Pyrrolidinone derivatives of hydroxamic acid, the retrieval method, the intermediate, the retrieval method (variants), the method of treatment

 

(57) Abstract:

Proposed new compounds of formula I and their pharmaceutically acceptable salts, where a represents hydrogen, hydroxy or shelter, where Y represents hydroxyamino group; AG represents phenyl, optionally substituted by one or more substituents selected from halogen, hydroxy, C1-C4of alkyl, C1-C4alkoxy, CF3WITH1-C4alkoxy-C1-C4alkyloxy; X represents a phenyl, naphthyl, biphenyl, benzofuranyl, benzothiophene, 1-tetralone-6-yl, C1-C4alkylenedioxy, pyridyl, and these groups are optionally substituted by substituents in the number to three, selected from halogen, C1-C4of alkyl, C1-C4alkoxy, hydroxy, NO2, CF3, SO2CH3and R represents hydrogen, C1-C4alkyl or hydroxyamino group. These compounds and containing pharmaceutical composition applicable as analgesic, anti-inflammatory, diuretic, anesthetic or neuroprotective means or as a means to treat sudden or functional bowel disease, such as abdominal bologny hydroxamic acids of formula I and their intermediate compounds of formula II. 6 C. and 6 C.p. f-crystals, 1 PL.

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The invention relates to new derivatives of hydroxamic acids and their pharmaceutically acceptable salts and containing pharmaceutical compositions. These compounds and compositions can be used as analgesic, anti-inflammatory, diuretic, anesthetic or neuroprotective means or as a means to treat sudden or functional bowel disease, such as abdominal pain, for the treatment of the subject is a mammal, especially man.

Background.

Opioid analgesics, such as morphine, are used for therapeutic purposes, but their use is strictly limited because of their side effects such as drug dependence. Thus, it is desirable the creation of analgesics with wide applicability and a reduced tendency to induction of drug dependence. Considerable pharmacological and biochemical studies, which led to the discovery of opioid peptides and opioid receptors and the discovery of subtypes of opioid receptors, such as, in the peripheral nerve in many species, including humans, put not as agonists - receptors was investigated different actions based on the agonist-receptor, from actions based on agonist - receptor. According to the above point of view recently reported selectively acting-agonists, for example, EMD-60400: A. Barber et al., Naunyn-Schmled. Arch. Pharmacol. , 345 (Suppl. ): Abst. 456. Some of them really were studied in clinical trials (Med. Res. Rev., 12, 525 (1992)).

However, even when applied selectively acting agonist-receptor, the use of high doses may cause side effects such as sedation. Thus, it would be desirable to create a connection with a higher agonistic activity toward opioid receptors, and, in particular, connections, providing only a small sedative effect.

Brief description of the invention.

The present invention relates to a compound of the following formula:

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and its salts, where A represents hydrogen, hydroxy or OY where Y is hydroxyamino group;

Ar represents phenyl, optionally substituted by one or more (preferably one to three) substituents selected from halogen, GI is B> alkyloxy, X represents a phenyl, naphthyl, biphenyl, benzofuranyl, benzothiophene, 1-tetralone-6-yl, C1-C4alkylenedioxy, pyridyl, and these groups are optionally substituted by substituents in the number to three, selected from halogen, C1-C4of alkyl, C1-C4alkoxy, hydroxy, NO2, CF3and SO2CH3;

R represents hydrogen, C1-C4alkyl or hydroxyamino group.

Derivatives of hydroxamic acids of the present invention of formula (I), where A represents hydrogen or hydroxy, and R represents hydrogen or C1-C4alkyl, exhibit significant agonist activity toward opioid receptors. Thus, the data-agonists, in particular, can be used as analgesic means for mammals, especially for humans. They can also be used as anti-inflammatory, diuretic, anesthetic or neuroprotective means or as a means to treat sudden or functional bowel disease, such as abdominal pain, for the treatment of the subject is a mammal, especially man.

Accordingly, the present invented the nutrient, diuretic, anesthetic or neuroprotective tool or as a means to treat sudden or functional bowel disease, such as abdominal pain, for the treatment of the subject is a mammal, especially human, which contains a therapeutically effective amount of hydroxamic acids of formula (I), where A represents hydrogen or hydroxy, and R represents hydrogen or C1-C4alkyl, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

The compounds of formula (I) where one or both OY and OR represents a protected hydroxy-group, can be used as intermediate products of the synthesis with respect to the agonist of formula (I). Typical hydroxyamine groups are benzyl, tetrahydropyranyl.

