Heterocyclic nitrogen-containing carboxylic acid derivatives, method for their production and pharmaceutical composition

 

(57) Abstract:

The proposed nitrogen-containing heterocyclic derivative of carboxylic acid or salt of formula I, where R1is a hydrogen atom, a group R3(C=O)- and R18S-; R2and R19is a hydrogen atom, a C1-C7the alkyl group, the aryl-(CH2)m-, where aryl is phenyl or naphthalenyl; group heteroaryl-(CH2)n- where heteroaryl - thienyl; n = 0 or 1; m = 0 or an integer from 1 to 6; R3- C1-C7-alkyl, aryl-(CH2)m-, where aryl is phenyl; R18- C1-C7-alkyl; X1group of the formula III, where R4and R5is a hydrogen atom, R6, R7- the hydrogen atom and the other or X1group of the formula IV, where R6, R7, R8and R9is a hydrogen atom or phenyl-(CH2)m-, where m has the value S = 0, r = 1 or X1group of formula V or a group of formula VI where Y1- atom oxygen, sulfur or the group-CH2- and-CH2-CH2or X1group of the formula VIII or IX, where Y2the sulfur atom or the group-CH2and v = 1 or 2; w = 1 or 2; or X1group of the formula XI, where Z is an oxygen atom, v = 1 or 2 or X1group of formula XII, where Z is an oxygen atom or two hydrogen atoms, or X1- Gruen allmernational acid of formula XIV with an intermediate compound of formula XV : H - X1with obtaining the compounds of formula XVI and then remove the acyl group R3- (C= O)- and ester protective group, R12. The proposed pharmaceutical composition having activity of inhibiting antiotensin-converting enzyme and inhibiting the neural endopeptidase, which contains compounds of the formula I and a pharmaceutically acceptable carrier. 3 s and 5 C.p. f-crystals.

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. The invention also relates to pharmaceutical compounds containing these compounds with dual inhibitory activity or farmatsevticheskii acceptable salts, and to a method of using these compositions. Connection with dual inhibitory activity considered in the invention are compounds of the formula

< / BR>
and their pharmaceutically acceptable salts,

where

R1represents hydrogen,

< / BR>
or

R18-S-;

R2and R19independently selected from hydrogen, alkyl, cycloalkyl-Rhyl-(CH2)m-;

n= 0 or 1, provided that n must be 0, if R2and R19both are not hydrogen;

m=0 or an integer from 1 to 6;

R3represents alkyl, substituted alkyl, cycloalkyl-(CH2)m-, aryl-(CH2)m-, substituted aryl-(CH2)m- or heteroaryl-(CH2)m-;

R18represents alkyl, substituted alkyl, cycloalkyl-(CH2)m-, aryl-(CH2)m-, substituted aryl-(CH2)m- heteroaryl-(CH2)m- or-S-R18forms a symmetrical disulfide wherein R18has the formula

< / BR>
X1has the formula

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

< / BR>
R4represents hydrogen, alkyl, substituted alkyl, alkenyl, replaced alkenyl, hydroxy, cycloalkyl-(CH2)m-, aryl-(CH2)m-, substituted aryl-(CH2)m- or heteroaryl-(CH2)m-;

R5represents hydrogen, alkyl, substituted alkyl, substituted alkyl, alkenyl, cycloalkyl-(CH2)m-, aryl-(CH2)msubstituted aryl-(CH2)mhydroxy, or R4and R5taken together with the carbon atom to which they sasatani carbon with which they are linked, form a keto-Deputy, i.e.,

< / BR>
R6, R8and R10independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH2)m-, aryl-(CH2)m-, substituted aryl-(CH2)m- and heteroaryl-(CH2)m;

R7, R9and R11independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH2)m-, aryl-(CH2)m-, substituted aryl-(CH2)mor R6and R7taken together with the carbon atom to which they are linked, form a saturated cycloalkyl ring with 3 to 7 carbon atoms, or R8and R9taken together with the carbon atom to which they are linked, form a saturated cycloalkyl ring with 3 to 7 carbon atoms;

b = 0 or 1;

q = an integer from 1 to 4;

r = 1 or 2;

s = 0, 1, or 2;

t = 1, 2, or 3;

v = 1 or 2;

w = 1 or 2;

Y1represents: -CH2-, -(CH2)2-, -(CH2)3)-, -O-,

< / BR>
-CH2-O, or

< / BR>
Y2represents-CH2-,

< / BR>
or 0;

Y3represents-CH2- or

< / BR>
Y4the t a O or two hydrogen atoms;

R12represents hydrogen, alkyl, substituted alkyl, aryl-(CH2)m-, substituted aryl-(CH2)m- heteroaryl-(CH2)m-,

< / BR>
or

< / BR>
R13represents hydrogen, lower alkyl, or substituted lower alkyl;

R14represents hydrogen, lower alkyl, cycloalkyl, or phenyl;

R15represents hydrogen, lower alkyl, lower alkoxy or phenyl;

R16represents lower alkyl, or aryl-(CH2)m-; and

R17represents hydrogen, alkyl, substituted alkyl, alkenyl, replaced alkenyl, cycloalkyl -(CH2)m-, aryl-(CH2)m-, substituted aryl-(CH2)m- or heteroaryl-(CH2)m-.

The term "alkyl" refers to radicals with a straight or branched chain having up to 7 carbon atoms. The term lower alkyl refers to radicals with a straight or branched chain having up to 4 carbon atoms and which is the preferred sub-group falling under the definition of "alkyl".

The term "substituted alkyl" refers to such straight or branched radicals with 1 to 7 carbon atoms, in which one or more, and preferably one that is issim-alkyl)2, lowest alkoxygroup, lower alkylthio group, or carboxy group.

The term "substituted lower alkyl" refers to such straight or branched radicals with 1 to 4 carbon atoms in which one hydrogen atom is substituted by hydroxy, amino, halogen, trifluromethyl, cyano, -NH(lower alkyl), -N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy.

The term "alkenyl" refers to a straight or branched radicals with 3 to 7 carbon atoms, having one or two double bonds. Preferred "alkyl" groups are radicals with a straight chain having 3 to 5 carbon atoms and one double bond.

The term "substituted alkenyl" refers to a straight or branched radicals with 3 to 7 carbon atoms which have 1 or 2 double bonds, and in which hydrogen is substituted by hydroxy, amino, halogen, trifluoromethyl, cyano, -NH(lower alkyl), -N(lower alkyl)2, lower alkoxy, lower alkylthio, or carboxy.

The terms "lower alkoxy" and "lower alkylthio" refers to lower alkyl groups as defined above, and associated with an atom of oxygen or sulfur.

The term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms.

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

The term "heteroaryl" refers to unsubstituted ring with 5 to 6 atoms containing one or two atoms O and S and/or 1 to 4 N atom, provided that the total number of heteroatoms in the ring is 4 or less. Heteroaryl ring is attached by an appropriate carbon atom or nitrogen. Preferred heteroaryl groups are 2-, 3-, or 4-pyridyl, 4-imidazolyl, 2 - and 3-thienyl, and 2 - and 3-furyl. The term heteroaryl also includes bicyclic ring with 5 or 6 members, which contains the atoms O, S and N, as described above, and which is fused with benzene or pyridinium ring. Preferred bicyclic rings are 2 - and 3-indolyl and 4 - and 5-chinoline. Mono-or bicyclic heteroaryl ring may be additionally substituted in the corresponding carbon atom of the lower alkyl, the corresponding N atom, this atom can also be substituted by an N-protecting group, such as

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

Compounds of the present invention, in which R1is hydrogen or

< / BR>
and R19is hydrogen, can be obtained by a reaction between allmerica-containing side chain of the formula

< / BR>
with an intermediate compound of the formula

H-X1(XV)

resulting in a product formula

< / BR>
where R12in the definition of X1is preferably easily removable ester protecting group such as methyl, ethyl or benzyl.

The above reaction can be carried out in an organic solvent, such as dimethylformamide and in the presence of combined reagent, such as benzotriazol-1-yloxytris dimethylamino of the phosphonium hexafluorophosphate, dicyclohexylcarbodiimide, or carbonyldiimidazole. Alternatively, allergopharma acid of formula XIV can be converted into an activated form prior to the reaction mixture, for example, such as an acid chloride, mixed anhydride, symmetrical anhydride, activated ester, etc.,

PR is 12 is hydrogen, standard ways. Conversely, if R3is stands, and R12is stands or ethyl, after processing methanol with sodium hydroxide receive the product, in which R1and R12are hydrogen, and when R3is stands, and R12is t-bootrom, after processing triperoxonane acid and then ammonia, receive the product, in which R1and R12are hydrogen.

Compounds of the invention in which R2and R19both are not hydrogen, and n = 0, can be obtained by reaction of a combination of side chain containing substituted mercaptopropyl and having the formula

< / BR>
with an intermediate compound of formula XV, as described above, resulting in a receive connection formulas

< / BR>
By processing the compounds of formula XVIII in a strong acid, such as trifluromethanesulfonate acid, remove methoxybenzyl protective group, and receive the corresponding product of formula I, where R1is hydrogen.

Compounds containing substituted mercapto group and having the formula XVII can be obtained by the reaction of disubstituted carboxylic acid of the formula

< / BR>
with bis[[(4-UB> contains a sulfoxide or sulfon, can be obtained using as a mercaptan intermediate compounds of formula XV, i.e., s = 0, in the process of combination reaction. The resulting product having the formula XVI or XVIII, then oxidized using known oxidizing reagent such as meta-chloroperbenzoic acid, peracetic acid, or monoperoxyphthalic acid, uranyl salts of magnesium, etc. By controlling the amount of oxidizing reagent, and the time of reaction receive the products, where s = 1 or 2.

The products of formula I, where R1is hydrogen, can be etilirovany using allvalid or anhydride of the formula

< / BR>
or

< / BR>
where the halogen is Cl or Br, resulting in getting other products of the formula I, where R1is

< / BR>
The products of formula I, where R1represent - S - R18and R18represents alkyl, substituted alkyl, cycloalkyl - (CH2)m-, aryl-(CH2)m-, substituted aryl - (CH2)mor heteroaryl- (CH2)m- can be obtained by using the reaction products of the formula I, where R1is hydrogen, with sulfonium connection formulas.

H

Symmetrical disulfide products of formula I can be obtained by direct oxidation of the product of formula I, where R1is hydrogen, using iodine (Ondetti and others, in U.S. patent 4105776).

The ester products of formula I, where R12represents a

< / BR>
or

< / BR>
can be obtained by treating the product of formula I, where R12is hydrogen, the compound of the formula

< / BR>
or

< / BR>
where L is a leaving group such as chloro, bromo, or tolilsulfonil.

Known allergiaprobleemide acid of formula XIV (Ondetti and other U.S. patents 4105776 and 4339600, Haslanger and others, U.S. patent 4801609, and others).

Intermediate compounds of formula XV are also described in the literature, or they can be obtained by modifications of known procedures. For example, intermediate compounds of formula XV, where X1is this how it was defined in the formula III is revealed Thorsett, etc., J. Med.Chem. 29, S. 251-260 (1988), Harris and others, in U.S. patent 4587050, 4587238, 4629787 and Yanagisawa and others, in U.S. patent 4734410. Intermediate compounds of formula X7) and 31, S. 422-428 (1988), Karanewsky in U.S. patent 4460579, Chevng and others, in U.S. patent 4594341, and Yanagisawa and others, in U.S. patent 4699905. Intermediate compounds of formula XV, where X1is this how it was defined in formula V are disclosed Karanewsky in U.S. patent 4460579 and 4711884. Intermediate compounds of formula XV, where X1are as defined in formula VI, and Y1is-CH2-, -(CH2)2- or -(CH2)3- open Watthey, etc., J. Med.Chem., 28, S. 1511-1516 (1985) and Watthey in U.S. patent 4410520, 4470988, 4473575, 4537885 and 4575503, and Parsons and others, in Biochemical and Biophysical Research Comm., 117 S. 108-113 (1983) and in U.S. patent 4873235. Intermediate compounds of formula XV, where X1is the same as defined in formula VI, and Y1is S or O, disclosed Slade and others, in J. Med.Chem., 28 c.1517-1521 (1985) and in U.S. patent 4477464, and Itoh and others, in Chem.Pharm.Bull., 34 c.1128-1147 (1986) and 34, S. 2078-2089 (1986), and Sugihara and others, in U.S. patent 4548932 (Y=0) and Katakami, and others, in U.S. patent 4539150 (Y=S). Intermediate compounds of formula XV, where X is as defined in formula VII can be obtained by recovering the corresponding intermediate compounds in which X1is the same as it was defined in formula VI. Intermediate compounds of formula XV, where X1is this how it was partitioned off in the formula IX, and Y2is S, SO or-SO2are disclosed Harris and others, and Patchett, and others, in U.S. patent 4415496 and 4617301. Intermediate compounds of formula XV, where X1is the same as it was defined in formula IX and Y2is CH2open Thorsett in Actual. Chim. Ther. , 13, S. 257-268 (1986). Intermediate compounds of formula XV, where X1is the same as it was defined in the formula XI, disclosed Attwood and others, Federation of European Biochemical Studies, 165, S. 201-206 (1984) and in U.S. patent 4512994, and Nataff and others, in Drugs of the Future, 12, S. 475-483 (1987). Intermediate compounds of formula XV, where X1is the same as it was defined in formula XII are disclosed Huang and others, in U.S. patent 4465679. Intermediate compounds of formula XV, where X1is the same as it was defined in formula XIII, reveals Bolos and others, in Tetrahedron 48, S. 9567-9576 (1992).

Intermediate compounds of formula XV, where X1is the same as it was defined in the formula III, g = 1 or 2, and R17is hydrogen, can be obtained as described below, which is also part of the invention.

N-phthalimido- -amino acid formula

< / BR>
and ester amino acid formula

< / BR>
where R12is an easily removable ester protective group, such is th combination is preferably carried out in the presence of binding reagent, such as benzotriazol-1-yl-oxytrol dimethylamino of the phosphonium hexafluorophosphate or ethyl-3-(3-dimethyl-amino)propellerpowered.

The compound of formula XXV is subjected to oxidation, for example by treatment with oxalylamino and dimethylsulfoxide or Tetra-n-Propylamine perruthenate and N-methylmorpholine N-oxide, resulting in a receive connection formulas

< / BR>
The compound of formula XXVI is subjected to cyclization by treatment with anhydrous acid, such as triperoxonane acid, trifluromethanesulfonate acid, hydrochloric acid, etc., resulting in a receive connection formulas

< / BR>
The intermediate compound of formula XV, where X1is the same as it was defined in the formula III, g = 1 or 2, and R6and R7are both hydrogen, can be obtained by treating the compounds of formula XXVII cilengitide, such as triethylsilane, diphenylmethylsilane, etc. and a catalyst such as Lewis acid, for example, tin chloride, titanium tetrachloride, methyl tin, Ateret boron TRIFLUORIDE, etc., with subsequent esterification of carboxyl groups, and then by treatment with hydrazine hydrate to remove N-falorni protective group.

The intermediate connection Faure is UB>6is not hydrogen, can be obtained from compounds of formula XXVII. For example, if R6is alkenyl or substituted by alkenyl with 3-7 carbon atoms, an intermediate compound is obtained by treatment of compound XXVII alkyl - or substituted by alkenylsilanes in the presence of Lewis acid as a catalyst, examples of which are listed above, followed by esterification of the carbonyl group, and then removing the N-falorni protective group. Alchemilla part can be subjected to hydrogenation to obtain the desired intermediate compounds in which R6is alkyl or substituted alkyl having 3-7 carbon atoms. If R6is not alkenyl or substituted by alkenyl, the desired intermediate compound is obtained by treatment of compound XXVII aluminum or titanium compound containing the corresponding R6in the presence of a Lewis acid followed by esterification of the carboxyl group, and then removing the N-falorni protective group.

The intermediate compound of formula XV, where X1is the same as it was defined in formula IX or X, Y2is-CH2and v=2, can be obtained as described below, so that the combination of complex ether - amino acid formula

< / BR>
in the presence of a catalyst reaction mix described above, resulting in a gain alcohol of the formula

< / BR>
The alcohol of formula XXX is subjected to oxidation, for example, by treatment with oxalylamino and receive the corresponding aldehyde, which is then treated with acid, such as triperoxonane acid or hydrochloric acid, resulting in a gain ester of carboxylic acid of the formula

< / BR>
After cyclization of compounds of formula XXXI strong acid, such as triftormetilfullerenov acid, followed by recrystallization carried out in the traditional way, and the processing of the sodium iodide receive a mixture of compounds of formulas

< / BR>
< / BR>
After removal of the N-naftanaila protective group of intermediate compounds of formula XXXIII, as described above, receive the desired compound of formula XV, where X1is the same as it was defined in formula X, and Y2is-CH2-.

Treatment of intermediate compounds of formula XXXII Tris (trimethylsilyl)silane or tri-n-butyanova hydride in the presence of catalytic amounts of azobisisobutyronitrile contributes iodo group. Then, as described above, remove the N-palolo GRU in the formula IX, v=2 and Y2is-CH2-. A similar procedure can be used to obtain the corresponding compound of formula XV, where X1is the same as it was defined in formula IX, v=1, and Y2is-CH2-.

Other procedures used to obtain the intermediate compounds of formula XV, as described in the examples.

The compounds of formula I contain one or more asymmetric centers. Thus, these compounds can exist in diastereoisomeric forms or as mixtures thereof, all of these forms are included in the scope of the invention. In the above-described methods, as starting materials can be used of the racemates, enantiomers, or diastereomers. If you want to get diastereoisomers connection, they can be separated by conventional methods, for example, by chromatography or fractional crystallization.

The compounds of formula I, where R12is hydrogen, can be obtained in the form of pharmaceutically acceptable salts. Suitable for these purposes salts are salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium or magnesium, and salts derived from amino acids, that is alentum Foundation, giving the desired ion in a medium in which the precipitated salt, or in an aqueous medium followed by lyophilization.

The compounds of formula I are inhibitors of double action, possessing the ability to inhibit angiotenzinkonvertiruyuschego enzyme and neutral endopeptidase. Therefore, the compounds of formula I, including pharmaceutically acceptable salts, can be used to treat physiological conditions, which shows the application or inhibitors of angiotensin-transforming enzyme, or inhibitors of neutral endopeptidase. Such physiological States are cardiovascular disease, for example, hypertension, congestive heart failure, renal failure, cirrhosis, and Energeticheskaya activity. Diuresis, natriuresis and blood pressure reduction can be stimulated by introducing to a mammal, such as man, about 1-100 mg per kg of body weight per day and preferably about 1-50 mg / kg of body weight per day of one or more inhibitors dual action formula I, or their pharmaceutically acceptable salts. Inhibiting compounds with dual action formula I is preferably used for oral Noah, intramuscular and intravenous. The daily dose can be entered as a single dose or in divided doses for 2-4 servings per day.

The dual action inhibitors of formula I can be introduced in combination with human ANF 99-126. This combination may contain an inhibitor of formula I in an amount of about 1-100 mg of body weight and human ANF 99-126 in an amount of about 0.001 to 0.1 mg per kg of body weight.

The dual action inhibitors of formula I can be introduced in combination with other classes of pharmaceutically active compounds, such as inhibitor calcium channel, potassium channel activator, a means for reducing the level of cholesterol, etc.

Inhibitors dual action formula I or their pharmaceutically acceptable salts, and other pharmaceutically acceptable ingredients can be used for the preparation of pharmaceutical compositions intended for such purposes. Suitable compositions for oral administration may be tablets, capsules, and elixirs; and suitable compositions for parenteral administration can serve as sterile solutions and suspensions. In accordance with standard pharmaceutical practice and acceptable content, carrier, binder, preservative, stabilizer, flavor, etc.

Preferred compounds of the present invention in relation to the mercapto-containing portion of the side chain having the formula

< / BR>
are compounds

where

R1represents hydrogen,

< / BR>
or

R18-S-,

R3represents a lower alkyl with 1-4 carbon atoms, or phenyl;

R18represents a lower alkyl with 1-4 carbon atoms;

n=0 or 1;

R2represents aryl-CH2-, substituted aryl-CH2heteroaryl-CH2-, or straight or branched alkyl with 1 to 7 carbon atoms;

R19represents hydrogen.

Most preferred are the above-mentioned mercapto-containing side chain, in which R1represents hydrogen, or

< / BR>
and especially hydrogen, n = 0, and R2represents benzyl, 2-thienyl methyl, or alkyl straight or branched chain having 1-5 carbon atoms, and more preferably, benzyl.

Preferred compounds of the present invention X1are the compounds of formula III in which g = 1 or 2, R4represents hydrogen, methyl, what etiam, or R6represents a lower alkyl with 1-4 carbon atoms, monosubstituted lower alkyl with 1-4 carbon atoms, or alkenyl with 3-5 carbon atoms having one double bond, and R7represents hydrogen, or R6and R7taken with the carbon atom to which they are bound, form cycloalkyl with 3-5 carbon atoms, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, b=0 or 1, R12is hydrogen or lower alkyl with 1-4 carbon atoms.

The most preferable of the above compounds of formula III are those compounds in which q = 2, R4and R5are both hydrogen, R6and R7both are stands, or R6is propylene, allyl or 2-hydroxyethyl and R7is hydrogen, b = 0, R10and R11are both hydrogen or one is hydrogen and the other is stands, R12is hydrogen.

Preferred compounds of the present invention in relation to the X1are the compounds of formula IV, in which v = 1, S = 0, R8is hydrogen, phenyl, or lower alkyl with 1 to 4 atoms of plastics technology: turning & the B>6is lower alkyl with 1-4 carbon atoms, or phenyl, and R7is hydrogen, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, b = 0, R12is hydrogen or lower alkyl with 1-4 carbon atoms.

The most preferable of the above compounds of formula IV are compounds in which R8is hydrogen or phenyl, R6and R7both are hydrogen, or R6is phenyl, and R7is hydrogen, R10, R11and R12are all hydrogen;

Preferred compounds of the invention in relation to the X1are the compounds of formula V in which S = 0, t = 1 or 2, R6and R7both are hydrogen or both are stands, or R6is lower alkyl with 1-4 carbon atoms, or phenyl, and R7is hydrogen, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, b = 0, R12is hydrogen or lower alkyl with 1-4 carbon atoms.

The most preferable of the above compounds of formula V are the SUB> are all hydrogen.

Preferred compounds of the invention in relation to the X1are the compounds of formula VI in which Y1is O, S or CH2, R6and R7both are hydrogen, or R6is lower alkyl with 1-4 carbon atoms, and R7is hydrogen, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, b = 0, R12is hydrogen or lower alkyl with 1-4 carbon atoms.

The most preferable of the above compounds of formula VI are compounds in which Y1is CH2, R6and R7are both hydrogen, R10, R11and R12all are hydrogen.

Preferred compounds of the invention in relation to the X1are the compounds of formula VII in which Y4is-CH2-, R6and R7are both hydrogen, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, but especially preferably, when both radicals are hydrogen, b = 0, R12is hydrogen, or lower arcticline compounds of the invention in relation to the X1are the compounds of formula VIII, in which R6and R7are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, and especially preferably, if both are hydrogen, b = 0, R12is hydrogen or lower alkyl with 1-4 carbon atoms, and especially preferably, if R12is hydrogen.

Preferred compounds of the invention in relation to the X1are the compounds of formula IX, where v = 1 or 2, and preferably 2, w = 1 or 2, Y2is S or CH2, R12is hydrogen or lower alkyl with 1-4 carbon atoms, especially preferably, if R12is hydrogen.

Preferred compounds of the invention in relation to the X1are the compounds of formula X in which Y2is CH2, w = 1 or 2, and preferably 2, R12is hydrogen or lower alkyl with 1-4 carbon atoms, and especially preferably, if R12is hydrogen.

Preferred compounds of the invention in related and hydrogen, and preferably two hydrogen atoms, R12is hydrogen or lower alkyl with 1-4 carbon atoms, and preferably hydrogen.

Preferred compounds of the invention in relation to the X1are the compounds of formula XII, in which z is 0, or two hydrogen atoms, and preferably 0, R17is lower alkyl with 1-4 carbon atoms, and preferably the stands, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, and preferably, if both are hydrogen, b = 0, R12is hydrogen or lower alkyl with 1-4 carbon atoms, and preferably hydrogen.

Preferred compounds of the invention in relation to the X1are the compounds of formula XIII where Y3is CH2or S, and preferably CH2, R13is hydrogen, R10and R11are both hydrogen or one is hydrogen and the other is lower alkyl with 1-4 carbon atoms, and preferably, if both are hydrogen, b = 0, R12is hydrogen or lower alkyl with 1-4 carbon atoms, and preferably hydrogen.

Example kasna acid.

a) (S)-2-[(Acetylthio)methyl]benzoylpropionate acid, avedisova salt.

A solution of (1R, 2S)-(-)-ephedrine (17.3 g, 105 mm) in diethyl ether (175 ml) was added in one portion entirely to a solution of 2-[(acetylthio)methyl]benzoylpropionic acid (50.0 g, 210 mm) in diethyl ether (175 ml). After keeping the resulting solution for 16 h at room temperature, crystallized ephedrinebuy salt was collected by filtration (19.7 g), so pl. 114 - 125oC []D= -40,6o(c = 1, methanol). After incubation for 20 h at room temperature, the filtrate was allocated an additional amount of solids in (8.9 g), so pl. 121 - 126oC []D= 57,2o(c = 1, methanol). Then the solids were combined and recrystallized from acetonitrile (1500 ml). After incubation for 16 h at room temperature, collected by 20.8 g of the solid product, so pl. 125 - 130oC []D= -47,5o(c = 1, methanol). This product is recrystallized in a similar way from acetonitrile (300 ml), resulting in a received 18,74 g of the product, so pl. 128 - 130oC []D= -48,9o(c = 1, methanol). After the third recrystallization from acetonitrile (225 ml) was received of 17.4 g of solid (S)-2-[(acetylthio)methyl]benzodiapines acid, efedra the SUB>14O3S C10H15NO:

Calculated,%: C 65,48; H 7,24; N 3,47; S 7,95;

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

b) [3R(S*)]-3,4-Dihydro-3-[[2-[(acetylthio)methyl]-1 - oxo-3-phenylpropyl] amino-4-oxo-1,5-benzothiazepin-5(2H)-acetic acid ethyl ester.

(S)-2-[(Acetylthio)methyl] benzoylpropionic acid ephedrinebuy salt (3,34 mm, 1,01 EQ.) suspended in ethyl acetate (66 ml), washed with diluted HCl (65 ml water + 4,7 ml of 1.0 N. hydrochloric acid, and then 31 ml of water and 1.6 ml of 1.0 N. hydrochloric acid), brine (10 ml), dried with anhydrous magnesium sulfate, filtered, and evaporated to dryness. Colorless syrup was dried in vacuum for 1.0 h with obtaining quantitative yield in the form of the free acid (836 mg).

The free acid was dissolved in anhydrous dimethylformamide (19 ml) was cooled to 0oC (ice/salt bath), treated with 1-hydroxybenzotriazole (470 mg, 3,48 mm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (690 mg, 3,60 mm), and then stirred for 1 h in argon atmosphere. The clear solution was treated with (R)-3,4-dihydro-3-amino-4-oxo-1,5 - benzothiazepin-5(2H)-acetic acid, ethyl ether complex, obtained in accordance with known procedure (Slade and others, J. Med. Chem. 28, S. 1517-1521 (1985)) (1,2 tour. The reaction mixture was diluted with ethyl acetate (80 ml), washed successively with water (12 ml), 5% potassium bisulfate (12 ml), water (12 ml), saturated sodium bicarbonate (12 ml), and brine, and then dried (anhydrous magnesium 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 and hexane (1: 4), resulting in a received 1.5 g of product in the form of syrup, Rf= 0,68 (ethyl acetate:hexane, 1:1)

c) (3R(S*)-3,4-Dihydro-3-[[2-(mercaptomethyl)-1-oxo-3 - phenylpropyl] amino]-4-oxo-1,5-benzothiazepin-5(2H)-acetic acid

A solution of the product of ethyl ether complex, obtained in part (a), (1.5 g, 2,996 mm) in anhydrous methanol (15 ml) was purged for 15 min with argon, was cooled to 0oC (ice/salt bath), and then drop was treated previously purged (argon, 30 minutes) solution of 1.0 n sodium hydroxide (12 ml, 4 EQ), and while adding and throughout the reaction, the solution was barbotirovany argon. Then the reaction mixture was stirred 1 h at 0oC, acidified (at 0oC) 5% potassium bisulfate (50 ml) to bring the pH to 1.0, and were extracted with ethyl acetate (2 100 ml). The organic extract was washed sole is accidenly product was dissolved in a mixture of methylene chloride (10 ml) and ethyl ether (5.0 ml), then the parts were treated with hexane (30 ml), stirring the mixture before formation of solids. The precipitate was filtered, washed with hexane (50 ml) for 48 h at room temperature in a nitrogen atmosphere, filtered and dried in vacuum for 5 h, which was obtained 1.01 g of product as an amorphous solid, Rf= 0,62(methylene chloride: methanol:acetic acid, 20:1:1), []D= -171,4o(c = 0,74, methanol).

1H-NMR(CDCl3): 2,47 - 2,90 (m, 6H); a-3.84 (DD, 1H); 4,13 (d, 1H, J = 17 Hz); 4,71 (m, 1H); 4,85 (d, 1H, J = 17 Hz); 6,88 - to 7.67 (m, 9H).

Elemental analysis for C21H22N2O4S2:

Calculated: C 58,59; H 5,15; N 6,51; S 14,89; SH 7,68;

Found: C 58,55; H 5,35; N 6,20; S 14,56; SH 7,54.

Example 2.

[R-(R*S*)] -3,4-Dihydro-3/-[(2-mercapto-1-oxo-3 - phenylpropyl)]-amino] -4-oxo-1,5-benzothiazepin-5(2H)-acetic acid.

a) (S)-2-(Acetylthio)benzoylpropionate acid, dicyclohexylamine salt.

Sodium nitrite (10.3 g, 280 mm) was added during 1 h to a solution of D-phenylalanine (30.0 g, 181 mm) and potassium bromide (73,5 g) in sulfuric acid (2,5 N. , 365 ml) while maintaining the temperature of the reaction mixture at 0oC. the mixture is Then stirred at 0oC for another 1 h, and then embedded temu the extraction of water, and the ether layer was dried with sodium sulfate. The ether was removed in vacuum, the oily residue person to distil, and received of 25.7 g (R)-2-bromo-3-benzoylpropionic acid, so Kip. 141oC (0.55 mm RT. Art. []D= +14,5o(=2,4, chloroform).

The mixture teoksessa acid (7 ml, 97,9 mm) and potassium hydroxide (5,48 g, 97,9 mm) in acetonitrile (of 180.5 ml) was stirred for 1.75 h at room temperature and in the presence of nitrogen. Then the mixture was cooled in an ice bath for 10 minutes was added a solution of (R)-2-bromo-3-benzoylpropionic acid (20.4 g, 89 mm) in acetonitrile (20 ml). The reaction mixture was stirred for 5 h at room temperature in an argon atmosphere, was filtered and the acetonitrile was removed in vacuum. The obtained oily residue was again dissolved in ethyl acetate and washed with 10% potassium bisulfate and water. After removal of the ethyl acetate in vacuo, received, and 19.6 g of the crude product. This product was purified in the form of its dicyclohexylamine salt, using isopropyl ether as a solvent for crystallization. An analytical sample of (S)-2-(acetylthio)benzoylpropionic acid, dicyclohexylamine salt was obtained by recrystallization from ethyl acetate, so pl. 146 - 147oC []D= -39,6o(C = 1,39, chloroform).

(b) [R-R*S*)] -3,4-Dihydro-3-[[2-(acetylthio)- 1-oxo-3-phenylpropyl] amino] -4-oxo-1,5-benzothiazepin-5(2H)-acetic acid ethyl ester.

A suspension of (S)-2-(acetylthio)benzoylpropionic acid, dicyclohexylamine salt (1,76 g, 4,34 mm, 1,01 EQ.) suspended in ethyl acetate (123 ml), washed with 5% potassium bisulfate (5 of 19 ml) and brine (25 ml) and then dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuum.

The free acid was dissolved in anhydrous methylene chloride (25 ml), cooled to 0oin an ice/salt bath, was treated with 1-hydroxybenzotriazole (611 mg, 4.52 mm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (897 mg, 4,68 mm) and stirred 1 h at 0oC. the resulting solution was treated with (R)-3,4-dihydro-3-amino-4-oxo-1,5-benzothiazepin-5(2H)-acetic acid ethyl ether complex, obtained in accordance with known procedure (Slade and others , J. Med. Chem. vol. 28, S. 1517 - 1521 (1985)) (1.55 g, 4,29 mm) and 4-methylmorpholine (of 0.48 ml, 4,37 mm), and then continued to stir 1 h at 0oC, and 1 h at room temperature. The reaction mixture was diluted with ethyl acetate (104 ml), washed successively with water (16 ml), 5% potassium bisulfate (2 16 ml), saturated b is perivale to dryness and dried in vacuum. The crude product was chromatographically on a column of silica gel (Merck), elwira a mixture of ethyl acetate and hexane (1: 4), resulting in a received 1,347 g of the product in the form of syrup, Rf= 0,80 (ethyl acetate:hexane, 1:1).

c) [R-(R*S*)] -3,4-Dihydro-3-[[(2-mercapto-1 - oxo-3-phenylpropyl)]-amino]-4-oxo-1,5-benzothiazepin-5(2H) acetic acid.

A solution of the product of ethyl ether complex, obtained in part (b), (1,347 g 2,768 mm) in methanol (14 ml) was purged for 30 min with argon, was cooled to 0oC in an ice/salt bath and was treated dropwise previously purged (argon, 30 minutes) solution of 1.0 n sodium hydroxide (11 ml, 4 EQ. ), and, while adding and during the reaction the solution was barbotirovany argon. Then the reaction mixture was stirred 1 h at 0oC, acidified at 0oC 5% potassium bisulfate (46 ml) to bring the pH to 2.0 and extracted with ethyl acetate (2 100 ml). The organic extracts were washed brine (25 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was dissolved in methylenechloride (10 ml) and the portions were treated with hexane (50 ml), stirring the mixture before formation of solids. The supernatant of decana 4 h with the first 100 ml of pentane, and then during the night even with 100 ml of pentane in an argon atmosphere. After that, the obtained product was dried in vacuum for 12 h and resulted 1,048 g of amorphous solids, Rf= 0,57 (methylene chloride:methanol:acetic acid, 20:1:1), []D= -169,9o(C = 0,61, methanol).

1H-NMR (CDCl3): 1,99 (d, 1H); was 2.76 (t, 1H, J = 11 Hz); 3,10 (m, 2H); of 3.54 (m, 1H); 3,76 (m, 1H); 4,10 (d, 1H, J = 17 Hz); the 4.65 (m, 1H), a 4.86 (d, 1H, J = 17 Hz); 7,12 - to 7.68 (m, 9H).

Analysis for C20H22N2O4S 0,17 C5H120,52 H2O:

Calculated: C 57,15; H and 5.30; N 6,40; S 14,64; SH 7,55;

Found: C 57,15; H 4,99; N 6,14; S 14,72; SH 8,02.

Example 3.

(S, S)-1,3,4,5-Tetrahydro-4-[[2-(mercaptomethyl)-1-oxo-3 - phenylpropyl] amino]-3-oxo-2H-2-benzazepin-2-acetic acid.

a) N-(N-phthaloyl-L-i.e. phenylalanyl)glycine, ethyl ester

Hydroxybenzotriazole (1.42 g, 10.5 mm) and 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (2.10 g, 11,0 mm) was added to a solution of N-phthaloyl-L-phenylalaninamide (2,95 g, 10.0 mm) in dry methylene chloride (30 ml) at 0oC in the presence of argon. After 30 minutes stirring at 0oC the resulting mixture was treated with glycine complex ethyl ester, hydrochloride (1,675 g, 12.0 mm) and N-methylmorpholine (1,32 ml, 12.0 mm).

oC, Rf= 0,33 (acetone:hexane, 2:3), []D= -99,7o(C = 0,61, chloroform).

b) (S)-1,3,4,5-tetrahydro-4-phthalimido-3-oxo-2H-2-benzazepin - 2-uksusnaya acid, ethyl ester.

The mixture pentoxide formula (9.6 g, 68 mm) and 85% phosphoric acid (6.0 ml) was heated, stirred, until, until you dissolve the phosphorus pentoxide. The obtained viscous liquid was dissolved in glacial acetic acid (36 ml) was treated sequentially with N-(N-phthaloyl - L-i.e. phenylalanyl)glycine ethyl ether complex (2,241 g 5,90 mm) and dioxane (0.75 g, 8.3 mm) and then was heated at 80oC (bath temperature) in an argon atmosphere. After a 6.5-hour stirring at 80oC, the mixture was additionally treated with trioxane (0.75 g, 8.5 mm). The mixture is then stirred for another 16 h at 80oC, after which it was rapidly cooled with a mixture of ice water and was extracted with ethyl acetate. Ethylacetate the extract was washed with water (3x), nasimento sodium and evaporated to dryness. The crude product was purified using flash chromatography on silica gel (Whatamann LRS-1), elwira a mixture of ethyl acetate and hexane (35: 65), and received 1,718 g of the product as a colorless foamy substance, Rf= 0,38 (ethyl acetate:toluene, 3:7).

c) (S)-1,3,4,5-tetrahydro-4-[[(phenylmethoxy)carbonyl] amino] -3 - oxo-2H-2-benzazepin-2-acetic acid, ethyl ester.

