Nitrogen-containing heterocyclic compounds, synthesis and use thereof as antibacterial medicinal agents

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), having antibacterial properties, a method for synthesis thereof, use thereof and a pharmaceutical composition based on said compounds. In general formula (I) R1 is a (CH2)n-NH2 or (CH2)n-NHR radical, where R is (C1-C6)alkyl and n equals 1 or 2; R2 is a hydrogen atom; R3 and R4 together form a nitrogen-containing aromatic 5-member heterocycle with 1, 2 or 3 nitrogen atoms, possibly substituted with one or more R' groups, where R' is selected from a group consisting of a hydrogen atom and alkyl radicals with 1-6 carbon atoms.

EFFECT: improved method.

13 cl, 4 ex

 

The invention relates to nitrogen-containing heterocyclic compounds, their preparation and application as antibacterial drugs.

In the application WO 02/100860 described compounds of the following formula:

where:

a) either R1represents a hydrogen atom, the radical COOH, CN, COOR, (CH2)n·R5, CONR6R7or

R is selected from the group consisting of the alkyl radical with the number of carbon atoms from 1 to 6, possibly substituted pyridium radical, CH2-alkenylphenol radical with a total number of carbon atoms from 3 to 9, (poly)CNS radical with oxygen atoms from 1 to 4 carbon atoms from 3 to 10, aryl radical with the number of carbon atoms from 6 to 10 or Arakelova radical with the number of carbon atoms from 7 to 11, where the aryl nucleus or Arakelova radical possibly substituted by a radical, HE, NH2, NO2, alkyl radical with the number of carbon atoms from 1 to 6, an alkoxy radical with the number of atoms of operads 1 to 6, or one or more halogen atoms,

R5selected from the group consisting of radical COOH, CN, HE, NH2, CO-NR6R7, COOR, OR, OCOH, OCOR, OCOOR, OCONHR, OCONH2, OSO2R, other, NHCOR, NHCOH, NHSO2R, NH-COOR, NH-CO-other, NH-CO-NH2or N3 where R is as defined above,

R6and R7that are the same or different, selected from the group consisting of a hydrogen atom, an alkyl radical with the number of carbon atoms from 1 to 6, an aryl radical with the number of carbon atoms from 6 to 10, Arakelova radical with the number of carbon atoms from 7 to 11 and the alkyl radical with the number of carbon atoms from 1 to 6, a substituted pyridium radical,

n' is 1 or 2,

R3and R4together form a phenyl or a five or six-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and possibly substituted by one or more groups R', where R' is selected from the group consisting of hydrogen atom and alkyl radicals with a number of carbon atoms from 1 to 6, possibly substituted by one or more radicals hydroxyl, oxo, halogen or cyano, or nitro, alkenyl with the number of carbon atoms from 2 to 6, the radicals halogen, amino, HE protected IT, -OR, -NHCOH, -NHCOR, NHCOOR, COOH, -COOR, -C6H5)3and-CH2-CH2-S(O)m-R, where R is as defined above, and m is 0, 1 or 2,

b) or R4represents a hydrogen atom or a group (CH2)n'1R5where n'1 is 0, 1 or 2 and R5is the same as defined above,

and R1and R 3together form a phenyl or a heterocycle, possibly substituted, as defined above,

in both cases a) and b)

R2selected from the group consisting of hydrogen atom, halogen atom and the radicals R, S(O)mR, OR, NHCOR, NHCOOR and NHSO2R, where m and R are as defined above,

X represents a divalent group-C(O) -, related to the nitrogen atom through a carbon atom,

Represents a bivalent group-O-(CH2)n-related to the carbonyl by the oxygen atom, the group-NR8-(CH2)n- or-NR8-O-, associated with the carbonyl by the nitrogen atom, n" is 0 or 1 and R8selected from the group consisting of a hydrogen atom, radical, HE, R, OR, Y, OY, Y1, OY1, Y2, OY2, Y3, O-CH2-CH2-S(O)m-R, SiRaRbRc and OSiRaRbRc, where Ra, Rb and Rc individually represent a straight or branched alkyl radical with the number of carbon atoms from 1 to 6 or an aryl radical with the number of carbon atoms from 6 to 10, and where R and m are as defined above.

Y is selected from the group consisting of radicals COR, COOR, CONH2, CONHR, CONHOH, CONHSO2R, CH2COOH, CH2COOR, CH2CONHOH, CH2CONHCN, CH2-tetrazol protected CH2-tetrazol, CH2SO3H, CH2SO2R, CH2PO(OR)2CH2PO(OR)(OH), CH2PO(R)(OH)and CH 2RHO(OH)2,

Y1selected from the group consisting of radicals SO2R, SO2NHCOH, SO2NHCOR, SO2NHCOOR, SO2NHCONHR, SO2NHCONH2and SO3H,

Y2selected from the group consisting of the radicals RO(OH)2, PO(OR)2, PO(OH)(OR) and PO(OH)(R),

Y3selected from the group consisting of radicals of tetrazole, tetrazole substituted by the radical R, Squamata, NH or NR of tetrazole, NH or NR of tetrazole substituted by the radical R, NHSO2R and NRSO2R, where R is as defined above,

n is 1 or 2,

as well as salts of these compounds with inorganic or organic bases or acids.

The asymmetric carbon atoms contained in the compounds of formula I can independently of each other to show the configuration of the R, S or RS, and the compounds of formula (I), therefore, are in the form of pure enantiomers or pure diastereoisomers, either in the form of mixtures of enantiomers, especially racemic mixtures or mixtures of diastereoisomers.

In addition, since, on the one hand, the substituents R1, R2or R4taken individually and, on the other hand, X can be in the CIS and/or TRANS-position is obtained to the ring with which they are associated, the compounds of formula (I) are in the form of CIS - or TRANS-isomers or mixtures.

In addition, related compounds described in the application WO 04/052891./p>

The applicant made the discovery that among the compounds described in the application WO 02/100860, some specific compounds, none of which are described in the experimental section of this application, have a very unexpected antibacterial properties.

The unique nature of the compounds according to the invention consists in the fact that they exhibit excellent activity against Pseudomonas aeruginosa, bacterial strain, often encountered in nosocomial infections and in patients suffering from cystic fibrosis.

This interesting and unexpected activity is not present in the compounds obtained in the application WO 02/100860 containing group, R1other than the group in the compounds according to the invention. This is illustrated below in the section describing the experiments.

In addition, it is shown that the compounds according to the invention is active in models of infections in animals, including strains are usually resistant to commonly used antibiotics. Compounds according to the invention can counteract the basic resistance mechanisms of bacteria that are β-lactamase, efflux pumps and mutation Parinov.

Compounds according to the invention are compounds of the following formula, where R2represents a hydrogen atom, R3and R4together form an aromatic containing nitrogen of the five-membered heterocycle, X depict is to place a divalent group-C(O)-NR 8-, where R8represents a radical OY1where Y1represents a radical-SO3H, and first of all:

R1represents an alkyl radical substituted by a radical of amino, or alkylamino.

Thus, the object of the invention are compounds of General formula (I)

where R1represents the radical (CH2)n-NH2or (CH2)n-Other, where R is a (C1-C6)alkyl and n is 1 or 2;

R2represents a hydrogen atom;

R3and R4together form an aromatic containing nitrogen of the five-membered heterocycle with 1, 2 or 3 nitrogen atoms, possibly substituted by one or more groups R', where R' is selected from the group consisting of hydrogen atom and alkyl radicals with a number of carbon atoms from 1 to 6;

in free form, in the form of zwitterions and in the form of salts with pharmaceutically acceptable inorganic or organic bases and acids.

The expression "alkyl radical with the number of carbon atoms from 1 to 6, as it is used here, is understood as meaning, in particular, methyl, ethyl, propyl, isopropyl radical, and straight or branched pentalonia or hexyl radicals.

The expression "alkanniny radical with the number of carbon atoms from 2 is about 6", as used here is understood as meaning, in particular, allyl radical, and straight or branched butenylamine, pentesilea and hexenoate radicals.

The term "aromatic heterocycle", as used here, is understood as meaning, in particular, selected from the list presented below, where two links represent the combination with nitrogen-containing ring (R3R4):

Among the acid salts of the products of formula (I) may be mentioned, among others, salts formed with inorganic acids such as hydrochloric, Hydrobromic, uudistoodetena, sulfuric or phosphoric acid, or with organic acids such as formic, acetic, triperoxonane, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, Glyoxylic, aspartic, alkanesulphonic acids such as methane - and econsultancy acid, arylsulfonic acids, such as benzene and para - toluensulfonate acid.

Among the basic salts of the products of formula (I) may be mentioned, among others, salts formed with inorganic bases, such as, for example, hydrox the d sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases, such as, for example, methylamine, Propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, Tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine, or postname salts such as alkylphosphonic, arylphosphine, alkilirovanii, alkenylsilanes, or Quaternary ammonium salt, such as salt, Tetra-n-butylamine.

