (2,56 g, 5,28 mmole) in methanol (50 ml) at 0oC was treated with sodium methoxide (25 wt.% in methanol, 3,62 ml, 15,84 mmole, 3 EQ.). After 10 minutes the mixture was marked with a saturated solution of ammonium chloride (40 ml), diluted with water (100 ml) and was extracted with ethyl acetate (300 ml). An ethyl acetate extract was washed with water (100 ml) and brine (150 ml), dried over magnesium sulfate, filtered and concentrated. The residue was cleaned chromatography on a column of 520 cm silica gel, elwira 1:1 (3 l) a mixture of ethyl acetate:hexane. The desired compound were combined and concentrated, obtaining 1,99 g specified in the product name in the form of oil. TLC (ethyl acetate:hexane, 8:1) Rf= 0,43.

h) Methyl ether /4S/4, 7, 9a// OK the ukta from part (g) (2.16 g, 4,88 mmole) in methylene chloride (50 ml) was treated with ion exchange resins - Amberlite15 (620 mg, pre sequentially washed with 6 N hydrochloric acid, water, tetrahydrofuran and methylene chloride). After stirring at room temperature for 3 hours the solution was filtered, concentrated and subjected to flash chromatographicaliy in column 520 cm silica gel, elwira 6:4 mixture of ethyl acetate: hexane, receiving of 1.34 g mentioned in the title product as a white foam. TLC (ethyl acetate:hexane, 8:2) Rfor = 0.51.

i) Methyl ether /4S-/2, 7, 9a//- 4-amino-octahydro-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

A solution of the product from part (h) (1.20 g, 3,17 mmole, remote toluene three times and dried in vacuum over night) in dry methylene chloride (40 ml) was treated with attributively (632 μl, of 4.44 mmole, 1.4 EQ.) and stirred at room temperature in an argon atmosphere for 1.5 hours. The mixture is extinguished with water (50 ml) was treated with 10% hydrochloric acid (5 ml, pH 1) and washed with ethyl acetate (50 ml). The aqueous phase was treated with 10% sodium hydroxide solution and was extracted with methylene chloride (three times). The collected extracts were dried over sodium sulfate, filtered, concentrated and dried in vacuo the/SUB> = 0,10.

j) /4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxopyrrolo [2,1 - b] /1,3/-thiazepine-7-carboxylic acid

Solution /S/-2-/acetylthio/benzoylpropionic acid in dry methylene chloride was treated with triethylamine. Then was added a solution of the product from part (i) in methylene chloride and then adding benzotriazol-1-yloxytris-/dimethylamine/ fosfodiesterasa. The resulting solution was treated as described in example 5 (e), receiving methyl ether /4S/4/R*/, 7, 9a//- octahydro-4-//2 - acetylthio/-1-oxo-3-phenylpropyl/amino/-5-oxopyrrolo[2.1-b]/1,3/- thiazepine-7-carboxylic acid.

The suspension of this methyl ester in a mixture of methanol: tetrahydrofuran was purged with argon, was cooled to 0oC and treated purged of 1.0 N sodium hydroxide solution. Treated thus, as described in example 5 (f), and has been specified in the product name.

Example 7

/4S/4/R*/, 7, 9a//- Octahydro-4-//3-cyclohexyl-2-mercapto-1-oxopropyl/amino/-5-oxopyrrolo[2,1-b]/1,3/-thiazepine-7-carboxylic acid

a/ Sol methyl ether /4S/4, 7, 9a//- 4-linearalgebra-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluensulfonate acid.

RA is Borovoy acid (obtained, as described in example 6 (h), 738 mg, 1,95 mmole, remote three times with toluene and dried in vacuum over night) in dry methylene chloride (25 ml) was treated with attributively (389 μl, 2,73 mmole, 1.4 EQ.) and stirred at room temperature in the atmosphere agona. After 2 hours the reaction mixture was treated with an additional quantity of attributively (40 ml) and was stirred for 30 minutes. A mixture of Hacili of 0.4 M hydrochloric acid in a solution of methanol:dioxane (9:1, 9.7 ml) and was stirred for 5 minutes. Volatiles were removed in vacuo (rotary evaporator) and the residue is divided between water and ethyl acetate. Separated an ethyl acetate layer was washed with water and the combined aqueous phase was washed with ethyl acetate. The aqueous phase was cooled to 0oC and brought the pH to 10.3 (indicated pH meter) of 1.0 N sodium hydroxide solution. The aqueous phase was extracted with methylene chloride (three times) and then the aqueous phase was saturated with salt and was again extracted with methylene chloride (three times). The collected extracts were dried over sodium sulfate, filtered, concentrated and dried in vacuum, obtaining 455 mg of the free amine as a clear oil, TLC (10% methanol in methylene chloride) Rf= 0,28.

This free amine was dissolved in ethyl acetate (5 ml) and obrazovyvalis white crystals. The crystals were kept in the refrigerator (5oC) for 30 minutes and then collected by filtration, well washed out with ethyl acetate, and dried overnight in vacuum to obtain 639 mg specified in the title product as a white solid.

b) Dicyclohexylamine salt /S/-2-/acetylthio/-3-cyclohexylpropionic acid

A solution of D-phenylalanine (5.20 g, 31.5 mmole) in 2 M hydrochloric acid solution (75 ml) in a 500 ml vessel for hydrogenation (Parr) was purged with gaseous nitrogen and was treated with platinum oxide (640 mg, 2,82 mmole). The hydrogenation was started at a pressure P03 kg/cm2in rolled back the flask, filling again, if necessary. The full amount of absorbed hydrogen was about 5.8 kg/cm2(theoretically 5,86 kg/cm2within 6 hours. The reaction mixture was purged with gaseous nitrogen and filtered through celite, washing the filter residue with hot water. The filtrate was concentrated to about 40 ml and kept overnight at 5oC. the Obtained solid was collected, washed with small amount of cold water and dried in vacuum at 60oC, receiving 5,46 g cleaners containing hydrochloride salt /R/-2-amino-3-cyclohexylpropionic acid.

To a stirred solution of this ghidrah, 4 mmole). The reaction mixture was cooled to -4oC was added in portions over 1 hour of solid sodium nitrite (1.75 g, 25.4 mmole), keeping the temperature below 0oC. the Reaction mixture was foam and started to produce oil. After the addition, the reaction mixture was stirred for 1 hour and then heated to room temperature and stirred for another 1 hour. The reaction mixture then was extracted twice with ether, the extracts dried (magnesium sulfate), filtered and evaporated, obtaining 2.3 g /R/-2-bromo-3-cyclohexylpropionic acid as a colourless oil.

To stir the slurry of thioacetate potassium (1.07 g, 9,36 mmole) in dry acetonitrile (15 ml) at 0oC in argon atmosphere was added a solution of /R/-2-bromo-3-cyclohexylpropionic acid (2.20 g, 9,36 mmole) in acetonitrile (3 ml) for 10 minutes. The reaction mixture was heated to room temperature and was stirred for 16 hours. The resulting slurry was filtered and evaporated. The residue was again dissolved in ethyl acetate, washed once with a 5% solution of potassium bisulfate, dried (sodium sulfate) and evaporated. The oily yellow residue (of 2.21 g) was dissolved in ether and treated with a solution of dicyclohexylamine (1.8 ml, 9.0 mmole) in 5 ml of ether. CA is, the.sq. 159 - 161oC []D= -41,2o(C=1.0, chloroform).

Data analysis for C23H41NSO3:

Calculated, %: C 67,11; N 10,04; 3,40 N; S 7,79

Found, %: C 66,95; N 10,12; N 3,25; S 7,89.

c) Methyl ether /4S/4/R*/, 7, 9a/- octahydro-4-//2-/acetylthio/-3-cyclohexyl-1-oxopropyl/amino/-5 - oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

Suspension dicyclohexylamine salt /S/-2-/-acetylthio/-3 - cyclohexylpropionic acid (285 g, 0,69 mmole, of 1.05 EQ) in ethyl acetate (15 ml), washed with 5% solution of potassium bisulfate (310 ml), 50% brine (10 ml) and brine (10 ml), dried (anhydrous magnesium sulfate), filtered, concentrated, removed with methylene chloride (twice) and dried in vacuum for 1 hour, receiving /S/-2-/-3-cyclohexylpropionic acid in the form of butter.

This free acid was dissolved in dry methylene chloride (5 ml), cooled to 0oC (bath with ice) and treated with triethylamine (96 μl, 0,69 mmole, of 1.05 equiv.) then the product from part (a) (275 mg, of 0.66 mmole), triethylamine (92 μl, of 0.66 mmole) and finally benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa/ 305 mg, 0,69 mmole. The resulting solution was stirred at 0oC for 1 hour and then at room temperature for 2 hours. Rea is sasenum solution of sodium bicarbonate (20 ml), brine (20 ml), dried (anhydrous magnesium sulfate), filtered and evaporated to dryness. The crude product was adsorbing on celite and chromatographically on a column of silica gel (2,510 cm), elwira 40% (1 l) a mixture of ethyl acetate/hexane. The desired fractions were combined and concentrated, obtaining 265 mg of pure indicated in the product name. TLC (ethyl acetate:hexane, 8:2) Rf=0,53.

d) /4S/4/R*/, 7, 9a//- Octahydro-4-//3-cyclohexyl-2-mercapto-1-oxopropyl/amino/ -5-oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (C) (245 mg, 0.54 mmole) in methanol (6 ml), purged with argon for 30 minutes, cooled to 0oC was treated dropwise previously purged (argon, 30 minutes) solution of 1.0 N sodium hydroxide (5 ml), continuing prorokowanie of argon throughout the addition of the solution and reaction. The reaction mixture was stirred at 0oC for 2 hours, acidified at 0oC 5% solution of potassium bisulfite to pH 2, then extracted with ethyl acetate (320 ml). The combined organic extracts were washed with 50% brine (20 ml) and brine (20 ml), dried (anhydrous magnesium sulfate), filtered and evaporated to dryness. The residue was cleaned chromatography on a column (2,510 sm) with si is l). The desired fractions were concentrated, was removed with methylene chloride and dried in vacuum, obtaining 172 mg specified in the title product as a white foam; []D= -116,9o(c=0.5 in methanol). TLC (1% acetic acid in ethyl acetate) Rf=0,35.

1H-NMR: 400 MHz; CDCl3: of 0.91 (m, 2H), 1,22 (m, 3H), of 1.44 (m, 1H), 1.55V (m, 1H), 1,68 (m's, 5H) and 1.83 (m, 1H), 1,97 (m S, 2H), 2,12 (m, 1H), 2,19 - 2,40 m' S, 3H), 2,53 (m, 1), 2,96 (m, 1H), 3,38 (m S, 2H), to 4.62 (t, 1H, J= 6,8 Hz), 4,70(m, 1H), 5.25 in (m, 1H), 7..55(d, 1H, J=6,4 Hz).

13C-NMR: 100 MHz; CDCl3: / 26,0, 26,1, 27,5, 31,5, 32,3, 33,0, 33,3, 35,2, 40,7, 43,0, 52,9, 60,6, 62,5, 170,9, 172,7, 175,3.

Data analysis for C18H28N2O4S2:

Calculated, %: C 53,98; N 7,05; N 6,99; S 16,01

Found, %: C 53,97; N 7,18; N 6,84; S Of 15.75.

HPLC: tR= 16 min/>99%, UV 217/; YMCS-3ODS /C-18/ 6,0 150 mm; 50% B:A to 100% B:A 25 minute linear gradient /A=90% water/methanol+0,2 phosphoric acid; B: 90% methanol/water+0.2% of phosphoric acid; flow rate at 1.5 ml/min

Example 8

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxohexyl/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

a) /S/-2-Bromhexina acid

Bromide of potassium (15.9 g, 133 mmole) was added to a stirred solution of D-norleucine (5.0 g, 38 mmole) in 2.5 N sulfuric acid (77 ml) at room temperature. The reaction mixture was cooled d>and -5oC. After the addition of the foaming reaction mass was stirred for 1 hour and then heated to room temperature and stirred for another 1 hour. Then the reaction mixture was extracted twice with ether, the ether extracts washed once with water and dried (magnesium sulfate), filtered and evaporated, receiving of 3.3 g of the crude indicated in the product name.

b) Dicyclohexylamine salt /S/-2-/acetylthio/hexanoic acid

To stir the slurry of diacetate potassium (2,11 g, 18.5 mmole) in 50 ml of dry acetonitrile at room temperature in an argon atmosphere was added a solution of the product from part (a) (3,27 g, a 16.8 mmole) in 26 ml of acetonitrile. The reaction mixture was stirred for 5 hours. The resulting slurry was filtered and evaporated. The residue was again dissolved in ethyl ether, washed once with a 5% solution of potassium bisulfate and once with brine, dried (magnesium sulfate) and evaporated. The residue was dissolved in ether (64 ml) and treated with dicyclohexylamine (3.4 ml, is 16.8 mmole/. The ethereal solution was concentrated in vacuo and triturated with hexane, getting a white solid, which was recrystallized from a mixture of ethyl ether/hexane, getting listed in the name of the product. Uterine races is a; so pl. 145 - 147oC; []D= -33,8o(C = 1,08, chloroform).

c) Methyl ether /4S/4/R*/, 7, 9a//- octahydro-4-//2-/acetylthio/-1-oxohexyl/amino/-5-oxopyrrolo- [2,1-b] /3,3/diazepin-7-carboxylic acid

Suspension dicyclohexylamine salt from part (b) (255 mg, RS 9.69 mmole, of 1.05 equiv.) in ethyl acetate (15 ml), washed with 5% solution of potassium bisulfate (3 5 ml) and brine (10 ml), dried (anhydrous magnesium sulfate), filtered, concentrated, removed with methylene chloride (twice) and dried in vacuum for 1 hour, obtaining the free acid in the form of butter.

This oil was dissolved in dry methylene chloride (6 ml), cooled to 0oC (bath with ice) and treated with triethylamine (96 μl, 0,69 mmole, 1.05 of EQ. ), then the salt of the methyl ester /4S/4, 7, 9a//- 4-aminooctane-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluensulfonate acid, obtained as described in example 7 (a), (275 mg, of 0.66 mmole), triethylamine (92 μl, of 0.66 mmole) and finally, benzotriazol-1-yloxytris/dimethylamine/ phosphodiesterases (305 mg, 0,69 mmole). The resulting solution was stirred at 0oC for 1 hour, then at room temperature for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with 5% restoreultra magnesium), was filtered and evaporated to dryness. The crude product was adsorbing on celite and chromatographically on a column (2.5 to 10 cm) with silica gel, elwira 40% (1 l) a mixture of ethyl acetate/hexane. The desired fractions were combined and concentrated, getting 258 mg of pure indicated in the product name. TLC (ethyl acetate:hexane 8:2) Rf= 0,54.

d) /4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxohexyl/-amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

A solution of the product from part (c) (255 mg, 0.54 mmole) in methanol (5 ml), purged with argon for 30 minutes, cooled to 0oC was treated dropwise previously purged (argon, 30 minutes) solution of 1.0 N sodium hydroxide (5 ml), maintaining the conditions of propulsive argon during the period of addition and reaction. The reaction mixture was stirred at 0oC for 2 hours, acidified at 0oC 5% solution of potassium bisulfate to pH 2, then extracted with ethyl acetate (3 20 ml). The combined organic extracts were washed with 50% brine (20 ml) and brine (20 ml), dried (anhydrous magnesium sulfate), filtered and evaporated to dryness. The residue was cleaned chromatography on a column of 2.5 to 10 cm silica gel, elwira 7:3 mixture of ethyl acetate:heptane (300 ml) and the reed and dried in vacuum, getting 170 mg specified in the title product as a white foam; []D= -135,1o(C = 0,5, methanol). TLC (1% acetic acid in ethyl acetate) Rf= 0,32.

1H NMR: 400 MHz; CDCl3: to 0.89 (t, 3H, J=7Hz), 1.32 to(m,4H), at 1.73(m,1H), 1,96(m, 2H), 2,00(d, 1H), J=8,6 Hz), 2,11(m, 1H), 2,32(m s, 3H), 2,52(m, 1H), 2,98(m, 1H), 3,32(m s, 2H), br4.61(t, 1H, J=7,1 Hz), 4.72 in(m, 1H, in), 5.25(m, 1H), 7,63(d, 1H, J=6,4 Hz).

13C - NMR: 100 MHz; CDCl3: 13,8, 22,2, 27,6, 29,2, 31,4, 32,6, 33,1, 35,3, 43,0, 52,8, 60,6, 62,42, 170,7, 172,5, 174,0.

Data analysis for C15H24N4O4S2O 0,08 H2O:

Calculated, %: C OF 49.79; H OF 6.73; N 7,74; S 17,72

Found, %: C 49,90; N 6,92; N 7,63; S 17,57.

HPLC: tR= 9,4 min (> 9%, UV 220); YMC S - 3 ODS (C-18) 6,0 150 mm; 50% B: A to 100% B: A 25 minute linear gradient /A=90% water/methanol + 0.2% of phosphoric acid; (B= 90% methanol/water + 0.2% of phosphoric acid/ flow rate at 1.5 ml/min

Example 9

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1 - oxo-4-were/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7 - carboxylic acid

a) /S/-2-Bromo-4-methylpentanoic acid

The potassium bromide (9.5 g, 80 mmole) was added to a stirred solution of D-leucine (3.0 g, 23 mmole) in 2.5 N sulfuric acid (47 ml) at room temperature. The reaction mixture was cooled to -10oC and portions was added solid sodium nitrite (2.4 g, 34 massively for 1 hour and then heated to room temperature and stirred another hour. Then the reaction mixture was twice extracted with ether, the ether extracts washed once with water, dried (magnesium sulfate), filtered and evaporated, obtaining 2.7 g of the crude indicated in the product name.

b) Dicyclohexylamine salt /S/-2-/acetylthio/-4-metilpentanovoyj acid

To stir the slurry of thioacetate potassium (1.7 g, 15,0 mmole) in 50 ml of dry acetonitrile at room temperature argon was added a solution of the product from part (a) (2.6 g, 13 mmole) in 17 ml of acetonitrile. The reaction mixture was stirred for 4 hours. The resulting slurry was filtered and evaporated. The residue was again dissolved in ethyl ether, washed once with a 5% solution of potassium hydrosulfate and once with brine, dried (magnesium sulfate) and evaporated. The residue was dissolved in ether (64 ml) and treated with dicyclohexylamine (2.7 ml, 1.4 mmole). From the solution immediately began to fall white solid. The solution was filtered and the collected white solid, obtaining 2.0 g specified in the product name, so pl. 153 - 158oC; []D= -54,5oC /s = 0,61, chloroform/.

c) Methyl ether /4S/4/R*/, 7, 9a//- octahydro-4-//2-/acetylthio/-1-oxo-4-methylpentyl/amino/-5-oxopyrrolo [2,1-b]/1,3/diazepin-7-carboxylic acid

is washed with 5% aqueous solution of potassium bisulfate (3 5 ml). The organic extract was dried (anhydrous magnesium sulfate), filtered and evaporated twice from hexane. The resulting oil was dissolved in methylene chloride (6 ml) and stirred under nitrogen atmosphere at 0oC. To this solution was added triethylamine (88 μl, to 0.63 mmole), then salt of methyl ester /4S/4, 7, 9a//- 4-amino-octahydro-5-oxopyrrolo[2,1-b] /1,3/-thiazepine-7-carboxylic acid and p-toluensulfonate acid (obtained as described in example 7 (a), 249 mg, 0.6 mmole), an additional amount of triethylamine (84 μl, 0,609 mmole) and after 10 minutes benzotriazol-1-yloxytris-/dimethylamino) - phosphonium hexaflurophosphate (279 mg, 0,63 mmole). After 1 hour the reaction mixture was heated to room temperature and was stirred for 2 hours. The obtained colorless solution was evaporated at a temperature below 30oC and the oily residue was again dissolved in ethyl acetate. The solution was washed once with a 5% solution of potassium bisulfate, once with saturated sodium bicarbonate solution and once with brine. The organic layer was dried (magnesium sulfate), filtered and evaporated on 5 g of silica gel. Clean flash chromatographytandem in column (2,515 cm, elution with a mixture of 1:1 ethyl acetate/hexane) to give 203 mg specified in the name of the product as white is= 0,19.

d) /4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxo-4-methylpentyl/amino/-5-oxopyrrolo [2,1-b]/1,3/-thiazepine-7-carboxylic acid

A solution of the product from part (c) (184 mg, of 0.44 mmole) in 5 ml of methanol was purged with nitrogen for 10 minutes and cooled to 0oC. To this solution was added dropwise 5 ml of purged with nitrogen solution of 1 M sodium hydroxide. Nitrogen slowly propulsively through the solution during the reaction. After 2 hours the reaction mixture was acidified with 2 ml of 6M hydrochloric acid, was extracted twice with ethyl acetate and the extracts were combined, dried (magnesium sulfate) and evaporated. Re-evaporation of the hexane and rubbing the residue in methanol/water gave 132 mg specified in the product name in the form of a solid crystalline substance, so pl. 94-96oC []D= -158,6oC (c = 0.42 and methanol). TLC (ethyl acetate:acetic acid 4:4:0,1), Rf= 0,13.