A solution of (S)-1,3,4,5-tetrahydro-4-phthalimido-3-oxo-2H-2 - acetic acid, ethyl ether complex (1,67 g, 4.26 deaths / mm) 1.0 M hydrazine hydrate in ethanol (9.0 ml, 9.0 mm) and stirred for 36 h at room temperature and in an atmosphere of argon. The resulting mixture was diluted with an equal volume of ethyl acetate, filtered, and the filtrate evaporated to dryness. The residue was dissolved in toluene and again evaporated to dryness. Colorless semi-solid residue (1,81 g) was dissolved in anhydrous methylene chloride (20 ml) was placed in an ice bath and treated successively with triethylamine (0,80 ml, 5.8 mm) and benzylchloride (of 0.77 ml, 5.4 mm). After 2 hours stirring at 0oC, the mixture was distributed between ethyl acetate and 5% potassium bisulfate. The organic phase is washed successively with 5% potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride and then dried sulfate Whatmann LRS-1) (eluant: a mixture of ethyl acetate and hexane, 1: 2) received 1,0747 g of the product as a colorless foamy substance, Rf= 0,52 (ethyl acetate: toluene, 3:7). After a simple crystallization from hexane received the product, so pl. 80 - 82oC []D= +87,2o(c = 0,53, chloroform).

d) (S)-1,3,4,5-Tetrahydro-4-amino-3-oxo-2H-2-benzazepin-2-acetic acid, ethyl ester

20% palladium hydroxide/carbon as a catalyst was added to a solution of (S)-1,3,4,5-tetrahydro-4-[[(phenylmethoxy)carbonyl] amino]- 3-oxo-2H-2-benzazepin-2-acetic acid, ethyl ether complex (1,037 g, 2,62 mm) in absolute ethanol (20 ml) and the resulting suspension stirred for 2 hours in an atmosphere of hydrogen (balloon). The mixture was filtered through celite and the filtrate evaporated to dryness. Semi-solid residue is triturated with hexane and got to 0.63 g of product as a white crystalline solid, so pl. 71 - 73oC, Rf= 0,38 (methanol : methylene chloride, 1:9), []D= 77,5o(c = 0,59, chloroform).

e) (S, S)-1,3,4,5-Tetrahydro-4-[[2-[(acetylthio)methyl]-1-oxo - 3-phenylpropyl]amino]-3-oxo-2H-2-benzazepin-2-acetic acid, ethyl ester

(S)-2-[(Acetylthio)methyl] benzoylpropionate acid [obtained from ephedrinebuy salt, as described previously] was subjected to reaction with the product from part (b) according to the/SUB> = 0,30 (ethyl acetate : hexane, 1:1).

f) (S, S)-1,3,4,5-Tetrahydro-4-[[2-(mercaptomethyl)-1-oxo-3 - phenyl-propyl]amino]-3-oxo-2H-2-benzazepin-2-acetic acid

A solution of the product obtained in part (e), in methanol was treated according to the procedure described in example 1, part (c) and obtained white solid product, so pl. 149 - 151oC (Razlog.), Rf= 0,47 (methylene chloride : acetic acid, methanol, 20:1:1), []D= +to 112.2o(c = 0,58, methanol).

Analysis for C22H24N2O4S:

Calculated: C 64,06; H 5,86; N 6,79; S to 7.77; SH 8,02;

Found: C 64,20; H 6,09; N To 6.43; S 7,68; SH 8,33.

Example 4.

(S, S)-1,3,4,5-Tetrahydro-4-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-3-oxo-2H-2-benzazepin-2-acetic acid

a) (S,S)-1,3,4,5-tetrahydro-4-[[2-(acetyl)-1-oxo-3 - phenylpropyl]-amino] -3-oxo-2H-2-benzazepin-2-acetic acid, ethyl ester

(S)-2-(Acetylthio)-benzoylpropionate acid [obtained from dicyclohexylamine salt, as described previously] was subjected to reaction with the product of example 3(d) according to the procedure described in example 2, part (b), and obtained target product as a colorless foamy substance; Rf= 0,35 (ethyl acetate : hexane, 1:1).

b) (S,S)-1,3,4,5-tetrahydro-4-[(2-mercapto-1-oxo-3-phenyl - propyl)amino] -3-oxo-2H-2-oxide sodium in accordance with the procedure described in example 2, part c, resulting in a received target product as a white solid, so pl. 181 - 183oC (decomposition), Rf= 0,49 (methylene chloride : acetic acid : methanol, 20:1:1), []D= +103,4o(c = 0,57, methanol).

Analysis for C21H22N2O4S:

Calculated: C 63,30; H 5,56; N 7,03; S 8,05; SH 8,30;

Found: C 63,35; H 5,65; N 6,87; S 8,07; SH 9,40.

Example 5.

[S-(R*, R*)] -2,3,4,5-tetrahydro-3-[[(2- (mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-2-oxo-1H-benzazepin-1 - acetic acid

a) [S-(R*, R*)-2,3,4,5-tetrahydro-3-[[2- [(acetylthio)methyl]-1-oxo-3-phenylpropyl] amino]-2-oxo-1H-benzazepin - 1-acetic acid, ethyl ester

(S)-2-[(Acetylthio)methyl]benzoylpropionic acid ephedrinebuy salt (1,547 g, 3,83 mm, 1,01 EQ. ) suspended in ethyl acetate (72 ml), washed with diluted hydrochloric acid (72 ml water + 5,4 ml of 1.0 N. hydrochloric acid, and then 36 ml of water and 1.8 ml of 1.0 N. hydrochloric acid) and a salt solution (12 ml), was dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. Colorless syrup was dried in vacuum for 1 h and was received of 1.062 g (S)-2-[(acetylthio)methyl]benzoylpropionic acid.

The free acid was dissolved in anhydrous dimethylformamide (21,8 ml), OHL(3-dimethylaminopropyl)carbodiimide (792 mg, 413 mm) and stirred for 1 h at 0oC in argon atmosphere. The clear solution was treated with (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepin-1-acetic acid ethyl ether complex, obtained in accordance with the description (Watthey, etc., J. Med.Chem., 28, pp. 1511-1516 (1985)) (1.0 g, 3,81 mm) and continued to stir for 1 h at 0oC and for 1 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 ml), washed successively with water (15 ml), 5% potassium bisulfate (215 ml), saturated sodium bicarbonate 15 ml) and brine (15 ml) and then dried with anhydrous magnesium 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 and hexane(1: 4, 1:2), resulting received 1,725 g of the product as a syrup, Rf= 0,42 (ethyl acetate : hexane, 1:1).

b) [S-(R*, R*)] -2,3,4,5-tetrahydro-3-[[2- (mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-2-oxo-1H-benzazepin - 1-acetic acid

A solution of the product of ethyl ether complex, obtained in part (a), (1,725 g 3,574 mm) in methanol (18,0 ml) was purged for 30 min with argon, was cooled to 0oC in an ice/salt bath, and then drop handle is occurring and during the entire reaction, the solution was barbotirovany argon. Then the reaction mixture was stirred for 1 h at 0oC, acidified at 0oC 5% potassium bisulfate (60 ml) to bring the pH to 1 and then were extracted with ethyl acetate (2 120 ml). The organic extracts were washed brine (30 ml), dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was dissolved in methylene chloride (10 ml) and treated in parts hexane (50 ml), stirring until the formation of solids. The supernatant decantation, and the solid residue triturated with more hexane (250 ml) and pentane (250 ml) and pentane (2100 ml), stirring for 4 h with the first 100 ml of pentane, and then overnight in an argon atmosphere with the latest 100 ml of pentane. The obtained product was dried in vacuum for 12 h, resulting in a received 1,438 g of amorphous solids, Rf= 0,53 (methylene chloride : methanol : acetic acid, 20:1:1), []D= -140,4o(c = 0,76, methanol).

Analysis for C22H24N2O4S 0,11 C5H12:

Calculated: C 64,42; H 6,07; N 6,66; S 7,63; SH 7,87;

Found: C 64,07; H 6,13; N 6,34; S 7,25; SH 7,14.

1H-NMR CDCl3: to 1.42 (t, 1H); 1,95 (m, 1H); 2,44-2,90 (m, 7H); with 3.27 (m, 1H); 4,37 (d, 1H, J = 17 Hz); to 4.52 (m, 1H); of 4.67 (d, 1H, J = 17 Hz); sawdust)amino]-2-oxo-1H-benzazepin-1-acetic acid

a) [S-(R*,R*)]-2,3,4,5-tetrahydro-3-[[2-(acetylthio)-2 - oxo-3-phenylpropyl]amino]-2-oxo-1H-benzazepin-1-acetic acid, ethyl ester

A suspension of (S)-2-(acetylthio) benzoylpropionic acid dicyclohexylamine salt (1.70 g, 4,19 mm) suspended in ethyl acetate (120 ml), washed with 5% potassium bisulfate (520 ml) and brine (25 ml), dried with anhydrous magnesium sulfate, filtered, evaporated to dryness, dried in vacuo, resulting in a received 954 mg of the free acid in the form of syrup.

This free acid was dissolved in dry methylene chloride (25 ml) and cooled to 0oC in an ice/salt bath, and then treated with 1-hydroxybenzotriazole (594 mg, 4,40 mm) and 1-ethyl-3-3-dimethylaminopropyl a carbodiimide (870 mg, of 4.54 mm) and stirred for 1 h at 0oC. the resulting solution was treated with a solution of ester ethyl (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepin-1-acetic acid obtained in accordance with known description (Watthey, etc., J. Med.Chem., 28, pp. 1511-1516 (1985)), (1.0 g, 3,81 mm) in dry methylene chloride (10 ml) and continued to stir for 1 h at 0oC for 1.5 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 ml), washed sequence is then dried with anhydrous sodium sulfate, was 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 and hexane(1:4, 1:2), and received 1,632 g of the product in the form of syrup. In addition, the speaker also received an additional 127 ml isomeric mixture (in the ratio 1:1), Rf= 0,50 (ethyl acetate : hexane, 1:1).

b) [S-(R*, R*)] -2,3,4,5-tetrahydro-3-[(2-mercapto - 1-oxo-3-phenyl-propyl)amino]-2-oxo-1H-benzazepin-1-acetic acid

A solution of the product of ethyl ether complex, obtained in part (a), (1,57 g, 3,35 mm) in methanol (17,0 ml) was purged with argon for 30 min, cooled to 0oC in an ice/salt bath, and then drop processed in advance purged (argon, 30 minutes) solution of 1.0 n sodium hydroxide (13.4 ml, 4.9 EQ. ), while adding and throughout the reaction, the solution was barbotirovany argon. Then the reaction mixture was stirred 1 h at 0oC, acidified at 0oC 5% potassium bisulfate (60 ml) to bring the pH to 1 and was extracted with ethyl acetate (2110 ml). The organic extracts were washed brine (30 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was dissolved in methylene chloride (10 liquid decantation, and the solids triturated with more hexane (250 ml) and pentane (2100 ml), and the first stirred with the first 100 ml of pentane for 4 h, and then the next 100 ml. overnight in an argon atmosphere. The obtained product was dried in vacuum for 12 hours and resulted 1,237 g, Rf= 0,58 (methylene chloride:methanol:acetic acid, 20:1:1), []D= -155,6o(c = 0,73, methanol).

Analysis for C21H22N2O4S 0.1 C5H120,18 H2O:

Calculated: C 63,14; H of 5.81; N 6,85; S 7,84; SH 8,09;

Found: C 63,14; H of 5.85; N To 6.58; S 7,50; SH 7,05.

1H-NMR (CDCl3): of 1.88 (m, 1H); 1,97 (d, 1H); 2,62 (m, 2H); of 3.07 (m, 2H); of 3.25 (m, 1H); 3,51 (m, 1H); 4,39 (d, 1H, J=17 Hz); of 4.45 (m, 1H); with 4.64 (m, 1H, J = 17 Hz); 7,07-7,41 (m, 9H).

Example 7.

[2S-[ 2, 5 (R*)] ] -5,6-Dihydro-5-[(2-mercapto-1-oxo - 3-phenylpropyl)amino]-4-oxo-2-phenyl-2H-1,3-triazine-3(4H)-acetic acid

a) (2S-CIS)-5,6-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazin - 3(4H)-acetic acid, ethyl ester

In accordance with the procedure described in U.S. patent N 4460579 (example 1(a) to 1(c) received 15.6 g of a mixture diastereomeric product. The mixture was heated under reflux for 4 hours in ether (500 ml), cooled in an ice bath and filtered in through the CSOs of ester, so pl. 166 - 168oC, Rf= 0,40 (hexane:ethyl acetate, 1:1), []D= was 72.9o(c = 1, chloroform).

Analysis for C22H20N2O5S:

Calculated: C 62,25; H 4,75; N 6,60; S TO 7.77;

Found: C 62,21; H 4,82; N 6,63; S 7,52.

After grinding the remaining product mixture with ether (125 ml) at a temperature of distillation was awarded a second party (0.9 g) (2R-TRANS)-isomer of the product. The residue is again triturated with ether at a temperature of distillation was obtained 0.75 g of insoluble substances, mainly (2R-TRANS)-isomer, and 7.1 G. of a material enriched (2S-CIS)-isomer. 6.0 g of this enriched (2S-CIS)-isomer of the material was chromatographically on two interconnected columns (Waters Prep LC, elwira mixture of hexanol and ethyl acetate (3:1). After combining the relevant fractions were obtained 4.8 g (2S-CIS)-5,6-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazin - 3(4H)-acetic acid ethyl ether complex, so pl. 66 - 68oC []D= -101,2o. TLC was performed as for isomer A.

Analysis for C22H20N2O5SH2O:

Calculated: C 61,83; H 4,79; N 6,55; S 7,50;

Found: C 61,83; H 5,07; N 6,25; S 7,42.

b) (2S-CIS)-5,6-Dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazin - 3(4H)-acetic acid, ethyl slojnye, 3.03 g, 7.1 mm) in chloroform (15 ml) was treated with methylhydrazine (850 μl, 736 mg, 16,0 mm). After 24 hours stirring at room temperature, the mixture was diluted with ethyl acetate and ethyl ether, and then filtered. The filtrate was extracted twice with 0.5 g of hydrochloric acid and the combined aqueous extracts were podslushivaet 1 N. sodium hydroxide. The aqueous mixture was extracted three times with methylene chloride and the combined methylenechloride extracts were dried with sodium sulfate, filtered and evaporated, resulting in a received 1,648 g of the product as a pale yellow oily substance, Rf= 0,43 (methylene chloride:acetic acid:methanol, 8: 1:1).

NMR analysis showed that the resulting product is approximately 84% diastereomeric clean.

c) [2S-[ 2, 5 (R*)]]-5,6-Dihydro-5-[[2-(acetylthio)-1-oxo - 3-phenylpropyl] amino] -4-oxo-2-phenyl-2H-1,3-thiazin-3(4H)-acetic acid, ethyl ester

(S)-2-(Acetylthio)benzoylpropionic acid dicyclohexylamine Sol (1, 318 g of 3.25 mm) was distributed between ethyl acetate and 5% potassium bisulfate. An ethyl acetate layer was washed with water and brine, and then dried with sodium sulfate, filtered and evaporated, resulting in the obtained free acid rescueremedies purity, 960 mg, 3,26 mm) was dissolved in methylene chloride (25 ml) was treated with 1-hydroxybenzotriazole (622 mg, 4.6 mm) and cooled to -10oC. Then the mixture was treated with 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (687 mg, to 3.58 mm). After a slow (over 1 h) heat up the 0oC, the mixture was heated to room temperature. After 4 h, the solution was diluted with ethyl acetate and washed successively with water, 5% potassium bisulfate, again with water, saturated sodium bicarbonate and brine, and then dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica, ethyl acetate:hexane = 1: 1) and received 804 mg of product as a colorless foamy substance, Rf= 0,33 (50% ethyl acetate in hexane). NMR analysis showed that in respect of acetylthiazole this product had diastereometric the purity of 91%.

d) [2S-[ 2, 5 (R*)]]-5,6-Dihydro-5-[[2-mercapto-1-oxo - 3-phenylpropyl] amino]-4-oxo-2-phenyl-2H-1,3-thiazin-3(4H)-acetic acid

The solution telefonnogo of the product obtained in part (c), (550 mg, 1.0 mm) in methanol (5 ml, deoksigenirovanii by ozonation of argon) at 0oC was treated with ice 1 N. sodium hydroxide (5 ml, deoksigenirovanii through barbotirovany 10% potassium bisulfite (15 ml), was diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, and then dried with sodium sulfate, filtered and evaporated, resulting in the obtained oily, foamy product. This product was subjected to flash chromatography (Merck silica, methylene chloride: methanol:acetic acid = 20:1:1). The fractions containing the desired product were combined and evaporated, and the residue was dissolved in ethyl acetate and washed successively with water, 0.5 to N. hydrochloric acid and brine, and then dried with sodium sulfate, filtered and evaporated. The obtained oily product was dissolved in a small amount of ethyl acetate and ethyl ether and triturated with hexane. The mixture was evaporated to dryness, suspended in hexane was again evaporated to dryness, dried in vacuum and received 392 mg of product as a white foamy substance, Rf= 0,24 (methylene chloride:methanol:acetic acid, 20:1:1, []D= -13,2o(c =0.5, chloroform).

HPLC: column UMC S3ODS (6,h mm); elution 44% A: 90% water - 10% methanol - 0.2% of phosphoric acid; and 56% B: 10% water - 90% methanol - 0.2% of phosphoric acid; flow rate 1.5 ml/min with detection at 220 nm; tR= 26,22 min and tR= 24,64 min (9,3% 5 (S*)-isomer).

Analysis of DL is co-2-phenyl-2H-1,3-thiazin-3(4H)-acetic acid

a) [2S - 2, 5 (R*)]]-5,6-Dihydro-5-[[2-[(acetylthio)methyl]-1-oxo - 3-phenylpropyl] amino-4-oxo-2-phenyl-2H-1,3-thiazin-3(4H)-acetic acid ethyl ester.

(S)-2-[(Acetylthio)methyl] benzoylpropionate acid (obtained from ephedrinebuy salt in accordance with the description above) was subjected to a reaction product obtained in example 7 (part b) in accordance with the procedure described in example 1 (part b), resulting in a received target product as a white foamy product, Rf= 0,29 (50% ethyl acetate in hexane). NMR analysis showed that the resulting product is diastereometric clean.

b) [2S - 2, 5 (R*)] ]-5,6-dihydro-5-[[2-(mercaptoethyl)-1-oxo - 3-phenylpropyl]amino-4-oxo-2-phenyl-2H-1,3-thiazin-3(4H)-acetic acid

A solution of the product obtained in part (a), in methanol was treated with 1 N. sodium hydroxide according to the procedure described in example 1 (part (c), resulting in a received target product as a white, relatively hard, foam-like substance, Rf= 0,29 (methylene chloride:methanol:acetic acid, 20:1:1), []D= +42,9o(c = 1.0, chloroform).

HPLC: column UMC S3ODS (6,0150 mm), elution 44% A: 90% water - 10% methanol - 0.2% of phosphoric acid, and 56% B: 10% water - 90% methanol - 0.2%of B>22H24N2O4S2:

Calculated: C 59,44; H 5,44; N 6,30; S 14,42; SH 7,44;

Found: C 59,63; H of 5.84; N 5,99; S 14,54; SH 6,83.

Example 9.

(S,S)-Hexahydro-3-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino - 2-oxo-1H-azepin-1-acetic acid

a) N2-[1,1-Dimethoxy)carbonyl]-N6- [(phenylmethoxy)carbonyl]-L-lysine, methyl ester

The cesium carbonate (4,28 g, 13.1 mm) was added to a mixture of N2-[(1,1-dimethylmethoxy)carbonyl] -N6- [(phenylethane)carbonyl]-L-lysine (10 g, 26,3 mm) and 20% of water and methanol (60 ml). After 5 min the solution became homogeneous, and then the solvent is evaporated and the residual water azeotropically removed using acetonitrile (3x). The obtained oily product was dried in vacuum, dissolved in anhydrous dimethylformamide and treated with methyliodide (3.2 ml, 2.0 EQ.). The reaction mixture was stirred 1.5 h at room temperature in an argon atmosphere, diluted with ethyl acetate (200 ml) and washed successively with water (226 ml), saturated sodium bicarbonate (25 ml) and brine (25 ml). The organic phase was dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in a received 10,11 g of the product as a pale yellow Sirop-he

The solution mutilating of the product obtained in part (a), (8,532 g, 21,63 mm) in dry methanol (100 ml) was treated with 10% palladianism carbon (catalyst, 2,13 g) and hydrogenosomal 2 h under a pressure of 50 psi (344,7 kPa). The mixture was diluted with methanol (100 ml) and filtered through a layer of celite in millipore.com the filter, carefully washing the layer with methanol (3100 ml). Transparent filtrate is evaporated to dryness, dried in vacuum and the resulting oily product was dissolved in dry xylene (70 ml). The solution was heated under reflux in the presence of argon for 20 h, and then cooled to room temperature, diluted with ethyl acetate (425 ml) and washed successively with 5% potassium bisulfate (85 ml), saturated sodium bicarbonate (85 ml) and saline solution (85 ml). The organic phase was dried with magnesium 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 and hexane (1:1) and received 2.76 g of white solid product, so pl. 146 - 147oC, Rf= 0,58 (ethyl acetate), []D= +4,5o(c = 1.0, methanol).

Analysis for C11H20N2O3:

Calculated: C 57,87; H 8,83; N 12,27;

Found: C 58,12; H 8,63; N Of 12.26.


A suspension of 2H-azepin-2-he-product obtained in part (b), (of 2.966 g 12,99 mm) in anhydrous tetrahydrofuran (21,0 ml) was treated with 0.1 M t-butoxide potassium/tetrahydrofuran (16,9 ml, 1.3 EQ.) and stirred in an argon atmosphere and at room temperature for 5min. Clear light brown solution drop by drop were treated with ethylbromoacetate (2,34 ml, 1.7 EQ), stirred 1 h at room temperature and then diluted with ethyl acetate (100 ml). The resulting mixture was washed with saturated sodium bicarbonate (20 ml), 5% potassium bisulfate (15 ml) and brine (15 ml), then dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was chromatographically on a column of silica gel (Merck), elwira hexane and mixtures of ethyl acetate:hexane(1:6, 1:3), resulting received 3,387 g of the product in the form of syrup, Rf= 0,55 (ethyl acetate: hexane, 1:1).

d) (S)-3-Amino-hexahydro-2-oxo-1H-azepin-1-acetic acid, ethyl ester, cleaners containing hydrochloride salt

A solution of the product of ethyl ether complex, obtained in part (c), (3,278 g, 10,13 mm) in dry dioxane (80 ml) was treated with 4.0 M hydrochloric acid/dioxane (31 ml, 0,124 M, 12 EQ.) and stirred at room temperature and in the atmosphere alli in vacuum, resulting received 2,541 g of the product as white hygroscopic solid crystals, Rf= 0,32 (methylene chloride: methanol:acetic acid, 8:1: 1).

e) (S, S)-3-[[2-[(Acetylthio)methyl] -1-oxo-3-phenylpropyl]amino]-2-oxo - 1H-azepin-1-acetic acid, ethyl ester

(S)-2-[(Acetylthio)methyl]benzoylpropionic acid ephedrinebuy salt (1,625 g, 4,028 mm, 1,01 equiv) suspended in ethyl acetate (75 ml), washed with diluted hydrochloric acid (75 ml water + 5,7 ml of 1.0 N. hydrochloric acid, and then 40 ml of water + 1.9 ml of 1.0 N. hydrochloric acid) and brine (15 ml), dried with anhydrous sulfate, filtered and evaporated until dry. Colorless syrup for 1 h and dried in a vacuum and received of 1.05 g of the free acid.

This free acid was dissolved in dry dimethylformamide (25 ml), cooled to 0oC in an ice/salt bath, was treated with 1-hydroxybenzotriazole (567 mg, 4,20 mm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (832 mg, 4,34 mm), and then stirred for 1 h at 0oC and in the presence of argon. The obtained clear solution was treated with a solution hydrochloride salt telefonnogo product. Obtained in part (d) (1.0 g, 3,988 mm) in dry dimethylformamide) (3.0 ml) and 4-methylmorpholine (0,45 ml, 1.0 EQ.) and washed successively with water (15 ml), 5% potassium bisulfate (g ml), saturated sodium bicarbonate (15 ml) and brine, and then dried with 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 and hexane(1:4, 1: 2), resulting received 1,618 g of the product in the form of syrup, Rf= 0,030 (ethyl acetate : hexane, 1:1).

f) (S,S)-Hexahydro-3-[[-mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-2-oxo-1H-azepin-1-acetic acid

A solution of the product of the ethyl ester obtained in part (e), (1,537, 3,53 mm) in methanol (18 ml) was purged for 30 min with argon, then was cooled to 0oC in an ice/salt bath and drop worked previously purged (argon, 30 minutes) solution of 1.0 n sodium hydroxide (to 14.2 ml, 4 equiv.) at the same time, while adding and during the reaction the solution was barbotirovany argon. Then the reaction mixture was stirred 1 h at 0oC, podkisst at 0oC 5% potassium bisulfate (60 ml) to bring the pH to 2, and then were extracted with ethyl acetate (2100 ml). The organic extracts were washed brine (25 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product is about substance. The supernatant decantation, and the solid residue triturated with more hexane (350 ml) and the resulting solid is evaporated from pentane (440 ml). The obtained product was dried in vacuum for 12 h, resulting in a received 1,261 g of amorphous solid product, Rf= 0,43 (methylene chloride: methanol: acetic acid, 20:1:1), []D= +20,2o(C = 0.61 methanol).

1H-NMR (400 MHz, CDCl3): of 1.46 (t, 3H); is 1.81 (m, 6H); 2,60 (m, 2H); 2,87 (m, 3H); is 3.21 (m, 1H); 3,71 (m, 1H); to 4.17 (s, 2H); and 4.68 (m, 1H); 7,13-of 7.23 (m, 5H).

Analysis for C18H24N2O4S 0,2 C5H120,45 H2O:

Calculated: C 58,96; H 7,11; N 7,24; S 8,28; SH 8,54;

Found: C 58,96; H 6,86; N 7,07; S 8,31; SH 8,43.

Example 10.

(S, S)-Hexahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -2-oxo-1H - azepin-1-acetic acid.

a) (S, S)-3-[[2-(Acetylthio)-1-oxo-3-phenylpropyl]amino]-2-oxo-1H - azepin-1-acetic acid, ethyl ester

A suspension of (S)-2-(acetylthio) benzoylpropionic acid dicyclohexylamine salt (2,81 g, 6,93 mm or 1.01 EQ.) suspended in ethyl acetate (200 ml), washed with 5% potassium bisulfate (530 ml) and brine (40 ml) and then dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried off in the Yu acid was dissolved in dry methylene chloride (30 ml) and cooled to 0oC in an ice/salt bath, and then treated with 1-hydroxybenzotriazole (978 mg, of 7.23 mm) and 1-ethyl-3-3-dimethyl-aminopropyl-carbodiimide (1,435 mg, 7,49 mm) and stirred 1 h at 0oC. the resulting solution was treated with a solution of (S)-3-amino-hexahydro-2-oxo-1H-azepin-1-acetic acid, ethyl ether complex, cleaners containing hydrochloride salt (1,58 g, 6,30 mm) in dry methylene chloride (10 ml) and 4-methylmorpholine (of 0.77 ml, 7,01 mm) and stirred 1 h at 0oC and 1.5 h at room temperature. The reaction mixture was diluted with ethyl acetate (170 ml) was washed successively with water (25 ml), 5% potassium bisulfate (225 ml), saturated sodium bicarbonate (25 ml) and brine (25 ml) and then dried with anhydrous magnesium 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 and hexane (3: 7), resulting in a received 2,045 g of the product in the form of syrup. In addition, speakers were given to 261 mg of the isomeric mixture (in the ratio 1:1), Rf= 0,45 (ethyl acetate: hexane, 1:1).

b) (S,S)-Hexahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2-oxo-1H-azepin-1-acetic acid

The solution telefonnogo of the product obtained in part (a), (2,044 g, a 4.86 mm) in methanol (25 m is Li purged (argon, 30 min) a solution of 1.0 n sodium hydroxide (19,55 ml, 4 equiv.) while adding and during the reaction the solution was barbotirovany argon. The reaction mixture was stirred at 0oC for 1 h, acidified at 0oC 5% potassium bisulfate (85 ml) to bring the pH to 2.0, and then was extracted with ethyl acetate (2140 ml). The organic extracts were washed brine (35 ml), was dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was dissolved in methylene chloride (10 ml) and was partially treated with hexane, resulting in the formed solid substance. The supernatant decantation, and the solid residues were washed with additional hexane (250 ml) and pentane (2100 ml), stirring for 4 h with the first 100 ml of pentane, and then during the night with the following 100 ml of pentane in the presence of argon. The obtained product was dried in vacuum for 12 h and resulted 1,618 g of amorphous solids, Rf= 0,53 (methylene chloride: methanol: acetic acid, 10:1:1); []D= +8,04o(C = 0,56, methanol).

1H-NMR (400 MHz, CDCl3): 1,71 (m, 6H); 2,02 (d, 1H); and 3.16 (m, 3H); 3,61 (m, 1H); 3,70 (m, 1H); to 4.17 (s, 2H); with 4.65 (m, 1H); 7.18 in - 7,72 (m, 5H).

Analysis for C17H22N2

[3R- [3, 6(S*), 9a] - Octahydro-6-[(2-mercapto-1-oxo-3-phenyl-propylamino]-5-oxadiazole [3,2-a]azepin-3-carboxylic acid

a) N2phthaloyl-L-lysine

A mixture of N6-[(1,1-dimethylmethoxy)carbonyl] -L-lysine (10,827 g, 43,9 mm) and sodium carbonate (4,665 g, 44,0 mm) stirred in 170 ml of ethanol and water (1: 3) for 2.5 hours and Then the ethanol was removed with a rotary evaporator, and the aqueous solution was treated with N-carboxyphenylazo (9,66 g, 44,0 mm). After stirring for 1.5 h at room temperature, the solution was filtered, treated with methylene chloride (200 ml) and the aqueous layer was acidified using 6 N. hydrochloric acid to a pH of 2.8. The layers were shaken and separated. The aqueous layer was extracted again with ethyl acetate and the combined organic layers were dried with magnesium sulfate, filtered and evaporated, resulting in a received almost glassy colorless oily substance (19,510 g).

The residue was cooled to 0oC, was treated triperoxonane acid (150 ml) and the resulting mixture was stirred 3 h at room temperature. Triperoxonane acid was removed with a rotary evaporator, and the residue azeotropically was obezvozhivani using toluene (2x). The crude product was dissolved in water and passed through a column of Dowex AG mixture of pyridine and water (5:95 (1000 ml). The desired fractions were combined, evaporated, dissolved in water and was liofilizovane, resulting received 7,850 g of white solid product, Rf= 0,57 (n-butanol:water, acetic acid: ethyl acetate, 1:1:1:1).

b) [2(S), 4R]-4-(Methoxycarbonyl)- - phthalimido-2-thiazolidinone acid

A suspension of N2-phthaloyl-L-lysine (7,710 g of 27.9 mm) in dry dimethylformamide (135 ml) was treated with 4-formyl-1-methylpyridine benzosulfimide (7,320 g, 26,2 mm). The obtained dark mixture gradually became homogeneous. After 1 hour stirring at room temperature, the mixture was treated with 1,8-diazabicyclo 5.4.0 undec-7-EN ω (8,15 ml, 8,30 g, 54,5 mm), and then after 5 min, treated with hydrochloride difficult methyl ester of L-cysteine (4,53 g, 26,3 mm). The dark solution stirred for 2.5 h, and then diluted aqueous hydrochloric acid (pH of 1.7, 300 ml) and chloroform. The aqueous layer was brought to pH of 4.3 and 4.4 with 0.5 n hydrochloric acid and then was extracted 5 times with chloroform. The combined chloroform extracts were washed with water (50 ml), dried sodium sulfate, filtered and evaporated. The residue was dissolved in ethyl acetate, filtered through celite and concentrated, resulting in a received 1.84 g of the crude product as an orange-red oily="ptx2">

c) [3R- (3, 6) ]-Octahydro-6-phthalimido-5-oxadiazole[3,2-a] azepin-3-carboxylic acid, methyl ester

A solution of the product obtained in part (b), (1.84 g, 4,7 mm) in tetrahydrofuran (70 ml) was treated with 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (1,400 g, 5,67 mm) and the resulting mixture stirred for 3 days at room temperature. The tetrahydrofuran was removed with a rotary evaporator, and the residue was dissolved in ethyl acetate and washed sequentially with 0.5 G. hydrochloric acid (2x), 50% saturated sodium bicarbonate, water and brine, and then dried with sodium sulfate, filtered and evaporated. The obtained orange oily substance was subjected to flash chromatography (Merck silica, 40 to 50% ethyl acetate in hexane), resulting in a received 1,126 g of the product as a mixture (1:1) of diastereomers, Rf= 0,22 and 0.20 (40% ethyl acetate in hexane).

d) [3R- (3, 6, 9a) ]-Octahydro-6-phthalimido-5-oxadiazole[3,2-a] azepin-3-carboxylic acid, methyl ester

A mixture of the product methyl ether complex, obtained in part (c), (1,110 land only g) and hydrate p-toluensulfonate acid (2,33 g) in benzene (20 ml) was heated under reflux for 2.5 h with removal of water (trap Dean-stark). The cooled mixture rozvody is a sodium atom, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica, 10 to 20% ethyl acetate in methylene chloride), which received a nearly pure product in the form of whitish foamy substance. This foamy substance was dissolved in a hot mixture of ethyl acetate and hexane, cooled and made the seed, resulting in the obtained thin white needle crystals (845 mg). Another 50 mg of solid product was obtained from the mother liquor, so in General, the number of pure product was 895 mg, so pl. 154 - 155oC []D= -31,8o(c = 0,52, chloroform), Rf= 0,22 (40% ethyl acetate in hexane).

e) [3R- (3, 6, 9a) ]-6-amino-octahydro-5-oxadiazole[3,2-a]-azepin-3 - carboxylic acid, methyl ester

A suspension of the product methyl ether complex, obtained in part (d), (875 mg, 2,34 mm) in absolute ethanol (50 ml) was treated with hydrazine hydrate (115 μl, 118 mg, 2,37 mm) and to promote solubilization, the solution was periodically heated within the first 2 hours After stirring for 3 days at room temperature, was added addition of hydrazine hydrate (80 μl, to 82.6 mg, 1,65 mm) and the resulting mixture stirred another day. Then the reaction mixture was evaporated to dryness and the white solid residue rasmei and the filtrate was podslushivaet to pH 11 - 12 with 1 n sodium hydroxide, and then extracted with methylene chloride (3x) and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, evaporated and received nearly colorless oily product (600 mg). This oily product was treated with water (10 ml) and 1.0 n hydrochloric acid (3.0 ml), vigorously stirred until then, until there is no longer the oiliness of the product, after which the mixture was liofilizovane and received 674 mg of yellowish solid product, Rf= 0,64 main spot (n-butanol : water : acetic acid : ethyl acetate 1:1:1:1).

f) [3R- [3, 6(S*) 9a] ]-Octahydro-6[[2-(acetylthio)-1-oxo-3-phenylpropyl] amino] -5-oxadiazole 3,2-alateen-3-carboxylic acid, methyl ester

Cleaners containing hydrochloride salt mutilating of the product obtained in part (e), (374 mg, 1,33 mm) was distributed between saturated sodium bicarbonate and methylene chloride. Methylenchloride the extract was dried with sodium sulfate, filtered, evaporated and obtained the free amine as a pale yellow oily substance (302 mg, 1,16 mm). In addition, dicyclohexylamine salt (S)-2-(acetylthio)benzoylpropionic acid (648 mg, 1,60 mm) was distributed between ethyl acetate and 5% potassium bisulfate. An ethyl acetate layer prom is received the free acid as an oily substance. A mixture of the free amine and free acid in methylene chloride (9 ml) was treated with hydroxybenzotriazole (550 mg, 4,07 mm), cooled to 0oC, and then were treated with 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (313 mg, 1,63 mm). The resulting mixture was stirred 1 h at 0oC, and then 3 h at room temperature. After this was added 100 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and continued to stir overnight. The solution was diluted with ethyl acetate and washed successively with water, 5% potassium bisulfate, water, 50% saturated sodium bicarbonate and brine, and then dried with sodium sulfate, filtered and evaporated. The obtained yellow oily substance was subjected to flash chromatography (Merck silica, 30% acetone in hexane), resulting in a received 396 mg of product as a mixture (87: 13) diastereomers side chain. Then this mixture was again subjected to flash chromatography (Merck silica, 35 - 40% ethyl acetate in hexane) and received 318 mg of product as a white foamy substance (94 - 95% diastereomeric net), Rf= 0,29, the main spot and 0.26 (small spot, [ 6(R*)- isomer], []D= -84,4o(c = 0,36, chloroform).

g) [3R- [3, 6(S*), 9a] ]]-Octahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl the military in paragraph (f), (308 mg, 0.68 mm) in methanol (4 ml, deoksigenirovanii by ozonation of argon) was treated with 1 N. sodium hydroxide (3.5 ml, deoksigenirovanii by ozonation argon) and homogeneous mixture stirred 2 h in the presence of argon. Then the mixture was acidified with 10% potassium bisulfate (15 ml), diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with saline, dried with sodium sulfate, filtered and evaporated, resulting in the obtained solid substance. This solid was dissolved in dimethylformamide (1 ml), diluted with ethyl acetate and subjected to flash chromatography (Merck silica, 5% acetic acid in ethyl acetate), resulting in a received desired product as a white solid, which was then pereirae with ethyl acetate ethyl ether, collected by filtration, dried off and got 144 mg of the product, so pl. 217 - 220oC, Rf= 0,52 (5% acetic acid in ethyl acetate), []D= -64,3o(c = 0,36, dimethylformamide). NMR analysis showed that the obtained product had a 93% diastereomeric purity, and 7% were appropriate 6(R*)- isomer.

