The method of obtaining substituted 3-aminopiperidine

 

(57) Abstract:

Usage: in medicine as an anti-inflammatory drug. The inventive products - substituted 3-aminopiperidine f-ly I, where R1is phenyl or substituted phenyl, C3-C7- cycloalkane, hydroxy, amino, C1-C4-alkylamino - C1-C4-alkyl, phenyloxy, naphthyl, thienyl, hinely, R2is phenyl. Reagent 1: aminopiperidin f-crystals II, where R2is phenyl. Reagent 2: aldehyde f-ly R1CHO. Reaction conditions: in the midst of a solvent in the presence of reductant: 9 C.p. f-crystals, 1 table.

The invention relates to new methods of stereoselective obtain derivatives substituted piperidino.

Substituted piperidine and related compounds, which can be obtained by the methods of the present invention are antagonists against the receptor for substance P, and therefore they can be used in the treatment of diseases associated with excessive amounts of substance P.

Substance P is a natural undecapeptide belonging to the peptide family of tachykinins, which was named due to its rapid stimulatory effect on smooth fabric is carried out in mammals (it was first isolated from the intestines) and has a characteristic amino acid sequence, illustrated by D. F. Veber, etc. in U.S. patent N 4680283.

Broad involvement of substance P and other tachykinins in the pathophysiology of a large number of diseases is sufficient detail in the literature. For example, it was shown that substance P is involved in the transmission of pain and migraine (see, B. E. B. Sandberg and others , Journal of Medicinal Chemistry, Vol. 25, p. 1009 (1982)), and Central nervous system disorders such as anxiety and schizophrenia; for respiratory and inflammatory diseases, such as asthma and rheumatoid arthritis, respectively; rheumatic diseases, such as fibrosis, and diseases of the gastrointestinal tract, such as ulcerative colitis and Crohn's disease, etc., (see D. Regoli in "Trends in Cluster Headache", ed. Sicnteri, etc., Elsevier Scientific Publishers, Amsterdam, 1987, p. 85-95).

Some substituted piperidine and related compounds that can be obtained by the methods of the present invention claimed in a patent application under the PCT (PCT/US 90/00116), filed on January 4, 1990; in application for U.S. patent reg. N 07/717943 filed June 20, 1991, and in the patent application U.S. reg. N 07/724268, podanej July 1991 under the name "3-Aminopiperidine Derivatives and Related Nitrogen Containing Hetercycles" ("3-aminopiperidine derivatives and related nitrogen-containing heterocycles"), and su is referred to in the application for U.S. patent, submitted November 27, 1991 and entitled "Preparation of Substitited Piperidines" ("Getting substituted piperidino"), and such application and the present application have a common assignee.

The present invention relates to a method for obtaining compounds of the formula:

< / BR>
where R1is an aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from tanila, furil, pyridine and chinoline, and cycloalkyl having 3-7 carbon atoms, where each of the aforesaid aryl and heteroaryl groups may be optionally substituted by one or more substituents, as indicated (C3-C7)-cycloalkyl group may be optionally substituted by one or two substituents, independently selected from chloro; fluorescent; bromo; iodo; nitro; (C1-C10)-alkyl, optionally substituted by 1-3 fluorescent-groups; (C1-C10)-alkoxy group, optionally substituted by 1-3 fluorescent-groups; amino; (C1-C10)-alkyl-S-; (C1-C10)-alkyl, (C1-C10)alkyl - SO2; phenyl; phenoxy; (C1-C10) alkyl-SO2NH -; AND (C1-C10)alkyl-SO2NH- (C1-C10)alkyl-; (C1-C10)alkyl-amino, di(C1-C10)alkyl; cyano; hydroxy>C10) alkyl , where the nitrogen atoms of these amino - and (C-C)-alkylamino-groups may be optionally protected with appropriate protecting group, and R2is thienyl, benzhydryl, naphthyl or phenyl, optionally substituted by 1-3 substituents selected from chloro-, bromo-, fluorescent-, iodo-, cycloalkane group having 3-7 carbon atoms; (C1-C10) alkyl, optionally substituted by 1-3 fluorescent-groups, and (C1-C10) alkoxy, optionally substituted 1-3 fluorescent-groups; this method lies in the fact that the compound of the formula:

< / BR>
where R1defined above,

subjected to the reaction of either (a) with the compound of the formula where R1defined above, and X is a leaving group (e.g. chloro, bromo, iodo, or imidazole), followed by treatment of the obtained amide reducing agent, or (b) with the compound of the formula R1CHO, where R1defined above, in the presence of a reductive agent, or (c) with the compound of the formula R1CH2X, where R1defined above, and X is a leaving group (e.g. chloro, bromo, iodo, mesilate or tosylate).

Used in the present description, the term "halogen" refers to chloro-, bromo-, fluorescent - Il is Temernik forms. The above formula I includes all optical isomers of these compounds and mixtures thereof.

The present invention also relates to a method for formula I above where R1and R2are the same as defined above, which compound of formula IV above where R2are such as it was defined above, is subjected to reaction with the compound of the formula R1CHO, where R1defined above, in the presence of a desiccant or using a device designed for azeotropic removal of the water formed, resulting in a gain amine of the formula:

< / BR>
where R1and R2defined above,

which is then subjected to reaction with a reducing agent and get a connection formula I above where R1and R2are the same as defined above.

The present invention also relates to a method for obtaining compounds of formula I above where R1and R2defined above, which compound of formula

< / BR>
where R2defined above,

is subjected to reduction reaction of obtaining the compounds of formula IV, the nogo thus the compounds of formula IV to the compound of formula I using one of the above procedures.

The present invention also relates to a method for obtaining compounds of formula I above where R1and R2defined above, which compound of formula

< / BR>
subjected to reaction with hydrogen in the presence of a catalyst containing a metal, and get a connection of the above formula IV, where R2defined above, which is then converted into a compound of formula I, using one of the above procedures.

The methods and products of the present invention is illustrated in the reaction scheme below. In this reaction scheme, as well as the following reasoning, formulas I, II, III, IV, and the substituents R1, R2and X are as defined above, if it is not specifically mentioned.

< / BR>
The reaction of the compound of formula IV with the compound of the formula R1CHO obtaining the compounds of formula I are usually carried out in the presence of a reducing agent, such as cyanoborohydride sodium, triacetoxyborohydride sodium, borohydride sodium, hydrogen and a metal catalyst, zinc and hydrochloric acid or formic acid at a temperature of from about -60oC to about 50oC. Suitable inert solvents for furan (THF). Preferably, if the solvent is acetic acid, the temperature is 25oC; regenerating agent is triacetoxyborohydride sodium. This reaction leads to the formation of compounds in which the joining of the side chain CH2R1the 3-amino group is selectively, and the isomer of the formula I is the only dedicated product.

The alternative reaction of the compound of formula IV with the compound of the formula R1CHO can be carried out in the presence of a drying agent or by using a device designed for azeotropic removal of the water formed, to obtain the imine of the formula:

< / BR>
and subsequent reaction of this imine with a reducing agent, described above, are preferably triacetoxyborohydride sodium, approximately at room temperature. Getting imine is usually carried out in an inert solvent, such as benzene, xylene or toluene, preferably toluene, at a temperature of from about 25oC to about 110oC, and preferably approximately at the temperature of distillation of the solvent. Suitable desiccant systems/solvent are titanium tetrachloride/dichloromethane, isopropoxide titanium/dichlorotriazinyl the compounds of formula IV with the compound of the formula R1CH2X mainly is carried out in an inert solvent such as dichloromethane or THF, preferably in dichloromethane, at a temperature of from about 0oC to about 60oC, preferably at about 25oC.

The reaction of the compound of formula IV with the compound of the formula mainly carried out in an inert solvent, such as tetrahydrofuran (THF) or dichloromethane, at a temperature of from about -20oC to about 60oC, and preferably in dichloromethane at about 0oC. Recovering the resulting imide carried out by processing the regenerating agent, such as dimethyl sulfide complex boron, alumoweld lithium or hydride diisobutylaluminum, in an inert solvent, such as ethyl ether or THF. The reaction temperature is in the range of about 0oC and approximately to the temperature of distillation of the solvent. Preferably, if the reduction is performed with the use of complex dimethylsulfate boron with THF at a temperature of about 60oC.

Reaction recovery of pyridine of the formula II to the corresponding piperidine derivatives of formula IV are usually conducted using either sodium in alcohol, or lithium aluminum hydride/trichloride aluminum; Elektricheskiye using sodium usually carried out in boiling alcohol, preferably butanol, at a temperature of from about 20oC and approximately to the temperature of distillation of the solvent, and preferably at about 120oC. Recovery using lithium aluminum hydride/trichloride aluminum is usually carried out in ether, THF or dimethoxyethane, preferably in air, at a temperature of from about 25oC to about 100oC, and preferably at room temperature. Electrolytic recovery is carried out preferably at room temperature, but are also acceptable temperature from about 10oC to about 60oC.

The preferred method of recovery is hydrogenation in the presence of a metal-containing catalyst. Suitable catalysts are palladium, Nickel, platinum oxide and rhodium. The preferred hydrogenation catalyst is platinized carbon. The reaction temperature may vary from about 10oC to about 50oC , and preferably the reaction temperature is about 25oC. the Hydrogenation is usually carried out at a pressure of about 1.5 ATM to about 4 ATM, and preferably at about 3.0 ATM, in a suitable inert solvent, such as acetic acid or nits the establishment carried out by hydrogenation in the presence of a metal-containing catalyst, they devised exclusively compound CIS-configuration, and in contrast to the 2-phenyl part of the pyridine ring selectively restore.

Obtaining compounds of formula IV from the corresponding compounds of the formula III is carried out, as described above, by treating compounds of formula III with hydrogen in the presence of metal catalyst such as platinum or palladium. Typically this reaction is carried out in an inert solvent, such as acetic acid or a lower alcohol, at a temperature of from about 0oC to about 50oC. Alternative the compounds of formula III can be processed soluble metal, such as lithium or sodium in ammonia at a temperature of from about -30oC to about -78oC, or formatted salt in the presence of palladium or cyclohexanol in the presence of palladium. Preferably the compounds of formula III is treated with hydrogen in the presence of palladium charcoal in a mixture of methanol and ethanol in water or methanol and ethanol containing hydrochloric acid, at a temperature of approximately 25oC. If the compounds of formula III is treated with hydrogen in the presence of a metal-containing catalyst, the only isolated product are desired connection Formonov ring (i.e., communication between the nitrogen in position 1 and the carbon in position 2).

The starting materials of the formula , R1CHO and R1CH2X, used in the above reactions are either commercially available materials, or materials obtained from commercially available materials by standard transformations well known to specialists in this field.

