Novel substituted tetracyclic derivatives of tetrahydropyran, pyrrolidine and tetrahydrothiophene

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted tetracyclic derivatives of tetrahydropyran, pyrrolidine and tetrahydrothiophene of general formula (I), their pharmaceutically acceptable addition salts, their stereochemically isomeric forms, their N-oxide forms, in which all substitutes are defined in claim 1 of the formula of invention. These compounds have binding affinity to serotonin receptors, particularly 5-HT2A and 5-HT2C receptors, and to dopamine receptors particularly D2 dopamine receptors, and have norepiniphrine reuptake inhibition properties. The invention also relates to a pharmaceutical composition containing said compounds, method of preparing said composition and use of said compounds as medicinal agents, particularly for preventing and/or treating several psychiatric and neurological disorders.

EFFECT: new compounds have useful biological properties.

12 cl, 3 tbl, 49 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to novel substituted tetracyclic derivative tetrahydropyrane, pyrrolidine and tetrahydrothiophene with affiniscape binding towards serotonin receptors, in particular receptors 5-HT2Aand 5-HT2Cand towards dopamine receptors, in particular dopamine receptors D2, and having the properties of inhibiting reuptake of norepinephrine, to pharmaceutical compositions containing the compounds according to the invention, their use as pharmaceuticals, in particular for the prophylaxis and/or treatment of several psychiatric and neurological disorders, in particular some psychotic, cardiovascular and gastrokinetic disorders, and to methods for their preparation.

The LEVEL of TECHNOLOGY

In WO 97/38991, published on 23 October 1997 (Janssen Pharmaceutica N.V.), described substituted tetracyclic derivatives of tetrahydrofuran, which can be used as therapeutic agents for the treatment or prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders. In particular, the compounds exhibit an affinity to the serotonin receptors 5-HT2in particular in relation to the receptors 5-HT2Aand 5-HT2C.

In WO 99/19317, op is blokowanie April 22, 1999 (Janssen Pharmaceutica N.V.), described substituted tetracyclic derivatives of tetrahydrofuran with a specific pattern of substitution of the halogen cycle dibenzoazepina, dibenzoxepin, dibenzothiophene or dibenzosuberane. Connection applicable for the treatment or prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders and show a more rapid onset of action compared with the compounds described in WO 97/38991.

In both applications for the grant of patent WO 03/048146, published June 12, 2003 (Janssen Pharmaceutica N. V.), and WO 03/048147, published June 12, 2003 (Janssen Pharmaceutica N. V.), describes how to obtain each of the 4 diastereomers CIS - TRANS-condensed derivatives of 3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan in stereochemical pure form from a single enantiomerically pure precursor. Compounds showing affinity to the serotonin receptors 5-HT2A, 5-HT2Cand 5-HT7and H1 receptors (pIC50= 7,15-7,89), receptors D2 and/or D3, and with respect to the vector reuptake of norepinephrine (pIC50= 6,01-7,34).

In WO 03/040122, published may 15, 2003 (Janssen Pharmaceutica N.V.), described salts formed almond acid and compounds according to the applications for the grant of patent WO 97/38991 and WO 99/19317. Unexpectedly, it was found that these salts are more stable when raised the Oh temperature and relative humidity, than the compounds described in WO 97/38991 and WO 99/19317.

Description of the INVENTION

The aim of the present invention to provide a new tetracyclic analogues derivatives tetrahydropyran according to the applications for the grant of patent WO 97/38991 and WO 99/19317 that differ from those derived by the fact that they in General are more selective with respect to the carrier reuptake of norepinephrine than the receptors 5-HT2A/5-HT2Cand the receptor dopamine D2with results in compounds which in respect of its antipsychotic properties have a more pronounced anti-depressive effect. The compounds of formula (I)below, in which the nitrogen atom of the base position C-2 is embedded in a cyclic system, have a powerful antagonistic action directed against the receptors 5-HT2A, 5-HT2Cand receptor dopamine D2.

The purpose is achieved through offering new compounds according to formula (I):

their N-oxide form, pharmaceutically acceptable additive salt or a stereochemical isomeric form, where:

the dotted line indicates an optional bond;

i and j denote integers, independently from each other equal to zero, 1, 2, 3 or 4;

A and b each independently from each other mean benzo-, avtogruppa or a radical selected the first group, consisting of furo-and thieno-; pyrrolo-; oxazolo-; thiazolo-; imidazole-; isoxazole-; isothiazole-; oxadiazole-; triazolo-; pyridine-; pyridazino-; pyrimidine-; pyrazino-; indole-; indolizino-; isoindole-; benzofuro-; isobenzofuran-; benzothieno-; indazole-; benzimidazole-; benzthiazole-; chinoline-; chinoline-; skinline-; phthalazine-; heatline-; chynoxaline-; chromeno and naphthyridinone;

each R9independently from each other selected from the group consisting of hydrogen; halogen; ceanography; hydroxy-group; carboxyl; nitro; amino; mono - or di(alkyl)amino; alkylcarboxylic; aminosulfonyl; mono - or di(alkyl)aminosulfonyl; alkyl; alkyloxy; alkylcarboxylic and allyloxycarbonyl;

X represents CR6R7, O, S, S(=O), S(=O)2or NR8;

where R6and R7each independently selected from the group consisting of hydrogen, hydroxy-group, the alkyl and alkyloxy; or

R6and R7taken together may form a radical selected from the group consisting of methylene (=CH2); mono - or di(cyano)methylene; a bivalent radical of formula -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -O(CH2)2O-, -O(CH2)3O-; or together with the carbon atom to which they are bound, may form a carbonyl;

R8in the bran from the group consisting of hydrogen; alkyl; alkylsulphonyl; arylcarbamoyl; arylalkyl; arylalkylamine; alkylsulfonyl; arylsulfonyl and arylalkylamine;

C means a group of formula (c-1), (c-2), (c-3) or (c-4);

where Y1means S; S(=O); S(=O)2or NR10; where R10selected from the group consisting of hydrogen, ceanography, alkyl, alkyloxyalkyl, formyl, alkylcarboxylic, allyloxycarbonyl, allyloxycarbonyl, arylcarbamoyl, arylalkyl, arylalkylamine, alkylsulfonyl, arylsulfonyl and arylalkylamine;

Y2means Y1or O;

R10and R11may together form a bivalent radical (e-1), (e-2) or (e-3);

-CH2-NH-CH2-(e-1)
-CH2-NH-CH2-CH2-(e-2)
-CH2CH2-NH-CH2-(e-3)

each bivalent radical (e-1), (e-2) and (e-3) optionally substituted by one or more substituents selected from the carbonyl group, tocography, alkyl and ancilliary;

R12means hydrogen or alkyl;

R13means hydrogen or alkyl;

R14means hydrogen, hydroxyprop is, oxoprop or a group of formula (d-1);

R11means a group of formula (d-1);

where n means zero, 1, 2, 3, 4, 5 or 6;

R1and R2each independently denote hydrogen; alkyl; alkylaryl; alkyloxyalkyl; alkylcarboxylic; allyloxycarbonyl; arylalkyl; arylcarbamoyl; allyloxycarbonyl; aryloxyalkyl; arylalkylamines; alkylaminocarbonyl; mono - or di(alkyl)aminocarbonyl; mono - or di(aryl)aminocarbonyl; mono - or di(arylalkyl)aminocarbonyl; mono - or di(allyloxycarbonyl)aminocarbonyl; alkylsulfonyl; arylsulfonyl; arylalkylamines; mono - or di(alkyl)aminothiophenol; mono - or di(aryl)aminothiophenol; mono - or di(arylalkyl)aminothiophenol; mono-, di or three(alkyl)amidinopropane; mono-, di -, or three(aryl)amidinopropane and mono-, di -, or three(arylalkyl)amidinopropane; or

R1and R2taken together with the nitrogen atom to which they are bound, may form a radical of formula (a-1), (a-2), (a-3), (a-4), (a-5) or (a-6);

where p is zero, 1, 2, 3 or 4;

q is 1 or 2;

m is zero, 1, 2 or 3;

each R3independently selected from the group consisting of hydrogen; halogen; hydroxy-group; ceanography; alkyl; alkyloxyalkyl; aryloxyalkyl; mono - or di(alkyl)aminol the sludge; hydroxyarylalkyl; allyloxycarbonyl; mono - or di(alkyl)aminocarbonyl; mono - or di(aryl)aminocarbonyl; mono - or di(alkyl)aminocarbonylmethyl; allyloxycarbonyl; arylaminovinylketones; arrangement.absolutely; aryl; alkyloxy; alloctype; alkylcarboxylic; arylcarboxylic; arylalkylamines; alkylsulphonyl; arylcarbamoyl; aryloxyalkyl; hydroxycarbonyl; allyloxycarbonyl; alkylcarboxylic; arylalkylamine; arylcarboxylic; allyloxycarbonyl; aminocarbonylmethyl; mono - or di(arylalkyl)aminocarbonylmethyl; alkylanthraquinones; or two radicals R3together may form a bivalent radical

-CR5R5-CR5R5-O-(b-1)
-O-CR5R5-CR5R5-(b-2)
-O-CR5R5-CR5R5-O-(b-3)
-O-CR5R5-CR5R5-CR5R5-(b-4)
-CR5R 5-CR5R5-CR5R5-O-(b-5)
-O-CR5R5-CR5R5-CR5R5-O-(b-6)
-O-CR5R5-CR5R5-CR5R5-CR5R5-(b-7)
-CR5R5-CR5R5-CR5R5-CR5R5-O-(b-8)
-O-CR5R5-CR5R5-CR5R5-O-(b-9)

where R5selected from the group consisting of hydrogen, halogen, hydroxy-group, alkyloxy and alkyl;

R4selected from the group consisting of hydrogen; alkyl; arylalkyl; alkyloxyalkyl; alkylcarboxylic; allyloxycarbonyl; arylcarbamoyl; alkylsulfonates; aryloxyalkyl; allyloxycarbonyl; alkylsulphonyl; arylalkylamine; alkylaminocarbonyl; arylcarbamoyl; allyloxycarbonyl; aryloxyalkyl; arylalkylamine; mono - or di(alkyl)aminocarbonyl; mono - or di(aryl)aminocarbonyl; mono - or di(arylalkyl)aminocarbonyl; mono - or di(allyloxycarbonyl)aminocarbonyl; alkylaminocarbonyl; mono-, di -, or three(alkyl)amidino the group; mono-, di -, or three(aryl)amidinopropane; mono-, di -, or three(arylalkyl)amidinopropane; alkylsulfonyl; arylalkylamine or arylsulfonyl;

aryl represents phenyl or naphthyl; each radical optionally substituted 1, 2 or 3 substituents selected from the group consisting of halogen, nitro, ceanography, hydroxy-group, alkyloxy or alkyl;

alkyl means a saturated hydrocarbon radical with unbranched or branched chain, having from 1 to 10 carbon atoms, a cyclic saturated hydrocarbon radical having from 3 to 8 carbon atoms or a saturated hydrocarbon radical containing unbranched or branched residue, having from 1 to 10 carbon atoms, and cyclic residue having from 3 to 8 carbon atoms, optionally substituted by one or more radicals: halogen, cyano, exography, hydroxy-group, formyl, carboxyla or amino group; and

halogen means fluorine, chlorine, bromine and iodine.

More specifically the invention relates to a compound according to formula (I), its pharmaceutically acceptable acid or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrug, where each of A and B represents anthropou, optionally substituted with fluorine. Preferably A unsubstituted, and B replacing the Yong fluorine in position 11.

More specifically the invention relates to a compound according to formula (I), its pharmaceutically acceptable acid or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrug, where C denotes a group of formula (c-1) or (c-2); where

Y1means S; S(=O); S(=O)2or NR10; where R10selected from the group consisting of hydrogen, ceanography, alkyl, alkyloxyalkyl, formyl, alkylcarboxylic, allyloxycarbonyl and allyloxycarbonyl;

adjacent R10and R11together may form a bivalent radical (e-1), (e-2) or (e-3);

each radical optionally substituted by one or more substituents selected from the carbonyl group, tocography, alkyl and ancilliary; and

R12means hydrogen.

More specifically the invention relates to a compound according to formula (I), its pharmaceutically acceptable acid or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrug, where C denotes a group of formula (c-3) or (c-4); where

Y2means O;

R12means hydrogen;

R13means hydrogen; and

R14means hydrogen, a hydroxy-group, oxoprop or a group of formula (d-1).

More specifically the invention relates to a compound according to formula (I), its pharmaceutically pickup is acceptable acidic or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrug, where (d-1) is defined as the connection in which:

n is zero or 1;

R1and R2each independently denote hydrogen; alkyl or allyloxycarbonyl; or R1and R2taken together with the nitrogen atom to which they are bound, may form a radical of formula (a-3), (a-5) or (a-6);

where p is zero or 1;

q is 1;

m is 1;

each R3independently selected from the group consisting of hydrogen and hydroxy-group; and

R4means alkyl.

More specifically, the invention relates to a compound according to General formula (I), its pharmaceutically acceptable acid or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrug,

where i and j are integers, independently of one another zero or 1;

A and B each independently from each other mean anthropou, optionally substituted by fluorine;

each R9independently from each other selected from the group consisting of hydrogen and halogen;

X is CH2and O;

C means a group of formula (c-1), (c-2), (c-3) or (c-4);

where Y1means S; S(=O); S(=O)2or NR10; where R10selected from the group consisting of hydrogen, ceanography, alkyl, alkyloxyalkyl, formyl, alkylcarboxylic, alkyloxyaryl the Nile and allyloxycarbonyl;

Y2means O;

adjacent R10and R11together may form a bivalent radical (e-1), (e-2) or (e-3); each radical optionally substituted by one or more substituents selected from the carbonyl group, tocography, alkyl and ancilliary;

R12means hydrogen;

R13means hydrogen;

R14means hydrogen, a hydroxy-group, oxoprop or a group of formula (d-1);

R11means a group of formula (d-1);

where n is zero or 1;

R1and R2each independently denote hydrogen; alkyl or allyloxycarbonyl; or R1and R2taken together with the nitrogen atom to which they are bound, may form a radical of formula (a-3), (a-5) or (a-6);

where p is zero or 1;

q is equal to 1;

m is 1;

each R3independently selected from the group consisting of hydrogen and hydroxy-group; and

R4means alkyl.

Preferably the alkyl is a methyl, ethyl or propyl, optionally substituted by one or more radicals: halogen, cyano, exography, hydroxy-group, formyl, carboxyla or amino group. Preferably alkyl optionally substituted by a hydroxy-group.

Preferably the aryl is a phenyl, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, nor is regroupe, ceanography, hydroxy-group, alkyloxy or alkyl. Preferably the unsubstituted aryl.

Preferably the halogen is a fluorine.

Preferred compounds are also such specific compounds according to the invention, in which the hydrogen atoms on the carbon atoms 3a and 12b are transconfiguration, and compounds having (2α, 3aα, 12bβ) stereochemical configuration.

The most preferred compounds are such compounds according to the invention, which is selected from the group consisting of the compounds defined by the compounds shown in tables 1-4.

Detailed description of the invention

Under this proposal, alkyl defined as a monovalent unbranched or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl and hexyl; alkyl also means a monovalent cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The definition of alkyl includes alkyl radical, which is optionally substituted on one or more carbon atoms by one or more radicals: phenyl, halogen, cyano, exography, guide what actigraphy, the formyl and amino group, such as hydroxyalkyl, in particular hydroxymethyl and hydroxyethyl, and POLYHALOGENATED, in particular deformity and trifluoromethyl.

Within this application the halogen is the common name of fluorine, chlorine, bromine and iodine.

In the framework of this application, the term "compounds according to the invention" means a compound according to General formula (I), its pharmaceutically acceptable acid or basic additive salt, its stereochemical isomeric forms, its N-oxide form and its prodrug.

In the framework of this application element, in particular when referred to in connection with the connection according to the formula (I)includes all isotopes and isotopic mixtures of such element, either naturally occurring or obtained synthetically or dominant in nature, form, or enriched in the isotope form. In particular, in the case when the specified hydrogen, it should be understood that it refers to1H,2H,3H and their mixtures; and if carbon, it should be understood that it refers to11C,12C,13C,14C and their mixtures; if the nitrogen, it should be understood that it refers to13N14N15N and their mixtures; if the oxygen, it should be understood that it refers to14O,15O,16O,17O,18O and their mixtures; and if the fluorine, it should be understood that it otnositsa 18F,19F and their mixtures.

Therefore the compounds according to the invention also include compounds with one or more isotopes of one or more elements and their mixtures, including radioactive compounds, also called radioactively labeled compounds where one or more non-radioactive atoms have been replaced by one of its radioactive isotopes. The term "radio-labeled compound" means any compound according to formula (I), its N-oxide form, its pharmaceutically acceptable additive salt or a stereochemical isomeric form, which contains at least one radioactive atom. For example, the compounds can be in the state of radioactive isotopes that emit positrons or gamma radiation. In the case of methods, the binding of radioactive ligand (analysis of membrane receptors) preferred atom to replace is the atom3H or atom125I. To render the most commonly used positron emitting (PET) radioactive isotopes are11C,18F,15O and13N, which are all produced using accelerators and which have half-lives of 20, 100, 2 and 10 minutes respectively. Because the half-lives of these isotopes are so small, their use is possible only in the institutions, which is s have the accelerator to receive them, which limits their application. The most widely used of them are18F,99mTc201Tl and123I. dealing with such radioactive isotopes, receipt, allocation and inclusion in the molecule are known to the expert.

In particular radioactive atom selected from the group consisting of hydrogen, carbon, nitrogen, sulfur, oxygen, and halogen. Preferably the radioactive atom selected from the group consisting of hydrogen, carbon and halogen.

In particular, a radioactive isotope selected from the group consisting of3H,11C,18F,122I123I125I131I75Br,76Br,77Br and82Br. Preferably a radioactive isotope selected from the group consisting of3H,11C and18F.

In the definition of pharmaceutically acceptable salts are included therapeutically active non-toxic acid-additive form salts, which are able to form compounds according to formula (I). These salts can be obtained by treating the base of the compounds of formula (I) with appropriate acids such as inorganic acids, for example halogen acid, in particular hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, hydroxyoctanoic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, almond acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, econsultancy acid, benzosulfimide acid, para-toluensulfonate acid, reklamowa acid, salicylic acid, para-aminosalicylic acid and pambou acid.

Compounds according to formula (I)containing a proton acid, can also be converted into their therapeutically active non-toxic form of the additive metal salts or amines by treatment with appropriate organic and inorganic bases. Suitable forms salts formed with bases include, for example, ammonium salts, salts of alkaline and alkaline-earth metals, in particular lithium salts, sodium, potassium, magnesium and calcium salts formed with organic bases, for example salt, benzathine, N-methyl-D-glucamine, hydramine, and salts of amino acids such as arginine and lysine.

On the contrary, these forms salts can be converted into a free form by treatment of the appropriate base or acid.

The term additive salt, which is used within the present application also includes a solvate, which is able to form compounds according to the forms of the Le (I), and also their salts. Such solvate represent, for example, hydrates and alcoholate.

Assume that the N-oxide forms of the compounds according to formula (I) include compounds of formula (I)in which one or more atoms of nitrogen oxidized to the so-called N-oxide, particularly those N-oxides in which one or several tertiary nitrogen atoms (for example, radical piperazinil or piperidinyl) N-oxidized. Such N-oxides can be easily obtained by a specialist without the inventor's experience, and they obviously are an alternative to compounds according to formula (I), since such compounds are metabolites that are formed during the oxidation in the body after absorption. It is well known that the oxidation is usually the first stage involved in the metabolism of drugs (Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages 70-75). Also it is well known that the form of the metabolite compounds can also be administered to the person instead of the connection itself almost with the same effect.

Compounds according to the invention have at least 1 oxidizable nitrogen atom (the remainder of the tertiary amines). Therefore, it is highly likely that N-oxides must be formed in the process of metabolism in humans.

The compounds of formula (I) can be converted into the corresponding N-oxide forms, the following well-known in the Noi the field of methods of transformation of trivalent nitrogen into its N-oxide form. This reaction N-oxidation may be carried out by reaction of the parent substance of the formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metals or alkaline-earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as benzonorbornadiene or halogensubstituted benzonorbornadiene, for example 3-chlorobenzalmalononitrile, paracalanidae acid, for example purakayastha acid, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

The term "stereochemical isomeric form," used above, defines all the possible isomeric forms, which may be of the compounds of formula (I). If not specified or not specified, the chemical names of the compounds means a mixture of all possible stereochemical isomeric forms, said mixtures containing all diastereomers and enantiomers main molecule the Noah patterns. More specifically, stereogenic centers may have the R - or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the CIS-or transconfiguration. Compounds containing double bonds, can be of E or Z stereochemistry at the specified double bond. Undoubtedly means that the stereochemical isomeric forms of the compounds of formula (I) are included in the scope of the present invention.

Following the rules of nomenclature CAS, in the case when the molecule contains two stereogenic center is known absolute configuration R or S-descriptor assign (based on the rules of the sequence Kanna-Ingold-Prelog) chiral center having the least number, reference center. Each of R* and S* indicate optically pure stereogenic centers with undetermined absolute configuration. If you use "α" and "β": the position of the highest priority substituent on the asymmetric carbon atom in the cyclic system having the lowest cycle number, arbitrarily is always in the "α-position from the mean plane defined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in compounds according to formula (I)) relative to the position of the highest priority substituent on rap is Pnom atom referred to as "α", if he is on the same side of the mean plane defined by the ring system, or "β", if it is on the other side of the mean plane defined by the ring system.

The numbering of the tetracyclic ring-system present in the compounds of formula (I-a) and (I-b), when A and B indicate anthropou, which is determined by the Chemical Abstracts nomenclature is shown below.

The compounds of formula (I-a) and (I-b) have at least two asymmetric center in the provisions of the carbon atoms 2 and 3. The specified asymmetric center and any other asymmetric center, which can be present (for example in the position of the atom 8 (I-a) or 9 (I-b)), indicated by the descriptors R and S. In the case when, for example, the remainder of monolinolein present in the compounds of formula (I-a) in regulation 8, this balance can be E - or Z-configuration.

The invention also relates to derivatives of compounds (usually referred to as "prodrugs") pharmacologically active compounds according to the invention, which disintegrate in vivo, giving compounds according to the invention. Prodrugs are usually (but not always) have a lower efficiency relative to the receptor target, than the connection to which they disintegrate. Prodrugs are especially applicable in the case when the requested connection has Khimich the ski or physical properties, which makes his introduction difficult or inefficient. For example, the desired compound can be only poorly soluble, it can badly be transported through the epithelium of the mucous membrane, or it may have undesirable short half-life in plasma. Additional discussion of prodrugs can be found in Stella, V.J. et al., "Prodrugs", Drug Delivery Systems, 1985, pp.112-176, and Drugs, 1985, 29, pp.455-473.

Forms of prodrugs of the pharmacologically active compounds according to the invention, typically, will be compounds according to formula (I), its pharmaceutically acceptable acid or basic additive salt, its stereochemical isomeric form and its N-oxide form, having a group of the acid, which etherification or liderovna. Such esterified acid groups include groups of the formula-COORxwhere Rxmeans C1-6-alkyl, phenyl, benzyl or one of the following groups:

Amidarone groups include groups of formula - CONRyRzwhere Rymeans H, C1-6-alkyl, phenyl or benzyl and Rzmeans-OH, H, C1-6-alkyl, phenyl or benzyl. Compounds according to the invention having the amino group, can be derivativea a ketone or aldehyde, such as formaldehyde, with the formation of Mannich bases. This base is either hydrolyzed to the kinetics of the first order in aqueous solution.

The compounds of formula (I), which is produced by the methods described below can be synthesized in the form of racemic mixtures of enantiomers which can be separated from each other is known in this field by the methods of separation. Racemic compounds of the formula (I) can be converted into the appropriate form diastereoisomeric salts as a result of interaction with a suitable chiral acid. These form the diastereomeric salts are then separated, for example, election or by fractional crystallization, and the enantiomers release with alkali. An alternative method of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction occurs stereospetsifichno. Preferably, if you want a specific stereoisomer, this connection can be synthesized stereospecifically methods of getting. These methods are mainly used enantiomerically pure source materials.

Pharmacology

Compounds according to the present invention show affinity to receptora-HT 2in particular in relation to the receptors 5-HT2Aand 5-HT2C(the item matches the description in D.Hoyer "Serotonin (5-HT) in neurologic and psychiatric disorders" edited by M.D.Ferrari and published in 1994 Boerhaave Commission of the University of Leiden), and the affinity to the D2 receptor and the activity, inhibitory reuptake of norepinephrine. Antagonistic towards serotonin properties proposed in the invention compounds can be demonstrated by their inhibitory action in the test for 5-hydroxy-tryptophane in rats, which is described in Drug Dev. Res., 13, 237-244 (1988).

Because of the ability to block receptors 5-HT2and , in particular, to block the receptors 5-HT2Aand 5-HT2Cand the D2 receptor and activity, inhibiting the reuptake of norepinephrine, the compounds according to the invention is applicable as a medicine, in particular for prophylactic and therapeutic treatment of conditions mediated by any of these receptors.

Therefore, the invention relates to a compound according to General formula (I), its pharmaceutically acceptable acid or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrug for use as a medicine.

The invention also relates to the use of compounds according about the her the formula (I), its pharmaceutically acceptable acid or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrugs for the production of pharmaceuticals for the treatment or prophylactic or therapeutic or both, States, mediated by receptors 5-HT2and receptor D2and inhibition of reuptake of norepinephrine.

Due to these pharmacological and physico-chemical properties of the compounds of formula (I) are applicable as therapeutic agents in the treatment or prevention of disorders of the Central nervous system, like anxiety, depression and mild depression, bipolar disorders, sleep disorders and sexual disorders, psychosis, borderline psychosis, schizophrenia, migraine, personality disorders or obsessive-compulsive disorders, social phobias or acute anxiety with panic reaction, organic mental disorders, mental disorders in children such as ADHD, aggression, memory disorders, and disorders of the sense of body position in space in the elderly, drug abuse, obesity, bulimia nervosa and related disorders. In particular, proposed in the invention compounds can be used as anxiolytics, antidepressants, antipsychotics, etc is depositfilescom funds anti-migraine and as a means to remove the addiction to narcotic drugs.

The compounds of formula (I) can also be used as therapeutic agents for the treatment of motor disorders. It may be preferable to use proposed in the present invention compounds in combination with classical in the case of such disorders therapeutic means.

The compounds of formula (I) can also be used for treatment or prevention of damage to the nervous system caused by trauma, stroke, neurodegenerative diseases, and the like; cardiovascular disorders like high blood pressure, thrombosis, stroke, and the like; and gastrointestinal disorders such dysfunction motility of the gastrointestinal system, and the like.

Due to the above applications of the compounds of formula (I), it follows that the present invention also relates to a method of treating warm-blooded animals suffering from such diseases, while this method involves the systematic introduction of a therapeutic amount of the compounds of formula (I), effective in the treatment of the above disorders, in particular in the treatment of anxiety, psychosis, depression, migraines and addiction to narcotic drugs.

So the m way the present invention also relates to compounds of formula (I)defined above for use as a medicine, in particular the compounds of formula (I) can be used for the manufacture of a medicinal product for the treatment of anxiety, psychosis, depression, migraines and addiction to narcotic drugs.

Specialists in the treatment of such diseases can define an effective therapeutic daily amount based on the test results below. Effective therapeutic daily amount may be from about 0.01 mg/kg to about 10 mg/kg body weight, more preferably from about 0.05 mg/kg to about 1 mg/kg of body weight.

The invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of the compounds according to the invention, in particular compounds according to formula (I), its pharmaceutically acceptable acid or basic additive salts, its stereochemical isomeric forms, its N-oxide form and its prodrugs.

