Derivatives pyridobenzoxazine, mixture of isomers, or individual isomers, its hydrates and salts

 

(57) Abstract:

Describes the new derivatives pyridobenzoxazine General formula (I), where R1is hydrogen, alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl or halogen; R2is independent of R1and means hydrogen or methyl; R3is hydrogen or alkyl with 1-4 carbon atoms; R4is hydrogen or alkyl with 1-4 carbon atoms; X1is hydrogen or halogen; Z is a residue of formula (II, III, IV), where R5is hydrogen; R6is hydrogen or ethyl; B is a group-CH2-, an oxygen atom or a direct bond; R7is hydrogen, hydroxyl, hydroxymethyl group,- CH2-NR10R11, -NR10R11where R10denotes hydrogen, alkyl with 1-3 carbon atoms, alkoxycarbonyl with 1-4 carbon atoms in the CNS part, and R11is hydrogen or methyl, R8is hydrogen, R9is hydrogen, a mixture of their isomers, or individual isomers, its hydrates and salts. The compounds of formula (I) have strong antibiotic effect with low toxicity and can be used in hemoterapia, medicine and veterinary medicine. 2 C.p. f-crystals, 1 PL.

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The invention relates to new derivatives pyridobenzoxazine with valuable pharmaceutical hydrogen, alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl or halogen,

R2is independent of R1and means hydrogen or methyl,

R3is hydrogen or alkyl with 1-4 carbon atoms,

R4is hydrogen or alkyl with 1-4 carbon atoms,

X1is hydrogen or halogen,

Z is a residue of the formula

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where R5is hydrogen, R6is hydrogen or ethyl, B is a group-CH2-, oxygen or a direct bond, R7is hydrogen, hydroxyl, hydroxymethyl, group-CH2-NR10R11, -NR10R11where R10denotes hydrogen, alkyl with 1-3 carbon atoms, alkoxycarbonyl with 1-4 carbon atoms in the CNS part, and R11is hydrogen or methyl, R8is hydrogen, R9is hydrogen,

mixtures of their isomers, or individual isomers, its hydrates and salts.

Preferred are the compounds of formula (I),

where

R1is hydrogen, alkyl with 1-3 carbon atoms, unsubstituted or substituted by hydroxyl,

R2is independent of R1and means hydrogen or methyl,

R3is hydrogen, methyl or ethyl,

R4is hydrogen, alkyl with 1-4 carbon atoms,

X1is hydrogen, fluorine or chlorine,

Z is a residue of the formula

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is hydrogen, hydroxyl, hydroxymethyl, group-CH2-NR10R11, -NR10R11where R10denotes hydrogen, alkyl with 1 to 2 carbon atoms, alkoxycarbonyl with 1-4 carbon atoms in the CNS part, a R11is hydrogen or methyl, R8is hydrogen, R9is hydrogen,

their pharmaceutically applied hydrates and acid additive salts, as well as their alkali, alkaline earth, silver and guanidinium salt.

Especially preferred compounds of formula (I),

where

R1is hydrogen or methyl,

R2is hydrogen,

R3is methyl or ethyl,

R4is hydrogen, methyl or ethyl,

X1- fluorine,

Z is a residue of the formula

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where R5is hydrogen, B is a group-CH2-, oxygen or a direct bond, R6is hydrogen, R7is hydrogen, hydroxyl, hydroxymethyl, group-CH2-NR10R11and-NR10R11where R10is hydrogen, methyl, alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part, a R11is hydrogen or methyl, R8is hydrogen, R9is hydrogen,

their pharmaceutically applied hydrates and acid additive salts, as well as their alkali, alkaline earth, silver and guanidinium salt.

Connect the R4and X1have the above significance and X2- halogen, in particular fluorine or chlorine,

and subjected to interaction with compounds of the formula (III),

Z - H,

where Z has the above meaning,

if necessary in the presence of an acid acceptor.

If to obtain the compounds of formula (I) is used, for example, 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] [1,3,4]- benzoxazepin-6-carboxylic acid and 2,8-diazabicyclo[4.3.0]nonan, the reaction can be illustrated by the following scheme:

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Used as starting compounds of the formula (II) are known or can be obtained by known methods. They can be used, if necessary, as racemates, enantiomers or pure diastereomers.

Most of the amines of the formula (III) used as starting compounds, is known. Chiral amines can be used both as racemates and as pure enantiomeric or diastereomeric compounds.

Popadayuschie the General formula (III) compounds of the formula

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where R7, R8, R9have the above meaning,

get due to the fact that suitable diene subjected to interaction with prigodnuyu, if necessary, conduct additional reactions, such as, for education pyrrolidone rings and the introduction of substituents that provide the desired biological effect, and as a final stage of detachment of the protective group pyrolidine nitrogen.

When intramolecular carrying out reaction according to the Diels-Alder reaction of compounds of formula (1) or (2)

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where R8and R9have the above meaning;

P - protective group (e.g. allyl, acyl, carbarnoyl or trityl),

Z is hydrogen, carboxyl, ester or amide of carboxylic acid, cyano or nitro,

turn to compounds of the formula (3) [on the basis of formulas (1)] or the formula (4) [on the basis of formula (2)]

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where R8, R9, P and Z have the above meaning.

Such intramolecular reaction of the Diels-Alder reaction is partly known (see J. M. Mellor, A. M. Wagland: J. Chem. Soc. Perkin I, pp. 997 - 1005 (1989): W. R. Roush, S. E. Hall, J. Am. Chem. Soc. 103 p. 5200 (1980): E. Ciganek: Organic Reactions 32, page 1 - 374 (1984)). In this literature are not available, however, indicate a protective group suitable for reaction and at the same time hassle-free otseplyaet.

When intermolecular carrying out reaction according to the Diels-Alder reaction diene formula is neobhodimosti, after modifying groups Z1and Z2for example , converting the cyclic anhydride of carboxylic acid in complex fluids during removal of the protective groups P1or P1and P2by cyclization turn to the lactams of the formula (8).

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In formulas(5), (6), (7) and (8) the radicals R8and R9have the above meaning,

P1- acyl or carnemolla protective group, if

P2hydrogen, or

P1together with P2forms imide,

Z1and Z2is hydrogen, carboxyl, ester or amide of carboxylic acid, cyano or nitro, and at least one of the groups Z1or Z2is an ester or amide of carboxylic acid, or cyano, or Z1and Z2together form a bridge, so that a cyclic carboxylic acid anhydride.

Preferred protective groups P, P1, P2such protective groups, which under the conditions used for their removal, are performed cyclization to the lactam and, if necessary, the esterification second, another free carboxyl function is used as the alcohol solvent without isolation of the intermediate product, so nakhonratchasima or difficultly separable mixture of isomers cannot take place.

As examples can be mentioned:

1. tert. butyloxycarbonyl protective group (the removal of aqueous or alcoholic acid);

2. phthalimido protective group (aminals primary amines in aqueous or anhydrous alcohols as solvent) (schemes a, B are given at the end of text).

Suitable for the implementation of the reaction Diels-Alder reaction diluents are all inert organic solvents, preferably ethers, such as diisopropyl ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran and anisole, hydrocarbons, such as hexane, methylcyclohexane, toluene, xylene and mesitylene, and halogenated hydrocarbons, such as chloroform, 1,2-dichloroethane and chlorobenzene. The reaction of the Diels-Alder reaction can, however, also be carried out without solvent.

The reaction temperature can be varied within a wide range. In General operate at temperatures between about -20oC and +200oC, preferably between -20oC and +150oC. the Reaction Diels-Alder reaction is usually carried out at atmospheric pressure. To accelerate the reaction can, however, apply pressure up to 1.5 GPA.

Subsequent translation of the compounds of formulas is eskay chemistry.

To obtain compounds of the formula (III) from compounds of formula (3), (4) or (8) requires an additional reaction. As examples we can mention the hydrolysis of ester to carboxylic acid, reduction of carbonyl groups, for example esters to aldehydes or alcohols, or lactamase groups to pyrrolidino, translation of hydroxyl functions in the amine function, the translation of the carboxyl function or its derivative at the amino function when removing one carbon atom, reductive amination of aldehyde present in the molecule amine function, reductive amination available in the molecule of the aldehyde function, an amine, the introduction of protective groups, cleavage of the protective group pyrolidine nitrogen so that the molecule remain possible additional protective group.

These reactions are carried out as described in the following examples, methods or according to conventional organic chemistry methods.

Further conversion of compounds of formula (3), (4) or (8) to compounds of formula (III) can be illustrated, for example, schemes I - III at the end of the text.

Most of the starting substances of the formula(1), (2), (5) and (6) is known or and the crystals of (II) with compounds of the formula (III), when the compounds of formula (III) can also be applied in the form of their salts, for example, hydrochloride, preferably carried out in an environment of a diluent, such as, for example, dimethylformamid, N,N-dimethylformamide, N-organic, triamid hexamethylphosphoric acid, tetramethylarsonium, acetonitrile, water, environment, alcohol, such as methanol, ethanol, n-propanol, isopropanol, simple glycolmonomethyl ether or pyridine. You can also use mixtures of these diluents.

As an agent that binds acid, it is possible to use all customary inorganic and organic agents for binding the acid. Here are preferably hydroxides of alkali metals, carbonates of alkali metals, organic amines and amidine. Particularly suitable are triethylamine, 1,4-diazabicyclo[2.2.2] octane, 1,8 - diazabicyclo[5.4.0]undec-7-ene or excess amine of the formula (III).

The reaction temperature can be varied within a wide range. In General operate at a temperature of 20 to 200oC, preferably 80 - 180oC.

The reaction may be carried out at atmospheric pressure but also at elevated pressure. In General operate at a pressure between 1 and 100 bar, preferably 1 and 10 bar.

Free amino groups can be protected during the reaction with a suitable amine protective group, for example, by using tert.butoxycarbonyl residue, which upon completion of the reaction can again be removed by treatment with a suitable acid, such as, for example, hydrochloric acid or triperoxonane acid (see Houben-Weyl. Methods der Organischen Chemie, volume E4. page 144 (1983): J. F. W. McOmie. Protective Groups in Organic Chemistry (1973), page 43).

Offer esters receive as a result of the interaction of alkali metal salt of the corresponding carboxylic acid, which can be protected at the nitrogen atom protecting group, such as, for example, tert.butoxycarbonyl balance, with suitable derivatives of halogenoalkane in the environment of a solvent, such as, for example, dimethylformamide, dimethylacetamide, N-organic, dimethylsulfoxide or tetramethylrhodamine, at temperatures from approximately 0 to 100oC, preferably from 0 to 50oC.

Getting acid additive salts of the proposed compounds carried out in the usual manner, for example by dissolving the corresponding carboxylic acid in a sufficient amount of aqueous acid and precipitating the salt orgao also to heat an equivalent amount of carboxylic acid and a salt-forming acid in water or alcohol as simple glycolmonomethyl ether, was evaporated to dryness or to suck precipitated salt. As used pharmaceutically salts include, for example, salts with a galacturonic, glucoboy, monowai, glutamic, aspartic, hydrochloric, sulfuric, acetic, glycolic, lactic, succinic, citric, tartaric acids, methanesulfonate, 4-toluensulfonate. In addition, you can link the proposed compounds with acidic or basic ion exchanger.

