Derivatives of 2-piperidino-1-alkanol

 

(57) Abstract:

Usage: the quality of medicines in the treatment of seizures or degenerative diseases of the Central nervous system. The inventive product 2-(8-azabicyclo[3,2,1]Oct-8-yl)alkaline formula 1, where R is H or C1-C3Q - group,- S - or-CH-CH-; X Is H, halogen, OR1COOR1NH2CONH2or R1CONH where R1- N or C1-C3D is a group of formula 2, where Y-N, Y1-benzyl, unsubstituted or 4-halo or 4-methoxyphenyl phenylthio or 2-tianity, Y HE, Y1is phenyl or benzyl, or Y4Y1together form the group-CH-C6H5or a group of the formula 3 or formula 4, where Y2is hydrogen, Y3- benzyl or (O)nSC6H5where n = 0 or 2 if Y2HE, Y3group of formula 5, where m = 0,1,2,3 or 4 and R2-H - N methyl or halogen, or D is a group of formula 6, where l = 0 or 1, or D is a group of the formula 7. Reagent 1: 3-phenylmethylene-8-azabicyclo [3,2,1] octane. Reagent 2: 4-(triisopropylsilane)- -bromopropiophenone. Reagent 3: triethylamine. Reaction conditions: reflux. Reagent 4: sociallyengaged. Reaction conditions: in tetrahydrofuran at room temperature. 16 C.p. f-the economic and blocking stimulatory amino acid receptors) 2-piperidino-1-alcoholnye derivatives, defined by the formulas (I), (II) and (III) below; and pharmaceutically acceptable salts thereof; a method of using these compounds in the treatment of seizures or degenerative diseases of the Central nervous system (CNS), such as Alzheimer's disease, Huntington's disease and Parkinson's disease; and some intermediate derived for them.

Ifenprodil is racemic, the so-called dl-eritropoietinei having the relative stereochemical formula

---(A) served as a hypotensive agent, separating the utility with a number of close analogues; Carron et al, U.S. patent 3509164; Carron and others, Drug Res., so 21, S. 1992-1999 (1971). Recently it was shown that ifenprodil has anti-ischemic activity block, stimulating amino acid receptors; Gotti and others , J. Pharm. Exp Therap, volume 247, S. 1211-21 (1988); same, C. 1222-32 (1988). The goal largely achieved by the present invention, was the search for compounds with such a neuroprotective effect in a satisfactory extent, and at the same time having reduced or no significant hypotensive effect.

It is also known that some structurally related 1-phenyl-3-(4-aryl-4-acrocephalidae)-1-propanol awallpapers)-1-alkanols and alkenone possess analgesic prativaga - pertensive, psychotropic or anti-inflammatory activity.

The present invention is directed to compounds of the formula:

where R is H, C1-C6-alkyl, C2-C6alkenyl or2-C6-quinil; X is hydrogen. WITH1-C3-alkyl, halogen, OR1, OCOR1, CO2R1, SR1, OTHER1, NHCOR1, CONH2or CN;

R1is hydrogen or C1-C3-alkyl;

Q is sulfur or CH=CH;

Y and Y1are taken together to represent

=CH(CH2)

or

< / BR>
or Y and Y1taken separately, and

Y is hydrogen or HE, and Y1connection f-crystals

-(CH2)

or Y is hydrogen, and Y1represents a

< / BR>
n is 0, 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

Q1is independent of the values of Q, as defined above;

X1is independent of the values of X, defined above;

represents 0, S, SO or SO2;

the compounds of formula:

< / BR>
where D represents a radical of the formula

,or< / BR>
Y2and Y3taken together, represent

=CH(CH2)

< / BR>
Y2and Y3taken separately, and Y2HE is a and Y3represents a radical of the formula

-(CH
where Y4represents H; and

R, R1, Q, Q1X, X1and Z have the meanings defined above;

and pharmaceutically acceptable additive, acid salts of these compounds.

The expression "pharmaceutically acceptable acid salt additive or additive, acid salts" includes, but is not limited to such salts as the hydrochloride, bromohydrin, loggedout, nitrate, acid sulfate, monopotassium phosphate, mesilate, maleate and succinate. Also salts are obtained by reaction of the free base form of compound (I), (II) or (III) with an appropriate acid, usually with one molar equivalent, and solvent. Those salts which are not directly precipitate, usually identified with the concentration of the solvent and/or add herstories.

Preferred compounds of the present invention typically have a substituent R in the form of methyl and have 1S*, 2S* or Treo relative stereochemistry of 1 - and 2-positions propanolol chain, i.e.

< / BR>
In addition, regardless of the value of R, the preferred compounds of the present invention are compounds of formula (I) or (II) with Y and Y1or Y<>3Q1/X1; or the compounds of formula (III). The preferred value of Z is s

The present invention is also directed to pharmaceutical compositions and methods of treating mammals, especially humans, suffering from disorders of the Central nervous system, which include the purpose specified mammal a neuroprotective effective amount of the compounds of formula (I), (II) or (III). These compositions and methods are particularly valuable in the treatment of strokes, Alzheimer's disease, Parkinson's disease, Huntington's disease, and disorders related to the Central nervous system.

The present invention is additionally directed to intermediate compounds of the formula

where a and b are taken together and represent oxygen, forming together with the carbon to which they are attached, a carbonyl group, or a and b taken separately, and a is hydrogen and R is hydroxy;

X2is hydrogen, (C1-C3)alkyl, halogen, OR1, OR2, COOR1, OCOR1, SR1, SR2, OTHER1, NR1R3, NHOR1, CONH2or CN;

R1is hydrogen or (C1-C3)alkyl;

R2- conventional protective group g is/SUP> and Y6taken together, represent a group

=CH(CH2)

or

< / BR>
Y5and Y6taken separately, and

Y5represents hydrogen or HE, and Y6is

-(CH2)

Y5is hydrogen, and Y6represents a group

< / BR>
X3represents independently of the values of the radical X2defined above; provided that when a and b taken separately (at least one of X2and X3is a OR2, SR2or NR1R3;

Z represents 0, S, SO or SO2; or

R, Q, Q1n and m have the meanings defined above;

intermediate compounds of formula

B

where E represents a group

,or;

Y7and Y8taken together and represent

=CH(CH2or

or

Y7and Y8taken separately, and Y7HE is a and Y8a group of the formula

-(CH2)

Y10represents a group of the formula

-(CH2)

and a, b, R, R1, R2, R3, Q, Q1X2X3n and m have the meanings defined above, with the same condition on a and b;

and the intermediate connection of the Century

Those compounds of formula (I) or (IV) specified as endo, have a hydroxy-group or oxiranyl oxygen on the same side piperidino rings, and the ethylene bridge.

Obviously you can see that those compounds of formula (I) to (VI), which are 1-alkanols have asymmetric C-1 carbon atom, while those compounds in which R is other than hydrogen, have an asymmetric center at C-2 carbon alkanol. Similarly, in the compounds of formulas (VI) - (VI), which are 1-alkanoate, in which R is other than hydrogen, there are p-2 asymmetric carbon. Specialists in the field of organic chemistry should be obvious that such compounds can be divided into optical isomers, showing equal but opposite rotation in the plane of polarized light. For example, all of these compounds are potentially split by means of fractional crystallization of their diastereomeric additive salts with optically active acid, as illustrated by the examples below; however, alcohols are also potentially split using chromatography or fractional crystallization of esters obtained from the reaction of the activated formy some of these compounds are obtained by interaction of the corresponding optically active amine with the epoxide, as shown in the examples below. Thus, the present invention should not be construed as limited racemic forms of these compounds.

Compounds of the present invention having the formula (I), (II) and (III) defined below, is easy and usually retrieved using nucleophilic substitution, followed by reduction of the resulting ketone in ethanol, as described below.

Previous ketones are usually first get with IT, SH-other1groups in protected form, i.e. in the form-OR2, - SR2or NR1R3groups in the compounds of formula (IV), (V) and (VI) where a and b taken together as oxygen, forming a carbonyl group. Such protected ketones usually are formed by nucleophilic substitution of suitably substituted 2-halogen, 2-alkanesulfonyl - or 2-arylsulfonate-1-Alcanena, substituted accordingly piperidinium derived, for example,

+H

where X4is a typical chlorine, bromine, mesilate or tosyloxy. This reaction is carried out under conditions typical for nucleophilic substitutions at all. When the two reagents are roughly equivalent to the OTE, when one of them is more readily available, is generally preferred to use a quantity of one in excess in order to facilitate this biomolecular reactions to complete it in a shorter period of time. The reaction is usually carried out in the presence of at least 1 molar equivalent of base, the derivative of piperidine, if it is readily available, but more typically, the tertiary amine, which is at least comparable in strength to the base with the nucleophilic piperidine; and in a reaction inert solvent such as ethanol. If necessary, the reaction is catalyzed by the addition of one molar equivalent or more iodide salt (e.g., NaI, KI). Temperature is not critical, but usually it is slightly increased in order to facilitate the completion of the reaction in a shorter period of time, but not so high as to cause excessive decomposition. Usually satisfactory is the temperature of 50-120aboutWith, in case the temperature of the reflux distilled reaction mixture.

In the same sense as it is used in the previous paragraph and hereinafter, the expression "reaction inert solvent" refers to any solvent in this way, which adversely affects the yield of the desired product.

If necessary, the ketone intermediate products, with HE-, SH - or other1groups in protected form (OR2, SR2or other1R3), can be released at this stage using conventional methods. For example, when R2represents triisopropylsilyl or tert-butyldimethylsilyl, the protective group is conveniently removed by reaction with fluoride tetrabutylammonium (usually with 2 molar equivalents) in a reaction inert solvent such as tetrahydrofuran. When R2represents benzyl, or R3is benzyloxycarbonyl, the protective group is typically removed using conventional hydrogenolysis over a noble metal catalyst in a reaction inert solvent, for example, using 10% Pd/C as catalyst, preferably at low pressures (e.g., 1-10 ATM) and temperatures (for example, 20-75aboutC) and usually in a reaction inert solvent such as methanol.

Usually, excluding ketone intermediate compounds containing ester group or a protective group, such as benzyloxycarbonyl (which usually is of protective groups, ketone intermediate substance conveniently converted to corresponding alcohols using the normal recovery sociallyengaged, usually taken in excess (for example, 1 mol 1 mol), in a reaction inert solvent such as tetrahydrofuran, at low temperature (e.g. -15 to 15aboutC). Alternatively, the ketone intermediate compounds, especially compounds containing ester groups, restores softer hydride regenerating agent such as NaBH4again - taken in excess, this time in proton solvent such as methanol or ethanol, typically at a slightly higher temperature, for example 15-45aboutC.