Compounds according to the invention, in particular compounds according to formula (I), their pharmaceutically acceptable acidic or basic additive salts, their stereochemical Isom rnie form, their N-oxide forms and their prodrugs, or any subset or combination can be prepared in various pharmaceutical forms for administration. As appropriate compositions can be listed all the songs, usually used in the case of systemically injected drugs. To prepare the pharmaceutical compositions according to the present invention, an effective amount of a particular compound, optionally in the form of a salt additive, as an active ingredient together in the form of a homogeneous mixture with a pharmaceutically acceptable carrier, and this carrier can have a wide variety of forms depending on the form of preparation desired for administration. Preferably, these pharmaceutical compositions had the standard dosage form that is suitable in particular for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. For example, upon receipt of a composition in oral dosage form, you can use any of the usual pharmaceutical environment, such as water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, thinners, moving substances is a, binder dezintegriruetsja tools and the like, in the case of powders, pills, capsules and tablets. Due to the simplicity of the introduction of tablets and capsules represent the most preferred oral dosage forms, and in this case, you typically use solid pharmaceutical carriers. In the case of parenteral compositions, the carrier will usually contain sterile water, at least mostly, although there may be included other ingredients such as Pro-solubility. For example, can be prepared injectable solutions, in which the medium contains a salt solution, a glucose solution or a mixture solution of salt and glucose. Can also be prepared injectable suspension, in which case can be used suitable liquid carriers, suspendresume agents and the like. Also included preparations in solid form, which are designed to turn immediately before use in the preparations in liquid form. In the compositions suitable for percutaneous administration, the carrier optionally contains a means of enhancing the permeability and/or a suitable moisturizer, optionally together with suitable additives of any nature in minor proportions, such additives do not have a significant harmful impact on the skin is. These supplements can facilitate the introduction into the skin and/or may be useful for the preparation of the desired composition. Such compositions can be introduced in various ways, for example in the form of a transdermal patch, in the form of locally applied patches, in the form of ointment. Especially preferably the preparation of the above pharmaceutical compositions in a dosage form for ease of administration and uniformity of dosage. Dosage form used in this sense refers to physically discrete units suitable as single doses, each unit contains a pre-determined quantity of active ingredient calculated to obtain the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including tablets scored or coated membranes tablets), capsules, pills, sachet powders, pills, suppositories, injectable solutions or suspensions and the like, and groups consisting of many separate these forms.

Since the compounds according to the invention are effective when administered orally compounds, especially preferred pharmaceutical compositions containing these compounds, the La introduction oral.

In order to improve the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions preferably it is possible to use α-, β - or γ-cyclodextrins or their derivatives, in particular substituted by hydroxyalkyl cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin. Also characterial, such as alcohols, can improve the solubility and/or stability of the compounds according to the invention in pharmaceutical compositions.

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Suitable schemes for preparing compounds according to the invention are described below.

The text uses the following abbreviations:

APCIchemical ionization at atmospheric pressure
AcOHacetic acid
AcSHteoksessa acid
Bun-butyl
Boctert-butyloxycarbonyl
Cbz-4-carboxybenzoyl (for example CBzCl)
Celite®diatomaceous earth from Celite Corporation
CI chemical ionization
CSAcamphorsulfonic acid
DBU1,8-diazabicyclo[5,4,0]undec-7-EN
DIADdiisopropylperoxydicarbonate
DMAP4-dimethylaminopyridine
DMFN,N-dimethylformamide
DOWEX®the ion-exchange resin from the DOW chemical company
DPPAdiphenylphosphoryl
EEDQ2 ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline
EIelectronic ionization
Etethyl
Et3Nthe triethylamine
EtOHethanol
Et2Odiethyl ether
EtOActhe ethyl acetate
HFIPhexafluoropropan the l
i-Disopropanol
IPy2BF4tetrafluoroborate bis(pyridine)iodone
t-BuOKpotassium salt of 2-methyl-2-propanol
mCPBAmeta-chloroperoxybenzoic acid
Memethyl
MeOHmethanol
Msmesyl (for example MsCl)
PCCchlorproma pyridinium
PNBz4-nitrobenzoyl
P(Ph)3triphenylphosphine
TFUtriperoxonane acid
THFtetrahydrofuran
THPtetrahydropyranyl
Trtrail (i.e. triphenylmethyl) (for example TrCl)
TsCltosyl (i.e. 4-toluensulfonyl)chlorite is

The following scheme of reactions A-D illustrate the formation of compounds of formula (I), in which C denotes a group of formula (c-1), where Y1means NH, and R11means a group of formula (d-1)represented by the formulas Ia and Ib below:

Ia: 2R,3aR,xS, where x means 12b, if A and B are anthropoi;

Ib: 2S,3aR,xS, where x means 12b, if A and B are anthropoi.

Method A: preparation of derivatives of pyrrolidine

Scheme A1: Synthesis of (2R,3aR,12bS)-intermediates.

Stage a): treatment of an intermediate compound 1 ketal-protected (S)-glyceraldehyde (protected, for example, Me), Lewis acid, such as magnesium halide, in particular magnesium bromide, and such as t-BuOK as a basic catalyst in an inert towards the reaction solvent, such as toluene or THF, for example at room temperature;

Stage b): hydrogenation of an intermediate compound 2, using as a catalyst of palladium on coal (1 ATM) in an inert towards the reaction, a solvent such as i-D, in the presence of a base such as a tertiary amine, in particular Et3N, for example at room temperature for about 4 hours;

Stage c): recovery of intermediate compound 3, for example, alkali metal borohydride, such ka is borohydride sodium, in phosphate buffer at a maximum pH 7, preferably at slightly acidic pH) and inert to the reaction solvent, such as i-D, or EtOH, for example at 0°C for 15 min with the formation of intermediate compound 4 in the CIS-configuration;

Stage d): the reaction of nucleophilic substitution of intermediate compound 4 with DPPA in the presence of a base, such as DIAD/P(Ph)3or DBU, in an inert towards the reaction solvent, such as THF, for example at a temperature of from about -15°C to room temperature for about 24 hours;

Stage e): remove the protection of the intermediate 5 using acid such as hydrochloric acid, in an inert towards the reaction solvent, such as THF, for example at room temperature for about 16 hours;

Stage f): trailerhouse intermediate compound 6 using Tr-halide, in particular TrCl or TrBr, and a catalyst, such as DMAP, in the presence of a base such as Et3N, inert to the reaction, a solvent such as CH2Cl2for example at room temperature for about 24 hours;

Stage g): treatment of an intermediate compound 7a MsCl or Ms-anhydride in the presence of a base such as Et3N, inert to the reaction, a solvent such as CH2Cl2e.g. the measures at a temperature of approximately -40°C to room temperature for about 4 hours;

Stage h): datetimerange intermediate compound 7b with the use of strong acids in non-aqueous environment, such as Amberlyst-15 (macromycetes from sulphonated polystyrene), in an inert towards the reaction solvent, such as methanol, for example at about 45°C for about 2-3 hours;

Stage i): treatment of an intermediate compound 8 base, such as K2CO3in inert towards the reaction, a solvent such as MeOH or EtOH, for example at room temperature for about 2 hours;

Stage j): hydrogenation of an intermediate compound (9) by using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, in the presence of a base such as Et3N, for example at room temperature for about 3 hours. The resulting intermediate compound 10 can be used as the starting material, as described in scheme A3.

Scheme 2: Synthesis of (2S,3aR,12bS)-intermediate and final compounds.

Stage a): totalrevenue intermediate compound 6 using TsCl in the presence of a base such as Et3N, and a catalyst, such as Bu2SnO, inert to the reaction, a solvent such as CH2Cl2for example at room temperature in ECENA about 16 hours;

Stage b): treatment of an intermediate compound (11 base, such as K2CO3in inert to the reaction solvent, such as MeOH, for example at room temperature for about 10 minutes.

Stage c): hydrogenation of an intermediate compound 12 using a catalyst of palladium on coal (1 ATM), in an inert towards the reaction solvent, such as MeOH, for example at room temperature for about 16 hours. The resulting compound 13 can be used as the starting material, as described in scheme A3.

Stage d): nucleophilic substitution of the intermediate 11 or 12 using alkali metal azide such as sodium azide, in an inert towards the reaction solvent, such as DMF, for example at a temperature of about 90°C;

Stage e): metilirovanie intermediate compound 14 MsCl and optional DMAP, using a tertiary amine base such as Et3N, inert to the reaction, a solvent such as CH2Cl2for example at a temperature of approximately -40°C to room temperature for about 4 hours;

Stage f): hydrogenation of an intermediate compound 15 using a catalyst of palladium on coal (1 ATM) in the presence of a base such as Et3N, inert with respect to the eacli solvent, such as MeOH, for example at room temperature for about 3 hours leads to the final compound of formula (I-b1), i.e. the compound of formula (I-b), in which both radicals R1and R2are hydrogen.

Stage g): inversion Mitsunobu intermediate 14 using DIAD/P(Ph)3and CbzOH in THF at a temperature from about 0°C to room temperature for about 2 hours;

Stage h) hydrolysis of the intermediate 14a using, for example, K2CO3in methanol.

Scheme A3: Synthesis of (2R,3aR,12bS)- and (2S,3aR,12bS)-end connections

Stage a) treatment of intermediate compound 10 or 13 CbzCl aqueous solution of base, such as K2CO3in inert to the reaction solvent, such as THF, for example at room temperature for 15 minutes.

Stage b): Method 1: oxidation of the intermediate compound 17 PCC; then reductive amination HNR1R2using a reducing agent such as NaBH4; or method 2: metilirovanie intermediate compound 17 MsCl and DMAP in the presence of a base such as Et3N, inert to the reaction, a solvent such as CH2Cl2; then nucleophilic substitution using excess HNR1R2not necessarily in the presence of bases of the tion, such as the K2CO3;

Stage c) removing the protective group Cbz by hydrogenation of the intermediate 18 using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, in the presence of a base such as Et3N, for example at room temperature for about 3 hours.

Intermediate compound 10 leads to the final compound of formula (Ia); intermediate compound 13 leads to the final compound of formula (Ib).

The following examples B-D represent alternative ways of obtaining the final compounds of formulas Ia and Ib:

Method B: Synthesis of (2R,3aR,12bS)- and (2S,3aR,12bS)-end connections

Stage a): hydrogenation of an intermediate compound 14 or 14b using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, in the presence of a base such as Et3N, for example at room temperature for about 3 hours;

Stage b): treatment of an intermediate compound 19 CbzCl, a base, such as K2CO3in inert towards the reaction mixture of solvents, such as THF-H2O;

Stage c): metilirovanie intermediate compound 20 MsCl and DMAP in the presence of a base such as Et3N, inert in relation to the structure to the reaction solvent, such as CH2Cl2for example at room temperature for about 16 hours;

Stage d): treatment of an intermediate compound 21 base, such as t-BuOK, in an inert towards the reaction of a polar aprotic solvent such as THF;

Stage e): hydrogenation of an intermediate compound 22 using a catalyst of palladium on coal (1 ATM), in an inert towards the reaction solvent, such as MeOH, for example at room temperature for about 3 hours;

Stage f) processing the final compounds Ia1 (with 2R(bottom)-configuration) aldehyde, such as formaldehyde, or ketone in an alcohol solvent in the presence of AcOH and reductant, such as hydrogen/palladium on coal or NaCNBH3leads to trehzameshchenny end connection Ia2.

Method C: Synthesis of (2RS,3aR*,12bS*)-end connections

Stage a): allilirovanie intermediate compound 1 base, such as NaH, and allylbromide in an inert towards the reaction solvent, such as THF, for example at a temperature of about 65°C for about 2-3 hours;

Stage b): recovery of intermediate compound 23 a reducing agent such as NaBH4(in phosphate buffer at pH 7), in an inert towards the reaction, a solvent such as i-D, for example at room temperature the e leads to the intermediate connection 24, containing enantiomeric mixture of 24a and 24b in the configuration with both substituents either in the upper or in the lower position;

Stage c): treatment of an intermediate compound 24 DPPA, DIAD/P(Ph)3in an inert towards the reaction solvent, such as THF, for example at a temperature of from about -15°C to room temperature for about 24 hours;

Stage d): recovery of intermediate compound 25 reducing agent, most preferably LiAlH4in inert to the reaction solvent, such as THF, for example at a temperature from about 0°C to room temperature;

Stage e): protection of intermediate compound 26 Boc2O using aqueous base, such as K2CO3in inert to the reaction solvent, such as THF, for example at room temperature;

Stage f): cyclization of an intermediate compound 27 under the action of iodine using IPy2BF4in an inert towards the reaction, a solvent such as CH2Cl2for example at room temperature;

Stage g): amination of the intermediate connection 28 with the use of excess HNR1R2in aqueous THF at about 135°C in the pressure vessel (for example in a steel tank) for about 3-6 hours; or an alternative such as using HNMe2 in anhydrous THF and calcium oxide to remove a group to delete.

Stage h): remove protection using acids, such as HBr in AcOH or HCl in MeOH, for about 1-2 hours at a temperature of education phlegmy or at room temperature.

Method D: Synthesis of (2RS,3aR,12bS)-end connections

Stage a): reaction Mitsunobu intermediate compound 10 or 13 with DIAD/P(Ph)3in an inert towards the reaction solvent, such as THF, for example at a temperature of from about -15°C to room temperature for about 24 hours;

Stage b): indirect attributively disclosure cycle of aziridine intermediate connection 29 with the subsequent interaction in situ with a suitable amine HNR1R2in boiling acetonitrile. Intermediate compound 10 leads to the final compound of formula Ia; interim connection 13 leads to the final compound of formula Ib.

Method E: preparation of derivatives of pyrrolopyrazole

The following reaction scheme illustrates the formation of compounds of formula (I)in which C is a group of formula (c-1), in which R11and R10form a condensed imidazole residue represented by the following formula II.

(II)

Scheme E

Stage a: the hydrogenation of the final compound I-b1 (with 2S(top)-configuration) using a catalyst of palladium on coal (1 ATM) and formaldehyde in an inert towards the reaction solvent, such as MeOH, for example at room temperature for about 3 hours to obtain the final compound 30;

Stage b): treatment of end connection 30 NaCNBH3/TFU in a solvent such as MeOH, to obtain the final compound 31;

Stage c): processing final compound I-a1 I-b1 (having respectively 2R (bottom)or 2S (top)-configuration) CS2in an inert towards the reaction solvent, such as DMF, for example at a temperature of about 50-60°C for about 30 minutes which results in final compounds 32;

Stage d): alkylation end connection 32, for example, alkylhalogenide in an inert towards the reaction, a solvent such as MeOH or Et3N, for example by boiling under reflux to obtain the final compound (II).

Method F: preparation of derivatives pyrrolopyrazine

The following scheme of reactions illustrate the formation of compounds of formula (I), in which C denotes a group of formula (c-1), in which R11and R10form a condensed balance piperazine represented by formula III below, where Rxmeans hydrogen or alkyl and the cycle piperazine has the S-configuration (scheme F1) or R-configuration (scheme F2):

Scheme F1

Stage a): education is minale of end connections Ib1 using acetone in an inert towards the reaction solvent, such as MeOH, for example at a temperature of about 60°C for about 4 hours;

Stage b): TRANS-aminelicia and reductive amination of the final connection 33 with a suitable aldehyde or ketone such as formaldehyde, and hydrogenation using a catalyst of palladium on coal (1 ATM);

Stage c): protection of end connections 33 CbzCl using a base, such as K2CO3in inert towards the reaction mixture of solvents, such as THF-H2O;

Stage d): hydrolysis of the intermediate 35 acid, such as hydrochloric acid, in aqueous THF, for example at room temperature for about 12 hours;

Stage e): acylation of the intermediate 36 halide acids, in particular BrC(=O)CH2Br, EtAc in the presence of aqueous sodium hydroxide;

Stage f): intramolecular cyclization of an intermediate compound 37 using a base, such as K2CO3in inert to the reaction solvent, such as DMF;

Stage g): removal of Cbz-balance the hydrogenation of an intermediate compound 38 using a catalyst of palladium on coal (1 ATM) and processing of in-situ aldehyde or ketone such as formaldehyde, in an inert towards the reaction solvent, such as MeOH, for example at room temperature for when is Erno 3 hours;

Scheme F2

Stage a): trailerhouse intermediate compounds Ia1 such as Fritillaria and DMAP usually in the presence of a base such as Et3N and is inert towards the reaction, a solvent such as CH2Cl2for example at room temperature for about 2 hours;

Stage b): interaction of intermediate 33a with BrCH2COBr in the presence of a base such as sodium bicarbonate, in an inert towards the reaction, a solvent such as CH2Cl2;

Stage c): interaction of intermediate compounds 34a with formic acid for about 3 hours and then with EEDQ in an inert towards the reaction solvent, such as CHCl3for example at room temperature for 30 minutes.

Stage d): cyclization of an intermediate compound 35a by using a base such as t-BuOK, in an inert towards the reaction, a solvent such as THF;

Stage e): remove the aldehyde groups of the intermediate compound 36a, for example by treatment with an acid, such as 2 M hydrochloric acid in methanol;

Stage f): reductive amination of the final compounds IIIb1 appropriate aldehyde or ketone and hydrogenation using a catalyst of palladium on coal (1 ATM).

Method G: Getting 8,8-C is displaced derived pyrrolidine

The following reaction scheme G illustrates the formation of compounds of formula (I), in which C denotes a group of formula (c-1), and X means a group of CR6R7different from the group of hydrogen, represented by the following formulas IV-VI.

Scheme G

Stage a): treatment of an intermediate compound 10 or 13 Boc2O and a base, such as aqueous KOH or NaOH, in a solvent such as THF or dioxane, for example at room temperature for about 6 hours;

Stage b): treatment of an intermediate compound 39 DIAD/P(Ph)3in a solvent such as THF, for example at a temperature of from about -15°C to room temperature;

Stage c): oxidation of intermediate 40 using KMnO4in the presence of a catalyst phase transfer, such as n-Bu4NHSO4in the solvent system, such as CH2Cl2-H2O, for example at room temperature for about 16 hours;

Stage d): hydrogenation of an intermediate connection 41 with the use of a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, for example at room temperature, followed by treatment of the aldehyde or ketone such as formaldehyde, in the presence of AcOH with the formation of intermediate soy is inane, in which each of R1and R2means alkyl;

Stage e) processing the intermediate connection 42 of 50%sulfuric acid in dioxane, for example at room temperature for 3 hours to remove the Boc protective group with formation of the final compound 42a;

Stage f): the target compound 42a is subjected to interaction in the Grignard reaction with bromide Metalmania in a solvent such as THF, for example at room temperature with formation of the final compound 43;

Stage g): treatment of end connections 43 sulphonylchloride and pyridine, for example at room temperature for 16 hours with the formation of the final compound 44;

Stage h): hydrogenation end connection 44 with the use of a catalyst of palladium on coal (1 ATM) in a solvent such as MeOH, for example at room temperature with formation of the final compound 45.

Method H: Obtaining 3-substituted derivatives of pyrrolidine

The following reaction scheme H illustrates the formation of compounds of formula (I), in which C denotes a group of formula (c-3), Y1means NH, and R11means a group of formula (d-1)represented by the following formula VII.

Scheme H

Stage a): oxidative cleavage of intermediate compound 6 with use the of NaIO 4in phosphate buffer (pH 7) in an inert towards the reaction solvent, such as THF, for example at a temperature from about 0°C to room temperature for about 4 hours;

Stage b): treatment of an intermediate compound 46 CH2(NMe2I and optional in AcOH inert to the reaction solvent, such as THF, for example at room temperature for about 3 hours;

Stage c): (i) intramolecular cyclization of an intermediate compound 47 associated with the polymer P(Ph)3in an inert towards the reaction solvent, such as THF, containing traces of water, for example at a temperature of about 40°C for about 1 hour; followed by (ii) recovering the resulting intermediate compound with the use of NaCNBH3and AcOH in an inert towards the reaction solvent, such as alcohol, in particular MeOH, for example at room temperature for about 3 hours;

Stage d): (i) processing the intermediate 48 ClCO2Me and aqueous sodium hydrogen in an inert towards the reaction, a solvent such as CH2Cl2; (ii) followed by treatment of the resulting intermediate compound NaBH4BF3Et2O in an inert towards the reaction solvent, such as THF, for example at room temperature in t is an increase of about 24 hours; and (iii) subsequent treatment of the resulting intermediate compound H2O2and aqueous KOH, for example at room temperature for about 3 hours;

Stage e): treatment of an intermediate compound 49 DIAD/P(Ph)3and DPPA in an inert towards the reaction solvent, such as THF, for example at a temperature of from about -15°C to room temperature;

Stage f): (i) intermediate connection 50 is subjected to the reaction of Staudinger or hydrogenation using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, for example at room temperature; and then (ii) carry out rehabilitation amination of an aldehyde or ketone such as formaldehyde.

Method I: Getting tetrahydrofuran-3-substituted derivatives

The following reaction scheme I illustrates the formation of compounds of formula (I), in which C denotes a group of formula (c-3), Y2means O and R11means a group of formula (d-1)represented by the following formula VIII.

Scheme I

Stage a): protection of the alcohol function of the intermediate 4 using DIAD/P(Ph)3and 4-nitrobenzoic acid (PNBzOH) in an inert towards the reaction solvent, such as THF, for example, when temperature is round about -15°C to room temperature for a suitable period of time, for example about 15 hours;

Stage b): treatment of an intermediate compound 51 hydrochloric acid in THF (for example in the form of a mixture of 1:1 using 1 n hydrochloric acid) for example at room temperature for about 5 hours;

Stage c): treatment of an intermediate compound 52 NaIO4at pH 7, using a phosphate buffer in an inert towards the reaction solvent, such as THF, for example at a temperature from about 0°C to room temperature for about 4 hours;

Stage d): treatment of an intermediate compound 53 CH2(NMe2I and AcOH in an inert towards the reaction solvent, such as THF, for example at room temperature for about 3 hours;

Stage e): restore the intermediate 54 in such a reducing agent as borohydride sodium, in an inert towards the reaction solvent, such as methanol, EtOH or i-D, for example at room temperature for about 4 hours;

Stage f): treatment of an intermediate compound 55a with sodium methoxide in an inert towards the reaction solvent, such as methanol, for example at room temperature for about 4 hours;

Stage g): treatment of an intermediate compound 55b mixture DIAD/tributylphosphine in an inert towards the reaction solvent, such as toluene, e.g. is at room temperature for about 3 hours;

Stage h): (i) hydroporinae intermediate connection 56 with sodium borohydride and BF3-Et2O in an inert towards the reaction solvent, such as THF, for example at room temperature for about 24 hours; and (ii) the processing of H2O2, an aqueous solution of sodium hydroxide in an inert towards the reaction solvent, such as THF, for example at room temperature for about 4 hours;

Stage i): treatment of an intermediate compound 57 DIAD/P(Ph)3, DPPA in an inert towards the reaction solvent, such as THF, for example at a temperature of from about -15°C to room temperature for about 15 hours;

Stage j): (i) intermediate connection 58 is subjected to the reaction of Staudinger or hydrogenation using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, for example at room temperature for about 1.5 hours; and (ii) reductive amination of an aldehyde or ketone such as formaldehyde in water AcOH and methanol.

Method J: Obtaining 3-substituted derivatives tetrahydropyran

The following reaction scheme J illustrates the formation of compounds of formula (I), in which C denotes a group of formula (c-2), Y2means O and R11means a group of formula (d-1)represented by the above neutrally IX. The connection can be either CIS- (figure J1), or transcontinenta (figure J2) with respect to oxygen.

Diagram J1 (CIS)

Stage a): monocotyledonae intermediate compound 52a (obtained similarly to the intermediate connection 52) TsCl, Et3N and Bu2SnO, for example at room temperature for about 16 hours in an inert towards the reaction solvent, such as toluene or CH2Cl2;

Stage b): treatment of an intermediate compound 59 DHP and CSA in an inert towards the reaction, a solvent such as CH2Cl2for example at room temperature for about 3 hours;

Stage c): deacetylation of the intermediate 60 base, such as K2CO3in inert to the reaction solvent, such as MeOH, for example at room temperature for about 3 hours with subsequent intramolecular cyclization using NaH in an inert towards the reaction solvent, such as THF, for example at a temperature from about 0°C to room temperature for about 4 hours;

Stage d): remove the protection of intermediate 61 by using Dowex in an inert towards the reaction, a solvent such as MeOH/H2O, for example at room t is mperature for about 2 hours;

Stage e): metilirovanie intermediate 62 MsCl, DMAP and Et3N inert to the reaction, a solvent such as CH2Cl2for example at room temperature for about 4 hours;

Stage f): treatment of an intermediate compound 63 NaN3in an inert towards the reaction solvent, such as DMF, for example at a temperature of about 90°C for about 2 hours;

Stage g): hydrogenation of an intermediate compound 64 using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction mixture of solvents, such as i-D/THF, for example at room temperature for about 3 hours;

Stage h): hydrogenation of an intermediate compound 65 using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction mixture of solvents, such as i-D/THF, and reductive amination of the aldehyde or ketone;

Stage i: the oxidation of the intermediate connection 62 with the use of the catalyst PCC in an inert towards the reaction, a solvent such as CH2Cl2for example at room temperature for about 24 hours;

Stage j): reductive amination of the intermediate connection 66 with a suitable R1R2NH-compound and hydrogenation using a catalyst of palladium on coal (1 ATM) in the Pris is under the base, such as Et3N, inert to the reaction solvent, such as MeOH, for example at room temperature for approximately 24 hours.

Scheme J2 (trance)

The reaction scheme for the J1 can also be applied to Transaero intermediate connection 52, causing transcontinential (IX) and (X).

Method K: obtain a 4-substituted derivatives tetrahydropyran

The following reaction scheme K illustrates the formation of compounds of formula (I), in which C denotes a group of formula (c-2), Y2means O, and R11means a group of formula (d-1)represented by the following formula X.

Scheme K

Stage a): treatment of an intermediate compound 67 3-pentanone and CSA, for example, at a temperature of about 50°C for about 16 hours;

Stage b): treatment of an intermediate compound 68 PCC in an inert towards the reaction, a solvent such as CH2Cl2with the use of molecular sieves (4A), for example, at a temperature from about 0°C to room temperature for approximately 75 minutes.

Stage c): interaction of intermediate 1 with intermediate connection 69, MgBr2using as catalyst t-BuOK in an inert towards the reaction solvent, Taconic PhMe/THF, for example at room temperature for about 23 hours; the above reaction must be carried out in the absence of oxygen, preferably in an argon atmosphere;

Stage d): hydrogenation of an intermediate compound 71 with hydrogen over a catalyst of palladium on coal (10%) in an inert towards the reaction solvent, such as Et3N, j-D or toluene or a mixture, for example at room temperature for about 15 hours;

Stage e): recovery of intermediate compound 72 in such a reducing agent as borohydride sodium in phosphate buffer at pH 7 in an inert towards the reaction, a solvent such as i-D, for example at a temperature from about 0°C to room temperature for about 1 hour;

Stage f): treatment of an intermediate compound 73a DIAD/P(Ph)3, 4-nitrobenzoic acid (PNBzOH) in an inert towards the reaction solvent, such as THF, for example at a temperature of from about -15°C to room temperature for about 15 hours;

Stage g): treatment of an intermediate compound 73b hydrochloric acid (1 m) in THF (1:1), for example, at room temperature for about 5 hours;

Stage h): totalrevenue intermediate compound 73c TsCl, Et3N, dibutil(oxo)tin (Bu2SnO) in an inert towards the reaction, a solvent such as CH2Cl2, for example at room temperature for about 12 hours;

Stage i: the cyclization of the intermediate 73d using sodium methoxide in an inert towards the reaction solvent, such as methanol, for example at room temperature for about 3 hours;

Stage j: totalrevenue intermediate 74 TsCl, Et3N and DMAP in an inert towards the reaction, a solvent such as CH2Cl2for example at room temperature for about 16 hours;

Stage k): treatment of an intermediate compound 75 compound of formula HNR1R2in an inert towards the reaction solvent, such as THF, in a steel tank at a temperature of about 135°C for about 15 hours.

Method L: Getting the tetrahydrothiophene-2-substituted derivatives

The following scheme of reactions L1-L3 illustrate the formation of compounds of formula (I), in which C denotes a group of formula (c-1), Y1means SO(n), and R11means a group of formula (d-1)represented by the following formula XIa-c and XIIa-c.

Diagram L1: Synthesis of intermediate compounds (2R,3aR,12bS)-tetrahydrothiophene

Stage a): treatment of an intermediate compound 59 sodium azide and ammonium chloride in an inert towards the reaction solvent, Taconic DMF, for example at a temperature of about 90°C;

Stage b): intermediate connection 76 is subjected to reaction Mitsunobu (providing additional inversion at the carbon atom) with DIAD/P(Ph)3and para-nitrobenzoic acid (PNBzOH) in an inert towards the reaction solvent, such as THF, for example at temperatures from 0°C to room temperature for about 2 hours;

Stage c): remove protection intermediate compound 77 with a solution of base, such as K2CO3/MeOH, for example at room temperature for about 2 hours;

Stage d): metilirovanie intermediate 78 MsCl and DMAP using a base such as Et3N, inert to the reaction, a solvent such as CH2Cl2for example at a temperature from about 0°C to room temperature for approximately 30 minutes followed by treatment in situ AcSH at a temperature of from about 0°C to room temperature for about 5 hours;

Stage e): diallylamine and concomitant cyclization of the intermediate 79 using a solution of base, such as K2CO3/MeOH, for example at room temperature for approximately 2 hours.

