Derivatives metanarrative, methods for their preparation and pharmaceutical composition having antidopaminergics activity

 

(57) Abstract:

Usage: in medicine as a means possessing antidopaminergic activity. The inventive products derived metanarrative f-ly I or their physiologically acceptable salts, where X and Y are selected from hydrogen, halogen and (1-6C) alkoxy, R1-(1-6C)alkyl, phenyl, phenyl(1-3C)alkyl, five - or six-membered heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur, heteroaryl(1-3C) alkyl. Reagent 1: compound f-ly II. Reagent 2: R1Li, where X, Y and R1have the meanings specified for compounds of f-crystals I. reaction Conditions: in an aprotic solvent. 3 S. and 8 C.p. f-l, 4 Il.

The invention relates to metanarratives compounds which are antagonists of dopamine at the receptor. The compounds exhibit antidopaminergics activity and useful for the relief of neuropsychiatric disorders, such as psychosis, antipsychotics and neuroleptics. In addition, as D2antagonists, the compounds according to the invention can be useful to reduce the intensity of other disorders, which plays the role of dopaminergic activity, such as gastrointestinal RA is I (formula along with other formulas corresponding Roman numerals in Fig. 1-4), or its pharmaceutically acceptable salt, in which

X and Y independently are selected from hydrogen, halogen, (1-6C)alkoxy;

R1choose from

(A) (1-6C)alkyl,

(B) phenyl and naphthyl, each of which may contain 0-3 substituent, independently selected from the group consisting of

(1-6C)alkyl, (1-6C)alkoxy, hydroxy, halogen, cyano, nitro, phenyl, benzyloxy, benzoyl, trifluoromethyl; aminosulfonyl having the formula SO2NRaRband aminocarbonyl having the formula CONRcRdin which Ra, Rb, Rcand Rdindependently selected from hydrogen, 2-pyrrolidinyl, and (1-6C)alkyl, or in which Raand Rband Rcand Rdtogether with the nitrogen atom to which each is attached, form a 5-membered or 6-membered heterocyclic ring, wherein said nitrogen is the only heteroatom; and

RhRiN(1-3C) alkyl, in which Rhand Riindependently selected from hydrogen and (1-3C)alkyl;

(C) phenyl(1-3C)alkyl and naphthyl(1-3C)alkyl, in which phenyl and naphthyl part may contain 0-3 substituents selected from the values phenyl and naphthyl substituents, the data in (B).

(D) five - and six-membered heteroaryl ring containing from 1-3 heteroatoms (1-6C)alkyl, hydroxy, (1-6C)alkoxy, which may contain triptorelin group, (1-6C)alkoxycarbonyl, (1-6C)hydroxyalkyl, benzyloxy, halogen, (1-3C)alkylaminocarbonyl(1-3C)alkyl, aminocarbonyl defined in (B), ReS(O)n, RfNH, and RgS, in which Reand Rfindependently selected from hydrogen and (1-6C)alkyl and n is 0, 1 or 2, and Rgselected from (1-3C)alquilervillapeniscola and di(1-3C) alkylamino(1-6C)alkyl; and

(E) heteroaryl(1-3C)alkyl in which the heteroaryl part is a five - or six-membered ring as defined in (D), and in which the heteroaryl portion may contain 0-2 substituent selected from the values heteroaryl substituents in (D).

The invention also provides a pharmaceutical composition comprising a compound of formula I, defined above, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable diluent or carrier.

The invention also provides a method of treating neuropsychiatric disorders, including reception of mammals (including man) in need of such treatment an effective amount of the compounds of formula I, defined above, or pharmaceutically acceptable salts thereof.

In Anaco you should understand that reference to an individual radical such as "propyl" or "propoxy" embraces only unbranched chain ("normal") radical, a branched chain isomer such as "isopropyl" or "isopropoxy" refer particularly.

The term "halogen" includes fluorine, chlorine, bromine and iodine, unless otherwise stated.

The specialist in this area should be clear that the compounds of formula I may contain asimmetricheskii substituted carbon and/or sulfur atom, and accordingly may exist and can be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It should be understood that the invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or a mixture, and this form possesses properties useful in the treatment of psychosis, and in this field it is well known how to prepare optically active forms (for example, by separation of the racemic form by using recrystallization techniques, by synthesis from optically active starting substances, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine effective the Qila include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and isohexyl.

Particular values of (1-3C)alkyl include methyl, ethyl and propyl.

Particular values of (1-6C)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, isopentane, neopentane, hexose, isohexane.

Particular values of (1-3C)alkoxy include methoxy, ethoxy and propoxy.

Specific values for five - and six-membered heteroaryl ring containing from 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, include 2, 3-, and 4-pyridyl, 2-pyrazinyl, 2 - and 4-pyrimidinyl, 3 - and 4-pyridazinyl, 3-, 4 - and 5-isothiazole, 2-, 4 - and 5-oxazolyl, 2-, 4 - and 5-thiazolyl, 4 - and 5-oxadiazolyl, 2 - and 3-furyl, 2-, 4-, and 5-imidazolyl, and 2 - and 3-thienyl. Previous rings arbitrarily may contain substituents previously marked.

Specific values for benzo-derivatives of five - and six-membered heteroaryl groups include different chinoline, ethanolic and benzothiazolyl group which may be substituted as defined previously.

Particular values of (1-6C)hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hexabutyl.

More particular values of X and Y include hydrogen and halogen.

More particular values of (1-6C)alkyl include values of (1-3C)alkyl, including methyl, ethyl, propyl, isopropyl and tert-butyl.

More particular values of (1-6C)alkoxy include values of (1-3C)alkoxy, including methoxy, ethoxy, propoxy, isopropoxy.

More specific values for five - and six-membered heteroaryl ring containing from 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, include 2, 3 - and 4-pyridyl, 3-, 4 - and 5-isothiazole, 2-, 4 - and 5-thiazolyl, and 2 - and 4-imidazolyl, and these rings may be arbitrarily substituted as defined previously.

More specific values for benzo-derivatives of five - and six-membered heteroaryl groups include 3-chinolin, 4-ethenolysis, 2-methoxy-3-chinolin, 2-benzothiazolyl, 6-methoxy-2-benzothiazolyl and 2-Bastiani.

More particular values of (1-6C)hydroxyalkyl include values of (1-3C)hydroxyalkyl, including hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and 3-hydroxypropyl.

The most preferred values for X and Y include a hydrogen and chlorine.

The preferred value of R1in the form (1-6C)alkyl is tert-butyl (also the a and naphthyl, substituted by 0-3 substituents include 2 - and 3-methoxyphenyl, phenyl, substituted in position 2 - or 3-aminosulfonyl formula RaRbNSO2in which Raand Rbindependently selected from hydrogen, methyl and ethyl.

Preferred values of R1in the form of a five-membered heteroaryl ring substituted by 0-2 substituents include thienyl and furyl.

Preferred values of R1in the form of a six-membered heteroaryl ring substituted by 0-2 substituents include 3-pyridyl or unsubstituted or substituted in 2-position (1-6C) alkylthio, (1-6C)alkylsulfonyl or (1-6C)alkoxy.

The preferred compound has the formula I, in which:

X and Y independently are selected from hydrogen and chlorine;

R1selected from the group consisting of:

(i) tert-butyl;

(ii) 2 - and 3-methoxyphenyl and phenyl, substituted in the 2 - or 3-position by aminosulfonyl formula RaRbNSO2in which Raand Rbindependently selected from hydrogen, methyl and ethyl;

(iii) thienyl, furyl, and 3-pyridyl optionally substituted in 2-position (1-6C)alkoxy, (1-6C)alkylthio or (1-6C)alkylsulfonyl.

Particularly preferred compounds are:

1-((9S, 10S)-2-chloro-9,10 Teal)-4-(2-ethylsulfinyl-3-pyridyl)piperidine-4-ol;

1-(9,10-dihydro-9,10-metanarration-9-ylmethyl)-4-(2-ethylthio-3-pyridyl)piperidine-4-ol; and

1-(2-chloro-9,10-dihydro-9,10-metanarration-9-ylmethyl)-4- (2-methoxy-3-pyridyl)piperidine-4-ol.

When X is chlorine and Y is hydrogen, generally, 9S, 10S stereochemistry is preferred. In this case, the stereochemistry may be determined by the interaction of the acid chloride of formula III (G chlorine) with a chiral compound, such as oxazolidinone of the formula IV, with the receipt of two diastereomers. Separation and recrystallization and subsequent structure determination using x-ray gives the absolute stereochemistry at the 9 and 10 positions.

The compound of the formula I can be obtained by using methods that include methods known in the chemical production of structurally analogous compounds. Such methods of production amide of formula I, defined above, provide additional features of the invention along with the chemical intermediates that are included here, and are illustrated by the following techniques, in which values are typical radicals are as defined above unless otherwise stated. Thus, the method can be carried out, mainly,

(a) processing piperidine having the formula II is but to obtain in situ by reacting the compounds of formula R1Z, in which Z is a halogen group or, in some cases, hydrogen, compound (1-6C)alkylate, for example n-utility, mainly at temperatures between -20 and -100oC.

(b) processing the corresponding amide of formula IIA suitable regenerating agent, such as sociallyengaged or complex barbadoro-dimethyl sulfide;

(c) treatment of the aldehyde of formula III (G is hydrogen) with an appropriate piperidine of formula IV in the presence of a reducing agent, such as cyanoborohydride sodium:

(d) for compounds of formula I, in which the value of (1-6C)alkoxy desirable for any X and Y, by treating the corresponding compounds of formula I, in which a value for X or Y is hydroxy, with a corresponding halide (1-6C)alkyl in the presence of a base (such as a hydride of an alkali metal). The reaction can be conducted at a temperature of from 0oC to room temperature in an appropriate solvent, such as THF. The sequence of reactions to generate the hydroxy precursor is illustrated by examples 89-91.

When the commercial unavailability of the necessary starting materials for methods, such as described above can be obtained by using the known, structurally similar compounds, or techniques which are similar to the above described methods or techniques described in the examples. It is noted that compounds having the formula, R1Z can be obtained by methods similar to or communicated Brandsma et.al. Preparative Polar Organometallic Chemistry I, Springer-Verlag, 1stedition, 1987. In the discussion which follows from the schemes of reactions concerning this used standard chemical abbreviations and acronyms, including: "Et" for ethyl; "THF" for tetrahydrofuran; "tBU for tert-butyl, "CT" for room temperature: "DMSO" for dimethylsulfoxide; "Me" for methyl, "CBS" for carbobenzoxy; and "Fe" for phenyl. "Z" means halogroup, such as chlorine, when referring to the Grignard agents or compounds alkylate.

Common intermediates for producing compounds according to the invention is an acid (G is hydroxyl or gelegenheid (G is a halogen group such as chlorine) of formula III. This intermediate can be obtained, as illustrated in figure 1 (presented along with other schemes mentioned here) on the pages after the samples and formulas). The anthraquinone of formula 10 can be restored in the corresponding anthracene of formula 12 using zinc and water s is N-methylformamide. Reaction of aldehyde 14 with vinyl acetate (reaction Diels-Alder) get United bridging the communication connection 16, which can then be oxidized with chromium trioxide (in the presence of sulfuric acid) to the corresponding acid 18. Acid 18 can then be treated with thionyl chloride (in, for example, toluene), to obtain the corresponding 9-halogenmethyl, followed by treatment with sodium azide in, for example, a mixture of water and acetone) to give the corresponding 9-acid chloride followed by heating (for example toluene), reaching the rearrangement into the corresponding isocyanate, followed by treatment with a hydroxide of alkaline metal (in alcohol, such as ethanol), turning the acetyl group in the hydroxy and gidrolizu isocyanate to amine, while getting a 9-amine 20. Amin 20 can then be treated with nitrite, alkali metals (e.g. sodium) (in, for example, acetic acid), reaching a narrowing of the cycle and thus the 9-aldehyde of formula 22. The aldehyde 22 can be oxidized with chromium trioxide in the presence of sulfuric acid to obtain the corresponding 9-acid of formula 24 (corresponding to the acid of formula III, G is hydroxyl). The corresponding 9-acid chloride can be obtained by treating acid 24 thionyl chloride or oxalyl chloride is as illustrated in the examples, on the basis of the (undivided) acid 24, which monogamist in the 2-position desired glaizanicole (e.g., chlorine), although in the discussion that follows, it is necessary to understand that optically enriched isomer (such as 26) can be used if you want the corresponding optically enriched diploidization product. Acid 24 can interact with thionyl chloride to obtain the corresponding 9-acid chloride and then adding a lower alcohol (such as methanol or ethanol), giving the lowest 9-alkyl ester. 2-halogen ester can then be subjected to nitration in the 7-position by reacting with a suitable nitrous agent such as a combination triperoxonane anhydride with ammonium nitrate in the atmosphere of inert gas (e.g. nitrogen). This reaction usually gives a mixture of 2-halogen-6-nitro and 2-halogen-7-nitro positional isomers that can be separated by conventional separation techniques, such as recrystallization or flash chromatography on silica gel. 2-halogen-7-nitrosomas can be restored to the corresponding 7-amino-2-galoisienne using a suitable reducing agent, such as douglaston tin, and thus obtained 7-amidate with diasterous agent, such as tert-butyl nitrite, followed by treatment with a halide of the divalent copper, such as copper chloride or copper bromide. Then ester can be cleaved with a suitable base (such as alkali metal hydroxide) to obtain the corresponding 2,7-dialoguescience acid.

It is further noted that if you want oxidized substituted metanarration (for example, 2-chloro-7-methoxypropane), it can be obtained, as illustrated in the examples here, based on 7-amino-2-galoidoproizvodnykh, as described above. Amin handle diastereomer agent such as tert-butylnitrite, followed by treatment of the salt of a suitable acid, such as triperoxonane acid (salt, for example, which is formed by potassium carbonate in triperoxonane acid as the solvent). The resulting triptorelin can be hydrolyzed by conventional means and (1-6C) altergroup can be associated with oxygen by treatment with a base in the presence of the corresponding (1-6C)alkylhalides compounds (such as methyl iodide).

Specified using the R, S system of notation in scheme 1, the acid 24 is a racemate. Separation of racemic acid 24 can be achieved fractional krn, of a suitable solvent, such as ethanol, to obtain the optically enriched acid 26. Processing 26 thionyl chloride gives the corresponding optically enriched acid chloride. Optically enriched intermediates can be used in chiral syntheses to obtain optically enriched compounds according to this invention.

Amide of formula IIa can be obtained by treating the acid chloride of formula III (G is chlorine) with a piperidine of formula IV in the presence of a base, such as trialkylamine, such as triethylamine.

Piperidin formula II can be obtained, as illustrated in scheme II, by oxidation of the corresponding hydroxypiperidine formula 32 using an appropriate oxidizing agent, such as (1) chromium trioxide in the presence of sulfuric acid and using a suitable solvent, such as acetone; (2) a complex of a sulfur trioxide-pyridine in the presence of a base, such as trialkylamine (and triethylamine shown in the illustration) and using a suitable solvent, such as a combination of methylene chloride and DMSO; or (3) combination of oxalicacid and DMSO followed by treatment with a base such as triethylamine and using a solvent, such as METI is included in the scheme II. 9-Aldehyde 22 can be directly processed 4-hydroxypiperidine with subsequent restoration (in the presence of a desiccant such as molecular sieves) cyanoborohydride sodium in a suitable solvent such as methanol with getting hydroxypiperidine 32.

Alternatively, 9-aldehyde 22 you can oxidize and turn in the appropriate 9-the acid chloride, as previously described, and the subsequent processing 4-hydroxypiperidine either in excess or with added base, such as trialkylamine (e.g., triethylamine), to obtain the corresponding amide 30. Can then be carried out restoration amide 30 sociallyengaged in diethyl ether or tetrahydrofuran to obtain hydroxypiperidine 32.

Piperidine having the formula IV can be synthesized as illustrated in scheme III. 4-Hydroxypiperidine 50 may be subjected to interaction with carbobenzoxy (CBZ-Cl) in the presence of a base such as Et3N to protect the nitrogen of piperidine and thereby to obtain the corresponding 1-(carbobenzoxy)piperidine-4-ol 52. The oxidation of the piperidine-4-ol 52 oxalylamino and DMSO and subsequent treatment with base (Et3N) in a solvent such okanicheskie connection R1Li or a Grignard reagent R1MgZ, at temperatures from -20 to -70oC and in a solvent such as THF or Et2O to obtain the corresponding protected hydroxypiperidine 56. With secure hydroxypiperidine 56 may be removed sewn by treatment with a catalyst of palladium-on-carbon (10% Pd/C) and cyclohexanol in a solvent such as ethanol, thereby obtaining the desired hydroxypiperidine formula IV.

It is noted that many of the initial substances for synthetic methods described above are commercially available and/or widely reported in the scientific literature.

Examples of suitable pharmaceutically acceptable salts are salts of the accession of organic acids formed with acids which form a physiological acceptable anion, for example tosylate, methanesulfonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, a-Ketoglutarate, and α-glycerol. Can be obtained acceptable inorganic salts such as sulfate, nitrate and hydrochloride. Pharmaceutically acceptable salts may be obtained using standard techniques, well known in this field, for example by reacting the compounds of formula I with a suitable acid, with half imaut in the form of appropriate pharmaceutical compositions which includes a compound of formula I, as defined previously, along with a pharmaceutically acceptable diluent or carrier, and the composition is chosen for a particular route of administration of the medicinal product. Such compositions provide an additional characteristic of the invention. They can be obtained using conventional methods and fillers and binders, and can be in many forms posing. For example, they may be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of a suppository for rectal admission; in the form of sterile solutions or suspensions for use by intravenous, vnutrepenialnyh, subcutaneous or intramuscular injection or infusion; or in the form of patches for transdermal application. Oral administration is preferred.

The dose of a compound of formula I, which take should vary according to principles well known in this field, taking into account the route of application, the severity of psychotic illness, physique and age of the patient. Typically, the compound of formula I should be used to warm-blooded mammal (such as a person) so as to achieve an effective dose, usually hedgehog intramuscularly, it is used in the range from about 0.01 to about 10 mg/kg of body weight. In the case of oral administration it is used in the range from about 0.1 to about 40 mg/kg body weight.

Specialist in this field should be obvious that the compound of formula I should be taken in conjunction with other therapeutic and preventive agents and/or medications that medical compatible with it. Typically, compounds within the scope of the invention do not show any hint of toxicity in the test animals at a dose that is a multiple of several times the minimum effective.

The compounds of formula I are antagonists of dopamine D-2 receptors and therefore, as such, are predicted useful as antipsychotic drugs. D-2 antagonism can be shown by standard tests, such as antagonism (3H)-spiperone binding (Test A), and/or antagonism caused by apomorphine climbing, and caused by apomorphine breakdown swimming (Test B).

Test A.

Used analysis of the binding of the receptor to measure the affinity of various compounds to the subtype of the dopamine (DA) D-2 receptor was the analysis described Saller and Salama in J. Pharmacol and washed once in 50 volumes in the corresponding Tris-HCl buffer. To analyze the binding of D-2 receptor veins membrane suspended to a final concentration of 8 mg/ml in 50 mm Tris-HCl with 40 nm ketanserina, pH of 7.7. Nonspecific binding of D-2 receptors was measured in the presence of 1.0 mm (+)-butaclamol. IC50s(concentration of drug that gives 50% displacement) for substitution of 0.5 nm (3H) spiperone determine, using at least five concentrations of each drug in triplicate. Palmierite suspension membrane incubated with the compound of interest, or excipient, or a nonspecific drug, ligand and the corresponding Tris-HCl buffer. The final volume of the reaction mixture is brought to 1 ml to each tube and incubated at 37oC for 15 min to facilitate the binding and to ensure balance. Filter system Brandel with filters GF/B can be used to separate bound from free drug. The amount of drug associated with membranes, determined using a liquid scintillation counter. IC50values obtained from regression least-squares logit-log transformation of the data. Typical IC50the results of ATOR CLASS="ptx2">

Female Swiss-Webster mice weighing approximately 20 g were deprived of food for about 24 hours and then they have introduced various oral doses of either filler, or the test agent in the range of doses ( N 20 mice in the treated group). 30 min later they were injected apomorphine HCl 1.25 mg/kg, subcutaneously, and were placed in a holding cell. The holding cell was 9 cm wide, 15 cm deep and 30 cm in height. One wall had 27 horizontal steps positioned with an interval of 1 cm in 30 minutes after administration of apomorphine each mouse was observed continuously for 1 min and recorded the highest and the lowest step, reached her front paws. The average of these two quantitative indicators are used as a quantitative indicator for the observed mouse. Highest and lowest quantitative indicators was 27 and 0, respectively). Immediately after 1 min observation period set the height of each mouse was placed in a round container for swimming for 2 min and counted the number of heats. Tank height was 15 cm and the diameter was 23 see Round the barrier size 10.5 cm in diameter and with a height of 17 cm was placed in the center of the vessel, creating a channel for swimming a width of 8.75 see the Level in the tee with an interval of 180 degrees. "Swim" is registered every time the mouse floated from one label to another. Mice were observed through the upper mirror and the number of 180 degree swims were recorded for each mouse. Activity in this test indicated a reduction in quantitative indication of climb, followed by an increase in the measure of races at a given dose of test compound. Typical results of this test for the values of the minimum effective dose was 1.3 mg/kg for the compound of example 49 and 20 mg/kg for the compound of example 5.

In General, compounds were considered active if they provided the IC50a value of 500 nm or less in test A, and/or were active when using oral dose of 40 mg/kg or less in test B.

The invention is illustrated further his non-limiting examples in which, unless otherwise stated:

(I) temperatures are given in degrees Celsius (C); Operations are performed at room temperature or ambient temperature, i.e. at a temperature in the range 18-25oC.

(II) evaporation of solvent is carried out using a rotary evaporator under reduced pressure (600-4000 PA, a 4.5-30 mm Hg) with a bath temperature of up to 60oC,

(III) f is on Analtech 0.25 mm on silica gel GHLF plates (Art 21521), supplied Analtech, Newark, DE, USA;

(IV) liquid chromatography high pressure (ghvd) to determine the optical purity of the chiral isomers of the compounds is carried out either in a column 25 cm x 4.6 mm Chiralcel#OD or column, 15 cm x 4.6 mm Ultron Ovomucoid supplied by JT Baker, Inc. Ehud analyses for most reaction mixtures and finished products is carried out either 25 x 4.6 mm Supelcosil#LC-8-DB column, supplied by Supelco, State College, PA, USA, or 25 cm x 4.6 mm Bond#RX column.

(V) in General, the course of reactions was monitored by TLC and/or jhud and reaction times are presented for illustration only;

(VI) the melting point is incorrect and (decomp) indicates decomposition, these melting points represent the melting point obtained for substances, prepared as described; polymorphism may result in the release of substances with different melting points in some syntheses;

(VII) all final products were purified by TLC and/or jhud and had satisfactory spectra of nuclear magnetic resonance (NMR) and the results of microanalysis;

(VIII) the outputs are given for illustration only;

(IX) reduced pressures are given as absolute pressures in Pascals (PA); other pressures are given as gauge pressure is (weight), so pl. (melting point), l (liter), ml (milliliters), g (gram), mmol (mmol), mg (milligrams), min (minute), h (hour);

(XI) the ratio of solvents is given in terms of volume:volume (V/V).

Example 1. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(3-pyridyl)piperidine-4-ol.

To a cooled solution (-90oC) n-utility (2.5 M in hexane, to 2.40 ml, 6.0 mmol, 1,5 EC) in tetrahydrofuran (40 ml) under nitrogen atmosphere add fresh 3-bromopyridin (0,540 ml, 5.6 mmol, 1,4 EC). The reaction metalhalide exchange is conducted by heating up to -75oC and maintained at this temperature for 1.5 hours during this time in dark green solution stand out thin (macro) particles. A solution of 1-(2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidinol (1.35 g, 4.0 mmol) in tetrahydrofuran (10 ml) furan (10 ml) is added dropwise, which is accompanied by a significant lightening of the color of the solution to dark yellow. The reaction mixture is heated to room temperature within 1 h and cooled water (50 ml). The aqueous phase is extracted with ethyl acetate (3 x 60 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and brought to the oil. The reaction mixture was purified using flash-jgogo substances. Analysis by thin-layer chromatography (TLC) (Rf0,20, ethyl acetate).