A preferred group of compounds--agonists of the present invention consists of compounds of formula (I), where A represents hydrogen or hydroxy, Ar is a phenyl, X represents phenyl, substituted with substituents in the number to three, selected from chlorine, methyl and CF3more preferably, 3,4-dichlorophenyl, and R represents hydrogen. Predpochtitel the mi individual compounds according to the invention are:

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[1-(S)-phenyl-2-(1-pyrrolidinyl) ethyl] ndimethylacetamide;

N-Hydroxy-N-[1-(S)-phenyl-2-(1 - pyrrolidinyl)ethyl] -2-(2,3,6-trichlorophenyl)ndimethylacetamide;

N-Hydroxy-N-[1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl] - 2-(4-triptoreline)ndimethylacetamide;

N-Hydroxy-N-[1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl] -2-(2,4,6 - trimetilfenil)ndimethylacetamide;

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(4-Bromophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide;

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl] -2- (4-triptoreline)ndimethylacetamide;

2-(4-Chlorophenyl)-N-hydroxy-N- [2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(2,3-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(2,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1-yl)- 1-(S)-phenylethyl]ndimethylacetamide;

2-(2,5-Dichlorophenyl)-N-hydroxy-N- [2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide;

2-(2,6-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl]ndimethylacetamide;

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl] - 2-(2,3,6-trichlorophenyl)ndimethylacetamide;

2-(3,4-Dichlorophenyl)-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide; and

2-(3,eenie relates to the compound of the formula:

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and its salts, where

A represents hydrogen, hydroxy or OY where Y is hydroxyamino group;

Ar represents phenyl, optionally substituted by one or more substituents selected from halogen, hydroxy, C1-C4of alkyl, C1-C4alkoxy, CF3C1-C4alkoxy-C1-C4alkyloxy;

R represents hydrogen, C1-C4alkyl or hydroxyamino group.

These compounds of formula (II) can be used as intermediates for producing compounds of formula (I).

Further, the present invention relates to methods for hydroxamic derivatives of the formula (I) and the intermediates of formula (II).

Detailed description of the invention.

Agonists of formula (I) according to this invention can be obtained in many ways. For example, they can be easily obtained by the method shown in Scheme 1 (see the end of the description).

Thus, compounds--agonists of formula (I), where A represents hydrogen or hydroxy, and R represents hydrogen, can be obtained by reacting the compounds of formula (VI) with a carboxylic kislovka. This is the usual reaction of acylation, which can be carried out by standard methods, well known to specialists in this field. However, a convenient way acylation of the compounds of formula (VI) with acid formula CCI2COOH includes the interaction of the two compounds in the presence of carbodiimide compounds. Particularly suitable carbodiimide compound is 1-ethyl-3-(3-dimethylamino - propyl)carbodiimide, which is sometimes referred to as water-soluble carbodiimide, or WRC. This reaction is performed by reacting essentially equivalent amounts of acid and amine with a slight excess of carbodiimide in a suitable solvent at a temperature in the range from -30 to 100oC, usually from 0 to 30oC. Suitable solvents are inactive aromatic hydrocarbons, ethers, halogenated hydrocarbons, especially dichloromethane. The reaction takes from about 30 minutes to 24 hours, usually 30 minutes to 3 hours at room temperature. The product can be isolated and purified by standard methods.

The protective group P and any protective group in A1remove the method that is appropriate for a particular protective of. Suitable hydrogenation catalysts are Pd/C, Pearlman catalyst, palladium black or Pd/BaSO4especially 10% Pd/C.

Another convenient protecting group for P and A1is tetrahydropyranyl group (Tgp). It can be removed by acid-catalyzed hydrolysis. Suitable acid catalysts are organic acid, inorganic acid or a Lewis acid such as AcOH, p-TsOH, HCl, Me2AlCl and so on, especially HCl.

Connection--agonists of formula (I), where R represents a C1-C4the alkyl group can be obtained by alkylation of the corresponding compounds of formula (I), where R represents hydroxy. This alkylation can be carried out by conventional methods. A particularly convenient method involves base catalyzed alkylation using alkylhalogenide in the presence of a catalyst phase transition, such as one-deputizing sulfate Tetra-n-butylamine. Intermediate hydroxylamine of the formula (VI) can be obtained from the alcohol (V) processing methanesulfonamido in the presence of a base, such as triethylamine, followed by the addition of the protected hydroxylamine (NH2OP).

The Alcohol (V) Is.

Compounds of formulas (III) and (IV) or are known compounds which can be obtained by known methods, or they are analogues of known compounds which can be obtained by methods analogous to known methods.

Intermediate compounds of formula (II), where Ar is a substituted phenyl, can be obtained in accordance with the methods shown in Scheme 2 (see the end of the description).

(Q represents, for example, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxy - C1-C4alkyloxy or CF3, n=1-5, preferably 1-3.)

As can be seen from Scheme 2, the compound (VII) can interact with substituted styrene oxide (VIII) formation of a mixture of compounds (IX) and (X). This reaction can be carried out in the absence or in the presence of a reaction inert solvent (e.g., methanol (MeOH), ethanol (EtOH), isopropyl alcohol, tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride (CH2Cl2), water, benzene, toluene, n-hexane, cyclohexane) at a temperature of from -78oC to the boiling point of the solvent, preferably from 0 to 25o

In accordance with the above methods, can be selectively installed R,S-configuration of the compounds (IX) and (X). In addition, in the above methods instead substituted styrene oxide (VIII) can be used 1-(substituted phenyl)-1,2-ethanediol-2-tosylate.