Diagram L2: Synthesis of intermediate compounds (2S,3aR,12bS)-tetrahydrothiophene

Stage a): processing prom is mediate connection 76 with a solution of the base, such as K2CO3/MeOH, for example at room temperature for about 2 hours;

Stage b): (i) processing the intermediate 82 (CH3SO2)2O, Et3N, DMAP in an inert towards the reaction, a solvent such as CH2Cl2for example at a temperature of about 0°C; or (ii) processing the intermediate 82 MsCl, DMAP and Et3N inert to the reaction, a solvent such as CH2Cl2at a temperature of about 0°C followed by treatment in situ AcSH at about 0°C for about 5 hours;

Stage c): diallylamine and concomitant cyclization of the intermediate 83 base, such as K2CO3/MeOH, for example at room temperature for about 30 minutes.

Scheme L3: Synthesis of derivatives of (2RS,3aR,12bS)-tetrahydrothiophene

2R,3aR,12bS: XIa (n=0), XIb (n=1), XIc (n=1), XId (n=2)

2S,3aR,12bS: XIIa (n=0), XIIb (n=1), XIIc (n=1), XIId (n=2)

Stage a): (i) processing the intermediate 80 or 84 using the reaction of Staudinger or hydrogenation using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, for example at room temperature; and (ii) reductive amination of the resulting intermediate compound with aldehyde or ketone;

Stage b): (i) processing PR is an interstitial compound 80 or 84 aqueous hydrogen peroxide in an inert towards the reaction solvent, such as HFIP, for example at room temperature for about 15 minutes; (ii) treating the resulting intermediate compounds using the reaction of Staudinger or hydrogenation using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, for example at room temperature; (iii) reductive amination of the resulting intermediate compound with aldehyde or ketone;

Stage c): (i) processing the intermediate 80 or 84 mCPBA in an inert towards the reaction, a solvent such as CH2Cl2; (ii) treating the resulting intermediate compounds using the reaction of Staudinger or hydrogenation using a catalyst of palladium on coal (1 ATM) in an inert towards the reaction solvent, such as MeOH, for example at room temperature; and (iii) reductive amination of the resulting intermediate compound with aldehyde or ketone.

The compounds of formula (I) can also be converted into each other following well-known in this field reactions of transformation. For example,

a) a compound of formula (I)in which R1and R2taken together with the nitrogen atom to which they are bound, form a radical of formula (a-2)may be converted into the corresponding primary the amine by treatment with hydrazine or aqueous alkali solution;

b) compound of formula (I)in which R1or R2is cryptomaterial, can be converted into the corresponding primary or secondary amine by hydrolysis with an aqueous solution of alkali;

c) the compound of formula (I)in which R1or R2means C1-6-alkyl, substituted C1-6-alkylcarboxylic may be gidralizovanny in the compound of formula (I)in which R1or R2means C1-6-alkyl, substituted hydroxy-group;

d) compound of formula (I), in which both radicals R1and R2are hydrogen, may be mono - or di-N-alkylated to the corresponding form amine;

e) compound of formula (I), in which both radicals R1and R2are hydrogen, R1or R2is hydrogen, can be N-etilirovany to the corresponding amide;

f) compound of formula (I)containing C1-6-allyloxycarbonyl group can be hydrolyzed to the corresponding carboxylic acids;

g) the compound of formula (I)in which R9means hydrogen, i.e. i and/or j is zero, can be converted into the corresponding allyloxycarbonyl connection processing suitable allermuir agent, such as a suitable allyloxycarbonyl in the presence of utility in hexane using an organic solvent, such as tetrahydrofuran; or

h) compound of formula (I)in which R9is allyloxycarbonyl, can be converted into the corresponding hydroxymethylcytosine recovery, such as LiAlH4for example in an organic solvent such as tetrahydrofuran.

The above-described methods can be modified using conventional methods, which are known to experts in this field to implement similar processes of preparing compounds of formula (I).

The above source materials are either commercially available or can be obtained according to known in the field of ways. For example, intermediate compounds 1 can be obtained according to the methods described in the application for patent WO 03/048146 and WO 03/048147 mentioned above, or similar methods.

Pure stereochemical isomeric forms of the compounds of formula (I) can be obtained by applying known in the field of methods. The diastereomers can be separated by physical methods such as selective crystallization and chromatographic methods, for example by counter current distribution, liquid chromatography and the like.

The compounds of formula (I), which is obtained by the methods described above generally represent racemic mixtures of enantiomers which can be separated others the g from each other is known in this field by the methods of separation. Racemic compounds of the formula (I), which have sufficient basic or acidic properties may be converted into a form corresponding diastereomeric salts as a result of interaction with a suitable chiral acid and, respectively, with a suitable chiral base. Then these forms of diastereomeric salts share, such as polling or by fractional crystallization, and the enantiomers release using alkali or acid. An alternative method of separating the enantiomeric forms of the compounds of formula (I) is liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction occurs stereospetsifichno. Preferably, if you want a specific stereoisomer, this connection will be synthesized stereospecifically methods of getting. These methods are mainly used enantiomerically pure source materials.

The following examples are intended to illustrate but not to limit the scope of the present invention.

Experimental part

A. Obtaining intermediates

Example A1

(11R)-11-{[(4R)-22-dimethyl-l,3-dioxolane-4-yl]methyl}-8-fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-he (intermediate compound 2)

the intermediate connection 1intermediate compound 2

A solution of the intermediate α,β-unsaturated ketone 1 (1,00 g, 2,96 mmol) and Et3N (0.63 ml, 4,50 mmol) in i-D (30 ml) was first made using 10% Pd/C at atmospheric pressure for 6 hours. The mixture is then filtered through a pillow celite and the solids were washed CH2Cl2(4×20 ml). After evaporation was added i-D (5 ml) and Et3N (1.20 ml) and the reaction mixture was stirred at 40°C for 1 hour. The reaction mixture was cooled to room temperature and allowed to crystallize. The crystals were filtered and dried in vacuum, obtaining the pure intermediate ketone 2 in the form of white crystalline powder (0,86 g, 86%); TPL: 144-146°C.

Mass spectrum: CI m/z (distribution, relative intensity) 341 (MH+, 2%), 283 (MH+- acetone, 100%); EI: m/z (distribution, relative intensity) 340 (M+., 1%), 282 (M+- acetone, 79%), 226 (M+- side chain + H, 100%); High resolution EI calculated C21H21FO3(M+.): 340,1475 found: 340,1479 (1%).

Example A2

(10R,11R)-11-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepta the-10-ol (intermediate compound 3)

intermediate compound 3

To a cooled on ice to a solution of intermediate ketone 2 (0,42 g of 1.23 mmol) in i-D (15 ml) was added a solution of phosphate buffer (pH 7, 5 ml) and then portions NaBH4(0,23 g, 6,16 mmol). The reaction mixture was stirred at room temperature for 1 hour. Then added 10 ml of NH4Cl (saturated aqueous solution), the mixture was extracted with CH2Cl2(3×15 ml) and the organic phase was dried over MgSO4. After removal of solvent the residue was purified on a column of silica gel using a mixture of ether/hexane (40:60)to give the intermediate compound 3 as a colorless oil (0,42 g, 99%).

Mass spectrum: CI m/z (distribution, relative intensity) 325 (MH+- H2O, 53%), 267 (MH+- H2O-acetone, 100%), 249 (MH+- 2H2O-acetone, 97%); EI: m/z (distribution, relative intensity) 342 (M+, 3%), 324 (M+- H2O 48%), 266 (M+- H2O-acetone, 35%), 209 (100%); High resolution EI calculated C21H23FO3(M+): 342,1631 found: 342,1627(5%).

Example A3

(4R)-4-{[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]methyl}-2,2-dimethyl-1,3-dioxolane (intermediate compound 4)

intermediate compound 4

To a cooled (-30°C) solution of DIAD (2,43 ml, represented 33.47 per mmol) in THF (10 ml) was added Prohm is filling the alcohol 3 (2.30 g, of 6.73 mmol) in THF (18 ml) and Ph3P (3,71 g, 14,07 mmol). After 20 minutes was added diphenylphosphoryl (DPPA) (3,62 ml, equal to 16.83 mmol) and the reaction mixture was allowed to warm to room temperature. After stirring overnight the solvent was removed in vacuum, obtaining a red oil. Crude product was purified by chromatography on a column using a mixture of ether/hexane (10/90)to give undivided a mixture of intermediate compound in the form of oil and Ph3PO (of 3.46 g).

Mass spectrum: CI m/z (distribution, relative intensity) 368 (MH+, 1%), 325 (MH+-HN3, 9%), 304 (13%), 276 (MH+-HN3-acetone, 100%), 248 (20%).

Example A4

(2R)-3-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-1,2-propandiol (intermediate compound 5)

the intermediate compound 5

To a solution of intermediate azide 4 (3,68 g, 10,02 mmol) in THF (30 ml) was added 1N HCl (30 ml) and the mixture was stirred at room temperature for 8 hours. Added K2CO3(saturated aqueous solution) at 0°C was extracted 3 times with CH2Cl2and was dried over MgSO4. The residue obtained by evaporation was purified by chromatography on a column of silica gel using a mixture of Et2O/heptane (30/70)to give an oily intermediate compound 5 (3,19 g, 91% for 2 stages, starting with 3).

Mass spectrum: CI m/z (assignment is executed, relative intensity) 328 (MH+, 2%), 310 (MH+-H2O, 2%), 300 (MH+-N2, 5%), 285 (MH+-HN3, 11%), 267 (MH+-HN3-H2O, 100%), 249 (MH+-HN3-2H2O, 33%), 225 (MH+-HN3-CH2OHCHO, 20%).

Example A5

(2R)-3-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-2-hydroxypropyl-4-methylbenzenesulfonate (intermediate compound 6)

the intermediate compound 6

To a solution of intermediate diol 5 (1.1 g, 3,39 mmol) in anhydrous toluene (10 ml) was added Bu2SnO (97,6 mg, 0,39 mmol), Et3N (1.07 ml, 7,74 mmol) and TsCl (0,739 g, a 3.87 mmol). The mixture was stirred at room temperature overnight. Added NH4Cl (saturated aqueous solution), was extracted 3 times with CH2Cl2and was dried over MgSO4. The residue was purified by chromatography on a column of silica gel using EtOAc/heptane (20/80)to give the intermediate compound 6 in the form of oil (1.55 g, 95%).

Mass spectrum: -CI m/z (distribution, relative intensity) 454 (MH+-N2, 1%), 421 (MH+-HN3-H2O, 1%), 282 (MH+-TsOH-HN3, 20%), 264 (MH+-TsOH-HN3-H2O, 15%), 173 (TsOH2+, 100%).

Example A6

(2R)-1-azido-3-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H - dibenzo[a,d]cyclohepten-10-yl]-2-propanol (intermediate compound 7)

intermediate compound 7

A solution of intermediate tosilata 6 (2.00 g, 4,15 mmol) in DMF (30 ml) was treated with sodium azide (810,8 mg, 12,47 mmol) and the mixture was stirred at 90°C in the dark for 2 hours. The reaction mixture was diluted with water and was extracted with CH2Cl2. The combined extracts were washed with a saturated solution of salt. After concentration of the organic phase the residue was purified by chromatography on a column of silica gel using heptane/EtOAc (80/20)to give the intermediate DIACID 7 (1.22 g, 88%) as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 325 (MH+-N2, 2%), 310 (MH+-HN3, 3%), 297 (MH+- N2-N2, 1%), 282 (MH+-HN3-N2, 52%), 268 (MH+-HN3-HN3, 3%).

Example A7

(1R)-2-azido-1-{[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]methyl}ethylmethanesulfonate (intermediate compound 8)

intermediate compound 8

To a solution of intermediate compound diazide 7 (65 mg, 0.18 mmol) in CH2Cl2(10 ml) was added DMAP (18.5 mg, 0.09 mmol), Et3N (0,13 ml, was 0.63 mmol) and MsCl (44,5 μl, 0.40 mmol). After stirring at room temperature for 10 minutes was added 10 ml of NH4Cl (saturated aqueous solution). Was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of the silica gel using a mixture of EtOAc/heptane (20:80) gave the intermediate compound 8 in the form of oil (of 78.2 mg, 98%).

Mass spectrum: -CI m/z (distribution, relative intensity) 403 (MH+-N2, 3%), 360 (MH+-N2-HN3, 43%), 307 (MH+- MeSO3H-N2, 50%), 264 (MH+-MeSO3H-HN3-N2, 58%), 250 (MH+-MeSO3H-HN3, -N3, 21%), 197 (100%).

Example A8

[(2S,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methanamine (intermediate compound 9)

intermediate compound 9

A solution of intermediate compound diazide 8 (of 98.2 mg, 0.23 mmol) in MeOH (10 ml) was first made at atmospheric pressure using 10% Pd/C for 1 night. The mixture is then filtered through a pillow celite and solids 4 times washed CH2Cl2. After evaporation of the filtrate crude product was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH/NH4OH (90/9/1). Purification gave the intermediate compound 9 in the form of oil (of 36.4 mg, 56%).

Example A9

(1S)-2-azido-1-{[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]methyl}ethyl-4-nitrobenzoate (intermediate compound 10)

intermediate compound 10

To a cooled (0°C) solution of DIAD (4,2 ml, 21,18 mmol) in THF (50 ml) was added to Ph3P (5,55 g, 21,18 mmol). Was stirred at 0°C for 30 minutes (the precipitation of white solids). The ZAT is added to a mixture of intermediate alcohol 7 (3,727 g, 10,59 mmol) and 4-nitrobenzoic acid (3,54 g, 21,18 mmol) in THF (50 ml). The reaction mixture was allowed to warm to room temperature and after stirring for 2 hours was added MeOH and stirring continued for another 30 minutes. After removal of solvent the crude product was purified by chromatography on a column using a mixture of EtOAc/heptane (20/80)to give the intermediate ester 10 in the form of oil (4,85 g, 91%).

Mass spectrum: -CI m/z (distribution, relative intensity) 431 (MH+-N2-HN3, 36%), 307 (MH+-N2-p-NO2PHCO2H, 2%), 264 (MH+-p-NO2PHCO2H-HN3- N2, 58%), 197 (100%), 182 (72%).

Example A10

(2S)-1-azido-3-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-2-propanol (intermediate compound 11)

intermediate compound 11

A solution of the above intermediate diazide 10 (78,0 mg, 0.15 mmol) in MeOH (2 ml) was treated with K2CO3(76,9 mg, 0.47 mmol) and the mixture was stirred for 1 hour. Added NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2and dried MgSO4. The residue was purified by chromatography on a column of silica gel using a mixture of EtOAc/heptane (20/80)to give the intermediate alcohol 11 in the form of oil (of 42.6 mg, 78%).

Mass spectrum: -CI m/z (distribution, relative intensity)325 (MH +-N2, 2%), 310 (MH+-HN3, 3%), 297 (MH+-N2-N2, 1%), 282 (MH+-HN3-N2, 52%), 268 (MH+-HN3-N3, 3%).

Example A11

(1S)-2-azido-1-{[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]methyl}ethylmethanesulfonate (intermediate compound 12)

intermediate compound 12

To a solution of intermediate diazide 11 (of 42.6 mg, 0.12 mmol) in CH2Cl2(5 ml) was added DMAP (12.7mm mg, 0.06 mmol), Et3N (0,047 ml, 0.42 mmol) and MsCl (33,9 μl, 0.30 mmol). Was stirred at room temperature for 10 minutes. Added 10 ml of NH4Cl (saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4; after evaporation of the solvent was obtained intermediate compound 12 in the form of oil (to 53.0 mg, 100%).

Mass spectrum: -CI m/z (distribution, relative intensity) 403 (MH+-N2, 3%), 360 (MH+-N2-HN3, 43%), 307 (MH+-MeSO3H-N2, 50%), 264 (MH+-MeSO3H-HN3-N2, 58%), 250 (MH+-MeSO3H-HN3-N3, 21%), 197 (100 %).

Example A12

[(1R,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methanamine (intermediate compound 13)

intermediate compound 13

A solution of intermediate diazide 12 (501,0 mg of 1.16 mmol) in MeOH (10 ml) was first made at a pressure of 1 atmosphere, using 10% palladium on coal, with vigorous stirring at room temperature for 1 night. The mixture is then filtered through a pillow celite and solids 4 times washed CH2Cl2. After evaporation crude product was purified by chromatography on a column of silica gel using CHCl3/MeOH/NH4OH (90/9/1). It was obtained intermediate compound 13 in the form of oil (of 270.0 mg, 82%).

Example A13

Benzyl[(2S,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methylcarbamate (intermediate compound 14)

intermediate compound 14

To a solution of intermediate diamine 9 (220,0 mg, 0.78 mmol) in CH2Cl2(5 ml) at -20°C was added Et3N (0,109 ml, 0.78 mmol) and benzylchloride (0,112 ml, 0.78 mmol). Then the mixture was stirred for 1 hour. Added 10 ml of NH4Cl (saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. The residue was purified by chromatography on a column of silica gel using a mixture of EtOAc/heptane (20/80)to give mono-Cbz-intermediate compound 14 (128,9 mg, 40%) and di-Cbz-derivative (84,5 mg).

Mass spectrum: -CI m/z (distribution, relative intensity) 417 (MH+, 100%), 397 (MH+-HF 8%), 311 (MH+-PhCHO, 7%), 309 (MH+-PhCH2OH, 32%), 283 (16%), 252 (MH+-PhCH2OCONHCH3, 24%).

Example A14/p>

Benzyl[(2S,3aR,12bS)-1-(bromoacetyl)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methylcarbamate (intermediate compound 15)

intermediate compound 15

To a solution of mono-Cbz-intermediate 14 (32,5 mg, 0,078 mmol) in EtOAc (3 ml) was added 1 ml of NaOH (saturated aqueous solution) and bromoacetamide (6,8 μl, 0,078 mmol). Two phases was stirred vigorously for 1 night. Added 10 ml of NH4Cl (saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/heptane (20/80) to give the intermediate compound 15 in the form of oil (of 31.4 mg, 62%).

Mass spectrum: -CI m/z (distribution, relative intensity) 457 (MH+-HBr, 3%), 413 (MH+-HBr-CO2, 1%), 365 (MH+-HBr-PhCH31%), 351 (MH+-PhCHO-HBr 2%), 323 (MH+-HBr-PhCHO-CO, 5%), 119 (8%), 91 (100%).

Example A15

Benzyl(5aS,14bR,15aS)-7-fluoro-4-oxo-1,3,4,5a,10,14b,15,15a, octahydro-2H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin-2-carboxylate (intermediate compound 16)

the intermediate connection 16

To a solution of the above intermediate carbamate 15 (91,7 mg, 0,17 mmol) in DMF (5 ml) was added K2CO3(103,0 mg, 0.75 mmol) and the mixture was stirred at room temperature for 36 hours. Added 10 ml of NH 4Cl (saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using EtOAc/heptane (30/70) gave polycyclic intermediate compound 16 (86,2 mg, 92%) as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 457 (MH+, 1%), 323 (MH+-PhCHO-CO, 5%), 279 (MH+-Cbz-CH2CO, 1%), 91 (10%).

Example A16

N-{[(2R,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}(triphenyl)methanamine (intermediate compound 17)

intermediate compound 17

To a cooled on ice to a solution of diamine 13 (to 41.6 mg, 0.15 mmol) in CH2Cl2(5 ml) was added Et3N (42,5 μl, 0.3 mmol), DMAP (9.4 mg, 0.07 mmol) and Fritillaria (46,1 mg, 0.16 mmol). Then the mixture was stirred at 0°C for 2 hours. Added 10 ml of NH4Cl (saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/heptane (20/80) gave crystalline intermediate compound 17 (52,6 mg, 68%); TPL: 58-60°C.

Mass spectrum: -APCI m/z (distribution, relative intensity) 525 (MH+, 38%), 390 (4%), 283 (MH+-(Tr-H), 15%), 252 (MH+-CH3NHTr, 27%), 243 (Tr+, 100%), 228 (7%), 165 (29%).

Example A17

N-{[(2R,3aR,12bS)-l-(bromoacetyl)-11-fluoro-1,2,3,3a,8,12b[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}(triphenyl)methanamine (intermediate compound 18)

intermediate compound 18

Intermediate diamine 17 (26,7 mg, 0.05 mmol) was added to a biphasic system consisting of 2 ml of CH2Cl2and 0.5 ml of Na2CO3(saturated aqueous solution)and the mixture was stirred for 10 minutes. After adding bromoacetamide (6,8 μl, 0.08 mmol) two phases vigorously stirred for 3 hours. Was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/heptane (20/80) to give the intermediate compound 18 in the form of oil (27.9 mg, 85%), characterized as a mixture of two conformers.

Mass spectrum: -APCI m/z (distribution, relative intensity) 645 (MH+, 39%), 601 (3%), 403 (MH+-(Tr-H), 7%), 321 (MH+-TrH-HBr, 21%), 243 (Tr+, 100%), 228 (3%), 165 (15%).

Example A18

N-{[(2R,3aR,12bS)-11-fluoro-1-(methoxyacetyl)-1,2,3,3a,8,12b-hexahydrobenzo-[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}(triphenyl)methanamine (intermediate compound 19)

intermediate compound 19

To a solution of intermediate 18 (530 mg, 0.82 mmol) in MeOH (15 ml) was added MeSO3H (3 ml) and the mixture was stirred at 60°C for 30 minutes. After complete evaporation of the solvent the residue was dissolved in a mixture of CH2Cl2/K2CO3(saturated aqueous solution) (15/15 ml) and the organic layer CTD is ranged. The aqueous layer was extracted with CH2Cl2(3×10 ml) and then the combined organic layers were dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/heptane (20/80) to give the intermediate compound 19 in the form of oil (231.3 of which mg, 47%), characterized as a mixture of two conformers.

Mass spectrum: -APCI m/z (distribution, relative intensity) 598 (MH+, 1%), 519 (2%), 355 (MH+-Tr, 13%), 283 (MH+-Tr-CO=CHOMe, 2%), 271 (10%), 243 (Tr+, 100%), 167 (21%).

Example A19

[(1R,3aR,12bS)-1-(bromoacetyl)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methylformamide (intermediate compound 20)

intermediate compound 20

N-Tr-protected amine intermediate 18 (100 mg, 0.15 mmol) was dissolved in 98% formic acid (2 ml) and the mixture was stirred at room temperature for 24 hours. After removal of the excess formic acid in vacuo, the residue was dissolved in CHCl3(2 ml) was added EEDQ (47 mg, 0,19 mmol). The solution was stirred at room temperature for 5 hours. After evaporation of the solvent the residue was purified by chromatography on a column of silica gel using a mixture of CH2Cl2/MeOH (98/2) as eluent. N-CHO-protected amine intermediate 20 (54,7 mg, 82%) was obtained as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 431, 433 (MH , 42%), 353 (MH+-HBr, 100%), 294 (MH+-HBr-CH3NHCHO, 9%), 249 (4%), 158 (2%), 130 (7%).

Example A20

(5aS,14bR,15aR)-7-fluoro-4-oxo-1,3,4,5a,10,14b,15,15a, octahydro-2H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin-2-carbaldehyde (intermediate compound 21)

the intermediate connection 21

To a solution of N-formyl-substituted amine intermediate 20 (91 mg, 0.21 mmol) in anhydrous THF (10 ml) solution was added t-BuOK (30,3 mg, 0.24 mmol) in THF (2 ml). The reaction mixture was stirred at room temperature for 30 minutes. Then added water (10 ml) and the mixture was extracted with CH2Cl2(10 ml). Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (97/3) gave the cyclic intermediate compound 21 (47,4 mg, 64%) as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 351 (MH+, 100%), 331 (MH+-HF, 5%), 323 (MH+-CO, 6%), 319 (8%), 219 (2%), 130 (4%).

Example A21

(10R,11R)-11-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylacetic (intermediate compound 22)

intermediate compound 3intermediate compound 22

To a solution of intermediate is pirta 3 (0,42 g, of 1.23 mmol) in CH2Cl2(30 ml) was added Et3N (0,43 ml of 3.07 mmol), DMAP (0.15 g, of 1.23 mmol) and the anhydride AcOH (0,29 ml of 3.07 mmol). Was stirred at room temperature for 1 hour, was added NH4Cl (saturated aqueous solution, 20 ml), was extracted with CH2Cl2(3×15 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of ether/hexane (30:70) gave a white crystalline intermediate compound 22 (0.45 g, 95%); TPL: 147-149°C.

Mass spectrum: -CI m/z (distribution, relative intensity) 385 (MH+, 1%), 325 (MH+-AcOH, 100%), 267 (MH+-AcOH-acetone, 43%), 249 (MH+-AcOH-acetone-H2O, 47%); EI: m/z (distribution, relative intensity) 324 (M+-AcOH, 46%), 266 (M+-AcOH-acetone, 20%), 209 (M+- AcOH - side chain, 100%); High resolution EI calculated C22H21FO2(M+-AcOH): 324,1526 found: 324,1521 (M+, 72%).

Example A22

(10R,11R)-11-[(2R)-2,3-dihydroxypropyl]-8-fluoro-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-10-ylacetic (intermediate compound 23)

intermediate compound 23

To a solution of intermediate acetal 22 (0.45 g, 1,17 mmol) in THF (10 ml) was added 1N HCl (10 ml). After stirring at room temperature for 8 hours was added 10 ml of Na2CO3(saturated aqueous solution) at 0°C. was Extracted with CH2Cl2(3×10 ml) and the left the house taking over MgSO 4. Purification on a column of silica gel using a mixture of EtOAc/hexane (70:30) gave diol intermediate 23 as a colourless oil (0.39 g, 96%).

Mass spectrum: -CI m/z (distribution, relative intensity) 345 (MH+, 1%), 327 (MH+-H2O, 3%), 309 (MH+-2H2O, 3%), 285 (MH+-AcOH, 17%), 267 (MH+-AcOH-H2O, 100%), 249 (MH+-AcOH-2H2O, 3%); EI: m/z (distribution, relative intensity) 326 (M+-H2O, 10%), 284 (M+-AcOH, 13%), 209 (M+-AcOH - side chain, 100%)); High resolution EI calculated C20H19FO3(M+-H2O): 326,1318 found: 326,1316 (31%).

Example A23

(10R,11R)-11-[(2S)-2,3-desigabriel]-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylacetic (intermediate compound 24)

intermediate compound 23intermediate compound 24

To the intermediate connection acetate-diolo 23 (0,59 g, 1,72 mmol) in CH2Cl2(15 ml) was added Et3N (of 0.96 ml, 6,86 mmol), DMAP (209 mg, 1,72 mmol) and MeSO2Cl (of 0.53 ml, 6,86 mmol) at 0°C. was Stirred at room temperature for 1 hour. Was treated by the addition of NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2and dried over gSO 4. Purification on a column of silica gel using a mixture of EtOAc/heptane (50/50) gave dieselstrasse connection in the form of oil (0.84 g, 98%). To the obtained compound (182,5 mg, 0.36 mmol) in DMF (10 ml) was added NaN3(95 mg, of 1.46 mmol). The reaction mixture was heated at 80°C for 3 hours. After cooling, was added NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2and was dried over MgSO4. After evaporation the residue was purified on silica gel using a mixture of EtOAc/heptane (20/80)to give the intermediate compound 24 in the form of an oily product (122,3 mg, 85%).

Example A24

(4S)-4-{[(10R,11R)-2-fluoro-11-hydroxy-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-10-yl]methyl}-2-imidazolidinone (intermediate compound 25)

intermediate compound 25

Intermediate DIACID 24 turned through an intermediate diazadispiro 24a in the diamine, which is then transformed into an intermediate connection 25. To a solution of dyazide 24 (120,1 mg, 0.30 mmol) in MeOH (10 ml) was added K2CO3(126,4 mg of 0.91 mmol). The reaction mixture was stirred at room temperature for 1 hour. Added NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of Et2O/heptane (40/60) gave intermediate diazadispiro 24a in the form of maslianico the product of 77.5 mg, 72%). The obtained compound (75 mg, 0.21 mmol) in MeOH (5 ml) was first made at 1 atmosphere pressure using 10% palladium on coal, with vigorous stirring at room temperature for 1 night. The mixture is then filtered through a pillow celite and solids 4 times washed CH2Cl2. After evaporation of solvent the crude product was dissolved in 5 ml of CH3CN was added Et3N (34 μl, 0.24 mmol). The reaction mixture was heated in an argon atmosphere at 70°C. After 1 hour, was added dropwise a solution of diphenylcarbonate (23 mg, 0.11 mmol) in CH3CN and the mixture was stirred at 70°C for 1 day. After evaporation crude product was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH (90/10)to give intermediate imidazolidinone 25 in the form of oil (to 34.4 mg, 48%).