HPLC: column UMC S3 ODS (150 mm 0,6); elution 44% A: 90% water - 10% methanol - 0.2% of phosphoric acid, and 5 12,27 min showed a purity > 95% (without division 6(S*) and 6(R*)- isomers identified by HPLC).

Analysis for C18H22N2O4S2O 4 H2O:

Calculated: C 53,82; H 5,72; N 6,97; S 15,96; SH 8,21;

Found: C 53,88; H 5,67; N Is 6.78; S shed 15.37; SH 4,91.

Example 12.

[3R- [3, 6(S*)-9a] ]]-Octahydro-6-[[2-(mercaptomethyl)-1-oxo-3 - phenylpropyl]amino]-5-oxo-thiazolo 3,2-Adatepe-3-carboxylic acid

Repeating the procedure of example 11, but using in paragraph (f) (S)-2-[(acetylthio)methyl] benzoylpropionic acid, obtained target product as a white solid, so pl. 212 - 213oC, Rf= 0,55 (5% acetic acid in ethyl acetate), []D= -36,5o(c = 0,36, dimethylformamide).

HPLC: column UMC S3 ODS (150 mm 6,0): elution 44% A: 90% water - 10% methanol and 0.2 phosphoric acid, and 56% B: 10% water - 90% methanol and 0.2% phosphoric acid, flow rate of 1.5 ml/min with detection at 220 nm, tR= 15,96 min showed a purity of 99.2%.

Analysis for C19H24N2O4S2:

Calculated: C 55,86; H of 5.92; N 6,86; S 15,70; SH 8,09;

Found: C 55,99; H 6,01; N 6,75; S 15,70; SH 7,81.

Example 13.

[S-(R*, R*)] -3,4-Dihydro-3-[[2-(mercaptomethyl)-1 - oxo-3-phenylpropyl] amino]-4-oxo-1,5-benzoxazepin-5(2H)-wxusa] -L-serine (24.3 g, amount of 0.118 M) in dry dimethylformamide (25 ml) drop by drop, for 1 h, was added to a cooled (0oC, an ice/salt bath) suspension of 60% sodium hydride (10.1 g, 0.25 M) in dry dimethylformamide (200 ml) and the resulting mixture was stirred at 0oC as long as you do not stop foaming (about 2 hours). The reaction mixture drop by drop within 20 min were treated with 1, fluorescent-2-nitrobenzene (14,3 ml of 0.13 M), stirred at 0oC and in the presence of argon for 4 h, and then poured into ice water (750 ml) and was extracted with ethyl acetate (2 100 ml). The aqueous phase is brought to pH of 1.0 with 6 N. hydrochloric acid (70 ml), was extracted with ethyl acetate (3 500 ml) and the combined organic extracts washed with brine (100 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product mixture was chromatographically on a column of silica gel (Merck), elwira mixture of methylene chloride, methanol and acetic acid (100:5:0,2), resulting in a received 27,22 g of the product as a viscous yellow syrup, Rf= 0,27 (methylene chloride : methanol : acetic acid, 100:5:0.5 to).

b) N-[(1,1-Dimethylmethoxy)-carbonyl]-O-(2-AMINOPHENYL)-L-serine

A solution of the product obtained in part (a), (27,1 g, 83 mm) in dry metanoe 2 hours The reaction mixture was filtered through a pad of celite in millipore.com the filter, carefully washing the pad with methanol (5 100 ml). The dark filtrate is evaporated to dryness and dried in vacuo, resulting in a received dark solid product. This crude product is triturated with a mixture of methylene chloride and hexane (1:4) and received 17,69 g light reddish-brown solid, Rf= 0,15 (methylene chloride : methanol : acetic acid, 20:1:1).

c) (S)-3-[[(Dimethylmethoxy)carbonyl] amino]-2,3-dihydro-1,5 - benzoxazepin-4(5H)-he

A solution of the product obtained in part (b), (16,69 g, 56,3 mm) in dry dimethylformamide (121 ml) was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (at 10.64 g, 55,5 mm) and stirred at room temperature for 3 hours the Reaction mixture was distributed between ethyl acetate (2 492 ml) and 1.0-called sodium bicarbonate (492 ml) and the combined organic extracts were washed with water (3 492 ml), brine (492 ml), dried with anhydrous magnesium 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 and hexane(1:4, 1:2, 1:1), as a result, we received a 10.5 g of the product in the form of whitish crystals, Rf is sepin-5(2H)-acetic acid, ethyl ester

A solution of the product obtained in part (c), (1.0 g, 3,59 mm) in dry tetrahydrofuran (10 ml) was cooled to 0oC (ice/salt bath) in the presence of argon, was treated with powdered potassium hydroxide (259 mg, 4.6 mm) and tetrabutylammonium bromide (172 mg, 0.53 mm), stirred for 5 minutes and then was treated with ethyl 2-bromoacetate (0,50 ml, 1.2 EQ. ). The reaction mixture was stirred at room temperature and in the presence of over 19 hours, distributed between methylene chloride (2 25 ml) and water (13 ml) and the combined organic extracts were washed with water (2 13 ml), brine (10 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product mixture was chromatographically on silica gel (Merck), elwira mixtures of ethyl acetate and hexane(1: 9, 1:4), resulting received 860 mg of the product in the form of syrup, Rf= 0,67 (ethyl acetate : hexane, 1:1).

e) (S)-3-Amino-3,4-dihydro-4-oxo-1,5-benzoxazepin-5(2H)- acetic acid, ethyl ester, cleaners containing hydrochloride salt

A solution of the product obtained in part (d), (4.0 g, 11 mm) in dry dioxane (85 ml) was treated with 4.0 M hydrochloric acid/dioxane (33.6 ml, 0,134 M or 12.2 EQ.) and stirred 20 h at room then was dried in vacuum, resulting received 3,466 g of the product as slightly Golden syrup, Rf= 0,48 (methylene chloride : methanol, 9:1).

f) [S(R*, R*)] -3-[[2-[(Acetylthio)methyl]-1-oxo-3 - phenylpropyl]amino]-3,4-dihydro-4-oxo-1,5-benzoxazepin-5(2H)-acetic acid, ethyl ester

(S)-2-[(Acetylthio)methyl] benzoylpropionate acid [obtained from ephedrinebuy salt in accordance with the description above] were subjected to the reaction product obtained in part (e), which was conducted in accordance with the procedure described in example 1 (part (b)), resulting in a received target product white foamy syrup, Rf= 0,62 (ethyl acetate : hexane, 1: 1).

g) [S-(R*,R*)]-3,4-Dihydro-3-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] amino]-4-oxo-1,5-benzazepin-5(2H)-acetic acid

A solution of the product obtained in paragraph (f), in methanol was treated with 1.0 N. the hydroxyl sodium in accordance with the procedure described in example 1 (part (c)), resulting in a received target product in the form of amorphous solids, Rf= 0,62 (methylene chloride : methanol : acetic acid, 20:1:1), []D= -140,2o(c = 0,61, methanol).

1H NMR (400 MHz, CDCl3): 1,43 (t, 1H); of 2.51 - 2,90 (m, 5H); to 4.17 (t, 1H, J = 10 Hz); the 4.29 (d, 1H, J = 17UB>S:

Calculated: C 60,86; H 5,35; N 6,76; S 7,74; SH 7,98;

Found: C 60,85; H 5,54; N 6,74; S 7,66; SH 6,29.

Example 14.

[S, (R*, R*)]-3,4-Dihydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl)-amino]-4-oxo-1,5-benzoxazepin-5(2H)-acetic acid

a) [S, R*R*)-3-[[2-(Acetylthio)-1-oxo-3-phenylpropyl] amino]-3,4-dihydro-4-oxo-1,5-benzoxazepin-5(2H)-acetic acid, ethyl ester

(S)-2-(Acetylthio)benzoylpropionic acid dicyclohexylamine salt (1.35 g, 3,81 mm) suspended in ethyl acetate (120 ml), washed with 5% potassium bisulfate (5 to 20 ml) and brine (25 ml), dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in the obtained free acid.

This free acid was dissolved in dry methylene chloride (25 ml), cooled to 0oC in an ice/salt bath, was treated with 1-hydroxybenzotriazole (541 mg, 4.0 mm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (792 mg, 4,13 mm) and stirred 1 h at 0oC in argon atmosphere. Then the solution was treated with (S)-3-amino-3,4-dihydro-4-oxo-1,5-benzoxazepin-5(2H)- acetic acid ethyl ether complex (1,147 g, 3,81 mm) and 4-methylmorpholine (of 0.47 ml, 4.2 mm), stirred 1 h at 0oC, 1 h at room temperature (2 15 ml), water (15 ml), saturated sodium bicarbonate (15 ml) and brine (15 ml) and then dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was chromatographically on silica gel (Merck), elwira a mixture of ethyl acetate and hexane (1:4), resulting in a received 1,21 g of the product in the form of syrup. It was also obtained 409,6 mg of the product (isomer mixture, 1:1) Rf= 0,67 (ethyl acetate : hexane, 1:4, then 1:1).

b) (S, R*,R*)-3,4-dihydro-3-[(2-mercapto-1-oxo-1 - 3-phenylpropyl)amino] -4-oxo-1,5-benzoxazepin-5(2H)-acetic acid

The solution telefonnogo of the product obtained in part (a), (1,81 g of 2.51 mm) in methanol (13 ml) was purged for 30 min with argon, was cooled to 0oC in a salt/ice bath, and then drop was treated previously purged (argon, 30 minutes) solution of 1.0 n sodium hydroxide (10 ml, 4.0 EQ.), when you add in the whole process of the reaction, the solution was barbotirovany argon. The reaction mixture was stirred 1 h at 0oC, acidified at 0oC 5% potassium bisulfate (45 ml) to pH 1 and extracted with ethyl acetate (2 80 ml). The combined organic extracts were washed with saline (20 ml), dried with anhydrous sodium sulfate, filtered, evaporated by Eana (100 ml), resulting in the formed solid substance. The supernatant decantation, and the solid residue triturated with hexane (50 ml) and pentane (2 100 ml), stirring for 4 h with the first 100 ml of pentane, during the night, with the following 100 ml of pentane in an argon atmosphere. Then the obtained product was dried in vacuum for 6 h resulted 969,7 ml in the form of amorphous solids, Rf= 0,47 (methylene chloride : methanol : acetic acid, 20:1:1), []D= -143,3o(c = 0,54, methanol).

1H NMR (400 MHz, CDCl3): 2,02 (d, 1H); of 3.07 (m, 2H); 3,59 (m, 1H; 4.09 to (t, 1H, J = 10 Hz); 4,24 (d, 1H, J = 17 Hz); 4,63 (t, 1H, J = 8 Hz); to 4.73 (d, 1H, J = 17 Hz); is 4.93 (m, 1H);? 7.04 baby mortality - 7,26 (m, 9H); 7,42 (d, 1H).

Analysis for C20H20N2O5S 0,147 C5H120,43 H2O:

Calculated: C 59,46; H 5,44; N 6,69; S 7,65; SH 7,89;

Found: C 59,46; H 5,25; N 6,65; S 7,88; SH 7,84.

Example 15.

[3S-[1(R*), 3 (R*)[-3-[(2-Mercapto-1-oxo-3-phenylpropyl)amino]- - methyl-2-oxohexyl-1H-azepin-1-acetic acid

a) [3S-[1(R*), 3 (R*)]-3-[[2-(acetylthio)-1 - oxo-3-phenylpropyl]amino]- - methyl-2-oxohexyl-1H-azepin-1-acetic acid, methyl ester

A cold (0oC) a solution of [S-(R*,R*) [3-aminohexyl- - methyl-2-oxo-1H-azepin-1-vinegar is R., "Peptides : Structure and Function", Proceeding 8th American Peptide Sumposium, S. 555 (1983)) and (S)-2-(acetylthio)benzodiapines acid (393 mg, about 1.75 mm) in methylene chloride (10 ml) was treated with triethylamine (245 μl, 178 mg, 1,76 mm), and then benzotriazol-1 yloxy-Tris dimethylamino of phosphorus hexafluorophosphate (775 mg, 1,65 mm). Transparent, almost colorless solution stirred 1 h at 0oC, and then 3 h at room temperature. After that, the mixture was distributed between ethyl acetate and 0.5 G. hydrochloric acid, and an ethyl acetate extract was washed successively with water, half-saturated sodium bicarbonate and saline. The solution was dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography on silica gel (Merck), elwira a mixture of ethyl acetate and hexane (70:30), resulting in a received 590 mg of the pure product as colorless oily/foamy substance, Rf= 0,43 (ethyl acetate : hexane, 75:25).

b) [3S-[1(R*), 3 (R*)]]-3-[(2-Mercapto-1-oxo-3 - phenylpropyl)amino]- - methyl-2-oxohexyl-1H-azepin-1-acetic acid

Chilled with ice a solution of the product obtained in part (a), (570 mg, 1,36 mm) in methanol (7 ml, deoxygenating by ozonation with argon) was treated with 1 N. sodium Hydroxide (5.5 ml, datadrill 1 N. hydrochloric acid (9 ml) and was extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, and then dried with sodium sulfate, filtered and evaporated, resulting in the obtained oily substance. This substance was subjected to flash chromatography on silica gel (Merck), (2% acetic acid in ethyl acetate). The desired fractions were combined and evaporated, and the residue was dissolved in ethyl acetate and washed successively with water and brine, and then dried with sodium sulfate, filtered and again evaporated. The obtained oily/foamy substance was washed first with ethyl ether and then with hexane, resulting received a white oily, foamy substance. This mixture was evaporated to dryness, suspended in hexane was again evaporated to dryness and dried in vacuo, resulting in a received 470 mg of product as a white foam; NMR analysis showed that the obtained product had diastereomeric purity of over 98%, Rf= 0,49 (5% acetic acid in ethyl acetate), []D= -37,1o(c = 0.6, chloroform).

HPLC: column UMC S3 ODS (150 mm 6,0), elution 44% A: 90 % water - 10% methanol - 0.2% of phosphoric acid, and 56% B : 10% water - 90% methanol and 0.2% phosphoric acid, flow rate 1.5 ml/min with detection PR,32; H 6,64; N 7,69; S 8,80; SH 9,07;

Found: C 59,27; H 6,92; N 7,37; S at 8.36; SH 8,75.

Example 16.

[6R(S*)-2,3,6,7-Tetrahydro-6-[[2-(mercaptomethyl)-1-oxo-3 - phenylpropyl] amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid

a) [2-[(Methylsulphonyl)oxy] ethyl]karamanova acid, 1,1-dimethylethylene ester

Di-tert-BUTYLCARBAMATE (21.8 g, 100 mm) in parts was added to a stirred solution of ethanolamine (6,1 g, 100 mm) in dichloromethane (100 ml) at 0 - 5oC. After complete addition, the cooling bath was removed and the solution for 5 h and stirred at room temperature. The solvent was removed under vacuum and the resulting material was dissolved in dichloromethane (100 ml) and triethylamine (21 ml, 150 mm), cooled to -10oC and drop within 10 min were treated with methanesulfonamide (9,25 g, 150 mm). The mixture was diluted with ethyl acetate (200 ml) and washed with 1 N. hydrochloric acid and water. An ethyl acetate layer was dried with magnesium sulfate, filtered, and the solvent was removed in vacuo, resulting received this product as a viscous oily substance, which is then used without purification.

b) S-[2-[[(1,1-Dimethylmethoxy)carbonyl] amino] ethyl] -N-[phenyl - methoxy)carbonyl]-L-cysteine, diphenylmethylene ester

A solution of N-[(phenylmethoxy the mm) in dimethylformamide (190 ml) was treated by spraying the dried potassium fluoride (25 g, 430 mm) and stirred 20 h at 70 - 75oC in argon atmosphere. After cooling, the mixture was distributed between ethyl acetate (800 ml) and water (400 ml). The organic layer was washed brine (300 ml), dried with magnesium sulfate, filtered, the solution was removed in vacuo and the resulted oily substance. This substance was chromatographically on silica gel (Merck, 1000 ml), elwira mixtures of ethyl acetate and hexane (1:4, 1:3 and 1: 2), resulting in a received 9,13 g, Rf= 0,35 (ethyl acetate:hexane, 1:2).

c) (R)-Tetrahydro-6-[[(phenylmethoxy)carbonyl] amino] -1,4 - diazepin-5(4H)he

A solution of the product obtained in part (b), (6,13 g, 10,86 mm) in anisole (30 ml) and triperoxonane acid (45 ml) and stirred 2 h at room temperature, and then concentrated in vacuum. The oily residue was diluted with isopropyl ether (40 ml), stirred, and Isopropylamine layer decantation. This procedure was repeated once, after which the residue was dried in vacuum. A mixture of the obtained material and diphenylphosphinite (4.4 g, 16 mm) in dry dimethylformamide (75 ml) in an argon atmosphere was cooled in an ice bath and stirring, drop by drop) was added 4-methylmorpholine (4,45 g, 44 mm). After complete addition, the mixture was heated to room temperature(100 ml). The layers were separated and the aqueous layer was again extracted with ethyl acetate (50 ml). The combined organic layers were washed with a saturated solution of potassium bisulfate (30 ml), saturated sodium bicarbonate solution (50 ml) and brine (50 ml), dried with magnesium sulfate, and the solvent was removed in vacuum. The residue is triturated with isopropyl ether and was received as a result of 2.45 g of white solid product, Rf= 0,27 (ethyl acetate : hexane, 1:1).

d) (R)-Tetrahydro-5-oxo-6-[[(phenylmethoxy)carbonyl]amino]-1,4 - thiazepine-4(5H)-acetic acid, ethyl ester

A solution of the product obtained in part (c), (3.55 g, 12,68 mm) in distilled tetrahydrofuran (40 ml) in an argon atmosphere was cooled to 0oC and was treated with powdered potassium hydroxide (2.16 g, 40 mm) and tetrabutylammonium bromide (420 mg, 1.3 mm). Then one drop was added ethylbromoacetate (2.58 g, 15,43 mm). The cold mixture is stirred for 2 hours, and then diluted with ethyl acetate (50 ml) was added anhydrous magnesium sulfate. The reaction mixture was filtered through magnesium sulfate layer and this layer is repeatedly washed with ethyl acetate. The filtrate was treated with 1 N. hydrochloric acid (50 ml) and the layers were separated. The organic layer was dried with magnesium sulfate, filter the Yu chromatography on silica gel, elwira 10 to 30% ethyl acetate in hexane, to obtain 3,22 g of product as a viscous oily substance, Rf= 0,60 (ethyl acetate : hexane, 1:1).

e) (R)-6-Aminotetraline-5-oxo-1,4-thiazepine-4(5H)acetic acid, ethyl ester, hydrobromide salt

The product obtained in part (d), (3,17 g, 8,65 mm) was treated with 30% bromovalerate in acetic acid (14 ml). The mixture is stirred at room temperature for 1 h, and then was added diethyl ether (200 ml). After 1 hour stirring at room temperature, the precipitated salt was collected by filtration and repeatedly washed simple ether. Received slightly resinous material was dissolved in hot ethanol, and the solvent was removed in vacuum. This procedure was repeated one more time. Then to the residue was added diethyl ether, and by filtering collected hydrobromide salt (2,52 g) as a yellow solid product.

f) [6R(S*)] -2,3,6,7-Tetrahydro-6-[[2-[(acetylthio)methyl] -1-oxo-3-phenylpropyl]amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester

(S)-2-[(Acetylthio)methyl] benzodiapines acid (obtained from ephedrinebuy salt, as described earlier) was subjected to a reaction product obtained in part (e), in accordance 1:1).

g) [6R(S*)]-2,3,6,7-Tetrahydro-6-[[2-(mercaptomethyl)-1 - oxo-3 - phenylpropyl]amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid

A solution of the product obtained in paragraph (f), in methanol was treated with 1 N. sodium hydroxide in accordance with the procedure described in example 1 (part (c)), resulting in a received target product as a solid foam-like substance, so pl. 85 - 101oC, Rf= 0,35 (8% methanol in dichloromethane + 2 drops acetic acid/5 ml), []D= -9,5o(c = 0.6, methanol).

HPLC : RT= 13,2 min, 50% aqueous methanol containing 0.2% phosphoric acid, of 1.05 ml/min, detection at 220 nm, YMCS 3 (ODS), 6,0 150 mm column with a spherical cap (3 μm). H. I => 95%.

Analysis for C17H22N2O4S20,15 H2O 0,15 C6H14:

Calculated: C 60,24; H 5,71; N 6,11; S 13,98;

Found: C 60,01; H 5,77; N 5,94; S 13,64.

Example 17. [6R(S*)-2,3,6,7-Tetrahydro-6-[(2-mercapto-1 - oxo-3-phenylpropyl)-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid

a) [6R(S*)-2,3,6,7-Tetrahydro-6-[[2-(acetylthio)-1-oxo-3 - phenylpropyl)-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester

(S)-2-(Acetylthio)benzodiapines acid (obtained from dicyclohexylamine salt, as described p in example 2 (part (b)), the result has been the target connection, Rf= 0,29 (ethyl acetate : hexane, 1:1).

b) [6R(S*)-2,3,6,7-Tetrahydro-6-[(2-mercapto-1-oxo-3 - phenylpropyl)-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid

A solution of the product obtained in part (a), in methanol was treated with 1.0 N. sodium hydroxide in accordance with the procedure described in example 2 (part (c)), resulting in a received target product as a solid foam-like substance, so pl. 69 - 76oC Rf= 0,29 (8% methanol in dichloromethane + 2 drops of acetic acid (5 ml).

Analysis for C22H24N2O4S20.1 C4H8O2:

Calculated: C 52,21; H 5,56; N 7,43; S 17,00;

Found: C 52,27; H 5,54; N 7,35; S 16,98.

Example 18.

[3R-[ 3, 6 (S*)] ] -Tetrahydro-6-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-5-oxo-phenyl-1,4-thiazepine-4(5H)-acetic acid

a) (3R-CIS)-Tetrahydro-5-oxo-3-phenyl-6-[[(phenylmethoxy) carbonyl] -amino]-1,4-thiazepine-4(5H)-acetic acid, ethyl ester

A solution of (3R-CIS)-tetrahydro-3-phenyl-6-[[(phenylmethoxy) carbonyl]amino] -1,4-diazepin-5(4H)-it's a (1,16 g, 3,25 mm) obtained in accordance with known description (Yanagisawa and others J. Med. Chem., page 1984-1991 (1987)), in distilled tetrahydrofuran (30 ml) and Atmos is home tetrabutylammonium (97 mg, 0.3 mm). Then, stirring, one drop was added ethylbromoacetate (501 mg, 3 mm). This mixture is refrigerated stirred 2 h, and then added another 501 mg (3 mm) ethylbromoacetate. Received the cold mixture is stirred for another 2 h, and then diluted with ethyl acetate (50 ml) was added anhydrous magnesium sulfate. The reaction mixture was filtered through a layer of magnesium sulfate, after which this layer is repeatedly washed with ethyl acetate. The filtrate was poured into cold 1 n hydrochloric acid (40 ml) and the layers were separated. The organic layer was dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo, was obtained oily substance was purified by chromatography on silica gel, elwira 10 to 30% ethyl acetate in hexane, resulting in received 730 mg of the product, Rf= 0,32 (ethyl acetate : hexane, 1:2).

(b) (3R-CIS)-6-Aminotetraline-5-oxo-3-phenyl-1,4-thiazepine - 4(5H)-acetic acid, ethyl ester, hydrobromide salt

The product obtained in part (a), (1,43 g, 3,23 mm) was treated with 30% bromadiolon in acetic acid (5.5 ml). The mixture is stirred 2 h at room temperature, and then added diethyl ether (100 ml). After 1 hour stirring at room temperature, the precipitated salt was collected is ejiogu solid product.

c) [3R-[ 3, 6 (S*)]]-6-[[2-(Acetylthio)-1-oxo-3 - phenylpropyl]amino]-tetrahydro-5-oxo-3-phenyl-1,4-thiazepine-4(5H)- acetic acid, ethyl ester

Suspension dicyclohexylamine salt (S)-2-(acetylthio)benzoylpropionic acid (736 g, 1,81 mm) in ethyl acetate (30 ml) twice washed with 0.1 G. of hydrochloric acid (40 ml 230 ml) and once with brine (20 ml), then were dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo received free acid in the form of an oily substance.

Hydrobromide salt of the product obtained in part (b), (640 mg of 1.65 mm) was dissolved in dichloromethane (30 ml), washed with sodium bicarbonate solution (220 ml) and then brine (20 ml), dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo received a free amine in the form of a viscous oily product (495 mg). This product and the free acid obtained as described above was dissolved in dichloromethane (20 ml) in the presence of argon and cooled to 0oC. then was added 1-hydroxybenzotriazole (256 mg, 1,90 mm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (362,5 mg, 1,90 mm). Received the cold mixture is stirred for 3 h, and then diluted with dichloromethane (30 ml). The solution was washed with water (15 ml),the solution was dried with magnesium sulfate, was filtered, and the solvent was removed in vacuum. The remaining material was chromatographically on silica gel (Merck, approximately 150 ml), elwira 25% ethyl acetate in hexane and got 610 mg of the product, Rf= 0,53 (ethyl acetate : hexane, 1:1).

d) [3R-[ 3, 6 (S*)] ]-Tetrahydro-6-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]5-oxo-3-phenyl-1,04-thiazepine-4(5H)-acetic acid, a mixture of methyl and ethyl esters

A solution of the product obtained in part (c), (610 mg, 1,185 mm) in methanol (12 ml) was purged for 15 minutes with argon, cooled in an ice/salt bath and while purging with argon and stirring, was treated with one drop of 1 N. a solution of sodium hydroxide and 4.75 ml) for 30 min before use was purged with argon. The cooled mixture was stirred for 75 min and then acidified to pH 1 with 5% aqueous solution of potassium bisulfate. The product was extracted into ethyl acetate (2 40 ml). The combined organic extracts were washed with saline, dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo received 533 mg of product, which slowly crystallized. NMR and mass spectroscopy showed that this product is a mixture of methyl and ethyl esters, Rf= 0,76 (5% methanol in phenylpropyl)amino]-5-phenyl-1,04-thiazepine-4(5H)-acetic acid

The product obtained in paragraph (d) (480 mg, approximately 1,03 mm) was added to a methanol (12 ml). After that was formed crystals. Then add distilled tetrahydrofuran (5 ml) and the mixture was taken form a clear solution, which for 15 min was purged with argon, cooled in an ice/salt bath and, while purging with argon and stirring, was treated with one drop of 1 N. a solution of sodium hydroxide (4 ml) for 30 min before use was purged with argon. The mixture was stirred in a cooled state and in an argon atmosphere for 27 hours Spent in this time TCX showed that the hydrolysis of ester ended. The mixture is then acidified to pH 1 using 5% aqueous solution of potassium bisulfate. The product was extracted in dichloromethane (230 ml). The combined organic extracts were washed with saline, dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo was obtained a white solid foamy substance. This substance was dissolved in dichloromethane and hexane was added to obtain a turbid solution. Then the solvent was removed in vacuum and obtained a solid residue. The residue is triturated with 20% hexane in ether. White solid was collected by filtration, propylamide + 2 drops acetic acid/5 ml), []D= +26,7o(C = 0.8, methanol).

HPLC: RT= 8,0 min, 66,8% aqueous methanol containing 0.2% phosphoric acid, 1.5 ml/min, detection at 220 nm, MB S-3 (ODS), 6.0 x 150 mm column with a spherical cap size 3 microns. H. 1>95%.

Analysis for C22H24N2O4S2:

Calculated: C 59,44; H 5,44; N 6,30; S 14,42;

Found: C 59,52; H 5,54; N Between 6.08; S 14,14.

Example 19.

[3R-[ 3, 6 (S*)] ]-Tetrahydro-6-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] amino]-5-oxo-3-phenyl-14-thiazepine-4(5H)-acetic acid

a) [3R-[ 3, 6 (S*)]]-tetrahydro-6-[[2-(acetyltributyl)-1-oxo-3 - phenylpropyl]amino]-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-acetic acid, a mixture of methyl and ethyl esters

Suspension ephedrinebuy salt (S)-2-[(acetylthio)methyl]benzoylpropionic acid (853 mg, 2,11 mm) in ethyl acetate (40 ml) were washed twice in 0.1 G. of hydrochloric acid (40 ml, 20 ml) and once with brine (20 ml), dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo received free acid in the form of an oily substance.

A mixture of methyl and ethyl esters (3R-CIS)-6-aminotetraline-5-oxo-3-phenyl-1,4-thiazepine-4(5H-acetic acid in the form of hydrobromide salt (320 mg ethyl slojnostyami in dichloromethane (30 ml), washed with sodium bicarbonate solution (220 ml), brine (20 ml), dried with magnesium sulfate, filtered, and the solvent was removed in vacuo, resulting in received a free amine in the form of a viscous oily substance (495 mg, 98%). This substance and previously obtained free acid was dissolved in dichloromethane (20 ml) in an argon atmosphere and cooled to 0oC. Then was added 1-hydroxybenzotriazole (285 mg, 2,11 mm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (403 mg, 2,11 mm. This cold mixture is stirred for 3.5 h, then was diluted with dichloromethane (30 ml). The resulting solution was washed with water (15 ml), 5% potassium bisulfate (15 ml), sodium bicarbonate (15 ml) and water (15 ml). The dichloromethane solution was dried with magnesium sulfate, filtered, and the solvent was removed in vacuum. The residue was chromatographically on silica gel (Merck, 170 ml), elwira 25% ethyl acetate in hexane, resulting in received 535 mg of product; Rf= 0.68 m to 0.63 (ethyl acetate : hexane, 1:1).

b) [3R-[ 3, 6 (S*)]]-Tetrahydro-6-[[2-(mercaptomethyl)-1-oxo-3 - phenylpropyl]amino]-5-oxo-3-phenyl-1,4-thiazepine-4(5H)-acetic acid

The product obtained in part (a), (493 mg, about 0,98 mm) was dissolved in methanol (12 ml) was purged for 15 minutes with argon, cooled in an ice/salt bath is ml), which for 30 minutes before use previously purged with argon. This mixture was stirred while cooling in an argon atmosphere for 48 hours TLC performed at this time showed that the hydrolysis of ester was completed. The mixture was acidified to pH 1 with 5% potassium bisulfate. The product was extracted into dichloromethane (2 30 ml). The combined organic extracts were washed with saline (20 ml), dried with magnesium sulfate, filtered, and the solvent was removed in vacuo, resulting received a white glassy foam substance. This substance was added 25% hexane in ether (20 ml), and after mixing, the formed white solid. This substance was collected by filtration and washed with 50% hexane in ether, resulting in the received 342 mg of the product, so pl. 170 - 174oC, Rf= 0,43, (5% methanol in methylene chloride + 2 drops acetic acid/5 ml), []D= +32,8o(c = 0.9, methanol).

HPLC: RT= 8,6 min, 66,8% aqueous methanol containing 0.2% phosphoric acid, 1.5 ml/min, detection at 220 min, MB S-3 (ODS), 6,0 150 mm column with a spherical cap size 3 μm. H. 1.>95%.

Analysis for C23H26N2O4S2:

Calculated: C 60,24; H 5,71; N 6,11; S 13,98;

Found: C 60,2 the filing] amino]-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-acetic acid

a) (2R-TRANS)-Tetrahydro-2-phenyl-6-[[(phenylmethoxy)carbonyl] amino] -1,4-diazepin-5(4H)-he

A suspension of (2R-TRANS)-6-aminotetraline-1,4-diazepin-5(4H)-it (of 5.82 g), obtained in accordance with known description (Yanagisawa and others, J. Med. Shem., vol. 30, S. 1984-1991 (1987)) in a mixture of dichloromethane (125 ml) and triethylamine (11 ml) was treated with distritbution (6 g) and stirred 4 h at room temperature. The mixture was diluted with dichloromethane (100 ml) and washed with water. The dichloromethane solution was dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo was obtained a pale yellow solid. This substance was chromatographically on silica gel, elwira a mixture of ethyl acetate and hexane (1: 1) and then with ethyl acetate, the resulting received a 2.01 g of white solid product.

b) (2R-TRANS)-Tetrahydro-5-oxo-2-phenyl-6-[[(phenylmethoxy)carbonyl] amino]-1,4-thiazepine-4(5H)-acetic acid, methyl ester

A solution of the product obtained in part (a), (1,95 g 6,05 mm) in distilled tetrahydrofuran in an argon atmosphere was cooled to 0oC and was treated with powdered potassium hydroxide (1.10 g, 18,15 mm) and tetrabutylammonium bromide (195 mg). Then for 30 min on a drop of added ethylbromoacetate (800 μl, 7,26 mm, 1.2 EQ.after this was added a dilute solution of hydrochloric acid (75 ml) and the layers were separated. The aqueous layer was again extracted with dichloromethane (100 ml). The combined organic layers were dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo received a white foamy substance. This substance was dissolved in a mixture of ethyl acetate and dichloromethane, and then was treated with excess amount of solution diazomethane in the air. The obtained methyl ester was purified by chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (1:1), and resulted 2,193 g; Rf= 0,49 (ethyl acetate : hexane, 1:1).

c) (2R-TRANS)-6-Aminotetraline-5-oxo-2-phenyl-1,4-diazepin-5(H)- acetic acid, methyl ester, cleaners containing hydrochloride salt

The product obtained in part (b), (2,19 g, 5.56 mm) was cooled in an ice bath and was treated with 4 N. solution cleaners containing hydrochloride salt in dioxane (15 ml). The cooled mixture was stirred for 1 h, and during this period he formed a gel. Then the cooling bath was removed and the mixture stirred at room temperature for 1 h the Solvent was removed under vacuum, was added toluene, and then removed in vacuo, resulting in a received 1.84 g of the product as a solid.

d) [2R-[ 2, 6 (S*)]]-Tetrahydro-6-[[2-[(acetylthio)methyl]-1-oxo is about)methyl] benzoylpropionic acid (obtained from ephedrinebuy salt in accordance with the description above) was subjected to a reaction product, obtained in part (c), according to the procedure described in example 1 (part b), resulting in a received target product; Rfor = 0.51 (ethyl acetate : hexane, 1:1).

e) [2R-[ 2, 6 (S*)] ]-Tetrahydro-6-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl] amino]-6-oxo-2-phenyl-1,4-thiazepine-4(5H)-acetic acid

A solution of the product obtained in part (d) in methanol was treated with 1 N. sodium hydroxide according to the procedure of example 1 (part (c)) and received in the target product, so pl. 197 - 199oC, Rf= 0,41 (5% methanol in dichloromethane + 2 drops of acetic acid.5 ml), []D= +27,1o(c = 0.5, methanol).

Analysis for C23H26N2O4S2:

Calculated: C 60,24; H 5,71; N 6,11; S 13,98;

Found: C 60,01; H 5,77; N 6,94; S 13,64.

Example 21.

[2R-[ 2, 6 (S*)]]-Tetrahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)-amino] -5-oxo-2-phenyl-1,4-thiazepine-4(5H)-acetic acid

a) [2R-[ 2, 6 (S*)]-Tetrahydro-6-[[2-acetylthio)-1-oxo-3-phenylpropyl] amino]-5-oxo-2-phenyl-1,4-thiazepine-4(5H)-acetic acid, methyl ester

Suspension dicyclohexylamine salt (S)-2-(acetylthio)benzoylpropionic acid (1.13 g, 2.8 mm) in ethyl acetate (50 ml) twice washed with 0.1 G. of hydrochloric acid (50 ml, 25 ml) and once with saline races the rim acid as an oily substance. This substance was dissolved in dichloromethane (15 ml) in an argon atmosphere and cooled to 0oC. Then was added 1-hydroxybenzotriazole (405 mg, 3.0 mm) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (592 mg, 3.1 mm). This mixture is refrigerated stirred 1 h, then was added the product cleaners containing hydrochloride salt of amine, obtained in accordance with the description in example 20 (c), (920 mg, 2,79 mm) and then were added 4-methylmorpholine (306 μl, and 2.79 mm). The mixture is stirred cold for 1 h, and then for 1 h at room temperature, after which it was diluted with dichloromethane (70 ml). The solution was washed with water (15 ml), 5% solution of potassium bisulfate (15 ml), sodium bicarbonate solution (15 ml) and water (15 ml). The dichloromethane solution was dried with magnesium sulfate, filtered, and the solvent was removed in vacuum. The remaining material was chromatographically on silica gel (Merck, 160 ml), elwira mixtures of ethyl acetate and hexane (1:3 then 1:2), resulting in a received 880 mg of the product, Rf=0,57 (ethyl acetate:hexane, 1:1).

b[2R-[ 2, 6 (SA)] ] -Tetrahydro-6-[2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo - 2-phenyl-1,4-thiazepine-4(5H)-acetic acid

A solution of the product obtained in part (a), (880 mg, about 1.75 mm) in methanol (12 ml) was purged with argon in the Wali drop of 1 N. a solution of sodium hydroxide (7.0 ml) for 30 min before use was purged with argon. The cooled mixture is stirred for 70 minutes, and then acidified to pH 1 with 5% solution of potassium bisulfate. The product was extracted into ethyl acetate (240 ml). The combined organic extracts were washed with saline, dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo received partially white solid material. Then was added ether and the white solid was collected by filtration, after which it was washed incremental amount of ether and received 494 mg of product; so pl. 181 - 183oC, Rf=0,43 (5% methanol in dichloromethane + 2 drops acetic acid/5 ml), []D= +6,7o(C = 0,7, methanol).

HPLC: RT= 9,6 min, 66,8% aqueous methanol containing 0.2% phosphoric acid, 1.5 ml/min, detection at 220 nm, MB S-3 (ODS), (6,0150 mm) column with a spherical cap size 3 μm. H. I.=98%. NMR showed the presence of approximately 0.1 M acetic acid ethyl ester.