1H NMR (D6DMCO, 300 MHz) 8,69 (W s, 1H), to 8.41 (d, J 4.5 Hz, 1H), 7,83 (dt, J 8.0 Hz, 1H), 7,29 (m, 5H), to 6.95 (m, 3H), of 5.05 (s, 1H), 4,35 (s, 1H), 3,41 (m, 2H), 3,34 (s, 1H), 2,75 (m, 4H), of 1.92 (m, 2H), 1,62 (m, 2H), MS (Cl, CH4) m/z 417 (M+1, 100), 419 (36), 445 (M+ 29, 15), 399 (15).

The free base was dissolved in diethyl ether containing a small amount of methylene chloride, acidified with ethereal HCl and the suspension of the hydrochloride diluted with additional ether. The salt is filtered off, washed with fresh ether and dried in vacuo (50oC, 13 PA, 18 h) to give white solid, so pl. 225-228oC (decomp.).

Analysis for C26H25ClN2O2,1HClH2O:

Calculated C 61,04, H 5,73, N 5,48

Found, C 60,91, H 5,64, N OF 5.29

The original piperidine receive the following way:

a. 2-Chloroanthracene.

Stir a suspension of 2-chloroanthraquinone (1260 g, 5,19 mol) in concentrated ammonium hydroxide (7.5 l) and water (2.5 l) was heated to 40oC. Powder zinc (845 g, 12,93 mol) is added in one portion, changing the color to dark red. The mixture is stirred for 45 min at 50oC, then carefully process the second portion of zinc powder (845 g). After the addition, stir the mixture and destroyed). The TLC analysis (silica gel; hexane:methylene chloride (3:1)) confirmed full conversion of anthraquinone ( Rf0,35) until the desired anthracene (Rf0,80). The reaction mixture was stirred over night, as it is cooled to room temperature. The cooled mixture is treated with methylene chloride (4 l), stirred for 2 h, then filtered through Celite to remove the excess zinc. The filter residue is washed with methylene chloride (6 x 1 l). The methylene chloride layer is separated from the water, then treated with 6N. hydrochloric acid (3 l) and stirred for 2 hours the First portion 2 chloroanthracene collected by filtration and washed with water (4 x 1 l). After vacuum drying receive light yellow crystalline product 804,6 g (so pl. 220-221oC). Methylenchloride part of the filtrate concentrated in vacuo to 10% of its original volume. So get an additional 158,5 g of the desired compound with a total output 963,1 g (87,2%).

1H NMR (CDCl3) 8,39 (s, 1H), 8.30 to (s, 1H), of 7.96 (s, 4H). 7,49 (s, 2H), was 7.36 (d, J 8.7 Hz, 1H).

b. 2-Chloro-9-formularized.

N-methylformamide (2,45 kg, 18,12 mol) is treated with phosphorus oxychloride (2.66 kg, of 17.35 mol) over a 40 min period at ambient temperature. Intermediate Vils-meier included the ore 1a) (933 g, a 4.53 mol) and o-dichlorobenzene (1.0 l). Received a bright yellow mixture is heated gradually over a period of 1.5 h to 90oC, and at this stage exothermically increasing the reaction temperature to 115oC. the Heat is removed until until ectotherm will weaken (45 min), after this time the mixture is heated for 9 hours at 90oC, then cooled. The TLC analysis (silica gel, ethyl acetate:hexane 1:4) indicates the presence of small amounts of unreacted anthracene (Rf0,90), a small amount of 3-chloridometer (Rf0.65) and 2-chloridometer (Rf0,58) as a main component. The cooled reaction mixture was poured into ice/water (27 l), precipitating a dark brown resin. The aqueous layer was decanted from the resin and shaken out with methylene chloride (5 x 2 l). The combined extracts are used to re-dissolve the resin. Methylenechloride solution was washed with 3n. hydrochloric acid (4 x 1.5 l), then water (2 l), then dried over magnesium sulfate. The extracts are filtered, and then filtered under pressure through a layer of silica gel, elwira with methylene chloride until then, until the desired connection is fully allocated. Eluent concentrate on a rotary evaporator, obtaining a suspension of bright yellow crystals (o-dichlorobenzene). Crystals sober-9-formulastring (so pl. 148-150oC).

1H NMR (CDCl3) 11,35 (s, 1H), 9,02 (d, J 0.9 Hz, 1H), 8,81 (d, J a 8.9 Hz, 1H), 8,56 (s, 1H), 7,98 (m, 1H), of 7.90 (d, J a 8.9 Hz, 1H), 7,66 (m, 1H), 7,53 (m, 1H), 7,42 (m, 1H).

c. 12-Acetoxy-2-chloro-9-formyl-9,10-dihydro-9,10-tenantbased (E and Z isomers).

A mixture of 2-chloro-9-formulastring (described in example 1b) (100.0 g, 0,415 mol) and vinyl acetate (400 ml, 374 g, 4,34 mol) is placed in a bomb stainless steel (PARR) and heated at 200oC (sand bath) for 24 h, then cooled. The reaction mixture was concentrated on a rotary evaporator to remove the excess vinyl acetate give crude product as a tan crystalline solid. The crude product from multiple downloads, which spent 670,0 g (2,78 mol) of 2-chloro-9-formulastring, unite. Kneading the powder with diethyl ether (1.0 l) gives no white crystalline solid, which is collected by filtration, washed with diethyl, ether (2x300 ml), then dried in vacuum, obtaining 629,0 g (69,1%) of these compounds (i.e pl. 145-153oC).

1H NMR (CDCl3) of 10.58 (s) and 10.64 (s, 1H), 7,63 (m) and 7,76 (d, J 1.5 Hz, 1H), 7,15 -7,36 (m, 6H), 5,46 (m, 1H), 4,29 (s, 1H), to 2.55 (m, 1H), 1,88 (C) and at 1.91 (s, 1H), 1.55V (m, 1H).

Evaporation of the filtrate and the wash water gives a thick layer of brown is Reid:hexane (1:1). The selected solid is recrystallized from a mixture of diethyl ether:hexane (1:1, 400 ml), receiving additional 175,5 g (19,3%) of the desired compound.

d. 12-acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-anthracene-carboxylic acid (E and Z isomers).

Mix a solution of 12-acetoxy-2-chloro-9-formyl-3,10 - dihydro-9,10-attanandana (described in example 1c) (629,0 g 1,925 mol) dissolved in acetone (8.0 l), treated with Jones reagent (1,50 l, approx. 1,93 mol, obtained as described in Fieser Fieser Vol. 1: PP. 142) during 1 h at 10-20oC. After the addition of Jones reagent, the reaction mixture was stirred for 4 h at room temperature. The TLC analysis (silica gel, methylene chloride) indicates a total expenditure of aldehyde (Rf0,73). Add isopropanol (100 ml) and the reaction mixture stirred for 18 h, to repay any excess Jones reagent that leads to the formation of a white suspension above the green-black precipitate (salt chromium). White supernatant is drained off and the precipitate washed with acetone (5x500 ml). Acetone washing combined with the supernatant and concentrate on a rotary evaporator to a final volume of 2 L. the Residue is poured into ice-water (10 l) and stirred vigorously for 5 h, not quite getting what was 65.3 g (quantitative) of the desired carboxylic acid (so pl. 270-273oC (decomp.)).

1H NMR (D6-DMCO) to 13.95 (s, 1H), 7,79 (m) and 7,87 (s, 1H), 7,12 was 7.45 (m, 6H), 5,27 (d, J 6.4 Hz, 1H), 4,48 (s, 1H), 2,35 (m, 1H), 1,81 (C) of 1.84 (s, 3H), 1,38 (m, 1H) IR max (KBr) 1690 cm-1, C=O, -COOH; 1740 cm-1, C=O, -COOCH3< / BR>
e. 12-Acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-anthracene-9-ylcarbonyl (E and Z isomers).

12-Acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-antratsenovoe acid (described in example 1d) (665,0 g, 1.94 mol) suspension in toluene (8.0 l). Add thionyl chloride (400 g, 3,36 mol) in one portion at room temperature, and then a catalytic amount (2 ml) of N,N-dimethylformamide. The mixture is gradually heated to boiling (80oC) for 1 h, then refluxed for 8 h, getting a clear amber solution. The cooled reaction mixture is concentrated on a rotary evaporator under forvacuum to remove the toluene. The crude acid chloride is isolated in the form of a waxy solid (804 g, 115% in theory), and used crude in the next reaction. A small sample of the substance is dried under high vacuum to obtain the sample for spectral analysis.

1H NMR (CDCl3) 7,87 (m, 1H), 7.18 in-7,40 (m, 6H), to 5.57 (m, 1H), 4,29 (s, 1H), 2,58 (m, 1H), 1.91 a (C) and of 1.94 (s, 3H), 1,50 (m, 1H), IR max (clear film): 1750 cm-1

Raw 12-acetoxy-2-chloro-9,10-dihydro-9,10-ethano-9-anthracene-9-incorporaled (described in example 1e) 804 g, approx. 1.94 mol) is dissolved in acetone (8.0 l) and the resulting solution is cooled using baths with ice/methanol -5oC. Stir the mixture was treated with an aqueous solution of sodium azide (380 g of 5.84 mol in 1.0 l of water) is added within 30 minutes of the Obtained reddish-brown suspension is stirred for 3 h at 0oC, then allow to warm to room temperature. The mixture is concentrated on a rotary evaporator at 15-20oC using forvacuum to remove the acetone. The residue is partitioned between water (5 l) and toluene (5 l), stirred for 1 h, then filtered. The two-phase filtrate are separated and the aqueous portion extracted with toluene (5 x 1 l). Toluene extracts are used to re-dissolve the precipitate filtered, selected previously. The combined toluene solutions are washed with a water solution (2 l), then dried over magnesium sulfate. The toluene was filtered, then concentrated to 1/2 volume on the rotary evaporator at 15-20oC under forvacuum. This gives a toluene solution acylated (output, as suggested, is quantitative), which is used in the following is e whitish sticky solids for spectral analysis.

1H NMR (CDCl3) 7,80 (m, 1H), 7,16-7,33 (m, 6H), of 5.39 (m, 1H), 4,27 (t, J 2.6 Hz, 1H), 2,50 (m, 1H), 1,89 (C) and 1.92 (s, 3H), 1,47 (m, 1H). IR max (nujol): 1720 cm-1, C=O, -CON3, 1750 cm-1, C=O, -COCH3: 2160 cm-1N=N=n

g). 12-Acetoxy-2-chloro-9-isocyanato-9,10-dihydro-9,10-ethanoanthracene (E and Z isomers).

Toluene solution of crude acylated highlighted in the previous reaction (approx. 713,5 g, 1.94 mol in 6.0 liters of toluene) is heated gradually over a 30 min period to 65oC. At this stage there is a rapid evolution of nitrogen, followed by a release of heat which raises the temperature of the reaction mixture to 95oC. Heating the mesh to remove until the exothermic reaction is complete (30 min), after which the reaction mixture is refluxed for 3 hours, then allow to cool. The toluene is removed on a rotary evaporator using forvacuum, highlighting the crude isocyanate in the form of a thick yellow oil (738,5 g, 112% of theory). This substance is used in subsequent reactions without further purification. A sample of the oil is dried under high vacuum to obtain the sample for spectral analysis.

1H NMR (CDCl3) rate of 7.54 (m, 2H), 7,15-7,30 (m, 5H), to 5.03 (m, 1H), 4.26 deaths (t, J 2.6 Hz, 1H), to 2.55 (m, 1H), 1,98 (s) and 2.00 (s, 3H), and 1.56 (m, nitro-9,10-ethanoanthracene (E and Z isomers).

Crude isocyanate from the previous reaction (738,5 g, 1.94 mol) is dissolved in absolute ethanol (7.0 l) to give a light yellow solution. Stir the solution is treated with 20% sodium hydroxide solution (800 g, 20.0 mol 4.0 l of water) added in one portion at room temperature. The reaction mixture immediately turns red-brown color adding base. The mixture is heated under reflux for 8 h, then cooled. The TLC analysis (silica gel, methylene chloride) indicated the complete consumption of the isocyanate (Rf0,80). The reaction mixture was concentrated on a rotary evaporator to remove the ethanol, leaving an aqueous suspension of the product, which is extracted with methylene chloride (3 x 5 l). The combined extracts washed with water (2 l) and brine solution (1 l), then dried over magnesium sulfate. By filtering, and then removing the solvent in vacuo, get raw amerosport in the form of a sticky yellow-brown solid. Grinding into powder with diethyl ether (1.0 l) receive a net connection in the form of a powder, cream colour weight 445,8 g (84,5%) (so pl. 164-167oC).

1H NMR (CDCl3) 7,09-the 7.43 (m, 7H), is 4.21 (t, J 2.6 Hz, 1H), of 3.77 (m, 1H), 2,35 (m, 1H), 2,25 (sh.with 3H), of 1.48 (m, 1H).

i). 2-Chloro-9-formyl-9,10-dihydro-9 is, of 1.64 mol) is dissolved in glacial acetic acid (4.0 l) and the resulting solution is cooled to 10oC. To the reaction mixture add a solution of sodium nitrite (340,0 g is 4.93 mol) in water (1.4 l) over a period of 1.75 hours the Temperature of the mixture support at the 10oC during the addition of nitrite and within 4 hours after that. The mixture is stirred overnight and allow to warm to room temperature. The TLC analysis (silica gel, toluene: ethyl acetate (4: 1)) indicates complete conversion of amerosport (Rf0,12) 2-chloro-9-formyl-9,10-dihydro-9,10-ethanoanthracene (Rf0,80). The reaction mixture was diluted with water (4 l), which causes the precipitation reddish-brown resin. The aqueous supernatant is decanted from the resin, diluted with an equal volume of crushed ice, then bring the pH to 5-6 with solid sodium hydroxide. The resulting aqueous mixture is extracted with ethyl acetate (3 x 1.5 l). United an ethyl acetate extracts are used to re-dissolve the resin, and the resulting solution was washed with brine (2 x 1 l), then dried over magnesium sulfate. By filtering, and then removing the solvent in vacuo get the crude product as a thick brown oil. Purification of this substance through the column chromatography what I yellow oil, which crystallizes upon standing (311,7 g, 74,6% ). Kneading the powder with a mixture of diethyl ether:hexane (1:6, 700 ml) gives the first portion of the pure titled compound as crystalline solid weighing 224,1 g (53,6% so pl. 91-92oC).

1H NMR (CDCl3) accounted for 10.39 (s, 1H), 7,50 (d, J 1.9 Hz, 1H), 7,39 (m, 1H), 7,31 (m, 1H), 7,20 (d, J 7.8 Hz, 1H), 7,01 (m, 3H), 4,37 (s, 1H), 2,80 (m, 2H).

Substance, isolated from the mother liquors and washes, re-purified by column chromatography, as described previously, receiving additional 65.0 g (15.5 per cent) of these compounds.

j. 2-Chloro-9,10-dihydro-9,10-methane-9-astratenkova acid.

To a cooled solution (0oC) 2-chloro-9-formyl-9,10-dihydro-9,10-ethanoanthracene (described in example 1i ) (20,0 g, 78.5 per mmol) in acetone (260 ml) was added Jones reagent (24 ml; 27 g of chromium trioxide, 23 ml of water, diluted to 100 ml reagent) portions. The reagent is added until until the orange color. The reaction mixture containing significant amounts of recovered chromium salts, warmed to room temperature. The solvent is removed in vacuum and replaced with water (300 ml), saturated sodium chloride. The aqueous phase is extracted with ethyl acetate (3x300 ml). United orgcom sodium, and extracted with ethyl acetate (4 x 300 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered, and concentrated to not quite white solid. The method gives 26,66 g (quantitative) of the titled compound. Additional purification is not required.

1H NMR (D6-DMCO, 300 MHz) 13,2 (bottom field), 7,46 (W s, 1H), was 7.36 (m, 3H), 7,02 (m, 3H), of 4.45 (s, 1H), to 2.67 (s, 2H), MS (Cl, CH4) m/z 271 (M+ 1, 100), 273 (34), 299 (M+ 29, 17), 253 (33), 243 (22), 227 (20).

k. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylcarbonyl)piperidine-4-ol.

To a solution of 2-chloro-9,10-dihydro-9,10-methane-9-intracisternally acid (described in example 1j) (6,51 g, 24,1 mmol) in toluene (70 ml) is added thionyl chloride (2,28 ml of 31.3 mmol, 1,3 EC). The reaction mixture is heated under reflux for controlling the allocation of gas by barbaterom with mineral oil. The system reaches steady state within 40 min, and at this time it is slightly cooled and to it add portions 4-hydroxypiperidine (between 6.08 g, 63.3 mmol, 2.5 EQ). Releases a significant amount of heat and the reaction mixture becomes dark. The suspension is heated under reflux for 2 h, cooled to room temperature and stirred for 18 hours. The reaction mixture R is the Organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to oil. The method gives of 6.95 g (82%) of the named compound as a viscous oil. No cleaning is required.

1H NMR (D6-DMCO, 250 MHz) 7,63 (m, 1H), 7,21 (m, 6H), to 4.41 (s, 1H), 4,18 (m, 1H), 3,65 (m, 2H), 3,25 (m, 2H), was 2.76 (m, 2H), 1,90 (m, 2H), 1,38 (m, 2H), MS (Cl, CH4) m/z 354 (M+ 1,100), 356 (36), 382 (M+ 29,19), 336 (27), 318 (9).

l. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol.

To a cooled suspension (0oC) 1-(2-chloro-9,10-dihydro-9,10 - ethanoanthracene-9-ylcarbonyl)piperidine-4-ol (described in example 1k) (6,95 g and 19.6 mmol) in diethyl ether (200 ml) under nitrogen add sociallyengaged (1,49 g of 39.2 mmol, 8 EQ. hydride) in portions and the suspension is stirred at 0oC for 30 min and warmed to room temperature. After 18 hours at room temperature, the excess reagent is carefully quenched as follows in the sequence, water (1.5 ml), 2,5 N. NaOH (1.5 ml) and additional water (4.5 ml). The suspension is intensively stirred in until the aluminum salts will not become granular white solid. The suspension is diluted with ethyl acetate (100 ml), dried small amount of anhydrous magnesium sulfate and filtered. The filter cake is thoroughly washed with ethyl acetate. The solvent is removed, produces the TLC (Rf0,15, 50% ethyl acetate in hexane).

1H NMR (CDCl3, 300 MHz), 7,20 (m, 4H), to 6.95 (m, 3H), 4,60 (s, 1H), 4,24 (s, 1H), 3,70 (m, 1H), 3,34 (s, 2H), 2,88 (m, 2H), 2,58 (s, 2H), is 2.37 (m, 2H), of 1.85 (m, 2H), 1.57 in (m, 2H), MS (Cl, CH4) m/z 340 (M+ 1,98), 342 (33), 322 (100), 368(M+ 29,22), 114 (26).

m. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidinol.

To a cooled solution (-78oC) oxalicacid (3,06 ml of 35.1 mmol, 2 EQ) in methylene chloride (100 ml) under nitrogen add distilled dimethyl sulfoxide (5,00 ml of 70.2 mmol, 4 EQ). After 10 min add 1-(2-chloro-9,10-dihydro-9,10 - ethanoanthracene-9-ylmethyl)piperidine-4-ol (described in example 1l) (5,96 g, 17.5 mmol) in solution in methylene chloride (10 ml). The reaction mixture was stirred at -78oC for 30 min before adding triethylamine (19.6 ml, 140 mmol, 8 EQ). The cooling bath removed and the reaction mixture was warmed to room temperature for 1.5 hours, the Reaction mixture was poured into a 2.5 N. NaOH (100 ml) and the aqueous phase is extracted with methylene chloride (3 x 100 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to oil. The crude reaction mixture was purified using flash chromatography on silica gel (400 ml, eluent: 20% ethyl acetate in hexane) to give 5.53 g (93%) of the named compound. Analysis is, ,49 (s, 2H), equal to 2.94 (t, J 6,1 Hz, 4H), 2,62 (s, 2H), 2,43 (t, J 6.0 Hz, 4H) MS (Cl, CH4) m/z 338 (M+ 1,100), 350 (35), 366 (M + 29, 31)

Climateneutral acid separated as follows.

n. Optical separation of (9S, 10S) 2-chloro-9,10-dihydro-9,10 - methane-9-intracisternally acid.

To a solution of racemic 2-chloro-9,10-dihydro-9,10-methane-9-intracisternally acid (described in example 1j) (100 g, and 0.37 mol) in ethyl acetate (1.5 l) and methanol (75 ml) is added solid (1S, 2S)-(+)-pseudoephedrine (61,1 g and 0.37 mol). With efficient stirring, the mixture is heated to boiling, kept at the boil under reflux for 30 min and slowly cooled to 25oC. After a minimum of 2 hours the suspension is filtered and washed with ethyl acetate, getting enriched diastereomer salt (88,6 g, 0.20 mol, 55% ratio of diastereomers 80:20, as determined using ghvd). Enriched salt is suspended in 3% methanol in ethyl acetate (2,74 l), heated to boiling and maintained at the boil under reflux for 30 minutes, the Suspension is cooled slowly to 25oC, stirred for 2 h, filtered and washed with ethyl acetate, receiving fortified salt (70 g, 0.16 mol, 79% ratio of diastereomers 95:5, as determined using ghvd). About the seal salt (60,0, 0.14 mol, 85% ratio of diastereomers 99:1, determined using ghvd). This salt (60 g, 0 to 14 mol) is added to water (1 l) and the resulting suspension is acidified to pH 2-3 with concentrated hydrochloric acid (15 ml) and then extracted with diethyl ether (3 x 500 ml). The combined organic extracts washed with brine, dried over anhydrous magnesium sulfate and evaporated to an oil. Hexane is added and concentrated in vacuo, obtaining enantiomerically enriched acid (36 g, 0.13 mol, 98% extract, the ratio of enantiomers 99:1, determined using ghvd) as a white solid. Crystallization from a mixture of hexane (360 ml) and cyclohexane (720 ml) obtain enantiomerically pure (9S, 10S)- 2-chloro-9,10-dihydro-9,10-methane-9-antratsenovoe acid as a white solid (30 g, 0.11 mol, 81%), so pl. 172-173oC. alpha rotation (sodium D): + 101 degrees (C=2 CHCl3)

Analysis for C16H11ClO2:

Calculated C 70,99, H 4,10

Found, C 70,81, H 4,21

1H NMR of 7.48 to 7.62 (m, 2H), 7,27-7,35 (m, 1H), 7,22 (d, J 7.8 Hz, 1H), 6.90 to-7,10 (m, 3H), 4,35 (s, 1H), 2,80-2,95 (m, 2H)

Analysis jhud: Column: Ultron Ovomucoid (ES-OVM) 15 cm x 6 mm

Eluent: 15% acetonitrile/85% water KH2PO4buffer (10 mm), brought to pH 5.5 1 M potassium hydroxide. Flow: 1 ml/min,<, 10-dihydro-methane-9-antratsenovoe acid allocate as follows.

o. Using a technique similar to the method described in example 1n, except that (1R, 2R)-(-)-pseudoephedrine as the authorizing agent, get (9R,10R)-(-)-2-chlor,10-dihydro-9,10-methane - 9-antratsenovoe acid, so pl. 169-170oC. alpha rotation (sodium D): 100,8 C (c 2,0, CHCl3).

Analysis for C16H11ClO2:

Calculated C 70,99; H 4,10

Found, C 70,75; H 4,18

1H NMR of 7.48-to 7.64 (m, 2H), 7,27-7,38 (m, 1H), 7.23 percent (d, J 7.8 Hz, 1H), 6.90 to for 7.12 (m, 3H), 4,36 (s, 1H), 2,80-2,95 (m, 2H)

Example 2. 1-(2-Chloro-9,10-dihydro-9,10-metanarration-9-ylmethyl)-4- (6-chinoline)piperidine-4-ol.

