Derivatives of amino acids

 

(57) Abstract:

Derivatives of amino acids of formula I, where R1is hydrogen or acyl; R2is hydrogen, lower alkyl, cycloalkyl, phenyl, possibly substituted by alkoxyl, halogen, phenyl or alkylsulfonamides, or thienyl, possibly substituted with halogen, m and n is an integer 0, 1 or 2; J is a group of formula (a-D), where R3is hydrogen or carboxyamide group; R4hydrogen, Y2group-CH2-, -S - or-O-; R10is hydrogen or phenyl; R11, R12is hydrogen, lower alkyl; R13is phenyl or a group-HSO2R18, R18is hydrogen or lower alkyl; R14, R15is hydrogen; or their pharmacologically acceptable salts have an inhibitory activity against angiotensin 1-converting enzyme. 32 C.p. f-crystals, 8 PL.

The present invention relates to a derived amino acids. More specifically, it relates to a derived amino acids, exhibiting excellent effects as drugs.

Description of the prior art

Among the diseases of the heart, commonly called heart failure, for ourselves is not only deadly acute heart failure, but also disease, Nona progresses. So for a long time actively conducted research medicines for the treatment of this disease, and now has developed a large number of drugs with different mechanisms of action to treat heart failure.

For example, cardiac glycosides represented by digitalis, have long been used as medicines that can increase the strength of cardiac contractions and the limits of tolerance without increasing heart rate. However, these cardiac glycosides have disadvantages such as the fact that each of them has a narrow field of security and can be assigned only to a limited number of patients. In addition, they show some side effects, such as causing the arrhythmia, which makes them less useful.

To facilitate hemostasis caused a small heart weakness, sometimes used diuretics, such as furosemide and spironolactone. Although these drugs have a positive quality that they are applicable in the case of a weak heart failure and reduce subjective symptoms, their disadvantage is the manifestation of side effects, for example, electrolytic disorders and metabolic disorders blood sugar, and they are directly the operating funds for the improvement of blood flow in coronary vessels are also used nitrates, such as isosorbidedinitrate, and agents blocking the receptors, presents bunazosin and prazosin. Although the first widely used since then, as has been characterized as debilitating pre-load and improves subjective symptoms and the limits of tolerance, showing an immediate action and do not have serious side effects, it has the disadvantage as the tendency to easy tolerantnosti. On the other hand, the latter is characterized by the weakening of both the preliminary and subsequent load (preload and postload) and increased heart rate. However, it was reported that these agents have no effect on the improvement of subjective symptoms or the limit of tolerance.

In addition, the known-stimulating drugs, such as dopamine and dobutamine, each having a significant effect on increasing heart sacramenti, as the primary tools in the provision of emergency assistance in the case of acute heart failure. However, these drugs tend to be tolerant and sometimes cause arrhythmia and so on, we also Know that they have some side effects inducyruya, such as diseases of the myocardium. Therefore, you must use ostore theoretical peptide hydrolases (neutral endopeptidase: NEP 24, II) and inhibitors of angiotensin 1-converting enzyme (hereinafter referred to reduce ACE) as new drugs for the treatment of heart failure.

The above trially naturethese peptide (hereinafter referred to reduction ANP) is a hormone found in nature. In addition to strong odnovremenno/natriuretic effect vasodilator effect, and so on, he has a depressive effect on the release norepinephrine by suppressing the sympathetic nervous system, the inhibitory effect on the secretion of renin from the kidneys and the inhibitory effect on the secretion of aldosterone from the adrenal gland and, further, has also an inhibitory effect on perfusion by increasing water permeability in Vienna, etc., In relation to the functions of ANP in patients suffering from congestive heart failure with increased preload, for example, is considered, the secretion of ANP increases in proportion to the stimulation trialnet by drawing and the quantity traded in the body of the thread thus compensating controlled. Indeed, the introduction of ANP patients with heart failure lowers blood pressure, pulmonary wedge, and observed the e, it was reported that ANP inhibits the release of endogenous hormones, promote the blood circulation in heart failure, for example, aldosterone, norepinephrine weaken pathological condition in heart failure with different angles of view. Is considered that these actions of ANP are preferred in the treatment of not only heart failure, and hypertension.

Due to the fact that ANP is a peptide, it cannot be administered orally and has only a weak metabolic stability, which creates the problem that at present it can be used clinically only in acute condition. It was also reported that the effect of ANP may deteriorate during prolonged administration. Thus, it should be used cautiously.

Considering the above characteristics of ANP, it is necessary to pay much attention to the above inhibitor, ANP hydrolases (hereinafter referred to in abbreviated form the NEP inhibitor) as an ANP-associated receipt for oral administration. It was reported that the purpose of the NEP inhibitor to a patient with heart failure increases the level of ANP in the blood and provides naturethese effect.can clearly demonstrate actions to reduce preload and postload (pre-and post-loading).

On the other hand, has been proven the usefulness of the ACE inhibitor, which is one of vasodilators, because it inhibits the formation of angiotensin II (hereinafter referred to in abbreviated form AI-II), which is an additional factor of heart failure through this significantly improves the degree NY HA and increases the limit of tolerance in chronic heart failure, and, thus, shows lengthening the life of the action. However, the effective ratio of available ACE inhibitors in patients is not always high and their effectiveness varies considerably from patient to patient. Besides, there is such a problem that ACE inhibitors have side effects, such as hypotension, which limits their use for those who suffer from reduced kidney function.

As discussed above, each of the existing inhibitors of NEP and ACE limited in application, although they have attracted attention as new drugs for the treatment of heart failure. Therefore, there is urgent need for a drug with both the NEP inhibitory activity and ACE inhibitory activity.

The present invention relates to an amino acid derivative of General formula 1, as well as pharmaceutical compositions containing a therapeutically or prophylactically effective amount of an amino acid derivative of General formula I or its pharmaceutically acceptable salt and pharmaceutically acceptable filler:

< / BR>
where R1represents a hydrogen atom or acyl group;

R2represents a hydrogen atom, a lower alkyl group, cycloalkyl group, arylalkyl group which may have a Deputy, or heteroallyl group which may have a Deputy, aryl group which may have a Deputy, or heteroalkyl group which may have a Deputy;

m and n represent each independently an integer of 0, 1 or 2; and

J represents a cyclic group having the, bladaya ACE inhibitory activity, as presented in the definition of J above formula (I) includes any group with ACE inhibitory activity, and which is saturated or unsaturated monocyclic or condensed ring. Specific examples include, but are represented by the following formula, however, is not limited to it

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where R3represents a hydrogen atom or a carboxy-protective group;

Y1refers to a group represented by the formula -(CR5R6)p-Z-(CR7R8)q- [where R5, R6, R7and R8are the same or different and each denotes a hydrogen atom, a lower alkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy or heteroalkyl group which may have a Deputy;

Z denotes a group represented by the formula -(CH2)r- (where r denotes an integer of 0 or 1), a group represented by the formula-S-, a group represented by the formula-SO-, a group represented by the formula-SO2-, a group represented by formula-O - or a group represented by the formula-NR5, R6, R7, R8and R9have an arbitrary Deputy selected from R5to R9attached to the same, adjacent to each other, the two carbon atoms and the two Deputy, attached thereto, can be connected with the formation of a benzene ring or heterocyclic ring which may have a Deputy; and that, when R2is an aryl group, p is 2, q is 2, Z represents a group represented by the formula -(CH2)r'- (where r' is 0) and two Deputy, randomly selected from R7'and R8'that are attached to two adjacent carbon atoms, together with the formation of the benzene ring, the indicated benzene ring must be substituted by an aryl group which may have a Deputy];

R4represents a hydrogen atom or a group that is used for the formation of 5 - to 7-membered ring which may contain one sulfur atom or oxygen in combination with R7or R8.

For further understanding of the present invention will hereinafter be presented specific examples of compounds according to the present image is SUP> represents a hydrogen atom or acyl group;

R2represents a hydrogen atom, a lower alkyl group, cycloalkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy;

R3represents a hydrogen atom or carboxyamide group;

R11and R12are the same or different from each other and each represents a hydrogen atom or a lower alkyl group;

u is 0, 1 or 2;

R19represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, hydroxyl group or halogen atom;

m and n represent each independently an integer of 0, 1 or 2;

R14and R15represent each a hydrogen atom, a lower alkyl group, lower alkoxygroup, hydroxyl group, halogen atom, aryl group which may have a Deputy or heteroaryl group, which may have a Deputy;

s and t are each an integer 0, 1 or 2;

Y9refers to a group represented by the formula -(CH2)w- (where w denotes an integer of 0 or 1), a group represented by the formula-S-, a group, before the polyurethane foam, represented by the formula-NR17- (where R17denotes a hydrogen atom or a lower alkyl group);

R10represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, hydroxyl group, halogen atom, aryl group which may have a Deputy, or a heteroaryl group which may have a Deputy;

Y4refers to a group represented by the formula -(CH2)x- (where x denotes an integer of 0 or 1), a group represented by the formula-S-, a group represented by the formula-SO-, a group represented by the formula-SO2-, a group represented by formula-O - or a group represented by the formula-NR17- (where R17denotes a hydrogen atom or a lower alkyl group); and

R18represents a hydrogen atom, a lower alkyl group, or aracelio group which may have a Deputy.

According to the present invention, the lower alkyl group, given in the definition of R2, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16, R17, R18and R19implies a linear or branched alkyl group having from 1 to 8, preferably from 1 to 6, carbon atoms. It priizobilno group, second-boutelou group, tert-boutelou group, pentelow (amylou) group, isopentyl group, neopentyl group, repentigny group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexoloy group, sexyloo group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyloxy group, etc. are Preferred examples include methyl group, ethyl group, through the group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group and isopentyl group. As R2in particular isobutylene groups, particularly preferred s-isobutylene group, it is possible to note 1(S)-methylpropyl group.

Lower CNS group, as it is given in the definition of R10, R13ethoxy, isopropoxy, n-butoxy, tert-butoxy etc.

As for the aryl group which may have a Deputy, as given in the definition of R2, R5, R6, R7, R8, R10, R14and R15, examples of the aryl can be phenyl, 2-naphthyl, 3-naphthyl, anthracene etc.

The Deputy in this case, it may imply a lower alkyl group such as methyl group, ethyl group, through the group of the isopropyl group, a lower CNS group such as a methoxy group, ethoxypropan, propoxylate and isopropoxy, aryl group, arylalkyl group, heteroaryl group, heteroallyl group, nitro group, hydroxyl group, amino group which may be mono - and di-substituted, acyl group such as formyl group or acetyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, karbamoilnuyu group, thiol group, allylthiourea, sulfonyloxy group, sulfonyloxy group, alkylsulfonyl group, alkylsulfonyl group, halogen atom, carboxyl group which may be protected, carboxialkilnuyu group which may be protected, arylalkyl group that the chalking R2, R5, R6, R7, R8, R10, R14and R15that means from a 3 - to 8-membered, preferably 5 - or 6-membered ring or condensed ring containing at least one heteroatom such as oxygen atom and a nitrogen atom.

Concrete examples include thienyl, furanyl, pyranyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, isothiazolin, isoxazolyl, furutani, benzothiazyl, isobenzofuranyl, bromanil, indolizinyl, isoindolyl, indolyl, purinol, hinolinol, ethanolic, hinely, phthalazine, chinadoll, carbazolyl, acridines, phenanthridines etc.

In this case, the substituent has the same meaning as for aryl, as described above.

As for arylalkyl group which may have a Deputy, as given in the definition of R2, R5, R6, R7, R8and R18the aryl may have the same meaning as the aryl described above.

In this case, the alkyl has the same meaning as the lower alkyl described above. Further, the substituent in this case has the same values as the Deputy for the aryl group as described above.

As for the heteroaryl group, Kotor is e same values as heteroaryl described above. 3-naphthyl, anthracene etc.

In this case, the alkyl has the same meaning as the lower alkyl described above. Further, the substituent in this case has the same values as the Deputy for the heteroaryl group as described above.

Halogen atom, as it is given in the definition of R10, R13, R14, R15and R19means fluorine atom, chlorine atom, bromine atom, iodine atom, etc.,

Carboxyterminal group, as it is given in the definition of R3means such that can be subjected to hydrolysis to the carboxylic group in vivo. Examples include lower alkyl groups such as methyl, ethyl and tert-butyl; a lower alkyl group, a substituted phenyl group which may have a Deputy, such as p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl and 2-Iodate; lower alkanoyloxy lower alkyl groups, such as pivaloyloxymethyl, acetoxymethyl, propionylacetate, butyraldoxime, valerolactone, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxymethyl and 2-pivaloyloxymethyl; the highest alkanoyloxy lower alkyl group is a lower alkyl group, such as methoxycarbonylmethyl, 1-butoxycarbonyloxyimino and 1-(isopropoxycarbonyl)ethyl; carboxy lower alkyl groups such as carboxymethyl and 2-carboxyethyl; heterocyclic groups such as 3-phthalidyl; benzoyloxy lower alkyl group which may have a Deputy, such as 4-glycidoxypropyl and 4-[N-(tert-butoxycarbonyl)glycolate] benzoyloxymethyl; (substituted dioxolene) lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolane-4-yl)methyl; cycloalkyl-substituted lower alkanoyl lower alkyl groups such as 1-cyclohexylacetate; and cycloalkylcarbonyl lower alkyl groups such as 1-cyclohexyloxycarbonyloxy.

Acyl group, as given in the definition of R1includes aliphatic and aromatic acyl groups derived from heterocyclic groups, for example, lower alcoholnye groups such as formyl group, acetyl group, propylaniline group, Butyrina group, valerina group, isovaleryl group and pivellina group, arolina group, such as benzoline group, colurella group and napolina group, heteroaryl group, such as frolina group, nicotine is mile group, acetyl group, benzoline group, etc.

As examples of pharmacologically acceptable salts of the present invention can be specified inorganic salts such as hydrochloride, sulfate, hydrobromide and phosphate, and organic acid salts such as formate, acetate, triptorelin, maleate, fumarate, tartrate, methanesulfonate, bansilalpet and toluensulfonate.

Compounds of the present invention exist in the form of various stereoisomers defined by their structure. It is necessary to say that each of them is included in the scope of the present invention.

The preferred compounds of the compounds of the present invention can specify the following compounds of General formula VII

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Although these compounds is optical isomers due to their structure, as indicated above, the compounds represented by the following General formula (VII') are preferred stereostructure:

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Compounds of the present invention, in which the side chain group is common to compounds represented by the General formula (VII), attached to a cyclic group that may have a better effect compared to other compounds with similar page is having a similar structure, when administered intravenously. In addition, they can show a considerably better activity compared to compounds with a similar structure, when administered orally, because they have the best bioavailability.

Below you will find the main method of obtaining the compounds of the present invention. It should be said that the compounds of the present invention can be obtained by combining known reactions in addition to ways of obtaining that will be given next.

The method of obtaining A-1

< / BR>
where R2represents a hydrogen atom, a lower alkyl group, cycloalkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy or heteroallyl group which may have a Deputy;

R10represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, hydroxyl group, halogen atom, aryl group which may have a Deputy, or a heteroaryl group which may have a Deputy;

R1arepresents an acyl group;

R3arepresents carboxy-saxicolinae a number from 0 to 2.

(Stage 1)

This stage is the stage at which the derivative of 3-amino-benzazepin-2-she (XX) condensed with carbocyclic derivative of the acid (XXI) or its active derivative, such as gelegenheid acid, obtaining as a consequence, the amide derivative (XXII). The condensation is carried out in the usual way. For example, a derivative of 3-amino-benzazepin-2-she (XX) interacts with the carboxylic acid derivative (XXI) in an inert solvent, represented by methylene chloride, tetrahydrofuran, etc., in the presence of condensing agent is usually used in this field, such as EEDQ (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEC [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride] or diethyl cyanophosphonate with obtaining as a consequence, the amide derivative (XXII). When the condensation process proceeds with the participation of chloranhydride carboxylic acid derivative (XXI), carboxylic acid derivative (XXI) is converted into its acid chloride acid in passing an inert solvent using glorieuses agent commonly used in this field, such as thionyl chloride and oxalicacid, with subsequent interaction with the derived 3-amines stage, in which the ether group and alltihopa in the amide derivative (XXII) obtained in stage 1, is subjected to removal of the protective group in the usual way with getting through this target compound (XXIII). Removing the protective groups are usually used in this field method. For example, it is possible to carry out the hydrolysis of the amide derivative (XXII) in a dilute aqueous solution of alkali such as sodium hydroxide or dilute aqueous solution of mineral acid.

The method of obtaining A-2

When R10is an aryl group which may have a Deputy, the compound (XX') can be synthesized in the following way:

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< / BR>
where R3aand p are each the same meaning as defined above;

R10represents an aryl group which may have a Deputy; and

X represents a halogen atom.

(Stage 1)

This stage is the stage at which the derivative hydroxytyramine (XXIV) triftoratsetofenona with getting tripterocalyx derivative (XXV). Triftormetilfullerenov carry out interaction derivative (XXIV) with triftormetilfullerenov or trifloromethyl the acid chloride in enerjak pyridine.

(Phase 2)

This stage is the stage at which tripterocalyx derivative (XXV) obtained in stage 1, interacts with the derived airborne acid (X) or a compound alloleva (XI) with getting through this derived aelterman (XXVI). The interaction of the compound (XXV) with a compound (X) or (XI) is carried out in a suitable organic solvent, which could not inhibit this reaction in the presence of a suitable base and a palladium catalyst. As examples of the solvent can specify hydrocarbons, such as toluene, amides such as N,N'-dimethylformamide. As examples of bases you can specify the carbonates of alkali and alkaline earth metals such as potassium carbonate and calcium carbonate, and organic bases such as triethylamine and N-methylmorpholine. As examples of the palladium catalyst can specify tetrakis(triphenylphosphine)palladium (O).

(Stage 3)

This stage is the stage at which benzazepine derivative (XXVII) are obtained from the derived aelterman (XXVI) obtained in stage 2, by rearrangement reaction, usually used in this field. The rearrangement can be carried out according to the JV is p. More specifically, in the case of the Beckmann rearrangement, benzazepine derivative (XXVII) can be obtained by processing the derived aelterman (XXVI) of hydroxylamine hydrochloride, with getting through this oxime and then, for example, by heating the oxime in the presence of a suitable acid. In the case of the Schmidt rearrangement by, for example, the method which consists in interaction of attestations acid or of sodium azide in the presence of a suitable acid. The acid can be used any commonly used acid. Examples include sulfuric acid, polyphosphoric acid, trichloroacetic acid, methanesulfonate acid, etc.

(stages 4 and 5)

These stages are stages in which benzazepine derivative (XXVII) obtained in stage 3, halogenous and restore with getting through this 3-halogenbenzonitriles derivative (XXIX).

Halogenoalkane and you can restore each in accordance with the method, usually used in this field. In particular, a preferred result can be achieved by conducting the reaction in accordance with the method Negasawa et al. [J. Med. Chem., 14, 501 (1979)].

is Br and Cl), obtaining thus dehalogenating benzazepine derivative (XXVIII), and then the compound (XXVIII) catalytically hydronaut in the presence of palladium catalyst to obtain through this 3-halogenbenzonitriles derivative (XXIX).

(Stage 6)

This stage is the stage at which the 3-galogenobenzene derivative (XXIX) obtained in stage 5, is subjected to sideropenia with getting through this azide (XXX).

Sideropenia perform a method commonly used in this area by interacting 3-halogenbenzonitriles derivative (XXIX) with sodium azide or lithium in a suitable solvent, for example, ethanol, dimethylformamide or dimethyl sulfoxide.

(Stage 7)

This stage is the stage at which the azide (XXX) obtained in stage 6, alkylate in the usual way with getting through this N-alkylated derivative (XXXI).

The alkylation can be performed in the usual way used in this area. For example, it is implemented by the interaction of azide (XXX) with modelcillit ether in a suitable solvent, for example dimethylformamide or tetrahydrofuran in the presence of a strong base such as sodium hydride. Alternatively, it is done by the interaction of azide (XXX) with halogenation esnoga transfer, such as Tetra-n-butylammonium bromide and benzyltriethylammonium iodide.

(stage 8)

This stage is the stage at which N-alkilirovanie derivative (XXXI), obtained in stage 7, restore the normal way with getting through the amine (XX').

Recovery can be accomplished by a method usually used in this field. It is possible to carry out catalytic hydrogenation of N-alkylated derivative (XXXI) in a suitable solvent, for example methanol, ethanol or ethyl acetate in the presence of a catalyst such as palladium on coal.

This amine (XX') is important as an intermediate product to obtain the compounds of General formula (II), where Y3is a group represented by-CH2-.

< / BR>
< / BR>
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In some formulas, R1arepresents an acyl group; R2represents a hydrogen atom, a lower alkyl group, cycloalkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy, or heteroallyl group which may have a Deputy; R3aand R3a'is carboxysome is alogena, aryl group which may have a Deputy, or a heteroaryl group which may have a Deputy; t represents an integer 0, 1 or 2; m represents the integer 0, 1 or 2; and n represents an integer of 0, 1 or 2.

(Stage 1)

This stage is the stage at which a derivative of 2-tierralinda (XLVII) protect through telemedicine the usual way of obtaining derived phthalimidopropyl acid (XLIII). The compound (XLIII) can be obtained in accordance with the method of telemedicine, which is usually used in this field. For example, phthalic anhydride and the compound (XLII) is heated in an inert solvent, for example dimethylformamide or aqueous dioxane, or without using any solvent in the presence of a base, such as triethylamine, or without any reason with getting through this derived phthalimidopropyl acid (XLIII). Alternatively, ftalimidnyi agent, such as ethoxycarbonylphenyl, interacts with the compound (XLII) in the presence of a base such as sodium carbonate and sodium bicarbonate, with getting through this derived phthalimidopropyl acid (XLIII).

(Phase 2)

This article is about active derivative, such as gelegenheid acid, condensed with ether derivatives of amino acids (XII) in the usual way with getting through this amide derivative (XLIV).

The condensation is carried out in the usual way used in this area. For example, the compound (XLIII) interacts with the ether derivative of the amino acid (XLII) in an inert solvent, represented by methylene chloride, tetrahydrofuran, etc. in the presence of commonly used condensing reagent such as EACH (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEK (hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or diethylthiophosphate, obtaining by this compound (XLIV).

When the condensation is carried out with the participation of the derivative of carboxylic acid (XLIII), the compound (XLIII) is converted into the acid chloride of the acid in a suitable inert solvent using commonly used glorieuses agent such as thionyl chloride and oxalicacid, and then thus obtained acid chloride acid is subjected to interaction with the ether derivative of the amino acid (XLII) with a certificate by this compound (XLIV).

(Stage 3)

This stage is what rucenim through this aldehyde derivative (XLV). The compound (XLV) can be also obtained by the method commonly used for the oxidation alilovic alcohols. For example, the aldehyde derivative (XLV) can be obtained by performing oxidation Swann (Swann) using oxalicacid and dimethyl sulfoxide or oxidation using carbon dioxide magnesium in a suitable aprotic solvent such as dichloromethane and chloroform.

(Stage 4)

This stage is the stage at which the derived aldehyde (XLIV), obtained in stage 3, cyclist direct receipt through this, through enaminone derived, the ether derivative (XLVI) or carboxylic acid derivative (XLVII). For example, the ether derivative (XLVI) can be obtained by treating compound (XLV) with triperoxonane acid in a suitable aprotic solvent such as dichloromethane and chloroform.

Alternatively, the carboxylic acid derivative (XLVII) can be obtained by treating compound (XLV) with a mixture triftormetilfullerenov acid and triperoxonane anhydride or one triftormetilfullerenov acid in a suitable aprotic solvent such as dichloromethane and chloroform.

(Stage 5)

This stage is the stage at which afobam with getting through this carboxylic acid derivative (XLVII). For example, the ether derivative (XLVI) was processed in a strong proton acid with triftormetilfullerenov acid proton solvent such as ethanol, to obtain by means of this carboxylic acid derivative (XLVII).

(Stage 6)

This stage is the stage at which the functional carboxyl group of the carboxylic acid derivative (XLVII) obtained at stages 4 and 5, is protected by esterification with getting through this ether derivative (XLVIII). As the ester group introduced a normal alkyl group, branched alkyl group or a group which can be selectively removed in such reaction conditions under which alltihopa connection (L), synthesized at the stage 8, is not hydrolyzed. The esterification is performed by the method usually used in this field. For example, the derived (XLVII) interacts with alcohol in the presence of a mineral acid, such as hydrochloric acid and sulfuric acid. Alternatively, the derivative (XLVII) interacts with, for example, diphenylmethane, triphenylmethane or trimethylsilylethynyl in an inert solvent, such as dimethylformamide and tetrahydrofuran, in the presence of a base, such as carbon is/BR> This stage is the stage at which talimena group ether derivative (XLVIII), obtained in stage 6, is subjected to removal of the protective group to obtain by means of this amine (XLIX). This method is in accordance with a customary method. For example, the ether derivative (XLVIII) is treated with hydrazine in a solvent such as water, alcohol, and tetrahydrofuran, and, through this, is removing the protective group at phthalimide. Thus can be obtained amine (XLIX).

(Stage 8)

This stage is the stage at which a derivative of the acid (XIII) or its active derivative, such as gelegenheid, condensed with the amine (XLIX), obtained in stage 7, with getting through this amide derivative (L). This reaction is carried out generally applicable method in this area. For example, the carboxylic acid derivative (XIII) interacts with the amine (XLIX) in an inert solvent such as methylene chloride and tetrahydrofuran in the presence of commonly used condensing reagent such as EEDQ, DCC, DEC or diethylthiophosphate, with getting through this connection (L). When the reaction is carried out with the participation of the acid chloride derivative of carboxylic acid (XIII), derived carbon is about agent, usually used in this field, such as thionyl chloride and oxalicacid, and then the obtained gelegenheid interacts with the amine (XLIX) with getting through this connection (L).

(Stage 9)

This stage is the stage at which either or both alltihopa and the ether group derived amide (L), obtained in stage 8, is exposed (are) removing the protective group in the usual way with getting through this carboxylic acid derivative (LI). When tsepliaeva (s) group (s) is (are) common (s) alkyl(s) group(s), extensive (s) alkyl (s) group(s), and so on, for example, the amide derivative (L) hydrolyzing in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute aqueous solution of mineral acid with getting through this mercaptopropanol carboxylic acid (LI), with R1arepresenting hydrogen. When tsepliaeva(s) group(s) is (are) tert-bucilina(s) group(s), arylalkyl(s) group(s), extensive(s) alkyl(s) group(s), etc., removing the protective group is carried out in such a conventional reaction conditions under which alltihopa remains stable, napatha acityabode carboxylic acid (LI).

(Stage 10)

This stage is the stage at which deltagraph, if any, of the carboxylic acid derivative (LI) obtained in stage 9, hydrolyzed with getting through this mercaptopropanol carboxylic acid (LII). The hydrolysis can be performed under the conditions of hydrolysis, which is usually used in this field, that is, in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute aqueous solution of mineral acid.

The method of obtaining B-2

When n is 0, the compound (I to IV) can be also synthesized by the following method:

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In some formulas, R1a, R2, R3a, R14, m and t each has the same significance as defined above.

(Stage 1)

This stage is the stage at which the derived - hydroxy carboxylic acid (XIV) condensed with the amine (XI, IX) obtained by the above method of obtaining a B-1, stage 7, in the usual way with getting through this amide derivative of hydroxy carboxylic acid (LII). Like a method of obtaining a B-1 stage 6, the compound (LIII) and (XL IX) interacts in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of congenerous the way you can obtain the amide derivative (LIII).

(Phase 2)

This stage is the stage in which the hydroxyl group derived amide (LIII), obtained in stage 1, is converted to alltihopa in the usual way with getting through this acityabode (LIV). The compound (LIV) can be synthesized according to the method commonly used to obtain acityabode. For example, the compound (LIII) is treated with a reaction type Motonobu (Mitsunobu) in an inert solvent such as methylene chloride and tetrahydrofuran, using triphenylphosphite and ester of azodicarboxylic acid, such as DYADS (diisopropylcarbodiimide). Thus can be obtained acityabode (LIV).

The method of obtaining B-3

The connection represented by the General formula VIb can be obtained in the following way:

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In some formulas, R1arepresents an acyl group; R2 represents a hydrogen atom, lower alkyl group, cycloalkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy, or heteroallyl group which may have a Deputy; R3arepresents the group hydroxyl group, halogen atom, aryl group which may have a Deputy; or heteroaryl group, which may have a Deputy; S represents an integer of 0, 1 or 2; m represents the integer 0, 1 or 2; and n represents an integer of 0, 1 or 2.

(Stage 1)

This stage is the stage in which the amino group of 3-tienlulinlang acid derivative (LV) is protected by telemedicine getting phthalimide carboxylic acid derivative (LVI). The compound (LVI) can be obtained by a method usually used in this field. For example, phthalimide carboxylic acid derivative (LVI) can be obtained by heating phthalic anhydride with the compound (LV) in an inert solvent, such as dimethylformamide and aqueous dioxane, or without using any solvent in the presence of a base such as triethylamine, or without any reason.

Alternatively, it can be obtained by heating phtalimide agent, such as ethoxycarbonylphenyl, with compound (LV), in the presence of a base such as sodium carbonate and sodium bicarbonate.

(Phase 2)

This stage is the stage at which phthalimide p the reed acid, condense with ether derivatives of amino acids (XII') in the usual way to obtain an amide derivative (LII).

The condensation is carried out in the usual way used in this area. For example, the compound (LVI) interacts with the ether derivatives of amino acids (XII') in an inert solvent, represented by methylene chloride, tetrahydrofuran, etc. in the presence of commonly used condensing reagent such as EACH (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEK (hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or diethylthiophosphate. Thus can be obtained compound (LVII). When the condensation is carried out with the participation of the acid chloride of compound (LVI), the compound (LVI) is converted into the acid chloride of the acid in a suitable inert solvent using commonly used glorieuses agent such as thionyl chloride and oxalicacid, and then thus obtained acid chloride acid is subjected to interaction with the ether derivatives of amino acids (XII') to obtain the compound (LVII).

(Stage 3)

This stage is the stage in which the hydroxyl group of the amide derivative (LVII), obtained in stage 2, Okino way usually used for oxidation alilovic alcohols. For example, the aldehyde derivative (LVIII) can be obtained by oxidation Swann (Swann) using oxalicacid and dimethyl sulfoxide, or by oxidation using carbon dioxide magnesium in a suitable aprotic solvent such as dichloromethane and chloroform.

(Stage 4)

This stage is the stage at which the derived aldehyde (LVIII), obtained in stage 3, cyclist in the usual way with getting through enaminone derived, the ether derivative (LIX). Alternatively, this stage is the stage at which the aldehyde derivative (LVIII) cyclist direct obtaining through enaminone derivative, carboxylic acid derivative (LX).

For example, the ether derivative (LIX)can be obtained by treating compound (LVIII) triperoxonane acid in a suitable aprotic solvent such as dichloromethane and chloroform.

Alternatively, the carboxylic acid derivative (LX) can be obtained by treating compound (LVIII) a mixture triftormetilfullerenov acid and triperoxonane anhydride or one triftormetilfullerenov acid in a suitable aprotic solvent, such as dichlormethane in stage 4, subjected to removal of the protective group to obtain carboxylic acid derivative (LX). For example, the ether derivative (LIX) is treated with a proton acid, such as triftormetilfullerenov acid proton solvent such as ethanol. Thus can be obtained carboxylic acid derivative (LX).

(Stage 6)

This stage is the stage at which the functional carboxyl group of the carboxylic acid derivative (LX) obtained at stages 4 and 5, are protected by esterification with obtaining ether derivative (LXIV).

As the ester group introduced a normal alkyl group, branched alkyl group or a group which can be selectively removed in such reaction conditions under which alltihopa compound (LXIII), synthesized at the stage 8, is not hydrolyzed. The esterification is performed by the method usually used in this field. For example, the carboxylic acid derivative (LX) interact with alcohol in the presence of a mineral acid, such as hydrochloric acid and sulfuric acid. Alternatively, the derivative (LX) interacts with, for example, diphenylmethane, triphenylmethane or trimethylsilylethynyl in an inert solvent, tak. Thus can be obtained ether derivative (LXIV).

(Stage 7)

This stage is the stage at which phthalimido group ether derivative (LXIV), obtained in stage 6, is subjected to removal of the protective group to obtain amine (LXII). This method is in accordance with a customary method. For example, the compound (LXIV) is treated with hydrazine in a solvent such as water, alcohol, and tetrahydrofuran, and, through this, is removing the protective group at phthalimide. Thus can be obtained amine (LXII).

(Stage 8)

This stage is the stage at which the carboxylic acid derivative (XIII) or its active derivative, such as gelegenheid, condensed with the amine (LXII), obtained in stage and 7, to obtain the amide derivative (LXIII). This reaction is carried out generally applicable method in this area. For example, the carboxylic acid derivative (XII) interacts with the amine (LXII) in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of commonly used condensing reagent such as EACH, DCK, DEK or diethylthiophosphate. Thus, it can be obtained the compound (LXIII). When the reaction is carried out, for example, involving chodashim inert solvent using a halogenation agent, usually used in this field, such as thionyl chloride, etc., and then received gelegenheid interact with the amine (LXII) to obtain the compound (LXIII).

(Stage 9)

This stage is the stage at which either or both alltihopa and the ether group derived amide (LXIII), obtained in stage 8, is exposed(are) removing the protective group in the usual way with getting carboxylic acid derivative (LIa). When tsepliaeva(s) group(s) is(are), for example, normal(s) alkyl(s) group(s), extensive(s) alkyl(s) group(s), etc., derived amide (LXIII) hydrolyzing in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute aqueous solution of mineral acid to obtain mercaptopropanol carboxylic acid (LIa) with RIa representing hydrogen. When tsepliaeva(s) group(s) is(are) tert-bucilina(s) group(s), alalalala(s) group(s)), branched(s) lillkyrka(s) group(s), etc., removing the protective group is carried out in such a conventional reaction conditions under which alltihopa remains stable, for example, by catalytic hydrogenation, treatment triperoxonane to the Oia 10)

This stage is the stage at which alltihopa, if any, of the carboxylic acid derivative (LIa) obtained in stage 9, hydrolyses getting mercaptopropanol carboxylic acid (LIb). The hydrolysis can be performed under the conditions of hydrolysis, which is usually used in this field, that is, in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or a dilute aqueous solution of mineral acid.

The method of obtaining B-4

When n is 0, the compound (LIVa) can also be synthesized in the following way:

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In some formulas, R1arepresents an acyl group; R2represents a hydrogen atom, a lower alkyl group, cycloalkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy, or heteroallyl group which may have a Deputy; R3arepresents a carboxy-protective group; R15represents a hydrogen atom, a lower alkyl group, lower CNS group, hydroxyl group, halogen atom, aryl group which may have a Deputy, or heteroaryl S="ptx2">

(Stage 1)

This stage is the stage at which the derived - hydroxy carboxylic acid (XIV) condensed with the amine (LXII) obtained by the above method of obtaining b-3, phase 7, the usual way to obtain an amide derivative-hydroxy carboxylic acid (LXV). Like the method of obtaining In-3, step 8, compound (XIV) and (IXII) interact in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of a condensing agent, commonly used in this field, for example, EE DQ, DCC, DEC or diethylthiophosphate. Thus, it is possible to obtain an amide derivative (LXV).

(Phase 2)

This stage is the stage in which the hydroxyl group of the amide derivative (LXV), obtained in stage 1, is converted to alltihopa obtaining acityabode (LVIa). Connection (LVIa) can be synthesized according to the method normally used to convert the hydroxyl group in alltihopa. For example, the compound (L XV) is treated with a reaction type Mitsunobu (Mitsunobu) in an inert solvent such as methylene chloride and tetrahydrofuran, using and triphenyl ester of azodicarboxylic acid, such as DIAD (diisopropylcarbodiimide). Takarasiennes General formula (VII), can be obtained in the following way:

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In some formulas, R2represents a hydrogen atom or acyl group; and J represents a cyclic group having ACE inhibitory activity.

(Stage 1)

Accordingly, this stage is the stage in which the amino group of D-ALLO-isoleucine (XXXII) is bromirovanii obtaining bromide (XXXIII). Bromide (XXXIII) can be obtained according to the method commonly used in this area for the stereoselective synthesized. For example, the compound (XXXII) is treated with a nitrite such as sodium nitrite and nitrite of silver in an aqueous solution of hydrogen bromide. Thus can be obtained bromide (XXXIII).

(Phase 2)

Accordingly, this stage is the stage at which the group of bromine to bromide (XXXIII), obtained in stage 1, is converted to alltihopa with getting through this acityabode acid XXXIV). This reaction is carried out in the usual way. For example, the bromide (XXXIII) is subjected to interaction with dicarboxylates, such as thioacetic potassium and thioacetal sodium in a polar organic solvent, such as acetonitrile and acetone. Alternatively, the bromide (XXXIII) interacts with thiocarbonates kikoti cesium carbonate. Thus can be derived alltypetable acid (XXXIV).

(Stage 3).

This stage is the stage at which the derivative alltypetable acid (XXXIV) obtained in stage 2, or its active derivative, such as gelegenheid acid, condensed with ether derivative of the amino acid (XXXV) with getting through this amide derivative (VII). For example, the derived alltypetable acid (XXXIV) interacts with the ether derivative of the amino acid (XXXV) in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of commonly used condensing reagent such as EEDQ (I-etoxycarbonyl-2-ethoxy-1,2-dihydroindole), DCC (1,3-dicyclohexylcarbodiimide), DEC (hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or diethylthiophosphate. Thus can be obtained amide derivative (VII). When the condensation is carried out with the participation of the acid chloride derived alltypetable acid (XXXIV), derived alltypetable acid (XXXIV) is converted into the acid chloride of the acid in a suitable inert solvent using commonly used glorieuses agent such as thionyl chloride and oxalicacid, and then p is(XXXV) to obtain the target compound (VII).

The method of obtaining p-2.

The connection represented by the General formula (VII) may be obtained in the following way:

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In some formulas, R1and J each have the same values as above.

(Stage 1)

Accordingly, this stage is the stage at which the brominated carboxylic acid derivative (XXXIII) obtained according to the method of obtaining C-2, stage 1, or its active derivative, such as gelegenheid, condense with ether derivative of the amino acid (XXXVII) to give the amide derivative (XXXVIII). Amide derivative (XXXVIII) can be obtained as well as method for producing a C-1, stage 3.

(Phase 2)

Accordingly, this stage is the stage at which the bromine group in the amide derivative (XXXVIII), obtained in stage 1, is converted to alltihopa with obtaining the amide derivative (VII), which is the same as the compound obtained by the method of obtaining C-1, stage 3. Amide derivative (VII) can be obtained by the same processing as the method of obtaining C-1, stage 2.

The method of obtaining C-3

Those of the compounds represented by the General formula (VII), where R3is hydrogen, can be obtained shadowskill carboxy-protective group; R4represents a hydrogen atom, a lower alkyl group or arylalkyl group which may have a Deputy; J has the same values as specified above.