Analysis for C22H24N2O4S2]D= -277o(c = 0.99, and ethanol). The residue from the combined mother solutions (21,5 g of 52.1 mm) suspended in ethyl acetate (340 ml), twice washed with 10% NH4OH (41 ml, and then 30 ml) and SOLEV who were given amine mixture (7.01 g), enriched in R-isomer. A solution of the isomeric mixture (2,285 g, 8,71 mm) in absolute ethanol (18 ml) was treated with D-tartaric acid (1.31 g, 8.73 mm) and heated on the steam bath until then, until it forms a solution. This clear solution was cooled to room temperature, left for two days to settle, and then was cooled to 0oC (ice/salt bath) and left in this condition until such time as you will not be formed crystals. The crude salt (2,585 g) was recrystallize from absolute ethanol (14 ml) and got the desired salt (2,158 g), []D= +154,1o(c = 0.6, methanol). Then the salt is suspended in ethyl acetate (35 ml), washed with 10% NH4OH (24 ml) and brine (6 ml), was dried with sodium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in a received 1,31 g, Rf= 0,60 (methylene chloride: methanol, 9:1), []D= +273,1o(c = 0,677, methanol).

b) [R-R*S*)]-2,3,4,5-Tetrahydro-3-[[2-(acetylthio)-1-oxo-3-phenylpropyl] amino]-2-oxo-1H-benzazepin-1-acetic acid, ethyl ester.

(S)-2-(Acetylthio)benzodiapines acid (obtained from dicyclohexylamine salt in accordance with the description above) was subjected to a reaction with the product, Eleveu product in the form of syrups; Rf= 0,57 (ethyl acetate:hexane, 1:1).

c) [R-(R*S*)]-2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-2-oxo-1H-benzazepin-1-acetic acid

A solution of the product obtained in part (b) in methanol was treated with 1 N. sodium hydroxide in accordance with the procedure described in example 2 (part (c)), resulting in a received target product in the form of amorphous solids, Rf= 0,67 (methylene chloride: methanol: acetic acid, 20:1:1), []D= -230,9o(c = 0,57, methanol).

Analysis for C21H22N2O4S;

Calculated: C 63,30; H 5,56; N 7,03; S 8,05; SH 8,30;

Found: C 63,23; H 5,80; N 6,76; S 7,99; SH to 7.67.

1H-NMR (400 MHz, CDCl3) : of 1.65 (m, 1H), 2.06 to (d, 1H), of 2.51 (m, 2H), equal to 2.94 (DD, 1H, J= 7,13 Hz), 3,17 (m, 2H), 3,40 (m, 1H), 4,39 (d, 1H), J=17 Hz); of 4.45 (m, 1H), 4,67 (d, 1H, J= 17 Hz), 7,05 - 7,31 (m, 9H).

Example 23.

[R-(R*S*)] -2,3,4,4,5-Tetrahydro-3-[[2-(mercaptomethyl)-1-oxo-3 - phenylpropyl]amino]-2-oxo-1H-benzazepin-1-acetic acid

Repeating the procedure of example 22, but using (S)-2-(acetylthio) methyl benzodiapines acid in part (b), obtained target product in the form of amorphous solids; Rf= 0,53 (methylene chloride:methanol:acetic acid, 20:1:1); []D= +253,9o(c = 0,38, meth is prohibited: C 63,83; H BETWEEN 6.08; N 6,40; S 7,75.

1H-NMR (400 MHz, CDCl3) : is 1.51 (m, 2H), 2,32 - 2,52 (m, 4H); 2,77 (m, 3H), 3,17 (m, 1H), 4,36 (d, 1H), J=17 Hz); 4,48 (m, 1H); 4,70 (d, 1H, J= 17 Hz), 6,53 (d, 1H); 7,11 - 7,30 (m, 9H).

Example 24.

[S-(R*S*)] -2,3,4,5-Tetrahydro-3-[(2-mercapto-1y-oxo-3-phenylpropyl) amino]-2-oxo-1H-benzazepin-1-acetic acid

a) (S)- - Bromobenzophenone acid

A solution of L-phenylalanine (30.0 g, 0,175 M) and potassium bromide (73,5 g, 0,618 M) 2.5 N. sulfuric acid (365 ml) was cooled to 0oC (ice/salt bath) and treated in portions during 1 h with sodium nitrite (19.3 g, 0,28 M). After stirring for 1 h at 0oC and for 1 h at room temperature, the reaction mixture was extracted with ether (3250 ml). The combined organic extracts were washed with water (100 ml) and brine (50 ml), dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in a received 34,46 g; Rf= 0,45 (toluene: acetic acid, 95:5).

b) (R) - (Acetylthio)benzoylpropionate acid, dicyclohexylamine salt

Suspension of thioacetate potassium (19,25 g has 0.168 M) in dry acetonitrile (300 ml) was cooled to 0oC in an ice/salt bath and treated drop by drop within 15 min a solution of the product is the temperature stirred 5 h in an argon atmosphere, and then was filtered, thoroughly washing the solid residue with acetonitrile (125 ml). Transparent filtrate is evaporated to dryness and dried in vacuum. Free acid (39,717 g, orange syrup) was dissolved in ether (400 ml) was treated with dicyclohexylamine (30,2 ml, 1.0 EQ.) and stirred 30 min at room temperature in an argon atmosphere. The white precipitate was filtered, thoroughly washed with ethyl ether (2100 ml), was dried in vacuum overnight at room temperature, resulting in a received 41,0 g of product; []D= +31,8o(c = 1.4%, in methanol).

c) [S-(R*S*)]-2,3,4,5-Tetrahydro-3-[[(2-aaltio)-1 - oxo-3-phenylpropyl]amino]-2-oxo-1H-benzazepin-1-acetic acid, ethyl ester

Suspension dicyclohexylamine salt of (R) - (acetylthio)benzoylpropionic acid (850 mg, 2.1 mm) in ethyl acetate (60 ml), washed with 5% potassium bisulfate (510 ml) and brine, and then dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in the obtained free acid in the form of a clear syrup (497 mg) in quantitative yield.

This free acid was dissolved in dry methylene chloride (12 ml), cooled to 0oC in an ice/salt bath and treated with 1-Hermes stirred at 0oC in the presence of argon for 1 h, and treated with (S)-2,3,4,5-tetrahydro-3-amino-2-oxo - 1H-benzazepin-1-acetic acid ethyl ether complex, obtained in accordance with known Watthey, etc. , J. Med. Chem., 28, S. 1511 - 1516 (1985)) (500 mg, 1,91 mm) and continued to stir 1 h at 0oC and 1 h at room temperature. The resulting solution was diluted with ethyl acetate (50 ml), washed successively with water (8.0 ml), 5% potassium bisulfate (28 ml), water (8.0 ml), saturated sodium bicarbonate (8.0 ml) and saline solution (8.0 ml) and then dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was chromatographically on silica gel (Merck), elwira with ethyl acetate: hexane (1:4), resulting in a received 714 mg of product as a clear syrup, Rf= 0,62 (ethyl acetate: hexane, 1:1).

d) [S-(R*S*)] -2,3,4,5-Tetrahydro-3-[(2 - mercapto-1-oxo-3-phenylpropyl)amino]-2-oxo-1H-1-benzazepin-1 - acetic acid

A solution of the product obtained in part (c), (714 mg, 1.52 mm) in methanol (9.0 ml) was purged for 30 min with argon, was cooled to 0oC in an ice/salt bath, and then drop handle purged solution of 1.0 n sodium hydroxide (6.0 ml, 4 equiv.) barbotine while argon Choi pH 2 with 5% potassium bisulfate (26 ml), and then was extracted with ethyl acetate (2 50 ml). The combined organic extracts were washed with saline solution (14 ml), was dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was dissolved in methylene chloride (5.0 ml) and in parts was treated with hexane (50 ml), stirring until the formation of solids. The supernatant decantation and the solid residue was washed with additional amount of hexane (50 ml) and pentane (2 100 ml), stirring for 4 h with the first 100 ml of pentane, and then during the night with the following 100 ml) in an argon atmosphere. The obtained product was dried in vacuum and amorphous solid, Rf= 0,47 (methylene chloride : methanol : acetic acid, 20:1:1), []D= -228o(c or = 0.51, methanol).

Analysis for C21H22N2O4S 0,26 C5H120,176 CH2Cl2:

Calculated: C 62,46; H 5,94; N 6,48; S 7,42;

Found: C 62,81, H By 5.87; N 6,53; S 7,29.

1H-NMR (400 MHz, CDCl3: of 1.65 (m, 1H); 2.06 to (d, 1H); of 2.51 (m, 2H); 2,95 (DD, 1H, J = 7,14 Hz); 3,17 (m, 2H); 4,39 (d, 1H, J = 17 Hz); to 4.46 (m, 1H); of 4.67 (d, 1H, J = 17 Hz), 7,02 - 7,31 (m, 9H).

Example 25.

[S-(R*, R*)] -Hexahydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-2-oxo-1(2H)-apocynaceae acid

a) [dimethylethylamine ester

Suspension dicyclohexylamine salt (S)-2-(acetylthio)-benzoylpropionic acid (2,63 g, 6,6 mm) in ethyl acetate (50 ml), washed two times with 0.1 G. of hydrochloric acid (50 ml, 25 ml) and once with brine (25 ml) and then dried with magnesium sulfate, filtered and, after removal of the solvent in vacuo received free acid in the form of an oily substance. This free acid and (S)-3-aminohexyl-2-oxo-1(2H)-asiankisses acid 1,1-dimethylethylamine ester obtained in accordance with known procedure (Thotsett and others, in J. Med. Chem., 29, 251-60 (1986)), (1,66 g, 6.5 mm) was dissolved in dichloromethane (30 ml) in an argon atmosphere and cooled to 0oC. Then was added 1-hydroxybenzotriazole (891 mg, 6,6 mm) and 1-ethyl-2-(3-dimethylamino-propyl)carbodiimide (1.26 g, 6,6 mm). The cooled mixture is stirred for 4 hours Then the mixture was diluted with dichloromethane (100 ml). The solution was washed with water (50 ml), 5% solution of potassium bisulfate (50 ml), sodium bicarbonate solution (50 ml) and brine (50 ml). The dichloromethane solution was dried with magnesium sulfate, filtered, and the solvent was removed in vacuum. Foamy residue was chromatographically on silica gel (Merck, 500 ml), elwira 25 - 50% ethyl acetate in hexane, resulting in received 2,252 g cont phenylpropyl]-amino] -2-oxo-1-(2H)-asiansexy acid

The product obtained in part (a), was dissolved in triperoxonane acid (20 ml) and stirred at room temperature for 1.75 h in argon atmosphere. Then triperoxonane acid was removed in vacuum, double was added toluene was removed in vacuo, resulting received the product as a white foamy substance.

c) [S-(R*, R*]-Hexahydro-3-[[(2-mercapto-1 - oxo-3-phenylpropyl]-amino] -2-oxo-1-(2H)-apocynaceae acid

A solution of the product obtained in part (b), (5.45 mm) in methanol (30 ml) was purged for 15 minutes with argon, cooled in an ice/salt bath and while purging with argon and stirring, this drop was treated with concentrated ammonium hydroxide solution (2.0 ml). After mixing in a chilled condition for 6.5 h, was added 1.0 ml of ammonium hydroxide solution, after which the mixture was sealed and left in the refrigerator for 18 hours Then the mixture was acidified to pH 2 with 5% solution of potassium bisulfate. The product was extracted into dichloromethane (3 50 ml). The combined organic extracts were dried with magnesium sulfate, filtered and, after removal under vacuum of the solvent was obtained a white foamy substance. This substance was added ether and hexane, and the resulting suspension stirred and hexane and dried in vacuum, resulting received 1,531 g of the product as a white foamy substance, so pl. 71 - 90oC, Rf= 0,41 (10% methanol in methylene chloride + 2 drops acetic acid / 5 ml), []D= +3,5o(c = 0.75, methanol).

Analysis for C18H24N2O4S:

Calculated: C 59,32; H 6,64; N 7,69; S 8,80;

Found: C 59,02; H 6,77; N To 7.67; S 8,70.

HPLC: RT= 6,1 min, 62% aqueous methanol containing 0.2% phosphoric acid, 1.5 ml/min, detection at 220 nm, MB S-3 (ODS), 6,0 150 mm column with a spherical cap with a diameter of 3 μm. H. I > 95%.

Example 26.

(3S)-2,3,4,5-Tetrahydro-3-[[(2-mercapto-3-(1-naphthalenyl)-1 - oxopropyl] amino]-2-oxo-1H-benzazepin-1-acetic acid

a) (Acetylamino)(1-naphthaleneacetic)proportionaly acid, diethyl ester

To a solution of ethoxide sodium (21% in ethanol, 4,613 g, 67,8 mm) in ethanol (100 ml) was added diethylacetamide (14,74 g, 67,8 mm), and then 1-(bromomethyl)naphthalene (10.0 g, 45.2 mm). The resulting solution was stirred 1 h at room temperature. Then the reaction mixture was concentrated to obtain an oily material orange. This substance was dissolved in ethyl acetate and washed with 50% saturated ammonium chloride, water and brine, and then dried sulphate is recristallization of ethyl acetate and hexane and was obtained as beige crystals mixed with malonate. The solid crystals were dissolved in 50% ethyl acetate in hexane and purified using flash chromatography on Merck silica gel in 50% ethyl acetate in hexane. The fractions containing pure product were combined and concentrated, resulting in a received 10,225 g of the product as a white solid, so pl. 105 - 108oC, Rf= 0,57 (50% ethyl acetate in hexane).

b) - Amino-1-nataliepopova acid

A solution of the product obtained in part (a), (16,182 g, 47.5 mm) suspended in 48% Pomodoro (100 ml) and was heated under reflux in the presence of argon for 14 hours Hydrobromic salt product was filtered from the solution and got a white solid, which was then dissolved in hot (50oC) water (500 ml) and the resulting solution was neutralized with concentrated ammonium hydroxide. The product was precipitated from solution in the form of a fine white solid. After filtration and drying under high vacuum overnight (18 hours) received 8,335 g of the product as chapeaurouge white solid substance, so pl. 264oC.

c) - Bromo-1-nataliepopova acid

To a solution of the product obtained in part (b), (4,000 g, 18.6 mm) and potassium bromide (7,63 g, 63,2 mm) 2.5 N. sulfuric acid (35 ml), cathouse 1 h at 0oC, and then heated to room temperature and stirred for 2.5 hours Then the reaction mixture was extracted with ether (3x). The ether layers were combined and washed with water and brine, and then dried with sodium sulfate, filtered and concentrated, resulting in a received orange oily product. This product was purified using flash chromatography on silica gel Merck 70% ethyl acetate in hexane with the addition of 1% acetic acid to reduce the tail fractions. The fractions containing bromide, were combined and concentrated, resulting in a received orange oily product with a small impurities, after which it keeping during the night was utverjdala. Rf= 0,40 (40% ethyl acetate in hexane with 1% acetic acid).

d) - (Acetylthio)-1-nataliepopova acid

To a suspension of thioacetate potassium (0,912 g, 8,00 mm) in acetonitrile (300 ml) at 0oC was added the product obtained in part (c), (2,030 g, 7,27 mm) in the form of a solution in acetonitrile (3 ml). The resulting solution was stirred at 0oC for 1 h, and then heated to room s and stirred for 15 hours then the reaction mixture was filtered potassium bromide, the filtrate was concentrated and the I and a salt solution then was dried with sodium sulfate, filtered, concentrated and received an orange oily product. This product was purified using flash chromatography on silica gel (Merck) in 50% ethyl acetate in hexane with the addition of 1% acetic acid to reduce the tail fractions. The fractions containing the desired product were all mixed with compounds with Rf= 0,43. These fractions were combined, concentrated and got orange oily compound. The crude product was purified using dicyclohexylamine salt, which was obtained by dissolving orange oily product in ether and adding one equivalent of dicyclohexylamine (18,13 g, 100 mm) to the resulting solution. This dicyclohexylamine salt was obtained in two camps in the form of brown crystals (1,450 g) and still had minor impurities. These crystals suspended in ethyl acetate and shaken with 10% potassium bisulfate (3x). The organic layer was washed with water and brine, and then dried with sodium sulfate, filtered and concentrated, resulting in a received 875 mg of product as a yellow oily substance, Rf= 0,40 (40% ethyl acetate in hexane with 1% acetic acid).

e) (3S)-2,3,4,5-Tetrahydro-3-[(private product, obtained in part (d), (338 mg, 1,23 mm) and (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-1-1-benzazepin - 1-acetic acid ethyl ester [obtained in accordance with the description Watthey, etc., J. Med.Chem., 28, pp. 1511-1516 (1985)] (321 mg, 1,23 mm) was dissolved in methylene chloride (11 ml) in an argon atmosphere at room temperature. The resulting mixture was cooled to 0oC and treated with hydroxybenzotriazole (166 mg, 1,23 mm) and 1-ethyl-3-(3-dimethyl-amino-propyl)carbodiimide (259 mg, 1.35mm). After 1 hour stirring, the mixture was heated to room temperature and stirred for another 4 h the Volatile components are evaporated, and the residue was dissolved in ethyl acetate and washed successively 1 N. hydrochloric acid, water, saturated sodium bicarbonate and saline. The organic layer was dried with sodium sulfate, filtered and concentrated, and the residue was subjected to flash chromatography on silica gel (Merck), elwira 50% ethyl acetate in hexane, resulting in received 510 mg of oily product (mixture of diastereoisomers, 1:1), Rf=0,40 (5% acetic acid in ethyl acetate).

f) (3S)-2,3,4,5-Tetrahydro-3-[[2-mercapto-3-(1-naphthalenyl)-1 - oxopropyl]amino]-2-oxo-1H-1-benzazepin-1-acetic acid

A solution of the product obtained in part (e), (508 mg, 0,98 mm) in mehanizacija sodium (6 ml, deoksigenirovanii by ozonation of argon). The resulting mixture was stirred 1 h in the presence of argon. The solution was acidified with 10% potassium bisulfate and extracted with ethyl acetate. The organic layer was washed with saline, dried with sodium sulfate, filtered, concentrated and received transparent oily residue. This residue was subjected to flash chromatography on silica gel (Merck), elwira 1% acetic acid in a mixture of hexane and ethyl acetate (1:1). The fractions containing pure product were combined, concentrated, azeotropically was obezvozhivani using ethyl acetate and washed with water to remove acetic acid. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate and triturated with ethyl ether and hexane. The solvent was removed and the residue is suspended in hexane, evaporated and dried in vacuo, resulting in a received 327 mg of the product as a white powdery foam-like substance, Rf= 0,64 (5% acetic acid in ethyl acetate), []D= -187,3o(c = 0,43, chloroform).

Analysis for C25H23N2O4S 0,42 H2O:

Calculated: C 65,98; H 5,28; N 6,16; S 7,05;

Found: C 66,29; H Of 5.29; N 5,85; S Of 6.65.

Example 27.

[S-(R*, R*)] -3-[[2-(Acetylthio)-1-oxo-3 - phenylpropyl] amino]-2,3,4,5-tetrahydro-2-oxo-1-benzazepin-1-acetic acid

The product obtained in accordance with the description given in example 6 (799 mg, 2.0 mm) was added to deoksigenirovanii (by ozonation argon) solution of potassium bicarbonate (378 mg, 3.8 mm) in water (25 ml). After dissolution of the source material, was added acetic anhydride (1.5 ml, of 1.62 g, 15,9 mm). The result has been a milky-white solution, which eventually turned into a resinous product. After stirring at room temperature for several minutes, the mixture was acidified with 10% hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate extract was washed with water (3 times) and brine, and then dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography on silica gel (Merck) (1% acetic acid in ethyl acetate) and the desired fraction was evaporated, azeotropically was obezvozhivani using ethyl acetate (3 times), was dissolved in a small volume of ethyl acetate and triturated with hexane. The solvent is kept off, and the residue is suspended and two rucka.

TLC: (1% acetic acid in ethyl acetate), Rf= 0,41, []D= -190,8o(c = 0,68, chloroform).

Analysis for C23H24N2O5S 0,13 C4H8O20.5 H2O:

Calculated: C 61,28; H 5,69; N BETWEEN 6.08; S OF 6.96;

Found: C 61,18; H 5,64; N The Ceiling Of 5.60; S 6,70.

Examples 28 to 30. Repeating the procedure described in example 27, but using benzoyl chloride as Alliluyeva agent received [S-(R*, R*)] -3-[[2-(benzylthio)-1-oxo-3 - phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-1-acetic acid, so pl. 170 - 171oC []D= -244o(c = 0,30, chloroform). TLC (hexane : ethyl acetate : acetic acid, 40:60:1); Rf= 0,31.

Analysis for C28H26N2O5S 0.1 C4H8O20,2 H2O:

Calculated: C 66,24; H 5,32; N 5,44; S 6,23;

Found: C 66,28; H 5,23; N 5,40; S 6,18.

Repeating the procedure described in example 27, but using propionic anhydride acid as Alliluyeva agent received [S-(R*,R*)] -2,3,4,5, -tetrahydro-[3-[[1 - oxo-1-(oxopropyl)thio]-3-phenylpropyl]amino]-2-oxo-1H - benzazepin-1-acetic acid, so pl. 156 - 157oC []D= -210o(c = 0.31, chloroform). TLC (hexane : ethyl acetate : acetic acid, 40:60:1); Rf= 0,34.

Repeating the procedure described in example 27, but using anhydride trimethylhexanoic acid as Alliluyeva agent received [S-(R*, R*)]-[3-[[2-[(2,2-dimethyl-1 - oxopropyl]-1-oxo-3-phenylpropyl]amino] -2,3,4,5 - tetrahydro-2-oxo-1H-benzazepin-1-acetic acid, so pl. 86 - 90oC []D= -190o(c = 3,06, chloroform). TLC (hexane : ethyl acetate : acetic acid, 30:70:1) Rf= 0,42.

Analysis for C26H30N2O5S 0,2 C6H140,25 H2O:

Calculated: C 64,78; H of 6.65; N 5,50; S 6,36;

Found: C 64,79; H 6,56; N Of 5.53; S 6,30.

Example 31.

[S-(R*, R*)]-3,4-Dihydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl]amino]-4-oxo-1,5-benzoxazepin-3(2H)propanoic acid

a) (S)-3-[[(Dimethylmethoxy)carbonyl] amino]-3,4-dihydro-4-oxo - 1,5-benzoxazepin-5(2H)-propanoic acid, ethyl ester

A solution of (S)-3-[[(dimethylmethoxy)-carbonyl]amino]2,3-dihydro-1,5 - benzoxazepin-4(5H)-it and received in accordance with the description given in example 13 (c), (1,49 g, 5,35 mm) in a mixture of tetrahydrofuran and t-butanol (2: 1,21 ml) was cooled to 0oC and was treated with ethyl acetate (0,81 ml, 7.50 mm, 1.4 EQ. ), and then to 1.0 N. potassium salt of t-butanol (535 μl, the argon. Then to the reaction mixture was added an additional amount of 1.0 N. potassium salt of t-butanol/tetrahydrofuran (270 µl of 0.05 EQ.). The reaction mixture was stirred at room temperature for 45 min, and then for 2 h was heated to 60oC. then the reaction mixture was extinguished 25% ammonium chloride (50 ml) and was extracted with ethyl acetate (2 100 ml). The combined organic layers were washed with 25% ammonium chloride (50 ml), water (50 ml) and brine (50 ml) and then dried with magnesium sulfate, filtered, concentrated and received transparent syrup. TLC of the residue showed two spots.

The reaction is again initiated by treatment of a solution of a mixture of (1.42 g 5,10 mm) in tetrahydrofuran: t-butanol (2:1, 15 ml), cooled to 0oC, acrylate (of 0.77 ml, 7,14 mm, 1.4 EQ.), and then of 1.0 N. potassium salt of t-butanol/tetrahydrofuran (510 μl, 0.1 EQ.). The reaction mixture was stirred 15 min at 0oC, and then 3 h at room temperature. After this reaction extinguished 25% ammonium chloride (50 ml) and was extracted with ethyl acetate (2100 ml). The combined organic layers were washed with 25% ammonium chloride (50 ml), water (50 ml) and brine (50 ml) and then dried with magnesium sulfate, filtered and concentrated, resulting floor is ethyl acetate and hexane (2:1). The desired fractions were combined, concentrated and resulted 1.40 g of target compound in the form of a transparent syrup. TLC (5% methanol/chloroform), Rf= 0,63.

b) (S)-3-Amino-3,4-dihydro-4-oxo-1,5-benzoxazepin-5(2H)-propanoic acid, ethyl ester, cleaners containing hydrochloride salt

The product obtained in part (a), (1.4 g, 3.7 mm) was treated with a mixture of 4.0 M hydrochloric acid and dioxane (20 ml, 80 mm) and cooled to 0oC. the resulting solution was stirred at 0oC for 30 min and then at room temperature for 2 hours the Reaction mixture was concentrated, was twice evaporated with ethyl ether three times subjected azeotropically distillation using toluene and dried in vacuum for 4 h, resulting in received of 1.05 g of the target compound.

c) [S-(R*, R*)] -3-[[2-(Acetylthio)-1-oxo-3 - phenylpropyl]amino]-3,4-dihydro-4-oxo-1,5-benzoxazepin-5(2H)- propanoic acid, a complex ethyl ester

Dicyclohexylamine salt (S)-2-(Acetylthio)benzodiapines acid (1.8 g, 4,40 mm) suspended in ethyl acetate (100 ml) and washed with 5% potassium bisulfate (525 ml) and brine (30 ml), dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in h is was ladli to 0oC in an ice/salt bath and treated with a solution of the product obtained in part (b), (1,05 g of 3.33 mm) in dry methylene chloride (25 ml), then triethylamine (of 0.62 ml of 4.44 mm, 1.3 EQ.) and hexafluorophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (1,96 g of 4.44 mm, 1.3 EQ.). The reaction mixture was stirred 1 h at 0oC, and then overnight at room temperature. Then the reaction mixture was concentrated to dryness, diluted with ethyl acetate (150 ml) and washed with 5% potassium bisulfate (250 ml), water (250) and brine (50 ml) and then dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was chromatographically in column (515 cm) with silica gel, elwira a mixture of 30% ethyl acetate and hexane. The desired fractions were combined and concentrated, resulting in a received 740 mg of the pure product.

TLC (10% methanol in chloroform), Rf= 0,74.

d) [S-(R*,R*)]-3,4-Dihydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)- amino] -4-oxo-1,5-benzoxazepin-5(2H)-propanoic acid

A solution of the product obtained in part (c), (740 mg, 1,53 mm) in methanol (15 ml) was cooled to 0oC in an ice/salt bath, was purged with argon for 30 min, and then treated drop by drop previously purged (argon, 30 minutes) R the shares. Then the reaction mixture was stirred 1 h at 0oC, acidified at 0oC 5% potassium bisulfate (150 ml) to pH 1.5 and were extracted with ethyl acetate (3100 ml). The combined organic extracts washed with brine (100 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting received a white foamy substance (612 mg). The residue was purified by column chromatography (515 cm) on silica gel, elwira of 0.5% acetic acid in ethyl acetate. The residue was dissolved in methylene chloride (5 ml) and 5 times was evaporated on a rotary evaporator using hexane, stirring the mixture until a white foamy solid. This substance was dried in vacuum over night and got 590 mg of the product. TLC (1% acetic acid in ethyl acetate), Rf= 0,42, []D= -127,6o(c = 1,12, methanol).

Analysis for C21H22N2O5S 0,03 H2O

Calculated: C 60,86; H are 5.36; N 6,75; S 7,73;

Found: C 61,08; H Of 5.68; N 6,45; S 7,51.

Example 32.

[2R-[ 2, 3 (S*)]]-3,4-Dihydro-3-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-2-methyl-4-oxo-1,5-benzoxazepin-5(2H)-acetic acid

a) N-[(1,1-Dimethylmethoxy)carbonyl]-O-(2-nitrophenyl)-L-threonine

A solution of N-[(1,1-dimethyl who Ardennes (0oC) suspension of 60% sodium hydride (1,93 g, 48,25 mm 2,11 EQ.) in dry dimethylformamide (40 ml). The reaction mixture was stirred at 0oC as long as you do not stop foaming (about 3.5 hours). The reaction mixture drop by drop within 20 min were treated with 1, fluorescent-2-nitrobenzol or 2.67 ml, 25,2 mm, 1.1 equiv. ) and stirred 2 h at 0oC in the presence of argon. Then the reaction mixture was placed in a cold room (5oC) and stirred over night. The reaction mixture was poured into ice water (500 ml) and was extracted with ethyl ether (2200 ml). The aqueous phase is brought to pH of 1.0 with 6 N. hydrochloric acid (200 ml) and was extracted with ethyl acetate (3300 ml). United an ethyl acetate extracts were washed with water (2300 ml) and brine (300 ml) and then dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude residue was loaded onto celite and purified by chromatography on a column (1020 cm) with silica gel. After elution with methylene chloride (3 l), with a mixture of methylene chloride and methanol (99:1, 2 l), with a mixture of methylene chloride and methanol (95:5) mixture of methylene chloride, methanol and acetic acid (100:5:0.5) with (5 l) were 6,07 g of target compound. TLC (methylene chloride:methanol:acetic acid, 100:5:0.5), and Rf= 0,16.

f= 0,16.

c) (2R-CIS)-3-[[(Dimethylmethoxy)carbonyl] amino] -2,3-dihydro-2-methyl - 1,5-benzoxazepin-4(5H)-he

A solution of the product obtained in part (b), (0.8 g, 2,58 mm) in dry dimethylformamide (6 ml) was treated with 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (495 mg, 2,58 mm) and stirred 3 h at room temperature. The reaction mixture was distributed between ethyl acetate (50 ml) and 50% sodium bicarbonate solution (50 ml). The aqueous layer was separated and was extracted with ethyl acetate (250 ml). The combined organic extracts were washed with water (350 ml) and brine (50 ml) and then dried with anhydrous magnesium sulfate, evaporated and assailable in column (515 cm) with silica gel, elwira 25% ethyl acetate/hexane and obtained 568 mg of the target compound in the form of a whitish solid, TLC (ethyl acetate:hexane, 1:1), Rf= 0,47.

d) (2R-CIS))-3-[[(Dimethyl)ethoxy)carbonyl]amino]-3,4-dihydro - 2-methyl-4-oxo-1,5-benzoxazepin-5(2H)-acetic acid, ethyl ester

A solution of the product obtained in part (c), (319 mg, 1,09 mm) and ethylbromoacetate (151, 3mm μl, 1,36 mm, 1.25 EQ.) in dry tetrahydrofuran (3 ml) was added to a cooled (0oC) suspension of 60% sodium hydride (53 mg, 1,32 mm 1,21 EQ. ), washed 3 times with hexane (dry tetrahydrofuran (THF) (2 ml) for 5 minutes, the Reaction mixture was stirred 1 h at 0oC, and then 30 min at room temperature. The reaction was suppressed to a 25% solution of ammonium chloride (5 ml) and was extracted with methylene chloride (220 ml). The combined organic extracts were washed with 25% solution of ammonium chloride (10 ml) and brine (10 ml) and then dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo, resulting in a received 400 mg of the target product. TLC (ethyl acetate:hexane, 1:1), Rf= 0,55.

e) (S)-3-Amino-3,4-dihydro-2-methyl-4-oxo-1,5-benzoxazepin - 5(2H)-acetic acid, ethyl ester, cleaners containing hydrochloride salt

4.0 M hydrochloric UP>oC. the resulting solution was stirred at 0oC for 30 min and then at room temperature for 3 hours, the Reaction mixture was evaporated on a rotary evaporator, concentrated with ethyl ether (310 ml) and dried in vacuum over night in the presence of sodium hydroxide, resulting in a received 350 mg of the target product. TLC (methylene chloride:methanol, 9:1), Rf= 0,49.

f) [2R-[ 2, 3 (S*)]]-3-[[(2-(Acetylthio)-1-oxo-3-phenylpropyl]amino]- 2-methyl-4-oxo-1,5-benzoxazepin-5(2H)-acetic acid

A suspension of (S)-2-(acetylthio)benzoylpropionic acid dicyclohexylamine salt (495 mg, 1,22 mm, 1.1 equiv.) in ethyl acetate (30 ml), washed with 5% potassium bisulfate (55 ml) and brine (10 ml) and then dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in the obtained free acid in the form of a clear syrup (278 mg) in quantitative yield.

This free acid was dissolved in dry methylene chloride (10 ml), cooled to 0oC in an ice/salt bath and treated with a solution of the product obtained in part (e), (350 mg, 1,11 mm) in dry methylene chloride (2 ml) and then treated with triethylamine (163 μl, 1,17 mm to 1.05 equiv.) and benzotriazol-1-yloxytris(dimethylamino)Fosi room temperature. Since the reaction was not complete as shown by TLC, added an additional amount of triethylamine (54 μl, 0,389 mm) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (172 mg, 0,389 mm) and stirred for 1 h, the Reaction mixture was concentrated to dryness, washed with 0.5 G. hydrochloric acid (210 ml), water (10 ml) and brine (10 ml) and then dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was chromatographically in column (316 cm) with silica gel, elwira a mixture of 20% ethyl acetate and hexane. The desired fractions were combined and concentrated, resulting in a received 378 mg of pure desired product. TLC (ethyl acetate:hexane, 1:1), Rf= 0,48.

g) [2R-[ 2, 3 (S*)]]-3,4-Dihydro-3-[(2-mercapto-1-oxo - 3-phenylpropyl] amino)-2-methyl-4-oxo-1,5-benzoxazepin-5(2H)-acetic acid

A solution of the product obtained in paragraph (f), (237 mg, and 0.61 mm) in methanol (4 ml) was purged with argon for 30 minutes, cooled to 0oC in an ice/salt bath, and then drop was treated previously purged (argon, 30 minutes) solution of 1.0 n sodium hydroxide (2,45 ml, 4 equiv.) barbotine while argon while adding and throughout the reaction. The reaction mixture was stirred 1 h at 0oC the volume (250 ml). The combined organic extracts washed with brine (25 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in a received glassy oily product (351 mg). The crude residue was dissolved in methylene chloride (5 ml) and was partially treated with hexane (50 ml), stirring the mixture before formation of solids. The supernatant decantation, and the solid residue triturated with more hexane (50 ml) and pentane (2100 ml), stirring for 4 h with the first 100 ml of pentane, and then during the night with the following 100 ml of pentane in an argon atmosphere. Pentane decantation, and amorphous white solid residue was dried in vacuum over night, resulting in a received 240 mg of the target product. TLC (2% acetic acid in ethyl acetate), Rf= 0,48; []D= -101,1o(C=1, methanol).

Analysis for C21H22N2O5S 0,40 C4H8O20,08 H2O:

Calculated: C 60,36; H 5,65; N 6,23; S 7,13;

Found: C 60,17; H To 5.57; N 6,16; S 7,45.

Example 33. Repeating the procedure described in example 32, but using ALLO-L-threonine, received [2s-[ 2, 3 (R*)]] -3,4-dihydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -2-methyl-4-oxo-1,5-benzoxazepin is 3.

Example 34.

(2S)-(2S)-3- [(2-Mercapto-1-oxo-3-phenylpropyl)amino] -3,4,5,6-tetrahydro-2-oxo-1-benzazocin-1(2H)acetic acid

a) 1-Benzocoumarin, oxime

A solution of hydroxylamine hydrochloride (2,39 g, 34,33 mm, 1.1 equiv.) in water (16 ml) was added to a solution of 1-benzocoumarin (4,67 ml, 31,21 mm) in pyridine (9.0 ml) and ethanol (16 ml). The reaction mixture was heated under reflux (bath temperature 105oC) for 35 minutes the Reaction mixture was cooled, diluted with ethyl acetate (100 ml) and water (40 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (250 ml). The combined organic extracts washed with 1 N. hydrochloric acid (3100 ml), dried with anhydrous magnesium sulfate, filtered and concentrated, resulting in a received untreated whitish solid residue (the ceiling of 5.60 g). This residue was purified by chromatography on a column (1020 cm) with silica gel, elwira hexane (2 l), and then a mixture of 10% ethyl acetate and hexane (5 l), resulting in received and 4.40 g of target compound in the form of a whitish solid product. TLC (10% ethyl acetate/hexane), Rf=0,35.

b) 3,4,5,6-Tetrahydro-1-benzazocin-2(1H)-he

Concentrated sulfuric acid (8,8 ml) was added a whole (in one piece) to a suspension of the product obtained mesh was heated to 160oC (oil bath) for 10 minutes and Then the reaction mixture was left to cool to room temperature, after which it was poured into ice water (100 ml). After that, the pH of the reaction mixture is brought to a value of 11 with 10 n sodium hydroxide solution. The mixture was diluted with ethyl acetate (250 ml) and water (100 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3100 ml). United an ethyl acetate extracts were washed with water (150 ml) and brine (150 ml), then was dried with anhydrous sodium sulfate, filtered and concentrated, resulting in a 2.8 g of the target product. TLC (ethyl acetate), Rf=0,33.

c) 3,4,5,6-Tetrahydro-3-bromo-1-benzazocin-2(1H)-he

A solution of the product obtained in part (b), (8,31 g, 47,42 mm) in chloroform (115 ml) was cooled to 0oC, was treated with pentachloride phosphorus (11,36 g, 54,53 mm, 1.15 EQ.) and iodine (114 mg) and stirred for 30 min at 0oC in argon atmosphere. The reaction mixture is yellow was treated with bromine (2,92 ml, 56.0 mm, 1.2 EQ.) was heated to room temperature and then was heated under reflux in an argon atmosphere for 3.5 hours then the reaction mixture was left to cool to room temperature and poured into ice-cold water (100 ml). With the Lee. The crude residue was recrystallized from hot ethyl acetate and received 8.69 g of the target product. TLC (ethyl acetate: hexane, 1:1), Rf=0,36.

d) 3,4,5,6-Tetrahydro-3-azido-1-benzazocin-2(1H)-he

A solution of the product obtained in part (c), (6,87 g, 27,03 mm) and sodium azide (2.28 g, 35,14 mm, 1.3 EQ.) in dimethyl sulfoxide (130 ml) was stirred at 60oC (oil bath) and in argon atmosphere for 5 hours, the Reaction mixture was cooled to room temperature, poured into cold water (400 ml) and stirred 15 minutes the Precipitate was filtered, the solid product was washed with water (1 l) and dried overnight in a vacuum oven, resulting in a received target product. TLC (ethyl acetate: hexane, 1:1), Rf=0,63.

e) 3-Azido-3,4,5,6, -tetrahydro-2-oxo-1-benzazocin-1(2H)-acetic acid complex ethyl ester

A solution of the product obtained in paragraph (d) (5,454 g, 25,22 mm) and ethylbromoacetate (3.5 ml, 31,53 mm, 1.25 EQ.) in dry tetrahydrofuran (50 ml) was added to a cooled suspension (0oC) 60% sodium hydride [1,23 g 30,77 mm, 1.22 EQ. , washed with hexane (310 ml)] in dry tetrahydrofuran 15 ml) for 15 minutes the mixture is Then stirred 1 h at 0oC and 30 min at room temperature. The reaction extinguished 25% solution of ammonium chloride (100 ml) and the ammonia (100 ml) and brine (100 ml), and then was dried with anhydrous magnesium sulfate, filtered and concentrated, resulting in a received target compound as a yellow oily product. TLC (35% ethyl acetate/hexane), Rf=0,35.

f) 3-Amino-3,4,5,6-tetrahydro-2-oxo-1-benzazocin-1 (2H)-acetic acid complex ethyl ester

A solution of the product obtained in part (e), (9.0 g, 29,83 mm) in absolute ethanol (50 ml) was treated with 10% palladium carbon (900 mg) and was first made at a pressure of 45 pounds per square inch (310,2 kPa), with the first 1.5 h the flask Parra twice ventolinbuy. The mixture was filtered through militarily filter, thoroughly rinsing with ethanol. Transparent filter, evaporated to dryness and dried in vacuo, resulting in received to 7.59 g of the desired product as a thick yellow syrup. TLC (10% methanol/telengard), Rf=0,29.

g) (2S)-3-[[2-(Acetylthio)-1-oxo-3-phenylpropyl] -amino] -3,4,5,6-tetrahydro-2-oxo-1-benzazocin-1-(2H)-acetic acid ethyl ester

A suspension of (S)-2-(acetylthio) benzoylpropionic acid dicyclohexylamine salt (2.1 g, 5,18 mm, 1.1 equiv.) in ethyl acetate (100 ml), washed with 5% potassium bisulfate (525 ml) and brine (30 ml), dried with anhydrous magnesium sulfate, was filtered, evaporated to dryness and dried off in the om.