Salts of alkaline or alkaline earth metals offer carboxylic acids can be obtained, for example, by dissolving the appropriate acid in an insufficient quantity of hydroxide of alkali or alkaline earth metals, filtering undissolved acid and evaporation of the filtrate to dryness.

Pharmaceutically suitable salts are sodium, potassium or calcium. By reacting salts of the alkali or alkaline earth metals with a suitable silver salt, e.g. silver nitrate, get the appropriate silver salt.

The proposed compounds have strong antibiotic action and low toxicity have a broad antibacterial spectrum against gram-positive and gram-negative germs, in particular against such, which is what isoglucose, sulfonamides, tetracyclines.

These valuable properties allow the application of the proposed compounds within chemotherapie in medicine and veterinary medicine and as substances for preservation of inorganic and organic materials, in particular all types of organic materials such as polymers, lubricants, paints, fibres, leather, paper and wood, food and water.

The proposed compounds are active against a very broad spectrum of microorganisms. You can use them to fight gram-negative and gram-positive bacteria and similar to bacteria, microorganisms, and can also prevent, improve and/or cure caused by these pathogens.

The proposed compounds differ enhanced action on inactive and resistant bacteria. In the case of inactive bacteria, i.e. bacteria, which are not provable growth, connections are at concentrations below concentrations known analogues. In addition, they also provide an increased rate of killing. These results can be seen in the case of gram-positive and gram-negative bacteria, in particular in the case of Staphylococcus aureus, Micrococcus the view known analogues, in particular resistant bacteria Staphylococcus aureus and Enterococcus faecalis, offer connections are active.

A special activity of the proposed compounds exhibit in the case of bacteria and microorganisms similar to bacteria. Therefore they are particularly suitable for the prevention and hemoterapia local and systemic infections in medicine and veterinary caused by these pathogens.

Furthermore, the new compounds are suitable for combating protocolname and worms.

The minimum concentration of inhibition is determined by the method of serial dilution on agar ISO-Sensitest. For each tested compound prepared a series of agar plates containing double dilution decreasing the concentration of the active substance. Agar plates grafted with multipoint inoculator firm Denley. For vaccinations applied grown in overnight cultures of the pathogens that are pre-diluted so that each point of inoculation contains about 104forming colonies particles. After vaccination agar plates incubated at temperature 37oC and microbial growth determine approximately 20 hours. Determine the minimum concentra observed microbial growth.

The table shows the minimum concentration of inhibition (ICB) of the proposed compounds according to examples 5, 6 and 8 in comparison with the known from the application EP N 259804 analogue, 9-fluoro-3-methyl-10-(4-methyl-1-piperazinil)-7-oxo-2,3 - dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6-carboxylic acid.

The following examples explain the formation of compounds of formula (I).

Abbreviations used in the examples of chemical formulas, have the following meanings:

Me = methyl

Et = ethyl

tBu = tert.butyl

rac = racemate

Example 1

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9-fluoro-3-methyl-10-(2-oxa-5,8-diazabicyclo[4.3.0] nonan-8-yl)-7 - oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] -[1,3,4]-benzoxazepin-6 - karbonovy acid

500 mg (1.77 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3 - d, e]-[1,3,4]-benzoxazepin-6-carboxylic acid together with 450 mg (3,51 mmol) of 2-oxa-5,8-diazabicyclo[4.3.0]nonane in 15 ml of pyridine is heated to 100oC in argon atmosphere for 8 hours. The mixture is concentrated under high vacuum, the residue will recrystallized from ethanol and dried.

Yield: 410 mg (59% of theory)

Melting point: 260 - 262oC (decomp.)

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10-(2,8-diazabicyclo[4,3,0] nonan-8-yl)-9-fluoro-3-methyl-7-oxo-2,3 - dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6">

Melting point: 256 - 258oC (decomp.)

Example 3

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10-((1S, 6S)-2,8-diazabicyclo[4,3,0]nonan-8-yl)-9-fluoro-3-methyl - 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] -[1,3,4]-benzoxazepin-6 - carboxylic acid

Repeat example 1 with the difference that using (1S,6S)-2,8 - diazabicyclo[4.3.0]nonan.

Melting point: 255 - 257oC (decomp.)

Example 4

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10-(2,7-diazabicyclo[3,3,0] nonan-7-yl)-9-fluoro-3-methyl-7-oxo - 2,3-dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6-carboxylic acid

100 mg (0.35 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-d, e] -[1,3,4] -benzoxazepin-6-carboxylic acid together with 80 mg (0.71 mmol) of 2,7-diazabicyclo[3,3,0] nonane in 4 ml of pyridine is heated to 100oC in argon atmosphere for 4 hours. The mixture is concentrated under high vacuum, the residue will recrystallized from ethanol and dried. The obtained target compound contains about 15% of regioisomer as an impurity.

Yield: 60 mg (46% of theory)

Melting point: 220 - 224oC (decomp.)

Example 5

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9-fluoro-3-methyl-10-(2-methylamino-8-azabicyclo[4,3,0] non-3-EN - 8-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] -[1,3,4]- benzoxazepin-6-carboxylic acid

150 mg (of 0.53 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro - 7H-pyrido[1,2,3-d, e] -[1,3,4] -benzoxazepin-6-carbonateserophene argon for 4 hours. The mixture is concentrated under high vacuum, the residue will recrystallized from methanol and dried.

Yield: 118 mg (54% of theory)

Melting point: 233 - 235oC (decomp.)

Example 6

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10-(2-amino-8-azabicyclo[4,3,0] -3-EN-8-yl)-9-fluoro-3-methyl-7 - oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6 - carboxylic acid

Repeat example 1 except for using 2-amino-8-azabicyclo-[4.3.0]non-3-ene.

Melting point: 246 - 250oC (decomp.)

Example 7

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10-(2-amino-5-isopropyl-8-azabicyclo[4,3,0] non-3-EN-8-yl)-9 - fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] -[1,3,4] - benzoxazepin-6-carboxylic acid

Repeat example 1 except for using 2-amino-5-isopropyl-8-azabicyclo[4,3,0]non-3-ene.

Melting point: 194 - 199oC (decomp.)

Example 8

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10-(2-amino-5-methyl-8-azabicyclo[4,3,0] non-3-EN-8-yl)-9 - fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]- benzoxazepin-6-carboxylic acid

150 mg (of 0.53 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro - 7H-pyrido[1,2,3-d, e] -[1,3,4] -benzoxazepin-6-carboxylic acid together with 120 mg (0,79 mmol) 2-amino-5-methyl-8-azabicyclo[4,3,0]non - 3-ene in 5 ml of pyridine is heated to 100oC in argon atmosphere for 4 hours. The mixture is concentrated under high vacuum, the residue perakisoC (decomp.)

Example 9

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10-(2-hydroxymethyl-8-azabicyclo[4,3,0] non-3-EN-8-yl)- 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]- benzoxazepin-6-carboxylic acid

150 mg (of 0.53 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro - 7H-pyrido[1,2,3-d, e] -[1,3,4] -benzoxazepin-6-carboxylic acid together with 120 mg (0.78 mmol) of 2-hydroxymethyl-8-azabicyclo[4.3.0]non - 3-ene in 5 ml of pyridine is heated to 115oC in argon atmosphere for 4 hours. The mixture is concentrated under high vacuum, the residue will recrystallized from methanol and dried.

Yield: 154 mg (70% of theory)

Melting point: 270 - 272oC (decomp.)

Example 10

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10-(2-methylaminomethyl-8-azabicyclo[4,3,0] non-3-EN-8-yl)-9-fluoro - 3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] -[1,3,4]- benzoxazepin-6-carboxylic acid

Repeat example 5 with the difference that use 2-methylaminomethyl-8-azabicyclo[4,3,0]non-3-ene.

Melting point: 272 - 274oC (decomp.)

Example 11

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10-(2-hydroxy-8-azabicyclo[4,3,0] non-3-EN-8-yl)-9-fluoro-3 - methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]- benzoxazepin-6-carboxylic acid

150 mg (of 0.53 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-d, e] -[1,3,4] -benzoxazepin-6-carboxylic acid together with 110 mg (0,79 mmol) 2-hydroxy-8-azabicyclo[4.3.0] noumi, the remainder will recrystallized from methanol and dried.

Yield: 63 mg (30% of theory)

Melting point: 248 - 250oC (decomp.)

Example 12

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10-(8-azabicyclo[4,3,0] non-2-EN-8-yl)-9-fluoro-3-methyl-7-oxo - 2,3-dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6-carboxylic acid

The mixture 846 mg (3.0 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro - 7H-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6-carboxylic acid, 553 mg (4.5 mmol) of 8-azabicyclo[4.3.0] non-2-ene (product following example A) and 24 ml of pyridine is stirred under nitrogen atmosphere at a temperature of 100oC for 4 hours. The mixture is concentrated under high vacuum, the crude product is mixed with methanol, sucked off and dried at 60oC.

Yield: 850 mg (66% of theory)

Melting point: 309oC (decomp.)

Example 13

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(1'SR, 2'RS, 6'SR)-10-(2'-ethoxycarbonyl-8'- azabicyclo[4.3.0] non-4'-EN-8'-yl)-9-fluoro-3-methyl-7-oxo-2,3 - dihydro-7H-pyrido[1,2,3-d, e]-[1,3,4]-benzoxazepin-6-carboxylic acid

A mixture of 282 mg (1.0 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3 - dihydro-7H-pyrido[1,2,3-d, e] -[1,3,4]-benzoxazepin-6-carboxylic acid, 315 mg (1.5 mmol) of (1SR,2RS,6SR)-2'-ethoxycarbonyl - 8-azabicyclo[4.3.0]non-4-ene (product following example) and 8.5 ml of pyridine is heated to 100oC for 4 hours in and the P>C.

Yield: 350 mg (74% of theory)

Melting point: 195oC (decomp.)

Example 14

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(1'SR, 2'RS, 6'RS)-10-(2'-amino-8'-azabicyclo-[4,3,0]non-4'- EN-8'-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] - [1,3,4]-benzoxazepin-6-carboxylic acid

A mixture of 480 mg (1.0 mmol) of the product of example 13, 640 mg (2.0 mmol) of octahydrate barium hydroxide, 5 ml of methanol and 2.5 mmol of water heated to 80oC for 4 hours. Add again the same amount of solvent and stirred for 36 hours at 80oC. After cooling, the precipitate is sucked off, washed with a small amount of methanol and water and dried. The resulting solid is suspended in 5 ml of water and alkalinized 1 n hydrochloric acid. The remaining solid is sucked off and dried.

Yield: 400 mg (98% of theory)

Melting point: > 300oC

Example 15

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(1'SR,2'RS,6'RS)-9-fluoro-3-methyl-10-(2'-methylamino-8'- azabicyclo-[4,3,0] non-4'-EN-8'-yl)-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-d, e] -[1,3,4]-benzoxazepin-6-carboxylic acid

Repeat example 12 with the difference that use 282 mg (1.0 mmol) of 9,10-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6 - carboxylic acid and 228 mg (1.5 mmol) of (1SR,2RS,6RS)-2-methylamino-8-azabicyclo[4.3.0]non-4-ene (product following example 0) 1'SR, 2'RS, 6'RS)-10-(2'-amino-8'-azabicyclo-[4,3,0]non-4'-EN - 8'-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] - [1,3,4]-benzoxazepin-6-carboxylic acid

Repeat example 12 with the difference that the use of 455 mg (1.6 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e]- [1,3,4]-benzoxazepin-6-carboxylic acid and 300 mg (2.1 mmol) of 2-amino-8-azabicyclo[4.3.0]-non-4-ene in 10 ml of pyridine.