Example A25

(11E)-11-{[(4R)-2,2-dimetil-1,3-dioxolane-4-yl]methylene}-8-Ferdinando[b,f]oxepin-10(11H)-he (intermediate compound 27)

the intermediate connection 26intermediate compound 27

To a suspension of intermediate 26 (0,228 g, 1 mmol) and MgBr2(0,202 g, 1.1 mmol) in anhydrous toluene (5 ml) was added acetonide (S)-glyceraldehyde (4 mmol, 1.5 M races is a thief in THF) and tBuOK (of 22.4 mg, 0.2 mmol) and was stirred for 3 hours at room temperature. Was added a saturated aqueous solution of NH4Cl (5 ml), the organic layer was separated and kept over anhydrous MgSO4. The solvent was removed under reduced pressure, followed by the separation of the α,β-unsaturated product flash chromatography using a mixture of EtOAc:heptane (1:9) as eluent, obtaining an intermediate compound 27 as a yellow liquid with a ratio of 85/15 E - and Z-isomers (85%, 0,289 g).

VRMS: calculated 340,1111; found 340,1122

Example A26

a) (10R,11R)-11-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-8-fluoro-10,11-dihydrobenzo[b,f]oxepin-10-ol (intermediate compound 29)

intermediate compound 29

To a solution of intermediate 27 (0,340 g, 1 mmol) in i-D (5 ml) was added Et3N (of 0.21 ml, 1.5 mmol) and the reaction mixture was first made at atmospheric pressure using 10% Pd/C (40 mg) as catalyst. After completion of the reaction (4 hours) the reaction mixture was passed through a small pillow celite and then washed CH2Cl2(2×5 ml) followed by evaporation of the solvent and obtaining the crude intermediate ketone 28.

the intermediate connection 28

b) thus Obtained crude intermediate compound 28 was dissolved in i-D (10 ml) of the EC it was added an aqueous solution of phosphate buffer (3 ml, pH 7). The temperature was lowered to 0°C and several parties were added NaBH4(0.152 g, 4 mmol) and then allowed to mix for 15 minutes at the same temperature. Was added an aqueous solution of NH4Cl (5 ml) and the reaction mixture was extracted using Et2O (3×5 ml). After drying over anhydrous MgSO4the solvent was removed under reduced pressure and the two diastereomeric alcohol (1:1) with slightly different polarity was shared by flash chromatography using a mixture of EtOAc:heptane (20:80) as eluent, getting more polar intermediate CIS-alcohol 29 in the form of a white solid (TPL: 59-61°C; 49%, 0.16 g).

VRMS: calculated 344,1424; found 344,1435.

Example A27

(10S,11R)-11-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-8-fluoro-10,11-dihydrobenzo[b,f]oxepin-10-Elazig (intermediate compound 30)

the intermediate connection 30

To a solution of P(Ph)3(0,524 g, 2 mmol) in anhydrous THF (5 ml) at -15°C was added a solution of DIAD (0,424 g, 2.1 mmol) in THF (2 ml) and the resultant complex was stirred for 20 minutes followed by the addition of the intermediate 29 (0,329 g, 1 mmol)dissolved in THF (2 ml)and a solution of DPPA (0,330 g, 1.2 mmol) in THF (1 ml). The reaction mixture was heated to room temperature and was stirred for 18 hours. After addition of MeOH, the reaction mixture is left the house taking in vacuum with subsequent separation of the azide using flash chromatography using a mixture of EtOAc:heptane (1:9) as eluent, obtaining an intermediate compound 30 as a colorless liquid (91%, 0,335 g).

VRMS: calculated 369,1489; found 369,1483.

Example A28

(2R)-3-[(10R,11S)-11-azido-2-fluoro-10,11-dihydrobenzo[b,f]oxepin-10-yl]-1,2-propandiol (intermediate compound 31)

the intermediate connection 31

To a solution of intermediate 30 (0,369 g, 1 mmol) in THF (5 ml) was added 1 M aqueous HCl solution (1 ml) and was stirred for 18 hours. THF was removed under reduced pressure and the diol was extracted using Et2O (3×10 ml). The organic layer was treated with aqueous solution of NaHCO3(5 ml) followed by washing with saturated salt solution (5 ml). After drying over anhydrous MgSO4the solvent was removed in vacuum, obtaining an intermediate compound 31 in the form of a thick viscous liquid (95%, 0,313 g).

VRMS: calculated 329,1176; found 329,1184.

Example A29

(2R)-1-[(10R,11S)-11-azido-2-fluoro-10,11-dihydrobenzo[b,f]oxepin-10-yl]-3-(trityloxy)-2-propanol (intermediate compound 32)

the intermediate connection 32

To a solution of intermediate 31 (0,329 g, 1 mmol) in CH2Cl2(10 ml) was added Et3N (of 0.28 ml, 2 mmol), DMAP (0.1 mmol, 12,2 mg) and TrCl (0,307 g, 1.1 mmol) and was stirred for 24 hours. The solvent was removed when igenom pressure and the crude reaction mixture was subjected to flash chromatography, using a mixture of EtOAc:heptane (1:9) as eluent, obtaining an intermediate compound 32 as a white solid (TPL: 58-59°C; 80%, 0,456 g).

VRMS: calculated 571,2271; found 571,2286.

Example A30

(1R)-2-[(10R,11S)-11-azido-2-fluoro-10,11-dihydrobenzo[b,f]oxepin-10-yl]-1-[(trityloxy)methyl]ethylmethanesulfonate (intermediate compound 33)

the intermediate connection 33

To a solution of intermediate 32 (0,571 g, 1 mmol) in CH2Cl2at -10°C was added Et3N (of 0.28 ml, 2 mmol), DMAP (to 12.2 mg, 0.1 mmol) and MsCl (0.126 g, 1.1 mmol). The reaction mixture was heated to room temperature and was stirred for 4 hours. Was added water (3 ml) and the organic layer was separated and dried over anhydrous MgSO4followed by purification with flash chromatography using a mixture of EtOAc:heptane (1:9) as eluent, obtaining an intermediate compound 33 as a white solid (TPL: 55-56°C; 85%, 0,515 g).

VRMS: calculated 649,2047; found 649,2064.

Example A31

(1R)-2-[(10R,11S)-11-azido-2-fluoro-10,11-dihydrobenzo[b,f]oxepin-10-yl]-1-(hydroxymethyl)ethylmethanesulfonate (intermediate compound 34)

the intermediate connection 34

To a solution of intermediate 33 (0,649 g, 1 mmol) in MeOH (5 ml)was added amberlyst-15 (0.1 g) and the reaction mixture was stirred at 40°C for chasov, then filtered to remove the catalyst. The solvent was removed under reduced pressure and the product was purified flash chromatography using EtOAc:heptane (2:8) as eluent, obtaining an intermediate compound 34 in the form of a thick viscous liquid (90%, 0,366 g).

VRMS: calculated 407,0951; found 407,0975.

Example A32

(10R,11S)-11-azido-2-fluoro-10-[(2S)-oxiranylmethyl]-10,11-dihydrobenzo[b,f]oxepin (intermediate compound 35)

the intermediate connection 35

A mixture of intermediate 34 (0,407 g, 1 mmol) and K2CO3(0,276 g, 2 mmol) was stirred in i-D (10 ml) for 8 hours, filtered to remove the K2CO3, and the solvent was removed under reduced pressure. The product was purified flash chromatography using a mixture of EtOAc:heptane (2:8) as eluent, obtaining an intermediate compound 35 as a colourless liquid (78%, 0,242 g).

VRMS: calculated 311,1070; found 311,1089.

Example A33

[(2R,3aR,12bS)-11-fluoro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]methanol (intermediate compound 36)

intermediate compound 36

To a solution of intermediate 35 (0,311 g, 1 mmol) in i-D (10 ml) was added Et3N (0,140 ml, 1 mmol). The mixture was first made at atmospheric pressure using 10% Pd/C (50 mg) as catalyst. After conclusion of the Oia reaction (3 hours) the mixture was passed through a small pillow celite and the catalyst was washed CH 2Cl2(2×5 ml). The combined organic layers were evaporated under reduced pressure and was purified flash chromatography using a mixture of EtOAC:heptane (1:1) as eluent, obtaining an intermediate compound 36 as a white solid (TPL: 108-109°C; 83%, 0,236 g).

VRMS: calculated 285,1165; found 285,1172.

Example A34

Methyl(2R,3aR,12bS)-11-fluoro-2-(hydroxymethyl)-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrole-1-carboxylate (intermediate compound 37)

the intermediate connection 37

To a solution of intermediate 36 (0.14 g, 0.5 mmol) in CH2Cl2(4 ml) at 0°C was added a saturated solution (water) NaHCO3(2 ml). After adding methylcarbamate (1.5 equivalents), the reaction mixture was vigorously stirred at 0°C for 20 minutes, heated to room temperature and was allowed to mix for another 0.5 hour. The organic layer was separated, dried over MgSO4and purified flash chromatography using a mixture of EtOAc:heptane (4:6) as eluent, obtaining an intermediate compound 37 in the form of a thick viscous liquid (83%, 0.14 g).

VRMS: calculated 343,1220; found 343,1218.

Example A35

Methyl(2R,3aR,12bS)-2-(aminomethyl)-11-fluoro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrole-1-carboxylate (intermediate compound 38)

intermediate compound 38

To a solution of P(Ph)3(0.26 g, 1 mmol) in anhydrous THF (4 ml) at -15°C was added a solution of DIAD (0,22 g, 1.1 mmol) in THF (1 ml) and the resultant complex was stirred for 20 minutes. After adding the intermediate 37 (0.17 g, 0.5 mmol) dissolved in THF (1 ml)and DPPA (0.14 g, 0.5 mmol) in THF (1 ml), the reaction mixture was heated to room temperature and was stirred for 18 hours. To the reaction mixture was added an excess of P(Ph)3(5 EQ) and water (0.5 ml) and then was heated at 40°C for 3 hours to restore the azide to the amine functionality. To the reaction mixture was added silica and the solvent was removed under reduced pressure, followed by purification of the product flash chromatography using a mixture of CH2Cl2/MeOH (9:1) as eluent, obtaining an intermediate compound 38 in the form of a thick viscous liquid (80%, 0.14 g).

VRMS: calculated 342,1380; found 342,1376.

Example A36

{(2R,3aR,12bS)-11-fluoro-1-[(2-nitrophenyl)sulfonyl]-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl}methyl-2-nitrobenzenesulfonate (intermediate compound 39)

the intermediate connection 39

To a solution of intermediate 36 (0.5 mmol, 0.14 g) Et3N (5 EQ) and DMAP (20 mol%) in CH2Cl2at -20°C was added o-nitrobenzenesulfonamide (3 is kV). The reaction mixture was heated to room temperature and left to stir over night. To the reaction mixture were added an aqueous solution of NaHCO3(2 ml) and the organic layer was separated and dried over MgSO4. After chromatography (SiO2) using EtOAc:heptane (1:1) as eluent received intermediate compound 39 as a yellow crystalline solid (TPL: 88-90°C, 71%, 0,23 g).

Example A37

a) (10R,11R)-8-fluoro-11-((2R)-2-hydroxy-3-{[(4-were)sulfonyl]oxy}propyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylacetic (intermediate compound 23a)

intermediate compound 23a

To a solution of intermediate acetate-diol 23 (0.12 g, 0,355 mmol) in anhydrous toluene (10 ml) was added n-Bu2SnO (9 mg, being 0.036 mmol), Et3N (0,13 ml, 0,888 mmol) and TsCl (0.10 g, of 0.533 mmol). Was stirred at room temperature for 24 hours, was added NH4Cl (saturated aqueous solution, 10 ml), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/hexane (30:70) gave the intermediate compound 23a in the form of a colorless oil (0.15 g, 84%).

Mass spectrum: CI m/z (distribution, relative intensity) 481 (MH+- H2O, 1%), 439 (MH+-AcOH, 4%), 421 (MH+-AcOH-H2O, 1%), 267 (MH+-AcOH-TsOH, 18%), 249 (MH+-AcOH-TsOH-H 2O, 100%); EI: m/z (distribution, relative intensity) 480 (M+-H2O, 1%), 438 (M+-AcOH, 36%), 266 (M+-AcOH-TsOH, 15%), 248 (M+-. -AcOH-TsOH-H2O, 18%); High resolution EI calculated C25H23FO4S (M+-AcOH): 438,1301 found: 438,1300 (51%).

b) (10R,11R)-11-[(2R)-3-azido-2-hydroxypropyl]-8-fluoro-10,11-dihydro-5H-dibenzo2[a,d]cyclohepten-10-ylacetic (intermediate compound 40)

the intermediate connection 40

To a solution of intermediate tosilata 23a (1.30 grams, 2,61 mmol) in DMF (25 ml) was added NaN3(0.51 g, 7,83 mmol). The reaction mixture was heated at 100°C for 1 night. After cooling, was added NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2and was dried over MgSO4. After evaporation the residue was purified on silica gel using a mixture of EtOAc/heptane (20/80)to give the intermediate compound 40 in the form of an oily product (0,79 g, 82%).

Example A38

(10R,11R)-11-[(2R)-3-azido-2-hydroxypropyl]-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (intermediate connection 41)

the intermediate connection 41

A solution of intermediate acetate 40 (454,9 mg of 1.23 mmol) in MeOH (10 ml) was treated with K2CO3(340,1 mg of 2.46 mmol) and the mixture was stirred at room temperature for 1 hour. Added NH4Cl (saturated is odny solution), 3 times was extracted with CH2Cl2and was dried over MgSO4. The solution was filtered and evaporated and the residue was purified by chromatography on a column of silica gel using a mixture of EtOAc/heptane (30/70)to give diol intermediate 41 (370,9 mg, 92%).

Example A39

S-((10S,11R)-11-{(2R)-3-azido-2-[(methylsulphonyl)oxy]propyl}-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)atantic (intermediate compound 42)

the intermediate connection 42

To the intermediate connection 41 (670 mg, 2.05 mmol) in CH2Cl2(25 ml) was added Et3N (2.30 ml, 16.4 mmol), DMAP (0.13 mg, of 1.02 mmol) and (CH3SO2)2O (1.07 g, x 6.15 mmol) at 0°C. was Stirred at room temperature for 1 hour, again cooled to 0°C, was added AcSH (of 0.44 ml, 6,15 mmol) and stirred at room temperature for 4 hours. Was treated by the addition of NH4Cl (saturated aqueous solution). 3 times was extracted with CH2Cl2. Chromatography on a column of silica gel using CH2Cl2(100%) gave the intermediate compound 42 in the form of an oil (0.68 g, 72%).

Example A40

(2S,3aR,12bS)-2-(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene (intermediate compound 43)

the intermediate connection 43

To the above intermediate compound 42 (0.15 g, 0,33 IMO the ü) in MeOH (5 ml) was added K 2CO3(92 mg, 0.67 mmol). After stirring at room temperature for 1 night and the mixture was treated by the addition of NH4Cl (saturated aqueous solution). 3 times was extracted with CH2Cl2and was dried over MgSO4. Purification on a column of silica gel using a mixture of CH2Cl2/heptane (40/60) gave the intermediate compound 43 in the form of an oily product (76 mg, 70%).

Mass spectrum: CI m/z (distribution, relative intensity) 326 (MH+, 25%), 298 (MH+-N2, 60%), 283 (MH+-HN3, 100%), 269 (MH+-N2-CH2NH, 12%), 249 (MH+-HN3-H2S, 25%), 235 (MH+-N2-CH2NH-H2S, 21%), 197 (61%).

Example A41

(2S,3aR,12bS)-2-(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-1,1-dioxide (intermediate compound 44)

the intermediate connection 44

To a solution of azide intermediate 43 (76,1 mg, 0.23 mmol) in CH2Cl2(5 ml) was added m-CPBA (meta-chloroperbenzoic acid) (173,2 mg, 0.70 mmol). The mixture was stirred at room temperature for 15 minutes was Added NaHCO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of EtOAc/heptane (50/50) gave the intermediate sulfon 44 persons (73.2 mg, 88%) as oil.

Mass spectrum: -CI m/z (distribution,relative intensity) 358 (MH +, 21%), 340 (MH+- H2O, 9%), 330 (MH+-N2, 9%), 303 (8%), 265 (24%), 264 (MH+-N2-H2SO2, 25%), 237(MH+-N2-H2SO2-HCN, 11%), 211 (15%), 197(66%).

Example A42

(10R,11R)-11-[(2S)-3-azido-2-hydroxypropyl]-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (intermediate compound 45)

the intermediate connection 45

To a solution of intermediate 40 (0,85 g, 2.32 mmol) in THF (10 ml) was added to Ph3P (1.22 g, 4,63 mmol) and DIAD (1,92 ml, 4,63 mmol). Then was added dropwise a solution paranitrobenzoic acid (0,77 g, 4,63 mmol) in THF (10 ml). The mixture was stirred at room temperature for 2 hours. Was treated by the addition of NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of CH2Cl2/heptane (70/30) gave a pair of nitrobenzoate (inverted secondary OH-group) in the form of oil (1.19 g, 99%). To a solution of the obtained compound (2,01 g of 4.05 mmol) in MeOH (50 ml) was added K2CO3(1.12 g, 8,10 mmol). The reaction mixture was stirred at room temperature for 3 hours. Added NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of EtOAc/heptane (30/70) gave an oily intermediate compound 5 (0.71 g, 98%).

Example A43

S-((10S,11R)-11-{(2S)-3-azido-2-[(methylsulphonyl)oxy]propyl}-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)atantic (intermediate compound 46)

the intermediate connection 46

To a solution of diol intermediate 45 (1.20 g, 3,66 mmol) in CH2Cl2(30 ml) was added Et3N (4,10 ml of 29.3 mmol), DMAP (0.22 mg and 1.83 mmol) and (CH3SO2)2O (1.92 g, 11.0 mmol) at 0°C. was Stirred at room temperature for 1 hour. Again cooled to 0°C and added AcSH (0,52 ml, 7,33 mmol) and stirred at room temperature for 5 hours. Was treated by the addition of NH4Cl (saturated aqueous solution), 3 times was extracted with CH2Cl2and was dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/heptane (30/70) to give the intermediate compound 46 in the form of oil (1,32 g, 78%).

Example A44

(2R,3aR,12bS)-2-(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo-[3,4:6,7]cyclohepta[1,2-b]thiophene (intermediate compound 47)

the intermediate connection 47

To a solution of the above intermediate compound 46 (1,32 g of 2.86 mmol) in MeOH (30 ml) was added K2CO3(0,79 g, 5,72 mmol). After stirring at room temperature for 2 hours, was added NH4Cl (saturated aqueous solution). 3 times was extracted with CH 2Cl2and was dried over MgSO4. Purification on a column of silica gel using a mixture of CH2Cl2/heptane (40/60) gave the intermediate compound 47 in the form of an oily product (0,82 g, 89%).

Mass spectrum: -CI m/z (distribution, relative intensity) 326 (MH+, 25%), 298 (MH+-N2, 60%), 283 (MH+-HN3, 100%), 269 (MH+-N2-CH2NH, 12%), 269 (MH+-HN3-H2S, 25%), 235 (MH+-N2-CH2NH-H2S, 21%), 197 (61%).

Example A45

(2R,3aR,12bS)-2-(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-1,1-dioxide (intermediate compound 48)

the intermediate connection 48

To a solution of azide intermediate 47 (136,1 mg, 0.41 mmol) in CH2Cl2(10 ml) was added meta-chloroperbenzoic acid (310,0 mg of 1.26 mmol). The mixture was stirred at room temperature for 30 minutes. Added NaHCO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of EtOAc/heptane (50/50) gave the intermediate sulfon 48 (146,5 mg, 98%) as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 358 (MH+, 21%), 340 (MH+-H2O, 9%), 330 (MH+-N2, 9%), 303 (8%), 265 (24%), 264 (MH+-N2-H2SO2, 25%), 237(MH+-N2-H2SO2-HCN, 11%, 211 (15%), 197 (66%).

Example A46

(2S,3aR,12bS)-2-(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-1-oxide (intermediate 49, 50)

the intermediate connection 49the intermediate connection 50

To a solution of azide intermediate 43 (0.34 g, 1.05 mmol) in hexafluoroisopropanol (5 ml) was added H2O2(30%, of 0.24 ml, 2.10 mmol). The mixture was stirred at room temperature for 30 minutes. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using Et2O (100%) gave the intermediate compound 49 (110 mg) and 50 (130 mg) with a total yield of 78%.

Mass spectrum: - CI m/z (distribution, relative intensity) 342 (MH+, 100%), 314 (MH+-N2, 49%), 299 (MH+-HN3, 47%), 264 (17%), 197 (96%).

Example A47

(2R,3aR,12bS) - 2(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[l,2-6]thiophene-1-oxide (intermediate 51, 52)

the intermediate connection 51the intermediate connection 52

To a solution of azide intermediate 47 (0.21 g, 0.64 mmol) in hexafluoroisopropanol (3 ml) was added H2O2(30%, 0.15 ml, of 1.27 mmol). The mixture was stirred at room temperature for 30 minutes. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using Et2O (100%) gave the intermediate compound 51 (120 mg) and 52 (86 mg) with a total yield of 95%.

Mass spectrum: - CI m/z (distribution, relative intensity) 342 (MH+, 100%), 314 (MH+-N2, 49%), 299 (MH+-HN3, 47%), 264 (17%), 197 (96%).

Example A48

(10S*,11R*)-11-allyl-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylacetic (intermediate compound 56)

the intermediate connection 55the intermediate connection 56

The intermediate alcohol 55 (1,72 g, 6.42 per mmol) was dissolved in CH2Cl2(30 ml). Added Et3N (1,79 ml, 12.8 mmol), DMAP (0,78 g, 6.42 per mmol) and the anhydride AcOH (1,21 ml, 12.8 mmol). Was stirred at room temperature for 1 hour and added rich waters of the initial solution of NH 4Cl (15 ml). 3 times was extracted with CH2Cl2(3×20 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of CH2Cl2/hexane (60:40) gave the intermediate compound 56 in the form of oil (1.77 g, 89%).

Mass spectrum: -CI m/z (distribution, relative intensity)311 (MH+, 5%), 251 (MH+-AcOH, 100%); EI: m/z (distribution, relative intensity) 250 (M+-AcOH, 16%), 209 (M+-AcOH-CH2CH2=CH2, 100%); High resolution EI calculated C18H15F (M+-AcOH): 250,1158 found: 250,1162 (26%).

Example A49

a) (2R)-1-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-3-(trityloxy)-2-propanol (intermediate compound 57)

the intermediate connection 57

A mixture of intermediate diol 5 (6,022 g is 18.40 mmol), Et3N (5,586 g, 55.2 mmol), 4-dimethylaminopyridine (138 mg, 1.13 mmol), trihybrid (9,444 g, 27.6 mmol) in CH2Cl2(180 ml) was stirred at room temperature under nitrogen atmosphere for 2 hours, then extinguished saturated aqueous NH4Cl (50 ml). The organic phase was separated, the aqueous layer was extracted with CH2Cl2(2×50 ml), the combined organic phases were washed with water (3×40 ml), saturated salt solution (40 ml), dried (MgSO4) and was evaporated in vacuum. Purification with flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-hept is h, from 5/95 to 10/90) to give the intermediate compound 57 (8,595 g, 15,09 mmol, 82%) as a brown semi-solid substance.

b) (1R)-2-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-1-[(trityloxy)methyl]ethylmethanesulfonate (intermediate compound 58)

the intermediate connection 58

A mixture of intermediate alcohol 57 (8,500 g, 14,92 mmol), Et3N (4,529 g, 44,76 mmol) and DMAP (84 mg, 0,689 mmol) in CH2Cl2(200 ml) was cooled to -78°C under nitrogen atmosphere. One portion was added MsCl (2,264 g, 22,38 mmol), the resulting solution was slowly heated to room temperature (about 40 min) and extinguished saturated aqueous NH4Cl (50 ml). The organic phase was separated, the aqueous layer was extracted with CH2Cl2(3×45 ml), the combined organic layers were washed with water (3×45 ml) and saturated salt solution (40 ml), dried (MgSO4) and was evaporated in vacuum. Due to the instability of the intermediate compound 58 was used immediately without further purification.

c) (1R)-2-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-1-(hydroxymethyl)ethylmethanesulfonate (intermediate compound 59)

the intermediate connection 59

The crude intermediate compound 58 (an unknown number, presumably 14,92 mmol), was dissolved in MeOH (200 ml), EXT is ulali dry Amberlyst-15 (15 g) and the mixture was stirred at 45°C for 4 hours; over the course of the reaction was monitored by TLC (Kieselgel on glass; EtOAc-heptane 30/70). The resin was filtered and washed with MeOH (2×40 ml), methanolic solution was concentrated in vacuo to 100 ml, and an intermediate connection 59 is directly used in the next stage.

d) (10S,11R)-8-fluoro-11-[(2S)-oxiranylmethyl]-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-10-Elazig (intermediate compound 60)

the intermediate connection 60

A methanol solution of intermediate 59, obtained as above, was treated with anhydrous K2CO3(4,146 g, 30 mmol) and stirred at room temperature for 3 hours. After treatment with water (100 ml), MeOH was removed in vacuo, the product was extracted with Et2O (3×75 ml). The combined organic layers were washed with water (3×75 ml) and saturated salt solution (40 ml), dried (MgSO4) and was evaporated in vacuum. Chromatographic purification (Kielselgel 60, 70-230 mesh, EtOAc-heptane 10/90) to give the intermediate compound 60 (3,185 g, 10,29 mmol, 69% of intermediate 57) as a colourless oil.

VRMS: calculated for C18H16FN3O: 309,1277; found: 309,1279.

e) [(2R,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methanol (intermediate compound 61)

the intermediate connection 61

Intermediate EPO is led 60 (3,108 g, 10,04 mmol) was dissolved in MeOH (50 ml)was added Et3N (1,012 g, 10 mmol) and 10% Pd-C (150 mg) and the resulting mixture was first made at atmospheric pressure for 5 hours. The catalyst was removed by filtration through a small pillow diatomaceous earth, MeOH and Et3N was removed in vacuum and the residue was purified by chromatography on a column (Kieselgel 60, 70-230 mesh, EtOH-CH2Cl25/95)to give the intermediate compound 61 (2,333 g, 8,23 mmol, 82%) as a yellow oil that slowly solidified upon standing.

VRMS: calculated for C18H18FNO: 283,1372; found: 283,1380.

f) Methyl(2R,3aR,12bS)-11-Fluoro-1-(hydroxymethyl)-3,3a,8,12b-tetrahydrobenzo-[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate (intermediate compound 62)

the intermediate connection 62

Intermediate pyrrolidin 61 (567 mg, 2.00 mmol) was dissolved at 0°C in a mixture of CH2Cl2(20 ml) and a saturated aqueous solution of NaHCO3(20 ml), then added methylchloroform (0,23 ml, 281 mg, 2,98 mmol), bath with ice was removed and the resulting mixture was stirred for 5 hours. The organic layer was separated, the aqueous phase was extracted with CH2Cl2(40 ml)then the combined organic layers were washed with water (2×40 ml), saturated salt solution (20 ml), dried (MgSO4) and was evaporated. The residue was purified by chromatography on a column of silica (CH2Clsub> 2-EtOH, 95/5)to give the intermediate carbamate 62 (669 mg, a 1.96 mmol, 98%) as a yellow-brown oil that solidified upon standing.

VRMS: calculated for C20H20FNO3: 341,1427; found: 341,1435.

g) (2R,3aR,12bS)-11-fluoro-2-(hydroxymethyl)-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carbaldehyde (intermediate compound 62a)

the intermediate connection 62a

A mixture of intermediate compound 61 (283 mg, 1 mmol), ethylformate (741 mg, 10 mmol) and acetonitrile (10 ml) was boiled under reflux for 18 hours, then evaporated in vacuum. The residue was purified by chromatography (Kieselgel 60, 70-230 mesh, EtOH-CH2Cl25/95), receiving 62a (283 mg, of 0.91 mmol, 91%) as a yellow-brown solid.

The product is a mixture of 2 rotamers (ratio 3:2).

CI-MS (CH4) 312 (MH+, 100%); 292 (MH+-HF, 13%).

Example A50

(2R,3aR,12bS)-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrole-1,2(2H)-dicarbollide (intermediate compound 63)

the intermediate connection 63

Chlorproma pyridinium (104 mg, 0.48 mmol) was added to a solution of the intermediate alcohol 62a (100 mg, 0.32 mmol) in CH2Cl2(10 ml) and the resulting suspension was stirred in nitrogen atmosphere for 3 hours. After addition of Et2O (20 ml), the mixture of the filter is Vali through silicon dioxide, the remainder of the resin in the flask was rinsed Et2O (40 ml)was again filtered, evaporated to dryness in vacuum. The crude intermediate aldehyde 63 (77 mg, 0.25 mmol, 78%) was obtained as a reddish oil containing traces of chromium. The product was used directly without purification.

CI-MS (CH4) 310 (100%, MH+), 290 (11%, MH+-HF); 282 (7%, MH+-CO).