The obtained free acid was dissolved in dry methylene chloride (45 ml), cooled to 0oC (in a bath of ice and salt) and treated with a solution of the product obtained in paragraph (f), (1.3 g, 4,71 mm) in dry methylene chloride (10 ml), followed by treatment with triethylamine (723 μl, 5,18 mm, 1.1 equiv.) and hexafluorophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (to 2.29 g, 5,18 mm, 1.1 equiv. ). The reaction mixture was stirred 1 h at 0oC, and then overnight at room temperature. After that, the mixture was concentrated to dryness, diluted with ethyl acetate (125 ml), washed with 0.5 G. hydrochloric acid (225 ml), water (25 ml) and brine (25 ml), dried with anhydrous magnesium sulfate and evaporated to dryness. The crude product was chromatographically on a column of silica gel (316 cm), elwira 30% ethyl acetate/hexane. The desired fractions were combined and concentrated, resulting in a received 1,77 g of pure target compound (1:1 - mixture of diastereomers). TLC (ethyl acetate: hexane, 1:1), Rf=0,39.

h) (2S) - 3-[(2-Mercapto-1-oxo-3-phenylpropyl)amino]-3,4,5,6-tetrahydro-2-oxo-1-benzazocin-1(2H)-acetic acid

A solution of the product obtained in paragraph (g), (1.75 g, 3,62 mm) in methanol (25 ml) was purged with argon for 30 min, cooled to 0oC (in the bath is the atrium (14,5 ml, 4 EQ.), barbotine, while argon while adding and during the whole reaction. The reaction mixture was stirred at 0oC for 1 h, acidified at 0oC 5% potassium bisulfate (200 ml) to pH 1.5, and then was extracted with ethyl acetate (2100 ml). The combined organic extracts washed with brine (200 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting received a white foamy substance (1,67 g). The crude residue was dissolved in methylene chloride (10 ml) and the portions were treated with hexane 50 ml), resulting in the formed solid substance. The supernatant decantation, and the solid residue triturated with hexane (50 ml) and pentane (2100 ml), stirring with the first 100 ml of pentane for 4 h and followed by a 100 ml overnight in an argon atmosphere. Pentane decantation and the resulting white amorphous solid was dried in vacuum over night, resulting in a received 1,388 g of target compound (mixture of diastereoisomers, 1:1), so pl. 107 - 111oC []D= +28,3o(C = methanol).

TLC (methylene chloride: methanol: acetic acid, 20:1:1), Rf=0,44.

Example 35.

[4S- [4, 7(R*), 10a] ] -Decahydro-7-[(2-mercapto-1-OK is dicyclohexylamine salt

The homogeneous solution of (S)-2-amino-4-pentalofos acid (2,988 g, 25,9 mm) and sodium carbonate (2,600 g, 24,5 mm) in water (55 ml) was treated with solid N-(carbethoxy)phthalamide (5,677 g, 25,9 mm). After 2.5 hours stirring at room temperature, the mixture was acidified using 10% hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate extract was washed with saline, dried with sodium sulfate, filtered and evaporated. The residue is twice subjected to flash chromatography (2% acetic acid in ethyl acetate), then the desired fractions of the product were combined, evaporated and subjected to the azeotropic distillation using toluene. The residue was dissolved in ethyl ether, was treated with 5.3 ml of dicyclohexylamine and introduced the seed crystal. The obtained white precipitate was collected by filtration, washed with ethyl ether, and dried under vacuum, resulting in a received 7,620 g of pure target product, so pl. 196 - 197oC []D= -13,9o(c = 0.8, methanol). TLC (5% acetic acid in ethyl acetate), Rf= 0,57.

b) [S-(R*,R*)]-2-[(2-phthalimido-1-oxo-4-pentyl amino]-6-Gidromekhanika acid, methyl ester

A suspension of (S)-2-amino-6-hydroxyhexanoic acid (2,42 g, 16.4 mm) in dry methanol (60 ml) store Merivale at room temperature for 2.5 hours After that, the solvent was evaporated, and the residue was subjected to azeotropic treatment (3 times) using toluene, resulting in the obtained crude methyl ester of (S)-2-amino-6-hydroxyhexanoic acid cleaners containing hydrochloride salt in the form of an oily product. This product was dissolved in dimethylformamide (20 ml) and methylene chloride (50 ml) and was treated with 4-methylmorpholine (3,20 ml, 2,94 g, 29,1 mm). The resulting mixture was cooled to 0oC and was treated with (S)-2-phthalimido-4-pentenol acid derived from 7.0 g, 16.4 mm salt product of part (a) by distributing between 10% potassium bisulfate and ethyl acetate, methylene chloride (10 ml) and then solid hydroxybenzotriazole (2,22 g, 16.4 mm) and cleaners containing hydrochloride salt of ethyl-3-(3-dimethylamino) propylbromide (3,458 g, 18,0 mm). The mixture is then stirred 0.5 h at 0oC and 2 h at room temperature and distributed between ethyl acetate and 0.5 G. hydrochloric acid. An ethyl acetate extract was washed successively with water, 50% saturated sodium bicarbonate and brine, and then dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica gel, ethyl acetate) and received the pure target compound in the form of an oily substance, which then from the tion and resulted 5,149 g of analytically pure product, so pl. 90 - 92oC []D= +25,6o(c= 1,1, chloroform). TLC (ethyl acetate) Rf= 0,36.

c)[S-(R*, R*)] -2-[(2-phthalimido-1-oxo-4-pentyl) amino]-6-oxohexanoate acid, methyl ester

Solution (-78oC) oxalicacid (1,38 ml, 0.95 g, 7.5 mm) in methylene chloride (70 ml) drop by drop was treated with a solution of dry dimethylsulfoxide (2.20 ml, 2.00 g, 25.6 mm) in methylene chloride (2 ml). After 10 minutes the mixture was treated with a solution of the product of part (b) (5,04 g, 13,0 mm) in methylene chloride (15 ml). Then after another 10 min was added triethylamine (9.0 ml) and the mixture stirred 5 min at -78oC, and then left to slowly warm to 0oC. thereafter, the mixture was distributed between ethyl acetate/ethyl ether and 0.5 N. hydrochloric acid. The organic extract was washed with 50% saturated sodium bicarbonate and brine, and then dried with sodium sulfate, filtered and evaporated. The residue was led from ethyl acetate/ethyl ether and received 4,567 g of the desired product as a white solid. The mother liquor was subjected to flash chromatography (Merck silica gel, 6/4-ethyl acetate/hexane) and was led, in the result of which was given to 184 mg of product (total of 4,751 g), so pl. 74 - 76oC []D= +25,2o(c = 1,3, chlorine is limido-4 - pentenyl)-2-piridinkarbonovaya acid, methyl ester

A solution of the product obtained in part (c), (to 3.657 g, 9,46 mm) triperoxonane acid (190 μl) in methylene chloride (70 ml) was heated in an argon atmosphere for 1.5 hours, the Cooled mixture is washed with diluted aqueous sodium bicarbonate, dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica gel, ethyl acetate: hexane = 1: 1) and received 3,417 g of the desired product in the form of oily and foamy product. TLC (ethyl acetate:hexane), Rf= 0,50.

e) [4S- (4, 7, 10a) ]-Decahydro-9-iodo-6-oxo-7-phthalimido-[1,2-a]azepin, 4-carboxylic acid, methyl ester

A solution of the product obtained in paragraph (d) (1,427 g, a 3.87 mm) in methylene chloride (8,8 ml) drop by drop) was added to the mixture triftormetilfullerenov acid (2.2 ml) and anhydride triftormetilfullerenov acid (210 ml) at room temperature. The solution is bright yellow stirred for 5.5 h, and then poured into ice water and was extracted with ethyl acetate. An ethyl acetate extract was washed with saline, dried with sodium sulfate, filtered and evaporated. The crude residue (mainly a mixture of carboxylic acids) was dissolved in methanol (3 ml) and methylene chloride (20 ml) and was treated for 25 mine, and the solvent evaporated. The residue was dissolved in methylethylketone (40 ml) and treated with sodium iodide (2,48 g). After 1 hour stirring at room temperature, the mixture was distributed between ethyl acetate and water, which contained a small amount of sodium bisulfate. The organic layer was washed with saline, dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica gel, ethyl acetate: hexane, 1:1) and then ethyl acetate: hexane) and received 1,125 g of the desired product as a white foamy substance []D= -17,1o(c = 0,7, chloroform). TLC (ethyl acetate:hexane, 6:4), Rf= 0,43.

In addition, received 206 mg [4S - (4, 7, 10a) ]- 1,2,3,4,6,7,8,10 a-octahydro-6-oxo-7-phthalimido-pyrido [1,2-a] azepine 4-carboxylic acid, methyl complex ether and triturated with ether, resulting in the obtained white solid, so pl. 162 - 166oC []D= -106,0o(c = 0.8, chloroform). TLC (ethyl acetate: hexane, 6:4), Rf= 0,36.

f) [4S- (4, 7, 10a) ] -Decahydro-6-oxo-7-phthalimido-pyrido [1,2-a] azepin, 4-carboxylic acid, methyl ester

The target solution of the product from part (e) (1,068 g, 2,15 mm) and Tris(trimethylsilyl) silane (1.0 ml, 806 mg, 3.2 mm) in dry benzene (10 ml) was heated d h was added 400 μl of silane, and the reaction continued. After 5 h slightly cloudy solution was cooled to room temperature and concentrated. The residue is triturated with ethyl ether, the resulting solid substance was collected by filtration and thoroughly washed with ethyl ether, the resulting received 522 mg is basically pure target product. The mother liquor was subjected to flash chromatography (Merck silica gel, ethyl acetate: hexane, 1:1) and received another 261 mg of the pure product (a total of 783 mg), so pl. 179 - 181oC []D= -10,6o(c = 0.9, chloroform). TLC (ethyl acetate: hexane, 1:1), Rf= 0,25.

g) [4S- [4, 7(R*), 10a] ]-Decahydro-7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-6-occupied- [1,2-a]azepin-4-carboxylic acid, methyl ester

The product obtained in paragraph (f) (786 mg, 2,12 mm) in methanol (10 ml) and methylene chloride (2 ml) was treated with hydrazine monohydrate (135 μl, 2.8 mm) and the resulting solution was stirred for 66 hours at room temperature. Then the mixture was filtered and the solid residue was washed with methanol. The filtrate was evaporated, triturated with methylene chloride and again filtered. The filtrate was washed with water, and the aqueous layer was subjected to reverse extraction with methylene chloride. United methylenechloride extracts were dried with sodium sulfate, filtered and upari the 1,2-a] azepin-4-carboxylic acid as a colorless oily product. TLC (10% methanol in methylene chloride), Rf= 0,18.

A cold (0oC) solution dicyclohexylamine salt (S)-2-(acetylthio)benzoylpropionic acid derived from dicyclohexylamine salt, as described above, (524 mg, 2,33 mm), triethylamine (295 μl, 214 mg, 2,11 mm) and previously received an amine in methylene chloride (15 ml) was treated with hexafluorophosphate benzotriazol-1-yloxytris - dimethylamino of phosphonium (940 mg, 2,12 mm). The resulting solution was stirred 1 h at 0oC and then 2 h at room temperature. After that, the solvent evaporated, and the residue was distributed between ethyl acetate and 1 N. hydrochloric acid. The organic layer was washed successively with water, 50% saturated sodium bicarbonate and brine, and then dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica gel, ethyl acetate: hexane, 1:1) and obtained the pure target compound (770 mg) as a white foamy product. TLC (ethyl acetate:hexane), Rf= 0,27.

h) [4S- [4-, 7(R*), 10a] ] - Decahydro-7-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-6-occupied [1,2-a]-alateen-4-carboxylic acid

A solution of the product obtained in paragraph (g), (755 mg, 1,70 mm) at room temperature in methanol (8 ml, desoxyribose the STV ozonation of argon). After 3 hours stirring, the mixture was oxidized with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. An ethyl acetate extract was washed with saline, dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica gel, 1% acetic acid in ethyl acetate). The desired product fractions were evaporated and subjected to azeotropic treatment (3 times) with ethyl acetate, was dissolved in a small amount of ethyl acetate and triturated with hexane. The solvents were removed on a rotary evaporator and the residue is again triturated with hexane, evaporated and dried in vacuo, resulting in a received 654 mg of the desired product as a white amorphous powder, []D= -31,0o(c = 0.8, chloroform). TLC (2% acetic acid in ethyl acetate), Rfor = 0.51.

Elemental analysis for C20H26N2O4S 0,16 C4H8O20,3 H2O;

Calculated: C 60,46; H 6,85; N 6,83; S 7,82;

Found: C 60,57; H 7,07; N 6,57; S 7,63.

Example 36.

[3S- [3(R*), 7] ] -Hexahydro-3-[(2-mercapto-2-oxo-3 - phenylpropyl)amino]-2-oxo-7-(2-propenyl-1H-azepin-1-acetic acid.

a) (S)-N-(2-Phthalimido-1-oxohexyl)glycine ethyl ester

Suspension glycine ml, 2,39 g 23.6 mm) and stirred 5 min at room temperature. Then the mixture was treated with (S)-2-phthalimido-6-hydroxyhexanoic acid (4,50 g, 16.2 mm) and hydroxybenzotriazole (2,225 g, 16.5 mm), cooled to 0oC and then was treated with ethyl-3-(3-dimethylamino)propylbromide cleaners containing hydrochloride salt (3,438 g, 17,9 mm). The mixture is then stirred 1 h at 0oC and 2 h at room temperature, after which it was distributed between ethyl acetate and 0.5 N. cleaners containing hydrochloride salt and three times were extracted with ethyl acetate. United an ethyl acetate extracts were washed successively with water, saturated sodium bicarbonate and brine, and then dried with sodium sulfate, filtered and evaporated, resulting in a received 5,77 g of the desired product as colorless oily substance. TLC (ethyl acetate), Rf= 0,34.

b) (S)-N-(2-Phthalimido-1,6-DIOXOLANYL)glycine, ethyl ester

The solution -78oC oxalicacid (1,67 ml, 2,43 g, 19,1 mm) in methylene chloride (50 ml) drop by drop was treated with a solution of dry dimethylsulfoxide (2,70 ml of 2.97 g, 38.0 mm) in methylene chloride (2 ml). After 15 min was added to a solution of the product of part (a) (5,770 g, 15,9 mm) in methylene chloride (25 ml). After another 15 min, the mixture was treated with 10.0 ml triethylamine, stirred 5 min pivim solution drained sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica gel, ethyl Acetate: hexane, 80:20) and received 5,170 g of target compound as a colorless oily substance.

c) (6S-TRANS)-Tetrahydro-6-phthalimido-oxazolo[3,2-b] -azepine - 2,5-(3H, 6H)-dione

A solution of the product obtained in part (b), (5,16 g, 14,3 mm) in triperoxonane acid (40 ml) and chloroform (160 ml) was heated under reflux in an argon atmosphere within 42 hours the mixture was cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with saline, dried with sodium sulfate and filtered through a small layer of silica gel, rinsing with a mixture (1:1) of ethyl acetate and methylene chloride. The filtrate was evaporated and obtained a solid residue. This solid residue is suspended in methylene chloride and triturated with ethyl ether, the resulting received 3,437 g of the desired product as white solid, so pl. 234-240oC. TCX (acetone: hexane, 1:1), Rfor = 0.51.

d) (3S-TRANS)-Hexahydro-3-phthalimido-2-oxo-7-(2-propenyl)- 1H-azepin-1-acetic acid

The solution is relatively at room temperature the tin bromide 4 (1.0 M in methylene chloride, of 16.5 ml, 16.5 mm). The resulting mixture was stirred 9 h at room temperature, and then 14 h at -20oC, after which the reaction extinguished with water and was extracted with a mixture of ethyl acetate and ethyl ether. The extract was washed with saline, dried with sodium sulfate, filtered and evaporated, resulting in the obtained oily substance milky-white color. This substance was subjected to flash chromatography (Merck silica gel, 2% acetic acid in ethyl acetate) resulting in the received 2,810 g diastereomeric pure target compound as a white foam. TCX (5% acetic acid in ethyl acetate), Rf= 0,55.

e) (3S-TRANS)-Hexahydro-3-phthalimido-2-oxo-7-(2-propenyl)- 1H-azepin-1-acetic acid, methyl ester

A cold (0oC) a solution of the product of part (d) (2.50 g, 7.0 mm) in methanol (20 ml) and ethyl ether (30 ml) was treated with excess ethereal diazomethane within 10 minutes This excess diazomethane was neutralized by adding acetic acid and the solvent was removed on a rotary evaporator, resulting in a yellow oily substance. This substance was subjected to flash chromatography (Merck silica gel, 1:1 ethyl acetate:hexane) and was obtained foamy product. This seed, resulting received 2,072 g of the crystal of the target product. The mother liquor gave another 262 mg of product (total of 2,334 g), so pl. 107 - 109oC. TLC (ethyl acetate:hexane, 1:1), Rf= 0,29.

f) [3S- [3(R*), 7] -Hexahydro-3-[[2-(acetylthio)-1-oxo - 3-phenylpropyl]amino]-2-oxo-(2-propenyl)-1H-azepin-1-acetic acid, methyl ester

The suspension of the crystalline product obtained in part (e), (492 mg, 1,33 mm) in methanol (10 ml) was treated with hydrazine monohydrate (142 μl, 147 mg of 2.93 mm), after which (for the implementation of the solubilization of the source material), the solution was rapidly heated. After 18 hours stirring at room temperature, the mixture was diluted with methylene chloride and filtered. The filtrate was evaporated, suspended in methylene chloride, filtered and again evaporated, resulting in the obtained crude amine (270 mg) as a colorless oily substance. A cold (0oC) a solution of amine and (S)-2-(acetylthio) benzoylpropionic acid (obtained from dicyclohexylamine salt as described above, 287 mg, 1,28 mm) in methylene chloride (12 ml) was treated with triethylamine (172 μl, 125 mg, 1,23 mm), and then hexafluorophosphate Tris(dimethylamino) phosphonium (547 mg, 1,24 mm). Transparent, nearly colorless solution was stirred at 0R
= 22,6 min admixture: tR= 28,7 min). The target product was obtained as a colorless oily substance with a purity of 98.2% (acetone:hexane, 4:6), Rf= 0,38.

g) [3S- [3(R*), 7] -Hexahydro-3-[2-mercapto-1-oxo-3-phenylpropyl) amino]-2-oxo-7-(2-propenyl)-1H-azepin-1-acetic acid

The solution to room temperature the product obtained in paragraph (f), (720 mg, 1,61 mm) in methanol (12 ml, deoxygenating by ozonation of argon) was treated with 1 N. sodium hydroxide (10 ml, deoxygenating through was Outragiously with ethyl acetate. An ethyl acetate extract was washed with water and brine, and then dried with sodium sulfate, filtered and evaporated, resulting in the obtained oily substance. This material was subjected to flash chromatography (Merck silica gel, 2-5% acetic acid in ethyl acetate). Product fractions were combined and evaporated, and the residue was subjected to azeotropic treatment (three times) with ethyl acetate. The obtained oily/foamy product was dissolved in a small amount of ethyl acetate and then triturated with hexane, resulting received a white oily/foamy product. The mixture was evaporated to dryness, suspended in hexane was again evaporated to dryness and dried in vacuo, resulting in a received 616 mg of the desired product as a solid foam product white color []D= -48,5o(c = 0,63, chloroform). TLC (5% acetic acid in ethyl acetate) Rf= 0,56.

Analysis for C20H26N2O4S 0,2 H2O:

Calculated: C 60,95; H of 6.75; N 7,11; S 8,14;

Found: C 60,98; H 6,93; N 6,93; S 7,94

Example 37.

[3S- [3(R*), 7] -Hexahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-2-oxo-7-propyl-1H-azepin-1-acetic acid

a) (3S-TRANS)-Hexahydro-3-phthalimido-2-oxo-7-propyl-1H - AML) and ethyl acetate (10 ml) was first made (hydrogen balloon) in the presence of palladium charcoal (10% palladium on charcoal, 62 mg) and at room temperature for 1 h the mixture was filtered through celite, evaporated, again dissolved in ethyl acetate, filtered through a layer of silica gel, again evaporated and got 780 mg of the desired product as colorless oily product. TLC (ethyl acetate:hexane = 1:1), Rf= 0,29.

b) [3S- [3(R*), 7] -Hexahydro-3-[[2-(acetylthio)-1-oxo-3-phenylpropyl] amino]-2-oxo-7-propyl-1H-azepin-1-acetic acid, methyl ester.

The product of part (a) (774 mg, 2,07 mm) in methanol (8 ml) was treated with hydrazine monohydrate (222 µl, 229 mg, 4,58 mm) and the resulting solution was stirred for 23 h at room temperature. The mixture was diluted to 0.5 N. hydrochloric acid (20 ml) and stirred at 0oC for 2 h Then the solution was filtered and the filtrate was washed with ethyl acetate. An ethyl acetate extract once was subjected to reverse the extraction of water and the combined aqueous layers were podslushivaet 1 N. sodium hydroxide. After extraction with methylene chloride (three times), followed by drying with sodium sulfate and evaporation of the solvent, was obtained the crude amine (354 mg) as a colorless oily product.

A cold solution (0oC) the above crude amine and (S)- (acetylthio) benzo is (12 ml) was treated with triethylamine (214 μl, 154 mg, 1,53 mm), and then benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (679 mg, 1,54 mm). Transparent, almost colorless solution stirred 1 h at 0oC and then 1 h at room temperature. After that, the mixture was evaporated and distributed between ethyl acetate and 0.5 G. hydrochloric acid. An ethyl acetate extract was washed successively with water, 50% saturated sodium bicarbonate and saline. Then the solution was dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (silica gel Megs, hexane:acetone = 6:4) and received 510 mg of pure desired product as colorless oily substance. TLC (acetone:hexane, 4:6) Rf= 0,31.

c) [3S- [3(R*), 7] ] -Hexahydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-2-oxo-7-propyl-1H-azepin-3-acetic acid.

Solution (room temperature) of the product of part (b) (502 mg, 1,12 mm) in methanol (8 ml, deoksigenirovanii by ozonation of argon) was treated with 1 N. NaOH (6 ml, deoksigenirovanii by ozonation of argon). After 25 minutes of mixing, the solution was acidified using 10% hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, and then the wasp is W-chromatography (Merck silica gel, 2% acetic acid in ethyl acetate). Product fractions were combined and evaporated, and the residue is twice subjected to azeotropic processing using ethyl acetate. The obtained oily/foamy material was dissolved in a small amount of methylene chloride, and then triturated with hexane, resulting received a white oily/foamy substance. The mixture was evaporated to dryness, suspended in hexane was evaporated again to dryness and dried in vacuo, resulting in a received 394 mg of the desired product as a solid white foam product; []D= -51,2o(C = 0,65, chloroform). TLC (2% acetic acid in ethyl acetate), Rf= 0,47.

Analysis for C20H28N2O4S 0,2 H2O:

Calculated: C 60,95; H of 6.75; N 7,11; S 8,14;

Found: C 60,98; H 6,93; N 6,93; S 7,94.

Example 38.

[3S- [3(R*), 7] ]-7-Cyclopropylmethyl)hexahydro-3-[(2-mercapto-1 - oxo-3-phenylpropyl)amino]-2-oxo-1H-azepin-1-acetic acid.

a) (3S-TRANS-7-(Cyclopropylmethyl)hexahydro-3-phthalimido-2 - oxo-1H-azepin-1-acetic acid, methyl ester.

To a solution of the product of example 36 (e) (700 mg, 1,879 mm) in 5 ml of methylene chloride, cooled to 0oC, was added 75 ml portion of a solution of diazomethane/the Tata palladium (II). In the reaction mixture was vigorous bubbling, and it became transparent. After 10 minutes of stirring, the reaction mixture was added 25 ml of diazomethane/ethyl ether. Then the reaction mixture was stirred 50 min at 0oC, filtered through celite and concentrated in vacuo, resulting in the obtained crude oily product. This product was subjected to flash chromatography (Merck silica gel, 50 to 150 nm, ethyl acetate/hexane, 1:2) and received 717 mg of the desired product as a white foamy substance.

b) [3S- [3(R*), 7] ]-7-(Cyclopropylmethyl)hexahydro-3-[[2-(acetylthio)- 1-oxo-3-phenylpropyl] amino] -2-oxo-1H-azepin-1-acetic acid, methyl ester.

To a solution of the product of part (a) (697 mg, 1,81 mm) in 8 ml of methanol, stirred at room temperature, one drop was added 92 μl (1,90 mm) of hydrazine monohydrate. The reaction mixture was stirred 48 hours at room temperature, and then filtered to remove solid by-products. The filtrate was concentrated in vacuo, dissolved in methylene chloride, was again filtered and again concentrated, resulting in the obtained crude oily material. This material was dried in vacuum and received 441 mg neo is additional purification.

To a cold (0oC) a solution of 420 mg (1,64 mm) of the crude amine and 384 mg (1,84 mm (S)-2-(acetylthio)benzoylpropionic acid (obtained from dicyclohexylamine salt, as described above) in 10 ml of chloroform was added to 280 μl (1,97 mm) of triethylamine. The reaction mixture was stirred 30 min, and then added 799 mg (1,81 mm) hexafluorophosphate benzotriazol 1 yloxytris(dimethylamino)phosphonium. The reaction mixture was stirred 48 h at 0oC, and then added another 399 mg (0,904 mm) hexafluorophosphate benzotriazol-1-yloxytris- (dimethylamino)phosphonium and 4 drops of triethylamine. The reaction mixture was stirred for another 24 h at 0oC, and then distributed between 50 ml of ethyl acetate and 50 ml of a 5% solution of potassium bisulfate. The aqueous layer was separated and was extracted with 2 - 25 ml-portions of ethyl acetate. United an ethyl acetate layers washed with 25 ml of 5% solution of potassium bisulfate, 40 ml saturated sodium bicarbonate and 40 ml brine, then were dried with magnesium sulfate and concentrated in vacuo, resulting in the obtained crude oily substance. This substance was subjected to flash chromatography (Merck silica gel, 50 to 200 nm, a mixture of ethyl acetate and hexane, 1:3 then 1:2) and received 678 mg of the desired product as a white foamy product is over-1H-azepin-1-acetic acid

The solution 658 mg (1,43 mm) product of part (b) in 10 ml of methanol was purged with argon for 30 min and was cooled to 0oC. To this solution drop by drop) was added 6 ml of 1M sodium hydroxide and again 30 min was purged with argon, and then cooled to 0oC. the Reaction mixture was stirred for 1 h at 0oC, continuing purging with argon, and then acidified to a pH of 1.5% solution of potassium bisulfate. The mixture was extracted 3-80 ml-portions of ethyl acetate, and the combined an ethyl acetate layers were dried with magnesium sulfate and concentrated in vacuo, resulting in the obtained crude oily substance. This substance was subjected to flash chromatography (Merck silica gel, 50 to 150 mm, 0.2% acetic acid/acetate) and received a white foamy substance. This foamy substance is triturated with methylene chloride/hexane, resulting in 490 mg of the desired product as a white solid product, []D= -78,9o(C = 1,0, CDCl3). TLC (5% methanol in methylene chloride + 3 drops of acetic acid), Rf= 0,41.

Analysis for C21H28N2SO40,50 H2O:

Calculated:C 61,00; H 7,07; N 6,77; C 7,93;

Found: C 61,40; H Of 6.75; N 6,37; S 7,75.

Example 39.

[3S- [3(R*), 7] ]-7-(Cyclopentyl)hexahydro-3-[(2-mercapto-1-OK is limido-2 - oxo-1H-azepin-1-acetic acid, methyl ester

The tin tetrachloride (5,1 l, 5.1 mm, 1 M methylene chloride) drop by drop) was added to a solution of the product of example 36(e) (800 mg, 2,55 mm) and (2-cyclopentenyl)trimethylsilane (2.85 g, 20,4 mm) in methylene chloride (60 ml). The mixture is stirred at room temperature for 18 h, after which the reaction was suppressed by adding 100 ml of water. The mixture was extracted 3 - 100 ml-portions of ethyl acetate and 2 - 100 ml-portions of ethyl ether, and the combined organic layers were washed with 100 ml of brine, dried with sodium sulfate and concentrated in vacuo, resulting in the obtained crude oily substance. This substance was subjected to flash chromatography (Merck silica gel, 50 to 100 mm, 1: 1 - mixture of ethyl acetate/hexane and then 2% acetic acid/ethyl acetate) and received 788 mg (3-TRANS)-7-(2-cyclopentyl)hexahydro-3-phthalimido-2 - oxo-1H-azepin-1-acetic acid as a white foamy substance.

The solution of this acid (768 mg, 2,01 mm) in methanol (7 ml)/ethyl ether (10 ml), stirred at room temperature, one drop was treated with a solution of diazomethane/ethyl ester obtained in accordance with known procedure (Fieser &Fieser so 1, S. 192). Then was added a solution of diazomethane/ethyl ether until then, while the reaction statem reaction was suppressed by adding a drop of 0.3 ml of acetic acid. The colorless solution was concentrated in vacuo and obtained the crude oily product. After flash chromatography of this product (Merck silica gel, 50 to 100 mm, 1:2 - mixture of ethyl acetate/hexane) received 640 mg of the target product as a foamy white substance.

b) (3S-TRANS)-7-(Cyclopentyl)hexahydro-3-phthalimido-2-oxo - 1H-azepin-1-acetic acid, methyl ester.

A solution of the product obtained in part (a), (700 mg, 1,89 mm) in 5 ml of methanol was purged for 15 minutes with argon and then was added 150 mg (25 wt.%) 10% palladium charcoal. Then the reaction vessel was removed and filled with hydrogen (3 times) and 5 h and stirred in hydrogen atmosphere (1 ATM, balloon). The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo, resulting in a received 594 mg of the desired product as a white foamy substance.

c) [3S- [3(R*), 7] ]-7-(Cyclopentyl)hexahydro-3-[[2-(acetylthio)-1 - oxo-3-phenylpropyl] amino] -2-oxo-1H-azepin-1-acetic acid, methyl ester.

A solution of the product obtained in part (b) in methanol was treated with hydrazine monohydrate in accordance with the procedure described in example 38, part (b), resulting in the obtained crude methyl ester (3S-tra is x2">

This foamy product was treated with (S)-(acetylthio)benzoylpropionic acid according to the procedure described in example 38, part (b), resulting in a received target product as a transparent oily substance.

d) [3S- [3(R*), 7] ]-7-(Cyclopentyl)hexahydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-2-oxo-1H-azepin-1-acetic acid.

A solution of the product obtained in part (C), in methanol was treated with 1 M sodium hydroxide according to the procedure described in example 38, part (c), resulting in a received target product as a white solid, []D= -78,1o(C = 1, CDCl3). TLC (5% methanol in methylene chloride + 3 drops of acetic acid), Rf= 0,39.

Analysis for C22H30N2SO40,03 H2O:

Calculated: C 63,06; H of 7.23; N 6,69; S 7,65;

Found: C 63,25; H 7,25; 6,50 N; S 7,55.

Example 40.

[S-(R*, R*)] -Hexahydro-3-[2-mercapto-2-oxo-3 - phenylpropyl)amino]-2-oxo-1H-azepin-1-propanoic acid

a) (S-3-[[(1,1-Dimethylamine)carbonyl]amino-hexahydro-2 - oxo-1H-azepin-1-propanoic acid, ethyl ester

A solution of the product get 9(b) (1.75 g, to 7.67 mm) in a mixture of tetrahydrofuran and t-butanol (2:1, 30 ml) was cooled EQ. ). The reaction mixture was stirred 15 min at 0oC and then 1 h at room temperature. After this reaction extinguished 25% ammonium chloride (50 ml) and was extracted with ethyl acetate (2 125 ml). The combined organic extracts washed with 25% ammonium chloride (50 ml), water (100 ml) and brine (100 ml) and then dried with magnesium sulfate, filtered and concentrated, resulting in the received transparent syrup. The residue was purified by chromatography on a column (5 to 15 cm) with silica gel, elwira a mixture of 30% ethyl acetate and hexane. The desired fractions were combined and concentrated, resulting in received of 2.18 g of the desired product as a transparent syrup. TLC (ethyl acetate : hexane, 1:1), Rf= 0,38.

b) [S-(R*,R*)]-Hexahydro-3-[[2-(acetylthio-1-oxo - 3-phenylpropyl]amino] -2-oxo-1H-azepin-1-propanoic acid, ethyl ester.

The product obtained in part (a), (2.15 g, 6,55 mm) were treated for 30 min and at 0oC 4 N. a mixture of 4 G. hydrochloric acid and dioxane (30 ml, 120 mm), and then stirred 2 h at room temperature. The reaction mixture was concentrated, twice evaporated with ethyl ether, 3 times subjected to the azeotropic distillation using toluene and within 5 h was dried in vacuum, in ro ethyl ester.

The obtained amine was subjected to reaction with (S)-(acetylthio)benzoylpropionic acid in the presence of triethylamine and benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexaflurophosphate as described in example 31, part (c), resulting in a received target product. TLC (ethyl acetate : hexane, 1:1), Rf= 0,19.

c) [S-(R*, R*)-Hexahydro-3-(2-mercapto-1-oxo-3 - phenylpropyl)-amino]-2-oxo-1H-azepin-1-propanoic acid.

The product obtained in part (b) in methanol was treated with 1 N. sodium hydroxide as described in example 31, part (d), resulting in a received target product as a white foamy substance []D= +of 4.44o(c = 1,24, methanol). TLC (1% acetic acid in ethyl acetate), Rf= 0,27.

Analysis for C18H24N2O4S 0,17 H2O:

Calculated: C 58,83; H 6,67; N 7.62MM; S 8,72;

Found: C 58,83; H 6,87; N 7,33; S 8,49.

Example 41.