Yield: 500 mg (78% of theory)

Melting point: 233oC

Example 17

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(1'SR, 2'RS, 6'RS)-9-fluoro-10-(2'-hydroxymethyl-8'-azabicyclo- [4,3,0]-non-4'-EN-8'-yl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido- [1,2,3-d, e]-[1,3,4] -benzoxazepin-6-carboxylic acid

Repeat example 12 with the difference that use 845 mg (3.0 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] - [1,3,4]-benzoxazepin-6-carboxylic acid and 690 mg (4.5 mmol) of 2-hydroxymethyl-8-azabicyclo-[4.3.0]non-4-ene in 24 ml of pyridine.

Yield: 650 mg (52% of theory)

Melting point: 240oC

Example 18

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(1'SR, 2'RS,6'RS)-10-(2'-amino-8'-azabicyclo-[4,3,0]-non-4'-EN - 8'-yl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e]-[1,3,4]- benzoxazepin-6-carboxylic acid

Repeat example 12 with the difference that use 425 mg (1.5 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-d, e] -[1,3,4]-benzoxazepin-6-careyi)

Melting point: 242oC

Example 19

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(1'SR, 2'RS, 6'RS)-10-(2'-tert. butyloxycarbonyl-8'- azabicyclo-[4,3,0] -non-4'-EN-8'-yl)-9-fluoro-3-methyl-7-oxo-2,3 - dihydro-7H-pyrido[1,2,3-d,e]-[1,3,4]-benzoxazepin-6-carboxylic acid

Repeat example 12 with the difference that the use of 469 mg (1.7 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d, e] - [1,3,4]-benzoxazepin-6-carboxylic acid and 665 mg (2.5 mmol) 2-tert.butyloxycarbonyl-amino-8-azabicyclo[4.3.0]non-4-ene in 15 ml of pyridine.

Yield: 550 mg (67% of theory)

Example 20

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Triptorelin (1'SR, 2'RS, 6'RS)-10-(2'-amino-8'-azabicyclo- [4,3,0]-non-4'-EN-8'-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-d, e]-[1,3,4] -benzoxazepin-6-carboxylic acid 500 mg (9.0 mmol) of target compound of example 19 is suspended in 10 ml ice triperoxonane acid, then the mixture is allowed to warm to room temperature, then leave to stand for one hour. The product is precipitated with methanol, sucked off and dried at a temperature of 50oC.

Yield: 500 mg (90% of theory)

Melting point: 247oC (decomp.)

Example 21

< / BR>
(1'SR, 2'RS, 6'RS)-9-fluoro-10-(2'-methylamino-8'-azabicyclo-[4,3,0]- non-4'-EN-8'-yl)-7-oxo-2,3-dihydro-7H-pyrido-[1,2,3-d, e] -[1,3,4]- benzoxazepin-6-carboxylic keys, the pyrido-[1,2,3-d,e]- [1,3,4]-benzoxazepin-6-carboxylic acid and 319 mg (2.1 mmol) of 2-methylamino-8-azabicyclo-[4,3,0]non-4-ene in 10 ml of pyridine.

Yield: 650 mg (98% of theory)

Melting point: 247oC (decomp.)

Example 22

< / BR>
(1'SR, 2'RS, 6'RS)-10-(2'(tert. butyloxycarbonyl)methyl - 8'-azabicyclo-[4,3,0] -non-4'-EN-8'-yl)-9-fluoro-7-oxo-2,3-dihydro - 7H-pyrido-[1,2,3-d,e]-[1,3,4]-benzoxazepin-6-carboxylic acid

Repeat example 12 with the difference that the use of 469 mg (1.7 mmol) of 9,10-debtor-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-[1,2,3-d, e] - [1,3,4]-benzoxazepin-6-carboxylic acid and 595 mg (2.5 mmol) 2-tert.butyloxycarbonyl)methyl-8-azabicyclo[4,3,0]non-4-ene in 15 ml of pyridine.

Yield: 580 mg (98% of theory)

Example 23

< / BR>
Triptorelin (1'SR,2'RS,6'RS)-10-(2'-aminomethyl-8'- azabicyclo-[4,3,0] -non-4'-EN-8'-yl)-9-fluoro-7-oxo-2,3-dihydro - 7H-pyrido-[1,2,3-d, e]-[1,3,4] -benzoxazepin-6-carboxylic acid

500 mg (1.0 mmol) of target compound of example 22 is subjected to interaction with 10 ml triperoxonane acid described in example 20.

Output: 480 mg (88% of theory)

Melting point: 251oC (decomp.)

The following examples explain the production of intermediate products for preparing compounds of formula (I).

An example of A

8-azabicyclo[4.3.0]non-2-EN

A. 1. (E)-1-bromo-2,4-pentadien

< / BR>
To 84 g (1.0 mol) of 1,4-pentadien-3-ol, fed to the reactor at 0othe temperature does not exceed 5oC. after the addition of acid is continued to stir at room temperature for one hour. The organic phase is separated and without treatment served on the following reaction.

Output: 107 - 129 g (73-88% of theory)

A. 2. (E)-1-(2-propylamino)-2,4-pentadien

< / BR>
In the reactor serves 228 g (4.0 mol) of 1-amino-2-propene. Under stirring was added dropwise to 58.8 g (0.4 mol) of (E)-1-bromo-2,4-pentadiene (target connection stage A. 1. ). The internal temperature by cooling is kept in the temperature range 20 - 30oC. the Mixture is stirred for 5 hours at room temperature, then concentrated to 150 mbar. To the mixture are added 20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water, the product is twice extracted with 100 ml methylene chloride, dried over sodium sulfate, and then add 0.1 g of 4-hydroxyanisole, concentrated and distilled at 40 mbar. To stabilize to the distillate add 10 h/mill. 4-hydroxyanisole.

Yield: 33 g (67% of theory)

Boiling point: 77 - 82oC at 40 mbar

1H-NMR (CDCl3): = 6,07 - 6.48 in (m, 2H): 5,64 - 6,07 (m, 2H); 5,00 at 5.27 (m, 4H); 3,19 - 3,36 h/mill. (m, 4H).

A. 3. N-[(E)-2,4-pentadienyl]-N-(2-propenyl)-ndimethylacetamide

< / BR>
In the reactor serves to 24.6 g (0.2 mol) of (E)-1-(2-propylamino)-2,4 - pentadiene (target with the e night. The mixture is thickened and without treatment served on the following reaction.

A. 4. 8-acetyl-8-azabicyclo[4,3,0]non-2-EN

< / BR>
33.1 g (0.2 mol) of N-[(E)-2.4-pentadienyl] -N-(2-propenyl)- ndimethylacetamide (target connection stage A. H.) dissolved in 200 ml of xylene for 15 minutes serves nitrogen, add 0.1 g of 4-hydroxyanisole and heated under reflux overnight. The product is concentrated and distilled in high vacuum.

Output: 23.1 g (70% of theory, calculated on the target connection example A. 2. )

Boiling point: 88 - 93oC at 0.05 mbar

A. 5. 5,8-azabicyclo[4.3.0]non-2-EN

< / BR>
16.5 g (0.1 mol) of 8-acetyl-8 - azabicyclo[4.3.0]non-2-ene (target connection phase A. 4.) in a mixture of 100 ml of 45% sodium lye 50 ml water and 100 ml of 1,2-ethanediol is heated under reflux for 3 hours. After cooling to 4 times extracted with 50 ml diethyl ether. The combined organic phases are dried over sodium sulfate, and then distilled in a high vacuum.

Yield: 6.6 g (54% of theory)

Boiling point: 36 - 44oC of 0.35 mbar

1H-NMR (CDCl3): = 5,79 (m, 1H); 5,74 (m, 1H); 3,02 - 3,17 (m, 2H); 2,47 - of 2.72 (m, 2H); 2.06 to 2,30 (m, 2H); 1.91 a - to 2.06 (m, 2H); 1,68 (m, 1H): 1,45 h/mill. (m, 1H).

Example B

Complex ethyl ester (1RS, 2RS,6SR)-8-azabicyclo[4.3.0]non - 4-e the OIC acid (diastereoisomer B)

B. 1. N-[(E)-2,4-pentadienyl]-phthalimide

< / BR>
To 185 g (1.0 mol) of phthalimide potassium in 800 ml of dimethylformamide was added dropwise with stirring 147 g (1.0 mol) of (E)-1 - bromo-2,4-pentadiene (target compound of example A. 1.), the internal temperature by cooling kept below 30oC. during the night stirred at room temperature. Then the mixture under stirring served in 1.6 l of ice water, the precipitate is sucked off, washed with water and dried at room temperature until reaching constant weight.

Output: 177 g (83% of theory)

Melting point: 118 - 121oC (after recrystallization from ethanol)

1H-NMR (CDCl3): = a 7.85 and 7,72 (m, 4H, aryl-H); a 6.2-6.4 (m, 2H, H at C-C and C-4); of 5.75 (dt, 1H, H at C-2, J = 14 and 6 Hz); 5,20 (d, 1H, Hathe C-5, J = 15 Hz); 5,10 (d, 1H, Hbthe C-5, J = 8 Hz); 4,33 h/mill. (d, 2H, H at C-1, J = 6 Hz).

B. 2. (E)-amino-2,4-pentadien

< / BR>
In a distillation apparatus with a capacity of 2 l, equipped with a column "in the Game" length 10 cm, serves 400 g of bis-(2-amino-ethyl)-amine and 213 g (1?0 mol) of N-[(E)-2,4-pentadienyl]-phthalimide (target connection stage B. 1.) and the mixture is boiled at 60 mbar. The product is distilled in the temperature range from 45 - 60oC at a pressure of 60 mbar. For stabilization to z add 10-20/mill. 4-hydroxyanisole.

Output is 6 g (0.5 mol) of (E)-1-amino-2,4-pentadiene (target connection stage B. 2. ) and 50.6 g (0.5 mol) of triethylamine in 250 ml of tetrahydrofuran is served in the reactor at 0oC and added dropwise to 96.5 g (0.5 mol) of a compound ethyl ester (E)-4-bromo-2-butenova acid dissolved in 250 ml of tetrahydrofuran. The internal temperature is kept below 5oC by cooling with ice. The mixture is then stirred for 5 hours at 0oC, then overnight at room temperature. Add 500 ml tert.butyl ether, and then 500 ml of 1 M sodium liquor, shaken, the phases are separated, the aqueous phase is extracted with 100 ml tert. butyl ether, the combined organic phases are dried over sodium sulfate, add 100 ml of toluene and 0.1 g of 4-hydroxyanisole and thicken (to avoid temperatures above 40oC). The residue is purified by column chromatography on 1 kg of silica gel using as eluent a mixture of cyclohexane and acetone in the ratio of 2 : 1. Before thickening to the product add 0.1 g of 4-hydroxyanisole. Thickening avoid temperatures above 40oC.