Using a methodology similar to that described in example 1, except for using 7-brainline, get a named connection with the release of 63% in the form of a white solid substance, so pl. 210-215oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz), 8,87 (DD, J of 1.6 and 4.2 Hz, 1H), 8,14 (d, J 7,1 Hz, 1H), 8,07 (d, J a 8.9 Hz, 1H), 7,92 (d, J 1.9 Hz, 1H), 7,86 (DD, J 2,0, 8,8 Hz, 1H), 7,38 (DD, J 4.2, and 8,3 Hz, 1H), 7,20 (m, 4H), to 6.95 (m, 3H), 4.26 deaths (s, 1H), of 3.46 (s, 2H), 2,87 (m, 2H), 2,78 (m, 2H), 2,64 (d, J 1.4 Hz, 2H), 2,24 (m, 2H), 1,89 (s, 1H), 1,80 (m, 2H) MS (Cl, CH4) m/z 467 (M+ 1,100), 469 (38), 495 (M+ 29, 19), 449 (15) salt of hydrochloric acid:

Analysis for C30H27N2OCl2HClH2O:

Calculated C -64,58; H ceiling of 5.60; N 5,02

Found, C -64,18; H 5,54; N 4,87

Example 3. illogical described in example 1, except for using 3-brainline, get the named compound with 50% yield as a white solid, so pl. 215-217oC-free basis:

1H NMR (CDCl3, 250 MHz) 9,07 (d, J 2.0 Hz, 1H), 8,21 (d, J 1.3 Hz, 1H), of 8.09 (d, J 8,4 Hz, 1H), 7,80 (d, J 8.1 Hz, 1H), 7,69 (DD, J a 7.5 and 7.6 Hz, 1H), 7,53 (DD, J with 7.6, 6.8 Hz, 1H), 7,22 (m, 4H), 6,98 (m, 3H), 4,28 (s, 1H), 3,48 (s, 2H), 2,96 (m, 2H), and 2.79 (m, 2H), 2,65 (s, 2H), 2,43 (m, 2H), 2,03 (s, 1H), of 1.84 (m, 2H) MS (Cl, CH4) m/z 467 (M + 1,100), 495 (M+ 29,20), 449 (15), 469 (37) chlorhydrate salt:

Analysis for C30H27N2OCl2HClH2O:

Calculated C 64,58; H ceiling of 5.60; N 5,02

Found, C 64,24; H 5,49; N 4,92

Example 4. 1-(2-Chloro-9,10-dihydro-9,10-metanarration-9-ylmethyl)-4- (2-thiazyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except using 2-bromothiazole, get a named connection from 78% yield as a white solid, so pl. 195-199oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) 7,71 (d, J 3.2 Hz, 1H), 7.23 percent (m, 2H), 7,19 (M, 2H), of 6.96 (m, 4H), 4,25 (W s, 1H), 3.43 points (s, 2H), 2,89 (m, 2H), was 2.76 (m, 2H), 2,60 (d, J 1.4 Hz, 2H, in), 2.25 (m, 2H), of 1.88 (m, 2H) MS (Cl, CH4) m/z 423 (M+ 1,100), 425 (43), 451 (M + 29,10), 405 (17) chlorhydrate salt:

Analysis for C24H23ClN2OS2HCl0,5H2O:

Calculated C 57,09, H 5,19, N 5,55

Found, C 56,94, H 5,03, N 5,23

Example 5. 1-(9,10-Dihydro-9,1 example 1 except that originate from 1-(9,10-dihydro-9,10-metanarration-9-ylmethyl)-4-piperidinol, get a named connection from 68% yield as a white solid, so pl. 188-190oC (decomp.), free base:

1H NMR (D6-DMCO, 300 MHz) 8,68 (d, J 2.2 Hz, 1H), 8,40 (DD, J 3.3 Hz, 1H), to 7.84 (m, 1H), 7,28 (m, 5H), 6,92 (m, 4H), 5,03 (W with 1H), 4,32 (W s, 1H), and 3.31 (s, 2H), and 2.79 (m, 2H), 2,70 (m, 2H), 1.91 a (m, 2H), 1,60 (m, 2H) MS (Cl, CH4) m/z 383 (M + 1,100), 411 (M+ 29,13), 365 (17), 304 (11), 80 (16) chlorhydrate salt:

Analysis for C26H26N2O2HCl0,7H2O:

Calculated C 66,72, H 6,33, N OF 5.99

Found, C 66,76, H 6,60, N BY 5.87

The original piperidine obtained as follows.

a. 9,10-Dihydro-9,10-methane-9-astratenkova acid.

Using a technique similar to the one described in example 1j, except that emanate from 9-formyl-9,10-dihydro-9, 10-metanarrative (obtaining literature: M. Sunagawa, et al. Chem. Pharm. Bull. Vol. 27(1979), PP. 1806-1812; U.S. Pat. SSA Sunagawa et al. Sumitomo Co., Ltd. St. 23, 1980; U.S. Pat. USA 4358620 Sunagava et al. Sumitomo Co., Ltd. November 9, 1982), get a named connection with 80% yield as a white solid. MS (Cl, CH4) m/z 237 (M + 1,100), 265 (M+ 29,10), 219 (22), 209 (15), 193 (20).

b. 1-(9,10-Dihydro-5,10-metanarration-9-ylcarbonyl)piperidine-4-ol.

Using a technique similar to that described in example who 5A) get a named connection with a quantitative yield as a viscous oil. The TLC analysis (Rf0,54, 10% methanol in chloroform). MS (Cl, CH4) m/z 320 (M + 1,100), 348 (M + 29,22), 302 (16)

c. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol

Using a technique similar to the one described in example 1l, except that on the basis of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylcarbonyl)piperidine-4-ol (described in example 5b) get a named connection with the release of 88% as a white solid. The TLC analysis (Rf0,59, 10% methanol in chloroform). MS (Cl, CH4) m/z 306 (M + 1,100), 334 (M+ 29,14), 288 (62), 114 (8).

d. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidinol.

Using a technique similar to the one described in example 1m, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol (described in example 5c) get a named connection with 80% yield as a white solid. The TLC analysis (Rf0,31, 2% methanol in methylene chloride). MS (Cl, CH4) m/z 304 (M + 1,100), 332 (M + 29,21).

Example 6. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(3-furanyl)- piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 3-bromofuran, received the tion:

1H NMR (CDCl3, 300 MHz) of 7.36 (m, 2H), 7.23 percent (DD, J 2.5 and 5.6 Hz, 2H), 7,17 (DD, J 2,0, a 5.4 Hz, 2H), 6,93 (m, 4H), 6,40 (m, 1H), 4,27 (s, 1H), 3,44 (s, 2H), 2,80 (m, 2H), 2,70 (dt, J is 2.8, 11.2 Hz, 1H), 2.60 (d, J1,5 Hz, 2H), 1.99 (dt, J 4.2, and 12.1 Hz, 2H), 1,80 (m, 2H), 1.55V (s, 1H), MS (Cl, CH4) m/z 372 (M + 1,100), 400 (M+ 29,21), 354 (57), 180 (16) chlorhydrate salt:

Analysis for C25H25NO2HCl0,1H2O:

Calculated C 73,28, H 6,44, N 3,42

Found, C 73,24, H of 6.49, N 3,30

Example 7. 4-(5-Bromo-2-methoxy-3-pyridyl)-1-(9,10-dihydro-9,10-methane - anthracene-9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and the use of 3,5-dibromo-2-methoxypyridine (obtaining literature: J. M. Barger, J. K. Dulworth, M. T. Kenny, R. Massao, J. K. Daniel, T. Wilson, R. T. Sargent. J. Med.Chem. 1986, 29, 1590), get a named connection with the release of 63% as not quite white solid substance, so pl. 250-251oC (decomp.), free base:

1H NMR (CDCl3O, 300 MHz) 8,08 (d, J 2.3 Hz, 1H), to 7.61 (d, J 2.3 Hz, 1H), 7,21 (m, 4H), 6.90 to (m, 4H), 4.26 deaths (s, 1H), of 3.97 (s, 3H), of 3.56 (s, 1H), 3,47 (s, 2H), a 2.36 (m, 2H), 2,77 (dt, J 2,6, and 11.4 Hz, 2H), 2,60 (d, J 1.4 Hz, 2H), a 1.96 (m, 4H), MS (Cl, CH4) m/z 491 (M+ 1,100), 483 (89), 492 (37), 494 (26), 521 (M + 29,13), 473 (28) chlorhydrate salt:

Analysis for C27H27BrN2O20,6 H2O:

The expect way.

a. 5-Chloro-2-methoxypyridine

Sodium hydride (60% in mineral oil, 5.50 g, 115 mmol, 2 EQ) is added by portions to the dry methanol (distilled over Mg, 25 ml) under nitrogen atmosphere. To this solution was added 2.5-dichloropyridine (10.0 g, 68 mmol). After boiling under reflux the resulting solution for 18 hours, the reaction mixture is cooled and treated with an excess of potassium bicarbonate. The reaction mixture was filtered and concentrated to 50% of its original volume, and the solution is solidified. The solid is washed with hexane and the combined washings are concentrated to oil. A named connection purified by distillation under pressure (102oC 2400 PA), receiving 6,30 g (65%) of colorless oil. MS (Cl, CH4) m/z 144 (M+ 1,100), 146 (44), 172 (M + 28,19), 124 (9)

b. 3-Bromo-5-chloro-2-methoxypyridine.

Using a technique similar to the one described in example 7, except that emanate from 5-chloro-2-methoxypyridine (described in example 8a), get a named connection from 41% yield. MS (Cl, CH4) 222 (M+ 1,74), 224 (100), 226 (24), 250 (5), 252 (6), 254 (1).

Example 9. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(3-chinoline)-piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-di named connection with the release of 44% in the form of a white solid, so pl. 205-207oC free base:

1H NMR (CDCl3, 300 MHz) 9,06 (d, J 3.6 Hz, 1H), to 8.20 (d, J 3.0 Hz, 1H), 8,08 (d, J 8.1 Hz, 1H), 7,80 (d, J 8.1 Hz, 1H), 7,68 (DD, J of 6.0 and 5.9 Hz, 1H), 7,54 (DD, J of 8.5, and 9.0 Hz, 1H), 7.23 percent (m, 4H), 6,94 (m, 4H), 4,30 (s, 1H), 3,52 (s, 2H), 2,98 (m, 2H), 2,78 (m, 2H), 2,64 (d, J 1.4 Hz, 2H), 2,24 (dt, J 3,9, and 11.6 Hz, 2H), 1,99 (s, 1H) and 1.83 (m, 2H) MS (Cl, CH4) m/z 433 (M+ 1,17), 415 (4), 211 (12), 89 (100), 79 (45), 73 (13) chlorhydrate salt:< / BR>
Analysis for C30H28N2O2HCl2,5H2O:

Calculated C 65,45, H 6,41, N -5,09

Found, C 65,47, H 5,93, N -4,94

Example 10. 4-(4-Ethenolysis)-1-(9,10-dihydro-9,10-ethanoanthracene-9-yl - methyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 4-bromo-isoquinoline, get a named connection from 53% yield as a white solid, so pl. 256-259oC (decomp), free base:

1H NMR (CDCl3, 250 MHz) 9,10 (s, 1H), 8,82 (d, J 7.5 Hz, 1H), and 8.50 (s, 1H), 7,95 (d, J 8.0 Hz, 1H), to 7.67 (m, 1H), 7,68 (m, 1H), 7,26 (m, 4H), 6,94 (m, 4H), 4,29 (s, 1H), 3,53 (s, 2H), 2.91 in (m, 4H), of 2.64 (d, J 1.3 Hz, 2H), of 2.28 (m, 4H) MS (Cl, CH4) m/z 433 (M + 1,100), 461 (M+ 29,14), 415 (26), 123 (12)

Analysis for C30H28N2O2,5HClH2O:

Calculated C 66,50, H 6,05, N -5,12

Found, C 66,37, H -5,89, N -5,03

Example 11. 1-(9,10-is the same as described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 5-bromo-2-methoxypyridine, get a named connection with the release of 81% in the form of a white solid substance, so pl. 218-222oC-free basis:

1H NMR (CDCl3, 250 MHz) of 8.28 (d, J 2.5 Hz, 1H), 7,69 (DD, J of 2.6, 8.7 Hz, 1H), 7,22 (m, 4H), to 6.95 (m, 4H), of 6.71 (d, J 8.7 Hz, 1H), 4,28 (s, 1H), 3,93 (s, 3H), of 3.48 (s, 2H), 2.91 in (m, 2H), 2,78 (dt, J 2,4, 11.7 Hz, 2H), 2,62 (d, J 1.4 Hz, 2H), 2,07 (dt, J 4,4, to 12.8 Hz, 2H), of 1.75 (m, 2H), 1,59 (s, 1H)

MS (Cl, CH4) m/z 413 (M + 1,100), 441 (M + 29,12), 395 (19) chlorhydrate salt:

Analysis for C27H28N2O22HCl0,5H2O:

Calculated C 65,59, H 6,32, N 5,67

Found, C 65,48, H 6,14, N 5,35

Source derived methoxypyridine obtained as follows.

a. 5-Bromo-2-methoxypyridine.

Using a technique similar to the one described in example 8a, except that originate from 2,5-dibromopyridine, get a named connection with 73% yield. MS (Cl, CH4) m/z 188 (M+ 1,90), 190 (100), 216 (16), 218 (15), 137 (27), 110 (35).

Example 12. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-pyrimidinyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-yl what hodom 60% in the form of a white solid, so pl. 298-300oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz) 9,12 (s, 1H), 8,86 (s, 2H), 7,26 (m, 2H), 7,18 (m, 2H), 6,94 (m, 4H), 4,29 (s, 1H), 3,49 (s, 2H), 2,96 (m, 2H), 2,70 (dt, J 2.5 and 12.0 Hz, 2H), 2,61 (d, J 1.5 Hz, 2H), 2,10 (dt, J 4,6, 13,0 Hz, 2H), 1,89 (s, 1H), 1,76 (m, 2H) MS (Cl, CH4) m/z 384 (M + 1,100), 412 (M + 29,20), 366 (13) chlorhydrate salt:

Analysis for C25H25N3OHCl0,4H2O:

Calculated C 70,30, H 6,32, N 9,84

Found, C 70,33, H 6,21, N 9,77

Example 13. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(6-methoxy - 2-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in examples 5d) and application of 2-bromo-6-methoxypyridine, get a named connection with the release of 98% in the form of a white solid substance, so pl. 193-195oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) EUR 7.57 (DD, J of 7.6 and 7.6 Hz, 1H), 7.23 percent (m, 4H), 6,94 (m, 5H, 6,63 (d, J 8.0 Hz, 1H), 4.75 in (s, 1H), 4,28 (s, 1H), 3,95 (s, 3H), 3,49 (s, 2H), equal to 2.94 (m, 2H), 2,77 (m, 2H), 2,64 (d, J 1.2 Hz, 2H), 2,04 (m, 2H), and 1.63 (m, 2H) MS (Cl, CH4) m/z 413 (M + 1,100; 441 (M + 29,12), 395 (18) chlorhydrate salt:

Analysis for C27H28N2O2HCl0,6H2O:

Calculated C 70,53, H 6,62, N 6,09

Found, C 70,22, H 6,46, N 6,04

Example 14. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-imeem, that they proceed from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and use 2-bromothiazole, get a named connection with the release of 77% as not quite white solid substance, so pl. 300-202oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) of 7.70 (d, J 3.2 Hz, 1H), 7.23 percent (m, 5H), 6,94 (m, 4H), 4.26 deaths (W s, 1H), 3,48 (s, 2H), 2,92 (m, 2H), 2,75 (m, 2H), 2,61 (d, J 1.3 Hz, 2H), 2,23 (m, 2H), of 1.85 (m, 2H) MS (Cl, CH4) m/z 389 (M + 1,100), 371 (8) chlorhydrate salt

Analysis for C24H24N2OS2HCl:

Calculated C 62,47, H of 5.68, N 6,07

Found, C 62,58, H by 5.87, N 5,76

Example 15. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(3-thienyl)- piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 3-bromothiophene, get a named connection with the release of 81% as not quite white solid substance, so pl. 273-277oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz) 7,17 (m, 7H), 6,94 (m, 4H), 4.26 deaths (s, 1H), 3.46 in (s, 1H), 2,84 (m, 2H), 2,71 (m, 2H), 2,60 (d, J 1.4 Hz, 2H), 2,12 (m, 2H) and 1.83 (m, 2H) MS (Cl, CH4) m/z 388 (M + 1,100), 416 (M+ 29,20), 370 (51), 304 (10), 196 (12) chlorhydrate salt:

Analysis for C25H25NOS1,6HClH2O:

Calculated C 64,73, H DIN-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and 2-bromopyridine, get a named connection with the release of 66% in the form of a white solid substance, so pl. 194-196oC-free basis:

1H NMR (CDCl3, 250 MHz), 8,53 (d, J 5.0 Hz, 1H), of 7.70 (DDD, J of 1.5 to 7.7, 7.7 Hz, 1H), 7,39 (d, J 7.8 Hz, 1H), 7,22 (m, 5H), 6,94 (m, 4H), 5,23 (s, 1H), 4,30 (s, 1H), 3,52 (s, 2H), 2,99 (m, 2H), 2,81 (dt, J 2,0, 12.0 Hz, 2H), to 2.65 (d, J 2.0 Hz, 2H), 2,07 (dt, J 5,0, 13,0 Hz, 2H), 1,60 (m,2H) MS (Cl, CH4) m/z 383 (M + 1,100), 411 (M+ 29,20), 365 (18), 364 (17) chlorhydrate salt:

Analysis for C26H26N2O2HCl0,1H2O:

Calculated C 63,30, H 6,22, N 6,13

Found, C 68,17, H 6,21, N 6,09

Example 17. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(3-methoxy - phenyl)-piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 3-bromoanisole get chlorhydrate salt of the above compound with a yield of 59% in the form of a white solid substance, so pl. 260-261oC.

Elemental analysis for C28H29NO2HCl0,4H2O:

Calculated C 73,88, H 6,82, N IS 3.08

Nydn), is 1.81 (d, J a 13.9 Hz, 2H) MS (Cl, CH4) m/z 413 (31), 412 (M+ 1,100), 4 11 (11), 3 94 (26)

Example 18. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(4-methoxide - nil)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and use 4-bromoanisole get chlorhydrate salt of these compounds with the outputs of 72% in the form of a white solid substance, so pl. 228-231oC.

Elemental analysis for C28H29NO2HCl:

Calculated C 75,07, H is 6.75, N 3,13

Found, C 74,93, H 6,74, N 3,14

1H NMR (D6-DMCO, D-TFA): 7,39 (m, 6H), 7,02 (m, 4H), 6,94 (d, J 8,8 Hz, 2H), 4,48 (s, 3H), 3,74 (s, 3H), 3,68-to 3.52 (m, 4H), was 2.76 (s, 2H), 2,35 (m, 2H), 1,81 (d, J a 13.9 Hz, 2H) MS (Cl, CH4) m/z 413 (33), 412 (M+ 1, 100), 411 (15), 394 (51)

Example 19. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-methoxy - phenyl)-piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10 - ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and use 2-bromoanisole get chlorhydrate salt of the above compound with a yield of 43% in the form of a white solid substance, so pl. 290-293oC.

Elemental analysis for C28H

Example 20. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-dimethyl - aminomethylphenol)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 2-bromo-N,N-dimethylbenzylamine get chlorhydrate salt of the above compound with a yield of 36% in the form of a white solid substance, so pl. 230-235oC.

Elemental analysis for C30H34N2O2,OHCl1,1H2O:

Calculated C 67,81, H 7,25, N 5,27

Found, C 67,83, H a 7.85, N 5,04

1H NMR (D6-DMCO, D-TFA): 7,41 (m, 8H), 7,02 (m, 4H), br4.61 (s, 2H), to 4.52 (s, 2H), 4,50 (s, 1H), to 3.73 (m, 2H), to 3.58 (m, 2H), 2,82 (s, 6H), was 2.76 (s, 2H), 2,52 (m, 2H), 2,12 (d, J 14.1 Hz, 2H), MS (Cl, CH4) m/z 440 (36), 439 (M + 1,100), 438 (15)

Example 21. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-phenylpiperidine.

To a methanol solution (80 ml) of 9-formyl-9,10-dihydro-9,10 - ethanoanthracene (described in example 5a) (of 5.00 g, 22.7 mmol) is added a large excess of sizeaction 3A molecular sieves (CA. 10 g) in a nitrogen atmosphere. Add 4-phenylpiperidine (of 4.57 g, 28 mmol, b ek), and then four portions is of 3 days at room temperature. The reaction mixture was treated with 2,5 N. NaOH (100 ml) and the aqueous phase extracted with ethyl acetate (1 x 400 ml). The organic phase is washed with water (3 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to oil. The reaction product was then purified flash chromatography on silica gel (300 ml, eluent: 50% methylene chloride in hexane), highlighting 1.20 g (15%) of the named compound. The TLC analysis (Rf0,19, 50% methylene chloride in hexane).

1H NMR (CDCl3, 300 MHz) 7,22 (m, 9H), 6,93 (m, 4H), 4,27 (s, 1H), 3.43 points (s, 2H), 3,13 (m, 2H), 2,62 (d, J 1.4 Hz, 2H), of 2.51 (m, 1H), 2,34 (m, 2H), 1,76 (m, 4H) MS (Cl, CH4) m/z 366 (M + 1,100), 3,94 (M + 29,16). The free base is dissolved in a minimum of methanol and chloroform, acidified with ethereal HCl and the resulting chlorhydrate salt is precipitated by dilution with ether. The solid is filtered off, washed with fresh ether, and dried in vacuo (50oC, 10 PA, 18 h), obtaining a solid substance, so pl. > 300oC.

Analysis for C27H27NHCl0,5H2O:

Calculated C 78,91, H 7,11, N 3,41

Found, C 78,91, H 6,92, N 3,38

Example 22. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(4-chlorophenyl)piperidine-4-ol.

Using a technique similar to that described in example 21, except for the use of 4-(4-chlorophenyl)-4-hydroxypiperidine receive hydrochloride is Alize for C27H26NOHCl0,25H2O:

Calculated C 70,97, H 6,05, N 3,06

Found, C, 71,28, H 6,03, N 3,02

1H NMR (D6-DMCO, D-TFA): 7,51-7,35 (m, 8H), 7,01 (m, 4H), 4,50 (s, 3H), 3.72 points-3,59 (m, 4H), was 2.76 (s, 2H), of 2.38 (m, 2H) and 1.83 (d, J 14,3 Hz, 2H) MS (Cl, CH4) m/z 418 (37), 417 (35), 416 (M+ 1,100), 400 (16), 399 (13), 398 (42).

Example 23. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-phenylpiperidine-4-ol.

Using a technique similar to that described in example 21, except for the use of 4-hydroxy-4-phenylpiperidine get chlorhydrate salt of the above compound with a yield of 18% in the form of a white powder, so pl. 273-275oC.

Elemental analysis for C27H27NOHCl:

Calculated C 77,58, H is 6.75, N 3,35

Found, C 77,51, H 6,79, N 3,32

1H NMR (D6-DMCO, D-TFA): 7,72-of 7.23 (m, 9H), 7,01 (m, 4H), 4,49 (s, 3H), of 3.64 (m, 4H), was 2.76 (s, 2H), 2,50 (m, 2H), 1,82 (d, J a 13.9 Hz, 2H) MS (Cl, CH4) m/z 383 (30), 382 (M+ 1,100), 381 (14), 380(14), 364 (25).

Example 24. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(3-Cryptor - were)piperidine-4-ol.

Using a technique similar to that described in example 21, except for the use of 4-hydroxy-4-(3-triptoreline)piperidine, get chlorhydrate salt of these compounds with 44% yield as a white powder, so pl. 268-270oC.

Elemental analysis for C28H26F3NOHCl0,25H2O:

P1 (m, 4H), a 4.53 (s, 2H), 4,50 (s, 1H), 3,70-3,61 (m, 4H), 2,78 (s, 2H), 2,47 (m, 2H), 1.85 to (l, J of 13.7 Hz, 2H) MS (Cl, CH4) m/z 451 (31), 450 (M+ 1,100), 449 (17), 448 (16), 433 (19), 432 (66), 431 (25), 430 (78)

Example 25. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(4-forfinal)piperidine-4-ol.