Data analysis for C15H24N2S2O40,75 H2O:

Calculated, %: C 48,17; N 6,87; N 7,49; S 17,15

Found, %: C 48,33; N 6,51; N 7,37; S 16,82.

HPLC: Rf= to 17.6 min; (99,2 %) YMC S-3-ODS(C-18), 6,0150 mm; 0% to 100% B:A 25 min linear gradient and 15 min of incubation, 1.5 ml/min

A = 90% water/methanol + 0.2% of phosphoric acid;

B = 90% methanol/water + 0,2 phosphate to the eno/-5-oxo-/1,4/oxazino [3,4-b]/1,3/oxazepine-7-carboxylic acid

a) 2-Propenyloxy ester 2,2,2-trichloroacetimidate acid

A suspension of 80% sodium hydride (945 mg, 31.5 mmole, twice washed with 25 ml of hexane) in dry ether (30 ml) was treated dropwise with a solution of 2-propen-1-I (21,4 ml, and 18.3 g, 315 mmole) in dry ether (45 ml) was stirred for 20 minutes at room temperature in an argon atmosphere and then cooled to 0oC (ice bath salt). Trichloroacetonitrile (30 ml or 42.3 g of 0.30 mol) was added over 15 minutes and the brown solution was stirred at 0oC for 40 minutes, with 10oC for 10 minutes and at room temperature for 10 minutes. The reaction mixture was concentrated to syrup was treated with a solution of methanol (1.2 ml) in pentane (30 ml) and was intensively stirred for 5.0 minutes. Light brown precipitate was filtered, washed with pentane (230 ml) and the combined filtrates were concentrated to a light brown liquid. The fluid was re-dissolved in pentane (30 ml) was stirred for several minutes and the resulting suspension was filtered and the obtained precipitation was washed with pentane (30 ml), repeating this procedure at least once. Clean the filtrate was concentrated and dried in vacuum, obtaining 54,0 g specified in the name soy is>.

b) Methyl ester of N-phthaloyl-L-serine

A suspension of methyl ester hydrochloride L-serine (25 g, 161 mmole) in water (350 ml) was diluted with dioxane (250 ml) and the resulting clear solution was treated with solid sodium carbonate (17.0 g, 1.0 EQ.) followed by treatment with N-carbenoxolone (37 g of 1.05 EQ.). The reaction mixture was stirred at room temperature for 2.5 hours in an argon atmosphere. The mixture was extracted with ethyl acetate (3500 ml) and the combined organic extracts were washed sequentially with 5% sodium bicarbonate solution (250 ml), 5% potassium bisulfate (250 ml) and brine (250 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The product mixture was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate: hexane(1: 3, 1: 2), and the desired fractions were combined, evaporated to dryness and dried in vacuum, obtaining 31 g mentioned in the title compound in the form of a viscous syrup. TLC/ethyl acetate:hexane, 1:1/Rf= 0,52.

c) Methyl ester of N-phthaloyl-1-/2-propanol/-L-serine

A solution of the product from part (b) (7,37 g of 29.5 mmole) in dry methylene chloride (30 ml) was treated with a solution of the product from part (a) (of $ 11.97 g, 59.1 mmole, 2 EQ.) in cyclohexane (60 ml) with subsequent clicks is for 20 hours in an argon atmosphere. Precipitation was filtered off, washed with a minimal amount of methylene chloride and the combined filtrates were washed with 5% sodium bicarbonate solution (30 ml) and water (30 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude mixture was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate:hexane (1:9). The desired fractions were combined, evaporated to dryness and dried in vacuum, obtaining 7,56 g mentioned in the title compound in the form of a clear viscous syrup.

TLC (ethyl acetate:hexane, 1:1), Rf= 0,70.

d) Methyl ester of N-phthaloyl-0-/acetaldehyde/-L-serine

A solution of the product from part (c) (2.5 g, 8,64 mmole) in a mixture of dry methylene chloride (46.4 ml) and methanol (4.6 ml) was cooled to -78oC (in a bath of dry ice-acetone) and treated with ozone until a stable blue color (about 15 minutes). Then the mixture was purged with nitrogen for 10 minutes (until the disappearance of the blue color), treated with dimethyl sulfide (14,0 ml to 0.19 mol, 22,1 equiv.) was heated to room temperature and was stirred for 2.5 hours under nitrogen atmosphere. The reaction mixture is evaporated to dryness and the residue in the form of syrup was dissolved in ethyl acetate (50 ml), washed with water (15 ml) and brine (15 ml), dried (the CT was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate: hexane(1:9; 1:4; 1:2) to obtain 1.54 g specified in the connection name. TLC (ethyl acetate:hexane, 1:1) Rf= 0,33.

e) Methyl ester of N-phthaloyl-0-/2.2-dimethoxymethyl/-L-serine

A solution of the product from part (d) (1.54 g, from 5.29 mmole) in a mixture of dry methylene chloride (8,3 ml) and dry methanol (8,3 ml) was treated trimethylamin ether of ortho-formic acid (0,84 ml of 7.68 mmole, 1.45 equiv.) and monohydrate p-toluensulfonate acid (92 mg). The reaction mixture was stirred at room temperature in an argon atmosphere for 2.5 hours, then was divided between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (15 ml). The organic phase is washed with water (15 ml) and brine (15 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude product was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate:hexane (1:4) to give 1.35 g specified in the product name in the form of a transparent viscous syrup. TLC (ethyl acetate:hexane, 1:1) Rf= 0,58.

f) Methyl ester O-/2.2-dimethoxymethyl/-L-serine

A solution of the product from part (e) (2.0 g, 5,93 mmole) in dry methanol (14 ml) was treated with hydrazinehydrate (0,30 ml, 6.1 mmole) and stirred at on the scrap (214 ml) and the filtrate was concentrated to dryness. The syrup was re-dissolved in methylene chloride and filtered by more than two times up until a precipitate no longer worked. Transparent filtrate was concentrated, receiving 1,17 g mentioned in the title product as a pale yellow syrup. TLC (methylene chloride:methanol, 9:1) Rf= 0,54.

g) N-//phenylmethoxy/carbonyl/-O-//1,1-dimethylethyl/-dimethylallyl/-L - homoserine

A solution of N-//phenylmethoxy/carbonyl/-L-homoserine /obtained as described in example 6(a), (3.0 g, 11,85 mmole) in dry dimethylformamide /65 ml/ processed //1,1-dimethylethyl/-dimethylallyl chloride (of 10.72 g, 71.1 mmole) and imidazole (9,65 g of 0.14 mol) and stirred at room temperature in an argon atmosphere for 24 hours. The reaction mixture was diluted with methanol (207 ml), was stirred for another 24 hours at room temperature and then concentrated to a syrup. The remaining syrup was dissolved in ethyl acetate (200 ml), washed with 10% citric acid (275 ml) and brine, dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude mixture was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate: hexane (1:1) followed by elution with a mixture of ethyl acetate: acetic acid (of 99.5: 0.5 to). The desired fractions were combined, the con is obraznogo solids. TLC (ethyl acetate:acetic acid, 95:5) Rf= 0,82.

h) Methyl ether N-/O-//1,1-dimethylethyl/ dimethylallyl/-N-//phenylmethoxy/ carbonyl/-L-gamesell/ -O-/2.2-dimethoxymethyl/-L-serine

A solution of the product from part (g) (2,18 g, 5,93 mmole) in dry methylene chloride to 0oC (ice bath salt) and treated sequentially with a solution of the product from part (f) (1,71 g, 5,65 mmole) in dry methylene chloride (5 ml), triethylamine (0,78 ml, 5,65 mmole) and benzotriazol-1-yloxytris-/dimethylamine/phosphodiesterases (2,63 g, 6.0 mmole). The reaction mixture was stirred at 0oC for 30 minutes and at room temperature for 1 hour and 45 minutes. The reaction mixture was separated between ethyl ether (2100 ml) and water (30 ml) and the combined organic extracts were washed with 50% saturated sodium bicarbonate solution (20 ml) and brine (25 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude mixture was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate: hexane(1:4, 1:3, 1:1), receiving of 2.38 g specified in the product name, TLC (ethyl acetate:hexane, 1:1) Rf= 0,40,

i) Methyl ether /4S/4, 7, 10a//- octahydro-4-//phenylmethoxy/-carbonyl/amino-5-oxo-/1,4/oxazino[3,4-b] /1,3/ oxazepan-7-the ion exchange resins - Amberlit15 (acidic form) and methanol (0.1 ml) and the resulting mixture was stirred at room temperature in an argon atmosphere for three days. The resin was filtered off, washed with a small amount of methylene chloride and the filtrate was concentrated to syrup. The crude mixture was chromatographically on a column of silica gel, elwira a mixture of ethyl acetate: hexane (1:1) to give 339 mg specified in the product name. TLC (ethyl acetate: hexane, 3:1) Rf= 0,53.

j) Methyl ether /4S/4, 7, 10a/- octahydro-4-amino-5-oxo/1,4/oxazino[3,4-b]/1,3/oxazepine-7-carboxylic acid

A solution of the product obtained as described in paragraph (i) (771 mg, 2,04 mmole) in dry methanol (25 ml) was treated with 10% palladium on coal as a catalyst (125 mg) and was first made (from a balloon) at room temperature for 16 hours. The reaction mixture was filtered through calinou substrate and the substrate was rinsed with methanol (2 25 ml). Transparent filtrate is evaporated to dryness and dried in vacuum, obtaining 448 mg specified in the product name in the form of syrup. TLC (methylene chloride:methanol, 9:1) Rf= 0,22.

k) Methyl ether /4S/4/R*/, 7, 10a/- octahydro-4-//2-/acetylthio/-1-oxo-3-phenylpropyl/amino/-5-oxo/1,4/oxazino [3,4-b] /1,3/oxazepine-7-carboxylic sour the ethyl acetate (70 ml), washed with 5% solution of potassium bisulfate (59.3 ml) and brine (9,3 ml), dried (anhydrous magnesium sulfate), filtered, evaporated to dryness and dried in vacuum.

This free acid was dissolved in dry methylene chloride (12 ml), cooled to 0oC (ice bath salt) and treated sequentially with a solution of the product from part (j) (448 mg, of 1.84 mmole) in dry methylene chloride (4.0 ml), triethylamine (0.25 ml, of 1.80 mmole) and benzotriazol-1-yloxytris/ dimethylamine/phosphodiesterases (823 mg, of 1.86 mmole). The reaction mixture was stirred at 0oC for 1 hour and at room temperature for 2 hours in argon atmosphere. The reaction mixture is kept dry and the resulting syrup was again dissolved in ethyl acetate (60 ml), washed with 0.5 N hydrochloric acid (211 ml), water (11 ml) and brine (11 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude mixture was chromatographically twice on a column of silica gel (Merck), elwira each time with a mixture of ethyl acetate:hexane(1:1, 1:1), getting 665 mg specified in the product name in the form of syrup. TLC (ethyl acetate:hexane, 3:1) Rf= 0,30.

i) /4S/4/R*/, 7, 10a//- Octahydro-4-//mercapto-1-oxo-3-phenylpropyl/amino/5-oxo /1,4/oxazino[3,4-b]/1,3/oxazep for 30 minutes, was cooled to 0oC (ice bath salt) and treated dropwise with a solution of 1.0 N sodium hydroxide (of 5.84 ml, previously purged with argon for 30 minutes), continuing prorokowanie argon in the process of adding and reaction. The reaction mixture was stirred at 0oC for 5,0 hours and extinguished at 0oC 5% solution of potassium bisulfate (25,4 ml). The mixture was heated to room temperature, extracted with ethyl acetate (350 ml) and the combined organic extracts were washed with brine (15 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude product is triturated with a mixture of hexane: methylene chloride (130: 7) and the obtained solid substance was chromatographically on a column of silica gel (Mecr), elwira a mixture of ethyl acetate (hexane) 1: 2, 1:1 (with subsequent elution with a mixture of methylene chloride: methanol:acetic acid (100:4:0,2). The desired fractions were combined, evaporated to dryness and the evaporation of the toluene was received 364 mg specified in the name of the product, which was dried in vacuum for 9 hours. The resulting product is then triturated with a mixture of methylene chloride: hexane (1:10), hexane (50 ml) and pentane (250 ml), stirring with the first 50 ml for 4 hours and sleduushemu in a period of 6.0 hours getting listed in title product in the form of a solid amorphous foam; []D= -49,1o(C = 0,48, methanol). TLC (toluene:acetic acid 5:1) Rf= 0,17.

Data analysis for C18H22N2O6S 0,56 H2O:

Calculated, %: C 53,45; N 5,76; N 6,98; S 7,92

Found, %: C 53,45; N. Of 5.53; N 6,75; S Of 7.48.

HPL C: Rt= 10,45 min; (98,3%); YMC S - 3 ODS(C=18) 6,0 150 mm; 44% (10% water - 90 methanol - 0.2% of phosphoric acid) (56%/ 90% water - 10% methanol - 0.2% of phosphoric acid), isocratic; 1.5 ml/min.

Example 11

/4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido [2,1-b] /1,3/ diazepin-7-carboxylic acid

The product of example 3 was also obtained in the following way:

a) N-//Phenylmethoxy/carbonyl/-O-//1,1-dimethylethyl/-dimethylallyl/-L-homoserine

//1,1-Dimethylethyl/dimethylallyl/chloride /37,5 g, 249 mmole/ was added to a solution of N-//Phenylmethoxy/ carbonyl/-L-homoserine (obtained as described in example 6 (a), 41,56 mmole) in dimethylformamide (125 ml) followed by addition of imidazole (33,95 g, 498 mmole). The obtained pale-yellow solution was stirred at room temperature for 22 hours. Was added methanol (500 ml), the reaction mixture was additionally stirred for 6 hours and then the methanol and most Noah acid (2300 ml) and the combined aqueous phases were extracted with ethyl acetate (300 ml). United an ethyl acetate phase was washed with water and brine, dried (sodium sulfate), concentrated and the residue evaporated with hexane to obtain a white powder. This powder was dried in vacuum, obtaining 12,942 g specified in the product name.

b) Methyl ether /S-/R*, R*//-2-//4-//1,1-dimethylethyl/hydroxy-1-oxo-2-//phenylmethoxy/carbonyl/-amino/ butyl/amino/-6,6-dimethoxycinnamic acid

To a solution of the product from part (a) (22,78 g, 61,97 mmole) in methylene chloride (100 ml), cooled to 0oC, was added N-methylmorpholine (for 6.81 ml, 61,97 mmole) followed by the addition of hydroxybenzotriazole (of 8.37 g, 61,97 mmole), methyl ether /S/-2-amino-6,6-dimethoxyethane acid obtained as described in example 1 (e), 10.6 g, to 51.64 mmole/ in methylene chloride (50 ml) and then 1-ethyl-3-/3-dimethylaminopropyl/carbodiimide (11,88 g, 61,97 mmole). The reaction mixture was stirred at 0oC for 1 hour and then at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (600 ml), washed with 5% solution of potassium bisulfate (200 ml), 0.5 N solution of sodium hydroxide (200 ml), water and brine, and dried (sodium sulfate). The filtrate was concentrated and the residue was placed in ethyl EPE is. iltram concentrated in vacuum to dryness, obtaining 30 g of the crude indicated in the name of the product in the form of an oily compound which was used in the next reaction without purification. TLC (ethyl acetate: hexane, 8:2) Rf= 0,55.

c) Methyl ether /S-/R*,R*//-2-//4-hydroxy-1 - oxo-2-//phenylmethoxy/carbonyl/amino/butyl/amino/-6,6 - dimethoxycinnamic acid

To a solution of the product from part (b) (30 g) in methanol (150 ml), cooled to 0oC, was added monohydrate p-toluensulfonate acid (1,96 g). The reaction mixture was stirred at 0oC for 2 hours before quenching it in an aqueous solution of sodium bicarbonate (1.3 g, of sodium bicarbonate in 100 ml of water). The mixture was concentrated in vacuo and the residue was separated between ethyl acetate (400 ml) and water (150 ml). The separated aqueous phase was extracted with ethyl acetate (2 150 ml). United an ethyl acetate layers were washed with 10% sodium bicarbonate solution, brine (2 times), dried (sodium sulfate), filtered and evaporated to dryness. The residue was subjected to flash chromatographicaliy on a column of 10 to 25 cm silica gel, elwira 80% ethyl acetate in hexane (5 l), ethyl acetate (3 l) and 2% methanol in ethyl acetate (5 l). The desired fractions were combined and concentrated and dried in vacuum,17.

d) Methyl ether /S-/R*,R*/-2-//4-/methanesulfonyl/hydroxy-1-oxo-2-// phenylmethoxy/carbonyl/amino/butyl/-amino/-6,6-dimethoxycinnamic acid

To a solution of the product from part (c) (17,40 g, 39,50 mmole) (remote with toluene three times and dried in vacuum over night) in dry methylene chloride (250 ml) cooled at -15oC (ice/acetone) was added triethylamine (compared to 8.26 ml, 59,28 mmole, fresh) followed by the addition of methanesulfonanilide (to 3.67 ml, 47.4 mmole) dropwise. The reaction mixture was stirred at -15oC for 30 minutes, then extinguished with a saturated solution of ammonium chloride (100 ml). After stirring for 5 minutes the mixture was diluted with ethyl acetate (600 ml) and washed with 5% solution of potassium bisulfate, brine, dried (sodium sulfate), filtered and evaporated to dryness. The residue was dried in vacuum, obtaining 20,40 g mentioned in the title compound as a yellow oil, which was used in the next reaction without purification. TLC (8:2 ethyl acetate:hexane) Rf= 0,35.

e) Methyl ether /S-/R*,R*//-2-//4-acetylthio/-1 - oxo-2-///phenylmethoxy/carbonyl/amino/butyl/amino/-6,6 - dimethoxycinnamic acid

To a solution of teoksessa acid (5,09 g, 71,10 mmole) in methanol (100 ml) was added whim acetone (3 times) and then dried in vacuum over pjatiokisi phosphorus during the night, getting thioacetate cesium.