Output: 52,7 to 58.6 g (54 - 60% of theory) of a yellowish oil

The value of Rf = 0,24

1H-NMR (CDCl3): = of 6.99 (dt, 1H, J = 15 and 5.5 Hz); 6,1 - of 6.45 (m, 2H); 5,98 (d, 1H, J = 15 Hz); of 5.75 (dt, 1H, J = 15 and 6.5 Hz); by 5.18 (d, 1H, J = 15 Hz); of 5.06 (d, 1H, J = 10 Hz); 4,19 (q, 2H); of 3.42 (DD, 2H); and 3.31 (d, 2H); 1.2-carboxylic acid (diastereomer a) and

Complex ethyl ester (1RS,2RS,6RS-8-TPAT.butyloxycarbonyl-8 - azabicyclo[4.3.0]non-4-ene-2-carboxylic acid (diastereoisomer B)

< / BR>
< / BR>
97.5 g (0.5 mol) of a compound ethyl ester (E)-4-[(E)-2,4-pentadienyl]-2 - butenova acid (target connection phase B. 3.), dissolved in 250 ml of toluene, was added dropwise of 114.5 g (0,525 mol) di-tert.butyl-dicarbonate dissolved in 250 ml of toluene, and stirred overnight at room temperature. Then within 15 minutes the mixture is poured in a strong stream of nitrogen, add 0.1 g of 4-hydroxyanisole, and then heated under reflux for 6 hours. The product is condensed and the residue purified by column chromatography on 1 kg of silica gel (63 - 200 µm) using as eluent a mixture of cyclohexane and acetone in the ratio of 8 : 1.

Output: 109 - 134 g (74 - 91% of theory) of a yellowish oil: mixture of two diastereoisomers a and B in the ratio 4 : 1.

Rf = 0.25 in

1H-NMR (Cl2DC-CDCl2; 80oC): = 5,77 (m, 1H(A) and 1H(B)); of 5.68 (m, 1H(A) and 1H(B)); to 4.14 (m, 2H(A) and 2H(B)); the 3.65 (m, 2H(A) and 1H(B)); of 3.48 (DD, 1H(B)); of 3.27 (DD, 1H(B)); 3,00 (m, 1H(A) and 1H(B)); to 2.85 (DD, 1H(A)); was 2.76 (m, 1H(B)); 2,60 (m, 1H(A)); 2,25 - to 2.55 (m, 3H(A) and 4H(B)); of 1.93 (m, 1H(A)); is 1.51 (s, 9H(B)); the 1.44 (s, 9H(A)); 1,25 h/mill. (t, 3H(A) and 3H(B)).

B. 5. Complex ethyl ester (1RS,2RS,6SR)-8-azabicyclo[4.3.0]non - 4-EN-2 - acid (diastereomer B)

< / BR>
< / BR>
In the reactor serves 6.0 g (20 mmol) of target compound phase B. 4. in 20 ml of dioxane. 20 ml conc. hydrochloric acid while cooling was added dropwise so that the internal temperature does not exceed 30oC. the mixture is Then stirred for 10 minutes, add 40 ml of methylene chloride and cooled with ice was added dropwise 40 ml of 20% aqueous cooled ice sodium lye. The organic phase is separated, the aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated. 3.0 g of the crude product purified by column chromatography on 100 g of silica gel using as eluent a mixture of cyclohexane, ethanol and 17% aqueous ammonia at a ratio of 1 : 2 : 0,1.

Exit; 0.8 g of diastereoisomer a and

0.8 g of diastereoisomer B

Rf = 0,79 target compound of example B. 4.

0.21 diastereoisomer B

0.11 diastereoisomer AND

1H-NMR (CDCl3):

The diastereoisomer A:

= of 5.83 (d, 1H); 5.69 (m, 1H); 4,15 (q, 2H); 3,21 - to 3.38 (m, 2H); 2,52 - 2,89 (m, 3H); 2.21 are 2,52 (m, 3H); 1,95 (m, 1H); 1,28 h/mill. (t, 3H).

The diastereoisomer B:

= 5,64 - by 5.87 (m, 2H); to 4.16 (q, 2H); 3,14 - to 3.33 (m, 2H); 2.82 from (DD, 1H); 2,15 -2,74 (m, 6H); 1,28 h/mill. (t, 3H).

Example:

(1SR,2RS,6SR)-2-ethoxycarbonyl-8-azabicyclo[4,3,0]non - 4-EN

Brookie potassium, dissolved in 500 ml of water, is fed into the reactor. Add a 147.7 g (0.5 mol) of target compound of example B. 4., dissolved in 500 ml of methanol, and stirred for 8 hours at a temperature of 60oC in nitrogen atmosphere. After cooling, the reaction solution was diluted with 500 ml of water and while stirring slowly add 125 ml of acetic acid, then add a 147.7 (0.5 mol) of target compound of example B. 4., dissolved in 500 ml of methanol, and stirred for 8 hours at 60oC in nitrogen atmosphere. After cooling, the reaction solution was diluted with 500 ml of water and with stirring, slowly add 125 ml of acetic acid. Then the reaction solution is left to stand in an ice bath for 30 minutes, the precipitate is sucked off, washed with water and at a temperature of 50oC dried to the constant weight.

Output: 84 g (63% of theory)

Melting point: 174 - 176oC (after recrystallization from a mixture of isopropanol and water in the ratio 1 : 1).

1H-NMR (Cl2DC-CDCl2; 80oC): = of 5.83 (m, 1H, H at C-5); 5,74 (m, 1H, H at C-4); 3,65 - of 3.80 (m, 2H, Haat C-7 and Hathe C-9); to 3.09 (DD, 1H, Hbthe C-9); of 2.92 (DD, 1H, HbC-7); 2,70 (m, 1H, H at C-2); 2,35 - 2,60 (m, 3H, Haand Hbthe C-C and H at the C-6); a 2.01 (m, 1H, H at C-1); 1,54/mill. (s, 9H).

the target compounds Century stage 1. and 22.2 g (0.22 mol) of triethylamine, dissolved in 200 ml of anhydrous tetrahydrofuran, served in the reactor. Upon cooling the mixture of ice and salt was added dropwise to 22.8 g (0.21 mol) of a solution of a complex of ethyl ether of Harborview acid in 40 ml of tetrahydrofuran so that the internal temperature does not exceed -10oC. and Then stirred for one hour at low temperature, and then cooled with ice a solution of 15.6 g (0.24 mol) of sodium azide in 50 ml of water with vigorous stirring was added dropwise so that the internal temperature does not exceed -10oC. Stirred for 30 minutes at low temperature, and then add 300 ml of water and 400 ml of toluene.

The organic phase is separated, dried over sodium sulfate and concentrated under 15 mbar up to half of the original volume (bath temperature below 25oC). Add 100 ml of ethanol, while stirring slowly heated (depending on the degree of nitrogen excretion) and after the nitrogen is heated under reflux for 4 hours. The mixture is concentrated and the crude product is recrystallized from a mixture of methanol and water in the ratio of 85 : 15, and then at 50oC dried to the constant weight.

Output: 24.2 g (39% of theory) CE is 1H, H at C-4); (4,59 Shire. s, 1H, NH); 4,12 (m, 2H, ethoxy-CH2); 3,90 (m, 1H, H at C-2); 3,74 and 3.67 (2m, 1H, HaC-7); 3,67 and 3,56 (2m, 1H, Hathe C-9); of 3.12 (m, 1H, Hbthe C-9); of 2.92 (m, 1H, HbC-7); to 2.67 (m, 1H, Hathe C-H); 2.49 USD (m, 1H, H at C-6); of 1.95 (m, 1H, Hbthe C-H); to 1.83 (m, 1H, H at C-1); of 1.46 (s, 9H); 1,24 h/mill. (m, 3H, ethoxy-CH3).

The aqueous phase by addition of 10% hydrochloric acid adjusted to pH 2-3, the mixture is left to stand in an ice bath for 30 minutes, the precipitate is sucked off, washed with water and dried to the constant weight at a temperature of 50oC.

Exit; 16.0 g (30%, in terms of the target compound of example C. 1.) (unreacted original connection recycle)

C. H. (1SR,2RS,6SR)-2-ethoxycarbonyl-8-azabicyclo- [4,3,0]non-4-EN

< / BR>
Suspension 31.0 g (0.1 mol) of target compound Century stage 2. 100 ml of a mixture of methanol and water in the ratio 1 : 1 served in the reactor, and then quickly served 100 ml conc. hydrochloric acid (slightly exothermically to about 40oC; get the homogeneous solution) and stirred until the evolution of gas (approximately 10 minutes). To the mixture is added 200 ml of ice water, then with stirring and ice cooling was added dropwise 70 ml of 45% sodium lye. Four times extracted with methylene chloride, taken in claut remaining solvent. Get the substance hardens thickening.

Exit; 13,7 g (65% of theory) of amorphous solids brown-pink color

Rf = 0,81 target compound of example C. 2.

0,11 target connection

A mixture of methylene chloride, methanol and 17% aqueous ammonia in a ratio of 15 : 4 : 0.5 in.

1H-NMR (CDCl3): = 5,78 (d, 1H, H at C-5); 5,63 (m, 1H, H at C-4); 4.94 (Shir. d, 1H, NH); 4,10 (m, 2H, ethoxy-CH2); 3,88 (m, 1H, H at C-2); or 3.28 (m, 1H, HaC-7); 3,19 (m, 1H, Hathe C-9); 2,84 (m, 1H, Hbthe C-9); 2.57 m - 2,62 (m, 2H, Hathe C-C and HbC-7); 2,43 (m, 1H, H at C-6); of 1.95 (m, 1H, Hbthe C-H); to 1.79 (m, 1H, H at C-1); 1,23 h/mill. (m, 3H, ethoxy-CH3).

Example D

(1SR,2RS,6SR)-2-methylamino-8-azabicyclo[4,C,0]non-4-EN

< / BR>
In the reactor serves to 1.9 g (50 mmol) of lithium aluminum hydride in 25 ml of anhydrous diethyl ether in a nitrogen atmosphere. Was added dropwise a 5.25 g (25 mmol) of target compound of example C. 3., dissolved in 50 ml of anhydrous tetrahydrofuran, and heated under reflux for 3 hours. Add 0.95 g (25 mmol) of lithium aluminum hydride and again heated under reflux for 3 hours. Under ice cooling slowly water was added dropwise until a white precipitate. The precipitate is sucked off and double-boiled in 100 ml of ethanol. Emanuele distilled off in high vacuum.

Output: 1,95 g (77% of theory) of amorphous solids

Rf=0,11

A mixture of methylene chloride, methanol and 17% aqueous ammonia in the ratio 2 : 4 : 1.

1H-NMR (CDCl3) = 5,77 (d, 1H, H at C=5); 5,67 (m, 1H, H at C-4); to 3.33 (DD, 1H, HaC-7); 3,26 (DD, 1H, Hathe C-9); 2,73 - 2,82 and 2.54 2.63 in (2m, 4H, H at C-2, HaC-3, Hbat C-7 and Hbthe C-9); to 2.41 (s, 3H, CH3N); of 2.34 (m, 1H, H at C-6); 1,90 (m, 1H, Hbthe C-H); 1.70 h/mill. (m, 1H, H at C-1).