[S-(R*, R*)] -Hexahydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl]amino-2-oxo- - (phenylmethyl)-1H-azepin-acetic acid

a) (R*)-N-(2-phthalimido-6-hydroxy-1-oxohexyl)-L - phenylalanine, ethyl ester

To a solution of cleaners containing hydrochloride salt of the ethyl ester of L-phenylalanine (998 mg, 4.3 mm) in dimethylformamide (10 ml) was dabolical to 0oC and treated consistently (S)-2-phthalimido-6-hydroxyhexanoic acid (1,002 g, 3.6 mm), hydroxybenzotriazole (582 mg, 4.3 mm) and cleaners containing hydrochloride salt of ethyl-3-(3-dimethylamino)propylbromide (770 mg, 4.0 mm). The resulting mixture was stirred for half an hour at 0oC and 1.5 h at room temperature. Then the solution was distributed between ethyl acetate and water and the organic extract was washed sequentially with 0.5 G. hydrochloric acid, water, 50% saturated sodium bicarbonate and brine, dried sodium sulfate, filtered and evaporated, resulting in a received 1.63 g is basically pure target product in the form of oily/foamy substance. TLC (acetone:hexane, 1:1), Rf= 0,30.

b) (R*)-N-(2-phthalimido-1,6-dicsovered)-L-phenylalanine, ethyl ester

Solution - 78oC oxalicacid (370 μl, 538 mg, 4.2 mm) in methylene chloride (10 ml) drop by drop was treated with a solution of dry dimethylsulfoxide (610 μl, 672 mg, 8,6 mm) in methylene chloride (1.5 ml). After 10 min was added to a solution of the product obtained in part (a), (1,616 g, 3.6 mm) in methylene chloride (10 ml). After another 15 min, the mixture was treated with triethylamine (4.0 ml), then stirred 5 min at -78oC and left to warm to 0oC. the Obtained white solution drained sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatographie (Merck silica gel 40:60 acetone:hexane) and received 1,474 g of the desired product as an oily/foamy substance. TLC (acetone : hexane, 12:1) Rf= 0,45.

c) [3S- (3, 6, 9a) ] -Tetrahydro-3-(phenylmethyl)-6-phthalimidobutyl[3,2 - a]azepine-2,5(3H,6H)-dione

A mixture of the product obtained in part (b), (6.11 g, 13,6 mm) and triperoxonane acid (34 ml) in chloroform (205 ml) was heated under reflux for 6 days. The solution was cooled to room temperature and neutralized with saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, dried with sodium sulfate, filtered and evaporated, resulting in the obtained oily substance dark yellow-orange color. The residue was subjected to flash chromatography (Merck silica gel, 40-60% ethyl acetate in hexane) and received 3,075 g of the desired product as a white foamy substance.

d) (S-(R*, R*] -Hexahydro-2-oxo-3-phthalimido- - (phenylmethyl)-1H-azepin-1-acetic acid, methyl ester

A solution of the product obtained in part (C), (1.40 g, of 3.46 mm) and triethylsilane (4,4 ml, 3,20 g, 27,5 mm) ve added titanium tetrachloride colorless transparent solution became bright yellow, but the precipitate was not formed. The resulting solution was stirred for 66 h, after which the reaction extinguished with water and was extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, dried sodium sulfate, filtered and evaporated, resulting in the obtained oily substance. After flash chromatography (Merck silica gel, ethyl acetate and then 2% acetic acid in ethyl acetate) was obtained 870 mg of [S-(R*,R*)]-hexahydro-2-oxo-3-phthalimido- - (phenylmethyl)-1H-azepin-1-acetic acid as a white foamy substance.

A cold solution (0oC) of the said acid (898 mg, 2,21 mm) in methanol (8 ml) and methylene chloride (12 ml) was treated with 5 min excessive amount of essential diazomethane. Then the excess of this diazomethane neutralized by adding acetic acid and the solvent was removed on a rotary evaporator, resulting in a yellow oily substance. This residue was subjected to flash chromatography (Merck silica gel, 50 to 60% ethyl acetate in hexane) and received 858 mg of the desired product as a white foamy substance. TLC (ethyl acetate : hexane, 1:1), Rf= 0,30.

e) [S-(R*,R*)]-Hexahydro-3-[(2-(acetylthio)-1 - oxo-3-phenylpropyl]amino] -2-Oeste (d), in methanol was treated with hydrazinoacetate in accordance with the procedure described in example 36, part (f), resulting in received [S-(R*,R*)]-Hexahydro-3-amino-2-oxo- - (phenylmethyl)-1H-azepin-1-acetic acid methyl ester as a pale yellow oily substance. TLC (methylene chloride : acetic acid : methanol, 8:1:1), Rf= 0,60.

A cold (0oC) solution of the obtained amine was subjected to reaction with (S)-2-(acetylthio) benzoylpropionic acid in the presence of triethylamine and hexafluorophosphate benzotriazol-1-yloxytris dimethylamine of phosphonium in accordance with the procedure described in Example 36 (f), resulting in the obtained colorless oily/foamy substance. TLC (acetone : hexane : 1:1), Rf= 0,54.

f) [S-(R*, R*)]-Hexahydro-3-(2-mercapto-1 - oxo-3-phenylpropyl]amino]-2-oxo- - (phenylmethyl)-1H-azepin-1 oxyana acid

A solution of the product obtained in part (e), in methanol was treated with 1 N. sodium hydroxide according to the procedure described in example 36, part (g), resulting in a received target product in the form of a relatively solid foamy substance; []D= -64,2oC (c = 0,54, chloroform). TLC (5% acetic acid in ethyl acetate), Rf= 0>/BR>Found: C 64,61; H Is 6.78; N Of 5.89; S 7,46.

Example 42.

[6(S)] -Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl amino]-2,2-dimethyl-7-oxo-1H-azepin-1-acetic acid

a) 2,2-Dimethylcyclohexanone, oxime

A solution of 2,2-dimethylcyclohexanone (8,960 g, 65 mm), pyridine (12.0 ml, 12,27 g, 155 mm) and hydroxylamine hydrochloride (10.30 g, 148 mm) in absolute ethanol (50 ml) was heated for 2 h at 85oC. the Cooled mixture was distributed between ethyl ether and water and the ether layer was washed successively 1 N. hydrochloric acid and brine, and then dried with sodium sulfate, filtered and evaporated. The solid residue was dissolved in a small amount of hot hexane and cooled to 0oC, resulting in a received 6,801 g of the desired product as white flakes, so pl. 91 - 93oC. TLC (ethyl acetate: hexane, 4:6), Rf= 0,60.

b) Hexahydro-3,3-sodium dichloro-7,7-dimethyl-2-oxo-2H-azepin

The cold suspension (0 to 10oC) pentachloride phosphorus (32.50 to g, 156,1 mm) in methylene chloride (250 ml) was treated with a solution of the product obtained in part (a), (7,353 g of 52.1 mm) in methylene chloride (50 ml) for 10 minutes the resulting mixture was heated to room temperature and after the solution was barbotirovany gaseous chlorine in half an hour and a half is so saturated sodium bicarbonate (150 ml). This required periodic cooling. A two-phase mixture was vigorously stirred 18 h at room temperature, after which the layers were separated and methylenchloride the extract was washed with saturated sodium bicarbonate and saline. The organic layer was dried with sodium sulfate, filtered, evaporated and subjected to flash chromatography (Merck silica gel, 2:8 ethyl acetate:methylene chloride). The desired product fraction was evaporated and the residue was dissolved in hot methylene chloride/ethyl acetate and cooled, resulting in a received 5,152 g of pure desired product. The mother liquor was again chromatographically (Merck silica gel, 1: 9 ethyl acetate:methylene chloride) and received another 2,054 g of pure product (total yield 7,206 g), so pl. 148 - 155oC (Shir. TCX (ethyl acetate:methylene chloride, 1:9), Rf= 0,36.

(c) Hexahydro-3-chloro-7,7-dimethyl-2H-azepin

A solution of the product obtained in part (b), (7,180 g, 34,2 mm) in glacial acetic acid (150 ml) was first made (the bottle.) in the presence of 10% palladium carbon (2.65 g) in a period of 1.75 hours the Mixture was filtered through celite, and the solvent was removed on a rotary evaporator. The residue was subjected to flash chromatography (silica gel, 3/7-ethyl acetate/methylene chloride) and received impurity of the target products is the query result which received 2,845 g of pure desired product as a white solid. The mother liquor was again chromatographically (Merck silica gel, 3/7-ethyl acetate/methylene chloride), which received more of 1.93 g of pure solid product. The solids were combined and received 4,755 g of pure target product, so pl. 115 - 117oC. TLC (ethyl acetate:methylene chloride, 3:7), Rf= 0,41.

d) Hexahydro-3-azido-7,7-dimethyl-2-oxo-2H-azepin

A suspension of the product obtained in part (c), (4,670 g of 26.6 mm) and sodium azide (4,360 g, 67,0 mm) in dry dimethylsulfoxide (100 ml) was heated for 6 h at 80oC. the Solution was cooled to 0oC and was treated with 175 milliliters of ice water. The obtained white-white precipitate was collected by filtration, washed with water and dried, resulting in a received 2,37 g of pure desired product. The filtrate was extracted with ethyl acetate and the organic extract is twice washed with water and once with saline, and then dried with sodium sulfate, filtered and evaporated. After trituration of the residue with ethyl ether and hexane, got 1,637 g of additional product. Selected solid fractions were combined and received 4,007 g of pure desired product; so pl. 98 - 100oC TLC (ethyl acetate:hexane, 75:25) Rfor = 0.51.

e) Hexahydro-3-[[(1,1-dimethylmethoxy)carbonyl] amino] - 7,7-dimethy is n) 1.5 h in the presence of 10% pallidipennis coal (850 mg). The mixture was filtered through celite, and the solvent was removed on a rotary evaporator. The residue evaporated from methylene chloride and was obtained the crude amine as a white solid. This solid was again dissolved in chloroform and treated sequentially with triethylamine (2.65 ml, 1.92 g, 19,0 mm) and t-tert-BUTYLCARBAMATE (5,00 g, 22,9 mm). After 1 hour stirring at room temperature, the solution evaporated and the residue triturated with ethyl acetate/ethyl ether, resulting in the received 2,668 g of the desired product as a white solid. The filtrate was subjected to flash chromatography (Merck silica gel, 2/8-ethyl acetate/methylene chloride) and received an extension of the pure product, which was combined with the above solid and has received a total of 4,082 g of pure target product, so pl. 156 - 158,5oC. TLC (ethyl acetate:methylene chloride, 2:8), Rf= 0,26.

f) Hexahydro-3-[[1,1-dimethylmethoxy)carbonyl] amino-7,7 - dimethyl-2-oxo-1H-azepin-1-acetic acid, ethyl ester

The solution to room temperature the product obtained in paragraph (e) (3,512 g of 13.7 mm) in dry tetrahydrofuran (110 ml) was treated with hexamethyldisilazane lithium (1.0 M in tetrahydrofuran (THF, 21 ml, 21 mm) and then ethylbromoacetate (3.0 ml, 4.52 g 27, the dark orange solution was stirred for further 30 minutes at room temperature, then the reaction was suppressed by the addition of saturated ammonium chloride and water. The mixture was extracted with ethyl acetate and the organic extract was washed with saline, dried with sodium sulfate, filtered and evaporated, resulting received a dark oily substance. This residue was subjected to flash chromatography (Merck silica gel, 35 - 50% ethyl acetate in hexane) and received 1,363 g of the crude desired product as a pale yellow oily substance. TLC (ethyl acetate:hexane, 1:1), Rf= 0,48.

g) [6(S)] -Hexahydro-6-[[2-acetylthio)-1-oxo-3-phenylpropyl] amino]-2,2-dimethyl-7-oxo-1H-azepin-1-acetic acid, ethyl ester.

A solution of the product obtained in paragraph (f) (1,349 g, 3,94 mm) in p-dioxane (3 ml) was treated with hydrochloric acid (4.0 M in p-dioxane, 12 ml). The mixture is stirred at room temperature for 1.5 hours the Solvent was evaporated and the residue is distributed between methylene chloride and 0.2 N. sodium hydroxide (26 ml). The layers were separated and the aqueous layer was extracted with ethyl ether/ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated, resulting in a received 982 mg of the crude free amine as a yellow oily substances is s (obtained from dicyclohexylamine salt as described previously (973 mg, 4.3 mm)] and the above crude amine in methylene chloride (30 ml) was treated with triethylamine (1,15 ml, 835 mg, 8.2 mm) and the resulting mixture was cooled to 0oC. Then was added benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium hexafluorophosphate (1,915 g, 4.3 mm) in the form of solids. The solution is stirred 1 hour at 0oC, and then 1.5 h at room temperature. The solvent is evaporated, and the residue was distributed between ethyl acetate and 0.5 G. hydrochloric acid. The organic layer was washed successively with water, 50% saturated bicarbonate sodium and salt solution, and then dried with sodium sulfate, filtered and evaporated. The residue was subjected to flash chromatography (Merck silica gel, acetone:hexane, 3:7) and received 1,564 g of the desired product as an oily substance (mixture of diastereoisomers, 1:1). TLC (acetone:hexane, 3:7), Rf= 0,30.

h) [6(S)] -Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-2,2-dimethyl-7-oxo-1H-azepin-1-acetic acid

The solution to room temperature the product obtained in paragraph (g) (1,548 g, 3.45 mm) in methanol (20 ml, deoksigenirovanii by ozonation of argon) was treated with 1 N. sodium hydroxide (15 ml, deoksigenirovanii by ozonation of argon). After a 30-minute razmeri Elam), the solution was acidified using 6 N. hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate extract was washed with water and brine, dried sodium sulfate, filtered and evaporated, resulting in the obtained oily substance. This substance was subjected to flash chromatography (Merck silica gel, ethyl acetate and then with 1.5% acetic acid in ethyl acetate). The fractions containing mainly pure target product were combined, evaporated and twice subjected to the azeotropic distillation using ethyl acetate. The mixture was dissolved in a small amount of ethyl acetate and triturated with hexane, resulting in received foamy substance. Volatiles evaporated and the residue is suspended in hexane, evaporated to dryness and dried in vacuo, resulting in a received 863 mg of the desired product in the form of a relatively solid white foam (mixture of diastereomers, 45:55). TLC (2% acetic acid in ethyl acetate), Rf= 0,40.

Analysis for C19H26N2O4S 0,2 H2O:

Calculated: C 59,73; H of 6.96; N 7,33; S 8,39;

Found: C 59,79; H 7,13; N 7,13; S 7,99.

Example 43.

[S-(R*S*)] -3,4-Dihydro-3-[(mercapto-1-oxo-3-phenylpropyl)amino] -4 - oxo-1,5-benzothiazepin-5(2H)-propanoic acid

is dimetoxy)carbonyl] amino] -1,5-benzothiazepin -4(5H)-he obtained in accordance with known procedure (Slade and others in J. Med. Chem. 28, S. 1517-1521 (1985)) (2,04 g, 6,21 mm) was subjected isotropes treatment with a mixture of methylene chloride and toluene (3x) and dried in vacuum for 1 h, the Suspension of this compound in a mixture of tetrahydrofuran and tert-butanol (2: 1, 21 ml), cooled to 0oC, was treated with acrylate (1.08 ml, 9,94 mm, 1.6 equiv.) and then of 1.0 N. potassium salt of t-butanol/tetrahydrofuran (621 μl, 0.1 EQ.). The reaction mixture was stirred 15 min at 0oC, and then 20 h at room temperature in argon atmosphere. After this reaction extinguished 50% ammonium chloride (50 ml) and was extracted with ethyl acetate (2150 ml). The combined organic extracts were washed with saturated ammonium chloride (75 ml), water (75 ml) and brine (100 ml), dried with magnesium sulfate, filtered and concentrated, resulting in the received transparent yellow syrup. The residue was purified by chromatography on a column (5 x 20 cm) with silica gel, elwira a mixture of 20% ethyl acetate and hexane (2l). The desired fractions were combined and concentrated, resulting in a received 2,33 g complex mixture of ethyl ester of 2,3-dihydro-3-[(3-ethoxy-3 - oxopropyl)-[(phenylmethoxy)carbonyl] amino] -4-oxo-1,5-benzothiazepin - 5(4H)-propanoic acid (25%) and the difficulty is(75%) as a clear syrup.

The above compound (698 mg, 1,32 mm) of the first connection and 1,698 g, 3,96 mm second connection) and a solution of 30% bromovalerate in acetic acid (8,71 ml, 41,98 mm) is stirred at room temperature in an argon atmosphere for 1.5 hours, the Reaction mixture was diluted with ethyl ether (200 ml), stirred until then, until it forms whitish precipitation, after which the mixture was filtered and the resulting orange solid was washed with ethyl ether (450 ml). The crude residue was dissolved in 1 N. hydrochloric acid (100 ml) and was extracted with ethyl acetate (2100 ml). Then the aqueous phase is brought to pH 9 with 1 n sodium hydroxide and was extracted with ethyl acetate (3100 ml) the combined organic extracts washed with brine (75 ml), dried with magnesium sulfate, filtered and concentrated, resulting in a received 1.50 g of the crude yellow oily substance. The residue was purified by chromatography on a column (520 cm) with silica gel, elwira 1% (2 l), 2% (1 l), and finally 5% (1 l) with methanol in methylene chloride. The desired fractions were concentrated and dried under vacuum, resulting in a received 1,163 g of the target product. TLC (methylene chloride: methanol, 9:1), Rf= 0,40.

b) [S-(R*, S*)]-3,4-Dihydro-3-[[2-(acetylthio)-1-oxo-3-phenyl who propanoic acid (obtained from dicyclohexylamine salt as described above) was dissolved in dry methylene chloride, was cooled to 0oC and treated with a solution of the product obtained in part (a), dry methylene chloride, and then with triethylamine and benzotriazol-1 iloxi(dimethylamino)phosphonium hexafluorophosphate in accordance with the procedure described in example 36, part (f), resulting in a received target product. TLC (ethyl acetate: hexane, 1:1), Rf= 0,39.

c) [S-(R*, R*)]-3,4-Dihydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -1,5-benzothiazepin-5(2H)-propanoic acid

A solution of the product obtained in part (b) in methanol was treated with 2 N. sodium hydroxide according to the procedure described in example 36, part (g), resulting in a received target product as a white foamy substance; []D= -161,6o(c = 1,16, methanol). TLC (1% acetic acid in ethyl acetate), Rf= 0,45.

Analysis for C21H22N2O4S 0,4 H2O:

Calculated: C 57,63; H 5,25; N 6,40; S 14,65;

Found: C 57,65; H 5,04; N 6,38; S 14,44.

Example 44.

[3(S)] -2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)- amino] -2-oxo-1H-1-benzazepin-1-propanoic acid

a) 3-Amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-propanoic acid, ethyl ester

A solution of 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin was cooled to 0oC and was treated with ethyl acetate and 1 N. potassium salt of t-butanol/tetrahydrofuran according to the procedure described in example 40, part (a), resulting in a received ethyl ester 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-propanoic acid in the form of syrup. TLC (ethyl ether: hexane, 1:1), Rf= 0,45.

A solution of this compound (2,258 g, 6,94 mm) in absolute ethanol was treated with 10% palladium charcoal, and then was first made 4 hours at a pressure of 40 pounds per square inch (275,76 kPa), and after the first hour of hydrogenation Parra was ventolinbuy. After that, the mixture was diluted with ethanol (50 ml) and filtered through a pad with ethanol (250 ml). Transparent filtrate is evaporated to dryness and dried in vacuo, resulting in a received 2,098 g of the desired product as a transparent slightly yellow syrup. TLC (methylene chloride: methanol, 9: 1), Rf= 0,32.

b) [3(S)] -2,3,4,5-Tetrahydro-3-[[2-(acetylthio)-1-oxo-3 - phenylpropyl] amino]-2-oxo-1H-1-benzazepin-1-propanoic acid

(S)-2-(Acetylthio)benzoylpropionate acid obtained from dicyclohexylamine salt as previously described, was dissolved in methylene chloride, cooled to 0oC, was treated sequentially with a solution of the product of part (a) in dry methylene chloride, ti of example 36, part (f), resulting in a received target product in the form of syrup. TLC (ethyl acetate: hexane, 1:1), R1= 0.56 and 0.52 in.

c) [3-(S)] -2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl] -amino] -2-oxo-1H-1-benzazepin-1-propanoic acid

A solution of the product obtained in part (b) in methanol was cooled to 0oC and treated with 1 N. sodium hydroxide according to the procedure described in example 36, part (g), resulting in a received target product as a solid foam-like substance; []D= +41,8o(C = 0,608, methanol). TLC (methylene chloride: methanol: acetic acid, 20:1:1), Rf= 0,47.

Analysis for C22H24N2O4S 0,25 C5H120,413 H2O:

Calculated: C 63,76; H 6,21; N 6,40; S 7,32;

Found: C 63,76; H 6,18; N 6,38; S 7,45.

Example 45.

[3(S)-2,3,4,5-Tetrahydro-3-[[2-(mercaptomethyl)-1-oxo-3 - phenyl-propyl] amino]-2-oxo-1H-1-benzazepin-1-propanoic acid

a)[3(S)] -2,3,4,5-Tetrahydro-3-[[2-[(acetylthio)methyl] -1 - oxo-3-phenylpropyl]amino]-2-oxo-1H-1-benzazepin-1-propanoic acid

(S)-2-[(Acetylthio)methyl] benzodiapines acid obtained from ephedrinebuy salt in accordance with the description above, was dissolved in dry methylene chloride, cooled to 0oC and amrabat) in dry methylene chloride in accordance with the procedure described in example 8, part (a), resulting in a received target product in the form of syrup. TLC (ethyl acetate: hexane, 1:1), Rf= 0,58.

b) [3(S)] -2,3,4,5-Tetrahydro-3-[[2-(mercaptomethyl)-1-oxo - 3-phenylpropyl]amino]-2-oxo-1H-1-benzazepin-1-propanoic acid

A solution of the product obtained in part (a), in methanol was cooled to 0oC and treated with 1 N. sodium hydroxide according to the procedure described in example 8, part (b), resulting in a received target product as an amorphous solid, []D= +46,9o(c = 0,608, methanol). TLC (chloroform: methanol: acetic acid, 20:1:1), Rf= 0,42.

Analysis for C23H26N2O4S 0,233 C5H120,61 H2O:

Calculated: C 63,89; H of 6.65; N 6,17; S 7,06;

Found: C 63,89; H 6,40; N 6,18; S 6,82.

Example 46.

[1S-[ 1,9 (R*)]]-Octahydro-9-[2-mercapto-1-oxo-3-phenyl - propyl)amino] -6,10-dioxo-6H-pyridazino [1,2-a][1,2] diazepin-1 - carboxylic acid

a)(1S-CIS)-Octahydro-9 phthalimido-6,10-dioxo-6H-pyridazino-[1,2-a] [1,2] diazepin-1-carboxylic acid, 1,1-dimethylethylene ether

5,6-Dihydro-1,3-(2H, 4H)-pyridineboronic acid 3-(1,1-dimethylethyl)-1-(phenylmethyl)ether obtained in a known manner, (Adams and others , Synthetic c Communications, 18(18), 2225-2231 (19 procedure (Attwood and others (J. Chem. Soc. Perkins Trans I, 1986, S. 1011-1019), which was obtained (S)-2-[2-phthalimido-1.5-dioxo-5-(phenylmethoxy)pentyl]-5,6-dihydro-1,3- (2H,4H)-pyridinedicarboxylic acid 3-(1,1-dimethylethyl)-1-(phenylmethy)ether.

A solution of the obtained material (12,11 g, 18.5 mm) in dry dimethylformamide (190 ml) was treated with 10% palladium carbon (372 mg) and was first made at room temperature for 24 h Then the mixture was filtered through a pad of celite and the resulting clear dark filtrate was evaporated to dryness, and the resulting syrup was again dissolved in methanol (200 ml). The solution was filtered through another strip of celite to remove any remaining trace amounts of the catalyst and the resulting clear filtrate is evaporated to dryness and dried in vacuum. The obtained product was dissolved in dry methylene chloride (185 ml), cooled to 0oC in an ice-salt bath and treated with thionyl chloride (1,56 ml, 21,35 mm, 1.15 EQ.). The reaction mixture was stirred at room temperature and in an atmosphere of argon for half an hour, and treated with a solution of potassium bicarbonate (3,95 g) in water (34 ml) and stirred for 10 minutes, the Phases were separated, the aqueous phase was extracted again another 270 ml of methylene chloride and the combined organic extracts were dried busway mixture was chromatographically on a column of silica gel (Merck), elwira mixtures of ethyl acetate and hexane(1:3, 1:1), resulting received 3,053 g of target compound in the form of solids. (TLC (ethyl acetate:hexane, 1:1), Rf= 0,40.

b) (1S-CIS)-Octahydro-9-amino-6,10-dioxo-6H-pyridazino[1,2-a] (1,2] diazepin-1-carboxylic acid, 1,2-dimethylethylene ether

A suspension of the product obtained in part (a), (1.0 g, 2,41 mm) in absolute ethanol was treated with hydrazine hydrate (of 0.26 ml, 2.2 EQ.) and stirred 1 h at room temperature in argon atmosphere. Then the mixture was evaporated to dryness, evaporated from toluene (25 ml), and the resulting residue stirred with 2.0 M acetic acid (10 ml) in an argon atmosphere for 24 hours, the Solids were filtered off, washed with 2.0 M acetic acid (5.0 ml) and water (22,0 ml) and the clear filtrate was brought to pH of 10.0 using solid sodium bicarbonate (1.8 g). The resulting mixture was extracted with methylene chloride (225 ml) and the combined organic extracts were washed with saline solution (6.0 ml), was dried with anhydrous sodium sulfate and filtered. The clear solution is evaporated to dryness and dried in vacuo, resulting in a received 755 mg of the desired product in the form of syrup. TLC (methylene chloride: methanol, 9:1), Rf= 0,20.

c) [1S-[1 1,9 (R*)]]-Octahydro-9-jatiluwih ether

Dicyclohexylamine salt (S)-2-(acetylthio)benzoylpropionic acid (1.07 g, 2.64 mm) suspended in ethyl acetate (80 ml), washed with 5% potassium bisulfate (5 12 ml) and saline solution (14 ml), was dried with anhydrous magnesium sulfate, filtered, evaporated dash and dried in vacuum.

The free acid was dissolved in dry methylene chloride (20 ml), cooled to 0oC (ice/salt bath), treated sequentially with a solution of the product of part (b) (755 mg, 2,41 mm) in dry methylene chloride (5.0 ml), triethylamine (0.33 ml, 2,37 mm) and hexafluorophosphate benzotriazol-1 yloxytris(dimethylamino) phosphonium (1.08 g, 2,44 mm). The reaction mixture was stirred 1 h at 0oC and 2 h at room temperature in argon atmosphere. After that, the mixture was evaporated to dryness, and the resulting syrup was again dissolved in ethyl acetate (80 ml), washed with 0.5 G. hydrochloric acid (2 14 ml), water (14 ml) and saline solution (14 ml), then dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was chromatographically on a column of silica gel (Merck), elwira mixtures of ethyl acetate and hexane(1:3, 1:1), resulting received 747 mg of the desired product as a transparent syrup. TLC (ethyl acetate : hexane, 1:1), Rf= 0,23.

d) [1S-[ 1,9 (R*)]]-OTA

A solution of the product obtained in part (c), (747 mg, 1,48 mm) in dry methylene chloride (10 ml) was treated with anisole (0,69 ml, 6.35 mm), and then triperoxonane acid (1,04 ml, 13.5 mm) and the reaction mixture is stirred at room temperature in an argon atmosphere for 5.5 days. The clear solution was evaporated to dryness, evaporated from ethyl acetate (2 100 ml) and the crude product was chromatographically on a column of Merck silica gel, elwira a mixture of ethyl acetate and hexane (4: 1) and then with a mixture of ethyl acetate, hexane and acetic acid (85:10:5). The desired fractions were combined, evaporated to dryness and evaporated from toluene (2 100 ml). The resulting syrup was again dissolved in ethyl acetate (59 ml), washed with water (3 10 ml) and brine (5.0 ml) and then dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in a received 556 mg of the desired product in the form of syrup. TLC (ethyl acetate : acetic acid, 95:5), Rf= 0,30.

e) [1S-[ 1,9 (R*)] ] -Octahydro-9-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-6,10 - dioxo-6N-pyridazine[1,2-a][1,2] diazepin-1-carboxylic acid

A solution of the product obtained in part (d), (556 mg, 1,24 mm) in methanol (7.0 ml) was cooled to 0oC (ice/salt bath), was purged for 30 min with argon and about batrovci argon while adding and throughout the reaction. Then the reaction mixture was stirred at 0oC for 30 min, brought to a pH of 2.0 with 5% potassium bisulfate (11,0 ml) at 0oC, was heated to room temperature and was extracted with ethyl acetate (2 40 ml). The combined organic extracts were washed with saline (11,0 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was dissolved in methylene chloride (5.0 ml) and the portions were treated with hexane (50 ml) until then, until he had a solid material. This material is triturated with 50 ml of hexane and 2 50 ml of pentane, and the specified solid 2 hours and stirred with the first 50 ml and during the night - with the following 50 ml at room temperature and in an atmosphere of argon. The obtained product was dried in vacuum and received, resulting in 468.5 mg of the desired product as a solid foam-like substance; []D= -83,5o(c = 0,492, methanol). TLC (ethyl acetate : acetic acid, 95:5), Rf= 0,33.

Analysis for C19H23N3O5S 0,34 H2O:

Calculated: C 55,45; H 5,80; N OF 10.21; S 7,79;

Found: C 55,45; H 5,95; N 9,84; S 7,49.

Example 47.

[1S-[ 1,9 (R*)]]-Octahydro-9-[(2-mercapto-1-oxo-3 - phenylpropyl)amino] -10-oxo-6N-pyridazino[1,2-a][1,2]diazepin-1-carboxylic acid
A solution of the product of example 46 (1.0 g, 2.35 mm) in dry tetrahydrofuran (8.0 ml) was cooled to about 5oC (ice/salt bath), treated for 30 min 1.0 M of DIBORANE/tetrahydrofuran (2,88 ml, 2,88 mm) was heated to room temperature and stirred overnight in an argon atmosphere. The reaction mixture was diluted with methylene chloride (14,0 ml) was treated with a 2.0 G. hydrochloric acid (6.8 ml) and stirred 15 minutes. Then pH of the mixture was brought to a value of 10.0 using anhydrous sodium bicarbonate (1.92 g), the phases were separated, the aqueous phase was again extracted with 30 ml methylenchloride. The combined organic extracts washed with brine (5.0 ml), was dried with anhydrous magnesium 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 and hexane(1:3, 1:1), and received 877 mg of the desired product in the form of syrup. TLC (ethyl acetate : hexane, 1:1), Rf= 0,63.

b) (1S-CIS)-Octahydro-9-amino-10-6N-pyridazino[1,2-a][1,2] diazepin-1-carboxylic acid, 1,1-dimethylethylene ether

A solution of the product obtained in part (a), (1,257 g, 3.0 mm) in absolute ethanol (13,0 ml) was treated with hydrazine hydrate (0.33 ml, 2.2 EQ.) in accordance with protein : methanol, 9:1), Rf= 0,35.

c) [1S-[ 1,9 (R*)]]-Octahydro-9-[[2-(acetylthio)-1-oxo-3 - phenylpropyl] amino] -10-oxo-6N-pyridazino[1,2-a] [1,2] diazepin-1 - carboxylic acid, 1,1-dimethylethylene ether

Dicyclohexylamine salt (S)-2-(acetylthio)benzoylpropionic acid (1.10 g, 2,71 mm) suspended in ethyl acetate (85 ml), washed with 5% potassium bisulfate (5 of 12.4 ml) and saline solution (14.4 ml), dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuum.

The free acid was dissolved in dry methylene chloride (21 ml) was cooled to 0oC (ice/salt bath), treated sequentially with a solution of the product obtained in part (b), (704 mg, 2,48 mm) in dry methylene chloride (5.0 ml), triethylamine (0,34 ml, 2,44 mm) and hexafluorophosphate benzotriazol-1-yloxytris dimethylamino of phosphonium (1,113 g, 2,55 mm). The reaction mixture for 1 h, stirred at 0oC and 2.5 h at room temperature in argon atmosphere. Then the mixture was evaporated to dryness and the resulting syrup was again dissolved in ethyl acetate (80 ml), washed with 0.5 G. hydrochloric acid (2 of 14.0 ml), water (14,0 ml) and brine (14,0 ml), dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product was chromatographically on syrup. TLC (ethyl acetate : hexane, 1:1), Rf= 0,53.

d) [1S-[[ 1,9 (R*)] ] -Octahydro-9-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-10-oxo-6N-pyridazino[1,2-a][1,2]diazepin-1 - carboxylic acid

A solution of the product obtained in part (c), (1,085 g, 2,216 mm) in dry methylene chloride (15 ml) was treated with anisole (of 1.03 ml, 9.5 mm), and then triperoxonane acid (1,56 ml, 20,2 mm) and the reaction mixture stirred 4 days at room temperature in argon atmosphere. The clear solution was evaporated to dryness, evaporated from ethyl acetate (2 150 ml) and the crude product is suspended in a mixture of ethyl acetate (10 ml) and hexane (50 ml). The solids were filtered off, thoroughly washed with hexane (50 ml), evaporated from toluene (2 100 ml) and dried under vacuum, resulting in a received 865 mg [1S-[ 1,9 (R*)]]-Octahydro-9-[[2-(acetylthio)-1-oxo-3-phenylpropyl] amino] - 10-oxo-6N-pyridazino[1,2-a][1,2]diazepin-1-carboxylic acid in the form of a solid substance.

The resulting material was suspended in methanol (15 ml), cooled to 0oC (ice/salt bath), was purged for 30 min with argon, and then drop handle purged solution of 1.0 n sodium hydroxide (6,03 ml, 3 equiv.) while bubbling argon during T in solution in the first 5 min was brought to pH 2 with 5% potassium bisulfate (26,6 ml), was heated to room temperature and was extracted with ethyl acetate (2 65 ml). The combined organic extracts were washed with saline solution (18 ml), was dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The product was dissolved in metilenhloride (7,0 ml) portions was treated with hexane (70 ml) until then, until he had a solid substance. This solid is triturated with hexane (100 ml) and pentane (2 100 ml), stirring 2 h with the first 100 ml and during the night with the following 100 ml at room temperature in argon atmosphere. The product was dried in vacuum and received 790,6 mg of target compound in the form of a solid foam-like substance; []D= -44,4o(c = 0,63, methanol). TLC (ethyl acetate : acetic acid, 95:5), Rf= 0,67.

Analysis for C19H25N3O4S 0,20 C5H120,80 H2O:

Calculated: C 57,11; H 6,95; N 9,99; S 7.62MM;

Found: C 57,11; H 6,72; N 9,83; S 7,44.

Example 48.

[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-2-methyl-3,7-dioxo-1H-1,2-diazepine-1-acetic acid

a) [2-[(1,1-Dimethylmethoxy carbonyl]hydrazino]acetic acid, ethyl ester

The triethylamine (13,94 ml, 0.1 M) was added to a solution of 1,1-dimethylethylene ether the ion mixture was heated under reflux (oil bath, 95 - 100oC) for 14 h, after which was added triethylamine (1.4 ml, 0.01 M), and then bromoacetate (1.1 ml, 0.01 M). After heating under reflux for another 8 hours, was added triethylamine (2 ml of 0.015 M) and ethylbromoacetate (1,4 ml of 0.013 M). The mixture was heated under reflux 14 h (36 h). After cooling to room temperature, the reaction mixture was filtered and the obtained cleaners containing hydrochloride salt of triethylamine was washed with a mixture of ethyl acetate/hexane (1:1). The combined filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried with sodium sulfate and filtered. The filtrate was concentrated in vacuum and received 19,38 g of the crude product as a yellow syrup, which was used in the next reaction without purification.

b) [2-[(1,1-Dimethylmethoxy)carbonyl]-1-[(phenylmethoxy)carbonyl] hydrazino]acetic acid, complex ethyl ester

The triethylamine (12,4 ml, 89 mm) was added to a solution of the crude product obtained in part (a), (19,38 g) in benzene (120 ml), and then one drop was added [(phenylmethoxy)carbonyl]-chloride (13.4 ml, 89 mm) in benzene (30 ml) for 30 minutes, the resulting suspension is stirred 20 h at room temperature in an argon atmosphere, and then distributed by sodium bicarbonate, water, saline solution, dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was led from ethyl acetate/hexane, resulting (after vacuum drying over phosphorus pentoxide) received 15,736 g of the desired product as a white crystalline substance with so pl. 117 - 119oC.

c) [2-[[(1,1-Dimethylmethoxy)carbonyl]-1-[(carbonyl)-1-phenylmethoxy carbonyl]-2-methyl]hydrazino]acetic acid, ethyl ester

Potassium carbonate (powdered and dried, to 11.8 g, 85,15 mm) was added to a solution of the product obtained in part b, (6.0 g, 17,03 mm) in anhydrous dimethylformamide (30 ml) and then added methyliodide (5,3 ml, 85,15 ml). After 17 hours of stirring at 40oC, was added 64 mm under the conditions and the reaction mixture stirred at 40oC 28 h Then the suspension was filtered and to the filtrate was added 6.0 g of fresh potassium carbonate (powdered and dried), and then 5.0 ml under the conditions. The suspension is stirred at 40oC for 21 h, then was added 1.2 ml under the conditions and the reaction mixture was stirred 17 h before until the source material will not be detected by TLC. Then the reaction mixture was filtered and the collected solid is washed and then diluted with 500 ml ethyl acetate, washed with water, brine and dried with magnesium sulfate. The filtrate was concentrated and the residue was dried under vacuum, resulting in a received 6,285 g of the crude product in the form of a colorless oily substance.

d) [2-[[(1,1-Dimethylmethoxy)carbonyl]-2-methyl]hydrazino]acetic acid, ethyl ester

A suspension of the product obtained in part (c), (6,285 g, 17,03 mm) and palladium hydroxide (800 mg) in ethanol (75 ml) was vigorously stirred 4 h in the presence of hydrogen (balloon). Then the suspension was filtered using milleporidae filter. The filtrate was concentrated, and the residue was dried under vacuum, resulting in the obtained 4.3 g of the desired product as a slightly yellow oily substance.

e) (S)-2-Phthalimido-1,5-pentagonia acid, 5-(phenylmethyl)ether)

N-(Carbethoxy)phthalimide (9.7 g, of 44.24 mm to 1.05 EQ) was added to a suspension of L-glutamic acid 5-(phenylmethyl) ether (10.0 g, 42,14 mm) and sodium bicarbonate (4,47 g, 42,14 mm) in water (80 ml) and dioxane (40 ml). After 2 - hour stirring was added 4.4 g (0.1 EQ.) N-carbethoxy phthalimide. The resulting mixture was stirred for another 2 hours After that, the pH of the reaction mixture brought up to 1-2 using solid potassium bisulfate and the resulting mixture was extracted was Atsushi sodium sulfate and filtered. The filtrate was concentrated in vacuum. The oily residue was diluted with ethyl acetate and treated with dicyclohexylamine (8,40 ml, 42,14 mm). After crystallization of the crude salt from ethyl acetate/hexane was obtained after vacuum drying) 13 g of the desired product in the form of dicyclohexylamine salt. The mother liquor is washed with 1 M disulfate potassium (2x), water, brine and dried with sodium sulfate. The filtrate was concentrated in vacuum. Oily residue was chromatographically with the use of 0.5% acetic acid in a mixture of heptane and ethyl acetate (3:7) as mobile phase. The desired fractions were collected and concentrically. The oily residue was dried in vacuum and received 9,644 g of the target product.

f) (S)-4-Phthalimido-5-oxo-5-[2-[(1,1-dimethylmethoxy)carbonyl] -1-(2-ethoxy-2 - oxoethyl)-2-methylhydrazino] pentane acid, fenilmetilovy ester

To a solution of the product obtained in part (e), (about 17,10 mm) (cooled to 0oC) in the simple ether (80 ml) was added pentachloride phosphorus (5.10 g, 24,5 mm). After 30 minutes stirring at 0oC and a 30-minute stirring at room temperature, the reaction mixture was concentrated in vacuum. The residue was evaporated with toluene (3x) and dried in vacuum for 2 chii.