Among the compounds of formula (I) specific object of the invention comprise compounds where R3and R4together form a heterocycle pyrazolyl or triazolyl, possibly substituted.

Among the compounds of formula (I) specific object of the invention comprise compounds where R1selected from the group consisting of groups (CH2)n-NH2and (CH2)n-NHCH3where n is as defined above, where the heterocycle formed by R3and R4substituted (C1-C6)alkyl radical.

Among the compounds of formula (I) specific object of the invention comprise compounds where R1represents the radical (CH2)n-NH2or (CH2)n-NHCH3where n is as defined above, and R3and R4together form a ring pyrazolyl, C is displaced (C 1-C6)alkyl radical.

Among the compounds of formula (I) is a very specific object of the invention comprise

- TRANS 8-(aminomethyl)-4,8-dihydro-1-methyl-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he,

- TRANS 8-(aminomethyl)-4,8-dihydro-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he

- TRANS 8-(methylaminomethyl)-4,8-dihydro-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he,

in free form, in the form of zwitterions and salts with pharmaceutically acceptable inorganic or organic bases and acids.

Another object of the invention is a method of producing compounds of the formula (I).

This method is characterized by the fact that it includes:

a) stage, during which the compound of formula (II) is subjected to interaction with carbonyliron agent, if necessary, in the presence of a base:

where:

R'1represents a radical CN, protected radical COOH, COOR radicals or (CH2)nR'5,

R'5is a protected radical, the radicals CN, NH2or protected radical other protected radical CO2N, radical CO2R

n, R, R3and R4are as defined above, where aminoalkyl substituents may present in the heterocycle, obrazovan is th R 3and R4if necessary, are protected,

ZH is a protected group-NHOH,

obtaining the result of the intermediate compounds of formula (III):

where:

R'1, R3and R4have the same meanings as defined above, and either X1represents a hydrogen atom or a protective group and X2represents a group-Z-CO-X3where X3represents the balance Carboniferous agent, or X2represents a group-ZH and X1represents a group CO-X3where X3is as defined above;

b) stage, during which the intermediate compound obtained above is subjected to cyclization in the presence of a base;

and in which:

C) if necessary, stage a) is preceded by and/or stage b) should one or more of the following reactions, in an appropriate order:

- protection of reactive functional groups,

- remove the protection from reactive functional groups,

- esterification,

- saponification,

- sulfation,

- recovery of ester,

- alkylation

- carbamylcholine,

- education sidegroup,

- restoration of azide to amine,

education salt,

ion exchange,

the division or separation of diaster the isomers.

As Carboniferous agent can use a reagent such as phosgene, diphosgene, triphosgene, allglorious, such as phenyl - or para-nitrophenylphosphate, aralkylamines, such as benzylchloride, alkyl - or alkenylboronic, such as methyl - or allylchloroformate, alkalicarbonate, such as tert-BUTYLCARBAMATE, carbonyldiimidazole and mixtures thereof, where the preferred diphosgene.

The reaction preferably proceeds in the presence of a base or mixture of bases which neutralize the generated acid. The Foundation may, in particular, be an amine such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine. However, it can also perform the reaction using the initial product of the formula II as a base. In this case, use the excess.

If necessary, the product of formula II is used in the form of an acid salt, such as hydrochloride or trifenatate.

As the basis for stage b) can also be used amines, or hydride, alcoholate, amide or carbonates of alkaline or alkaline earth metals.

Amines can choose, for example, from the above list.

As hydride may, in particular, to use sodium hydride or potassium.

As an alcoholate of an alkali metal, preferably using tert-butyl potassium.

As the amide of an alkali metal may, in particular, to use bis(trimethylsilyl)amide and lithium.

As carbonate may, in particular, to use a carbonate or bicarbonate of sodium or potassium.

If necessary, the intermediate compound of formula III can be obtained in the form of an acid salt formed in the reaction of carbonyl and, in particular, hydrochloride. Then it is used in the cyclization reaction in this form.

Preferably the cyclization carried out without isolating the intermediate compounds of formula III.

The reaction mentioned on stage), as a rule, are conventional reactions well known to specialists in this field of technology. Examples of conditions described in the application WO 02/100860, as well as in the application 04/052891.

Reactive functional groups that require protection, if needed, are a functional group of carboxylic acid, amine, amide, hydroxy and hydroxylamine.

Protected acidic functional group perform, in particular, in the form alilovic ethers, allyl, benzyl, benzhydryl or para-nitrobenzyl esters.

Removing the protection is carried out by saponification, acid hydrolysis, hydrogenolysis or splitting using soluble complexes of palladium-O.

Examples of such protection and remove protection before the taulani in the application WO 02/100860.

Protection of amines, heterocyclic nitrogen atoms and amides in particular provide, depending on the situation, in the form of a benzyl or trailrunner derivatives, in the form of carbamates, in particular, allyl-, benzyl-, phenyl - or tert-BUTYLCARBAMATE, either in the form similarbank derivatives such as tert-butultimately-, trimethyl-, triphenyl - or diphenyl-tert-butylsilane derivatives, or derivatives of phenylsulfonyl or cyanoalanine.

Removing protection is held, depending on the nature of the protective group, with sodium or lithium in liquid ammonium chloride, by hydrogenolysis or by using soluble complexes of palladium-On, under the action of acid or under the action of tetrabutylammonium fluoride or strong bases such as sodium hydride or tert-butyl potassium.

Protection hydroxylamino perform, in particular, in the form of a benzyl or allyl ethers.

Cleavage of the esters is carried out by hydrogenolysis or use of soluble complexes of palladium-O.

Protection of alcohols and phenols perform in a conventional manner in the form of ethers, esters or carbonates. Ethers can be alkalemia or alkoxyalkyl esters, preferably methyl or methoxyethoxymethyl esters, arrowie ester or preferably Arakelova esters, for example, be Silovye esters, or Silovye esters, for example, siciliane derivatives mentioned above. Esters can be any split ether, known to experts in the art, and preferably the acetate, propionate, benzoate, or a pair of nitrobenzoate. Carbonates can represent, for example, methyl, tert-butyl-, allyl-, benzyl or para-nitrobenzylamine.

Remove protection carried out by methods known to experts in the field of technology, in particular, by saponification, hydrogenolysis, splitting soluble palladium complexes, hydrolysis in the acidic environment or, for similarbank derivatives by treatment with tetrabutylammonium fluoride.

Examples are given in the section describing the experiments.

The sulfation reaction is carried out under the action of SO3-amines, such as SO3-pyridine or SO3-dimethylformamide, processing in pyridine, and the resulting salt, such as salt of pyridine, can then be subjected to ion exchange, for example, with a salt of another amine, Quaternary ammonium or alkali metal. The example given in the section describing the experiments.

The alkylation reaction is carried out by action on gidroksilirovanii derivatives, enolate ether or ketone, heterocyclic amines or nitrogen atoms, depending on the situation, alkylsulfate or alkylhalogenide is m, or substituted by alkyl, in particular, free or esterified carboxy radical. The alkylation reaction can also be achieved through reductive amination.

The formation of salts with acids is carried out, if necessary, by adding acid to the soluble phase connection. The formation of salts with bases functional group sulfoxy can perform using pyridinium salt, obtained by effects at SO3-pyridine, and pyridinium salts get other salts. Can also perform ion exchange, ion-exchange resin.

The reaction carbamylcholine can be performed with chloroformiate or reagent type Boc-ON, then amine or, if necessary, ammonium chloride.

Sidegroup can enter, for example, by exposure of Attica sodium in the intermediate connection mutilator type or by reaction type Mitsunobu.

The restoration of the azide group can be achieved through the impact trialkyl or triarylphosphine.

Separation of enantiomers and diastereoisomers can be carried out in accordance with techniques known to experts in the art, in particular, by using chromatography.

In addition to the above methods, compounds of formula (I) can be obtained by methods in which the source is used as a compound of the formula (II), g is e R' 1, R3, R4and HZ are the values that allow you to get directly (without conversion) connection that you want to receive. If necessary, the connection of these groups, which should include a reactive functional group such as mentioned above, protect, and removing the protection is carried out after stage b) cyclization or in any other suitable point of fusion. Then the introduction of protection and removal of protection is held, as described above.

Another object of the invention is a method corresponding to the above, characterized in that the compound of formula (II) are obtained, which compound of formula (IV):

where R'1, R3and R4are as defined above, and a represents a hydrogen atom or a group protecting the nitrogen atom, is treated regenerating agent, to obtain the compounds of formula (V):

where A, R'1, R3and R4retain the above values, where, if necessary, the group HE substituted leaving group, to obtain compounds of formula (VI):

where A, R'1, R3and R4retain the above significance, and R9represents a leaving group, which is treated with a compound of the formula Z1/sub> H2where Z1is a protected group-HN-OH, and then, if necessary, the agent for removing protection from the corresponding nitrogen atom.