Example A51

(2aS,11bR,12aR)-4-fluoro-1,2a,7,11b,12,12a-hexahydropyrazino[1,2-a]dibenzo[3,4:6,7]cyclohepta[1,2-d]pyrrole (intermediate compound 64)

the intermediate connection 64

Poly(triphenylphosphine) (0.33 g, about 1 mmol Ph3P) were subjected to swelling in an argon atmosphere in anhydrous CH2Cl2(10 ml), then through the membrane was added diisopropylcarbodiimide (222 mg, 1.1 mmol) in THF (3 ml) at 0°C. the Suspension was stirred for 30 minutes at 0°C followed by the addition of intermediate compound 61 (104 mg, 0,366 mmol) in THF (4 ml). The cooling bath was removed and the reaction mixture was stirred at room temperature for 12 hours, then added water (0.1 ml), the resin was filtered and washed with THF (15 ml), the combined organic layers were evaporated and purified by chromatography on a column (Kieselgel 60, 230-400 mesh mesh, CH2Cl2-EtOH from 100/0 to 96/4)to give the intermediate compound 64 (63 mg, 0,238 mmol, 65%) as a yellowish oil.

VRMS: calculated for C1 H16FN: 265,1267; found: 265,1270.

Example A52

a) {(2R,3aR,12bS)-11-Fluoro-1-[(2-nitrophenyl)sulfonyl]-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl}methyl-2-nitrobenzenesulfonate (intermediate compound 65)

the intermediate connection 65

A solution of intermediate pyrrolidine 61 (567 mg, 2.00 mmol), Et3N (1,012 mmol, 10,00 mmol), dimethylaminopyridine (40 mg, 0.33 mmol) in CH2Cl2(30 ml) was treated with 2-nitrobenzenesulfonamide (1,330 g, 6,00 mmol) and the resulting mixture was stirred at room temperature for 3 hours, then extinguished saturated aqueous NH4Cl (30 ml). After extraction CH2Cl2(3×30 ml) the combined organic phases are washed with 1N HCl (15 ml), saturated aqueous K2CO3(40 ml), water (3×40 ml), a saturated solution of salt, dried (MgSO4), evaporated and purified by chromatography on a column of silica (heptane-EtOAc, 95/5 → 85/15)to give the intermediate compound 65 (1,203 g of 1.84 mmol, 92%) as yellow crystals rapidly decomposed upon standing.

1H NMR (300M Hz, CDCl3) δ compared to 8.26-to 7.50 (m, 8H, Ar-H, the remains of 2-nosila); 7,20-7,03 (m, 6H, Ar-H, part dibenzosuberone); for 6.81 (TD, J=8,3, 2.7 Hz, 1H, Ar-H); of 5.40 (d, J=to 11.0 Hz, 1H, CH-12b); 4,69 (d, J=16,7 Hz, 1H, CH2-8); 4,60 (m, 2H, CH2ONs); and 4.40 (m, 1H, CH-2); to 3.73 d, J=16,7 Hz, 1H, CH2'-8); 3,55 is 3.40 (m, 1H, CH-3a); 2,80 (DD, J=13,0, 6,2 is C, CH2-3); 2,33-to 2.18 (m, 1H, CH2'-3).

b) 2-[4-({(2R,3aR,12bS)-11-fluoro-1-[(2-nitrophenyl)sulfonyl]-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl}methyl)-1-piperazinil]ethanol (intermediate compound 66a) and 2-[({(2R,3aR,12bS)-11-fluoro-1-[(2-nitrophenyl)sulfonyl]-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl}methyl)(methyl)amino]ethanol (intermediate compound 66b)

the intermediate connection 66a
the intermediate connection 66b

A mixture of intermediate biznesie 65 (0.35 g, 0.54 mmol) and the appropriate amine (3 mmol) in dioxane (10 ml) was boiled under reflux for 4 hours, cooled to ambient temperature, diluted with water (100 ml), precipitiously product was filtered, washed with water (100 ml)was dissolved in EtOAc, the solution was washed with saturated salt solution, dried (K2CO3), evaporated and used in the next stage without purification.

Example A53

a) 2-[(4S)-2,2-diethyl-1,3-dioxolane-4-yl]ethanol (intermediate compound 67b)

sub the internal connection 67b

To a solution of intermediate (S)-1,2,4-butanetriol 67a (6,76 g, 63,68 mmol) in fresh distilled pentane-3-one (320 ml) was added para-toluensulfonate acid (p-TSA) (6,06 g, 31,84 mmol). The reaction mixture was stirred at 53°C for 16 hours, then was added Et3N (10 ml) and the reaction mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. Gradient flash chromatography (CH2Cl2/MeOH from 100:0 to 97:3 to 95:5) gave the intermediate protected alcohol 67b (9,84 g, 89%) as a colourless oil.

b) [(4S)-2,2-diethyl-1,3-dioxolane-4-yl]acetaldehyde (intermediate compound 67c)

intermediate compound 67c

To a solution of intermediate compound 67b 2(S)-2-(2,2-diethyl-[1,3]dioxolane-4-yl)ethanol (4,00 g, 22,96 mmol) and molecular sieves 4A (11,50 g) in CH2Cl2(200 ml), stir at 0°C for 5 minutes, was added chlorproma pyridinium (PCC) (9,90 g, 45,92 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 1 hour. The crude reaction mixture was filtered through a bed of silica, washed with Et2O (50 ml) and concentrated under reduced pressure, obtaining the intermediate aldehyde 67c (of 3.56 g, 90%) as a colourless oil.

c) 11-{2-[(4S)-2,2-diethyl-1,3-dioxolane-4-yl]this is Liden}-8-fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-he (intermediate compound 67d)

intermediate compound 67d

MgBr2(0,733 g, 3,98 mmol) was added to 8-fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-ONU (0.75 g, of 3.32 mmol) in toluene (15 ml) and the reaction mixture was stirred at room temperature for 30 minutes. Added intermediate aldehyde 67c (2,05 g, 11,92 mmol) in THF (10 ml), and t-BuOK (0,074 g, 0.66 mmol). The reaction mixture was stirred for 22 hours at ambient temperature, then was added a saturated aqueous solution of NH4Cl (15 ml). Product three times was extracted with Et2O (3×30 ml), the combined organic phases were washed with water (2×35 ml), saturated salt solution (25 ml), dried over MgSO4. After evaporation of the toluene, the residue was purified on a column of silica gel using a mixture of Et2O/heptane (10/90)to give the intermediate compound 67d (1,079 g, 86%) as a yellowish oil.

VRMS (EI): calculated for C24H25FO3: 380,1800; found: 380,1785.

d) (11R)-11-{2-[(4S)-2,2-diethyl-1,3-dioxolane-4-yl]ethyl}-8-fluoro-5,11-dihydro-10H-dibenzo-[a,d]cyclohepten-10-he (intermediate connection 67e)

the intermediate connection 67e

10% Pd-C (200 mg) and Et3N (is 0.135 ml, 0.97 mmol) was added to intermediate compound 67d (0,246 g, 0,647 mmol) in i-D (25 ml) and toluene (15 ml) and subjected to hydrogenation over night at room temperature. Rea is operating and the mixture was dissolved in CH 2Cl2was filtered through celite and the solvent evaporated. The residue was purified on a column of silica gel using a mixture of Et2O/heptane (30/70)to give the intermediate compound 67e (151 mg, 61%) as a yellowish oil.

VRMS C24H27FO3: 382,1944; found: 382,1951.

e) (10R,11R)-11-{2-[(4S)-2,2-diethyl-1,3-dioxolane-4-yl]ethyl}-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (intermediate connection 67f)

the intermediate connection 67f

Borohydride sodium (1.78 g, 46,84 mmol) was added to intermediate compound 35 (2.0 g, 5,88 mmol), dissolved in a mixture of i-D (80 ml)/phosphate buffer pH 7 (30 ml) at 0°C. After interaction for 1 hour at room temperature was added NH4Cl (saturated aqueous solution) and the mixture three times was extracted with CH2Cl2. The organic phase was dried over MgSO4and the solvent evaporated. The product was purified on silica gel using a mixture of Et2O/heptane (30/70)to give the intermediate compound 67f (1,96 g, 97%) as a colourless oil.

VRMS: calculated for C21H23FO3: 342,1631; found: 342,1627.

f) (4S)-4-{2-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]ethyl}-2,2-diethyl-1,3-dioxolane (intermediate connection 67g)

the intermediate connection 67g

The intermediate connection 67g received that is named the same way as described for intermediate 30.

g) (2S)-4-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-l,2-butanediol (intermediate connection 67h)

the intermediate connection 67h

The intermediate connection 67h was obtained in the same manner as described for intermediate 31.

h) (2S)-4-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-2-{[(4-were)sulfonyl]oxy}butyl-4-methylbenzenesulfonate (intermediate connection 67i)

the intermediate connection 67i

A mixture of intermediate (2S)-4-[(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-1,2-butanediol 67h (225 mg, 0.66 mmol), Et3N (506 mg, 5.0 mmol), dimethylaminopyridine (12 mg, 0.1 mmol) and TsCl (503 mg, of 2.64 mmol) in CH2Cl2(25 ml) was stirred at room temperature under nitrogen atmosphere for 15 hours. After quenching with a saturated aqueous solution of ammonium chloride (15 ml) the organic phase was separated and the aqueous layer was extracted with CH2Cl2(3×20 ml). The combined organic phases were washed with water (3×30 ml), saturated salt solution (25 ml), dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on a column (Kieselgel 60, 70-230 mesh, heptane-ethyl acetate 90/10)to give the intermediate compound 67i (352 mg, 0.54 mmol, 82%) as bescoto the semi-solid substance.

i) [(2R,4aR,13bS)-12-fluoro-2,3,4,4a,9,13b-hexahydro-1H-dibenzo[3,4:6,7]cyclohepta[1,2-b]pyridine-2-yl]methyl-4-methylbenzenesulfonate (intermediate connection 67k)

the intermediate connection 67k

Intermediate bestself 67i (340 mg, 0.52 mmol) was dissolved in MeOH (15 ml)was added Et3N (1,012 g, 10 mmol) and 10% Pd-C (150 mg) and the resulting mixture was first made at atmospheric pressure for 5 hours. The catalyst was removed by filtration through a small bed of diatomaceous earth was added anhydrous K2CO3(138 mg, 1 mmol) and the resulting suspension was stirred at room temperature for 5 hours. After filtering off solids MeOH and Et3N was removed in vacuum and the residue was purified flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOH-CH2Cl2from 5/95 to 12/88), receiving the intermediate connection 67k (153 mg, 0,338 mmol, 65%) as a yellowish oil.

CI-MS (CH4) 452 (MH+, 1%); 280 (MH+-TsOH, 100%).

Example A54

a) (10S,11R)-11-{2-[(4S)-2,2-diethyl-1,3-dioxolane-4-yl]ethyl}-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate connection 610)

the intermediate connection 68a

A solution of triphenylphosphine (910 mg, 3.5 mmol) in anhydrous THF (25 ml) were placed in a two-neck flask with a volume of 100 ml, equipped with a membrane inlet for Argo is a and a magnetic stirrer. After cooling to -15°C through the membrane were added undiluted diisopropylsalicylic (708 mg, 3.5 mmol) under vigorous stirring. The resulting yellow suspension was stirred at the above temperature for 30 minutes, then was added a solution of 4-nitrobenzoic acid (585 mg, 3.50 mmol) and intermediate alcohol 67f (673 mg, about 1.75 mmol) in THF (25 ml) for 10 minutes. The resulting yellow suspension was allowed to warm to room temperature and then was stirred for 12 hours. Was added water (0.3 ml), then silica gel (Kieselgel 60, 70-230 mesh, 4 g), THF was removed in vacuum and the powder of silicon dioxide was used for flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-heptane, from 5/95 to 15/85)to give the intermediate nitrobenzoate 610 (795 mg, 1,49 mmol, 85%) as an orange semi-solid substance.

b) (10S,11R)-11-[(3S)-3,4-dihydroxybutyl]-8-fluoro-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate compound 68b)

intermediate compound 68b

Hydrolysis of the intermediate dioxolane 610 (795 mg, 1,49 mmol) was carried out in the same manner as described in example A28, receiving the intermediate diol 68b (695 mg, 1,49 mmol, 100%) as an orange semi-solid substances. The product was used without purification.

c) (10S,11R)-8-fluoro-11-((3S)-3-hydroxy-4-{[(4-were)sulfonyl]oxy}Buti is)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate compound 68)

the intermediate connection 68

A mixture of diol intermediate 68b (695 mg, 1,49 mmol), Et3N (607 mg, 6 mmol), dibutil(oxo)tin (141 mg, 0,566 mmol) and TsCl (431 mg, and 2.26 mmol) in CH2Cl2(20 ml) was stirred at room temperature under nitrogen atmosphere for 12 hours. After quenching with a saturated aqueous solution of NH4Cl (15 ml) the organic phase was separated and the aqueous solution was extracted with CH2Cl2(3×30 ml). The combined organic phases were washed with water (3×20 ml), filtered through a 5 cm layer MgSO4and was evaporated in vacuum, obtaining the crude intermediate compound 68 (601 mg, 0.97 mmol, 65%) as a yellowish semi-solid mass, which was subjected to transformation without further purification.

d) [(2R,4aR,13bS)-12-fluoro-2,3,4a,9,l3b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-2-yl]methanol (intermediate connection 68d)

the intermediate connection 68d

A mixture of intermediate tosilata 68 (601 mg, 0.97 mmol), sodium methoxide (162 mg, 3.0 mmol) and MeOH (10 ml) was stirred at room temperature for 3 hours. After treatment with water (100 ml) the product was extracted with diethyl ether (3×30 ml). The combined organic phases were washed with water (3×40 ml) and saturated salt solution (40 ml), dried (MgSO4) and was evaporated in vacuum. Chromatographic purification (Kielselgel 60, 70-230 the Yosh, EtOAc-heptane from 10/90 to 25/75) to give the intermediate compound 68d (211 mg, 0.71 mmol, 73%) as a colourless oil.

VRMS: calculated for C19H19FO2: 298,1369; found 298,1350.

e) [(2R,4aR,13bS)-12-fluoro-2,3,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-2-yl]methyl-4-methylbenzenesulfonate (intermediate connection e)

the intermediate connection 68e

A mixture of intermediate alcohol 68d (211 mg, 0,708 mmol), Et3N (209 μl, 287 mg of 2.83 mmol), DMAP (86,5 mg, 0,708 mmol) and TsCl (270 mg, of 1.42 mmol) in CH2Cl2(10 ml) was stirred at room temperature under nitrogen atmosphere for 16 hours. After quenching with a saturated aqueous solution of NH4Cl (10 ml) the organic phase was separated and the aqueous solution was extracted with CH2Cl2(3×15 ml). The combined organic phases were washed with water (3×15 ml), dried (MgSO4) and was evaporated in vacuum, obtaining the crude intermediate connection 68e (282 mg, of 0.62 mmol, 88%) as a yellowish oil which was used without further purification.

Example A55

a) (10S,11R)-11-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl}-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate compound 69a)

intermediate compound 69a

A solution of triphenylphosphine (1049 mg, 4.0 mmol) in anhydrous THF (20 ml) were placed in a two-neck flask is the total volume 100 ml, equipped with a membrane inlet and magnetic stirrer. After cooling to -15°C through the membrane were added undiluted diisopropylsalicylic (809 mg, 4.0 mmol) under vigorous stirring. The resulting yellow suspension was stirred at the above temperature for 30 minutes, then was added a solution of 4-nitrobenzoic acid (4.0 mmol) and 11-(2,2-dimethyl[1,3]dioxolane-4-ylmethyl)-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (intermediate compound 3) (685 mg, 2.0 mmol) in THF (25 ml) for 10 minutes. The resulting yellow suspension was allowed to warm to room temperature and then was stirred for 12 hours. Was added water (0.3 ml), then silica gel (Kieselgel 60, 70-230 mesh, 4 g), THF was removed in vacuum and the powder of silicon dioxide was used for flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-heptane, from 5/95 to 10/90)to give the intermediate nitrobenzoate 69a (875 mg, 1.78 mmol, 89%) as an orange semi-solid substance.

b) (10S,11R)-11-[(2R)-2,3-dihydroxypropyl]-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate compound 69b)

intermediate compound 69b

Intermediate compound 69b was obtained from the intermediate acetal 69a (860 mg, about 1.75 mmol) in the same manner as described for intermediate 5. Chromatogra the Oia column (Kieselgel 60, 70-230 mesh, EtOAc-heptane, from 35/65 to 50/50) gave diol intermediate 69b (774 mg, 1,715 mmol, 98%) as a yellow semi-solid substance.

c) (10S,11R)-8-fluoro-11-(2-oxoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate compound 69c)

intermediate compound 69c

The intermediate diol 69b (774 mg, 1,715 mmol) was dissolved at 0°C in a mixture of THF (25 ml) and phosphate buffer pH 7 (5 ml), then one portion was added periodate sodium (642 mg, 3 mmol) at 0°C, the cooling bath was removed and the resulting mixture was stirred at room temperature for 4 hours. Was added water (50 ml), the product was extracted with diethyl ether (3×30 ml). The combined organic phases were washed with saturated aqueous solution of sodium metabisulfite (50 ml), water (2×50 ml), saturated salt solution (30 ml), dried over magnesium sulfate and evaporated in vacuum, obtaining the intermediate aldehyde 69c (680 mg, of 1.66 mmol, 97%) as a yellow foam. The product was used directly without purification.

d) (10S,11S)-8-fluoro-11-(1-formylphenyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate connection 69d)

the intermediate connection 69d

A mixture of intermediate aldehyde 69c (680 mg, of 1.66 mmol), AcOH (240 mg, 4.0 mmol), bis(dimethylamino)methane (719 mg, 7.0 mmol) and THF (30 ml) was stirred PR the room temperature for 3 hours. Was added water (50 ml), the product was extracted with diethyl ether (3×30 ml). The combined organic phases are washed with saturated aqueous sodium bicarbonate (25 ml), water (2×50 ml), saturated salt solution (30 ml), dried over magnesium sulfate and evaporated in vacuum, obtaining the intermediate unsaturated aldehyde 69d (680 mg, was 1.58 mmol, 95%) as a yellow oil.

e) (10S,11S)-8-fluoro-11-[1-(hydroxymethyl)vinyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-4-nitrobenzoate (intermediate connection 69e)

the intermediate connection 69e

Borohydride sodium (190 mg, 5.00 mmol) was added at room temperature over 10 minutes to a solution of intermediate aldehyde 69d (680 mg, was 1.58 mmol) in MeOH (30 ml). The reaction mixture was stirred at room temperature for 4 hours, reduce saturated aqueous ammonium chloride (20 ml) and was extracted with Et2O (3×30 ml). The combined organic phases were washed with water (2×50 ml), saturated salt solution (30 ml), dried over magnesium sulfate and evaporated in vacuum, obtaining the intermediate alcohol 69e (582 mg, of 1.34 mmol, 85%) as an orange oil.

f) (10S,11S)-8-fluoro-11-[1-(hydroxymethyl)vinyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (intermediate connection 69f)

the intermediate connection 69f

A mixture of intermediate nitrobenzo is that 69e (582 mg, of 1.34 mmol), sodium methoxide (162 mg, 3.0 mmol) and MeOH was stirred at room temperature for 4 hours. Was added water (70 ml), the product was extracted with EtOAc (3×30 ml). The combined organic phases were washed with water (2×50 ml), saturated salt solution (30 ml), dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-heptane, from 35/65 to 60/40)to give the intermediate diol 69f (286 mg, 1,005 mmol, 75%) as a colourless oil.

g) (3a5,12bS)-11-fluoro-3-methylene-3,3a,8,12b-tetrahydro-2H - dibenzo[3,4:6,7]cyclohepta-[1,2-b]furan (intermediate connection 69g)

the intermediate connection 69g

Tributylphosphine (405 mg, 2.0 mmol) was dissolved in toluene (25 ml) in an argon atmosphere. Was added dropwise diisopropylethylamine (405 mg, 2.0 mmol) in toluene (3 ml), then a solution of intermediate diol 69f (270 mg, 0.95 mmol). The resulting mixture was stirred at room temperature for 3 hours, then the reaction is extinguished by water (1 ml). Was added silica gel (Kieselgel 60, 70-230 mesh, 1.3 g), toluene was removed under vacuum and the powder of silica was subjected to flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-heptane, from 5/95 to 12/88), receiving the intermediate THF-derived 69g (205 mg, 0.77 mmol, 81%) as a colourless foam.

h) [(3aR,12bS)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-3-yl]methanol (about eroticne connection 69h)

the intermediate connection 69h

Athirat of boron TRIFLUORIDE (of 0.43 ml, 3.54 mmol) in THF (1 ml) was added at room temperature in an argon atmosphere to a solution of intermediate THF 69g (188 mg, 0.66 mmol), sodium borohydride (496 mg, of 2.64 mmol) in anhydrous THF (2 ml). The resulting solution was stirred in an argon atmosphere for 24 hours, the excess borohydride was carefully dissolved in water (3.8 ml)was added MeOH (1.5 ml), then 3 M NaOH (3.8 ml) and 30% hydrogen peroxide (0,55 ml). The reaction mixture was allowed to mix for 4 hours at room temperature, then the product was extracted with Et2O (3×30 ml). The combined organic phases were washed with water (2×50 ml), saturated salt solution (30 ml), dried over magnesium sulfate and evaporated in vacuum. The residue was purified flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-heptane, from 5/95 to 20/80)to give intermediate derived THF 69h (139 mg, 0.49 mmol, 74%) as a colourless oil.

i) (3aR,12bS)-3-(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan (intermediate connection 69i)

the intermediate connection 69i

Poly(triphenylphosphine) (0.33 g, about 1 mmol Ph3P) were subjected to swelling at room temperature in an argon atmosphere in anhydrous THF (10 ml), then through the membrane was added diisopropyl who, in primary forms (222 mg, 1.1 mmol) in THF (3 ml) at -15°C. the Suspension was stirred for 30 minutes at -15°C, then one portion was added intermediate alcohol 69h (139 mg, 0.49 mmol) in anhydrous THF (2.5 ml), then was added dropwise diphenylphosphoryl (160 mg, of 0.58 mmol) in THF (3 ml). The resulting suspension was stirred in an argon atmosphere for 12 hours. After quenching with water (0.3 ml) the resin was filtered and the solvent was removed in vacuum. The residue was purified flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-heptane, 15/85)to give the intermediate azide 69i (136 mg, 0.44 mmol, 90%) as a colourless foam.

Example A56

a)(2R)-3-[(10R,11R)-2-fluoro-11-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]-1,2-propandiol (intermediate compound 70a)

the intermediate connection 70a

Intermediate triol 70a received from the intermediate compound 3 (514 mg, 1.50 mmol) in the same manner as described in example A5. The crude intermediate compound 70a (449 mg, of 1.485 mmol, 99%) was obtained as a colourless oil and used without purification.

b) (3aR,12bR)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-ol (intermediate compound 70b)

the intermediate connection 70b

The intermediate connection 70b received from the intermediate triol 70a (449 mg, of 1.485 mmol) in the same manner as described for compound 44. F. the ash-chromatography (Kieselgel 60, 230-400 mesh mesh, EtOAc-heptane, from 10/90 to 33/67) to give the intermediate compound 70c (357 mg, 1,32 mmol, 89%) as a yellow-brown solid.

(C) (3aR,12bR)-3-[(dimethylamino)methyl]-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo-[3,4:6,7]cyclohepta[1,2-b]furan-2-ol (intermediate compound 70c)

intermediate compound 70c

The reaction in the case of intermediate compound 70c (335 mg, 1,24 mmol) was carried out in the same manner as described for compound 45. Received complex, inseparable mixture of products and used in the next stage without purification.

d) (10R,11R)-11-[2-(dimethylamino)-1-(hydroxymethyl)ethyl]-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (intermediate compound 70d)

intermediate compound 70d

The reaction mixture containing the intermediate compound 70c, carried out in the same manner as described for compound 46. Purification RP-HPLC (Waters Xterra® C18, 19×50 mm, MeOH-water 50/50, then pure MeOH, 4 ml/min) gave the intermediate compound 70d (135 mg, 0.41 mmol, 33%, based on the intermediate compound 70b) as a yellow oil.

Example A57

a) [(10R,11S)-11-azido-2-fluoro-10,11-dihydro-5H-dibenzo[a,dl]cyclohepten-10-yl]acetaldehyde (intermediate compound 71a)

the intermediate connection 71a

The reaction using temporarily the CSOs diol 5 (0,99 g, to 3.02 mmol) was carried out in the same manner as described for compound 44. Purification by chromatography on a column (Kieselgel 60, 230-400 mesh mesh, diethyl ether-heptane, 50/50) to give the intermediate aldehyde 71a (778 mg, 2,63 mmol, 87%) as a colourless oil.

b) 2-[(10S,11S)-11-azido-1-fluoro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acrylaldehyde (intermediate compound 71b)

intermediate compound 71b

The reaction using intermediate compound 71a (618 mg, of 2.09 mmol) was carried out in the same manner as described for compound 45. The crude intermediate aldehyde 71b (605 mg, 1.97 mmol, 94%) was obtained as a colourless oil and used without further purification.

c) (3aS,12bS)-11-fluoro-3-methylene-1,23,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta-[1,2-b]pyrrole (intermediate compound 71c)

intermediate compound 71c

Poly(triphenylphosphine) (1.40 g, about 4.2 mmol Ph3P) were subjected to swelling at room temperature in an argon atmosphere in THF (30 ml), then was added the intermediate aldehyde 71b (405 mg, of 1.32 mmol) in THF (10 ml) and water (0,19 g). The resulting mixture was stirred in argon atmosphere at 50°C for 1 hour. After a specified period of time the resin was filtered and THF was removed in vacuum. The residue was dissolved in MeOH (10 ml)was added AcOH (1 ml) and cyanoborohydride the sodium (200 mg, 3.2 mmol) and the resulting mixture was stirred at room temperature for 2 hours, then extinguished concentrated HCl (1 ml), was treated with saturated aqueous NaHCO3(15 ml) and podslushivaet 1N sodium hydroxide (3 ml). The product was extracted with CH2Cl2(3×50 ml), the combined organic phases were washed with water (2×30 ml), saturated salt solution (30 ml), dried (MgSO4) and was evaporated in vacuum, obtaining the intermediate pyrrolidin 71c (258 mg, 0.97 mmol, 74%) as a yellow foam. Intermediate compound 71c used without further purification.

d) Methyl(3aS,12bS)-11-fluoro-3-methylene-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate (intermediate compound 71d)

intermediate compound 71d

The reaction using intermediate compound 71c (258 mg, 0.97 mmol) was carried out in the same manner as described for compound 9. Flash chromatography (Kieselgel 60, 230-400 mesh mesh, heptane-EtOAc from 50/50 to 0/100) to give the intermediate compound 71d (282 mg, 0.87 mmol, 90%) as a yellow oil.

e) Methyl(3aR,12bS)-11-fluoro-3-(hydroxymethyl)-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate (intermediate compound 71e)

the intermediate connection 71e

The reaction using 71d (255 mg, of 0.79 mmol) was carried out so well the way as described for compound 49. Flash chromatography (Kieselgel 60, 230-400 mesh mesh, EtOH-CH2Cl2from 1/99 to 3/97) gave 71e (215 mg, 0,63 mmol, 80%) as a colourless oil.

f) Methyl(3aR,12bS)-3-(azidomethyl)-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate (intermediate compound 71f)

the intermediate connection 71f

The reaction using the intermediate 71f (215 mg, 0,63 mmol) was carried out in the same manner as described for compound 50. Flash chromatography (Kieselgel 60, 230-400 mesh mesh, ethyl acetate) gave the intermediate compound 71f (194 mg, of 0.53 mmol, 84%) as a colourless oil.

B. obtain the final compounds

All compounds obtained as described hereinafter, are mixtures of isomeric forms, unless specifically provided otherwise.

Example B1

(4aS,13bR,14aS)-6-fluoro-2-methyl-1,2,3,4a,9,13b,14,14a-octagenarians[3',4':6',7]cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazole (final connection 1)

end connection 1

To a solution of intermediate diamine 9 (130 mg, 0.3 mmol) in MeOH (5 ml) was added Et3N (126,5 µl of 0.91 mmol) and the mixture was first made at 1 atmosphere pressure using 10% palladium on coal, with vigorous stirring at room temperature. After 1 hour, was added formaldehyde (112,8 μl, 1.5 mmol) and the mixture was first made back in an hour. C is the suspension was filtered through a pad celite and solids 4 times washed CH 2Cl2. After evaporation crude product was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH (95/5). Purification gave the target compound 1 in the form of oil (50.5 mg, 54%).

Mass spectrum: -CI m/z (distribution, relative intensity) 309 (MH+, 100%), 289 (MH+-HF, 26%); EI: m/z (distribution, relative intensity) 308 (M+68%), 279 (M+-CH2NH, 4%), 265 (M+-CH3NCH2, 100%), 197 (23%); High resolution EI calculated C20H21FN2(M+): 308,1689 found: 308,1684 (35%).