Namely, either an ether or both terrestrial and atillio group of the compound (XL) obtained according to the methods of obtaining the C-1 and C-2 subject(are) removing the protective group in the usual way with getting through this carboxylic acid derivative (XLI). When tsepliaeva(s) group(s) is(are), for example, normal(s) alkyl(s) group(s), extensive(s) alkyl(s) group(s), etc., amide derivative (VII) hydrolyzing in a dilute aqueous solution of alkali such as lithium hydroxide, or in a dilute water solution of a mineral acid derivatization kurbinovo acid (XLI) with R1representing hydrogen. When tsepliaeva(s) group(s) is(are) tert-bucilina(s) group(s), branched lillkyrka(s) group(s), such(s) as benzydamine group, similarily(s) group(s), such(s) as trimethylsilyl group, and so on, is removing the protective group is only part of the ester groups in such reaction conditions under which alltihopa remains stable, for example, XLI).

The method of obtaining D-1

The connection represented by the following General formula (D) can be obtained in the following way:

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where R1, R2, R3, R18, m and n each have the same meanings as described above:

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In some formulas, representing the above method of obtaining D-I, R2, R3a, 18 and n each have the same meanings as described above; and R1arepresents a group selected from those given in the definition of R1with the exception of the hydrogen atom.

(Stages 1)

Specifically, this stage, which includes the nitration widely known derived cyclic amine (I) or a derivative of a cyclic amine (I), obtained in the usual way.

Nitration described above, carried out in the usual way. You can specify the method that includes processing nitrous agent commonly used in this field, for example, nitrone tetrafluoroborate or so on, in an inert solvent, for example, chloroform, dichloromethane, or etc., used for the implementation of the nitration, the method which includes the implementation of nitration with fuming nitric acid or etc., in the presence of acetic acid, acetic anhydride, sulfuric kissonline group of carboxylic acids, nitro compounds, (II), obtained in stage 1.

As the above ester group introduced a normal alkyl group or a group which can be selectively removed in such reaction conditions under which diacetylene group of compound (IX), synthesized at the stage 8, is not hydrolyzed. The ester compound (IV) can be obtained, for example, by the interaction of the nitro compounds (II) with an alcohol in the presence of a mineral acid, such as hydrochloric acid and sulfuric acid, or, alternatively, by the interaction of the nitro compounds (II) with diphenylmethane, triphenylmethane or trimethylsilylethynyl in an inert solvent, such as dimethylformamide and tetrahydrofuran, in the presence of a base such as cesium carbonate and potassium carbonate.

(Stage 3)

This is the stage that includes the restoration of the nitro group of the compound (IV) obtained in stage 2, the usual way of obtaining aniline compound (VI).

Recovery described above can be carried out by the method usually used in this field. For example, you can specify a catalytic reduction using palladium, platinum, etc., as a catalyst or restoration with metal, tallichet interaction of aniline compound (VI), obtained in stage 3, with the available derived chlorosulfonic acid or with a derivative of chlorosulfonic acid obtained widely known method of obtaining sulfanilamide derivative (VII).

For example, sulfanilamide derivative (VII) can be obtained by the interaction with the aniline compound (VI) with the derived chlorosulfonic acid using inert solvent, such as acetonitrile, tetrahydrofuran, toluene and dichloromethane, in the presence of a base, such as pyridine, triethylamine and sodium carbonate.

(Stage 5)

This stage is the stage that includes removing the protective group sulfonamidnuyu derivative (VII) obtained in stage 4, to obtain amino compounds (VIII).

Removing the protective group is carried out in the usual way. Aminosidine (VIII) can usually be obtained, for example, by treating compound (VII) with hydrazine in a solvent such as water, alcohol and tetrahydrofuran, with the removal by means of this protective group phthalimide group.

(Stage 6)

This stage is the stage, including condensation widely known carboxylic acid derivative or a carboxylic acid derivative obtained is of (VIII), received at stage 5, to obtain the amide derivative (IX).

Condensation described above, can be carried out in the usual way. For example, the above carboxylic acid derivative interacts with aminoguanidinium (XIII) in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of a condensing reagent such as EACH (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEK (hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or diethylthiophosphate. Thus can be obtained amide derivative (IX). When the condensation is carried out with the participation of the acid chloride derivative of carboxylic acid, carboxylic acid derivative is converted into the acid chloride of the acid in a suitable inert solution with gloriouse agent such as thionyl chloride and oxalicacid, and then thus obtained acid chloride is subjected to interaction with aminoguanidinium (VIII) to give the amide derivative (IX).

(Stage 7)

This stage is the stage that involves the removal of the protective group of people or both ester group and diacetylene group derived amide (IX) obtained in the above stage 6, with Paul the other group and so on, derived amide (X) hydrolyzing in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute solution of mineral acid to obtain mercaptopropanol carboxylic acid (X) containing R1representing hydrogen. When the ester group is tert-bucilina group, lillkyrka group, branched lillkyrka group and so on, removing the protective group is carried out in such reaction conditions under which alltihopa remains stable, for example, by catalytic hydrogenation, using triperoxonane acid or so on, obtaining diacetylene carboxylic acid derivative (X).

The method of obtaining D-2

Those of the compounds represented by the General formula (D), where n is 0, can be obtained in the following way:

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In some formulas above, R1a, R2, R3a, R18and m each have the same values as above.

(Stage 1)

This stage is the stage that involves the condensation of a derivative - hydroxy carboxylic acid (XI) or a derived - hydroxycarbonic acid (XI), obtained by a commonly known method aminoguanidinium (VIII) obtained in the bathroom condensation, such a method for producing D-1, step 6, compound (XI) and (VIII) interact in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of condensing Regent, such as EACH (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEK (hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or diethylthiophosphate. Thus it is possible to obtain an amide derivative (XII).

(Phase 2)

This stage is the stage that includes theatrification hydroxyl group of the amide derivative (XII) obtained in stage 1, with getting through this acetylthio derivative (XIII). The compound (XIII) can be synthesized according to the method commonly used for diatrypaceae hydroxyl group. For example, the compound (XII) is treated with a reaction type Mitsunobu (Milscenobu) in an inert solvent such as methylene chloride and tetrahydrofuran, using triphenylphosphite and ester of azodicarboxylic acid, such as DYADS (diisopropylcarbodiimide). Thus can be obtained acetyltyrosine (XIII).

(Stage 3)

This stage is the stage that involves removing the protective group at either or both afernoons carboxylic acid (XIV). Thus, the carboxylic acid derivative (XIV) can be synthesized by the same method as the above method of obtaining D-1, stage 7.

The way to obtain E-1

The connection represented by the following General formula (E) can be obtained in the following way:

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where R1represents a hydrogen atom or acyl group;

R2represents a hydrogen atom, a lower alkyl group, a heteroaryl group which may have a Deputy, or arylalkyl group which may have a Deputy;

R3represents a hydrogen atom, a lower alkyl group or arylalkyl group;

R19represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, hydroxyl group or halogen atom;

p, m and n represent each independently an integer of 0, 1 or 2;

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In some formulas above, R2, R19, p, n and m each have the same meaning described above; R1arepresents a group selected from the groups of the data in the definition of R1with the exception of the hydrogen atom; R3arepresents a group selected from the groups of the data in the definition of R3with the exception of the hydrogen atom.

(the purposes of the General formula (IV) is protected by telemedicine with getting through this phthalimide carboxylic acid derivative (V). Palmitinovaya can be carried out by a method commonly used in this field. For example, phthalimide carboxylic acid derivative (V) can be obtained by heating phthalic anhydride with the compound (IV) in an inert solvent, such as dimethylformamide and dioxane, or without using any solvent. Alternatively, it can be obtained by heating phtalimide agent, such as ethoxycarbonylphenyl, with compound (IV) in the presence of a base such as sodium carbonate and sodium bicarbonate.

(Phase 2)

This stage is the stage at which phthalimide carboxylic acid derivative (VI obtained in stage 1, or its active derivative, such as gelegenheid acid, condensed with ether derivatives of amino acids represented by the General formula (VI) ordinary General formula (VI) in the usual way to obtain an amide derivative (VII). The condensation can be performed in the usual way used in this area. For example, compounds (V) and (VI) interact in an inert solvent, represented by methylene chloride, tetrahydrofuran, etc. in the presence of commonly used condensing reagent such as EACH (1 toxica the-ethylcarbodiimide) or diethylthiophosphate. Thus can be obtained compound (VII). When the condensation is carried out with the participation of the acid chloride of compound (V), the compound (V) is converted into the acid chloride of the acid in a suitable inert solvent using commonly used glorieuses agent such as thionyl chloride and oxalicacid, and then thus obtained acid chloride acid is subjected to interaction with the ether derivative of the amino acid (VI) with a compound (VII).

(Stage 3)

This stage is the stage in which the hydroxyl group of the amide derivative (VII), obtained in stage 2, is oxidized in the usual way with getting through this aldehyde derivative (VIII). The compound (VIII) can be also obtained by the method commonly used for oxidation alilovic alcohols. For example, the aldehyde derivative (VIII) can be obtained by performing oxidation Swann (Swann) using oxalicacid and dimethyl sulfoxide or oxidation using pyridine of chloroformiate dioxide or magnesium in a suitable aprotic solvent such as dichloromethane and chloroform.

(Stage 4)

This stage is the stage at which the derivative of the aldehyde (VIII), obtained which may be obtained, for example, treatment of the aldehyde derivative (VIII) triperoxonane acid in a suitable aprotic solvent such as dichloromethane and chloroform.

(Stage 5)

This stage is the stage at which enaminone compound (IX) obtained in stage 4, is subjected to the reaction of the Friedel-Craftsa with receiving tricyclic derivative (X). This reaction can be carried out in accordance with the usual method used in this area. For example, tricyclic derivative (X) can be obtained by treating compound (IX) a mixture of triftormetilfullerenov acid and triperoxonane anhydride or one triftormetilfullerenov acid in a suitable aprotic solvent such as dichloromethane and chloroform.

(Stage 6)

This stage is the stage at which the functional carboxyl group of the carboxylic acid derivative (X), obtained in stage 5, protected by esterification with obtaining ether derivative (XI). As the ester group introduced a normal alkyl group, branched alkyl group or a group which can be selectively removed in such reaction conditions under which alltihopa compounds (XIV), synthesized at the stage of 8, not hydroly the functioning alcohol in the presence of mineral acid, such as hydrochloric acid and sulfuric acid. Alternatively, compounds (X) interacts with, for example, diphenylmethane, triphenylmethane or trimethylsilylethynyl in an inert solvent, such as dimethylformamide and tetrahydrofuran, in the presence of a base such as cesium carbonate and potassium carbonate. Thus can be obtained ether derivative (XI).

(Stage 7)

This stage is the stage at which phthalimido group ether derivative (XI), obtained in stage 6, is subjected to removal of the protective group to obtain compounds amine (XII). This reaction can be performed in the usual way. For example, compound (XI) is treated with hydrazine in a solvent such as water, alcohol, and tetrahydrofuran, and through this comes the removal of the protective group at phthalimide. Thus can be obtained amine (XII).

(Stage 8)

This stage is the stage at which the carboxylic acid derivative represented by the General formula (XIII) or its active derivative, such as gelegenheid, condensed with the amine (XII) obtained in stage 7, to obtain the amide derivative (XIV). This reaction is carried out generally applicable method in this area. For example, dimethylaniline and tetrahydrofuran, in the presence of commonly used condensing reagent such as EACH, DCK, DEK or diethylthiophosphate. Thus can be obtained compound (XIV). When the reaction is carried out, for example, with the participation of the acid chloride derivative of carboxylic acid (XIII), carboxylic acid derivative (XIII) is converted into its acid chloride in a suitable inert solvent, using a halogenation agent, commonly used in this field, such as thionyl chloride, and oxalicacid, and then the obtained gelegenheid subjected to interaction with amino derivatives (XII) obtaining by means of this compound (XIV).

The way to obtain E-2

When R3in the above General formula (E) is a hydrogen atom, the compound can be obtained in the following way:

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In some formulas above, R1, R2, R3a, R19, p, n and m each have the same values as above.

Specifically it is a method which includes removing the protective group of the amide derivative represented by the General formula (XIV'), the usual way of obtaining carboxylic acid derivative represented by the General formula (XV).

Removing the protective groups are the method which is the acyl group, as the parent compound derived choose acid, where R2ais, for example, tert-butilkoi group or arylalkyl group, and then subjected to the original connection to removing the protective group in such conditions, under which alltihopa remains stable, for example, catalytic hydrogenation or treatment triperoxonane acid. Thus can be obtained target compound (XV).

When R1in the carboxylic acid derivative (XV), that is, the target compound is a hydrogen atom, as the source connection choose amide derivative, where R2ais lower alkyl, and hydrolyzing in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute aqueous solution of mineral acid with getting through this target compound (XV).

The way to obtain E-3

When R1and R2in the above General formula (E) are each a hydrogen atom, compound (XV') can be obtained in the following way:

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In some formulas above, R1a, R2, R3a, R19, p, n and m each have the same values as above.

Specifically, this reaction obtaining mercapto derivative of carboxylic acid (XVI).

The hydrolysis can be performed by a method commonly used in this field. For example, the original connection can hydrolyze in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute aqueous solution of mineral acid.

The way to obtain E-4

When m in the above General formula (E) is 0, the compound (XVI') can also be synthesized in the following way:

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In some formulas above, R1a, R2, R3a, R19, p, n and m each have the same values as above.

(Stage I)

This stage is the stage at which the derived - hydroxy carboxylic acid (XVII) condense with aminoguanidinium (XII) obtained in the above-mentioned method of obtaining E-1, stage 7, with getting through this amide derivative - hydroxy carboxylic acid (XVIII). Like a way to obtain E-1, step 8, compound (XII) and (XVII) interact in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of a condensing agent, commonly used in this field, such as, AEDH, MCM, DEK or diethylthiophosphate. Thus it is possible to obtain an amide derivative (XVIII).

(Stadia stage 1, converted to alltihopa obtaining acityabode (XIV'). The compound (XIV') can be synthesized according to the method normally used to convert the hydroxyl group in alltihopa. For example, the compound (XVIII) is treated with a reaction type Mitsunobu (Mitsunobu) in an inert solvent such as methylene chloride and tetrahydrofuran, using triphenylphosphite and ester of azodicarboxylic acid, such as DIAD (diisopropylcarbodiimide). Thus can be obtained acityabode (XIV').

The method of obtaining an F-1

Those of the compounds represented by the following General formula (F), which are different than when R1and R2each represent a hydrogen atom, can be obtained in the following way:

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where R1represents a hydrogen atom or acyl group;

R2represents a hydrogen atom, a lower alkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy, heteroallyl group which may have a Deputy, or lower CNS group;

R3represents a hydrogen atom or carbocyanine above, R2, m and n each have the same meanings as described above; R1arepresents a group selected from the groups of the data in the definition of R1with the exception of a hydrogen atom; and R3arepresents a group selected from the groups of the data in the definition of R3with the exception of the hydrogen atom.

Namely, this method, which involves the condensation of the carboxylic acid derivative represented by the General formula I, or its active derivative, such as gelegenheid acid, amine derivatives represented by General formula II with getting through this amide derivative (III).

The condensation can be performed in the usual way. For example, it is possible to carry out the condensation in the presence of commonly used condensing reagent such as 1-etoxycarbonyl-2-ethoxy-1,2 - dihydroquinoline (denoted here as EACH, hydrochloride 1,3-dicyclohexylcarbodiimide (denoted here as DPC) or diethylthiophosphate.

As the organic solvent may be used any organic solvent inert in the reaction. Examples include methylene chloride, tetrahydrofuran, etc.

When the condensation is carried out with the participation derived chlorine acid in a suitable inert solvent using commonly used glorieuses agent, such as thionyl chloride and oxalicacid, and then thus obtained acid chloride acid is subjected to interaction with amino derivatives of II to obtain compound III.

The method of obtaining F-2

Those of the compounds represented by the following General formula (F), where R1and R3each represent a hydrogen atom, can be obtained in the following way:

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In some formulas above, R2, m, n, R1aand R3aeach have the same values as above.

Specifically, this reaction, which involves the hydrolysis of the amide compounds of General formula (III) in the usual way with getting mercapto carboxylic acid derivative (IV). For the implementation of hydrolysis can be used in the manner normally used in this field. For example, you can specify a process involving the reaction of the amide compound III in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute aqueous solution of mineral acid, and others.

The method for obtaining F-3

Those of the compounds represented by General formula (F), where n is 0, can be obtained in the following way:

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In some formulas above, R2, m and R1 which includes condensation, derived lactic acid represented by the General formula (V) or its active derivative, such as halogenide acid, amine derivatives (II) to give the amide derivative (VI). Like the above method of obtaining F-I, the compound (V) and (II) interact in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of a condensing agent such as EEDQ or diethylthiophosphate. Thus it is possible to obtain an amide derivative (VI).

(Phase 2)

Namely, this is the stage where the hydroxyl group of the amide derivative (VI), obtained in stage I, tjetervizion the usual way of obtaining acetyltyrosine (VII).

Examples of the method of diatrypaceae hydroxyl group include a method, which consists in treating compound (VI) by reaction type Mitsunobu (Mitsunobu ) in an inert solvent such as methylene chloride and tetrahydrofuran, using and triphenyl ester of azodicarboxylic acid, such as diisopropylcarbodiimide (here called DIAD) to obtain the target compound (VII).

Further, those compounds represented by the General formula (F), where R2and R3each is hydrogen, can be polumsky basic methods of synthesis of the starting compounds, used in the methods of obtaining the F-1 and F-2.

The method of obtaining F-4

Of the compounds represented by the above General formula (V) used in the method of obtaining F-3, and compounds represented by the above General formula (I) used in the method of obtaining F-1, those in which n is 0 can be synthesized in the following way:

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In some formulas, R2, m, and R3aeach have the same meanings as described above; and R20represents a group of the formula: -CHPh2(where Ph represents a phenyl group), a group represented by formula-CPh3or a group represented by the formula -(CH2)2-Si(CH3)3.

(Stage 1)

Specifically, this stage, which involves hydroxylation of the derived amino acid represented by the General formula (VIII), with a derivative of lactic acid (V), which is the initial product of the method of obtaining F-3.

The above derived lactic acid (V) can be synthesized by hydroxylation of the usual amino acids. Derived lactic acid (V) can be synthesized, for example, processing the derived amino acid (VIII) and aidarous agent such as sodium nitrite and nitrite is"ptx2">

(Phase 2)

Specifically, this stage, which includes the protection of functional carbocyclic group derived lactic acid (V), obtained in stage 1, by esterifying derivative (IX).

As a suitable protective group is introduced such that it can be selectively removed in such reaction conditions under which alltihopa compounds (X), synthesized in stage 3, does not undergo hydrolysis. For example, a derivative of lactic acid (V) interacts with diphenylmethane, triphenylmethane or trimethylsilylacetamide in an inert solvent, usually used in this field, such as dimethylformamide and tetrahydrofuran, in the presence of a base such as cesium carbonate and potassium carbonate. Thus can be obtained lactate derivative (IX).

(Stage 3)

Specifically, this stage, which includes thioacetimidate hydroxyl group lactate derived (IX) obtained in stage 2.

This stage can be done in the same way as described for the method of obtaining F-3, stage 2.

(Stage 4)

Specifically, this stage, which includes removing the protective group of an ester group acityabode (X), Paluch arylalkyl group, such as diphenylmethyl and triphenylmethyl, acityabode (X) process triperoxonane acid and anisole to obtain carboxylic acid derivative (XI). When the protective ester group, R4 is sillankorva group, such as trimethylsilylmethyl, acityabode (X) is treated with a compound of fluoride such as potassium fluoride and tetrabutylammonium, to obtain the carboxylic acid derivative (XI).

Compounds of the present invention can be obtained by methods usually used in this field, or a combination of these methods. Next will be described the main methods of obtaining.

The method of obtaining 1

Of the compounds represented by the General formula (1), compounds (X), where R1 is a group other than a hydrogen atom, can be obtained in the following way:

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< / BR>
In some formulas, R1arepresents an acyl group; R2represents a hydrogen atom, a lower alkyl group, cycloalkyl group, aryl group which may have a Deputy, a heteroaryl group which may have a Deputy, arylalkyl group which may have a Deputy or heteroallyl group which may have a Deputy; m and n represents the cue against the angiotensin 1-converting enzyme.

Specifically, this stage is the stage involving the condensation of a derivative of the amino acid of General formula (VIII) with a carboxylic acid derivative represented by the General formula (XI) or its active derivative, such as gelegenheid acid in the usual way m getting amide derivative represented by the General formula (X).

The condensation can be performed by a method commonly used in this field. For example, the derived amino acid (VIII) interacts with the carboxylic acid derivative (IX) in an inert solvent, represented by methylene chloride and tetrahydrofuran, in the presence of commonly used condensing reagent such as EACH (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEK (hydrochloride of 1-(3-demetilamoniopropil)-3-ethylcarbodiimide) or diethylthiophosphate. Thus can be obtained amide derivative (X).

When the condensation is carried out with the participation of the acid chloride of carboxylic acid derivative (IX), carboxylic acid derivative (IX) is converted into the acid chloride of the acid in a suitable inert solvent gloriouse agent such as thionyl chloride and oxalicacid, and then received in affect, the acid (X) in the form of target compounds.

The method of obtaining 2

When R1is a hydrogen atom, the compound (XI) can also be obtained in the following way:

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In some formulas, R1a, R2, J, n and m each have the same values as above.

Specifically, this method includes removing the protective group of an ester group and alltihopa amide derivative (X) obtained by the method of obtaining 1, the usual way of obtaining amino acid derivative, that is, the target compound (XI).

Removing the protective group can be performed by a method commonly used in this field. Namely, it is carried out by hydrolysis of the amide derivative (X) in a dilute aqueous solution of alkali such as sodium hydroxide and lithium hydroxide, or in a dilute aqueous solution of mineral acid.

The method of obtaining 3

Of the compounds represented by the General formula (I), compound (XIV), where n is 0, may also be obtained in the following way:

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In some formulas, R1a, R2, m and J each have the same values as above.

(Stage 1)

Specifically, this stage involves the condensation of a derivative of lactic acid represented by the General formula (XII), or its reactionary (VII), obtaining amide derivative (XIII). Like the above-described method for producing a 1, the compounds (XII) and (VIII) interact in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of a condensing agent, such as EACH or diethylthiophosphate. Thus it is possible to obtain an amide derivative (XII).

(Phase 2)

Namely, this is the stage which is diatrypaceae hydroxyl group of the amide derivative (XIII) obtained in stage 1, the usual way of obtaining the target compound represented by the General formula (XIV).

Examples of the method of diatrypaceae hydroxyl group include a method consisting in processing amide derivative (XIII) by reaction type Mitsunobu (Mitsunobu) in an inert solvent such as methylene chloride and tetrahydrofuran, using triphenylphosphite and ester of azodicarboxylic acid, such as diisopropylcarbodiimide (here called DIAD) to obtain the target compound (XIV).

The method of obtaining 4

The connection represented by the General formula (VII) can also be obtained in the following way:

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In some formulas, R1and J each have the same values as above.

solatina (XV) to give the bromide (XVI). The compound (XVI) can be obtained according to the method commonly used in this area for the stereoselective synthesized. For example, the compound (XVI) is treated with a nitrite such as sodium nitrite and nitrite of silver in an aqueous solution of hydrogen bromide. Thus can be obtained bromide (XVI).

(Phase 2)

Specifically, this stage is the stage, which consists in the substitution of bromine to bromide (XVI) obtained in stage 1, acoltiodropmis with derivatization alltypetable acid (XVII). This reaction is carried out in accordance with a customary method. For example, the bromide (XVI) is subjected to interaction with dicarboxylates, such as thioacetic potassium and thioacetal sodium in a polar organic solvent, such as acetonitrile and acetol. Alternatively, the bromide (XVI) interacts with thiocarbonic acid, such as teoksessa acid and diamentina acid, in the presence of a base such as potassium carbonate and cesium carbonate. Thus can be derived alltypetable acid (XVII).

(Stage 3)

This stage is the stage, which consists in condensing a derivative alltypetable acid (XVII) obtained in stage 2, or Etsy widely known compound or received a widely known method, to obtain the target compound (VII). For example, atillio derivative (XVII) interacts with the ether derivative of the amino acid in an inert solvent such as methylene chloride and tetrahydrofuran, in the presence of commonly used condensing reagent such as EACH (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide), DEK [hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide] or diethylthiophosphate. Thus can be obtained compound (VII). When the condensation is carried out with the participation of the acid chloride acityabode (XVII), acityabode (XVII) is converted into the acid chloride of the acid in a suitable inert solvent using glorieuses agent such as thionyl chloride and oxalicacid, and then thus obtained acid chloride acid is subjected to interaction with the ether derivatives of amino acids with getting through this target compound (VII).

The method of obtaining 5

The connection represented by the General formula (VII) can also be obtained in the following way:

< / BR>
In some formulas, R1represents a hydrogen atom or acyl group; and J has the same values as specified above.

(Stage 1)

the s (XVI), obtained by the method of 4, stage 1, or its active derivative, such as gelegenheid acid, ether derivatives, amino acids (XVIII) in the usual way to obtain an amide derivative (XIX). Amide derivative (XIX) can be obtained by the same processing as described in method 4, step 3.

(Phase 2)

Specifically, this stage is the stage that is in the conversion of the bromo group in the amide derivative (XIX) obtained in stage 1, alltihopa with obtaining the target compound. The target compound (VII) can be obtained by the same processing as described in the production method, stage 2.

To illustrate the activity of the compounds of the present invention further examples of pharmacological research.

Example pharmacological studies A-1

The definition of NEP inhibitory activity of the drug using the kidney cortex of rats

1. Research methods

The NEP activity was determined using the membrane fraction obtained from the cortical substance of the kidney in rats in accordance with the method of Booth and Kenny (a Rapid Method for the Perification of Microvilli from Rabbit kidney, Andrew J. Booth and John A. Kenny, J. Biochem, 1974, 142, 575 - 581).

The activity of NEP ODA is itaries, Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 20, 4942 - 4950).

As the substrate used benzoyl-glizid-arginyl-arginyl-2-naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem. , Switzeland). In the presence of the drug enzyme NEP and excess leucine amino peptidases (Sigma Chemical Co. , U. S. A.), released naphtylamine subjected to color expression using the first garnet (garnet-) (Sigma Chemical Co., U. S. A.), followed by measuring the absorbance at a wavelength of 540 nm.

As for NEP inhibitory activity, the inhibitor is added to the monitoring system described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm, build inhibition curve and then the concentration at which achieved 50% inhibition is taken as the IC50.

2. The results of the study

Table A-1 shows the results of the above studies together with the results of the following example pharmacological studies A-2.

Example pharmacological studies A-2

Determination of ACE inhibitory activity of the drug using rat lung.

1. Method research

The ACE activity was determined using the membrane fraction obtained from rat lung with the ys. Res. Commun., 1990, 171, 1291 - 1296).

The ACE activity determined using a modification (modified borate buffer, pH 8,3) method of Cushman and Cheung (Spectrophotometric Assay and Properties of Angiotensiu - Converting Euzyme of Rabbit Zung, Cushmen, D. W. and H. S. Cheung, 1971, 20, 1637 - 1648).

In the presence of ACE hippurate released from hippuris-histidyl-leucine (Hippuris-His-Leu (Peptide Institute Inc., Japan)) is extracted with ethyl acetate and then the adsorption is measured at a wavelength of 228 nm.

As for ACE inhibitory activity, the inhibitor is added to the monitoring system described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm, build inhibition curve and then the concentration at which achieved 50% inhibition is taken as the IC50.

2. The results of the study

Table A-1 shows the results of a study conducted in accordance with the above-described method of study,

Example pharmacological studies B-1

The definition of NEP inhibitory activity of the drug using the kidney cortex of rats

1. Research methods

The NEP activity was determined using the membrane fraction obtained from the cortical substance of the kidney in rats in accordance with the method of Booth and Kenny (a Rapid Method for the Perification obom in accordance with the method Orlowsky and Wilk (Purification and Specificity of Membrane. - Bound Metalloendopepdidase from Bovine Pituitaries, Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 20, 4942 - 4950).

As the substrate used benzoyl-glycyl-arginine-arginine-2-naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem., Switzerland)). In the presence of the drug enzyme NEP and excess leucine amino peptidases (Sigma Chemical Co. , U. S. A.) released naphtylamine subjected to color expression using the first garnet (first grenade - Tr) (Sigma Chemical Co., U. S. A.), followed by measuring the absorbance at a wavelength of 540 nm.

As for NEP inhibitory activity, the inhibitor is added to the monitoring system described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm, build inhibition curve and then the concentration at which achieved 50% inhibition is taken as the IC50.

2. The results of the study

Table B-1, which will be described later, shows the results of the above studies together with the results of the following example pharmacological studies B-2.

An example of pharmacological research, B-2

Determination of ACE inhibitory activity of the drug using rat lung

1. Research methods

The ACE activity was determined Euzime in Rat Zung., Junshyum R. Wu-Wong. Gerald, P. Budgik, Edward M. Devine and Terry J. Opgenorth, Biochem., Biophys. Res. Commun., 1990, 171, 1291-1296).

The ACE activity determined using a modification (Modified borate buffer, pH 8,3) method of Cushman and Cheung (Spectrophotomeric Assay and Propeoties of Augiotensiu - Conoerbiug Enjyme of Rabbit Zunh., Cusbman, D. W. and H. S. Cheung, 1971, 20, 1637 - 1648).

In the presence of ACE hippurate released from hyperelliptical-leucine (Hippuris-His-Leu (Peptide Institute Iuc., Japan)) is extracted with ethyl acetate and then the adsorption is measured at a wavelength of 228 nm.

As for ACE inhibitory activity, the inhibitor is added to the monitoring system described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm, build inhibition curve and then the concentration at which achieved 50% inhibition is taken as the IC50.

2. The results of the study

Table B-1 shows the results of a study conducted in accordance with the above-described test methods.

Example pharmacological studies C-1

1. Research methods

The activity of NEP define a method in accordance with the method Orlawsky and Wilk (Punfication adn Specificity of Membrane-Bund Metalloendopeptidase from Bovine Pituitaries Marian Orlowsky and Showin Wilk Biochemistoy 1981, 20, 4942-4950).

As the substrate ISPR drug NEP enzyme and excess leucine amino peptidases (Sigma Chemical Co. , U. S. A.), released naphtylamine subjected to color expression using the first garnet (garnet - Tr) (Sigma Chemical Co., U. S. A.), followed by measuring the absorbance at a wavelength of 540 nm.

As for NEP inhibitory activity, the test compound is added to the monitoring system described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm, build inhibition curve and then the concentration at which achieved 50% inhibition is taken as the IC50. In the link quality comparison using [4S -[4,7 (R*), 12b ]]-7-[(1-oxo-2-(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12 b-octahydro-6-occupied[2,1-a][2] benzazepine-4-carboxylic acid.

2. The results of the study

Table C-1, which will be described later, shows the results of the above studies together with the results of the following example pharmacological studies C-2.

Example pharmacological studies C-2.

Determination of ACE inhibitory activity of the drug using rat lung

1. Research methods

The ACE activity was determined using the membrane fraction obtained from rat lung in accordance with the method of Wu-Wong et al.,2">

The ACE activity determined using a modification (modified borate buffer, pH 8,3) method of Cushman and Cheung (Spechrophobomebic Assay and Propeobies of Augioteusin - Couverting Euzyme of Rabbit Zung., Cushman, D. W. and Cheung, H. S., 1971, 20, 1937-1648).

In the presence of ACE hippurate released from hippuris-histidyl-leucine (Hippuris-His-Leu (Peptide Justitute Juc., Japan)) is extracted with ethyl acetate and then the adsorption is measured at a wavelength of 228 nm.

As for ACE inhibitory activity, the test compound is added to the monitoring system described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm, build inhibition curve and then the concentration at which achieved 50% inhibition, take 1050. In the link quality comparison using [4S -[4,7(R*), 12b ]]-7-[(1-oxo-2-(S) - thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12, b-octahydro-6-occupied[2,1-a][2]benzazepine-4-carboxylic acid.

2. The results of the study

Table C-1 shows the results of a study conducted in accordance with the above-described method of study.

Example pharmacological studies C-3

Downward pressure effect on rats 2K, 1C Goldblatt with high blood pressure

1. Research methods

Silver bracket with size is three weeks away rats, whose systolic blood pressure is shown as 180 mm RT.article or higher. From one to several drops of 1 n aqueous sodium hydroxide solution are added dropwise in purified water and dissolved or emuleret each test compound for the preparation of a dosage of 5 ml/kg with subsequent introduction of oral. After keeping the rats in the incubator at 45oC for 5 to 10 minutes measured systolic blood pressure indirectly plethysmography combined tail artery. In the link quality comparison using [4S -[4,7(R*),12b]] 7-[(1-oxo-2-(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12 b-octahydro-6-occupied[2,1-a][2] benzazepine-4-carboxylic acid.

2. The results of the study

Table C-2 shows the result of research conducted in accordance with the above method.

As described above, downward pressure action of the compounds of the present invention is superior in three or more times the action of the compounds of the comparison.

Example pharmacological studies C-4

Diuretic effect on AND treated rats with spontaneous hypertension

1. Research methods

50 ng/kg/min rat trialing natriyureticheskoe). When the dynamics of the blood and the level of r-ANP in the blood become stable after 1 hour explore the diuretic effect of each test compound. Diuretic effect is determined by the intravenous injection of the test compound and measuring the increase (% variation) collected urine for 20 min In the link quality comparison using [4S -[4,7(R*),12b]]- 7-[(1-oxo-2-(S)-thio-3-phenylpropyl)amino] -1,2,3,4,5,6,7,8,12 b-octahydro-6-occupied[2,1-a] [2] benzazepine-4-carboxylic acid.

2. The results of the study

Table C-3 shows the results obtained in the above study.

As shown by these results, the activity of the tested compounds on diuretic action exceeds three times the potency of the compound comparison.

Example pharmacological studies C-5

Downward pressure effect on rats with spontaneous hypertension (SHR)

Rats SHR age from 15 to 20 weeks were shot intraperitoneal introduction of thiopental sodium (50 mg/kg). Deep anesthesia was maintained, not necessarily carrying out additional anesthesia (5 mg/kg, intravenously). In the left common carotid artery and veins, respectively, enter kayem blood pressure as a basis for calculation.

When the blood pressure is stabilized after surgery, intravenous connection comparison at doses of 0.1, 0.3 and 1.0 mg/kg and measure the blood pressure and heart rate. After the injection of the measurement carried out after 10 minutes in the case of 0.1 and 0.3 mg/kg or 30 minutes in the case of 1.0 mg/kg of the Compound according to the invention are administered intravenously in doses of 0.03, 0.1 and 0.3 mg/kg and measurements carried out 10 minutes after the injection in the case of 0.03 and 0.1 mg/kg or 30 minutes after injection in the case of 0.3 mg/kg

The connection of the comparison shows a continuing decrease in blood pressure effect on 3 to 4% at the dose of 0.3 mg/kg or above and from 12% to 13% in the case of 1.0 mg/kg, and the blood pressure does not return to the original within 30 minutes after injection. Heart rate tends to decrease.

The compound of the present invention shows an obvious downward pressure effect on about 8% at a dose of 0.03 mg/kg or higher, and then shows a continuing decrease in blood pressure effect from 13 to 15% at the dose of 0.1 mg/kg and 23% at the dose of 0.3% mg/kg Heart rate does not change.

Thus, this suggests that the compound of the present invention problemanalysis study C-6

Downward pressure effect by oral administration to SHR

Using male rats with spontaneous hypertension (aged 16 to 17 weeks), administered orally, the compound of example C-8 and comparative compound [S-(R*, R*] - 2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxohexyl)amino]-2-oxo-1H-benzazepin-1-acetic acid having the following structural formula, each dissolved in a 0.5% methylcellulose. Downward pressure effect is measured by the method of the cuff on the tail and compare the data obtained prior to oral administration and after 2, 4 and 8 hours. Downward pressure effect achieved 1.0 mg/kg compound of example C-8 was comparable to the effect achieved 10 mg/kg of the above compounds comparison. Accordingly, the compound of example C-8 has an activity of about 10 times higher than the comparative compound.

Comparative compound

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An example of pharmacological research, D-1. The definition of inhibiting NEP and ACE activity

1. Research methods

As the source of enzyme NEP membrane fraction derived from the cortical substance of the kidney in rats in accordance with the method Boofh u Kenny (a Rapid Mefhod for the Purification of Microvelli from Rabbit Kidney, Andrew G. Boofh and A. John Kenny. Biochem. J., 1974, 142, 575-581). endopeotidase from Bovine Pitutaries, Maran Orlowsky and Shruru Wilk, Biochenustry, 1981, 20, 4942-4950). Next, the method will be briefly described.

As the substrate used benzoyl-glycyl-arginine-arginine-2-naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem., Surtgeland)). In the presence of the drug enzyme NEP and excess leucine amino peptidases (Sigma Chemical Co. , U. S. A.), released naphtylamine subjected to color expression using the first garnet (garnet) - (Sigma Chemical Co., U. S. A.), followed by measuring the absorbance at a wavelength of 540 nm.

As the source of enzyme ACE membrane fraction obtained from rat lung in accordance with the method of Wu-Wong et al., (Characterization of Endthelin Engyme in Rat Zung, Junshyum R. Wu-Wong Gerald, P. Budzik, Edward M. Devine and Terry J. Opgenorth, Biochem, Biophys. Res. Commun, 1990, 171, 1291-1296). The ACE activity determined using a modification (modified borate buffer, pH 8,3) method of Cushman and Cheung (Spectrophotometric Assay and Properties of Angioteusen - Canerting Enzyme of Rabbet Zung, Cushman D. W. and H. S. Cheung, 1971, 20, 1637 - 1648).

In the presence of ACE hippurate released from hyperelliptical-leucine (Hippuris-His-Leu (Peptide Justitute Inc., Japan)) is extracted with ethyl acetate and then the adsorption is measured at a wavelength of 228 nm.

To determine NEP inhibitory activity and ACE inhibitory activity of the inhibitor added to the system under study activity both parmegiani. Then the concentration at which achieved 50% inhibition, take on the IC50.

2. Results studies

Table D-1 shows the results of a study conducted in accordance with the above method research D-1.

An example of pharmacological research, D-2

1. Research methods

Rats with spontaneous hypertension (SHR) age from 15 to 20 weeks were shot intraperitoneal introduction of thiopental sodium (50 mg/kg). Deep anesthesia support optional carrying out additional anesthesia (5 mg/kg, intravenously). In the left common carotid artery and vein, respectively, introducing the catheter to measure blood pressure and to inject the drug. Heart rate calculated using blood pressure as a basis for calculation.

When the blood pressure is stabilized after surgery, intravenous connection comparison or connection example 9 in doses of 0.1, 0.3 and 1.0 mg/kg and measure the change in blood pressure and heart rate. After the injection of the measurement carried out after 10 minutes in the case of 0.1 and 0.3 mg/kg or 30 minutes in the case of 1.0 mg/kg

2. The results of 3 to 4% at the dose of 0.3 mg/kg or above and from 12% to 13% in the case of 1.0 mg/kg, and the blood pressure does not return to the original within 30 minutes after injection. While the heart rate tends to decrease.