The compounds of formula (I) according to this invention are basic, and thus, they will form the salt of the added acid. All such salts fall within the scope of this invention. However, you must use salt add acids which are pharmaceutically acceptable for administration to a mammal. Salt add acids can be obtained by conventional methods, for example by interaction of the basic and acidic compounds in essentially equivalent ratios in water or in an organic solvent such as methanol or ethanol or their mixture. Salt can be isolated by evaporation of the solvent. Typical salts which may be formed are the hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, p-toluensulfonate, oxalate, pamoate (1,1'-methylene is adored, are acidic, and they will form basic salts. All such salts fall within the scope of this invention. However, it is necessary to apply basic salts that are pharmaceutically acceptable for administration to a mammal. Basic salts can be obtained by conventional methods, for example by interaction of acidic and basic compounds in essentially equivalent ratios in water or in an organic solvent such as methanol or ethanol or their mixture. Salt can be isolated by evaporation of the solvent. Typical basic salts that can be formed are the salts of sodium, potassium, calcium and magnesium, and salts of ammonia and amines, such as salt of ethylamine, diethylamine, triethylamine, cyclohexylamine, piperidine and research.

Also included in the scope of the present invention are biological precursors (also called prodrugs) compounds--agonists of formula (I). Biological predecessor-agonist of formula (I) represents its chemical derivative, which in biological systems easily converted back to the original compound of formula (I). In particular, the biological precursor-agonist of formula (I) Preobrazhenie the IAOD the body of the subject is a mammal, for example, person. For example, you can create a biological precursor-agonist according to the invention of formula (I) in which one or both of A and OR represent a hydroxy-group, through the formation of ester of the hydroxy-group. When only one of the And and OR represents a hydroxy-group, can be obtained complex mono - and diesters (which may be the same or different). Typical esters are typically esters of alkanoates, such as acetate, propionate, butyrate, etc., In addition to this, when A or or represent a hydroxy-group, biological precursors can be obtained by converting the hydroxy-group in acyloxymethyl derived (for example, pivaloyloxymethyl derived through interaction with acyloxymethyl (for example, pivaloyloxymethyl).

Connection--agonists of the present invention of formula (I) exhibit significant agonist activity toward opioid receptors and, thus, can be used as analgesic, anti-inflammatory, diuretic, anesthetic and neuroprotective tool or as a means to treat sudden or fu urdumaza in such media.

The activity of compounds agonists of formula (I) according to the present invention is demonstrated by the activity of binding to opioid receptors. Such activity can be determined in homogenates of whole brain of the Guinea pig, as shown Regina A. et al. in J. Res Receptor. 12: 171-180, 1992. Briefly, tissue homogenate incubated at 25oC for 30 minutes in the presence of labeled ligand and a test compound. Sections have been labelled with 1 nm (3H)-[D-Al2, MePhe4, Gly-ol]enkefalina (DAMGO), - areas - through (3H)-[D-Pen2,5]enkefalina DPDPE) and-sections - with 0.5 nm (3H)-Cl-977. Nonspecific binding is measured by applying a 1 μm Cl-977 (a), 1 μm (DAMGO) (), 1 μm (DPDPE) (). Data expressed as KI values50obtained using nonlinear selection using the equation of Cheng and Prusoff. Some compounds obtained in the Examples show a low value KI50in the range from 0.01 to 100 nm.

The activity of compounds--agonists can also be demonstrated using the formalin test, as described by Wheeler-Aceto, H. et al. in Psychopharmacology 104: 35-44, 1991. In this test, male SD rats (80-100 g) injected subcutaneously with the test compound, dissolved in 0.1% ( formalin injection count the number of vylizyvanie paws, in which an injection was used and expressed as % inhibition compared with the control group, which was introduced to the media.

Activity-agonists can also be demonstrated using the test with a rotating rod, as described Hayes, A. G. et al. in Br. J. Pharmacol. 79: 731-736, 1983. In this test a group of 6-10 male SD rats (100-120 g) are chosen on their ability to maintain balance on a rotating rod (diameter 9 cm, the rotation speed of 5 rpm). Selected rats and then injected subcutaneously with the test compound, dissolved in 0.1% solution of methylcellulose. Animal test again in 30 min after injection; a rat fell from the rod more than two times within 150 seconds, consider showing a motor deficiency and write information about performing animal tests (i.e. the time of the rod). In the control group watched the ED50 value, defined as the dose of the drug, which reduces the execution time by half.

Connection--agonists of formula (I) according to this invention can be applied to mammals either orally or parenterally, or topically. In General, these compounds are most preferably administered to humans in doses from 0.01 mg to 50 mg per day, although the need is, the selected route of administration. However, the most desirable for use in patients suffering from pain in the postoperative period, the doses are in the range of from 0.01 mg to 1 mg per kg of body weight per day, in single or split dose.

Compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the above ways, and such introduction can be carried out in single or multiple dose. More specifically, a new therapeutic agent according to the invention can be administered in a wide range of different dosage forms, i.e., they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, pellets, lozenges, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents, etc. in Addition, pharmaceutical compositions for oral administration can be suitably podkosheny and/elgot in such dosage forms at concentration level in the range of from 5 to 70% by weight, preferably from 10 to 50% by mass.