Example B2

[(2S,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine (final compound 2)

end connection 2

The above compound 1 (0,114 g and 0.37 mmol) was dissolved in MeOH (10 ml) and added TFU (0,071 ml of 0.93 mmol), NaCNBH3(0,058 g of 0.93 mmol) and stirred at room temperature for 1 hour. Added 10 ml of K2CO3(saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (10%) gave the target compound 2 in the form of oil (0,067 g, 59%).

Mass spectrum: -CI m/z (distribution, relative intensity) 311 (MH+, 100%), 291 (MH+-HF, 25%), 282 (MH+CH2NH), 266 (MH+NH(CH3)2 , 13%), 252 (8%); EI: m/z (distribution, relative intensity) 310 (M+26%), 266 (M+-(CH3)2N, 76%), 252 (M+-CH3)2NCH2, 70%), 235 (100%), 209 (61%); High resolution EI calculated C20H23FN2(M+): 310,1845 found: 310,1820 (5%).

Example B3

(4aS,13bR,14aS)-6-fluoro-1,4a,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazol-3(2H)-tion (target compound 3)

the target compound 3

To a solution of intermediate diamine 9 (238,6 mg, 0.85 mmol) in DMF (3 ml) was added carbon disulfide (0,076 ml, 1.28 mmol). Was stirred at 60°C for 20 minutes. After evaporation of the solvent the residue was purified by chromatography on a column of silica gel using a mixture of EtOAc/heptane (50/50)to give compound 3 in the form of a semi-final compounds (124,6 mg, 45%).

Mass spectrum: -CI m/z (distribution, relative intensity) 325 (MH+, 100%), 252 (1%), 224 (2%).

Example B4

(5aS,14bR,15aS)-7-fluoro-2-methyl-1,2,3,5a,10,14b,15,15a, octahydro-4H-dibenzo[3',4':6',7']cyclohepta-[1',2':4,5]pyrrolo[1,2-a]pyrazin-4-one (final compound 4)

the target compound 4

A solution of the above intermediate carbamate 16 (86,2 mg, 0,19 mmol) in MeOH (3 ml) was first made at 1 atmosphere pressure using 10% palladium on coal, with vigorous stirring at room is the temperature. After the interaction for 1 hour was added formaldehyde (70,7 μl, of 0.94 mmol) and the mixture was first made back in an hour. The suspension was filtered through a pad celite and solids 4 times washed CH2Cl2. After evaporation of solvent the crude product was purified by chromatography on a column of silica gel using CHCl3receiving the target compound 4 (18.6 mg, 29%).

Mass spectrum: -CI m/z (distribution, relative intensity) 337 (MH+, 100%), 317 (MH+-HF, 18%), 309 (MH+-CO, 9%), 161 (9%), 133 (75%), 93 (72%).

Example B5

[(2R,3aR,12bS)-11-fluoro-1-methyl-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine (target compound 5)

the target compound 5

To a solution of intermediate diamine 13 (28,7 mg, 0.05 mmol) in MeOH (2 ml) was added Et3N (21,4 μl, 0.15 mmol) and formaldehyde (18,8 μl, 0.25 mmol) and the mixture was treated with hydrogen at a pressure of 1 atmosphere and using 10% palladium on coal with vigorous stirring at room temperature. After the interaction, within 1 hour, the suspension was filtered through a pad celite and solids 4 times washed CH2Cl2. After evaporation crude product was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH (90/10). Purification gave the target compound 5 in the form of oil (16,7 mg, 9%).

Mass spectrum: -CI m/z (distribution, relative intensity) 325 (MH+, 100%), 323 (25%), 305 (MH+-HF, 19%), 280 (MH+-HN(CH3)2, 12%), 266 (MH+-CH3N(CH3)2, 36%).

Example B6

(4aS,13bR,14aR)-6-fluoro-1,4a,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazol-3(2H)-he (the target compound 6)

the target compound 6

To a solution of intermediate diamine 13 (40,4 mg, 0.14 mmol) in CH3CN (2 ml) was added Et3N (50 μl, 0.36 mmol) and the mixture was heated in an argon atmosphere at 70°C. After 1 hour, was added dropwise a solution of diphenylcarbonate (36,6 mg, 0,17 mmol) in CH3CN and the mixture was stirred at 70°C for 2 days. After evaporation crude product was purified by chromatography on a column of silica gel using a mixture of EtOAc/heptane (20/80)to give the target compound is urea 6 in the form of oil (23 mg, 52%).

Mass spectrum: -CI m/z (distribution, relative intensity) 309 (MH+, 100%), 308 (12%), 289 (MH+-HF, 20%), 279 (3%), 113 (8%).

Example B7

(4aS,13bR,14aR)-6-fluoro-2-methyl-1,4a,9,13b,14,14a-hexahydrobenzo[3',4':6',7]cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazol-3(2H)-he (the target compound 7)

the target compound 7

To a solution of compound urea 6 (29 mg, 0.10 mmol) in THF (3 ml) was added NaH (15,9 mg, 0.31 mmol) and the mixture was stirred at room temperature is re within 20 minutes. Then add Me2SO4(25,4 mg, 0.26 mmol) and the mixture was stirred additionally for 30 minutes. Added 10 ml of NH4Cl (saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/heptane (40/60) gave the target compound is methylated urea 7 in the form of oil (19 mg, 63%).

Mass spectrum: -CI m/z (distribution, relative intensity) 323 (MH+, 100%), 303 (MH+-HF, 26%), 209 (2%), 127 (3%).

Example B8

(4aS,13bR,14aR)-6-fluoro-1,4a,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazol-3(2H)-tion (final compound 8)

the target compound 8

To a solution of intermediate diamine 13 (54 mg, 0,19 mmol) in DMF (3 ml) was added carbon disulfide (17,3 μl, 0.29 mmol). After stirring at 60°C for 20 minutes, subsequent evaporation of the solvent purification on a column of silica gel (eluent: EtOAc/heptane (50/50)) gave crystalline target compound 8 (27.3 mg, 44%); TPL: 150-151°C.

Mass spectrum: -CI m/z (distribution, relative intensity) 325 (MH+, 100%), 252 (1%), 224 (2%).

Example B9

(4aS,13bR,14aR)-6-fluoro-3-(methylsulfanyl)-1,4a,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazole (target compound 9)

end with the unity 9

To a solution of final compound 8 (140,6 mg, 0.43 mmol) in MeOH (10 ml) was added methyliodide (of 53.5 μl, 0.86 mmol) and Et3N (129 μl, 0.86 mmol). After stirring at 80°C for 2 days, the solvent and the reagents are evaporated. Purification on a column of silica gel (eluent: EtOAc/heptane (40/60)) gave S-methylated target compound 9 as an oil (72,7 mg, 49%).

Mass spectrum: -CI m/z (distribution, relative intensity) 339 (MH+, 100%), 319 (MH+-HF, 4%), 268 (8%), 266 (3%).

Example B10

[(2R,3aR,12bS)-11-fluoro-1-(methoxyacetyl)-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-6]pyrrol-2-yl]-N,N-dimethylethanamine (target compound 10)

end connection 10

To a solution of intermediate 19 (265,3 mg, 0.44 mmol) in MeOH (20 ml) was added MeSO3H (2 ml) and the mixture was stirred at 60°C for 30 minutes. After evaporation of solvent was added NaHCO3(saturated aqueous solution) (15 ml) and the mixture was extracted with CH2Cl2(3×10 ml). The combined organic layers were dried over MgSO4. Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (5%) gave aminosidine (125 mg, 79%). The latter was then dissolved in MeOH (30 ml). After adding formaldehyde (80 μl, 1.06 mmol) the mixture was first made (1 ATM)using 10% palladium on coal with vigorous stirring at room temperature the f within 6 hours. Then the suspension was filtered through a pad celite and solids 4 times washed CH2Cl2. After evaporation of solvent the crude product was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH (95/5). The target compound 10 (90,1 mg, 67%) was obtained as oil (mixture of conformers).

Mass spectrum: -APCI m/z (distribution, relative intensity) 383 (MH+, 100%), 369 (4%), 367 (4%), 363 (MH+-HF, 5%), 354 (2%), 351 (2%).

Example B11

Methyl({[(2R,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}amino)acetate (target compound 11)

the target compound 11

The intermediate connection 21 with 53.4 mg, 0.15 mmol) was dissolved in a saturated solution of HCl in MeOH (10 ml) and the mixture was stirred at 60°C over night. After removal of solvent was added to 10 ml of K2CO3(saturated aqueous solution) and the mixture was extracted with CH2Cl2(3×10 ml). Purification on a column of silica gel using a mixture of CHCl3/MeOH (97/3) gave compound complex aminoether 11 (20 mg, 37%) as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 355 (MH+, 100%), 335 (MH+-HF, 14%), 295 (MH+-CH3OH-CO, 4%), 252 (MH+-CH3OH-CH2CO-NHCH2, 8%), 169 (5%), 141 (46%); EI m/z (distribution, relative intensity) 354 (M+, 3%), 295 (M -CH3OCO, 4%), 252 (M+-CH3OCOCH2NHCH2, 100%), 235 (M+-CH3OCOCH2NHCH2-NH3, 68%), 223 (8%), 209 (22%); High resolution EI calculated C21H23N2O2F (M+): 354,1744 found: 354,1751 (9%).

Example B12

(5aS,14bR,15aR)-7-fluoro-1,2,3,5a,10,14b,15,15a, octahydro-4H-dibenzo[3',4':6',7]cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin-4-one (final compound 12)

end connection 12

Intermediate compound 21 (250 mg, 0.71 mmol) was dissolved in 10 ml of HCl in MeOH (saturated solution) and the mixture was stirred at room temperature overnight. The reaction was suppressed by adding 10 ml of K2CO3 (saturated aqueous solution). Then the mixture 3 times was extracted with 10 ml of CH2Cl2. The combined organic layers were dried over MgSO4and was evaporated. Purification on a column of silica gel using a mixture of CHCl3/MeOH (95/5) gave the target compound 12 (67,6 mg, 29%) as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 323 (MH+, 100%), 303 (MH+-HF, 20%), 295 (MH+-CO, 2%), 252 (MH+-COCH2-NHCH2, 1%), 188 (2%), 160 (5%); EI m/z (distribution, relative intensity) 322 (M+, 100%), 252 (M+-COCH2N=CH2, 40%), 235 (68%), 223 (M+-COCH2N=CH2- CH2NH, 44%), 207 (13%), 209 (88%), 209 (22%); High resolution EI calculated C20H19N2OF (M+. ): 322,1481 found: 322,1484 (100%).

Example B13

(5aS,14bR,15aR)-7-fluoro-2-methyl-1,2,3,5a,10,14b,15,15a, octahydro-4H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin-4-one (final compound 13)

end connection 13

To a solution of final compound 12 (82,3 mg, 0.25 mmol) in MeOH (10 ml) was added formaldehyde (96 μl, 1,22 mmol) and the mixture was first made (1 ATM)using 10% palladium on coal, with vigorous stirring at room temperature for 1 hour. The mixture is then filtered through a pillow celite and solids 4 times washed CH2Cl2. After evaporation crude product was purified by chromatography on a column of silica gel using CHCl3/MeOH (3%) as eluent. The target compound 13 (43,4 mg, 50%) was obtained as a solid substance; TPL: 139-141°C.

Mass spectrum: -CI m/z (distribution, relative intensity) 337 (MH+, 100%), 317 (MH+-HF, 30%), 279 (1%), 251 (1%), 209 (1%); EI m/z (distribution, relative intensity) 336 (M+, 74%), 293 (M+-COCH3, 13%), 265 (M+-CO=CHNHCH3, 9%), 233 (18%), 209 (42%), 196 (26%), 57 (100%); High resolution EI calculated C21H21N2OF (M+): 336,1638 found: 336,1641 (100%).

Example B14

(5aS,14bR,15aR)-7-fluoro-2-methyl-1,3,4,5a,10,14b,15,15a, octahydro-2H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin (target compound 14)

end connection 14

To a solution of final compound 13 (to 34.3 mg, 0.1 mmol) in THF (10 ml) was added BH3·Me2S (100 μl, 0.2 mmol) and the mixture was heated at 85°C during the night. After evaporation of the solvent the residue was dissolved in 10 ml of HCl in MeOH (saturated solution) and the mixture is boiled under reflux for 30 minutes. After removal of solvent was added to 10 ml of K2CO3(saturated aqueous solution) and a solution of 4 times was extracted with CH2Cl2. Then the combined organic layers were evaporated and the crude product was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH (3%) as eluent. The target compound 14 (15,9 mg, 50%) was obtained as oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 323 (MH+, 73%), 303 (MH+-HF, 18%), 247 (4%), 219 (3%), 43 (100%); EI m/z (distribution, relative intensity) 322 (M+, 73%), 278 (M+-N(CH3)2, 44%), 266 (M+-N(CH2)3, 85%), 264 (M+-CH2CH2NHCH3, 94%), 251 (M+-CH2CH2- CH2N(CH3), 100%), 209 (68%), 196 (38%); High resolution EI calculated C21H23N2F (M+.): 322,1845 found: 322,1849 (100%).

Example B15

(4aS,13bR,14aS)-6-fluoro-1,4a,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazol-3(2H)-he (the target compound 15)

the target compound 15

To the above intermediate compound 25 (13.5 mg, 0.04 mmol) in CH2Cl2(1 ml) was added CH3SO3H (1,3 ál, 0.02 mmol). After stirring at room temperature for 1 minute and the mixture was treated by the addition of Na2CO3(saturated aqueous solution). 3 times was extracted with CH2Cl2and was dried over MgSO4. Purification on a column of silica gel using a mixture of CHCl3/MeOH (95/05) gave the target compound 15 in the form of an oily product (10.5 mg, 82%).

Mass spectrum: -CI m/z (distribution, relative intensity) 309 (MH+, 100%), 289 (MH+-HF, 17%), 257 (1%).

Example B16

(4aS,13bR,14aS)-6-fluoro-2-methyl-1,4a,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-c]imidazol-3(2H)-he (the target compound 16)

the connection 16

To a solution of final compound imidazolone 15 (10 mg, 0.03 mmol) in THF (1 ml) was added NaH (5 mg, 0.1 mmol) and the mixture was stirred at room temperature for 20 minutes. Then add Me2SO4(8 μl, 0.08 mmol) and the mixture was stirred for 30 minutes was Added 10 ml of NH4Cl (saturated aqueous solution), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of EtOAc/heptane (50/50) gave the target compound N-meilir the bath imidazole 16 (8,4 mg, 80%) in the form of oil.

Mass spectrum: -CI m/z (distribution, relative intensity) 323 (MH+, 100%), 303 (MH+-HF, 6%), 257 (11%), 252 (MH+-CH2N(CH3)CO, 9%), 229 (9%).

Example B17

[(2R,3aR,12bS)-11-fluoro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]-N,N-dimethylethanamine (target compound 17)

connection 17

To a solution of intermediate 38 (0.17 g, 0.5 mmol), CH2O (3 EQ) and AcOH (3 EQ) in MeOH (5 ml) at 0°C in several portions were added NaCNBH3(4 EQ). The reaction mixture was heated to room temperature and was stirred for 6 hours. To the reaction mixture was added solid NaHCO3(0.5 g) and stirred for 0.5 hours. To remove inorganic complexes, the reaction mixture was applied to a short filtration column and diluted with a mixture of CH2Cl2:MeOH (of 9.5:0.5 to). Thus obtained crude intermediate connection

was dissolved in i-D (4 ml) and to it was added a solution of KOH (56 mg) in water (0.5 ml) and then boiled under reflux for 3 hours. To the reaction mixture was added silica and the solvent was removed under reduced pressure, and then the compound was purified flash chromatography using a mixture of CH2Cl2/MeOH (9:1) as eluent, obtaining the target compound 17 as thick is askoy fluid (60%, 93 mg).

VRMS: calculated 312,1638; found 312,1633.

Examples B18-20

a) To a solution of intermediate 39 (0.5 mmol, 0.33 g) in dioxane (5 ml) was added the appropriate amerosport (5 EQ) and then boiled under reflux for 6 hours. The solvent was removed under reduced pressure followed by chromatography (silica gel) using a mixture of CH2Cl2:MeOH (9:1) as eluent, receiving the intermediate 39a, 39b and 39c in the form of a thick viscous liquids with a total yield of 40-50%.

intermediate compound 39aintermediate compound 39b
intermediate compound 39c

b) a Mixture of the corresponding intermediate nasilnikov 39a, 39b and 39c (about 0.4 mmol), thiophenol (110 mg, 1.0 mmol), anhydrous K2CO3(138 mg, 1 mmol) and DMF (20 ml) was stirred at 80°C for 4 hours, cooled to ambient temperature, diluted with water, the product was extracted with EtOAc (3×50 ml), the combined organic phases were washed with water (4×50 ml), saturated of rest the rum salt (35 ml), dried (K2CO3), evaporated and purified by solid-phase extraction on alkaline alumina (activity Brockman II, heptane-ethyl acetate 50/50, then ethyl acetate-MeOH from 100/0 to 96/4 to 90/10)to give the final compounds 18, 19 and 20.

2-[{[(2R,3aR,12bS)-11-fluoro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]methyl}(methyl)amino]ethanol (target compound 18)

end connection 18

VRMS: calculated 342,1744; found 342,1750.

2-(4-{[(2R,3aR,12bS)-11-fluoro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]methyl}-1-piperazinil)ethanol (target compound 19)

the target compound 19

VRMS: calculated 397,2166; found 397,2158.

1-{[(2R,3aR,12bS)-11-fluoro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]methyl}-3-pyrrolidino (target compound 20)

the target compound 20

VRMS: calculated 354,1744; found 354,1755.

Example B21

[(2S,3aR,12bS)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 21)

end connection 21

To a solution of the above intermediate compound 43 (81 mg, 0.25 mmol) in THF and water (3 ml/1 ml) was added to Ph3P (of 0.13 g, 0.50 mmol). The reaction mixture was stirred at room temperature overnight. After evaporation of solvent was added MeOH (5 ml), HCHO (37% of the mass. an aqueous solution of 0.20 ml, 2.5 mmol), AcOH (1 ml) and NaCNBH3(75 mg, 1.20 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using EtOAc gave the target compound 21 in the form of an oily product (70 mg, 86%).

Mass spectrum: -CI m/z (distribution, relative intensity) 328 (MH+, 100%), 308 (MH+-HF, 20%), 283 (MH+-Me2NH, 40%), 249 (MH+-Me2NH - H2S, 12%).

Example B22

[(2S,3aR,12bS)-11-fluoro-1,1-dioxido-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 22)

the target compound 22

To a solution of the above intermediate sulfonated 44 (133,5 mg of 0.37 mmol) in THF (8 ml) was added water (67,0 μl, 3,74 mmol) and Ph3P (of 0.13 g, 0.50 mmol). The reaction mixture was stirred at room temperature for 1 night. After evaporation of solvent was added 5 ml of MeOH, HCHO (37% of the mass. an aqueous solution of 0.24 ml, 2,98 mmol), AcOH (0.5 ml) and NaCNBH3(94 mg, 1,49 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl . Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (95/05) gave the target compound 22 in the form of an oily product (60,7 mg, 45%).

Mass spectrum: -CI m/z (distribution, relative intensity) 360 (MH+, 100%), 358 (6%), 340 (MH+-HF, 12%), 303 (8%), 294 (MH+-H2SO2, 4%), 250 (1%).

Example B23

[(2R,3aR,12bS)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 23)

the target compound 23

To a solution of the above intermediate compound 47 (0.15 g, 0.46 mmol) in THF and water (5 ml/1 ml) was added to Ph3P (of 0.13 g, 0.50 mmol). After stirring at room temperature for 1 night and evaporation of the solvent was added 5 ml of MeOH, HCHO (37% of the mass. an aqueous solution of 0.20 ml, 2.5 mmol), AcOH (1 ml) and NaCNBH3(75 mg, 1.20 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using EtOAc gave the target compound 23 in the form of an oily product (70 mg, 86%).

Mass spectrum: -CI m/z (distribution, relative intensity) 328 (MH+, 100%), 308 (MH+-HF, 20%), 283 (MH+-Me2NH, 40%), 249 (MH+-Me2NH-H2S, 12%).

Example B24

[(2R,3aR,12bS)-for-1,1-dioxido-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 24)

the target compound 24

To a solution of the above intermediate sulfonated 48 (146,5 mg, 0.41 mmol) in THF (8 ml) was added water (74,0 μl, 4,10 mmol) and Ph3P (0,215 mg, 0.82 mmol). The reaction mixture was stirred at room temperature for 1 night. After evaporation of solvent was added 5 ml of MeOH, HCHO (37% of the mass. an aqueous solution of 0.28 ml, 3,51 mmol), AcOH (0.5 ml) and NaCNBH3(110,0 mg, about 1.75 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (90/10) gave the target compound 24 in the form of an oily product (105,0 mg, 71%).

Mass spectrum: -CI m/z (distribution, relative intensity) 360 (MH+, 100%), 358 (6%), 340 (MH+-HF, 12%), 303 (8%), 294 (MH+-H2SO2, 4%), 250 (1%).

Example B25

[(2S,3aR,12bS)-11-fluoro-1-oxido-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 25)

the target compound 25

To a solution of the above intermediate compound 49 (107,9 mg, 0.32 mmol) in THF (5 ml) was added water (57 μl, and 3.16 mmol) and Ph3P (166,0 mg, to 0.63 mmol). The reaction mixture was stirred at room temperature techenie night. After evaporation of solvent was added 5 ml of MeOH, HCHO (37%, of 0.26 ml of 3.33 mmol), AcOH (0.5 ml) and NaCNBH3(104,7 mg, 1,67 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (95/05) gave the target compound 25 in the form of an oily product (80.4 mg, 74%).

Mass spectrum: -CI m/z (distribution, relative intensity) 344 (MH+, 100%), 328 (MH+-O, 13%), 326 (MH+-H2O, 15%), 324 (MH+-HF, 15%), 182 (14%), 100 (27%).

Example B26

[(2S,3aR,12bS)-11-fluoro-1-oxido-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 26)

end connection 26

To a solution of the above intermediate compound 50 (133,4 mg, 0,39 mmol) in THF (5 ml) was added water (70 μl, 3,91 mmol) and Ph3P (205,2 mg, 0.78 mmol). The reaction mixture was stirred at room temperature for 1 night. After evaporation of solvent was added 5 ml of MeOH, HCHO (37%, of 0.24 ml, 2,99 mmol), AcOH (0.4 ml) and NaCNBH3(94,0 mg, 1.50 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Cleaning the colon is e with silica gel using a mixture of CH 2Cl2/MeOH (95/05) gave the target compound 26 in the form of an oily product (to 85.2 mg, 63%).

Mass spectrum: -CI m/z (distribution, relative intensity) 344 (MH+, 100%), 328 (MH+-O, 10%), 327 (12%), 326 (MH+-H2O, 46%), 324 (MH+-HF, 22%), 283 (12%).

Example B27

[(2R,3aR,12bS)-11-fluoro-1-oxido-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 27)

the target compound 27

To a solution of intermediate 51 (85 mg, 0.25 mmol) in THF (5 ml) was added water (45 μl, 2.49 mmol) and Ph3P (130, 8mm mg, 0.50 mmol). The reaction mixture was stirred at room temperature for 1 night. After evaporation of solvent was added 5 ml of MeOH, HCHO (37%, and 0.08 ml of 1.03 mmol), AcOH (0.3 ml) and NaCNBH3(32 mg, 0.52 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (95/05) gave the target compound 27 in the form of an oily product (35 mg, 41%).

Mass spectrum: -CI m/z (distribution, relative intensity) 344 (MH+, 100%), 328 (MH+-O, 4%), 327 (3%), 326 (MH+-H2O, 10%), 324 (MH+-HF, 8%), 281 (6%).

Example B28

[(2R,3aR,12bS)-11-fluoro-1-oxido-3,3a,8,12b-tetrahydro-2H-Deeb is the site, located between[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine (target compound 28)

the target compound 28

To a solution of the above intermediate compound 52 (158,5 mg, 0.46 mmol) in THF (5 ml) was added water (84 μl and 4.65 mmol) and Ph3P (243,8 mg of 0.93 mmol). The reaction mixture was stirred at room temperature for 1 night. After evaporation of solvent was added 5 ml of MeOH, HCHO (37%, of 0.32 ml of 4.05 mmol), AcOH (0.5 ml) and NaCNBH3(130 mg, 2.03 mmol). Stirring was continued at room temperature for 1 day. Added Na2CO3(saturated aqueous solution), 3 times was extracted with CH2Cl2. Purification on a column of silica gel using a mixture of CH2Cl2/MeOH (95/05) gave the target compound 28 in the form of an oily product (by 115.7 mg, 72%).

Mass spectrum: -CI m/z (distribution, relative intensity) 344 (MH+, 100%), 328 (MH+-O, 3%), 327 (3%), 326 (MH+-H2O, 13%), 324 (MH+-HF, 14%), 281 (6%).

Example B29

(3R,4aR,13bR)-12-fluoro-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-ol (target compound 29)

intermediate compound 23athe connection 29

Intermediate compound 23a (1.31 g, 2,63 mmol) was dissolved in CH2Cl2(50 ml). Added on gidropony (1.20 ml, 13,2 mmol) and camphorsulfonic acid (6 mg, was 0.026 mmol). Was stirred at room temperature for 5 hours. The solvent is evaporated and the residue was dissolved in 50 ml of MeOH. Added K2CO3(0.73 g, 5,26 mmol) and stirred at room temperature for 1 night. Was treated by the addition of saturated aqueous solution of NH4Cl (30 ml), was extracted with CH2Cl2(3×15 ml) and dried over MgSO4. The solvent is evaporated and the residue was dissolved in anhydrous THF (50 ml). Added NaH (0.24 g, 7,78 mmol) and stirred at room temperature for 1 day. Added 30 ml of a saturated aqueous solution of NH4Cl was extracted with CH2Cl2(3×20 ml) and the organic phase was dried over MgSO4. Purification on a column of silica gel using a mixture of ether/hexane (35/65) gave an oil (0,86 g, 90%from 2). The oil obtained (0,86 g, 2.34 mmol) was dissolved in 20 ml of MeOH/H2O (9/1) was added Dowex 50WX8-100 (1,00 g). The mixture was heated at 50°C for 1 night. Filtered through the filter P3, the solids were washed CH2Cl2(5×15 ml) and the solvent evaporated. Purification on a column of silica gel using a mixture of ether/hexane (70:30) gave the target compound 29 in the form of oil (0,61 g, 93%).

Mass spectrum: -CI m/z (distribution, relative intensity) 285 (MH+, 25%), 267 (MH+-H2O, 100%), 249 (MH+-2H2O, 36%); EI: m/z (distribution, tosichella intensity) 284 (M +, 1%), 209 (M+-CH2CHOHCH2OH, 100%); High resolution EI calculated C18H17FO2(M+): 284,1213 found: 284,1204 (2%).

Example B30

a)(3R,4aR,13bR)-12-fluoro-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-elmersolver (intermediate compound 53)

the intermediate connection 53

The target compound 29 (0,61 g of 2.16 mmol) was dissolved in CH2Cl2(50 ml). Added Et3N (of 0.60 ml, 4,32 mmol), DMAP (0,13 g at 1.08 mmol) and MsCl (0.25 ml, 3,24 mmol). Was stirred at room temperature for 4 hours. Was treated by the addition of saturated aqueous solution of NH4Cl (20 ml), was extracted with CH2Cl2(3×20 ml) and dried over MgSO4. Purification on a column of silica gel using CH2Cl2gave the intermediate compound 53 in the form of oil (0,76 g, 97%).

Mass spectrum: -CI m/z (distribution, relative intensity) 363 (MH+, 1%), 267 (MH+-MsOH, 100%), 249 (MH+-MsOH-H2O, 33%); EI: m/z (distribution, relative intensity) 362 (M+, 5%), 266 (M+-MsOH, 3%), 248 (M+-MsOH-H2O, 4%), 209 (M+-CH2CHOMsCH2OH, 100%); High resolution EI calculated C19H19FO4S (M+): 362,0988 found: 362,0984 (12%).

b) (3S,4aR,13bR)-3-azido-12-fluoro-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran (intermediate compound 54)

the intermediate connection 54

Intermediate mesilate 53 (0.29 grams, of 0.79 mmol) dissolved in DMF (10 ml)was added NaN3(0.10 g, was 1.58 mmol) and the mixture is heated at 90°C for 2 hours. Was added a saturated aqueous solution of NH4Cl (10 ml), was extracted with CH2Cl2(3×10 ml) and dried over MgSO4. Purification on a column of silica gel using a mixture of CH2Cl2/heptane (40:60) gave the intermediate compound 54 in the form of a crystalline product (0,22 g, 88%); TPL: 91-93°C.