On the other hand, the compound of example D-6 shows an obvious downward pressure action (3 to 4%) at a dose of 0.1 mg/kg or higher, and shows a continuing decrease in blood pressure steps from 10 to 13% at the dose of 0.3 mg/kg and 25% at the dose of 1.0 mg/kg while the heart rate tends to decrease.

Accordingly, based on the results of case study D-2 described above, it was confirmed that the downward pressure action connection example D-6 in SHR was about three times higher than the connection of the comparison.

An example of pharmacological research, E-1

(Definition of inhibiting NEP and ACE activity)

1. Research methods

As the source of enzyme NEP membrane fraction derived from the cortical substance of the kidney in rats in accordance with the method of Booth and Kenny (Raped A Method for the Purification of Microvilli from Rattit Kidney., Andrew G. Both and A. John Kenny, Biochem. J., 1974, 142, 575-581). The NEP activity is determined in the following way in accordance with the method Orlowsky and Wilk (Perification and Specifecity of Membrane - Bound Metalloendopeptidase from Bovine Pituifaries. Maria is comfort benzoyl-glycyl-arginyl-arginyl-2-naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem, Switzerlaud)). In the presence of the drug enzyme NEP and excess leucine amino peptidases (Sigma Chemical Co. , U. S. A.) released naphtylamine subjected to color expression using the first garnet (first grenade (Sigma Chemical Co., U. S. A.), followed by measuring the absorbance at a wavelength of 540 nm.

As the source of enzyme ACE membrane fraction obtained from rat lung in accordance with the method of Wu-Wong et al., (Churacterization of Endtelin Enzyme in Rat Lung., hunshyum R. Wu-Wong, Gerald, P. Budzik, Edward M. Devire and Terry I. Opgenorth, Biochem., Biophys. Res. Commun., 1990, 171, 1291-1296). The ACE activity determined using a modification (modified borate buffer, pH 8,3) method Cushmann Cheung (Spectrophotometric Assay and Properties of Angiotensin - Converting Enzyme of Rabbit Lung., Cushman, D. W. and Cheung, H. S., 1971, 20, 1637-1648). Next, the method will be briefly described.

In the presence of ACE hippurate released from hyperelliptical-leucine (Hippuric-His-Leu (Pertide Institute Inc., Japan)), extracted with ethyl acetate and then the adsorption is measured at a wavelength of 228 nm.

To determine NEP inhibitory activity and ACE inhibitory activity of the inhibitor added to the system under study the activity of both enzymes described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm, and build a curve of inhibition. Then the concentration at which dostigaetca E-1 shows the results of a study conducted in accordance with the above-described method of study.

An example of pharmacological research, E-2

The male Wistar rats aged 11 to 13 weeks was injected intravenously (1 mg/kg) and oral appoint (10 mg/kg, 30 mg/kg) compound of example E-6 or comparative compound E-1. Then recorded changes in the level of each drug in the blood over time using liquid chromatography. In the case of compound E-6 level of the drug in the blood was determined by measuring UV absorption (257 nm). Whereas in the case of compound comparison E-1 level of the drug in the blood was determined by the method of fluorescent labels using ABD-F. bioavailability of the compound of example E-6, calculated from the AUC oral administration and AUC of intravenous administration, was respectively of 24.6% (30 mg/kg, p. O. (oral)) and 18.8% (10 mg/kg, p. O.). On the other hand, the dynamics in vivo connections compare E-1 measured in the same way. It is determined that the bioavailability was 7.8 per cent (30 mg/kg, p. O. ) and 4.3% (10 mg/kg, p. O.). Accordingly, the compound of example E-6 is superior in absorption with oral administration of the compounds comparison of E-1.

Example pharmacological studies E-3. The study SWAT units (3,69 nm) [3H]-Arg-vasopressin, 25 g (1 mg protein/ml) of each sample membrane and the investigational product (10-7up to 10-5M) inhibited when the total volume of 250 l of the investigated buffer (pH 7,4) containing 10 mm NgCl2, 2 mm EGTA and 20 mm HEPES at 4oC during the day and night. Then incubat washed 5 times in portions of 5 ml of the buffer for the Department through this sample membranes associated with vasopressin followed by filtration using a glass filter (GF/F). This glass Frit is dried for about 3 hours, and mixed with a cocktail for liquid scintillation (10 ml, ACSII). After standing over night determine the number of [3H]-Arg-vasopressin, is associated with the membrane, using a counter liquid scintillation, and the degree of inhibition calculated in accordance with the following formula:

The degree of inhibition (%) = 100 - [(C1 - B1)/(C0 - B1)]100

where

B1 - the number of [3H]-Arg-vasopressin, is associated with the membrane, in the presence of excess vasopressin (10 g)

C0 is the number of [3H] -Arg-vasopressin, is associated with the membrane, in the absence of the investigated drug

and

C1 is the number of [3H]-Arg-vasopressin, is associated with the membrane, in the presence of the investigational product in a known quantity and [3Nia, in accordance with the above formula, and take over the IC50.

IC50the compound of example E-10, above a certain way to receptor (V1) vasopressin is 10 M or higher, while for the receptor (V2) vasopressin is 4,49 M

An example of pharmacological research, F1 (Definition of inhibiting NEP and ACE activity)

1. Research methods

As the source of enzyme NEP membrane fraction derived from the cortical substance of the kidney in rats in accordance with the Booch method and Kenny (a Rapid Method for tfe Purification of Microvilli from Rabbit Kidney., Andrew J. Booth and A, John Kenny, Biochem. J., 1974, 142, 575-581). The NEP activity is determined in the following way in accordance with the method Orlowsky and Wilk (Purification and Specificity of Membrane - Bound Metalloendopeptidase from Bovine Pituitaries. , Marian Orlowsky and Shrwin Wilk, Biochemistry, 1981, 20, 4942-4950). Next, the method will be briefly described.

As the substrate used benzoyl-glycyl-arginyl-arginyl-2-naphthylamide (benzoyl-Gly-Arg-Arg-2-naphthylamide (Nova Biochem, Swifzerland)). In the presence of the drug enzyme NEP and excess leucine amino peptidases (Segma Chemical Co. , U. S. A.) released naphtylamine subjected to color expression using the first garnet (first grenade - Tr) (Sigma Chemical Co., U. S. A.), followed by measuring the absorbance at a wavelength of 540 nm.

In the presence of ACE hippurate released from hippuris-histidyl-leucine (Hippuris - His-Leu (Peptude Sustitufe Suc., Japan)) is extracted with ethyl acetate and then the adsorption is measured at a wavelength of 228 nm.

To determine NEP inhibitory activity and ACE inhibitory activity of the inhibitor added to the system under study the activity of both enzymes described above, thus giving a final concentration of at 1, 3, 10, 30, 100, 300 and 1000 nm and build a curve of inhibition. Then the concentration at which achieved 50% inhibition is taken as the IC50.

2. The results of the study

Table F1 shows the results of a study conducted in accordance with the above-described method of study.

Example pharmacological studies F-2. Study of the binding of receptors V1 and V2

We used the samples of the membranes of the rat lung (V1) and rat of bookreport (10-7up to 10-5M) inhibited when the total volume of 250 l of the investigated buffer (pH = 7,4) containing 10 mm MgCl2, 2 mm EGTA and 20 mm HEPES at 4oC during the day and night. Then incubat washed 5 times in portions of 5 ml of the buffer for the Department through this sample membranes associated with vasopressin followed by filtration using a glass filter (GF/F). This glass Frit is dried for about 3 hours and mixed with a cocktail for liquid scintillation (10 ml, ACS II). After standing overnight, determine the number of [3H] -Arg-vasopressin, is associated with the membrane, using a counter liquid scintillation, and the degree of inhibition calculated in accordance with the following formula:

The degree of inhibition (%)

= 100 - [(C1 - B1)/(C0 - B1)] 100

where

B1 - the number of [3H]-Arg-vasopressin, is associated with the membrane, in the presence of excess vasopressin (10 g)

C0 is the number of [3H]-Arg - vasopressin, is associated with the membrane, in the absence of the investigated drug and

C1 is the number of [3H]-Arg-vasopressin, is associated with the membrane, in the presence of the investigational product in a known quantity and [3H]-Arg-vasopressin.

Determine the number of studied patients is P CLASS="ptx2">

IC50the compound of example 10, above a certain way to receptor (VI) vasopressin is 10 M or higher, while for the receptor (V2) vasopressin is 1,39 m .

The results of the experiments described above clearly indicate that the connection according to the invention have an inhibiting ACE activity, inhibiting NEP action or action vasopressin antagonist. Therefore, the compounds of the present invention inhibit the formation of al-P, which is a factor contributing to heart failure along with increase the actions of ANP, which is involved in the compensation mechanism for symptoms of heart failure, and therefore, as expected, has a different therapeutic effect in heart failure, for example, reduces the liquid body, facilitates pre-load, facilitates subsequent load or the like. In addition, these compounds are useful as antihypertensive diuretic. Further, the compounds of the present invention are effective in such diseases that can be treated and use of NEP inhibition action or ACE inhibitory actions udna toad or high blood pressure, kidney weakness, swelling, delay salts, pulmonary edema, pain, in the treatment of mental conditions such as depression, angina, premenstrual syndrome, Meniere disease, hyperaldosteronism, hypercalcinuria, glaucoma, asthma, gastrointestinal diseases, such as diarrhea syndrome intestinal irritation and increased acidity induced by cyclosporine kidney weakness and the like.

In addition, the above examples pharmacological studies clearly show that the compounds of the present invention are comparable or even superior to existing and presents ACE and NEP-dual inhibitors on ACE inhibitory and NEP-action and exceed their hypotensive and diuretic effects. In addition to the above examples, pharmacological studies were separately conducted studies that used the SHR for the study of the antihypertensive effect when administered intravenously. It is shown that when comparing commonly used well-known dual inhibitors (1) [S-(R*, R*)- 2,3,4,5-tetrahydro-3-[(2-mercapto-I-oxohexyl-3-phenylpropyl)] -2-oxo - 1H-benzazepin-1-acetic acid and (2) [S-(R*, R*)- 2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-and the example C-10, inhibitors (1) and (2) can be introduced at a dose of 1.0 mg/kg for lowering blood pressure by 10%, whereas with the introduction of from 0.03 to 0.1 mg/kg of the compound of example C-8 and the introduction of from 0.1 to 0.3 mg/kg compound of example C-10, in each case, achieving the same effect.

It was also found that the compounds of the present invention have the advantage that they possess a excellent effect when administered orally. This property is excellent actions when oral administration is highly preferred from the viewpoint that the disease, which use compounds of the present invention, usually require long-term administration.

Of the present invention is also clear that the compounds of the present invention is particularly excellent in oral administration are those that are radical (2S, 3S)-3-methyl-2-thiapentanal acid in the side chain.

Because compounds of the invention have low toxicity and high safety, they are substances, each of which is particularly preferable when used as a medicine.

In addition, the compounds of the present invention have an antagonistic effect in respect to the Noah failure, increased pressure or the like. It is believed that this action increases the effectiveness of the compounds of the present invention when the above-mentioned diseases.

When the compound of the present invention is used as a preventive or therapeutic agent in the treatment of the above diseases, it can be entered as oral and parenteral. It dose not specifically limited, but varies depending on, for example, status, age, sex, and drug susceptibility of the patient, route of administration, time of administration, the frequency of introduction, properties of drugs, type of drug and type of active ingredient. Typically, the preferred dose is from about 0.1 to 1000 mg/day for an adult, from disposable to reception a few times.

Compounds of the present invention can be included in a medicinal product in the usual way using fillers for drugs commonly used in this field.

Namely, in the manufacture of solid pharmaceutical preparation for oral administration add media to the primary agent, and if necessary, a binder, razryhlitel formed in the usual way into tablets, coated tablets, granules, powders, capsules, etc.

As the above-mentioned fillers are used, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide.

As a binder used, for example, polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum Arabic, tragakant, gelatin, shellac, hydroxypropyl-cellulose, hypromellose, calcium citrate, dextrin, pectin and the like. As lubricating agents are used, for example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil and the like.

As coloring agents can be used such that are approved for addition to drugs. As flavouring additives used cocoa powder, mint, aromatic powder, peppermint oil, borneol and powdered cinnamon bark, and the like. As antioxidants can be used such that encouraged to add to medicines, such as ascorbic acid (vitamin C) and tocopherol (vitamin E). Needless to say, if necessary, these tablets and granules may be subjected to nasenyana, in the manufacture of injection was added when necessary, pH regulators, buffers, suspendresume agents, agents that promote dissolution, stabilizers, isotonic agents, antioxidants, preservatives, and the like. Thus can be obtained drugs for intravenous, subcutaneous and intramuscular injection. The preparation for injection can be optionally made in the form of dried freezing form.

Examples of the above suspendida agents include methylcellulose, Polysorbate 80, hydroxyethyl cellulose, gum Arabic, powder tragakant, sodium carboxymethylcellulose, polyoxyethylenesorbitan monolaurate and the like.

Examples of agents that promote dissolution include polyoxyethylene, utverjdenie castor oil. Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Marcogol, castor oil, ethyl ester of the fatty acid and the like.

As the stabilizers used, for example, sodium sulfate, metasulfite sodium, ether and the like. Examples of conservatives include methyl para-hydroxybenzoate, ethyl of parahydroxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.

P is to say, that the present invention is not limited to only them.

Examples of the synthesis of the starting compounds is also described hereinafter, before the examples.

Synthetic example a-1

7 tripterocalyx-3,4-dihydro-1(2H)-naphtalene

< / BR>
In 100 ml 9,94 g (61,29 mmol) of 7-hydroxy-3,4-dihydro-1(2H)-naftalina and 24.8 ml (306 mmol) of pyridine in dichloromethane, mixed at 0oC add amounts dropwise up 11,86 ml triftormetilfullerenov anhydride, keeping the temperature no higher than 5oC. After stirring at the same temperature for 10 min and then at room temperature for 30 min, added to the reaction mixture water. Separated dichloromethane layer was washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is subjected to column chromatography on silica gel. After stepwise elution with hexane: ethyl acetate in a ratio varying from 10:1 (by volume) up to 8:1 (by volume), get 15,33 g specified in the title compounds as a pale yellow oily product.

Yield 85%.

1H NMR (400 MHz, CDCl3) :

to $ 7.91

Synthetic example a-2

7-Phenyl-3,4-dihydro-1(2H)-naphtalene

< / BR>
To stir at room temperature a mixture containing 15,31 g (52,06 mmol) 7-tripterocalyx-3,4-dihydro-1(2H)-naftalina obtained in synthesis example A-1, 12.7 g (104,12 mmol) of phenylboric acid, 10.8 g (78,09 mmol) of potassium carbonate and 450 ml of toluene, propulsive nitrogen, for 30 minutes. Then there is added 1,81 g (1.57 mmol) of tetranitroaniline palladium. The mixture is slowly heated, continuing transmission of nitrogen, to a temperature of about 90oC. After stirring at this temperature for 90 minutes, the reaction mixture is cooled and water is added. Insoluble products are collected by filtration on celite and thoroughly washed with ethyl acetate. The organic phase is collected, washed successively with saturated aqueous sodium hydrogen carbonate solution, water, 1 n hydrochloric acid, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is subjected to column chromatography on silica gel. After stepwise elution with hexane: ethyl acetate in a ratio varying from 20:1 (by volume) to 12:1 (by volume), get 9.53 g specified the 1H, d, J = 2 Hz), 7,72 (2H, DD, J = 8,2 Hz).

of 7.64 - 7,33 (8H, m), a 3.01 (2H, t, J = 6 Hz).

a 2.71 (1H, d, J = 6 Hz), 2,69 (1H, d, J = 6 Hz).

to 2.18 (2H, Quint. J = 6 Hz).

Synthetic example a-3

8-Phenyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-he

< / BR>
The mixture 9,19 g (41,34 mmol) 7-phenyl-3,4-dihydro-1-(2H)-naftalina obtained in synthetic example A-2, 150 g of polyphosphoric acid was stirred at 50 to 60oC and to it was added by portions 2,96 g (got 45.47 mmol) of sodium azide in solid form. After stirring at this temperature for an additional 90 minutes, the reaction mixture was poured into ice water. The resulting crystals are collected by filtration, washed with water and n-hexane and dried in hot air at 70oC during the night. Thus obtained 9.3 g specified in the header of the product. Yield 95%.

1H NMR (400 MHz, DMSO-d6) :

a 9.60 (1H, s), 7,58 (2H, d, J = 8 Hz), 7,44 (2H, t, J = 8 Hz),

7,35 - 7,29 (3H, m), 7,22 (1H, d, J = 2 Hz),

2,69 (2H, t, J = 7 Hz), 2,17 (2H, t, J = 7 Hz),

of 2.09 (2H, Quint, J = 7 Hz).

Synthetic example a-4

3,3-Dichloro-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
To the mixture to 8.94 g (37,67 mmol) of 8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-it is obtained by synthetic example A-3, with 180 ml of XI the 90oC for 30 minutes to the reaction mixture, water is added, followed by neutralization with an aqueous solution of sodium bicarbonate. After extraction with dichloromethane dichloromethane phase is washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the oily residue is crystallized by adding ethyl acetate. So get 2,60 g is specified in the header of the product. The mother liquor is subjected to column chromatography on silica gel. After stepwise elution with hexane : ethyl acetate in a ratio varying up to 20:1 (by volume), get another 0,38 g specified in the connection header. By combining both of the above product, get the total output 2,98 g specified in the connection header.

Yield 26%.

1H NMR (400 MHz, CDCl3) :

of 7.70 (1H, d, J = 2 Hz), to 7.61 - to 7.35 (3H, m)

7,21 (1H, d, J = 8 Hz), 3,09 - a 3.01 (4H, m).

Synthetic example a-5

3-Chloro-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
A mixture containing 2,88 g (9.4 mmol) of 3,3-dichloro-8-phenyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-it is obtained by synthetic example A-4, 0,89 g (11,89 mmol) of sodium acetate, 0.2 g of 10%, Pallady is. After removal by filtration of the insoluble product, the filtrate is concentrated. Then to the residue add dichloromethane, followed by neutralization with an aqueous solution of sodium bicarbonate. The dichloromethane phase is separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, to the residue is added a small amount of dichloromethane, followed by the separation of the crystals by filtration. So get 0,53 g is specified in the header of the product. The mother liquor is subjected to column chromatography on silica gel. After stepwise elution with hexane : ethyl acetate in the ratio varied from 6:1 (by volume) up to 3:1 (by volume) and then dichloromethane : methanol in the ratio 200:1 (by volume) receive an additional 0.4 g specified in the connection header. By combining both of the above products, just get 0,93 g specified in the connection header.

Yield 36%.

1H NMR (400 MHz, CDCl3) :

7,55 - 7,21 (8H, m), 4,55 (1H, DD, J = 11 Hz),

3,09 - 2,61 (4H, m).

Synthetic example a-6

3 Azido-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
A mixture containing 0.93 g (3,42 mmol) 3-chloro-8-phenyl - 2,3,4,5-Tetra the sulfoxide is stirred at 80oC for 3 hours. After further adding 0.05 g of sodium azide and stirred for 30 minutes, the reaction mixture was poured into ice water. The crystals are collected by filtration and dried under reduced pressure to get 0,77 g specified in the connection header. Yield 81%.

1H-NMR (400 MHz, DMSO-d6) :

7,60 - 7,33 (7H, m), 7,24 (1H, d, J = 2 Hz), of 3.97 (1H, DD, J = 11.7 Hz), 2,81 - 2,69 (2H, m), is 2.40 (1H, m), 2,10 (1H, m).

Synthetic example a-7

3 Azido-1-ethoxycarbonylmethyl-8-phenyl-2,3,4,5-tetrahydro - 1H-[1] -benzazepin-2-he

< / BR>
With stirring to 30 ml of a mixture of 0.75 g (2,70 mmol) 3-azido-8-phenyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-it is obtained by synthetic example A-6, 0.083 g (in 0.288 mmol of Tetra-n-butylammonium bromide, 0.17 g (3.03 mmol) of powdered sodium carbonate, and tetrahydrofuran (THF) at room temperature add 0.35 ml (3,16 mmol) ethylbromoacetate, followed by stirring for 2 hours. After adding to the reaction mixture ethyl acetate the mixture is washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is subjected to column chromatography on silica gel. After elution Geno-yellow, oily product. Yield 81%.

1H-NMR (400 MHz, CDCl3) :

7,55 - 7,34 (7H, m), 7,31 (1H, d, J = 8 Hz), 4,78 (1H, d, J = 17 Hz), 4,47 (1H, d, J = 17 Hz), 4,20 (2H, DK, J = 7,3 Hz), a 3.87 (1H, user. t, J = 9 Hz), 3,40 (1H, m), is 2.74 (1H, m), 2,52 is 2.33 (2H, m) of 1.26 (3H, t, J = 7 Hz).

The synthesis example B-1

(S)-2-(1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yl)- 3-(2-thienyl)propanoic acid

< / BR>
To 29.3 g (171 mmol) of L-(S)-3-(2-thienyl)alanine add 257 ml of dioxane, 86 ml of water, with 25.9 g (175 mmol) of phthalic anhydride and 23.9 ml (171 mmol) of triethylamine. While stirring the mixture at room temperature for 1 hour to add it to 23.9 ml of triethylamine. Add 342 ml of dioxane and the mixture is heated to boiling under reflux. When the pH of the distilled liquid shows a lack of grounds, heating stopped and the reaction mixture is concentrated under reduced pressure. Add 10 ml of diethyl ether and 684 ml of 0.5 n hydrochloric acid and the mixture is vigorously stirred. Precipitated crystals thus collected by filtration, washed with a small amount of water and dried by passing dry nitrogen. Get 40,7 g specified in the title compounds as pale yellow crystals (yield 79%).

Mass m/e (FAB); 320 (NH+)

So pl. 172 - 173oC.

1H-NMR (400 MHz,d, J = 1,6, 4,8 Hz), 7,70 - 7,74 (2H, m), 7,80 - a 7.85 (2H, m).

Synthetic example B-2

Ethyl ester of N-[(S)-2-(1,3-dihydro-1,3-dioxo-2H - isoindole-2-yl)-3-(2-thienyl)propanoic]-6-hydroxyatrazine

< / BR>
K 21.8 g (to 102.9 mmol) of the hydrochloride of the ethyl ester of 6-hydroxy-DL-norleucine add 686 ml dichloromethane and 17.0 ml (164 mmol) of N-methylmorpholine at 0oC with getting through this homogeneous solution. Then added 31.0 g (to 102.9 mmol) of the compound obtained in synthesis example B-1, and 38.2 g (154 mmol) AEDH and the resulting mixture is stirred overnight while slowly warming at room temperature. The reaction mixture was washed with 1000 ml of 1 n hydrochloric acid, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. Thus obtained residue is purified column chromatography (dichloromethane/ethyl acetate = 3 ---> 2). So get 22,8 g specified in the title compounds as a pale yellow solid product (yield 48%).

Mass m/e (FAB); 4592 (NH+)

So pl. 102 - 104oC.

1H-NMR (400 MHz, CDCl3, Me4Si) :

1,22 - of 1.27 (3H, m), 1,28 is 1.96 (7H, m), 3,57 - the 3.65 (2H, m), 3,74 - a 3.87 (2H, m), 7,81 - a 7.85 (2H, m).

Synthetic example B-3

Ethyl [5S -(5,8, (R*), 11]- 5-(1,3-dihydro-1,3-dioxo-2H - isoindole-2-yl)-6-oxo-4,5,6,8,9,10,11,11 a-octahedrite[1,2-a] thieno [3,2-c] azepin-5-carboxylate

< / BR>
In a stream of nitrogen is cooled to -65oC 93 ml of dichloromethane and add to it 1,71 ml (at 19.6 mmol) oxalicacid. After the addition dropwise of 1.53 ml (21,3 mmol) of DMSO, the mixture is stirred for 30 minutes. There is added dropwise a solution of 3.00 g (6,54 mmol) of the compound obtained in example B-2, in dichloromethane (24 ml) and the resulting mixture is stirred for 30 minutes. Then added dropwise to 9.1 ml (65 mmol) of triethylamine and the mixture is slowly heated to 0oC. Three hours later, add a solution of 12.2 g of peroxymonosulfate potassium (OXONE R) in water (50 ml) at 0oC and the mixture is vigorously stirred. After 10 minutes the organic phase is separated, washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solution is concentrated to a volume of about 65 ml at 20oC and below. At 0oC thereto are added dropwise to 6.5 ml triperoxonane acid and the resulting mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was concentrated under reduced pressure the creative aqueous sodium hydrogen carbonate solution and solid sodium bicarbonate and the mixture is vigorously stirred. The organic phase is separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The crude product is purified column chromatography on silica gel (hexanelactam-3) with getting through this 540 ml specified in the title compound as white crystals.

So pl. 140 - 150oC.

1H-NMR (400 MHz, CDCl3, Me4Si) :

of 0.94 (3H, t, J = 7.2 Hz), 1,62 - of 1.95 (3H, m), 2,14 - of 2.20 (2H, m), 2,41 - 2,49 (1H, m), 3,44 (1H, DDD, J = 1,6, 4,0, is 16.8 Hz), 3.72 points - of 3.80 (1H, m), a 3.87 - of 3.95 (1H, m), 4,58 (1H, m t), 5,32 (1H, DD, J = 1,6, to 7.67 C), are 5.36 (1H, user., t), the 6.06 (1H, DD, J = 4,0, to 13.6 Hz), 6,83 (1H, d, J = 5.4 Hz), to 7.09 (1H, d, J = 5.4 Hz), 7,70-7,76 (2H, m), 7,86 - a 7.92(2H, m).

Synthetic example B-4

2-(1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yl)-3-(3-thienyl)propanoic acid

< / BR>
56,0 g (269,6 mmol) of DL-3-(3-thienyl)alanine is subjected to interaction by the same method as in synthetic example B-1. So get to 68.4 g specified in the title compound as yellow crystals (yield 84%).

Mass m/e (FAB); 302 (MH+)

So pl. 162 - 165oC.

1H-NMR (400 MHz, CDCl3, Me4Si) : 3,55 (1H, DD, J = 4,8, or 15.0 Hz), and 3.72 (1H, DD, J = 11,6, 15,0 Hz), to 5.21 (1H, DD, J = 4,8, and 11.6 Hz), 6,91-6,93 (1H, m), 6,97 (1H, m as broadened. C), 7,18 (1H, DD, J = 3.2, and 4.8 Hz), ol-2-yl)- 3-(3-thienyl)propanoic]-6-hydroxyisoleucine

< / BR>
23,0 g (108,7 mmol) of the hydrochloride of the ethyl ester of 6-hydroxy-DL-norleucine and 32,74 g (108,7 mmol) of the compound obtained in synthetic example B-4, is subjected to the interaction with the same method as in synthetic example B-2. So get 25,9 g specified in the title compounds as pale yellow crystals (yield 52%).

Mass m/e (FAB); 458 (MH+)

So pl. 80 - 85oC.

1H-NMR (400 MHz, CDCl3, Me4Si) : 1,23-of 1.30 (3H, m), 1,31 is 1.96 (6H, m), 3,54-to 3.67 (4H, m), 4,06-4,24 (2H, m), 4,58-and 4.68 (1H, m), 5,11-5,17 (1H, m), 6,68-6,77 (total 1H, each broadened. d), 6,93-7,01 (2H, m), 7,17-7,22 (1H, m), 7,70-7,74 (2H, m), 7,79-to 7.84 (2H, m).

Synthetic example B-6

Ethyl 5-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-6-oxo - 4,5,6,8,9,10,11,11 a-octahedrite[1,2-a]thieno[3,2-c]azepin-8-carboxylate

< / BR>
2 g (4,36 mmol) of the compound obtained in synthetic B-5, is subjected to the interaction by the same method as in synthetic example B-3. So get mentioned in the title compound as white crystals in a mixture of two diastereomers (1,25 g, 67%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 0.92 and 1,25 (total 3H, each t, each J = 7.2 Hz), 1,65-of 2.50 (6H, m), 3,20 and 3.30 (total 1H, each DDD, each J = 1,6, 4,0, is 16.8 Hz), 3,76-7.23 percent (total 2H, m), 4,28-4,45 (when J = 4,0, of 14.0 Hz), 6,84 and 6,87 (total 1H, each d, each J = 5,2 Hz and J = 5.6 Hz), 7,13-7,16 (total 1H, m), 7,72 to 7.75 (2H, m), a 7.85-of 7.90 (2H, m).

Synthetic example C-1

(2R,3S)-2-Bromo-3-methylpentanoic acid

< / BR>
1.50 g (11,43 mmol) of D-ALLO-isoleucine [(2R, 3S)-2-amino-3-methylpentanoic acid] was dissolved in a mixed solvent of 12.7 ml aqueous solution of hydrogen bromide from 12.7 ml of water, then cooled to 0oC. To it is slowly added dropwise a solution of 1.20 g of sodium nitrite in 3.0 ml of water with such speed that the reaction temperature did not exceed 5oC. the mixture is Then stirred at 0oC for 30 min and then at room temperature for 3 hours. After distillation of the excess nitric acid in the form of gas under reduced pressure to conduct extraction with ether. The organic phase is washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. So get mentioned in the title compound as a yellow oil. Yield 95%.

1H-NMR (400 MHz, CDCl3) : the 4.29 (1H, d, J = 7 Hz), a 2.01 (1H, m), of 1.52 (1H, m) of 1.33 (1H, m) a 1.08 (3H, d, J = 7 Hz), of 0.95 (3H, d, J = 7 Hz).

Synthetic example C-2

(2R,3S)-2-Acetylthio-3-methylpentanoic acid

< / BR>
2,11 g (10,8 mmol) (the type of 1.41 g of thioacetate potassium at 0oC. the Mixture was stirred at 0oC for 30 minutes and then at room temperature for 5 hours. After removal by filtration of the insoluble product, the filtrate is concentrated. To the residue is added ether and saturated aqueous sodium hydrogen carbonate solution, followed by separation of the phases. The aqueous phase is acidified by addition of 2 n hydrochloric acid solution at low temperature and then extracted with ether. The ether phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. Thus obtain 1.68 g specified in the title compounds as colorless oil (yield 82%).

1H-NMR (400 MHz, CDCl3) : is 4.21 (1H, d, J = 7 Hz), 2,39 (3H, s) 2,02 (1H, m), 1,58 (1H, m), 1,22 (1H, m) of 1.03 (3H, d, J = 7 Hz), to 0.92 (3H, d, J = 7 Hz).

Synthetic example C-3

- (1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)-4-propanoic acid

< / BR>
43,70 g (181,3 mmol) - amino(1,1'-biphenyl)-4-propanoic acid and 26,80 g (181,3 mmol) of anhydrous fumaric acid are suspended in 100 ml of dimethylformamide, followed by heating at 120oC for 2.5 hours. Then, the thus obtained clear solution is poured into 1.2 l of ice water, followed by vigorous stirring. While the issue. So get 65,5 g is specified in the header of the product in the form of white crystals (yield 73%).

1H-NMR (400 MHz, DMSO-d6) : 7,83 (4H, s), 7,58 (2H, d, J = 8 Hz), 7,51 (2H, d, J = 8 Hz), 7,40 (2H, t, J = 8 Hz), 7,31 (1H, t, J = 8 Hz), 7,26 (2H, d, J = 8 Hz), 5,16 (1H, DD).

Synthetic example C-4

Methyl ester of (S)-N- [- (1,3-dihydro-1,3-dioxo-2H-isoindole - 2-yl)-(1,1'-biphenyl)-4-propionyl]-6-hydroxyisoleucine

< / BR>
To mix the solution 28,53 g (76,90 mmol) - (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)-4-propanoic acid obtained in synthetic example C-3, and 19,10 g (96,70 mmol) of methyl ester hydrochloride (S)-6-hydroxyisoleucine and 600 ml of dichloromethane add 42,47 ml of N-methylmorpholine. After a homogeneous solution was added 1-hydroxybenzotriazole hydrate and 28,92 g (150,87 mmol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide at 0oC. the Reaction mixture was stirred at 0oC for 30 minutes and then overnight at room temperature and washed with 2 N. aqueous solution of hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and an aqueous solution of sodium chloride. The dichloromethane phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromate colorless amorphous product (yield 63%).

1H-NMR (400 MHz, CDCl3) : 7,79 (2H, m), 7,69 (2H, m), 7,52 - 7,22 (9H, m), 6,77 and 6.68 (total 1H, each user. D., J = 8 Hz), 5,19 (1H, m), 4,63 (1H, m), 3.72 points and 3,71 (total 3H, each s), 3,68 - to 3.52 (4H, m), 1,97 - of 1.30 (6H, m).

Synthetic example C-5

Methyl ester of (S)-N- [- (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)-4-propionyl]-6-exonerating

< / BR>
The solution 9,82 ml (115,35 mmol) oxalicacid in 330 ml of dichloromethane is cooled to -70oC and added slowly, dropwise, a solution 8,18 ml (115,35 mmol) of dimethylsulfoxide in dichloromethane (70 ml) for 15 minutes. This reaction mixture is stirred at -70oC for 15 minutes. Then slowly added dropwise a solution of 24,80 g (48,20 mmol) of methyl ester of (S)-N- [- (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)-4-propionyl]-6 - hydroxyisoleucine obtained in synthetic example C-4, in dichloromethane (130 ml) in the temperature range from -70oC to -60oC for 40 minutes. After stirring the reaction mixture at -70oC for 20 minutes slowly added dropwise 52,66 ml of triethylamine. The reaction mixture was stirred at 0oC for 1 hour and then added dropwise in the temperature range from 0 to 5oC solution 70,18 g peroxymonosulfate potassium (OXONE R) in water (830 ml) with plorida sodium, dried over anhydrous magnesium sulfate and concentrated. So get mentioned in the title compound as a brown oil. This oldaged not purified and used in subsequent reactions (synthesis example C - 6).

1H-NMR (400 MHz, CDCL3) : 9,71 and 9,70 (total 1H, m), 7,78 (2H, m), 7,68 (2H, m), 7,50 - 7,20 (9H, m), 6.82 and 6,78 (total 1H, each user. d, J = 8 Hz), 5,20 (1H, m), br4.61 (1H, m), 3,91 (3H, s), 3.75 to to 3.52 (4H, m), 2,50 - 1,30 (total 6H, m).

Synthetic example C-6

Methyl (S)-1- [- (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)-4-propionyl]-1,2,3,4 - tetrahydro-2-piridincarboxilic

< / BR>
To methyl ether (S)-N- [- (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)-4-propionyl] -6 - exonerating obtained in synthetic example C-5 (crude product, 48.2 mmol), immediately add 60 ml triperoxonane acid at 0oC. the Solution thus obtained, was stirred at room temperature for 2 hours. The mixture is concentrated and the remaining oil is subjected to azeotropic distillation with benzene. The brown oily residue partitioned between dichloromethane and water and washed with saturated aqueous bicarbonate, water and saturated aqueous sodium chloride. The dichloromethane phase is dried over a CDMA (eluent - dichloromethane). So get to 8.70 g specified in the title compounds as a colorless amorphous product (yield calculated on the synthesis example C - 4 37%).

1H-NMR (400 MHz, CDCL3) : 7,84-7,74 (2H, m), 7,69 (2H, m), 7,53-7,20 (9H, m), 6.73 x and 6,51 (total 1H, each user. d, J = 8 Hz), 5,52, and 5.42 (total 1H, each DD, J = a 12.7 Hz), of 5.29 and 5,24 (total 1H, each dt), 5.03 and 4,88 (total 1H, each m), 2,39 (1H, m), 2,10 - of 1.75 (3H, m).

Synthetic example C - 7

[4S- (4,7(R*), 12b ]-7-(1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid

< / BR>
A solution of methyl (S)-1- [- (1,3-Ligero-1,3-dioxo-2H-isoindol-2-yl)-(1,1'-biphenyl)-4-propionyl] -1,2,3,4-tetrahydro-2-pyridinecarboxylic (to 8.70 g, 17,61 Mall, a mixture of 1:1 diastereomers) obtained in synthetic example C-6, in dichloromethane (58 ml) is added dropwise to the solution mixture was 10.82 g (2 mmol) triftormetilfullerenov acid and triperoxonane anhydride (TFAA, 2,75 ml, 19,51 mmol) at 0oC. After stirring under nitrogen atmosphere at room temperature for 30 hours, the mixture was poured into ice-cold water followed by extraction with ethyl acetate. An ethyl acetate phase is washed with water and saturated aqueous sodium chloride, dried n the gel (eluent - trichloromethane : methanol = 99:1). So get 1,80 g specified in the title compound as an amorphous product (yield 42%).

1H-NMR (400 MHz, CDCl3) : for 7.78 (2H, DD, J = 8,4 Hz), 7,66 (2H, DD, J = 8,4 Hz), 7,49 (2H, DD, J = 8,2 Hz), the 7.43 (1H, d, J = 2 Hz), 7,37 (3H, m), 7,28 (1H, TT, J = 7,2 Hz), 7,14 (1H, d, J = 8 Hz), 5,78 (1H, DD, J = a 10.6 Hz), and 5.30 (1H, t, J = 6 Hz), 5,14 (1H, DD, J = 8,4 Hz), of 4.05 (1H, DD, J = 16,10 Hz), 3,44 (1H, d, J = 16,62 Hz), 2,52 of - 2.32 (2H, m), 2,10 - of 1.97 (2H, m), 1,88 = of 1.66 (2H, m)

Synthetic example C-8

Diphenylmethyl [4S- (4,7(R*), 12b ]-7-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8, 12b-octahedrite[2,1-a][2] benzazepine-4-carboxylate

< / BR>
To a solution of 1.80 g (375 mmol) of [4S -(4,7(R*),12b]- 7-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite [2,1-a][2]benzazepine-4-carboxylic acid, obtained in synthetic example C - 7, in dimethylformamide (40 ml) was added 1.54 g (4,21 mmol) of cesium carbonate. The resulting mixture was stirred for 30 minutes. It added to 1.30 g (a 5.25 mmol) bromodiphenylmethane and stirred at room temperature for 5 hours. Distributed between ethyl acetate and water. An ethyl acetate phase is washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The amorphous residue eyes is mentioned in the title compounds as a colorless amorphous product (yield 84%).

1H-NMR (400 MHz, CDCl2) : 7,86 2H, user. C) of 7.69 (2H, DD, J = 8,4 Hz), 7,44 - 6,98 (7H, m), to 6.58 (1H, d, J = 8 Hz), 6,18 (1H, s), 6,03 (1H, DD, J = a 10.6 Hz), 5,42 (1H, t, J = 6 Hz), 5,14 (1H, DD, J = 8,4 Hz), 4,35 (1H, DD, J = 16,10 Hz), up 3.22 (1H, DD, J = 16.6 Hz), is 2.37 (2H, m), is 2.05 (1H, m), 1,80 - and 1.63 (3H, m).