For oral administration can be applied to tablets, containing a variety of diluents such as microcrystalline cellulose, sodium citrate, calcium carbonate, disubstituted potassium phosphate and glycine, along with various disintegrators such as starch and preferably corn, potato starch or starch from tapioca, alginic acid and certain complex silicates, together with granulating binders like polyvinylpyrrolidone, sucrose, gelatin and Arabic gum. In addition, often for tableting are highly applicable lubricants such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may be employed as fillers in gelatin capsules; in this regard, the preferred substances also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When for oral administration, preferred are aqueous suspensions and/or elixirs, the active ingredient may be combined with a variety of sweeteners and flavoring agents, coloring matter or CrazyTalk water, ethanol, propylene glycol, glycerin and other, as, for example, a combination of both.

For parenteral use may be applied to the solutions of the compounds of the present invention in either sesame or peanut oil or in aqueous propylene glycol. Aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the liquid diluent, you must first make isotonic. Data aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. Preparation of all these solutions under sterile conditions with ease perform according to standard pharmaceutical technology, well known to specialists in this field. In addition, also possible is the topical application of the compounds of the present invention in the treatment of inflammatory conditions of the skin, and it preferably can be carried out with the help of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical procedures.

Examples and Receiving.

The present invention is illustrated in the following Examples and Receipts. However, the perceptions were measured on the implant for measuring the melting point Buchi and are given in the interval of values. Infrared absorption spectra (IR) were measured on an infrared spectrometer Shimazu (IR-470).1H and13C spectra of nuclear magnetic resonance (NMR) were measured in CDCl3the NMR-spectrometer JEOL (JNM-GX270, 270 MHz), unless specifically stated otherwise, and the provisions of the peaks are indicated in ppm (M. D.) on tetramethylsilane. The shape of the peaks are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; OSiR., widened.

Receiving 1.

(S)-N-Benzyloxy-1-phenyl-2-pyrrolidineethanol.

To a stirred solution of (R)-2-phenyl-2 - pyrrolidineethanol (E. Brown et al. , Tetrahedron: Asymmetry, 1991, 2, 339; 4,78 g, 25 mmol) and triethylamine (3,95 ml, 28 mmol) in CH2Cl2(50 ml) was added dropwise methanesulfonanilide (2 ml, 26 mmol) at 0oC (ice bath). After stirring for 3 h at room temperature (RT), the reaction mixture was washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated to obtain 5,88 g of a mixture of yellow solid and a brown viscous oil. To this mixture was added O-benzylhydroxylamine (it was obtained from O-benzylhydroxylamine (of 5.99 g, 37.5 mmol) by alkalizing) and ethanol (6 ml) and the mixture was stirred at 8 is ay filtration and washed with ethanol/simple ether with the receipt of 6.96 g (83,7%) of the hydrochloride of the desired product as a white crystalline substance, so pl. 161-162oC.

1H NMR (270 MHz, CDCl3) 7,44-of 7.25 (10H, m), 6,40 (1H, user. C) and 4.68 (1H, d, J= 11.7 Hz), 4,68-to 4.62 (1H, m), 4,63 (1H, d, J=11.7 Hz), 3,90-3,70 (1H, m), 3,60 (1H, DD, J=7,7, 13,2 Hz), 3,55 is 3.40 (1H, m), 3,05 (1H, DD, J= 5,5, 13,2 Hz), 2,80-to 2.65 (1H, m), 2,65 at 2.45 (1H, m), 2,25-of 2.05 (2H, m), 2.05 is and 1.80 (3H, m).

Anal. Calc. for C19H24N2O HCl: C, 68,56; H, EUR 7.57; N, 8,42; Cl, 10,65.

Obtained: C, 68,36; H, Of 7.70; N, 8,39; Cl, 11,13.

This hydrochloride (80 mg) was podslushivaet the ammonium hydroxide solution, was extracted with CH2Cl2, dried (Na2SO4) and concentrated to obtain 67 mg of the derivative of the free amine as a colorless oil.

1H NMR (270 MHz, CDCl3) 7,46 for 7.12 (10H, m), 6,53 (1H, user. C) a 4.53 (1H, d, J=11.0 in Hz) of 4.45 (1H, d, J=11,4 Hz), 4,20 (1H, DD, J=3,7, and 11.4 Hz), 2,90 (1H, DD, J=11,4, 12,5 Hz), 2,70 - 2,60 (2H, m), 2,50 to 2.35 (2H, m), 2,28 (1H, DD, J=4,0, 12,5 Hz), 1,80 is 1.70 (4H, m).

IR (pure): 3250 cm-1< / BR>
[]D= +44,6 (=to 0.67, MeOH).

Example 1.

N-Benzyloxy-2-(3,4-dichlorophenyl)-N-[1-(S)- phenyl-2-(1-pyrrolidinyl)ethyl] ndimethylacetamide.