Any protective groups that still exist after recovery of the ketone, and then removed according to the methods described above. Some other transformations such as hydrogenation of olefins epoxidation and recovering a mixture of sodium/liquid ammonia epoxides, for example

,

also optional are later in the sequence of synthesis, for example, after combination with the formation of ketone, after removal of the protective groups (if vulnerable groups do not interfere with the transformation) and/or the settlement is through reaction of methylene connection with one molar equivalent of m-chlormadinone acid in a reaction inert solvent, such as CH2CL2. The recovery of the epoxy alcohol is easily achieved by using a normal mixture of sodium/liquid ammonia, it is usually carried out at temperatures below the boiling point of liquid ammonia (for example, when -78aboutWith the bath temperature from a mixture of acetone and dry ice) in the presence of a reaction inert solvent such as tetrahydrofuran.

Source materials and reagents required for the synthesis of compounds of the present invention, are readily available, or produced in industry, according to the methods described in the literature or by methods shown in the examples of the preparation below.

These compounds of formula (I), (II) and (III) have a selective neuroprotective activity, based on their antiischemic activity and the ability to block the stimulating amino acid receptors, while at the same time they usually have low, or do not have any significant hypotensive activity. Anti-ischemic activity of these compounds is determined in accordance with one or more methods that were described in the papers above, or by similar methods. Sposoby their ability to block induced by N-methyl-D-aspartic acid (NMDA) increase (elevation) cGMP in the cerebellum of neonatal (newborn) rats in accordance with the following procedure. The cerebellum of 10 Wistar rats aged 8-14 days were rapidly dissected and placed them in the Krebs/bicarbonate buffer with a temperature of 4aboutC, pH 7.4, and then cut into pieces with a size of 0.5 x 0.5 mm using dangeresque Mc vain (firm "nickl Lab Engineering Co., Comshall, Surrey, England). The resulting pieces of the cerebellum was transferred into a 100 ml Krebs/bicarbonate buffer at 37aboutWith that continuously balanced with a mixture of 95: 5 02/CO2. Slices of cerebellum were incubated thus for 90 min with three changes of buffer. The buffer is then decantation, the tissue was centrifuged (1 min, 3200 rpm. /min), and the tissue re-suspended in 20 ml of Krebs/bicarbonate buffer. Then 250 ál aliquots (approximately 2 mg) was removed and placed in 1.5 ml of microfuge-tube. These tubes were added 10 μl of the compounds of the initial solution, and then adding after a 10-minute incubation period, 10 μl of a 2.5 mm solution of NMDA to start the reaction. The final concentration of NMDA was 100 μm. The control does not contain NMDA, i.e. NMDA added. Tube (test tube) were incubated for 1 min at 37aboutWith to shake a water bath, and then to terminate the reaction was added 750 μl of 50 mm Tris-Cl, 5 mm EDTA solution. The tube was placed. in 15 seconds using a probe homogenate installed on the energy level of three. 10 ál was removed and the protein was determined by Lowry method, Anal. Biochem 100:201-220 (1979). The tubes then were centrifuged (5 min, h), 100 μl of the surface layer was removed and analyzed the levels of cyclic GMP (cGMP) using analysis GMP PIA New England nuclear (Boston, mA), according to the methodology of the supplier. Data are reported as p-mol, cGMP generated per 1 mg protein. Using known methods also determined unwanted hypotensive activity, for example according to methods Tarron and others, also shown above.

Such selective neuroprotective anti-ischemic activity and the activity of blocking stimulatory amino acid receptors inestimable usefulness of these compounds in the treatment of degenerative Central nervous system disorders such as stroke and Alzheimer's disease, Parkinson's disease and Huntington's disease, without the significant potential concomitant excessive fall in blood pressure. Systemic treatment of these diseases neuroprotective amount of compounds of formula (I), (II) or (III) the dose in a typical case is approximately 0.02 - 10 mg/kg/day (1-500 mg/day for zaznaczenie. Of course, depending on the exact type of connection and the specific nature of individual diseases doctors can prescribe the dose that is outside of this interval. Generally preferred oral method of administration of the preparation. However, if the patient cannot swallow, or oral absorption for some reason is broken, the preferred method of appointment will be parenteral (wew - ramesey, intravenous and topical or local the way to the destination.

Compounds of the present invention are usually prescribed in the form of pharmaceutical compositions comprising at least one of the compounds of formula (I), (II) or (III) together with a pharmaceutically acceptable carrier or diluent. Such compositions are usually formed in the usual way using solid or liquid carriers or diluents, depending on what corresponds to the way the appropriate destination: oral assignments in the form of tablets, hard or soft gelatin capsules, suspensions, grain, powders, etc. for parenteral purposes - in the form of injectable solutions or suspensions, and so on; and for topical purposes - in the form of solutions, lotions, ointments, etc.

Now from the.

All nonaqueous reactions were carried out in nitrogen atmosphere for convenience and, usually, to increase output to maximum. All systems solvents/thinners were subjected to drying in accordance with the standard described in the literature procedures, or purchased on the market in a pre-dried form. All of the reaction mixture was stirred or magnetic, or mechanical means. NMR spectra were recorded at 300 MHz and are given in million shares. Solvent NMR was CDCl3if not specified otherwise. IR spectra are given in cm-1usually indicates only the strong signals.

P R I m e R 1. 2-(3-Phenylmethylene-8-azabicyclo/3-2-1/Oct-8-yl)-1- [4-(triisopropylsilyl)phenyl]-1-propanone

A mixture of 3-phenylmethylene-8-azabicyclo/3.2.1/octane (1,09 g, to 4.87 mmol), 4-(triisopropylsilane)- -bromopropiophenone (1.88 g, 4,88 mmol) and triethylamine (1.5 ml, of 10.76 mmol) in ethanol (75 ml) was heated under reflux for 22 hours, After cooling, was added ether (50 ml) and the mixture was filtered through diatomaceous earth. The filtrate was concentrated and chromatographically on silica gel (2 x 6 inches/ 2,53 x 6 cm), hexane, then ethyl acetate (hexane gradient) to give 0.56 g (23%) orange product in the form of butter;

NMR 8,18 (d, 2H), 7,25 (m, 2H), 7,12 (d, 3H), 6,86 (d, 2H), 6,29 is orites), of 1.40 (d, 3H), 1,25 (m, 3H), of 1.09 (d, N).

P R I m m e R 2. Mix /1R*, 2S*/ - /1S*, 2S*/-2-(3-phenylmethylene-8-azabicyclo-(3-2-1)Oct-8-yl)-1-4- (triisopropylsilyl)phenyl-1-propanol

To a suspension of sociallyengaged (0,61 g, 16,07 mmol) in tetrahydrofuran (50 ml) at 0aboutTo add a target product of the preceding example (of 8.04 g, 15,96 mmol) in tetrahydrofuran (150 ml) for 15 min. the Mixture was stirred for 15.5 hours at room temperature, then carefully extinguished with water (1.2 ml), filtered through diatomaceous earth and concentrated, giving a yellow oil. This racemic mixture of the target product was used directly in the next reaction without purification.

P R I m e R 3. (1S*, 2S*)- and (1R*, 2S*)-1-(4-hydroxyphenyl)-2-(3-phenylmethylene-8-azabicyclo/3.2.1/Oct-8 - yl)-1-propanol

The target product of the preceding example (7,15 g, 14,14 mmol) was dissolved in tetrahydrofuran (250 ml) was added tetrabutylammonium fluoride (to 28.5 ml, 28.5 mmol, 1 M in tetrahydrofuran) all at once. The solution was mixed at room temperature for 18 h, then concentrated and chromatographically on silica gel (4 x 6 inches, ethyl acetate/hexane gradient with subsequent methanol/an ethyl acetate gradient), giving first racemic (1S*, 2S)-target product (1,58 g is ylmethylene-8-azabicyclo/3.2.1/Oct-8-ilen side chain, each of these products represents the actual mixture of two racemates).

(1S*, 2S*)-product precrystallization from a mixture of ethyl acetate/hexane, giving 0,923 g white solids; so pl. 175-177aboutC;

NMR includes: 4,10 (t, J = 7.7 Hz, 1H).

Analysis %: 78,77; N. Of 7.90; N To 3.92.

Calculated,%: C 79,05; N. Of 7.90; N To 3.92.

(1R*, 2S*)-the product was further purified using radial chromatography using elution of a mixture of 60% ethyl acetate/hexane, yielding 0.24 g of colorless oil. This oil was crystallized from a mixture of ether/hexane, yielding 0.17 g crystalline solids; so pl. of 78.5 85aboutC. the Latter was turned into its HCl-salt by using ozonation of HCl gas in ether solution of the compound for 3 minutes a White precipitate was collected and recrystallized from ethanol, yielding (1R*, 2S*)-chlorhydrate salt in the form of its hemihydrate; so pl. 215-218aboutC; NMR (DBCO-d6) includes: 5,17 (S., 1H), 1H and 4,60-3,93 (m, 2H).

Found,%: C 70,00; N 7,45; N 3,35.

Calculated,%: C 69,95; N 7,40; N 3,54.

P R I m e R 4. 2-[4-(phenylthio)piperidino]-1-[4-(tert-butyldimethylsilyloxy)- phenyl]-1-propanone

This product was used in accordance with the procedure of example 1 using 4-phenylthiophene (1.13 g, 5,85 mm the heating under reflux 21,5 PM The product was isolated using instant chromatography on silica gel using ethyl acetate/hexane gradient elution. The solution was 1.29 g of the desired product as a yellow oil:

NMR of 8.00 (d, J = 9 Hz, 2H), 7,35 (d, J = 7.8 Hz, 2H), 7,35 (m, 3H), for 6.81 (d, J = 8,4 Hz, 2H), 4.00 points (kV, J = 6,8 Hz, 1H), 3,03 (m, 1H), 2.91 in-2,87 (m, 1H), 2,80 was 2.76 (m, 1H), 2,44 (D. t, J = 9,5, and 2.6 Hz), 2,29-2,19 (m, 1H), 1093-1,85 (m, 2H), 1,66-is 1.51 (m, 2H partially below the water peak of the solvent), to 1.22 (d, J = 7,1 Hz, 3H), of 0.97 (s, N) and 0.22 (s, 6N).

Later fractions from the chromatography were given a 0.51 g of product which was desilicious during the reaction. This material could also be converted to the final target compound using the procedures presented below.

Using the same methods 4-(triisopropylsilyl)- -bromopropiophenone (becomes 9.97 g of 25.9 mmol) was transformed into chromatographically 2-[4-(phenylthio)piperidino] -1-4-(triisopropylsilyl)phenyl-1-propane-it is in the form of a light orange oil:

8,32 d; NMR of 8.00 (d, J = 8,8 Hz, 2H), 7,37 (DD, J = 1,5, and 8.4 Hz, 2H), 7,29-to 7.18 (m, 3H), 6,86 (d, J = 8,8 Hz, 2H), was 4.02 (q, J = 6,8 Hz, 1H), is 3.08 3.00 for (m, 1H), 2,85 (d, J = 26,2 Hz, 1H), 2,75 (d, J = 16.6 Hz, 1H), 2,45 (D. t, J = 11, and 2.6 Hz, 1H), 2,23 (D. t, J = 9,8, 2.5 Hz, 1H), 1,96-of 1.88 (m, 2H), 1,71 of 1.50 (m, 5H), of 1.09 (d, J = 7 Hz, N).