Another object of the invention is a method corresponding to the above, characterized in that the compound of formula (II) are obtained by a method where the compound of formula (IV) is treated as described above, with hydroxylamine protection of the hydroxyl group to obtain the compounds of formula (VII):

where A, R'1, R'2, R3, R'4, n and R'8are as defined above, and subjected him to interact with regenerating agent in order to obtain the compounds of formula (VIII):

where A, R'1, R3, R4n and ZH are as defined above, which process, if necessary, the agent for removing protection from the corresponding nitrogen atom.

Agent protecting the nitrogen atom, in particular represents one of the aforementioned agents.

Reducing agent, in particular, is a borohydride of an alkali metal.

Leaving group, in particular, represents a sulfonate, for example, mesilate or toilet resulting from the action of the corresponding sulphonylchloride in the presence of a base, or halogen, in private the tee, chlorine, bromine or iodine, obtained, for example, by the action of thionyl chloride or P(C6H5)3CBr4or PBr3or, in the case of an iodine atom, by the action of iodide of alkali metal sulfonate.

Agent for removing protection, in particular, represents one of the aforementioned agents.

Reducing agent used in the case of the compounds of formula (VII), in particular, represents a cyano or acetoxyvalerenic sodium.

As indicated above, compounds of General formula (I) have excellent antibiotic activity against Pseudomonas aeruginosa and in models of infection animal strains that are resistant to commonly used antimicrobial agents. This remarkable and unexpected antibiotic activity was observed in compounds, as described in the application WO 02/100860.

These properties make these compounds suitable, in free form, in the form of zwitterions or salts of pharmaceutically acceptable acids and bases, for use as drugs in the treatment of severe Pseudomonas infections, particularly nosocomial infections, and in General, generalized infections in subjects at risk. These infections may, in particular, to represent respiratory tract infections for example, acute pneumonia or chronic infections of the upper respiratory tract, in which eccii blood, for example, septicemia, acute or chronic urinary tract infections, infections of the auditory system, for example, malignant external otitis or chronic purulent otitis media, infections of skin and soft tissues, for example, dermatitis, infected wounds, folliculitis, pyoderma, sustainable forms of acne, eye infections, for example, corneal ulcers, infections of the nervous system, in particular, meningitis and brain abscesses, heart infections, such as endocarditis, infections of bones and joints, such as Sterno-articular pietros, osteomyelitis of the spine, pubic simpatic, infections of the gastrointestinal tract, such as necrotorous enterocolitis and perirectal infections.

Thus, an object of the present invention are also the compounds of formula (I)as defined above, for use as medicines, especially as antibiotics.

Among the compounds of formula (I) object of the invention, in particular, is the use as a drug compounds, where R3and R4together form a heterocycle pyrazolyl or triazolyl, possibly substituted, and among them are those where R1selected from the group consisting of groups (CH2)n-NH2and (CH2)n-NHCH3where n is as defined above, where the heterocycle formed by R3and R4substituted (C -C6)alkyl radical.

Among the compounds of formula (I) object of the invention, in particular, is the use as a drug compounds, where R1represents the radical (CH2)n-NH2or (CH2)n-NHCH3where n is as defined above, and R3and R4together form pyrazolidine ring, substituted (C1-C6)alkyl radical.

Among the compounds of formula (I) is a more specific object of the invention is the use as a drug:

- TRANS 8-(aminomethyl)-4,8-dihydro-1-methyl-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he,

- TRANS 8-(aminomethyl)-4,8-dihydro-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he

- TRANS 8-(methylaminomethyl)4,8-dihydro-5-(sulfoxy)-4,7 - methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he,

in free form, in the form of zwitterions and salts with pharmaceutically acceptable inorganic or organic bases and acids.

The next object of the invention is a pharmaceutical composition with at least one of the compounds according to the invention, as defined above, as the active substance.

These compositions can be entered through the mouth, through the rectum, parenteral, particularly intramuscular injection, or topically by local inflicted on the I on the skin and mucous membranes.

Compositions according to the invention can be solid or liquid and are present in the pharmaceutical forms currently used in medicine, such as, for example, simple tablets or coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared in accordance with conventional ways. The active substance or substances can be included in the excipients usually used in these pharmaceutical compositions, such as talc, Arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or other medium, fatty substances of animal or vegetable origin, derived paraffin, glycols, various moisturizing, dispersing or emulsifying agents, preservatives.

These compositions can be, in particular, in the form of a lyophilisate, intended for dissolution in a suitable solvent, for example, sterile pyrogen-free water.

Enter the dose may vary depending on the condition to be treated, from the subject, route of administration and drug used. It can, for example, be between 0,250 and 10 g per day by oral administration in humans when used in the preparation described in example 1, or to be between 0.25 and 10 g per day by intramuscular or intravenous injection.

Drugs of formula (I) can the e to use as a disinfectant for surgical instruments.

The following examples illustrate the invention.

EXAMPLES

EXAMPLE 1: Sodium and three fluorine cetatenie salt of TRANS - [[8-(aminomethyl)-4,8-dihydro-1-methyl-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3.4-e][1.3] diazepin-6(5H)-it

Stage A:

4,7-dihydro-1-methyl-4-((phenylmethoxy)amino)-1H-pyrazolo[3,4-C]pyridine-6(5H),7-dicarboxylate-(1,1-dimethylethyl) and 7-methyl (In)

DerivedAnd(4,7-dihydro-4-hydroxy-1-methyl-1H-pyrazolo[3,4-C]pyridine-6(5H),7, in primary forms 6-(1,1-dimethylethyl) and 7-methyl, as described in the application WO 02100860 (10 g, 32,12 mmol)placed in a suspension in dichloromethane (100 ml) at ambient temperature under nitrogen atmosphere with stirring. The suspension dissolved after addition of triethylamine (14,30 ml, 10,28 mmol, 3.2 EQ.). The solution methanesulfonanilide (11,4 ml, 96,36 mmol, 3 EQ.) in dichloromethane (12 ml, 1 vol.) is added dropwise to the reaction mixture, cooled to -78°C. After 30 min of interaction between alcohol And completely converted to mesilate.

Prepare a fresh solution of O-benzylhydroxylamine in dichloromethane from About-benzylhydroxylamine hydrochloride (25.4 g, 160,6 mmol, 5 EQ.). O-benzylhydroxylamine hydrochloride dissolved in a mixture of O-benzylhydroxylamine hydrochloride (100 ml) and water (50 ml). At 0°C. add a solution of 2 N. caustic soda (85 ml, 176,66 mmol). After 10 min of interaction and decanting, the organic phase is dried on magnesium phosphate in the tech is of 45 min, then concentrated to half volume. Dropwise within 1 hour at -78°C. to this solution add mesilate obtained above. The reaction mixture was stirred, allowing a gradual increase of temperature to the ambient temperature. Add water (200 ml) and dilute it dichloromethane (100 ml), stirred, decanted, and then the aqueous phase is re-extracted with dichloromethane. The organic phase is washed with saturated NaCl solution (200 ml), dried, then concentrated to dryness. Emit a white amorphous powder, which after chromatography gives the expected derivedIn(8,25 g, 66%).

MS (ES (+)): m/z [M+]=417,2

1H NMR (400 MHz, CDCl3): one diastereoisomer (2 rotamer) δ (m-1)=1.43 (s, S, tBu), 3.15 (dd, 1H, N-CH2-CH-N), 3.68/3.70 (s, 3H, CH3), 3.84 (s, 3H, CH3), 3.98 (m, 2H, N-CH2-CH-N), 4.6-4.8 (massive, 3H, NH-O-CH2-Ph and N-CH2-CH-N), 5.40/5.8 (s, 1H,CH-CO2IU), 7.22-7.31 (massive, 5H, Ph), 7.40 (s, 1H, H pyrazole)

Stage:

TRANS 1-methyl-6-oxo-5-(phenylmethoxy)4,5,6,8-tetrahydro-4,7-methane-1H-pyrazolo[3,4-e][1,3]diazepin-8(7H)methylcarbazole (C)

4 n HCl/dioxane (400 ml,15 EQ.) poured into a solution ofIn(21 g, 50,42 mmol) in dioxane (50 ml) at ambient temperature.

The reaction mixture was stirred for 30 min, then the dioxane is evaporated. The residue is dissolved when peremeci is assured in a mixture of water (100 ml) and ethyl acetate (500 ml). At 0°C. add a solution of ammonia, concentrated to 20% (42 ml). Stirring is continued for 30 minutes After decanting, the aqueous phase is re-extracted with ethyl acetate (2×300 ml), and the last extraction is carried out after saturating the aqueous phase with Sodium chloride. The organic phase is dried, and then concentrated. The intermediate connection is not protected pyridine is obtained in the form of a yellow oil (m=15.7 g, 98%)which was dissolved in acetonitrile (400 ml). To this mixture, cooled to 0°C. add triethylamine (21 ml, 151,2 mmol, 3 equiv.) then diphosgene (3.04 from ml to 25.2 mmol, 0.5 EQ.) dropwise within 30 minutes After the reaction occurring during the night when ambient temperature, the mixture is concentrated, then dissolved in ethyl acetate (500 ml) and treated with 10% solution of tartaric acid (200 ml). The mixture is stirred and decanted. The organic phase is washed with a solution of 10% tartaric acid (2*200 ml), then saturated NaCl solution, then dried and concentrated under reduced pressure. The obtained white product (m=15.3 g, 89%) was dissolved in dichloromethane (150 ml). Added dropwise 1-8-diazabicyclo[5.4.0]undec-7-ene (7,53 ml, 50,04 mmol). The mixture is stirred for 2 hours, treated with water (200 ml), stirred, and decanted. The organic phase is washed with water (2×200 ml), then saturated NaCl solution (1 x 200 ml) and dried on MgSO4, then concentrate to dryness.