Synthetic example C-9

Diphenylmethyl [4S-(4,7(R*),12b]- 7-amino-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]-benzazepin-4-carboxylate

< / BR>
2,03 g (314 mmol) diphenylmethyl [4S-(4,7(R*),12b- -7-(1,3-dihydro-1,3-dioxo - 2H-isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2] benzazepine-4-carboxylate, obtained in synthetic example C-8, is dissolved in a solution mixture of 40 ml of methanol and 20 ml of tetrahydrofuran. Add to 0.34 ml (7,10 mmol) of hydrazine monohydrate, followed by heating under reflux for 3 hours. The reaction mixture is concentrated and the remaining solid product is dissolved in dichloromethane, the insoluble material removed by filtration. The filtrate is concentrated and sticky residue purified column chromatography on silica gel (eluent - chloroform : methanol : aqueous ammonia = 98 : 2 : 0.2 to). Thus obtain 1.20 g specified in the title compounds as a colorless amorphous product (yield 74%).

1H-NMR (400 MHz, CDCl3) : :

7,40 (, ,42-5,33 (2H, m), a 4.53 (1H, DD, J = a 10.6 Hz), 3,17 (1H, DD, J = 16,8 Hz), 2,58 (1H, DD, J = 16,19 Hz), 2.40 a (2H, m), of 1.94 (1H, m), 1.85 to was 1.58 (3H, m).

Synthetic example C-10

[4S -(4,7(R*),12b]- 7-(1,3-Dioxo-1,3-dihydroindol-2-yl)-9-nitro-6-oxo - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid and

[4S -(4,7(R*), 12b ]-7-(1,3-dioxo-1,3-dihydroindol-2-yl)-11 - nitro-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4 - carboxylic acid

8,30 g of 20.5 mmol) of [4S -(4,7(R*),12b]- 7-(1,3-dioxo-1,3-dihydroindol-2 - yl)-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4 - carboxylic acid are dissolved in 110 ml of methylene chloride and then cooled to -60oC. and Then added dropwise a solution obtained by dissolving nitrone of tetrafluoroborate (0.5 M solution in sulfolane 148 ml, 74 mmol) in 90 ml of methylene chloride. The mixture is then slowly heated to 2oC for 10 hours and then stirred at 2oC for 5 hours. Then it is distributed in 500 ml of methylene chloride and 1200 ml of water. Then, after separation of the organic phase it is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solution concentrated under reduced pressure. Thus obtained residue is purified flash chromatography on silikatobetonnye in the connection header.

Synthetic example C-11

Methyl [4S -(4,7(R*),12b]- 7-(1,3-dioxo-1,3-dihydroindol-2-yl)-9-nitro-6-oxo - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylate and

methyl [4S -(4,7(R*),12b]- 7-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-11-nitro - 6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4 - carboxylate

5,47 g (12.2 mmol) of a mixture of [4S -(4,7(R*),12b]- 7-(1,3-dioxo-1,3-dihydroindol-2-yl)-9-nitro-6-oxo-1,2,4,6,7,8,12 b-octahedrite [2,1-a] [2] benzazepine-4-carboxylic acid and [4S -(4,7(R*),12b]- 7-(1,3-dioxo-1,3-dihydroindol-2-yl)-11-nitro-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid obtained in the above synthetic example C-10, is dissolved in 80 ml of dimethylformamide. To this solution add value of 4.76 g (14.6 mmol) of cesium carbonate at room temperature. Thus obtained mixture was stirred in nitrogen atmosphere for 30 minutes and then add 2,42 g (17,0 mmol) under the conditions. The resulting mixture was stirred for 11 hours. Next peremeshannyj solution is distributed into 300 ml of water and two 250-ml portions of ethyl acetate. Then after washing the separated organic phase with a saturated aqueous solution of sodium chloride it is dried over anhydrous magnesium sulfate and the solvent concentrated at the pony who chromatography on silica gel (1:1 ethyl acetate/hexane). So get of 1.62 g (yield: 29%) specified in the header compounds having a nitro-group in the 11-position and 1.78 g (yield : 31%) indicated in the title compound having a nitro-group in the 9-position.

Synthetic example C-12

Methyl [4S -(4,7(R*),12b]- 11-amino-7-(1,3-dioxo-1,3-dihydroindol-2 - yl)-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine - 4-carboxylate

< / BR>
of 1.62 g (32.5 mmol) of Methyl [4S -(4,7(R*)-12b]- -7-(1,3-dioxo-1,3 - dihydroindol-2-yl)-11-nitro-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylate obtained in the above synthetic example C-11 was dissolved in 5 ml of acetic acid and 60 ml of dimethylformamide. Then to this solution was added 230 g of 10% palladium on coal, followed by shaking at room temperature for 2 hours. Then add 150 ml of methanol to shake the solution followed by filtration. The filtrate is concentrated under reduced pressure and then the subsequent 1.50 g specified in the procurement of the connection.

1H-NMR (400 MHz, CDCl3, Me4Si) :

1,70 at 2.45 (6H, m), 3,20 (3H, s),

3,30 (1H, DD, J = 16,6, 6,7 Hz),

4.26 deaths (1H, DD, J = 16,6, 12.1 Hz), 5,19 (1H, m)

of 5.34 (1H, m), 5,98 (1H, DD, J = 12.1 is of 6.7 Hz),

6,56 (2H, m), 6,98 (1H, d, J = 8,8 Hz), 7,70-of 7.90 (4H, m).


< / BR>
1.50 g (3.5 mmol) of Methyl [4S -(4,7(R*),12b] -1-amino-7-(1,3-dioxo - 1,3-dihydroindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2] benzazepine-4-carboxylate obtained in the above synthetic example C-12 was dissolved in 50 ml of methylene chloride. Then to this solution was added 3 ml of pyridine and 440 g (3.8 mmol) of methanesulfonamide while cooling with ice. The mixture is then stirred under nitrogen atmosphere at room temperature for 2 hours. Then to mix the solution add 100 ml of 1N aqueous solution of hydrochloric acid while cooling with ice, extracted with methylene chloride. After drying over anhydrous magnesium sulfate concentrated under reduced pressure. Next, the residue is purified column chromatography on silica gel (3 : 1 methylene chloride/ethyl acetate). So get 1,14 g specified in the title compound (yield : 64%).

1H-NMR (400 MHz, CDCl3, Me4Si) :

1,60 is 2.46 (6H, m) of 3.00 (3H, s), 3,23 (3H, s),

of 3.42 (1H, DD, J = 17,6, 7,0 Hz).

to 4.46 (1H, DD, J = 17.1 to, to 11.9 Hz), to 5.21 (1H, m)

5,44 (1H, m), 6,04 (1H, DD, J = 11,9, 7,0 Hz).

of 6.65 (1H, s), 7,05 (1H, DD, J = 8,2, 2.2 Hz),

7,19 (1H, d, J = 8,2 Hz), 7,24 (1H, d, J = 2.2 Hz),

7,74-790 (4H, m).

Synthetic example C-14

Methyl [4S -(4,7(R*),12b] -11-matilal is) Methyl [4S-(4,7(R*),12b]- 11-methylsulfonylamino-7-(1,3 - dioxo-1,3-dihydroindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylate obtained in the above synthetic example C-13 dissolved in 49 ml of methanol. Then to this solution was added 123 ml (2,46 mmol) of hydrazine hydrate is added. Then the mixture is stirred in an argon atmosphere at room temperature for 66 hours. Stir the solution is concentrated under reduced pressure. Then the concentrate was added methylene chloride. After removal of insoluble material by filtration the filtrate is added ethyl acetate. Thus obtain 0.50 g (yield: 59%) indicated in the title compound as white crystals.

1H-NMR (400 MHz, CDCl3, Me4Si) : 1,60-of 2.45 (6H, m), 2,87 (1H, DD, J = 17,6, a 12.7 Hz). to 2.94 (3H, s), of 3.13 (3H, s), 3,40 (1H, DD, J = 17,6, 6,0 Hz). the 4.65 (1H, DD, J = 12,7, 6,0 Hz), and 5.30 (1H, m), 5,43 (1H, m), 7,02 (1H, DD, J = 8,2, 2,2 Hz). 7,11 (1H, d, J = 8,2 Hz), 7,16 (1H, d, J = 2,4 Hz).

Synthetic example D-1

[4S- [4,7 (R*), 12b ]]-7-(1,3-Dioxo-1,3 - dihydroindol-2-yl)-9-nitro-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid and

[4S-[4 ,7 (R*), 12b ]]-7-(1,3-dioxo-1,3 - dihydroindol-2-yl)-11-nitro-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid

the lot (8,30 g, of 20.5 mmol) dissolved in methylene chloride (110 ml) and then cooled to -60oC. and Then added dropwise a solution obtained by dissolving nitrone of tetrafluoroborate (0.5 M solution in sulfolane 148 ml, 74 mmol) in methylene chloride (90 ml). The mixture is then slowly heated to 2oC for 10 hours and then stirred at 2oC for 5 hours. Then it evenly in methylene chloride (500 ml) and water (1200 ml). Then, after separation of the organic phase it is washed with saturated aqueous sodium chloride, dried (use MgSO4) and the solution concentrated under reduced pressure. Thus obtained residue is purified flash chromatography on silica gel (1:1 ethyl acetate/hexane _ ethyl acetate containing 5% added acetic acid). So get listed in the connection header.

Synthetic example D-2

Methyl [4S -[4,7 (R*), 12b ]]-7-(1,3-dioxo-1,3 - dihydroindol-2-yl)-9-nitro-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylate and

methyl [4S-[4 ,7 (R*), 12b ]]-7-(1,3-dioxo-1,3 - dihydroindol-2-yl)-11-nitro-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylate

The mixture (vs. 5.47 g, 12.2 mmol) of [4S-[ 4,7 (R*), 12b ]]-7- (1,3-dioxo-1,3-dihydroindol-2-yl)-9-nitro-6-hoizontal-2-yl)-11 - nitro-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine - 4-carboxylic acid, obtained in the above synthetic example D-1, dissolved in dimethylformamide (80 ml). To this solution was added cesium carbonate (4,76 g, 14.6 mmol) at room temperature. Thus obtained mixture was stirred in nitrogen atmosphere for 30 minutes and then add 2,42 g (17,0 mmol) under the conditions. The resulting mixture was stirred for 11 hours. Next, the mixed solution is distributed in water (300 ml) and ethyl acetate (250 ml 2). Then after washing the separated organic phase with a saturated aqueous solution of sodium chloride her dried (use MgSO4) and the solvent concentrated under reduced pressure. After concentrating, the resulting residue purified and separated with flash chromatography on silica gel (1 : 1 etelaat/hexane). Thus receive specified in title 11-nitrosoaniline (1,62 g, 29%), and specified in title 9-nitrosoaniline (1.78 g, 31%).

Synthetic example D-3

Methyl [4S -[4,7 (R*), 12b ]]-11-amino-7-(1,3-dioxo - 1,3-dihydrazino-2-yl)-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a][2]benzazepine-4-carboxylate

< / BR>
Methyl [4S(4,7 (R*), 12b ]-7-(1,3-dioxo-1,3 - dihydroindol-2-yl)-11-nitro-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepin-4-carboxylate (1,62 g, 3.5 formamide (60 ml). Then to this solution was added 10% palladium on coal (230 mg), followed by shaking at room temperature for 2 hours. Then add methanol (150 ml) to shake the solution is filtered and the filtrate concentrated under reduced pressure. So get mentioned in the title compound (1.50 g)

1H-NMR (400 MHz, CDCl3, Me4Si) : 1,70-of 2.45 (6H, m), 3,20 (3H, s), 3,30 (1H, DD, J = 16,6, 6,7 Hz), 4.26 deaths (1H, DD, J = 16,6, 12.1 Hz), 5,19 (1H, m), of 5.34 (1H, m), 5,98 (1H, DD, J = 12.1 is of 6.7 Hz), 6,56 (2H, m), 6,98 (1H, d, J = 8,8 Hz), 7,70-of 7.90 (4H, m).

Synthetic example E-1

-(1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)- 4-propanoic acid

< / BR>
- Amino(1,1'-biphenyl)-4-propanoic acid (43,70 g, 181,3 mmol) and anhydrous fumaric acid (26,80 g, 181,3 mmol) are suspended in 100 ml of dimethylformamide (DMF) followed by heating at 120oC for 2.5 hours. Then, the thus obtained clear solution is poured into ice water (1.2 l), followed by vigorous stirring. Fall at the same time white crystals. These crystals are collected by filtration (washed with water and hexane and dried with hot air. So get listed in title product as white crystals (65,5 g, yield 73%).

1H-NMR (400 MHz, DMCO-dDD).

Synthetic example E-2

Methyl ester of (S)-N -[- (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)- (1,1'-biphenyl)-4-propionyl]- 6-hydroxyisoleucine

< / BR>
To mix the solution - (1,3-dihydro-1,3-dioxo-2H - isoindole-2-yl)-(1,1'-biphenyl)-4-propanoic acid (28,53 g, 76,90 mmol) obtained in synthetic example E-1, methyl ester hydrochloride (S)-6-hydroxyisoleucine (19,10 g, 96,70 mmol) in 600 ml of dichloromethane (CH2C12) add 42,47 ml of N-methylmorpholine (HMM). After a homogeneous solution was added 1-hydroxybenzotriazole hydrate (HOBT) hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DPC) (28,92 g, 150,87 mmol) at 0oC. After stirring the reaction mixture at 0oC for 30 minutes and then overnight at room temperature, washed 2 N. aqueous solution of hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and an aqueous solution of sodium chloride. CH2Cl2phase over anhydrous magnesium sulfate and concentrated. The remaining oil is purified column chromatography (eluent - chloroform (CHCl3): methanol (CH3OH) = 99:1). So get specified header colorless amorphous product (14,80 g, yield 63%).

1H-NMR (400 MHz, CDCl3) : 7,79 (2H, m), 7,69 (2H,m), 1,97-of 1.30 (6H, m).

Synthetic example E-3

Methyl ester of (S)-N-[ - (1,3-dihydro-1,3-dioxo-2H-isoindole - 2-yl)-(1,1'-biphenyl)-4-propionyl]-6-exonerating

< / BR>
The solution oxalicacid (9,82 ml, 115,35 mmol) in CH2Cl2(330 ml) is cooled to -70oC and added slowly, dropwise, a solution of dimethyl sulfoxide (DMSO, 8,18 ml, 115,35 mmol) in CH2Cl2(70 ml) for 15 minutes. This reaction mixture is stirred at -70oC for 15 minutes. Then slowly added dropwise a solution of methyl ester (S)-N-[ - (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-(1,1'-biphenyl)-4 - propionyl] -6-hydroxyisoleucine (24,80 g, 48,20 mmol) obtained in synthetic example E-2 in CH2Cl2(130 ml) in the temperature range from -70oC to -60oC for 40 minutes. After stirring the reaction mixture at -70oC for 20 minutes slowly added dropwise a triethylamine (tea, 52,6 ml). The reaction mixture was stirred at 0oC for 1 hour and then added dropwise in the temperature range from 0 to 5oC solution peroxymonosulfate potassium (OXONE, 70,18 g) in water (830 ml) followed by extraction of CH2Cl2CH2Cl2the phase is washed with water and saturated aqueous sodium chloride, dried over without cinefogo oil. This aldehyde is not purified and used in subsequent reactions (synthesis example E-4).

1H NMR (400 MHz, CDCl3) : 9,71 and 9,70 (total 1H, m), 7,78 (2H, m), 7,68 (2H, m), 7,50 - 7,20 (9H, m), 6.82 and 6,78 (total 1H, each user. d, J = 8 Hz), 5,20 (1H, m), br4.61 (1H, m), 3,91 (3H, s), 3.75 to to 3.52 (4H, m), 2,50 - 1,30 (total 6H, m).

Synthetic example E-4

Methyl (S)-1-[ - (1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl- (1,1'-biphenyl)-4-propionyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylic

< / BR>
To methyl ether (S)-N-[ - (1,3-dihydro-1,3-dioxo-2H - sandal-2-yl)-(1,1'-biphenyl)-4-propionyl] -6-exonerating obtained in synthetic example E-3 (crude product, 48.2 mmol), are added at once triperoxonane acid (TN, 60 ml) at 0oC. the Solution thus obtained, was stirred at room temperature for 2 hours. The mixture is concentrated and the remaining oil is subjected to azeotropic distillation with benzene. The brown oily residue partitioned between CH2Cl2and water and CH2Cl2the phase is washed with saturated aqueous bicarbonate, water and saturated aqueous sodium chloride. CH2Cl2the phase is dried over anhydrous magnesium sulfate and concentrated. The remaining oil is purified column chromatography on silica compound is a course based on the example of the synthesis of E-2 37%).

1H NMR (400 MHz, CDCl3) : 7,84 - 7,74 (2H, m), 7,69 (2H, m), 7,53 - 7,20 (9H, m), 6.73 x and 6,51 (total 1H, each user. D. J = 8 Hz), 5,52, and 5.42 (total 1H, each DD, J = a 12.7 Hz), of 5.29 and 5,24 (total 1H, each dt), 5.03 and 4,88 (total 1H, each m), a 3.87 - 3,47 (2H, m), 3,75, and the 3.65 (total 1H, each s), 2,39 (1H, m), 2,10 - of 1.75 (3H, m).

Synthetic example E-5

[4S -(4,7 (R*)-, 12b ]-7-(1,3-Dihydro-1,3-dioxo-2H - isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
A solution of methyl (S)-1-[ - (1,3-dihydro-1,3-dioxo-2H - isoindole-2-yl)-(1,1'-biphenyl)-4-propionyl] -1,2,3,4 - tetrahydro-2-pyridinecarboxylic (to 8.70 g, 17,61 mmol, a mixture of 1:1 diastereomers) obtained in synthetic example E-4, CH2Cl2(58 ml) is added dropwise to the solution mixture triftormetilfullerenov acid (10,82 g, 122 mmol) and triperoxonane anhydride (TFAA, 2,75 ml, 19,51 mmol) at 0oC. the Mixture is stirred under nitrogen atmosphere at room temperature for 30 hours, and then poured into ice water. Thus obtained mixture is extracted with ethyl acetate. An ethyl acetate phase is washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The amorphous residue is purified column chromium is in the form of an amorphous product (1.80 g, yield 42%).

1H NMR (400 MHz, CDCl3) : for 7.78 (2H, DD, J = 8,4 Hz), 7,66 (2H, DD, J = 8,4 Hz), 7,49 (2H, DD, J = 8,2 Hz), the 7.43 (1H, d, J = 2 Hz), 7,37 (3H, m), 7,28 (1H, TT, J = 7,2 Hz), 7,14 (1H, d, J = 8 Hz), 5,78 (1H, DD, J = a 10.6 Hz), and 5.30 (1H, t, J = 6 Hz), 5,14 (1H, DD, J = 8,4 Hz), of 4.05 (1H, DD, J = 16,10 Hz), 3,44 (1H, d, J = 16,62 Hz ), 2,52 of - 2.32 (2H, m), 2,10 - of 1.97 (2H, m), 1,88 - of 1.66 (2H, m).

Synthetic example E-6

Diphenylmethyl [4S-[4,7 (R*), 12b ]]-7-(1,3-dihydro - 1,3-dioxo-2H-isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2] benzazepine-4-carboxylate

< / BR>
To a solution of [4S-[4,7 (R*), 12b ]]-7-(1,3-dihydro - 1,3-dioxo-2H-isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid (1.80 g, 375 mmol) obtained in synthesis example E-5, in DMF (40 ml) was added cesium carbonate (1,34 g is 4.21 mmol). The mixture is stirred for 30 minutes. To the resulting mixture add bromodiphenylmethane (1,30 g's, 5.25 mmol) and the mixture is stirred at room temperature for 5 hours. The reaction mixture is distributed between ethyl acetate and water. Then an ethyl acetate phase is washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The amorphous residue is purified column chromatography on silica gel (eluent - CHCl3: hexane (Hex) = 4 : 1). The same is S="ptx2">

1H NMR (400 MHz, CDCl3) : a 7.85 (2H, user. C) of 7.69 (2H, DD, J = 8,4 Hz), 7,44 - 6,98 (7H, m), to 6.58 (1H, d, J = 8 Hz), 6,18 (1H, s), 6,03 (1H, DD, J = a 10.6 Hz), 5,42 (1H, t, J = 6 Hz), 5,14 (1H, DD, J = 8,4 Hz), 4,35 (1H, DD, J = 16,10 Hz). up 3.22 (1H, DD, J = 16.6 Hz), is 2.37 (2H, m), is 2.05 (1H, m), 1,80 - and 1.63 (3H, m).

An example of the synthesis of F-1

Getting diphenylmethyl 3-(4-forfinal)lactate

< / BR>
To 4-pertanyaannya (4,99 g of 27.2 mmol) is added 0.5 n aqueous HCl (123 ml). The resulting mixture was cooled to 0oC while cooling with ice and then add the silver nitrite (5.6 g, and 36.2 mmol) in several portions over 1 hour with vigorous stirring. Six hours later, the resulting mixture was warmed to room temperature and then stirred for 1 day. Fell while silver chloride is removed by filtration and the filtrate is extracted with diethyl ether (200 ml 4). Diethylamino phase dried (use MgSO4). Diethylamino phase is filtered and concentrated under reduced pressure. Thus obtained crude product (4,69 g) 3-(4-forfinal)lactic acid. Then the crude product (4,69 g) dissolved in dry dimethylformamide (80 ml) and added cesium carbonate (8,58 g of 26.3 mmol). Thus obtained mixture was stirred at room temperature for 40 minutes, and then it added bromodiphenylmethane . the received mixture is extracted with ethyl acetate (100 3). Then the organic phase is washed with saturated aqueous sodium hydrogen carbonate (100 ml) and saturated aqueous sodium chloride (100 ml) and dried over anhydrous magnesium sulfate. After filtering the precipitate (13,4 g), which is obtained by concentration of the filtrate under reduced pressure, purified column chromatography on silica gel (hexane : ethyl acetate = 90 : 10). So get mentioned in the title compound (4,2 g, 44%) as white crystals.

1H NMR (400 MHz, CDCl3) : is 2.74 (1H, d, J = 6.2 Hz), 2,98 (1H, DD, J = 6,2, 14.1 Hz), of 3.13 (1H, DD, J = 4,8, 14.1 Hz), 4,55 (1H, q, J = 5.4 Hz), 6,85 (2H, t, J = 8,4 Hz) 6,94 (1H, s), of 6.99 (2H, DD, J = 5,6, and 8.4 Hz), 7,28 - 7,38 (10H, m)

Mass m/e (FAB); 373 (MNa+)

So pl. 52 - 54oC.

Synthetic example F-2.

Getting diphenylmethyl 2 acetylthio-3-(4-forfinal)propionate

< / BR>
Triphenylphosphine (3,99 g of 15.2 mmol) dissolved in dry tetrahydrofuran (78 ml) and then cooled to 0oC while cooling with ice. Then with stirring, added dropwise aminobutiramida azodicarboxylate (DYADS (2,99 g of 15.2 mmol)). Thirty minutes later added dropwise a solution mixture teoksessa acid (1.25 ml, 17.6 mmol) with diphenylmethyl 3-(4-ftoh to react at 0oC for 3 hours. Then the ice bath removed and the reaction mixture is heated to room temperature and left to react at this temperature over night. Then the reaction mixture was concentrated under reduced pressure. Thus obtained reaction mixture was concentrated under reduced pressure. Thus obtained residue is subjected to column chromatography on silica gel (hexane : ethyl acetate = 6 : 1) to obtain by means of this crude product (4.7 g). This crude product is crystallized from diisopropyl ether and hexane (20 ml - 30 ml). Fallen thus the solid product removed by filtration and the filtrate concentrated under reduced pressure to get through this specified in the connection header (3,54 g, 76%) as an oily product.

of 2.33 (3H, s), a 3.01 (1H, DD, J = 6,6, of 14.0 Hz), 3,19 (1H, DD, J = 8,8, of 14.0 Hz) to 4.52 (1H, t, J = 8.6 Hz), for 6.81 (1H, s), 6,85 (2H, t, J = 8.6 Hz), 7,05 (2H, DD, J = 5,8, and 7.8 Hz), 7,14 - 7,17 (2H, m), 7,26 and 7.36 (8H, m).

Synthetic example F-3

Getting 2-acetylthio-3-(4-forfinal)propionic acid

< / BR>
Diphenylmethyl 2 acetylthio-3-(4-forfinal)propionate (3,38 g of 8.27 mmol) is dissolved in anisole (9.0 ml) and then cooled to -10oC. To this solution is further added cap on the low pressure. To the concentrate is added diethyl ether (80 ml) and the resulting solution was extracted with saturated aqueous sodium hydrogen carbonate (100 ml of 2). To the alkaline solution, thus obtained, is added 2 n aqueous solution of hydrochloric acid until then, until the solution becomes acidic. Then it is extracted with methylene chloride (100 ml 3). The organic phase is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The filtrate, obtained by filtration, after drying concentrated under reduced pressure. So get mentioned in the title compound (1,96 g, 98%) as colorless crystals.

1H NMR (400 MHz, CDCl3): a 2.36 (3H, s) of 3.00 (1H, DD, J = 7,4, of 14.2 Hz), 3,26 (1H, DD, J = 7,8, of 14.2 Hz), and 4.40 (1H, t, J = 7,6 Hz), 6,99 (2H, t, J = 8.6 Hz), 7,20 (2H, DD, J = 5,6, and 8.4 Hz),

Mass m/e (FAB); 243 (MH+)

So pl. 44 - 46oC.

Synthetic examples from F-4 to F-6

In accordance with the methods of synthetic examples from F-1 to F-3 receive the following connections.

Synthetic example F-4

(S)-2-Acetylthio-3-phenylpropionate acid

< / BR>
Using D-phenylalanine as the original product it was synthesized in accordance with the method according to synthetic examples from F-1 d is C), 7,21 - 7,33 (5H, m).

Mass m/e (FAB); 225 (MH+)

So pl. 59 - 61oC.

Synthetic example F-5

(S)-2-Acetylthio-3-(1,4-biphenyl)propionic acid

< / BR>
1H NMR (400 MHz, CDCl3) : a 2.36 (3H, s), of 3.07 (1H, DD, J = 7,6, 14.4 Hz), to 3.34 (1H, DD, J = 7,6, 14.4 Hz), 4,48 (1H, t, J = 7,6 Hz), 7,29 - to 7.59 (9H, m).

Mass m/e (FAB); 301 (MH+)

So pl. 122 - 123oC.

Synthetic example F-6

(S)-2-Acetylthio-3-(4-methoxyphenyl)propionic acid

< / BR>
1H-NMR (400 MHz, CDCl3) : of 2.34 (3H, s), of 2.97 (1H, DD, J = 7,6, 14.4 Hz), 3,23 (1H, DD, J = 7,6, 14.4 Hz), with 3.79 (3H, s), 4,39 (1H, t, J = 7,6 Hz), for 6.81 - 6,86 (2H, m), 7,12-7,17 (2H, m).

Mass m/e (FAB); 255 (MH+)

So pl. 95 - 96oC

Example a-1

3-Amino-1-ethoxycarbonylmethyl-8-phenyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-he

< / BR>
A mixture containing 0,785 g (2,15 mmol) 3-azido-1-ethoxycarbonylmethyl - 8-phenyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-it is obtained by synthetic example A-7, 0.05 g of 10% palladium-on-coal and 20 ml of ethanol is catalytically hydronaut at room temperature under 4 ATM for 1 hour. After separation of the catalyst by filtration, the filtrate is concentrated. Thus obtained 0.73 g specified in the title compounds as a pale yellow oily product. Output 100%.

Example a-2

3-[(S)-Acetylthio-3-phenylpropionylamino] -1-ethoxycarbonylmethyl - 8-phenyl-1H-[1]benzazepin-2-he

< / BR>
341 mg (1 mmol) 3-amino-1-ethoxycarbonylmethyl-8-phenyl-2,3,4,5 - tetrahydro-1H-[1]benzazepin-2-it, obtained in example A-1, and 247 mg (1.1 mmol) of (S)-2-acetylthio-3-phenylpropionic acid dissolved in 20 ml of dichloromethane. There is added 300 mg (1,21 mmol) AEDH (N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) and is obtained by mixing the solution stirred overnight. The reaction mixture was washed with 1 n hydrochloric acid, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to chromatography on a column of silica gel. After the sequential elution with hexane:ethyl acetate 15:1 (by volume) up to 3:1 (by volume) receive 329 mg specified in the title compounds as a colorless amorphous product. Yield 72%.

1H-NMR (400 MHz, CDCl3) : 7,55-7,15 (13H, m),? 7.04 baby mortality and 6,88 (total 1H, each user. ), 4,82 and 4,78 (General H, each d, J = 17 Hz), 4,50 (1H, m), 4,39 and 4.34 (total H, each d, J = 17 Hz), 4,27-4,12 (3H, m), 3,42-up 3.22 (2H, m) to 2.94 (1H, m), 2.77-to 2,49 (2H, m), 2,34 and 2,33 (total 3H, to the Il-1H-[1] benzazepin-2-he

< / BR>
To a mixture of 358 g (0,657 mmol) 3-[(S)-acetylthio-3-phenylpropionylamino]- 1-ethoxycarbonylmethyl-8-phenyl-1H-[1]benzazepin-2-it, obtained in example A-2, and 10 ml of degassed ethanol add 3.3 ml of degassed 1N aqueous sodium hydroxide solution at 0oC in nitrogen atmosphere with stirring. Thus obtained mixture was stirred at room temperature for 2.5 hours. The reaction mixture is cooled and acidified with 1 n hydrochloric acid and then add water. Besieged thus white crystals are collected by filtration, washed with water and n-hexane and dried under reduced pressure. So get 267 g specified in the connection header. Yield 86%.

1H-NMR (400 MHz, CDCl3) : 7,54-7,14 (13H, m), 4,74 and 4.73 (total 1H, each d, J = 17 Hz), of 4.54 (1H, m), and 4.45 to 4.47% (total 1H, each d, J = 17 Hz), 3,56, and 3,42 (total 1H, each m), 3,3-and 3.16 (2H, m), 3,06 (1H, DD, J = 14,7 Hz), 2,98 (1H, DD, J = 14,7 Hz), 2,74-2,52 (2H, m), 2,08, and 1,97 (total 1H, each d, J = 9 Hz).

Example a-4

3-[(S)-Acetylthio-3-methylbutylamine] -1-ethoxycarbonylmethyl-8 - phenyl-1H-[1]benzazepin-2-he

< / BR>
352 mg (1.04 mmol) of 3-amino-1-ethoxycarbonylmethyl-8-phenyl-2,3,4,5 - tetrahydro-1H-[1] benzazepin-2-it, obtained in example A-1, and 202 mg (1,14 mmol) of (S)-2-acetylthio-3-metaboman the tion in the title compounds as a colorless amorphous product. Yield 77%.

1H-NMR (400 MHz, CDCl3) : 7,55-7,29 (8H, m), 7,10 and 7,03 (total 1H, each user. d, J = 7 Hz), 4,86 and a 4.83 (total 1H, each d, J = 17 Hz), br4.61-of 4.54 (1H, m), and 4,39 4,37 (total 1H, each d, J = 17 Hz), 4,24-4,13 (3H, m), 3,85, and 3,84 (total 1H, each d, J = 7 Hz), 3,40 (1H, m), 2,80-2,60 (2H, m), is 2.37 (3H, s), of 2.26 and 2.95 (total 1H, each m), 1,25 (3H, q, J = 7 Hz), of 0.99 and 0.96 (total 6H, each d, DD, each J = 7 Hz, J = 7,2 Hz).

Example a-5

1-Carboxymethyl-3-[(S)-2-mercapto-3-methylbutylamine] -8-phenyl - 1H-[1] benzazepin-2-he

< / BR>
347 mg (0.7 mmol) of 3-[(S)-2-Acetylthio-3-methylbutylamine]-1 - ethoxycarbonylmethyl-8-phenyl-1H-[1]benzazepin-2-he obtained in example A-4, hydrolyzing the same way as in example A-3. So get 243 g specified in the title compound as white crystals. Yield 81%.

1H-NMR (400 MHz, CDCl3) : 7,55 - 7,29 (8H, m), 4,80, and 4,78 (total 1H, each d, J = 17 Hz), 4,60 (1H, m), 4,48, and to 4.46 (total 1H, each d, J = 17 Hz), to 3.33 (1H, m), 3,11 (1H, m), 2,78 - 2,62 (2H, m) to 2.18 (1H, m), a 2.01 (1H, m), 1,84 and 1.83 (total 1H, each d, J = 9 Hz), of 0.99 and 0.94 (6H, m).

Example A-6.

3-[(S)-Acetylthio-3-phenylpropionylamino]-1-ethoxycarbonylmethyl-1H- [I]benzazepin-2-he

< / BR>
To mix the solution 0,76 g (2.9 mmol) of 3-amino-1-ethoxycarbonylmethyl-1H-[1] benzazepin-2-it, 0.65 g (2.9 mmol) of (S)-2-acetylthio-3-phenylpropyl) 1-hydroxybenzotriazole. Thus obtained mixture was stirred at room temperature for 5 hours. After adding water to the reaction mixture it is extracted with ethyl acetate. The organic phase is washed with water, 1 n hydrochloric acid and water and dried over anhydrous magnesium sulfate. The solvent of the organic phase is distilled off under reduced pressure and the residue is subjected to chromatography on a column of silica gel. After elution with toluene: ethyl acetate at a ratio of 7:1 (by volume) to obtain 0.95 g specified in the title compounds as a colorless amorphous product. Yield 70%.

1H-NMR (400 MHz, CDCl3) : 7,30 - 7,08 (9H, m),? 7.04 baby mortality and 6,88 (total 1H, each user, J = 7 Hz), 4,77 and 4,72 (total 1H, each d, J = 17 Hz), 4,42 (1H, m), 4,33 and 4,28 (total 1H, each d, J = 17 Hz), 4,24 - 4,08 (3H, m), 3,38 - is 3.21 (2H, m), with 2.93 (1H, m), 2,75 is 2.46 (2H, m), 2,33 and 2,32 (total 3H, each s), 1.83 and of 1.66 (total 1H, each m)

Example a-7

1-Carboxymethyl-3-[(S)-2-mercapto-3-phenyl-propionamido] -1H- [1]benzazepin-2-he

< / BR>
To a stirred solution of 0.65 g (1,39 mmol) 3-[(S)-acetylthio - 3-phenylpropionylamino]-1-ethoxycarbonylmethyl-1H-[1]benzazepin-2-it, obtained in example A-6, and 10 ml of degassed ethanol, add 7 ml of degassed 1 n aqueous sodium hydroxide solution at 0oC in atmospheres of the hours. After cooling the reaction mixture and the acidification of 1 n hydrochloric acid and extracted with dichloromethane. The dichloromethane phase is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent of the organic phase is distilled off under reduced pressure. So get 0,53 g specified in the title compounds as a colorless amorphous product. Yield 96%.

1H-NMR (400 MHz, CDCl3) : 7,31 - 7,11 (9H, m), 4,68 with 4.65 (total 1H, each d, J = 17 Hz), 4,51 - to 4.38 (2H, m), 3,55 and 3,42 (total 1H, each m), 3,28 - 3,14 (2H, m), 3.05, and 2,97 (total 1H, each DD, J = 14,7 Hz). 2,72 - 2,48 (2H, m), 2,07 and 1.96 (total 1H, each d, J = 9 Hz). and 1,64 1,88 (total 1H, each m).

Example a-8

3-[(2S, 3S)-Acetylthio-3-methylalanine]-1 - ethoxycarbonylmethyl-1H-[1] benzazepin-2-he

< / BR>
0,525 g (2 mmol) 3-amino-1-ethoxycarbonylmethyl-1H- [1]benzazepin-2-it 0,418 g (2.2 mmol) (2S, 3S)-2-acetylthio - 3-methylvaleramide acid is subjected to interaction in the same way as in example A-2. So get 0,42 g specified in the title compounds as a colorless amorphous product. Yield 48%.

1H-NMR (400 MHz, CDCl3) : 7,31 - 7,00 (5H, m), 4,81 and 4,78 (total 1H, each d, J = 17 Hz). 4,53 is 4.45 (1H, m), 4,33 and or 4.31 (total 1H, each d, J = 17 Hz), 4,22 - 4,12 (2H, m), 3,91 and 3.8 every t, each J = 7 Hz),

Example a-9

1-Carboxymethyl-3-[(2S, 3S)-2-mercapto-3-methylvaleramide]- 1-1H-[1]-benzazepin-2-he

< / BR>
To mix the solution 0,385 g (0.89 mmol) of 3-[(2S, 3S)- acetylthio-3-methylvaleramide]-1-ethoxycarbonylmethyl-1H-[1]benzazepin - 2-it, obtained in example A-8, and 15 ml of degassed ethanol acidified with 7 ml of degassed 1 n hydrochloric acid with stirring at 0oC in nitrogen atmosphere. Extracted with ethyl acetate. The organic phase is washed with water and dried over anhydrous magnesium sulfate. The solvent of the organic phase is distilled off under reduced pressure. Thus obtained 0.34 g specified in the title compounds as a colorless amorphous product (yield quantitative).

1H-NMR (400 MHz, CDCl3) : 7,39 - 7,14 (5H, m), 4,74 and 4,71 (total 1H, each d, J= 17 Hz), 4,57 ñ 4.50 (1H, m), of 4.44 and 4,43 (total 1H, each d, J = 17 Hz), 3,34 - 3,10 (2H, m), 2.77 - to of 2.58 (2H, m), 2,03 - to 1.87 (2H, m), 1.85 to and 1,84 (total 1H, each d, J = 9 Hz), 1,64 of 1.50 (1H, m), 1,22 - of 1.15 (1H, m) of 0.95 (3H, d, J = 7 Hz), 0,86 (3H, t, J = 7 Hz).

Example a-10

(S)-3-[(2S, 3S)-2-Acetylthio-3-methylvaleramide] -1-ethoxycarbonylmethyl-2,3,4,5 - tetrahydro-1H-[1]benzazepin-2-he

< / BR>
0.55 g (2.1 mmol) of (S)-3-amino-1-ethoxycarbonylmethyl-1H-2,3,4,5 - tetrahydro-[1] benzazepin-2-it 0,434 g (2.3 mmol) (2S, 3S)-2-azet the m receive 0,614 g specified in the title compounds as a colorless amorphous product. Yield 67%.

1H-NMR (400 MHz, CDCl3) : 7.31-7.17(3H, m), 7.12 (1H, DD, J = 8.1 Hz), 7.01 (1H, user. d, J=7 Hz), 4.78 (1H, d, J=176 Hz), 4.49 (1H, dt, J=11.8 Hz), 4.33 (1H, d, J=17 Hz), 4.24-4.12 (2H, m), 3.89 (1H, d, J=7 Hz), 3.88 (1H, m), 2.74-2.56 (2H, m), 2.37 (3H, s) 2.04-1.87 (2H, m), 1.56 (1H, m), 1.25 (3H, t, J=7 Hz), 1.14 (1H, m), 0.96 (3H, d, J=7 Hz), 0.86 (3H, t, J=8 Hz)

Example a-11

(S)-3-[(2S, 3S)-2-Mercapto-3-methylmalonyl-amino] -1 - carbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
0.6 g (1.38 mmol) of (S)-3-[(2S, 3S)-2-acetylthio-3-methylvaleramide]-1-ethoxycarbonylmethyl-2,3,4,5 - tetrahydro-1H-[1]-benzazepin-2-she received about example A-10, hydrolyzing the same way as in example A-9. So get 0,49 g specified in the title compounds as a colorless amorphous product. Yield 97%.