P R I m e R 5. (1S*, 2S*)- and (1R*, 2S*)-2-(4-phenylthio)piperidine-1,4-(Trisha example (8,32 g, of 16.7 mmol) using chromatography on silica gel with elution ethyl acetate/hexane gradient for separation of the isomers was developed in the 6.06 g of the less polar (1S*, 2S*)-target product in the form of oil:

NMR: 7,41 (d, J = 6,7 Hz, 2H), 7,32-7,24 (m, 3H), 7,15 (d, J = 8.5 Hz, 2H), PC 6.82 (d, J = 8,4 Hz, 2H), 4,14 (d, J = 9.7 Hz, 1H), 3,11 (m, 1H), 2,88 (m, 1H), 2,69 (m, 1H), 2,69 is 2.55 (m, 2H), 2,21 (t, 1H), 2,03 (m, 2H), 1.85 to was 1.58 (m, 3H), 1,35-1,20 (m, 2H), 1,23 (d, J = 15 Hz, N), of 1.07 (d, J = 7 Hz, 3H), and 0.2 g of the more polar (1S*, 2S*)-target product NMR: to 7.35 (d, J = 7 Hz, 2H), 7,28-7,16 (m, 3H), was 7.08 (d, J = 9 Hz, 2H), 6,78 (d, J = 9 Hz, 2H), and 4.68 (d, J = 5 Hz, 1H), 3,10-2,98 (m, 1H), 2,98-2,87 (m, 1H), 2,75-2,60 (m m, 2H), 2,33 (t, J = 9 Hz, of 2.16 (t, J = 11 Hz, 1H), 1.91 a (t, J = 15 Hz, 2H), 1.70 to to 1.48 (m, 2H), 1.32 to-1,12 (m, 4H), of 1.06 (d, J = 9 Hz, N), from 0.88 to 0.78 (m, 3H).

P R I m e R 6. (1S*, 2S*)-1-(4-Hydroxyphenyl)-2-[4-(phenylthio)piperidino]-1-Pro-panol

Method AND

To a suspension of sociallyengaged (0.11 g, 2.9 mmol) in tetrahydrofuran (25 ml), cooled to 0aboutWith added target product of example 4 (1.29 g, is 2.88 mmol) in tetrahydrofuran (50 ml). The reaction mixture was warmed up to ambient temperature for 2 h, was heated under reflux for 3 h and left to mix for a period of 72 hours, the Mixture carefully extinguished with water and filtered through diatomaceous earth. The filtrate was concentrated to VLA), concentrated, giving 0,41 g of a white solid substance, and he was precrystallization from a mixture of ether/hexane, yielding 0.16 g of the target product; so pl. 155-157aboutC; NMR includes: 4,12 (d, 1H).

Found,%: C 69,57; N 7,28; N 3,95.

Calculated,%: C 69,94; N 7,34; N 4,08.

Oxide-aluminum salt of the reaction was extracted in to conventional Soxhlet extractions with ethyl acetate for 24 hours of Concentration gave additional 0.3 g of product.

Method C.

The same product was obtained from (1S*, 2S*)-target product of the preceding example according to the method of example 3.

P R I m e R 7. (1R*, 2S*)-1-(4-Hydroxyphenyl)-2-[4-(phenylthio)piperidino] -1-Pro-panol

Using the procedure of example 3 real target product was obtained from (1R*, 2S*)-target product of example 5 (0.2 g, 0.4 mmol) and tetrabutylammonium fluoride (0.8 ml, 0.8 mmol, 1 M in tetrahydrofuran) in tetrahydrofuran (5 ml) at ambient temperature for 72 hours Product was received with instant chromatography on silica gel (6 x 1 inches, elution ethyl acetate/hexane gradient), yielding 0.14 g of semi-solid substances. Recrystallization from a mixture of methylene chloride/hexane gave 0,056 g white solids: I. pl. 124,5-126aboutC.

NMR includes: 4.72 in (d, (1S*, 2S*(-1-(4-Hydroxyphenyl)-2-4-(phenylsulfonyl)piperidine-1 - propanol

The target product of example 6 (0,13 g, 0,378 mmol) was dissolved in methylene chloride (20 ml) was added m-chlorodeoxyadenosine acid (0,23 g, 1,133 mmol) all at once. The solution was stirred for 23 h, then dropped precipitated material was filtered, giving 0,154 g of white solid, which was crude intermediate N-oxide. The latter was first made in the apparatus Parra in methanol (20 ml) using 10% palladium catalyst on coal (0.03 g) under hydrogen pressure of 50 psi (3,515 kg/sq. cm). The reaction was completed after 6 h, the mixture was filtered through diatomaceous earth and concentrated, obtaining 0,166 g yellow oil. This oil was taken in methylene chloride and washed with saturated sodium bicarbonate. The organic phase was dried (magnesium sulfate) and concentrated, obtaining 0,106 g of yellow oil, which crystallized from a mixture of ethyl acetate and hexane, giving 0,076 g white solids; so pl. 169-175aboutC. a Portion of the product (0,045-0,050 g) was further purified using vigorous mixing with saturated sodium bicarbonate and ethyl acetate for 15 minutes, the Phases were separated and the aqueous phase was further extracted with ethyl acetate (2 times). The combined organic phases is a received 0.02 g of a white powder; so pl. 195-196aboutC.

NMR 7,88 includes: 4,15 (d, J = 9.7 Hz, 1H).

Found,%: C 63,77; N Is 6.61; N 3,61.

Calculated,%: C 63,98; N. Of 6.71; N To 3.73.

P R I m e R 9. (1S*, 2S*)-1-(4-hydroxyphenyl)-2-[4-(phenylsulfonyl)piperidine]-1 - propanol

The target product of example 6 (0.5 g, of 1.46 mmol) was dissolved in methylene chloride (40 ml) was added m-chlorodeoxyadenosine acid (0.3 g, 1.48 mmol) all at once. After stirring over night at ambient temperature the mixture was concentrated directly onto silica gel and subjected to instant chromatography (6 x 1 inch, ethyl acetate/hexane gradient), yielding 0,34 mg crude product as a white solid, which was further purified using distribution between saturated sodium bicarbonate and ethyl acetate with vigorous stirring for 20 minutes, the Phases were separated and the organic layer was concentrated, giving an oily solid, which was crystallized from a mixture of ethyl acetate and hexane, giving 0,122 g white solids; so pl. 110aboutC.

NMR includes: 4,16 (paired on the long area, J = 9.7 Hz, 1H); signal: 360.635.

Calculated: 360.1626.

P R I m e R 10. 1-[4-(benzyloxy)phenyl]-2-(4-benzyl-4-hydroxypiperidine)-1-Pro - P6 mmol), triethylamine (1,46 ml of 10.47 mmol) and 4-benzyloxy- -bromopropiophenone (3.33 g, 10,43 mmol) in ethanol (50 ml) at reflux for 24 hours of Real racemic product was obtained after instant chromatography on silica gel with elution ethyl acetate/hexane gradient. The solution was 2,88 g (64%) of yellow solid.

NMR of 8.06 (d, 2H), 7,52-was 7.08 (m, 10H), 6,97 (d, 2H), 5,11 (s, 2H), 4.00 points (kV, 1H), 2,72 (s, 2H), 2,72 of $ 2.53 (m, 2H), 2,43 (t, 1H), 1.85 to 1,39 (m, 6N), of 1.23 (d, 3H).

Theorm 412.2348.

Calculated (HE) 412.2273.

P R I m e R 11. (1S*, 2S*(-1-4-(Benzyloxy)phenyl-2-(4-benzyl-4-hydroxypiperidine)-1-propanol

Sodium borohydride (0.25 g, is 6.61 mmol) was added all at once to a solution of the target product of the preceding example (2,88 g, 6,70 mmol) in ethanol (50 ml). The mixture was stirred for 20 h at room temperature, the formed precipitate. The solid was filtered and dried, obtaining 60 g of the target product; so pl. 147-148aboutC.

NMR includes: 4,17 (d, J = 10 Hz, 1H).

IR (kV): 3387, 3024, 2936, 1611, 1513, 1453, 1239, 1026, 1011, 695.

The filtrate from the above reaction was concentrated, the residue was distributed between ethyl acetate and water and the phases were separated. The aqueous phase was extracted with ethyl acetate. The joint organization of the spruce product.

P R I m e R 12. (1S*, 2S*)-1-(4-Hydroxyphenyl)-2-(4-benzyl-4 - hydroxypiperidine)-1-propanol

The target product of the preceding example (0,49 g to 1.14 mmol) and tetrahydrofuran (30 ml) was cooled to -78aboutWith, and ammonia gas (30 ml) was condensed into the mixture. Was added sodium (0,082 g of 3.57 mmol) in four portions. The reaction mixture, which was blue, which was mixed for 15 min, and then was extinguished ammonium chloride (0.29 grams). The reaction mixture was allowed to warmed to room temperature, and the ammonia was boiled off. The reaction mixture was concentrated, and the residue was taken into ethyl acetate and was washed with water and brine. The organic phase was dried (calcium sulfate) and concentrated, yielding 0.39 g of a white solid. Recrystallization from hexane gave to 0.19 g of the target product.

NMR (DCO-d6) 7,25-7,11 (m, 5H), was 7.08 (d, J = 8,2 Hz, 2H), of 6.68 (d, J = 8.6 Hz, 2H), 4,14 (s, 1H), 4.09 to (d, J = 9,2 Hz, 1H), 3.33 and (s, 2H), 3,30 (s, 1H), 2,74 (m, 1H partially below the water peak from NMR solvent), 2,60 to 2.35 (m, 4H partially below the peak of the solvent), 1.70 to the 1.44 (m, 4H), 7,63 (d, J = 6,7 Hz, 3H).

Deuterium oxide was washed singlets at 4,14 and 3.30 million dollars.

This product was precrystallization from ethyl acetate, giving a purified target product 8,03, N 4,01.

Calculated: 73,87, N Of 7.97, N 4,10.

P R I m e p 13. 1-(4-(tert-Butyldimethylsilyloxy)phenyl)-2-(3-phenylthio-8-asabis-ILO /3.2.1/Oct-8-yl)-1-propanone

When using the procedure of example 1, this product was cooked for 4-tert-butyldimethylsilyloxy-alpha-d - propiophenone (1,25 g, 3.65 mmol), 3-phenylthio-8-azabicyclo/3.2.1/octane (0.8 g, 3.65 mmol) and triethylamine (0.51 ml, 3.65 mmol) in ethanol (30 ml) at reflux over night. The product was subjected to instant chromatography on silica gel (10% ethyl acetate-hexane elution mixture); 0.889 g (51%).