A solution of the product from part (d) (20,40 g, 39,50 mmole) in dry dimethylformamide (150 ml) was added via cannula to a suspension of thioacetate cesium (10,576 g, 50,85 mmole) in dimethylformamide (50 ml). The obtained yellow solution was stirred in an argon atmosphere at room temperature overnight, then concentrated under high vacuum to remove most of the dimethylformamide. The residue was placed in ethyl acetate (1 l), washed with 10% sodium bicarbonate solution (200 ml), water (4 200 ml), brine (400 ml) and dried (sodium sulfate). The filtrate was concentrated and the residue evaporated with toluene (3 times), then dried in vacuum, obtaining 20 g mentioned in the title compound as a pale yellow solid, which was used for next reaction without purification. TLC (8:2 ethyl acetate:hexane) Rf= 0,47.

f) Methyl ether /S-/R*,R*//-2-//4-mercapto-1 - oxo-2-//phenylmethanesulfonyl/amino/butyl/amino/-6,6 - dimethoxycinnamic acid

A solution of the product from part (e) (20 g, 39,50 mmole) in methanol (250 ml) at 0oC was purged with argon for 15 minutes. Was added dropwise a solution of 25% (weight/weight, density = 0,945) of sodium methoxide in methanol (9,17 ml, 40 mmole) in continuous purge of argon. Sdelali between ethyl acetate (1 l) and water (200 ml). The aqueous phase was extracted with ethyl acetate (200 ml). United an ethyl acetate extract was washed with a saturated solution of ammonium chloride (400 ml), brine (400 ml), dried (sodium sulfate), filtered and concentrated in vacuum, obtaining 17,5 g mentioned in the title product as a yellow oil, which was used for next reaction without purification. TLC (8:2 ethyl acetate:hexane) Rf= 0,45.

(g) Methyl ether /4S/4, 7, 10a/- octahydro-4-///phenylmethoxy/carbonyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

To a solution of the product from part (f) (17.5 g, 38,3 mmole) in methylene chloride (600 ml) was added ion-exchange resin - Amberlit15 (6 g, pretreated 6 N hydrochloric acid, water, tetrahydrofuran and methylene chloride and dried). The suspension was stirred in an argon atmosphere at room temperature for 18 hours and filtered. The filtrate was concentrated and the residue was adsorbing on celite, was purified on a column of silica gel (10 to 30 cm), elwira 20 - 30% ethyl acetate in hexane. The desired fractions were combined and evaporated in vacuum to dryness, obtaining 9,18 g mentioned in the title product as a yellow oil. TLC (1:1, ethyl acetate:hexane) Rf= 0,32.

h) Methyl ether /4S/4, 7,) (9,1 g, 23,19 mmole, evaporated with toluene three times and dried in vacuum over night/ in dry methylene chloride (150 ml) was added attributively (4,95 g, 34,78 mmole) dropwise. The obtained yellow solution was stirred in an argon atmosphere at room temperature for 1.5 hours, then extinguished with 0.4 N hydrochloric acid in methanol/dioxane (120 ml). Volatiles were removed in vacuum and the residue was divided between ether (500 ml) and water (700 ml). The organic phase was extracted with 0.1 N hydrochloric acid (150 ml) and the combined acidic aqueous extracts were cooled to 0oC, brought to alkaline pH 10.5 solution of 1.0 N sodium hydroxide (for pH values of m), then was extracted with methylene chloride (4 400 ml). The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuum, obtaining 6,45 g mentioned in the title product as a yellow oil, which was used for next reaction without further purification. TLC (1:9 methanol:methylene chloride) Rf= 0,20.

i) /4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5 - oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid

A cold (0oC) a solution of /S/-/2-acetylthio/benzoylpropionic acid and triethylamine in IU the azole-1-yloxytris/dimethylamine/phosphodiesterases. The reaction was carried out according to the procedure described in example 3 (c), receiving methyl ether /4S/4/R*/, 7, 10a//- octahydro-4-//2-/acetylthio/-1-oxo-3 - phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid.

The solution of this mutilating product in obeskislorozhennuju methanol was treated with 1 N solution of sodium hydroxide according to the procedure of example 3 (d), receiving specified in the product name.

Example 12

/4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercaptomethyl/-1-oxo-3-phenylpropyl/amino/-5 - oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid

a) Efedrina salt /S/-2-//acetylthio/methyl/benzoylpropionic acid

Solution /1R,2S/-/-/-ephedrine (17.3 g, 105 mmole) in diethyl ether (175 ml) was added in one portion to a solution of 2-//acetylthio/methyl/benzoylpropionic acid (50.0 g, 210 mmole) in diethyl ether (175 ml). After staying at room temperature for 16 hours crystallized salt of ephedrine was collected by filtration (19, d); so pl. 114 - 125oC; []D= -40,6o(c = 1, methanol). Additionally, the amount of solids in (8.9 g); so pl. 121 - 126o; []D= -47,2o(c = 1, methanol) was isolated from the filtrate after their stay at room temperature for 20 hours. The solid is of 20.8 g of solid substance, so pl. 125 - 130oC; []D= -48,9o(c = 1, methanol). This substance was recrystallized in the same way from acetonitrile (300 ml), receiving 18,7, so pl. 128 - 130o; []D= -48,9o(c = 1, methanol).

A third recrystallization from acetonitrile (225 ml) was given to 17.4 g of solid /S/-2-//acetylthio/methyl/benzoylpropionic acid, ephedrinebuy salt, so pl. 128 - 129oC; []D= -50,1o(c = 1, methanol).

Data analysis for C12H14O3S C10H15NO:

Calculated, %: C 65,48; N 7,24; N 3,47; S OF 7.95

Found, %: C 65,46; N 7,34; N 3,21; S 8,00.

b) Methyl ether /4S/4/R*/, 7, 10a//- octahydro-4-//2-//acetylthio/methyl/-1-oxo - 3-phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

Mixed suspension ephedrinebuy salt from part (a), (333,1 g, 0,822 mmole) in ethyl acetate (5 ml) was washed three times with portions of 5 ml of 1N hydrochloric acid. The organic extracts were combined, washed with brine, dried (magnesium sulfate), filtered, concentrated and dried in vacuum for 30 minutes. The resulting oil was dissolved in methylene chloride (2 ml) and stirred under nitrogen atmosphere at 0oC. To this solution was added a solution of methyl ester /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-p is Ried im Innkreis (6 ml), then triethyl (0,113 ml, 0,813 mmole) and, finally, benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (360,0 mg, 0,813 mmole). The reaction mixture was stirred at 0oC and allowed to slowly warm to room temperature. After 19 hours the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. Solution once washed with 5% solution of potassium bisulfate (20 ml), once with saturated sodium bicarbonate solution (20 ml) and once with brine. The organic layer was dried (magnesium sulfate), filtered and concentrated to a yellow foam. Clean flash chromatography (silica gel, 230 - 400 mesh when the nitrogen pressure of 0.7 - 1.4 kg/cm2) with elution with a mixture of 4:3 ethyl acetate/hexane gave 303 mg of product as a clear oil.

c) /4S/4/R*/, 7, 10a//- Octahydro-4//2/mercaptomethyl/-1-oxo-3-phenylpropyl/amino/-5-oxo - 7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (b), (303,1 mg, 0,635 mmole) in methanol (6.5 ml, obeskislorozhennuju propulsiveness nitrogen) was cooled to 0oC and was treated with 1N solution of sodium hydroxide (6.5 ml, obeskislorozhennuju propulsiveness nitrogen). After stirring for 1 hour at 0oC with continuous purging with nitrogen, the reaction mixture is of Ulfat and potassium were extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried /sodium sulfate/, filtered and concentrated in vacuum, getting 219 mg specified in the title product as white solids; so pl. 200oC (decomposition). TLC (6: 0,01: 3,99 ethyl acetate/acetic acid/hexane) Rf= 0,15.

HPL C: tR=26,3 minutes impurities in 27,0 minutes; YMC. S-3 ODS (C-18) 6,0 150 mm 0% to 100% B:A 30 min. linear gradient and 10 min. siderian. 1.5 ml/min; A = 90% water:methanol + 0.2% of phosphoric acid, B = 90% methanol:water + 0.2% of phosphoric acid; 220 nm.

Data analysis for C20H26O4N2S20,11 C4H8O20,07 CH2Cl2:

Calculated, %: C 56,22; N 6,21; N 6,39; S 14,63

Found, %: 56,46; N 6,28; N Of 6.31; S 14,59.

Example 13

/4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-4-methyl-1-oxobutyl/amino/-5 - oxo-7H-pyrido[2,1-b]/1,3/-thiazepine-7-carboxylic acid

a) /R/-2-Bromo-4-methylpentanoic acid

The potassium bromide (9.5 g, 80 mmole) was added to a stirred solution of D-leucine (3.0 g, 23 mmole) in 2.5 N sulfuric acid (47 ml) at room temperature. The reaction mixture was cooled to -10oC and solid sodium nitrite (2.4 g, 34 mmole) was added in portions, keeping the temperature between -10oand -5oC. After URY and stirred another hour. Then the reaction mixture was twice extracted with ether, the ether extracts washed once with water, dried with magnesium sulfate, filtered and evaporated, obtaining 2.7 g of the crude product indicated in the title.

b) Dicyclohexylamine salt /S/-2-/acetylthio/-4-/methylpentanoic acid

To stir the slurry of thioacetate potassium (1.7 g, 15,0 mmole) in 50 ml of dry acetonitrile at room temperature in an argon atmosphere was added a solution of the product from part (a) (2.6 g, 13 mmole) in 17 ml of acetonitrile. The reaction mixture was stirred for 4 hours. The resulting slurry was filtered and evaporated. The residue was re-dissolved in ethyl ether, washed once with a 5% solution of potassium bisulfate and once with brine, dried (magnesium sulfate) and evaporated. The residue was dissolved in ether (64 ml) and treated with dicyclohexylamine (2.7 ml, 14 mmole). Immediately began the precipitation of white solids from the solution. The solution was filtered and the collected white solid, obtaining 2.0 g specified in the product name, so pl. 153 - 158oC; []D= -54,5o(c = 0,61, chloroform).

c) Methyl ether /4S/4/R*/, 7, 10a//- octahydro-//2-acetylthio/-4-methyl-1-oxobutyl/amino/-5-oxo-7H - pyrido[2,1-b]/1,3/diazepin-7-karbonovy times in portions of 5 ml of 5% solution of potassium bisulfate. The organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, concentrated and dried in vacuum for 30 minutes. The oil obtained (179,4 mg, 0,943 mmole) was dissolved in methylene chloride (2 ml) and stirred under nitrogen atmosphere at 0oC. To this solution was added a solution of methyl ester /4S/4, 7, 10a/// octahydro-4-amino-5-oxo-7H - pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid (232,0 mg, 0,898 mmole, obtained as described in example (c)) in methylene chloride (6 ml), then triethylamine (0,131 ml, 0,943 mmole) and, finally, benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (417,1 mg 0,943 mmole). The reaction mixture was stirred at 0oC for 1 hour and 3.5 hours at room temperature. Through the full 4.5 hours the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed once with a 5% solution of potassium bisulfate (20 ml), once with saturated sodium bicarbonate solution (20 ml) and once with brine. The organic layer was dried (magnesium sulfate), filtered and concentrated to a yellow foam. Clean flash chromatography (silica gel 230 - 400 mesh, 0.7 to 1.4 kg/cm2the nitrogen pressure) with elution 2: 3 mixture of ethyl acetate: hexane gave 209,4 mg specified in the name PAMINO/-5 - oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (c) (209,4 mg, 0,486 mmole) in methanol (5 ml, obeskislorozhennuju propulsiveness nitrogen) was cooled to 0oC and was treated with 1N solution of sodium hydroxide (5 ml, obeskislorozhennuju propulsiveness nitrogen).

After stirring for 1 hour at 0oC with a continuous purge of nitrogen, the reaction mixture was heated to room temperature. Through the full 2.5 hours, the reaction mixture was acidified to pH 1 with 5% solution of potassium bisulfate and extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried (sodium sulfate), filtered and concentrated in vacuum. Clean flash chromatography (silica gel, 230 - 400 mesh, at nitrogen pressure of 0.7 - 1.4 kg/cm2) and elution with passing nitrogen mix 6:0,01: 3,99 ethyl acetate/acetic acid/hexane gave 142,0 mg specified in the title product as a white solid. TLC (6:0,1:3.9 ethyl acetate/acetic acid/hexane) Rf=0,20 []D= (c=0,43, chloroform).

HPLC: tR= 26,7 minutes ; YMC S-3ODS (C-18) 6,0150 mm; 0% to 100% B:A 30 min. linear gradient and 10 minutes videris. 1.5 ml/min, A=90% water:methanol+0.2% of phosphoric acid, B=90% methanol:water+0.2% of phosphoric acid; 220 nm.

Data analysis for C16H26O4N Found, %: C 50,57; N 7,20; N 6,83; S 14,75.

Example 14

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxobutyl/amino/-5-oxopyrrolo[2,1-b]/ 1,3/diazepin-7-carboxylic acid

a) /R/-2-Bromotova acid

Bromide of potassium (a 7.85 g, 65,94 mmole) was added to a solution of /R/-2-aminobutanoic acid (2.0 g, 19,40 mmole) in 2.5 N sulfuric acid (25 ml) and cooled to 0oC. sodium Nitrite (to 2.06 g, 29,87 mmole) was slowly added in several portions. The temperature was kept at least below 2oC during this process of adding. The reaction mixture was stirred at 0oC for 1 hour and at room temperature for 16 hours, then was extracted with 3 portions of 50 ml of ethyl acetate. United an ethyl acetate layers were washed with 2 portions of 50 ml of water and one portion of 50 ml of brine, dried (magnesium sulfate) and concentrated in vacuum, obtaining 2.86 g specified in the product name in the form of crude oil.

b) Dicyclohexylamine salt /S/-2-/acetylthio/butane acid

To the slurry 2.14 g (18,77 mmole) of thioacetate potassium in 15 ml of acetonitrile, stirred at room temperature, was added dropwise over 15 minutes a solution of /R/-2-bromoethanol acid (2.83 g, 17,07 mmole) in 15 ml of acetonitrile. The reaction mixture is TRANS and the oil obtained was dissolved in 30 ml of ethyl ether. The ether layer was washed with 2 portions of 20 ml of 5% solution of potassium bisulfate, 2 20 ml of water, 2 portions of 20 ml of brine, dried (magnesium sulphate) and filtered. To the filtrate was added 3.4 ml (17,07 mmole) of dicyclohexylamine. After stirring at room temperature for 2 hours the slurry was filtered, getting 1.24 g dicyclohexylamine salt product. The second portion dicyclohexylamine salt product 724 mg was obtained from the filtrate.

c) Methyl ether /4S/4/R*/, 7, 9a//-octahydro-4-//2-/acetylthio/-1-oxobutyl/amino/-5-oxopyrrolo[2,1-b] 1,3/diazepin-7-carboxylic acid

Dicyclohexylamine salt product from part (b) (227 mg, of 0.66 mmole) was dissolved in 15 ml ethyl acetate and washed three times with 10 ml of the potassium bisulfate, one portion of 10 ml of brine, dried (magnesium sulfate) and concentrated in vacuo getting 108 mg /S/-2-/acetylthio/butane acid in the form of a clear oil.

To a solution of this free acid (108 mg, of 0.66 mmole) in 5 ml of dry methylene chloride, cooled to 0oC, was added triethylamine (90 μl, of 0.66 mmole) followed by the addition of salt methyl ether /4S/4, 7, 9a//- 4-amino-octahydro-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluensulfonate acid (250 mg, 0,66 the ing the mixture was stirred at 0oC for 20 minutes, then in one portion was added benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (292 mg, of 0.66 mmole). The reaction mixture was stirred at 0oC for 1 hour left in the fridge for 56 hours, then stirred at room temperature for 3 hours. Then the reaction mixture was concentrated in vacuo, re-dissolved in 30 ml ethyl acetate and washed with 20 ml of 5% solution of potassium bisulfate, 20 ml saturated sodium bicarbonate solution, 20 ml of brine, dried (magnesium sulfate) and concentrated in vacuum, obtaining the crude oil. Crude oil flush was chromatographically (Merck silica gel, 25100 mm, 2:3 ethyl acetate/hexane, getting 208 mg specified in the title product as a white foam.

d) /4S/4/R*/, 7, 9a//- octahydro-4-//2-mercapto-1-oxobutyl/amino/-5-oxopyrrolo[2,1-b]/1.3 diazepin-7-carboxylic acid

A solution of the product from part (c) (225 mg, 0,559 mmole) in methanol (5 ml) was purged with argon for 30 minutes and was cooled to 0oC. To this solution was added dropwise 5 ml of a 1 M solution of sodium hydroxide, was also purged with argon for 30 minutes and was cooled to 0oC. the Reaction mixture was stirred at 0oC for 3 hours with continuous blowdown arg is an ethyl acetate and the combined layers were dried (magnesium sulfate) and concentrated in vacuum, receiving untreated foam. The crude product is flash-chromatographical (Merck silica gel, 25180 mm, 3% acetic acid/ethyl acetate) to give a white foam which was dissolved in methylene chloride and triturated with hexane, getting 176 mg specified in the product name in the form of a compact white foam, []D= -125,4o(c=1.0, chloroform). TLC (methanol/methylene chloride 1:9) Rf=0,16.

HPLC:tR=15,5 min (97% full size, UV 220 nm); line 25 min gradient (A= 90% water/methanol+0.2% of phosphoric acid) B=90% methanol/water+0.2% of phosphoric acid; flow rate 1.5 ml/min

Data analysis for C13H20N2S2O40,8 H2O 0,2 C6H140,1 CH2Cl2: Calculated, %: C 46,10; N 6,66; N 7,52; S 17,21

Found, %: C 46,00; N 6,17; N 7,52; S 16,82.

Example 15

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxobutyl/amino-5-oxopyrrolo [2,1-b]/1,3/diazepin-7-carboxylic acid

a) /R/-2-Bromopentanoate acid

Following the procedure of example 14 (a), but using D-Norvaline instead of /R/-2-aminobutanoic acid, obtained /R/-2-bromopentanoate acid in the form of a transparent liquid.

b) Dicyclohexylamine salt /S/-2-acetylthio/pentanol acid

Interaction /R/-2-bromopentanoate acid with TIA the EPA 14 (b) received dicyclohexylamine salt /S/-2-/acetylthio/pentanol acid in the form of a solid substance.

c) Methyl ether /4S/4/R*/, 7, 9a//- octahydro-4-//2-acetylthio/-1-oxobutyl/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

The interaction of the free acid dicyclohexylamine salt from part (b) with methyl ether /4S/4, 7, 9a//- -4-amino-octahydro-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid according to the procedure of example 14 (c) were specified in the title product as a white foam.

d) /4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxobutyl/amino-5 - oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (c) in methanol was treated with 1 M solution of sodium hydroxide according to the procedure of example 14 (d), getting listed in title product in the form of compact white foam; []D= -122,8o(c=1,0, CDCl3). TLC (methanol/methylene chloride, 1:9), Rf=0,15.