1H-NMR (400 MHz, CDCl3) : 7.40 (1H, usher, J=7 Hz), 7.33-7.14 (4H, m), 4.71 (1H, d, J=17 Hz), 4.54 (1H, dt, J=11, 7 Hz), 4.44 (1H, d, J=17 Hz), 3.29 (1H, m), 3.17 (1H, DD, J=9.7 Hz), 2.74-2.59 (2H, m), 2.04-1.89 (2H, m), 1.84 (1H, d, J=9 Hz) 1.55 (1H, m), 1.17 (1H, m), 0.95 (3H, d, J=7 Hz), 0.86 (3H, t, J=7 Hz)

Example B-1

Ethyl [5(S)-(5,8(R*),11]- 5-amino-6-oxo-4,5,6,8,9,10,11,11 a-octahedrite[1,2-a]thieno[3,2-c] azepin-8-carboxylate

< / BR>
540 mg (1,23 mmol) of the compound obtained in synthetic example B-3, is dissolved in 31 ml of ethanol and add 0,072 mg (1.48 mmol) of hydrazine monohydrate. Thus obtained mixture is billaut dichloromethane. Obtained by filtration, the filtrate is again concentrated. The residue is purified by chromatography on a column of silica gel (dichloromethane/methanol/aqueous ammonia = 98 /2/ of 0.3) to give 332 mg specified in the title compound (yield 88%).

Mass m/e (FAB); 309 (MH+).

So pl. 92 - 97oC.

1H-NMR (400 MHz, CDCl3, Me4Si) : 0.881 (3H, t, J=7.2 Hz), 1.57-1.94 (5H, m), 2.03-2.21 (2H, m), 2.40-2.47 (1H, m), 2.95 (1H, m t), 3.32 (1H, DDD, J= 1.6, 4.8, 16.8 Hz), 3.67-3.75 (1H, m), 3.81-3.88 (1H, m), 4.61 (1H, DD, J=4.8, 13.2 Hz), 5.1 (1H, user.t, J=6.4 Hz), 5.30 (1H, DD, J=1.6, 8.0 Hz), 6.78 (1H, d, J=5.0 Hz), 7.04 (1H, d, J=5.0 Hz)

Example B-2

Ethyl [5S -(5,8(R*), 11 ]]-5-[[(S)-2-acetylthio-1-oxo-3-phenylpropyl] amino] -6-oxo-4,5,6,8,9,10,11,11 a-octahedrite[1,2-a] thieno [3,2-c]azepin-8-carboxylate

< / BR>
150 mg (0.49 mmol) of the compound obtained in example B-1, dissolved in 12 ml of dichloromethane, is added at 0oC 120 mg, 0.54 mmol) 2(S)-acetylthio-3-phenylpropane acid and 144 mg (of 0.58 mmol) EACH. Thus obtained mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate = 3) to give 168 mg specified in the title compound (yield 67%) as an amorphous product.

1H-is 14.0 Hz), 3.34 (1H, DD, J=7.6, 14.0 Hz), 3.51 (1H, m DD) 3.68-3.88 (2H, m), 4.33 (1H, t, J=7.6 Hz), 5.19-5.25 (2H, m), 5.50-5.57 (1H, m), 6.75 (1H, d, J=5.2 Hz), 7.04 (1H, d, J=5.2 Hz), 7.21-7.33 (5H, m), 7.50 (1H, user.e)

Example B-3

[5S -(5,8 (R*), 11 ]]-5-[[(S)-2-Mercapto-1-oxo-3 - phenylpropyl]amino] -6-oxo-4,5,6,8,9,10,11,11 a-octahedrite [1,2-a]thieno[3,2-c]azepin-8-carboxylic acid

< / BR>
To 163 mg (0.32 mmol) of the compound obtained in example B-2, add a 12.7 ml of degassed methanol. Then added to 3.8 ml of degassed 1 n aqueous solution of sodium hydroxide. Thus obtained mixture was stirred at 40oC. Seven hours later cooled to 0oC. To the reaction mixture of 5.7 ml of 2 n hydrochloric acid. The mixture is then concentrated to a certain number under reduced pressure. The crystals precipitated by adding a small amount of water, collected by filtration and dried over pjatiokisi phosphorus under reduced pressure. Thus obtain 92 mg of the mixture specified in the connection header with its epimerase at a ratio of 4 : 3 (yield 60%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 1.63 - 2.43 (6H, m), 2.54 - 4.30 (5H, m), 5.16 and 5.24 (total 1H, each m), 5.31 and 5.40 (total 1H, each m), 5.62 and 5.79 (total 1H, each m), 6.73 - 6.78 (total 1H, each m), 6.90 - 7.04 (total 1H, each m), 7.19 - 7.91 (total 6H, each m)

Example B-4]thieno[3,2-c]azepin-8-carboxylate

< / BR>
170 mg (0.55 mmol) of the compound obtained in example B-1, and (S)-2-acetylthio-3-methylbutanoic acid (107 mg, 0.61 mmol) is subjected to interaction in the same way as in example B-2. Thus obtain 203 g specified in the connection header with its epimerase (yield 79%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 0.88 and 0.89 (total 3H, each t, each J = 7.2 Hz), 1.00 and 1.01 (total 3H, each d, each J = 6.8 Hz), 1.05 and 1.06 (total 3H, each d, each J = 6.4 Hz), 1.59 - 2.24 (total 5H, m), 2.32 - 2.48 (total 2H, m), 2.40 and 2.42 (total 3H, s) 2.84 - 2.98 (total 1H, m), 3.49 - 3.58 (total 1H, m) 3.68 - 3.96 (total 3H, m), 5.23 - 5.29 (total 2H, m), 5.58 - 5.66 (total 1H, m), 6.76 (total 1H, m), 7.04 (total 1H, m) 7.52 - 7.59 (total 1H, m)

Example B-5

[5S -(5,8 (R*), 11 ]]-5-[[(S)-2-Mercapto-3 - methyl-1-oxobutyl] amino]-6-oxo-4,5,6,8,9,10,11,11 a - octahedrite[1,2-a]thieno[3,2-c]azepin-8-carboxylic acid

< / BR>
200 mg of ethyl [5S -(5,8 (R*), 11 ]]-5-[[(S)-2 - acetylthio-3-methyl-1-oxobutyl] amino] -6-oxo-4,5,6,8,9,10,11,11 a - octahedrite[1,2-a] thieno[3,2-c] azepin-8-carboxylate obtained in example B-4, is subjected to the interaction in the same way as in example B-3. So get a stereoisomeric mixture specified in the title compound as a white solid (127 mg, 74%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 6.79 (total 1H, m), 7.00 - 7.05 (total 1H, m), 7.37 - 8.23 (total 1H, m)

Example B-6

Ethyl 5-amino-6-oxo-4,5,6,8,9,10,11,11 a - octahedrite[1,2-a] thieno[3,2-c]azepin-8-carboxylate

< / BR>
1.28 g (2,92 mmol) of the compound .obtained in synthetic example B-6, is subjected to the interaction in the same way as in example B-1. Thus receive 581 mg of the mixture of diastereomers specified in the connection header in the form of a racemic modification (65%).

Mass m/e (FAB); 3,09 (MH+)

1H-NMR (400 MHz, CDCl3, Me4Si) :

0.87 and 1.30 (total 3H, each t, each J = 7.2 Hz), 1.60 - 2.48 (total 8H, m), 2.77 (total 1H, m kV) 3.13 - 3.21 (total 1H, m), 3.71 - 3.91 and 4.24 (total 2H, each m, q, each J = 7.2 Hz), 4.47 and 4.57 (total 1H, each DD. each J = 4.8, 12.8 Hz), 4.76 and 5.28 (total 1H, each DD, each J = 5.0 Hz and J = 1.6, 7.6 Hz), 5.43 and 5.49 (total 1H, each user. t and user. C ) 6.77 - 6.81 (total 1H, m), 7.07 - 7.11 (total 1H, m)

Example B-7

Ethyl 5-[(S)-2-acetylthio-1-oxo-3-phenylpropyl]-amino-6-oxo - 4,5,6,8,9,10,11,11 a-octahedrite-[1,2-a]thieno[2,3-c]azepin-8-carboxylate

< / BR>
581 mg (1.88 mmol) of the compound obtained in example B-4, and (S)-2-acetylthio-3-phenylpropane acid (423 mg, 1.88 mmol) is subjected to interaction in the same way as in example B-2. After purification by chromatography on a column (hexane/ethyl acetate = 3) persihed 33%) 1:1-mixture of diastereomers, different from those contained in the first fraction.

The first fraction

1H-NMR (400 MHz, CDCl3), Me4Si) : : 0.86 and 1.29 (total 3H, each t, each J= 7.2 Hz), 1.62 - 2.48 (total 6H, m), 2.34 and 2.36 (total 3H, each s) 2.58 - 2.70 (total 1H, m kV) 2.96 - 3.06 (total 1H, m), 3.30 - 3.42 (total 2H, m), 3.72 - 3.88 and 4.23 (total 2H, each m, q, each J = 7.2 Hz), 4.28 - 4.35 (total 1H, m) 4.80 and 5.19 - 5.23 (total 1H, each user. t and m 5.34 - 5.54 (total 2H, m), 6.74 - 6.77 (total 1H, m), 7.06 - 7.10 (total 1H, m), 7.20 - 7.47 (total 6H, m)

Subsequent fraction

1H-NMR (400 MHz, CDCl3, Me4Si) : 0.85, and 1.29 (total 3H, each t, each J = 7.2 Hz), 1.60 - 2.44 (total 6H, m), 2.34 and 2.40 (total 3H, each s) 2.44 - 3.37 (total 4H, m), 3.69 - 3.88 and 4.18 - 4.30 (total 3H, m), 4.78 and 5.22 (total 1H, each user. t and m), 5.35 - 5.55 (total 2H, m), 6.71 (total 1H, T. J = 5.2 Hz), 7.08 (total 1H, DD, J = 5.2, 8.4 Hz), 7.21 - 7.36 (total 6H, m)

Example B-8

5-[(S)-2-Mercapto-1-oxo-3-phenylpropyl]-amino-6-oxo-4,5,6,8,9,10,11,11 a - octahedrite[1,2-a] thieno[2,3-c]azepin-8-carboxylic acid

< / BR>
227 mg (0.44 mmol) of the compound obtained from the first fraction in example B-7, is subjected to the interaction in the same way as in synthetic example B-3. Thus Paul 143 mg specified in the title compound, which is a mixture of two diastereomers with a ratio of 7:3 as a white m kV) 3.06 - 3.15 (total 1H, m), 3.25 - 3.41 (total 2H, m), 3.58 - 3,65 (total 1H, m), 4.80 and 5.20 (total 1H, each DD and m as d, each J = 3.8, 5.0 Hz), 5.40 - 5.63 (total 2H, m), 6.71 - 6.79 (total 1H, m), 7.05 - 7.14 (total 1H, m), 7.21 - 7.61 (total 6H, m)

Example B-9

< / BR>
320 mg (of 0.62 mmol) of the compound obtained from the subsequent fraction from example B-7, is subjected to the interaction in the same way as in synthetic example B-3. So get 1893 mg specified in the title compound, which is a mixture of two diastereomers with a ratio of 1:1, in the form of white crystals (yield 63%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 1.68-2.52 (total 7H, m), 2.64-3.63 (total 5H, m), 4.76 and 5.17-5.21 (total 1H, each user. t and m as user. d, each J = 4.6 Hz), 5.39-5.63 (total 2H, m), 6.67 and 6.71 (total 1H, each d, and d, each J = 5.2 Hz and J = 5.2 Hz), 7.03 and 7.11 (total 1H, each d, and d, each J = 5.2 Hz and J = 4.8 Hz), 7.20-7.33 (total 6H, m).

1H-NMR (400 MHz, CDCl3, Me4Si) : 1.60-2.42 (6H, m), 2.15 (1H, d, J = 9.2 Hz), 2.61 (1H, m DD, J = 12.8, 16.0 Hz), 3.07 (1H, DD, J = 6.4, 13.6 Hz), 3.24-3.32 (2H, m), 3.45-3.51 (1H, m), 5.21 (1H, DD, J = 2.0, 7.6 Hz), 5.29-5.34 (1H, m), 5.59-5.66 (1H, m), 6.76 (1H, d, J = 5.2 Hz), 7.01 (1H, d, J = 5.2 Hz), 7.20-7.34 (6H, m).

Example C-1

Methyl [3R- [3,6(S*),9a ]]-6-[[(2S, 3S)-2-acetylthio-3-methyl-1 - oxobutyl]amino]octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
Dissolve the IDA (17 ml) is cooled to 0oC by cooling with ice. Then to this solution are successively added a solution of 193 mg (1.01 mmol) of (2S, 3S)-2-acetylthio-3-methylpentanoic acid in methylene chloride (6 ml) and 296 mg (1.20 mmol) EACH. Then the ice bath removed and the mixture stirred at room temperature overnight under nitrogen atmosphere. It is then concentrated by evaporation under reduced pressure to a certain extent. Further, the residue is dissolved in ethyl acetate. Thus obtained mixture was successively washed with 1 n hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The remainder, which is obtained by filtering and concentrating the filtrate under reduced pressure is purified by chromatography on a column (hexane: ethyl acetate = 3). Thus obtain 206 mg specified in the title compound as an amorphous product (yield 54%). 1

1H-NMR (400 MHz, CDCl3) : 0.88 (3H, t, J = 7.6 Hz), 0.99 (3H, d, J = 6.8 Hz), 1.10-1.22 (1H, m), 1.51-1.70 (2H, m), 1.82-2.14 (6H, m), 2.38 (3H, s), 3.20 (1H, DD, J = 6.4, 11.8 Hz), 3.28 (1H, DD, J = 2.4, 11.8 Hz), 3.79 (3H, s), 3.98 (1H, d, J = 6.8 Hz), 4.54 (1H, DD, J = 6.4, 10.4 Hz), 5.02 (1H, d, J = 8.8 Hz), 5.28 (1H, DD, J = 2.4, 6.4 Hz), 7.41 (1H, d, J = 6.0 Hz).

Example C-2

Methyl [3R - [3R,[3,6 (Silat

< / BR>
In the same way as in example C-1, and from 170 mg (of 0.62 mmol) of methyl [3R, [3,6 (S*), 9a ]]-6-amino-2,2 - dimethyl-5-oxo-octahedrites[3,2-a] azepin-3-carboxylate and 131 mg (0.69 mmol) (2S, 3S)-2-acetylthio-3-methylpentanoic acid obtained in synthetic example C-2, obtain 136 mg specified in the title compounds as a colorless amorphous product (yield 49%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 0.88 (3H, t, J = 7 Hz), 0.99 (3H, d, J = 7 Hz), 1.10 - 1.21 (1H, m), 1.41 (3H, s) 1.55 (3H, s) 1.50 - 1.62 (2H, m), 1.84 - 2.32 (6H, m), 2.38 (3H, s) 3.79 (3H, s) 3.98 (1H, d, J = 7 Hz), 4.52 - 4.57 (1H, m), 4.77 (1H, s) 5.11 (1H, d, J = 10 Hz), 7.43 (1H, d, J = 6 Hz)

Example C-3

3-[[(2S, 3S)-2-Acetylthio-3-methyl-1-oxo-pentyl]amino]-1 - ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
Using 0,525 g (2.00 mmol) of 3-amino-1-ethoxycarbonylmethyl - 2,3,4,5-tetrahydro-1H-[1] benzazepin-2-it 0,418 g (2,20 mmol) (2S, 3S)-2-acetylthio-3-methylpentanoic acid obtained in example C-2, repeat the processing of example C-1. So get 0,420 g specified in the title compounds as a colorless amorphous product (yield 48%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 7.31 - 7.00 (5H, m), 4.81 and 4.78 (total 1H, each d, J = 17 Hz), 4.53 - 4.45 (1H, m), 4.33 and 4.31 (total 1H, each d, J = 17 Hz), 4.22 - 4.12 (2H, m), 3.91 and 3.89 (total 1H, each (total 3H, each t, J = 7 Hz)

Example C-4

(S)-3-[[(2S, 3S)-2-Acetylthio-3-methyl-1-oxobutyl] amino]-1 - ethoxycarbonylmethyl-2,3,4,5)-etagere-1H-[1]benzazepin-2-he

< / BR>
0,550 g (2.10 mmol) of (S)-3-amino-1 - ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1] benzazepin-2-it 0,434 g (2,30 mmol) (2S, 3S)-2-acetylthio-3-methylpentanoic acid is subjected to interaction in the same way as in example C-1. So get 0,614 g specified in the title compounds as a colorless amorphous product (yield 67%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 7.31 - 7.17 (3H, m), 7.12 (1H, DD, J = 8.1 Hz), 7.01 (1H, user. d, J = 7 Hz), 4.78 (1H, d, J = 17 Hz), 4.49 (1H, dt, J = 11.8 Hz), 4.33 (1H, d, J = 17 Hz), 4.24 - 4.12 (2H, m), 3.89 (1H, d, J = 7 Hz), 3.38 (1H, m), 2.74 - 2.56 (2H, m), 2.37 (3H, s) 2.04 - 1.87 (2H, m), 1.56 (1H, m), 1.25 (1H, t, J = 6 Hz), 1.14(1H, m), 0.96 (3H, d, J = 7 Hz), 0.86 (3H, t, J = 8 Hz)

Example C-5

(R)-3-[[(2S, 3S)-2-Acetylthio-3-methyl-1-oxobutyl] amino]-5 - ethoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-he

< / BR>
0,208 g (2,74 mmol) (P)-3-amino-5-ethoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin - 4(5H)-she 0,166 g (0,872 mmol) (2S, 3S)-2-acetylthio-3-methylpentanoic acid obtained in example C-2, is subjected to the interaction in the same way as in example C-1. So get 0,200 g specified in the title compounds as colorless amorphous PRD, J = 8.2 Hz), 7.25 (1H, dt, J = 8.2 Hz), 7.08 (1H, user. d, J = 7 Hz), 4.81 (1H, d, J = 17 Hz), 4.67 (1H, dt, J = 11.7 Hz), 4.25 (2H, d, J = 7 Hz), 4.15 (1H, d, J = 17 Hz), 3.87 (1H, d, J = 8 Hz), 3.83 (1H, dt, J = 11.7 Hz), 2.77 (1H, t, J = 11 Hz), 2.37 (3H, s) 2.00 (1H, m), 1.54 (1H, m), 1.29 (3H, t, J = 7 Hz), 1.33 (1H, m), 0.94 (3H, d, J = 7 Hz), 0.85 (3H, t, J = 7 Hz)

Example C-6

Diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[[(2S, 3S) - 2-acetylthio-3-methyl-1-oxobutyl] amino] -6-oxo-11-phenyl-1,2, 3,4,6,7,8,12 b-octahedrite[2,1-a][2]-benzazepin-4-carboxylate

< / BR>
In the same way as in example C-1, and according to 1.23 g (of 2.38 mmol) diphenylmethyl [4S -(4,7 (R*)-12b ]]-7-amino-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2]- benzazepin-4-carboxylate, obtained in synthetic example C-9, and 0.52 g (2,74 mmol) (2S, 3S)-2-acetylthio-3-methylpentanoic acid obtained in synthetic example C-2, obtain 1.22 g specified in the title compounds as a colorless amorphous product (yield 74%).

1H-NMR (400 MHz, CDCl3) : 7.55-6.91 (17H, m), 6.67 (1H, d, J = 8 Hz), 6.27 (1H, s) 5.65 (1H, Quint , J = 6 Hz), 5.47 (1H, e) 5.41 (1H, e) 4.05 (1H, d, J = 7 Hz), 3.42 (1H, DD, J = 16.6 Hz) 2.61-2.40 (2H, v) 2.14 (1H, m), 2.00 (1H, m) 1.92=1,58 (5H, m), 1.24 (1H, m), 1.05 (3H, d, 7 Hz), 0.94 (3H, t, J = 7 Hz)

Example C-7

Methyl [4S, (4,7 (R*), 12b ]]-11-methylsulphonyl-amino-7-[[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl] -amino] -6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]Benz,8,12 b-octahedrite-[2,1-a] [2] benzazepine-4-carboxylate, obtained in synthetic example C-14, and 77 mg (0,405 mmol) (2S, 3S)-2-acetylethyl-3-methylpentanoic acid dissolved in 10 ml of methylene chloride and 10 ml of ethanol. To this solution was added 118 mg (0,477 mmol) N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EACH) at room temperature. Thus obtained mixture is stirred for 19 hours in a nitrogen atmosphere and concentrated under reduced pressure. To the residue was added 1 n hydrochloric acid followed by extraction with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Thus obtained residue is purified by chromatography on a column of silica gel (2:98, ethanol:dichloromethane) to obtain thus 198 mg (yield 98%) specified in the connection header.

1H-NMR (400 MHz, CDCl3) : 0.92 (3H, t, J = 8 Hz), 1.04 (3H, d, J = 7 Hz), 1.10-1.15 (2H, m), 1.60-2.12 (6H, m), 2.39 (3H, m), 2.41 (3H, s) 2.81 (1H, DD, J = 17.2, 12.8 Hz), 2.93 (3H, s) 3.09 (3H, s) 3.48 (1H, DD, J = 17.2, 5.9 Hz), 4.03 (1H, in, J = 7 Hz), 5.26 (1H, m), 5.36 (1H, m), 5.68 (1H, m), 6.94-7.68 (5H, m)

Example C-8 [3R, [3,6, (S*9a ]]-6-[[(2S, 3S)-3-Methyl-1-oxo-2-thiopental]amino]octahydro-5-oxadiazol[3,2-a]azepin-3 - carboxylic acid

< / BR>
200 mg (0.48 mmol) of methyl[3R, [3,6 (S*0, 9 for example C - 1, is placed in a flask and add 8 ml of degassed ethanol, followed by cooling to 0oC in nitrogen atmosphere. Added to 3.8 ml of degassed 1 n aqueous solution of lithium hydroxide and the resulting mixture was stirred at room temperature for 50 minutes. Thus obtained reaction mixture is acidified by the addition of 2.9 ml of 2 n aqueous solution of hydrochloric acid at 0oC and then extracted with dichloromethane. Then the organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The precipitate is recrystallized from hexanediamine. Thus receive 150 mg specified in the title compound as white crystals (87%).

1H-NMR (400 MHz, CDCl3) : 0.90 (3H, t, J = 7 Hz), 1.00 (3H, d, J = 7 Hz), 1.24 (1H, m), 1.55 - 1.74 (2H, m), 1.87 (1H, d, J = 8 Hz), 1.90 - 2.10 (6H, m), 3.20 (1H, DD, J = 6, 12 Hz), 3.24 (1H, d, J = 7 Hz), 3.36 (1H, d, J = 2, 12 Hz), 4.62 (1H, DD, J = 6, 10 Hz), 5.07 (1H, t, J = 6 Hz), 5.29 (1H, DD, J = 2, 6 Hz), 7.69 (1H, d, J = 6 Hz)

Example C-9

[3R -[3,6 (S*), 9a ]]-6-[[(2S, 3S)-3-Methyl-1-oxo-2-thiopental]amino] -2,2-dimethyl-5-oxooctanoate[3,2-a] azepin-3-carboxylic acid

< / BR>
130 mg (0.29 mmol) of methyl [3R, [3,6 S*)-9a ]]-6-[[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl]amino]-2,2-dimethyl-5 - oxo is one of methanol. To the resulting mixture degassed 1 n aqueous solution of sodium hydroxide (2,3-ml) under nitrogen atmosphere. The resulting mixture was stirred at 45oC for 8 hours. To the reaction mixture of 1.8 ml of 2 n hydrochloric acid and concentrated. To the concentrate was added water (50 ml). Dropped when the crystals are collected by filtration and dried in air for some time. Thus receive 80 mg specified in the title compound (71% yield).

1H-NMR (400 MHz, CDCl3) : 0.90 (3H, t, J=7 Hz), 1.01 (3H, d, J=7 Hz), 1.17-1.29 (1H, m), 1.53 (3H, s) 1.56 (3H, s) 1.52-1.68 (2H, m), 1.86 (1H, d, J= 9 Hz), 1.88-2.28 (6H, m), 3.27 (1H, DD, J=6, 9 Hz), 4.58-4.66 (1H, m), 4.79 (1H, s) 5.15 (1H, d, J=10 Hz), 7.84 (1H, d, J=6 Hz)

Example C-10

1-Carboxymethyl-3-[[(2S, 3S)-3-methyl-1-oxo-2-thiopental] amino] -2,3,4,5-tetrahydro-1H- [1]benzazepin-2-he

< / BR>
To mix the solution 0,385 g (0.89 mmol) of 3-[(2S, 3S)-acetylthio-3-methyl-1-oxobutyl] amino] -1-ethoxycarbonylmethyl-1H- [1]benzazepin-2-ONU obtained in example C-3, and 15 ml of degassed ethanol added degassed 1 n aqueous sodium hydroxide solution under stirring at 0oC in nitrogen atmosphere. Thus obtained mixture is stirred for 1 hour at room temperature. The reaction mixture is cooled, acidified by adding 1 n hydrochloric kislota distillation of the solvent from the organic phase obtain 0.34 g specified in the title compounds as a colorless amorphous product (quantitative yield).

1H-NMR (400 MHz. CDCl3) : 7.39-7.14(5H, m), 4.7-4.71 (total 1H, each d, J= 17 Hz), 4.57-4.50 (1H, m), 4.44-4.43 (total 1H, each d, J=17 Hz), 3.34-3.10 (2H, m), 2.77-2.58 (2H, m), 2.03-1.87 (2H, m), 1.85-1.84 (total 1H, each d, J=9 Hz), 1.64-1.50 (1H, m) 1.22-1.15 (1H, m), 0.95 (3H, d, J=7 Hz), 0.86 (3H, t, J=7 Hz)

Example C-11

(S)-1-Carboxymethyl-3-[[(2 S, 3S)-3-methyl-1-oxo-2-thiopental] amino]-2,3,4,5-tetrahydro-1H- [1]benzazepin-2-he

< / BR>
0,600 g (1.38 mmol) of (S)-3-[[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl] amino] -1-ethoxycarbonylmethyl - 2,3,4,5-tetrahydro-1H-[1] benzazepin-2-she obtained in example C-4, hydrolyzing the same way as in example C-10. So get 0,490 g specified in the title compounds as a colorless amorphous product (yield 97%).

1H-NMR (400 MHz, CDCl3) : 7.40(1H, user.d, J=7 Hz), 7.33-7.14(4H, m), 4.71 (1H, d, J=17 Hz), 4.54 (1H, dt, J=11, GC) 4.44 (1H, d, J=17 Hz), 3.29 (1H, m), 3.17 (1H, DD, J=9, 7 Hz), 2.74-2.59 (2H, m), 2.04-1.89 (2H, m), 1.84 (1H, d, J=9 Hz), 1.55 (1H, m), 1.17 (1H, m), 0.95 (3H, d, J=7 Hz), 0.86 (3H, t, J=7 Hz)

Example C-12

(R)-3-[[(2S, 3S)-3-Methyl-1-oxo-2-thiopental] -amino]-5 - carboxymethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-he

< / BR>
0.187 g (0.43 mmol) of (R)-3-[[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl] amino] -5-ethoxycarbonylmethyl - 2,3-dihydro-1,5-benzodiazepine-4(5H)-she obtained in example C-5, podvergaut processing in the same manner as in example C-10. The 1
H-NMR (400 MHz, CDCl3) : 7.67 (1H, DD, J=8.1 Hz), 7.53 (1H, d, J=7 Hz), 7.46 (1H, dt, J=8, 2 Hz), 7.36 (1H, dt, J=8,2 Hz), 7.29 (1H, dt, J=8, 1 Hz), 4.91 (1H, d, J=18 Hz), 4.72 (1H, dt, J=11.7 Hz) 4.16 (1H, d, J=18 Hz), 3.83 (1H, DD, J= 11, 7 Hz), 3.19 (1H, DD, J=9, 6 Hz), 2.88 (1H, t, J=11 Hz), 1.94 (1H, m), 1.85 (1H, d, J=9 Hz), 1.54 (1H, m), 1.20 (1H, m), 0.95 (3H, d, J=7 Hz), 0.86 (3H, t, J=7 Hz), 0.95 (3H, d, J=7 Hz), 0.86 (3H, t, J=7 Hz)

Example C-13

[4S, (4,7 (R*), 12b ]]-7-[[(2S, 3S)-2-Acetylthio-3-methyl-1-oxobutyl] amino] -6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
In a mixed solution of 1.22 g (1,773 mmol) diphenylmethyl [4S, (4,7 (R*), 12b ]]-7-[[(2S, 3S)-2-acetylthio-3-methyl-1 - oxobutyl]amino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2] benzazepine-4-carboxylate obtained in example C-5, and 1.92 ml of anisole are added dropwise br11.01 ml triftormetilfullerenov acid at 0oC. After stirring the reaction mixture at 0oC for 40 minutes it was concentrated at a temperature not exceeding 40oC. the resulting oil twice subjected to the azeotropic distillation with toluene. The resulting oil purified by chromatography on a column of silica gel (eluent - chloroform : hexane = 4:1 and chloroform : methanol = 98,5: 1,5, sequentially). So get mentioned in the title compound as a colourless amorphous product, is), 5.18 (1H, m), 4.02 (1H, d, J = 7 Hz), 3.54 (1H, m), 2.86 (1H, DD, J = 16, 12 Hz), 2.51 (1H, m), 2.40 (3H, s), 2,28 (1H, m), 2.11 (1H, m), 2.04-1.56 (5H, m), 1.20 (1H, m) of 1.02 (3H, d, J = 7 Hz), of 0.91 (3H, T., J = 7 Hz)

Example C-14

[4S -(4,7 (R*), 12b ]]-7-[[(2S, 3S)-3-Methyl-1-oxo-2 - thiopental]amino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
0,780 g (1,492 mmol) of [4S, (4,7 (R*), 12b ]]-7- [[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl] amino] -6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid obtained in example C-13, was dissolved in 20 ml of degassed ethanol and at 0oC add 4,48 ml degassed 1N aqueous solution of lithium hydroxide. The solution mixture was stirred in nitrogen atmosphere for 40 minutes.

The resulting reaction mixture is acidified by the addition of 20.0 ml of water and 2n aqueous solution of hydrochloric acid. The solid white product precipitated in this case, is collected by filtration and washed with water. So get 0,622 g specified in the title compound (yield 87%).

1H-NMR (400 MHz, CDCl3) : 7.66 (1H, d, J = 7 Hz), 7.53-7.32 (7H, m), 7.08 (1H, d, J = 8 Hz), 5.72 (1H, Quint., J = 6 Hz), 5.52 (1H, m), 5.25 (1H, m), 3.60 (1H, DD, J = 17.6 Hz), 3.23 (1H, DD, J = 9, 7 Hz), 2.93 (1H, DD, J = 17, 13 Hz), 2.55 (1H, m), 2.34 (1H, m), 2.00 (2H, m), 1.92 (1H, d, J = 8 Hz), 1.98-1.61 (4H, m), 1.25 (1H, m), 1.03 (3H, d, J = 7 Hz), 0.93 (3H, o] -6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
198 mg (0,158 mmol) of methyl [4S, (4,7 (R*), 12b ]]-11 - methylsulfonylamino-7-[[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl] amino] - 6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4 - carboxylate obtained in example C-7, is placed in a flask, followed by sufficient purging with nitrogen. Then add 5 ml of degassed ethanol and the flask was cooled in an ice bath. Then add 3.6 ml of degassed 1 n aqueous solution of sodium hydroxide. After removal of the flask from the ice bath is slowly heated to room temperature and continue stirring for 1 hour and 40 minutes. To the reaction system, add 10 ml of 1 n aqueous solution of hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over anhydrous magnesium sulfate. The organic phase is concentrated under reduced pressure and the residue crystallized from dichloromethane. Thus obtain 84 mg specified in the title compound (yield 47%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 0.93 (3H, t, J = 8 Hz), 1.04 (3H, d, J = 7 Hz), 1.22-1.35 (2H, m), 1.65-2.10 (6H, m), 2.41 (2H, m), 2.90 (1H, m), 2.91 (3H, s), 3.23 (1H, d, J = 8 Hz), 3.56 (1H, DD, J = 17.3, 6.1 Hz), 5.23 (1H, m), 5.48 (1H, m), 5.71 (1H, m), 7.01-7.16 (3H, m), 7.82 (1H, d, J = 6.6 Hz)

Example D-1

Obtaining methyl [4S -(4,7 (R*), 12b ]]-11 - BR>< / BR>
Methyl [4S -[4,7 (R*), 12b ]]-11-amino-7-(1,3-dioxo - 1,3-dihydroindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylate (1.50 g, 3.5 mmol) obtained in the above synthetic example D-3, dissolved in methylene chloride (50 ml). Then to this solution was added pyridine (3 ml) and methanesulfonamide (440 mg, 3.8 mmol) under cooling with ice. The resulting mixture was stirred in nitrogen atmosphere for 2 hours at room temperature. Then to mix the solution was added 1 n aqueous solution of hydrochloric acid (100 ml) under ice cooling, followed by extraction with methylene chloride. Methylenchloride phase is dried (use MgSO4) and then concentrated under reduced pressure. Then the residue purified by chromatography on a column of silica gel (3: 1 methylene chloride/ethyl acetate) to obtain the thus specified in the connection header (1,14 g, 64%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 1.60-2.46 (6H, m), 3.00 (3H, s), 3.23 (3H, s), 3.42 (1H, DD, J = 17.1, 7.0 Hz), 4.46 (1H, DD, J = 17.1, 11.9 Hz), 5.21 (1H, m), 5.44 (1H, m), 6.04 (1H, DD, J = 11.9, 7.0 Hz), 6.65 (1H, s), 7.05 (1H, DD, J = 8.2, 2.2 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.24 (1H, d, J = 2.2 Hz), 7.74-7.90 (4H, m).

Example D-2

Methyl [4S -(4,7 (R*),12b ]]-11-methylsulfonylamino - 7-amino-6-oxo-1,2,3,4,6,7,8,12 b-octahydro the-dihydroindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylate (1,14 g, of 2.23 mmol) obtained in the above example S-1, is dissolved in methanol (49 ml). Then to this solution was added hydrazine hydrate (123 mg, of 2.46 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 66 hours. Stir the solution is concentrated under reduced pressure. Further to the concentrate was added methylene chloride and the insoluble material removed by filtration. Then to the filtrate was added ethyl acetate. So get mentioned in the title compound as white crystals (0.50 g, 59%).

1H-NMR (400 MHz, CDCl3/CD3OD, Me4Si) : 1.60-2.45 (6H, m), 2.87 (1H, DD, J = 17.6, 12.7 Hz), 2.94 (3H, s), 3.13 (3H, s), 3.40 (1H, DD, J = 17.6, 6.0 Hz), 4.65 (1H, DD, J = 12.7, 6.0 Hz), 5.30 (1H, m), 5.43 (1H, m), 7.02 (1H, DD, J = 8.2, 2.2 Hz), 7.11 (1H, d, J = 8.2 Hz), 7.16 (1H, d, J = 2.4 Hz).

Example D-3

Methyl [4S -(4,7 R*), 12b ]]-11-methylsulfonylamino - 7-[[(S)-2-acetylthio-3-phenyl-1-oxopropyl] -amino] -6-oxo - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylate

< / BR>
Methyl [4S -(4,7 R*), 12b ]]-11-methylsulfonylamino-7 - amino-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine - 4-carboxylate (310 mg, 0.81 mmol) obtained in the above example D-2, and (S)-acetylthio-3-phenylpropionic acid (183 mg, 0.81 mmol) is dissolved in the stands shall quinoline (EACH, 221 mg, 0.89 mmol). Then thus obtained mixture was stirred in nitrogen atmosphere for 20 hours and stir the solution is concentrated under reduced pressure. Further to the concentrate was added 1 n aqueous solution of hydrochloric acid followed by extraction with methylene chloride. Then after washing the organic phase of 1 n hydrochloric acid, water and saturated aqueous sodium chloride it dry (use MgSO4) and concentrate under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (1:1 hexane/ethyl acetate) to obtain the thus specified in the title compound (240 mg, 50%).

1H-NMR (400 MHz, CDCl3, Me4Si) : 1.66-2.40 (6H, m), 2.36 (3H, s), 2.72 (1H, DD, J = 17.4, 12.4 Hz), 2.93 (3H, s), 3.06 (1H, DD, J = 14.1, 7.9 Hz), 3.10 (3H, s), 3.35 (1H, DD, J = 14.1, 7.1 Hz), 3.46 (1H, m), 4.36 (1H, t, J = 7.4 Hz), 5.23 (1H, m), 5.33 (1H, m), 5.58 (1H, m), 6.93-7.56 (10H, m).

Example D-4

Methyl [4S -(4,7 R*), 12b ]]-11-methylsulfonylamino - 7-[[(S)-2-acetylthio-3-(4-methoxyphenyl)-1-oxopropyl] amino] -6-oxo - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylate

< / BR>
Methyl [4S [(4,7 R*), 12b ]]-11-methylsulfonylamino - 7-amino-6-oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine - 4-carboxylate (188 mg, 0.49 mmol) obtained in which Langlade (10 ml), tetrahydrofuran (20 ml) and ethanol (40 ml). Then to this solution was added 405 mg (1,64 mmol) EACH at room temperature. Then thus obtained mixture was stirred in nitrogen atmosphere for 5 hours and stir the solution is concentrated under reduced pressure. Further to the concentrate was added 1 n aqueous solution of hydrochloric acid followed by extraction with methylene chloride. Then the organic phase is washed with 1 n hydrochloric acid, water and saturated aqueous sodium chloride and then dried (use MgSO4) and concentrate under reduced pressure. The obtained residue purified by chromatography on a column of silica gel (1: 1 hexane/ethyl acetate) to obtain the thus specified in the title compound (133 mg, 44%).