In each of the above reactions, where one piperidino derived transform into another piperidino derived (i.e. III _ IV and IV _ I), the absolute stereochemistry at carbons at positions 2 and 3 piperidino ring is retained. Therefore, for each of these reactions, racemic mixture, or pure enantiomer can be obtained using the appropriate starting material, having the same stereochemistry.

The separation of racemic mixtures of compounds of formula I to obtain (+) enantiomer of the compounds, usually carried out using an inert solvent, such as methanol, ethanol or isopropanol, preferably isopropanol. This separation is preferably conducted by mixing a racemic mixture of compounds of formula I and (R)-(-)-almond acid in isopropanol, and mix atorny the precipitate recrystallized twice from isopropanol, then the recrystallized precipitate is transformed into free base of optically pure compounds of formula I by its distribution between dichloromethane and aqueous base, such as sodium hydroxide, sodium bicarbonate or potassium bicarbonate, preferably sodium hydroxide, or by mixing an alcoholic solution of the salt with a basic ion exchange resin. The free base is dissolved in methylene chloride, may then be converted into the corresponding salt of hydrochloric acid. The selection of mandelate can be carried out at a temperature of from about 0oC to 40oC. the Preferred temperature is about 25oC.

In each of the reactions discussed or illustrated above, pressure is not critical, unless otherwise noted. Usually acceptable pressure is from about 0.5 MPa to about 5.0 MPa, for the sake of convenience it is preferable to ambient pressure, i.e., about 1 ATM.

The compounds of formula I and their pharmaceutically acceptable salts detect antagonistic activity against the receptor for substance P, and therefore they can be used for the treatment and prevention Shiro is: reduction of the level of neurotransmission, mediated by substance P. These conditions are inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory diseases of the intestinal tract), anxiety, depression, or dysthymia, colitis, psychosis, pain, allergies such as allergic eczema and rhinitis, chronic obstruction of respiratory tract disorders associated with increased sensitivity, such as poisoning; violations associated with narrowing of the blood vessels, such as angina, migraine and Raynaud's disease; fibrosis and collagen disorders, such as scleroderma and eosinophilic fascioliasis; reflex sympathetic dystrophy such as shoulder syndrome; addiction, for example, chronic alcoholism; somatic disorders associated with stress; peripheral neuropathy, neuralgia, neurotic diseases disorders, such as Alzheimer's disease; dementia associated with AIDS, diabetic neuropathy and multiple sclerosis; disorders associated with increased or immune suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrosis. Therefore, these compounds can be easily adapted for use as antagonists to the receptor substan the tea man.

The compounds of formula I and their pharmaceutically acceptable salts can be administered orally, parenterally, or by external application. Most preferably, if the daily dose of these compounds is from about 5.0 mg to about 1500 mg, although this dose may vary depending on the weight and condition of the patient, and the specific way of introduction. However, the most preferred interval used dose ranges from about 0.07 mg to about 21 mg per day.

The following examples are only illustrative of the methods and compounds of the present invention, but not limit its scope.

As mentioned above, the source materials used in reactions of this invention are commercial products or can be obtained from commercially available materials by implementing standard transformations well known to specialists in this field. The following table shows the derivation of the aldehydes of the formula R1CHO used in the examples. Standard transformation used to obtain these aldehydes, identified by one or more lowercase letters in a column of the table entitled "serial reaction is according to the standard reaction schemes:

a) Cl2CHOCH3, TiCl4;

b) Dimethylsulfate;

c) Br2/HOAc;

d) Cyclopentylamine;

e) Methyliodide;

f) acetylchloride;

g) NaOCH2CF3;

h) the Nickel catalyst of the Raney, HCO2H;

i) SeO2;

j) 1) Carbonyldiimidazole, 2) N,O-dimethylhydroxylamine, 3) diisobutylaluminum hydride;

k) BBr3;

l) t-butyl chloride/AlCl3;

m) Cl2CHOCH3/AlCl3;

n) Ethyliodide;

p) ClF2CH;

q) Isopropylamine;

r) H2Pd/C, HCHO;

c) 1) Methanol/HCl, 2) methylsulfinylpropyl, 3) methyliodide, 4) diisobutylaluminum hydride, 5) MnO2;

t) the set of metilsulfate boron; monoperoxyphthalic acid, uranyl salts of magnesium; H2-Pd/BaSO4.

Example 1. (+)-(2S,3S)-3-Amino-2-phenylpiperidine.

In a vessel were placed 9 g of 10% palladium charcoal, 180 ml of methanol, 275 ml of ethanol, and 6.5 ml of concentrated hydrochloric acid and 9 g of hydrochloride (2S, 3S)-3-(2-methoxybenzylamine)-2-phenylpiperidine. The resulting mixture was shaken in a hydrogen atmosphere (40 psi = 275,76 kPa) during the night, then to this was added 9 g of catalyst, and the mixture was shaken in a hydrogen atmosphere for 1 day. After that, the mixture was diluted with water and ltrate concentrated to a final volume of about 600-700 ml, was podslushivaet concentrated aqueous solution of sodium hydroxide and was extracted with chloroform, and the chloroform extracts were dried with sodium sulfate and concentrated, resulting in a received 4.4 g of the target compound as a colorless oily substance.

[D] (HCl salt) = + 62,8o(c = 0,46, methanol (CH3OH)).

1H-NMR (CDCl3) : 1,68 (m, 4H); 2,72 (m, 1H); 2,94 (Shir. s, 1H); and 3.16 (m, 1H); of 3.80 (d, 1H, J=3); from 7.24 (m, 5H).

VRMS for C11H16N2(high resolution mass spectroscopy): calculated: 176,1310; found: 176,1309.

Calculated for C11H16N22HCl1/3H2O: C 51,78; H OF 7.36; N 10,98.

Found: C 51,46; H 7,27; N 10,77.

Example 2. (+)-(2S,3S)-3-(2,5-Dimethoxyaniline)-2-phenylpiperidine.

In a round bottom flask under nitrogen atmosphere were placed 600 mg (3.4 mm) of (+)-(2S, 3S)-3-amino-2-fenpiverinia, 8 ml of acetic acid and 622 mg (3.7 mm) of 2,5-dimethoxybenzaldehyde, and the resulting mixture stirred for 30 minutes Then to this system was added 1,58 (7.5 mm) triacetoxyborohydride sodium, and the mixture was stirred at room temperature overnight. After the mixture was concentrated, acidified using 1M aqueous solution of sodium hydroxide and was extracted with methylene chloride. Extracts met the slots were podslushivaet 1M aqueous solution of sodium hydroxide and was extracted with methylene chloride. The methylene chloride extracts were dried with sodium sulfate and concentrated, resulting in a received 528 mg of colorless oily substance. This oily substance was dissolved in methylene chloride and the resulting solution was added ether saturated with hydrogen chloride. The obtained white solid was collected by filtration and stirred in isopropanol at 60oC for 2 hours by filtering the received 414 mg of the target compound as hydrochloride. Supplementary material (400 mg) was obtained by extraction of the source of the base layer with the addition of methylene chloride, dried with sodium sulfate and concentration.

[D] (HCl-salt) = + 60,5o(c = 0,58, CH3OH).

1H-NMR (CDCl3) : to 1.38 (m, 1H); was 1.58 (m, 1H); of 1.88 (m, 1H); 2.13 in (m, 1H); 2,78 (m, 2H); of 3.25 (m, 1H); to 3.36 (d, 1H, J=18); 3,44 (s, 3H); 3,62 (d, 1H, J=18); and 3.72 (s, 3H); 3,88 (d, 1H, J=3); 6,62 (m, 3H); from 7.24 (m, 5H).

MS: m/z 326.

Calculated for C20H26N2O22HCl0,25H2O: C 59,48; H 7,11; N 6,93.

Found: C 59,33; H 6,91; N 7.23 Percent.

Example 3. CIS-amino-2-phenylpiperidine.

In a vessel were placed 2.65 g (15,6 mm) 3-amino-2-phenylpiperidine, 10.6 g of a 5% platinized carbon and 106 ml of 1.5 M HCl in methanol. The mixture was shaken in an atmosphere of hydrogen is Loy diatomaceous earth, then this layer is washed with approximately 700 ml of water. The obtained filtrate was podslushivaet using solid sodium hydroxide and was extracted with two portions of dichloromethane. Then the combined organic fractions were washed with water, dried with sodium sulfate and concentrated on a rotary evaporator, resulting in a 2.4 g of the target compound as a yellow oily substance.

Elemental analysis for CH11H16N2O0,25H2O:

Calculated: C 73,08; H 9,20; N 15,89.

Found: C 72,80; H 9,46; N 15,84.

The target compounds of examples 4-23 and 25-81 were obtained either from (+)-(2S, 3S)-3-amino-2-phenylpiperidine, or from the corresponding racemate by applying an appropriate aldehyde and procedure analogous to the procedure described in example 2.

Example 4. CIS-3-(4,5-Diptera-2-methoxybenzylamine)-2-phenylpiperidine

1H-NMR (CDCl3) : of 1.30 (m, 1H); of 1.62 (m, 2H); 1,96 (m, 1H); of 2.68 (m, 2H); 3,18 (m, 2H); of 3.32 (s, 3H); 3,44 (d, 1H, J=14); 3,82 (d, 1H, J=3); 6,38 (DD, 1H, J=6,12); 6,66 (DD, 1H, J=8,10); 7,16 (m, 5H).

VRMS for C19H22N2F2O: calculated: 332,1697. Found: 332,1698.

Elemental analysis for C19H22N2OF22HCl0,85H2O:

Calculated: C 54,25; H X 6.15; N 6,66.>SUP>1H-NMR (CDCl3) : the 1.44 (m, 1H); to 2.06 (m, 1H); 2,78 (m, 2H); 3.24 in (m, 1H); 3.40 in (d, 1H, J=12); 3,88 (d, 1H, J=3); of 6.75 (m, 1H); 6,92 (m, 2H); 7,26 (m, 5H).

VRMS for C18H20N235ClF: calculated: 318,1294. Found: 318,1280.

Example 6. CIS-3-(2-ethoxybenzylidene)-2-phenylpiperidine.

1H-NMR (CDCl3) : of 1.10 (t, 3H, J=5); of 1.40 (m, 1H); of 1.62 (m, 1H); 1,90 (m, 1H); and 2.14 (m, 1H); 2,80 (m, 2H); 3.27 to (m, 1H); 3,38 (d, 1H, J=15); of 3.69 (m, 3H); 3,86 (d, 1H, J=2); only 6.64 (d, 1H, J=8); is 6.78 (t, 1H, J=6); 6,94 (d, 1H, J=6); for 7.12 (t, 1H, J=8); from 7.24 (m, 5H).

VRMS for C20H26N2O: calculated: 310,2041. Found: 310,2045.

Example 7. CIS-3-(2-hydroxyethylamino)-2-phenylpiperidine.