HPLC: tr=20,5 min; (97% of the total area, UV 220 nm), YMC S-3ODS (C-18, 120 A) 6150 mm; 0% B:A = 100% B:A, line 25 min gradient (A=90% water:methanol+0.2% of phosphoric acid); (B=90% methanol:water+0.2% of phosphoric acid; flow rate=1.5 ml/min

Data analysis for C14H22N2S2O40,65 H2O 0,20 C6H14:

Calculated, %: 48,63; N 7,01; N 7,46; S 17,08

Found, %: C 48,86; N 6,70; N 7,24; S 16,74.

Bespin-7-carboxylic acid

a//R, 2-Bromo-4,4-dimethylpentane acid

A solution of /R/-2-amino-4,4-dimethylpentane acid (950 mg, 6,55 mmole) in 2.5 N sulfuric acid (13 ml, 33 mmole) was cooled to -5oC and treated with potassium bromide (2,72 g, 22.9 mmole) in one portion. The colorless solution was treated with sodium nitrite (680 mg, 9,86 mmole) in portions, keeping the temperature between 0 and 3oC for 25 minutes. The reaction mixture was stirred at 0oC for one hour and at room temperature for 1.5 hours. The reaction mixture was poured into water (10 ml). The product was extracted with ether (60 ml), washed with water (20 ml) and brine (20 ml), dried (magnesium sulfate) and concentrated in vacuo, getting listed in title product as a colourless liquid.

b) /S/-2-Acetylthio/-4,4-dimethylpentane acid

The slurry of thioacetate potassium (750 mg, to 6.58 mmole) and acetonitrile (10 ml, dried over molecular sieves) was cooled to 0oC and treated with a solution of /R/-2-bromo-4,4-dimethylpentane acid from part (a) acetonitrile (2 ml) for 5 minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 2.5 hours. The slurry was filtered. The filtrate was concentrated in vacuum. The residue was diluted with ether (50 mg) and concentrated in vacuum. Pale yellow oil was clean flash chromatography (Merck silica gel, 123 cm, 10% methanol/methylene chloride) to give 575 mg specified in the name of the product as a pale yellow oil.

C) Methyl ether /4S/4/R*/, 7, 9a//- octahydro-4-//2-acetylthio/-4,4-dimethyl-1 - oxobutyl/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

A clear solution of the product from part (b) (148 mg, 0.72 mmole) in methylene chloride (5 ml, dispersed over calcium hydride) was cooled to 0oC and treated with a solution of salt of methyl ether /4S/4, 7, 9a//- -4-amino-octahydro-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluensulfonate acid (250.0 mg, 0.60 mmole, obtained from the substance described in example 5 (d)) in methylene chloride (3 ml, dispersed over calcium hydride), triethylamine (122 mg, 1.2 mmole), with the subsequent processing of benzotriazol-1-yloxytris/dimethylamine/phosphodiesterases (319 ml, 0.72 mmole). The reaction mixture was stirred at 0oC for 24 hours and at room temperature for 5 hours. The crude reaction mixture was concentrated in vacuum. The residue was diluted with ethyl acetate (50 ml), washed with 5% aqueous solution of potassium bisulfate (50 ml), 50% saturated aqueous sodium bicarbonate (50 ml) and RA is Ali (Merck, silica gel 20 g, ethyl acetate) to give 244 mg specified in the title product as a white foam.

d) /4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-4,4-dimethyl-1-oxobutyl/amino/-5 - oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid

A clear solution of the product from part (c) (240 mg, of 0.56 mmole) in methanol (2 ml, purged with nitrogen) was cooled to 0oC and treated dropwise 1 N sodium hydroxide solution of 2.27 ml, of 2.24 mmole, purged with argon) with continuous bubbling at 0oC. the Mixture was allowed to mix for 3 hours at 0oC and at room temperature for 3 hours. The mixture was acidified to pH 15% aqueous solution of potassium bisulfate (barbotirovany argon). The product was extracted with methylene chloride (50 ml, was barbotirovany nitrogen), washed with brine, dried (sodium sulfate) and concentrated in vacuum. The crude product is recrystallized from a mixture of methylene chloride/hexane, receiving 75 mg specified in the title product as white solids; so pl. 124 - 126oC; []D= -175oC (c=0.25, methanol). TLC (acetic acid/methanol/methylene chloride 1:5:94) Rf= 0,65.

HPLC: tR(YMC S-3 ODS (C-18) 6,0150 mm; 1.5 ml/min: linear gradient 0 to 100% B over 30 min, Buffer A = methanol/water/fo CLASS="ptx2">

Data analysis for C16H26N2O4S20,13 C6H14:

Calculated, %: 52,24; N 7,28; N 7,26; S 16,62

Found, %: C 51,97; N 7,26; N 7,09; S 16,23.

Example 17.

/4S/4/R*/, 7, 9a//- Octahydro-4-//2-mercapto-1-oxopropyl/amino/-5-oxopyrrolo[2,1-b]/1,3/ diazepin-7-carboxylic acid

a) /R-2-Bromopropane acid

Following the procedure of example 14 (a), but using D-alanine instead of /R/-aminobutanoic acid, obtained /R/-bromopropane acid as a pale yellow oil.

b) /S/-2-/Acetylthio/propanoic acid

To light green solution thioacetate potassium (3.94 g, 34.5 mmole) in acetonitrile (150 ml) was added a solution of /R/-2-bromopropane acid (4.8 g, 31 mmole) in acetonitrile (12 ml) at room temperature in argon atmosphere. The obtained white slurry was stirred at room temperature for 2 hours, then filtered. The filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate (100 ml), washed with 10% aqueous solution of potassium bisulfate (50 ml) and brine, dried (sodium sulfate) and concentrated in vacuum. The crude product (4.61 in), clean flash chromatography (60 g of Merck silica gel, 1: 45:54 acetic acid/ acetate/hexane/ receiving 3.7 g of the specified name */, 7, 9a//- octahydro-4-//2-acetylthio/-1-oxopropyl/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

A clear solution /S/-2-/acetylthio/propanoic acid (86 mg, of 0.58 mmole) in methylene chloride (5 ml, dispersed over calcium hydride) was cooled to 0oC and treated with a solution of salt of methyl ether /4S/4, 7, 9a//- 4-aminooctane-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluensulfonate acid (200.0 mg, 0.48 mmole, obtained from the substance described in example 5 (d)) in methylene chloride (5 ml, dispersed over calcium hydride), triethylamine (98 mg, 0.97 mmole), with the subsequent processing of benzotriazol-1-yloxytris/dimethylamine/fotoricettore.htm (255 mg, of 0.58 mmole). The reaction mixture was stirred at 0oC for 22 hours and at room temperature for 2 hours. The crude reaction mixture was concentrated in vacuum. The residue was diluted with ethyl acetate (100 ml), washed with 5% aqueous solution of potassium bisulfate (30 ml), 50% saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuum. The crude product was purified flash chromatographytandem (40 g, Merck silica gel, ethyl acetate) to give 180 mg specified in the title product as a white solid fuel is 5 - oxopyrrolo [2,1-b]/1,3/diazepin-7-carboxylic acid

A clear solution of the product from part (c) (180 mg, 0.48 mmole) in methanol (2 ml) in an argon atmosphere was cooled to -10oC and was treated dropwise with bubbling argon 1 N solution of sodium hydroxide (1,95 ml of 1.95 mmole), keeping the temperature below 0oC. the Mixture was allowed to mix with bubbling argon at 0oC for 3 hours. The mixture was acidified to pH 1 with 5% aqueous solution of potassium bisulfate in an argon atmosphere. The product was extracted by ethyl acetate with bubbling of nitrogen (100 ml), washed with brine, dried (sodium sulfate) and concentrated in vacuum. The crude product was cleaning the flash chromatographytandem (40 g, Merck silica gel, 1:5:94 acetic acid/methanol/methylene chloride) to give 154 mg specified in the title product as a white solid, so pl. 150 - 152oC []D= 156o(c = 0,50, methanol). TLC (1:5;94 acetic acid/methanol/methylene chloride) Rf= 0,28.

HPL C: tR(YMC S - 3 ODS (C-18) 6,0150 mm; 1.5 ml/min, linear gradient 0 to 100 % B over 30 minutes. Buffer A = methanol/water/phosphoric acid (10: 90: 0,2), Buffer B = methanol/water/phosphoric acid (90:10:0,2) = 14,69 min, more than 95% of the total peak area at 254 nm.

Data analysis for C12H18N2O4S20,75 CH3
/4S/4/R*/, 7, 9a//- Octahydro-4-/3-cyclopropyl-2-mercapto-1-oxopropyl/amino/- 5-oxopyrrolo[2,1-b]/1,3/-thiazepine-7-carboxylic acid

a) /R/-2-///Phenylmethoxy/carbonyl/amino/-4-pentane acid

A mixture of D-allylglycine (2.8 g, a 24.3 mmole), 1 M aqueous solution of sodium hydroxide (25 ml) and tetrahydrofuran (10 ml, distilled from life) was stirred at room temperature to obtain a homogeneous solution, then cooled in a bath of ice. To the resulting byistroprodavaemoy solution was added about 5 ml of 1.0 M aqueous solution of sodium hydroxide, is then added dropwise to about 1 g benzylchloride. This operation is repeated a further 4 times up until it was added the total amount of 28 ml of 1.0 M aqueous solution of sodium hydroxide and 4,80 g (95%, 27 mmole) of benzylchloride. The reaction mixture was stirred for 15 minutes at 0oC, then for 30 minutes at room temperature and then was extracted with 50 ml of ether. The aqueous layer was acidified (pH 1.5) adding 6 N hydrochloric acid (about 10 ml), then was extracted with 3 portions of 50 ml of ether. Three ether extracts were combined, dried (magnesium sulfate) and concentrated in vacuum, obtaining 6,01 g mentioned in the title product as a colourless oil.

b) Fenilmetilovy is astory of the product from part (a) (5,96 g, 23.9 mmole) in anhydrous dimethylformamide (25 ml) at room temperature. The reaction mixture was stirred for 20 minutes, then quickly added benzylbromide (4.5 g, to 26.3 mmole, slightly exothermic). The mixture was stirred for 30 minutes, then was divided between 100 ml of water and 100 ml of ether. The organic layer was separated, washed with three portions of 100 ml of water, 50 ml brine, dried (magnesium sulfate) and concentrated in vacuo to obtain an oil. The crude substance was cleaning the flash chromatographytandem (Merck silica gel, 245,0 cm, 1:10 ethyl acetate: hexane, then 1:4 ethyl acetate/hexane) to give 6,13 g mentioned in the title product as a colourless oil.

c) Fenilmetilovy ether /R/ -- ///phenylmethoxy/carbonyl/amino/ cyclopropanemethanol acid

Palladium acetate (II) (65 mg, 0,29 mmole) was added to a solution of the product from part (b) (5,78 g, 17.1 mmole) in anhydrous ether (60 ml) and was stirred for 10 minutes. The resulting mixture was cooled to 0oC, was added excess ethereal diazomethane (obtained from 12 g of N-methyl-N'-nitro-II-nitrosoguanidine (120 ml ether) in portions over 15 minutes. The reaction mixture was stirred for 15 minutes, then snuffed out by adding 1 ml of glacial acetic acid. The solution was transferred into deleteln the magnesium) and concentrated in vacuum, getting a yellow oil. The crude substance was cleaning the flash chromatographytandem (Merck silica gel, 205,0 cm, 1:4 ethyl acetate/hexane), receiving a grade of 5.74 g mentioned in the title product as a colourless oil.

d) /R/ -- Amino/cyclopropanecarbonyl acid

The catalyst is palladium on coal (10%, 1,14 g) was added to a solution of the product from part (c) (5,71 g, 16.2 mmole) in methanol (75 ml) and was stirred in hydrogen atmosphere (balloon) at room temperature for 48 hours. The reaction mixture was filtered to remove the catalyst and the catalyst was washed with warm water. Then, the filtrate was passed through a polycarbonate membrane filter of 0.5 μm. The filtrate was concentrated in vacuum, obtaining 2,03 g mentioned in the title product as a white solid.

e) /S/ -- /Acetylthio/cyclopropanecarbonyl acid

A mixture of the product from part (d) (2.00 g, a 15.5 mmole) in 2.5 N aqueous solution of sulfuric acid (30 ml) was stirred at room temperature to obtain a homogeneous solution and then cooled to -5oC. To this solution portions were added potassium bromide (6.50 g, 54,6 mmole). The mixture was stirred to obtain a homogeneous solution. Then in small portions was added sodium nitrite (1.60 g, 23,2 mmole) for 25 minutes and at 0oC, then at room temperature for 1.5 hours. The resulting mixture was diluted with 30 ml water and was extracted with three portions of 30 ml of ether. The combined ether extracts were washed with 25 ml of brine, dried (magnesium sulfate) and concentrated in vacuum, obtaining 2,82 g crude /R/--bromine/cyclopropanemethanol acid in the form of a pale yellow oil.

The solution of this crude /R/-- bromine/cyclopropanemethanol acid in acetonitrile (10 ml) was added within 5 minutes to mix the slurry of thioacetate potassium (1,83 g, 16,1 mmole) in acetonitrile (20 ml) under cooling in a bath of ice. The reaction mixture was stirred at 0oC for 1 hour, then at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuum, obtaining oil. The oil was divided between 50 ml of ether and 50 ml of 5% aqueous sodium thiosulfate solution. The organic layer was separated, washed with 25 ml of brine, dried (magnesium sulfate) and concentrated in vacuo to obtain a yellow oil. The crude substance was cleaning the flash chromatographytandem (Merck silica gel, 125,0 cm 1:19 methanol/methylene chloride) to give 1.52 g mentioned in the title product as a yellow oil.

f) Methyl ether /4S/4/R*
Benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (292 mg, of 0.66 mmole) was added in one portion to a mixture of salts of methyl ester /4S/4, 7, 9a//- octahydro-4-amino-5-oxopyrrolo [2,1 - b] /1,3/diazepin-7-carboxylic acid and n-toluensulfonate acid (250 mg, 0.60 mmole, obtained from the substance described in example 5 (d)) in methylene chloride (3 ml, dispersed over calcium hydride), triethylamine (121 mg, 1.20 mmole) and the product from part (e) (122 mg, 0.65 mmole) in methylene chloride (3 ml, dispersed over calcium hydride). The reaction mixture was stirred at 0oC for 1 hour, then at room temperature for 1.5 hours. The resulting mixture was divided between 20 ml ethyl acetate and 20 ml of 1 M aqueous solution of potassium bisulfate. The organic layer was separated, washed with 20 ml of 5% aqueous sodium bicarbonate solution, 20 ml of brine, dried (magnesium sulfate) and concentrated in vacuum, obtaining oil. The crude substance was cleaning the flash chromatographytandem (Merck silica gel, 123,0 cm, 1:1 ethyl acetate/hexane) to give 191 mg specified in the title product as a solid white foam.

g) /4S/4/R*/, 7, 9a//- Octahydro-4-//3-cyclo-propyl-2-mercapto-1-oxopropyl/ amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

The solution productsale 1 M aqueous solution of sodium hydroxide (3 ml, siebenbuergen with argon for 10 minutes). The reaction mixture was stirred for 2.5 hours at room temperature with continuous bubbling with argon, then was acidified by adding 20 ml of 1 M solution of potassium bisulfate and extracted with 20 ml ethyl acetate. The organic extract was washed with 20 ml of brine, dried (sodium sulfate) and concentrated in vacuo, collecting the resin. The resin was washed with anhydrous ether, then concentrated in vacuo, getting 121 mg specified in the title product as a white foam; []D= -103o(=to 0.23, methanol). TLC (1:10:90, acetic acid/methanol/methylene chloride) Rf= 0,46.

HPLC: tR(YMC S-3 ODS 6,0 150 mm, 1.5 ml/min linear gradient 0-100% B over 30 min, Buffer A = methanol/water/phosphoric acid (10:90:0,2), Buffer B = methanol/water/phosphoric acid (90:10:0,2) = 20.7 minutes more than 97% of the total peak area at 254 nm).

Data analysis for C15H22N2O4S20,20 H2O:

Calculated, %: 49,77; N 6,23; N 7,74; S 17,71

Found, %: C Repossessed A 50.01; H 6,27; N 7,50; S 17,40.

Example 19

/4S/4, 7, 9a//- Octahydro-4-///1-mercaptonicotinic/carbonyl/amino/-5 - oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

a) 1-Mercaptotetrazole acid

The solution is the Ksan, of 15.4 ml of 38.5 mmole) in tetrahydrofuran (17.6 ml), maintaining the temperature between -3oC and 0oC. After stirring for 15 minutes was added cyclopentanecarbonyl acid (2.0 g, 17.5 per mmole) in tetrahydrofuran (2 ml) at 0 to 3oC for 25 minutes. After the reaction for 15 minutes at 0oC bath was removed and the reaction was stirred 15 minutes, causing a temperature rise to 15oC. a Milky-white solution was cooled to -78oC and added sulfur in the form of a solid substance (S8, 618,0 mg, and 19.3 mmole), maintaining the temperature at -78oC. the Reaction mixture was allowed to warm to room temperature in situ. After 70 hours, the reaction mixture was cooled to 0oC, extinguished with water (pH 8-9) and quickly acidified to pH 1 6 N hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 30 ml), washed with brine, dried (magnesium sulfate), filtered and concentrated, obtaining 2,62 g mentioned in the title product as a yellow oil.

b) 1-/Acetylthio/cyclopentanecarbonyl acid

To a solution of the product from part (a) (1.44 g, 9,89 mmole) in barotrauma nitrogen 1N solution of sodium hydroxide (20 ml, 19.7 mmole) at 0oC was added acetic anhydride (0,93 ml, 9,89 mmole). Added tetrahydrofuran (13 ml) > (pH 7), the reaction mixture was heated to room temperature and added additional acetic anhydride (0,47 ml, 4.9 mmole) and potassium carbonate (2,04 g of 14.8 mmole) to pH 10 and tetrahydrofuran (4 ml). After stirring over night at room temperature the reaction mixture was acidified to pH 1 1 N hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate extracts were combined, washed with brine, dried /magnesium sulfate/, filtered and concentrated in vacuum, obtaining a yellow solid (1,61 g). The solid is recrystallized twice from a mixture of ethyl acetate/hexane, getting 614 mg specified in the name of the product as a light brown substance, so pl. 119 - 121, 5oC.

c) Methyl ether /4S/4, 7, 9a//- octahydro-4-//acetylthio/cyclopentyl/carbonyl/amino-5-/oxopyrrolo [2,1-b] /1,3/diazepin-7-carboxylic acid

To a solution of the product from part (b) (94,5, 0,502 mmole) in methylene chloride (3.6 ml) at 0oC in an atmosphere of nitrogen was added triethylamine (70 μl, 0,502 mmole) followed by the addition of salt methyl ether /4S/4, 7, 9a//- 4-amino-octahydro-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluensulfonate acid derived from a substance described in example 5 (d), 198 mg, 0,478 mmole/ in one piece, Then added benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (222,0 mg, 0,502 mmole) as a solid. The reaction was stirred at 0oC for 1 hour and then at room temperature for 2.25 hours. The reaction mixture was concentrated in vacuo and the residue was separated between ethyl acetate and 5% aqueous solution of potassium bisulfate (20 ml). The organic layer was washed polysystem with sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered and concentrated to a clear oil. Clean flash chromatographytandem, elution with a mixture of 11:9 ethyl acetate:hexane gave 169,3 mg specified in the name of the product as a clear oil.

d) /4S/4, 7, 9a//- Octahydro-4-//1-mercaptonicotinic/carbonyl/amino/-5 - oxopyrrolo[2,1-b]/1,3/diazepin-7-carboxylic acid.