NMR 8,13 (d, J = 9 Hz, 2H), 7,38 (m, 2H), 7,30-to 7.15 (m, 3H), 6,83 (d, J = 9 Hz, 2H), 3,93 (kV, J = 7 Hz, 1H), 3,42 of 3.28 (m, 3H), 2.05 is-of 1.56 (m, N), 1,32 (d, J = 7 Hz, 3H), 0,99 (s, N), and 0.25 (s, 6N).

IR: 2940, 2840, 1600, 1390-1290 (W), 910.

P R I m e R 14. A mixture of (1R*, 2S*)- and (1S*, 2S*)-1-4-(tert-butyldimethylsilyloxy)-Hairdryer - yl-2-(3-phenylthio-8-azabicyclo/3.2.1/Oct-8 - yl)-1-propanol

This product was prepared as in example 2, under stirring over night at ambient temperature from the product of the preceding example (0,85 g, 1.77 mmol) and aluminiumhydride lithium (0,153 g, 4.0 mmol) in tetrahydrofuran (24 ml). The product separated as a yellow oil (0,78 g, 91%) as a racemic mixture of the target product is

The target product of the preceding example (0,78 g, 1.6 mmol) was desilicious according to the procedure of example 3 using tetrabutylammonium fluoride (1.6 ml, 1.6 mmol, 1M in tetrahydrofuran) within 5 minutes of reaction. The resulting mixture of racemates were separated using instant chromatography on silica gel (elution with a mixture of 50% ethyl acetate/hexane). The first was elyuirovaniya (1S*, 2S*)-target product, of 0.133 g

NMR (DMCO-d6) 7,40-7,21 (m, 5H), 7,06 (d, J = 8.5 Hz, 2H), 6,63 (d, J = 8.0 Hz, 2H), 4,35 (d, J = 5.0 Hz, 1H), 3,54 is 3.40 (m, 2H), 3,35 be 3.29 (m, 2H), 2,70-2,62 (Shir.t, 1H), 2,50 (m, 1H), 1,80-and 1.54 (m, 6N), was 0.63 (d, J = 6.5 Hz, 3H).

Continuous elution gives (1R*, 2S*)-target product.

NMR 7,45-7,40 (m, 2H), 7,32-7,22 (m, 3H), 7,15 (d, 2H), 6,76 (d, 2H), 4,80 (d, 1H), 3,60-to 3.52 (m, 2H), 3,51-to 3.38 (m, 1H), 2,80-of 2.72 (m, 1H), 2.00 in of 1.65 (m, 8H), of 0.68 (d, 3H).

This product (80 mg) was transformed into its HCl-salt by dissolving in 15 ml simple ether, ozonation in him dry Hcl for 2 min, and rubbing the resulting oily solid with ether, yielding 30 mg as a white solid.

P R I m e R 16. 2-(4-Benzyl-4-hydroxypiperidine)-1-4-(triisopropylsilyl)-phenyl-1-propane he

This product was obtained in accordance with the procedures of example 1 from 4-hydroxy-4-0 ml, 14,35 mmol) in ethanol (50 ml) at the time of heating under reflux for 17 h, giving to 4.92 g (70%) chromatographic purification of the desired product as an orange oil.

NMR 8,01 (d, J = 8,8 Hz, 2H), 7,31-7,22 (m, 3H), 7.18 in-to 7.15 (m, 2H), 6.87 in (d, J = 8,8 Hz,2H), 4,03 (kV, J = 6,7 Hz, 1H), 2,72 (s, 2H), 2,68-to 2.57 (m, 3H), of 2.45 (d,t, 1H), 1,78-of 1.42 (m, 4H), 1,40-1,25 (m, 7H), of 1.10 (d, J = 7 Hz, N).

P R I m e R 17. (1S*, 2S*)- and (1R*, 2S*)-2-(4-benzyl-4-hydroxypiperidine)-1-4-tree - supraphysiologic)phenyl-1-propanol

The target product of the preceding example (4,92 g, was 9.33 mmol) was dissolved in ethanol (100 ml) was added sodium borohydride (0,38 g, 10 mmol) all at once. After stirring over night at ambient temperature was allocated (1S*, 2S*)-target product by filtration; 2,11,

NMR 7,46-7,17 (m, 7H), at 6.84 (d, J = 7 Hz, 2H), 4,18 (d, J = 11 Hz, 1H), 2,86 (Shir. t, 1H), 2,77 (s, 2H), 2,70-to 2.42 (m, 4H), 1,89-of 1.55 (m, 6N), 1,30-of 1.13 (m, 3H), 1,10 (doctor J = 8.6 Hz, N in), 0.75 (d, J = 6 Hz, 3H).

The filtrate was concentrated, and the residue was dissolved in ethyl acetate, was extracted with water (2x) and brine, dried (calcium sulfate), concentrated to 2.33 g of light yellow solid, and were subjected to instant chromatography on silica gel (2 x 6 inches, elution using ethyl acetate/hexane gradient), yielding SNN), 2,80-2,39 (m, 5H), 1,88 was 1.43 (m, 6N), 1,31-of 1.13 (m, 8H), of 1.08 (d, J = 6,7 Hz, N), from 0.84 (d, J = 6 Hz, 3H).

P R I m e R 18. (1R*, 2S*)-2-(4-benzyl-4-hydroxypiperidine)-1- (4-hydroxyphenyl)-1-propanol

According to the method of example 3 using chromatography, elution gradient of ethyl acetate/hexane, (1R*, 2S*)-target product of the preceding example (0,46 g to 0.92 mmol) was turned into a 0.24 g (74%) of the desired product in the form of a monohydrate, so pl. 173-174aboutC.

NMR (DCO with the addition of D2O) 7,21 for 7.12 (m, 5H),? 7.04 baby mortality (d, J = 7,6 Hz, 2H), 6,64 (doctor J = 8.6 Hz, 2H), with 4.64 (d, J = 8.6 Hz, 1H), 2,59 (s, 2H), 2,59-2,49 (m, 5H-partially below the NMR solvent) 1,50 to 1.31 (m, 4H), of 0.82 (d, J = 7 Hz, 3H).

Found,%: C 70,26; N. Of 7.96; N 3,85.

Calculated for monohydrate: 70,17; N 8,13; N 3,90.

P R I m e R 19. 2-(4-benzyl-4-hydroxypiperidine)-1-(4-forfinal)-1-propanol

Target product, obtained as in example 10, with the release of 80%, precrystallization of simple ether; so pl. 119,5-120aboutC.

Found,%: C 73,41, N 7,08; N Is 4.03.

Calculated,%: C 73,87; N To 7.09; N 4,10.

P R I m e R 20. (1S*, 2S*)- and (1R*, 2S)-2-(4-benzyl-4-hydroxy - piperidino)-1-(4-forfinal)-1-propanol.

Getting as in example 17, the target products were separated using instant chromatography on silica gel (using at% in the form of solids, which was precrystallization from a mixture of ethanol and simple ether, so pl. 153,5-154,5aboutC.

Found,%: C 73,53; N To 7.67; N 4,08.

Calculated,%: C 73,44; N 7,63; N 4,08.

P R I m e R 21. 2-(3-Phenylmethylene-8-azabicyclo/3.2.1/Oct-8 - yl)-1-(4-benzyloxyphenyl)-1-propanone

The target product is obtained following the procedure of example 1, from 4-benzyloxy- -bromopropiophenone, was obtained with the yield of 40-60% after instant chromatography on silica gel.

NMR to 8.34 (d, 2H), 7,56 was 7.45 (m, 7H), 7,20 (m, 3H), 7,03 (d, 2H), 6,36 (s, 1H), 5,14 (s, 2H), 4,13 (kV, 1H), 3,56-3,30 (m, 2H), 2,81 (t, 1H), 2,70-to 2.40 (m, 2H), 2,10 to 1.76 (m, 3H), 1066 (m, 1H), 1,45 (d, 3H).

P R I m e R 22 (1S*, 2S*)-2-(3-Phenylmethylene-8-azabicyclo/3.2.1/ act-8-yl)-1-(4-benzyloxyphenyl)-1-propanol

Target product prepared using the procedure of example 3 with the reaction time of 1.25 hours, was obtained in pure form by using instant chromatography on silica gel, so pl. 145-148aboutC.

Found,%: C 81,69; N 7,46. N to 3.02.

Calculated,%: C 81,97; N EUR 7.57; N 3,19.

P R I m e R 23. (1S*, 2S*)-2-(3-benzyl-8-azabicyclo/3.2.1/Oct - 8-yl)-1-(4-hydroxyphenyl)-1-propanol

The target product of the preceding example (0,23 g, 0,523 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78aboutC. To the solution was condensed ammonia (30 ml). Added intothree what itCOM ammonium chloride, and the mixture was allowed to warmed to room temperature with evaporation of ammonia. The residual mixture was concentrated, and the residue was extracted with ethyl acetate. Filtration and concentration gave 0.24 g of oily solid, which was subjected to instant chromatography on silica gel (6 x 1 inch, by elution using ethyl acetate/hexane gradient, followed by evaporation of methanol). This gave first regenerated starting material, and then the product (0,071 g). The product was further purified via recrystallization (ethyl acetate/hexane). During this process, leaked some portions, but 0.005 g of white solid product was obtained in a 1:3 mixture of epimeres benzyl group.

NMR 7,30-7,10 (m, 7H), 6,72 (J = 8,5 Hz) and 6.71 (J = 8.6 Hz), (a pair of overlapping D. just 2H), 4,11 (d, J = 8.6 Hz, 1H), 3.45 points (s, 1H), 3,31 or 3.24 (pair d, 2H), 2,61 (quintet, J = 7,6 Hz, 1H), 2,11 (m, 1H), 1,86-1,17 (m, 10H), 0,81 (d, J = 6,7 Hz, 3H).

A receiver array: 352.2276.

Calculated: for MN+: 352.2278.

P R I m e R 24. 2-(4-Benzyl-4-hydroxypiperidine)-1-(4-chlorophenyl)-1-propanone

The target product was obtained from 4-chloro - bromopropiophenone, using the procedure of example 10 with the release of 72%, were cleaned using instant chromatog is 0,11; N 6,70; N 3,85.

Calculated,%: C 70,48; G 6,76; N 3,91.

P R I m e R 25. (1S*, 2S*)- and (1R*, 2S*)-2-(4-benzyl-4-hydroxypiperidine)-1-(4-chloro - phenyl)-1-propanol

Target products obtained using the procedure of example 17, were separated using the same procedure chromatography. (1S*, 2S*)-product was obtained with the yield of 70%, so pl. 159,5-160,5aboutWith; (ethanol/simple ether).