1H-NMR (CDCl3) : of 1.62 (m, 3H); 2,10 (m, 1H); and 2.79 (m, 1H); 2,92 (m, 1H); 3,20 (m, 1H); of 3.48 (s, 2H); 3,82 (d, 1H, J=2); 6,72 (m, 3H); was 7.08 (m, 1H); of 7.36 (m, 5H).

VRMS for C18H22N2O: calculated: 282,1732. Found: 282,1724.

Elemental analysis for C18H22N2O2HCl2H2O:

Calculated: C 55,26; H 7,20; N 7,16.

Found: C 55,13; H 7,12; N 6,84.

Example 8. CIS-3-(3,5-Diptera-2-methoxybenzylamine)-2-phenylpiperidine.

1H-NMR (CDCl3) : of 1.45 (m, 3H); of 1.64 (m, 1H); to 1.86 (m, 1H); of 2.08 (m, 1H); 2,80 (m, 2H); 3.24 in (m, 1H); 3,44 (d, 1H, J=15); of 3.54 (d, 1H, J=15); 3,68 (s, 3H); 3,90 (d, 1H, J=3); to 6.57 (DD, 1H, J=8, 9); 6,69 (DD, 1H, J=9, 12); 7,28 (m, 5H).

VRMS for C19H22N2HCl:

Calculated: C 56,30; H 5,97; N 6,92.

Found: C 56,17; H Of 5.84; N 6,59.

Example 9. CIS-3-(2-chloro-6-foraminiferida)-2-phenylpiperidine.

1H-NMR (CDCl3) :of 1.40 (m, 1H); of 1.66 (m, 1H); 1,90 (m, 1H); to 2.15 (m, 1H); 2,78 (m, 2H); 3,26 (m, 1H); 3,68 (d, 2H, J=18); and 3.72 (d, 1H, J=18); PC 6.82(m, 1H);? 7.04 baby mortality (m, 2H); 7,22 (m, 5H).

VRMS for C18H20N2ClF2HCl2/3H2O:

Calculated: C 53,56; H Of 5.83; N 6,95.

Found: C 53,63; H Of 5.53; N 6,83.

Example 10. (2S, 3S)-3-(5-chloro-2-methoxybenzylamine)-2-phenylpiperidine.

So pl. 275-277oC (HCl-salt).

1H-NMR (CDCl3) : of 1.40 (m, 1H) and 1.60 (m, 1H); 1,90 (m, 1H); of 2.08 (m, 1H); and 2.79 (m, 2H); 3,26 (m, 1H); to 3.36 (d, 1H, J=15); of 3.45 (s, 3H); of 3.60 (d, 1H, J= 15); 3,88 (d, 1H, J=3); 6,56 (d, 1H, J=8); 6,92 (d, 1H, J=3); 7,06 (DD, 1H, J=3, 8); 7,28 (m, 5H).

Mass spectrum: m/z 330.

Example 11. CIS-3-(5-chloro-2-methoxybenzylamine)-2-phenylpiperidine.

1H-NMR (CDCl3) : to 1.37 (m, 1H); and 1.56 (m, 1H); to 1.86 (m, 1H); to 2.06 (m, 1H); was 2.76 (m, 2H); 3,23 (m, 1H); of 3.32 (d, 1H, J=15); of 3.42 (s, 3H); to 3.58 (d, 1H, J= 15); of 3.85 (d, 1H, J=3); is 6.54 (d, 1H, J=8); make 6.90 (d, 1H, J=3);? 7.04 baby mortality (DD, 1H, J=3, 8); from 7.24 (m, 5H).

Example 12. CIS-3-(2,5-dimethoxyaniline)-2-phenylpiperidine.

So pl. 250-252oC (HCl-salt).

1H-NMR (CDCl3) : 1,28-of 1.40 (m, 1H); 1,48-of 1.92 (m, 2H); 2,02 with 2.14 (m, 1H); 2,66 is 2.80 (m, 2H); 3,14-3,24 (m, 1H); of 3.32 (d, 1H, J=18); to 3.38 (s, 3H); of 3.56 (d, 1H, J= 18); 3,66 (s, 3H); network: 326,1959.

Elemental analysis for C20H26N2O22HCl0,3H2O:

Calculated: C 59,34; H 7,12; N 6,92.

Found: C 59,33; H Of 6.96; N 6,76.

Example 13. CIS-3-(5-fluorescent-2-methoxybenzylamine)-2-phenylpiperidine.

So pl. 270-272oC (HCl-salt).

VRMS for C19H23FN2O: calculated: 314,1791. Found: 314,1766.

Elemental analysis for C19H23FN2O2HCl0,5H2O:

Calculated: C 57,78; H Is 6.61; N 7,07.

Found: C 57,35; H 6,36; N 7,08.

1H-NMR (CDCl3) : 1,30-of 1.42 (m, 1H); 1,48-2,12 (m, 2H); 2,64-2,82 (m, 2H); 3,12-3,26 (m, 1H); of 3.32 (d, 1H, J=12); of 3.42 (s, 3H); of 3.56 (d, 1H, J= 12); of 3.84 (d, 1H, J= 3); 6,53 (DD, 1H, J=5, 10); only 6.64 (DD, 1H, J=3, 8); 6,70-6,80 (m, 1H); 7,12-7,40 (m, 5H).

Example 14. CIS-2-phenyl-3-[2-(prop-2-yloxy)benzylamino]piperidine.

1H-NMR (CDCl3) : of 1.00 (m, 6H); 1.30 on (m, 1H); to 1.70 (m, 2H); 2,10 (m, 1H); 2,72 (m, 1H); 3,18 (m, 1H); 3,30 (m, 1H); 3,50 (m, 1H); 3,80 (Shir.s, 1H); 4,06 (m, 1H); 6,66 (m, 2H); 6.90 to (m, 1H); 7,05 (m, 1H); 7,20 (m, 5H).

VRMS for C21H28N2O: calculated: 324,2197. Found: 324,2180.

Elemental analysis for C21H28N2O2HCl1,66H2O:

Calculated: C 59,02; H A 7.85; N 6,55.

Found: C 59,07; H To 7.77; N 6,69.

Example 15. CIS-3-(3-fluorescent-2-methoxybenzylamine)-2-phenylpiperidine.

1H-NMR (CDCl3) : 1,40 SUB>19H23FN2O: calculated: 314,1794. Found: 314,1768.

Elemental analysis for C19H23FN2O2HCl1,5H2O:

Calculated: C 55,08; H To 6.80; N 6,76.

Found: C 54,89; H 6,48; N 6,79.

Example 16. CIS-3-(5-chloro-2-methoxybenzylamine)-2-phenylpiperidine.

1H-NMR (CDCl3) : of 1.42 (m, 1H); and 1.54 (m, 1H); of 1.80 (m, 1H); to 2.06 (m, 1H); 2,78 (m, 2H); 3,20 (m, 1H); 3.42 points (d, 1H, J=15); to 3.58 (d, 1H, J=15); of 3.64 (s, 3H); 3,86 (m, 1H); 6,66 (d, 1H, J=9); 6,91 (d, 1H, J=9); to 7.6 (m, 5H).

VRMS for C19H22FN2OCl: calculated: 348,1401. Found: 348,1406.

Example 17. CIS-3-(3-chloro-5-fluorescent-methoxybenzylamine)-2-phenylpiperidine.

1H-NMR (CDCl3) : the 1.44 (m, 1H); was 1.58 (m, 1H); of 1.80 (m, 1H); to 2.06 (m, 1H); 2,80 (m, 2H); 3,22 (d, 1H, J=18); of 3.54 (d, 1H, J=18); 3,66 (s, 3H); 3,88 (d, 1H, J=2); 6,55 (d, 1H, J=6); 6,92 (d, 1H, J=9); 7,26 (m, 5H).

VRMS for C19H22ClFN2O: calculated: 348,1401. Found: 348,1411.

Elemental analysis for C19H22ClFN2O2HCl0,25H2O:

Calculated: C 53,53; H 5,79; N 6,57.

Found: C 53,58; H Ceiling Of 5.60; N 6,41.

Example 18. CIS-3-(3,5-sodium dichloro-2-methoxybenzylamine)-2-phenylpiperidine.

1H-NMR (CDCl3) : the 1.44 (m, 1H); and 1.56 (m, 1H); to 1.82 (m, 1H); of 2.08 (m, 1H); 2,80 (m, 2H); 3,20 (m, 1H); 3,50 (m, 2H); to 3.64 (s, 3H); 3,88 (m, 1H); of 6.68 (s, 1H); 7,26 (m, 6H).

VRMS for C19H22Cl2O: 1,28-of 1.40 (m, 1H); 1,44-of 1.88 (m, 2H); 1,92-2,02 (m, 1H); 2,64-2,84 (m, 2H); 3,10-up 3.22 (m, 1H); 3,19 (d, 1H, J=12); 3,39 (d, 1H, J= 12); 3,70 (s, 3H); 3,81 (d, 1H, J=3); of 6.65 (d, 1H, J=8); 6,83 (d, 2H, J= 6); 7,12-7,28 (m, 5H).

VRMS for C19H24N2O: calculated: 296,1885. Found: 296,1871.

Elemental analysis for C19H24N2O2HCl0,6H2O:

Calculated: C 60,03; H 7,21; N 7,37.

Found: C 60,08; H 7,11; N 7,45.

Example 20. CIS-2-phenyl-3-(Tien-2-ylmethylamino)piperidine.

So pl.: 250-252oC (HCl-salt).

1H-NMR (CDCl3) : 1,30-1,40 (m, 1H); 1,46-of 1.52 (m, 1H); 1,68 is 1.86 (m, 1H); 1,92 is 2.00 (m, 1H); 2,64-2,78 (m, 1H); 2,84 of 2.92 (m, 1H); 3,12-up 3.22 (m, 1H); 3,44 (d, 1H, J=12); of 3.54 (d, 1H, J=12); 3,81 (d, 1H, J=3); 6,53 (d, 1H, J=3); 6,72-to 6.80 (m, 1H); 7,02 (d, 1H, J=6); 7,12-7,30 (m, 5H).

VRMS for C16H20N2S: calculated: 272,1373. Found: 272,1327.

Elemental analysis for C16H20N2S2HCl1H2O:

Calculated: C 52,62; H 6,67; N To 7.67.

Found: C 52,64; H 6,38; N 7,65.

Example 21. CIS-3-(2-metaxilat-1 ylmethylamino)-2-phenylpiperidine.

So pl. 222-225oC (HCl-salt).

1H-NMR (CDCl3) : 1,36 is 1.48 (m, 1H); 1,52-2,04 (m, 2H); 2,18 of-2.32 (m, 1H); 2,68-2,82 (m, 1H); 2,90 (d, 1H, J=3); 3,18 of 3.28 (m, 1H); to 3.64 (s, 3H); of 3.80 (d, 1H, J= 12); 3,86 (d, 1H, J=4); 4,07 (d, 1H, J=12); 7,02-to 7.32 (m, 8H); EUR 7.57 (d, 1H, J=8); 7,60-of 7.70 (m, 2H).