1H-NMR (400 MHz, CDCl3, Me4Si): : 1.66 - 2.05 (6H, m), 2.37 (3H, c). 2.72 (1H, DD, J = 17.3, 12.7 Hz), 2.94 (3H, s) of 3.00 (1H, DD, J = 14,3, 7,7 Hz), 3.11 (3H, s), 3.28 (1H, DD, J = 14.3, 7.7 Hz), 3.48 (1H, DD, J = 17.3, 5.7 Hz), 3.79 (3H, s), 4.30 (1H, t, J = 7.7 Hz), 5.23 (1H, user, d), 5.33 (1H, user, d), 5.57 (1H, Quint, J = 6.2 Hz), 6,83 (2H, d, J = 8.7 Hz), 6.97 (1H, d, J = 8.2 Hz), 7.01 (1H, DD, J = 8.2, 2 Hz), 7.24 (1H, s), 7.16 (2H, d, J = 8.7 Hz), 7.50 (1H, d, J = 6.2 Hz)

Example D-5

[4S( (4,7 (R*), 12b ]-11-Methylsulfonylamino - 7-[[(S)-2-mercapto-3-phenyl-1-oxopropyl]amino]-6-oxo - 1,2,3,4,6,7,8,12 b-octave is[[(S)-2-acetylthio-3-phenyl-1-oxopropyl] amino]-6-oxo - 1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylate (228 mg, 0,39 mmol) obtained in the above example D-3, is placed in a flask, followed by sufficient purging with nitrogen. Then the flask was added degassed tetrahydrofuran (1 ml) and methanol (6.2 ml) the flask was cooled in an ice bath. To the resulting solution was added degassed 1 n solution of lithium hydroxide (3.3 ml). After removing the ice bath, the flask is slowly heated to room temperature and the resulting mixture is stirred for 5 hours. Next, stir the solution is concentrated under reduced pressure and the concentrate is extracted with dichloromethane. Then the aqueous phase is separated and set the pH to 1 with 1 n aqueous solution of hydrochloric acid. The concentrate is extracted with methylene chloride. Then the organic phase is dried (use MgSO4) and then concentrated under reduced pressure. To the concentrate was added diisopropyl ether and then triturated. So get mentioned in the title compound (110 mg, 53%).

1H-NMR (400 MHz, CDCl3/CD3OD, Me4Si) : 1.70 - 2.50 (6H, m), 2.85 (1H, DD, J = 17.4, 12.7 Hz), 2.90 (3H, s), 3.12 (1H, DD, J = 13.8, 7.5 Hz), 3.29 (1H, DD, J = 13.8, 6.6 Hz), 3.52 (1H, m), 3.67 (1H, m), 5.19 (1H, m), 5.47 (1H, m), the 5.65 (1H, m), 7.03 - 7.80 (10h, m)

Example D-6
<6,7,8,12 b-octahedrite[2,1-a][2]-benzazepin - 4-carboxylic acid

< / BR>
Methyl [4S, (4,7 (R*), 12b ]]-11-methylsulfonylamino - 7-[[(S)-2-acetylthio-3-(4-methoxyphenyl)-1-oxopropyl]-amino]-6-oxo - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylate (133 mg, 0.22 mmol) obtained in the above example D-4, placed in the flask, followed by sufficient purging with nitrogen. Then the flask was added degassed ethanol (20 ml) and then degassed 1 n aqueous sodium hydroxide solution (5 ml). The resulting mixture was stirred at room temperature for 3 hours. Further to mix the solution was added 1 n aqueous solution of hydrochloric acid (10 ml), concentrated, followed by concentration under reduced pressure. To the concentrate was added methylene chloride and water, followed by extraction with methylene chloride. Then the organic phase separated and dried (using MgSO4) and concentrate under reduced pressure to get so specified in the title compound (80 mg, 65%).

1H-NMR (400 MHz, CDCL3/CD3OD, Me4Si) : 1.74 - 1.86 (3H, m), 1.92 - 2.07 (1H, m), 2.37 - 2.49 (2H, m), 2.83 (3H, s), 2.83 (1H, m), 3.11 (1H, DD, J = 14.0, 6.9 Hz), 3.23 (1H, DD, J = 13.8, 6.5 Hz), 3.55 - 3.66 (2H, m), 3.80 (3H, s), 5.26 (1H, user.d), 5.43 (1H, user,d), 5,62 (1H, Quint, J = 6.0 Hz), to 6.57(1H, d, J = 6,1 Hz), 6.86 (2H, d, J = 8.7 Hz), 6.96 (1H, d, J = 6.1 Hz), 7.13 - 7.19 (3H, m 2,3,4,6,7,8,12 b-octahedrite [2,1-a][2]-benzazepin-4-carboxylate

< / BR>
Diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-(1,3-dihydro - 1,3-dioxo-2H-isoindole-2-yl)-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylate (2,03 g, 3.14 mmol) obtained in synthetic example E-6, is dissolved in a solution mixture of methanol (40 ml) with tetrahydrofuran (THF, 20 ml), followed by addition of hydrazine monohydrate (0,34 ml, 7,10 mmol). Thus obtained mixture is heated under reflux for 3 hours. The reaction mixture is concentrated and to the residue are added-CH2Cl2and insoluble material removed by filtration. The filtrate is concentrated and sticky residue purified by chromatography on a column of silica gel (eluent - CHCl3: MeOH : aqueous ammonia (NH4OH) = 98 : 2 : 0.2 to). So get mentioned in the title compound as a colorless amorphous product (1.20 g, yield 74%).

1H-NMR (400 MHz, CDCl3) : 7.40 (4H, m), 7.31 (1H, TT, J = 7,2 Hz), 7.24 (1H, d, J = 2 Hz), 7.15 (1H, DD, J = 8,2 Hz), of 6.99 (2H, DD, J = 8,4 Hz), 6.87 (2H, DD, J = 8,2 Hz), 6.3 (1H, d, J = 8 Hz), 6.20 (1H, s), 5.42 - 5.33 (2H, m), 4.53 (1H, DD, J = a 10.6 Hz), 3.17 (1H, DD, J = 16.6 Hz), 2.58 (1H, DD, J = 16,10 Hz), 2.40 a (2H, m), 1.94 (1H, m), 1.85 - 1.58 (3H, m)

Example E-2

Diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[[(s)-2 - acetylthio-3-phenylpropionylamino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2, is hydroperiod[2,1-a] [2]benzazepine-4-carboxylate (0,59 g, to 1.14 mmol) obtained in example E-1, and (S)-2-acetylthio-3-phenylpropionate acid (0.27 g, 1.20 mmol) dissolved in CH2Cl2(30 ml) and add EACH (0,37 g, 1.48 mmol). The solution mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2and water and CH2Cl2the phase is washed with water, saturated aqueous sodium bicarbonate saturated aqueous solution of sodium chloride. CH2Cl2phase is dried over magnesium sulfate. So get mentioned in the title compound as a colorless amorphous product (0,89 g, exit 109%). This product is not purified, but used in the subsequent stage as such.

1H-NMR (400 MHz, CDCl3) : 7.52 - 7.41 (4H, m), 7.40 - 7.12 (15H, m), 7.04 (2H, DD, J = 8.4 Hz), 6.93 (2H, DD, J = 8.2 Hz), 6.67 (1H, d, J = 8 Hz), 6.26 (1H, s), 5.59 (1H, Quint, J = 6 Hz), 5.44 (1H, m), 5.38 (1H, d, J = 6 Hz), 4.39 (1H, t, J = 7 Hz), 3.41 (1H, DD, J = 16.6 Hz), 3.36 (1H, DD, J = 14,7 Hz), 3.07 (1H, DD, J = 14,7 Hz), 2.54 (1H, DD, J = 16,10 Hz), 2.47 (2H, m), 2.40 (3H, s), 2.00 (1H, m), 1.87 - 1.70 (3H, m)

Example E-3

Diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[[(S)-2-acetylthio-3- (4-methoxyphenyl)propionamido] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2]benzazepine-4-carboxylate

< / BR>
In the same way as in example E-2, and based on diphenyl, ,14 mmol) obtained in example E-1, and (S)-2-acetylthio-3-(4-methoxyphenyl)propionic acid (0.31 g, 1.20 mmol) get mentioned in the title compound as a colorless amorphous product (0,81 g, yield 95%).

1H-NMR (400 MHz, CDCl3) : 7.42 - 7.34 (4H, m), 7.31 (1H, m), 7.24 - 7.04 (10H, m), 7,42 - 7.34 (4H, m), 7.31 (1H, m), 7.24 - 7.04 (10H, m), 6.96 (2H, DD, J = 8,4 Hz), 6.86 (2H, DD, J = 8,2 Hz), 6.77 (2H, d, J = 8 Hz), 6.59 (1H, d, J = 8 Hz), 6.19 (1H, s), 5.51 (1H, Quint, J = 6 Hz), 5.37 (1H, m), 5.31 (1H, d, J = 6 Hz), 4.31 (1H, t, J = 7 Hz), 3.72 (3H, s), 3.34 (1H, DD, J = 16.6 Hz), 3.20 (1H, DD, J = 14,7 Hz), 2.94 (1H, DD, J = 14,7 Hz), 2.47 (1H, DD, J = 16,10 Hz), 2.40 (2H, m), 2.33 (3H, s), 1.92 (1H, m), 1.81 - 1.62 (3H, m)

Example E-4

[4S -(4,7 (R*), 12b ]]-7-[[(S)-2-Acetylthio-3 - phenylpropionylamino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid

< / BR>
To mix the solution diphenylmethyl [4S-(4,7(R*), 12b ]]-7-[[(S)-2-acetylthio-3-phenylpropionylamino]- 6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylate (0,89 g, about to 1.14 mol), obtained according to example E-2, with anisole (1,24 ml) was added dropwise triftormetilfullerenov acid (TFA, 7,08 ml) at 0oC. After stirring the reaction mixture at 0oC for 20 minutes it was concentrated at a temperature not exceeding 40oC. the oil Obtained double-rayed - CH2Cl2: Hex = 1 : 2 and CHCl3: MeOH = 99 : 1, sequentially). So get mentioned in the title compound as a colorless amorphous product (0.64 g, yield 100%, stage 2 of example E-1).

1H-NMR (400 MHz, CDCl3) : 7.38 - 7.14 (12H, m), 7.00 (1H, d, J = 8 Hz), 5.57 (1H, Quint, J = 6 Hz), 5.41 (1H, m), 5.14 (1H, d, J = 6 Hz), 4.29 (1H, t, J = 7 Hz), 3.51 (1H, DD, J = 16.6 Hz), 3.28 (1H, DD, J = 14,7 Hz), 2.99 (1H, DD, J = 14,7 Hz), 2.73 (1H, DD, J = 16,10 Hz), 2.46 (1H, m), 2.29 (3H, s), 2.26 (1H, m), 2.00 - 1.60 (4H, m)

Example E-5

[4S -(4,7 (R*), 12b ]]-7-(S)-2-Acetylthio-3-(4-methoxyphenyl)propionamido] -6-oxo-11 - phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4 - carboxylic acid

< / BR>
In the same way as in example E-4, and based on diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[(S)-2-acetylthio-3-(4-methoxyphenyl)propionamido] -6-oxo-11 - phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2]benzazepine-4 - carboxylate (0,81 g at 1.08 mmol) obtained in example E-3, get mentioned in the title compound as a colorless amorphous product (0.52 g, yield 81%).

1H-NMR (400 MHz, CDCl3) : 7.45 - 7.32 (5H, m), 7.29 - 7.24 (3H, m), 7.08 (2H, d, J = 8 Hz), 6.96 (1H, d, J = 8 Hz), 6.76 (2H, d, J = 8 Hz), 5.53 (1H, Quint, J = 6 Hz), 5.38 (1H, user. d), 5.09 (1H, user. d, J = 6 Hz), 4.22 (1H, t, J = 7 Hz), 3.72 (3H, s), 3.47 (1H, DD, J = 16.6 Hz), 3.19 (1H, DD, J = 14,7 Hz), 2.92 (1H, DD, J = 14,7 Hz), 2.71 (1H, DD, J = 16,10, ylamino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2]benzazepin-4-carboxylic acid

< / BR>
[4S -(4,7 (R*), 12b ]]-7-[(S)-2-Acetylthio-3 - phenylpropionylamino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2]benzazepine-4-carboxylic acid obtained in example E-4, was dissolved in degassed THF (2.0 ml) and methanol (10 ml). To this solution was added lithium hydroxide (4,00 ml). The mixture is stirred at room temperature under nitrogen atmosphere for 45 minutes. To the mixture are added dropwise an aqueous solution of 2.0 n hydrochloric acid (to 3.00 ml) and then add water. The resulting mixture was vigorously stirred. Fallen so white crystals are collected by filtration and dried under reduced pressure. So get mentioned in the title compound (0.45 g, yield 87%).

1H-NMR (400 MHz, CDCl3) : 7.75 (1H, d, J = 7 Hz), 7.66 (2H, d, J = 8 Hz), 7.59 (2H, t, J = 8 Hz), 7.55 - 7.37 (7H, m), 7.22 (1H, d, J = 8 Hz), 5.81 (1H, Quint, J = 6 Hz), 5.65 (1H, m), 5.36 (1H, d, J = 6 Hz), 3.82 - 3.68 (2H, m), 3.45 (1H, DD, J = 14,7 Hz), 3.30 (1H, DD, J = 14,7 Hz), 2.99 (1H, DD, J = 17,12 Hz), 2.70 (1H, m), 2.50 (1H, m), 2.21 (1H, d, J = 9 Hz), 2.23 - 1.85 (4H, m)

Example E-7

[4S -(4,7 (R*), 12b ]]-7-[(S)-2-Mercapto-3-(methoxyphenyl) propionamido] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
In the same way as in example E-6, and on the basis of [4S -(4,7 (R*), 12 ] ] -7-[(S)-2-acetylthio-3- (4-IU the g 0,708 mmol) obtained in example E-5, get mentioned in the title compound as white crystals (from 0.37 g, yield 95%).

1H-NMR (400 MHz, CDCl3) : 7.51 (1H, d, J = 7 Hz), 7.43 (2H, d, J = 8 Hz), 7.36 (2H, t, J = 8 Hz), 7.28 (2H, m), 7.08 (2H, d, J = 8 Hz), 6.99 (1H, d, J = 8 Hz), 6.78 (2H, d, J = 8 Hz), 5.57 (1H, Quant, J = 6 Hz), 5.42 (1H, m), 5.13 (1H, both d, J = 6 Hz), 3.73 (3H, s), 3.50 (2H, m), 3.14 (1H, DD, J = 14, 7 Hz), 3.03 (1H, DD, J = 14, 7 Hz), 2.76 (1H, DD, J = 17, 12 Hz), 2.47 (1H, m), 2.28 (1H, m), 1.97 (1H, d, J = 9 Hz), 2.00 - 1.63 (4H, m)

Example E-8

Diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[(S)-2-acetylthio-3-methylbutylamine] -6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylate

< / BR>
In the same way as in example E-2, and on the basis of diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-amino-6-oxo-11-phenyl - 1,2,3,4,6,8,7,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylate (0,59 g to 1.14 mmol) obtained in example E-1, and (S)-2-acetylthio - 3-methylbutanoic acid (0,136 g, 0,774 mmol) get mentioned in the title compound as a colorless amorphous product (0.36 g, yield 69%).

1H-NMR (400 MHz, CDCl3) : 7.54 - 6.92 (1H, m), 6.68 (1H, d, J = 8 Hz), 6.28 (1H, s), 5.65 (1H, Quint. J = 6 Hz), 5.49 - 5.40 (1H, d, J = 7 Hz), 4.00 (1H, d, J = 7 Hz), 3.42 (1H, DD, J = 16, 6 Hz), 2.60 - 2,37 (7H, m), 2.02 (1H, m), 1.88 - 1.72 (3H, m), 1.08 (3H, d, J = 7 Hz), 1.04 (3H, d, J = 7 Hz)

Example E-9

[4S -(4,7 (R*), 12b ]]-7-[(S)-the and

< / BR>
In the same way as in example E-4, and based on diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[(S)-2-acetylthio-3 - methylbutylamine]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylate (0.36 g, of 0.533 mmol) obtained in example E-8, get mentioned in the title compound as a colorless amorphous product (of) 0.157 g, yield 58%).

1H-NMR (400 MHz, CDCl3) : 7.55 - 7.28 (8H, m), 7.03 (1H, user. s), 5.69 (1H, Quint, J = 6 Hz), 5.46 (1H, m), 3.97 (1H, d, J = 7 Hz), 3.51 (1H, m), 2.96 - 2.82 (2H, m), 2.56 - 2.20 (7H, m), 2.00 - 1.60 (4H, m), 1.05 (3H, d, J = 7 Hz), 1.01 (3H, d, J = 7 Hz)

Example E-10

[4S -(4,7 (R*), 12b ]]-7-[(S)-2-Mercapto-3 - methylbutylamine]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
[4S -(4,7 (R*), 12b ]]-7-[(S)-2-Acetylthio-3 - methylbutylamine]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid (0,147 mg, 0,289 mmol) obtained in example E-9, was dissolved in degassed ethanol (5 ml). To this solution was added 1.0 n aqueous solution of lithium hydroxide (0.9 ml). The mixture is stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture is acidified by addition of an aqueous solution of 1.0 n hydrochloric acid under ice cooling and stirring, followed Exton magnesium sulfate. After removal of the solvent from the organic phase obtained residue is crystallized from dichloromethane-hexane. Further, the mother liquor is evaporated to dryness and then treated with isopropyl ether-hexane. So get 0,103 g specified in the title compound (yield 76%).

1H-NMR (400 MHz, CDCl3) : 7.68 (1H, d, J = 7 Hz), 7.51 (2H, d, J = 8 Hz), 7.44 (2H, d, J = 8 Hz), 7.39 - 7.33 (3H, m),7.08 (1H, d, J = 8 Hz), 5.73 (1H, Quint. J = 6 Hz), 5.53 (1H, m), 5.26 (1H, m), 3.61 (1H, DD, J = 17, 6 Hz), 3.19 (1H, DD, J = 9, 7 Hz), 2.93 (1H, DD. J = 17, 13 Hz), 2.60 - 2.22 (3H, m), 2.08 - 1.70 (4H, m), 1.05 (6H, d, J = 7 Hz)

Example E-11

Diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[[(2S, 3S)-2 - acetylthio-3-methylvaleramide]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2]benzazepine-4-carboxylate

< / BR>
In the same way as in example E-2, and on the basis of diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-amino-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylate (0,59 g to 1.14 mmol) obtained in example E-1, and (2S, 3S)-2-acetylthio-3-methylvaleramide acid (0.52 g, is 2.74 mmol) get mentioned in the title compound as a colorless amorphous product (1.22 g, yield 74%),

1H-NMR (400 MHz, CDCl3) : : 7.55 - 6.91 (17H, m), 6.67 (1H, d, J = 8 Hz), 6.27 (1H, s). 5.65 (1H, Quint, J = 6 Hz), 5.47 (1H, e), 5.41 (1H, e), 4.05 (1H, d, J = 7 Hz), 3.42 (1H, DD, J = 16, 6 Hz), 2.64,7 (R*)-12b ]]-7-[(2S, 3S)-Acetylthio-3 - methylvaleramide]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a] [2]benzazepine-4-carboxylic acid

< / BR>
In the same way as in example E-4, and based on diphenylmethyl [4S -(4,7 (R*), 12b ]]-7-[[(2S, 3S)-2-acetylthio-3 - methylvaleramide]-6-oxo-11-phenyl-1,2,3,4,6,8,7,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylate (1.22 g, 1,773 mmol) obtained in example E-11, get mentioned in the title compound as a colorless amorphous product (0,897 g, yield 58%).

1H-NMR (400 MHz, CDCl3) : 7.52 - 7.31 (8H, m), 7.04 (1H, d, J = 8 Hz), 5.69 (1H, Quint, J = 6 Hz), 5.48 (1H, m), 5.18 (1H, m), 4.02 (1H, d, J = 7 Hz), 3.54 (1H, m), 2.86 (1H, DD, J = 16, 12 Hz), 2.51 (1H, m), 2.40 (3H, s), 2.28 (1H, m), 2.11 (1H, m), 2.04-1.56 (5H, m), 1.20 (1H, m), 1.02 (3H, d, J = 7 Hz), 0.91 (3H, t, J = 7 Hz).

Example E-13

[4S -(4,7 (R*), 12b ]]-7-[(2S, 3S)-2-Mercapto-3 - methylvaleramide] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[1,2-a][2]benzazepine-4-carboxylic acid

< / BR>
[4S -(4,7 (R*), 12b ]]-7-[(2S, 3S)-2-Acetylthio-3 - methylvaleramide] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite- [2,1-a] [2]benzazepine-4-carboxylic acid (0,780 g 1,429 mmol), dissolved in degassed ethanol (20 ml). To this solution was added 1.0 n aqueous solution of lithium hydroxide (4,48 ml) at 0oC. a Mixed solution obtained thus is m addition of water (20,0 ml) and 2.0 aqueous solution of hydrochloric acid. Fallen in this solid product is collected by filtration (washing H2O) with getting through this specified in the connection header (0,622 g, yield 87%).

1H-NMR (400 MHz, CDCl3) : : 7.66 (1H, d, J = 7 Hz), 7.53 - 7.32 (7H, m), 7.08 (1H, d, J = 8 Hz), 5.72 (1H, Quint, J = 6 Hz), 5.52 (1H, m), 5.25 (1H, m), 3.60 (1H, DD, J = 17, 6 Hz), 3.23 (1H, DD, J = 9, 7 Hz), 2.93 (1H, DD, J = 17, 13 Hz), 2.55 (1H, m), 2.34 (1H, m), 2.00 (2H, m), 1.92 (1H, d, J = 8 Hz), 1.98 - 1.61 (4H, m), 1.25 (1H, m), 1.03 (3H, d, J = 7 Hz), 0.93 (3H, t, J = 7 Hz)

Example F-1

Methyl[3R- [3,6 (S*), 9a ]]-6-[[(S)-1-oxo-2-acetylthio-3-(4-forfinal)propyl]amino]-octahydro-5 - oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
To methyl [3R-[3 ,6,(S*),9a ]]-6-aminooctane-5-oxadiazol[3,2-a] azepin - 3-carboxylate (681 mg, and 2.79 mmol) is added a solution of 2-acetylthio-3-(4-forfinal)propionic acid (743 mg, of 3.07 mmol) obtained in synthetic example F-3, in methylene chloride (28 ml). The resulting mixture was cooled to 0oC while cooling with ice bath. After addition of N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EACH, 793 mg, is 3.21 mmol) in the ice bath removed. The resulting mixture was stirred in nitrogen atmosphere at room temperature for 3 hours. The resulting mixture was washed with 0.5 n hydrochloric acid (15 ml 2), water (10 ml) and saturated aqueous hydrotreat. Next, the filtrate is concentrated under reduced pressure to get crude product mixture epimeres (1.39 g). This crude mixture of epimeres separated and purified by chromatography on a column of silica gel (hexane: ethyl acetate = 3:1). The result is indicated in the title compound (500 mg, 38%) as the first epimer of the first fraction.

1H-NMR (400 MHz, CDCl3) : 1.55-2.02 (6H, m), 2.34 (3H, s), 2.97 (1H, DD, J = 7.2, 14.2 Hz), 3.18 (1H, DD, J = 6.6, 11.6 Hz), 3.27 (1H, DD, J = 2.4, 11.6 Hz), 3.27 (1H, DD, J = 7.6, 14.2 Hz), 3.78 (3H, s), 4.24 (1H, t, J = 7.4 Hz), 4.44 (1H, DD, J = 6.0, 11.2 Hz), 4.99 (1H, d, J = 9.2 Hz), 5.25 (1H, DD, J = 2.4, 6.6 Hz), 6.95 (2H, t, J = 8.6 Hz), 7.18 (2H, DD, J = 5.2, 8.4 Hz), 7.31 (1H, d, J = 3.2 Hz).

Mass m/e (FAB); 469 (MH+)

So pl.: 53-57oC

Example F-2

Methyl [3R-[3 ,6 (S*), 9a ]]-6-[[(S)-1-oxo-2-acetylthio - 3-(4-forfinal)propyl]amino]-octahydro-5-oxadiazol[3,2-a]azepin - 3-carboxylate

< / BR>
Following the first epimer obtained in example F-1 from the column as a second epimer get mentioned in the title compound (486 mg, 37%).

1H-NMR (400 MHz, CDCl3) : 1.45-2.02 (6H, m), 2.33 (3H, s), 2.93 (1H, DD, J = 6.8, 13.6 Hz), 3.16 (1H, DD, J = 6.8, 12.0 Hz), 3.26 (1H, DD, J = 2.4, 12.0 Hz), 3.28 (1H, DD, J = 8.8, 13.6 Hz), 3.77 (3H, s), 4.19 (1H, DD, J = 6.8, 8.8 Hz), 4.45 (1H, DD, J = 6.2, 11.2 Hz), 4.97 (1H, d, J = 8.8 Hz), 5.26 (1H, DD, J = 2.4, 6.8 Hz), 6.96 (2H, t, J = 8.8 Hz), 7.19 (2H, DD,Teal, [3R -[3,6 (S*), 9a ]]-6-[[(S)-1-oxo-2-acetylthio - 3-phenylpropyl]amino]-octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
A solution of methyl [3R-[3,6 (S*), 9a ]]-6-aminooctane-5 - oxadiazol[3,2-a] azepin-3-carboxylate (430 mg, of 1.76 mmol) in methylene chloride (17.6 ml) cooled to 0oC while cooling with ice bath. Next, to this solution was added sequentially (S)-2-acetylthio-3-phenylpropionate acid (395 mg, of 1.76 mmol) obtained in synthetic example F-4, and N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EACH, 479 mg, 1.94 mmol). Then the ice bath and leave the resulting mixture is stirred under nitrogen atmosphere at room temperature for 6 hours. The mixture is then washed with 0.5 n aqueous solution of hydrochloric acid (10 ml x 2), water (10 ml), saturated aqueous sodium hydrogen carbonate (10 ml x 2) and saturated aqueous sodium chloride (10 ml) and dried over magnesium sulfate. Next, the filtrate, which is obtained it by filtration, concentrated under reduced pressure. Thus obtained residue purified column chromatography (methylene chloride:ethyl acetate = 20:1). So get mentioned in the title compound as an amorphous product (563 mg, 71%).

1H-NMR (400 MHz, CDCl3) : 1.50-2.03 ( J = 7.6 Hz), 4.46 (1H, DD, J = 6.4, 10.4 Hz), 4.99 (1H, d, J = 8.8 Hz), 5.24 (1H, DD, J = 2.4, 6.4 Hz), 7.18-7.36 (6H, m).

Mass m/e (FAB); 451 (MH+)

So pl. is not defined due to the amorphous form

Example F - 4

Methyl [3R -[3,6 (S*), 9a ]]-6-[[(S)-1-oxo-2-acetyltributyl-3-phenylpropyl]amino]-octahydro-5-oxadiazol [3,2-a]azepin-3-carboxylate

< / BR>
A solution of methyl [3R-[3,6 (S*), 9a ]]-6-aminooctane-5-oxadiazol[3,2-a] azepin-3-carboxylate (375 mg, 1.53 mmol) in methylene chloride (15.3 ml) cooled to 0oC while cooling with ice bath. Next, to this solution was added sequentially (S)-2-acetyltributyl-3-phenylpropionate acid (365,8 mg, 1.54 mmol) and N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EACH, 418 mg, was 1.69 mmol). Then the ice bath and leave the resulting mixture is stirred under nitrogen atmosphere at room temperature for 6 hours. The mixture is then washed with 0.5 N. aqueous solution of HCl (10 ml of 2), water (10 ml), saturated aqueous Na2CO3(10 2 ml) and saturated aqueous sodium chloride (10 ml) and dried (using MgSO4). Next, the filtrate, which is obtained it by filtration, concentrated under reduced pressure. Thus obtained residue purified column chromatography (methylene chloride: ethyl acetate = 20 : 1). The UP>H-NMR (400 MHz, CDCl3) : 1.55 - 2.11 (6H, m), 2.32 (3H, s), 2.62 - 2.70 (1H, m), 2.82 (1H, DD, J = 6.8, 14.Hz), 2.97 (1H, DD, J = 8.4, 14 Hz), 3.03 (1H, DD, J = 8.8, 13.6 Hz), 3.11 (1H, DD, J = 5.2, 13.6 Hz), 3.17 (1H, DD, J = 6.8, 11.6 Hz), 3.27 (1H, DD, J = 2.8, 11.6 Hz), 3.78 (3H, s), 4.40 - 4.44 (1H, m kV), 4.98 (1H, d, J = 8.8 Hz), 5.20 (1H, DD, J = 2.8 6.8 Hz), 6.79 (1H, d, J = 6 Hz), 7.15 - 7.28 (5H, m)

Mass m/e (FAB); 465 (MH+).

So pl. is not defined due to the amorphous form.

Example F-5

Methyl [3R - [3,6 (S*), 9a ]]-6-[[(2S, 3S)-1-oxo-2-acetylthio-3-methylpentyl]amino]-octahydro-5-oxo-thiazole[3,2-a] azepin-3-carboxylate

< / BR>
A solution of methyl [3R,[3,6 (S*), 9a ]]-6-aminooctane-5-oxadiazol[3,2-a] azepin-3-carboxylate (225 mg, of 0.92 mmol) in methylene chloride (17 ml) is cooled to 0oC while cooling with ice. Next, to this solution was added sequentially a solution of (2S, 3S)-2-acetylthio-3-methylpentanol acid (193 mg, 1.01 mmol) in methylene chloride (6 ml) and EACH (296 mg, 1.20 mmol). Then the ice bath is removed and the thus obtained mixture was stirred in nitrogen atmosphere at room temperature overnight. The mixture is then concentrated by evaporation to a certain extent. Next, the residue is dissolved in ethyl acetate and the resulting solution was washed with 1 N. aqueous HCl solution, saturated aqueous Na2CO3and saturated water R. the shape under reduced pressure. Thus obtained residue purified column chromatography hexane : ethyl acetate = 3 : 1). So get mentioned in the title compound as an amorphous product (206 mg, 54%).

1H-NMR (400 MHz, CDCL3) : 0.88 (3H, t, J = 7.6 Hz), 0.99 (3H, d, J = 6.8 Hz), 1.10-1.22 (1H, m), 1.51-1.70 (2H, m), 1.82-2.14 (6H, m), of 2.38 (3H, c), 3.20 (1H, DD, J = 6.4, 11.8 Hz), 3.28 (1H, DD, J = 2.4 11.8 Hz), 3.79 (3H, s), 3.98 (1H, DD, J = 6.8 Hz), 4.54 (1H, DD, J = 6.4, 10.4 Hz), 5.02 (1H, d, J = 8.8 Hz), 5.28 (1H, DD, J = 2.4, 6.4 Hz), 7.41 (1H, d, J = 6.0 Hz)

Examples from F-6 to F-13

Connection examples from F-6 to F-13, shown below, is obtained by the same methods as in examples F-1 to F-5.

Example F-6

Methyl [3R - [3,6 (S*), 9a ]]-6-[[(S)-1-oxo-2-acetylthio-3-(3-methoxyphenyl)propyl]amino]-octahydro-5 oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
1H-NMR (400 MHz, CDCl3) : 1.55-2.04 (6H, m), 2.33 (3H, s), 2.94 (1H, DD, J = 7.6, 14.4 Hz), 3.18 (1H, DD, J = 6.8, 11.6 Hz), 3.24 (1H, DD, J = 7.2, 14.4 Hz), 3.27 (1H, DD, J = 2.4, 11.6 Hz), 3.78 (6H, s), 4.24 (1H, t, J = 7.6 Hz), 4.45 (1H, DD, J = 6.0, 10.8 Hz), 4.99 (d, J = 8.8 Hz), 5.24 (1H, DD, J = 2.4, 6.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.32 (H, d, J = 6.4 Hz), 7.32

Mass m/e (FAB); 481 (MH+).

So pl. is not defined due to the amorphous form.

Example F-7

Methyl[3R - 3,6 (S*), 9a ]]-6-[[[(S)-1-oxo-2-acetylthio-3-(1,4-biphenyl)propyl]amino]-octahydro-5-oxot), 3.11 (1H, DD, J=6.6, 12.0 Hz), 3.23 (1H, DD, J=2.4, 12.0 Hz), 3.34 (1H, DD, J=7.6, 14.4 Hz), 3.77 (3H, s), 4.32 (1H, t, J=7.6 Hz), 4.45 (1H, DD, J=6.4, 11.6 Hz), 4.98 (1H, d, J=8.4 Hz), 5.21 (1H, DD, J= 2.4, 6.6 Hz), 7.26-7.60 (10H, m)

Mass m/e (FAB); 527 (MH+).

So pl. 68-72oC.

Example F-8

Methyl [3R -[3,6 (S*), 9 ]]-6-[[(R)-1-oxo-2-acetylthio-3-(1,4-biphenyl)propyl]amino]-octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
1H-NMR (400 MHz, CDCl3) : ; 1.46-2.00(6H, m), 2.34 (3H, s), 3.01 (1H, DD, J= 7.2, 14.0 Hz), 3.15 (1H, DD, J=6.4, 12.0 Hz), 3.25 (1H, DD, J=2.4, 12.0 Hz), 3.36 (1H, DD, J=8.8, 14.0 Hz), 3.76 (3H, s), 4.28 (1H, DD, J=7.2, 8.8 Hz), 4.45-4.49 (1H, m kV), 4.97-4.99 (1H, m d), 5.26 (1H, DD, J= 2.4, 6.4 Hz), 7.29-7.59 (10H, m)

Mass m/e (FAB); 527 (MH+).

So pl. 77-80oC.

Example F-9

Methyl [3R-[3,6 S*),9a]- 6-[[(S)-1-oxo-2-acetylthio-3-(2-thienyl)propyl] amino]-octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
1H-NMR (400 Hz, CDCl3) : 1.50-1.70(2H,m), 1.86-2.08 (4H, m), 2.36 (3H, s), 3.18 (1H, DD, J=6, 12 Hz), 3.27 (1H, DD, J=2, 12 Hz), 3.29 (1H, DD, J= 7,14 Hz), 3.49 (1H, DD, J=7,14 Hz), 3.78 (3H, s), 4.30 (1H, d, J=1 Hz), 4.49 (1H, DD, J= 6, 10 Hz), 5.00 (1H, d, J=9 Hz), 5.26 (1H, DD, J=2,6 Hz), 6.86 (1H, user. d, J= 4 Hz), 6.90 (1H, DD, J=3.5 Hz), 7.14 (1H, DD, J=2.5 Hz), 7.40( 1H, d, J=6 Hz)

Example F-10

Methyl [3R-[3,6 S*),9a]- 6-[[(2S, 2R)-1-oxo-2-acetylthio-3-methylpentyl] amino] -octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
Example F-11

Methyl [3R - [3,6 S*), 9a ]]-6-[[(S)-1-oxo-2-acetyltributyl]amino]-octahydro-5-oxadiazol-[3,2-a] azepin-3-carboxylate

< / BR>
1H-NMR (400 MHz, CDCl3) : 0.98 (3H, t, J = 7 Hz), 1.67 (1H, m), 1.77 (1H, m), 1.86-2.06 (6H, m), 2.37 (3H, s), 3.19 (1H, DD, J = 6, 12 Hz), with 3.27 (1H, DD, J = 2, 12 Hz), 3.79 (3H, s), of 3.96 (1H, t, J = 6 Hz), 4.54 (1H, DD, J = 6, 10 Hz), 5.02 (1H, d, J = 9 Hz), 5.28 (1H, DD, J = 2, 6 Hz), 7.35 (1H, d, J = 6 Hz).

Example F-12

Methyl [3R- -[3,6 (S*), 9a ]]-6-[[(S)-1-oxo-2-acetylthio-3-methylbutyl]amino]-octahydro-5-oxadiazol [3,2-a]azepin-3-carboxylate

< / BR>
1H-NMR (400 MHz, CDCl3) ; 0.97 (3H, d, J = 7 Hz), 1.02 (3H, d, J = 7 Hz), 1.65 (1H, m), 1.88-2.06 (4H, m), 2.35 (1H, m), 2.39 (3H, s), 3.20 (1H, DD, J = 6, 12 Hz), 3.28 (1H, DD, J = 2, 12 Hz), 3.80 (3H, s), 3.91 (1H, d, J = 7 Hz), 4.54 (1H, DD, J = 6, 10 Hz), 5.02 (1H, d, J = 9 Hz), 5.28 (1H, DD, J = 2, 6 Hz), 7.40 (1H, d, J = 6 Hz)

Example F-13

Methyl [3R- -[3,6 (S*), 9a [[-6-(S)-1-oxo-2-acetylthio-3,3-dimethylbutyl]amino]-octahydro-5 - oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
1H-NMR (400 MHz, CDCl3) : 1.02 (9H, s), 1.63 (1H, m), 1.88-2.09 (5H, m), 2.17 (3H, s), 3.20 (1H, DD, J = 6, 12 Hz), 3.28 (1H, DD, J = 2, 12 Hz), 3.77 (1H, s), 3.80 (3H, s), 4.57 (1H, DD, J = 6, 10 Hz), 5.03 (1H, d, J = 9 Hz), 5.28 (1H, DD, J = 2, 6 Hz), 7.20 (1H, d, J = 6 Hz).

Example F-14

< / BR>
Methyl [3R - [3,6 (S*), 9a ]]-6-[(S)-1-oxo-2-acetyl-thio-3-(4-forfinal)propylamino] octahydro-5 - oxadiazol[3,2-a]azepin-3-carboxylate (384 mg, 0.82 mmol) obtained in example F-1, placed in the flask, followed by sufficient purging with nitrogen. After addition of degassed tetrahydrofuran (1,95 ml) and methanol (11.7 ml) the flask was cooled to 0oC. To the thus obtained mixture degassed 1 N. aqueous solution of lithium hydroxide (6.6 ml). The resulting mixture is brought to room temperature and stirred for 1 hours. After re-cooling the mixture to 0oC was added 1 n aqueous solution of hydrochloric acid (10 ml). The resulting mixture was extracted with chloroform (50 ml of 2). The organic phase is washed with saturated aqueous sodium chloride (30 ml) and then dried over magnesium sulfate. Then the organic phase is filtered and the filtrate concentrated under reduced pressure to a certain extent. To the concentrate was added toluene (50 ml) followed by re-concentration. Next, the residue is dissolved in a small amount (about 1 ml) of chloroform and diisopropyl ether (about 1 ml) and recrystallized. To the thus obtained crystals add hexane (3 ml). After grinding, Filia (362 mg, 107%) as white crystals.

1H-NMR (400 MHz, CDCl3) : 1.55-1.68 (1H, m), 1.90-2.06 (6H, m), 3.09 (1H, DD, J = 6.8, 14.0 Hz), 3.18-3.25 (2H, m), 3.34 (1H, DD, J = 2.4, 12.0 Hz), 3.51-3.56 (1H, m kV), 4.52 (1H, DD, J = 6,4, 11.2 Hz), 5.03 (1H, t, J = 5.2 Hz), 5.26 (1H, DD, J = 2.4, 6.4 Hz), 6.97 (2H, t, J = 8.8 Hz), 7.17 (2H, DD, J = 5.8, 8.2 Hz), 7.52 (1H, d, J = 6.0 Hz)

Mass m/e (FAB); 413 (MH+).

So pl. 209-211oC.