Using a technique similar to that described in example 21, except for the use of 4-(4-forfinal)-4-hydroxypiperidine get chlorhydrate salt of these compounds with the release of 26% in the form of a white powder, so pl. 262-266oC.

Elemental analysis for C27H26FNOHCl:

Calculated C 74,38, H 6,24, N 3,21

Found, C 74,41, H 6,24, N 3,17

1H NMR (D6-DMCO, D-TFA): 7,51 (m, 2H), 7,37 (m, 4H), 7,21 (m, 2H), 7,02 (m, 4H), 4,49 (s, 3H), 3,62 (m, 4H), was 2.76 (s, 2H), 2,41 (m, 2H), 1,82 (d, J 14,2 Hz, 2H) MS (Cl, CH4) m/z 401 (26), 400 (M+ 1,100), 398 (15), 382 (33), 380 (17)

Example 26. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4- (4-chlorophenyl)piperidine-4-ol.

Using a technique similar to that described in example 21, except that originate from 2-chloro-9-formyl-9,10 - dihydro-9,10-ethanoanthracene (described in example 1i) and 4-(4-chlorophenyl)-4-hydroxypiperidine get chlorhydrate salt of these compounds with 29% in the form of a white powder, so pl. 261-263oC.

Elemental analysis for C27H25Cl2NOHCl:

Calculated C 66,61, H 5,38, N 2,37

N is 1 (m, 4H), 2,78 (KAB, JAB at 9.0 Hz, 2H), 2,39 (m, 2H) and 1.83 (d, J 14,3 Hz, 2H) MS (Cl, CH4) m/z 454 (10), 453 (16), 452 (54), 451 (30), 450 (M+ 1,100), 435 (13), 434 (47), 433 (24), 432 (86), 289 (24), 97 (46), 79 (99)

Example 27. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(4 - forfinal)piperidine-4-ol.

Using a technique similar to that described in example 21, except that originate from 2-chloro-9-formyl-9,10 - dihydro-9,10-ethanoanthracene (described in example 1i) and 4-(4-forfinal)-4-hydroxypiperidine get chlorhydrate salt of these compounds with the release of 27% in the form of a white powder, so pl. 280-281oC.

Elemental analysis of C27H25ClFNOHCl0,5H2O:

Calculated C 67,64, H of 5.68, N 2,92

Found, C 67,70, H 5.40, is N 2,84

1H NMR (D6-DMCO, D-TFA): EUR 7.57 (d, J 1.8 Hz, 1H), 7,54-to 7.35 (m, 5H), 7,19 (t, J a 8.9 Hz, 2H), 7,03 (m, 3H), to 4.52 (s, 1H), to 4.52 (KAB, JAB a 14.1 Hz, 2H), 3,70-of 3.53 (m, 4H), 2,77 (KAB, JAB by 6.8 Hz, 2H), 2,34 (m, 2H), 1,84 (d, J 14,0 Hz, 2H) MS (Cl, CH4) m/z 437 (10), 436 (37), 435 (33), 434 (M+ 1,100), 418 (18), 417 (15), 416 (50).

Example 28. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4 - phenylpiperidine-4-ol.

Using a technique similar to that described in example 21, except that originate from 2-chloro-9-formyl-9,10-dihydro-9,10-ethanoanthracene (described in example 1i) and 4-hydroxy-4-phenylpiperidine get chlorhydrate salt named connection in the>O:

Calculated C 71,40, H 6,04, N 3,09

Found, C 71,20, H 6,02 N 3,00

1H NMR (D6-DMCO, D-TFA): 7,58 (s, 1H), 7,52-7,25 (m, 6H), 7,05 (m, 3H), 4.53-in (kAB, JAB of 14.2 Hz, 2H), to 4.52 (s, 1H), 3.75 to to 3.56 (m, 4H), 2,77 (m, 2H), 2,39 (m, 2H), 1,86 (d, J 14.4 Hz, 2H) MS (Cl, CH4) m/z 419 (10), 418 (38), 417 (34), 416 (M+ 1,100), 400 (12), 398 (33)

Example 29. 4-(2-Biphenyl)-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- piperidine-4-ol.

To a cooled (-72oC) a solution of t-utility (1.7 M in pentane, 3,00 ml, 5,12 mmol) in tetrahydrofuran (4.0 ml) is added dropwise 2-bromobiphenyl (0,49 g, 2,12 mmol, of 1.6 EQ) in tetrahydrofuran (2 ml). The resulting solution was stirred for 2 hours in nitrogen atmosphere. A solution of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) (0.40 g, 1.3 mmol) in tetrahydrofuran (4 ml) is added dropwise to ditiberio and the reaction mixture was allow to warm to room temperature over 45 minutes, the Stirring is continued at room temperature for 3 hours. The excess reagent is quenched with water (10 ml) and the aqueous phase extracted with ethyl acetate (2 x 100 ml). The combined organic extracts washed with water (2 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to a solid. The reaction product was then purified on a flash chromatography on si is wow substances. The TLC analysis (Rf0,23, 20% diethyl ether in hexane).

1H NMR (CDCl3, 250 MHz) to 7.50 (m, 1H), 7,32 (m, 6H), 7,25 (m, 3H), 7,14 (m, 2H), 7,06 (DD, J 1,1, 7.5 Hz, 1H), 6,91 (m, 4H), 4,24 (s, 1H), of 3.56 (s, 2H), 2,75 (m, 2H), by 2.55 (d, J 1.4 Hz, 2H), has 2.56 (m, 2H), 2,13 (dt, J 4,5, 13,2, 12.3 Hz, 2H), 1,72 (m, 2H), of 1.52 (s, 1H) MS (Cl, CH4) m/z 458 (M + 1,100), 486 (M+ 29,35), 440 (14), 304 (6). Chlorhydrate salt is obtained by treatment of the ether solution of the free base with excess ethereal HCl. The obtained solid is filtered off, washed with fresh ether, and dried in vacuo (50oC, 10 PA, 18 h) to give white solid, so pl. 269-270oC.

Analysis for C33H31NOHCl0,75H2O:

Calculated C 78,09, H of 6.65, N WAS 2.76

Found, C 77,98, H of 6.49 N 2,7

Example 30. 4-(4-Biphenyl)-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- piperidine-4-ol.

Using a technique similar to that described in example 29, except use 4-bromobiphenyl, get the named compound in 70% yield as a white solid, so pl. 262 - 263oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz) of 7.60 (m, 1H), EUR 7.57 (s, 5H), 7,42 (m, 2H), 7,34 (m, 1H), 7.23 percent (m, 4H), 6,94 (m, 4H), 4,28 (s, 1H), 3,49 (s, 2H), 3,00 (m, 2H), 2,74 (m, 2H), 2,64 (d, J 1.3 Hz, 2H), 2,16 (m, 2H), of 1.75 (m, 2H), 1,63 (s, 1H) MS (Cl, CH4) m/z 458 (M + 1,100), 486 (M+ 29,18), 440 (39), 441 (14), 304 (13) chlorhydrate salt:

Elemental analysis for CYl)-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- piperidine-4-ol.

Using a technique similar to that described in example 29, except use 3-bromobiphenyl, get a named connection 64% yield as a white solid, so pl. 259-260oC-free basis:

1H NMR (CDCl3, 250 MHz) 7,72 (m, 1H), 7,58 (m, 2H), 7,43 (m, 5H), 7,22 (m, 5H), 6,94 (m, 4H), 4,27 (s, 1H), 3,49 (s, 2H), 2,93 (m, 2H), 2,74 (dt, J 2,4, to 11.9 Hz, 2H), 2.63 in (d, J 1.4 Hz, 2H), 2,18 (dt, J of 4.8, 12.3 Hz, 2H), to 1.76 (m, 2H), 1,64 (s, 1H) MS (Cl, CH4) m/z 458 (M + 1,100), 486 (M + 29,15), 440 (19) chlorhydrate salt:

Analysis for C33H31NOHCl0,25H2O:

Calculated C 79,50, H 6,57, N 2,81

Found, C, 79,35, H 6,45, N 2,77

Example 32. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-methoxy - 3-pyridyl)piperidine-4-ol.

To a cooled solution (-72oC) t-utility (1.7 M in pentane, 5,38 ml, to 9.15 mmol, of 2.8 EQ) in tetrahydrofuran (24 ml) under nitrogen is added dropwise bromethalin (of 0.64 ml, 4,18 mmol, 1,3 EC). Metal-halogenoalkane the reaction mixture is stirred for one hour, during which time a white precipitate is formed. 2-Methoxypyridine (0.50 g, of 4.38 mmol, 1.4 EQ) is added to this suspension, the reaction mixture is warmed to room temperature and stirred at this temperature for 4 hours Metallizovannyj pyridine is cooled to -72oC and a solution of 1-(9,10-dihydro-9,10-ethanoanthracene the mixture is heated to room temperature for 1.5 hours After stirring for 18 h the reaction mixture was quenched by addition of water (10 ml). The aqueous phase is extracted with ethyl acetate (200 ml). The organic extract was washed with water (2 x 100 ml), dried with anhydrous sodium sulfate, filtered and concentrated to oil. The product was then purified on a flash chromatography on silica gel (100 ml, eluent: 30% ethyl acetate in hexane) to give 0,99 g (73%) of the named compound as a white solid. The TLC analysis (Rf0,23, 30% ethyl acetate in hexane).

1H NMR (CDCl3, 300 MHz) with 8.05 (DD, J of 4.9, 1.7 Hz, 1H), 7,49 (DD, J of 7.5, 5.7 Hz, 1H), 7,22 (m, 4H), 6,92 (m, 5H), 4,27 (s, 1H), was 4.02 (s, 3H), of 3.78 (s, 1H), 3,48 (s, 2H), and 2.83 (m, 4H), 2,61 (d, J 1.4 Hz, 2H), 2,00 (m, 4H), MS (Cl, CH4) m/z 413 (M + 1,100), 441 (M+ 29,13), 395 (24).

The free base is dissolved in methylene chloride, diluted with ether and acidified with ethereal HCl. Received chlorhydrate salt is filtered off, washed with fresh ether, and dried in vacuo (50oC, 10 Pascal, 18 h) to give white solid, so pl. 225-228oC (decomp.)

Analysis for C27H28N2O2HCl0,2H2O:

Calculated C 71,65, H 6,55, N IS 6.19

Found, C 71,43, H 6,46, N OF 5.84

Example 33. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(4-methoxy - 3-pyridyl)piperidine-4-ol.

Using a technique similar to the one described in example the CSO solids, so pl. 207-210oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) 8,43 (s, 1H), 8,42 (d, J 5.1 Hz, 1H), 7.23 percent (m, 4H), 6,93 (m, 4H), PC 6.82 (d, J 5.7 Hz, 1H), 4,27 (s, 1H), 3,92 (s, 3H), of 3.48 (s, 2H), 3.43 points (s, 1H), 2,84 (m, 4H), 2,62 (d, J 1.4 Hz, 2H), 2,13 (dt, J 4,9, of 12.4 Hz, 2H), up to 1.98 (m, 2H), MS (Cl, CH4) m/z 413 (M + 1,100), 441 (M + 29,12), 395 (14) chlorhydrate salt:

Analysis for C27H28N2O22HCl1,5H2O:

Calculated C 63,88, H of 6.49, N 5,47

Found, C 62,92, H 6,20, N 5,43

Example 34. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2 - methoxy-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 32, except that originate from 1-(2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 1m), get a named connection with the release of 85% as a white solid, so pl. 195-200oC-free basis:

1H NMR (CDCl3, 250 MHz) with 8.05 (DD, J 1.6, the 4,9 Hz, 1H), 7,51 (DD, J of 7.4 and 1.7 Hz, 1H), 7,20 (m, 4H), of 6.96 (m, 2H), to 6.88 (m, 2H), 4,25 (s, 1H), a 4.03(s, 3H), of 3.77 (s, 1H), 3.43 points (s, 2H), 2,82 (m, 4H), 2,61 (d, J 1.1 Hz, 2H), to 1.99 (m, 4H), MS (Cl, CH4) m/z 447 (M + 1,100), 475 (M+ 29,15), 429 (27), 449 (37) chlorhydrate salt:

Analysis for C27H27N2O2Cl:

Calculated, C 64,64, H 5,73, N 5,58

Found, C 64,66, H 5,66, N 5,34

Example 35. 1-(2,7-Dichloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4- (2-methoxy-3-perto come from 1-(2,7-dichloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidinol, get a named connection with the release of 36% in the form of a white solid substance, so pl. 187-189oC (decomp.). The TLC analysis on free base (Rf0,31, 40% ethyl acetate in hexane), the free base:

1H NMR (CDCl3, 300 MHz) of 8.06 (DD, J of 1.8, 4.9 Hz, 1H), 7,52 (DD, J 1,8, 7,4 Hz, 1H), 7,18 (m, 4H), 6.90 to (m, 3H), 4,23 (s, 1H), a 4.03(s, 3H), of 3.77 (s, 1H), 3,39 (s, 2H), 2,82 (m, 4H), 2,61 (d, J 1.4 Hz, 2H), 2,01 (m, 4H), MS (Cl, CH4) m/z 481 (M+1,100), 483 (63), 485 (12), 509 (M + 29,9), 463 (26), chlorhydrate salt:

Analysis for C27H26Cl2N2O21,9 HCl:

Calculated C 66,76, H 6,01, N OF 5.99

Found, C 66,98, H 5,90, N 5,93

Example 37. 4-(4-Hydroxy-3-pyridyl)-1-(9,10-dihydro-9,10-ethanoanthracene - 9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 36, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(4-methoxy-3-pyridyl)piperidine-4-ol (described in example 33), get a named connection with the release of 94% in the form of a white solid substance, so pl. 233-235oC-free basis:

1H NMR (D6DMCO, 250 MHz) of 7.64 (s, 1H), 7.62mm (d, J 7,1 Hz, 1H), 7,26 (DD, J 2,1, 6.2 Hz, 2H), 7,20 (DD, J of 1.7, 7.7 Hz, 2H), 6,91 (m, 4H), 6,55 (s, 1H), 6,12 (d, J 6.9 Hz, 1H), or 4.31 (s, 1H), 3,38 (s, 2H), 2,69 (m, 4H), 2,48 (s, 2H), a 1.96 (m, 2H), 1,59 (m, 2H), MS (Cl, CH4) m/z 399 (M + 1,100), 427 (M + 29,15), 381 (88), chlorhydrate salt:

Analysis for C26H26Proxy-2-pyridyl)-1-(9,10-dihydro-9,10-ethanoanthracene - 9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 36, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(6-methoxy-2-pyridyl)piperidine-4-ol (described in example 13), get a named connection with the release of 65% in the form of a white solid substance, so pl. 218-222oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz) 7,39 (DD, J 7,1, 7.7 Hz, 1H), 7,20 (m, 4H), 6,94 (m, 4H), 6.42 per (d, J a 8.9 Hz, 1H), x 6.15 (d, J 6.4 Hz, 1H), 4,50 (W s, 1H), 4,27 (s, 1H), 3,47 (s, 2H), equal to 2.94 (m, 2H), by 2.73 (m, 2H), 2,59 (d, J 1.0 Hz, 2H), to 1.98 (dt, J 4,5, and 12.7 Hz, 2H), 1,79 (m, 2H), MS (Cl, CH4) m/z 399 (M + 1,3), 427 (M+ 29,03), 443 (41), 381 (0,4), 19 (100) chlorhydrate salt:

Analysis for C26H26N2O22HCl0,75H2O:

Calculated C 64,40, H 6,13, N 5,78

Found, C 64,40, H 6,28, N 5,72

Example 39. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N-methyl - amino-3-pyridyl)piperidine-4-ol.

A solution of n-utility (2.0 M in hexane, 7.0 ml, 14 mmol, 6.3 EQ) are added to a tetrahydrofuran (25 ml), previously cooled to -72oC in nitrogen atmosphere. A large excess of methylamine (40 ml) condense with the help of the vessel with dry ice with double walls and added dropwise to a solution of utility. After stirring for 15 min, 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-methoxy-3-pyridyl)piperidine-4-ol is ü to warm to room temperature and remove excess methylamine. After boiling under reflux for 18 h, the vessel is cooled to room temperature and treated with water (25 ml). The aqueous phase is extracted with ethyl acetate (3 x 25 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to oil. The reaction mixture was purified flash chromatography on silica gel (60 ml, eluent: 40% ethyl acetate in hexane) to give 520 mg (57%) of the named compound as a white solid. The TLC analysis (Rf0,16 30% ethyl acetate in hexane).

1H NMR (CDCl3, 300 MHz) with 8.05 (DD, J of 1.4, 4.9 Hz, 1H), 7,22 (m, 5H, 6,93(m, 4H), 6,47 (DD, J 5,0, 7,3 Hz, 1H),6,42 (m, 1H), 4,27 (s, 1H), 3,47 (s, 2H), 2,97 (DD, J 4,2 Hz, 3H), 2,90 (m, 2H), 2,73 (DDD, J3,3, 11,1 11,1 2H), 2,60 (d, J 1.0 Hz, 2H), 2,03 (m, 2H), 1,65 (m, 2H), MS (Cl, CH2) m/z 412 (M + 1,100), 440 (M + 29,15 ), 394 (25). The free base is dissolved in methylene chloride, treated with excess ethereal HCl and precipitated chlorhydrate salt dilution with diethyl ether. Chlorhydrate salt is filtered off, washed with fresh ether and dried in vacuo (50oC, 10 PA, 18 h), receiving not quite white solid, so pl. 220-221oC (decomp.)

Analysis for C27H29N3O2HClH2O:

Calculated C 64,54, H 6,62, N AT 8.36

Found, C 64,62, H 6,64, N 8,12

Example 40. 1-(9,10-Dihydro-9,10-metanoia is authorized in example 39, in addition to the use of Propylamine, get a named connection with the release of 79% in the form of a white solid substance, so pl. 215-220oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) 8,01 (DD, J of 1.7, 4.9 Hz, 1H), 7,21 (m, 5H), 6,93 (m, 4H), of 6.45 (DD, J 4,9, 4,9 Hz, 1H), 4,27 (s, 1H), 3,47 (s, 2H), 3,39 (dt, J 7,1, 5,2 Hz, 2H), 2,90 (m, 2H), by 2.73 (dt, J 2,9, 11,0, 11.2 Hz, 2H), 2,60 (d, J 1.4 Hz, 2H), 2,02 (m, 4H), of 1.65 (m, 2H), 0,99 (t, J 7.4 Hz, 3H) MS (Cl, CH4) m/z 440 (M + 1,100), 468 (M + 29,15), 422 (11) chlorhydrate salt:

Analysis for C29H33N3O2HCl0,6H2O:

Calculated C 66,56, H 6,97, N 8,03

Found, C 66,39, H of 6.96, N 7,66

Example 41. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N-Pro - piumino-5-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 39, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-methoxy-5-pyridi - l)piperidine-4-ol (described in example 11) and applying Propylamine, get a named connection with the release of 83% in the form of a white crystalline solid, so pl. 235-237oC (decomp.). Analysis of the TLC of the free base (Rf0,25 in ethyl acetate). Free base:

1H NMR (CDCl3, 250 MHz) 8,18 (d, J 2.5 Hz, 1H), 7,54 (DD, J 2.5 and 8.7 Hz, 1H), 7,21 (m, 4H), 6,93 (m, 4H), 6.35mm (d, J 8.7 Hz, 1H), 4,50 (W t, J 5.6 Hz, 1H), 4,27 (s, 1H) of 3.46 (s, 2H), 3,20 (dt, J of 7.0 and 5.9 Hz, 2H), 2,88 (m, 2H), 2,71 68 (M + 29,18), 422 (56) chlorhydrate salt:

Analysis for C29H33N3O2HCl0,25H2O:

Calculated C 67,37, H 6,92, N 8,13

Found, C 67,35, H 6,93, N 8,12

Example 42. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-methoxy - 3-chinoline)piperidine-4-ol.

To a cooled solution (-72oC) or t-butyllithium (1.7 M in pentane, limiting reagent, 1.90 ml, 3,19 mmol) in tetrahydrofuran (24 ml) under nitrogen add a few drops of Diisopropylamine (catalytic amount). Following this, add 2-methoxyaniline (0,69 ml, 4,39 mmol, 1.38 EQ). The reaction mixture was stirred at -72oC for 1 h, warmed to 0oC and stirred at this temperature for 3 hours After re-cooling to -72oC, a solution of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) (1,00 g, 3,30 mmol, of 1.03 EQ) in tetrahydrofuran (3.0 ml) is added dropwise to a solution of laihinen. The reaction mixture was stirred at room temperature for 13 h and quenched with water (10 ml). The aqueous phase is extracted with ethyl acetate (200 ml). The organic extract was washed with water (2 x 200 ml), dried with anhydrous sodium sulfate and concentrated to oil. The reaction mixture was purified flash chromatography on silica gel (100 ml, lueh (Rf0,19, 25% ethyl acetate in hexane).

1H NMR (CDCl3, 250 MHz) 7,89 (s, 1H), 7,81 (d, J 8,4 Hz, 1H), 7,88 (d, J 7.7 Hz, 1H), to 7.59 (DD, J of 6.8, and 7.3 Hz, 1H), 7,38 (DD, J of 7.4, 7.5 Hz, 1H), 7.23 percent (m, 4H), 6,93 (m, 4H), 4,27 (s, 1H), 4.16 the (s, 3H), 3,80 (s, 1H), 3,49 (s, 2H), 2,87 (m, 4H), 2.63 in (s, 2H), 2,09 (m, 4H), MS (Cl, CH4) m/z 463 (M + 1,100), 491 (M+ 29,19), 445 (23).

The free base is dissolved in methylene chloride, treated with ethereal HCl, and the precipitated clorhidrato Sol essential dilution. The solid is filtered off, washed with fresh diethyl ether and dried in vacuo (50oC, 10 PA, 18 h) to give white solid, so pl. 213-217oC (decomp.)

Analysis for C31H30N2O21,5 HCl:

Calculated C 71,98, H 6,14, N 5,42

Found, C 71,78, H 6,07, N 5,40

Example 43. 4-(2-Benzothiazyl)-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 42, in addition to the use of benzothiazole, get a named connection with the release of 65% in the form of a white solid substance, so pl. 307-310oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) of 7.97 (d, J 8.0 Hz, 1H), 7,87 (d, J 8.0 Hz, 1H), 7,47 (DD, J of 8.0, 8.0 Hz, 1H), 7,37 (DD, J of 8.0, 8.0 Hz, 1H), 7.23 percent (m, 4H), 6,94 (m, 4H), 4,30(s, 1H), 3,50 (s, 2H), 3,10 (s, 1H), 2,97 (m, 2H), was 2.76 (m, 2H), 2,63 (s, 2H), 2,32 (m, 2H), 1,89 (m, 2H) MS (Cl, CH4) m/z 439 (M + 1,100), 467 (M+ 29,18), 421 (15), ,29

Found, C, 63,26, H 5,38, N 4,76

Example 44. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-pyridyl - methyl)piperidine-4-ol.

Using a technique similar to that described in example 42, in addition to the use of 2-picoline, get a named connection with a quantitative yield in the form of a white solid substance, so pl. 205-207oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz), 3,40 (s, 1H), 7,53 (d, J 7.7 Hz, 1H), 7,17 (m, 6H), 6,91 (m, 4H), 4,25 (s, 1H), 3,42 (s, 2H), 2,78 (m, 2H), 2,71 (s, 2H), 2,58 (s, 2H), 2,54 (m, 2H), by 1.68 (m, 2H), 1,46 (m, 2H), MS (Cl, CH4) m/z 397 (M + 1,100), 425(M + 29,19), 379 (17) chlorhydrate salt:

Analysis for C27H28N2O2HCl1,5H2O:

Calculated C 65,32, H 6,69, N 5,64

Found, C 65,34, H 6,46, N 5,50

Example 45. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2 - methoxy-3-chinoline)piperidine-4-ol.