Withallocate (m=14,72 g, 85%) in the form of a white solid.

MS (ES (+)): m/z [M+]=343

1H NMR (400 MHz, CDCl3): δ (m-1)=3.25 (d, 1H, N-CH2-CH-N), 3.45 (d, 1H, N-CH2-CH-N), 3.80 (s, 3H, CH3), 3.88 (s, 3H, CH3), 3.9 (s, 1H, N-CH2-CH-N), 4.7 (d, 1H, N-O-CH2-Ph), 5.02 (d, 1H, N-O-CH2-Ph), 5.22 (s, 1H,CH-CO2Me), 7.39-7.43 (massive, 6H, H pyrazole + Ph)

Stage With:

4,8-dihydro-8-(hydroxymethyl)-1-methyl-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3] diazepin-6(5H)-he (D)

SolutionWith(5 g, 14,60 mmol) in a mixture of anhydrous tetrahydrofuran (150 ml)/methanol (50 ml), under nitrogen atmosphere with stirring, cooled to -10°C. To the reaction mixture are added lithium borohydride (668 mg, 30,67 mmol, 1.2 EQ.). After stirring for 2 h at -10°C. add an additional 1.2 EQ. LiBH4. After 2 h, the reaction mixture is treated with a cold solution of 10% NaH2PO4Tetrahydrofuran and methanol is evaporated under reduced pressure (200 mbar, 40°C). The residual mixture is diluted with ethyl acetate (200 ml), stirred and decanted. The aqueous phase is re-extracted with 100 ml of ethyl acetate. The organic phase is dried on magnesium sulfate, then concentrated to dryness. The obtained pale yellow powder (6.6 g) is subjected to chromatography on silica (eluent - ethyl acetate) to obtain the derivedD(3.2 g, 10,18 mmol, 64%).

MC(ES(+)):m/z[M+]=315

1H NMR (400 MHz, DMSO-d6): δ (m-1)=3.16 (dd, 1H, N-CH2-CH-N), 3.48 (d, 1H, N-CH2-CH-N), 3.71 (s, 3H, CH3), 3.81-3.91 (massive, 2H, CH2IT), 4.44 (m, 1H, N-CH2-CH-N), 4.48 (m, 1H,CHCH2IT), 4.88 (m, 2H, N-O-CH2-Ph), 5.20 (m, 1H, HE), 7.35-7.40 (massive, 6N, N pyrazole + Ph).

Stage D:

TRANS-4,8-dihydro-1-methyl-8-[(methylsulphonyl)oxymethyl)]-5-(phenylmethoxy)-4,7-means-7H-pyrazolo[3,4-e][1,3] diazepin-6(5H)-he (E)

DerivedD(2.76 g, 8,78 mmol) dissolved in dichloromethane (100 ml) at ambient temperature under nitrogen atmosphere with stirring. After cooling to 0°C. add triethylamine (1,83 ml, 13,17 mmol, 1.5 equiv.) then add dropwise a solution of methylchloride (1,61 g 14,05 mmol) in dichloromethane (100 ml). At the end of the addition the ice bath removed. After one hour of interaction with the ambient temperature, the reaction mixture was treated with 10% solution of NaH2PO4(80 ml) under stirring. After stirring and decanting, the aqueous phase is re-extracted with dichloromethane (50 ml). The organic phase is dried, then concentrated under reduced pressure to obtain the expected derivative (3,44 g, quantitative yield).

MS(ES(+)):m/z [M+]=393

1H NMR (400 MHz, DMSO-d6): δ (m-1)=3.23 (dd, 1H, N-CH2-CH-N), 3.26 (s, 3H, CH3), 3.45 (d, 1H, N-CH2-CH-N), 3.76 (s, 3H, CH3), 4.52 (m, 1H, N-C 2-CH-N), 4.58 (dd, 1H, CH-CH2-OMs), 4.66 (dd, 1H, CH-CH2-OMs), 4.88 (m, 3H,CHCH2OMs and N-O-CH2-Ph), 7.35-7.45 (massive, 6H, H pyrazole + Ph).

Stage E:

TRANS 8-(azidomethyl)-4,8-dihydro-1-methyl-5-(phenylmethoxy)-4,7-means-7H-pyrazolo[3,4-e][1,3] diazepin-6(5H)-he (F)

Sodium azide added all at once (1,71 g of 26.3 mmol) to a solution ofE(3,44 g, 8,78 mmol) in dimethylformamide (70 ml) at ambient temperature under nitrogen atmosphere with stirring. The reaction mixture is heated to 65°C overnight, then treated with an aqueous solution of 10% NaH2PO4(50 ml). After stirring and decanting, the aqueous phase is re-extracted with dichloromethane (2*50 ml). The organic phase is dried, then concentrated under reduced pressure obtaining of 3.96 g of the expected derivativeF(3 g, 8,78 mmol).

MS(ES(+)):m/z[M+]=340

1H NMR (400 MHz, DMSO-d6): δ (m-1)=3.20 (dd, 1H, N-CH2-CH-N), 3.48 (d, 1H, N-CH2-CH-N), 3.66 (dd, 1H, CH-CH2-N3), 3.72 (s, 3H, CH3), 3.92 (dd, 1H, CH-CH2-N3), 4.50 (d, 1H, N-CH2-CH-N), 4.76 (dd, 1H, CHCH2ON3), 4.89 (m, 2H, N-O-CH2-Ph), 7.35-7.45 (massive, 6N, N pyrazole + Ph).

Stage F:

TRANS [[4,dihydro-1-methyl-6-oxo-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-carbamate 1,1-dimethylethyl (G)

Molar solution trimethylphosphine (3.4 ml, 3.4 mmol) is added dropwise to a solution ofF/u> (1,15 g, 3,39 mmol) in a mixture of toluene (5 ml) and tetrahydrofuran (5 ml) at ambient temperature under nitrogen atmosphere with stirring. After 3 h of interaction is added dropwise a solution of BOC-ON (to 0.92 g, 3.6 mmol) in tetrahydrofuran (10 ml) to the reaction mixture, cooled to 0°C. Stirring is continued for 3 h at ambient temperature. The reaction mixture was treated with 10% aqueous solution of NaHCO3(50 ml). After stirring and decanting, the aqueous phase is re-extracted with ethyl acetate (50 ml). The organic phase is dried, then concentrated under reduced pressure to obtain 2.2 g of oil. The crude product is subjected to chromatography on a column of silica (eluent cyclohexane/ethyl acetate 5/5). Get the expected product (0,62 g, 1,49 mmol, 70%).

MC(ES(+)):m/z[M+]=414

1H NMR (400 MHz, CDCl3): δ (m-1)=1.39 (s, 9H, tBu), 3.05 (dd, 1H, N-CH2-CH-N), 3.19 (dd, 1H, CH-CH2-NHBOC), 3.27 (dd, 1H, N-CH2-CH-N), 3.72 (s, 3H, CH3), 3.78 (m, 1H, CH-CH2-NHBOC), 3.88 (d, 1H, N-CH2-CH-N), 4.48 (dd, 1H,CHCH2NHBOC), 4.79 (d, 1H, N-O-CH2-Ph), 4.92 (d, 1H, N-O-CH2-Ph), 5.18 (m, 1H, H mobile), 7.35 (s, 1H, H pyrazole), 7.37-7.48 (massive, 5H, Ph)

Stage G:

Pyridinium salt of TRANS - [[4,8-dihydro-1-methyl-6-oxo-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-carbamate 1,1-dimethylethyl (H)

10% palladium on coal (140 mg) are added to races the thief G (0.6 g, 1,45 mmol) in methanol (10 ml). The reaction mixture was subjected to hydrogenation for 3 hours and Then the methanol is evaporated under reduced pressure to get dibenzylamino derived.

MS(ES(+)):m/z [M+]=324

Dibenzylamino intermediate compound is dissolved in pyridine (3 ml) in the presence of a complex of pyridine/sulfur trioxide (462 mg, 2.9 mmol). The reaction of the support with stirring at ambient temperature overnight. The mixture is then concentrated under reduced pressure. The crude reaction product is subjected to chromatography on a column of silica (eluent 100% dichloromethane, then the gradient with methanol from 5% to 20%) to obtain the derivedN(0,49 g, 1.25 mmol, 84%).