A solution of the product from part (c) (167,3 mg, 0,404 mmole) in methanol (4 ml, obeskislorozhennuju propulsiveness nitrogen) was cooled to 0oC and treated with 1 N sodium hydroxide solution (4 ml, obeskislorozhennuju propulsiveness nitrogen). After stirring for 1.5 hours at 0oC and continuous aeration with nitrogen the reaction was heated to room temperature. After three hours the reaction mixture was acidified to pH 1 with 5% solution of potassium bisulfate and extracted with ethylacetate. The organic layers about the re-evaporated from hexane, getting a white solid. The compound was dissolved in dioxane (anhydrous) and liofilizovane, receiving 110 mg specified in the title product as a white solid; []D= - 106,5o(C = 0,68, chloroform). TLC (7:2,9:0.1, ethyl acetate/hexane/acetic acid) Rf= 0,12.

HPLC : tR= 21,5 minutes; YMC S - 3 ODS (C-18) 6,0 150 mm; O - 100% B:A 30 minute linear gradient and 10 minutes of exposure, 1.5 ml/min, A = 90% water/10% methanol + 0.2% of phosphoric acid, B = 90% methanol/10% water + 0.2% of phosphoric acid; 220 nm.

Data analysis for C15H22N2O4S20,15 C4H8O20,7 H2O 0,08 C6H14: Calculated, %: 49,37; N 6,63; N 7,16; S 16,39

Found, %: C 49,03; N 6,37; N 7,21; S 16,65.

Example 20

/4S/4, 7, 10a//- -4-//2-Carboxyl-1-oxo-3-phenylpropyl/amino/octahydro-5 - oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid.

a) Monotropy ether 3-/phenylmethyl/papandonatos acid

Diethyl ether 3-/phenylmethyl/propandiol acid (2.5 g, 10 mmol) in 10 ml of tetrahydrofuran was stirred overnight with 10 ml of 1 N solution of lithium hydroxide. The reaction mixture was acidified 11 ml of 1 N hydrochloric acid and was extracted with two portions of 50 ml of ethyl acetate. An ethyl acetate extracts were washed with brine, with whom (80 g), using 5% methanol:chloroform. The appropriate fractions were combined, concentrated, receiving 1,23 g specified in the product name.

b) Methyl ether /4S/4, 7, 10a//- -4-//2-/etoxycarbonyl/-1-oxo-3-phenylpropyl/amino/octahydro - 5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

The product from part (a) (0,222 g, 1 mmol) and methyl ether /4S/4, 7, 10a//- octahydro-4-amino-4-amino-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid (0,258 g, 1 mol, obtained as described in example 3 (c)) was dissolved in methylene chloride (5 ml) and cooled to 0oC. was Added triethylamine (of 0.14 ml, 1 mmol) and the reaction mixture was stirred for 1 hour. Added benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (0,442 g, 1 mmol) and the solution was stirred at 0oC for 1 hour and at room temperature for 2.5 hours. The reaction mixture was diluted with 50 ml of methylene chloride and washed with water, 10% solution of sodium bisulfate, saturated aqueous sodium bicarbonate, dried (sodium sulfate), filtered and concentrated in vacuum. The residue was chromatographically on silica gel using 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated in vacuum, obtaining 0,22 g stated in on the,3/diazepin-7-carboxylic acid

The product from part (b) (0,22 g, 0,476 mmole) was stirred with 1 N solution of lithium hydroxide (5 ml) in tetrahydrofuran (5 ml) at room temperature for 3 hours. The reaction mixture was acidified to pH 2 1 N hydrochloric acid and concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with water, brine, dried (sodium sulfate) and concentrated in vacuo to 3 ml, to a state in which the product crystallized. After a stay at 0oC overnight, the solid was filtered and dried, obtaining 0.16 g specified in the product name in the form of a white solid, so pl. 159 - 162oC; 84,92o(C = 0,7, methanol) TLC/chloroform:methanol, 9:1/Rf= 0,23; 0,28.

HPLC : tR= 16,15, 16,35 minutes; (UV 254 nm); YMC S-3 ODS (C-18) 6,0150 mm, 3 micron column plugged the end, a linear gradient of 50 - 90% methanol containing 0.2% phosphoric acid, 20 min; 1.5 ml/min (44.9 percent, 55.1 per cent isomeric mixture).

Data analysis for C20H24N2SO60,1 H2O:

Calculated, %: 56,89; N 5,78; N 6,66; S TO 7.59

Found, %: C 56,98; N. Of 5.68; N To 6.58; S 7,15.

Example 21.

/4S/4,R*7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-/1,4/oxazino [3,4-b]/1,3/-thiazepine-7-carboxylic acid

a) Methyl affililates/dimethylallyl/-N-//phenylmethoxy/carbonyl/-L-gamesell/ -O-/2.2-dimethoxymethyl/-L-serine /5,56 g, 10 mmole, obtained as described in example 10 (h)/ methanol (65 ml) was cooled to 0oC (ice bath with salt) were treated with monohydrate p-toluene-sulfonic acid (386 mg, 2.0 mmole) and stirred at 0oC for 1.5 hours. The reaction was suppressed by sodium bicarbonate solution (198 mg, 20 ml of water) was stirred for 5 minutes, then evaporated to remove methanol. The aqueous phase was extracted with ethyl acetate (2200 ml) and the combined organic extract was washed with water (110 ml), 5% sodium bicarbonate solution (80 ml) and brine (80 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude product was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate:hexane (2:1) and a mixture of ethyl acetate:methanol (98:2), receiving 3,975 g specified in the product name in the form of syrup. TLC (ethyl acetate:hexane, 4:1) Rf= 0,17.

b) Methyl ester 0 - /2.2-dimethylacetal/-N-/O-/methylsulphonyl/-N-//phenylmethoxy/carbonyl/-L - gamesell/-L-serine

A solution of the product from part (a) (3,975 g, 8,98 mmole) in dry methylene chloride (52 ml) was cooled to -15oC, was treated with triethylamine (is 1.82 ml, 13.1 mmole) and methanesulfonamide (of 0.82 ml, 10.6 mmole) and stirred at -15oC for 30 minutes. Rea is by ethyl acetate (750 ml). The organic phase is washed with 5% solution of potassium bisulfate (100 ml), 50% saturated brine (100 ml) and saturated brine (100 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum, obtaining 4.9g specified in the product name in the form of a waxy solid. TLC (ethyl acetate:hexane, 4:1) Rf= 0,32.

c) Methyl ester of N-/S-acetyl-N-//phenylmethoxy/-carbonyl/L-homocysteine/-O- /2.2-dimethoxymethyl/-L-serine

The cesium carbonate (5,56 g, 17,04 mmole) was added to a solution of teoksessa acid (2.6 ml) in dry methanol (40 ml) was stirred for 10 minutes, then evaporated to dryness. The obtained solid is triturated with acetone (78 ml) and the resulting sverbelo solid was dried in vacuum, obtaining 4,39 g cesium salt teoksessa acid.

A suspension of cesium salt teoksessa acid (2,43 g, 1.3 EQ.) in dry dimethylformamide (8.0 ml) was treated with a solution of the product from part (b) (4.9 g, 8,98 mmole) in dry dimethylformamide (24 ml) and was stirred for 16 hours at room temperature in argon atmosphere. The mixture was diluted with ethyl acetate (1.0 l), washed successively with 5% sodium bicarbonate solution (2150 ml), water (2150 ml) and brine (150 ml), dried (anhydrous sulfate is e with silica gel (Merck), elwira mixtures of ethyl acetate: hexane(1:1, 2:1), getting 3,93 g specified in the product name in the form of a waxy solid. TLC/ethyl acetate:hexane, 4: 1/Rf= 0,63.

d) Methyl ester O-/2.2-dimethoxymethyl/-N-/N-//phenylmethoxy/carbonyl-L-homocysteine/-L-serine

A solution of the product from part (c) (200 mg, of 0.49 mmole) in methanol (8.0 ml) was purged with argon for 30 minutes, cooled to 0oC (ice bath salt) and was treated with 25% solution of sodium methoxide in methanol (0,11 ml, 0.5 mmole), continuing prorokowanie argon in the process of adding and reaction. After 5 minutes at 0oC and the mixture was marked 25% solution of ammonium chloride (2.3 ml), and was divided between ethyl acetate (212 ml) and water (2.3 ml). The combined organic extracts were washed with 25% solution of ammonium chloride (4.6 ml) and brine (4.6 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum, obtaining 183,2 mg specified in the title product as a white solid. TLC (ethyl acetate:hexane, 4:1) Rf= 0,62.

e) /4S/4, 7, 10a//- Octahydro-5-oxo-4-///phenyl-methoxy/carbonyl/amino//1,4/oxazino [3,4-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (d) (150 mg, of 0.11 mmole) in dry methylene chloride (2.0 ml), quenching the temperature in an argon atmosphere, processed another resin Amberlite15 (13 mg) and stirred additionally for 3 days. The solution decantation and was chromatographically on a column of silica gel (Merck), elwira mixtures eilatin:hexane(1:3, 1:1), getting to 21.1 mg specified in the product name in the form of syrup. TLC/ethyl acetate:hexane, 4:1/Rf= 0,70

f) Methyl ether /4S/4, 7, 10a//- -octahydro-4-amino-5-oxo-/1.4/-oxazino [3,4-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (e) (421 mg, 1,01 mmole) in dry methylene chloride (25 ml) was treated with trimethylsilylimidazole (0,72 ml of 5.06 mmole) and stirred at room temperature in an argon atmosphere for 1.75 hours. The mixture is evaporated to dryness and the resulting syrup was divided between ethyl ether (50 ml) and 0.2 N hydrochloric acid (225 ml). The aqueous phase is brought to pH 10 with saturated sodium bicarbonate solution (25 ml) was treated with solid sodium chloride (2.0 g) and was extracted with methylene chloride (375 ml) to give 219 mg specified in the product name in the form of syrup. The second treatment of the aqueous phase sodium chloride (2.0 g) and re-extraction with methylene chloride (2100 ml) gave an additional 37 mg specified in the product name. TLC (methylene chloride:methanol, 9:1) Rf= 0,23.

(g) Methyl ether /4S/4, 7, 10a//- -SS="ptx2">

Dicyclohexylamine salt /S/-2-/acetylthio/benzene-propanoic acid (516 mg, 1,32 mmole, 1.2 EQ.) suspended in ethyl acetate (42 ml), washed with 5% solution of potassium bisulfate (56,0 ml) and brine (6.0 ml), dried (anhydrous magnesium sulfate), filtered, evaporated to dryness and dried in vacuum.

The free acid was dissolved in dry methylene chloride (9.5 ml), cooled to 0oC (ice bath salt) and treated sequentially with a solution of the product from part (f) (285,5 mg, 1.09 mmole) in dry methylene chloride (4,2 ml), triethylamine (0,14 ml, 1.15 mmole) and benzotriazol-1-yloxytris/-dimethylamine/phosphodiesterases (484 mg, 1.09 mmole). The reaction mixture was stirred at room temperature for 1 hour and at room temperature for a period of 2.0 hours in an argon atmosphere, and then drove to dryness. The residual syrup was dissolved in ethyl acetate (40 ml), washed with 0.5 N hydrochloric acid (2 of 6.6 ml), water (6.6 ml) and brine (6,6 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The crude product was chromatographically on a column of silica gel (Merck), elwira mixtures of ethyl acetate:hexane(1:2, 1:1), getting 382,9 mg specified in the product name in the form of syrup. TLC (ethyl acetate:hexane, 1:1) Rf= 0,28.azepin-7-carboxylic acid

A solution of the product from part (g) (382,9 mg of 0.82 mmole) in methanol (9.0 ml) was purged with argon for 30 minutes, cooled to 0oC (ice bath salt), then treated with 1.0 N sodium hydroxide solution (3,32 ml, 4.0 EQ., purged with argon for 30 minutes), continuing prorokowanie in the process of adding and during the reaction. The reaction mixture was stirred at 0oC for 5,0 hours and at room temperature for 1.0 hour, brought to PH 2.0 to 5% solution of potassium bisulfate (14,5 ml) was heated to room temperature and was extracted with ethyl acetate (250 ml). The combined organic extracts were washed with brine (10 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuum. The resulting syrup is evaporated twice from hexane (25 ml) and the resulting solid foam was chromatographically on a column of silica gel (Merck), elwira mixtures of toluene: acetic acid(100:1, 50:1, 20:1), getting 212 mg specified in the product name in the form of solids, I. pl. 224 - 226oC; []D= -50,2o(C = 0.45, and methanol). TLC (toluene: acetic acid 5:1) Rf= 0,28.

HPLC: tR= lower than the 5.37 min (UV 220 nm) (98.9 per cent); YMC S - 3 ODS (C-18) 6,0150 mm; 60% (10% water - 90% methanol - 2,0% phosphoric acid) (40% to 90% in the B>5S20,14 H2O:

Calculated, %: 52,34; N 5,44; N IS 6.78; S 15,53

Found, %: C 52,58; N To 5.57; N 6,44; S 15,16.

Example 22

/4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido [2,2-b]/1,3/-thiazepine-7-carboxylic acid

The product of examples 3 and 11 were awarded as follows:

a) salt of methyl ester /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluolsulfonic acid

Methyl ether /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid (6.11 g) was dissolved in ethyl acetate (about 100 ml) and treated with a solution of the monohydrate p-toluolsulfonic acid (4.52 g) in methanol (3 ml) and ethyl acetate (20 ml). Immediately precipitate formed. The mixture was further diluted with ethyl acetate and the solid collected by filtration. The solid is washed with ethyl ether and dried in vacuum, obtaining 7,908 g mentioned in the title product as a pale yellow solid with 98% purity; so pl. 179 - 181oC (decomposition).

b) Methyl ether /4S/4/R*/, 7, 10a//- octahydro-4-//2-/acetylthio/-1-oxo-3-phenylpropyl/amino/-5-oxo - 7H-pyrido[2,1-b] /1,3/diazepin-7 - carboxylic acid

The crude product from frequent is 1.48 mmol) followed by treatment of 1-hydroxy-7-isobenzofuranone (208 mg, 1.52 mmole). The bright yellow solution was then treated with /S/-2-/acetylthio/benzoylpropionic acid (333 mg, 1.48 mmole) in methylene chloride (5 ml) and cooled in a bath of ice. Was added ethyl-3-/dimethylamine/propellerpowered, cleaners containing hydrochloride salt (2,88 mg, 1.50 mmole) and the mixture was stirred at 0oC for 1 hour and at room temperature for 1.5 hours. The solvent was removed on a rotary evaporator and the residue was separated between ethyl acetate and 0.5 N hydrochloric acid. An ethyl acetate extract was washed successively with water (twice), 50% saturated sodium bicarbonate solution and brine, then dried (sodium sulfate), filtered and drove away, getting 651,2 mg specified in the title product as a white foam.

c) /4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenyl-propyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/-thiazepine-7-carboxylic acid

A solution of methyl ester product from part (b) in obeskislorozhennuju methanol was treated with 1 N solution of sodium hydroxide according to the procedure of example 3(d), getting listed in the name of the connection.

Example 23

/4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/-thiazepine-7-carboxylic acid

The product of examples 3, 11 and 22 Polyanichko stirrer and internal thermometer, dissolved sodium hydroxide (61,65 g 1,541 mol) in distilled water (1000 ml). To this solution was added L-methionine (100.0 g, 0,670 mmole) at room temperature. The solution was cooled in a bath of ice (internal temperature for 3oC) was added benzylchloride (110 ml, 0,737 mmole) for 10 minutes. After a 15 minute induction period, the internal temperature rose from 3oC to 12oC for 30 minutes and then decreased to 0oC for 15 minutes. The reaction mixture was stirred at 0oC for 2 hours, the time during which the initially cloudy reaction mixture became homogeneous. Bath ice was removed and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was transferred into a separating funnel and washed with hexane (2300 ml). The aqueous layer was acidified using 6 N hydrochloric acid to pH 5 and was diluted with ethyl acetate (600 ml). The mixture was then acidified to pH 2. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3600 ml). The organic extracts were combined, washed with brine (750 ml), dried (sodium sulfate), filtered and concentrated in vacuum, obtaining a light yellow oil. The crude product (oil) was dissolved in toluene (1500 ml) and rest the way, what remained 650 ml of toluene. This solution was stored overnight at 5oC, the time during which some part of the product was crystallized from solution. The solid was again dissolved by warming to room temperature. Then added toluene (134 ml) (few crystals). Added heptane under mechanical stirring (500 ml) 30 ml with an interval of 10 minutes (approx 3 hours - total added). At this point, the product began to crystallize from solution. Added additional portion of heptane (1020 ml) for 1.5 hours and the resulting slurry was stirred for 2 hours. The product was collected by vacuum filtration, washed with a mixture of 1:1 toluene: heptane (3150 ml) and heptane (3500 ml) and dried in the air, getting 158,6 g mentioned in the title product as a white solid; I. pl. 66oC; []D= -1,5o(c = 1.95% ethanol), TLC (ethanol/water, 3:1) Rf= 0,78.

Data analysis for C13H17NO4:

Calculated, %: C 55,11; N equal to 6.05; N 4,94

Found, %: C 54,96; N. Of 6.20; N Of 4.83.

b) Methyl ester of N-//phenylmethoxy/carbonyl/-L-methionine

In a 3 l flask equipped with a mechanical stirrer and enter to purge with argon, dissolved the product from Zinnow the mixture was stirred in an argon atmosphere for 21 hours. Was added triethylamine /4.9g, a 0.035 mol/ and the reaction mixture was additionally stirred for 15 minutes. The reaction mixture was concentrated in vacuo to a pale yellow oil. The oil was dissolved in ethyl acetate (900 ml) and the solution washed with 1 N hydrochloric acid (740 ml), saturated sodium bicarbonate solution (2740 ml) and brine (740 ml). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo to a light yellow oil. The oil was concentrated from hexane (2100 ml), receiving 98,22 g mentioned in the title product as a white solid.

c) Methyl ester of N-//phenylmethoxy/carbonyl/-L-methanesulfonamide

In a 3 l flask equipped with a mechanical stirrer was dissolved product from part (b) (97,95 g, 0,329 mol) in methanol (1675 ml) and distilled water (215 ml). The solution was cooled in a bath of ice was added sodium bicarbonate (28.5 g, 0,339 mol). Small portions was added N-chlorosuccinimide (44,0 g of 0.29 mole) in 25 minutes so that the internal temperature did not exceed 7oC. the Mixture was stirred in the bath with ice for 1 hour and then allowed to warm to room temperature over 1 hour. The mixture was concentrated in vacuum to remove about 75% of the methanol, the m (2200 ml). The organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo to a clear viscous oil. The oil was concentrated from toluene (3100 ml) and the residual solvent was removed under high vacuum, receiving untreated indicated in the name of the substance in the form of a clear oil, which was turned into a white solid (to 131.4 g). The crude product contained 12 weight % of succinimide and 9 weight of toluene according to NMR data. The product was a mixture of sulfoxide diastereomers.

d) Methyl ester S-//atomic charges/methyl/-N-//phenylmethoxy/carbonyl-L-homocysteine

In a 1 l flask containing the product from part (c) (102,8 g, fixed weight, 0,328 mole), was added toluene (480 ml), sodium acetate (32,3 g, 0,394 mole) and acetic anhydride (186 ml, 1,970 mol). The resulting mixture was boiled under reflux in an argon atmosphere (118oC) for 18 hours. The dark brown reaction mixture was allowed to cool to room temperature. After 1 hour at room temperature, the reaction mixture became very viscous and solid inclusions. A solid substance was dissolved with ethyl acetate (100 ml) and the mixture was partially concentrated in vacuo to a viscous brown residue. The remainder of concentra and saturated sodium bicarbonate solution (4680 ml). The organic layer was washed with brine (450 ml), dried (magnesium sulfate), filtered and concentrated in vacuum. Residual solvent was removed under high vacuum to obtain a light brown solid. The crude product was dissolved in n-butyl acetate (450 ml) with heating (35oC) and stirring. After cooling to room temperature was slowly added hexane (200 ml) to the solution under stirring for 15 minutes. At this point, the product crystallized from solution. Added additional portion of hexane (700 ml) for 30 minutes and the resulting slurry was stirred for 3 hours. The product was collected by filtration, washed with a mixture of 1:2 n-butyl acetate:hexane (200 ml), 1:4 n-butyl acetate: hexane (2 240 ml) and hexane (2 250 ml). The product was air-dried, then dried under high vacuum, receiving 87,7 g mentioned in the title product as a pale brown solid, so pl. 73oC; []D= -1,6o(c = 1.95% ethanol). TLC (5% methanol/methylene chloride) Rf= 0,80.