Example D

(1RS,2RS,6SR)-2-hydroxymethyl-8-azabicyclo[4.3.0]non-4-EN

D. 1. (1RS, 2RS,6SR)-8-tert.butylcarbamoyl-2-gipoksiei-8 - azabicyclo[4.3.0]non-4-ene (diastereoisomer a) and

(1RS, 2RS, 6RS)-8-tert. butyloxycarbonyl-2-hydroxymethyl-8 - azabicyclo[4.3.0]non-4-ene (diastereomer B)

< / BR>
< / BR>
In the reactor serves to 29.5 g (0.1 mol) of target compound of example B. 4. in 200 ml of anhydrous 1,2-dimethoxyethane in nitrogen atmosphere. When the internal temperature < -65oC was added dropwise 150 ml of hydride diisobutylaluminum in toluene (0,225 mol). Then remove the cooling bath and the reaction mixture allowed to warm to room temperature. Stirred for 2 hours at room temperature.

With vigorous stirring was added dropwise 60 ml of methanol (exothermic reaction). The internal temperature by cooling in cold water b is s 10 minutes. The precipitate is sucked off, double boil while stirring in 150 ml of ethanol, atanasie extracts and reaction solution are combined to thicken, remaining solvent is distilled off in high vacuum, and the residue purified by column chromatography on 250 g of silica gel (63 - 200 µm) using as eluent a mixture of cyclohexane and acetone in the ratio of 4 : 1.

Output: 12,9 g (51% of theory) of a yellowish oil; mixture of diastereomers a and B in the ratio 4 : 1.

Rf= 0,36 target compound of example B. 4.

0,12 target compounds a and B

The crude product solidified after prolonged standing. By recrystallization from a simple mixture of ether and petroleum ether can be obtained pure major diastereoisomer A.

1H-NMR (CDCl3): (diastereoisomer A) = 5,67 - of 5.82 (m, 2H, H at C-4 and C-5); 3,50 - of 3.77 (m, 4H, HaC-7, Haat C-9 and hydroxymethyl-CH2); to 3.02 (dt, 1H, Hbthe C-9); to 2.85 (m, 1H, HbC-7); 2,2-2,4 (m, 3H); 1,87 is 2.00 (m, 3H); of 1.62 (m, 1H, H at C-1); 1,46 h/mill. (s, 9H).

D. 2. (1RS,2RS,6SR)-2-hydroxymethyl-8-azabicyclo[4.3.0]non - 4-EN

< / BR>
In the reactor serves 2.5 g (10 mmol) of target compound And stage E. 1. in 10 ml of methanol. Quickly served 10 ml conc. hydrochloric acid and stirred for 30 minutes. Water dilute to Costigan the possible values of pH 12. The product is concentrated, the residue under stirring twice boiled in ethanol, the ethanol extracts are concentrated and the residues of the solvent is distilled in a high vacuum.

Exit; 2.1 g (product contains traces of sodium chloride)

Rf = 0.20 to

A mixture of methylene chloride, methanol and 17% aqueous ammonia in the ratio 2 : 4 : 1

1H-NMR (d6-DMSO): = 5,76 (d, 1H); 5,62 (d, 1H); 3,47 of 3.56 (m, 2H, Haat C-7 and Hathe C-9); 3,32 - 3,47 (m, 1H, Hafrom hydroxymethyl-CH2); 3,23 - of 3.32 (m, 1H, Hbfrom hydroxymethyl-CH2); 2,77 (t, 1H, Hbthe C-9); of 2.64 (t, 1H, HbC-7); 2,10 - of 2.24 (m, 2H, Hathe C-C and H at the C-6); 1,77-of 1.88 (m, 1H, Hbthe C-H); 1.69 in (m, 1H, H at C - 2); 1,40 h/mill. (m, 1H, H at C-1).

Example E

(1RS,2RS,6SR)-2-ethoxycarbonylmethyl-8-azabicyclo[4.3.0]-non-4-EN

E. 1. (1RS,2RS,6SR)-8-tert.butyloxycarbonyl-2-(4 - toluensulfonate)-8-azabicyclo[4.3.0]non-4-ene (diastereoisomer A)

and

(1RS, 2RS, 6RS)-8-tert. butyloxycarbonyl-2-(4 - toluensulfonate)-8-azabicyclo[4.3.0]non-4-ene (diastereoisomer B)

< / BR>
< / BR>
In the reactor serves 12.7 g (0.05 mol) of target compound of example D. 1. (crude mixture of diastereomers a and B) in 25 ml of anhydrous pyridine and cooled to -15oC. of 11.0 g (0,0575 mol) of acid chloride of 4-toluenesulfonic acid portions are served so that the DNAs is on - 15oC, and then stirred for further 3 hours at room temperature. Add 5 g of ice, stirred for 5 minutes, served in 50 ml water, the precipitate is sucked off, washed with water and dried to the constant weight at a temperature of 50oC.

Yield: 14.4 g (71% of theory) solid light pink color - a mixture of diastereomers a and B

By recrystallization from methanol gives a net main diastereoisomer A.

The melting point; 111 - 113oC

1H-NMR (CDCl3): (diastereoisomer A) = 7,79 (m, 2H, aryl-H); of 7.36 (d, 2H, aryl-H); 5,74 and 5,78 (2D, 1H, H at C-5); 5,64 (m, 1H, H at C-4); a 3.87 - of 3.97 (m, 2H, tosyl-OCH2-); 3,59 and 3.67 (DD, 1H, HaC-7); of 3.48 (DD, 1H, Hathe C-9); 2,78 - 2,96 (m, 2H, Hbat C-7 and Hbthe C-9); 2,47 (s, 3H, aryl-CH3); 2,22 - of 2.36 (m, 2H, Hathe C-C and H at the C-6); to 2.06 (m, 1H, H at C-2); 1,80-to 1.98 (m, 1H, Hbthe C-H); to 1.59 (m, 1H, H at C-1); to 1.45 and 1.47 h/mill. (2s, 9H).

E. 2. (1RS, 2RS,6SR)-8-tert.butyloxycarbonyl-2 - ethoxycarbonylmethyl-8-azabicyclo[4.3.0]non-4-ene (diastereoisomer A)

and

(1RS, 2RS, 6RS)-8-tert.butyloxycarbonyl-2 - ethoxycarbonylmethyl-8-azabicyclo[4,3,0]non-4-ene (diastereoisomer B

< / BR>
< / BR>
20.5 g (0.05 mol) of target compound of example E. 1. (crude mixture of diastereomers a and B) and 6.5 g (0.1 mol) of sodium azide in 100 ml of di is 200 ml petroleum ether, phase petroleum ether washed with 50 ml of water, dried over sodium sulfate and concentrated at room temperature.

The remainder served in 80 ml of tetrahydrofuran and added dropwise to 13.1 g (0.05 mol) of triphenylphosphine dissolved in 80 ml of tetrahydrofuran. Then stirred at room temperature for 20 hours, then slowly added dropwise 150 ml of water, then stirred for 15 more minutes. When cooling was added dropwise hydrochloric acid (mixture of conc. hydrochloric acid and water in the ratio 1 : 3) to achieve pH 3 to 4. The tetrahydrofuran is distilled off in vacuum at room temperature, the reaction solution is cooled to 0oC, the precipitated triphenylphosphine oxide sucked off or, if oily, served in the tert.butyl ether.

The aqueous phase is brought to pH 12 by adding 10% sodium lye, twice extracted with methylene chloride, taken in an amount of 100 ml, the combined extracts dried over sodium sulfate, and then add 6,0 (0.06 mol) of triethylamine, with stirring, was added dropwise 6.0 g (by 0.055 mol) of a compound of the ethyl ether of Harborview acid, dissolved in 20 ml of methylene chloride, continue to stir at room temperature overnight, the reaction restorm column chromatography on 100 g of silica gel (63 - 200 μm) using as eluent a mixture of cyclohexane and acetone in the ratio of 4 : 1.

Yield: 12.4 g (76% of theory) of a viscous oil, a mixture of diastereomers a and B

Rf = 0.32 diastereoisomer AND

0.29 diastereoisomer B

A mixture of cyclohexane and acetone in the ratio of 2 : 1.

The diastereomers a and B purified by column chromatography on 250 g of silica gel (35 to 70 μm) using as eluent a mixture of cyclohexane and acetone in the ratio of 8 : 1.

Yield: 4.3 g (26% of theory) of diastereoisomer A (viscous oil)

2.4 g (15% of theory) of mixed fractions

0.6 g (4% of theory) of diastereoisomer B

1H-NMR (Cl2DC-CDCl2; 80oC):

The diastereoisomer A:

of 5.75 (d, 1H, H at C-5); to 5.66 (m, 1H, H at C-4); 4,67 (width, 1H, NH); 4,08 (q, 2H, ethoxy-CH2); 3,62 (width, 2H, Haat C-7 and Hathe C-9); 3,19 (width, 1H, Hathe CH2-NH); 3,05 (width, Hbthe CH2-NH); 2,96 (DD, 1H, Hbthe C-9); of 2.81 (DD, 1H, HbC-7); 2,24 - of 2.34 (m, 2H, Hathe C-C and H at the C-6); 1,78 - of 1.94 (m, 2H, H at C-2 and Hbthe C-H); and 1.54 (m, 1H, H at C-1); USD 1.43 (s, 9H); 1,22 h/mill. (t, 3H, ethoxy-CH3).

The diastereoisomer B:

5,69 (m, 1H, H at C-4); to 5.57 (m, 1H, H at C-5); 4.65 (width, 1H, NH), 4,08 (q, 2H, ethoxy-CH2); to 3.52 (DD, 1H, Haat C-7 and Hathe C-9); to 3.41 (DD, 1H, Hathe C-9); 3,29 (DD, 1H, Hbthe C-9); 3,24 (DD, 1H, Hathe CH2bthe C-H); USD 1.43 (s, 9H); 1,22 h/mill. (t, 3H, ethoxy-CH3).

E. 3. (1RS, 2RS, 6SR)-2-ethoxycarbonylmethyl-8 - azabicyclo[4,3,0] non-4-EN

< / BR>
In the reactor serves 1.6 g (5.7 mmol) of target compound And stage E. 2. in 10 ml of methanol. Quickly serves 8 ml conc. hydrochloric acid and stirred for 30 minutes. Water dilute to achieve double the volume, then under stirring and ice cooling was added dropwise 45% sodium lye to achieve a pH of 12. Four times extracted with methylene chloride, the combined organic phases are dried over sodium sulfate, concentrated and the residues of the solvent is distilled in a high vacuum.

Yield: 0.8 g (63% of theory) of a viscous oil

Rf = 0,16

A mixture of methylene chloride, methanol and 17% aqueous ammonia in a ratio of 15 : 4 : 0.5 in.

1H-NMR (CDCl3): = of 5.81 (d, 1H, H at C-5); 5,67 (m, 1H, H at C-4); 5,00 (Shir. , 1H, NH); 4,10 (q, 2H, ethoxy-CH2); 3,18 3.28 and is 3.08 (m, 3H and m, 1H; HaC-7, HaC-9, Haand Hbthe CH2-NH-CO) to 2.67 (DD, 1H, Hbthe C-9); of 2.53 (DD, 1H, HbC-7); of 2.34 (m, 1 H, Hathe C-H); to 2.25 (m, 1H, H at C - 6); 1,79 is 1.96 (m, 2H, H at C-2 and Hbthe C-H); 1,50 (m, 1H, H at C-1); 1,24 h/mill. (t, 3H, ethoxy-CH3).