To a stirred solution of (S)-1-(2-O-benzylhydroxylamine-2 - phenylethyl)pyrrolidinecarboxamido (2,88 g, 8,65 mmol) and 3,4-dichlorophenylamino acid (2,05 ml, 10 mmol) in CH2Cl2(30 ml) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and water and saturated aqueous NaHCO3, dried (Na2SO4) and concentrated to obtain 4.44 g of a pale brown viscous oil. To this oil was added methanol (2 ml) and left to stand for 1 h the Resulting white crystalline substance was collected by filtration to obtain 1.60 g of white powder. The filtrate was concentrated to obtain 2,84 g of a mixture of oil and solids, which was purified by the method of column chromatography (silica gel; 100 g, CH2Cl2/MeOH: 40/1) to obtain the 0,82 g of clear yellow viscous oil, which was led by addition of methanol (0.2 ml).

The total yield amounted to 2.42 g (57.9 per cent). So pl. at 88.5-90oC.

1H NMR (270 MHz, CDCl3) 7,46-7,21 (12H, m), 6,98 (1H, DD, J=2,2, 8,4 Hz), 5,80-the 5.65 (1H, m), to 4.73 (1H, d, J=10.3 Hz), 4,43 (1H, d, J=a 10.6 Hz), of 3.77 (1H, d, J to 15.8 Hz), 3,61-3,51 (2H, m, including 1H, d, J=15,4 Hz at 3,54 M. D.), 2,75-2,60 (3H, m), 2,55-to 2.40 (2H, m), 1,80 of 1.50 (4H, m).

IR (Nujol): 1670 cm-1.

Example 2.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[1-(S)- phenyl-2-(1-pyrrolidinyl)ethyl] ndimethylacetamide.

Suspended mixture of N-benzyloxy-2-(3,4-dichlorophenyl)-N-[1-(S)-phenyl-2-(1-pyrrolidinyl) ethyl] ndimethylacetamide (1.60 g, 3.3 mmol), 10% palladium on coal (0.16 g) and methanol saturated with gaseous HCl (20 ml) in methanol (20 ml) was stirred in the atmosphere is celite, the filtrate was concentrated to obtain 1.63 g purple viscous oil, which was podslushivaet with NH4OH and was extracted with CH2Cl2(20 ml x 3). The combined extract was dried (Na2SO4) and concentrated to obtain a brown crystalline substance was collected by filtration and washed with simple ether/hexane to obtain 1.04 g (80%) of pale yellow powder. So pl. 118-120oC.

1H NMR (270 MHz, CDCl3) 7,44 (1H, d, J=1,8 Hz), 7,37-7,24 (6H, m, including 1H, d, J=8,4 Hz of 7.36 M. D.), 7,17 (1H, DD, J=1,8, 8,4 Hz) to 5.56 (1H, DD, J=5,9, 10,3 Hz), 3,90 (1H, d, J=14,3 Hz), 3,70 (1H, d, J=a 13.9 Hz), and 3.31 (1H, DD, J= 10,6, 12,5 Hz), 2,73 (1H, DD, J=5,9, 12,5 Hz), 2,60 at 2.45 (4H, m), 1,80-of 1.55 (4H, m).

IR (CH2Cl2): 3450, 1650 cm-1.

MS m/z: 394 (M++2, 0,48), 392 (M++, 1,1), 211 (4,8), 173 (3,1), 149 (12,9), 132 (12,8), 99 (28,8), 84 (100).

925 mg of This crystalline substance was dissolved in CH2Cl2(10 ml). To this solution was added a simple ether saturated with gaseous HCl (10 ml) at room temperature. The solution mixture was concentrated to obtain a white crystalline substance was collected by filtration and washed with simple ether with getting 971 mg of the hydrochloride as a white powder.

So pl. 161-162oC.

[]D= +119,8 (=0,884, MeOH).

Anal. Calc. for C20/P>Example 3.

2-(3,4-Dichlorophenyl)-N-methoxy-N-[1-(S)- phenyl-2-(1-pyrrolidinyl)ethyl] ndimethylacetamide.

A mixture of 2-(3,4-dichlorophenyl)-N-hydroxy-N-[1-(S)-phenyl-2- (1-pyrrolidinyl)ethyl]ndimethylacetamide (598 mg, 1.5 mmol), one-deputizing of tetrabutylammonium sulfate (10 mg), 50% aqueous NaOH solution (1 ml) and iodomethane (0,12 ml, 2 mmol) in toluene (4 ml) was stirred at room temperature for 3 hours the Mixture was extracted with ethyl acetate (20 ml x 2). The combined extract was washed with saline, dried (Na2SO4) and concentrated to obtain a brown viscous oil, which was purified by the method of column chromatography (silica gel 60 g, CH2Cl2/MeOH: 20/1) to give 304 mg (49,8%) of yellow viscous oil.

1H NMR (270 MHz, CDCl3) 7,41-7,26 (7H, m), to 7.09 (1H, DD, J=1,8, 8.1 Hz), 5,70-the ceiling of 5.60 (1H, m), 3,83 (1H, d, J=15,4 Hz), the 3.65 (1H, d, J=15,4 Hz), 3,50 (3H, s), 3,50 (1H, DD, J=9,9, 12,5 Hz), 2,75-to 2.57 (3H, m, including 1H, DD, J=4,8, 12,5 Hz at 2,60 M. D.), 2,55-to 2.40 (2H, m) to 1.70 (4H, m).