MS(ES(+)):m/z[M+]=402

1H NMR (400 MHz, DMSO-d6): δ (m-1)=1.41 (s, 9H, tBu), 3.30-3.80 (massive, 4H, 2CH2), 3.72(s, 3H, CH3), 4.42 (dd, 1H, CHCH2ONHBOC), 4.64 (d, 1H, N-CH2-CH-N), 7.21 (m, 1H, H mobile), 7.35 (s, 1H, H pyrazole), 8.02 (dd, 2H, pyridine), 8.54 (m, 1H, pyridine), 8.91 (m, 2H, pyridine)

Stage 3:

Sodium salt of TRANS - [[4,8-dihydro-1-methyl-6-oxo-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-carbamate 1,1-dimethylethyl (I).

A suspension of 60 g of resin DOWEX 50WX8 in solution 2 N. caustic soda (300 ml) is stirred for one hour, then poured onto a chromatographic column. Her elute with demineralised water until Nate the real pH then the column balance a 90/10 mixture of water/THF. DerivedN(0,49 g, 1.01 mmol) is dissolved in the minimum of water, placed on a column, then elute with a mixture of 90/10 water/THF. The fractions containing the substrate, unite and zamorazhyvanyy solution lyophilizer to obtain the expected productI(0,44 g of 1.03 mmol, 100%).

MS(ES(+)):m/z[M+]=402

1H NMR (400 MHz, DMSO-d6): δ (m-1)=1.39 (s, 9H, tBu), 3.30-3.72 (m, 7H, 2CH2CH3), 4.42 (m, 1H, CHCH2ONHBOC), 4.64 (s, 1H, N-CH2-CH-N),7.16 (m, 1H, H mobile), 7.35 (s, 1H, H pyrazole).

Stage I:

Sodium and trifurcata salt of TRANS - [[8(aminomethyl)-4,8-dihydro-1-methyl-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-it (J)

The solution triperoxonane acid (10 ml) in dichloromethane (10 ml) is poured dropwise into a solution ofI(0.15 g, 0.35 mmol) in dichloromethane (5 ml) under nitrogen atmosphere and cooled to 0°C. the Reaction support under stirring for 1 h at ambient temperature. The mixture is evaporated to dryness and dissolved in a minimum of water. The solution is frozen, then lyophilizer to obtain the expected derivedJ(193 mg, 0.35 mmol, 100%).

MS(ES(+)):m/z [M-]=301

1H NMR (400 MHz, DMSO-d6): δ (m-1)=3.32 (dd, 1H, N-CH2-CH-N), 3.33-3.37 (m, 2H, 2CH), 3.43 (d, 1H, N-CH2-CH-N), 3.74 (s, 3H, CH3), 4.73 (m, 2H, CH-CH2-NH3+), 7.41 (s, 1H, H pyrazole), 8.10 (m, 3H, NH3+/sup> )

Example 2: Sodium and triptorelin salt of TRANS - [[8-(aminomethyl)-4,8-dihydro-5-(sulfoxy)-4,7-methane-7/-/-pyrazolo[3,4-e][1,3]diazepin-6(5H)-it

Stage A:

TRANS-8-(Hydroxymethyl)-4,5,6,8-tetrahydro-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he

Methyl ester of TRANS-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-carboxylate, described in the application WO 2004/052891 (Example 1, stage C) 5 g of 15.2 mmol) is dissolved in a 1/1 mixture of anhydrous methanol/tetrahydrofuran (100 ml) under nitrogen atmosphere. Then gradually add NaBH4(2.3 g, 60,9 mmol). The reaction mixture was stirred at ambient temperature overnight, then treated with 10% aqueous solution of NaH2PO4(100 ml). After evaporation to dryness, the reaction mixture is dissolved in water. The precipitate is stirred over night in the ice, then filtered and dried for at least 24 h in vacuum in the presence of P2O5to obtain the expected compound (3.3 g, 11.0 mmol, 72%) in the form of white powder.

MS(ES(+)):m/z[M+]=301

1H NMR (400 MHz, DMSO-d6): δ (m-1)=3.18-3.50 (AVH, 2H, N-CH2-CH-N), 3.65-3.76 (AVH, 2H, N-CH-CH2-OH), 4.34 (t, 1H, N-CH-CH2-OH), 4.46 (d, 1H, N-CH2-CH-N), 4.88 (s, 2H,CH2-Ph), 7.29-7.43 (m, 5H, Ph), 7.66 (s, 1H, H pyrazole), 12.72 (broad, 1H, HE).

Stage B:

TRANS [[4,8-Digi the ro-6-oxo-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-carbamate 1,1-dimethyl

The alcohol obtained in stage a of example 2 (1.73 g, USD 5.76 mmol), dissolved in anhydrous pyridine (35 ml), under nitrogen atmosphere at 0°C. is Added dropwise methanesulfonanilide (1,78 ml, 23 mmol). After 2 h 30 min of stirring at ambient temperature the reaction mixture was treated with saturated aqueous ammonium chloride (100 ml), then extracted with ethyl acetate. Then the combined organic phases are washed 5 times with saturated aqueous ammonium chloride, dried on sodium sulfate, filtered and concentrated in vacuo to obtain the expected demetilirovannogo derived in the form of a yellow oil.

This dimethylalanine derived dissolved in anhydrous dimethylformamide (45 ml), under nitrogen atmosphere, in the presence of sodium azide (1.12 g, 17.3 mmol). The reaction mixture is heated to 70°C for 24 hours. If necessary, add 1 EQ. azide to the transformation was complete. When the reaction is complete, the mixture is treated with 10% aqueous solution of NaH2PO4(100 ml), then extracted with dichloromethane. The combined organic phases are dried on sodium sulfate, filtered, then concentrated in vacuo to obtain the expected azide in the form of a yellow oil.

This intermediate compound is placed in the reaction mixture in a nitrogen atmosphere in absolute ethanol (17.5 ml). Then add di-Tr is t-BUTYLCARBAMATE (1,38 g, 6,34 mmol), triethylsilane (1,38 ml, 8,64 mmol) and 10% palladium hydroxide on coal (52 mg). After one night at ambient temperature, the reaction mixture is filtered, and then concentrated to obtain the crude yellow oil. This crude oil is purified by chromatography on a column of silica (gradient eluent CH2Cl2/MeOH from 100/0 to 95/5 by 1%) to obtain the expected compound (1,36 g, 3,40 mmol, 34%) as a white solid.

MS(ES(+)):m/z[M+]=401

1H NMR (400 MHz, MeOH-d4): δ (m-1)=1.51 (s, 9H, C(CH3)3), 3.21-3.59 (m, 4H, N-CH2-CH-N and N-CH-CH2-NHBoc), 4.36 (m, 1H, N-CH-CH2-OH), 4.46 (m, 1H, N-CH2-CH-N), 4.99 (AB, 2H,CH2-Ph), 7.41-7.52 (m, 5H, Ph), 7.63 (s, 1H, H pyrazole).

Stage With:

TRANS-[[4,8-dihydro-1-tert-butoxycarbonyl-6-oxo-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-carbamate 1,1-dimethyl

The compound obtained in stage b of example 2 (104 mg, 0.26 mmol), dissolved in anhydrous dichloromethane (2.5 ml), then added to the mixture of di-tert-BUTYLCARBAMATE (114 mg, 0.52 mmol) and dimethylaminopyridine (32 mg, 0.26 mmol). After stirring for one night at ambient temperature, the reaction mixture is treated with water. The phases are separated, then the organic phase is washed with saturated aqueous sodium chloride, dried on sodium sulfate, filtered, then it will centerour in vacuum. Thus obtained crude product is purified by chromatography on silica (eluent: CH2Cl2/AcOEt 90/10) to obtain the expected product (76 mg, 0.15 mmol, 59%).

MS(ES(+)):m/z[M+]=500

Stage D:

Pyridinium salt of TRANS - [[4,8-dihydro-1-tert-butoxycarbonyl-6-oxo-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-carbamate 1,1-dimethyl

The compound obtained in stage With example 2 (76 mg, 0.15 mmol), dissolved in a nitrogen atmosphere in a mixture of anhydrous dimethylformamide/CH2Cl21/3 (0,87 ml). Add 10% palladium on coal at 50% in water (49 mg). After three blowing vacuum/nitrogen the reaction mixture is placed in an atmosphere of hydrogen until the disappearance of the original product by HPLC (high performance liquid chromatography). The mixture is then concentrated in vacuo, then together evaporated three times with anhydrous dichloromethane and then dried under reduced pressure in the presence of P2About5within 2 hours

Dibenzylidene derivative is dissolved in anhydrous pyridine (of 0.43 ml) in nitrogen atmosphere in the presence of a complex of pyridine/sulfur trioxide (48 mg, 0.30 mmol). The reaction mixture was stirred at ambient temperature until complete conversion by HPLC, then evaporated to dryness after treatment with addition of water. Thus obtained crude product is purified by chromatography is and silica (eluent: CH 2Cl2/Meon 90/10) to obtain the expected product (47 mg, 0,083 mmol 55%).