VRMS for C23H26N2O: you what: 264-267oC (HCl-salt).

1H-NMR (CDCl3) : 1,30-1,40 (m, 1H); 1,46-of 1.64 (m, 1H); 1.70 to a 1.88 (m, 1H); 1,92-2,02 (m, 1H); 2,68-2,78 (m, 1H); 2,80-is 2.88 (m, 1H); 3,14-up 3.22 (m, 1H); and 3.31 (d, 1H, J=12); of 3.48 (d, 1H, J=12); of 3.84 (d, 1H, J=3); of 6.65 (d, 1H, J=6); 6,72 (d, 1H, J=3);? 7.04 baby mortality-7,10 (m, 1H); 7,14-7,28 (m, 5H).

VRMS for C16H20N2S: calculated: 272,1342. Found: 272,1364.

Elemental analysis for C16H20N2S2HCl0,6H2O:

Calculated: C 53,96; H To 6.57; N 7,87.

Found: C 53,97; H 6,25; N To 7.77.

Example 23. CIS-3-(2,5-Diferentseerumine)-2-phenylpiperidine.

So pl.: 274-276oC (HCl - salt).

1H-NMR (CDCl3) : 1,28-of 1.40 (m, 1H); 1,44-of 1.62 (m, 1H); 1,66-of 1.84 (m, 1H); 1,90-2,00 (m, 1H); 2,64 was 2.76 (m, 2H); 2,10-3,20 (m, 1H); of 3.32 (d, 1H, J= 12); 3,44 (d, 1H, J=12); 3,81 (d, 1H, J=3); 6,50 return of 6.58 (m, 1H); 6,62-of 6.78 (m, 2H); 7,10-7,26 (m, 5H).

VRMS for C18H20F2N2: calculated: 302,1590. Found: 302,1560.

Elemental analysis for C18H20F2N22HCl0,2H2O:

Calculated: C 57,06; H 5,96; N 7,39.

Found: C 56,94; H 5,94; N 7,37.

Example 24. (2S, 3S)-3-Amino-2-phenylpiperidine.

In a vessel were placed 31 g 10% palladium carbon, 50 ml of water, 300 ml of methanol and 450 ml of concentrated aqueous hydrochloric acid and 15 g (0.04 M) cleaners containing hydrochloride salt of (2S, 3S)-3-(2-methoxybenzyl)amino-2-peripipherally diatomaceous earth. Then this layer was carefully washed 2 N. aqueous solution of hydrochloric acid HCl, water, ethanol and again with water, and then concentrated on a rotary evaporator. To the obtained residue was added water and the mixture was podslushivaet using 4 N. of an aqueous solution of sodium hydroxide NaOH. After that, the mixture was extracted with four portions of dichloromethane, and the extracts were dried with magnesium sulfate (MgSO4) and concentrated, resulting in received of 2.23 g of the target compound. Water fraction was concentrated to dryness and pereirae with chloroform. As a result of concentration of a solution of chloroform was given 4.15 g of the target compound. Thus obtained product had spectral properties identical to the properties of the product described in example 1.

Example 25. CIS-3-(2,4-dimethoxybenzyl)amino-2-phenylpiperidine.

1H-NMR (CDCl3) : to 1.38 (m, 1H); of 1.65 (m, 1H); 1,9 (m, 2H); to 2.15 (m, 1H); 2,8 (m, 2H); of 3.25 (m, 1H); 3,35 (d, 1H, J=15); 3,4 (s, 3H); 3,6 (d, 1H, J= 15); of 3.78 (s, 3H); of 3.85 (d, 1H, J=3); and 6.25 (d, 1H, J=3); 6,35 (DD, 1H, J=10, 3); 6,85 (d, 1H, J=10); 7,30 (m, 5H).

MS: m/z 326 (source).

Elemental analysis for C20H26N2O22HCl:

Calculated: C 60,14; H 7,07; N 7,02;

Found: C 59,66; H 7,11; N 6,83.

Example 26. CIS-3-(2,4-sodium dichloro-6-methoxybenzyl)amino-was 1.94 (m, 1H); 2,2 (m, 1H); of 2.68 (m, 1H); was 2.76 (m, 1H); was 2.76 (m, 1H); 3,2 (m, 1H); to 3.38 (s, 3H); 3,4 (d, 1H, J=10); of 3.45 (d, 1H, J=10); a-3.84 (m, 1H); 6.48 in (d, 1H, J=3); at 6.84 (d, 1H, J=3); to 7.2 (m, 5H).

MS: m/z 364 (source).

Elemental analysis for C19H22Cl2N2O: 1,4 (m, 1H); 1,6 (m, 3H); of 1.92 (m, 1H); of 2.16 (m, 1H); was 2.76 (m, 1H); 3,2 (m, 1H); to 3.58 (d, 1H, J=12); 3,70 (s, 3H); 3,74 (d, 1H, J= 12); 3,86 (d, 1H, J=3); 6,66 (m, 2H); to 7.2 (m, 5H).

MS: m/z 364 (source).

Elemental analysis for C19H22Cl2NO2: 1,4 (m, 1H); 1,65 (s, 2H); 1,9 (m, 1H); is 2.05 (m, 2H); 2,8 (m, 4H), of 3.25 (m, 1H); of 3.45 (d, 1H, J=15); and 3.6 (d, 1H, J=15); of 3.9 (m, 4H); of 6.65 (d, 1H, J=10); make 6.90 (d, 1H, J=10); and 7.3 (m, 5H).

VRMS for C19H22Cl2N2O: 1,44 (m, 1H); 1,6 (m, 1H); 2.0 (m, 2H); 2,8 (dt, 2H, J=12, 3); 2,92 (m, 1H); 3,26 (m, 1H); 3.43 points (d, 1H, J=10); to 3.52 (s, 3H); of 3.53 (d, 1H, J=10); of 3.78 (s, 3H); a-3.84 (m, 1H); 3,90 (d, 1H, J=3); of 6.52 (d, 1 H, J=10); 6,72 (d, 1H, J=10); at 6.84 (d, 1H, J=10); of 7.82 (m, 5H).

VRMS for C20H26N2O2: calculated: 326,2058. Found: 326,1991.

Elemental analysis for C20H26N2O22HCl1/2H2O:

Calculated: C 58,82; H 7,16; N 6,86.

Found: C 58,63; H 7,26; N For 6.81.

Example 30. CIS-3-(5-bromo-2-methoxy-3-methylbenzyl)amino-2-phenylpiperidine.

So pl.: 236-238oC (HCl-salt).

1H-NMR (CDCl3) : the 1.44 (m, 1H); of 1.64 (m, 1H); 1,90 (m, 1H); of 2.16 (s, 3H); 2,80 (m, 2H); 3,26 (m, 1H); to 3.36 (d, 1H, J=12); 3,43 (s, 1H); 3,52 (d is prohibited: 388,1153.

Example 31. (2S, 3S)-3-(2,4-dimethoxybenzyl)amino-2-phenylpiperidine.

1H-NMR (CDCl3) : 1,4 (m, 1H); was 1.58 (m, 1H); of 1.94 (m, 2H); 2,1 (m, 1H); 2,8 (m, 2H); or 3.28 (m, 1H), 3,34 (d, 1H, J=15); 3,38 of 3.64 (d, 1H, J=15); 3,76 (s, 3H); 3,88 (d, 1H, J=3); 6,24 (d, 1H, J=3); 6,30 (DD, 1H, J=10, 3); 6,86 (d, 1H, J=10) 7,26 (m, 5H).

VRMS for C20H26N2O2: calculated: 326,1988. Found: 326,1986.

Elemental analysis for C20H26N2O22HCl1/4H2O:

Calculated: C 59,48; H 7,11; N 6,95.

Example 32. (2S, 3S)-3-(2-Cyclopentylacetyl)amino-2-phenylpiperidine.

So pl.: 230-232oC (HCl-salt).

1H-NMR (CDCl3) : of 1.75 (m, 13H); and 2.14 (m, 1H); 2,80 (dt, 2H, J=12, 3); 2,90 (m, 1H); or 3.28 (m, 1H); to 3.36 (d, 1H, J=15); of 3.60 (d, 1H, J=15); 3,88 (Shir. s, 1H); 4,58 (m, 1H); 6,74 (m, 2H); at 6.84 (d, 1H, J=10); for 7.12 (m, 1 H); 7,30 (m, 5H).

VRMS for C23H40N2O: calculated: 350,2351. Found: 350,2332.

Elemental analysis for C23H30N2O2HCl2H2O: calculated: C 60,12; H 7,33; N 6,10. Found: C 59,10; H 7,19; N 6,09.

Example 33. (2S, 3S)-3-(2-Cyclopentyloxy-5-methoxybenzyl)amino-2-phenylpiperidine.

So pl.: 217-219oC (HCl-salt).

1H-NMR (CDCl3) : of 1.66 (m, 13H); and 2.14 (m, 1H); 2,82 (dt, 2H, J=12, 3); 2,92 (m, 1H); 3,14 (m, 2H); 3,54 (d, 1H, J=15); and 3.72 (s, 3H); 3,90 (d, 1H, J=15); 4,50 (m, 1H); only 6.64 (m, 3H); 7,30 (m, 5H).

VRMS for C2N2O22HClH2O:

Calculated: C 60,14; H Of 7.70; N 5,94.

Found: C 61,05; H To 7.67; N Of 5.92.

Example 34. (2S, 3S)-3-(5-tert-Butyl-2-methoxybenzyl)amino-2-phenylpiperidine.

So pl.: 262 to 264oC (HCl-salt).

1H-NMR (CDCl3) : 1,22 (c, 9H); to 1.38 (m, 2H); 1,90 (m, 1H); and 2.14 (m, 1H); 2,80 (m, 2H); 3,26 (m, 1H); to 3.36 (d, 1H, J=15); 3,44 (s, 3H); 3,62 (d, 1H, J= 15); 3,86 (d, 1H, J=3); 6,60 (d, 1H, J=10); 7,00 (d, 1H, J=3); for 7.12 (m, 1H); 7,26 (m, 5H).

VRMS for C23H32N2O: calculated: 352,2507. Found: 352,2512.

Elemental analysis for C23H32N2O2HCl0,5H2O:

Calculated: C 63,58; H 8,12; N 6,45.

Found: C 63,75; H 8,00; N, 6.42 Per.

Example 35. (2S, 3S)-3-(5-sec-Butyl-2-methoxybenzyl)amino-2-phenylpiperidine.

So pl.: 260-263oC (HCl-salt).