Mass spectrum: -CI m/z (distribution, relative intensity) 310 (MH+, 13%), 282 (MH+-N2, 100%); EI: m/z (distribution, relative intensity) 281 (M+-N2, 28%), 208 (100%); High resolution EI calculated C18H16FNO (M+-N2): 309,1216 found: 309,1223 (40%).

c) (3S,4aR,13bR)-12-fluoro-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-amine (final compound 30)

end connection 30

Intermediate compound 54 (0.16 g, 0.52 mmol) was dissolved in i-D/THF (2:1, 15 ml). Was added 10% Pd-C (about 100 mg) was subjected to hydrogenation (pressure 1 ATM) for 1 night. Filtered through a pillow celite, the solids were washed CH2Cl2(5×10 ml) and the filtrate was evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH (75:25), receiving end of a connection is a group of 30 in the form of a crystalline product (0.14 g, 94%); TPL: 74-76°C.

Mass spectrum: -CI m/z (distribution, relative intensity) 284 (MH+, 100%); EI: m/z (distribution, relative intensity) 283 (M+; 5%), 209 (M+.-CH2CHNH2CH2OH, 100%); High resolution EI calculated C18H18FNO (M+.): 283,1372 found: 283,1370 (43%).

Example B31

(4aR,13bR)-12-fluoro-4,4a,9,13b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3(2H)-he (the target compound 31)

the target compound 31

The target compound 29 (77 mg, 0.27 mmol) was dissolved in CH2Cl2(10 ml) and added chlorproma pyridinium (131 mg, 0.54 mmol). Was stirred at room temperature for 20 hours. Filtered through a pillow celite, the solids were washed CH2Cl2(5×20 ml) and the filtrate was evaporated. Purification on a column of silica gel using a mixture of ether/hexane (50:50) gave the target compound 31 as a white crystalline product (61 mg, 80%); TPL: 146-148°C.

Mass spectrum: -CI m/z (distribution, relative intensity) 283 (MH+, 11%), 265 (MH+-H2O, 100%), 237 (MH+-H2O-CO, 22%); EI: m/z (distribution, relative intensity) 282 (M+, 26%), 209 (M+-CH2COCH2OH, 100%); High resolution EI calculated C18H15FO2(M+): 282,1056 found: 282,1057 (40%).

Example B32

(3S,4aR,13bR)-12-fluoro-N,N-DIMET the l-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-amine (final compound 32)

end connection 32

Intermediate compound 54 (0.24 g, from 0.76 mmol) was dissolved in i-D/THF (2:1, 15 ml). Was added 10% Pd-C (150 mg) and the mixture was subjected to hydrogenation (pressure 1 ATM) for 1 night. Added 35% aqueous solution of CH2O (0,60 ml, 7.6 mmol) and continued hydrogenation for 2 days. Was filtered through celite and washed with CH2Cl2(5×15 ml). The organic phases were combined and dried over MgSO4. The solution was filtered and evaporated and the residue was purified by chromatography on a column of silica gel using a mixture of CHCl3/MeOH (90:10)to give the target compound 32 MH-170 in the form of oil (0,22 g, 93%).

Mass spectrum: -CI m/z (distribution, relative intensity) 312 (MH+, 100%); EI: m/z (distribution, relative intensity) 311 (M+, 7%).

Example B33

(3R,4aR,13bR)-12-fluoro-N-methyl-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-amine (final compound 33)

the target compound 33

The target compound 31 (0.18 g, to 0.63 mmol) was dissolved in I-D/THF (2:1, 10 ml). Was added 10% Pd-C (about 100 mg), Et3N (of 0.87 ml, 6.3 mmol) and MeNH2·HCl (0,42 g, 6.3 mmol). The mixture was subjected to hydrogenation (pressure 1 ATM) for 1 night. Filtered through a pillow celite and the solids were washed CH2Cl2(5×15 ml). The solution was filtered and pariva is and the residue was purified by chromatography on a column of silica gel, using a mixture of CHCl3/MeOH (90:10), receiving two diastereoisomer (0.18 g, 95%) in the ratio 5:1, while the main (3R)-isomer (target compound 33) may be partially separated.

Mass spectrum: -CI m/z (distribution, relative intensity) 298 (MH+, 100%); EI: m/z (distribution, relative intensity) 297 (M+, 5%), 266 (M+-CH3NH2, 19%); High resolution EI calculated C19H20FNO (M+): 297,1529 found: 297,1528 (3,5%).

Example B34

(4aR*,13bS*)-12-fluoro-4,4a,9,13b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3(2H)-he (the target compound 34)

the intermediate connection 56the target compound 34

a) Conversion of the alkene then reduced to diastereoisomeric diols. Intermediate compound 56 (1.40 g, to 4.52 mmol) was dissolved in acetone (30 ml). Added a small crystal OsO4(catalytic amount) and N-methylmorpholin-N-oxide (0,63 g, 5,42 mmol). Was stirred at room temperature for 1 day. The solvent was removed under reduced pressure and the residue was purified by chromatography on a column of silica gel using a mixture of EtOAc/hexane (80:20)to give a mixture of two diastereoisomeric diols (oil, 1.45 g, 93%).

b) Election monot solirovanie primary alcohol group. The above diols (1.45 g, 4,22 mmol) was dissolved in toluene (50 ml). Added Et3N (of 1.76 ml, 12.6 mmol), TsCl (1,05 g of 5.48 mmol) and Bu2SnO (0.10 g, 0.42 mmol). Was stirred at room temperature for 1 day. Was added a saturated aqueous solution of NH4Cl (30 ml), was extracted with CH2Cl2(3×20 ml) and dried over MgSO4. The solution was filtered and evaporated and the residue was purified by chromatography on a column using a mixture of EtOAc/hexane (40:60), receiving diastereoisomers derivative of monotonicity corresponding electoral sulfonylamino primary OH-groups (oil, 1,74 g, 83%).

c) protection of the secondary alcohol group. Monotonicity (1,74 g, to 3.49 mmol) was dissolved in CH2Cl2(60 ml) was added dihydropyran (1,59 ml, 17.5 mmol), camphorsulfonic acid (10 mg, 0.035 mmol). Was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure.

d) removing the protection and cyclization of benzyl alcohol. The residue was dissolved in MeOH (50 ml). Added K2CO3(0,79 g of 6.99 mmol) and stirred at room temperature for 1 night. Was treated by the addition of saturated aqueous solution of NH4Cl (30 ml), 3 times was extracted with CH2Cl2(3×20 ml) and dried over MgSO4. The solvent is evaporated and the residue containing benzyl alcohol, was dissolved in anhydrous THF (50 ml). Add recipients who do NaH (0.21 g, of 6.99 mmol) and stirred at room temperature for 3 days to effect the cyclization. Was treated by the addition of saturated aqueous solution of NH4Cl (30 ml) and was extracted with CH2Cl2(3×20 ml). Dried over MgSO4and the solvent evaporated.

e) removing the protection and oxidation of the secondary alcohol group. The residue (1.70 g) was dissolved in 20 ml of MeOH/H2O (9:1) was added Dowex 50WX8-100 (1,00 g). The mixture was heated at 50°C for 2 hours. Filtered through the filter P3, the solids were washed CH2Cl2(5×15 ml) and was evaporated. Purification on a column of silica gel using a mixture of ether/hexane (70:30) gave an oil (two diastereoisomeric alcohol) (0.87 g, 88%). The above oil (0.87 g, a 3.06 mmol) was dissolved in CH2Cl2(40 ml). Added chlorproma pyridinium (1,32 g, 6,13 mmol) and stirred at room temperature for 1 night. Filtered through a pillow celite, the solids were washed CH2Cl2(5×20 ml) and evaporated. Purification on a column of silica gel using a mixture of CH2Cl2/hexane (80:20) gave the target compound 34 in the form of oil (0.66 g, 76%).

Mass spectrum: -CI m/z (distribution, relative intensity) 283 (MH+, 25%), 265 (MH+-H2O, 100%); EI: m/z (distribution, relative intensity) 282 (M+, 39%), 209 (M+-CH2COCH2OH, 100%).

Example B35

u> (3S*,4aR*,13bS*)-12-fluoro-N-methyl-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-amine (final compound 35)

the target compound 35

The target compound 34 (0,23 g, 0.83 mmol) was dissolved in i-D (15 ml). Added Et3N (of 1.15 ml, 8.25 mmol), MeNH2HCl (0.56 g, 8.25 mmol) and 10% Pd/C (150 mg). Was subjected to hydrogenation (pressure 1 ATM) for 1 night. Filtered through a pillow celite and the solids were washed CH2Cl2(5×10 ml). The solution was filtered and evaporated and the residue was purified by chromatography on a column of silica gel using CHCl3/MeOH (90:10)to give the target compound 35 as almost the only diastereoisomer (0,23 g, 95%).

Mass spectrum: -CI m/z (distribution, relative intensity) 298 (MH+, 100%); EI: m/z (distribution, relative intensity) 209 (M+CH2CH(NHMe)CH2OH, 100%).

Example B36

a) Methyl(2R,3aR,12bS)-2-(aminomethyl)-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate (intermediate compound 62b), [(2R,3aR,12bS)-1-acetyl-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methanamine (the intermediate connection 62c) and (2R,3aR,12bS)-2-(aminomethyl)-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carbaldehyde (intermediate connection 62d)

intermediate soy is inania 62b R=OMe

the intermediate connection 62c R=Me

the intermediate connection 62d R=H

A typical method is the synthesis of methyl(2R,3aR,12bS)-2-(aminomethyl)-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate (intermediate compound 62b):A solution of triphenylphosphine (996 mg, 3.8 mmol) in anhydrous THF (20 ml) were placed in a two-neck flask with a volume of 100 ml, equipped with a membrane inlet for argon, and a magnetic stirrer, cooled to -15°C. After the membrane was added undiluted diisopropylsalicylic (768 mg, 3.8 mmol) under vigorous stirring. The resulting yellow suspension was stirred at the above temperature for 30 minutes, then one portion was added intermediate carbamate 62 (650 mg, 1.9 mmol) in THF (5 ml). After 5 min stirring was added dropwise diphenylphosphoryl (606 mg, 2.2 mmol) in THF (3 ml) for 3 minutes, the resulting turbid mixture was allowed to warm to room temperature and then was stirred for 12 hours. After a specified period of time was added water (0.2 ml) and triphenylphosphine (996 mg, 3.8 mmol) and the solution was stirred at 45°C for 2 hours. After cooling to room temperature was added silica gel (Kieselgel 60, 70-230 mesh, 4 g), THF was removed in vacuum and the powder of silica was subjected to flash chromatography (Kieselgel 60, 230-400 mesh mesh, CH2C 2-MeOH from 100/0 gradually to 85/15)to give the desired amine intermediate 62b (401 mg, 1.18 mmol, 62%) as a colourless oil which darkened upon standing.

The intermediate connection 62b

VRMS: calculated for C20H21FN2O2: 340,1587; found: 340,1588.

The intermediate connection 62c:there are two rotamer (in a ratio of about 2:1)

CI-MS (CH4) 325 (MH+, 100%); 305 (MH+-HF, 10%).

VRMS: calculated for C20H21FN2O: 324,1638; found: 324,1644.

The intermediate connection 62d:there are two rotamer (in a ratio of about 5:2)

VRMS: calculated for C19H19FN2O: 310,1481; found: 310,1480.

b) Methyl(2R,3aR,12bS)-2-[(dimethylamino)methyl]-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate (target compound 36a),

[(2R,3aR,12bS)-1-acetyl-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine (target compound 36b) and

(2R,3aR,12bS)-2-[(dimethylamino)methyl]-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carbaldehyde (final connection 36c)

the target compound 36a R=OMe

the target compound 36b R=Me

end connection 36c R=H

A typical method is the synthesis of methyl(2R,3aR,12bS)-2-[(dimethylamino)methyl]-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-is carboxylate (final compound 36a)

Intermediate amine 62b (401 mg, 1.18 mmol) was dissolved in MeOH (30 ml)was added AcOH (1 ml) and 35% aqueous formaldehyde solution (1 g, 11.7 mmol), then cyanoborohydride sodium (628 mg, 10 mmol). The resulting mixture was stirred at room temperature for 4 hours, extinguished concentrated HCl (5 ml)was treated with solid NaHCO3(of 8.4 g, 100 mmol), 1N sodium hydroxide (15 ml). Precipitiously product was filtered, washed with water (5×25 ml), was dissolved in ethyl acetate, washed with saturated salt solution (30 ml), dried (K2CO3), was evaporated in vacuum and purified by chromatography on a column (Kieselgel 60, 230-400 mesh mesh, CH2Cl2-From MeOH 95/5 to 90/10 to 85/15)to give the target compound 36a (313 mg, 0.85 mmol, 72%) as a yellowish oil.

The target compound 36a:

VRMS: calculated for C22H25FN2O2: 368,1900; found: 368,1895.

The target compound 36b:two rotamer in a ratio of about 3:2.

VRMS: calculated for C22H25FN2O: 352,1951; found: 352,1955.

End connection 36c:two rotamer in a ratio of about 5:3.

VRMS: calculated for C21H23FN2O: 338,1794; found: 338,1790.

Example 37

[(2R,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine (target compound 37)

of course the connection 37

A mixture of final compound 36a (100 mg, 0.27 mmol), i-D (10 ml), potassium hydroxide (560 mg, 10 mmol) and water (0.1 ml) was boiled under reflux in nitrogen atmosphere for 12 hours (oil bath temperature 135°C), then cooled to room temperature. After dilution with water (50 ml), extraction with EtOAc (3×40 ml) the combined organic phases were washed with water (3×40 ml), saturated salt solution (40 ml), dried over K2CO3and evaporated, obtaining the pure target compound 37 (84 mg, 100%) as a yellowish semi-solid substance that has been turned into cleaners containing hydrochloride salt (target compound 37a).

VRMS: calculated for C20H23FN2: 310,1845; found: 310,1851.

Example B38

(2R,3aR,12bS)-11-fluoro-2-[(methylamino)methyl]-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]-cyclohepta[1,2-b]pyrrol-1(2H)-carbaldehyde (final compound 38)

end connection 38

A mixture of intermediate aldehyde 63 (50 mg, rate £ 0.162 mmol), methylamine hydrochloride (218 mg, 3,24 mmol), Et3N (405 mg, 4.0 mmol), 10% Pd-C (30 mg) and MeOH (12 ml) was first made in 2 hours at atmospheric pressure. The reaction mixture was filtered through diatomaceous earth, which is then washed with EtOAc (2×10 ml). The combined solution was evaporated in vacuum and the residue was purified by chromatography on a column (Kieselgel 60, 70-230 mesh, CH2Cl2/MeOH from 100/0 to 85/15)to give the final connection is 38% (21 mg, 0,065 mmol, 40%) as a brown oil.

There are four rotamer (in the ratio 10:6:4:1).

CI-MS (CH4): 325 (100%, M+H+), 305 (12%, -HF). VRMS: calculated for C20H21FN2O: 324,1638; found: 324,1650.

Example B39

2-((2R,3aR,12bS)-2-[(dimethylamino)methyl]-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-yl)ethanol (final connection 39)

the target compound 139

Dimer of hydroxyacetaldehyde (2,5-dihydroxy-1,4-dioxane) (240 mg, 2.0 mmol) was dissolved in MeOH (25 ml) and stirred at 40°C for 30 minutes, then was added amine 37 (124 mg, 0.40 mmol) and stirring at 40°C was continued for another 30 minutes. After cooling to room temperature was added AcOH (120 mg, 2.0 mmol), then cyanoborohydride sodium (188 mg, 3.0 mmol) and the resulting mixture was stirred for 2 hours. After a specified period of time the mixture is extinguished concentrated HCl (2 ml)was treated with solid NaHCO3(2,94 g, 35 mmol), 1N sodium hydroxide (3 ml). About 20 ml MeOH was removed in vacuo, the residue was diluted with water (30 ml) and was extracted with EtOAc (3×30 ml). The combined organic phases were washed with water (5×25 ml), saturated salt solution (30 ml), dried (K2CO3), was evaporated in vacuum and purified by chromatography on a column (Kieselgel 60, 230-400 mesh mesh, CH2Cl2-From MeOH 95/5 to 90/10 to 85/15), receiving from the Association amine 39 (80 mg, 0,244 mmol, 61%) as a colourless oil.

VRMS: calculated for C22H27FN2O: 354,2107; found: 354,2107.

Example B40

[(2R,3aR,12bS)-11-fluoro-1-(2-methoxyethyl)-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine (target compound 40)

end connection 40

2-((2R,3aR,12bS)-2-[(Dimethylamino)methyl]-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-yl)ethanol, compound 39 (50 mg, 0,153 mmol) was dissolved in anhydrous THF (10 ml), then was added a 60% dispersion of NaH (8 mg, 0.2 mmol), then dimethylsulfate (25 mg, 0.2 mmol). The resulting mixture was stirred in argon atmosphere at 60°C for 5 hours, then cooled and extinguished concentrated ammonium hydroxide (2 ml), diluted with water (40 ml). After extraction of the product EtOAc (3×25 ml) the combined organic phases were washed with water (3×25 ml), saturated salt solution (25 ml), dried over K2CO3, was evaporated in vacuum and the residue was purified by chromatography on a column (Kieselgel 60, 230-400 mesh mesh, CH2Cl2-From MeOH 95/5 to 90/10 to 85/15)to give the target compound 40 (39 mg, 0,107 mmol, 70%) as a yellowish oil.

VRMS: calculated for C23H29FN2O: 368,2264; found: 368,2270.

Example B41

[(2R,3aR,12bS)-1-cyano-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine (to acnee connection 41)

the target compound 41

Poly(4-vinylpyridine), cross crosslinked with 2% divinylbenzene (0.5 g) were subjected to swelling within 1 hour, using CH2Cl2(10 ml), then one portion was added to the target compound 37 (57 mg, 0,184 mmol) in CH2Cl2(2 ml) followed by the addition of cyanogenmod (39 mg, 0,367 mmol), then the suspension was stirred at room temperature for 30 minutes. The resin was filtered, the filtrate was treated with saturated aqueous K2CO3(10 ml), the organic phase was separated, evaporated in vacuo and the residue was purified by chromatography on a column (Kieselgel 60, 230-400 mesh mesh, CH2Cl2-From MeOH 95/5 to 90/10 → 87/13), obtaining the target compound 41 (24 mg, 0,077 mmol, 42%) as a brownish oil.

CI-MS (CH4): 308 (100%, M+H+), 288 (8%, -HF).

VRMS: calculated for C19H18FN3: 307,1485; found: 307,1499.

Example B42

(2R,3aR,12bS)-11-fluoro-2-(4-morpholinylmethyl)-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrole (target compound 42)

end connection 42

To a solution of intermediate aziridine 64 (63 mg, 0,237 mmol) in acetonitrile (1 ml) was added sodium iodide (107 mg, 0,711 mmol) and trimethylsilane (90 μl, 0,711 mmol) at room temperature. After stirring the solution for 2 hours to a mixture kapl the m was added morpholine (44 mg, 0.5 mmol) in acetonitrile (0.5 ml). The solution was heated to the boiling temperature of the solvent for 2 hours. The dark brown reaction mixture is extinguished 1,2n aqueous solution of HCl and then treated with saturated solution of NaHCO3. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×10 ml). The combined organic extracts were washed with 20 ml of saturated salt solution, dried over anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by chromatography on a column of alkaline aluminum oxide (activity Brockman III, EtOAc-MeOH from 100/0 to 98/2 to 95/5)to give the target compound 42 (38 mg, 0.11 mmol, 45%) as a brownish oil.

CI-MS (CH4): 353 (100%, M+H+); 333 (-HF, 7%).

VRMS: calculated for C22H25FN2O: 352,1951; found: 352,1966.

Example B43

2-(4-{[(2R,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}-1-piperazinil)ethanol (final connection 43a) and

2-[{[(2R,3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}(methyl)amino]ethanol (final compound 43b)

compound 43a
connection 43b

A mixture of the corresponding intermediate nonylamine 66a or 66b (about 0.4 mmol), thiophenol (110 mg, 1.0 mmol), anhydrous K2CO3(138 mg, 1 mmol) and DMF (20 ml) was stirred at 80°C for 4 hours, cooled to ambient temperature, diluted with water, the product was extracted with EtOAc (3×50 ml), the combined organic phases were washed with water (4×50 ml), saturated salt solution (35 ml), dried (K2CO3), evaporated and purified by solid-phase extraction on alkaline alumina (activity Brockman II, heptane-ethyl acetate 50/50, then EtOAc-MeOH from 100/0 to 96/4 to 90/10)to give compound 43a (111 mg, 0.28 mmol, 52% of intermediate 65) or compound 43b (80 mg, 0.24 mmol, 44% of the intermediate compound 65), both in the form of a brownish oil.

Compound 43a (TK-895):

VRMS: calculated for C24H30FN3O: 395,2373; found: 395,2374.

Compound 43b (TK-1013):

VRMS: calculated for C21H25FN2O: 340,1951; 340,1943.

Example B44

[(2R,4aR,13bS)-12-fluoro-2,3,4,4a,9,13b-hexahydro-1H-dibenzo[3,4:6,7]cyclohepta[1,2-b]pyridine-2-yl]-N,N-dimethylethanamine (compound 44)

the connection 44

Intermediate tosylate 67k (153 mg, 0,338 mmol), 40% aqueous solution of methylamine (15 ml) and THF (35 ml) was heated in the tank from arabeya steel at 135°C for 15 hours. After cooling, the bottle was opened, THF and methylamine evaporated in vacuo, the residue was extracted with CH2Cl2(4×20 ml). The combined organic phases were washed with water (3×20 ml), dried (K2CO3), evaporated and purified by chromatography on a column (Kieselgel 60, 230-400 mesh mesh, CH2Cl2-MeOH from 98/2 to 85/15)to give the target compound 44 (32 mg, 0,098 mmol, 29%) as a brown oil, which was converted into the oxalate salt (target compound 44a).

VRMS: calculated for C21H25FN2: 324,2002; found: 324,1995.

Example B45

Methyl(2R,4aR,13bS)-2-[(dimethylamino)methyl]-12-fluoro-2,3,4,4a,9,13b-hexahydro-1H-dibenzo[3,4:6,7]cyclohepta[1,2-b]pyridine-1-carboxylate (target compound 45)

the target compound 45

Transformation end connection 44 (48 mg, 0.15 mmol) using methylcarbamate carried out in the same manner as described for intermediate connection 62. Chromatography on a column (Kieselgel 60, 70-230 mesh, MeOH-CH2Cl2from 3/97 to 15/85) to give the target compound 45 (45 mg, 0.118 the mmol, 79%) as a colourless oil.

VRMS: calculated for C23H27FN2O2: 382,2057; found: 382,2064.

Example B46

[(2R,4aR,13bS)-12-fluoro-2,3,4,4a,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-2-yl]-N-methylmethanamine (target compound 46)

the target compound 46

Intermediate tosylate 68e (282 mg, of 0.62 mmol), 40% aqueous solution of methylamine (25 ml) and THF (35 ml) was heated in a steel tank at 135°C for 15 hours. After cooling, the bottle was opened, THF and methylamine evaporated in vacuum. The residue was extracted with CH2Cl2(4×30 ml) and the combined organic phases were washed with water (3×20 ml), dried (K2CO3) and was evaporated. Crystallization from a mixture of CH2Cl2/hexane gave the target compound 46 (70 mg, 0,225 mmol, 36%) as a beige powder.

VRMS: calculated for C20H22FNO: 311,1685; found: 311,1700.

Example B47

[(3aR,12bS)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-3-yl]-N,N-dimethylethanamine (target compound 47)

the target compound 47

Intermediate azide 69i (122 mg, 0,39 mmol) was dissolved in MeOH (10 ml), was added 10% palladium on coal (40 mg) and the mixture was subjected to hydrogenation at atmospheric pressure for 1.5 hours, then was added 35% aqueous formaldehyde solution (1 g) and AcOH (120 mg, 2 mmol) and the hydrogenation was continued for 2 hours. After filtration through a small pillow celite and add EtOAc (45 ml), the reaction mixture was washed with saturated aqueous sodium bicarbonate (25 ml), water (2×50 ml), saturated salt solution (30 ml), dried over K2CO3and evaporated the vacuum. The residue was purified by chromatography on a column (Kieselgel 60, 70-230 mesh, ethyl acetate : MeOH from 100/0 to 95/5 to 92/8 to 87/13), obtaining the target compound 47 (77 mg, 0,248 mmol, 63%) as a yellow oil. The product is a mixture of 2 epimeres (in the ratio of 12.8:1).

VRMS: calculated for C20H22FNO: 311,1685; found: 311,1680.

CI-MS (CH4) 312 (MH+, 100%); 292 (MH+- HF, 9%).

Example B48

[(3aR,12bR)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-3-yl]-N,N-dimethylethanamine (target compound 48)

end connection 48

The reaction using the intermediate 70d (100 mg, 0,304 mmol) was carried out in the same way as described for the target connection 47. Purification by solid-phase extraction (Alltech C18cartridge 2G, water-MeOH from 100/0 to 50/50 to 0/100) to give compound 48 (57 mg, 0.18 mmol, 59%). The product is a mixture of 2 epimeres (in the ratio 2:1).

VRMS: calculated for C20H22FNO: 311,1685; found: 311,1692.

CI-MS (CH4) 312 (MH+, 100%); 292 (MH+- HF, 12%).

Example B49

[(3aR,12bS)-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-3-yl]-N,N-dimethylethanamine (target compound 49)

the target compound 49

A mixture of intermediate compound 71f (194 mg, of 0.53 mmol) and 10% palladium on coal (50 mg) in MeOH (35 ml) was first made when at uspernom pressure for 40 minutes, then was added 35% aqueous formaldehyde solution (1 ml) and hydrogenation was continued for another 40 minutes. After filtration through a small pillow celita the reaction mixture was evaporated in vacuum. The residue was dissolved in i-D (20 ml), was added KOH (560 mg, 10 mmol) and water (0.1 ml) and the resulting solution was boiled under reflux in nitrogen atmosphere for 12 hours (oil bath temperature 135°C), then cooled to room temperature. After dilution with water (50 ml) and extraction with EtOAc (3×40 ml) the combined organic phases were washed with water (3×40 ml), saturated salt solution (40 ml), dried over K2CO3and evaporated in vacuum. The residue was purified by chromatography on a column (alkaline aluminum oxide, the degree of activity by Brockmann I, ethyl acetate-MeOH from 100/0 to 85/15)to give the pure target compound 49 (102 mg, 0.33 mmol, 62%) as a brown oil. The product is a mixture of 2 epimeres (in the ratio 1:1).

VRMS: calculated for C20H23FN2: 310,1845; found: 310,1833.

In tables 1-3 lists the compounds of formula (I)obtained according to one of the above examples.

C. Pharmacological examples

Example C.1: the Affinity of binding in vitro to the receptors 5-HT2Aand 5-HT2C

The interaction of compounds of formula (I) with the receptor 5-HT2Aand 5-HT2Cwas evaluated in experiments binding of radioactive ligand in vitro. In General, radioactive ligand with high affinity binding with respect to the receptor at low concentrations, incubated with the sample preparation tissue enriched with a specific receptor (1-5 mg tissue) in buffered medium (0.2 to 5 ml). During incubation, the radioactive ligand bound to the receptor. When equilibrium is reached binding associated with the receptor radioactivity was separated from unbound radioactivity and calculate associated with receptor activity. The interaction of test compounds with receptors evaluated in experiments on competitive binding. Various concentrations of test compounds are added to the incubation mixture containing the drug tissue and the radioactive ligand. The binding of the radioactive ligand is inhibited test compound is proportional to the affinity of its binding and its concentration. Aff is nasty compounds in relation to the receptors 5-HT 2was measured using studies of the binding of radioactive ligand conducted using: (a) the cloned receptor 5-HT2Aman, expressed in L929 cells, with the use of [125I]R91150 as a radioactive ligand, and (b) the cloned receptor 5-HT2Cman, expressed in CHO cells, using [3H]mesulergine as a radioactive ligand.