A solution of sodium bicarbonate (4 g, 46 ml of water) was added to a cold (0oC) a solution of the product obtained in part (d) in toluene (40 ml). Stirring, the above compound in toluene (30 ml) drop by drop) was added via cannula. After the addition, the reaction mixture was stirred at room temperature and in an atmosphere of argon for 19 hours Then the reaction mixture was diluted with ethyl acetate (300 ml), washed with water, 5% potassium bisulfate, water, brine, and then dried with sodium sulfate. The filtrate was concentrated, and the residue was dried under vacuum, resulting in the obtained target compound in the form of an oily substance.

g) (S)-4-Phthalimido-5-oxo-5-[1-(2-ethoxy-2-oxoethyl)-2-methylhydrazino] pentane acid, fenilmetilovy ether

To a cooled (-10oC) solution of the crude product obtained in paragraph (f), in methylene chloride (55 ml) was added drop by drop the anisole (7,4 ml) and then tetrapterys acid (13,10 ml, 170 mm). After complete addition, the reaction mixture is stirred at -10oC for 1 h Then the reaction mixture was heated to room temperature and continued to stir for 14 hours After removal of volatiles in vacuo, the residue was diluted with 200 ml of ethyl acetate, promantra was concentrated in vacuum, and the residue was chromatographically, using as mobile phase 20-40% ethyl acetate/hexane. The desired fractions were collected and concentrated, and the residue was dried under vacuum, resulting in a received 7,254 g of the target product as a pale yellow oily substance.

h) (S)-4-Phthalimido-5-oxo-5-[-(2-ethoxy-3-oxoethyl)-2-methylhydrazino] pentane acid

The palladium hydroxide (1.0 g) was added to a solution of the product obtained in paragraph (g) (6,436 g, 13,38 mm) in warm ethanol (100 ml). The suspension is vigorously stirred in the presence of hydrogen (balloon) for 4 h Then the suspension was filtered and the catalyst washed with ethanol. The combined filtrate was concentrated. The residue was evaporated with toluene (2x) and dried in vacuum over night, resulting in a received 5,86 g of the product as colorless oily substance, which was used in the next reaction without purification.

i) (S)-Hexahydro-2-methyl-3,7-dioxo-6-phthalimido-1H-1,2-diasorin-1 - acetic acid, ethyl ester.

Thionyl chloride (1.1 ml) was added drop by drop to a cooled solution (0oC) the product obtained in part (h), (5,86 g, 13,38 mm) in methylene chloride (120 ml). The reaction mixture was stirred 15 min at 0oC, and then 3 h at com h then the reaction extinguished solution bicarbonate potassium (2.7 g of potassium bicarbonate in 27 ml in water). Selected organic phase is washed with saturated sodium bicarbonate. The aqueous phase was extracted with methylene chloride (2x). United methylenchloride phase was washed with water, brine and dried with magnesium sulfate. The filtrate was concentrated, and the residue was dried under vacuum, resulting in a received 4,70 g of the desired product.

j) (S)-Hexahydro-2-methyl-3,7-dioxo-6-amino-1H-1,2-diacetin-1-acetic acid, ethyl ester

Hydrazine monohydrate (255 μl, 5.25 mm) was added to a suspension of the product obtained in part (i), (1,867 g, 5.0 mm) in ethanol (30 ml) and methylene chloride (10 ml). After stirring the mixture for 2 h, the volatiles were removed in vacuo and the residue was evaporated with toluene (2x), and then dried in vacuum. The residue was diluted with 2M aqueous acetic acid (20 ml) and the resulting solution was stirred 14 h at room temperature. The suspension was filtered. The filtrate was podslushivaet solid sodium bicarbonate to pH 10 and extracted with methylene chloride (3x). United methylenchloride phase was washed with 50% brine, dried sodium sulfate, filtered and evaporated. The residue was chromatographically to use the yellow oily product.

k) [S-(R*,R*)-Hexahydro-6-[[2-(acetylthio)-1-oxo-3 - phenylpropyl]amino] -2-methyl-3,7-dioxo-1H-1,2-diazepine-1-acetic acid, ethyl ester

The triethylamine (302 μl, 2,171 mm) was added to a cooled (0oC) a solution of (S)-2-(acetylthio)benzodiapines acid (obtained from dicyclohexylamine salt as described previously, 486 mg 2,17 mm), and then added the product obtained in paragraph (j) (480 mg, 1,973 mm) in methylene chloride (3 ml) and hexafluorophosphate benzotriazol-1-yloxytris dimethylamino Pospisil (960 mg, 2,171 mm). The resulting mixture was stirred 1 h at 0oC and then 2 h at room temperature. Volatiles were removed in vacuum. The residue was dissolved in ethyl acetate (100 ml), washed with 5% potassium bisulfate, 50% saturated sodium bicarbonate, brine, dried magnesium sulfate, filtered and evaporated to dryness. The crude product was subjected to flash chromatography, using as mobile phase of 50% - 70% ethyl acetate/hexane and obtained 824 mg of the desired product as a white foamy substance.

l) [S-(R*, R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3 - phenylpropyl)-amino] -2-methyl-3,7-dioxo-1H-1,2-diazepine-1-acetic acid

A solution of the product obtained in paragraph (k) (800 mg, 1,78 mm) in methanol (9 ml), and ohmori sodium hydroxide (mg 7,12, 4.0 EQ). The reaction mixture was stirred at 0oC, barbotine argon for 1.5 h, after which the mixture was acidified using 1M potassium bisulfate to bring the pH to 1-2 and extracted with ethyl acetate (3x). United an ethyl acetate extracts washed with brine (2x), dried with magnesium sulfate, filtered and evaporated to dryness. The residue was subjected to flash chromatography, using as mobile phase of 2% acetic acid/utilized, and received 668 mg of the desired product as a white foamy substance. When combining the product column fractions used chloroform, []D= -54,8o(c=0.8, methanol). TLC (3% acetic acid/acetate), Rf= 0,12.

Analysis for C17H21N3O5S 0,57 CHCl3:

Calculated: C 47,16; H a 4.86; N 9,39; S 7,16;

Found: C 47,48; N 4,56; N 9,01; S 7,17.

Example 49.

[S-(R*, R*)] -Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-2-methyl-7-oxo-1H-1,2-diazepine-1-acetic acid

a) (S)-Hexahydro-2-methyl-7-oxo-6-phthalimido-1H-1,2-diazepine-1 - acetic acid, ethyl ester

A solution of the product obtained in example 48, part (i), (375 mg, 1.0 mm) in dry tetrahydrofuran (2.4 ml) was cooled to 0oC and processed up to drops of 1M-solution(during this time the mixture became gel-like). Then the cooled mixture is stirred for another 1 h at room temperature, after which the mixture was diluted with 2 ml of methylene chloride and 2 ml of 2 M aqueous hydrochloric acid. After 15 minutes of stirring, the mixture was diluted with 20 ml of methylene chloride and carefully washed with saturated sodium bicarbonate. Selected aqueous phase was extracted with methylene chloride (3x). United methylenchloride extract is washed with a 5% salt solution, saline solution and dried with sodium sulfate. The filtrate is evaporated in vacuum to dryness and received 344 mg of the crude product as an oily substance, which was used in the next reaction without purification.

b) (S)-Hexahydro-2-methyl-7-oxo-6-amino-1H-1,2-diazepine-1-acetic acid, ethyl ester

A solution of the product obtained in part (a), (344 mg, 0,958 mm) in ethanol (3 ml) was treated with hydrazine monohydrate (54,8 μl, 1,13 mm) in accordance with the procedure described in example 48, part (j), resulting in a received 169 mg of the target compound as a pale yellow oily product.

c) [S-(R*, R*)-Hexahydro-6-[(2-acetylthio)-1-oxo-3-phenylamino]-2-methyl-7-oxo-1H-1,2-diazepine-1-acetic acid, ethyl ester

A cold (0oC) solution of (S)-2-(acetylthio)boride (1 ml) was treated with triethylamine (123 μl, 0,88 mm), the product obtained in paragraph (b) (169 mg, 0,738 mm) in methylene chloride ( 2 ml) and hexafluorophosphate benzotriazol-1-yloxytris dimethylamino of phosphonium (392 mg 0,885 mm). The resulting mixture was stirred 1 h at 0oC and then 2 h at room temperature. Volatiles were removed in vacuum. The residue was dissolved in ethyl acetate (50 ml), washed with 5% potassium bisulfate, saturated sodium bicarbonate, 50% salt solution, saline solution and dried with magnesium sulfate. The filtrate is evaporated to dryness and the residue was subjected to flash chromatography using 40 to 50% ethyl acetate/hexane as the mobile phase, and received 260,5 mg of the desired product as colorless oily substance.

d) [S-(R*, R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)-amino] -2-methyl-7-oxo-1H-1,2-diazepine-1-acetic acid

A solution of the product obtained in part (c), (235 mg, 0,54 mm) in methanol (3 ml) and cooled to 0oC, was purged for 30 min with argon, and then drop handle purged with 1M sodium hydroxide solution (2.20 ml, 4.0 EQ). The reaction mixture was stirred at 0oC, barbotine while argon for 2 h, then was acidified using 1M potassium bisulfate to pH 1 to 2 and was extracted with ethyl acetate (3x). United dry. The residue was subjected to flash chromatography using 2% acetic acid/ethyl acetate as the mobile phase, resulting in received of 182.2 mg of the desired product as a white foaming compounds; []D= -9,6o(c = 0.3, and methanol). TLC (3% acetic acid in ethyl acetate), Rf= 0,26.

Analysis for C17H23N3O4S 0,2 H2O:

Calculated: C 55,32; H to 6.39; N IS 11.39; S 8,69;

Found: C 55,73; H 6,44; N 10,98; S 8,56.

Example 50.

[S-(R*, R*)]-2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxohexyl)-amino]-2 - oxo-1H-benzazepin-1-acetic acid

a) (S)-2-Bromhexina acid

Bromide of potassium (15.9 g, 133 mm) was added to stirred solution of D-norleucine (5.0 g, 38 mm) 2.5 N. sulfuric acid (77 ml) at room temperature. The reaction mixture was cooled to -10oC and parts) was added solid sodium nitrite (3.94 g, 57 mm), while maintaining the temperature of (-10) - (-5)oC. After complete addition, the foaming reaction mixture is stirred for 1 h, and then heated to room temperature and stirred for another 1 h then the reaction mixture is twice was extracted with ether, the ether extracts once washed with water, dried with magnesium sulfate, filtered and evaporated in financial p is illinova salt

To a stirred suspension of thioacetate potassium (2,11 g, 18.5 mm) in 50 ml of dry acetonitrile at room temperature and in an atmosphere of argon was added a solution of the product obtained in part (a), (3,27 g, 16,8 mm) in 26 ml of acetonitrile. The reaction mixture is stirred for 5 hours. The resulting suspension was filtered and evaporated. The residue was again dissolved in ethyl ether, once washed with 5% solution of potassium bisulfate and once with saline, then was dried with magnesium sulfate and evaporated. The residue was dissolved in ether (64 ml) and treated with dicyclohexylamine (3.4 ml, 16,8 mm). The ethereal solution was concentrated in vacuo and triturated with hexane, resulting in the obtained white solid, which was recrystallized from a mixture of ethyl ether and hexane and was obtained target product. The mother liquor was concentrated and twice recrystallized, resulting in generally received 2.2 g of the target product; so pl. 145 - 147oC; []D= -33,8o(c = 1,08, chloroform).

c) [S-(R*, R*)]-2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxohexyl)-amino] -2 - 1H-benzazepin-1-acetic acid, ethyl ester

Posted by suspension of the product obtained in part (b), (295 mg, 0,795 mm) in 5 ml of ethyl acetate twice, washed the, concentrated and dried in vacuum for 20 min Obtained oily substance was dissolved in 3 ml of methylene chloride and stirred in an argon atmosphere at 0oC. To this solution was added a solution of (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H - benzazepin-1-acetic acid ethyl ester, obtained in a known manner (Watthey, and others, in J. Med. Chem, 28, S. 1511 - 1516 (1985)) (149 mg, 0,57 mm) in methylene chloride (3 ml), then was added triethylamine (83 μl, 0,60 mm), and finally benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (264 mg, 0,60 mm). After 1 h the reaction was heated to room temperature and stirred for 90 minutes the resulting solution was evaporated at less than 30oC and the residue was again dissolved in ethyl acetate. The solution was washed once with 1M hydrochloric acid, once with water, once with saturated sodium bicarbonate solution and once with brine. The organic layer was dried with magnesium sulfate, filtered and evaporated. After purification using flash chromatography (using a mixture (1:3) ethyl acetate: hexane) received 193 mg of the target product; []D= -284,3o(c = 0,21, chloroform).

d) [S-(R*, R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto - 1-oxo-hexyl-3-phenylpropyl)amino]-2-oxo-1H-benzazepin-1-axokine 5 min, and then was cooled to 0oC. To this solution drop by drop) was added to 3.8 ml, purged with nitrogen 1M sodium hydroxide. In the reaction, the solution was slowly barbotirovany nitrogen. After 1 h the reaction mixture was heated to room temperature and stirred for 1 h Then the mixture was acidified with 5% solution of sodium bisulfate, were extracted with ethyl acetate, and the extracts were washed with water and saturated sodium chloride solution, dried with magnesium sulfate and evaporated. After re-evaporation of hexane was obtained white solid. This solid is slightly heated in ethyl ether and was led with hexane, resulting in received 117 mg of the target compound in the form of a white solid product; so pl. 151 - 153oC; []D= -214,1o(c = 0,46, chloroform).

TLC (ethyl acetate/hexane/acetic acid, 4:4:0,1),

Rf= 0,23.

Analysis for C18H24N2O4S:

Calculated: C 59,32; H 6,64; N 7,69; S 8,80;

Found: C 59,10; H 6,62; N 7,72; S 8,63.

Example 51.

[3S- [3(R*), 7] ] - Hexahydro-7-(2-hydroxyethyl)-3-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-2-oxo-1H-azepin-1-acetic acid

a) (3S-TRANS)-Hexahydro-3-[[(1,1-dimethylmethoxy)carbonyl] amino] -2-oxo-7-(2-propenyl)-1H-is a solution of (3S-TRANS)hexahydro-3-phthalimido-2-oxo-7-(2-propenyl)- 1H--acetic acid methyl ester, obtained in accordance with the procedure described in example 36, part (e), 609 mg, of 2.45 mm. The reaction mixture was stirred at room temperature for 64 h, and then filtered to remove by-products. The filtrate was concentrated in vacuo, dissolved in methylene chloride, was again filtered and again concentrated, resulting in the obtained crude oily substance. This substance was dried in vacuum and received 656 mg of crude methyl ester of (3S-TRANS)-hexahydro-3-amino-2-oxo-7-(2-propenyl)-1H - azepin-1-acetic acid as a yellow oily product.

To a solution of this crude amine (589 g 2,455 ml) in methylene chloride (10 ml), purged with argon, was added 510 µl (3,68 mm) of triethylamine. The reaction mixture was stirred 10 min, then was added 642 mg (2,94 mm) of di-t-BUTYLCARBAMATE. The reaction mixture was stirred at room temperature for 16 h, and then added the second portion 170 µg (1,23 mm) of triethylamine and 160 mg (0,74 mm)of di-t-BUTYLCARBAMATE. The reaction mixture is stirred for another 16 h at room temperature and was diluted with 20 ml of methylene chloride. The organic layer was washed 2-10 ml-portions of water, dried with magnesium sulfate and concentrated in vacuo, resulting in a received raw MacLean, and then 1:4 ethyl acetate:hexane) and received 651 mg of the desired product as a transparent oily substance.

Hydrazine monohydrate 133 μg, 2,70 mm drop) was added to a solution of (3S-TRANS)hexahydro-3-phthalimido-2-oxo-7-(2-propenyl)-1H - acetic acid methyl ester, obtained according to the procedure described in example 36, part (e), 609 mg, of 2.45 mm. The reaction mixture was stirred at room temperature for 64 h, and then filtered to remove by-products. The filtrate was concentrated in vacuo, dissolved in methylene chloride, was again filtered and again concentrated, resulting in a received neojidannoe oily substance. This substance was dried in vacuum and received 656 mg of crude methyl ester of (3S-TRANS)-hexahydro-3-amino-2-oxo-7-(2-propenyl)-1H-azepin-1 - acetic acid as a yellow oily product.

To a solution of this crude amine (589 g 2,455 ml) in methylene chloride (10 ml), purged with argon, was added 510 µl (3,68 mm) of triethylamine. The reaction mixture was stirred 10 min, then was added 642 mg (2,94 mm) of di-t-BUTYLCARBAMATE. The reaction mixture was stirred at room temperature for 16 h, and then added the second portion 170 µg (1,23 mm) of triethylamine and 160 20 ml of methylene chloride. The organic layer was washed 2 - 10 ml-portions of water, dried with magnesium sulfate and concentrated in vacuo, resulting in the obtained crude oily product. This product was subjected to flash chromatography (silica Merck, h mm, 1:6 ethyl acetate:hexane, then 1:4 ethyl acetate:hexane) and received 651 mg target product as a transparent oily substance.

b) (3S-TRANS)-Hexahydro-3-[[(1,1-dimethylmethoxy)carbonyl] amino] -2-oxo-7-(hydroxyethyl)-1H-azepin-1-acetic acid, methyl ester.

To a solution of the product obtained in part (a), (554 mg, 1,63 mm) in 3 ml water and 3 ml of dioxane was added 731 mg (3,42 mm) periodate sodium, and then drop by drop in the course of 10 min was added 400 μl (0,98 mm) tetroxide OS. The reaction mixture was stirred at room temperature for 16 h, filtered and washed with ethyl acetate. The obtained filtrate was concentrated in vacuo without heating and subjected to flash chromatography (silica Merck, 25 to 120 mm, 1: 4 ethyl acetate/hexane - without pressure), resulting in a received 309 mg of 3(S)-TRANS)-hexahydro-3-[[(1,1-dimethylmethoxy)carbonyl]amino]-2-oxo-7 - acetaldehyde-1H-azepin-1-acetic acid methyl ether complex as a transparent oily substance.

To the) of sodium borohydride. The reaction mixture was stirred 1.5 h at 0oC, after which the reaction was suppressed by adding one drop of 0.5 ml of water and warmed up to room temperature. The mixture is then distributed between 25 ml of ethyl acetate and 25 ml of 1M hydrochloric acid, and the aqueous layer was extracted with 2-20 ml portions of ethyl acetate. United an ethyl acetate layers were washed with 10 ml of saturated sodium bicarbonate and 10 ml of brine, dried with magnesium sulfate and concentrated in vacuo, resulting in the obtained crude oily substance. This substance was subjected to flash chromatography (silica Merck, 25 to 90 mm, 2:1 - ethylacetat/hexane, then ethyl acetate) and received 292 mg of the desired product as a transparent oily substance.

c) [3S- [3(R*), 7] ] - Hexahydro-3-[(2-(acetylthio)-1-oxo-3 - phenylpropylamine]-7-(2-hydroxyethyl)-2-oxo-1H-azepin-1-uksusnaya acid, methyl ester

To a solution of the product obtained in part (b), (292 mg, 0.85 mm) in dioxane (1 ml), cooled to 0oC, was added in portions (2.5 ml 9,35 mm, 4 M hydrochloric acid/dioxane. The reaction mixture was heated to room temperature and stirred 16 h, and then concentrated in vacuo and subjected to azeotropic treatment with the use of toluene in CEG is and cleaners containing hydrochloride salt in the form of a crude oily substance.

To a solution of the amine cleaners containing hydrochloride salt (189 mg, 0.67 mm) and (S)-2-(acetylthio)benzodiapines acid (obtained from dicyclohexylamine salt as described previously, 157 mg, 0,74 mm) in methylene chloride (10 ml), cooled to 0oC, was added triethylamine (230 μl, 1,68 mm). This mixture is stirred for 20 min, and then added hexafluorophosphate benzotriazol-1-yloxytris-dimethylamino of phosphonium (327 mg, 0,74 mm). The reaction mixture was stirred 1 h at 0oC, and then 3 h at room temperature. Then the reaction mixture was distributed between 20 ml ethyl acetate and 20 ml of a 5% solution of potassium bisulfate. The aqueous layer was separated and was extracted with 2-20 ml-portions of ethyl acetate, and the combined an ethyl acetate layers were washed with 20 ml of a 5% solution of potassium bisulfate, 20 ml saturated sodium bicarbonate, 2-20 ml portions of brine, dried with magnesium sulfate and concentrated in vacuo, resulting in the obtained crude oily substance. This substance was subjected to flash chromatography (silica Merck, 25 to 80 mm, 1:4 ethyl acetate/hexane) and received 84 mg of the desired product as a white foamy substance.

d) [3S- [3(R*), 7] ]- Hexahydro-7-(2-hydroxyethyl)-3-[(2-mercapto-1-oxo-3-phenylpropyl) amino]-2-oxo-1H-azepin-1-I for 30 min and was cooled to 0oC. To this solution drop by drop) was added 2 ml of 1M sodium hydroxide, also purged with argon for 30 min, and was cooled to 0oC. the Reaction mixture was stirred at 0oC for 1 h, continuing purging with argon, and then acidified with 5% solution of potassium bisulfate to bring the pH to 2. The resulting mixture was extracted with 3-20 ml-portions of ethyl acetate, and the combined an ethyl acetate layers were dried with magnesium sulfate and concentrated in vacuo, resulting in a received untreated foamy substance. This substance was subjected to flash chromatography (silica Merck, 15 to 60 mm, 0.5:5:95 - acetic acid: methanol: methylene chloride) and received a white foamy substance was subjected to azeotropic treatment with the use of toluene and dried under vacuum, resulting in a received 48 mg of the desired product as a white foamy substance; []D= -42,9o(c = 1,0, CDCl3). TLC (acetic acid: methanol: methylene chloride, 1:10:90), Rf= 0,25.

Analysis for C19H26N2O5S 0,5 H2O:

Calculated: C 56,55; H of 6.75; N 6,94; S 7,94;

Found: C 56,55; H 6,64; N 6,77; S 7,51.

Example 52.

[1S- [ 1, 9 ]] -Octahydro-9-[[2-mercapto-1-oxo-3-(2-thienyl) propyl] amino]-10-oxo-6H-pyridazino[1,2-a][1,2]diazepin-1-carretero - -(2-thienyl)-D-alanine (1,37 g, 8,03 mm) 2.5 n hydrochloric acid (25 ml) at room temperature and in an atmosphere of argon. After 10 minutes of stirring, the mixture was cooled to 0oC and treated with sodium nitride (720 mg, 10,44 mm). After 2.5 h the reaction mixture was heated to room temperature and stirred for 1 h then the mixture was distributed between water and ethyl acetate and the organic layer was dried with sodium sulfate, was chromatographically and concentrated. The residue was subjected to flash chromatography (silica gel Merck), elwira 1% acetic acid mixture (3:1) of hexane and ethyl acetate, resulting in a received 760 mg (R) - - -chloro-2-thiophencarboxylic acid as a yellow oily product.

To the solution containing the above chloride (750 mg, 4,73 mm) in dimethylformamide (15 ml) at room temperature and in an atmosphere of argon was added thioacetic cesium (2,95 g, 14,19 mm). After 2-hour stirring, the reaction mixture was distributed between 10% potassium bisulfate and ethyl acetate. The organic layer was washed with saline, dried with sodium sulfate, filtered and concentrated, and the residue was subjected to flash chromatography (silica gel Merck), elwira 1% acetic acid in a mixture (4:1) of hexane and etelaat in a mixture (3:1) ethyl acetate and hexane), Rf= 0,73.

b) [1S-[ 1, 9 (R*)]]-Octahydro-9-[[2-(acetylthio)-1-oxo-3-(2-thienyl) propyl] amino]-10-oxo-6H-pyridazino[1,2-a][1?2]-diazepin-1 - carboxylic acid

The product obtained in part (a), (246 mg, 1,07 mm) and (1S-CIS)-octahydro-9-amino-10-oxo-6H-pyridazino [1,2-a][1,2]diazepin-1-carboxylic acid, 1,1-dimethylethylene ester, obtained as described in example 47 (b), (370 mg, 1,17 mm) was dissolved in methylene chloride (10 ml) at room temperature in argon atmosphere. The resulting mixture was cooled to 0oC was added triethylamine (0.15 ml, of 1.07 mm). The resulting mixture was stirred 5 min, and then added hexafluorophosphate benzotriazol-1-yloxytris dimethylamino of phosphonium (517 mg, 1,17 mm). After 1 hour stirring at 0oC, the reaction mixture was heated to room temperature and stirred for 16 hours Volatiles evaporated and the residue was dissolved in ethyl acetate and washed successively 1 N. hydrochloric acid, water, 50% saturated sodium bicarbonate and saline. The organic layer was dried with sodium sulfate, filtered and concentrated, and the residue was subjected to flash chromatography (silica gel Merck), elwira mixture (3:2) of hexane and ethyl acetate. Then the product was again subjected to flash chromatography, elwira mixture (3:1 the Ino]-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-carboxylic acid, 1,1-dimethylethylene of ester as a white foamy substance. TLC (ethyl acetate: hexane, 1:1), Rf= 0,43.

To the solution obtained above product (390 mg, 0,82 mm) in methylene chloride (6 ml) at room temperature and in an atmosphere of argon was added anisole (0,38 ml, 3,52 mm). The resulting mixture was treated triperoxonane acid (of 0.58 ml, 7.5 mm) and stirred for 36 hours Volatiles were removed and the residue was separated using toluene and removed, resulting in a received 380 mg of a yellow oily substance. This substance was purified by column chromatography (silica gel Merck), elwira 1% acetic acid in a mixture (1:1) of ethyl acetate and hexane and then 1% acetic acid in a mixture of ethyl acetate and hexane, resulting in received 360 mg of the target product.

TLC (1% acetic acid in a mixture (1:1) of ethyl acetate and hexane), Rf= 0,28.

c) [1S-[ 1, 9 (R*)] ] -Octahydro-9-[[(2-mercapto-1-oxo-3- (2-thienyl)propyl] amino] -10-oxo-6H-pyridazino [1,2-a][1,2]diazepin - 1-carboxylic acid

A solution of the product obtained in part (b), (328 mg, 0.75 mm) in methanol (5 ml, dezoksiepinefrinom by ozonation of argon) was cooled to 0oC and treated with 1 N. sodium hydroxide (4 ml, desoxycholate 10% potassium bisulfate and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried sodium sulfate, filtered and concentrated, the result has been a transparent oily substance. The residue was subjected to flash chromatography (silica gel Merck), elwira 1% acetic acid in a mixture (1:2) of hexane and ethyl acetate. The fractions containing the pure desired product were combined, evaporated, and subjected to azeotropic processing using ethyl acetate and washed with water to remove acetic acid. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate and triturated with hexane. The solvent was removed and the residue is suspended in hexane, evaporated and dried in vacuo, resulting in a received 165 mg of the desired product as a white powdery foam-like substance. []D= -131,6o(c = 0,43, methylene chloride), Rf= 0,36.

Analysis for C17H23N4O4S20,09 C6H140,13 C4H8O2:

Calculated: C 51,58; H 6,17; N 9,99; S 15,25;

Found: C 51,24; H between 6.08; N RS 9.69; S 15,22

Example 53.

[IS-[1, 8 (R*)] ] -Hexahydro-8-[[(2-mercapto-1-oxo-3-phenylpropyl] amino]-9 - oxo-IH,5H-pyrazolo[1,2-a][1,2]diazepin-1-carboxylic KIS>A solution of 3-pyrazolidinone acid 1,1-dimethylethylene of ester (10,935 g, 63.5 mm) in dry acetonitrile (90 ml) was cooled to 0oC (ice-salt bath) and treated with dry pyridine (11,0 ml), and then the solution benzylchloride (12,54 g, 10.5 ml, 69,9 mm) in dry acetonitrile (25 ml), the reaction mixture was stirred 3 h at 0oC, evaporated to dryness and the resulting syrup was again dissolved in ethyl acetate (250 ml). The solution was washed with 5% bicarbonate sodium (225 ml) and brine (25 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product mixture was chromatographically on a column of silica gel (Merck), elwira mixtures of ethyl acetate and hexane (1:4, 1:2) resulting in the received 11,144 g of the desired product in the form of syrup. TLC (ethyl acetate: hexane, 1:1), Rf= 0,25.

b) (S-2-[2-Phthalimido-1.5-dioxo-5-(phenylmethoxy)-pentyl] -1,3 - pyrazolidinone acid, 3-(1-dimethylethyl)-1-fenilmetilovy ether

Dicyclohexylamine salt (S)-2-phthalimidomethyl acid 5-(phenylmethyl)ether (11,548 g, 21 mm) suspended in ethyl acetate (700 ml), washed with 5% potassium bisulfate (5100 ml) and brine (100 ml), dried sodium sulfate, filtered, evaporated to dryness and dried off with adanai-salt bath), handled pentachloride phosphorus (4,45 g, 21 mm) and stirred 30 min at 0oC and then 15 min at room temperature. The reaction mixture was evaporated to dryness, evaporated from toluene (2230 ml) and dried in vacuum. The crude acid chloride was dissolved in toluene (46 ml) was added to a cooled solution (10oC, an ice-salt bath) of the product obtained in part (a), (5,52 g, 18 mm) in toluene (35 ml) and bicarbonate sodium (4.77 g, 46 ml) of water, was heated to room temperature and stirred for 20 h in an argon atmosphere. The reaction mixture was diluted with ethyl acetate (650 ml), washed with 5% potassium bisulfate (2140 ml) and brine (140 ml), dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuo, resulting in a received 11,587 g of the target product.

c) (IS-CIS)-Hexahydro-8 phthalimido-5,9-dioxo-IH, 5H-pyrazolo-[1,2-a] [1,2]diazepin-1-carboxylic acid, 1,1-dimethylethylene ether

A solution of the product obtained in part (b), (12,653 g, 18 mm) in dry dimethylformamide (196 ml) was treated with 10% palladium charcoal (2,19 g) and was first made 24 h at room temperature. The reaction mixture was diluted with methanol (200 ml) and filtered through a pad of celite, carefully rinsing the pad with methanol (tie color. The crude product was dissolved in dry methylene chloride (185 ml), cooled to 0oC (ice-salt bath), treated with thionyl chloride (1,62 ml, 22.2 mm) and stirred for 15 minutes at 0oC, and then 6,0 h at room temperature. The reaction mixture was extinguished with a solution of bicarbonate potassium (3,93 g) in water (34 ml), stirred for 10 to 15 min, and then were extracted with methylene chloride (2290 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product mixture was chromatographically on a column of silica gel (Merck), elwira mixtures of ethyl acetate and hexane(1:3, 1:2), resulting received 2,427 g of target compound. TLC (ethyl acetate: hexane, 1:1), Rf= 0,37.

d) (IS-CIS)-Hexahydro-8 phthalimido-9-oxo-IH, 5H-pyrazolo [1,2-a] [1,2] diazepin-1-Kurbanova acid, 1,1-dimethylethylene ether

A solution of the product obtained in part (c), (607 mg, 1,43 mm) in dry tetrahydrofuran (12 ml) was cooled to 0oC (ice-salt bath) and treated with 1.0 M DIBORANE/tetrahydrofuran according to the procedure described in example 47, part (a), resulting in a received 528 g of the desired product in the form of syrup. TLC (ethyl acetate: hexane, 1:1), Rf= 0,38.

f) [IS-[ 1, 8 (R*)]]-Hexahydro-8-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-9 - oxo-1H, 5H-pyrazolo [1,2-a] [1,2]diazepin-1-carboxylic acid

(S)-2-(Acetylthio)benzoylpropionate acid obtained from 554 mg dicyclohexylamine salt, as previously described, was dissolved in methylene chloride (11 ml), cooled to 0oC (ice/salt bath) and treated sequentially with a solution of the product obtained in part (e), (350 mg, 1.25 mm) in dry methylene chloride (2.5 ml), triethylamine (0.17 ml, 1,22 mm) and hexafluorophosphate benzotriazol-1-yloxytris dimethylamino of phosphonium (561 mg, 1,29 mm) in sootvetstvii with the procedure in example 47, part (c), which received 400 mg [IS - [ 1, 8 (R*)]]-hexahydro-8-[[2-(acetylthio)-1-oxo-3-phenylpropyl] amino] -9-oxo-IH, 5H-pyrazolo [1,2-a] [1,2] diazepin-1-carboxylic acid 1,1-dimethylethylene ether in the form of syrup. TLC (ethyl acetate: hexane, 1:1), Rf= 2,28.

The solution obtained material embedded in example 47, part (d), resulting in a received target product in the form of solids; []D= -111,5o(C = 0,48, methanol). TLC (ethyl acetate: acetic acid, 95:5), Rf= 0,38.

q) [IS-[ 1, 8 (R*)] ] -Hexahydro-8-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-9-oxo - IH,5H-pyrazolo[1,2-a][1,2]diazepin-1-carboxylic acid

A solution of the product obtained in paragraph (f), in dry methanol was treated with 1.0 N. sodium hydroxide according to the procedure described in example 47, part (d), resulting in a received target product as a white amorphous solid foamy substance: []D= -71o(C = 0,50, methanol). TLC (ethyl acetate: acetic acid, 95:5), Rf= 0,25.

Analysis for C18H23N3O4S 0,13 C5H120,20 H2O:

Calculated: C 57,36; H 6,44; N 10,76; S 8,21

Found: C 57,36; H 6,50; N 10,47; S 8,10.

Example 54.

[IS-[ 1, 8 (R*)] ] -Hexahydro-8-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -5,9 - dioxo-1H, 5H-pyrazolo[1,2-a] [1,2] diazepin-1-carboxylic acid

a) (IS-CIS)-Hexahydro-8-amino-5,9-dioxo-1H, 5H-pyrazolo [1,2-a][1,2] diazepin-1-carboxylic acid, 1,1-dimethylethylene ether

A solution of the product obtained in example 53, part (c), (700 mg, 1.6 mm) in absolute ethanol (7.4 ml) was treated with Hydra who were given 436 mg of the desired product as a white foamy substance. TLC (methylene chloride: methanol, 9:1), Rf= 0,30.

b) [IS-[ 1, 8 (R*)] ] -Hexahydro-8-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -5,9-dioxo-IH, 5H-pyrazolo[1,2-a] [1,2] diazepin-1-carboxylic acid

The product obtained in part (a) was subjected to reaction with (S)- 2-acetylthio)benzoylpropionic acid in the presence of triethylamine and hexafluorophosphate benzotriazol-1-yloxytris(dimethylamino)-phosphine in accordance with the procedure described in example 53, part (f), which was obtained [1S-[1, 8 (R*)]]-hexahydro-8-[[2-acetylthio)-1-oxo-3-phenylpropyl]amino]-5,9 - dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepin-1-carboxylic acid 1,1-dimethylethylene ester in the form of syrup. TLC (ethyl acetate: hexane, 1:1), Rf= 0,22.

This material was treated with anisole, and then triperoxonane acid according to the procedure described in example 53, part (f). The obtained acidic product was dissolved in methanol and treated with 1.0 N. sodium hydroxide in accordance with the procedure of example 53 (g), resulting in a received target product as a white amorphous solid foamy substance; []D= -95,8o(C = 0,72: methanol). TLC (methylene chloride: methanol:acetic acid, 20:1:1), Rf= 0,13.

Analysis for C18H21N

Example 55.

[3S-[1(R*), 3(R*), 7 ] ] -Hexahydro - - methyl-3-[(2-mercapto-1-oxo-3-phenylpropyl]amino]-2-oxo-7-propyl-1H-azepin-1-acetic acid

a) [3S-[1(R*), 3, 7 ]]-Hexahydro- - methyl-3-phthalimido-2-oxo-7-(2-propenyl)-1H-azepin-acetic acid, methyl ester

Allyltrimethylsilane (1,53 ml, 9.6 mm) was added to a solution of [S-(R*,R*)]- hexahydro- - - methyl-3-phthalimido-2-oxo-1H-azepin-1-acetic acid, methyl ether complex (485 mg, 1,48 mm) in methylene chloride (20 ml) at room temperature and in an atmosphere of argon. After adding tin bromide (1.0 M) in methylene chloride (2,52 ml, 2,52 mm), the mixture was stirred for 4 hours Then added another portion bromide tin (1,48) ml and the mixture is stirred for 48 hours, the Reaction mixture was extinguished aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was washed with saline, dried with sodium sulfate, filtered and concentrated, resulting in a received 1.2 g of a yellow residue. The crude acid was dissolved in methanol, cooled to 0oC and was treated with diazomethane to obtain methyl ether complex. Volatiles were removed and the residue was subjected to flash chromatography (silica gel Merck), E3 effects mg of the desired product as a white foamy substance; []D= -13,7o(C = 0,54, methylene chloride).