Using a technique similar to that described in example 42, except that originate from 1-(2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidone (described in example 1m), get a named connection from 46% yield as a white solid, so pl. 225-230oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz) of 7.90 (s, 1H), 7,82 (d, J 8.2 Hz, 1H), 7,69 (DD, J 1,1, 8,1 Hz, 1H), 7,60 (DDD, J of 1.5 to 7.1, and 8.2 Hz, 1H), 7,38 (m, 1H), 7,20 (m, 4H), 6,94 (m, 4H), 4,25 (s, 1H), 4,17 (s, 3H), 3,79 (s, 1H),Liz C31H29N2O2ClH2O:

Calculated C 67,51, H of 5.84, N 5,08

Found, C 67,63, H 5,51, N 5,02

Example 46. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(4-methoxy - benzyl)piperidine-4-ol.

Magnesium turnings (0.32 g, 1,32 mmol, 1.3 EQ) was stirred in the absence of solvent for 15 min under nitrogen. Add diethyl ether (20 ml) and catalytic lithium iodide, and the suspension is stirred vigorously for an additional 15 min, and at this time in the reaction vessel portions inject 4-methoxybenzylamine (1.08 ml, 7.0 mmol, 8 EQ). The reaction mixture was refluxed for 3 h to ensure the formation of Grignard and cooled to room temperature. Add dropwise 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) (0,30 g, 1.00 mmol) in solution in tetrahydrofuran (25 ml). After stirring for 18 h the reaction mixture was quenched with water (10 ml). The aqueous phase is extracted with ethyl acetate (200 ml). The organic extract was washed with water (2x100 ml), dried with anhydrous sodium sulfate, filtered and concentrated to oil. The reaction mixture was purified flash chromatography on silica gel (25 ml, eluent: 20% ethyl acetate in hexane) to give 0.29 grams (69%) of these with whom), of 3.78 (s, 3H), 3,41 (s, 2H), was 2.76 (m, 2H), 2,66 (s, 2H), 2.57 m (d, J 1.2 Hz, 2H), 2,52 (m, 2H), 1,67 (m, 2H), 1,47 (m, 2H), 1.57 in (s, 1H), MS (Cl, CH4) m/z 426 (M + 1,100), 454 (M + 29,13), 408 (20). The free base is dissolved in methanol and methylene chloride, acidified with ethereal HCl and the precipitated salt is essential dilution. Chlorhydrate salt is filtered off, washed with fresh ether and dried in vacuo (50oC, 10 PA, 18 h) to give white solid, so pl. 267-268oC (decomp.)

Analysis for C29H31NO2HCl0,7H2O:

Calculated C 73,39, H 7,09, N 2,95

Found, C 73,48, H 6,85 N 2,85

Example 47. 4-(4-Chlorobenzyl)-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- piperidine-4-ol.

Using a technique similar to that described in example 46, except use 4-chlorobenzylchloride, get a named connection with the release of 36% in the form of a white solid substance, so pl. 264-265oC-free basis:

1H NMR (CDCl3, 250 MHz) 7,22 (m, 8H), 6,93 (m, 4H), of 4.66 (s, 1H), 4,25 (s, 1H), 3,40 (s, 2H), 2,77 (m, 2H), 2,69 (s, 2H), 2,56 (d, J 1.5 Hz, 2H), 2.49 USD (m, 2H), of 1.66 (m, 2H), 1,45 (m, 2H), MS (Cl, CH4) m/z 430 (M + 1,100), 458 (M+ 29,25), 412 (39), 431 (35), 432 (36), 125 (30), 113 (22) chlorhydrate salt:

Analysis for C28H28NOClHCl0,1H2O:

Calculated C 71,82, H 6,29, N, 2,99

Found, C 71,66, H of 6.31, N 2,94

Example 48. 4-Benzyl-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)Aida, get a named connection with the release of 54% in the form of a white solid substance, so pl. 193-195oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz) 7,21 (m, 9H), 6,93 (m, 4H), 4,25 (s, 1H), 3,41 (s, 2H), 2,78 (m, 2H), 2,73 (s, 2H), 2.57 m (s, 2H), 1.69 in (dt, J 4,4, to 13.4 Hz, 2H), and 1.56 (s, 1H), 1,47 (m, 2H), MS (Cl, CH4) m/z 396 (M + 1,100), 424 (M + 29,17), 378 (10) chlorhydrate salt:

Analysis for C28H29NOHCl0,3H2O:

Calculated C 76,89, H 7,05, N 3,20

Found, C 76,68, H 7,12, N 3,21

Example 49. 1-(Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(1,1 - dimethylethyl)piperidine-4-ol.

To a cooled solution (-78oC) lithium bromide (770 mg, a 3.87 mmol, 1.5 EQ) in tetrahydrofuran (60 ml) under nitrogen add only that m t-utility (1.7 M in pentane, 4,20 ml, 7,10 mmol, 1.2 and EC). Received bright yellow color of the solution quenched by adding a solution of 1-(2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 1m) (2.00 g, of 5.92 mmol) in tetrahydrofuran (15 ml). The reaction mixture was warmed to room temperature for 10 min and quenched with water (60 ml). The aqueous phase is extracted with ethyl acetate (3x60 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to oil. The reaction mixture was purified using flash chromatograph Agogo substances. The TLC analysis (Rf0,23, 20% ethyl acetate in hexane).

1H NMR (CDCl3, 300 MHz) of 7.24 (m, 1H), 7,14 (m, 2H), to 6.95 (m, 3H), 6.87 in (m, 1H), 4,24 (W s, 1H), of 3.56 (s, 2H), 2,82 (m, 2H), 2,59 (d, J 1.4 Hz, 2H), 2,50 (m, 2H), 1,74 (m, 2H), 1,50 (m, 2H), 0,91 (W s, 9H); MS (Cl, CH4) m/z 396 (M+ 1,100), 398 (35), 424 (M+ 29,17), 378 (45), 360 (6)

The free base was dissolved in diethyl ether containing a small amount of methylene chloride and acidified with ethereal HCl. Chlorhydrate salt is filtered off, washed with fresh ether and dried in vacuum (60oC, 13 Pascal, 18 h) to give white solid, so pl. 294-296oC.

Analysis for C25H30ClNOHCl0,5H2O:

Calculated C 68,02, H 7,31, N 3,17

Found, C 67,96, H 6,98, N 3,03

Example 50. 1-(2,7-Dichloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4- (1,1-dimethylethyl)piperidine-4-ol.

Using a technique similar to that described in example 49, except that originate from 1-(2,7-dichloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 35h) get a named connection from 51% yield as a white solid, so pl. 194-196oC. TLC Analysis on free base (Rf0,27, 20% ethyl acetate in hexane), the free base:

1H NMR (CDCl3, 300 MHz) to 7.15 (d, 1.8 Hz, 2H), 7,13 (d, J 7.8 Hz, 2H), 6.90 to (DD, J of 1.8, 7.7 Hz, 2H),, 32 (60), 434 (11), 458 (M+ 29,14), 412 (61), 414 (44), 394 (11), 170 (11) chlorhydrate salt:

Analysis for C25H29Cl2NOHCl:

Calculated C 64,32, H 6.48 in, 3,00 N

Found, C 64,03, H 6,33, N 2,89

Example 51. 4-Butyl-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 49, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of n-utility, get a named connection in the form of a white solid substance, so pl. 194-196oC. TLC Analysis on the basis of (Rf0,22, 30% ethyl acetate in hexane), the free base:

1H NMR (CDCl3, 250 MHz) 7,20 (m, 4H), to 8.94 (m, 4H), 4.26 deaths (s, 1H), 3,41 (s, 2H), by 2.73 (m, 2H), 2,60 (d, J 2.0 Hz, 2H), 1,53 (m, 10H), and 0.9 (t, 3H), MC (Cl, CH4) m/z 362 (M + 1,100), 390 (M+ 29,13), 344 (47), 304 (44) chlorhydrate salt:< / BR>
Analysis for C25H31NOHCl0,6H2O:

Calculated C 73,45, H 8,18, N 3,43

Found, C 73,09, H 7,80, N 4.09 TO

Example 52. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(6-methoxy - 2-benzothiazyl)piperidine-4-ol

To a cooled solution (-72oC) n-utility (2.5 M in hexane, from 0.84 ml, 2.1 mmol, of 1.05 EQ) in tetrahydrofuran (20 ml) under nitrogen add 6-methoxybenzothiazole (obtaining literature: M. D. Friedman, P. L. Stotter, T. H. Porter, K. Folkers, J. Med. Chem. the R (3 ml) of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) is added dropwise and warmed to room temperature for 30 minutes The reaction mixture was stirred for 3 h and quenched with water (20 ml). The aqueous phase is extracted with ethyl acetate (200 ml). The organic phase is washed with water (2 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to oil. The reaction mixture was purified flash chromatography on silica gel (100 ml, eluent: 30% ethyl acetate in hexane) to give 0.74 g (72%) of the named compound in the form of not-quite-white solid. The TLC analysis (Rf0,21, 30% ethyl acetate in hexane).

1H NMR (CDCl3, 250 MHz) of 7.82 (d, J a 8.9 Hz, 1H), 7,30 (d, J 2.5 Hz, 1H), 7,25 (DD, J 3.1 and 5.8 Hz, 2H), 7,17 (DD, J of 2.2, and 5.2 Hz, 2H),? 7.04 baby mortality (DD, J 2.5 and 9.0 Hz, 1H), 6,93 (m, 4H), 4,27 (s, 1H), 3,85 (s, 3H), of 3.48 (s, 2H), 3,10 sh. C. 1H), 2.95 and (m, 2H), 2,74 (dt, J 2.2, while the 11.6 Hz, 2H), 2,61 (d, J 1.2 Hz, 2H), 2,28 (dt, J 4,5, 12,5 Hz, 2H), to 1.87 (m, 2H), MC (Cl, CH4) m/z 469 (M + 1,100), 497 (M+ 29,19), 451 (17).

The free base was dissolved in diethyl ether containing a small amount of methylene chloride, acidified with ethereal HCl, and the suspension chlorhydrate salt diluted with additional ether. The salt is filtered off, washed with fresh ether and dried in vacuo (50oC, 10 PA, 18 h), receiving not quite white solid, so pl. 249-251oC (decomp.).

Analysis for C29H28N2O22HCl0,25H2O:

Calculated C 63,79, H 5,63, N 5,13

On the="ptx2">

Using a technique similar to that described in example 52, in addition to the use of benzothiophene, get a named connection with the release of 90% in the form of a white solid substance, so pl. 278-285oC-free basis:

1H NMR (D6-DMSO, 300 MHz) 7,87(d, J 7.5 Hz, 1H) 7,72 (d, J 6.0 Hz, 1H), 7,26 (m, 7H), 6,92 (m, 4H), 4,32 (s, 1H), 3,41 (s, 2H), and 2.79 (m, 2H), 2,69 (m, 2H), 2,50 (s, 2H), of 1.97 (m, 2H), equal to 1.82 (m, 2H), MC (Cl, CH4) m/z 438 (M + 1,100), 446 (M + 29,20), 420 (35) chlorhydrate salt:

Analysis for C29H27NOSHCl0,2H2O:

Calculated C 72,92, H of 5.99, N 2,93

Found, C, 72,72, H 5,80, N 2,87

Example 54. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-furanyl)- piperidine-4-ol.

Using a technique similar to that described in example 52, in addition to the use of furan, get a named connection with the release of 33% as not quite white solids, I. PP. 265-272oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) of 7.24 (m, 5H), 6,93 (m, 4H), 6.30-in (m, 1H), 6,20 (m, 1H), 4.26 deaths (sh.with. 1H), 3.43 points (s, 2H), 2,70 (m, 4H), 2,59 (d, 2H), 2.05 is (m, 2H), 1,92 (m, 2H), MC (Cl, CH4) m/z 372 (M + 1,100), 400 (M+ 29,17), 354 (60), 332 (22) chlorhydrate salt:

Analysis for C25H25NO21,3HCl0,2H2O:

Calculated C 71,07, H 6,37, N 3,12

Found, C is 70.94, H 6,13, N 3,17

Example 55. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-thionyl)- piperidine-4-ol.

Use the Odom 72% in the form of a white solid, so pl. 134-138oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) 7,20 (m, 4H), 6,94 (m, 7H), 4,27 (sh.with. 1H), 3,48 (s, 2H), 2,86 (m, 2H), by 2.73 (m, 2H), 2,61 (s, 2H), 2.13 in (m, 2H), 1.93 and (m, 2H), MC (Cl, CH4) m/z 388 (M + 1,100), 416 (M+ 29,24), 370 (76), 304 (19), 196 (12), 91 (17) chlorhydrate salt:

Analysis for C25H25NOS1,4HCl0,1H2O:

Calculated C 68,16, H 6,09, N 3,18

Found, C 67,78, H 5,72, N 3,14

Example 56. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-thiazyl)- piperidine-4-ol.

Using a technique similar to that described in example 52, in addition to the use of thiazole, get a named connection with the release of 28% in the form of a white solid substance, so pl. 196-198oC (decomp. ). Analysis of the TLC of the free base (Rf0,14, ethyl acetate). Free base:

1H NMR (CDCl3, 300 MHz) 8,71 (s, 1H), 7,76 (s, 1H), 7,24 (m, 2H), 7,16 (m, 2H), 6,95 (m, 4H), 4,27 (sh.with. 1H), 3.46 in (s, 2H), 2,87 (m, 2H), 2,74 (m, 2H), 2,60 (d, J 1.4 Hz, 1H), and 2.14 (m, 2H), 1.93 and (m, 2H) MC (Cl, CH4) m/z 389 (M + 1,100), 417 (M + 29,23), 371 (23), chlorhydrate salt:

Analysis for C24H25N2OS2HCl1,1H2O:

Calculated C 59,90, C 5,90, N OF 5.82

Found, C 59,52, H 5,64, N 5,64

Example 57. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5 - thiazyl)piperidine-4-ol.

Using a technique similar to that described in example 52, except for the use of 2-(trimethylsilyl)thiazole and 1-(2-chloro-9,1 output 40% in the form of a white solid, so pl. 206-210oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) 8,71 (s, 1H), 7,76 (s, 1H), 7,20 (m, 1H), 7.14 (m, 2H), 6,97 (m, 2H), 6.89 in (DD, J of 1.8, 7.7 Hz, 1H), 4.26 deaths (sh.with. 1H), 3,42 (sh. C. 2H), 2,84 (m, 2H), by 2.73 (m, 2H), 2,61 (sh.with. 2H), 2.13 in (m, 2H), up to 1.98 (m, 2H). MC (Cl, CH4) m/z 423 (M+ 1,100), 425 (40), 451 (M + 29,19), 405 (24) chlorhydrate salt:

Analysis for C24H23ClN2OS2HCl0,5H2O:

Calculated C 57,09, H 5,19, N 5,55

Found, C 56,80, H 5,12, N lower than the 5.37

The original 2-(trimethylsilyl)thiazole receive the following way.

a. 2-(Trimethylsilyl)thiazole.

To a cooled solution (-98oC) n-utility (2.5 M in hexane, 5,39 ml of 13.4 mmol, 1.1 EQ) in tetrahydrofuran (100 ml) under nitrogen is added a solution of 2-bromothiazole (2.00 g, 12.2 mmol) in tetrahydrofuran (30 ml). The suspension in the form of a substrate type. After stirring at -90oC for 30 minutes add the fresh trimethylsilane (of 1.55 ml, 12.2 mmol, 1.0 EQ). The reaction mixture is heated to -30oC for 1 h and quenched with saturated aqueous sodium bicarbonate (50 ml). The aqueous phase is extracted with diethyl ether (2 x 40 ml). The combined organic extracts washed with aqueous bicarbonate (2 x 40 ml), saturated salt solution (1 x 40 ml) and dried with anhydrous sodium sulfate. The solvents were removed and the product purified bolshimi quantities initial substance and is considered without further purification. The exact output is not selected. MC (Cl, CH4) m/z 158 (M + 1,100), 186 (M + 29,17).

Example 58. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-fluoro-3 - pyridyl)piperidine-4-ol.

To a cooled solution (-72oC) the relocated Diisopropylamine (9,86 ml, or 56.1 mmol, 1.3 EQ) in a mixture tetrahydrofuran/hexane (57 ml/37 ml) under nitrogen is added n-utility (2.5 M in hexane, 239 ml, to 59.4 mmol, 1.4 EQ). The resulting solution is heated to -20oC to ensure deproteinization and then again cooled to -72oC. tertrahydrofuran ring (13 ml) solution of 2-herperidin (4,50 ml of 53.5 mmol, 1.25 EQ) is then added dropwise a yellow precipitate. Deprotonirovannoi the reaction mixture is heated at -50oC for 45 min and briefly allow to reach -30oC before re-cooling -72oC. To this solution was added a mixture of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) (13,0 g, 42,9 mmol) and lithium bromide (7,45 g, to 85.8 mmol, 2 EQ) in tetrahydrofuran (43 ml) dropwise. When you add yellow precipitate dissolves. The reaction mixture is heated to -20oC for 1.5 h and quenched with acetic acid (10 ml). The solution was diluted with water (400 ml), alkalinized to 2.5 N. NaOH and extracted with ethyl acetate (3 x 300 ml). About the th substance. The product was then purified by recrystallization from ethyl acetate (3 times) to give 13.3 g (77%) of the named compound as a white solid. The TLC analysis (Rf0,22, 30% ethyl acetate in hexane).

1H NMR (CDCl3, 300 MHz) of 8.09 (d, J 8.2 Hz, 1H), to $ 7.91 (DD, J 8,2, 9.4 Hz, 1H), 7,21 (m, 5H), 6,94 (m, 4H), 4,27 (s, 1H), 3,48 (s, 2H), 2.91 in (m, 2H), 2,74 (m, 2H), 2,62 (s, 2H), and 2.26 (m, 2H), 1,78 (m, 2H), MC (Cl, CH4), m/z 401 (M + 1,100), 429 (M + 29,15), 383 (21). The free base is dissolved in ether and acidified with ethereal HCl. Chlorhydrate salt is filtered, washed with fresh ether and dried in vacuo (room temperature, 10 PA, 13 h), receiving a white solid, so pl. 188-191oC (decomp.)

Analysis for C26H25FN2OHCl0,4H2O:

Calculated C 70,31, H between 6.08, N OF 6.31

Found, C 70,65, 6,12 H, N OF 5.83

Example 59. 1-(9,10-Dihydro-9,10-metanarration-9-ylmethyl)-4-(3 - pyridyl-methyl)piperidine-4-ol.

Using a technique similar to that described in example 58, except for the application of 3-picoline, get a named connection with the release of 46% in the form of a white solid substance, so pl. 140-142oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz), 8,48 (d, J 3.0 Hz, 1H), to 7.61 (DDD, J 1,8, and 7.7, 7.7 Hz, 1H), 7,20 (m, 6H), 6,92 (m, 4H), 4,24 (s, 1H), 3,42 (s, 2H), 2,88 (s, 2H), 2,70 (m, 4H), 2.57 m (s, 2H), and 1.54 (m, 4H), MC (Cl, CH4) m/z 397 (M + 1,100), 425 (M+ 29,14), 379 (16), 304 (16), 89 (32)Hargita is but C 65,31, H 6,59, N 5,31

Example 60. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-aaltio - 3-pyridyl)piperidine-4-ol.

To a solution of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4- (2-fluoro-3-pyridyl)piperidine-4-ol (described in example 58) (2.00 g, 5.00 mmol, 1 EQ) in tetrahydrofuran (50 ml) under nitrogen is added sodium salt ethanethiol (0,90 g of 10.7 mmol, 2,2 EC). Thiolato salt is obtained from ethanthiol and sodium hydride under standard conditions. The reaction mixture is heated under reflux for 18 h and quenched by pouring into water (100 ml). The aqueous phase is extracted with diethyl ether (2 x 100 ml). The combined organic extracts washed with water (2 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to oil. The reaction product was then purified on a flash chromatography on silica gel (200 ml, eluent: 50% ether in hexane) to give 2.00 g (90%) of the named compound. The TLC analysis (Rf0,29, 50% ether in hexane).

1H NMR (CDCl3, 250 MHz) 8,35 (DD, J 1.6, the 4,7 Hz, 1H), 7,58 (DD, J of 1.7, 7.7 Hz, 1H), 7,22 (m, 4H), to 6.95 (m, 5H), 4,27 (s, 1H), to 3.58 (s, 1H), 3,48 (s, 2H), 3,28 (K, J 7,3 Hz, 2H), 2,89 (m, 2H), 2,80 (DDD, J 9,3, 14,9, to 10.7 Hz, 2H), 2,62 (d, J 1.5 Hz, 2H), 2,12 (m, 4H), of 1.35 (t, J 7.2 Hz, 3H), MC (Cl, CH4) m/z 443 (M + 1,100), 471 (M+ 29,16), 425 (25).

The free base is dissolved in ether and acidified with ethereal HCl. Georgia, 18 h) to give white solid, I. PP. 176-179oC (decomp.)

Analysis for C28H30N2OS2HCl0,5H2O:

Calculated C 64,11, H 6,34, N 5,34

Found, C 64,05, H 6,32, N 5,26

Example 61. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-propyl - oxy-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 60, except using n-propanol, get a named connection with 86% yield as a white solid, so pl. 172-175oC (decomp.), free base:

1H NMR (CDCl3, 200 MHz) 8,03 (DD, J of 1.7, 5.0 Hz, 1H), 7,53 (DD, J of 1.8, 7.5 Hz, 1H), 7,22 (m, 4H), 6,92 (m, 5H), 4,37 (t, J 6.5 Hz, 2H), 4,29 (s, 1H, 3,88 (s, 1H), 3,48 (s, 2H), 2,80 (m, 4H), 2,62 (s, 2H), 2,02 (m, 4H) and 1.83 (m, J 6,7, and 7.3 Hz, 2H), was 1.04 (t, J 7.4 Hz, 3H), MC (Cl, CH4) m/z 441 (M + 1,100), 469 (M+ 29,14), 423 (31), 206 (4), 138 (8) chlorhydrate salt:

Analysis for C29H32N2O22HCl0,5H2O:

Calculated C 66,66, H is 6.75, N ARE 5.36

Found, C 67,76, H 6,59, N 5,16

Example 62. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-(2,2,2- triptoreline)-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 60, except for the use of 2,2,2-triptoreline, get a named connection with the release of 94% in the form of a white solid substance, so pl. 165-170oC (decomp.), free base:

1H NMR (CDCl), 2,80 (DDD, J 2,3, and 11.6, 11.7 Hz, 2H), 2,61 (d, J 1.4 Hz, 2H), 2,12 (DDD, J 4,5, 12,0, to 11.9 Hz, 2H), 1,92 (m, 2H), MC (Cl, CH4) m/z 481 (M + 1,100), 509 (M + 29,1), 463 (27) chlorhydrate salt:

Analysis for C28H27N2O2F32HClH2O:

Calculated C 68,39, H 6,26, N A 4.83

Found, C, 68,30, H 6,00, N equal to 4.97

Example 64. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-methoxy - 3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 60, in addition to the use of methanol, get a named connection with the release of 94% in the form of a white solid substance, so pl. 225-228oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz), with 8.05 (DD, J of 4.9, 1.7 Hz, 1H), 7,49 (DD, J of 7.5, 5.7 Hz, 1H), 7,22 (m, 4H), 6,92 (m, 5H), 4,27 (s, 1H), was 4.02 (s, 3H), of 3.78 (s, 1H), 3,48 (s, 2H), and 2.83 (m, 4H), 2,61 (d, J 1.4 Hz, 2H), 2,00 (m, 4H), MC (Cl, CH4) m/z 413 (M + 1,100), 441 (M + 29,13), 395 (24) chlorhydrate salt:

Analysis for C27H28N2O2HCl0,2H2O:

Calculated C 71,65, H 6,55, N IS 6.19

Found, C 71,43, H 6,46, N OF 5.84

Example 65. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4- (2-(1-methylethoxy)-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 60, except for the use of 2-propanol, get a named connection with a quantitative yield in the form of a white solid substance, so pl. 156 to 160oC (decomp.), freedom is 7.5 Hz, 1H), 5,48 (m, 1H), 4,27 (sh.with. 1H), 4.09 to (sh.with. 1H), 2,82 (m, 4H), 2,61 (d, J 1.4 Hz, 2H), 1,99 (m, 4H), of 1.39 (d, J 6.2 Hz, 6H), MC (Cl, CH4) m/z 441 (M + 1,100), 469 (M+ 29,8), 423 (27), 399 (22), 304 (2), 249 (9), 235 (5), 192 (9), 164 (69) chlorhydrate salt:< / BR>
Analysis for C29H32N2O22,3 HClH2O:

Calculated C 64,20, H 6,74, N 5,16

Found, C 64,55, H 6,27, N 4,71

Example 66. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-(N-PIR rollitini)-3-pyridyl)piperidine-4-ol.