Found,%: C 70,13; N 7,50; N 3,91.

Calculated,%: C 70,08; N 7,28; N 3,89.

1R*, 2S*, a product was obtained with a yield of 7%; so pl. 150,5-151,5aboutC (ethanol/simple ether).

Found,%: C 69,92; N 7,38; N To 3.92.

Calculated,%: C 70,08; N 7,28; N 3,89.

P R I m e R 26. 2-(4-benzyl-4-hydroxypiperidine)-1-(4-chlorophenyl)-1-alanon

The target product was prepared using the procedure of example 10 from 4-chloro - bromoacetophenone with the release of 76%.

NMR of 7.93 (d, J = 8.5 Hz, 2H), 7,39 (d,J = 8.6 Hz, 2H), 7,31-7,16 (m, 5H), 3,74 (s, 2H), 2,74 (s, 2H), 2,73-a 2.71 (m, 2H), 2,43 (D. t, J = 11,5, 2.2.4 Hz, 2H), 1,80 (D. t, J = 12,7, 4,3 Hz, 2H), 1,50 (Shir.d, J = 13,8 Hz, 2H).

P R I m e R 27. 2-(4-Benzyl-4-hydroxypiperidine)-1-(4-chlorophenyl)ethanol

The target product was obtained from 4-chloro - bromoacetophenone using the procedure of example 17 with the release of 83%, precrystallization from a mixture of ethanol-ether, so pl. 151-152aboutC.

NMR 7,34-58-1,50 (m, 2H), 1,24 (s, 1H).

P R I m e R 28. 2-(4-Benzyl-4-hydroxypiperidine)-1-(4-forfinal)-1-alanon

Target product were prepared using the procedure of example 10 to yield 59% of 4-fluoro- -bromoacetophenone.

NMR 8,05-to 7.99 (m, 2H), 7,33? 7.04 baby mortality (m, 7H), 3,76 (s, 2H), 2,83-a 2.71 (m, 4H), 2,43 (D. t, J = 11,5, 2,1 Hz, 2H), 1,82 (D. t, J = 12,7, 4,3 Hz, 3H) and 1.51 (Shir.d, J = 11.5 Hz, 2H).

P R I m e R 29. 2-(4-Benzyl-4-hydroxypiperidine)-1-(4-forfinal)-1-ethanol

The target product is obtained following the procedure of example 17 with the release of 85%, recrystallized from a mixture of ethanol/ether; so pl. 144,5-146aboutC.

NMR 7,35-7,25 (m, 5H), 7,19 (d, J = 6,4 Hz, 2H), 7,01 (t, J = 8.7 Hz, 2H), 4,67 (D. d, J = a 10.5, 3.5 Hz, 1H), 4,18 (Shir.s, 1H), 2,88 (Shir.d, J = 11.2 Hz, 1H), was 2.76 (s, 2H), 2,68-2,31 (m, 5H), 1,81-of 1.66 (m, 2H), 1,58 of 1.50 (m, 2H), 1.28 (in s, 1H).

P R I m e R 30. Endo-1-4-(triisopropylsilyl)phenyl-2-(3' - perspire 8-azabicyclo/3.2.1/octane-3,2'-oxiran - 8-yl) - propanone

The target product of example obtaining 13 below (0,72 g, to 3.34 mmol), the target product of example 10, below (1.29 g, 3.35 mmol) and sodium carbonate (0,93 g, 6.7 mmol) were combined in tetrahydrofuran (80 ml) was heated under reflux for 30 h, cooled and filtered through diatomaceous earth. The filtrate was concentrated and chromatographically product as a mixture of diastereoisomers. Epoxy protons was observed at the 3.65 and of 3.60 million dollars. the NMR spectrum.

The corresponding Exo-isomer were prepared similarly from the other isomer of example get 13 with the release of 37%. Epoxy protons in the mixture of the diastereomeric products were observed when 3,80 and 3,86 million dollars. the NMR spectrum.

P R I m e R 31. Endo - and Exo-(1S*, 2S*) - and (1R*, 2S*)-1-4-(triisopropylsilane (-phenyl-2-(3-perspire 8-azabicyclo/3.2.1/octane-3,2-oxiran-8-yl)-1-disappear-Nol

The mixture of these endo-target product was obtained from the endo - target product of the preceding example with the release of 82% using the procedure of example 17. Instant chromatography gave pure faster running (1S*, 2S)-isomer.

NMR 7,34-of 7.23 (m, 5H), 7,17 (d, J = 8.5 Hz, 2H), PC 6.82 (d, J = 8.5 Hz, 2H), was 4.02 (d, J = 8 Hz, 1H), 3,65 (s, 1H), 3.45 points (Shir.s, 1H), 3,28 (Shir.s, 1H), 2,65 (quintet, J = 7.2 Hz, 1H), 2,54 (D. d, J = 13,8, and 3.2 Hz, 1H), 2,15 (kV, J = 8.6 Hz, 2H), 1.93 and-1,72 (m, 4H), of 1.40 (d, J = 13,8 Hz, 2H).

More slow going (1R*, 2S*)-isomer, which shows the characteristic of the NMR-signal when to 4.81 million dollars. (S. broad, 1H), obtained in the form of a mixture of (1S*, 2S*)-isomer.

The corresponding Exo-isomers was obtained similarly from the Exo-isomer of the previous example with the release of 82% in a 3:1 mixture of (1S*, 2S*)- and (1R*, 2S*)-isomers. Epoxy protons in the about 8-azabicyclo/3.2.1/octane-3,2' -oxiran - 8-yl)-1 - propanol

Using the method of example 3, endo-(1S*, 2S*)-target product of the preceding example was turned into a real target product with a yield of 62%; so pl. 204,5-205aboutC (chloroform/hexane).

NMR 7,32-7,25 (m, 5H), of 1.17 (d, J = 8,4 Hz, 2H), 6.73 x (d, J = 6.6 Hz, 2H), 5.25 in (lat.s, 1H)-4,01 (d, J = 8,2 Hz, 1H), 3,66 (s, 1H), 3,47 (Shir.s, 1H), 3,31 (Shir.s, 1H), 2,65-of 2.54 (m, 2H), 2,16 (d, J = 8 Hz, 2H), 1,89-of 1.73 (m, 3H), 1,44 (width,d, J = a 13.9 Hz, 1H), 1,24 (Shir.D. J = 14 Hz, 1H), or 0.83 (d, J = 6,7 Hz, 3H).

P R I m e R 33. Endo-(1S*, 2S*)-2-(3-benzyl-3-hydroxy-8-azabicyclo/3.2.1/Oct-8-yl)-1-(4 - triisopropylsilane)phenyl-1-propanol

Endo-(1S*, 2S*) (1R*, 2S*) mixture of example 31 (0,19 g, 0.36 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78aboutC. In a solution are condensed ammonia (30 ml) was added sodium metal (0.08 g) in the form of small pieces for 1 h At this time the mixture became dark blue. The reaction mixture was stirred for another 10 min, then extinguished solid ammonium chloride. The ammonia was allowed to evaporate, the residual mixture was distributed between ethyl acetate and water, and the aqueous layer was extracted with fresh ethyl acetate. The combined organic layers were washed with saline, dried over calcium sulfate and concentrated, yielding 0.18 g (95%) of light yellow oil, which the new gradient), giving 0.1 g of colorless oil, which was (1S*, 2S*)-target product.

NMR 7,33-7,25 (m, 3H), 7,18 (d, J = 8,3 Hz, 4H), at 6.84 (d, J = 8,4 Hz, 2H), 4,08 (d, J = 7.5 Hz, 1H), 3,42 (Shir. s, 1H), 3,13 (Shir. s, 1H), 2,70-of 2.58 (m, 3H), 2,11 is 1.91 (m, 4H), 1,73-is 1.51 (m, 4H), 1.30 and of 1.16 (m, 5H), of 1.09 (d, J = 6,9 Hz, N), 0,86 (d, J = 6,7 Hz, 3H).

P R I m e R 34. Endo-(1S*, 2S*)-2-(3-benzyl-3-hydroxy-8-azabicyclo/3.2.1/Oct-8-yl-1-(4-hydroxyphenyl)- 1 - propanol

Using the procedure of example 3, the target product of the preceding example was turned into a real target product with a yield of 38% after instant chromatography and recrystallization from a mixture of ethyl acetate/hexane; so pl. 162-163aboutC.

13C-NMR: 156,97; 138,80. 135,86, 131,73, 129,11, 128,70, 127,07, 115,58, 76,09, 71,74, 64,64, 62,36, 54,62, 52,97, 45,82, 45,68, 29,28, 28,85, 14,50.

Using the procedure of the previous example, the target product of example 32 turns in the same product.

P R I m e R 35. Exo-(1S*, 2S*)- and (1R*, 2S*)-1-(4-hydroxyphenyl)-2-(3-perspire--8-azabicyclo/3.2.1/octane-3,2-oxir EN)-8-yl)-1-propanol

Using the procedure of example 3, Exo-(1S*, 2S*)/(1R*,2S*) mixture of example 31 was turned into a mixture of these target products with a yield of 93%. (1S*, 2S*)-isomer was separated with the help of immediate - tion chromatography and precrystallization from a mixture of ether and hexane; so pl. 115-117aboutC. the process chromatography also precrystallization from a mixture of ether and hexane; so pl. 107-110aboutC.

P R I m e R 36. 1-[4-(Triisopropylsilane(phenyl)-2-(4-hydroxy-4-finalpaper - Dino)-1-propanone

Using the procedure of example 1 4-hydroxy-4-phenylpiperidine turned into a real target product with a yield of 37% in the form of a light oil.

NMR 8,03 (d, J = 8.5 Hz, 2H), 7,47 (d, J = 8 Hz, 2H), 7,33 (t, J = 7.5 Hz, 2H), 7,26-7,24 (m, 1H), 6.89 in (d, J = 8.5 Hz, 2H), 4,08 (kV, J = 7.5 Hz, 1H), 2,90-2,60 (m, 2H), 2,25-2,10 (m, 2H), 1.85 to about 1.75 (m, 2H), 1,65-of 1.55 (m, 2H), 1.32 to-1,22 (m, 6N), 1,10 (d, J = 7 Hz, N).

P R I m e R 37. (1S*, 2S*)-1-[4-(Triisopropylsilyl)phenyl]-2- (4-hydroxy-4-phenylpiperidine)-1-propanol

Using the procedure of example 17, the target product of the preceding example was turned into a real target product with a yield of 87%; so pl. 148-151aboutC.

NMR 7,52 (d, J = 7 Hz, 2H), 7,38 (t, J = 7 Hz, 2H), 7,30-7,25 (m, 1H), 7,19 (d, J = 8.5 Hz, 2H), at 6.84 (d, J = 8.5 Hz, 2H), 4,23 (d, J = 9.5 Hz, 1H), 3,13-to 3.02 (m, 1H), 2,80-of 2.58 (m, 3H), 2,30-of 2.08 (m, 2H), 1,90-of 1.78 (m, 2H), 1,29-1,17 (m, 3H), of 1.09 (d, J = 7 Hz, N), of 0.79 (d, J = 6.5 Hz, 3H).