Example G

(1RS,2SR,6RS)-2-oxymethyl-8-azabicyclo[4.3.0]non-4-EN

J. 1. ((target compound of example B. 2.) in 50 ml tert.butyl ether, and add 20 mg of 4-axinite. Then, when the temperature of the reaction mixture comprising 20 to 30oC, drops add a solution of 22.9 g (0,105 mol) di-tert.butyl-dicarbonate in 50 ml tert.butyl ether. After adding stirred at room temperature for 20 hours, concentrated, and the remains of di-tert.butyl-dicarbonate is distilled in a high vacuum at a temperature of 40oC.

Output: 18,9 g (crude product) of colorless oil

The value of Rf= 0,25

A mixture of cyclohexane and acetone in the ratio of 4 : 1.

1H-NMR (CDCl3): 6,05 - to 6.43 (m, 2H, H at C-C and C-4); of 5.68 (DD, 1H, H at C-2, J = 14 and 6 Hz); 5.17 to (DD, 1H, Hathe C-5, J = 16 Hz); 5,07 (DD, 1H, Hbthe C-5, J = 10 Hz); 4.75 in (lat., 1H, NH); of 3.77 (t, 2H, H at C-1); 1,45 h/mill. (s, 9H).

J. 2. (1RS,2RS,6RS)-2-tert.butyloxycarbonyl-7,9 - dioxo-8-oxabicyclo[4.3.0]non-3-EN

< / BR>
In the reactor serves to 83.2 g (1.0 mol) of (E)-1-amino-2,4-pentadiene (target compound of example B. 2.) 250 ml tert.butyl ether and add 0.1 g of 4-axinite. Then, when the temperature of the reaction mixture comprising 20 to 30oC, add drops of the solution 229,2 g (1.05 mol) di-tert.butyl-dicarbonate 250 ml tert.butyl ether. After adding stirred at room temperature for th acid and stirred for 24 hours at the temperature of the reaction mixture, component 60oC. the Precipitate is sucked off, washed with toluene and dried at a temperature of 50oC until the weight no longer changes.

Output: 208,2 g (74% of theory) of white crystalline solid

Melting point: 157 - 159oC

1H-NMR (d6-DMSO): = of 5.81 (m, 1H, H at C-4); 5,59 (d, 1H, H at C-H); of 3.77 (DD, 1H, Hathe CH2-NH); 3,44 (m, 2H, H at C-1 and Hbthe CH2-NH); to 2.94 (m, 1H, H at C-2), of 2.66 (m, 1H, H at C-6); of 2.16 (m, 1H, HaC-5); to 2.06 (m, 1H, HbC-5); 1,43 h/mill. (s, 9H).

J. H. methyl ester (1RS,2SR,6RS)-8-oxo-8 - azabicyclo[4.3.0]non-3-ene-carboxylic acid.

< / BR>
In the reactor serves to 83.2 g (1.0 mol) of (E)-1-amino-2,4-pentadiene (target compound of example B. 2.) in 250 ml of tetrahydrofuran and add 0.1 g of 4-axinite. Then, when the temperature of the reaction mixture comprising 20 to 30oC, add drops of the solution 229,2 g (1.05 mol) di-tert.butyl-dicarbonate in 250 ml of tetrahydrofuran. After adding stirred at room temperature for 20 hours, then add 103,0 g (1.05 mol) maleic anhydride and refluxed for 5 hours. The reaction mixture was concentrated, the residue is absorbed in 500 ml of methanol and add 30 ml of p-toluenesulfonic acid, and then boiled the mi add a solution of 20 g of sodium carbonate in 500 ml of water. The reaction mixture is left to stand in an ice bath for 30 minutes, then the precipitate is sucked off, washed with a small amount of water and dried at a temperature of 50oC until the weight no longer changes.

Yield: 125 g (64% of theory) of white crystalline solid

Melting point: 190 - 193oC

1H-NMR (d6-DMSO): = 7,50 (s, 1H, NH); 5,77 (m, 1H, H at C-4); to 5.56 (m, 1H, H at C-5); of 3.60 (s, 3H, CH3O); of 3.42 (DD, 1H, HaC-7); and 3.16 (DD, 1H, H at C-1); 3,00 (m, 1H, H at C-6); is 2.88 (DD, 1H, HbC-7); to 2.67 (m, 1H, H at C-2); 2,02 - 2,18 h/mill. (m, 2H, Haand Hbthe C-H).

J. 4 (1RS,2SR,6RS)-2-oxymethyl-8-azabicyclo[4.3.0]non-3-EN

< / BR>
In the reactor in an atmosphere of inert gas serves a suspension of 19.6 g (0.1 mol) obtained at the stage of J. H. compounds in 100 ml of tetrahydrofuran. Then, when the temperature of the reaction mixture, containing 10 - 20oC, drops add 100 ml (0.15 mol) of a 1.5 m solution of di(isobutyl)aluminum hydride in toluene. Thus obtained transparent, homogeneous solution drops added to a suspension of 1.9 g of alanate lithium in 50 ml of tetrahydrofuran. After adding stirred at room temperature for 15 minutes, then boiling for 30 minutes. After cooling portions add 3.8 g (0.1 mol) of alanate lit the keys 50 ml of water and 10 ml of 1 M sodium lye, the precipitate is sucked off and extracted three times with ethanol, each time using 150 ml of ethanol. The filtrate and extracts are combined and thickened.

Yield: 16.4 g (product contains lithium hydroxide and aluminum)

The value of Rf: 0,3

A mixture of methylene chloride, methanol and 17% aqueous ammonia in the ratio 2 : 4 : 1

Example 3

(1RS,2SR,6RS)-2-ethoxycarbonylmethyl-8-azabicyclo- [4.3.0]non-4-EN

Z. 1. (1RS, 2SR, 6RS)-8-tert.butyloxycarbonyl-2-oxymethyl-8 - azabicyclo[4,3,0]-non-4-EN

< / BR>
of 16.4 g of the crude product according to example G. 4. (corresponds to 0.1 mol of target compound of example g 4. ) dissolved in 100 ml of tetrahydrofuran. Then, when the temperature of the reaction mixture comprising 0 to 5oC, drops add a solution of 22.9 g (0,105 mol) di-tert.butyl-dicarbonate in 100 ml of tetrahydrofuran, and then stirred at a temperature of 0oC for 24 hours and then at room temperature for further 24 hours. Concentrated and the crude product is purified by chromatography on a column filled with 250 g of silica gel (particle size of 63 - 200 µm), using as eluent a mixture of cyclohexane and acetone in the ratio of 2 : 1.

Output: 13,7 g (54% of theory, calculated on the original connection in the example of J. 4.) viscous mA,2SR,6RS)-8-tert.butyloxycarbonyl-2-(4 - toluensulfonate)-8-azabicyclo[4.3.0]non-4-EN

< / BR>
The target connection receive analogously to example E. 1. from get on stage Z. 1. connection.

Output: 81-83% theory

The melting point; 160 - 162oC

1H-NMR (CDCl3): 7,79 (m, 2H, aryl-H); 7,37 (d, 2H, aryl-H); 5,67 (m, 1H, H at C-4); vs. 5.47 (d, 1H, H at C-5); 3,78 - of 3.97 (m, 2H, tosyl-SON2-); 3,13 - of 3.42 (m, 3H, CH2N); 2,95 (t, 1H, CH2-N) to 2.74 (m, 1H); to 2.54 (m, 1H); 2,47 (s, 3H, aryl-CH3); 2,32 (m, 1H, H at C-2); to 2.06 (m, 1H, Hathe C-H); 1,66 of-1.83 (m, 1H, Hbthe C-H); 1.44 x/mill. (s, 9H).

Z. 3. (1RS,2SR,6RS)-8-tert.butyloxycarbonyl-2 - autolackiererei-azabicyclo[4.3.0]non-3-EN

< / BR>
The target connection receive analogously to example E. 2. of the target compound with z stage 2. The crude product is purified by chromatography on filled with silica gel (particle size of 63 - 200 µm) column using as eluent a mixture of cyclohexane and acetone in the ratio of 2 : 1.

Yield: 76% of theory; transparent, viscous oil

The value of Rf: 0,35 (a mixture of cyclohexane and acetone in the ratio 2 : 1)

1H-NMR (Cl2CD CDCl2; 80oC): 5,69 (m, 1H, H at C-4); vs. 5.47 (d, 1H, H at C-5); 4,59 (Shir. , 1H, NH); 4,10 (q, 2H, ethoxy-CH2); to 3.38 (DD, 1H); of 3.32 (m, 1H); 3.24 in (m, 1H); 3,01 - is 3.08 (m, 3H); and 2.79 (m, 1H). 2,47 (m, 1H); 2,07 (m, 2H); of 1.78 (m, 1H); of 1.42 (s, 9H); 1,22 h/mill. (t, 3H, ethoxy-CH3).

Yield: 42% of theory

The value of Rf: 0,93 target connection stage Z. 3.

0,23 target connection

A mixture of methylene chloride, methanol and 17% aqueous ammonia in a ratio of 15 : 4 : 0.5 to

Example

(1SR, 2RS, 3RS,6SR)-2-ethoxycarbonyl-3-methyl-8 - azabicyclo[4.3.0] non-3-EN

I. 1. N-[(2E,4E)-2,4-hexadienyl]-phthalimide

< / BR>
The target connection receive analogously to example b 1. from (2E,4E)-1-bromo-2,4-hexadiene.

Output: 77 - 79% of theory

Melting point: 114 - 117oC (recrystallized from ethanol)

1H-NMR (CDCl3): a 7.85 (m, 2H); 7,72 (m, 2H); and 6.25 (DD, 1H); 6,00 (DDD, 1H); at 5.5 to 5.8 (m, 2H); 4,29 (d, 2H); 1.7 h/mill. (d, 3H).

I. 2. (2E.4E)-1-amino-2,4-hexadien

< / BR>
The target connection receive analogously to example B. 2. of the target compound of example I. 1. Boiling temperature: 40 - 70oC at a pressure of 16 to 18 mbar.

Yield: 67% of theory

I. 3. Complex ethyl ester (E)-4-[(2E,4E)-2,4-hexadienyl]- 2-butane acid

< / BR>
The target connection receive analogously to example b 3. of the target compound of example I. 2.

Yield: 46% of theory

1H-NMR (CDCl3): = 6,98 (dt, 1H); 5.9 to of 6.25 (m, 3H); at 5.5 to 5.8 (m, 2H); 4,19 (q, 2H); 3.40 in (DD, 2H); 3.27 to (d, 2H); to 1.76 (d, 3H); 1,29 h/mill. (t, 3H).
and complex ethyl ester (1RS,2RS,3SR,6RS)-8 - tert.butyloxycarbonyl-3-methyl-8-azabicyclo[4,3,0]-non-4-ene - 2-carboxylic acid (diastereoisomer B)

< / BR>
< / BR>
The target compounds get analogously to example b 4. of the target compound of example I. 3.