To a cooled solution (0oC) pyrrolidine (0,417 ml, 5.00 mmol, 5 EQ) in tetrahydrofuran (10 ml) under nitrogen is added n-utility (2.5 M in hexane, of 1.92 ml, 4,80 mmol, 4.8 EQ). Then add 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- 4-(2-fluoro-3-pyridyl)piperidine-4-ol (described in example 58) (0.400 g, 1 00 mmol) in tetrahydrofuran (10 ml). Bath removed and the solution warmed to room temperature for 1.5 h Interaction is not obvious for 18 hours to speed up the reaction, 18-crown-6 (0,528 g, 2.00 mmol, 2.0 EQ) is added and the solution heated to 60oC for 5 h the Reaction is quenched with water (30 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to oil. The reaction product was then purified on a flash chromatography on silica gel (35 ml, eluent: 50% atrazine).

1H NMR (CDCl3, 300 MHz) 8,35 (DD, J of 1.7, 4.6 Hz, 1H), 7,63 (DD, J of 1.8, 7.9 Hz, 1H), 7,22 (m, 4H), 7,12 (DD, J of 7.9, 4.6 Hz, 1H), 6,93 (m, 4H), 4,27 (W s, 1H), 3,48 (s, 2H), 3,21 (m, 4H), 2,85 (m, 2H), was 2.76 (m, 2H), 2.63 in (d, J 1.3 Hz, 2H), 2,01 (m, 6H), to 1.70 (m, 2H), MS (Cl, CH4) m/z 452 (M + 1,100), 480 (M + 29,12), 434 (16). The free base is dissolved in ether and acidified with ethereal HCl. Chlorhydrate salt is filtered off, washed with fresh ether and dried in vacuum (60oC, 16 PA, 18 h) to give white solid, so pl. 249-253oC.

Analysis for C30H33N3O2HClH2O:

Calculated C 66,60, H 6,86, N TO 7.77

Found, C up 66,78, H 6,66, N OF 7.64

Example 67. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-(N-methylethylamine)-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 66, except for the use of N-methylethylamine, get a named connection with the release of 59% in the form of a white solid substance, so pl. 179-182oC (decomp.), free base:

1H NMR (CDCl3, 250 MHz) at 8.36 (DD, J of 1.8, 4.6 Hz, 1H), to 7.67 (DD, J of 1.7, 7.9 Hz, 1H), 7.23 percent (m, 4H), 7,13 (DD, J 5,1, 8.5 Hz, 1H), 6,93 (m, 4H), 4,27 (s, 1H), 3,48 (s, 2H), 3,05 (K, J 7,1 Hz, 2H), 2,80 (m, 4H), 2,68 (s, 3H), 2.63 in (d, J 1.3 Hz, 2H), 2,03 (DDD, J 4,8, to 11.9, 12.0 Hz, 2H), 1.70 to (m, 2H), 1,58 (W s, 1H), of 1.07 (t, J 7,3 Hz, 3H), MS (Cl, CH4) m/z 440 (M + 1,100), 468 (M+ 29,15), 422 (21), 420 (13), 248 (8), 137 (9) chlorhydrate salt:

Analysis for C29H33

Using a technique similar to that described in example 66, except for the use of methylamine, get a named connection with the release of 89% in the form of a white solid substance, so pl. 220-221oC (decomp.), free base:

1H NMR (CDCl3, 300 MHz) with 8.05 (DD, J of 1.4, 4.9 Hz, 1H), 7,22 (m, 5H), 6,93(m, 4H), 6,47 (DD, J 5,0, 7,3 Hz, 1H), 6.42 per (m, 1H), 4,27 (s, 1H), 3,47 (s, 2H), 2,97 (d, J 4,2 Hz, 3H), 2,90 (m, 2H), by 2.73 (DDD, J 3,3, to 11.1 and 11.1 Hz, 2H), 2,60 (d, J 1.0 Hz, 2H), 2,03 (m, 2H), 1,65 (m, 2H), MS (Cl, CH4) m/z 412 (M + 1,100), 440 (M + 29,15 ), 394 (25) chlorhydrate salt:

Analysis for C27H29N3O2HClH2O:

Calculated C 64,54, H 6,62, N AT 8.36

Found, C 64,62, H 6,64 N 8,12

Example 69. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5- (hydroxymethyl)-3-pyridyl)piperidine-4-ol

Tertrahydrofuran ring solution (15 ml) of 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(2-chloro-9,10-dihydro-9,10 - ethanoanthracene-9-ylmethyl)piperidine-4-ol (1.70 g, 3.04 from mmol) cooled at 0oC under nitrogen and treated with tetrabutylammonium fluoride (a 1.0 N in tetrahydrofuran, 3,20 ml, 3,20 mmol, of 1.05 EQ). The reaction mixture is heated at room temperature and stirred at the same temperature for 3 hours, water is Added (15 ml) and the resulting aqueous phase is extracted with ethyl acetate (3 x 15 ml). The combined organic extracts was dried su is from TLC (Rf0,11, 5% methanol in diethyl ether). Additional purification was not required.

1H NMR (CDCl3, 250 MHz) to 8.62 (s, 1H), 8,42 (s, 1H), to 7.84 (s, 1H), 7,21 (m, 4H), 6,94 (m, 3H), 4,69 (s, 2H), 4,27 (s, 1H), 3,44 (s, 2H), 2,90 (m, 2H), 2,74 (m, 2H), 2,62 (d, J 1.3 Hz, 2H), 2,11 (m, 2H), 1,76 (m, 2H), MS (Cl, CH4) m/z 447 (M+ 1,100), 449 (32), 475 (M+ 29,19), 429 (71), 431 (25).

The free base is dissolved in ether and acidified with ethereal HCl. Chlorhydrate salt is filtered off, washed with fresh ether and dried in vacuo (room temperature, 10 PA, 18 h) to give white solid, so pl. 235-240oC (decomp.)

Analysis for C27H27N2O22HCl0,7H2O:

Calculated C 60,55, H 6,23, N 5,23

Found, C, 60,26, H 5,71, N 5,13

Source silloway ether was prepared as follows.

A. 3-Bromo-5-(hydroxymethyl)pyridine.

To a toluene suspension (100 ml) of 5-bromonicotinic acid (15,00 g of 74.3 mmol) is added thionyl chloride (6,00 ml of 81.7 mmol, 11 EQ). The suspension is heated under reflux for controlling the allocation of gas by barbaterom with mineral oil. After 60 min, the system becomes homogeneous and reaches stable conditions relating to the allocation of gas. The reaction mixture is cooled to room temperature. Remove excess thionyl chloride and dissolve 241 mmol, 13 EQ) is added to absolute ethanol (200 ml) and cooled to -10oC under nitrogen. The acid chloride added in portions over 20 min, maintaining the reaction temperature at 0oC in this period. After complete addition the reaction mixture is heated to room temperature and stirred for 1 h, Add water (200 ml) and the aqueous phase extracted with diethyl ether (2 x 200 ml). The combined organic extracts washed with water (100 ml), dried over anhydrous potassium carbonate and filtered. The dry product in the form of its chlorhydrate salt by treatment of an ethereal solution of HCl. The solid is dried in vacuo (room temperature, 16 PA, 7 h). Additional purification is not required. The result chlorhydrate salt 10,04 g (60%) of the named compound. MS (Cl, CH4) m/z 188 (M+ 1,100), 190 (99), 216 (M+ 29,8), 218 (8), 170 (25), 172 (24)

b. 3-Bromo-6-(tert-butyldimethylsilyl)oxymethylphenyl.

To methylenchloride solution (20 ml) of 3-bromo-5-(hydroxymethyl)pyridinecarboxamide (described in example 69A) (1,00 g), 4,48 mmol) under nitrogen was added triethylamine (2,50 ml of 17.9 mmol, 4 EQ) and tert-butyldimethylsilyl (0.75 g, 5.0 mmol, 1.1 EQ). The resulting solution is heated back to the refrigerator for 18 h, cooled to room temperature the major salt solution (1 x 100 ml). The ether solution is dried with anhydrous magnesium sulfate, filtered and concentrated to a colorless oil. The result of 1.10 g (81% ) of the named compound. The product does not require additional purification. The TLC analysis (Rf0,19, ethyl acetate) MS (Cl, CH4) m/z 302 (M+ 1,100), 304 (96), 330 (M + 29,4), 332 (4)

c. 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except for the application of 3-bromo-5-(tert-butyldimethylsilyl)oksietilpiperazina (described in example 69b) and 1-(2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 1m), get a named connection from 51% yield in the form of oil. The TLC analysis (Rf0,20, 25% ethyl acetate in hexane) MS (Cl, CH4) m/z 561 (M+ 1,100), 563 (40), 589 (M+ 29,20), 545 (26), 429 (26).

Example 70. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(hydroxy - methyl)-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 69, except that extend from 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(9,10-dihydro-9, - 10-ethanoanthracene-9-ylmethyl)piperidine-4-ol, get a named connection with the release of 85% as a white solid, so pl. 210-215oC, freedoms is 9 (W t, 1H), 4,63 (d, J 2.8 Hz, 2H), 4,46 (W s, 1H), 4,29 (s, 1H), 3,49 (s, 2H), 2,87 (m, 4H), 2.63 in (s, 2H), 2.06 to (m, 2H), 1,73 (m, 2H), MS (Cl, CH4) m/z 413 (M + 1,100), 441 (M + 29,17), 395 (61) chlorhydrate salt:

Analysis for C27H28N2O22HCl0,9H2O:

Calculated, C 64,64, H 6,39, N 5,58

Found, C 64,50, H 6,34, N 5,48

Source silloway ether was prepared as follows.

a. 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(9,10 - dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10 - ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 3-bromo-5-(tert-butyldimethylsilyl)oksietilpiperazina (described in example 69b), get a named connection with the release of 62% in the form of oil. The TLC analysis (Rf0,25, 30% ethyl acetate in hexane). MS (C2, CH4) m/z 527 (M + 1,100), 555 (M+ 29.14), 509 (20), 395 (20)

Example 71. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-(hydroxy-methyl)-5-thiazyl)piperidine-4-ol.

Using a technique similar to that described in example 69, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(2-(tert-butyldimethylsiloxy)ciazil)) piperidine-4-ol, get a named connection with the release of 48% W/P> Free base:

1H NMR (CDCl3, 300 MHz) 7,56 (s, 1H), 7,25 (m, 2H), 7,16 (m, 2H), 6,94 (m, 4H), 4,39 (s, 2H), 4,28 (W s, 1H), 3.46 in (s, 2H), 2,85 (m, 2H), by 2.73 (m, 2H), 2,11 (m, 2H), 1.93 and (m, 2H), MS (Cl, CH2) m/z 419 (M + 1,100), 447 (M+ 29,16). 401 (42), 304 (50) chlorhydrate salt:

Analysis for C25H26N2O2SC6H8O7:

Calculated C 60,97, H 5,61, N 4,59

Found, C 60,86, H 5,80, N 4,35

Source silloway ether was prepared as follows.

a. 2-Formilleza.

To a cooled solution (-95oC) t-utility (1.7 M in pentane, to 17.9 ml of 30.5 mmol, 2.0 EQ in tetrahydrofuran (150 ml) under nitrogen was added 2-bromothiazole (2.50 g, and 15.3 mmol). The resulting suspension was stirred at below -80oC for 45 minutes the Solution literaturnogo thiazole transferred via cannula into a solution of dimethylformamide (1,42 ml) in tetrahydrofuran (100 ml) at -90oC. the Reaction mixture was allow to warm to room temperature over 2 h and quenched by adding water (100 ml). The aqueous phase is extracted with ethyl acetate (3 x 75 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to crude oil with 87% yield. The TLC analysis (Rf0,50, 40% ethyl acetate in hexane). Further characterizatio not predusmatriva kemetyl)thiazole.

To a cooled solution (0oC) 2-formulate (described in example 71a) (1.50 g, of 13.27 mmol) in methanol (25 ml) under nitrogen is added sodium borohydride (0,300 g, 7,94 mmol). After the addition the reaction mixture is heated to room temperature within 1 h and stirred at room temperature for 3 hours, the Excess reagent is quenched with acetone (10 ml) and stirred for 18 hours, the Reaction mixture was acidified with 3n. HCl (25 ml), cooled to 0oC and alkalinized to 2.5 N. NaOH (40 ml). The aqueous phase is extracted with ethyl acetate (3 x 25 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to a relatively pure oil with a yield of 62% TLC Analysis (Rf0,15, 40% ethyl acetate in hexane). Further purification is not required. MS (Cl, CH4) m/z 116 (M + 1,82), 144 (M+ 29,17), 98 (100).

c. 2-(tert-butyldimethylsilyl)assimetrical.

Using a technique similar to the one described in example 69b, except that originate from 2-(hydroxymethyl)thiazole (described in example 71b), get a named connection with the release of 92% TLC Analysis (Rfof 0.21, 10% ether in hexane). MS (Cl, CH4) m/z 230 (M + 1,26), 258 (M+ 29,11), 214 (24), 172 (100).

d. 4-(2-(tert-butyldimethylsilyl)oxymethyl-5-thiazyl)-1-(9,10-dihydro-9,10-metanoia, that they proceed from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 2-(tert-butyldimethylsilyl)oxymethylene (described in example 71c) get a named connection from 58% yield as a yellow oil. The TLC analysis (Rf0,19, 25% ethyl acetate in hexane). MS (Cl, CH4) m/z 533 (M + 1,100), 561 (M+ 29,16), 515 (21), 475 (12)

Example 72. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-N-methyl - carbamoylmethyl-3-pyridyl)piperidine-4-ol.

To a solution of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- 4-(5-(hydroxymethyl)-3-pyridyl)piperidine-4-ol (described in example 70) (0.50 g, 112 mmol) in methylene chloride (5 ml) was added methyl isocyanate (0,070 ml, 118 mmol, of 1.05 EQ) and N-methylpiperidin (0.10 ml, 0.82 mmol, 0.75 mmol). The resulting solution was heated under reflux for 9 h, cooled to room temperature and diluted with ethyl acetate (100 ml). The organic phase is washed with water (2 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The reaction product was then purified on a flash chromatography on silica gel (80 ml, eluent: 75% ethyl acetate in hexane) to give 0,380 g (87%) of the named compound as a white solid. The TLC analysis (Rf0,22, 75% ethyl acetate in hexane).

1H NMR (CDCl3, 250 MHz)m, 2H), 2,62 (s, 2H), 2,10 (m, 2H), 1.77 in (m, 2H). MS (Cl, CH4) m/z 504 (M+ 1,100 ), 506 (38), 532 (M+ 29,11), 486 (25), 447 (45), 429 (32).

The free base is dissolved in ether containing methylene chloride and acidified with ethereal HCl. Chlorhydrate salt is precipitated by ether dilution, filtered, and dried in vacuo (room temperature, 10 PA, 13 h), receiving a white solid, so pl. 200-204oC (decomp.).

Analysis for C29H30ClN3O3H2O

Calculated C 58,54, H 5,76, N 7,06

Found, C 58,56, H 5,67, N 7,10

Example 73. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(1-hydroxyethyl)-3-pyridyl)piperidine-4-ol.

A suspension of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-formyl-3-pyridyl)piperidine-4-ol(0,350 g, 0,852 mmol) in tetrahydrofuran (20 ml) under nitrogen cooled to 0oC. Motility (1.0 M in diethyl ether, 1,72 ml, 2 EQ) is added dropwise, followed by dissolution of the suspension. The solution becomes Golden brown. The reaction mixture is heated to 10oC and stirred at this temperature for 2.5 hours At the end of this period the reaction mixture was quenched with water (25 ml) and the aqueous phase extracted with ethyl acetate (3 x 20 ml). The combined organic extracts dried over anhydrous magnesium sulfate, f is t: 10% methanol in diethyl ether), getting 0,280 g (77%) of the named compound as a white solid. The TLC analysis (Rf0,17, 10% methanol in diethyl ether).

1H NMR (CDCl3, 300 MHz) 8,65 (d, J 2.2 Hz, 1H), 8,48 (d, J 2.0 Hz, 1H), 7, 83 (t, J 2.1 Hz, 1H), 7,24 (m, 2H), 7,18 (m, 2H), 6,95 (m, 4H), 4.95 points (K, J 6.5 Hz, 1H), 4,28 (W s, 2H), 3,49 (W s, 2H), equal to 2.94 (m, 2H), 2,74 (m, 2H), 2,63(W s, 2H), 2.13 in (m, 2H), 1,76 (m, 2H), 1,59 (m, 3H), MS (Cl, CH4) m/z 427 (M + 1,100), 455 (M+ 29,17), 409 (62), 235 (11), 221 (22), 206 (17), 169 (28).

The free base is dissolved in methylene chloride containing a small amount of methanol, and acidified with ethereal HCl. Chlorhydrate salt is precipitated by ether dilution, filtered, washed with fresh ether and dried in vacuum (60oC, 10 PA, 18 h) to give white solid, so pl. 177-183oC. Analysis dihydrochloride is not in accordance with the calculation: 1H NMR and MS salt fully comply with the proposed structure.

Source derived pyridine anhydride was prepared as follows.

a. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-formyl - 3-pyridyl)piperidine-4-ol.

To a cooled solution (-78oC) oxalicacid (0,537 ml, at 6.84 mmol, 2 EQ) in methylene chloride (15 ml) under nitrogen add fresh dimethyl sulfoxide (0,971 ml, 13,68 mmol, 4 EQ). After 10 min 1-(9,10-d is the mole) is added in the form of a solution in dimethyl sulfoxide (15 ml). The reaction mixture was stirred at -78oC for 1 h before addition of triethylamine (3,81 ml, a 27.4 mmol, 8 EQ). The cooling bath removed and the reaction mixture is heated to room temperature within 2 hours Add water (35 ml) to quench the reaction and the product is extracted with methylene chloride (3 x 20 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to a solid. The reaction product was then purified flash chromatography on silica gel (35 ml, eluent: 10% hexane in ethyl acetate to transition directly to ethyl acetate) to give 1.04 g (74%) of the named compound. The TLC analysis (Rfof 0.25, 10% hexane in ethyl acetate). MS (Cl, CH4) m/z 411 (M + 1,100), 439 (M+ 29,14), 393 (18), 260 (7), 219 (10), 206 (25), 169 (12).

Example 74. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(methoxy - carbonyl)-3-pyridyl)piperidine-4-ol.

To a heterogeneous solution of (1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(4-methyl-2,6,7 - dioxabicyclo[2,2,2]Oct-yl)-3-pyridyl) piperidine-4-ol (0,970 g, 1,90 mmol) in methanol (5 ml) under nitrogen add sulfuric acid (of 0.21 ml, 2 EQ). The suspension dissolves as soon as you add the acid. The reaction mixture was stirred for 24 h and alkalinized to 2.5 N. NaOH (25 ml). The aqueous phase is extracted with these the center to the oil. The reaction product was then purified on a flash chromatography on silica gel (65 ml, eluent: 20% hexane in ethyl acetate), obtaining 0,560 g (67%) of the named compound as a white solid. The TLC analysis (Rf0,21, 20% hexane in ethyl acetate).

1H NMR (CDCl3300 MHz) 9,10 (d, J 1.8 Hz, 1H), 8,93 (d, J 2.3 Hz, 1H), scored 8.38 (t, J 2.1 Hz, 1H), 7,27(m, 2H), 7,18 (m, 2H), 6,95 (m, 4H), 4,29 (W s, 1H), 3,95 (s, 3H), 3,49 (s, 2H), 2.95 and (m, 2H), by 2.73 (m, 2H), 2.63 in (s, 2H), of 2.15 (m, 2H), 1,76 (m, 2H) MS (Cl, CH4) m/z 441 (M + 1,100), 469 (M+ 29,15), 423 (11), 145 (9), 103 (11), 85 (20).

The free base is dissolved in ether containing methylene chloride and acidified with ethereal HCl. Chlorhydrate salt is precipitated by ether dilution, filtered, washed with fresh ether and dried in vacuum (60oC, 10 PA, 18 h) to give white solid, so pl. 243-247oC (decomp.)

Analysis for C28H28N2O32HClH2O:

Calculated C 63,28, H 6,07, N 5,27

Found, C, 63,24, H 5,90, N 5,03

The original ortho-ester was obtained as follows.

a. 3-Methyl-3-oxetanyl-5-bromonicotinate.

To a suspension (50 ml) in toluene 5-bromonicotinic acid (5,02 g, 24,9 mmol) is added thionyl chloride (2.0 ml, a 27.4 mmol, 1.1 EQ). The suspension is heated under reflux for controlling the allocation of gas by barbaterom with minnesotacare. The reaction mixture is cooled to room temperature. The excess thionyl chloride and the solvent is removed in vacuum and replaced with methylene chloride (50 ml), add oxetane methanol (2,73 ml, a 27.4 mmol, 1.1 EQ), and then triethylamine (8,70 ml of 62.3 mmol, 2.5 EQ). Produce large amounts of sediment, as soon as the reaction mixture is stirred at room temperature under nitrogen. After 24 hours, the excess reagent is quenched with water (40 ml) and the aqueous phase is extracted with methylene chloride (2 x 50 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to oil. The reaction product was then purified on a flash chromatography on silica gel (250 ml, eluent: 20% ethyl acetate in hexane) to give 5.10 g (72%) of the named compound in the form of high crystalline white solid. The TLC analysis (Rf0,15, 20% ethyl acetate in hexane). MS (Cl, CH4) m/z 286 (M+ 1,100), 288 (99), 314 (M + 29,15), 316 (15)

b. 3-Bromo-5-(4-methyl-2,6,7-dioxabicyclo[2.2.2]octyl)pyridine.

Solution (30 ml) in methylene chloride 3-methyl-3-oxetanyl 5-bromonicotinate (described in example 74a) (2.50 g, 8,73 mmol) cooled to 0oC under nitrogen. Add nortriptilina (of 1.34 ml, 10.9 mmol, 1.25 EQ) and the resulting solution was stirred at 0oC for 25 hours Reactionintravenous through silica gel (20 g, pre-treated with 10 triethylamine in ether) to remove basic impurities. The reaction product was then purified on a flash chromatography on silica gel (150 ml, eluent:15% ethyl acetate in hexane) to give 2,02 g (81% ) of the named compound as a colourless oil. The TLC analysis (Rf0,29, 20% ethyl acetate in hexane containing 1% triethylamine). MS (Cl, CH4) m/z 286 (M+ 1,100), 288 (99), 222 (19), 314 (M+ 29,19), 316 (19).

c. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(4- methyl-2,6,7-dioxabicyclo[2.2.2]-1-octyl)-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 1, except that originate from 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 5d) and application of 3-bromo-5-(4-methyl-2,6,7-dioxabicyclo[2.2.2] octyl)pyridine (described in example 74b), get a named connection with 75% yield as a white solid. The TLC analysis (Rfof 0.25, 20% hexane in ethyl acetate) MS (Cl, CH4) m/z 511 (M + 1,100), 539 (M + 29,16), 493 (16)

Example 75. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(N-propylnitrosamine)-3-pyridine)piperidine-4-ol.

A solution of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(5-(methoxycarbonyl)-3-pyridyl)piperidine-4-ol (described in example 74) (0,560 g, 127 mmol) Propylamine (5 ml) directiony the product was then purified on a flash chromatography on silica gel (35 ml, eluent: ethyl acetate), obtaining 0,450 g (76%) of the named compound. The TLC analysis (Rf0,19, ethyl acetate).

1H NMR (CDCl3, 250 MHz) 8,84 (d, J 2.2 Hz, 1H), 8,81 (d, J 2.0 Hz, 1H), 7,26 (m, 2H), 7,19 (m, 2H), 6,94 (m, 4H), 4,29 (W s, 1H), 3,49 (s, 2H), 3,42 (m, 2H), 2.95 and (m, 2H), 2,72 (m, 2H), 2,62 (d, J 1.4 Hz, 2H), and 2.14 (m, 2H), a 1.75 (m, 2H), 1,64 (m, 2H), 0,99 (t, J 7.5 Hz, 3H), MS (Cl, CH4) m/z 468 (M + 1,100), 496 (M+ 29,16), 450 (14).