MS(ES (-):m/z[M-2*BOC]=388

1H NMR (400 MHz, MeOH-d4): δ (m-1)=1.52 (s, 18H, 2 S(CH3)3), 3.50 (m, 4H, N-CH2-CH-N andCH2-NHBoc), 4.62 (m, 1H,CH-CH2-NHBoc), 4.85 (d, 1H, N-CH2-CH-N), 7.72 (s, 1H, H pyrazole).

Stage D:

Sodium and trifurcata salt of TRANS - [[8-(aminomethyl)-4,8-dihydro-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he

A suspension of 6 g of resin DOWEX 50WX8 2 N. the solution of caustic soda (30 ml) is stirred for 1 h, then poured onto a chromatographic column. After washing N2About to neutral pH balance column with a mixture of THF/N2About 10/90. The compound obtained in stage G of example 2 (47 mg, 0.08 mmol), dissolved in the minimum of methanol, are then placed on the column. After elution with a mixture of THF/N2About 10/90 fractions containing the expected product, freeze, then lyophilizer to obtain the expected sodium salt.

This sodium salt is dissolved in anhydrous dichloromethane (1,04 ml) in nitrogen atmosphere, then cooled to 0°C. Add dropwise a solution of triperoxonane acid/anhydrous dichloromethane 1/1 (2,04 ml). Then the reaction mixture was stirred at ambient temperature for 45 minutes After evaporation to dryness, and then the joint evaporation with anhydrous d is chlormethine compound is dissolved in water (~2 ml), then freeze and lyophilizer to obtain the expected salt (16 mg, 0,030 mmol, 36%) in the form of a pale yellow powder.

MS(ES (-):m/z[M-]=288

1H NMR (400 MHz, Meon-d4): δ (m-1)=3.37-3.69 (m, 4H, N-CH2-CH-N and CH-CH2-NH2), 4.81 (dd, 1H, CH-CH2-NH2), 4.98 (d, 1H, N-CH2-CH-N), 7.79 (s, 1H, H pyrazole).

Example 3: Sodium and trifurcata salt of TRANS 8-(methylaminomethyl)-4,8-dihydro-1-methyl-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-it

Stage A:

TRANS [[[4,5,6,8-tetrahydro-1-methyl-6-oxo-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-methylamino]trimethylphosphine iodide

Molar solution trimethylphosphine (1.5 ml, 1.5 mmol) is added dropwise to a solution of the derivative obtained in stage E of example 1 (0.5 g, 1.25 mmol), in solution in tetrahydrofuran (15 ml) at ambient temperature under nitrogen atmosphere with stirring. After 2 h stirring to the reaction mixture add iodide methane (0.21 g, 3.75 mmol). Quickly formed a light yellow precipitate. After one night of stirring at ambient temperature the reaction mixture was concentrated under reduced pressure. The crude product is triturated in dichloromethane. The precipitate is filtered to obtain the expected product (0,42 g, 1.04 mmol, 84%) in the form of yellowish salt of iodine.

1H NMR (400 MHz, CDCl3) in the form of 2 conformers: δ (m -1)=2.04 (s, 3H),CH3R), 2.32 (s, 3H),CH3R), 2.35 (s, 3H),CH3R), 3.03 (s, 3H, P-NCH3(A)-(CH2), 3.05 (s, 3H, P-NCH3(B)-CH2), 3.37 (m, 1H, N-CH2-CH-N or CH-CH2-N(CH3)P), 3.44 (m, 1H, N-CH2-CH-N or CH-CH2-N(CH3)P), 3.69 (m, 1H, N-CH2-CH-N or SN-CH2-N(CH3)P), 3.82 (s, 3H, CH3), 3.88 (m, 1H, N-CH2-CH-N or CH-CH2-N(CH3)P), 4.05 (d, 1H, N-CH2-CH-N), 4.59 (d, 1H,CH-CH2-N(CH3)P), 4.88 (d, 1H, N-O-CH2-Ph), 5.00 (d, 1H, N-O-CH2-Ph), 7.35 (s, 1H, H pyrazole), 7.37-7.45 (massive, 5H, Ph)

Stage:

TRANS 8-(methylaminomethyl)-4,8-dihydro-1-methyl-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-he

To aqueous solution of sodium carbonate (2,5 N., 9 ml) add the derivative obtained in stage a of example 3, (0,42 g, 1.04 mmol). The reaction mixture was stirred at 55°C for 3 h 30 min After cooling at ambient temperature, the reaction mixture is saturated with sodium chloride in the presence of ethyl acetate (25 ml). The aqueous phase is extracted with ethyl acetate (3×25 ml). The organic phase is dried on magnesium sulfate, then concentrated under reduced pressure to obtain a yellow oil (0.26 g). The crude reaction product is purified by chromatography on silikagelevye column (eluent dichloromethane 100%, then the gradient of methanol from 2% to 10%) to obtain the ones which will be derived (0,084 g, 0,256 mmol, 26%).

MS(ES(+)):m/z[M+H]+=328

1H NMR (400 MHz, CDCl3): δ (m-1)=2.97-3.00 (dd, 1H, N-CH2-CH-N), 3.00 (CHCH2-NCH3), 3.15 (dd, 1H, CH-CH2-NCH3), 3.9 (dd, 1H, N-CH2-CH-N), 3.75 (s, 3H, CH3), 3.98 (d, 1H,CH-CH2-N(CH3)Boc), 4.72 (dd, 1H, N-CH2-CH-N), 4.90 (d, 1H, N-O-CH2-Ph), 5.03 (d, 1H, N-O-CH2-Ph), 7.30 (s, 1H, H pyrazole), 7.34-7.44 (massive, 5H, Ph)

Stage With:

TRANS [[4,5,6,8-tetrahydro-1-methyl-6-oxo-5-(phenylmethoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-methyl-carbamate 1,1-dimethylethyl

The derivative obtained in stage b of example 3 (80 mg, 0,244 mmol)are placed in solution in dichloromethane (1 ml), and then when the ambient temperature is sequentially added triethylamine (60 μl, 0,488 mmol) and di-tert-BUTYLCARBAMATE (106 mg, 0,488 mmol). After 4 h stirring at ambient temperature to the reaction mixture is added a saturated solution of sodium chloride (5 ml). The aqueous phase is extracted with dichloromethane (3×20 ml). The organic phase is dried on magnesium sulfate, then concentrated under reduced pressure to obtain an amorphous white powder (157 mg). The crude reaction product is subjected to chromatography on silikagelevye column (eluent dichloromethane 100%, then the gradient of ethyl acetate from 20% to 30%) to obtain the expected derivative (0,068 g, strength of 0.159 mmol, 60%).

MS(ES(+)): m/z[M+H +=428

1H NMR (400 MHz, CDCl3): δ (m-1)=1.59 (s, 9H, C(CH3)3), 3.05 (s, 3H),CH3NBoc-CH2), 3.10 (m, 3H, N-CH2-CH-N CH-CH2-NBoc), 3.75 (m, 1H, N-CH2-CH-N), 3.85 (s, 3H, CH3), 3.99 (s, 1H, N-CH2-CH-N), 4.75 (m, 1H,CH-CH2-N(CH3)Boc), 4.90 (d, 1H, N-O-CH2-Ph), 5.02 (d, 1H, N-O-CH2-Ph), 7.37 (s, 1H, H pyrazole), 7.40-7.46 (massive, 5H, Ph)

Stage D:

Pyridinium salt of TRANS - [[4,5,6,8-tetrahydro-1-methyl-6-oxo-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-methylcarbamate 1,1-dimethylethyl

After processing as described for stage G of example 1, from the compound obtained in stage With example 3 (0,068 g, strength of 0.159 mmol), in methanol (5 ml) in the presence of 10% palladium on carbon (25 mg) receive dibenzylamine product.

MS(ES(+)): m/z[M+H]+=337

From dibenzylamino intermediate compounds, pyridine (1 ml), pyridine/sulfur trioxide (50 mg, 0,318 mmol) get the expected salt (0,045 g, 0,090 mmol, 100%).

MC(ES ( -): m/z[M-H]-=416

1H NMR (400 MHz, MeOH-d4) in the form of 2 conformers: δ (m-1)=1.53 (s, N, (CH3)3, 3.09 (s, 3H),CH3(A)NHBoc), 3.10 (s, 3H),CH3(C)NHBoc), 3.37 (m, 1H, BocN(CH3)-CH2-CH or N-CH2-CH-N), 3.58 (m, 1H, BocN(CH3)-CH2-CH or N-CH2-CH-N), 3.75 (s, 3H, CH3), 3.84 (m, 1H, BocN(CH3)-CH2-CH and the N- CH2-CH-N), 3.90 (m, 1H, BocN(CH3)-CH2-CH or N-CH2-CH-N), 4.90 (m, 2H, N-CH-CH2-N, N-CH2-CH-N + signal H2O), 7.54 (s, 1H, H pyrazole), 8.16 (dd, 2H, pyridine), 8.70 (dd, 2H, pyridine), 8.94 (d, 1H, pyridine)

Stage E:

Sodium salt of TRANS - [[4,5,6,8-tetrahydro-1-methyl-6-oxo-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-8-yl]methyl]-methylcarbamate 1,1-dimethylethyl

When processed as described for stage N of example 1, from the salt obtained in stage D of example 3 (0,045 g, 0,090 mmol), using a resin DOWEX 50WX8 (30 g) and 2 N. caustic soda (150 ml) receive the expected sodium salt (0,039 g 0,090 mmol, 100%).