Data analysis for C16H21NO6S:

Calculated, %: 54,07; N 5,95; N 3,94

Found, %: C 53,48; N 5,74; N 3,82.

e) S-Acetyl-N-//Phenylmethoxy/carbonyl/-L-homocysteine

In a 1 l flask a solution of probanka, equipped with a mechanical stirrer and input for argon, and 86.8% solution of potassium hydroxide (62,7 g, 0,969 mol) in distilled water was purged with argon for 15 minutes.

Tertrahydrofuran ring solution was rapidly added to a solution of potassium hydroxide (internal temperature of 20oC) through the cannula with intensive stirring in argon atmosphere. The flask containing the product from part (d), washed with 20 ml of tetrahydrofuran (purged with argon for 15 minutes and wash was added to the reaction mixture. After 30 minutes the reaction mixture was transparent and is divided into two phases and took place isothermal reaction to the 28oC.

After another 2 hours the reaction mixture was cooled to 1oC (internal) was added in one portion sodium hydroxide (2,75 g, 0,073 mol) (exothermic reaction to 6.8oC). The reaction mixture was additionally stirred for 20 minutes at 0oC and then allowed to warm up to the 11oC for 30 minutes. The reaction mixture was cooled to 1oC for 10 minutes was added acetic anhydride (68,6 g, 0,727 mol). During the addition was exothermic reaction up to 10oC. the Internal temperature again dropped to 4oC before the end of add. Ohlazhdeniya">

The reaction mixture was concentrated in vacuo to approximately half its volume, acidified to pH 2 6 N hydrochloric acid (175 ml) and was extracted with ethyl acetate (2 1.1 l). The combined organic extracts were washed with brine (560 ml). The organic layer was treated with activated carbon and anhydrous magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. Was added n-butyl acetate (380 ml) and the solution was concentrated in vacuo (45oC) half of its volume. Added a second portion of n-butyl acetate (190 ml/ and again concentrated so that left 190 ml of n-butyl acetate. Was slowly added heptane (300 ml) with stirring until the veil was added as seed crystals. After 15 minutes from the solution crystallized white solid. Was slowly added to the second portion of heptane (570 ml) for 30 minutes and the resulting slurry was stirred at room temperature overnight. The product was collected by filtration, washed with a mixture of 1:3 n-butyl acetate:heptane (2 275 ml) and hexane (2 275 ml), dried in air and then dried in high vacuum, receiving 50,1 g mentioned in the title product as white solids; so pl. 73 - 74oC; []D= -1,3oR>
Calculated, %: 54,01; N. OF 5.50; N 4,50

Found, %: C 53,88; N. Of 5.45; N Of 4.44.

The filtrate was concentrated so that there is 100 ml of n-butyl acetate. This solution was treated with 310 ml of heptane, as described above, receiving the second portion of 8.4 g mentioned in the title product as a white solid with a total yield of 58.5 g

f) Methyl ether /S-/R*,R*/-2-//4-/acetylthio/-1 - oxo-2-///phenylmethoxy/carbonyl/amino/butyl/amino/-6,6 - dimethoxycinnamic acid

S-Acetyl-N-//phenylmethoxy/carbonyl/-L-homocysteine (0,456 mol) was dissolved in a mixture of methylene chloride (600 ml) and dimethylformamide (90 ml) was added hydroxybenzotriazole hydrate (64,72 g, 0,479 mol). The mixture was cooled in a bath with ice and the solution was added methyl ether /S/-2-amino-6,6-dimethoxycinnamic acid (obtained as described in example 1 (e), 93,7 g, 0,456 mole) dissolved in methylene chloride (600 ml). Finally, added cleaners containing hydrochloride salt of ethyl-3-/dimethylamine/propylbromide (91,83 g, 0,479 mol) and the reaction mixture was stirred for 1 hour at 0oC, then at room temperature for 2 hours. At the end of this time the reaction mixture was concentrated in vacuo and the residue was separated between ethyl acetate (3 l) and saturated aqueous races of the ode (1 l) and brine (1 l), then was dried (sodium sulfate) and concentrated in vacuo to 238 g of the crude product. The crude product was dissolved in a mixture of ethyl acetate: methylene chloride (1:1, 300 ml) and transferred to the substrate column with silica gel (Merck) 10 15 see Elution with a mixture of 8:2 ethyl acetate:hexane (7 l), followed by elution with ethyl acetate (4 l) gave 205,28 g specified in the product name.

(g) Methyl ether /4S/4, 7, 10a//- octahydro-4-///phenylmethoxy/carbonyl/amino/-5-oxo-7H - pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

A solution of the product from part (f) (205,28 g, 0,412 mol), dried by evaporation with a mixture of methylene chloride/toluene/ methanol (2 l) was cooled to 0oC (bath with ice) and was purged with argon for 30 minutes. Quickly added a 25 wt.% a solution of sodium methoxide in methanol (95,1 ml of 1.01 EQ.) with a continuous purge of argon, and the reaction mixture was stirred 10 minutes, then extinguished the addition of 1 l of a saturated solution of ammonium chloride, diluted with 0.5 l of water and was treated with 3 l of ethyl acetate. The resulting mixture was divided into two portions, each of which was separately concentrated in vacuo to remove the organic (ethyl acetate and methanol). The concentrated residues were combined and treated with 1 l of ethyl acetate. Organic slotstravel with 1 l ethyl acetate The organic extracts were combined and washed with 1 l of water and two portions of 1 l of brine, dried (sodium sulfate), filtered and concentrated. Next, the residue is evaporated with methylene chloride and dried in vacuum, obtaining 182,65 g free sulfhydryl product from part (f).

This free intermediate sulfhydryls product (0,400 mol) was dissolved in methylene chloride (4 l) and treated 30,8 ml (0,400 mole) triperoxonane acid. The reaction mixture is boiled under reflux for 16 hours, then cooled and concentrated in vacuum. The obtained residue was dissolved in 2 l of ethyl acetate, then washed with 400 ml of 0.1 N hydrochloric acid solution, 1 l water, 1 l of saturated sodium bicarbonate solution, 1 l of water and 1 l of brine, dried (sodium sulfate), filtered and concentrated. The residue is evaporated with methylene chloride and dried in vacuum, obtaining 166,24 g specified in the product name.

h) Methyl ether /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

Attributively (76,6 ml, 0,538 mol) was added to the solution under argon containing the product from part (g) (162,43 g, 0,414 mole) dissolved in methylene chloride (1.5 l). After stirring the reaction mixture for 1, the allocation of CO2pH of 1.2). An ethyl acetate layer was separated and was extracted with 300 ml of 1 N hydrochloric acid. The combined acidic aqueous extracts were then washed in 1 l of ethyl acetate, then was cooled to 0oC and brought to a pH of 10.0 4 N solution of sodium hydroxide (approximately 275 ml). The aqueous layer was saturated with solid sodium chloride, and then was extracted with 5 portions 1 l of methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuum. The residue was re-dissolved in 1 l of methylene chloride and washed with 0.5 l of brine, dried (sodium sulfate), filtered and concentrated, obtaining 98,8 g specified in the product name.

i) Methyl ether /4S/4/R*/, 7, 10a//- octahydro-4-//2-/acetylthio/-1-oxo-3-phenylpropyl-amino/-5-oxo-7H - pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

Dicyclohexylamine salt /S/-2-/acetylthio/benzoylpropionic acid (173,1 g, 0,427 mol) was divided between atelocerata (1 l) and 10% solution of potassium bisulfate (800 ml). The organic layer was separated and washed with 5% aqueous solution of potassium bisulfate (1 l), 50% brine (1 l) and brine (1 l), dried (sodium sulfate), filtered and concentrated in vacuum. The residue is evaporated several times with methylene chloride, then dried over night in LTI/benzoylpropionic acid (0.4 g, 27 mmole) dissolved in methylene chloride (900 ml), cooled in a bath of ice and treated with a solution of the product from part (h) (100,28 g, 0,388 mol) in methylene chloride (600 ml), triethylamine (154,2 ml, 0,388 mmole), and, finally, was added in one portion benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (188,9 g, 0,427 mol). After 1 hour at 0oC and 2 hours at room temperature the reaction mixture was concentrated in vacuo and dissolved in 2 l of ethyl acetate. The organic solution was washed with 0.5 l of brine, 1 l of 0.5 N hydrochloric acid, 1 l of water, 2 l of saturated sodium bicarbonate solution, 1 l of water and 1 l of brine, dried (sodium sulfate), filtered and concentrated. By this time, the wash water, which contained the product (TLC definition), re-extracted with ethyl acetate. An ethyl acetate extracts were processed in the usual way and all were United, receiving crude yellow oily product. Yellow oil, cooked in a mixture of 1:1 ethyl acetate:hexane, subjected to processing on a column of silica gel 15 of 15 cm and was suirable 7 ml of a mixture of ethyl acetate:hexane 1:1, followed by elution with 4 l of a mixture of 6:4 ethyl acetate:hexane, and finally, 2 l of a mixture of 7:3 ethyl acetate: hexane. The filtrate containing the desired product were concentrated, produces the sawdust/-5-oxo-7H-pyrido[2,1-b]- /13,/diazepin-7-carboxylic acid

A 12 l three-neck flask, equipped with a separating funnel and mechanical stirrer, was placed a solution of the product from part (i), (96,0 g, 0,207 mmol) in methanol (1.1 l). The solution was purged for 30 minutes, then cooled in a bath with ice until reaching an internal temperature of +7oC. for 1 hour was added to the total number of 1.45 l of 1 N sodium hydroxide solution (preferably purged with argon for 30 minutes). The reaction mixture was continuously purged with argon before adding them. The reaction temperature was raised to +12oC and was maintained during the addition. The reaction mixture was additionally stirred for 30 minutes, then was heated to room temperature water bath to ambient temperature and was stirred with barbotirovanie with a period of 2.5 hours. About 250 ml of 6 N hydrochloric acid was added dropwise over a 15 - 250 minutes to reach pH 2. In the process of acidification formed a resinous precipitate. After continuous stirring additionally for 2 hours the precipitate was changed to white fine solids with larger lumps of solid matter. The product was collected on a 600 ml filter SCHOTT. Washing the collected solids 1 l of water with PEFC is the form of finely dispersed solids, so pl. 218 - 220oC (decomposition). TLC (1:99 acetic acid/acetate) Rf=0,48

HPLC: tR(YMC S-3 ODS 6,0150 mm, 1.5 ml/min, isocratic 60% B, Buffer A = methanol/water/phosphoric acid (10:90:0,2), Buffer B = methanol/water/phosphoric acid (90:10:0,2) = was 9.33 min, 99.3% of the total peak area at 220 nm.

Data analysis for C19H24N2O4S2:

Calculated, %: C 55,86; N. OF 5.92; N 6,86; S 15,70

Found, %: C 55,83; N. Of 5.83; N Of 6.96; S 15,70.

Example 24

Methyl ether /4S/4/R*/, 7, 10a//- octahydro-4-//2-acetylthio/-1-oxo-3 - phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid

The reaction mix described in examples 3 (c), 11 (i), 22 (b), and 23 (i), was also conducted as follows.

Solution /S/-2-/acetylthio/benzoylpropionic acid (1,83 g, 8,14 mmole) and methyl ether /4S/4, 7, 10a//- -octahydro-4-amino-5-oxo-7H-pyrido [2,1-b]/1,3/diazepin-7-carboxylic acid (2,11 g, 8,17 mmole) in dry methylene chloride (20 ml) was cooled to 0oC and was added in one portion cleaners containing hydrochloride salt of ethyl-3-/dimethylamine/propyl/carbodiimide (1.77 g, to 9.32 mmole). The reaction mixture was stirred at 0oC for 6 hours and then concentrated to an oily foam. Then the residue was separated between ethyl acetate (100 ml) and 1 N solution solenta sodium (250 ml) and saturated aqueous sodium chloride (50 ml), was dried (anhydrous sodium sulfate), filtered and concentrated in vacuum, obtaining 3,43 g mentioned in the title product as a white foam.

Example 25

1,1-Dimethylethylamine salt /4S/4/R*/, 7, 10a//- octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

15 ml 3-necked flask equipped with a reflux condenser, was evacuated and re-filled three times with argon. The flask was loaded /4S/4/R*/, 7, 10a//- octahydro-4-//2-mercapto-1-OCXO-3-phenylpropyl/amino/- 5-oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid (0.20 g) and a 1:1 solution obezhirennogo absolute ethanol and acetonitrile (1.0 ml). As soon as the heterogeneous mixture was stirred, was added dropwise tert-butylamine (63,0 μl, 1.03 EQ). The solution became homogeneous after 3 minutes after the addition of amine. Solution (internal temperature about 20oC) slowly dropwise was diluted by the addition of acetonitrile to a final volume of 10 ml After additional stirring for 2 hours, the solid was filtered, washed once with 100% acetonitrile (5 ml), dried in air and placed under high vacuum for 2 hours to remove residual solvents, receiving a 20.2 g ukedo substance United with matter from other experiments and recrystallized as follows. a 25 ml 3-necked flask, equipped with reflux condenser, magnetic stirrer and addition funnel, was evacuated three times and filled with argon. To the flask was added the download 1,1-dimethylamino salt (0,37 g) and 59% acetonitrile/methanol (2,28 ml). The flask and contents were heated to 29 - 32oC to dissolve the solids. The solution was diluted with acetonitrile (27 ml). Bath for heating was removed and the flask was allowed to cool to room temperature (20oC). After an hour of additional stirring, the mixture was filtered and the solids were washed once with acetonitrile (10 ml), dried in air and placed in conditions of high vacuum to remove residual solvent, getting 0.29 grams mentioned in the title product as a white crystalline solid: so pl. with shrinkage 160oC and slow melting and decomposition when the temperature is increased to 190 - 191oC (190 - 191oC remaining shiny substance quickly melts).

Example 26

Methyl ether /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid

This intermediate connection examples 3 (c) and 11 (h) and 23 (h) was also obtained as follows:

a) Diethyl ether 2-/acetylamino/-2-/4-/acation dimethylformamide (500 ml) in an argon atmosphere was cooled to 0oC (in the bath with ice). The solution diethylacetamide (500 g, 2,302 mmole) in anhydrous dimethylformamide (1.2 l) was added over 45 minutes while maintaining the reaction temperature below 18oC. After adding turbid solution was gradually heated to room temperature. After stirring for 1 hour at room temperature was added 4-bromobutyrate (471,5 g 2,417 mol). Then the mixture was stirred at 59 - 60oC for 18 hours. The resulting slurry was cooled to room temperature, extinguished absolute ethanol (40 ml) and glacial acetic acid (4 ml), was stirred for about 15 minutes, poured into a 10% solution of lithium chloride and was extracted with ethyl acetate (23 l). United an ethyl acetate extracts were washed with 10% lithium chloride (33 l), dried with anhydrous sodium sulfate) and evaporated in vacuo, receiving 750 g specified in the product name in the form of butter.

b) 2-/Acetylamino/-6-hydroxyhexanoic acid

The product from part (a) (730 g of 2.2 mol) was weighed into a 5 l 3-necked flask (equipped with a thermometer, magnetic stirrer and air refrigerator) and diluted with absolute ethanol (300 ml) followed by addition of aqueous 6 N sodium hydroxide (1.6 l and 9.6 mol). Reactionto temperature and was slowly added 6 N hydrochloric acid (1,32 l) to a pH of 1.3. The flask was equipped with a short reflux condenser for distillation of ethanol, when the temperature slowly rose to 87 - 90oC, and this temperature was maintained for 8.5 hours. Has been a slow release of carbon dioxide. The full amount of distillate was 600 ml. pH of the final solution was a 3.0. The reaction mixture was concentrated under vacuum until complete evaporation of the water and then concentrated from toluene (2500 ml). Semi-solid mass was washed with absolute ethanol (1 l), filtered and washed with additional absolute ethanol (500 ml). The filtrate was concentrated in vacuum, obtaining 509 g of the crude oil (82% purity), which contained ethanol and toluene.

c) /S/-2-Amino-6-hydroxyhexanoic acid

The crude product from part (b) (443 g, including a certain amount of ethanol and toluene (set the weight of the original substance was 394 g), was dissolved in water (3.3 l) was added a 1N solution of lithium hydroxide to pH 7.5 (it took 1,53 l). The mixture was heated to 35oC, was added acylase (grade I from porcine kidney, 0.4 g) and the reaction mixture was stirred for 24 hours. At the end of this time the pH was 7,33. Drove pH 7.5 1 N solution of lithium hydroxide (about 2 ml), was added an additional amount of the celite (20 g) and charcoal (20 g) and the reaction was heated to 92oC and maintained the temperature for 5 minutes. The reaction mixture was filtered through zletovo substrate and concentrated in vacuo to propertiesname state (441 g). This substance was washed with 900 ml of a mixture 1: 5:10 water: ethanol:dimethylformamide. It took some warming up to the destruction of the original lump. The reaction mixture was kept in the refrigerator overnight, filtered and washed with 200 ml of the above solvent mixture, receiving 214 g of the crude substances (40% N-acetyl substances). This substance is suspended in methanol (500 ml), was heated on the steam bath, maintained for 2 hours and filtered. This procedure was repeated twice, getting 108 g specified in the product name; []D= +22o(c=1,44, 6 N hydrochloric acid).

Or stage (b) and (c) also conducted as follows:

b) 2-/Acetylamino/-6-hydroxyhexanoic acid

a 5 l three-neck flask equipped with a mechanical stirrer and a thermometer with a thermocouple downloaded the product from part (a) (631 g 1,933 mol) and tetrahydrofuran (259 ml). To the stirred solution was added dropwise 6 N solution of sodium hydroxide (1385 ml, 8,31 mmole) in 40 minutes. There was a strong exothermic reaction and the tours below 60oC. the Reaction mixture is then heated to a temperature close to the boiling point under reflux (temperature of the reactor 67 - 68o) for 5.5 hours.