P R I m e R 38. (1S*, 2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine)-1-propanol

Target product, obtained using the procedure of example 3 from the target product of the preceding example with the release of 65%, was precrystallization from ethanol; i.e 8,05; N 4,00.

P R I m e R s 39-76. Using the methods of the previous examples was obtained following additional compounds, the yield is indicated by the purified material at the final stage:

39. 2-(4-Benzyl-4-hydroxypiperidine)-1-(4-hydroxyphenyl)-ethanol; 42%; so pl. 98-99oC (from ethanol);

40. (1S*, 2S*)-2-(4-benzyl-4-hydroxypiperidine)-1-(4-methoxyphenyl)-1-propanol; 36%; so pl. 145,5-146about(From a mixture of ethanol/ether);

41. (1S*, 2S*)-2-(4-benzyl-4-hydroxypiperidine)-1-(4-hydroxyphenyl)-1-pentanol; 55%; so pl. 158-159about(From a mixture of ethanol and ether);

42. (1R*, 2S*)-2-(4-benzyl-4-hydroxypiperidine)-1-(4-hydroxyphenyl)-1-pentanol; 37%; so pl. 156-157aboutC (from ether);

43. (1S*, 2S*)-2-(4-benzyl-4-hydroxypiperidine)-1-(4-hydroxyphenyl)-1-butanol; 53%; so pl. 190-191aboutC (from ethanol);

44. (1S*, 2S*(-2-(4-benzyl-4-hydroxypiperidine)-1-(4-methoxyphenyl)-1-butanol; 61%; so pl. 143-144about(Cleaned by using instant chromatography on silica gel using ethyl zitat/hexane gradient elution).

45. 2-(4-Benzyl-4-hydroxypiperidine)-1-(4-cyanophenyl)-ethanol; 52%; so pl. 142-143about(From a mixture of ethanol/ether/hexane);

46. 2-(4-Benzyl-4-hydroxypiperidine)-1-(2-hydroxyphenyl)ethanol; 43%; so pl. 172-173,6aboutC (from ethanol);

about(From a mixture of ethanol/ether);

49. (1S*, 2S*)-2-4-(4-chlorophenyl)-4-hydroxypiperidine)-1-(4 - hydroxyphenyl)-1-propanol; 59%; so pl. 204-206aboutC (from ethyl acetate);

50. 2-(4-Hydroxy-4-phenylpiperidine)-1-(2-thienyl/ethanol; 54% ; so pl. 167-168aboutC (from ethanol);

51. (1S*, 2S*)-Exo-1-(4-hydroxyphenyl)-2-[3-(2-tianity)-8-azabicyclo/3.2.1/Oct - 8-yl)-1-propanol; 30%; so pl. of 127.5-129about(From a mixture of ethyl acetate/hexane);

52. (1R*, 2S*)-Exo-1-(4-hydroxyphenyl)-2-3-(2-tianity)-8-azabicyclo/3.2.1/Oct-8-yl) -1-A19%; so pl. 141-142aboutC (from ethyl acetate);

53. (1S*, 2S*)-Exo-2-3-(4-chlorophenylthio)-8-azabicyclo/3.2.1/Oct - 8-yl)-1-(4-hydroxyphenyl)-1-propanol; 84%; so pl. 181-182aboutC (from ethyl acetate);

54. (1R*, 2S*)-Exo-2-3-(4-chlorophenylthio)-8-azabicyclo/3.2.1/Oct-8 - yl)-1-(4-hydroxyphenyl)-1-propanol; 94%; so pl. 154-156about(From a mixture of ethyl acetate and hexane);

55. (1S*, 2S*)-Exo-1-(4-hydroxyphenyl)-2-3-(4-methoxybenzylthio)- 8-azabicyclo/3.2.1/Oct-8-yl)-1-propanol; 55%; so pl. 118-119about(From a mixture of ethyl acetate and hexane);

56. (1R*, S*)-Exo-1-(4-hydroxyphenyl)-2-3-(4-methoxybenzylthio)- 8-azabicyclo/3.2.1/Oct-8-yl)-1-propanol; 37%; so pl. 72-75about(Instant chromatography on silica gel with elution using ethyl acetate/hexane gradient and trituration with hexane);

57. 1-(4-Cryptomate modafinil)-2-(4-hydroxy-4-phenylpiperidine)ethanol; 34%; so pl. 217-218aboutC (from ethanol);

59. (1S*, 2S*)-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(2-phenylethyl)-piperidino]-1 - propanol; 51%; so pl. 200-201aboutC (from ethyl acetate);

60. (1S*, 2S*)-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(3-phenylpropyl) piperidine]-1-propanol; 46%; so pl. 200,5-201aboutC (from ethyl acetate);

61. (1S*, 2S*)-2-[4-(4-forfinal)-4-hydroxypiperidine]-1-(4-hydroxyphenyl)-1-propanol ; 37%; so pl. 197-198aboutC (from ethyl acetate);

62. 1-(4-Cyanophenyl)-2-(4-hydroxy-4-phenylpiperidine)ethanol; 51%; so pl. 140-140,5about(From a mixture of ethanol and ether);

63. (1S*, 2S*)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-(4-were) piperidino)-1-propanol; 41%; so pl. 188-189aboutC;

64. 1-(4-Carbamoylphenoxy)-2-(4-hydroxy-4-phenylpiperidine)ethanol; 3%; so pl. 213,5-215aboutC (from ethanol);

65. (1S*, 2S*)-1-(4-hydroxyphenyl)-2-(3-endo-hydroxy-3-phenyl-8 - azabicyclo/3.2.1/Octan-8-yl)-1-propanol; 60% ; so pl. 216-217about(From a mixture of ethanol and ether);

66. (1S*, 2S*)-1-(4-forfinal)-2-(4-hydroxy-4-phenylpiperidine-1 - propanol; 44%; so pl. 177-179aboutC (from ethanol);

67. (1R*, 2S*)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine)-1-propanol; 25%; so pl. 162-155aboutC (from ethanol);

68. (1S*, 2S*)-2-(4-hydroxy-4-phenylpiperidine)-1-phenyl-1-propanol; 50% ; so pl. 149-152about(From a mixture of ethyl acetate and hexane);

69. (1S*, 2S*)-1-(4-horfe is hydroxy-4-phenylpiperidine)-ethanol; 47%; so pl. 156,5-158about(From a mixture of ethyl acetate/ether);

71. (1S*, 2S*)-2-(3-benzyl-3-hydroxypyrrolidine)-1-(4-hydroxyphenyl)-1-Pro - panol; 71%; so pl. 134-136aboutC;

72. (1S*, 2S*)-1-(4-Hydroxyphenyl)-2-(3-hydroxy-3-phenylpyrrolidine)-1-disappear - Nol; 56%; so pl. 74-78aboutC;

73. (1S*, 2S*)-1-(4-Chlorophenyl)-2-(4-hydroxy-4-(2-phenylethyl) piperidine)-1-propanol; 33%; so pl. 152-154aboutC (from ethanol);

74. (1S*, 2S*)-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(4-phenylbutyl)piperidine]-1-propane l; 44%; so pl. 191-192aboutC (from ethanol);

75. 1-(4-Carboxyphenyl)-2-(4-hydroxy-4-phenylpiperidine)ethanol; 98%; so pl. 254,5-255about(Of water);

76. 2-(4-Hydroxy-4-phenylpiperidine)-1-(4-methoxycarbonyl)phenyl)ethanol; 57%; so pl. 138,5-139,5about(From a mixture of ethanol and ether.

P R I m e R 77. (R-1-(4-Chlorophenyl)-2-(4-hydroxy-4-phenylpiperidine)ethanol

4-Hydroxy-4-phenylpiperidine (177 mg, 1 mmol) was dissolved in dry tetrahydrofuran (13 ml) and cooled to -15aboutWith under stirring in nitrogen atmosphere. Dropwise over 3 min was added utility (0.8 ml, 2 mmol, 2,5 BC).Oxide (-)-R-1-(4-chlorophenyl)ethylene (155 mg, 1 mmol), J. Am. Chem. cos., , 7925 (1987); J.Org. Chem. , 2861 (1988) was dissolved in 1 ml of tetrahydrofuran and added to the cold reaction mixture with rinsing (1 ml). The mixture was heated to room t is mperature and extinguished solid sodium bicarbonate. The crude reaction mixture was directly chromatographically on silica gel using elution utilize - tat/hexane gradient. The product-containing fractions carefully re-chromatographically on silica gel with elution with a mixture of 50% ethyl acetate/hexane, giving 112 mg (33%) of product as an oily foam. Rubbing with a mixture of ether-hexane gave 15,2 cream-colored product, which had so pl. 110-113aboutC; [ ]D= -18o.

(S)-1-(4-chlorophenyl)-2-(4-hydroxy-4-Fe - rilpivirine)ethanol having the same physical properties except the sign of rotation, were prepared in the same manner from (+)-S-1-(4-chlorophenyl)ethylene oxide.

P R I m e R 78. Enantiomeric (1S, 2S)- and (1R, 2R)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine)-1-propanol

(+)-Tartaric acid (300 mg, 2 mmol) was dissolved in 30 ml of warm methanol. Was added all at once racemic 1S*, 2S*-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenyl - piperidine)propanol (655 mg, 2 mmol). With stirring and gentle heating was obtained a colorless homogeneous solution. After standing at ambient temperature for 24 h was obtained 319 ml (66% ) of white crystalline precipitate. This product was precrystallization from methanol, Yes aboutC; [ ]D= -36,2aboutC. This salt (115 mg) was added to 50 ml saturated sodium bicarbonate. Ethyl acetate (5 ml) and this mixture was vigorously stirred for 30 minutes the Aqueous phase was re-extracted with ethyl acetate. Organic salts were combined and were washed with saline, dried over calcium sulfate and concentrated. Reddish-brown residue was precrystallization from a mixture of ethyl acetate/hexane, yielding 32 mg (39%) white programalso target product; so pl. 203-204aboutC; [ ]D= +56,9about.

Found,%: C 72,61; N 7,45; N 4,21.

WITH20H25NO3< / BR>
Calculated,%: C 73,37; N. Of 7.70; N 4,28.

The filtrate after receipt of (+)-tartrate above salt was treated with 100 ml saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The combined organic extracts were washed with saline, dried over calcium sulfate and concentrated, yielding 380 mg of recovered starting material (partially split). This material was processed (-)-tartaric acid (174 mg) in 30 ml of methanol, as described above. After standing for 24 h, filtration gave 320 mg (66%) of product, which was further precrystallization from methanol, giving 239 mg (-)-tamales in levogyrate target product as described above to yield 49%; so pl. 204-205aboutC; [ ]D= -58,4about.