Yield: 70% of theory) of a mixture of the 2 diastereoisomers a and B in the ratio 4 : 1.

The value of Rf: 0,49 (a mixture of cyclohexane and acetone in the ratio 2 : 1)

I. 5. (1RS, 2RS,3RS,6SR)-8-tert.butyloxycarbonyl-3-methyl-8-azabicyclo- [4,3,0]non-4-ene-3-carboxylic acid

< / BR>
In the reactor submit a solution of 1.17 g (21 mmol) of potassium hydroxide in 20 ml of water. To it add a solution of 5.9 g (19 mmol) of target compound phase I. 4. in 20 ml of methanol, and nitrogen atmosphere is refluxed for 48 hours. Condense, absorb water, again extracted with methylene chloride, and adding acetic acid, the aqueous phase is brought to a pH value equal to 3 or 4. The formed precipitate is sucked off, washed with water, dried at room temperature and recrystallized from a mixture of cyclohexane and acetone in the ratio of 6 : 1.

Yield: 2.25 g (42% of theory)

Melting point: 189oC

1H-NMR (d6-DMSO) 5,77 (d, 1H); 5,61 (m, 1H); to 3.67 (m, 1H); of 3.54 (m, 1H); 2,61 - 2,95 (m, 4H); 2,30 (m, 1H), equal to 1.82 (m, 1H); of 1.40 (s, 9H); 0,90 h/mil is n-4-EN

< / BR>
The target connection receive analogously to example C. 2. from 2.25 g (8 mmol) of target compound phase I. 5. Differences from Century example 2: refluxed in ethanol for 4 hours, and 8 hours; purification by chromatography on filled with 100 g of silica gel (particle size of 63 - 200 µm) column using as eluent a mixture of toluene and complex ester of acetic acid in the ratio 2 : 1.

Yield: 1.6 g (59% of theory) of a clear oil

1H-NMR (CDCl3): 5.68 and 5,72 (2D, 1H); 5,61 (m, 1H); to 4.81 (m, 1H); 4,0 - 4,2 (m, 3H); 3,53 (m); 3,62 (m) and 3.72 (DD) [2H]; is 3.08 (t, 1H); 2,92 (t, 1H); to 2.75 (m, 1H); 2,47 (m, 1H); to 1.83 (m, 1H); to 1.47 (m, 9H); 1,25 (m, 3H); 0,97 h/mill. (d, 3H).

I. 7. (1SR,2RS,3RS,6SR)-2-ethoxycarbonyl-3-methyl-8 - azabicyclo-[4,3,0]-non-4-EN

< / BR>
The target connection receive analogously to example C. 3. from 1.6 g (4.7 mmol) of target compound phase I. 6.

Yield: 0.7 g (70% of theory) of a yellowish oil

The value of Rf= 0,09

A mixture of methylene chloride. methanol and 17% aqueous ammonia in a ratio of 15 : 4 : 0.5 to

Example TO

(1RS,2RS,6RS)-2-ethoxycarbonylmethyl-8-azabicyclo- [4.3.0]non-4-EN

K. 1. Complex diethyl ether 3-phthalimidomethyl-cyclohex-4-ene-1,2-dicarboxylic acid

< / BR>
10,67 g (50 mmol) of N-[(E)-2,4-pentadienyl]-phthalimid the reflux for 2 days. The reaction mixture was concentrated, and the residue is subjected to chromatography on silica gel using as eluent a mixture of cyclohexane and acetone in the ratio of 8 : 1.

Yield: 14.8 g (77% of theory)

Melting point: 80 - 84oC

K. 2. Complex ethyl ester (1RS,2RS,6RS)-9-oxo-8-azabicyclo- [4.3.0]-non-4-ene-2-carboxylic acid

and

Complex ethyl ester (1RS,2RS,6SR)-9-oxo-8-azabicyclo- [4,3,0]-non-4-ene-carboxylic acid (B)

< / BR>
< / BR>
150,3 g (to 0.39 mol) of target compound stage K. 1. served in 720 ml of ethanol and cooled with ice drops add to 173.3 g (2.9 mol) of ethylene diamine. Stir at room temperature for 20 hours, concentrated in vacuo, diluted with the addition of approximately 700 ml of water and adding concentrated hydrochloric acid adjusted to pH = 2 - 3. After this three times extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated in vacuum. Separation of the diastereomers is carried out by chromatography, and as eluent a mixture of cyclohexane and acetone in the ratio 1 : 1.

Output: 36,7 g of product (45% of theory);

the value of Rf= 0,47 (a mixture of cyclohexane and acetone in the ratio 1 : 1) of 27.0 g of product B (45% of theory);

is R

< / BR>
to 5.2 g (25 mmol) of a compound ethyl ester (1RS,2RS,6RS)-9 - oxo-8-azabicyclo[4.3.0] non-4-ene-2-carboxylic acid (product stage And K. 2.) in the atmosphere of nitrogen dissolved in 50 ml of tetrahydrofuran, and then drops add 130 ml of 1.5 molar solution of di(isobutyl)aluminum hydride (195 mmol). The resulting solution is heated under reflux for 16 hours. After reaching full conversion consistently drops add 60 ml of methanol, 30 ml of a simple tert.butyl methyl ether and 10 ml of water and sucked off adding tonsil. The balance of the double-suction stirred with a mixture of ethanol, concentrated ammonia and water in the ratio of 10 : 1 : 1, then sucked off again. The combined filtrates concentrated, and the crude product is purified by chromatography using as eluent a mixture of dichloromethane, methanol and concentrated ammonia in the ratio 2 : 4 : 1.

Yield: 2.7 g (71% of theory)

1H-NMR (DMSO-d6): 5,69 (m, 1H, 4-H); the ceiling of 5.60 (m, 1H, 5-H); 3,39 (DD, 1H, 10A-H); 3,26 (DD, 1H, 10b-H); of 2.97 (m, 2H, 7a-H, 9a-H); 2.63 in (m, 1H, 9b-H); 2,38 (Shir. s, 1H, 6-H)M; 2,32 (DD, 1H, 7b-H); to 2.06 (m, 1H, 3A-H); 1,95 (m, 1H, 1-H); 1.77 in (m, 1H, 3b-H); 1.44 x/mill. (m, 1H, 2-H).

K. 4. (1RS,2RS,6RS)-8-tert.butyloxycarbonyl-2-oxymethyl-8 - azabicyclo-[4,3,0]non-4-EN

< / BR>
The target connection recip is The value of Rf: 0,25 (a mixture of cyclohexane and acetone in the ratio 2 : 1)

K. 5 (1RS, 2RS,6RS)-8-tert.butyloxycarbonyl-2-(4 - toluensulfonate)-8-azabicyclo[4,3,0]non-4-EN

< / BR>
The target connection receive analogously to example E. 1. from the product stage K. 4.

Yield: 97% of theory

The value of Rf: 0,40 (a mixture of cyclohexane and acetone in the ratio 2 : 1)

K. 6. (1RS,2RS,6RS)-8-tert.butyloxycarbonyl-2-azidomethyl-8-azabicyclo- [4,3,0]non-4-EN

< / BR>
A solution of 33 g (0.08 mol) of (1RS,2RS,6RS)-8-tert.butyloxycarbonyl - 2-(4-toluene-sulfonyloxy)-8-azabicyclo[4.3.0] non-4-ene (target connection stage K. 5.) and 15.8 g (0.24 mol) of sodium azide in 200 ml of N,N-dimethylformamide is stirred at a temperature of 70oC for 40 hours. The cooled solution was diluted with water (500 ml) and extracted three times, each time using 250 ml simple petroleum ether. The combined organic phase washed with 5% sodium bicarbonate solution, dried over sodium sulfate and concentrated.

Output: 21,6 g (97% of theory)

1H-NMR (CDCl3): 5,71 (m, 1H, C=CH); to 5.58 (m, 1H, C=CH); 3,61 - up 3.22 (m, 2H); 3,10 (m, 1H); 2,70 (Shir.s, 1H); 2,24 (m, 2H); 1,19 (m, 2H); 1,47 h/mill. (s, 9H, tert.butyl).

K. 7. (1RS, 2RS,6RS)-8-tert.butyloxycarbonyl-2-aminomethyl-8 - azabicyclo-[4.3.0]non-4-EN

< / BR>
A solution of 21.6 g (78 m the ice saturate serostim hydrogen, then leave to stand at room temperature for 20 hours. After reaching full conversion concentrated in vacuo, re-distilled with the use of toluene and the residue is subjected to chromatography using as eluent a mixture of cyclohexane and acetone in the ratio 1 : 1.

Output: 11,0 g (66% of theory)

The value of Rf: 0,12 (a mixture of cyclohexane and acetone in the ratio 1 : 1)

K. 8. (1RS, 2RS,6RS)-8-tert.butyloxycarbonyl-2 - ethoxycarbonylmethyl)-8-azabicyclo[4.3.0]non-4-EN

< / BR>
In the reactor serves 3.7 g (15 mmol) of (1RS,2RS,6RS)-8 - tert.butyloxycarbonyl-2-aminomethyl-8-azabicyclo[4.3.0]non-4-ene in 40 ml of dioxane and 15 ml of water, add 2.3 g (16 mmol) of potassium carbonate and at room temperature add drops of 1.75 g (16 mmol) of a compound of the ethyl ether of Harborview acid. Stir for 2 hours, then concentrated in vacuo, the residue is absorbed in 70 ml of dichloromethane, shaken twice, each time using 25 ml of water, dried over sodium sulfate and concentrated. The crude product is purified by chromatography using as eluent a mixture of cyclohexane and acetone in the ratio of 2 : 1.

Exit; 2.8 g (59% of theory)

The value of Rf: 0,53 (a mixture of cyclohexane and acetone in the ratio of 1 (23 mmol) of the product, get on stage K. 8., 100 ml of a mixture of methanol and water in the ratio 1 : 1, and at room temperature, add 30 ml policecontributing hydrochloric acid. After gas evolution is additionally stirred for 30 minutes, then diluted with about 100 ml of ice water and adding concentrated sodium liquor is brought to a pH equal to 12. The aqueous phase is extracted four times, each time using 100 ml of dichloromethane. The extracts are combined, dried over sodium sulfate and concentrated in vacuum.

Yield: 3.9 g (76% of theory)

The value of Rf: 0,45 (a mixture of dichloromethane, methanol and concentrated ammonia in the ratio 2 : 4 : 0,1)

Example L

bis-triftorbyenzola (1RS, 2RS, 6RS)-2-aminomethyl-8 - azabicyclo-[4.3.0]non-4-ene

< / BR>
To a solution of 2.0 g (8 mmol) of (1RS,2RS,6RS)-8 - tert.butyloxycarbonyl-2-aminomethyl-8-azabicyclo-[4.3.0]non-4-ene (target compound of example K. 7.) in 30 ml of dichloromethane add 30 ml triperoxonane acid and left to stand at room temperature for 30 minutes. The solvent and the acid is distilled in the presence of toluene and re-advanced distilled in the presence of toluene. The resulting product is dried in a vacuum desiccator over a mixture of potassium hydroxide and floor>: 5,78 (m, 1H, C=CH); the ceiling of 5.60 (m, 1H, C=CH); to 3.34 (m, 2H); 3.03 (m, 1H); 2,87 (m, 2H); 2,73 (m, 1H); of 2.45 (m, 1H); of 2.34 (m, 1H); 2,22 (m, 1H); 1.94-h/mill. (m, 2H).