The free base is dissolved in methanol, acidified with ethereal HCl and diluted with ether to precipitate the salt. Chlorhydrate salt is filtered, washed with fresh ether and dried in vacuum (60oC, 10 PA, 18 h) to give white solid, so pl. 205-208oC.

Analysis for C30H33N3O22HCl0,4H2O:

Calculated C 65,79, H 6,59, N TO 7.67

Found, C 65,70, H 6,64, N 7,47

Example 76. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N,N - dimethylsulphamoyl)piperidine-4-ol.

A solution of n-utility (1,21 ml 2.29 M solution in hexano, 2.77 mmol) in tetrahydrofuran (10 ml) is cooled to -30oC and treated with a solution of N,N-dimethylbenzenesulfonamide (510 mg, 2.77 mmol) in tetrahydrofuran (5 ml). The mixture is heated to 0oC and stirred for 20 min, then cooled to -30oC and treated with a solution of 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-Piperi is URS, stirred for 0.5 h, then poured into 1N. aqueous sodium hydroxide (25 ml). The mixture is extracted with chloroform (3 x 50 ml). The organic extracts washed with brine (50 ml) are pooled, dried over anhydrous potassium carbonate, filtered and evaporated, getting petrified foam (1.3 g). Purification using flash chromatography (eluent: 6:1 3:1 hexane/acetone) yields a white powder (502 mg). This solid is dissolved in diethyl ether and treated with ethereal hydrogen chloride, getting chlorhydrate salt of the above compound (486 mg, of 0.92 mmol, 40%) as a white powder, so pl. 220-223oC.

Analysis for C29H32N2O3SHCl0,25H2O:

Calculated C 65,77, H 6,38, N OF 5.29

Found, C 65,92, H 6,35, N 5,12

1H NMR (D6-DMCO, D TFA): 7,70-7,35 (m, 8H), 7,03 (m, 4H), 4,49 (s, 3H), of 3.75 (m, 2H), only 3.57 (m, 2H), 2,96 (s, 6H), was 2.76 (s, 2H), 2,46 (m, 2H), 2,32 (m, 2H), MS (Cl, CH4) m/z 490 (36), 489 (M+ 1,100), 471 (11).

Example 77. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N-methyl - sulfamoyl)piperidine-4-ol.

According to the method similar to that described in example 76 except using N-methylbenzenesulfonamide in direct response litrovaya, get a named connection in the form of a white powder (42%), so pl. 179-182oC.

Analysis is P (D6-DMCO): 7,98 (d, J 6.9 Hz, 1H), 7,65 (d, J 8,3 Hz, 1H), 7,55 (t, J 7.2 Hz, 1H), 7,43 (t, J 7.2 Hz, 1H), 7,26 (m, 4H), 6.89 in (m, 5H), 5,44 (s, 1H), or 4.31 (s, 1H), 3,42 (s, 2H), 2,78 (m, 4H), of 2.50 (s, 3H), of 2.45 (s, 2H), 2,02 (W s, 4H), MS(Cl, CH4) m/z 476 (31), 475 (M + 1,100), 457 (18)

Example 78. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N,N-di - methylsulfanyl-5-methoxyphenyl)piperidine-4-ol.

According to the method similar to that described in example 76 except using N, N-dimethyl-4-methoxybenzenesulfonamide in direct response litrovaya, get a named connection in the form of a white powder (26%), so pl. 101-103oC.

Analysis for C30H34N2O4S:

Calculated C 69,42, H is 6.61, N 5,40

Found, C, 69,25, H 6,48, N 5,30

1H NMR (D6-DMCO): of 7.69 (d, J a 8.9 Hz, 1H), 7.23 percent (m, 5H), 6,91 (m, 5H), of 5.05 (s, 1H), or 4.31 (S, 1H), 3,83 (s, 3H), 3,41 (s, 2H), and 2.79 (s, 6H), of 2.72 (m, 4H), 2.49 USD (s, 2H), 2,12 (m, 2H), 1,90 (l, J and 12.4 Hz, 2H) MS (Cl, CH4) m/z 520(34), 519 (M+ 1,100), 518 (15), 501 (11).

Example 79. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N-methyl - sulfamoyl-5-methoxyphenyl)piperidine-4-ol

According to the method similar to that described in example 76 except using t-methyl-4-methoxybenzenesulfonamide in direct response litrovaya, get a named connection in the form of a powder (23%), so pl. 209-211oC.

Analysis for C29H32N2O4S:

RA is 1H), make 6.90 (m, 6H), 5,44 (s, 1H), or 4.31 (s, 1H, 3,81 (s, 3H), 3,41 (s, 2H), 2,72 (m, 4H), 2.50 each (s, 2H), 2,41 (d, J 4.5 Hz, 3H), 2,03 (m, 4H) MS (Cl, CH4) m/z 506 (35), 505 (M + 1,100).

Example 80. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N-propyl - sulfamoyl-5-methoxyphenyl)piperidine-4-ol

According to the method similar to that described in example 76 except using N-propyl-4-methoxybenzenesulfonamide in direct response litrovaya, get a named connection in the form of a white powder (34%), so pl. 169-170oC.

Elemental analysis for C31H36N2O4S:

Calculated C 69,90, H for 6.81, N 5,26

Found, C 69,79, H 6,92, N OF 5.29

1H NMR (D6-DMCO): of 7.96 (d, J 8,8 Hz, 1H), 7,28 (m, 4H), 7,05 (m, 1H), 6,98 (m, 4H), 5,51 (s, 1H), 4,32 (s, 1H), 3,82 (s, 3H), 3,42 (s, 2H), 2,68 (m, 6H), of 2.51 (s, 2H), 2,03 (m, 4H), of 1.41 (m, 2H), 0,32 (t, J 7.4 Hz, 3H), MS (Cl, CH4) m/z 506 (35), 505 (M + 1,100).

Example 81. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N-Pro - philselfology)piperidine-4-ol.

According to the method similar to that described in example 76 except using N-propylbenzenesulfonyl in direct response litrovaya, get a named connection in the form of a white powder (54%), so pl. 131-133oC.

Elemental analysis for C30H34N2O3S0,25H2O:

Calculated C 71,04, H 6,85, N 5,52

Found, C 71,03, H 6,82 with, 2H), and 3.31 (m, 2H), 2,73 (m, 6H), 2,03 (W s, 4H), of 1.41 (m, 2H), 0,81 (t, J 7,3 Hz) MS (Cl, CH4) m/z 504 (35), 503 (M + 1,100).

Example 82. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2 - pyrrolidinylcarbonyl)piperidine-4-ol.

According to the method similar to that described in example 76 except using pyrrolidinecarboxamido in direct response litrovaya, get a named connection in the form of a white powder (15%), so pl. 203-204oC.

Elemental analysis for C31H34N2O3:

Calculated C 72,34, H 6,66, N 5,44

Found, C 72,22, H 6,72, N 5,41

1H NMR (D6-DMCO: 7,76 (m, 2H), 7,56 (t, J 7.7 Hz, 1H), 7,45 (t, J 7,6 Hz, 1H), 7.23 percent (m, 4H), 6,92 (m, 4H), free 5.01 (s, 1H), or 4.31 (s, 1H), 3,40 (s, 2H), 3,30 (m, 4H), by 2.73 (m, 4H), 2.49 USD (s, 2H), 2,09 (m, 2H), of 1.88 (m, 6H), MS (Cl, CH4) m/z 516 (33), 515 (M + 1,100).

Example 83. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N-ethyl - sulfamoylbenzoyl)piperidine-4-ol.

According to the method similar to that described in example 76 except using N-ethylbenzylamine in direct response litrovaya, get a named connection in the form of a white powder (52%), so pl. 184-185oC.

Elemental analysis for C29H32N2O3S0,2H2O:

Calculated C 71,28, H 6,60, N 5,73

Found, C 70,90 H 6,66, N 5,79

1H NMR (D6-DMCO): 9,02 (d, J 7,9 H), of 2.51 (s, 2H), 2,04 (s, 4H), of 1.02 (t, J 7.0 Hz, 3H), MS (Cl, CH4) m/z 490 (31), 489 (M+ 1,100), 471 (11).

Example 84. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N - methylsulfonyl-5-methoxyphenyl)piperidine-4-ol.

According to the method similar to that described in example 76 except using N-methyl-4-methoxybenzenesulfonamide in direct response litrovaya and 1-(2-chloro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidone (described in example 1m), get a named connection in the form of a white powder (29%), so pl. 179-182oC.

Elemental analysis for C29H31ClN2O4S:

Calculated C 64,61, H 5,79, N 5,19

Found, C 64,30, H 5,90, N 5,18

1H NMR (D6-DMCO): 7,94 (d, J 8,8 Hz, 1H), 7,26 (m, 4H), 7,05 (s, 1H), 6,97 (m, 4H), for 6.81 (K, J 5.2 Hz, 1H), the 5.45 (s, 1H), 4,30 (s, 1H), 3,82 (s, 3H), 3,41 (s, 2H), 2,78 (m, 4H), 2.50 each (s, 2H), 2,42 (d, J 5.2 Hz, 3H), 2,04 (s, 4H), MS (Cl, CH4) m/z 542 (13), 541 (43), 540 (38), 539 (M + 1,100)

Example 85. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-N, N - dimethylsulphamoyl-5-methoxyphenyl)piperidine-4-ol.

According to the method similar to that described in example 76 except using N, N-dimethyl-4-methoxybenzenesulfonamide in direct response litrovaya and 1-(2-chloro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidone (described in example 1m), get a named connection in the form of white parochka, C 65,15, H 6,01, N 5,06

Found, C 64,86, H 5,98, N 4,80

1H NMR (D6-DMCO): of 7.69 (d, J a 8.9 Hz, 1H), 7.23 percent (m, 5H), 6,97 (m, 4H), of 5.05 (s, 1H), 4,34 (s, 1H), 3,82 (s, 3H), 3,39 (W s, 2H), 2,79 (W m, 10H), 2,50 (s, 2H), 2.13 in (m, 2H), of 1.88 (m, 2H), MS (Cl, CH4) m/z 556 (10), 555 (34), 554 (31), 553 (M + 1,100), 535 (13)

Example 86. 1-((9S, 10S)-2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- 4-(2-N-methylsulfonyl-5-methoxyphenyl)piperidine-4-ol.

According to the method similar to that described in example 76 except using N-methyl-4-methoxybenzenesulfonamide in direct response litrovaya and 1-((9S, 10S)-2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidone, get a named connection in the form of a white powder (44%), so pl. 140-142oC.

Elemental analysis for C29H31ClN2O4S:

Calculated C 64,18 H of 5.83, N 5,16

Found, C 64,14, H 5,94, N 4,19

1H NMR (D6-DMCO): 7,94 (d, J 8,8 Hz, 1H), 7,25 (m, 4H), 7,05 (d, J 2.5 Hz, 1H), 6,98(m, 4H), 6,80 (K, J 5.1 Hz, 1H), 5,43 (s, 1H), 4,34 (s, 1H), 3,81 (s, 3H), 3,40 (s, 2H), 2,78 (m, 4H), 2.50 each (s, 2H), 2,42 (d, J 5.2 Hz, 3H), 2,04 (s, 4H), MS (Cl, CH4) m/z 542 (14), 541 (38), 540 (26), 539 (M + 1,100)

Example 87. 1-(2,7-Dichloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4- (3-pyridyl)piperidine-4-ol.

To a solution (10 ml) in tetrahydrofuran 1-(2,7-dichloro-9,10 - dihydro-9,10-ethanoanthracene-9-ylcarbonyl)-4-(3-pyridyl)piperidine-4-ol (280 mg, 0,602 mmol) under nitrogen add ing the mixture is heated at the boiling temperature for 24 hours After this time a solution of methanol and 3n. HCl (25 ml, 1:1 by volume) is added and boiling is continued an additional 20 minutes, the Reaction mixture was cooled to room temperature and alkalinized to 2.5 N. NaOH (20 ml). The aqueous phase is extracted with ethyl acetate (3 x 20 ml). The combined organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated to oil. The reaction product was then purified on a flash chromatography on silica gel (30 ml, eluent: ethyl acetate) to give 190 mg (70%) not quite white foam. The TLC analysis (Rf0,19, ethyl acetate).

1H NMR (CDCl3, 300 MHz) 8,76 (d, J 2.1 Hz, 1H), and 8.50 (DD, J of 1.5 to 4.7 Hz, 1H), 7,80 (dt, J of 2.0, 8.0 Hz, 1H), 7,27 (m, 1H), 7,16 (m, 4H), 6,92 (DD, J of 1.8, 7.8 Hz, 2H), 4,25 (W s, 1H), 3,42 (W s, 2H), 2,90 (m, 2H), was 2.76 (m, 2H), 2,63 (W s, 2H), 2.13 in (m, 2H), 1,80 (m, 2H), MS (Cl, CH4) m/z 451 (M+ 1,100), 453 (60), 479 (M+ 29,16), 481 (11), 433 (17), 435 (11).

The free base is dissolved in methanol/methylene chloride, acidified with ethereal HCl and the precipitated clorhidrato Sol essential dilution. Chlorhydrate salt is filtered off, washed with fresh ether and dried in vacuum (60oC, 10 PA, 18 h) to give white solid, so pl. 252-254oC (decomp.)

Analysis of C26H25Cl2N2OH2O:

Calculated C 55,37, H 5,38, N equal to 4.97

Found on: C 55,26, H 4,96, N 4,70
the Nile)-4-(3-pyridyl)piperidine-4-ol.

To a solution (10 ml) in toluene 2,7-dichloro-9,10-dihydro-9,10-methane-9-intracisternally acid (described in example 35e) (0,363 g, 1,19 mmol) is added thionyl chloride (0,087 ml, 1.2 mmol, 1 EQ). The reaction mixture is heated under reflux to boiling for 2 h, controlling the emission using barbaterom with mineral oil. The toluene is removed, replace with fresh toluene and evaporated to dryness. This procedure is repeated twice. The residue is dissolved in tetrahydrofuran (10 ml). To this solution is added triethylamine (0.17 ml, 1.2 mmol, 1 EQ) and 4-hydroxy-4-(3-pyridyl)piperidine (0,212 g, 1 2 mmol, 1 EQ). Solution in tetrahydrofuran is heated to boiling under reflux for 18 h, cooled to room temperature and poured into ethyl acetate (200 ml). The organic phase is washed with saturated sodium bicarbonate (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to oil. The reaction product was then purified using flash chromatography on silica gel (50 ml, eluent: 10% methanol in methylene chloride with up to 20% methanol in methylene chloride) to give 0.29 grams (52%) of white solids. The TLC analysis (Rf0,23, 10% methanol in diethyl ether). MS (Cl, CH4) m/z 465 (M+ 1,100), 447 (16), 97 (28), 779 (64)

Source pyridineacetonitrile (25,0 g, 0,247 mol) in methylene chloride (2000 ml) is cooled to 0oC under nitrogen with stirring over the top. The triethylamine (86,1 ml, 0,618 mol, 2.5 EQ) is added, and then benzylchloride (35,3 ml, 0,247 mol, 1.0 EQ). The reaction mixture is heated at room temperature for 1 h and maintain at this temperature for 5 hours a Significant amount of amine hydrochloride precipitates in the course of this technique. The organic phase is washed with 3n. HCl (3 x 250 ml), dried over anhydrous sodium sulfate and filtered. The solvent is removed in vacuum, obtaining of 47.0 g (81%) of the titled compound as oil. The product does not require any additional purification to Swern oxidation. The TLC analysis (Rf0,17, 50% ethyl acetate in hexane). MS (Cl, CH4) m/z 236 (M+ 1,42), 218 (4), 192 (10), 181 (9), 174 (15), 91 (100)

c. 1 Carbobenzoxy-4-piperidone.

To a cooled solution (-78oC) oxalicacid (fresh, 18.2 ml, 0.21 mol, 1.5 EQ) in methylene chloride (1400 ml) under nitrogen add fresh dimethyl sulfoxide (up 29.6 ml, 0.42 mol, 3.0 EQ). The solution is stirred for 10 minutes, then add via cannula a solution (150 ml) in methylene chloride 1-carbobenzoxy-4-ol (described in example 87b) (32.76ˆ g, 0,139 mmol). The solution is maintained at -78oC for 30 minutes T the 5 o'clock At room temperature the reaction mixture was quenched with 3n. HCl (400 ml). The organic phase is washed with 3n. HCl (2 x 400 ml), 2,5 N. NaOH (2 x 400 ml) and saturated salt solution (1 x 400 ml). Methylenchloride phase is dried over anhydrous magnesium sulfate, filtered through 100 g of silica gel and concentrated to oil. The result of 23.8 g (73%) of the named compound that does not require any additional purification.

1H NMR (CDCl3, 300 MHz) 7,34 (m, 5H), is 5.18 (s, 2H), 3,80 (t, J 6.2 Hz, 4H), 2,46 (sh. t, 4H), MS (Cl, CH4) m/z 234 (M + 1,39), 262 (M + 29,10), 91 (100)

d. 1 Carbobenzoxy-4-(3-pyridyl)piperidine-4-ol.

To a cooled solution (-78oC) n-utility (2.0 M in hexane, 12.9 ml, 28.3 mmol, 1.2 EQ) in tetrahydrofuran (200 ml) under nitrogen was added 3-bromopyridin of 2.27 ml, 23.6 mmol, 1.1 EQ). The solution becomes dark green color when added pyridine. The reaction mixture is stirred at this temperature for 1 h and at this time add 1 carbobenzoxy-4-piperidone (described in example 87c) (5,00 g, with 21.4 mmol) in solution (20 ml) in tetrahydrofuran). The cooling bath removed and the reaction mixture is heated to room temperature, stirring at this temperature for 18 hours, the Reaction mixture was quenched by addition of water (125 ml) and the aqueous phase extracted with et will centerour to oil. The reaction product was then purified using flash chromatography on silica gel (300 ml, eluent: ethyl acetate), obtaining of 5.00 g (75%) of the titled compound as oil.

The TLC analysis (Rf0,10, ethyl acetate).

MS (Cl, CH4) m/z 313 (M + 1,100), 341 (M + 29,15), 295 (15)

e. 4-(3-Pyridyl)piperidin-4-ol.

To a solution of 1-carbobenzoxy-4-(3-pyridyl)piperidine-4-ol (described in example 87d) (3,17 g of 10.3 mmol) in ethanol (100 ml) is added 10% palladium on carbon (2.0 g). Then add cyclohexane (50 ml) in a large excess. The reaction mixture is heated to boiling under reflux under nitrogen for 2 hours, the Suspension is cooled, filtered and the catalyst washed with fresh ethanol. The filtrate was concentrated in vacuo, receiving 1.70 g (94%) not quite white solid, which does not require any additional purification.

1H NMR (D6-DMCO, 300 MHz) 8,68 (d, J 2.0 Hz, 1H), 8,42 (DD, J 1.5 and 4.6 Hz, 1H), 7,83 (DDD, J of 1.9 and 2.1, 4.0 Hz, 1H), 7,35 (DD, J of 4.8, 8.0 Hz, 1H), 2,97 (DDD, J 2,3, and 12.2 Hz, 2H), 2,78 (m, 2H), to 1.86 (DDD, J 4,5, 12.9 Hz, 2H), and 1.56 (m, 2H), of 2.50 (m, 1H), MS (Cl, CH4) m/z 179 (M + 1,100), 207 (M+ 29,16), 161 (39).

Examples 88, 90 and 91 illustrate a specific sequence of reactions to obtain the compounds of formula I, in which values corresponding to X and Y are halogen, hydrotalcite derivatives.

Example 88. 1-(2-Chloro-7-nitro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- 4-(3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 87, except that originate from 1-(2-chloro-7-nitro-9,10 - dihydro-9,10-ethanoanthracene-9-ylcarbonyl)-4-(3-pyridyl)piperidine-4-ol, get a named connection with the release of 84% in the form of a white solid substance, so pl. 207-210oC (decomp.), free base:

1H NMR (D6-DMCO, 300 MHz) 8,68 (d, J 2.1 Hz, 1H), to 8.41 (d, J 3.5 Hz, 1H), 8,03 (d, J 1.7 Hz, 1H), 7,92 (DD, J of 2.0, 8.0 Hz, 1H), to 7.84 (DD, J of 1.6 to 3.8 Hz, 1H), 7,56 (d, J 8.0 Hz, 1H), 7,35 (m, 3H), 7,02 (DD, J of 1.7, 7.8 Hz, 1H), 5,07 (W s, 1H), 4,56 (W s, 1H), 3,51 (d, J 3.6 Hz, 2H), 2,80 (m, 4H), 2,64 (W s, 2H),1,93 (m, 2H), 1.61 of (m, 2H) MS (Cl, CH4) m/z 462 (M+ 1,100), 464 (38), 490 (M+ 29,24), 444 (14), 432 (13) chlorhydrate salt:< / BR>
Analysis for C26H24ClN3O30.5 H2O:

Calculated C 57,42, H 5,00, N 7,72

Found, C 57,71, H 5,70, N 6,50

The original amide was obtained as follows.

a. 2-Chloro-7-nitro-9,10-dihydro-9,10-methane-9-astratenkova acid.

Using a technique similar to the one described in example 35e, except that originate from methyl 2-chloro-7-nitro-9,10 - methane-9-astrazenecanexium (described in example 35b), get a named connection with a quantitative yield. Additional research is n-9-ylcarbonyl)-4-(3-pyridyl)piperidine-4-ol.

Using a technique similar to the one described in example 87a, except that originate from 2-chloro-7-nitro-9,10 - dihydro-9,10-methane-9-intracisternally acid (described in example 89a), get a named connection with the release of 59% in the form of not-quite-white foam. The TLC analysis (Rf0,20, ethyl acetate)

MS (Cl, CH4) m/z 476 (M+ 1,100), 478 (33), 504 (M+ 29,21), 446 (25), 458 (30)

Example 89. 1-(2-Amino-7-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- 4-(3-pyridine)piperidine-4-ol.

Using a technique similar to that described in example 87, except that originate from 1-(2-amino-7-chloro-9,10 - dihydro-9,10-ethanoanthracene-9-ylcarbonyl)-4-(3-pyridyl)piperidine-4 - ol, get a named connection with the release of 88% as not quite white solid substance, so pl. 275-278oC(decomp. ) free base:

1H NMR (CDCl3, 300 MHz) 8,76 (d, J 2.1 Hz, 1H), and 8.50 (DD, J of 1.6, 4.8 Hz, 1H), 7,80 (dt, J of 1.9, 8.1 Hz, 1H), 7,27 (m, 1H), 7,11 (m, 2H), 7,00 (d, J 7.7 Hz, 1H), to 6.88 (DD, J of 1.8, 7.7 Hz, 1H), 6,60 (d, J 2.1 Hz, 1H), 6,24 (DD, J of 2.0 and 7.6 Hz, 1H), 4,16 (W s, 1H), 3,38 (W s, 2H), 2,90 (m, 2H), 2,70 (m, 2H), has 2.56 (m, 2H), 2,10 (m, 2H), 1,76 (m, 2H), MS (Cl, CH4) m/z 432 (M+ 1,53) 434 (21), 460 (M+ 29,1), 414 (7), 97 (31), 79 (100) chlorhydrate salt:< / BR>
Analysis for C26H26ClN3O3HCl0,5H2O:

Calculated C 56,74, H 5,49, N 7,63

Found, C 57,02, H 5,95, N 7,10

The starting amine get the trail is Zuya technique similar to that described in example 35e, except that originate from methyl 2-amino-7-chloro-9,10-dihydro-9,10-methane-9-astrazenecanexium (described in example 35e), get a named connection from 51% yield as a white solid. The TLC analysis (Rf0,23, 20% ethyl acetate in hexane). MS (Cl, CH4) m/z 300 (M+ 1,100), 302 (37), 328 (M+ 29,17), 264 (36), 227 (91), 201 (55)

Example 90. 1-(2-Chloro-7-hydroxy-9,10-dihydro-9,10-ethanoanthracene-9-yl - methyl)-4-(3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 87, except that on the basis of 1-(2-chloro-7-hydroxy-9,10 - dihydro-9,10-ethanoanthracene-9-ylcarbonyl)-4-(3-pyridyl)piperidine-4-ol, get a named connection from 55% yield as a white solid, so pl. 224-228oC (decomp. ) free base:

1H NMR (D6-DMCO, 300 MHz) to 9.15 (s, 1H), 8,69 (sh.s, 1H), to 8.41 (d, J 4.4 Hz, 1H), 7,83 (d, J 8.0 Hz, 1H), 7,31 (DD, J of 4.6, 7.9 Hz, 1H), 7,25 (m, 2H), 7,02 (d, J 7.8 Hz, 1H), 6,94 (DD, J of 1.6 and 7.6 Hz, 1H), 6,70 (d, J 1.8 Hz, 1H), 6,27 (DD, J of 1.8, 7.7 Hz, 1H), of 5.05 (sh.with 1H), 4,22 (sh.s, 1H), 2,75 (m, 2H), 2,59 (m, 1H), 2,48 (m, 3H), of 1.92 (m, 2H), 1.61 of (m, 2H), MS (Cl, CH4) m/z 433 (M+ 1,100), 435 (36), 461 (M + 29,22), 415 (16) hydrochloride: analysis dihydrochloride is not in accordance with the calculated 1H NMR and MS completely appropriate.