MC(ES ( -): m/z[M-H]-=416

1H NMR (400 MHz, MeOH-d4) in the form of 2 conformers: δ (m-1)=1.56 (s, N, (CH3)3), 3.09 (s, 3H),CH3(A)NHBoc), 3.10 (s, 3H),CH3(B)NHBoc), 3.37 (m, 1H, BocN(CH3)-CH2-CH or N-CH2-CH-N), 3.64 (m, 1H, BocN(CH3)-CH2-CH or N-CH2-CH-N), 3.75 (s, 3H),CH3), 3.84 (m, 1H, BocN(CH3)-CH2-CH or N-CH2-CH-N), 3.93 (m, 1H, BocN(CH3)-CH2-CH or N-CH2-CH-N), 4.90 (m, 2H, N-CH-CH2-N, N-CH2-CH-N + signal H2O), 7.55 (s, 1H, H pyrazole).

Stage F:

Sodium and trifurcata salt of TRANS 8-(methylaminomethyl)-4,8-dihydro-1-methyl-5(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e][1,3]diazepin-6(5H)-it

When processing as described on the I stage I of example 1, sodium salt, obtained in stage E of example 3, (0,039 g, 0,088 mmol) in dichloromethane (5 ml) and the mixture triperoxonane acid/anhydrous dichloromethane 1/1 (4 ml) receive the expected product (39 mg, 0.08 mmol, 100%).

MC(ES ( -): m/z[M-H]-=315

1H NMR (400 MHz, DMSO-d6): δ (m-1)=2.76 (s, 3H),CH3NH+2-CH2), 3.30-3.50 (m, 4H, N-CH2-CH-N, NH+2-CH2-CH), 3.75 (s, 3H, CH3), 4.74 (m, 1H, N-CH2-CH-N), 4.82 (d, 1H,CH-CH2-NH+2CH3), 7.43 (s, 1H, H pyrazole), 8.67 (m, 2H, NH3+)

Example 4: a Pharmaceutical composition

Preparing a composition for injection containing:

Connections example 1: 500 mg

Sterile water excipient: enough (D.K.). 5 cm3

PHARMACOLOGICAL study of the PRODUCTS ACCORDING to the INVENTION

Activity in vitro, methods of cultivation in liquid medium:

Prepare a series of tubes, in which is placed an equal amount of sterile nutrient medium in each test tube is placed increasing number of investigational product, then each tube is seeded with a bacterial strain. After 24 hours incubation in an incubator at 37°C, the growth inhibition is assessed through transillumination, which allows to determine the minimum inhibiting concentration (MIC)expressed in µg/ml.

Thus test the products according to the about Examples 1 and 2 and compare them with the products according to Examples 18 and 19 applications WO 02/100860. It turned out that the products according to Examples 1 and 2 very active against Pseudomonas aeruginosa, which is absolutely not true in all cases, the comparative products.

Activity against Pseudomonas aeruginosa (comparison with other examples) {MIC (µg/ml 124 h)Connection Example 1The compound of Example 2The pyrazole amide (PR. 19 PCT application WO 02/100860)The pyrazole ester (PR. 18 PCT application WO 02/100860)
1771 strains of wild-type0,120,25>32>32

Pseudomonas aeruginosa strain, showing the mechanism of resistance (MIC (µg/ml)24 h)Connection Example 1The compound of Example 2ImipenemCeftazidim
1771 strains of wild-type0,120,2511
RA wild type1- 12
Sustainability through β-lactamase [8 strains]1-20.25 to 12-322-32
Resistance0,5-4/-/0,5-10,25-4<=0,03-8
by0,25-0,5
efflux pumps [11/5 strains]
Resistance through mutations Parinov [1 strain]2-162

1. Compounds of General formula (I)

where R1represents the radical (CH2)n-NH2or (CH2)n-Other, where R is a (C1-C6)alkyl and n is 1 or 2;
R2represents a hydrogen atom;
R3and R4together form an aromatic nitrogen-containing 5-membered heterocycle with 1, 2 or 3 ATO the AMI nitrogen, possibly substituted by one or more groups R', where R' is selected from the group consisting of hydrogen atom and alkyl radicals with a number of carbon atoms from 1 to 6;
in free form, in the form of zwitterions and in the form of salts with pharmaceutically acceptable inorganic or organic bases and acids.

2. Compounds according to claim 1, characterized in that R3and R4together form a possibly substituted radical pyrazolyl or triazolyl.

3. Compounds according to claim 1 or 2, characterized in that R1selected from the group consisting of groups (CH2)n-NH2and (CH2)n-NHCH3where n is as defined in claim 1, where the heterocycle formed by R3and R4substituted (C1-C6)alkyl radical.

4. Compounds according to claim 1 or 2, characterized in that R1represents the radical (CH2)n-NH2or (CH2)n-NHCH3where n is as defined in claim 1, and R3and R4form pyrazolidine ring, substituted (C1-C6)alkyl radical.

5. TRANS 8-(aminomethyl)-4,8-dihydro-1-methyl-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e] [1,3]diazepin-6(5H)-he,
TRANS 8-(aminomethyl)-4,8-dihydro-5-(sulfoxy)-4,7-methane-7H-pyrazolo[3,4-e] [1,3]diazepin-6(5H)-he and TRANS 8-(methylaminomethyl)-4,8-dihydro-5-(sulfoxy)-4,7-methane-7H-feast of the olo[3,4-e] [1,3]diazepin-6(5H)-he,
in free form, in the form of zwitterions and in the form of salts with pharmaceutically acceptable inorganic or organic bases and acids.

6. The method of obtaining compounds of formula (I), characterized in that it includes:
a) the stage at which the compound of formula (II) is subjected to interaction with carbonyliron agent, if necessary, in the presence of a base:

where R'1represents a radical CN, protected radical COOH, COOR radicals or (CH2)nR'5,
R'5is a protected radical, the radicals CN, NH2or protected radical other protected radical CO2N, radical CO2R,
n, R, R3and R4are as defined above, where aminoalkyl substituents may present the heterocycle formed by R3and R4when necessary, are protected,
ZH is a protected group NHOH,
obtaining the result of the intermediate compounds of formula (III):

where R'1, R3and R4have the same meanings as above, and either X1represents a hydrogen atom or a protective group and X2represents a group-Z-CO-X3where X3represents the balance Carboniferous agent, or X2the present is the focus of a group-ZH and X 1represents a group CO-X3where X3is as defined above;
b) the stage at which the intermediate compound obtained above is subjected to cyclization in the presence of a base;
and in which:
C) if necessary, stage a) is preceded by and/or stage b) should one or more of the following reactions, in an appropriate order:
- protection of reactive functional groups,
- remove the protection from reactive functional groups,
- esterification,
- saponification,
- sulfation,
- recovery of ester,
- alkylation,
- carbamylcholine,
- education sidegroup,
- restoration of azide to amine,
- formation of salt
ion exchange,
- the division or the Department of diastereoisomers.

7. The method according to claim 6, characterized in that carbonyloxy agent selected from the group consisting of phosgene, diphosgene, triphosgene, aryl-, aralkyl-, alkyl - and alkenylboronic, alkalicarbonate, carbonyldiimidazole and mixtures thereof.

8. The method according to claim 6 or 7, characterized in that the carbonylation reaction is carried out in the presence of amine.

9. The method according to claim 6, characterized in that the compound of formula (II) are obtained, which compound of formula (IV):

where R'1, R3and R4are such as op is Adelino in claim 6, and a represents a hydrogen atom or a group protecting the nitrogen atom, is treated regenerating agent, to obtain the compounds of formula (V):

where A, R'1, R3and R4retain the above values, where, if necessary, the group HE substituted leaving group, to obtain compounds of formula (VI):

where A, R'1, R3and R4retain the above significance, and R9represents a leaving group, which is treated with a compound of the formula Z1H2where Z1is a protected group-HN-OH, and then, if necessary, the agent for removing protection from the corresponding nitrogen atom.

10. The method according to claim 6, characterized in that the compound of formula (II) are obtained by a method where the compound of formula (IV) is treated as described above, with hydroxylamine protection of the hydroxyl group, to obtain compounds of formula (VII):

where A, R'1, R R3and R4are as defined in claim 9, and subjected him to interact with regenerating agent, to obtain the compounds of formula (VIII):

where A, R'1, R3, R4n and ZH are as defined above, which process, if needed the IMO, agent for removing protection from the corresponding nitrogen atom.