Example F-15

[3R 3,6 (S*), 9a ]]-6-[[(2S, 3S)-Oxo-2-thio-3 - methylpentyl]amino]octahydro-5-oxadiazol[3,2-a]-azepin-3-carboxylic acid

< / BR>
Methyl [3R -[3,6 (S*), 9a ]]-6-[[(2S, 3S)-1-oxo-2-acetylthio-3-methylpentyl]amino]-octahydro-5-oxadiazol[3,2-a] azepin-3-carboxylate (200 mg, 0.48 mmol) obtained in example F-5, is placed in a flask followed by the addition of degassed ethanol (8 ml). The flask was cooled to 0oC in nitrogen atmosphere. To the mixture was added degassed 1 n aqueous solution of lithium hydroxide (3.8 ml). The resulting mixture was stirred at room temperature for 50 minutes. The resulting mixture is acidified by addition of 2 n aqueous solution of hydrochloric acid (2.9 ml) at 0oC. the resulting mixture was extracted with methylene chloride. After washing the organic phase with a saturated aqueous solution of sodium chloride should not be dried over magnesium sulfate and concentrated. Obtained the head of the compound (150 mg, 87%) as white crystals.

1H-NMR (400 MHz, CDCl3) : 0.90 (3H, t, J = 7 Hz), 1.00 (3H, d, J = 7 Hz), 1.24 (1H, m), 1.55-1.74 (2H, m), 1.87 (1H, d, J = 8 Hz), 1.90-2.10 (6H, m), 3.20 (1H, DD, J = 6, 12 Hz), 3.24 (1H, d, J = 7 Hz), 3.36 (1H, DD, J = 2, 12 Hz), 4.62 (1H, DD, J = 6, 10 Hz), 5.07 (1H, t, J = 6 Hz), 5.29 (1H, DD, J = 2, 6 Hz), 7.69 (1H, d, J = 6 Hz).

Example F-16

[3R-[3,6(S*),9a]] -6-[[(R)-1-Oxo-2-thio-3-(4-forfinal]propyl]amino] octahydro-5-oxadiazol- [3,2-a]-azepin-3-carboxylic acid

< / BR>
The compound of example F2 is subjected to interaction in the same way as in example F-14, with getting through this specified in the connection header.

1H-NMR (400 MHz, CDCl3) ; 1.44-1.56 (1H, m), 1.82-2.03 (5H, m), 2.08 (1H, d, J = 9.2 Hz), 3.03 (1H, DD, J = 6.8, 14 Hz), 3.20 (1H, DD, J = 6.8, 11.6 Hz), 3.25 (1H, DD, J = 8.0, 14.0 Hz), 3.34 (1H, DD, J = 2.0, 11.6 Hz), 3.45 (1H, q, J = 8.0 Hz), 4.53 (1H, DD, J = 6.4, 10.8 Hz), 5.02-5.04 (1H, m), 5.27 (1H, DD, J = 2.0, 6.8 Hz), 6.97 (2H, t, J = 8.6 Hz), 7.17 (2H, DD, J = 5.4, 8.6 Hz), 7.34 (1H, d, J = 6.0 Hz)

Mass m/e (FAB); 413 (MH+).

So pl. 98-105oC.

Examples from F-17 to F-26

Connection examples from F-17 to F-26, shown below, is obtained by the same methods as in examples from the F-14 and F-15 using the compounds of examples F-3, F-4 and F-6 to F-13.

Example F-17

[3R-[3,6(S*)9a]]- 6-[[(S)-1-Oxo-2-thio-3-phenylpropyl] amino]oktay m), 3.10 (1H, DD, J = 6.8, 13.6 Hz), 3.19 (1H, DD, J = 6.6, 12.0 Hz), 3.27 (1H, DD, J = 6.8, 13.6 Hz), 3.34 (1H, DD, J = 2.4, 12.0 Hz), 3.59 (1H, sq J = 6.8 Hz), 4.51-4.56 (1H, m DD), 5.02-5.04 (1H, m t), 5.26 (1H, DD, J = 2.4, 6.6 Hz), 7.17-7.30 (5H, m), 7.53 (1H, d, J = 6.0 Hz)

Mass m/e (FAB); 395 (MH+).

So pl. 232-235oC.

Example F-18

[3R - [3,6 (S*), 9a ]]-6-[[(S)-1-Oxo-2-thiomethyl-3 - phenylpropyl]amino] octahydro-5-oxadiazol[3,2-a]-azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ;

1.46 (1H, t, J = 8.4 Hz), 1.59-1.70 (1H, m), 1.84-2.14 (5H, m), 2.55-2.68 (2H, m), 2.76-2.83 (2H, m), 2. 97 (1H, DD, J = 7.0, 13.4 Hz), 3.21 (1H, DD, J = 6.8, 12.0 Hz), 3.35 (1H, DD, J = 2.4, 12.0 Hz), 4.54-4.59 (1H, m kV), 5-02-5.05 (1H, m t), 5.24 (1H, DD, J = 2.4, 6.8 Hz), 6.98 (1H, d, J = 6.0 Hz), 7.12-7.30 (5H, m)

Mass m/e (FAB); 409 (MH+).

So pl. 210-212oC.

Example F-19

[3R-[3,6(S*),9a]]- 6-[[(S)-1-Oxo-2-thio-3-(4-methoxyphenyl)propyl] amino] octahydro-5-oxadiazol-[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 1.55-1.68 (1H, m), 1.88-2.09 (6H, m), 3.07 (1H, DD, J = 6.8, 14.4 Hz), 3.18 (1H, DD, J = 6.8, 14.4 Hz), 3.20 (1H, DD, J = 6.8, 12.0 Hz), to 3.34 (1H, DD, J = 2.4, 12.0 Hz), 3.55 (1H, dt, J = 8.8, 6.8 Hz), 3.79 (3H, s), 4.52-4.56 (1H, m DD), 5.02-5.05 (1H, m t), 5.25 (1H, DD, J = 2.4, 6.8 G C), 6.82 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 7,56 (1H, d, J = 6.4 Hz)

Mass m/e (FAB); 425 (MH+)

So pl.: 182-183oC

Example F-20

[3R - [3,6(S*),9a 1H-NMR (400 MHz, CDCl3) ; 1.55-1.67 (1H, m), 1.88-2.08 (5H, m), 2.05 (1H, d, J = 8.8 Hz), 3.12 (1H, DD, J = 6.6, 12.0 Hz), 3.16 (1H, DD, J = 6.8, 14.0 Hz), 3.26-3.31 (2H, m), 3.60 (1H, q, J = 6.8 Hz), 4.50-4.54 (1H, m kV), 5.00-5.03 (1H, m), 5.20 (1H, DD, J = 2.4, 6.8 Hz), 7.28-7.59 (10H, M)

Mass m/e (FAB); 471 (MH+< / BR>
So pl.: 106-117oC

Example F-21

[3R - [3,6(S*),9a]]- 6-[[(S)-1-Oxo-2-thio-3-(1,4-biphenyl)propyl]amino] octahydro-5-oxadiazol[3,2-a]-azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 1.44-1.56 (1H, m), 1.84-2.00 (5H, m), 2.12 (1H, d, J = 9.6 Hz), 3.08 (1H, DD, J = 6.4, 14.0 Hz), 3.16 (1H, DD, J = 6.8, 12.0 Hz), 3.29-3.50 (2H, m), 3.50-3.55 (1H, m kV), 4.52-4.57 (1H, m, CVR DD), 5.01-5.04 (1H, m), 5.25 (1H, DD, J = 2.4, 6.8 Hz), 7.26-7.58 (10H, m)

Mass m/e (FAB); 471 (MH+< / BR>
So pl.: 109-116oC

Example F-22

[3R - [3,6(S*),9a]]- 6-[[(S)-1-Oxo-2-thio-3-(2-thienyl)propyl] amino] octahydro-5-oxadiazol[3,2-a]-azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 1.64 (1H, m), 1.90-2.12 (5H, m), 2.09 (1H, d, J = 8 Hz), 3.20 (1H, DD, J = 6.12 Hz), 3.34 (1H, DD, J = 2, 12 Hz), 3.44 (2H, d, J = 6 Hz), 3.58 (1H, m), 4.57 (1H, DD, J = 6, 10 Hz), 5.05 (1H, m), 5.26 (1H, DD, J = 2, 6 Hz), 6.87 (1H, user.d, J = 4 Hz), 6.93 (1H, DD, J = 3, 5 Hz), 7.17 (1H, DD, J = 2, 5 Hz), 7.65 (1H, d, J = 6 Hz)

Example F-23

[3R -[3,6(S*),9a]]- 6-[[(2S, 3S)-1-Oxo-2-thio-3-methylpentyl] amino] octahydro - 5-oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) : .62 (1H, DD, J = 6, 10 Hz), 5.06 (1H, m), 5.30 (1H, DD, J = 2, 6 Hz), 7.94 (1H, d, J = 6 Hz).

Example F-24

[3R - [3,6(S*),9a]]- 6-[(S)-1-Oxo-2-dibutyl] amino]octahydro-5 - oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 1.00 (3H, t, J = 7 Hz), 1.70 (1H, m), 1.79 (1H, m), 1.90-2.10 (7H, m), 3.19-3.30 (2H, m), 3.35 (1H, DD, J = 2, 12 Hz), 4.62 (1H, DD, J = 6, 10 Hz), 5.06 (1H, m), 5.29 (1H, DD, J = 2, 6 Hz), 7.61 (1H, d, J = 6 Hz).

Example F-25

[3R - [3,6(S*),9a]]- 6-[[(S)-1-Oxo-2-thio-3-methylbutylamine] octahydro-5 - oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 0.99 (2H, d, J = 7 Hz), 1.03 (3H, d, J = 7 Hz), 1.69 (1H, m), 1.85 (1H, d, J = 9 Hz), 1.90-2.10 (5H, m), 2.25 (1H, septet, J = 7 Hz), 3.16-3.26 (2H, m), 3.35 (1H, DD, J = 2, 12 Hz), 4.61 (1H, DD, J = 6, 10 Hz), 5.06 (1H, t, J = 6 Hz), 5.30 (1H, DD, J = 2, 8 Hz), 7.67 (1H, d, J = 6 Hz).

Example F-26

[3R - [3,6(S*),9a]]- 6-[(S)-1-Oxo-2-thio-3,3-dimethylbutylamino] octahydro - 5-oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CD3OD) : 1.06 (9H, s), 1.74 (1H, m), 1.85-2.10 (5H, m), 3.25-3.35 (3H, m), 4.58 (1H, m), 5.17-5.25 (2H, m).

Example 101

Methyl- {3R-[3,6(S*),9a]}- 6-[[(2S, 3S)-2-acetyl-thio-1-oxo-3 - phenylbutyl]amino]octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
a) (4S)-3[(3R)-1-oxo-3-phenylbutyl]-4-phenylmethyl-2-oxazolidinone

< / BR>
5,96 g (R)-3-phenylbutanoate acid is added dropwise to 9.5 ml of oxalicacid. Thus obtained mixture was stirred at room temperature for 0.5 hours and then concentrated. The residue is dissolved in 60 ml of tetrahydrofuran. Next of 0.44 g (S)-4-phenylmethyl-2-oxazolidinone dissolved in 120 ml of tetrahydrofuran. In the resulting solution was added dropwise to 14.5 ml of 2.5 M solution of n-utility in hexane in a nitrogen atmosphere at -70oC. the resulting mixture was stirred at the same temperature for 20 minutes and then add the prepared solution of the carboxylic acid in tetrahydrofuran. Then thus obtained mixture was stirred at -70oC for 30 minutes and then heated at room temperature. The reaction mixture was concentrated. Add ethyl acetate and water and the target compound is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate and concentrated. The concentrate is purified column chromatography on silica gel with getting through this 9.7 g specified in the title compound (yield 83%).

1H-NMR (400 MHz, CDCl3) : 7.33-7.18 (8H, m), 7.07 (2H, DD, J = 2, 8 Hz), 4.63 (1H, m), 4.16 (1H, DD, J = 8, 8 Hz), 4.11 (1H, DD, J = 9, 3 Hz), 3.45 (2H, m), 3.08 (2H, m), 2.59 (1H, 1H, DD, J = 14, 9 Hz), 1.36 (3H, d, J = 7 Hz).

(b) (4S)-3-[(til-2-oxazolidinone dissolved in 50 ml of dichloromethane. To the solution add 10 ml of diisopropylethylamine and 12.5 ml of di-n-butalbitaltadalafil acid in a nitrogen atmosphere at -70oC. the resulting mixture was stirred at the same temperature for 15 minutes and then at 0oC for 1 hour. The reaction mixture is cooled to -70oC. the Mixture obtained by suspendirovanie of 3.64 g of N-bromosuccinimide in 20 ml of dichloromethane, prepared in another vessel, and thereto was added the above reaction mixture in a nitrogen atmosphere at -70oC. the resulting mixture was stirred at the same temperature for 1.25 hours and then poured into a solution containing 0.5 n sodium sulfate and a saturated solution of sodium chloride. The resulting mixture is extracted with dichloromethane. The organic phase is dried over anhydrous magnesium sulfate, concentrated and purified column chromatography on silica gel. So get 3,43 g specified in the title compound (yield 85%).

1H-NMR (400 MHz, CDCl3) : 7.38 - 7.24 (10H, m), 5.96 (1H, d, J = 10 Hz), 4.76 (1H, m), 4.23 (2H, m), 3.57 (1H, DD, J = 10,7 Hz), 3.34 (1H, DD, J = 14,3 Hz), 2.81 (1H, DD, J = 14,10 Hz), 1.38 (3H, d, J = 7 Hz)

(c) (4S)-3-[(2R, 3S)-2-azido-1-oxo-3-phenylbutyl]-4 - phenylmethyl-2-oxazolidinone

< / BR>
to 6.43 g of (4S)-3-[(2R, 3S)-2-bromo-1-oxo-3-phenylbutyl]-4 - phenylmethy is andini azide in 20 ml of dichloromethane at 0oC. the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 2.5 hours. Then heated under reflux for 8 hours. To the thus obtained reaction mixture was added a saturated solution of sodium bicarbonate. The resulting mixture is extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate and concentrated. After purification column chromatography on silica gel get 4,33 g specified in the title compound (yield 74%)

1H-NMR (400 MHz, CDCl3) : 7.37 - 7.22 (8H, m), 6.99 (2H, DD, J = 8,2 Hz), 5.37 (1H, d, J = 9 Hz), 4.60 (1H, m), 4.12 (1H, DD, J = 9.9 Hz) 3.45 (1H, m), 2.80 (1H, DD, J = 14,4 Hz) 1.98 (1H, DD, J = 14,10 Hz), 1.50 (3H, d, J = 7 Hz)

(d) (2R,3S)-2-azido-3-phenylbutanoate acid

< / BR>
4,32 g of (4S)-3-[(2R, 3S)-2-azido-1-oxo-3-phenylbutyl]-4 - phenylmethyl-2-oxazolidinone dissolved in 60 ml of tetrahydrofuran - water (4 : 1). To the thus obtained solution was added to 7.75 ml of 30% hydrogen peroxide and an aqueous solution containing 0.73 g of lithium hydroxide at 0oC. the resulting mixture was stirred at 0oC for 1 hour and then added an aqueous solution (57 ml) containing 9,58 g sulfate NetRom and then set the pH to 1 with conc. hydrochloric acid followed by extraction with ethyl acetate. An ethyl acetate phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate and concentrated. Thus obtain 2.30 g of target compound (yield 95%).

1H-NMR (400 MHz, CDCl3) : 7.37 - 7.27 (5H, m), 4.09 (1H, d, J = 6 Hz), 3.39 (1H, DQC, J = 7,7 Hz), 1.39 (3H, d, J = 7 Hz)

(e) (2R,3S)-2-amino-3-phenylbutanoate acid

< / BR>
2.20 g (2R, 3S)-2-azido-3-phenylbutanoate acid are dissolved in 40 ml of methanol. To the resulting solution was added a 2.71 g of ammonium formate and 0.36 g of 10% palladium-on-coal (water-containing product) with subsequent interaction at room temperature for 1.5 hours. After removal of catalyst by filtration and concentrating the filtrate to the residue was added 300 ml of a mixed solvent containing methanol and dichloromethane (1:9) followed by extraction. After concentration of the extract prepared 2,43 g of target compound (crude product).

1H-NMR (400 MHz, CDCl3) : 7.32 - 7.16 (5H, m), 3.78 (1H, d, J = 5 Hz), 3.38 (1H, m), 1.23 (3H, d, J = 7 Hz)

(f) (2R, 3S)-2-bromo-3-phenylbutanoate acid

< / BR>
1.70 g (2R, 3S)-2-Amino-3-phenylbutanoate acid are dissolved in a mixed solution containing 7.2 ml of water and 10.5 ml of 47% bromine, the mixture is stirred for 30 minutes and then at room temperature for 2 hours. Then add water and diethyl ether, followed by extraction. The ether phase is washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated. Thus obtain 1.84 g of the target compound as a crude product.

1H-NMR (400 MHz, CDCl3) : 7.38 - 7.18 (5H, m), 4.35 (1H, d, J = 10 Hz), 3.36 (1H, m), 1.23 (3H, d, J = 7 Hz)

(g) (2S, 3S)-2-acetylthio-3-phenylbutanoate acid

< / BR>
of 1.80 g (7,35 mmol) (2R,3S)-2-Bromo-3-phenylbutanoate acid are dissolved in 40 ml of acetonitrile. To the resulting solution was added 1.01 g (88,2 mmol) thioacetate potassium at -10oC. the resulting mixture was stirred at 0oC for 30 minutes and then at room temperature overnight. Insoluble material is removed by filtration and the solution concentrated. To the residue obtained after concentration, was added diethyl ether and sodium bicarbonate, followed by extraction of the target compounds in the aqueous phase. Set the pH of the aqueous phase 1 with dilute hydrochloric acid followed by extraction with diethyl ether. The organic phase is washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and concentrated. Thus Pol.33 (1H, m), 2.25 (3H, s) of 1.43 (3H, d, J = 7 Hz)

(h) methyl-(3R -[3,6(S*),9a]]- 6-[[2S, 3S)-2-acetylthio-1-oxo-3-phenylbutyl] amino]octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
0.3 g (1,23 mmol) methyl-(3R, [3,6 (S*), 9a ]]-6-aminooctane - 5-oxadiazol[3,2-a] azepin-3-carboxylate dissolved in 10 ml of dichloromethane. To the resulting solution was successively added a solution of 0.32 g (1.35 mmol) (2S, 3S)-2-acetylthio-3-phenylbutanoate acid in 10 ml of dichloromethane and 0.43 g (1.6 mmol) EACH at 0oC in nitrogen atmosphere. Thus obtained mixture was stirred at room temperature overnight. Then it sequentially treated with 1 N. hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, concentrated and purified by chromatography on a column of silica gel. Thus obtain 0.27 g of the target compound.

1H-NMR (400 MHz, CDCl3) : 7.34 - 7.15 (5H, m), 5.28 (1H, DD, J = 6.2 Hz) 5.02 (1H, d, J = 9 Hz), 4.56 (1H, DD, J = 11.7 Hz) 4.22 (H, d, J = 10 Hz), 3.79 (3H, s), 3.45 (1H, m), 3.28 (1H, DD, J = 12.3 Hz) 3.19 (1H, DD, J = a 12.7 Hz), 2.23 (3H, m), 2.04 - 1.88 (6H, m), 1.37 (3H, d, D = 7 Hz)

Example 102

(3S)-{ [2S, 3S)-2-Acetylthio-1-oxo-3-phenylbutyl]-amino}-1 - ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

1H-NMR (400 MHz, CDCl3) : to 7.32-7.10 (9H, m), 6.99 (1H, d, J = 7 Hz), 4.77 (1H, d, J = 17 Hz), 4.50 (1H, m), 4.34 (1H, d, J = 17 Hz), 4.22-4.13 (3H, m), 3.42-3.30 (2H, m), 2.71 -2.54 (2H, m), 2.22 (3H, s), 1.81 (1H, m), 1.33 (3H, d, J = 7 Hz), 1.25 (3H, t, J = 7 Hz).

Example 103

{ 3R -[3,6(S*),9a]}- -6- {[(2S, 3S)-1-Oxo-3-phenyl-2-dibutyl]amino} octahydro-5-oxadiazol[3,2-a]- azepin-3-carboxylic acid

< / BR>
0.25 g (0,539 mmol) of methyl-{3R -[3,6(S*),9a]}- -6-{[(2S, 3S)-2-acetylthio-1-oxo-3-phenylbutyl] amino}octahydro-5-oxadiazol [3,2-a]azepin-3-carboxylate obtained in example 101, dissolved in 10 ml of ethanol. To the resulting solution was added 10 ml of 1 n aqueous solution of lithium hydroxide in a nitrogen atmosphere at 0oC. the resulting mixture was stirred at room temperature for 1 hour and then cooled to 0oC with the subsequent establishment of the pH to 1 with dilute hydrochloric acid. From the reaction mixture is distilled ethanol under reduced pressure. To the residue was added water and dichloromethane, followed by extraction. Then the organic phase is washed with saturated aqueous sodium chloride and suscr (400 MHz, CDCl3) : 7.61 (1H, d, J = 6 Hz), 7.34-7.18 (5H, m), 5.29 (1H, DD, J = 7, 2 Hz), 5.06 (1H, m), 4.62 (1H, DD, J = 11, 7 Hz), 3.51 (1H, DD, J = 8, 7 Hz), 3.45 (1H, m), 3.35 (1H, DD, J = 12, 2 Hz), 3.21 (1H, DD, J = 12, 7 Hz), 2.10-1.90 (6H, m), 1.73 (1H, DD, J = 8 Hz), 1.39 (3H, d, J = 7 Hz)

Example 104

1-Carboxymethyl-3-{[2S, 3S)-1-oxo-3-phenyl-2-dibutyl]amino}- 1H-[1]benzazepin-2-he

< / BR>
0.35 g (0,726 mmol) of (3S)-{[2S, 3S)-2-acetylthio-1-oxo-3-phenylbutyl] amino] -1 - ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1] benzazepin-2-she obtained in example 102, dissolved in 10 ml of ethanol. To the resulting solution was added 10 ml of 1 n aqueous sodium hydroxide solution under nitrogen atmosphere at 0oC. the resulting mixture was stirred at room temperature for 1 hour and then set the pH to 1 by addition of hydrochloric acid at 0oC. Add water and loose while the crystals are collected by filtration. Thus obtain 0.25 g of the target compound.

1H-NMR (400 MHz, CDCl3) : 7.34 - 7.13 (9H, m), 4.68 (1H, d, J = 17 Hz), 4.52 (1H, m), 4.45 (1H, d, J = 17 Hz), 3.47 (1H, DD, J = 8 Hz), 3.41 (1H, DQC, J = 8, 7 Hz), 3.23 (1H, m), 2.71 -2.56 (2H, m), 1.83 (1H, m), 1.69 (1H, d, J = 8 Hz), 1.34 (3H, DD, J= 7 Hz).

Example 105.

Methyl [3R-[3,6(S*),9a]}- -6-[[(2S, 3S)-2-acetylthio-1-oxo-3,4-dimethylpentyl]amino]octahydro-5 - oxadiazol[3,2-a]azepin-3-carboxylate

< / BR>
(a) (2S, the s as the source of the product and in the same way, as in example 101 (a) - (g) are obtained 1.2 g of (2S, 3S)-2-acetylthio-3,4-dimethylpentane acid.

1H-NMR (400 MHz, CDCl3) : 4.21 (1H, d, J = 8 Hz), 2.38 (3H, s), 1.87 (1H, m), 1.63 (1H, m), 0.97 (3H, d, J = 7 Hz), 0.93 (3H, d, J = 7 Hz), 0.80 (3H, d, J = 7 Hz)

(b) methyl [3R-[3,6(S*),9a]} -6-{[2S, 3S)-2-acetylthio-1-oxo-3,4-dimethylpentyl]amino}octahydro-5-oxo the thiazole[3,2-a]azepin-3-carboxylate

< / BR>
0,275 g (1.35 mmol) (2S, 3S)-2-acetylthio-3,4-dimethylpentane acid obtained by the method above, and 0,300 g (1,23 mmol) of methyl-{3R- -[3,6(S*),9a]} - 6-aminooctane-5-oxadiazol[3,2-a] -3-carboxylate is subjected to interaction in the same way as in example 101 (h). Thus obtained is 0.260 g of target compound.

1H-NMR (400 MHz, CDCl3) : 5.28 (1H, DD, J = 6, 2 Hz) 5.02 (1H, d, J = 9 Hz), 4.54 (1H, m), 3.95 (1H, d, J = 9 Hz), 3.79 (3H, s), 3.28 (1H, DD, J = 12, 2 Hz), 3.20 (1H, DD, J = 132, 7 Hz), 2.36 (3H, s), 2.10 - 1.87 (6H, m), 1.72 - 1.60 (2H, m), 0.94 (3H, d, J = 7 Hz), 0.89 (3H, d, J = 7 Hz), 0.75 (3H, d, J = 7 Hz)

Example 106

(3S)-[[2S, 3S)-2-Acetylthio-1-oxo-3,4-dimethyl-1-occupancy] amino]-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1-H-[1]-benzazepin-2-he

< / BR>
0,500 g (1,91 mmol) of (3S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-he 0,430 g (2.1 mmol) (2S, 3S)-2-acetylthio-3,4-dimethylpentane acid is subjected to interaction in the same way as in NMR (400 MHz, CDCl3) : 7.32-7.10 (4H, m), 4.78 (1H, d, J = 17 Hz), 4.50 (1H, m), 4.34 (1H, d, J = 17 Hz), 4.22-4.14 (3H, m), 3.87 (1H, d, J = 10 Hz), 3.42-3.32 (1H, m), 2.75-2.63 (1H, m), 2.35 (3H, s) 2.02-1.86 (3H, m), 1.25 (1H, t, J = 7 Hz), 0.91 (3H, d, J = 7 Hz), 0.85 (3H, d, J = 7 Hz), 0.72 (3H, d, J = 7 Hz)

Example 107 [3R - [3,6(S*),9a]}- 6-[[(2S, 3S)-3,4-Dimethyl-1-oxo-2-thiopental]amino]octahydro-5-oxadiazol-[3,2-a] azepin-3-carboxylic acid

< / BR>
In the same way as in example 104 and based on 0,200 g (0,465 mmol) of methyl [3R- [3,6(S*),9a]}- 6-[[(2S, 3S)-2-acetylethyl-1-oxo-3,4-dimethylpentyl/amino/octahydro-5-oxo-thiazol-[3,2-a] azepin-3-carboxylate obtained in example 105, receive 0,150 g specified in the connection header.

1H-NMR (400 MHz, CDCl3) : 7.42 (1H, d, J = 6 Hz), 5.29 (1H, DD, J = 6, 2 HZ), 5.07 (1H, m), 4.65 (1H, DD, J = 10, 6 Hz), 3.35 (1H, DD, J = 12, 2 Hz), 3.23 (1H, DD, J = 12, 7 Hz), 3.14 (1H, DD, J = 9, 8 Hz), 2.25-1.92 (6H, m), 1.93 (1H, d, J = 9 Hz), 1.82-1.62 (2H, m), 0.95 (3H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz), 0.77 (3H, d, J = 7 Hz)

Example 108

1-Carboxymethyl-(3S)[[(2S, 3S)-3,4-dimethyl-1-oxo-2-thiopental]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
In the same way as in example 104 and based on 0,300 g (0.67 mmol) of (S)-[[(2S, 3S)-2-acetylthio-1-oxo-3,4-dimethyl-1-oxobutyl] amino] -1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-she obtained in example 106, receive 0,200 g specified in the connection header.

t, J = 9 Hz), 2.70 (1H, m), 2.61 (1H, m), 2.15 (1H. m), 1.99 (1H, m), 1.90 (1H, t, J = 8 Hz), 1.72 (1H, m), 0.91 (3H, d, J = 7 Hz), 0.79 (3H, d, J = 7 Hz), 0.72 (3H, d, J = 7 Hz)

Examples 109 - 138

Compounds that are described later in examples 109 - 138 synthesized in accordance with the methods of examples 101 to 108 when using the appropriate starting materials.

Example 109

[4S[4 ,7 (R*), 12b ]]-7-[[(2S)-1-Oxo-2-thiopropyl]amino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.65 (1H, d, J = Hz), 7.50 (2H, d, J = 8 Hz), 7.43 (1H, t, J = 8 Hz), 7.38-7.33 (3H, m), 7.05 (1H, d, J = 8 Hz), 5.68 (1H, Quint, J = 6 Hz), 5.50 (1H, user d) 5,23 (1H, user. d)3.56 (1H, DD, J = 17, 6 Hz), 3.46 (1H, Quint, J = 7 Hz), 2.90 (1H, DD, J = 17, 13 Hz), 2.53 (1H, m), 2.32 (1H, m), 2.14 (1H, d, J = 10 Hz), 2.05-1.70 (4H, m), 1.46 (3H, d, J = 7 Hz)

Example 110

[4S [4,7(R*),12b]]- -7-[[(2S)-4-Methyl-1-oxo-2-thiopental]amino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.51 (3H, m), 7.44 (2H, t, J = 8 Hz), 7.39-7.32 (3H, m), 7.08 (1H, d, J = 8 Hz), 5.71 (1H, Quint, J = 6 Hz), 5.52 (1H, m), 5.25 (1H, m), 3.60 (1H, DD, J = 17, 6 Hz) 3,37 (1H, kV, J = 7 Hz), 2.91 (1H, DD, J = 17, 13 Hz) 2.55 (1H, m), 2.36 (1H, m), 2.05-1.72 (6H, m), 2.03 (1H, d, J = 8 Hz), 1.60 (1H, m), 0.96 (3H, d, J = 7 Hz), 0.92 (3H, d, J = 7 Hz)

Example 111

[4S [4,7(R*),12b]]- -7-[[(2S)-1-Oxo-2-dibutyl] amino]-6-oxo-11-Fe is ) ; 7.59 (1H, d, J = 8 Hz), 7.51 (2H, d, J = 8 Hz), 7.44 (2H, t, J = 7 Hz), 7.39-7.32 (3H, m), 7.09 (1H, d, J = 8 Hz), 5.71 (1H, Quint, J = 6 Hz), 5.54 (1H, m), 5.26 (1H, m), 3.62 (1H, DD, J = 17, 6 Hz) with 3.27 (1H, kV, J = 7 Hz), 2.94 (1H, DD, J = 17, 13 Hz), 2.56 (1H, m), 2.37 (1H, m), 2.08-1.72 (6H, m), 2.04 (1H, d, J = 8 Hz), 1.04 (3H, t, J = 7 Hz)

Example 112

[4S- [4,7(R*),12b]]- 7-[(1-Oxo-2-phenyl-2-thioethyl)amino]-6-oxo-11 - phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4 - carboxylic acid (isomer A)

A:B = 2:1

< / BR>
1H-NMR (400 MHz, CD3OD) ; 7.57-7.26 (13H, m), 7.19 (1H, d, J=8) 5.78 (1H, DD, J=9, 6 Hz), 5.67 (1H, m), 5.16 (1H, e) 3.50 (1H, DD, J=17, 6 Hz), 3.12 (1H, DD, J=17, 13 Hz), 2.58 (1H, m), 2.40 (1H, m), 2.15-1.76 (4H, m)

Example 113

[4S- [4,7(R*),12b]]- 7-[(1-Oxo-2-phenyl-2-thioethyl)amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid (isomer B)

A:B = 1:2

< / BR>
1H-NMR (400 MHz, CD3OD) : 7.57-7.27 (13H, m), 7.08 (1H, d, J=8 Hz), 5.77 (1H, DD, J=9, 6 Hz), 5.67 (1H, m), 5.20 (1H, e) 3.49 (1H, DD, J=17, 6 Hz), 3.06 (1H, DD, J=17, 13 Hz), 2.60 (1H, m), 2.42 (1H, m), 2.17-1.75 (4H, m)

Example 114

[4S- [4,7(R*),12b]]- 7-[[(2R)-3-Methyl-1-oxo-2-dibutyl]]amino]-6-oxo-11 - phenyl] -1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4 - carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.51 (1H, d), J=8 Hz), 7.47-7.24 (7H, m), 7.03 (1H, d, 8 Hz), 5.67 (1H, Quint, J=6 Hz), 5.47 (1H, m), 5.20 (1H, e) 3.57 (1H, DD, J= 17, 6 Hz), 3.09 (1H, t, J=7 Hz), 2.89 (1H, DD, J=17, 13 Hz), 2.50 (1H, m)/SUP>),9a]]- 6-[[1-Oxo-3-phenyl-2(S)thiopropyl]amino]-2,2-dimethyl-5 - oxooctanoate-[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) : 7.61(1H, d, J=6 Hz), 7.31-7.19 (5H, m), 5.12 (1H, d, J=10 Hz), 4.74 (1H, s) 4.53 (1H, how DD, J=12, 6 Hz), 3.60 (1H, dt, J= 9, 7 Hz), 3.26 (1H, DD, J=14, 6 Hz), 3.12 (1H, DD, J=14, 7 Hz), 2.25-2.13 (1H, m) 1.99 (1H, d, J=9 Hz), 2.07-1.84 (4H, m), 1.60-1.50 (1H, m), 1.55 (3H, s) 1.51 (3H, s)

Example 116

[3R- [3,6(S*),9a]]- 6-[[3-Methyl-1-oxo-2(S)-dibutyl] amino] -2,2 - dimethyl-5-oxooctanoate-[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) : 7.81 (1H, d, J=6 Hz), 5.15 (1H, d, J=10 Hz), 4.79 (1H, s) 4.61 (1H, m), 3.21 (1H, dt, J=9, 6 Hz), 2.33-1.88 (6H, m), 1.83 (1H, d, J=9 Hz), 1.69-1.57 (1H, m), 1.56 (3H, s) 1.52 (3H, s) 1.04 (3H, d, J=7 Hz) 0.98 (3H, d, J=7 Hz)

Example 117

[4R [4,7(R*),12b]]- 7-[[(2S, 3R)-3-Methyl-1-oxo-(2-thiopental]amino] 6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.91 (1H, d, J = 8 Hz), 7.51 (2H, d, J = 8 Hz), 7.44 (2H, t as t, J = 8 Hz), 7.38-7.32 (3H, m), 7.06(1H, d, J = 8 Hz), 5.71 (1H, Quint, J = 6 Hz), 5.52 (1H, user.d), 5.23 (1H, m), 3.58 (1H, DD, J = 17, 6 Hz), 3.39 (1H, DD, J = 9, 7 Hz), 2.91 (1H, DD, J = 17, 13 Hz), 2.54 (1H, m), 2,32 (1H, m), 2.12 (1H, septet, J = 7 Hz), 2.00 (1H, m), 1.87 (1H, m), 1.80 (1H, d, J = 8 Hz), 1.82-1.70 (2H, m), 1.51 (1H, m), 1.34 (1H, m), 0.97 (3H, d, J = 7 Hz), 0.93 (3H, t, J = 7 Hz)

Example 118

[3R - [3 ,6 (S*), 9a]]-6-[[3-(4-methoxyphenyl)-oxo - 2(S)-l3) ; 7.63 (1H, d, J = 6 Hz), 7.12 (2H, d, J = 8 Hz), 6.82 (2H, d, J = 8 Hz), 5.12 (1H, d, J = 10 Hz), 4.74 (1H, s), of 4.54 (1H, DD, J = 11, 6 Hz), 3.78 (3H, s), of 3.57 (1H, dt, J = 9, 7 Hz), 3.18 (1H, DD, J = 14, 6 Hz), 3.07 (1H, DD, J = 14, 7 Hz), 2.25-2.14 (1H, m), 1.98 (1H, d, J = 9 Hz), 2.07-1.84 (4H, m), 1.60-1.50 (1H, m), 1.55 (3H, s), 1.51 (3H, s)

Example 119

[4S- [4,7(R*),12b]]- 7-[[(2S)-3-(4-Fluoro-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][a]benzazepin-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, DMSO-d6) ; 8.37 (1H, d, J = 7 Hz), 7.62 (2H, d, J = 8 Hz), 7.46 (3H, t, J = 8 Hz), 7.41 (1H, s), 7,35 (1H, t, J = 8 Hz), 7.29 (2H, DD, J = 8, 6 Hz), 7,19 (1H, d, J = 8 Hz), 7.12 (2H, t, J = 8 Hz), 5.62-5.71 (2H, m), 5.05 (1H, m), 3.94 (1H, m), 3.87 (1H, m), 3.19 (1H, DD, J = 14, 7 Hz), 2.95 (1H, DD, J = 17, 13 Hz), 2.88-2.80 (2H, m), 2.52 (1H, m), 2.22 (1H, m), 1.96 (1H, m), 1.65-1.80 (3H, m)

Example 120

[4S- [4,7(R*),12b]]- 7-[[(2R)-3-(4-Forfinal)-1-oxo-2-thiopropyl] amino] - 6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2] benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, DMSO-d6) ; 8.31 (1H, d, J = 7 Hz), 7.61 (2H, d, J = 8 Hz), 7.46 (3H, t, J = 8 Hz), 7.39 (1H, s), 7,35 (1H, t, J = 8 Hz), 7.30 (2H, DD, J = 8, 6 Hz), 7,16 (2H, d, J = 8 Hz), 7.03 (1H, d, J = 8 Hz), 5.58-5.70 (2H, m), 5.06 (1H, m), 3.94 (1H, m), 3.10 (1H, DD, J = 14, 9 Hz), 2.98-2.88 (1H, mm), 2.63 (2H, DD, J = 17, 12 Hz), 2.49 (1H, m), 2.23 (1H, m), 1.97 (1H, m), 1.78-1.63 (3H, m)

Example 121

[4S- [4,7(R*),12b]]- 7-[[(2S)-3-(5-Bromo-2-thienyl)-1-oxo-2-thiopropyl] amino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid, Is, J = 8 Hz), 6.89 (1H, d, J = 4 Hz), of 6.66 (1H, d, J = 4 Hz), 5.66 (1H, Quint, J = 6 Hz), 5.50 (1H, user.D.), 5.22 (1H, m), 3.62-3.49 (2H, m), 3.36 (2H, d, J = 6 Hz), 2.86 (1H, DD, J = 17, 13 Hz), 2.54 (1H, m), 2.34 (1H, m), 2.15 (1H, d, J = 10 Hz), 2.10-1.71 (4H, m)

Example 122

[4S [4,7(R*),12b]]- 7-[[(2S)-3-Phenyl-1-oxo-2-dimethylpropyl]amino] -6-oxo-11-phenyl-1,2, 3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, DMSO-d6) ; 8.29 (1H, d, J = 7 Hz), 7.62 (2H, d, J = 8 Hz), 7.46 (3H, t, J = 8 Hz), 7.41 (1H, s), 7.38-7.17 (7H, m), 5.77-5.66 (2H, m), 5.04 (1H, d as d) 3.07-2.96 (2H, m), 2.90 (1H, m), 2.73-2.64 (2H, m), 2.55 (1H, m), 2.43 (1H, m), 2.29 (1H, m), 2.24 (1H, m), 1.99 (1H, m), 1.78-1.67 (3H, m)

Example 123

[4S- [4,7(R*),12b]]- 7-[[(2S)-1-Oxo-2-tygacil]amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.55 (1H, d, J = 7 Hz), 7.51 (2H, d, J = 8 Hz), 7.42 (1H, t, J = 8 Hz), 7.40-7.28 (3H, m), 7.09 (1H, d, J = 8 Hz), 5.71 (1H, Quint, J = 6 Hz), 5.52 (1H, user.d), 5.23 (1H, user.d), 3.61 (1H, DD, J = 17, 6 Hz), 3.30 (1H, q, J = 7 Hz), 2.92 (1H, DD, J = 17, 13 Hz), 2.57 (1H, m), 2.37 (1H, m), 2.02 (1H, d, J = 10 Hz), 2.05-1.70 (6H, m), 1.50-1.20 (4H, m), 0.91 (3H, s)

Example 124

[4S- [4,7(R*),12b]]- 7-[[(2S)-3-(2-thienyl)-1-oxo-2-thiopropyl]amino] -6-oxo - 11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2]benzazepine-4 - carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.67 (1H, d, J = 6 Hz), 7.51 (2H, d, J = 8 Hz), 7.43 (2H, t, J =21 (1H, m), 3.64-3.54 (2H, m), 3.50-3.40 (2H, m), 2.84 (1H, DD, J = 17, 13 Hz), 2.54 (1H, m), 2.33 (1H, m), 2.15 (1H, d, J = 10 Hz), 2.10-1.70 (4H, m)

Example 125

[4S- [4,7(R*),12b]] -7-[[(2S)-1-Oxo-2-thio-pentyl]amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; ; 7.57 (1H, d, J = 7 Hz), 7.51 (2H, d, J = 8 Hz), 7.44 (1H, t, J = 8 Hz), 7.38-7.32 (3H, m), 7.07 (1H, d, J = 8 Hz), 5.71 (1H, Quint), J = 6 Hz), 5.52 (1H, user.D.), 5.23 (1H, user.d), 3.58 (1H, DD, J = 17, 6 Hz), 3.32 (1H, sq J = 7 Hz), 2.81 (1H, DD, J = 17, 13 Hz), 2.54 (1H, m), 2.33 (1H, m), 2.09 (1H, d, J = 10 Hz), 2.10-1.67 (6H, m), 1.55-1.35 (2H, m), 0.94 (3H, t, J = 7 Hz)< / BR>
Example 126

[4S- [4,7(R*),12b]]- 7-[[(2S)-3-(3-Methylsulfonylamino)-1-oxo-2 - thiopropyl] amino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite [2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; ; 7.71 (1H, d, J = 7 Hz), 7.61 (1H, user.s), 7.47 (2H, d, J = 8 Hz), 7.40 (2H, t, J = 8 Hz), 7.36-7.28 (3H, m), 7.22 (1H, d, J = 8 Hz), 7.16 (1H, d, J = 8 Hz), 7.03-6.98 (3H, m), 5.68 (1H, Quint, J = 6 Hz), 5.45 (1H, user.d), 5.06 (1H, d e), 3.63 (1H, m), 3.44 (1H, DD, J = 17, 6 Hz), 3.24-3.06 (2H, m), 2.90 (3H, s), 2.82 (1H, DD, J = 17, 13 Hz), 2.51 (1H, m), 2.32 (1H, m), 2.20 (1H, d, J = 10 Hz), 2.05-1.70 (4H, m)< / BR>
Example 127

[4S- [4,7(R*),12b]]- 7-[[(2S)-3-(3-Thienyl)-1-oxo-2-thiopropyl] amino-6-oxo - 11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3

Example 128

[4S- [4,7(R*),12b]]- 7-[(2-Methyl-1-oxo-2-thiopropyl)amino]-6-oxo-11 - phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 8.11 (1H, d, J = 7 Hz), 7.50 (2H, d, J = 8 Hz), 7.43 (1H, t, J = 8 Hz), 7.38-7.32 (3H, m), 7.08 (1H, d, J = 8 Hz), 5.65 (1H, Quint, J = 6 Hz), 5.52 (1H, user. d), 5.23 (1H, user. d), 3.59 (1H, DD, J = 17, 6 Hz), 2.81 (1H, DD, J = 17, 13 Hz), 2.53 (1H, m), 2.32 (1H, m), 2.32 (1H, s), 2.06-1.70 (4H, m), 1.63 (3H, s), 1.64 (3H, s).