1H-NMR (CDCl3) : 0,8 (2T, 3H, J=6); of 1.16 (2D, 3H, J=7), and 1.5 (m, 4H); 1,9 (m, 1H); 2,12 (m, 1H); to 2.46 (m, 1H); 2,8 (m, 3H); or 3.28 (m, 1H); 3.42 points (d, 1H, J=15); 3,44 (s, 3H); 3,66 (d, 1H, J=15); 3,90 (d, 1H, J=3); 6,60 d, 1H, J=10); 6,78 (Shir. s, 1H); 6,92 (d, 1H, J=10); and 7.3 (m, 5H).

VRMS for C23H32N2O: calculated: C 62,29; H 8,18; N 6,32. Found: C 62,95; H A 7.62; N 6,61.

Example 36. (2S, 3S)-3-(5-Fluorescent-2-methoxybenzyl)-2-phenylpiperidine.

So pl.: 270oC (HCl-salt).

1H-NMR (CDCl3) : to 1.38 (m, 1H); and 1.56 (m, 1H); 1,90 (m, 1H); to 2.06 (m, 1H); to 2.66 (m, 2H); 3,26 (m, 1H); 3,30 (d, 1H, J=s C19H23FN2O5HCl0,75H2O:

Calculated: C 57,57; H Is 6.61; N 7,06.

Found: C 57,83; H Of 6.31; N 7,06.

Example 37. (2S, 3S)-3-(4,5-Diptera-2-methoxybenzyl)amino-2-phenylpiperidine.

1H-NMR (CDCl3) : of 1.36 (m, 1H); of 1.55 (m, 1H); of 1.84 (m, 1H); 2,02 (m, 1H); 2,72 (m, 2H); 3,20 (m, 1H); 3,26 (d, 1H, J=14); of 3.42 (s, 3H); to 3.52 (d, 1H, J= 14); of 3.84 (d, 1H, J=3); 6.42 per (DD, 1H, J=6, 12); 6,70 (DD, 1H, J=8, 10); 7,20 (m, 5H).

Elemental analysis for C19H22F2N2O2HCl055H2O:

Calculated: C 54,96; H 6,09; N 6,74.

Example 38. (2S, 3S)-3-(2-Acetamidobenzoyl)amino-2-phenylpiperidine.

So pl.: 187-195oC (HCl-salt).

1H-NMR (CDCl3) : of 1.52 (m, 1H); to 1.61 (s, 3H); to 1.70 (m, 1H); 2,10 (m, 2H); 2,80 (m, 2H); 3,18 (m, 1H); of 3.32 (d, 1H, J=16); of 3.54 (d, 1H, J=16); the 3.89 (d, 1H, J=3); to 6.88 (m, 2H); 7,26 (m, 7H).

VRMS for C20H25N3O: calculated: 323,1997. Found: 323,1972.

Example 39. (2S, 3S)-3-(2-Methoxybenzyl)amino-2-phenylpiperidine.

1H-NMR (CDCl3) :of 1.36 (m, 1H); and 1.54 (m, 1H); 2.0 (m, 2H); 2,78 (m, 2H); 3,23 (m, 1H); to 3.36 (d, 1H, J=14); to 3.41 (s, 3H); 3,63 (d, 1H, J=14); 3,83 (Shir. s, 1H); is 6.61 (d, 1H, J=8); 6,74 (t, 1H, J=7); 6,91 (d, 1H, J=7); was 7.08 (t, 1H, J=8); for 7.12 (m, 5H).

Example 40. (2S, 3S)-3-(2-Methoxy-5-methylmercaptopurine-2-phenylpiperidine hydrochloride.

So pl.: 257-259oC (Razlog.)

1H-NMR (free base; CDCld, 1H, J=10); make 6.90 (d, 1H, J=3);? 7.04 baby mortality (DD, 1H, J=3, 10); to 7.2 (m, 5H).

VRMS for C20H26N2OS: calculated: 342,1760. Found: 342,1770.

Elemental analysis for C20H26N2OS 2HCl0,25H2O:

Calculated: C 57,20; H 6,84; N 6,67.

Found: C 57,35; H 6,76; N 6,61.

Example 41. (2S, 3S)-3-(2-Methoxy-5-methylsulfonylamino)-2-phenylpiperidine hydrochloride.

So pl.: 209oC (Razlog.)

1H-NMR (free base; CDCl3) : of 1.40 (m, 1H); and 1.56 (m, 1H); 1,90 (m, 1H); 2,10 (m, 1H); 2,59, 2,62 (2S, 3H); was 2.76 (m, 2H); up 3.22 (m, 1H); 3.42 points (m, 1H); 3,49, 3,52 (2S, 3H); 3,66 (m, 1H); 3,86 (d, 1H, J=3); 6,76 (m, 1H); from 7.24 (m, 6H); 7,46 (m, 1H).

VRMS for C20H27N2O2S(M+1): 359,1787. Found: 359,1763.

Example 42. (2S, 3S)-3-(2-Methoxy-5-methylsulfonylbenzoyl)-2-phenylpiperidine hydrochloride.

So pl.: >260oC.

1H-NMR (free base; CDCl3) : of 1.40 (m, 1H); was 1.58 (m, 1H); of 1.88 (m, 1H); 2,10 (m, 1H); 2,78 (m, 2H); 2,96 (s, 3H); 3.24 in (m, 1H); 3,38 (d, 1H, J=15); 3,54 (c, 3H); 3,66 (d, 1H, J=15); 3,90 (d, 1H, J=3); 6,74 (d, 1H, J= 10); 7,26 (m, 5H); 7,58 (d, 1H, J=3); 6,74 (d, 1H, J=10); 7,26 (m, 5H); 7,58 (d, 1H, J=3); 7,72 (d, 1H, J=10).

VRMS for C20H26N2O3S: calculated: 374,1658. Found: 374,1622.

Example 43. (2S, 3S)-3-(2-Methoxy-5-phenoxybenzamine)-2-phenylpiperidine hydrochloride.

So pl. 1H); of 3.32 (d, 1H, J=15); 3,44 (c, 3H); of 3.60 (d, 1H, J=15); of 3.85 (d, 1H, J=3); 6,60 (d, 1H, J=9); to 6.67 (d, 1H, J=3); is 6.78 (DD, 1H, J=6, 9); 6,86 (d, 2H); 7,00 (t, 1H, J=6); 7,22 (m, 7H).

VRMS for C25H28N2O2: calculated: 388,2151. Found: 382,2137.

Example 44. (2S, 3S)-3-(2-Methoxy-5-N-methylethylenediamine)-2 - phenylpiperidine hydrochloride.

1H-NMR (free base; CDCl3) : of 1.42 (m, 1H); of 1.74 (m, 2H); 2,12 (m, 1H); 2,78 (m, 5H); 3,20 (s, 3H); 3.24 in (m, 1H); to 3.36 (d, 1H, J=15); 3,52 (c, 3H); to 3.64 (d, 1H, J=15); the 3.89 (d, 1H, J=3); only 6.64 (d, 1H, J=9); 6,98 (d, 1H, J=3); 7,14 (DD, 1H, J=3, 9); 7,26 (m, 5H).

VRMS for C21H29N3O3S: calculated: 403,1992. Found: 403,1923.

Elemental analysis for C21H29N3O3S 2HCl1/3H2O:

Calculated: C 52,28; H Is 6.61; N 8,71.

Found: C 52,09; H 6,63; N 8,68.

Example 45. (2S, 3S)-3-(2,2,2-Trichoroethylene)-2-phenylpiperidine hydrochloride

So pl. > 275oC.

1H-NMR (free base; CDCl3) : the 1.44 (m, 1H); of 1.62 (m, 1H); 1,90 (m, 1H); 2,10 (m, 1H); 2,82 (m, 2H); 3,26 (m, 1H); 3,38 (d, 1H, J=15); 3,66 (d, 1H, J=15); to 3.92 (d, 1H, J=3); 4,06 (m, 2H); 6,66 (d, 1H, J=10); 6,94 (m, 2H); 7,16 (m, 1H) 7,30 (m, 5H).

VRMS for C20H24F3N3O(M+1): calculated: 365,1835. Found: 385,1908.

Elemental analysis for C20H23F3N2O 2HCl1/3H2O:

So pl. 267-269oC.

1H-NMR (free base; CDCl3) : of 1.40 (m, 1H) and 1.60 (m, 1H); to 1.82 (m, 1H); 2,02 (m, 1H); was 2.76 (m, 2H); 3,20 (m, 1H); or 3.28 (d, 1H, J=15); to 3.52 (d, 1H, J=15); of 3.84 (d, 1H, J=3); 4,00 (m, 2H); is 6.54 (d, 1H, J=10); 6,92 (d, 1H, J=3);? 7.04 baby mortality (m, 1H); from 7.24 (m, 5H).

VRMS for C20H22ClF3N2O: calculated: 398,1368. Found: 398,1352.

Elemental analysis for C20H22ClF3N2O: 1,4 (m, 1H); and 1.54 (m, 1H); of 1.80(m, 1H); 1,96 (m, 1H); to 2.74 (m, 2H); 3,18 (m, 1H); 3,30 (d, 1H, J=15); of 3.46 (d, 1H, J= 15); 3,82 (d, 1H, J=3); to 6.80 (s, 1H); at 6.84 (d, 1H, J=10); 6,92 (m, 1H); for 7.12 (m, 1H); from 7.24 (m, 5H).

VRMS for C19H21F3N2O: calculated: 350,1601. Found: 350,1609.

Elemental analysis for C19H21F3N2O 2HCl:

Calculated: C 53,91; H 5,48; N 6,62.

Found: C 53,84; H 5,07; N 6,59.

Example 48. (2S, 3S)-3-(5-t-Butyl-2-triphtalocyaninine)-2 - phenylpiperidine hydrochloride.

So pl.: 262 to 264oC.

1H-NMR (free base; CDCl3) : of 1.20 (s, 9H); of 1.40 (m, 1H); of 1.52 (m, 1H); of 1.84 (m, 1H); to 2.06 (m, 1H); 2,80 (m, 2H); up 3.22 (m, 1H); 3,38 (d, 1H, J= 15); to 3.58 (d, 1H, J=15); 3,86 (d, 1H, J=3); 6,98 (m, 1H); for 7.12 (m, 2H); 7,26 (m, 5H).

VRMS for C23H29F3N2O: calculated: 406,2225. Found: 406,2271.

Elemental analysis for C23H29F3N2O 2HCl1/3H2O:

You the toxi)benzylamino] -2 - phenylpiperidine hydrochloride.

So pl. > 280oC.

1H-NMR (free base; CDCl3) : of 1.12 (m, 6H); 1,4 (m, 1H); of 1.62 (m, 1H); to 1.82 (m, 1H); of 2.08 (m, 1H); was 2.76 (m, 3H); up 3.22 (m, 1H); 3,30 (d, 1H, J=15); to 3.38 (d, 1H, J=15); 3,82 (d, 1H, J=3); was 4.02 (m, 2H); 6,56 (d, 1H, J=10); is 6.78 (d, 1H, J=3); 6,94 (m, 1H); from 7.24 (m, 5H).