IR (pure): 1670 cm-1.

304 mg of This crystalline substance was dissolved in MeOH (5 ml). To this solution was added a simple ether saturated with gaseous HCl (5 ml) at room temperature. The solution mixture was concentrated to obtain a white crystalline substance, which was collected

So pl. 161-162oC.

Anal. Calc. for C21H24Cl2N2O2HCl 0.5 H2O: C, 55,70; H, 5,79; N IS 6.19.

Obtained: C, 55,53; H, 5,80; N Is 6.19.

Example 4.

N-Hydroxy-N-[1-(S)-phenyl-2-(1-pyrrolidinyl) ethyl] -2-(2,3,6-trichlorophenyl)ndimethylacetamide.

This compound is obtained from (S)-1-(2-O-benzyl-hydroxylamino-2 - phenylethyl)pyrrolidine exit 68% in accordance with methods similar to those described in Examples 2 and 3.

So pl. 217-218,5oC (hydrochloride)

1H NMR (270 MHz, free amine, CDCl3) 7,44-7,20 (8H, m), 5,61 (1H, DD, J=5,9, a 10.6 Hz), 4,36 (1H, d, J=16,9 Hz), 4.26 deaths (1H, d, J=and 17.2 Hz), 3,40 (1H, DD, J=10,6, 12,5 Hz), 2,80 (1H, DD, J=5,9, 12,5 Hz), was 2.76-to 2.55 (4H, m), 1,90 is 1.70 (4H, m).

IR (pure, free amine): 1670 cm-1.

Anal. Calc. for C20H21Cl3N2O2HCl 0.5 H2O: C, 50,76; H, THE 4.90; N, OF 5.92.

Obtained: C, 50,58; H And 4.65; N, Of 5.83.

Example 5.

N-Hydroxy-N-[1-(S)-phenyl-2-(1-pyrrolidinyl) ethyl] -2-(4-triptoreline)ndimethylacetamide.

This compound is obtained from (S)-1-(2-O-benzyl-hydroxylamino-2 - phenylethyl)pyrrolidine with the release of 66.6% in accordance with methods similar to those described in Examples 2 and 3.

So pl. to 172.8-177oC (hydrochloride)

1H NMR (270 MHz, swobo), 3,30 (1H, DD, J=10,6, 12,5 Hz), 2,71 (1H, DD, J=5,9, 12,5 Hz), 2,60-to 2.40 (4H, m), 1,80 of 1.50 (4H, m).

IR (pure, free amine): 3150, 1650 cm-1.

Anal. Calc. for C21H23F3N2O2HCl H2O: C, 56,44; H, A 4.86; N, 6,27.

Obtained: C, 56,16; H, 5,77; N, 6,76.

Example 6.

N-Hydroxy-2-(1-naphthyl)-N-[1-(S)-phenyl-2-(1 - pyrrolidinyl)ethyl]ndimethylacetamide.

This compound is obtained from (S)-1-(2-O-benzyl-hydroxylamino-2-phenylethyl)pyrrolidine with the release of 65.1% in accordance with methods similar to those described in Examples 2 and 3.

So pl. 81,0-83,5oC (hydrochloride)

1H NMR (270 MHz, free amine, CDCl3) 7,55-7,20 (13H, m), 5,59 (1H, DD, J=5,9, 10,3 Hz), 4,43 (1H, d, J=14,7 Hz), 4,10 (1H, d, J=15,0 Hz) and 3.31 (1H, DD, J=11,0, 12.1 Hz), 2,65 (1H, DD, J=5,9, 12,5 Hz), 2,55 to 2.35 (4H, m), 1.60-to of 1.35 (4H, m).

IR (pure, free amine): 3150, 1650 cm-1.

Anal. Calc. for C24H26N2O2HCl 1,2 H2O: C, 66,64; H, 6,85; N, 6.48 IN.

Obtained: C, 66,93; H, 6,50; N, 6,02.

Example 7.

N-Hydroxy-N-[1-(S)-phenyl-2-(1-pyrrolidinyl) ethyl] -2-(2,4,6-trimetilfenil)ndimethylacetamide.

This compound is obtained from (S)-1-(2-O-benzyl - hydroxylamino-2-phenylethyl)pyrrolidine with the release of 58.9% in accordance with methods similar to those described in Examples 2 Prov.), PC 6.82 (2H, s), 5,70-of 5.55 (1H, m), 3,86 (2H, user. C) to 3.38 (1H, DD, J=10,6, 12.1 Hz), is 2.74 (1H, DD, J=5,9, 12,5 Hz), 2,70 is 2.55 (4H, m), 2,22 (9H, s), 1.85 to about 1.75 (4H, m).

IR (pure, free amine): 3220, 1640 cm-1.

Anal. Calc. for C23H30N2O2HCl 1,3 H2O: C, 64,79; H, 7,94; N, 6,57.

Obtained: C, 64,51; H, Of 7.48; N, Of 6.31.