Example 129

[4S- [4,7(R*),12b]]- 7-[[(2S)-3-(4-Methylsulfonylamino)-1-oxo-2 - thiopropyl] amino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

1H-NMR (400 MHz, CDCl3) ; 7.83 and 7.53 (total 1H, each user s), 7.60-7.02 (total 12H, m), 6.89 and 6.80 (total 1H, each d, J = 8 Hz), 5.66 and 5.64 (total 1H, each Quint., J = 6 Hz), 5.44 (total 1H, m), 5.08 and 4.97 (total 1H, each user. d), 3.54-3.00 (4H, m), 2..83 and 2.82 (total 3H, each s), 2.72 and 2.20 (total 2H, m), 2.21 and 2.19 (total 1H, each d, J = 10 Hz), 2.04-1.90 (total 4H, m).

Example 130

[4S- [4,7(R*),12b]]- 7-[(2-Cyclohexyl-1-oxo-2-tiapamil)amino]-6-oxo-11 - phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid (isomer A)

Example 131

[4S- [4,7(R*),12b]]- 7-[(2-Cyclohexyl-1-oxo-2-thioethyl)amino] -6-oxo-11 - phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid (isomer B)

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.53 (1H, d, J = 7 Hz), 7.51 (2H, d, J = 8 Hz), 7.44 (1H, t, J = 8 Hz), 7.38-7.32 (3H, m), 7.05 (1H, d, J = 8 Hz), 5.61 (1H, Quint, J = 6 Hz), 5.51 (1H, user. d), 5.21 (1H, user. d), 3.57 (1H, DD, J = 17, 6 Hz), 3.42 (1H, DD, J = 7, 6 Hz), 2.90 (1H, DD, J = 17, 13 Hz), 2.52 (1H, m), 2.31 (1H, m), 2.04-1.64 (9H, m), 1.90 (1H, d, J = 10 Hz), 1.36-1.95 (6H, m).

Example 132

[4S- [4,7(R*),12b]]- 7-[(2-Cyclopentyl-1-oxo-2-thioethyl)amino] -6-oxo-11 - phenyl-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid (isomer A)

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.45 (2H, d, J = 8 Hz), 7.40-7.25 (6H, m), 7.02 (1H, d, J = 8 Hz), 5.66 (1H, Quint., J = 6 Hz), 5.47 (1H, m), 5.17 (1H, e), 3.54 (1H, DD, J = 17, 6 Hz), 3.13 (1H, t, J = 7 Hz), 2.85 (1H, DD, J = 17, 13 Hz), 2.49 (1H, m), 2.33-2.20 (2H, m), 2.00-1.46 (10H, m), 1.97 (1H, d, J = 8 Hz), 1.37-1.23 (2H, m)

Example 133

[4S- [4,7(R*),12b]]- -7-[(2-Cyclopentyl-1-oxo-2-thioethyl)amino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] benzazepine-4-carboxylic acid (isomer B)

< / BR>
1H-NMR (400 MHz, CDClC), 2.88 (1H, DD, J=17, 13 Hz), 2.50 (1H, m), 2.36-2.22 (2H, m), 1.98 (1H, d, J=8 Hz), 2.02-1.18 (12H, m)

Example 134

[4S- [4,7(R*),12b]]- -7-[[(2R)-3-(3-Thienyl)-1-oxo-2-thiopropyl]amino] -6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[1,2-a][2]benzazepine-4-carboxylic acid

< / BR>
HNMR(400 MHz, CDCl3) ; ;

7.49 (2H, d, J=8 Hz), 7.43 (2H, t, J=8 Hz), 7.39-7.32 (4H, m), 7.08 (1H, user. d, J=8 Hz), 7.02-6.96 (2H,m), 5.64 (1H, Quint,J =6 Hz), 5.47 (1H, user. d) 5.18 (1H, m), 3.48 (1H, m),3.40-3.25 (2H, m), 3.13 (1H, DD, J=17, 6 Hz), 2.65 (1H, DD, J=17, 13 Hz), 2.52 (1H, m), 2.31 (1H, m), 2.15 (1H, d, J=10 Hz), 2.04-1.68 (4H, m)

Example 135

[4S- [4,7(R*),12b]]- -7-[(3-Ethyl-1-oxo-2-thiopental)amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, DMSO-d6) ; ;

8.42 and 8.38 (total 1H, each d, J=7 Hz), 7.62 (2H, d, J=8 Hz), 7.46 (3H, t, J= 8 Hz), 7.41 (1H,s), 7.35 (1H, t, J=8 Hz), 7.18 (total 1H, each d, J=8 Hz), 5.77-5.65 (Ls. 2H, m), 5.06 (total 1H, e), and 3.54 3.58 (total 1H, each t, J= 7 Hz), 3.30 -3,17 (total 1H, m), 2.58-2.47 (total 1H, m), 2.23 (1H, m), 1.98 (1H, m), 1.80-1.60 (8H, m), 0.87 (3H, t, J=7 Hz), 0.82(3H, t, J=7 Hz)

Example 136

[4S-[4,7(R*),12b]]- -7-[[(3S)-3-Hydroxy-1-oxo-2-dibutyl] amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; ;

7.56-7.92 (1H, m), 7.52-7.30 (7H, m), 7.10-6.94 (1H, m), 5.81-5.66 (1H, m), 5.56-5.48 (1H, m), 5.26-5.19 (1H, m), 3.68-2.8 is the overall 3H, each, J=7 Hz)

Example 137

[4S- [4,7(R*),12b]]- -7-[[(2S, 3R)-3-Methoxy-1-oxo-2-dibutyl]amino] -6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ;;

7.84 (1H, d, J=7 Hz), 7.51 (2H, d, J=8 Hz), 7.43 (2H, t, J=8 Hz), 7.38-7.31 (3H, m), 7.09 (1H, d, J=8 Hz), 5.61 (1H, Quint, J=6 Hz), 5.53 (1H, m), 5.25 (1H, m), 3.70 (1H, Quint, J=7 Hz), 3.62 (1H, DD, J=17, 6 Hz), 3.40 (3H, s), 3.39 (1H, t, J=7 Hz), 2.94 (1H, DD, J=17, 13 Hz), 2.55 (1H, m), 2.36 (1H, m), 2.27 (1H, d, J=8 Hz), 2.08-1.72 (4H, m), 1.30 (3H, d, J=7 Hz)

Example 138

[4S- [4,7(R*),12b]]- 7-[(3-Methyl-1-oxo-2-tygacil)amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; ; 7.70 and 7.61 (total 1H, each d, J = 7 Hz), 7.50 (2H, d, J = 8 Hz), 7.43 (2H, t, J = 8 Hz), 7.40-7.30 (3H, m), 7.07 and 7.06 (total 1H, each d, J = 8 Hz), 5.71 (1H, Quint, J = 6 Hz), 5.52 (1H, m), 5.23 (1H, m), 3.59 (1H, m), 3.29 (1H, DD, J = 17, 12 Hz), 2.92 (1H, DD, J = 17, 12 Hz), 2.54 (1H, m), 2.34 (1H, m), 2.10-1.94 (2H, m), 1.94-1.82 (1H, m), 1.80-1.70 (1H, m), 1.56 (1H, m), 1.41 (1H, m), 1.35-1.14 (2H, m), 1.03 and 1.02 (total 3H, each d, J = 7 Hz), 0.92 and 0.91 (total 3H, each t, J = 7 Hz)

Example 139

Triptorelin [4S- [4,7(R*),12b]]- 7-[[(2S, 3S)-3-methyl-2-(4-morpholinyl) acetylthio-1-oxobutyl] amino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
(a) diphenylmethyl [4S- [4,7 (R*xelat

< / BR>
0,500 g (at 0.730 mmol) Diphenylmethyl [4S - 4,7 (R*), 12b ]]-7-[[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl]amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylate obtained in example C-6, dissolved in 10 ml of dry ethanol. To the thus obtained solution was added 10 ml of 12% (by weight) ammonia-alcohol solution under ice cooling. The resulting mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure and diluted with dichloromethane. Washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. So get 0,468 g is specified in the header of the product (yield 99%).

1H-NMR (400 MHz, CDCl3) : ; 7.72 (1H, d, J = 6 Hz), 7.50-6.92 (17H, m), 6.70 (1H, d, J = 8 Hz), 6.30 (1H, s) 5.67 (1H, dt, J = 13, 6 Hz), 5.49 (1H, m), 5.42 (1H, both d, J = 4 Hz), 3.45 (1H, DD, J = 18, 6 Hz), 3.28 (1H, DD, J = 8, 7 Hz), 2.61 (1H, DD, J = 18, 13 Hz), 2.55-2.45 (2H, m), 1.95 (1H, d, J = 8 Hz), 1.62-2.08 (6, m), 1.37-1.25 (1H, m), 1.06 (3H, d, J = 7 Hz), 0.96 (3H, t, J = 7 Hz).

(b) diphenylmethyl [4S- [4,7 (R*), 12b ]]-7-[[(2S, 3S)-3-methyl-2-(4-morpholinyl)acetylthio-1-oxobutyl]amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylate

< / BR>
0,262 g (1.44 mmol) of the hydrochloride of 4-martinjlucey sour the Ute 0,176 g (1,08 mmol) carbodiimide while cooling with ice. The resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was again cooled with ice and added dropwise a solution of 0,467 g (to 0.72 mmol) diphenylmethyl [4S- [4,7 (R*), 12b ]]-7-[[(2S, 3S)-methyl-1-oxo-2-thiopental]amino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b - octahedrite[2,1-a] [2] -benzazepin-4-carboxylate obtained above (a) in degassed tetrahydrofuran (7.2 ml). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to reduce the volume of liquid by half. Add ethyl acetate and the resulting mixture washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. So get 0,500 g target derived research (yield 90%).

1H-NMR (400 MHz, CDCl3) : ; 7.54 (1H, d, J = 6 Hz), 7.49-6.92 (17H, m), 6.67 (1H, d, J = 8 Hz), 6.29 (1H, s), 5.64 (1H, dt, J = 13, 6 Hz), 5.44-5.49 (1H, m), 5.40-5.36 (1H, m), 3.99 (1H, d, J = 7 Hz), 3.80 (4H, t, J = 5 Hz), 3.41 (1H, DD, J = 16, 7 Hz), 3.35 (2H, s), 2.71-2.60 (4H, m), 2.60-2.44 (2H, m), 2.21-1.59 (7H, m), 1.31-1.91 (1H, m), 1.06 (3H, d, J = 7 Hz), 0.94 (3H, t, J = 7 Hz)

(c) triptorelin [4S- [4,7 (R*), 12b ]]-7-[[(2S, 3S)-3-methyl-2-(4-morpholinyl)acetylthio-1-oxobutyl]amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-about the*), 12b ]]-7-[[(2S, 3S)-3-methyl-2-(4-morpholinyl)-acetylthio-1-oxobutyl] amino] -6-oxo-11 - phenyl-1,2,3,4, 6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylate obtained above (b), and 0.54 ml (5.00 mmol) of anisole in dichloromethane (6.2 ml) is added dropwise to 0.95 ml (12,00 mmol) triperoxonane acid at -50oC. the thus Obtained mixture is heated to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue is recrystallized from diethyl ether-hexane. So get 0,414 g specified in the title compound (yield 89%)

1H-NMR (400 MHz, CDCl3) : ; 7.59-7.30 (8H, m), 7.09 (1H, d, J = 9 Hz), 5.74-5.65 (1H, m), 5.54-5.47 (1H, m), 5.20-5.14 (1H, m), 4.06 (1H, d, J = 7 Hz), 3.81 (4H, m), 3.67 (2H, s), 3.54 (1H, DD, J = 17, 6 Hz), 3.52-3.30 (2H, user. ), 3.02-2.90 (5H, m), 2.55 (1H, user.d), 2.36 (1H, user.D.), 2.17-1.74 (5H, m), 1.66-1.55 (1H, m), 1.26-1.14 (1H, m), 1.03 (3H, d, J = 7 Hz), 0.92 (3H, t, J = 7 Hz)

Example 140

Triptorelin [4S-[4,7(R*), 12b]]-7-[[(2S, 3S)-2-(Diethylamino)acetylthio-3-methyl-1-oxobutyl] amino] -6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
In the same way as in example 139 except that instead of the hydrochloride of 4-martinjlucey acid used 0,526 g (3.14 mmol) of the hydrochloride of N, N-dimethanol] -amino] -6-oxo-11-phenyl -1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylate get 0,896 g specified in the connection header with the release of 81% in two stages

1H-NMR (400 MHz, CDCl3) : 7.79 (1H, d, J = 7 Hz), 7.50 - 7.03 (8H, m), 5.75 (1H, dt, J = 13, 6 Hz), 5.55 - 5.48 (1H, m), 5.18 - 5,16 (1H, m), 4.22 (1H, d, J = 7 Hz), 4.14 - 4.04 (2H, m), 3.46 (1H, DD, J = 17, 6 Hz), 3.30 - 3.20 (4H, m), 2.98 (1H, DD, J = 17, 13 Hz), 2.57 (1H, user.d J = 12 Hz), 2.40 (1H, user. d, J = 12 Hz), 2.17 - 1.74 (5H, m), 1.67 - 1.56 (1H, m), 1.25 (6H, t, J = 7 Hz), 1.28 - 1.16 (1H, m), 1.05 (3H, d, J = 7 Hz), 0.92 (3H, t, J = 7 Hz)

Example 141

Triptorelin [4S- [4,7 (R*), 12b ]]-7-[[(2S,3S)- 2-(1-Imidazoline)acetylthio-3-methyl-1-oxobutyl]amino]-6-oxo-11-phenyl-1,2,3,4,6,7,8,12 b-octahedrite-[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
In the same way as in example 139 except that instead of the hydrochloride of 4-martinjlucey acid when changing 0,287 g (1,76 mmol) of the hydrochloride of 1-imidazolylalkyl acid, and on the basis of 0,570 g (0.88 mol) diphenylmethyl [4S- [4,7 (R*), 12b ]]-7-[[(2S,3S)-3-methyl-1-oxo-2-thiopental] amino]-6-oxo-11-phenyl - 1,2,3,4,6,7,8,12 b-octahedrite[2,1-a] [2] benzazepine-4-carboxylate get 0,355 g specified in the title compound as a white amorphous product with a yield of 57% in two stages.

1H-NMR (400 MHz, CDCl3) : 7.09 (1H, user.s), 7.03-6.98 (2H, m), 5.65 (1H, dt, J = 13, 6 Hz), 5.48-5.42 (1H, m), 5.10-5.04 (1H, m), 5.01 (1H, d, J = 18 Hz), 4.92 (1H, d, J = 18 Hz), 4.16 (1H, d, J = 6 Hz), 3.41 (1H, DD, J = 17, 6 Hz), 2.92 (1H, DD, J = 17, 13 Hz), 2.55 (1H, user. d), 2.32 (1H, user. d), 2.16-2.07 (1H, m), 2.04 - 1.86 (2H, Ia-3-methyl-1-oxo-pentyl]amino] -2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
In accordance with example 117 synthesize specified in the header of the connection.

1H-NMR (400 MHz, CDCl3) : 7.60 (1H, user.d, J = 7 Hz), 7.33 - 7.44 (4H, m), 4.70 (1H, d, J = 17 Hz), 4.35 (1H, dt, J = 11, 7 Hz), 4.44 (1H, d, J = 17 Hz), 3.35-3.24 (2H, m), 2.74-2.59 (2H, m), 2.06-1.96 (2H, m), 1.74 (1H, d, J = 9 Hz), 1.44 (1H, m), 1.26 (1H, m), 0.87 (6H, m)

Example 143

Ethyl (3S)-[[(2S, 3S)-2-acetylthio-3-methyl-1-oxobutyl]amino]-4-oxo-2,3,4,5 - tetrahydro-1,5-benzoxazepine-5-acetate

< / BR>
528 mg of ethyl (3S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate and 419 mg (1.1 EQ.) (2S, 3S)-2-acetylthio-3-phenylpentane acid are dissolved in 40 ml of methylene chloride. To the thus obtained solution was added 544 mg (1.1 EQ) EACH while cooling with ice. The resulting mixture was further stirred at room temperature for 21 hours. The reaction mixture was then rapidly acidified with 1 N. hydrochloric acid under ice cooling and separating methylenchloride phase. After twice washing methylenchloride phase saturated aqueous sodium chloride her dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified by chromatography on a column of silica gel (ethanol : chloride= 1,5 : 98,5 - 4:96). Thus obtain 370 mg specified in the connection header.

1, 3 (1H, DD, J = 18 Hz), 4.25 (2H, sq J = 7 Hz), 4.13 (1H, t, J = 10 Hz), 3.92 (1H, d, J = 7 Hz), 2.02 (1H, m), 1.56 (1H, m), 1.26 (3H, t, J = 7 Hz), 1.14 (1H, m), 0.96 (3H, d, J = 7 Hz), 0.85 (3H, t, J = 7 Hz)< / BR>
Example 144

(3S)-[[(2S, 3S)-3-Methyl-1-oxo-2-thiopental] -amino] -4-oxo - 2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid

< / BR>
360 ml of ethyl (3S)-[[(2S, 3S)-2-Acetylthio-3-methyl-1-oxobutyl]amino]-4-oxo-2,3,4,5 - tetrahydro-1,5-benzoxazepine-5-acetate obtained in example 143, dissolved in 6 ml of degassed ethanol. To the thus obtained solution was added degassed 1 n aqueous solution of sodium hydroxide under ice cooling. The resulting mixture was further stirred at room temperature for 320 minutes and then quickly acidified by adding 1 n hydrochloric acid, followed by extraction with chloroform (15 ml 2). The organic phase is washed with water and then dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure to obtain 250 mg (yield 83%) specified in the connection header.

1H-NMR (400 MHz, CDCl3) :

7.41 (1H, d, J = 7 Hz), 7.18 - 7.29 (4H, m), 4.90 (1H, dt, J = 10, 7 Hz), 4.78 (1H, d, J = 18 Hz), 4.69 (1H, DD, J = 10, 7 Hz), 4.30 (1H, d, J = 18 Hz), 4.22 (1H, t, J = 10 Hz), 3.23 (1H, DD, J = 9, 6 Hz), 1.94 (1H, m), 1.88 (1H, d, J = 9 Hz), 1.53 (1H, m), 1.22 (1H, m), 0.96 (3H, d, J = 6 Hz), 0.87 (3H, t, J = 7 Hz)

Example 145

[3R- [3BR>< / BR>
In accordance with example 144 synthesize specified in the header of the connection.

1H-NMR (400 MHz, CDCl3) : 7.80 (1H, d, J = 6 Hz), 5.30 (1H, DD, J = 7, 2 Hz), 5.08 - 5.06 (1H, m), 4.63 (1H, DD, J = 11, 6 Hz), 3.37 - 3.33 (2H, m), 3.22 (1H, DD, J = 12, 7 Hz), 2.14 - 1.90 (6H, m), 1.79 (1H, d, J = 9 Hz), 1.75 - 1.64 (1H, m) 1.55 - 1.43 (1H, m), 1.36 - 1.22 (1H, m), 0.92 (3H, d, J = 7 Hz), 0.92 (3H, t, J = 7 Hz)

Example 146

[3R- [3,6 (S*), 9a ]]-6-[[(2R, 3S)-3-Acetyl-diameter - 3-methyl-1-oxobutyl]amino]octahydro-5-oxadiazol[3,2-a]azepin-3 - carboxylic acid

< / BR>
0,200 g (0,550 mmol) of [3R - 3,6 (S*), 9a ]]-6-[[(2R, 3S)-3-methyl-1-oxo-2-thiopental] amino] octahydro-5 - oxadiazol[3,2-a] azepin-3-carboxylic acid obtained in example C-8, and 0,058 ml (0,610 mmol) of acetic anhydride dissolved in 6 ml of acetonitrile-tetrahydrofuran (1 : 1). The resulting solution was added dropwise into a solution of 0.022 g (0,170 mmol) of cobalt chloride (II) in 5 ml of acetonitrile. Then thus obtained mixture is stirred for 7 hours, concentrated under reduced pressure and add it to the water, followed by extraction with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained solid product is recrystallized from ethyl is ASS="ptx2">

1H-NMR (400 MHz, CDCl3) : 7.44 (1H, d, J = 6 Hz), 5.30 (1H, DD, J = 7, 2 Hz), 5.05 (1H, t, J = 5 Hz), 4.60 (1H, DD, J = 11, 6 Hz), 3.97 (1H, d, J = 7 Hz), 3.35 (1H, DD, J = 12, 2 Hz), 3.21 (1H, DD, J = 12, 7 Hz), 3.28 (3H, s) 2.14 - 1.86 (6H, m), 1.72 - 1.52 (2H, m), 1.24 - 1.10 (1H, m), 1.00 (3H, d, J = 7 Hz), 0.88 (3H, t, J = 7 Hz)

Example 147

(3S)-[[(2S, 3S)-2-Acetylthio-3-methyl-1-oxobutyl]amino]- 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-he

< / BR>
0,547 g (1.5 mmol) of (S)-1-Carboxymethyl-3-[[(2S,3S)-3-methyl - 1-oxo-2-thiopental] amino] -2,3,4,5-tetrahydro-1H-[1] benzazepin-2-she obtained in example C-11, and has 0.168 ml (1,650 mmol) of acetic anhydride dissolved in 7 ml of acetonitrile. The resulting solution was added dropwise into a solution of 0.075 g (0,577 mmol) of cobalt chloride (II) in 10 ml of acetonitrile. Then thus obtained mixture is stirred for 2 hours, concentrated under reduced pressure and to it was added water, followed by extraction with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. So get 0,43 g specified in the title compounds as a colorless amorphous product.

1H-NMR (400 MHz, CDCl3) :

7.30 - 7.09 (5H, m), 4.76 (1H, d, J = 17 Hz), 4.49 (1H, dt, J = 11, 7 Hz), 4.39 (1H, d, J = 17 Hz), 3.88 (1H, d, J = 7 Hz), 3.30 accordance with the method, described above in examples 101 to 108, receive compound in examples 148 - 152.

Example 148

[4S- [4,7(R*),12b]]- -7-[[(2S, 3S)-3-Methyl-1-oxo-2-thiopental]amino] -6 - oxo-1,2,3,4,6,7,8,12 b-octahedrite[2,1-a][2]benzazepine-4-carboxylic acid

< / BR>
1H-NMR (400 MHz, CD3OD) ; 7.69 (2H, d, J = 8 Hz), 7.17 - 7.05 (3H, m), 7.02 (1H, d, J = 8 Hz), 5.69 (1H, Quint, J = 6 Hz), 5.48 (1H, user. d, J = 6 Hz), 5.20 (1H, m), 3.52 (1H, DD, J = 17.6 Hz) 3.21 (1H, DD, J = 9.7 Hz) 2.90 (1H, DD, J = 17,13 Hz), 2.50 (1H, m), 2.35 (1H, m), 1.92 - 2.03 (2H, m), 1.92 (1H, d, J = 8 Hz), 1.27 (1H, m), 1.02 (3H, d, J = 7 Hz), 0.93 (3H, t, J = 7 Hz)

Example 149

[3R- [3,6(S*),9a]]- 6-[[(2S, 3S)-3-Methyl-1-oxo-2-thiopental]amino] octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.78 and 7.84 (total 1H, each d, J = 7 Hz), 5.56 - 4.58 (3H, m), 3.82 - 2.92 (3H, m), 2.34 - 1.45 (9H, m), 1.30 - 1.18 (1H, m), 0.88 - 1.00 (6H, m)

Example 150

[3R- [3,6(S*),9a]]- 6-[[(2S, 3S)-4-Methyl-1-oxo-2-thiopental]amino] octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>
1H-NMR (400 MHz, CDCl3) ; 7.56 - 7.60 (1H, t) 5.29 (1H, DD, J = 7,3 Hz) 5.08 - 5.06 (1H, m), 4.65 - 4.61 (1H, m), 3.40 - 3.33 (2H, m), 3.23 (1H, DD, J = a 12.7 Hz), 2.08 - 1.90 (6H, m), 1.88 - 1.64 (3H, m), 1.60 - 1.52 (1H, m), 0.94 (3H, d, J = 6 Hz), 0.90 (3H, d, J = 7 Hz)

Example 151

[3R- [3,6(S*),9a]]- 6-[[(S)-1-Oxo-2-tygacil] amino] octahydro-5 - oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>< / is) 3.30 (1H, dt, J = 8.7 Hz) 3.22 (1H, DD, J = a 12.7 Hz), 2.10 - 1.90 (6H, m), 2.00 (1H, d, J = 8 Hz), 1.76 - 1.64 (2H, m), 1.46 - 1.24 (4H, m), 0.90 (3H, t, J = 7 Hz)

Example 152

[3R- [3,6(S*),9a]]- 6-[[(2S, 3S)-2-Benzylthio-3-methyl-1-oxobutyl] amino]octahydro-5-oxadiazol[3,2-a]azepin-3-carboxylic acid

< / BR>
In the same way as in example 146, replacing acetic anhydride with benzoyl chloride, get mentioned in the title compound as a white product (147 mg, 51% yield).

1H-NMR (400 MHz, CDCl3) ; 0.92 (3H, t, J = 7 Hz), 1.06 (3H, d, J = 6 Hz), 1.20 - 1.30 (1H, m), 1.58 - 1.72 (2H, m), 1.90 - 2.03 (5H, m), 2.13 - 2.23 (1H, m), 3.19 (1H, DD, J = 7,12 Hz), 3.33 (1H, DD, J = 2,12 Hz), 4.20 (1H, d, J = 7 Hz), 4.62 (1H, DD, J = 7,11 Hz) 5.02 - 5.08 (1H, m), 5.28 (1H, DD, J = 2.7 Hz) 7.43 - 7.61 (4H, m), 7.97 - 7.99 (2H, m)

In tables 1 and 2 presents data on the biological activity of the proposed new compounds described in these examples.

1. Derivatives of amino acids of General formula I

< / BR>
where R1means a hydrogen atom or acyl group;

R2means a hydrogen atom, a lower alkyl group, cycloalkyl group, phenyl which may be substituted by alkoxygroup, halogen atom, phenyl and alkylsulfonamides, or thienyl, which may be substituted by a halogen atom;

m and n each represents an integer 0, 1 or 2;aroda or carboxyamide group;

R4is a hydrogen atom;

Y2group-CH2-, -S - or-O-;

R10is a hydrogen atom or phenyl;

group of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R11and R12- same or different and represent a hydrogen atom or a lower alkyl group;

n is an integer 0, 1 or 2;

group of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R13is phenyl or a group - NHSO2R18where R18is a hydrogen atom or a lower alkyl group;

group of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R14is a hydrogen atom;

and groups of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R15- the hydrogen atom

provided that if J denotes a group of General formula

< / BR>
where R13is a hydrogen atom or phenyl,

that should be adhered to at least one of the following conditions: n is 0, R1cannot be a hydrogen atom, acetyl or benzoline group and R2cannot be a hydrogen atom, a lower alkyl group and a phenyl

or their pharmacologically
where R1, R2, J, m, and n each has the meaning given above.

3. The derived amino acid under item 1, which is represented by the General formula II'

< / BR>
where R1, R2, R3, R10, Y3, m, and n each has the meaning given above.

4. The derived amino acid on p. 1, which presents the General formula III'

< / BR>
where R1, R2, R3, R11, R12and u, m, and n each has the meaning given above.

5. The derived amino acid on p. 1, which presents the General formula IV'

< / BR>
where R1, R2, R3, R13, m, and n each has the meaning given above.

6. The derived amino acid on p. 1, which presents the General formula V'

< / BR>
where R1, R2, R3, R14, m, and n each has the meaning given above.

7. The derived amino acid on p. 1, which presents the General formula VI'

< / BR>
where R1, R2, R3, R15, m, and n each has the meaning given above.

8. The derived amino acid under item 1, which is represented by the General formula II'

< / BR>
where R1, R2, R3, R10, Y3and m each has a value UP>1, R2, R3, R11, R12, m and u, everyone has the meaning given above.

10. The derived amino acid on p. 1, which presents the General formula IV

< / BR>
where R1, R2, R3, R13and m each has the meaning given above.

11. The derived amino acid on p. 1, which presents the General formula V"

< / BR>
where R1, R2, R3, R14m each has the meaning given above.

12. The derived amino acid on p. 1, which presents the General formula VI

< / BR>
where R1, R2, R3, R15m each has the meaning given above.

13. The derived amino acid on p. 1, which presents the General formula VII

< / BR>
where R1means a hydrogen atom or acyl group;

J represents a group chosen from:

group of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R4is a hydrogen atom;

Y2group-CH2-, -S - or-O-;

R10is a hydrogen atom or phenyl;

group of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R11and R12same or different is a General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R13is phenyl or a group - NHSO2R18where

R18is a hydrogen atom or a lower alkyl group;

group of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R14is a hydrogen atom;

group of General formula

< / BR>
where R3is a hydrogen atom or carboxyamide group;

R15- the hydrogen atom.

14. The derived amino acid on p. 1, which presents the General formula VII'

< / BR>
where R1represents a hydrogen atom or acyl group;

J matter described in paragraph 1.

15. The derived amino acid under item 1, which is represented by General formula IIIa

< / BR>
where R1represents a hydrogen atom or acyl group;

R3represents a hydrogen atom or carboxyamide group;

R11and R12are the same or different from each other and each represents a hydrogen atom or a lower alkyl group;

u, m and n are each independently 0, 1 or 2.

16. The derived amino acid on p. 1, which presents the General formula IIa'

< / BR>
where R1, R3, R10
< / BR>
where R1, R11, R12u everyone has the meaning given above.

18. The derived amino acid under item 1, which is represented by the General formula IVa'

< / BR>
where R1, R3, R13everyone has the meaning given above.

19. The derived amino acid under item 1, which is represented by the General formula Va'

< / BR>
where R1, R3, R14everyone has the meaning given above.

20. The derived amino acid under item 1, which is represented by the General formula VIa'

< / BR>
where R1, R3, R15everyone has the meaning given above.

21. The derived amino acid under item 1, which is represented by the following General formula:

< / BR>
where R1, R3, R4, R10everyone has the meaning given above.

22. The derived amino acid under item 1, which is represented by the following General formula:

< / BR>
where R1, R3, R4, R10everyone has the meaning given above.

23. The derived amino acid under item 1, which is represented by the following General formula:

< / BR>
where R1, R3, R11, R12everyone has the meaning given above.

24. Derived am everyone has value, defined above.

25. The derived amino acid under item 1, which is represented by the General formula Va

< / BR>
where R1, R3, R14everyone has the meaning given above.

26. The derived amino acid under item 1, which is represented by the General formula VIa'

< / BR>
where R1, R3, R15everyone has the meaning given above.

27. The derived amino acid of General formula I on p. 1, represented by formula

< / BR>
28. The derived amino acid of the formula I on p. 1, represented by formula

< / BR>
29. The derived amino acid of General formula I on p. 1, represented by formula

< / BR>
30. The derived amino acid of General formula I on p. 1, represented by formula

< / BR>
31. The derived amino acid of General formula I on p. 1, represented by formula

< / BR>
32. The derived amino acid of General formula I on p. 1, represented by formula

< / BR>
33. The derived amino acid of General formula I on p. 1, represented by formula

< / BR>
Priority signs:

11.06.93 - J represents a group

< / BR>
where R11, R12is a hydrogen atom, R3is a hydrogen atom or carboxyamide group; R1is a hydrogen atom or acyl group, R2- phenyl, CT group

< / BR>
where R3is a hydrogen atom or carboxyamide group; R13group NHSO2R18where R18- lower alkyl group, R1is a hydrogen atom or acyl group, R2is phenyl which may be substituted by alkoxygroup, m = 1, n = 0;

06.07.93 - J represents a group

< / BR>
where R13- phenyl, R3is a hydrogen atom or carboxyamide group; R1is a hydrogen atom or acyl group, R2- lower alkyl group, phenyl which may be substituted by alkoxygroup, m = 0, 1, or 2, n = 0 or 2;

28.10.93 - J represents a group

< / BR>
or

< / BR>
where R3is a hydrogen atom or carboxyamide group; R4is a hydrogen atom, R10- phenyl, Y3group-CH2-; R1is a hydrogen atom or acyl group, R2- lower alkyl group, phenyl or thienyl, m = 0 or 1, n = 0;

08.11.93 - J represents a group

< / BR>
< / BR>
or

< / BR>
where R3is a hydrogen atom or carboxyamide group; R4is a hydrogen atom, R10, R14, R15is a hydrogen atom, Y3group-CH2-; R1is a hydrogen atom or acyl group, R2- lower alkyl group, phenyl, or thienyl, substituted with halogen, m = 0 or 1, n = 1;

16.11.93 - J representation is UP> is a hydrogen atom; R10is a hydrogen atom, R11, R12is a hydrogen atom or a lower alkyl group; R13is phenyl or the group NHSO2R18where R18lower alkyl group; Y3group - CH2-. -O - or-S-; R1is a hydrogen atom or acyl group, R2- lower alkyl group, m = 0, n = 0;

17.12.93 - J represents a group

< / BR>
where R3is a hydrogen atom or carboxyamide group; R13is phenyl; R1is a hydrogen atom or acyl group, R2- lower alkyl group, m = 0, n = 0;

08.02.94 - J represents a group

< / BR>
or

< / BR>
where R3is a hydrogen atom or carboxyamide group; R10, R11, R12is a hydrogen atom, u = 0, Y3group-CH2-, R1is a hydrogen atom or acyl group, R2- lower alkyl group, m = 0, n = 0;

07.03.94 - J represents a group

< / BR>
where R3is a hydrogen atom, R1is a hydrogen atom, R1is a hydrogen atom or acyl group, R2- lower alkyl group, m = 0, n = 0;

10.06.94 - R2- alkylsulfonamides; u = 1 or 2.

 

Same patents:

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

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

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

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

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

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

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

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

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

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

(I)

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

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

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

where R1- C1-C6-alkoxy or phenylaminopropyl,

R2- C1-C6-alkyl or phenyl,

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

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

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

The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
where X is-CH=CH -, or S; R1- lower alkyl or trifluoromethyl; R2is chlorine or fluorine; R3is a radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC -, where n is an integer of 0,1 or 2; s is 0 or 1; R4is phenyl or mono-, di - or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms O or S and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine; R5is phenyl or pyridyl radical, provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center, their enantiomers and racemates and pharmaceutically-acceptable salts accession acids exhibiting the properties of antagonists of platelet activating factor (PAF) and, respectively, with angioprotective, immunological, is omposition based on them

The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General formula I:

I,

where X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula R4-(CH2)nC or R5-O-CH2-C_C-, where n is the integer 0, 1 or 2;

R4phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms 0 or S, and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine,

R5phenyl or pyridylethyl provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5attached via a carbon to oxygen connection with RAG-antagonistic properties

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to new compounds of the formula

< / BR>
to pharmaceutically acceptable additive salts of the acid and stereoisomers of these compounds, which are used as antagonists of mediators and have a high activity against Central nervous system

The invention relates to new heterocyclic substances exhibiting antagonist against angiotensin II action
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