TLC (ethyl acetate: hexane, 1:1), Rf= 0,50.

b) [3S-[1(R*), 3, 7 ]]-Hexahydro- - -methyl-3-phthalimido-2-oxo-7-propyl-1H-azepin-1-acetic acid, methyl ester

A solution of the product obtained in part (a), (463 mg, 1,24 mm) in a mixture of methanol/methyl acetate (1: 1, 14 ml) was first made 3 h in the presence of 10% palladium charcoal (41 mg). The resulting mixture was filtered through celite, volatiles were removed and received 483 mg of the desired product as a yellow oily product.

c) [3S-[(R*), 3(R*), 7 ]]-Hexahydro- - - methyl-3-[(2-acetylthio)-1-oxo-3-phenylpropyl] amino] -2-oxo-7-propyl-1H - azepin-1 Oksana acid, methyl ester

The product obtained in part (b), (483 mg) suspended in methanol (7 ml) at room temperature and in an atmosphere of argon. The resulting mixture was treated with hydrazine monohydrate (0,07 ml of 1.45 mm), the mixture became homogeneous and stirred for 18 hours the Mixture was filtered to remove the white precipitate and the filtrate was evaporated, treated with methylene chloride, filtered and again evaporated, resulting in a received 282 mg [3S-[1(R*), 3, 7 ]]-hexahydro- - - methyl-3-amino-2-oxo-7-propyl-1H-azepin-1-acetic acid, m is obtained from 491 mg dicyclohexylamine salt, as described previously) was dissolved in methylene chloride (15 ml) at room temperature in the presence of argon. After adding the above amine (282 mg, 1,10 mm) and the mixture was cooled to 0oC and treated with triethylamine to 0.17 ml, 1,21 mm and hexafluorophosphate benzotriazol-1-yloxytris dimethylamino of phosphonium (511 mg, 1,16 mm) in accordance with the procedure described in example 36 part (f), resulting in a received 385 mg of the desired product as a white foamy substance.

TLC (ethyl acetate: hexane, 1:1), Rf= 0,43.

d) [3S-[1(R*), 3(R*), 7 ]]-Hexahydro - - methyl-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2-oxo-7-propyl-1H-azepin - 1-acetic acid.

A solution of the product obtained in part (C), (385 mg, or 0.83 Mm) in methanol (10 ml) was treated with 1 N. sodium hydroxide (8 ml) according to the procedure described in example 36, part (g), resulting in a received 142 mg of the desired product as a white poroshkoobraznogo foamy substance; []D= -51,6o(C = 0,48, methylene chloride ). TLC (1% acetic acid in a mixture (2:1) ethyl acetate/hexane), Rf= 0,60.

Analysis for C21H30N2O4S, 0,14 H2O:

Calculated: C 61,67; H 7,46; N 6,85; S 7,84;

Found: C 61,97; H 7,50; N 6,55; S A 7.62.

P[1,2]diazepine-1-acetic acid

a) [S-(R*,R*)]-2,3,4,5-Tetrahydro-3-[[2-(acetylthio)-1-oxo-3-phenylpropyl] amino]-2-oxo-1H-pyrrolo[1,2-b][1,2]diazepine-1-acetic acid, ethyl ester

(S)-3-Amino-2-oxo-1H-pyrrolo[1,2-b] [1,2] diazepin-1-ukrasni acid ethyl ester, obtained in a known manner ((Bolos and other J.Org. Chem. 57, S. 3535-3339, 1992), were subjected to reaction with (S)-2-(acetylthio) benzoylpropionic acid in the presence of triethylamine and hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium in accordance with the procedure described above in example 36, part (f), resulting in a received target product as a colorless oily substance.

b) [S-(R*, R*)] -2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-2-oxo-1H-pyrrolo[1,2-b][1,2]diazepine-1-acetic acid

A solution of the product obtained in part (a), (135 mg, 0.30 mm) in methanol (2 ml), tetrahydrofuran (1 ml) and water (1 ml) was barbotirovany for 30 min with argon. To this solution at room temperature was added Monohydric lithium hydroxide (50 mg, 1.2 mm). The reaction mixture is stirred for 2 hours, continuing to barbthroat argon, and then acidified by addition of 1M aqueous solution of hydrochloric acid (1.4 ml), after which the mixture was added to 20 ml of water, and then extra in vacuum, the result that was obtained oily substance. This substance was purified using flash chromatography (silica Merck, 1:99 acetic acid:ethyl acetate) and received 115 mg of the target compound as a white foamy solid product; []D= -67o(C = 0,26, methanol), TLC (acetic acid: methanol: methylene chloride, 1:10:90), Rf= 0,43.

Analysis for C19H21N3O4S:

Calculated: C 58,90; H 5,46; N 10,85; S 8,27;

Found: C 58,55; H 5,50; A 10.74 N; S 8,17.

Example 57.

[1S-[1, 9 (R*)] ] -Octahydro-9-[[2-matildico)-1-oxo-3-phenylpropyl] amino]-10 - oxo-6-H-pyridazino [1,2-a][1,2]diazepin-1-carboxylic acid

A solution of the product of example 47 (100 mg, 0,247 mm) in ethanol (1.5 l) and water (0.15 ml) was cooled to 0oC and treated with methylmethanesulfonate (30,5 μl, or 37.4 mg, 0,296 mm). After stirring for 2 h at 0oC and 6 h at room temperature, the reaction mixture was diluted with water and was extracted with a mixture of ethyl acetate and ethyl ether. The organic extract was washed with water and brine, dried with magnesium sulfate and concentrated in vacuo, resulting in a received 157 mg of the crude product. After flash chromatography on 12 g of silica gel (Merck) with elution was first geolocal the purified product. This product is triturated with a mixture of ethyl acetate and hexane, and was received with 85.4 mg of target compound as a white foamy solid product; []D= -104,2o(C = 0,18, chloroform). TLC (hexane: ethyl acetate: acetic acid, 4:4:0,1), Rf= 0,16.

Analysis for C20H27N3O4S 0,05 C4H8O20,01 C6H14:

Calculated: C 54,95; H 6,27; N 9,49; S 14, 48MM;

Found: C 55,03; H 6,22; N 9,49; S 14,40.

Example 58.

[S-(R*, R*)]-2,3,4,5-Tetrahydro-3-[[2-(methylthio)-1-oxo-3 - phenylpropyl] -amino]-2-oxo-1H-benzazepin-1-acetic acid

A solution of the product of example 6 (100 mg, 0,235 mm) in ethanol (1.2 ml) and water (0,112 ml) was cooled to 0oC and treated with methylmethanesulfonate (29 μl, 35.6 mg, 0,282 mm). After 1-hour incubation at 0oC, the reaction mixture was stirred for 8 h at room temperature, after which the mixture was placed overnight in a refrigerator. Then the mixture was diluted with water and was extracted with a mixture of ethyl acetate and ethyl ether. The organic extract was washed with water and brine. Was dried by magnesium sulfate and concentrated in vacuo, resulting in a received 123 mg of the crude product. After flash chromatography on 9 g of silica gel (Merck) with elution was cycloleucine 108 mg of product. This product is triturated with a mixture of ethyl acetate and hexane and received 97 mg of the desired product as white solids; so pl. 83 - 95oC; []D= -185,17o(C = 0.3, and chloroform). TLC (hexane: ethyl acetate: acetic acid, 4:4:0,1), Rf= 0,16.

Analysis for C22H24N2O4S20,84 H2O 0,07 C4H8O20,07 C6H14:

Calculated: C 57,78: H 5,81: N 5,94: S 13,59;

Found: C 57,70: H 6,13: N 6,27: S 13,20.

Example 59.

[S-(R*, R*)] -2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxo-4 - methylpentyl)amino]-2-oxo-1H-benzazepin-1-acetic acid

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

The potassium bromide (9.5 g, 80 mm) was added to a stirred solution of D-leucine (3.0 g, 23 mm) 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 mm), while maintaining the temperature of (-10)-(-5)oC. After complete addition, the reaction mixture was stirred for 1 h then warmed up to room temperature and stirred for another 1 h then the reaction mixture two times were extracted with ether and the ether extracts once washed with water, dried with magnesium sulfate, filtered and vepari the new acid, dicyclohexylamine salt

To a stirred suspension of diacetate potassium (1.7 g, 15.0 mm) in 50 ml of dry acetonitrile at room temperature m in argon atmosphere was added a solution of the product obtained in part (a ), (2.6 g, 13 mm) in 17 ml of acetonitrile. The reaction mixture is stirred for 4 hours, the resulting suspension was filtered and evaporated. The residue was again dissolved in ethyl ether, once washed with 5% potassium bisulfate and once with saline, and then dried with magnesium sulfate and evaporated. The residue was dissolved in ether (64 ml) and treated with dicyclohexylamine (2.7 ml, 14 mm). Immediately after treatment of the solution began to fall a white solid precipitate. This solution was filtered, the white solid precipitate was collected and was obtained 2.0 g of the target product; so pl. 153 - 158oC; []D= -54,5o(=0,61, chloroform).

c) [S-(R*, R*)] -2,3,4,5-Tetrahydro-3-[[2-(acetylthio)-1-oxo- -4-methylpentyl]amino]-2-oxo-1H-benzazepin-1-acetic acid, ethyl ester

Stirred suspension of the product obtained in part (b), (312 mg, 0,840 mm) in 5 ml of ethyl acetate twice, washed with 5 ml portions of a 5% solution of potassium bisulfate. The organic extract was dried with sodium sulfate, filtered, koncentrirovannaya at 0oC in argon atmosphere. To this solution was added a solution of (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H-benzazepin-1-acetic acid ethyl ether complex, obtained in a known manner (Watthey), etc., J. Med. Chem, 28, S. 1511-1516) (142 mg, 0,54 mm) in methylene chloride (3 ml) and then was added triethylamine (80 μl, 0.58 mm) and finally hexafluorophosphate benzotriazol-1-yloxytris (dimethylamino)phosphonium (251 mg, 0,57 mm). After 1 h the reaction mixture was heated to room temperature and stirred for 90 min Obtained colorless solution was evaporated at less than 30oC and the oily residue was again dissolved in ethyl acetate. The resulting solution was once washed with 1M hydrochloric acid, once with water, once with saturated sodium bicarbonate solution and once with brine. The organic layer was dried with magnesium sulfate, filtered and evaporated. After purification using flash chromatography (elution with a mixture (2:5) ethyl acetate/hexane) received 223 mg of the target product; []D= -243,9o(C = 0,62, chloroform).

d) [S-(R*, R*)] -2,3,4,5-Tetrahydro-3- [(2-mercapto-1-oxo-4-methylpentyl)amino] -2-oxo-1H-benzazepin-1-acetic acid

A solution of the product obtained in part (c), (190 ml, 0.44 mm) in 4 ml of methanol was purged 5 min azo is the process of reaction, nitrogen was slowly barbotirovany through the solution. After 1 h the reaction was heated to room temperature and stirred for 1 h Then the reaction was acidified with 5% solution of potassium bisulfate and extracted with ethyl acetate, and the extracts were washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated. After re-evaporation of hexane was obtained a white solid residue. This solid residue was gently heated in ethyl ether, filtered to remove nerastvorimogo oily matter and was led with hexane, resulting in received 117 mg of the desired product as a white oily solid substance; so pl. 143 - 144oC; []D= -224,3o(C= 0,46, chloroform). TLC (ethyl acetate/hexane/acetic acid, 4:4:0,1), Rf= 0,19.

Analysis for C18H24N2O4S 0,02 C4H10O:

Calculated: C 59,34; H 6,67; N 7,66; S 8,76;

Found: C 58,97; H 6,72; N 7,52; S 8,67.

Example 60.

[R - (R*S*)] -2,3,4,5-Tetrahydro-3- [(2-mercapto-2-methyl-1-oxo-phenylpropyl)amino]-2-oxo-1H-benzazepin-acetic acid

a) S,S'-Bis(4-methoxy- - colortool)

A solution of 4-methoxy- - colortool (25 g, 0.16 M) in benzene (200 ml) was added to the carbonate solution is as long until resistant colour of iodine. The reaction mixture is stirred for 15 minutes, after which excess iodine was neutralized by adding solid sodium sulfite (10 g). The reaction mixture was diluted with benzene (200 ml) and distributed, again extragere the aqueous phase further 100 ml of benzene. The combined organic extracts were washed with water (100 ml), 5% sodium sulfite (100 ml) and brine (50 ml), then dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product is recrystallized from ethyl acetate (200 ml) and filtered, washing precipitation cream color with ethyl acetate (25 ml), resulting in a received 16,596 g of the target product; so pl. 99 - 100oC, TLC (methylene chloride: methanol, 9:1), Rf=0,57.

b) - Methyl-hydracarina acid

Solution - methylcatechol acid (10.0 g, 61,7 mm) in dry methanol (250 ml) was treated with 10% palladium charcoal and was first made (using a balloon) at room temperature for 16 hours, the Reaction mixture was diluted with methanol (250 ml), filtered through a pad of celite in millipore.com filter, thoroughly washed specified gasket methanol (2100 ml).

transparent filter, evaporated to dryness and the floor of the ranks acid

The solution Diisopropylamine (1,69 ml, 12.2 mm) in dry tetrahydrofuran (9.0 ml) was cooled to -30oC (in a bath of acetonitrile and dry ice) was treated with 2,5 M utility (4,84 ml, 12,1 mm) and stirred 20 min at -30oC. the resulting solution of diisopropylamide lithium was treated with a solution - methyl-hydrocoritsone acid (1.0 g, 6.1 mm) in dry tetrahydrofuran (1.0 ml), was heated to room temperature and stirred in an argon atmosphere for 1.5 hours Then the reaction mixture was cooled to 0oC (ice-salt bath), treated with a solution of S,S'-bis(4-methoxy- - colortool) (1,869 g, 6.1 mm) in dry tetrahydrofuran (6.0 ml) and stirred 45 min at 0oC in the presence of argon. After this mixture was slowly added to 1.0 N. hydrochloric acid (19,0 ml) and the resulting aqueous mixture was extracted with ethyl acetate (2250 ml). The combined organic extracts were washed with water (15 ml) and brine (15 ml), dried with anhydrous magnesium sulfate, filtered, evaporated to dryness and dried in vacuum. The crude product mixture was chromatographically on silica gel (Merck), elwira mixtures of ethyl acetate and hexane(1:4, 1:2), and then with a mixture of ethyl acetate and acetic acid (100:2), resulting in a received 1.45 g of the target product.

d) [R-(R*SUsna acid, 1,1-dimethylethylene ester and [S- (R*, R*)]-2,3,4,5,tetrahydro-3-[[2-[[(4-methoxyphenyl)methyl] thio] -2-methyl-1-oxo-3-phenylpropyl]amino]-2-oxo-1H-benzazepin-1 - acetic acid, 1,1-dimethylethylene ester

A solution of the product obtained in part (c), (497 mg, 1,57 mm 1,09 EQ.) was cooled to 0oC (ice/salt bath), treated with a solution of (S)-2,3,4,5-tetrahydro-3-amino-2-oxo-1H - benzazepin-1-acetic acid, 1,1-dimethylethylene of ester obtained in accordance with known procedure (Watthey, etc., J. Med. Chem., 28 c. 1511-1516), (417 mg, 1,44 mm) in dry methylene chloride (2.9 ml) and then treated with triethylamine (0.2 ml, of 1.45 ml) and hexafluorophosphate benzotriazol-1-yloxytris dimethylamino of phosphonium (642 mg, 1,45 mm). The reaction mixture was stirred 1 h at 0oC, and then 2.5 h at room temperature, after which the mixture is evaporated to dryness. The resulting syrup was again dissolved in ethyl acetate (50 ml) and the solution was washed with 0.5 G. hydrochloric acid (28,3 ml), water (8,3 ml) and brine (8,3 ml), dried with 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 and hexane (1:4), resulting in a received 709 mg compounds is by Kagel, using as eluent a mixture of ethyl acetate and methylene chloride (1: 99, 2: 98) received 340 mg target [R-(R*S*)]-product; []D= -72o(C = 0,66, methanol); TLC (ethyl acetate:hexane, 1:1), Rf= 0,70 and 316 mg target [S-(R*, R*)]-product; []D= -142o(C = 0,5, metasol); TLC (ethyl acetate: hexane, 1:1) Rf=0,87.

e) [R- (R*S*)] -2,3,4,5-Tetrahydro-3- [(2-mercapto-2-methyl-1-oxo-3-phenylpropyl)amino] -2-oxo-1H-benzazepin-1-acetic acid

The solution (R-, R*S*) product from part (d) (300 mg, 0.51 mm) in triperoxonane acid (2.5 ml) was cooled to 0oC (ice-salt bath), treated with anisole (0.25 ml, 2.3 mm) and trifluromethanesulfonate acid (0,13 ml of 1.47 mm) and stirred at 0oC in the presence of argon for 2.5 hours the Reaction mixture was evaporated to dryness, viparita residual syrup from ethyl acetate (215 ml) and dried in vacuum. The crude product mixture was chromatographically on a column of silica gel (Merck), elwira with ethyl acetate and a mixture of ethyl acetate and acetic acid (100:2). The first batch of the desired fractions were combined and distributed between ethyl acetate and 1.0 G. hydrochloric acid, resulting in a received 91,0 mg of the crude product. This product was combined with the second batch of the desired fractions, which were also separately chromatographical impurities. After re-chromatography on the third column of silica gel with elution with a mixture of toluene: acetic acid, 6:1 received 156 mg of pure desired product as a solid foamy substance; []D= -248,3o(c = 0,73, methanol). TLC (toluene: acetic acid: 5:1), Rf= 0,23.

Analysis for C22H24N2O4S 0,21 C6H140,54 H2O:

Calculated: C 63,82; H of 5.85; N 6,40; S 7,32;

Found: C 63,82; H 6,14; N 6,21; S 7,16.

Example 61.

[S-(R*, R*)]-2,3,4,5-Tetrahydro-3-[(2-mercapto-2-methyl-1-oxo-3 - phenylpropyl)amino]-2-oxo-1H-benzazepin-1-acetic acid

A solution of [S-(R*, R*)] the product of example 60, part (d) (316 mg, 0,54 mm) in triperoxonane acid (2,63 ml) was cooled to 0oC and was treated with anisole (of 0.26 ml, 2.30 mm) and triftormetilfullerenov acid (0,14 ml, 1,58 mm) in accordance with the procedure described in example 60, part (e), resulting in a received 209,8 mg of target product; []D= -123o(c = 0,48, methanol). TLC (toluene: acetic acid 5:1), Rf= 0,35.

Analysis for C22H24N2O4S 0,4 C6H14:

Calculated: C 64,22; H 5,95; N OF 6.73; S 7,70;

Found: C 64,38; H Is 6.19; N 6,27; S 7,05.

Example 62.

[3R- [3, 6(S*), 9] ]-Octahydro-6-[(UP>), 9] ]-Octahydro-6-[[2-(acetylthio)-1-oxo-3 - phenylpropyl] amino] -5-oxadiazole[3,2-a] azepin-3-carboxylic acid 1-oxide, methyl ester

A solution of the product of example 11, part (f), (301 mg, 0.67 mm) in chloroform (9,5 ml) was cooled to 0 to 5oC. To this solution was added a solution of meta-chloroperoxybenzoic acid (137 mg, 0,79 mm) in chloroform (7 ml). The reaction mixture was stirred at 0oC in the presence of nitrogen. After 1 h, TLC showed no starting material. The reaction mixture was diluted with chloroform (66 ml), washed with diluted sodium bicarbonate (213 ml) (pH 10), water (27 ml) and was dried with sodium sulfate. Then the mixture was filtered and concentrated in vacuo, resulting in a received foamy solid. This solid was subjected to flash chromatography on silica gel [Merck (30 ml) using a mixture of ethyl acetate and acetonitrile (95:5) (400 ml)] and received 263 mg of the desired product in the form of a 55: 45 mixture of diastereoisomers (R,S - mixture of sulfoxide). TLC (ethyl acetate:acetonitrile, 95:5), Rf= 0,23.

b) [3R- [3, 6(S*), 9] ]-Octahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]- 5-oxadiazole[3,2-a]azepin-3-carboxylic acid 1-oxide

A solution of the product obtained in part (a), (263 mg, 0.56 mm) in methanol (3.4 ml), desoxypeganine by ozonation of argon, and the clear solution stirred at room temperature and in the presence of argon. After 2 h TLC showed no starting material. The solution was acidified with 10% potassium bisulfate (12.5 ml), diluted with water (17 ml) and was extracted with ethyl acetate (360 ml). An ethyl acetate extract was washed with water (25 ml), brine (50 ml) and dried with sodium sulfate. After filtration and concentration was obtained oily residue. This residue was treated with hexane and ethyl ether, and received solid (230 mg). The obtained solid was subjected to flash chromatography on silica gel (Merck, 50 ml) using a mixture of ethyl acetate/acetonitrile/acetic acid (50:50:6-7, 600 ml) and received 142 mg of a solid product. This substance (142 mg) was dissolved in methanol (2 ml) and was diluted with ethyl acetate (25 ml). Then the solution was washed with 10% potassium bisulfate (3 ml, pH 2) and diluted with water (8 ml). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (310 ml). United an ethyl acetate extract was washed with water (5 ml), brine (5 ml), dried sodium sulfate, filtered and concentrated, resulting in the obtained oily residue. After trituration of the residue with ethyl acetate/ethyl ether, received 102 mg zelenog (ethyl acetate/acetonitrile/acetic acid), Rf= 0,26.

Analysis for C18H22N2O5S20,56 H2O:

Calculated: C 51,48; H 6,62; N OF 6.49; S 14,87;

Found: C 51,32; H Of 5.34; N 6,74; S 14,50.

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

Inhibitory activity against angiotensinase enzyme (ACE) inhibitors was determined in accordance with the known method (Cushman et al., Biochem. Pharmacol., so 20, S. 1637-1648 (1971)). As the source of enzyme extract was used rabbit lung and recorded the rate of formation of the hippuric acid from the substrate hippuris-L-histidine-L-leucine (HHL). After 30 min incubation of test compounds with the enzyme and substrate reaction was stopped by adding HCl. Added ethyl acetate. The ethyl acetate layer was removed and evaporated to obtain a dry product, formed hippuric acid was again dissolved in water and spectrophotometrically determined its concentration. Defined concentration of test compound which inhibited the reaction by 50% (IC50).

Activity against neutral endopeptidase kidney (NEPP) was determined by comparing it with purified neutral endopeptidase kidney rats using fluorometric analysis. th is extracted from the mixture, acidified ethyl acetate and is a strong fluorescent. The test compound is pre-incubated for 10 min with an enzyme preparation before starting the reaction by addition of the substrate. After 30 min incubation the reaction was stopped by adding HCl. Dis-Gli was extracted into ethyl acetate. The relative fluorescence intensity of the extract was measured using a spectrometer. Defined concentration of test compound which inhibited the reaction by 50 % (IC50) ( see table).

Was determined inhibitory activity in vivo in relation to the PFA in accordance with the modification of a known method (Rubin et al., J. Pharmacol. Exsper., so 204, S. 271-280 (1978)). The male rats Sprague-Dawley was established catheters in the abdominal aorta and Vena cava. Two weeks or more in generalizirovanny rats produced fixation blood pressure in the aorta direct way. Pressor response to on/injections of angiotensin 1 (A1) at a dose of 310 mg/kg was obtained before (control) and with 2-30 min intervals up to 6 h after intravenous introduction of the test compounds. For each interval was determined by the inhibition of the Pressor response to A1 (% change compared to control). The curve of response to dose is built using the point in time after whether by interpolation.

Test-connection - Pressor A1/ED50< / BR>
1 - 3,96

2 - 0,143

5 - 0,517

6 - 0.020

9 - More than 5

10 - 0,838

11 - 0,071

12 - 0,799

13 of 5.84

14 - 0,262

15 - 1,22

17 - 4,4

18 - 0,49

20 - More than 1.5

21 - Less than 1,5

26 - 0,27

31 - 1,2

32 - 0,015

33 - 2,14

35 - 0,12

36 - 0.04

37 - 0,06

42 - 0,27

43 - 0,33

44 - 1,34

45 - 13,3

48 - 0,13 (short duration)

50 - 0,06

51 - 0,08

52 - 0,025 (good length)

55 - 0,12

59 - 0,28 (good length)

62 - 0,11

Example 63. 1000 tablets, each of which contained the following ingredients:

[S-(R*, R*)-2,3,4,5-Tetrahydro-3-[(2-mercapto-1-oxo-3 - phenylpropyl)amino]-2-oxo-1H-benzazepin-2-acetic acid - 200 mg

Corn starch 100 mg

Gelatin 20 mg

Avicel (microcrystalline cellulose), 50 mg

Magnesium stearate - 5 kg 375 mg

received from sufficient bulk quantities by mixing the product of example 6 and corn starch with an aqueous solution of gelatin. The resulting mixture was dried and crushed to obtain a fine powder. Then to the mixture was mixed with avicel, and then the magnesium stearate and the mixture was granulated. After that, the mixture was pressed into tablets (1000 tablet the tablet, containing 200 mg of the product obtained in accordance with the procedure described in any of examples 1-5 and 7.62 self.

A similar procedure can be used to obtain tablets or capsules, containing 50 to 500 mg of active ingredient.

1. Heterocyclic nitrogen-containing carboxylic acid derivatives of General formula I

< / BR>
and their pharmaceutically acceptable salts,

where R1represents a hydrogen atom, a group R18-S-;

R2and R19independently from each other selected from hydrogen, C1-C7the alkyl group, the aryl -(CH2)m- where aryl represents phenyl or naphthalenyl, and group heteroaryl -(CH2)m- where heteroaryl means thienyl;

n is 0 or 1;

m is 0 or an integer from 1 to 6;

R3represents a C1-C7-alkyl, aryl -(CH2)m- where aryl represents phenyl;

R18represents a C1-C7-alkyl;

X1choose from a range that contains a group of General formula III

< / BR>
where R4and R5represent a hydrogen atom; R6and R7independently from each other represent a hydrogen atom, a C1-C7-alkyl, possibly substituted hydro is value;

q is 2 or 3;

a group of General formula IV

< / BR>
where R6and R7, R8and R9independently from each other represent a hydrogen atom or phenyl -(CH2)m-, where m is the specified value;

s = 0;

r = 1;

a group of the General formula V

< / BR>
where R6and R7independently from each other represent a hydrogen atom or phenyl -(CH2)m-, where m is the specified value;

s = 0;

t = 1;

a group of the General formula VI

< / BR>
where R6and R7independently of one another denote a hydrogen atom and C1-C7-alkyl;

Y1denotes an oxygen atom, sulfur or the group-CH2- and-CH2-CH2-;

a group of General formula VIII

< / BR>
where R6and R7is hydrogen;

a group of General formula IX

< / BR>
where Y2denotes a sulfur atom or the group-CH2and

v is 1 or 2;

w is 1 or 2;

a group of General formula XI

< / BR>
where Z represents an oxygen atom or two hydrogen atoms;

v is 1 or 2;

a group of General formula XII

< / BR>
where Z represents an oxygen atom or two hydrogen atoms;

R17stands WITH1-C7-alkyl;

a group of General formula XIII

< / BR>
where Y3means g is UGA denote a hydrogen atom WITH1-C7-alkyl or phenyl -(CH2)m-, where m is the specified value;

R12denotes a hydrogen atom;

b is 0 or 1.

2. Derivatives under item 1, where R1represents a hydrogen group and R18-S-; R3represents a C1-C4-alkyl or phenyl; R18represents a C1-C4-lower alkyl; n = 0 or 1; R2represents aryl-CH2- where aryl represents phenyl or naphthalenyl, heteroaryl-CH2- where heteroaryl denotes thienyl1-C7-alkyl; R19represents hydrogen.

3. Derivatives under item 2, where X1has the formula III and q = 2; R4represents hydrogen; R5represents hydrogen; R6and R7both represent hydrogen or methyl, or R6represents a C1-C4-alkyl, C1-C4-alkyl, monosubstituted by hydroxy-group, or WITH3-C5alkenyl having one double bond, and R7represents hydrogen; or R6and R7taken together with the carbon atom to which they are bound, form a3-C5-cycloalkyl; R10and R11are both hydrogen or one is hydrogen and the other WITH8represents hydrogen, phenyl; R9represents hydrogen; R6and R7both are hydrogen, or R6represents phenyl, and R7represents hydrogen; R10and R11are both hydrogen or one is hydrogen and the other is a C1-C4is lower alkyl; b = 0, R12is hydrogen; or X1has the formula V and s = 0, t = 1; R6and R7both are hydrogen, or R6is phenyl, and R7is hydrogen; R10and R11are both hydrogen or one is hydrogen and the other is a C1-C4is lower alkyl; b = 0; and R12is hydrogen; or X1has the formula VI, and Y1= O, S, or CH2; R6and R7both are hydrogen, or R6is1-C4-lower alkyl, and R7is hydrogen; R10and R11are both hydrogen or one is hydrogen and the other is a C1-C4is lower alkyl; b = 0; and R12is hydrogen; or X1has the formula VIII and R6and R7both are hydrogen; R10and R11are both hydrogen or one is hydrogen and the other I had Lu IX and v is 1 or 2; w is 1 or 2; Y2is S or CH2and R12is hydrogen; X1has the formula XI and v is 1 or 2; Z is O or two atoms of hydrogen and R12is hydrogen; or X1has the formula XII, and Z is O or two hydrogen atoms; R17is (C1-C4)lower alkyl; R10and R11are both hydrogen or one is hydrogen and the other is a C1-C4is lower alkyl; b is zero and R12is hydrogen.

4. Derivatives under item 3, where R1is hydrogen; n is zero; R2represents benzyl, (2-thienyl)methyl, or straight or branched alkyl with 1 to 5 carbon atoms.

5. Derivatives under item 4, where X1has the formula III and q is 2; R4and R5both are hydrogen; R6or R7both are stands, or R6is propylene, allyl or 2-hydroxyethyl and R7is hydrogen, b = 0, R10and R11are both hydrogen or one is hydrogen and the other is stands; and R12is hydrogen; or X1has the formula IV and r = 1; b = 0; s = 0; R8is hydrogen or phenyl; R6or R7both are hydrogen, or R1has the formula V, s = 0; t = 2; R6is phenyl, and R7is hydrogen; b = 0 and R10, R11and R12are all hydrogen; or X1has the formula VI, Y1is CH2; b = 0 and R6, R7, R10, R11and R12are all hydrogen; or X1has the formula IX and v = 2; w = 1 or 2; Y2is S or CH2; and R12is hydrogen; or X1has the formula XI and v = 2; Z represents two hydrogen atoms, and R12is hydrogen.

6. Derivatives under item 1, chosen from:

[S-(R*, R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxohexyl)-amino]-2-oxo-1H-benzazepin-1-acetic acid;

[S-(R*, R*)] -2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-4-methylpentyl)amino] -2-oxo-1H-benzazepin-1-acetic acid; [S-(R*, R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -2-oxo-1H-benzazepin-1-acetic acid; [1S-[1, 9(R*)]]-octahydro-9-[-(2-mercapto-1-oxo-3-(2-thienyl)propyl)amino] -10-oxo-6H-pyridazino[1,2-a] [1,2]diazepin-1-carboxylic acid; [1S-[1, 9(R*)]]-octahydro-9-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -10-oxo-6H-pyridazino[1,2-a] [1,2]-diazepine-1-carboxylic acid; [1S-[1, 9(R*)] ] -octahydro-9-[(2-mercapto-1-oxo-3-phenylpropyl)amino) - Rev.-3-phenylpropyl)amino] -6-occupied[1,2-a]azepin-4-carboxylic acid; [3R-[3, 6(S*), 9a] ] -octahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -5-oxadiazol[3,2-a] azepin-3-carboxylic acid; [3S-[1(R*), 3(R*), 7]]-hexahydro--methyl-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -2-oxo-7-propyl-1H-azepin-1-acetic acid; [6(S)] -hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropylamine] -2,2-dimethyl-7-oxo-1H-azepin-1-acetic acid; [3S-[3( R*), 7] ]-hexahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2-oxo-7-propyl-1H-azepin-1-acetic acid; and [3S-[3(R*), 7]]-hexahydro-3-[(2-mercapto-1-oxo-3-phenylpropyl)amino] -2-oxo-7-(2-propenyl)-1H-azepin-1-acetic acid.

7. Pharmaceutical composition having activity of inhibiting angiotensin converting enzyme and inhibiting neutral endopeptidase, characterized in that it contains nitrogen-containing heterocyclic carboxylic acid derivatives or their pharmaceutically acceptable salts under item 1 and a pharmaceutically acceptable carrier.

8. The method of obtaining nitrogen-containing heterocyclic carboxylic acid derivatives of General formula

< / BR>
where R1, R2, R19X1and n are defined in paragraph 1,

wherein if R1is hydrogen or R19is hydrogen, allergizatsiya with an intermediate compound of formula XV

H - X1,

resulting in a product of formula XVI

< / BR>
where R12in the definition of X1is easily removable ester protecting group,

and then remove the acyl group and an ester protective group, R12.

 

Same patents:

The invention relates to new derivatives of N-acyl-2,3-benzodiazepine General formula [I]

< / BR>
in which R is C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkylamino, di(C1-4alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s), or R is a benzoyl, cyclopropanecarbonyl, C1-5-carbarnoyl or phenylcarbamoyl group, or R is absent when the N(3) and C(4) atoms there is a double bond, R1represents a hydrogen atom, or R1no, when between N(3) and C(4) atoms there is a double bond, R2represents C1-3alkyl, or R1and R2together represent a methylene group, and between the N(3) and C(4) atoms, no double bond, R3means a hydrogen atom or a C1-4-aliphatic acyl group, R4represents a hydrogen atom, a C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkyl-amino-, di (C1-4alkyl) amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen (s), and benzoyl, Palmitoyl, cyclo who can present valence bonds, provided that, when both of the substituent R3and R4represent hydrogen atoms between the N(3) and C(4) atoms, no double bonds, as well as the stereoisomers of these compounds along with acidic salts accession (when possible) and pharmaceutical compositions containing these compounds

The invention relates to a new derived 5H-2,3-benzodiazepine of the formula (I), namely 1-(3-chlorophenyl)-4-oxymethyl-7,8-dimethoxy-5H-2,3-benzodiazepine and its salts accession acid formula

< / BR>
(I)

Known derived 5H-2,3-benzodiazepine, namely 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Grandaxin) (Patent Hungary N 155572, U.S. patent N 3736 315) affecting the Central nervous system
The invention relates to a method for blocked e-caprolactam toluylene diisocyanate (mixture of 2,4 - and 2,6-isomers in a ratio of 80:20 or 65:35), the melt which is granulated below the temperature of dissociation of the product to the original substance

The invention relates to 6-oxo-asiminoaei compounds, namely to new derivatives of 6-oxo-3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indole with, if necessary, in the 3rd or 4th position of the skeleton of the ring substituted aminoalkyl balance, and their acid salts of accession, and to pharmaceutical preparations containing these compounds, process for the preparation of these compounds and intermediates for their production

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

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

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

CHY5ororwhere Y3, Y5have the specified values;

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

The invention relates to medicine, specifically to pharmacology
The invention relates to pharmaceutical industry and relates to the creation of new dosage forms in the form of ointments with photosensitizers that may be used in medical practice, in particular when conducting photodynamic therapy

The invention relates to the compound of formula (I):

< / BR>
where

Ar is chosen from the group including

(a) phenyl, naphthyl and diphenyl, each of which optionally contains from one to three substituents selected from the group including:

C1-4alkyl, C1-4halogenated, C1-4hydroxyalkyl, C1-4alkoxy, C1-4halogenoalkane, C2-4alkoxyalkane, C1-4alkylthio, hydroxy, halogen, cyano, amino, C1-4alkylamino, di (C2-8) alkylamino, C2-6alkanolamine, carboxy, C2-6alkoxycarbonyl, phenyl, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano group or halogen, phenoxy, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen; phenylthio group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halog is selected from the group including C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen;

(b) furyl, benzo (b) furyl, thienyl, benzo/b/thienyl, pyridyl and chenail, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, halogen, C1-4alkoxy, hydroxy, phenyl, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano or halogen, phenoxy group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano group and halogen; phenylthio group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen

The invention relates to new derivatives of 1,4-diazepine and their pharmacologically acceptable salts, methods for their production and pharmaceutical applications

The invention relates to derivatives of 2, 3, 4, 5-tetrahydro - 1,4-benzothiazepine, containing pharmaceutical compositions, and methods for their preparation and to their use in the treatment of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors means to prevent such painful conditions as paralysis

The invention relates to compounds of formula (1)

< / BR>
in which

R1is a hydrogen atom;

R2is a hydrogen atom, (C3-C12) alkenylboronic, (C3-C12)cycloalkylcarbonyl, (C3-C12)cycloalkylcarbonyl, (C3-C12)alkylcarboxylic, (C3-C12)cycloalkyl (C1-C12)alkylcarboxylic, pyridyloxy, morpholinoethoxy or tetrahydropyranyloxy, halogen(C1-C6)alkylsulfonate, (C1-C6)alkylsilane;

R3is a hydrogen atom or halogen;

R4is a hydrogen atom or a (C1-C6)alkyl, or geometric, optical or stereoisomers, or pharmaceutically acceptable additive salts, which are useful for the treatment of various memory disorders characterized by a decrease cholinergic function such as Alzheimer's disease

The invention relates to novel 4,5-dihydro-1H-2,4-allowin the benzodiazepines and benzodiazipine appropriate diamines and aminoamides, to methods for their preparation and to methods and compositions for treating arrhythmia in mammals with said 4,5-dihydro-1H-2,4-ariovich of benzodiazepines and benzodiazipines
The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to a method of obtaining a tablet form of the drug
The invention relates to medicine, gynecology

The invention relates to medicine, in particular to rheumatology, and for the treatment of arthritis
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