Example 8.

N-Hydroxy-2-(4-pyridyl)-N-[1-(S)-phenyl-2- (1-pyrrolidinyl)ethyl] ndimethylacetamide.

This compound is obtained from (S)-1-(2-O-benzyl-hydroxylamino-2-phenylethyl)pyrrolidine with access to 67.9% in accordance with methods similar to those described in Examples 2 and 3.

1H NMR (270 MHz, free amine, CDCl3) 8,46 (2H, d, J=5,9 Hz), 7,40-to 7.18 (8H, m), 5,61 (1H, DD, J=5,5, to 10.6 Hz), 3,91 (1H, d, J=14,3 Hz), of 3.77 (1H, d, J=a 13.9 Hz), to 3.33 (1H, DD, J=11,0, 12.1 Hz), 2,68 (1H, DD, J= 5,5, 12,5 Hz), 2.57 m-2,40 (4H, m), 1,80-of 1.55 (4H, m).

IR (pure, free amine): 1640 cm-1.

Example 9.

2-(Benzo[b] furan-4-yl)-N-hydroxy-N-[1-(S)-phenyl-2- (1-pyrrolidinyl)ethyl]ndimethylacetamide.

This compound is obtained from (S)-1-(2-O-benzyl-hydroxylamino-2-phenylethyl)pyrrolidine with the release of 73.5% in accordance with methods similar to those described in Examples 2 and 3.

1H NMR (270 MHz, CDCl3) to 7.59 (1H, d, J=1,8 Hz), 7,45-7,20 (9H, m), 6,98 (1H, user. C) to 5.58 (1H, DD, J=5,9, a 10.6 Hz), 4,24 (1H, d, J=13,6 Hz), 3,91 in): 1650 cm-1.

Getting 2.

1,4-Dead-2-(S)-(tetrahydropyranyloxy)butane.

To mix the solution(3)-(-)-1,2,4-butanetriol (10,61 g, 0.1 mol) in pyridine (100 ml) portions was added p-toluensulfonate (38,13 g, 0.2 mol) at 0oC. After stirring for 2 h the reaction mixture was poured into 10% aqueous HCl solution, containing ice, and acidified to pH 2. The mixture was extracted with ethyl acetate (150 ml x 3). The combined extract was washed with saline, dried (Na2SO4) and concentrated to obtain 42,88 g of colorless oil. A mixture of this crude of ditosylate (42,88 g, 0.1 mol) and NaI (44,79 g, 0.3 mol) in acetone (300 ml) was heated under reflux with stirring for 5 hours Sadassa solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with an aqueous solution of Na2S2O3and a salt solution. After drying (Na2SO4) the solvent is evaporated and the residue was purified by the method of column chromatography (250 g silica gel, hexane/ethyl acetate: 10/1) to obtain the 24,81 g of colorless oil. A mixture of this oil (24,81 g, with 76.1 mmol), 3,4-dihydro-2H-Piran (of 21.9 ml, 0.24 mol) and p-toluensulfonate pyridinium (125 mg) in CH2Cl2(1 ml), washed with aqueous NaHCOs solution and dried (Na2SO4). Evaporation of the solvent gave 33,56 g of pale yellow oil, which was purified by the method of column chromatography (250 g silica gel, hexane/ethyl acetate: 20/1) to obtain the 28,75 g (70.1 percent for stage 3) colorless oil.

1H NMR (270 MHz, CDCl3) 4,80-of 4.75 (1H, m), as 4.02-of 3.85 (1H, m), 3,70-3,17 (6H, m), 2,27 is 2.01 (2H, m), 1,90-of 1.55 (6H, m).

Getting 3.

2-(R)-Phenyl-2-(3-(S)-tetrahydropyranyloxy-1-yl)ethanol.

Suspension a mixture of 1,4-dead-2-(S)-(tetrahydropyranyloxy)butane (12,50 g, 30 mmol), R-(-)-phenylglycinol (3,43 g, 25 mmol) and K2CO3(6,91 g, 50 mmol) in ethanol (50 ml) was heated under reflux with stirring for 6 hours White solid was removed by filtration and the filtrate was concentrated. The residue was diluted aqueous solution of NaHCO3(30 ml) and was extracted with CH2Cl2(20 ml x 3). After drying (Na2SO4) the solvent is evaporated, which gave 9,54 g of clear yellow oil, which was purified by the method of column chromatography (silica gel 150 g, CH2Cl2/MeOH: 20/1) to obtain the 7,22 g (99%) of colorless viscous oil.

1H NMR (270 MHz, CDCl3) 7,37-7,27 (5H, m), br4.61-4,51 (1H, m), 4,40-to 4.28 (1H, m), 3,91 of 3.75 (3H, m), 3,55-3,42 CLASS="ptx2">

Getting 4.

1-(S)-Phenyl-N-tetrahydropyranyloxy-2-(3- (S)-tetrahydropyranyloxy-1-yl)ethylamine.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and O-tetrahydropyranyloxy (R. N. Warrener and E. N. Cain, Angew. Chem. Int. Edit. 1996, 5, 511) with the release of 42.5% in the form of a brown oil in accordance with the method similar to that described in Obtaining 1.