The mixture was stirred at room temperature overnight (16.5 hours). Drove pH was 12.75 1.3 gradual addition of 6 N hydrochloric acid (1150 ml, 6.9 mmole), keeping the temperature about 25oC. the Mixture was gradually heated with a short reflux to distillation and evolution of gas (carbon dioxide) (the temperature of the reactor 72,3othe temperature of the reflux condenser 70oC) until, until stopped Stripping and gas development was very slow (94,1oC reactor temperature, 50othe temperature of the reflux condenser). The full amount of collected distillate was 410 ml and the residue in the reactor had a pH of 3.9. Heating was continued for another 10 minutes without additional gas evolution. Full heating time from the beginning of the distillation was 7.5 hours.

After stirring at room temperature overnight, transparent reaction mixture (pH 3,50) drove on a rotary evaporator under vacuum at 60othe bath temperature and the pasty residue was stirred with absolute ethanol (750 ml). Received Tok separated absolute ethanol (2750 ml). To the final residue was added absolute ethanol (1500 ml) and the mixture was stirred at a bath temperature of 60ountil then, until it turned into a slurry with fine crystalline formations, within 20 minutes, and then stirred at room temperature for 20 minutes. The suspension was filtered and the residue was washed with absolute ethanol (2300 ml). The filtrates were visible turbidity and were further purified by filtration through zletovo substrate. New transparent filtrate drove on a rotary evaporator, getting 434,6 g mentioned in the title product as a thick amber syrup. TLC (10:1:1, methanol:acetic acid:water) Rf=0,59.

c) /S/-2-Amino-6-hydroxyhexanoic acid

a 5 l three-neck flask equipped with a mechanical stirrer and a thermometer, was loaded with product from part (b) (434 g of 1.93 mol) and water (3 l). the pH of the cloudy solution was brought from 4,05 to 7.50 addition of 1 N solution of lithium hydroxide (705 ml). The solution was heated to 36oand added acylase from pig kidney I (0,710 g). The mixture was stirred at a temperature of 35 - 36oC for the period of 23.5 hours. The reaction mixture was cooled to room temperature and brought to pH from 7.0 to 5.9 by the addition of glacial acetic acid (4.4 ml). Added zavolali to cool to room temperature. The suspension was filtered through a paper filter 18.5 cm and the obtained residue was intensively washed with water. Colorless filtrate (about 3.9 l) was concentrated on a rotary evaporator at 60oC, getting 476 g of a transparent viscous oil. Added absolute ethanol (7250 ml) and the mixture was stirred until then, until it became homogeneous suspension containing crystals. Once again drove the solvent was added absolute ethanol (1584 ml) to a white solid residue. The suspension was spun in a rotary evaporator overnight (15 hours) at room temperature and was filtered through a paper filter 18,5 see the Residue was washed with absolute ethanol (7 100 ml) and dried to constant weight in a vacuum, getting to 85.8 g of white crystalline specified in the product name. TLC (methanol:water:acetic acid 10:1:1) Rf=0,62.

Data analysis for C6H13NO3:

Calculated, %: C 48,25; N TO 8.94; N 9,38

Found, %: C 48,66; N 8,77; N 9,43

d) Methyl ether /S-/R*, R*/-2-/4-/acetylthio/-1-oxo-2-///phenylmethoxy/carbonyl/ amino/butyl/amino/-6-hydroxyhexanoic acid

Sludge /S/-2-amino-6-hydroxyhexanoic acid (1.0 g, 6.8 mmole) in methanol (20 ml) was stirred at room temperature in an argon atmosphere and obrachenie 18 hours. The volume of solvent was reduced to 3.5 ml under reduced pressure. Added acetonitrile (5 ml) and the solution was cooled to -10oC. Then was added N,N-diisopropylethylamine /84,15 ml of 23.8 mmole/ and the solution was cooled to -40oC, obtaining a solution containing methyl ether /S/-2-amino-6-hydroxyhexanoic acid.

In a separate flask a solution of S-acetyl-N-//phenylmethoxy/carbonyl/homocysteine (obtained as described in example 23 (e), 2,117 g, 6.8 mmole) in acetonitrile (5 ml) was treated at 0oC N,N-diisopropylethylamine (1.20 ml, 6.8 mmole). In another flask hydroxybenzotriazole hydrate (0.104 g g, 0.68 mmole) and methanesulfonylaminoethyl (1,450 g, 6.8 mmole) was dissolved in acetonitrile and cooled to -18oC. prior S-acetyl-N-//phenylmethoxy/carbonyl/homocysteine was then added dropwise to this solution while maintaining the internal temperature below -10oC. After stirring at temperatures from -18o-12oC for 3 hours the resulting solution was added dropwise to the solution described above containing methyl ether /S/-2-amino-6-hydroxyhexanoic acid at -40oC. the Mixture was allowed to slowly warm up to the 16oC for 18 hours. Then the reaction mixture vilify layer was extracted with ethyl acetate (2 x 50 ml). The organic layers were combined and then washed with 1 N hydrochloric acid (100 ml), saturated sodium bicarbonate solution (100 ml). The solution was dried over magnesium sulfate, filtered and concentrated to a white solid. This solid matter was added tert-butyl methyl ether (20 ml) and the resulting slurry was stirred at room temperature for 4 hours and filtered. The product was washed tert-butylmethylamine with ether, and dried, obtaining 2,087 g specified in the product name, so pl. 89 - 90oC.

e) Methyl ether /S-/R*, R*//-2-//4-acetylthio/-1 - oxo-2-//phenylmethoxy/carbonyl/ amino/butyl/amino/-6 - oxohexanoate acid

To a solution of oxalicacid (546 μl, 6,27 mmole) in dry methylene chloride (16 ml) at -65oC (internal temperature) was added dropwise a solution of dimethylsulfoxide (905 μl, 12,54 mmole) in methylene chloride (13 ml) for 12 minutes while maintaining the internal temperature between -65oC and 60oC. a solution of the product from part (d) (1.90 g, 4,18 mmole) in methylene chloride (7 ml) was added to the reaction flask over 20 minutes, making the mix muddy. For the final translation of the alcohol in the reaction flask used additional amount (1 ml) of methylene chloride and reactio is to 3.7 ml, 20,90 mmole), thus making the solution transparent. After additional stirring for 90 minutes at -65oC the reaction was allowed to warm up to -18oC for 2 hours. The reaction was suppressed to 10% aqueous solution of potassium bisulfate (30 ml) and then heated to room temperature. The reaction mixture was diluted with 25 ml of water, stirred and the phases were separated. The aqueous fraction was back extracted with methylene chloride (CH ml). The combined organic extracts were washed with 10% aqueous solution of potassium bisulfate (25 ml), saturated aqueous sodium bicarbonate (CH ml), brine (25 ml), dried (magnesium sulfate), filtered and concentrated in vacuum, obtaining 1.84 g mentioned in the title product as a white solid.

f) Methyl ether /4S/4, 7, 10a//- octahydro-4-///phenylmethoxy/carbonyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/- thiazepine-7-carboxylic acid

A dry flask under argon was downloaded the product from part (e) (1,76 g, to 3.89 mmole) and methanol (17 ml). The solution was cooled to 0oC and barbotirovany with argon for 25 minutes. A solution of sodium methoxide (25 wt.% in methanol, 983 μl, 4,28 mmole) was added to the reaction mixture for 15 seconds. After one hour the reaction was suppressed 1 N hydrochloric acid (20 ml) and then podvodnuju fraction was back extracted with ethyl acetate (CH ml). The combined organic fractions washed with 1 N hydrochloric acid (15 ml), brine, dried (magnesium sulfate), filtered and concentrated in vacuum,polucha,himmelbauer/S-/R*,R*//2-//4-mercapto-1-oxo///phenylmethoxy/carbonyl/amino/ butyl/amino/-6-oxohexanoate acid as a white foam.

The solution of this white foam and triperoxonane acid (305 μl, of 3.95 mmole) in methylene chloride (17 ml) was boiled under reflux for 2.25 hours. After cooling to room temperature the reaction mixture was concentrated and the residue was dissolved in ethyl acetate (25 ml), washed with saturated sodium bicarbonate solution (2x20 ml), brine, dried (magnesium sulfate), filtered and concentrated in vacuum, obtaining 1.50 g mentioned in the title product as a white foam.

(g) Methyl ether /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-pyrido[2,1-b]/1,3/ diazepin-7-carboxylic acid.

Treatment of the product from part (f) attributively, according to the procedure of example 23 (h) or 11 (h), removing the N-protecting group and gave the desired 4-amino product.

Example 27

/S/-2-phthalimido-6-hydroxyhexanoic acid

This is an intermediate compound of example 1 (C) was also obtained as follows.

oC for 5 hours, then at 90 - 95oC for distillation, mostly ethanol. The reaction was cooled and acidified to a pH of 1.3, using 6 N hydrochloric acid (about 1.3 l), then was heated at 90 - 100oC to achieve decarboxylation conditions. At the end of the crude reaction mixture was cooled to room temperature.

The above crude reaction mixture was heated to 35oC and was treated with 600 ml of 6 N sodium hydroxide followed by treatment of 1 N solution of sodium hydroxide to achieve a pH of 7.5 (total volume was approximately 5.3 l). To this mixture was added 0.6 g acylase 1 pork kidney. After stirring at 35oC during the night the pH was 7,25. the pH was brought to 7.5 and added additional amount acylase (300 mg). After stirring overnight the reaction was ended at about 90%. The reaction mixture then was treated with 20 g of coal and 20 g of celite, then was heated to 85oC and maintained at this temperature for 10 minutes, then cooled to 50oC and filtered. At this point, the full volume of the filtrate was about 4.9 liters of the Filtrate ohla who,04 g to 1.2 mol) in one portion was added sodium carbonate as needed to maintain pH at a 9.3. After 2 hours at 5oC and then 3 hours at room temperature, the pH fell to 8.5 and most of the reagents were dissolved. The reaction mixture was filtered, cooled to 5oC and acidified to pH 2.3 6 N hydrochloric acid. Precipitated solid substance was collected by filtration and washed with 200 ml of cold water, then dried in vacuum, obtaining 220 g specified in the product name.

Example 28

/4S/4, 7, 10a//- Octahydro-4/ /2-mercapto-3/1-naphthalenyl/-1-oxopropyl/ amino/-5-oxo-7H-pyrido [2,1-b]/1,3/ diazepin-7-carboxylic acid

a) Diethyl ether/acetylamino//1-naphthaleneacetic/-papandonatos acid

To a solution of ethoxide sodium (21% in ethanol, 4,613 g, 67,8 mmole) in ethanol (100 ml) was added diethylacetamide (14,74 g, 67,8 mmole), then 1-methyl bromide/naphthalene (10.0 g, 45.2 mmole). The solution was stirred at room temperature for one hour. The reaction mixture concentration to an orange oil. The oil was dissolved in ethyl acetate and washed with 50% saturated solution of ammonium chloride, water and brine, then dried over sodium sulfate, filtered and concentrated, obtaining an orange solid. TV is isacetaminophen. The solid was dissolved in 50% ethyl acetate in hexane and cleaned the flash chromatographytandem on silica gel (Merck) in 50% ethyl acetate in hexane. The fractions containing pure product were combined and concentrated, obtaining 10,225 g of the product as a white solid, so pl. 105 - 108oC = 0,57 (50% ethyl acetate in hexane).

b) - Amino-1-nataliepopova acid

A solution of the product from part (a) (16,182 g, and 47.5 mmole) suspended in 48% hydrogen bromide (100 ml) and boiled under reflux under argon for 14 hours. Hydrobromide salt product was filtered from the solution in the form of a white solid, was then placed in hot water (50oC) (500 ml) and the solution neutralize concentrated ammonium hydroxide. The product was precipitated from solution in the form of finely dispersed solids. During the filtration drying under high vacuum overnight (18 hours) received 8,335 g of the product as a fluffy white solid, so pl. 264oC.

c) - Bromo-1-nataliepopova acid

To a solution of the product from part (b) (4,000 g of 18.6 mmole) and potassium bromide (7,63 g, 63.2 mmole) in 2.5 N sulfuric acid (35 ml) maintained at 0oC, was added sodium nitrite (1.92 g, while 27.8 mmole) for 1 hour. The mixture dopolnenie 2.5 hours. The reaction mixture then was extracted with ether (three times). The ether layers were combined and washed with water and brine, then dried over sodium sulfate, filtered and concentrated, obtaining an orange oil. Oil was clean flash chromatographytandem on Merck silica gel, 70% ethyl acetate in hexane with the addition of 1% acetic acid to lower the tail. These fractions containing bromides, were combined and concentrated, gaining slightly contaminated product as an orange oil, which was hard when you save during the night. Rf= 0,40 (40% ethyl acetate in hexane with 1% acetic acid).

d) - /Acetylthio/-1-nataliepopova acid

To a slurry of diacetate potassium (0,912 g, 8,00 mmole) in acetonitrile (300 ml) at 0oC was added the product from part (c) (2,030 g, 7,27 mmole) in solution in acetonitrile (3 ml). The solution was stirred for one hour at 0oC, then heated to room temperature and was stirred for 15 hours. Then the potassium bromide was filtered from the reaction mixture and the filtrate was concentrated to obtain an orange oil. The oil was dissolved in ethyl acetate and washed with a 10% solution of potassium bisulfate and brine, then dried over sodium sulfate, filtered and concentrated, proobably 1% acetic acid to lower the tail. All fractions containing the product were contaminated with connection Rf= 0,43.

These fractions were defended and concentrated, obtaining an orange oil. The crude product was cleaned through dicyclohexylamine salt by dissolution of the orange oil in ether and adding an equivalent amount of dicyclohexylamine (1,32 g, 7,27 mmole) to a solution. Received dicyclohexylamine salt in the form of two types of brown crystals (1,450 g), still slightly contaminated with impurities. Crystals suspended in ethyl acetate and shaken with a solution of 10% potassium bisulfate (three times). Then the organic layer was washed with water and brine, then dried over sodium sulfate, filtered and concentrated, obtaining 875 mg of product as a yellow oil; Rf= 0,40 (40% ethyl acetate in hexane with 1% acetic acid).

e) Methyl ether /4S/4, 7, 10a//- octahydro-4-//2-/acetylthio/-3-/1-naphthalenyl/-1-oxopropyl/ amino/-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

A solution of racemic acid product from part (d) in methylene chloride and a solution of methyl ester /4S/4, 7, 10a//- //-octahydro-4-amino-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7 - carboxylic acid in methylene chloride was reacted in the presence of triethylamine and benzotriazol-1-yloxytris/dimate the>/P>f) /4S/4, 7, 10a//- Octahydro-4-//2-mercapto-3-/1-naphthalenyl/-1-oxopropyl/amino/-5-oxo - 7H-pyrido[2,10-b]/1,3/diazepin-7-carboxylic acid

A solution of the product from part (e) in methanol was treated with 1 N solution of sodium hydroxide according to the procedure of example 23 (j), getting listed in the product name.

Example 29

/4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-/2-thienyl/propyl/ amino/-5-oxo-7H-pyrido [2,1-b]/1,3/-diazepin-7-Kurbanova acid

a) /S/ -- Acetylthio/-2-/difenilamina acid

Potassium chloride (3.0 g, 40.1 per mmole) was added to the solution /2-thienyl/-D-alanine (1,37 g, 8.03 mmole) in 2.5 N hydrochloric acid (25 ml) at room temperature under argon. After stirring for 10 minutes the mixture was cooled to 0oC and treated with sodium nitrite (720 mg, 10,44 mmole). After 2.5 hours, the reaction mixture was heated to room temperature and was stirred for 1 hour. The mixture was divided between water and ethyl acetate and the organic layer was dried (sodium sulfate), filtered and concentrated. The residue was subjected to flash chromatographicaliy (Merck silica gel), elwira 1% acetic acid in 3: 1 mixture of hexane/ethyl acetate, getting 760 mg /R/ -- chloro-2-thiophenecarbonitrile acid as a yellow oil.

Toolbarmanager (15 ml) at room temperature under argon. After stirring for 2 hours the reaction mixture was divided between 10% potassium bisulfate and ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), filtered and concentrated and the residue was subjected to flash chromatographicaliy (Merck silica gel), elwira 1% acetic acid in a mixture of 4:1 hexane/ethyl acetate, receiving 500 mg specified in the product name in the form of oil. TLC (2% acetic acid in a mixture of 3:1 ethyl acetate/hexane) Rf= 0,73.

b) Methyl ether /4S/4/R*/, 7, 10a//- octahydro-4-//2-/acetylthio/-1-oxo-3-/2-thienyl/propyl/amino/- 5-oxo-7H-pyrido[2,1-b] 1,3/diazepin-7-carboxylic acid

The acid solution of the product from part (a) in methylene chloride methyl ether /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid in methylene chloride interacted in the presence of triethylamine and benzotriazol-1-yloxytris/dimethylamine/-fosfodiesterasa according to the procedure of example 23 (i), giving specified in the product name.

c) /4S/4/R*/, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-/2-thienyl/propyl/amino-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

A solution of the product from part (b) in methanol was treated with 1 N sodium hydroxide solution according proto-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/ -5-oxo-7H-pyrido[2,1-b] /1,3/-thiazepine-7-carboxylic acid

a) Dicyclohexylamine salt /R/-2-/acetylthio/benzoylpropionate acid

Following the procedure of example 1 (h), but substituting L-phenylalanine, D - phenylalanine, got dicyclohexylamine salt /R/-2-/acetylthio/benzodiapines acid.

b) Methyl ether /4S/4/S*/, 7, 10a/// octahydro-4-//2-/acetylthio/-1-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid

Stir the suspension dicyclohexylamine salt /R/-2-/acetylthio/benzodiapines acid (353,5 mg, 0,872 mmole) in ethyl acetate (5 ml), washed with 5% solution of potassium bisulfate (3 5 ml). The organic extracts were combined, washed with brine, dried (magnesium sulfate), filtered, concentrated, dried in vacuum and drove twice from hexane to obtain /R/-2-/acetylthio/benzodiapines acid in the form of butter.

The obtained free acid (181, 4 mg, 0,809 mmole) was dissolved in methylene chloride (2 ml) and stirred under nitrogen at 0oC. To this solution was added a solution of methyl ester /4S/4, 7, 10a//- octahydro-4-amino-5-oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid (200 mg, 0,774 mmole) in methylene chloride (6 ml), then triethylamine (0,113 ml, 0,813 mmole) and, finally, benzotriazol-1-yloxytris/dimethylamine/fosfodiesterasa (360 mg, 0,813 mmole). Reaction the reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate and the solution washed with 5% solution of potassium bisulfate, saturated sodium bicarbonate solution and brine. The organic layer was dried (magnesium sulfate), filtered and concentrated to a yellow solid. Clean flash chromatographytandem (elution 2:3 mixture of ethyl acetate:hexane) gave 261,7 mg specified in the name of the product as a clear oil.

c) /4S/4/S*/, 7, 10a//- octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido [2,1-b] /1,3/-thiazepine-7-carboxylic acid

A solution of the product from part (b), (261,1 mg, 0,562 mmole) in methanol (6 ml, obeskislorozhennuju propulsiveness nitrogen) was cooled to 0oC and treated with 1 N sodium hydroxide solution (6 ml, obeskislorozhennuju propulsiveness nitrogen). After stirring for 1 hour at 0oC with continuous blowing of nitrogen, the reaction was heated to room temperature. After stirring for 30 minutes at room temperature was obtained a clear solution. After 5.5 hours the reaction was acidified to pH 1 with 5% solution of potassium bisulfate and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried (sodium sulfate), filtered and concentrated in vacuum. the Institute of product as a white solid; []D= -87,5o(or = 0.51, chloroform). TLC (6:0,01:3,99, ethyl acetate: acetic acid:hexane) Rf= 0,20.