VRMS for C23H30F3N2O(M+1): calculated: 407,2303. Found: 407,2287.

Elemental analysis for C23H29F3N2O 2HCl1/2H2O:

Calculated: C 56,55; H 6,60; N 5,70.

Found: C 56,17; H To 6.39; N 5,77.

Example 50.

(2S, 3S)-3-(2-Methoxy-5-methylaminomethyluridine)-2-phenylpiperidine hydrochloride.

So pl.: 242oC (Razlog.).

1H-NMR (free base; CDCl3) : of 1.36 (m, 1H); was 1.58 (m, 1H); 1,90 (m, 1H); 2,10 (m, 1H); of 2.38 (s, 3H); 2,80 (m, 2H); up 3.22 (m, 1H); 3.42 points (m, 4H); of 3.56 (s, 2H); to 3.64 (d, 1H, J=15); 3,86 (d, 1H, J=3); 6,60 (d, 1H, J= 10); 6,86 (d, 1H, J=3); 7,02 (m, 1H); 7,26 (m, 5H).

VRMS for C21H30N3O(M+1): calculated: 340,2382. Found: 340,2400.

Example 51. (2S, 3S)-3-[5-Dimethylamino-2-(2,2,2-trichoroethane)benzylamino]-2 - phenylpiperidine hydrochloride.

So pl.: 250-252oC.

1H-NMR (free base; CDCl3) : of 1.40 (m, 1H) and 1.60 (m, 1H); to 1.86 (m, 1H); 2,10 (m, 1H); 2,82 (m, 8H); up 3.22 (m, 1H); 3,34 (d, 1H, J=15); to 3.58 (d, 1H, J=15); 3,88 (d, 1H, J=3); 4,00 (m, 2H); 6.42 per (d, 1H, J=3); 6,50 (m, 1H); only 6.64 (d, 1H, J=10); 7,30 (52 Yo. (2S, 3S)-3-(2-Deformedarse-5-methylmercaptopurine)-2 - phenylpiperidine hydrochloride.

So pl.: 254-256oC.

1H-NMR (free base; CDCl3) : 1,45 (m, 1H) and 1.60 (m, 1H); of 1.80 (m, 1H); 2,10 (m, 1H); 2.40 a (s, 3H); 2,80 (m, 2H); 3,20 (m, 1H); 3,30 (d, 1H, J= 15); 3,55 (d, 1H, J=15); 3,90 (d, 1H, J=3); 6,10 (t, 1H, J=85); to 6.95 (m, 3H); 7,25 (m, 5H).

VRMS for C20H25OF2Cl21/4H2O:

Calculated: C 52,69; H 5,86; N 6,14.

Found: C 52,36; H 5,86; N 6,14.

Elemental analysis for C20H25Cl2F2N2OS(M+1): calculated: 379,1650. Found: 379,1668.

Example 53. (2S, 3S)-3-(5-sec-Butyl-2-methoxybenzyl)amino-2-phenylpiperidine.

So pl.: 260-263oC (HCl salt).

1H-NMR (free base; CDCl3) : 0,8 (2T, 3H, J=6); of 1.16 (2D, 3H, J= 7), and 1.5 (m, 4H); 1,9 (m, 1H); 2,12 (m, 1H); to 2.46 (m, 1H); 2,8 (m, 3H); or 3.28 (m, 1H); 3.42 points (d, 1H, J=15) 3,44 (s, 1H); 3,66 (d, 1H, J=15); 3,90 (d, 1H, J=3); 6,60 (d, 1H, J=10); 6,78 (Shir. s, 1H); 6,92 (d, 1H, J=10); and 7.3 (m, 5H).

VRMS for C23H32N2O: calculated: 352,2507. Found: 352,2525.

Example 54. (2S, 3S)-3-(4-Amino-5-chloro-2-methoxybenzyl)amino-2-phenylpiperidine hydrochloride.

So pl.: 200-203oC (Razlog.).

1H-NMR (free base; CDCl3) : of 1.35 (m, 1H); and 1.56 (m, 1H); to 1.86 (m, 1H); is 2.05 (m, 1H); to 2.75 (m, 2H); up 3.22 (m, 2H); to 3.36 (s, 3H) 3,48 (d, 1H, is prohibited: 345,1589.

Example 55. (2S, 3S)-3-(2-Methoxy-5-phenylendiamine)-2-phenylpiperidine hydrochloride.

So pl.: 238-239oC (Razlog.).

1H-NMR (free base; CDCl3) : to 1.38 (m, 1H) and 1.60 (m, 1H); of 1.88 (m, 1H); 2,12 (m, 1H); 2,80 (m, 2H); 3,23 (m, 1H); to 3.45 (m, 4H) 3,70 (d, 1H, J=12); 3,86 (d, 1H, J=3); 6,70 (d, 1H, J=6); 7,34 (m, 12H).

VRMS for C25H28N2O: calculated: 372,2197. Found: 372,2172.

Example 56. (2S, 3S)-2-Phenyl-3-(quinoline-8-yl)methylpiperidine hydrochloride.

So pl.: 252-253oC (Razlog.).

1H-NMR (free base; CDCl3) : to 1.38 (m, 1H); was 1.58 (m, 1H); of 1.94 (m, 1H); 2,17 (m, 1H); 2,78 (m, 2H); 3.24 in (m, 1H); 3,83 (d, 1H, J=3); of 3.96 (d, 1H, J=15); to 4.28 (d, 1H, J=15); 7,14 (m, 6H); 7,32 (m, 2H); 7,58 (t, 1H, J=4); 7,98 (d, 1H, J=6); 8,46 (m, 1H).

VRMS for C21H23N3: calculated: 317,1887. Found: 317,1883.

Example 57. (2S, 3S)-3-(5-Heptyloxy-2-methoxybenzyl)amino-2-phenylpiperidine hydrochloride.

So pl.: 230oC (Razlog.).

1H-NMR (free base; CDCl3) : 0,90 (m, 2H); to 1.38 (m, 10H); to 1.76 (m, 4H); 2,12 (m, 1H); 2,80 (m, 2H); 3,26 (m, 1H); 3,38 (d, 1H, J=16); of 3.42 (s, 3H); 3,62 (d, 1H, J=15); 3,82 (t, 2H, J=6); 3,88 (d, 1H, J=3); 6,62 (m, 3H); 7,28 (m, 5H).

VRMS for C26H38N2O2: calculated: 410,2928. Found: 410,2953.

Example 58. (2S, 3S)-3-(2-Heptyloxy-5-methoxybenzyl)amino-2-fenil the DCl3) : of 0.90 (m, 3H) and 1.60 (m, 13H); 2,12 (m, 1H); 2,80 (m, 2H); 3,26 (m, 1H); to 3.36 (d, 1H, J=15); 3,62 (m, 6H); 3,86 (d, 1H, J=3); 6,60 (m, 3H); 7.23 percent (m, 5H).

VRMS for C26H38N2O2: calculated: 410,2928. Found: 410,2912.

Example 59. (2S, 3S)-3-(5-Heptyloxy-2-methoxybenzyl)amino-2-phenylpiperidine hydrochloride.

So pl.: 242-243oC (Razlog.).

1H-NMR (free base; CDCl3) : 0,88 (m, 3H) and 1.60 (m, 13H); and 2.14 (m, 1H); 2,44 (t, 2H, J=6); 2,78 (m, 2H); 3,26 (m, 1H); 3.40 in (m, 4H); to 3.64 (d, 1H, J=15); 3,86 (d, 1H, J=2); to 6.58 (d, 1H, J=6); to 6.75 (d, 1H, J=2); 6,92 (d, 1H, J=6); 7,26 (m, 5H).

VRMS for C26H38N2O: calculated: 394,2977. Found: 394,3009.

Example 60. (2S, 3S)-3-(2-Methoxy-5-n-propylbenzyl)amino-2-phenylpiperidine hydrochloride.

So pl.: 245-247oC (Razlog.).

1H-NMR (free base; CDCl3) : of 0.9 (t, 3H, J=10); 1,4 (m, 1H); and 1.54 (m, 2H); of 1.92 (m, 1H); and 2.14 (m, 1H); 2,44 (t, 2H, J=6); 2,80 (m, 2H); 3,26 (s, 1H); 3.40 in (d, 1H, J=15); 3,44 (s, 3H); 3,66 (d, 1H, J=15); 3,90 (s, 1H); 6,56 (d, 1H, J=10); 6,76 (s, 1H); 6,92 (d, 1H, J=10); 7,26 (m, 5H).

VRMS for C22H30N2O: calculated: 338,2351. Found: 338,2339.

Elemental analysis for C22H30N2O2HCl 0,25 H2O:

Calculated: C 63,57; H 7,81; N 6,74.

Found: C 63,59; H 7,66; N Of 6.73.

Example 61. (2S, 3S)-3-(4,5-Dimethyl-2-methoxybenzyl)amino-2-penile : 1,40 (m, 1H) and 1.60 (m, 1H); to 1.96 (m, 2H); and 2.14 (s, 3H); to 2.18 (s, 3H); 2,80 (m, 2H); 3,30 (m, 1H); 3.40 in (d, 1H, J= 15); of 3.42 (s, 3H); 3,62 (d, 1H, J=15); 3,90 (d, 1H, J=3); 6.48 in (s, 1H); 6,70 (s, 1H); 7,28 (m, 5H).

VRMS for C21H28N2O: calculated: 324,2195. Found: 324,2210.

Elemental analysis for C21H28N2O2HCl 0,25 H2O:

Calculated: 62,80; H 7,60; N 6,99.

Found: C 62,64; H 7,31; N 6,86

Example 62. (2S, 3S)-3-(5-t-Butyl-2-hydroxybenzyl)amino-2-phenylpiperidine hydrochloride.

So pl.: 267-269oC (Razlog.).

1H-NMR (free base; CDCl3) : 1,3 (s, 9H); 1,6 (m, 3H); to 2.18 (m, 1H); 2,82 (m, 1H); 2,98 (m, 1H); up 3.22 (m, 1H); 3,44 (d, 1H, J=15); of 3.56 (d, 1H, J=15); to 3.92 (m, 1H); 6,70 (m, 2H); 7,14 (m, 1H); 7,40 (m, 5H).

VRMS for C22H30N2O: calculated: 338,2351. Found: 338,2384.

Example 63. (2S, 3S)-3-(5-Carbomethoxy-2-methoxybenzyl)amino-2-phenylpiperidine hydrochloride.

So pl.: 238-240oC.

1H-NMR (free base; CDCl3) : 1,4 (m, 1H); 1,6 (m, 1H); of 1.88 (m, 1H); 2,1 (m, 1H); to 2.75 (m, 2H); 3,2 (m, 1H); 3,35 (d, 1H, J=15); of 3.45 (s, 3H); 3,7 (d, 1H, J=15); of 3.85 (m, 4H); of 6.65 (d, 1H, J=10); to 7.2 (m, 5H); of 7.70 (d, 1H, J=3); a 7.85 (m, 1H).