Found,%: C 72,94; N. Of 7.64; N 4,24.

P R I m e R 79. (1S*, 2S*)-1-(4-Hydroxyphenyl)-2-(1,2,3,6-tetrahydro-4-penilee - to)-1 - propanol

By using the methods of examples 1, 2 and 3 4-(triisopropylsilyl)- -bromopropiophenone and 1,2,3,6-tetrahydro-4-phenylpyridine turned into a real target product with a yield of 14% on last stage; so pl. 208-211aboutC (decomp.).

The 8 preparation of 1-(2,2,2-Trichlorocyanuric)-3-Fe-ylmethylene-8-azabicyclo/3.2.1/octane

The solution benzyltriphenylphosphonium (13,26 g, to 43.1 mmol) in tetrahydrofuran (400 ml) was cooled to -78aboutWith and added utility (to 13.6 ml, 2.5 M in hexane, 34 mmol). This resulted in a heterogeneous organic mixture, which was stirred 5 min at -78aboutC and then warmed to 0aboutC. the Solution became nearly homogeneous red and added 11-2,2,2 trichlorocarbanilide (7,1 g, with 23.3 mmol; Montzka and others, Tetrahedron Letters, so-14, S. 1325, 1974) in tetrahydrofuran (20 ml with 20 ml of liquid after rinsing). The reaction mixture was heated at the temperature of reflux distilled for 4 days, cooled and filtered. The concentration of the filter gave a viscous brown oil. Instant chromatography on silica gel (3 x 6 inches) with the use of the so pl. 88-89aboutC; IR (KBr): 3437, 2958, 1700, 1445, 1425, 1321, 1125, 711.

Found,%: C 54,89; N 4,82; N Of 3.77.

Calculated,%: From 54.9; H 4,84; N 3,74.

Preparation of 2

3-Phenylmethylene-8-azabicyclo/3.2.1/octane

The mixture of the target product of the preceding preparation (1.0 g, to 2.67 mmol), powdered zinc (0.88 g, 46 mmol) and acetic acid (50 ml) stirred over night. The reaction mixture then was heated at 70aboutC for 22 h, then cooled and concentrated. The residue was distributed between a mixture of simple ether/ethyl acetate and saturated sodium bicarbonate, and the mixture is stirred for 30 min and then filtered through diatomaceous earth. The aqueous phase was separated and then extracted with ethyl acetate (2x). The combined organic layers were washed with water and brine, dried (CaSO4) and concentrated, giving 0.5 g of light yellow oil. Further purification was carried out by taking the oil in a 10% hydrochloric acid. This acidic solution was extracted with ethyl acetate (2x). The acid layer was neutralized ice with sodium hydroxide and again extracted with ethyl acetate. This organic layer was dried (CaSO4) and concentrated, obtaining 0.24 g (40%) light yellow oil;

NMR of 7.24 (m, 2H), 7,13 (d, J= 6,6 Hz, NR> An alternative product is transformed into its salt of hydrochloric acid by treating an acetone solution of gaseous hydrogen chloride.

Preparation of 3

4-(tert-Butyldimethylsilyloxy)impregnated - openen

4-Hydroxypropiophenone (15 g, 100 mmol) and imidazole was dissolved in dimethylformamide (50 ml). tert-Butyldimethylsilyloxy (19.6 g, 130 mmol) in dimethylformamide (40 ml) was added dropwise at room temperature. The mixture was stirred for 18 h, then was diluted with water (300 ml) and was extracted with ether (4 x 200 ml). The combined ether layers were washed 1M LiCl and brine, dried (CaSO4), was concentrated to obtain a solid oily substance, instant chromatography on silica gel using a mixture of 1: 10 ethyl acetate/hexane as eluent gave 26 g of the desired product which was then purified using a driving, giving of 23.2 g (88%) of purified target product as a hygroscopic white solid; T. pl. 30-31aboutC.

NMR 7,76 (d, J = Hz, 2H), 6,74 (d, J = Hz, 2H), 2,82 (kV, J = Hz, 2H), 1,09 (t, J = Hz, 3H), 0,87 (s, N), 0,11 (C, 6N).

Preparation of 4

4-(tert-Butyldimethylsilyloxy) - bromo - propiophenone

4-(tert-Butyldimethylsilyloxy(impregnated - openon (20 g, to 75.8 mmol) RA is Java color of bromine remained for about 1 min and then the reaction mixture is quickly discolor, once added bromine. The reaction mixture was stirred for 1 h, then concentrated, and instant chromatography of the residue on silica gel (elution with hexane) gave 7,12 g of oily product.

NMR a 7.92 (d, J = 9 Hz, 2H), 6,86 (d, J = 9 Hz, 2H), 5,22 (kV, J = 6,5 Hz, 1H), 1,85 (d, J = =6,5 Hz, 3H), of 0.96 (s, N) and 0.22 (s, 6N).

13WITH NMR: 76,73; 59,55; 40,47; 38,59; 37,68; 25,42.

Preparation of 5

O-methanesulfonate

According to the (14.2 g, 100 mmol) was dissolved in methylene chloride (210 ml) and triethylamine (23 ml, 160 mmol) was added to the solution. Methanesulfonanilide (9.3 ml, 120 mmol) was rapidly added dropwise. This caused a mild deregulirovanie methylenechloride solution. The mixture is stirred for 1 h, then was extracted with cold 0.5 M sodium hydroxide, water, brine, were dried by filtration through paper to separate the phases and concentrated, yielding 13.8 g (65%) of the desired product as a yellow solid.

NMR: 4,88 (t, J = 5 Hz, 1H), 3,10 was 3.05 (m, 2H), equal to 2.94 (s, 3H), 2,22 (s, 3H), 2,20-2,10 (m, 2H), 2,02-of 1.88 (m, 6H).

Preparation of 6

3 Phenylthio-8-methyl-8-azabicyclo/3.2. 1/octane

NaH (60% in oil; 2,77 g, 69 mmol) was washed three times with hexane and then suspended in tetrahydrofuran (300 ml). Type heaven was formed with the release of hydrogen, was stirred 10 min and then all at once was added O-methanesulfonate (13.8 g, 63 mmol in 25 ml of tetrahydrofuran). The mixture was heated at the temperature of reflux distilled over night, cooled and filtered through diatomaceous earth with simple washing with ether. The filtrate was diluted with ethyl acetate and washed with cold 1M NaOH, water and brine, dried (CaSO4) and concentrated, earning of $ 11.48 g (78%) of the desired product as a yellow solid.

NMR: 7,50-to 7.18 (m, 5H), 3,32-is 3.21 (m, 1H), 3,15-to 3.09 (m, 2H), of 2.25 (s, 3H), 2,02-of 1.94 (m, 2H), 1,79-1,72 (m, 4H), 1.60-to is 1.51 (m, 2H).

13WITH NMR: 134,8; 132,3; 128,8; 126,9; 61,16; 39,21; 38,38; 37,72; 26,42.

Preparation of 7

3 Phenylthio-8-(2,2,2-trichlorethene - bonyl)-8-azabicyclo/3.2.1/octane

The target product of the preceding preparation (11,48 g, to 49.3 mmol) and potassium carbonate (0.75 g, 5.4 mmol) was mixed with benzene (200 ml), and quickly was added dropwise 2,2,2-trihloretilamina (7.5 ml, of 54.4 mmol). The reaction mixture was heated at the temperature of reflux distilled for 2 hours, cooled, filtered and concentrated. The orange oily residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate and then brine, dried (CaSO4) and concentrated. The residue was purified instant chromatographie the rd thiophenol from the previous reaction and then the target product as a yellow oil. (13 g, 67%).

NMR 7,42-of 7.23 (m, 5H), 4.72 in (AV kV, J =12 Hz, 2H), 4,35-4,30 J (m, 4H), 2,73 (septet, J = =6 Hz, 1H), 2.05 is by 1.68 (m, 6N).

The oil was aterials by trituration with hexane; so pl. 83-84,5aboutC.

Found,%: C 48,47; N 4,58; N 3,49.

Calculated,%: C 48,58; N 4,60; N 3,55.

Preparation of 8

3 Phenylthio-8-azabicyclo/3.2.1/octane

The target product of the preceding preparation (13,0 g, 33 mmol) was dissolved in acetic acid (400 ml) was added powdered zinc (11 g, 168 mmol). The mixture was heated to 10aboutWith overnight, then concentrated and the residue was divided between methylene chloride and saturated sodium bicarbonate. The resulting emulsion was purified by filtration through diatomaceous earth. The phases were separated and the organic layer was dried using filter paper to separate the phases and concentrated, giving 6,1 g (84%) of the desired product as a yellow oil which hardened on standing.

NMR: 7,38 and 7.36 (m, 2H), 7,29-7,20 (m, 3H), 3,52 (s, 2H), 3,36 (septet, J = 6 Hz, 1H), 1,94-and 1.54 (m, 8H).

13WITH NMR: 134,0; 132,43; 128,83; 127,06; 54,93; 40,81; 39,01; 28,98.

Preparation of 9.

4-(Triisopropylsilyl)propipe-non

Using the method of preparation 3 4-hydroxypropiophenone and triisopropylsilyl(d, J = 8.5 Hz, 2H), 6.89 in (d, J = 8.5 Hz, 2H), 2,94 (kV, J = 7 Hz, 2H), 1.32 to to 1.15 (m, 3H), of 1.20 (t, J =7 Hz, 3H), of 1.09 (d, J = 7 Hz, N).

Preparation 10

4-(Triisopropylsilyl)- -bromopropiophenone

The target product of the preceding preparation (60,63 g, 198 mmol) was dissolved in carbon tetrachloride (1100 ml) was added dropwise a solution of bromine (11 ml, 210 mmol in 60 ml of CCl4). After was added portion of a solution of bromine, without any noticeable discoloration after 15 min, the two portions was added acetic acid (1.0 ml). The solution was bleached for 20 min and the addition was completed quickly and the Mixture was stirred for another 15 min; then volatile HBr was partially removed using a stream of nitrogen. The reaction mixture was poured into water (600 ml) and the phases were separated. The organic layer was washed with water, saturated sodium bicarbonate, water and brine, dried (CaSO4) and concentrated, giving the 76.2 g (100%) of the desired product as a transparent yellow oil.

NMR 7,94 (d, J = 9 Hz, 2H), 6,91 (d, J = 9 Hz, 2H), 5,24 (kV, J = 6,5 Hz, 1H), 1,87 (d, J = 6,5 Hz, 2H), 1,33-1,17 (m, 3H), 1,10 (d, J = 7 Hz, N).

Preparation 11

4-Fluoro - bromopropiophenone

Target product, prepared as in preparation 4, with 86% yield after distillation, Perekrest is,%: 46,47; N 3,38.