MC (fast atom bombardment): M+1=153.

Example M

(1RS,2RS,6SR)-2-ethoxycarbonylmethyl-8-azabicyclo- [4.3.0]non-4-EN

(This product is identical with the target compound of example E.)

M. 1. (1RS,2RS,6RS)-2-oxymethyl-8-azabicyclo-[4,3,0]non-4-EN

< / BR>
Complex ethyl ester (1RS,2RS,6RS)-9-oxo-8-azabicyclo- [4.3.0]non-4-ene-2-carboxylic acid (product 6 example K. 2.) subject interaction as in example K. H.

Yield: 75% of theory

The value of Rf: = 0,22 (a mixture of dichloromethane, methanol and concentrated ammonia in a ratio of 15 : 4 : 0,5)

M 2. (1RS, 2RS, 6SR)-8-tert.butyloxycarbonyl-2-oxymethyl-8 - azabicyclo-[4.3.0]non-4-EN

< / BR>
Get on stage M. 1. the product is transferred to the target product as in example 4 K..

Yield: 64% of theory

The value of Rf: 0,23 (a mixture of cyclohexane and acetone in the ratio 2 : 1)

M 3. (1RS,2RS,6SR)-8-tert.butyloxycarbonyl-2-(4 - toluensulfonate)-8-azabicyclo[4.3.0]non-4-EN

< / BR>
The target connection receive analogously to example E. 1. from the obtained at stage M 2. product.

Yield: 91% of theory

The value of Rf: 0,59 (mixture C,3,0]non-4-EN

< / BR>
To a solution of 13.0 g (32 mmol) obtained in stage M z product in 80 ml of N, N-dimethylformamide added 4.15 g (64 mmol) of sodium azide and stirred at a temperature of 70oC for 4 hours. Then again add the same amount of sodium azide and then stirred at a temperature of 100oC for 6 hours. Then processed as described in example K. 6. method.

Exit; 7.0 g (79% of theory)

The value of Rf: 0,55 (a mixture of cyclohexane and acetone in the ratio 2 : 1)

M 5. (1RS, 2RS,6SR)-8-tert.butyloxycarbonyl-2-aminomethyl-8 - azabicyclo-[4,3,0]non-4-EN

< / BR>
The target connection receive analogously to example K. 7. from etidocaine obtained at stage M 4.

Chromatography is carried out using as eluent a mixture of methanol, dichloromethane and concentrated ammonia in a ratio of 15 : 2 : 0,1.

Yield: 75% of theory

The value of Rf: 0,12 (a mixture of methanol, dichloromethane and concentrated ammonia in a ratio of 15 : 2 : 0,1)

M. 6. (1RS,2RS,6SR)-8-tert.butyloxycarbonyl-2- (ethoxycarbonylmethyl)-8-azabicyclo[4,3,0]non-4-EN

< / BR>
In the reactor serves 4.3 g (17 mmol) of the amino compounds obtained in stage 5 M., and 1.9 g (19 mmol) of triethylamine in 50 ml dichloromethane. P is the notes in 10 ml of dichloromethane, then additionally stirred at room temperature for 24 hours. To the resulting solution add 50 ml of water, and the phases are separated. The aqueous phase is extracted three times, each time with 40 ml of dichloromethane. The combined organic phases, dried over sodium sulfate and concentrated.

Output: 5.3v g (96% of theory)

1H-NMR (CDCl2-CDCl2, 80oC): 5,79 (DDD, 1H, C=CH); to 5.58 (m, 1H, C=CH); br4.61 (Shir. s, 1H, carbamate-NH); to 4.23 (m, 1H); of 4.12 (q, 2H, ethyl-CH2); 3,99 (m, 1H); 3,20 - is 3.08 (m, 2H); 2,82 (m, 2H); to 2.25 (m, 2H); of 2.09 (m, 1H); of 1.84 (m, 2H); of 1.42 (s, 9H, tert.butyl); 1,37 h/mill. (t, 3H, ethyl-CH3).

M. 7. (1RS,2RS,6SR)-2-(ethoxycarbonylmethyl)-8 - azabicyclo[4,3,0] -non-4-EN

(1RS,2RS,6SR)-8-tert.butyloxycarbonyl-2- (ethoxycarbonylmethyl)-8-azabicyclo[4.3.0]non-4-ene transferred to the target product described in example K. 9. method.

Yield: quantitative

The value of Rf: 0,55 (a mixture of methanol, dichloromethane and concentrated ammonia in a ratio of 15 : 4 : 0,5)

Example H

(1SR,2RS,6RS)-2-methylamino-8-azabicyclo[4.3.0]non-4-EN

N. 1. (1RS,2RS,6RS)-9-oxo-azabicyclo[4.3.0]non-4-ene-2-carboxylic acid

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at 8.36 g (40 mmol) of a compound ethyl ester (1RS,2RS,6RS)-9-oxo-8-azabicyclo[4.3.0] non-4-ene-2-carboxylic acid (product a of example K. 2.) together with ogladanie the product precipitates. The precipitate was washed with small amount of cold water and dried in a vacuum drying Cabinet at a temperature of 50oC.

Exit; 4,80 g (66% of theory)

1H-NMR (DMSO-d6): to 12.35 (s, 1H, COOH); of 7.60 (s, 1H, lactam-NH); 5,74 (m, 1H, C=CH); 5,59 (m, 1H, C=CH); of 3.45 (DD, 1H, 7a-H); 2,95 - to 2.85 (m, 4H, 1-H, 2-H, 6-H, 7b-H) to 2.29 (m, 1H, 3A-H); 2,00 h/mill. (m, 1H, 3b-H).

N. 2. (1SR, 2RS,6RS)-2-ethoxycarbonyl-9-oxo-8-azabicyclo- [4,3,0] non-4-EN

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(1RS, 2RS, 6RS)-9-oxo-8-azabicyclo[4.3.0] non-4-ene-2-carboxylic acid (obtained in stage N. 1. the product is transferred to the target product as in example C. 2.

Yield: 68% of theory

The value of Rf: 0,06 (a mixture of cyclohexane and acetone in the ratio 1 : 1)

N. 3. (1SR,2RS,6RS)-2-methylamino-8-azabicyclo[4.3.0]non-4-EN

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The target compound is obtained by interaction obtained at stage N. 2. product with 10 equivalents of di(isobutyl)aluminum hydride and processing as in example K. H.

Yield: 51% of theory

1H-NMR (CDCl3): 5,72 (m, 1H, C=CH); of 5.68 (m, 1H, C=CH); 3,19 - 3,10 (m, 2H); is 2.88 (DD, 1H); 2,60 (DD, 1H); 2.50 each (m, 1H), 2,44 (s, 3H, N-CH3); 2,33 - of 2.28 (m, 2H); 2,19 (m, 1H); 1.89 h/mill. (m, 1H).

Example OF

(1SR,2SR,6RS)-2-methylamino-8-azabicyclo[4.3.0]non-4-EN

O. 1. (1RS,2SR,6RS)-9-oxo-azabicyclo[4.3.0]non-4-ene-2-carboxylic acid

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the lots. Small amounts added to 9.8 g (50 mmol) of the compound obtained according to example J. H. Stirred at a temperature of 60oC for 5 hours. Processing is as follows. Add a solution of 0.8 g of sodium bicarbonate in 10 ml of water, and then concentrated in vacuum. The residue is suspended in 40 ml of water and transferred into a solution by adding ice cooling the concentrated sodium lye. After extraction from the insoluble components is acidified by adding policecontributing hydrochloric acid and again cooled to a temperature of 0oC. the Precipitated product is washed with small amount of cold water and dried in a vacuum drying Cabinet at a temperature of 50oC.

Yield: 4.8 g (53% of theory)

Melting point: 192 - 193oC

O. 2. (1SR,2SR,6RS)-2-ethoxycarbonyl-9-oxo-8 - azabicyclo[4,3,0]non-4-EN

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Get on stage O. 1. (1RS,2SR,6RS)-9-oxo-8 - azabicyclo[4.3.0] non-4-ene-2-carboxylic acid is transferred to the target product as in example C. 2.

Yield: 68% of theory

Melting point: 160 - 164oC

O. 3. (1SR,2SR,6RS)-2-methylamino-8-azabicyclo[4.3.0]non-4-EN

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The target compound is obtained by interaction of the compound obtained in stage Acting 2., with 10 equivalents of the Oria

1H-NMR (CDCl3): 5,72 (m, 1H, C=CH); of 5.50 (m, 1H, C=CH); 3.04 from - 2,77 (m, 6H); 2,60 (m, 1H); 2.49 USD (s, 3H, N-CH3), 2,31 (BS, 2H, 2xNH); to 2.25 (m, 1H); 1.89 h/mill. (m, 1H).

1. Derivatives pyridobenzoxazine General formula (I)

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where R1is hydrogen, alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by hydroxyl or halogen;

R2is independent of R1and means hydrogen or methyl;

R3is hydrogen or alkyl with 1 to 4 carbon atoms;

R4is hydrogen or alkyl with 1 to 4 carbon atoms;

X1is hydrogen or halogen;

Z is a residue of the formula

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where R5is hydrogen;

R6is hydrogen or ethyl;

B - group-CH2-, an oxygen atom or a direct link;

R7is hydrogen, hydroxyl, hydroxymethyl, group-CH2NR10R11, -NR10R11where R10denotes hydrogen, alkyl with 1 to 3 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part, and R11is hydrogen or methyl;

R8is hydrogen;

R9is hydrogen,

the mixture of isomers, or individual isomers, its hydrates and salts.

2. Derivatives pyridobenzoxazine formula I on p. 1, where R1is hydrogen, alkyl with 1 to 3 carbon atoms, unsubstituted or substituted Gil or ethyl;

R4is hydrogen, alkyl with 1 to 4 carbon atoms;

X1is hydrogen, fluorine or chlorine;

Z is a residue of the formula

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where R5is hydrogen;

R6is hydrogen;

B - group-CH2-, oxygen or a direct link;

R7is hydrogen, hydroxyl, hydroxymethyl, group-CH2NR10R11, -NR10R11where R10denotes hydrogen, alkyl with 1 to 2 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part, and R11is hydrogen or methyl;

R8is hydrogen;

R9is hydrogen,

pharmaceutically applied hydrates and acid additive salts, as well as their alkali, alkaline earth, silver and guanidinium salt.

3. Derivatives pyridobenzoxazine formula (I) under item 1, where R1is hydrogen or methyl; R2is hydrogen; R3is methyl or ethyl; R4is hydrogen, methyl or ethyl; X1- fluorine; Z is a residue of the formula

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< / BR>
< / BR>
where R5is hydrogen;

B - group-CH2-, oxygen or a direct link;

R6is hydrogen;

R7is hydrogen, hydroxyl, hydroxymethyl, group-CH2NR10R11, -NR10R11where R10is hydrogen, methyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol is citiesi used hydrates and acid additive salt, as well as their alkali, alkaline earth, silver and guanidinium salt.

 

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