VRMS for C21H26N2O3: calculated: 354,1937. Found: 354,1932.

Example 64. (2S, 3S)-3-(6-n-Butyl-2-methoxybenzyl)amino-2-phenylpiperidine hydrochloride.

So ); to 2.18 (m, 1H); 2.50 each (t, 2H, J=10); of 2.86 (m, 2H); 3,30 (m, 1H); 3,44 (d, 1H, J=15); of 3.48 (s, 3H); 3,68 (d, 1H, J=15); 3,82 (d, 1H, J=3); 6,62 (d, 1H, J=10); to 6.80 (s, 1H); 6,86 (d, 1H, J=10); to 7.3 (m, 5H).

VRMS for C23H32N2O: calculated: 352,2507. Found: 352,2509.

Elemental analysis for C23H32N2O2HCl 1/2H2O:

Calculated: C 64,03; H 8,09; N 6,50.

Found: C 64,39; H Of 7.90; N 6,59.

Example 65. (2S, 3S)-3-(5-Isopropyl-2-methoxybenzyl)amino-2-phenylpiperidine hydrochloride

So pl.: 252-254oC.

1H-NMR (free base; CDCl3) :to 1.14 (d, 6H, J=6); of 1.36 (m, 1H); was 1.58 (m, 1H); of 1.88 (m, 1H); 2,1 (m, 1H); was 2.76 (m, 3H); 3.24 in (m, 1H); to 3.36 (d, 1H, J=15); of 3.42 (s, 3H); of 3.60 (d, 1H, J=15); 3,86 (d, 1H, J=3); 6,56 (d, 1H, J=10); to 6.80 (d, 1H, J=3); at 6.84 (m, 1H); from 7.24 (m, 5H).

VRMS for C22H30N2O: calculated: 338,2351. Found: 338,2377.

Elemental analysis for C22H30N2O2HCl 1/4H2O:

Calculated: C 63,52; H 7,88; N 6,74.

Found: C 63,33; H Of 7.64; N 6,75.

Example 66. (2S, 3S)-3-(2-Deformedarse-5-N,N-dimethylaminobenzylidene-2 - phenylpiperidine hydrochloride.

So pl.: 243-245oC (Razlog.).

1H-NMR (free base; CDCl3) : the 1.44 (m, 1H); 1,72 (m, 2H); 2,10 (m, 1H); 2,84 (m, 8H); is 3.21 (m, 1H); or 3.28 (d, 1H, J=15); 3,55 (d, 1H, J=15); 3,88 (d, 1H, J=3); between 6.08 (t, 1H, J=72); 6,36 (d, 1H, J=3); 6,46 (DD, 1H, J=3, 9); 6,86 (d, 1H, J=9); 7,28 (m, 5H).< the analysis for C21H27F2N3O 3HCl1/2H2O:

Calculated: C 51,07; H 6,44; N 8,51.

Found: C 50,71; H Between 6.08; N 8,28.

Example 67. (2S, 3S)-3-(2,5-[bis-(deformedarse)benzyl)amino]-2-phenylpiperidine hydrochloride.

So pl.: 238-239oC.

1H-NMR (free base; CDCl3) : of 1.64 (m, 3H); 2,04 (m, 1H); was 2.76 (m, 2H); 3,18 (m, 1H); or 3.28 (d, 1H, J=12); to 3.52 (d, 1H, J=12); of 3.84 (d, 1H, J= 3); 6,12 (t, 1H, J=65); 6,40 (t, 1H, J=75); to 6.75 (m, 2H); 6,94 (d, 1H, J= 9); from 7.24 (m, 5H).

VRMS for C20H22F4N2O2: calculated: 398,1612. Found: 398,1591.

Example 68. (2S, 3S)-3-(5-t-Butyl-2-deformationally)-2-phenylpiperidine hydrochloride.

So pl.: 263-264oC (Razlog.).

1H-NMR (free base; CDCl3) : 1,24 (s, 9H); to 1.42 (m, 1H); of 1.62 (m, 1H); of 1.80 (m, 1H); 2,10 (m, 1H); 2,80 (m, 2H); 3.24 in (m, 2H); to 3.58 (d, 1H, J= 12); a 3.87 (Shir.s, 1H); 6,18 (t, 1H, J=72); 6,86 (d, 1H, J=6); 7,00 (Shir. s, 1H); for 7.12 (m, 1H); from 7.24 (m, 5H).

VRMS for C23H30F2N2O: calculated: 388,2321. Found: 388,2336.

Example 69. (2S, 3S)-3-(5-Dimethylamino-2-methoxybenzylamine)-2-phenylpiperidine hydrochloride

So pl. > 275oC.

1H-NMR (free base; CDCl3) : of 1.34 (m, 1H); to 1.70 (m, 2H); 2,10 (m, 1H); was 2.76 (m, 8H); 3,20 (m, 1H); to 3.34 (m, 4H); of 3.56 (d, 1H, J=12); 3,82 (d, 1H, J=2); 6,50 (m, 3H); 7,22 (m, 5H).

UB>29
N3O3HCl H2O:

Calculated: C 54,02; H 7,34; N 9,00.

Found: C 53,84; H Of 7.55; N 8,92.

Example 70. (2S, 3S)-3-(2-Isopropoxy-5-trifluromethanesulfonate)-2-phenylpiperidine hydrochloride.

So pl.: 245-246oC (Razlog.).

1H-NMR (free base; CDCl3) : a 1.08 (d, 3H, J=6); of 1.12 (d, 3H, J= 6); of 1.40 (m, 1H); of 1.64 (m, 1H); to 1.87 (m, 1H); of 2.08 (m, 1H); 2,78 (m, 2H); to 3.02 (m, 1H); 3,34 (d, 1H, J=15); 3,51 (d, 1H, J=15); of 3.85 (d, 1H, J=2); to 4.28 (m, 1H); 6,01 (d, 1H, J=9); of 3.85 (d, 1H, J=2); to 4.28 (m, 1H); 6,01 (d, 1H, J=9); PC 6.82 (m, 1H); 6,91 (m, 1H); from 7.24 (m, 5H).

VRMS for C22H27F3N2O2: calculated: 408,2024. Found: 408,2019.

Elemental analysis for C22H27F3N2O2: the 1.44 (m, 1H); was 1.58 (m, 1H); of 1.78 (m, 1H); 2,03 (m, 1H); 2,78 (m, 2H); 3,20 (m, 1H); of 3.32 (d, 1H, J=15); of 3.54 (d, 1H, J=15); a 3.87 (d, 1H, J=2); x 6.15 (t, 1H, J=72); 6,94 (m, 3H); 7,26 (m, 5H).

VRMS for C20H21F5N2O2: calculated: 416,1523. Found: 416,1501.

Elemental analysis for C20H21F5N2O21/3H2O:

Calculated: C 48,50; H To 4.81; N 5,65.

Found: C 48,45; H Of 4.57; N 5,66.

Example 72. (2S, 3S)-3-(2-Ethoxy-5-trifluromethanesulfonate)-2-phenylpiperidine hydrochloride

So pl. > 275oC (Razlog.).

1H-NMR (free base; CDCl3) : of 1.13 (t, 3H, J=6); 5H).

VRMS for C21H25F3N2O2: calculated: 394,1868. Found: 394,1875.

Elemental analysis for C21H25F3N2O2: to 1.16 (t, 3H, J=9); of 1.36 (m, 1H); 1.57 in (m, 1H); of 1.88 (m, 1H); 2,12 (m, 1H); 2,48 (q, 2H); was 2.76 (m, 2H); 3.24 in (m, 1H); to 3.38 (m, 4H); of 3.60 (d, 1H, J=12); 3,86 (d, 1H, J=3); to 6.57 (d, 1H, J=6); 6,74 (d, 1H, J=3); 6,92 (DD, 1H, J=3, 6); from 7.24 (m, 5H).

VRMS for C21H28N2O: calculated: 324,2202. Found: 324,2202.

Example 74. (2S, 3S)-3-(2-Deformedarse-5-nitrobenzylamine)-2-phenylpiperidine hydrochloride.

1H-NMR (free base; CDCl3) : 1,50 (m, 1H); of 1.66 (m, 1H); to 1.98 (m, 2H); 2,82 (m, 2H); or 3.28 (m, 1H); 3.42 points (d, 1H, J=15); of 3.64 (d, 1H, J=15); of 3.95 (d, 1H, J=2); 6,30 (t, 1H, J=72); was 7.08 (t, 1H, J=8) 7,30 (m, 5H); of 8.04 (m, 2H).

FAB-VRMS for C19H21F2N3O3(M+1): calculated: 378,1629. Found: 378,1597.

Example 75. (2S, 3S)-3-(2-Deformedarse-5-isopropylbenzylamine)-2-phenylpiperidine hydrochloride.

So pl.: 245-247oC (Razlog.).

1H-NMR (free base; CDCl3) : 1,19 (2D, 6H, J=7); 1,50 (m, 1H); to 1.75 (m, 2H); 2,12 (m, 1H); and 2.83 (m, 3H); of 3.25 (m, 1H); 3,35 (d, 1H, J=14); of 3.60 (d, 1H, J=14); 3,90 (d, 1H, J=3); of 6.20 (t, 1H, J=75); 6,90 (m, 2H) 7,00 (m, 1H); 7,30 (m, 5H).

VRMS for C22H28F2N2O: calculated: 374,2170. Found: 374,2207.

Elemental analysis for C22Htx2">

Example 76. (2S, 3S)-3-(2-Methoxy-5-hydroxyethylamino)-2-phenylpiperidine hydrochloride.

So pl.: 239-240oC (Razlog.).

1H-NMR (free base; CDCl3) : of 1.42 (m, 1H); of 1.64 (m, 1H); 1,90 (m, 1H); of 2.16 (m, 1H); 2,82 (m, 2H); 3,26 (m, 1H); to 3.36 (d, 1H, J=15); of 3.42 (s, 3H); to 3.58 (d, 1H, J=15); to 3.92 (d, 1H, J=2); 6,37 (d, 1H, J=2); of 6.52 (m, 2H); 7,26 (m, 5H).

VRMS for C19H24N2O2: calculated: 312,1836. Found: 312,1865.

Example 77. (2S, 3S)-3-(2-Methoxy-5-trifluromethane)-amino-2-phenylpiperidine hydrochloride.

So pl.: > 250oC.