11. The use of compounds according to any one of claims 1 to 4, and their salts with pharmaceutically acceptable acids and bases as medicines, which have antibacterial properties.

12. The use of compounds according to claim 5 as medicines, which have antibacterial properties.

13. Pharmaceutical composition having antibacterial properties, containing as active ingredient one medicinal agent according to any one of claims 1 to 4 and 5.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaadamantane derivatives of formula (I), to their pharmaceutically acceptable salts possessing the properties of nAChR ligands, their application, a method of treating and based pharmaceutical compositions, and also to intermediate compounds of formula (VI) and (VII) and to application of the compound of formula (V) for preparing the compound (I). In general formulas

L1 represents -O- or -NRa-; A represents -Ar1 or -Ar2-L2- Ar3; Ar1 represents 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxyalkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2, (NH2)carbonyl and oxido; Ar2 represents 5-6-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxy alkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2 and (NH2) carbonyl; Ar3 represents aryl, optionally substituted alkoxy, alkoxyhalogenalkyl, alkyl, aryl, halogenalkoxy, halogen, hydroxy and -NH2; or Ar3 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, carboxy, carboxyalkyl, halogenalkyl, heterocyclyl and tritylaryl; L2 represents a bond, -O- or -C(O)NRa-; and Ra represents hydrogen.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of nAChR ligands.

41 cl, 11 dwg, 162 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new N-cyclic sulphonamido-compounds and their pharmaceutically acceptable salts of formula : of formula 1a of formula 1b of formula 1c where the ring A means phenyl, thienyl which can be substituted by halogen, or pyridinyl; a value of the ring B is presented in the patent claim, and also a pharmaceutical composition containing them, and a method of treating Alzheimer's disease.

EFFECT: compounds are gamma-secretase inhibitors and can be used for treating Alzheimer's disease.

16 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: medicine, chemical-pharmaceutical industry, chemical technology.

SUBSTANCE: invention relates to using biologically active derivatives of ajmaline possessing anti-arrhythmic effect. Method for synthesis of N4-propylajmalinium salts with carboxylic acids is carried out by neutralization of N4-propylajmalinium hydroxide with equivalent amount of carboxylic acid in homogenous phase. The end substance is isolated by distillation of solvent with the yield of salts 97-99%. Method provides preparing acetate, l-lactate, hydrooxalate, hydromalonate, hydrosuccinate, hydroglutarate, l-hydrotartrate, hydrocitrate, salicylate and p-aminobenzoate. Stable solution of N4-propylajmalinium hydromalonate in water for injection of a medicinal agent comprises sodium metabisulfite as antioxidant, 5-30 mg/ml of N4-propylajmalinium hydromalonate, ascorbic acid as antioxidant taken in the effective amounts. Preferably, stable solution of N4-propylajmalinium hydromalonate comprises 10 mg of N4-propylajmalinium hydromalonate/ml of solution, 0.20 wt.-% of sodium metabisulfite and 0.05 wt.-% of ascorbic acid as measured for solution of N4-propylajmalinium hydromalonate. Invention provides the development stable aqueous compositions of N4-propylajmalinium salts for injection of medicinal agent by selection of antioxidants.

EFFECT: improved preparing method.

7 cl, 5 tbl, 5 ex

FIELD: organic chemistry, chemical technology, virology.

SUBSTANCE: invention relates to a new method for synthesis of a novel compound - 3,6-diazahomoadamantane of the formula: . Compounds of 3,6-diazahomoadamantane class possess an antiviral effect comparable with antiviral effect of aminoadamantane, elicit strychnine-like activity and show bactericidal, fungicide and algicidal properties and can be used as an antiviral preparation. Method for synthesis of 3,6-diazahomoadamantane involves interaction of 1-phenylthio-3,6-diazahomoadamantane-9-one with 65-66% hydrazine hydrate at boiling to form 1-phenylthio-3,6-diazahomoadamantane-9-one hydrazone that is subjected for reduction in Kizhner-Wolf reaction by alloying with alkali and then 1-phenylthio-3,6-diazahomoadamantane is desulfurized with Raney nickel in isopropyl alcohol at boiling.

EFFECT: improved method of synthesis.

2 cl, 1 ex

The invention relates to methods for producing compounds of formula (XVIIb):

where

R1represents optionally protected or modified iminomethylene group, optionally protected or modified hydroxymethylene group; and

R4is-H; or

R1and R4together form a group of the formula (IV), (V), (VI) or (VII):

R5represents-H or-IT;

R7represents-och3and R8is HE, or R7and R8together form a group-O-CH2-O-;

R14aand R14bthey are both-H or one is-H and the other represents-OH, -och3or-och2CH3or R14aand R14btogether form ketogroup; and R15

and derivatives of 21-cyanocobalamine formula (XVIb):

The invention also relates to new compounds:

These compounds possess both antibacterial and antitumor activity

The invention relates to pharmaceutical industry and relates to new compounds of the hydrochloride of N-(-hydroxyethyl)tsitizina formula (I) exhibiting high antiarrhythmic activity and low toxicity

Liquid hardening // 2447114

FIELD: chemistry.

SUBSTANCE: invention relates to curing agents for air-drying alkyd-based resins, coating compositions, such as paint, varnish, wood stain, inks and linoleum floor coverings. Described is a curable liquid medium containing a) from 1 to 90 wt % of an alkyd-based resin and b) from 0.0001 to 0.1 wt % of a siccative in form of an iron or manganese complex with a tetradentate, pentadentate or hexadentate nitrogen donor ligand.

EFFECT: said siccative has high activity and enables hardening of compositions at relatively low concentration in a curable liquid medium.

19 cl, 8 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (III) in form of a free base or an acid addition salt, use thereof as a pharmaceutical agent for preventing, treating and/or inhibiting progression of psychotic and neurodegenerative disorders, as well as pharmaceutical compositions based on said compound.

EFFECT: novel compound which can be used to prevent, treat or inhibit progression of diseases or a pathologic condition in which nAChR α7 activation participates or plays a role.

8 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to new 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazolyl derivatives of formula I or to their pharmaceutically acceptable salts; where Ar represents a phenyl group substituted by methylene dioxy or ethylene dioxy. Also, the invention refers to a pharmaceutical composition exhibiting cholinergic receptor activity on the basis of said compounds.

EFFECT: what is produced are new compounds and based pharmaceutical composition which can be effective for treating various diseases or disorders, such as those associated with the cholinergic system of the central nervous system, peripheral nervous system, diseases or disorders associated with smooth muscle contracture, endocrine diseases or disorders, neurodegenerative diseases or disorders, inflammatory diseases or disorders, pain and withdrawal syndromes caused by addictive chemical withdrawal.

10 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising amides of peridine carboxylic acid of formula (I) , in which W denotes a phenyl ring or a six-member, non-benzocondensed aromatic ring, having one nitrogen atom, where said rings are substituted in the para-position through V; V denotes a bond; -A-(CH2)S- or -A-(CH2)v-B-; A and B independently denote -O-; U denotes mono-, di-, tri- or tetra-substituted aryl, in which substitutes are independently selected from a group consisting of halogen, alkyl and -CF3; Q denotes methylene; M denotes an aryl group, where the said group can be optionally mono- or di-substituted with substitutes independently selected from a group comprising alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4-CH2- and R'2N-(CH2)0-4-CH2-, where R' is independently selected from a group comprising hydrogen, alkyl (optionally substituted with one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)-R", where R" denotes C1-C4-alkyl or -CH2-CF3; R1 denotes cycloalkyl; n equals 0 or 1; s equals 3; v equals 2; and substitutes in the ring, -CON(R1)-Q-M and -W-V-U, are in trans-position relative each other if n equals 1, and where configurations in positions 3 and 4 of the piperidine ring of formula (I) are 3R and 4R, respectively, if n equals 0; and optically pure enantiomers, mixture of enantiomers, such as racemates, diastereomers, mixture of diastereomers, diastereomer racemates, mixture of diastereomer racemates, and mesoforms, as well as to salts of such compounds. Invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having non-peptide rennin inhibiting activity.

12 cl, 27 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes with general formula: The method involves reacting aliphatic aldehyde (acetic, propionic, butyric, valerianic, caproic) saturated with hydrogen sulphide with 1,2-diaminoethane in molar ratio diamine:aldehyde:hydrogen sulphide equal to 1:3:2, at 0°C for 3 hours. 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes can be used as selective sorbents and extraction agents of precious metals, as antibacterial, antiviral, fungicidal and acaricidal agents.

EFFECT: stereoselective synthesis of one conformationally pure 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3,2,1]octane isomer; the method is also distinguished by simplicity of carrying experiments and availability of initial reagents.

1 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a deuterium-enriched α-ketoamide compound of formula wherein: D means a deuterium atom; the values R1-R5 are presented in cl.1 of the patent claim, and to a based pharmaceutical composition.

EFFECT: method improvement.

32 cl, 3 ex

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