HPLC: tR= 25,3 min; UMC S-3 ODS (C-18) 6.0 x 150 mm, 0% to 100% B: A 30 min linear gradient and 10 minutes had passed, 1.5 ml/min: A = 90% water: methanol + 0.2% of phosphoric acid, B = 90% methanol:water + 0.2% of phosphoric acid, 220 nm.

Data analysis for C19H24O4N2S20,15 C4H8O20,15 C7H160,39 H2O:

Calculated, %: C 55,89; N 6,45; N OF 6.31; S accounted for 14.45

Found, %: C 56,19; N 6,50; N Of 6.71; S 13,96.

Example 31

/4S/4, 7, 10a//- Octahydro-4-//2-mercapto-1-oxo-3-/4-thiazolyl/propyl/amino/- 5-oxopyrrolo [2,1-b]/1,3/ diazepin-7-carboxylic acid

a) /R/-2-amino-3-/4-thiazolyl/propanoic acid

A solution of 4N hydrochloric acid in dioxane (10 ml) was added to a solution of /R/-2-//1,1-dimethylmethoxy/carbonyl/amino-3-/4-thiazolyl/propanoic acid (2.0 g, 7.3 mmole) in dioxane (2 ml the Reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo and the residue was dissolved in water (3 ml). the pH was brought to 6.5 1N solution of sodium hydroxide and this solution was passed through 20 ml of resin DowexAG 50 (H+). The column was suirable water (250 ml) followed by elution of 2% pyridinoyl.

b) /R/-2-Bromo-3-/4-thiazolyl/propanoic acid

A solution of the product from part (a) (0,516 g, 3 mmole) and potassium bromide (1.19 g, 10.1 mmole) in water (5,94 ml) and sulfuric acid (0,43 ml) was stirred at -10oC for 10 minutes followed by the addition portions of sodium nitrite (0,318 g, br4.61 mmole) for 10 minutes. The reaction mixture was additionally stirred for 10 minutes at 0oC and at room temperature for one hour and then was extracted with ether (3 x 100 ml). The ether extracts were washed with brine (2 x 20 ml), dried (sodium sulfate), filtered and concentrated in vacuum, obtaining 0,37 g specified in the product name, []D= + 37,35o(c = 0,7,methanol). The second experiment was carried out on the basis of 2.67 mmol of the product from part (a) using the same procedure, and has received additional 0.35 g specified in the product name.

c) /S/-2-/Acetylthio/-3-/4-thiazolyl/propanoic acid

The product from part (b) (0,72 g of 3.05 mmole) and thioacetic potassium (0.35 g, of 3.05 mmole) was stirred in acetonitrile (9 ml) overnight at room temperature and at 30oC for one hour. The reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The filtrate was concentrated in vacuum. The residue was again dissolved in ethyl acetate (100 m is e, getting 0.52 g specified in the product name; []D= - 15,89o(c = 0,6: methanol).

d) Methyl ether /4S/4, 7, 9a//- octahydro - 4-//2-/acetylthio/- 1-oxo-3-/4-thiazolyl/ propyl/amino/-5 - oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid

Salt of the methyl ester /4S/4, 7, 9a//- 4-aminooctane-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid and p-toluensulfonate acid (0,367 g, 0,882 mmole), obtained from the substance described in example 5 (d), was dissolved in methylene chloride (5 ml) 0oC followed by the addition of triethylamine (0,12 ml, 0,868 mmole). The product from part (c) (0.2 g, 0,865 mmole) was added to this solution followed by the addition of the second portion of triethylamine (0,12 ml, 0,865 mmole). Added benzotriazol-1-yloxytris-/dimethylamine/fosfodiesterasa (0,383 g, 0,865 mmole) and the reaction mixture was stirred at 0oC for one hour and at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (60 ml). The organic extract washed with 5% aqueous solution of potassium bisulfate (10 ml) and brine (2 x 10 ml), dried (sodium sulfate), filtered and concentrated in vacuum. This crude substance was chromatographically on silica gel Merck 100 g using 0,2 I 0,134 g specified in the product name.

e) /4S/4, 7, 9a//- Octahydro-4-//2-mercapto-1-oxo-3-/4-thiazolyl/propyl/amino/-5-oxopyrrolo [2,1-b]/1,3/-thiazepine-7-carboxylic acid

The product from part (d) is 0.135 g of 0.29 mmole) was dissolved in methanol and the solution propulsively argon for 30 minutes at 0oC. 1N solution of sodium hydroxide (1,32 ml), purged with argon, was added to the above solution and the reaction mixture was stirred at 0oC propulsiveness argon through the solution for 1 hour and at room temperature for 2 hours. The reaction was suppressed by the addition of 5% aqueous solution of potassium bisulfate (20 ml) and the organic salts were extracted with ethyl acetate (3 x 50 ml). An ethyl acetate solution was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuum. The concentrate was chromatographically on Merck silica gel 40 g, using chloroform containing 5% methanol and 0.5% acetic acid. The appropriate fractions were combined, concentrated and separated between 20 ml ethyl acetate and 5% aqueous solution of potassium bisulfate. An ethyl acetate solution was washed with water and brine, dried (sodium sulfate) and concentrated in vacuum. The residue was liofilizovane of dioxane (4 ml) to give 36 mg specified in the product name in the form of a 70:30 mixture of isomers, so pl. 9

HPLC: tR= 3,06 min, MB S-3 ODS (C-18) 6.0 x 150 mm, 3 micron column plugged the end, isocratic. 60% aqueous methanol containing 0.2% phosphoric acid, 25 min, 1.5 ml/min (95.4 percent).

Data analysis for C15H19N3O4S30,2 C4H8O20,9 H2O:

Calculated, %: C 43,59; N 5,19; N 9,65; S 22,09

Found, %: C 43,54; N 4,89; N 9,44; S 21,90.

Example 32

1000 tablets each containing the following ingredients:

/4S/4/R*/, 7, 10a//- octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido [2,1-b]/1,3/diazepin-7 - carboxylic acid 100 mg

Corn starch 100 mg

Gelatin 20 mg

Avicel (microcrystalline cellulose), 50 mg

Magnesium stearate 5 mg to 275 mg

get of sufficient weight mixture of the product of example 3, and corn starch with an aqueous solution of gelatin. The mixture is dried and ground to fine powder. Avicel and then magnesium stearate is mixed with the granulation. The mixture is then pressed into the press to tablets with the formation of 1000 tablets each containing 100 mg of active ingredient.

The same method can be obtained tablets containing 200 mg of the product of examples 1, 2, 4 - 23, 25 and 28 to 31.

Such is radiant.

Data and methods biological tests

Activity in vitro of the compounds in the examples were determined by the following methods.

Inhibitory activity of the enzyme converting angiotensin (ACE) was determined by the method of Cushman et al., Biochem. Pharmacol., vol. 20, p. 1637-1648 (1971).

Extract of rabbit lung was used as the source of ACE and traced the rate of formation geparinova acid from the substrate hippuris-L-histidyl-L-leucine (HHL). After 30 minutes incubation of the test compounds to the enzyme and substrate reaction was stopped by adding HCl. Added ethyl acetate. An ethyl acetate layer was separated and evaporated to a dry residue; the resulting hippuric acid was recovered in the water and it was determined the concentration of test compound that slows the reaction by 50% (IC50).

The activity of renal neutral endopeptidase (PREP) was determined relative to the purified neutral endopeptidase kidneys of rats using the method fluorometric analysis. The analysis is based on the decomposition of the fluorescent dancelot Tripeptide Dns-Gly-Phe-Arg with the formation of Dns-Gly; the latter were extracted from the acidified mixture with ethyl acetate and he was very fluorescinated. The test compound is pre-incubated in t incubation the reaction was stopped by adding HCl. Dns-Gly were extracted with ethyl acetate. Relative fluorescence intensity was measured with a spectrometer. Determined concentration of the test compound that causes slow reaction by 50% (IC50). The test results presented in the table.

1. Compounds containing condensed bicyclic core formula

< / BR>
or their pharmaceutically acceptable salt,

where A represents the

< / BR>
or

< / BR>
X represents O or S;

R1and R12independently selected from the group consisting of hydrogen, C1- C5-alkyl straight or branched chain, phenyl-(lower)alkylene, naphthyl-(lower)alkylene, C3- C7-cycloalkyl-(lower)alkylene, thienyl-(lower)alkylene, or R1and R12taken together with the carbon atom to which they are attached, close C5- C6-cycloalkyl ring;

R2represents hydrogen or

R3and R7independently selected from the group consisting of hydrogen or lower alkyl;

R6is lower alkyl;

m is 0 or 1;

Y is CH2or 0, provided that Y is 0 only if m is 1;

n is 1 or 2;

r is 0 or 1.
R3represents hydrogen or lower alkyl with 1 to 4 carbon atoms;

r is 0 or 1;

R1- C1- C5-alkyl straight or branched chain, phenyl - (CH2)-, naphthyl - (CH2), thienyl - (CH2)-, (C3- C7-cycloalkyl - (CH2)-;

R12is hydrogen or R1and R12taken together with the carbon atom to which they are attached, close C5- C6-cycloalkyl ring;

R6is lower alkyl with 1 to 4 carbon atoms;

n is 1 or 2;

m is 0 or 1;

X represents O or S;

Y represents O or CH2provided that Y represents O only if m is equal to 1.

3. Connection on p. 2, where R2represents hydrogen or R3is hydrogen; r is 0 or 1; R1- C3- C5-alkyl straight or branched chain; R12is hydrogen; n is 1 or 2; m is 0 or 1; X represents O or S; Y is O or CH2provided that Y represents O only if m is equal to 1.

4. Connection on p. 3, where X represents S, Y represents CH2, n is 2, m is 1, r is 0 or 1; R2is hydrogen; R1represents benzyl or isobutyl and R12predstavlenoj; R1represents benzyl; R12represents hydrogen; or X represents S; Y represents CH2; n is 2; m is 0; r is 0; R2is hydrogen; R1represents benzyl, cyclopropylmethyl, n-butyl, isobutyl, n-propyl or CH2C(CH3)3; and R12represents hydrogen; or X represents O; Y represents CH2; n is 2; m is 1, r is 0; R2is hydrogen; R1represents benzyl; R12represents hydrogen, or X is O; Y is CH2; n is 2; m is 0; r is 0; R2is hydrogen; R1represents benzyl; R12represents hydrogen; or X represents O; Y represents O; n is 2, m is 1; r is 0; R2is hydrogen; R1represents benzyl; R12represents hydrogen; or X represents S; Y represents O; n is 2, m is 1; r is 0; R2is hydrogen, R1represents benzyl; R12represents hydrogen.

5. Connection on p. 4, which represents /4S/4/R*/,7,10 a//-octahydro-4-//2-mercapto-1-oxo-3-/phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/-thiazepine-7-carboxylic acid;

1,1-dimethylethylamine salt /4S/4/R*/,7,10 a//-octahydro-4-//2-mercapto-1-OKS//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/-thiazepine-7-carboxylic acid;

/4S/4/R*/,7,10 a//-octahydro-4-//2-mercaptomethyl/-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrido[2,1-b] /1,3/diazepin-7-carboxylic acid;

/4S/4/R*/,7,10 a//-octahydro-4-//2-mercapto-4-methyl-1-oxobutyl/-amino/-5-oxo-7H-pyrido[2,1-b]/1,3/diazepin-7-carboxylic acid;

/3R-/3/S*/,6,9 a//-hexahydro-3-//2-mercapto-1-oxo-3-phenylpropyl/amino/-4-oxo-2N,6N-pyrido[2,1-b]/1,3/diazepin-6-carboxylic acid;

/4S/4/R*/,7,9 (a//-octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxopyrrolo[2,1-b] /1,3/-thiazepine-7-carboxylic acid;

/4S/4/R*/,7,9 (a//-octahydro-4-//3-cyclopropyl-2-mercapto-1-oxopropyl/amino/-5-oxopyrrolo[2,1-b] /1,3/-thiazepine-7-carboxylic acid;

/4S/4/R*/,7,9 (a//-octahydro-4-//2-mercapto-1-oxohexyl/amino/-5-oxopyrrolo[2,1-b] /1,3/-thiazepine-7-carboxylic acid;

/4S/4/R*/,7,9 (a//-octahydro-4-//2-mercapto-1-oxo-4-methylpentyl/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid;

/4S/4/R*/,7,9 (a//-octahydro-4-//2-mercapto-1-oxobutyl/amino/-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid;

/4S/4/R*/,7,9 (a//-octahydro-4-//2-mercapto-4,4-dimethyl-1-oxobutyl/amino-5-oxopyrrolo[2,1-b] /1,3/diazepin-7-carboxylic acid;

/4S/4/R*/,7,10 a//-octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-7H-pyrid the lo[2,1-b] /1,3/oxazepine-7-carboxylic acid;

/4S/4/R*/,7,10 a//-octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-/1,4/oxazino[3,4-b] /1,3/oxazepine-7-carboxylic acid, or

/4S/4/R*/,7,10 a//-octahydro-4-//2-mercapto-1-oxo-3-phenylpropyl/amino/-5-oxo-/1,4/oxazino[3,4-b] /1,3/ diazepin-7-carboxylic acid.

6. The connection formulas

< / BR>
or its pharmaceutically acceptable salt.

7. Pharmaceutical composition for inhibiting the turning of the enzyme and angiotensin neutral endopeptidase, characterized in that it includes a pharmaceutically acceptable carrier and an effective amount of one or more compounds of the formula

< / BR>
or its pharmaceutically acceptable salt,

where A, X, Y, n, m and R3have the meanings as defined under item 1.

8. The compound containing a condensed bicyclic ring, formulas

< / BR>
or its pharmaceutically acceptable salt,

where X is O or S,

n is 1 or 2;

m is 0 or 1;

Y is CH2or O, provided that

Y represents O, only if m is 1;

R3represents hydrogen or lower alkyl, provided that when X is O, n is 1, Y is a group CH2then m must be equal to 1.

9. The way poluchi side chain of the formula

< / BR>
or its activated form with an amine of the formula

< / BR>
in the presence of reagent combinations,

where X, Y, m, n, R6, r, R1and R12defined in paragraph 1;

R3represents lower alkyl, acid protecting group,

obtaining the compounds of formula

< / BR>
b) treatment of the product from step a) to remove the acyl group and kislotnosti group R3obtaining the target product, which is optionally converted into its pharmaceutically acceptable salt.

10. Method of producing compounds of the formula

< / BR>
where X is O or S;

n is 1 or 2;

n is 0 or 1;

Y is CH2or O, provided that Y represents O, only if m is 1;

R3is acid protecting group,

characterized in that it includes:

a) combination of the amino acid formula

< / BR>
with ether amino acid formula

< / BR>
with the formation of the dipeptide

< / BR>
where P1is aminosidine group or a group which together with the N-atom forms a protecting group;

P2represents hydroxy or mercaptothiadiazole group;

b) selective removal of P2protecting group from the product of part (a);

) to give the desired product.

11. Method of producing compounds of the formula

< / BR>
where X is S;

n is 1 or 2;

Y is CH2;

m is 0 or 1,

characterized in that it includes:

a) combination of the amino acid formula

< / BR>
c ether amino acid formula

< / BR>
with the formation of the dipeptide of the formula

< / BR>
where P1is aminoamides group or a group which together with the N-atom forms a protecting group;

P2represents a hydroxy protecting group;

b) selective removal of P2protective groups of the product of part (a) with formation of the corresponding hydroxycodone;

c) the transformation of the hydroxy product from part (b) a mercaptan of the formula

< / BR>
(d) cyclization of the mercaptan product of part (C),

with the formation of the compounds of formula

< / BR>
e) removing the P1protective groups of the product of part (d) with the formation of the desired product.

12. Method of producing compounds of the formula

< / BR>
where X is S;

n = 2;

Y represents O; and

m is 1;

characterized in that it includes:

a) combination of the amino acid formula

< / BR>
with ether amino acid formula

< / BR>
with the formation of the dipeptide of the formula
P2is hydroxyamino group;

b) selective removal of P2protective groups of the product of part (a) with formation of the corresponding hydroxy compounds;

c) the transformation of the hydroxy product from part (b) a mercaptan of the formula

< / BR>
(d) cyclization of the mercaptan product of part (c),

education

< / BR>
e) removing the protective group P1from the product of part (d), with the formation of the desired product.

13. Method of producing compounds of the formula

< / BR>
where X is O or S;

n is 1 or 2;

m is 0 or 1;

R3represents an acid protective group,

characterized in that it includes:

a) combination of the amino acid formula

< / BR>
with ether hydroxynicotinate formula

< / BR>
with the formation of the dipeptide of the formula

< / BR>
where P1is aminosidine group or a group which together with the N-atom forms a protective group;

P2represents hydroxy or mercaptohexanol group:

b) oxidation of the hydroxy product of part (a) to the aldehyde of the formula

< / BR>
c) selective removal of P2the protective group of the aldehyde product of part (b);

d) cyclization of the product of part (c),

with OBRAZOVANIJA product.

 

Same patents:

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

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

< / BR>
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,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new cephalosporins, namely to derive 1-zetia-diazaphosphorines General formula 1:

(I)

where the wavy line represents a CIS - or TRANS-configuration; R1-C1-C4alkyl, if necessary, replaced by carboxypropyl;

R2-tetrazol-5-yl, if necessary, replaced by stands, methylthiourea or dihydroxyphenylethylamine, thiadiazole-2-yl, if necessary, replaced by stands, methylthio-, amino-, pyridylcarbonyl-, 3,4-diacetoxybiphenyl - carbonylmethyl - or 1-methylprednisolone - amino group of the purine-6-yl, 1,2,3-triazole-5-yl, 1,2,4-triazolyl, if necessary, replaced by stands and trifluoromethyl, thiazolo (5,4-C) pyridin-2-yl or 5,6-dioxo-1,2,4-triazinyl, replaced by chlorpropamide, cooa group COOH or R2-1 methylpyridine, sooa-radical soo-that may find application as antibacterial substances in medicine

The invention relates to new biologically active chemical compounds, specifically to derived dihydropyrimidine formula I

where R1- C1-C6-alkoxy or phenylaminopropyl,

R2- C1-C6-alkyl or phenyl,

R3is a hydrogen atom or a C1-C6-alkyl,

R4- C1-C6-alkyl or phenyl which may be substituted by one or more identical or different substituents from the group halogen, nitro, C1-C6-dialkylamino,1-C6-alkyl, C1-C6-alkoxy and hydroxy-group, or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

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

< / BR>
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,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions

The invention relates to methods of optical separation pornoencaricaturas compounds, which are important intermediate product in the synthesis of optically active derivative of pianolasociety, useful in the treatment of hypertension (hypertension) and asthma

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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