1H-NMR (free base; CDCl3) : 1,36 (s, 1H); and 1.54 (m, 1H); to 1.86 (m, 1H); to 2.06 (m, 1H); was 2.76 (m, 2H); up 3.22 (m, 1H); of 3.32 (d, 1H, J=15); of 3.48 (s, 3H); to 3.58 (d, 1H, J=15); of 3.85 (d, 1H, J=3); to 6.57 (d, 1H, J=9); to 6.80 (d, 1H, J=3); 6,92 (DD, 1H, J=3,9); 7,22 (m, 5H).

VRMS for C20H23F3N2O2: calculated: 380,1711. Found: 380,1704.

Elemental analysis for C20H23F3N2O20,2 H2O:

Calculated: C 52,57; H Ceiling Of 5.60; N 6,13.

Found: C 52,58; H Of 5.40; N 5,97.

Example 78. (2S, 3S)-3-(2-Hydroxy-5-trifluromethanesulfonate)-2-phenylpiperidine hydrochloride.

1H-NMR (free base; CDCl3) : 1,60 (m, 3H); 2,04 (m, 1H); was 2.76 (m, 1H); is 2.88 (m, 1H); 3,18 (m, 1H); 3.42 points (s, 2H); 3,90 (m, 1H); of 6.52 (m, 1H); only 6.64 (d, 1H, J=9); 6.89 in (m, 1H); 7,30 (P> Elemental analysis for C19H21F3N2O21/3H2O:

Calculated: C 51,25; H 4,90; N 6,29.

Found: C 51,30; H 4,75; N 6,22.

Example 79. (2S, 3S)-3-[5-Acetamido-2-(2,2,2-trichoroethane)benzylamino] -2 - phenylpiperidine hydrochloride.

So pl.: > 270oC.

1H-NMR (free base; CDCl3) : of 1.46 (m, 1H); to 1.82 (m, 1H); of 2.08 (m, 1H); 2,12 (s, 3H); was 2.76 (m, 2H); 3,20 (m, 1H); 3,48 (d, 1H, J=15); to 3.58 (d, 1H, J=15); 3,82 (m, 1H); 4,08 (m, 2H); 6,44 (m, 1H); to 6.58 (d, 1H, J=10); is 6.78 (m, 1H); 7,26 (m, 5H); 7,58 (m, 1H).

Example 80. (2S, 3S)-3-(2-Deformedarse-5-ethylbenzylamine)-2 - phenylpiperidine hydrochloride.

So pl.: 254-255oC.

1H-NMR (free base; CDCl3) : of 1.12 (t, 3H, J=10); of 1.36 (m, 1H); of 1.44 (m, 1H); to 1.82 (m, 1H); 2,10 (m, 1H); 2,48 (square, 2H, J=10); 2,8 (m, 1H); 3,10 (m, 1H); 3,34 (d, 1H, J=15); to 3.58 (d, 1H, J=15); of 3.9 (d, 1H, J=3); 6,12 (t, 1H, J=85); to 6.78 (s, 1H); 6.90 to (m, 2H); 7,28 (m, 5H).

Elemental analysis for C21H26F2N2O 2HCl:

Calculated: C 58,19; H 6,51; N 6,47.

Found: C 57,90; H Of 6.52; N 6,64.

Example 81. (2S, 3S)-3-(5-Chloro-2-deformationsvetsaren)-2 - phenylpiperidine hydrochloride.

So pl.: 272-274oC.

1H-NMR (free base; CDCl3) : to 1.48 (m, 1H); of 1.64 (m, 1H); of 1.84 (m, 1H); of 2.08 (m, 1H); 2,84 (m, 2H); 3.24 in (m, 1H); 3,34 (d, 1H, J=15); of 3.56 (d, 1H, J= 15); 3,90 (d, 1H, J=3);2O1/3H2O:

Calculated: C 51,20; H 5,33; N 6,29.

Found: C 51,30; H 5,32; N 6,30.

Example 82. (2S, 3S)-Phenyl-3-(2-trichoroethylene)aminopiperidine hydrochloride.

So pl.: 231-233oC.

1H-NMR (free base; CDCl3) : of 1.40 (m, 1H) and 1.60 (m, 1H); of 1.84 (m, 1H); is 2.05 (m, 1H); 2,78 (m, 2H); up 3.22 (m, 1H); 3.42 points (d, 1H, J=15); of 3.56 (d, 1H, J=15); 3,86 (d, 1H, J=3); was 7.08 (m, 4H); from 7.24 (m, 5H).

Mass spectrum: m/z 350 (source).

Elemental analysis for C19H21F3N2O 2HCl025H2O:

Calculated: C 53,34; H 5,54; N 6,54.

Found: C 53,19; H Of 5.40; N 6,54.

1. The method of obtaining substituted 3-aminopiperidine General formula I

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where R1phenyl which may be substituted by one or more substituents, selected from the group of chlorine, fluorine, bromine, C1- C7-alkyl or C1WITH7-alkoxygroup, which may be substituted by 1 to 3 fluorine atoms, WITH3WITH7-cycloalkane, hydroxy, nitro, amino, C1WITH4-alkylamino-C1WITH4-alkyl, C1WITH4-dialkylamino,1WITH4-alkyl-S-, C1WITH4-alkyl-S (O)-, C1WITH4-alkyl-SO2- WITH1- C4-alkoxy-SO2WITH1WITH4-alkyl-SO2NH-, C1WITH4-alkyl -) - Rev. 4-alkoxygroup, thienyl, hinely;

R2phenyl,

characterized in that 3-aminopiperidin General formula II

< / BR>
where R2phenyl,

subjected to interaction with the aldehyde of General formula

R1CHO,

where R1has the specified values,

in the presence of a reducing agent.

2. The method according to p. 1, characterized in that in use as a reducing agent triacetoxyborohydride sodium.

3. The method according to p. 2, wherein the process is conducted in acetic acid at temperatures from minus 60 to plus 50oC.

4. The method according to p. 1, characterized in that the starting compound of formula II is obtained by reduction of compound of formula III

< / BR>
where R2phenyl.

5. The method according to p. 1, characterized in that the starting compound of formula II is produced by the interaction of the compounds of formula

IV

where R2phenyl,

with hydrogen in the presence of a metal-containing catalyst.

6. The method according to p. 5, characterized in that as the metal-containing catalyst is used palladium on coal.

7. The method according to p. 5, wherein the process is conducted in a solvent consisting of water, lower alcohol and hydrochloric acid.

2phenyl.

9. The method according to p. 4, characterized in that the recovery is carried out using hydrogen in the presence of a metal-containing catalyst.

10. The method according to p. 9, characterized in that the catalyst used is platinum on coal.

 

Same patents:

The invention relates to the compound N-pyridylsulfonyl-N'-pyrimidinylidene formula 1

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where R1denotes methyl or methoxy and R2denotes hydrogen or methyl; compounds and salts of these compounds with amines, bases, alkali or alkaline earth metal or Quaternary ammonium bases have good herbicide and regulating plant growth properties during selective use before and after germination

The invention relates to compounds of formula (I) listed in the description, where R1represents a hydrogen atom or unsubstituted or substituted alkyl group; and A represents the number of cyclic or acyclic nitrogen containing groups

The invention relates to a new derived pikolinos acid, useful as components of the herbicide compositions, herbicide compositions containing it, which can be used in rice fields, cultivated fields and non-agricultural land

The invention relates to certain new derivative thimerisol, provides a way of obtaining them and relates to methods and compositions for use as antibacterial agents

The invention relates to new 1-aryl-5-(substituted)alkylidene the pyrazoles, methods for their preparation, to compositions containing these compounds, to methods of their use for combating arthropods, nematodes, helminths or protozoa pests

The invention relates to new biologically active compounds that can be used as plant growth regulators

The invention relates to new methods of production and separation of racemates substituted piperidines and related compounds, and to novel intermediate compounds used in these methods

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved method for production of 3-aminopyperidine derivatives of formula Ib useful in production of protein kinases, wherein R1 is C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl; R3 is hydrogen, C1-C6-alkyl; R13 is phenyl; n = 1-4. Said method includes reduction of compound of formula II, , wherein R14 is C1-C6-alkyl with reducing agent.

EFFECT: improved method for production of 3-aminopyperidine derivatives.

7 cl, 3 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: or its pharmacologically acceptable salts, where n equals 1, 2 or 3; and values of R1, R2, R3, R4, R3', R10, R11 are given in i.1 of formula.

EFFECT: compounds I have ability to inhibit release and/or synthesis of β-amyloid peptide, which allows to apply them in pharmaceutical composition.

25 cl, 3 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a novel method of producing pyrrolo[2,3-d]pyrimidine derivatives of general formula V, which have protein kinase inhibiting properties, including a method of producing novel intermediate compounds. The method of producing compounds of formula V , where X1 is an activating group selected from chlorine, bromine, iodine, R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl, involves linking an activated pyrrolopyrimidine compound of formula IIa , where L1 is a leaving group and X is an activating group selected from chlorine, bromine, iodide; with an amine of formula IIIa or its salt, where R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl and P is a nitrogen protecting group labile to hydrogenolysis, such as benzyl; in the presence of a base to obtain a compound of formula IVa and subsequent removal from the obtained compound of formula IVa of the activating group X1 and the nitrogen protecting group P through hydrogenolysis in the presence of hydrogen or a hydrogen source and a catalyst in any order.

EFFECT: method increases output of the desired product.

26 cl, 8 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds specified in a group shown below. The compounds contain at least 5 rings including a fragment with a bridge structure with a carbon side of the central group C(O)-NH-SO2, piperidinyl, or piperazinyl, or phenyl; phenyl attached to each carbon and sulphur atom of the group C(O)-NH-SO2, wherein phenyl from the sulphur atom side is substituted by a nitro group and NH-CH2(tetrahydro-2H-pyran-4-yl or cyclohexyl) group. The compounds possess the properties of Bcl-2 antiapoptotic protein activity inhibitor and can be used in treating the diseases expressing Bcl-2 protein. These diseases are malignant diseases specified in bladder cancer, cerebral cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukaemia etc. The compounds of the present invention are specified in a group consisting of 4-(4-{acetyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)benzamide; 4-(4-{benzoyl[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)benzamide; N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)-3′-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}biphenyl-4-carboxamide; N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)-4-(4-{(phenylacetyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide; N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulphonyl)-4-(4-{2-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]benzylidene}piperidin-1-yl)benzamide; 4-[4-(2-{5-[8-azabicyclo[3.2.1]oct-8-ylmethyl]-2-thienyl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulphonyl)benzamide; N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide; 4-{4-[adamantan-1-ylmethyl]piperazin-1-yl}-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)benzamide; 4-(4-{2-[adamantan-1-yl]-2-oxoethyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)benzamide; N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulphonyl)-4-{4-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazin-1-yl}benzamide and other compounds or their therapeutically acceptable salts listed in the patent claim.

EFFECT: compounds possess the properties of Bcl-2 antiapoptotic protein activity inhibitor and can be used in treating the diseases expressing Bcl-2 protein.

6 cl, 1 tbl, 85 ex

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