The original amide was obtained as follows.

b) 2-Chloro-7-hydroxy-9,10-dihydro-9,10-methane-9-astratenkova acid

Using a technique similar to the one described in example 35e, except that originate from methyl 2-chloro-7-hydroxy,10-dihydro-9,10-methane-9-astrazenecanexium (described in example 90a), get a named connection from 87% yield as a white solid. The TLC analysis (Rf0,15, 20% ethyl acetate in hexane), additional research is necessary to binding assays.

c. 1-(2-chloro-7-hydroxy-9,10-dihydro-9,10-ethanoanthracene-9 - ylcarbonyl)-4-(3-pyridyl)piperidine-4-ol

Using a technique similar to the one described in example 87a, except that originate from 2-chloro-7-hydroxy-9,10 - dihydro-9,10-methane-9-intracisternally acid (described in example 90b), get a named connection with the release of 37% in the form of not-quite-white rates. The TLC analysis(Rf0,18, 5% methanol in ether). MS (Cl, CH4) m/z 447 (M+ 1,100), 449 (38), 475 (M + 29,25), 429 (35)

Example 91. 1-(2-Chloro-7-methoxy-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- 4-(3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 87, except that based on the connection with 63% yield as a white solid, so pl. 249-253oC (decomp.). TLC analysis of the free base (Rf0,18, ethyl acetate). Free base:

1H NMR (CDCl3, 300 MHz) 8,75, (W.s, 1H), 8,48 (d, J 2.4 Hz, 1H), 7,81 (d, J 8.1 Hz, 1H), 7,27 (m, 1H), 7,14 (m, 3H), 6.89 in (DD, J of 1.8, 7.8 Hz, 1H), for 6.81 (d, J 2.3 Hz, 1H), gold 6.43 (DD, J 2,3, 7.9 Hz, 1H), 4,21 (sh.s, 1H), 3,74 (s, 3H), 3,41 (s, 2H), 2,89 (m, 2H), 2,74 (m, 2H), 2,60 (sh.s, 2H), 2,12 (m, 2H), of 1.75 (m, 2H), MS (Cl, CH4) m/z 447 (M + 1,100), 475 (M+ 29,22), 429 (23), 191 (9) chlorhydrate salt:

Analysis for C27H27ClN2O20.5 H2O:

Calculated C 61,31, H 5,72, N OF 5.29

Found, C 60,91, H 5,90, N 4,92

The original amide was obtained as follows.

a. Methyl 2-chloro-7-methoxy-9,10-dihydro-9,10-methane-9-astrazenecanexium.

To the ethanol solution of methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methane-9-astrazenecanexium (described in example 90a) add potassium carbonate and methyl iodide. The suspension is heated to boiling, cooled and diluted with diethyl ether, filtered to remove salts, and concentrated to a solid. Formed a named connection with 90% yield. TLC analysis (Rf0,40, 20% ethyl acetate in hexane). MS (Cl, CH4) m/z 315 (M + 1,100), 343 (M+ 23,13), 301 (38), 237 (9), 279 (14), 265 (6), 255 (42)

b. 2-Chloro-7-methoxy-9,10-dihydro-9,10-methane-9-astratenkova acid

Using a technique similar to opinnoista (described in example 91a), get a named connection with a quantitative yield. Additional research is necessary to binding assays.

c. 1-(2-Chloro-7-methoxy-9,10-dihydro-9,10-ethanoanthracene-9 - ylcarbonyl)-4-(3-pyridyl)piperidine-4-ol and 1-(2,6-dichloro-7-methoxy-9,10-dihydro-9,10-ethanoanthracene-9 - ylcarbonyl)-4-(3-pyridin)piperidine-4-ol.

To a solution (10 ml) in toluene 2-chloro-7-methoxy-9,10-dihydro-9,10-methane-9-intracisternally acid (described in example 91b) (1,15 g is 3.82 mmol) is added thionyl chloride (0,56 ml, 7.6 mmol, 2 EQ). The reaction mixture is heated to boiling under reflux for 1 h, monitoring the emission using barbaterom with mineral oil. The toluene is removed, replace with fresh toluene and evaporated to dryness. This procedure is repeated twice. The residue is dissolved in tetrahydrofuran (10 ml). To this solution add triethylamine (of 0.53 ml, 3.8 mmol, 1 EQ) and 4-hydroxy-4-(3-pyridyl)piperidine (described in example 87e) (0.75 g, 4.2 mmol, 1.1 EQ). Tertrahydrofuran ring solution is heated to boiling under reflux for 18 h, cooled to room temperature and poured into diethyl ether (100 ml). The organic phase is washed with a 2.5 N. NaOH (3 x 25 ml) and saturated brine solution (25 ml), su is matography on silica gel (60 ml, eluent: ethyl acetate), obtaining of 1.00 g of white solid. TLC analysis (Rf0,20, ethyl acetate). The solid consists of an inseparable mixture of the desired amide (23% of the total) and 2,6-dichloro-7-methoxymethane amide (36% overall). Additional studies of the mixture is taken as concentrated products share flash chromatography.

Example 92. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-ethyl - sulfinil-3-pyridyl)piperidine-4-ol

To a cooled solution (0oC) 1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-ethylthio-3 - pyridyl)piperidin-ol (described in example 60) (0,500 g, 1.13 mmol) in a mixture of acetic acid/water (ml/5ml) is added an aqueous solution (8 ml of water) potassium permanganate (0,179 g, 1.13 mmol, 1.0 EQ per manganese) dropwise. The reaction mixture was monitored by TLC or jhud (reversed phase methanol/water, C18 column). Sulfon begins to form after the addition of 6 ml of oxidizing solution. The oxidation is completed almost immediately. The reaction is quenched with saturated aqueous sodium bisulfite (50 ml) and alkalinized water sodium hydroxide. The aqueous phase is extracted with ethyl acetate (3 x 100 ml). The combined organic extracts dried over anhydrous sodium sulfate, Phi is tracecut), getting 260 mg (50%) of the named compound as a white solid. Non-polar components chromatography again treated fresh silica gel (60 ml, eluent: 80% diethyl ether/hexane) to 170 mg (37%) of the corresponding sulfone (example 98). TLC analysis (sulfoxide: Rf0,24, sulfon Rf0,73, eluent: 15% methanol/ethyl acetate). Both the free base is dissolved in methylene chloride, acidified with ethereal HCl and diluted with ether. Received chlorhydrate salt is filtered off, washed with fresh ether and dried in vacuo (55oC, 10 PA, 18 h) to give white solids, so pl. sulfoxide 214-216oC (decomp), sulfone 225-228oC (decomp), chlorhydrate salt:

1H NMR (D6-DMCO, 300 MHz) 10,19 (W s, 1H), 8,69 (d, J 4.4 Hz, 1H), 7,63 (sh.d, J 7.9 Hz, 1H), EUR 7.57 (m, 1H), 7,37 (m, 4H), 7,00 (m, 4H), of 4.44 (m, 3H), to 3.58 (m, 4H), 3,11 (m, 1H), 2,86 (m, 1H), was 2.76 (sh.s, 2H), 2,30 (sh.m, 2H), 1,97 (sh. m, 2H), of 1.18 (t, J 7.5 Hz, 3H), MS (Cl, CH4) m/z 459 (M + 1,100), 487 (M+ 29,16), 441 (21), 413 (12)

Analysis for C28H30N2O2S2HCl0,75H2O:

Calculated C 61,70, H is 6.19, N 5,14

Found, C 61,48, H 6,07, N 5,07

Example 93. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-ethyl - sulfonyl-3-pyridyl)piperidine-4-ol.

Using the procedure described in example 97, allocate a named connection J 7.2 Hz, 1H), 7,72 (doctor of medicine from.d, J 4,5, 8,1 Hz, 1H), 7,35 (m, 4H), of 6.99 (m, 4H), 4,43 (m, 3H), 3,61 (K, J 7.2 Hz, 2H), 3,45-3,90 (m, 6H), is 2.74 (m, 2H), and 2.26 (m, 2H), 1,21 (t, J 7,3 Hz, 3H), MS (Cl, CH4) m/z 475 (M + 1,100), 503 (M + 29,3), 79 (83)

Analysis for C28H30N2O3S1,75HCl:

Calculated C 62,46, H 5,94, N 5,20

Found, C 62,30, H of 5.75, N 5,02

Example 94. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2 - fluoro-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 58, except that originate from 1-(2-chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 1m), get a named connection with the release of 64% in the form of a white solid substance, so pl. 199-203oC (decomp.), hydrochloride:

1H NMR (CDCl3, 300 MHz) to 8.12 (m, 1H), 7,89 (m, 1H), 7,15-7,30 (m, 5H), of 6.96 (m, 4H), 4,36 (s, 1H), 4,16 (sh.s, 2H), 3,50-3,70 (sh.m, 4H), 3.04 from (sh.s, 3H), 2,17 (sh.m, 2H), MS (Cl, CH4) m/z 435 (M + 1,100), 463 (M+ 29,25 ), 417 (22), 354 (10)

Analysis for C26H24ClFN2O1,5HCl:

Calculated C 63,78, H a 5.25, N 5,72

Found, C 63,79, H 5,38, N 5,58

Example 95. 1-(2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2 - ethylthio-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 60, except that originate from 1-(2-chloro-9,10-dihydro-9,10 - ethanoanthracene-9-ylmethyl)-4-(2-fluoro-3-pyridyl)piperidine-4-ol (OPI the/SUP>C (decomp), hydrochloride:

1H NMR (CDCl3, 300 MHz) 8,40 (sh.s, 1H), 8,02 (sh.s, 1H), 6,9-7,35 (m, 8H), to 4.38 (s, 1H), 4,14 (sh.s, 2H) 3.45 points to 3.7 (m, 4H), 3,35 (sh.s, 2H), 3,05 (sh. s, 4H), of 2.56 (m, 2H), 1,32 (sh.t, 3H) MS (Cl, CH4) m/z 477 (M+ 1,100), 479 (40), 505 (M + 29,20), 459 (17)

Analysis for C28H29ClN2OS2,5HCl2H2O

Calculated C 55,66, H of 5.92, N WITH 4.64

Found, C 55,58, 5,30 H, N 4,60

Example 96. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-(1,1- dimethylethyl)-3-pyridyl)piperidine-4-ol

Using a technique similar to that described in example 60, except that originate from t-butylthio, get a named connection with the release of 70% in the form of a citrate salt, so pl. 135-140oC (decomp.), citrate:

1H NMR (d6-DMSO 300 MHz) to 8.41 (doctor of medicine from.d, J 1.6, the 4,7 Hz, 1H), 7,68 (doctor of medicine from.d, J a 1.6, 8.0 Hz, 1H), 7,37 (m, 4H), 7,14 (doctor of medicine from.d, J a 4.7, 7.9 Hz, 1H) 7,05 (m, 4H) and 4.65 (s, 1H), 4,48 (s, 4H), of 3.60 (m, 5H), is 2.74 (m, 6H), was 2.34 (m, 4H), and 1.56 (s, 9H), MC (Cl, CH4) 471 (M+ 1,62), 415 (8), 193 (24), 175 (38), 147 (43), 113 (100)

Analysis for C30H34N2OS C6H8O7H2O

Calculated 63,50 C, H 6,51, N 4,11

Found, C, 63,24, H 6,44, N 3,86

Example 97. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-methylthio-3 - pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 60, except that on the basis of matertial, get a named connection from 63% yield in B92 (sh.with. 1H), and 7.1 to 7.4 (m, 5H), 6,98 (m, 4H), 4,39 (s, 1H), 4,17 (sh.s, 2H), 3,5-of 3.75 (m, 4H), 2,9-3,1 (m, 4H), 2,70 (s, 3H), 2,48 (m, 2H), MC (Cl, CH4) m/z 429 (M + 1,100), 457 (M+ 29,29), 411(48).

Analysis for C27H28N2OS2HCl0,2H2O:

Calculated C 64,20, H 6,06, N, 5,54

Found, C 64,20, H 6,04, N 5,40

Example 98. 1-(9,10-Dihydro-9,10-ethanoanthracene-9-ylmethyl)-4-(2-(2-N,N - dimethylaminoethyl)-3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 60, except that on the basis of 2-dimethylaminoethanol, get a named connection from 58% yield as a white chlorhydrate salt, so pl. 215-220oC (decomp.), hydrochloride:

1H NMR (d6-DMCO, 300 MHz) 8,43 (doctor of medicine from.d, J 1,4, 48 Hz, 1H), 7,65 (sh.d, J 6.5 Hz, 1H), 7,38 (m, 4H), 7,21 (doctor of medicine from.d, J 4,7, and 7.8 Hz, 1H), 7,02 (m, 4H), 4,50 (m, 2H), 3,30-3,74 (m, 9H), is 2.88 (s, 4H), was 2.76 (s, 1H), 2,31 (m, 2H), MC (Cl, CH4) m/z 486 (M + 1,100), 514 (M+ 29,11), 468 (10), 413 (7)

Analysis for C30H35N3OS3HCl1,25H2O:

Calculated C 58,34, H is 6.61, N 6,80

Found, C 58,19, H 6,30, N 6,54

Example 99. 4-(2-(4-Acetamidophenyl)-3-pyridyl)-1-(9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)piperidine-4-ol.

Using a technique similar to that described in example 60, except that extend from 4-acetamidophenol, get a named connection with the release of 26% in the form of white chlorhydrate salt, so pl. 190-195o,26 (doctor of medicine from.d, J of 4.9, 7.9 Hz, 1H), 7,02 (m, 4H), 4,51 (m, 3H), of 3.69 (m, 5H), 2,77 (sh.s, 2H), 2,35 of 2.6 (m, 4H), of 2.09 (s, 3H), MC (Cl, CH4) m/z 548 (M + 1,100), 576 (M+ 29,13), 530 (13), 239 (6)

Analysis for C34H33N302S2HCl1,5H2O

Calculated C 63,05, H 5,91, N OF 6.49

Found, C 63,10, H 5,59, N 6,37

Example 100. 1-((9S,10S)-2-Chloro-9,10-dihydro-9,10-ethanoanthracene-9-ylmethyl)- 4-(1,1-dimethylethyl)piperidine-4-ol.

Using a technique similar to that described in example 49, except that originate from 1-((9S,10S)-2-chloro-9,10-dihydro - 9,10-ethanoanthracene-9-ylmethyl)-4-piperidine (described in example 1m, obtaining optically active acid, described in example 1n) get a named connection with the release of 29% in the form of white chlorhydrate salt, so pl. 291-293oC, hydrochloride:

1H NMR (CDCl3, 300 MHz) of the 6.9 and 7.3 (m, 7H), 4,35 (s, 1H), 4,05 (sh.s, 2H), 3,39 (m, 4H), 3,07 (sh.s, 2H), 2,71 (m, 2H), 1,71 (m, 2H), 1,42 (s, 1H), and 0.98 (s, 9H), MC (Cl, CH4) m/z 396 (M+ 1,100), 398 (43), 424 (M+ 29,24), 380 (26), 378 (54), 360 (10), 170 (11)

Analysis for C25H30ClNOHCl0,3H2O:

Calculated C 68,58, H 7,27, N 3,20

Found, C 68,52, H 7,02, N 3,14

Example 101. 1-(9,10-Dihydro-9,10-methane-2-mitoxantrone-9-ylmethyl)-4- (3-pyridyl)piperidine-4-ol.

Using a technique similar to that described in example 87, except that originate from 1-(9,10-dihydro-9,10-methane-2 - mitoxantrone-9-icarbon Tatnai salt, T. PP. 243-246oC (decomp.), hydrochloride:

1H NMR (CDCl3, 300 MHz) 9,37 (m, 1H), 8,95 (m, 1H), at 8.60 (m, 1H), 7,97 (m, 1H), 6,85 of 7.3 (m, 6H), of 6.45 (d, J 7,6 Hz, 1H), 4,34 (s, 1H), 3,9-4,3 (m, 4H), to 3.58 (m, 2H), 3.33 and (m, 2H), 3,01 (m, 2H), remnant of the spectrum of resonances is hidden in the base line, quickly reintensification MC (Cl, CH4) m/z 413 (M + 1,100), 441 (M + 29,16), 395 (28)

Analysis for C27H28N2O22,4 H2O1,8H2O

Calculated C 60,90, H to 6.43, N 5,26

Found, C 60,84, H 5,95, N 5,15

The original amide was obtained as follows.

a. 9,10-Dihydro-9,10-methane-2-methoxyacetophenone acid.

Using a technique similar to that described in example 108, except that originate from 2-chloro-9,10-dihydro-9,10 - methane-7-mitoxantrone carboxylic acid (decommissioned in example 91b), get a named connection with the release of 65% in the form of a white solid. Product oharakterizovat only using mass spectrometry. MC (Cl, CH4) m/z 267 (M + 1,100), 284 (M+ 29,50), 249 (9), 221 (11).

b. 1-(9,10-Dihydro-9,10-methane-2-mitoxantrone-9-ylcarbonyl)- 4-(3-pyridyl)piperidine-4-ol.

Using a technique similar to the one described in example 87a, except that originate from 9,10-dihydro-9,10-methane-2-methoxyacetophenone acid (described in example 101a), get nazvanie Hz, 1H), 7,81 (m, 1H), 6,95 to 7.4 (m, 7H), 6,46 (m, 1H), 4,87 (m, 1H), 4,25 (s, 1H), 3,90 (m, 1H), 3,37 (m, 2H), 2,87 (m, 2H), remnant of the spectrum of resonances is hidden in the base line, quickly unidentifiable MC (Cl, CH4) m/z 427 (M + 1,100), 455 (M + 29,22), 409 (17)< / BR>
Example 102. The following illustrative of representative pharmaceutical dosage forms containing the compound of formula I, as illustrated in any of the earlier examples (denoted below as "compound X"), for therapeutic or prophylactic use for a person:

(a) Tablet, mg:

Connection X 50,0

Mannitol, USP 223,75

Crosscarmellose sodium 6,0

Corn starch 15,0

The hypromellose (HPMC) OF 2.25

Magnesium stearate 3,0

(b) Capsule

Compound X 10.0

Mannitol 488,5

Crosscarmellose sodium 15,0

Magnesium stearate 1.5 to

The above formulations may be obtained using conventional techniques well known in the pharmaceutical art. Tablets can be coated intersolubility shell in the usual ways, for example by ensuring coverage of phthalate acetylcellulose.

Structural formulas and schemes I-III shown in Fig. 1-4.1

1. Derivatives metanarrative General formula I

< / BR>
and the>
-alkoxy;

R1represents: (A) C1C6-alkyl; (C) phenyl, which optionally contains 1 or 2 substituent, independently selected from the group consisting of C1C6-alkoxy, halogen, phenyl, trifloromethyl; aminosulfonyl having the formula SO2NRaRbwhere Raand Bbindependently selected from hydrogen, 2-pyrrolidinyl and C1WITH3-alkyl, and RhRiN C1WITH3-alkyl, in which Rhand Riindependently selected from hydrogen and C1WITH3-alkyl; (C) phenyl-C1WITH3-alkyl, in which phenyl may contain 1 or 2 substituent mentioned for phenyl in (B); (D) five - or six-membered heteroaryl rings containing 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur, and their lansoprozole, which may contain 1 or 2 substituent selected from hydroxy, C1-C6-alkoxy, which may contain triptorelin group, C1- C6-alkoxycarbonyl, C1C6-hydroxyalkyl, benzyloxy, halogen, C1C3-alkylaminocarbonyl-C1- C3-alkyl, aminocarbonyl formula CONRcRdwhere Rcand Rdindependently selected from hydrogen and C1-C6and the 6
-alkyl, and RgS, where Rgselected from C1WITH6-alquilervillapeniscola and di-C1WITH3-alkylamino-C1C6- alkyl,

and (E) heteroaryl-C1- C3- alkyl, where heteroaryl defined in (D) and where heteroaryl may contain 1 to 2 substituent selected from the values heteroaryl substituents specified in (D).

2. Connection on p. 1, wherein X and Y independently are selected from hydrogen and halogen.

3. Connection on p. 2, wherein X and Y independently are selected from hydrogen and chlorine; R1selected from the group comprising: (I) tert-butyl, (II) 2 -, or 3-methoxyphenyl and phenyl, substituted at the 2 - or 3-position by aminosulfonyl formula RaRbNSO2where Raand Rbindependently selected from hydrogen, methyl and ethyl, (III) thienyl, furyl and 3-pyridyl optionally substituted in 2-position WITH1C6-alkoxy, C1C6-alkylthio or C1- C6-alkylsulfonyl.

4. Connection on p. 3, wherein selected from the group including: 1-(9S, 10S)-2-chloro-9,10-dihydro-9,10-metanarration-9-ylmethyl)-4-(1,1-dimethylethyl)piperidine 4-ol; 1-(9,10-dihydro-9,10-metanarration-9-ylmethyl)-4-(2 ethylsulfinyl-8 pyridyl)piperidine-4-ol; 1-(9,10-dihydro-9)-4-(2-methoxy-8-pyridyl)piperidine-4-ol.

5. Pharmaceutical composition having antidopaminergic activity, comprising an active compound and a pharmaceutically acceptable diluent or carrier, wherein as the active ingredient it contains an effective amount of the compounds of formula I or its pharmaceutically acceptable salt as defined in any of paragraphs. 1 4.

6. Derivatives metanarrative formula II

< / BR>
in which X and Y have the meanings given in paragraph 1

7. Derivatives metanarrative formula IIA

< / BR>
in which X, Y and R1have the meanings given in paragraph 1.

8. Derivatives metanarrative formula III

< / BR>
where X and Y have the meanings given in paragraph 1, and G is chosen from chlorine, OH and H, provided that X and Y both cannot be hydrogen when G is hydrogen or OH.

9. The method of obtaining derivatives of metanarrative formula I or their pharmaceutically acceptable salts under item 1, characterized in that the derived metanarrative formula II

< / BR>
subjected to interaction with organolithium compound R1Li, where X, Y and R1have the meanings defined for compounds I on p. 1,

in an aprotic solvent, followed by treatment of the resulting seinarukana derived metanarrative formula I or their pharmaceutically acceptable salts under item 1, characterized in that the derived metanarrative formula IIa

< / BR>
where X, Y and R1have the meanings defined for compounds I on p. 1, is subjected to the interaction with a reducing agent followed by treatment of the resulting compound I, if necessary, acid to obtain a pharmaceutically acceptable salt.

11. The method of obtaining derivatives of metanarrative formula I or their pharmaceutically acceptable salts under item 1, characterized in that the derived metanarrative formula III

< / BR>
where X and Y have the meanings defined for compounds I on p. 1; G is hydrogen,

subjected to interaction with a piperidine of the formula

< / BR>
where R1has the meanings given for compounds I on p. 1,

in the presence of a reducing agent followed by treatment of the resulting compound I, if necessary, acid to obtain a pharmaceutically acceptable salt.

 

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