Calculated,%: C 4,78; N 3,49.

Cooking 12

4-Chloro - bromopropiophenone

The product prepared using the procedure 10 to 98% yield, was precrystallization from ethanol; so pl. 78-79aboutC.

Found,%: C 43,74; N 3,17.

Calculated,%: C 43,67; N 3,26.

Preparation of 13

Endo - and Exo-8-(2,2,2-trichlorocyanuric)-3-perspira-8 sabicic - lo/3.2.1/octane-3,2-oxiran)

The target product of preparation 2 (5.0 g, 13,34 mmol) was dissolved in dichloromethane (80 ml) was added m-perchlorobenzene acid (2,71 g, 13,35 mmol), 85% purity). After stirring at a suitable temperature overnight the mixture was extracted with saturated sodium bicarbonate, then with water and brine, dried with patristically paper and concentrated, giving 5.3g vitreous yellow oil, which was chromatographically on silica gel (elution gradient of ethyl acetate/hexane). The selected source material was elyuirovaniya first, and then quickly moving endo-epoxide product (2,23 g, 42.8 per cent); so pl. 78-79aboutC.

Found,%: C 52,75; N. Of 4.44; N 3,20.

Calculated, % : C 52,26; N With 4.64; N 3,59; and finally slowly moving Exo-epoxide product (2,32 g, 44.5 percent); so pl. 107-10 Olenye 14

Endo - and Exo-3-perspira-8-azabicyclo/3.2.1/octane-3,2-oxiran

Fast-moving endo-product of the preceding example (1.55 g, of 3.97 mmol) was dissolved in tetrahydrofuran (30 ml) was added zinc powder (9.3 g, 142 mmol) and 1M monopotassium phosphate (10 ml). After stirring over night the mixture was diluted with water (10 ml), the pH value was brought to 10-11 using NaCO3and filtered through diatomaceous earth, washing with ethyl acetate and water. The water layer in the combined filtrate and washing was separated and washed with fresh ethyl acetate. The combined organic layers were washed with saline, dried (calcium sulfate) and atarivalis, giving 0,85 g (100%) endo-target product as a yellow oil. Distillation (bath temperature 110-115aboutWith 0.5 mm) gave endo-target product as a clear colorless oil.

NMR: 7,34-of 7.23 (m, 5H), 3,63-of 3.60 (m, 2H), 3,55 (m, 1H), 2,36 (D. d, J = 14.1 and 3.5 Hz, 1H), 2,17-2,12 (m, 2H), 1,83-of 1.81 (m, 2H), 1.70 to to 1.61 (m, 2H), 1,42 (dt, J =11,9 and 2.2 Hz, 1H), 1,18 (dt, J = 14.5 m, and 2.3 Hz, 1H).

S 215.1301.

Calculated: 215.1308.

Using this same method of slow moving isomer of the preceding preparation was transformed into the corresponding Exo-isomer with the release of 96%, was purified by distillation (isleno,%: 78,10; N OF 7.96; N 6,51.

1. DERIVATIVES of 2-PIPERIDINO-1-ALKANOL General formula I

< / BR>
where R is hydrogen or C1- C3-alkyl;

Q is the group - CH=CH - or - S -;

X is hydrogen, halogen, OR1, COOR1, NH2, CONH2or R1CONH, where R1is hydrogen or C1- C3-alkyl;

D - group

< / BR>
where Y is hydrogen

Y1- benzyl, unsubstituted or 4-halogen, or 4-methoxyphenyl phenylthio or 2-tianity, when Y OH Y1is phenyl or benzyl, or Y and Y1together form the group =CH - C6H5or

or group

< / BR>
where Y2- hydrogen Y3- benzyl or (O)nSC6H5where n = 0 or 2 if Y2- OH

where m = 0,1, 2, 3, or 4,

R2is hydrogen, methyl or halogen,

or D - group

< / BR>
where l = 0 or 1,

or D - group

< / BR>
2. Connection on p. 1, wherein Q is - CH=CH - , X is a substituent in the 4-position of the phenyl ring and represents hydroxy, fluorine or chlorine, D is a

< / BR>
3. Connection on p. 2, characterized in that R is methyl having the 1S*, 2S*the relative stereochemistry:

< / BR>
4. Connection on p. 3, wherein X is 4-hydroxy and Y

6. Connection on p. 3, characterized in that X represents a 4-hydroxy and Y3- phenyl or 4-chlorophenyl.

7. Connection on p. 6, characterized in that D is a

< / BR>
8. Connection on p. 7, characterized in that Y2represents hydroxy and Y3is phenyl.

9. Connection on p. 8, characterized in that it is a (+) - (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine)-1-propanol.

10. Connection on p. 8, characterized in that it is a (-) - (1R, 2R)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine)-1-propanol.

11. Connection on p. 1, wherein D represents the

< / BR>
12. Connection on p. 11, characterized in that R is methyl having the 1S*,2S*the relative stereochemistry of

< / BR>
13. Connection on p. 12, wherein Q represents - CH= CH - and X is hydroxy.

14. Connection on p. 13, wherein Y and Y1taken together and represent phenylmethylene.

15. Connection on p. 13, wherein Y and Y1taken together and represent

< / BR>
16. Connection on p. 13, wherein Y and Y1taken separately.

17. The compound of General formula
< and B together form = 0 or one of a or B - the hydroxyl and the other is hydrogen;

E - group

< / BR>
where Y is hydrogen, Y1- C6H5S Y OH Y1is phenyl or benzyl, or E - group

< / BR>
where Y2- hydrogen Y3- C6H5S, when Y2- OH Y3- benzyl, or Y2and Y3together form a group



 

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FIELD: pharmaceutical industry.

SUBSTANCE: invention is characterized by that system contains underlayer, therapeutical substance storage layer, and agent attaching the system on the person's skin and allowing access of nicotine to skin. System is transparent (opacity factor below 48.6%).

EFFECT: facilitated transcutaneous transport of nicotine.

8 cl, 1 tbl

FIELD: medicine, gynecology, anesthesiology.

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7 tbl, 4 ex

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SUBSTANCE: method involves delivering nicotine to patient organism and administering medicament by smearing internal surface of superior and inferior nasal passage part. Treatment is carried out with cigarette consumption being retained. Smell receptor canal blocker like rapid sodium canal blocker lidocaine is used as the medicament. Its aerosol is introduced immediately before smoking action as single jet in each nasal passage. Medicament introduction is localized with epithelial smell receptor cells arrangement.

EFFECT: enhanced effectiveness of treatment.

2 cl, 2 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the development of medicines used for enhancing resistance of humans and animals to hypothermia. Agent for enhancing resistance of humans and animals to hypothermia comprises nicotinic acid, glutamic acid, riboflavin, ascorbic acid, uniquinone, succinic acid, polyethylene oxide and water taken in the definite ratio. Also, invention proposes a method for enhancing resistance of humans and animals to hypothermia involving administration of the abovementioned agent 30 min before works associated with hypothermia and after its termination for activation of vital essential biochemical processes. Invention provides enhancing resistance to overcooling under extreme conditions and using in surgery practice in cooling organs (in operations in heart and brain).

EFFECT: enhanced effectiveness and valuable medicinal properties of agent.

2 cl, 2 tbl, 1 dwg, 2 ex

FIELD: medicine, vitamins.

SUBSTANCE: invention proposes a composition of vitamins riboflavin and nicotinic acid (niacin) or nicotinamide for treatment of primary headaches representing usual migraine, classic migraine, migraine combined with "histamine" headache. The composition comprises the combination of 0.5-750 mg of nicotinic acid (niacin or nicotinamide) and 0.1-250 mg of riboflavin. Also, the invention involves the corresponding method for treatment. Proposed treatment provides body with necessary NAD/NADP and FAD/FMN in order to modulate activity of mast cells when changes in their secretion results to migraine. Method provides disappearance of all migraine symptoms during the next 20 months of dispensary observation.

EFFECT: enhanced medicinal effectiveness of vitamins.

13 cl

FIELD: pharmacy.

SUBSTANCE: invention proposes a liquid pharmaceutical composition containing nicotine in any form for administration into the mouth cavity and alkalinized with a buffer and/or by regulation of pH value. Administration is carried out preferably by spraying and the most preferably by sublingual spraying. Also, invention relates to a method for preparing the indicated composition. Use of indicated composition in therapy, such as therapy for treatment of addiction to tobacco.

EFFECT: valuable pharmaceutical properties of composition.

51 cl, 11 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) and its pharmaceutically acceptable salts. In general formula (I) , Y represents group -CONH(Q)- or -NHCONH(Q)-; Q represents 6-member aromatic ring or 5-10-member heteroaromatic ring, containing one or two N heteroatoms or two O heteroatoms; R represents hydrogen, halogen, linear or branched (C1-C6)alkyl; (C1-C6)alkoxy; di-(C1-C6)alkylamino, 5-member heteroaromatic ring, containing one O or S heteroatom; 6- or 9-member heteroaromatic ring, containing one or two N heteroatoms; phenyl, mono- or disubstituted with halogen, (C1-C6)alkyl, halogeno(C1-C6)alkyl, (C1-C6)alkoxy, acyl; hydroxy; piano; di-(C1-C6)alkylamino, acylamino' carbamoyl; X represents group : where Z represents CH2, N or O; m represents integer number from 1 to 3; p is equal 0, 1; R" is selected from group, consisting of di-( C1-C6)alkylaminocarbonyl, (C1-C6)alkyl, acyl. Invention also relates to pharmaceutical composition, containing as active ingredient, invention compound, to application of invention compound for manufacturing pharmaceutical composition, to method of inhibition of nicotinic acetylcholine receptor α7.

EFFECT: obtaining compound, which possesses agonistic activity with respect to nicotinic acetylcholine receptor (nAChR) α7.

7 cl, 2 tbl, 4 dwg, 270 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemical derivatives of adamantane and specifically to a novel method of producing 2-(2-alkyl(dialkyl)amino)adamantyl-alkyl(aryl)ketones of general formula R=-NHCH3: R1=Et,-CH2-CH=CH2; : R1=Me, Et,-CH2-CH=CH2, Ph,-CH2Ph; : R1= Me, Etwhich can be used as intermediate products in synthesis of certain biologically active substances. The novel method involves reacting 2-alkylamino(dialkylamino)-2-cyanoadamantanes from the group: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents from the group: methylmagnesium iodide, ethylmagnesium bromide, allylmagnesium chloride, phenylmagnesiuim bromide, benzylmagnesium chloride in a medium of dry diethyl ether or a tetrahydrofuran-ether mixture in molar ratio of reagents equal to 1:2-2.03, respectively, at temperature 30-45°C for 4-5 hours.

EFFECT: wider range of adamantane derivatives, design of a method for synthesis of novel adamantane derivatives with high output.

9 ex

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