Example C.2: Determination of the inhibition of reuptake NET in vitro

The cerebral cortex of rats were collected and homogenized using a homogenizer (Ultra-Turrax T25 and Dual homogenizer in ice-cold buffer for homogenization, containing Tris, NaCl and KCl (50 mm, 120 mm and 5 mm, respectively, a pH of 7.4), and then diluted to the appropriate concentration of protein that is optimized for specific and nonspecific binding. The binding was carried out with radioactive ligand [3H]nicoteine (NEN, NET-1084, specific activity ~70 curies/mmol)diluted in ice-cold buffer for analysis, containing Tris, NaCl and KCl (50 mm, 300 mm and 5 mm, respectively, a pH of 7.4), at a concentration of 20 nmol/L. Then cooked radioactive ligand (50 µl) were incubated (60 min, 25°C) with membrane preparations, pre-diluted to the appropriate concentration of protein (400 μl)and 50 μl or control 10% DMSO, mazindol (final concentration 10-6

Example C.3 : the binding Affinity of in vitro by receptor D2Lperson

Frozen membranes of CHO cells, transfected with the receptor dopamine D2Lman, thawed, briefly homogenized using a homogenizer (Ultra-Turrax T25, and was diluted in Tris-HCl-buffer for analysis, containing NaCl, CaCl2, MgCl2, KCl (50, 120, 2, 1 and 5 mm, respectively, brought to a pH of 7.7 with HCl) to the appropriate concentration of protein, optimized in terms of specific and nonspecific binding. The radioactive ligand [3H]-spiperone (NEN, specific activity ~70 curies/mmol) was diluted in buffer for analysis at a concentration of 2 nmol/L. Then cooked radioactive ligand (50 μl) VM is the degree with 50 ál or control 10% DMSO, butaclamol (final concentration of 10-6mol/l)or interest compounds were incubated (30 min, 37°C) with 400 μl of the solution prepared membranes. Associated with the membrane activity was filtered through a device for collecting Packard Filtermate using filters GF/B Unifilterplates, and washed with ice-cold Tris-HCl buffer (50 mm; pH 7,7; 6×0.5 ml). The filters are allowed to dry before adding scintillation fluid and counted with a scintillation counter Topcount. Specific binding in the interest and competitive binding curves were determined using a computer program S-Plus (Insightful).

Table 4
Pharmacological data
No.
connection
h-5HT2Ah-5HT2Ch-D2LReuptake inhibition NET
176,246,305,638,13
37A7,357,306,458,10
475,42 5,80n.d.of 7.96
43b7,177,056,367,80
326,17to 6.88<67,71
236,186,64and 5.30at 7.55
16,946,82the 5.656,94
397,067,33<66,90
285,11of 5.75n.d.6,84
48to 5.215,52n.d.6,65
36C6,267,115,316,65
57,568,27to 6.886,54
30to 6.576,84<66,52
467,868,235,206,40
20n.d.of 6.966,456,38
40to 6.43to 6.58<66,32
386,20of 6.735,15of 6.31
36A<6<6<66,16
45n.d.the 5.65<56,10
7<6<6lt; 66,05
87,076,60<55,66
155,085,63<55,62
25<5the 5.65n.d.5,54
14a8,909,058,815,50
12n.d.of 7.23between 6.085,46
36b<6<6<65,41
9<6<6<6of 5.40
225,07by 5.87n.d.5,32
10 6,166,37<65,32
426,206,26n.d.5,26
3<66,62<65,24
137,066,926,37<5
35<65,58<6<6
43A6,376,39n.d.<5
26<5<5<5<5
19n.d.lower than the 5.376,95<5
16<5<5<5 <5
4<6<6<6<5
n.d. = not determined

D. Examples of compositions

Active ingredient (AI) used in the examples, the meaning relates to the compound of formula (I), its pharmaceutically acceptable acid salt additive, its stereochemical isomeric form or its N-oxide form.

Example D.1: ORAL SOLUTION

Methyl-4-hydroxybenzoate (9 g) and propyl-4-hydroxybenzoate (1 g) was dissolved in purified boiling water (4 l). In 3 l of the resulting solution was first dissolved 2,3-dihydroxybutanedioate acid (10 g), then AI (20 g). The latter solution was combined with the remaining part of the above-mentioned solution, and thereto was added 1,2,3-propantriol (12 l) and 70% sorbitol solution (3 l). Saccharin sodium (40 g) was dissolved in water (500 ml) and added raspberry essence (2 ml) and the essence of gooseberry (2 ml). The latter solution was combined with the above, was added water q.s. up to a volume of 20 l, receiving oral solution containing 5 mg of active ingredient in a teaspoon (5 ml). The resulting solution was filled in suitable containers.

Example D.2: film-COATED TABLETS

Obtain core tablets

A mixture of the (100 g), lactose (570 g) and starch (200 g) were well mixed and then moistened with a solution of sodium dodecyl sulfate (5 g) and polyvinylpyrrolidone (10 g) in water (200 ml). The wetted powder mixture was sieved, dried and again sieved. Then added microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g). All was well mixed and extruded tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Floor

To a solution of methyl cellulose (10 g) in denatured ethanol (75 ml) was added a solution of ethyl cellulose (5 g) in dichloromethane (150 ml). Then added dichloromethane (75 ml) and 1,2,3-propantriol (2.5 ml). Polyethylene glycol (10 g) was melted and dissolved in dichloromethane (75 ml). The latter solution was added to the above and then added octadecanoate magnesium (2.5 g), polyvinylpyrrolidone (5 g) and a concentrated suspension of the dye (30 ml) and all homogenized. The core tablets were coated thus obtained mixture in a device for coating tablets.

Example D.3: INJECTION SOLUTION

Methyl-4-hydroxybenzoate (1.8 g) and propyl-4-hydroxybenzoate (0.2 g) was dissolved in boiling water (500 ml) for injection. After cooling to approximately 50°C under stirring was added lactic acid (4 g), propylene glycol (0.05 g) and AI (4 g). The solution was cooled to room t is mperature and added water for injection to achieve a volume of 1000 ml, receiving a solution containing 4 mg/ml AI. The solution was sterilized by filtration and the resulting solution was filled in sterile container.

1. The compound of formula (I)

its N-oxide form, pharmaceutically acceptable additive salt or a stereochemical isomeric form, where
i and j denote integers, independently of one another zero or 1;
And In the mean benzo;
each R9means halogen;
X is CR6R7or; where
R6and R7each means hydrogen;
With means a group of formula (C-1), (2), (3) or (4);

where Y1means S; S (=O); S(=O)2or NR10; where R10selected from the group consisting of hydrogen, ceanography, alkyl, alkyloxyalkyl, formyl, alkylcarboxylic, allyloxycarbonyl, dialkylaminoalkyl and allyloxycarbonyl;
Y2means Y1or;
R10and R11may together form a bivalent radical (e-1), (e-2) or (e-3);



each bivalent radical (e-1), (e-2) and (e-3) optionally substituted by one or more substituents selected from the carbonyl group, tocography and alkyl;
R12OZNA the AET hydrogen;
R13means hydrogen;
R14means hydrogen, a hydroxy-group, oxoprop or a group of formula (d-1);
R11means a group of formula (d-1);
.
where n is zero or 1;
R1and R2each independently denote hydrogen; alkyl, optionally substituted hydroxy-group; alkylaryl; alkyloxyalkyl; alkylcarboxylic; allyloxycarbonyl; or
R1and R2taken together with the nitrogen atom to which they are bound, may form a radical of formula (a-3), (a-5) or (a-6);

where p is zero or 1;
q is 1;
m is 1;
each R3independently means a hydroxy-group;
R4selected from the group consisting of hydrogen or alkyl, optionally substituted hydroxy-group;
alkyl means a saturated hydrocarbon radical with unbranched or branched chain, having from 1 to 10 carbon atoms; and halogen means fluorine, chlorine, bromine and iodine;
with the exception of the compounds of formula (I), where X=CH2, i=0, j=1, R9=F, means a group of formula (C-4), where Y=O, R13=H, and R14means oxoprop, the hydroxy-group or a group of formula (d-1), where n=0, R1= hydrogen and R2= methyl.

2. The compound according to claim 1, in which means a group of formula (C-1) or (C-2); where
Y 1means S; S (=O); S(=O)2or NR10; where R10selected from the group consisting of hydrogen, ceanography, alkyl, alkyloxyalkyl, formyl, alkylcarboxylic, allyloxycarbonyl and allyloxycarbonyl;
adjacent R10and R11together may form a bivalent radical (e-1), (e-2) or (e-3); each radical optionally substituted by one or more substituents selected from the carbonyl group, tocography and alkyl; and R12means hydrogen.

3. The compound according to claim 1, in which means a group of formula (C-3) or (4); where
Y2means Of;
R12means hydrogen;
R13means hydrogen; and
R14means hydrogen, a hydroxy-group, oxoprop or a group of formula (d-1).

4. The compound according to claim 1, in which the (d-1) has the meaning given in claim 1, where
n is zero or 1;
R1and R2each independently denote hydrogen; alkyl or allyloxycarbonyl; or R1and R2taken together with the nitrogen atom to which they are bound, may form a radical of formula (a-3), (a-5) or (a-6); where
p is zero or 1;
q is 1;
m is 1;
each R3independently selected from the group consisting of hydrogen and hydroxy-group; and R4means alkyl.

5. The compound according to claim 1, in which
i and j are integers, independently of one another zero or 1;
A and b each is th independently from each other mean anthropou, optionally substituted by fluorine;
each R9independently from each other selected from the group consisting of hydrogen and halogen;
X is CH2and;
With means a group of formula (C-1), (2), (3) or (4); where
Y1means S; S (=O); S(=O)2or NR10; where R10selected from the group consisting of hydrogen, ceanography, alkyl, alkyloxyalkyl, formyl, alkylcarboxylic, allyloxycarbonyl and allyloxycarbonyl;
Y2means Of;
adjacent R10and R11together may form a bivalent radical (e-1), (e-2) or (e-3); each radical optionally substituted by one or more substituents selected from the carbonyl group, tocography and alkyl;
R12means hydrogen;
R13means hydrogen;
R14means hydrogen, a hydroxy-group, oxoprop or a group of formula (d-1);
R11means a group of formula (d-1); where
n is zero or 1;
R1and R2each independently denote hydrogen; alkyl or allyloxycarbonyl; or R1and R2taken together with the nitrogen atom to which they are bound, may form a radical of formula (a-3), (a-5) or (a-6); where
p is zero or 1;
q is 1;
m is 1;
R3means a hydroxy-group; and
R4means alkyl.

6. The compound according to claim 1 for use as a drug, possess and what hindostani binding in relation to the serotonin receptors 5-HT 2Aand 5-HT2C, dopamine receptors D2 and properties of inhibiting reuptake of norepinephrine.

7. The compound according to claim 1, in which the hydrogen atoms at the carbon atoms 3A and 12b have the TRANS configuration and have (2A, 3α, 12bβ) - stereochemical configuration.

8. The compound according to claim 1, wherein the compounds are selected from the group including
(4aS,13bR,14aS)-6-fluoro-2-methyl-1,2,3,4a,9,13b,14,14a-octagenarians[3',4':6',7]cyclohepta[1',2':4,5]pyrrolo[1,2-C]imidazole;
[(2S,3aR,12bS)-11-fluoro-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine;
(4aS,13bR,14aS)-6-fluoro-1,4A,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-C]imidazol-3(2H)-tion;
(5aS,14bR,15aS)-7-fluoro-2-methyl-1,2,3,5A,10,14b,15,15A, octahydro-4H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin-4-one;
[(2R,3aR,12bS)-11-fluoro-1-methyl-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine;
(4aS,13bR,14aR)-6-fluoro-1,4A,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-C]imidazol-3(2H)-he;
(4aS,13bR,14aR)-6-fluoro-2-methyl-1,4A,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-C]imidazol-3(2H)-he;
(4aS,13bR,14aR)-6-fluoro-1,4A,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-C]imidazol-3(2H)-tion;
[(2R,3aR,12bS)-11-fluoro-1-(methoxyacetyl)-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine;
methyl({[(2R,3aR,12bS)-11-fluoro-1,2,3,3A,8,12b-hexahydrobenzo[3,:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}amino)acetate;
(5aS,14bR,15aR)-7-fluoro-1,2,3,5A,10,14b,15,15A, octahydro-4H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin-4-one;
(5aS,14bR,15aR)-7-fluoro-2-methyl-1,2,3,5a,10,14b,15,15A, octahydro-4H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin-4-one;
(5aS,14bR,15aR)-7-fluoro-2-methyl-1,3,4,5A,10,14b,15,15A, octahydro-2H-dibenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-a]pyrazin;
(4aS,13bR,14aS)-6-fluoro-1,4A,9,13b,14,14a-hexahydrobenzo-[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-C]imidazol-3(2H)-he;
(4aS,13bR,14aS)-6-fluoro-2-methyl-1,4A,9,13b,14,14a-hexahydrobenzo[3',4':6',7']cyclohepta[1',2':4,5]pyrrolo[1,2-C]imidazol-3(2H)-he;
[(2R,3aR,12bS)-11-fluoro-2,3,3A,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]-N,N-dimethylethanamine;
2-[{[(2R,3aR,12bS)-11-fluoro-2,3,3A,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]methyl}(methyl)amino]ethanol;
2-(4-{[(2R,3aR,12bS)-11-fluoro-2,3,3A,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]methyl}-1-piperazinil)ethanol;
1-{[(2R,3aR,12bS)-11-fluoro-2,3,3A,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepin[4,5-b]pyrrol-2-yl]methyl}-3-pyrrolidino;
[(2S,3aR,12bS)-11-fluoro-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine;
[(2S,3aR,12bS)-11-fluoro-1,1-dioxido-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine;
[(2R,3aR,12bS)-11-fluoro-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine;
[(2R,3aR,12bS)-11-fluoro-1,1-dioxido-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimetime anamin;
[(2S,3aR,12bS)-11-fluoro-1-oxido-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine;
[(2S,3aR,12bS)-11-fluoro-1-oxido-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine;
[(2R,3aR,12bS)-11-fluoro-1-oxido-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine;
[(2R,3aR,12bS)-11-fluoro-1-oxido-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]Tien-2-yl]-N,N-dimethylethanamine;
(3R,4aR,13bR)-12-fluoro-2,3,4,4A,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-ol;
(3S,4aR,13bR)-12-fluoro-2,3,4,4A,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-amine (compound 30);
(4aR,13bR)-12-fluoro-4,4A,9,13b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3(2H)-he;
(3S,4aR,13bR)-12-fluoro-N,N-dimethyl-2,3,4,4A,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-amine;
(3R,4aR,13bR)-12-fluoro-N-methyl-2,3,4,4A,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]Piran-3-amine (compound 33);
methyl(2R,3aR,12bS)-2-[(dimethylamino)methyl]-11-fluoro-3,3A,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carboxylate;
[(2R,3aR,12bS)-1-acetyl-11-fluoro-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine;
(2R,3aR,12bS)-2-[(dimethylamino)methyl]-11-fluoro-3,3A,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-carbaldehyde;
[(2R,3aR,12bS)-11-fluoro-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine;
(2R,3aR,12bS)-11-fluoro-2-[(methylamino)methyl]-3,3A,8,12b-then it is carbonated is radiant[3,4:6,7]-cyclohepta[1,2-b]pyrrol-1(2H)-carbaldehyde;
2-((2R,3aR,12bS)-2-[(dimethylamino)methyl]-11-fluoro-3,3a,8,12b-tetrahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-1(2H)-yl)ethanol;
[(2R,3aR,12bS)-11-fluoro-1-(2-methoxyethyl)-1,2,3,3a,8,12b-hexahydrobenzo[3,4:6,7]-cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine;
[(2R,3aR,12bS)-1-Sueno-11-fluoro-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]-N,N-dimethylethanamine;
(2R,3aR,12bS)-11-fluoro-2-(4-morpholinylmethyl)-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrole;
2-(4-{[(2R,3aR,12bS)-11-fluoro-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}-1-piperazinil)ethanol;
2-[{[(2R,3aR,12bS)-11-fluoro-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-2-yl]methyl}(methyl)amino]-ethanol;
[(2R,4aR,13bS)-12-fluoro-2,3,4,4A,9,13b-hexahydro-1H-dibenzo[3,4:6,7]cyclohepta[1,2-b]pyridine-2-yl]-N,N-dimethylethanamine;
methyl(2R,4aR,13bS)-2-[(dimethylamino)methyl]-12-fluoro-2,3,4,4A,9,13b-hexahydro-1H-dibenzo[3,4:6,7]cyclohepta[1,2-b]pyridine-1-carboxylate;
[(2R,4aR,13bS)-12-fluoro-2,3,4,4A,9,13b-hexahydrobenzo[3,4:6,7]cyclohepta-[1,2-b]Piran-2-yl]-N-methylmethanamine;
[(3aR,12bS)-11-fluoro-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-3-yl]-N,N-dimethylethanamine;
[(3aR,12bR)-11-fluoro-3,3A,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-3-yl]-N,N-dimethylethanamine;
[(3aR,12bS)-11-fluoro-1,2,3,3A,8,12b-hexahydrobenzo[3,4:6,7]cyclohepta[1,2-b]pyrrol-3-yl]-N,N-dimethylethanamine.

9. The use of compounds according to any one of claims 1 to 8 to obtain drugs for which ecene and/or prevention of disorders of the Central nervous system, like anxiety, depression and mild depression, bipolar disorders, sleep disorders and sexual disorders, psychosis, borderline psychosis, schizophrenia, migraine, personality disorders or obsessive-compulsive disorders, social phobias or acute anxiety with panic reaction, organic mental disorders, mental disorders in children, aggression, memory disorders, and disorders of the sense of body position in space in the elderly, drug addiction, obesity, bulimia nervosa and related disorders.

10. The use of compounds according to any one of claims 1 to 8 to obtain drugs for the treatment and/or prevention of anxiety, depression, psychosis, schizophrenia, migraine and addiction to narcotic drugs.

11. Pharmaceutical composition having an affinity to the serotonin receptors 5-HT2Aand 5-HT2C, dopamine receptors D2 and properties of inhibiting reuptake of norepinephrine containing a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 8.

12. The method of obtaining the composition of claim 11, wherein the pharmaceutically acceptable carrier is thoroughly mixed with a therapeutically effective amount of a compound according to any one of claims 1 to 8.


 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel amino acid derivatives of formula or formula , their synthesis methods and their use as intermediate products during synthesis of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (asenapine), which have central nervous system depressant effect, as well as antihistamine and antiserotonin effect.

EFFECT: use of intermediate compounds I and II considerably increases output of asenapine.

12 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new tricyclic derivatives of the formula (I) and their pharmaceutically acceptable salts, where: 1 to 3 of A1, A2, A3 and A4 are nitrogen atoms, while the rest are -CH- groups; G1 is a group selected out of -CH2-O-, -CH2-CH2-, - CH=CH-; -N(C1-C4alkyl)-CH2; G2 is a group selected out of -O-CH2-, -CH=CH-, -CH2- CH2-; R4 can be identical or different and are selected out of a group including hydrogen or halogen atoms; p are independently equal to 0, 1 or 2; Y is and optionally substituted residuum selected out of the group of alkyl, cycloalkyl, alkylaryl, alkylcycloalkylalkyl; Z is a tetrazolyl, -COOR5, -CONR5R5, NHSO2R5 or -CONHSO2R5 group, where R5 is hydrogen or optionally substituted alkyl or aryl. The invention also concerns a method of obtaining the claimed compounds.

EFFECT: possible application in treatment and prophylactics of inflammation and allergy diseases.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):

R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.

EFFECT: obtaining new biologically active compounds.

26 cl, 12 dwg, 4 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel derivatives of benzo[7,8]azonino[5,4-b]indoles, 7,9-etheno-azecino[5,4-b]indoles and 7,9-ethano-azecino[5,4-b]indoles with general structural formulae: , , , I, IV, VII X=H,Y=CO2Me; II, V, VIII X=H, Y=COMe; III, VI, IX X=Y=CO2Me, which have proved to be cytostatic and cytotoxic compounds. The method involves dissolving 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolysino[8,7-b]indole, ethyl eburnamenine-14-carboxylate or methyl (3-α, 14-β, 16α)-14-hydroxy-14,15-dihydro eburnamenine -14-carboxylate in methanol and then reaction with excess dimethyl acetylenedicarboxylate (ADCX) or methyl propiolate or acetyl acetylene, while stirring at +40-+50°C, with subsequent removal of the solvent and grinding the residue in hexane or a mixture of hexane with ethylacetate (ether) or purified using column chromatography on aluminium oxide.

EFFECT: design of an efficient method of obtaining hazardous compounds.

9 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula: , where R1 - C1-C6alkyl, C1-C6alkoxy, halogen, CN, C(O)NH2 or OCH2CH2OCH3; R2-C1-C6alkyl, possibly substituted with halogen, a halogen, C1-C6alkoxy, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, where n equals 1 or 2; m equals 2 or 3; R6 -R7 -C1C6alkyl, and R8 -OCH2CH2OCH3; or R7 and R8 together with the nitrogen atom to which they are bonded form a 6-member heterocycle which additionally contains one oxygen atom or one nitrogen atom, which in the latter case is substituted with C1-C4alkyl; or R1 and R2 together form a 5-member heterocyclic ring system containing two oxygen atoms as heteroatoms; R3 - hydrogen or C1-C6alkyl; R4 - hydrogen, halogen or C1-C6alkoxy; or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds with kinase inhibiting properties, particularly CDK2, or angiogenesis inhibiting properties and can be used in treating malignant growths, particularly in mammary glands, large intestines, lungs and prostate glands.

60 cl, 7 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): or pharmaceutically acceptable salts thereof, where X is CH; R1 is phenyl or a 6-member heteroaryl which contains 1 or 2 nitrogen atoms as heteroatoms, independently and optionally substituted with up to five groups J; R2 and R3 each independently represents hydrogen, halogen, -V-R or -V-Ra; R5 is R; R is H or an optionally substituted C1-6aliphatic group, where the substitutes are selected from -OR0, phenyl, substituted R0, -N(R0)2; where each independent R0 is selected from hydrogen, halogen, C1-6aliphatic group; Ra is morpholine, V is a bond or Q; Q is -NR5-; each J group independently represents a halogen, -N(R5)2. The invention also relates to a pharmaceutical composition with protein kinase inhibiting properties, and to methods of inhibiting Aurora A protein kinase using the said compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which can be used in medicine to treat or alleviating a proliferative disorder, such as cancer, in a patient.

25 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to pyrido[1,2-a]benzimidazole derivatives of general formula I, where R=alkyl; R1=alkyl, aryl; R2=alkyl. The invention also relates to a method of producing formula I compounds.

EFFECT: novel to pyrido[1,2-a]benzimidazole derivatives with antibacterial activity are obtained.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to 3 - (2-methoxy-4-pyrazol-1-ilfenil) -2,5-dimethyl-7-(3-methylpyridine-2-yl) pyrazolo [1.5-a] pyrimidine or its pharmaceutically acceptable salts, solvate, stereoisomer, having the following structural formula, which are antagonists of CRF-receptors and can be used in treatment of various disorders that cause hypersecretion of CRF in warm-blooded animals, such as at the sudden attack. Also the invention refers to intermediate compounds, pharmaceutical compositions on the basis of this compound and method of treating disorder causing hypersecretion of CRF in mammals.

EFFECT: improvement of composition.

15 cl, 14 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention discloses pharmaceutical compositions based on telozolomide-8-carboxylate compounds of general formula I, as well as a method of preparing the said compositions. The disclosed composition has anti-tumour activity and can be especially useful during transdermal application.

EFFECT: obtaining compositions which, along with conventional pharmaceutical carriers, contain a component of acidic nature which gives the pharmaceutical composition high resistance to pH fluctuation.

16 cl, 2 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used in treating and preventing various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly cognitive disorders, neurodegenerative diseases and psychiatric disorders. The compounds have anxiolytic and nootropic effect and can also be used for preventing and treating anxiety disorder and for enhancing metal capacity. In formula 1 , R1 is a hydrogen atom, C1-C3 alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R2 is a hydrogen atom, halogen atom, C1-C3 alkyl, phenyloxy or pyridyloxy; R3 is a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R4 is C1-C3 alkyl; R5 is a hydrogen atom, one or two halogen atoms, C1-C3 alkyl, C1-C3 alkyloxy or hydroxyl; X is a sulphur atom or thionyl group (SO).

EFFECT: obtaining compounds which can be used in treating and preventing various diseases of the central nervous system.

24 cl, 9 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.

EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.

25 cl, 12 dwg, 3 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula (I) where: A is an aryl or a 5-member heteroaryl containing a S heteroatom, possibly substituted with one or two substitutes selected from a group consisting of halogen, C1-6-alkyl or C1-6-alkoxy; n equals 1 or 2; p equals 1, 2, 3 or 4; q equals 1; r equals 0 or 1; R1 is C2-6-alkynyl substituted with aryl, or C1-6-alkyl possibly substituted with one-five substitutes selected from a group consisting of halogen, hydroxy, C1-6-alkyl, C1-6-halogenoalkyl, -OC(O)-C1-6-alkyl, C3-10-cycloalkyl, C1-6-alkoxy, possibly substituted with one, two or three halogens or aryl, aryl which is possibly substituted with a halogen or C1-6-alkoxy, 5-9-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N or O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl, and phenoxyl, or is C1-6-alkoxy, or is C3-10-cycloalkyl which is possibly substituted with one or more Ra, or is a 5- or 6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with one or more Ra, or is an aryl possibly substituted with one or more Ra, or is a 5-10-member heteraryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, possibly substituted with one or more Ra, or is -NRbRc, where Rb is H or C1-6-alkyl and where Rc is H, C1-6-alkyl or aryl, possibly substituted with one or more Ra, where Ra is selected from: halogen, cyano, oxo, hydroxy, halogenobenzenesulfonyl, C1-6-alkyl, possibly substituted with one, two or three substitutes selected from a group consisting of 5-10-member heterocycloalkyl and aryl, which is possibly substituted with halogen or C1-6-alkoxy, C1-6-halogenoalkyl, C1-6-halogenoalkoxy, C1-6-alkoxy, possibly substituted with aryl or 5-10-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, which is possibly substituted with C1-6-alkyl, aryloxy, -NH(CO)-C1-6-alkyl, -O(CO)-C1-6-alkyl, C1-6-alkylsulfonyl, aryl, 4-6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-6-alkyl or oxo, 5-10-member heteroaryl,one, two or three ring atoms of which are heteroatoms selected from N and O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl or oxo, and di(C1-6)alkylamino; R2 is H, OH, C1-6-alkyl or halogen; as well as their pharmaceutically acceptable salts. The invention also relates to medicine and to use of the compounds in any of paragraphs 1-24.

EFFECT: obtaining novel biologically active compounds with affinity to dopamine D3 receptor and to serotonin 5- HT2a receptor.

27 cl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of the formula I, where R1 is alkyl; phenylalkyl optionally substituted by halogen; phenyl optionally substituted by halogen, halogen alkyl or alkoxy; thienyl optionally substituted by halogen; or benzo[b]thienyl optionally substituted by halogen; R2 is pyridyl or pyrimidinyl; R3 is alkyl; halogen alkyl; phenyloxylalkyl optionally substituted by halogen or alkyl; phenyl optionally substituted by halogen, alkyl or alkoxy; thienyl or alkylsilyl; R4 is H; or its salt, and methods of obtainment thereof. Additionally invention claims intermediate compound of the formula VI and method of its obtainment, composition for control of pathogenic microbes, and various methods of pathogenic microbe control.

EFFECT: improved efficiency of application.

29 cl, 1 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: agent is a 6-bromo-5-methoxy-indole-3-carboxylic acid derivative of general formula (I) , where B is a N(R)2 group, where both R groups together with the nitrogen atom to which they are bonded form a 5-6-member heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, such as pyrrolidine, piperidine, piperazine or morpholine, where each of the said heterocyclic rings can be substituted with C1-4alkyl, phenyl, benzyl, phenethyl, carbonylamino, -COOC1-4alkyl group or -COOC1-4alkyl group and phenyl, which can also be substituted or have substitutes selected from halogen, C1-4alkyl, C1-4alkoxy, and alkyl in the said groups can be linear or branched; R1 is C1-4alkyl, phenyl, possibly substituted with C1-4alkyl or C1-4alkoxy, halogen atoms; R2 is -S-phenyl, -S-benzyl, -O-phenyl, where in each of the said groups, the phenyl ring is possibly substituted with C1-4alkyl, C1-4alkoxy, halogen atoms, or R2 denotes a -N(R)2 group, or pharmaceutically acceptable salts thereof.

EFFECT: agent has antiviral activity towards influenza A virus.

3 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-phenylpyrimidine-2-carbonitrile of formula

(values of R, R1, R2 are given in the formula of invention) or their pharmaceutically acceptable salts which have inhibition properties towards catepsin K and catepsin S. The invention also relates to use of derivatives of formula I for treating catepsin K and catepsin S related disorders, as well as to a pharmaceutical composition containing the said derivative.

EFFECT: improved properties of derivatives.

9 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula ; or their pharmaceutically acceptable salts, where A is phenyl, X is CH2- or C=O; Y is O; k equals 1; m equals 0; R2 and R3 each independently represents hydrogen or alkyl, R4 is a group of formula or . Disclosed compounds have selective affinity to 5-HT6 and 5-HT2A receptors. Also described is a pharmaceutical composition containing said compounds and use of the said compounds in making a medicinal agent for treating diseased conditions of the central nervous system.

EFFECT: more effective treatment.

49 cl, 1 tbl, 16 ex

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