1H NMR (270 MHz, CDCl3) 7,45-of 7.25 (5H, m), 6,51 (1H, user. C) 4,80-to 4.73 (1H, m), 4,65-4,55 (1H, m), 4,45-to 4.33 (1H, m), 4,28-to 4.15 (1H, m), 4.00 points of 3.75 (2H, m), 3,70 is 2.55 (9H, m), 2,30-2,05 (1H, m), 1,90-of 1.35 (12H, m).

Example 10.

2-(3,4-Dichlorophenyl)-N-tetrahydropyranyloxy-N- [2-(3-(S)-tetrahydropyranyloxy-1-yl)-1-(S)- phenylethyl]ndimethylacetamide.

This compound was obtained from 1-(S)-Phenyl-N-tetrahydropyranyloxy - 2-(3-(S)-tetrahydropyranyloxy-1-yl)ethylamine and 3,4-dichlorophenylamino acid with a yield of 69.8% in the form of a clear brown viscous oil in accordance with the method similar to that described in Example 1.

1H NMR (270 MHz, CDCl3) 7,43-7,15 (7,4 H, m), 6,98-6,91 (0,6 H, m) 5,69 (0,4 H, DD, J=4.0 a, and 11.0 Hz), 5,58 (0,6 H, DD, J=4,8, and 11.4 Hz), 5,35-5,20 (1H, m), 4,65-a 4.53 (1H, m), to 4.41-is 4.21 (1H, m), 4,15-of 3.80 (4H, m), 3,68-3,10 (4H, m), 3,03 is 2.80 (2H, m), 2,70 to 2.35 (3H, m), 2,20-1,10 (13H, m).

Example 11.

arvanil)-N-tetrahydropyranyloxy-N-[2-(3-(S)- tetrahydropyranyloxy-1-yl)-1-(S)-phenylethyl] ndimethylacetamide (1.13 g, a 1.96 mmol) and saturated with gaseous HCl in MeOH (4 ml) in MeOH (20 ml) was stirred at room temperature for 7 hours, the Solvent is evaporated. The residue was podslushivaet with saturated aqueous NaHCO3, was extracted with CH2Cl2and dried (Na2SO4). Evaporation of the solvent gave 0,80 g of brown viscous oil, which was led by adding a simple ether and trituration. The crystalline substance was collected by filtration and washed with simple ether with getting 377 mg (47,1%) of white powder.

So pl. of 98.5-99,5oC

1H NMR (270 MHz, CDCl3) 7,45-7,20 (7H, m), 7,14 (1H, DD, J=1,8, 9.9 Hz), 5,62 (1H, DD, J=5,5, and 11.0 Hz), 5,00-of 3.00 (2H, almost flat user. C), 4,35-of 4.25 (1H, m), 3,85 (1H, d, J=14,3

Hz), to 3.73 (1H, d, J=a 13.9 Hz), to 3.38 (1H, DD, J=11,0, 12,5 Hz), 2,95 (1H, dt, J=5,1, 8,8 Hz), 2,73 (1H, d, J=a 10.6 Hz), 2,65 (1H, DD, J=5,5, 12,5 Hz), of 2.51 (1H, DD, J=5,5, to 10.6 Hz), 2,40-of 2.27 (1H, m), 2,22-2,07 (1H, m), 1,65 of 1.50 (1H, m).

IR (Nujol): 3070, 1640 cm-1.

MS m/z: 412 (M++4, 10,3), 410 (M++2, 85,7), 408 (M+100), 304 (8,6), 149 (50,2), 114 (22,7), 112 (24,2).

[]D= +102,9 (=0,516, MeOH).

Hydrochloride: so pl. 65,5-67,0oC

Anal. Calc. for C20H22Cl2N2O3HCl 0.5 H2O: C, 52,82; H, 5,32; N, 6,16.

Obtained: C, 53,09; H, From 5.29; N, 6,17.

1H NMR (270 MHz, CDCl3) 7,30 (2H, DD, J=5,5, 8,4 Hz), 7,03 (2H, t, J= 8,4 Hz), of 4.05 (1H, DD, J=4,4, 8.1 Hz), 3,71 (1H, DD, J=4,4, to 10.6 Hz), 3,53 (1H, DD, J=8,4, a 10.6 Hz), 2,19 (3H, user. C).

IR (KBr): 3350, 3280 cm-1.

Getting 6.

2-(R)-(4-Forfinal)-2-(3-(S)-tetrahydropyranyloxy-1-yl)ethanol.

This compound was obtained from 2-(R)-(-)-2-(4- forfinal)glycinol with access to 68.8% in the form of a brown oil in accordance with the method similar to that described in 3.

1H NMR (270 MHz, CDCl3) 7,31-7,26 (2H, m), 7,03 (2H, DD, J=8,4, 8,8 Hz), 4,65-4,51 (1H, m), 4,40-4,27 (1H, m), 3,90 of 3.75 (3H, m), 3,55 is 3.40 (2H, m), 2,90-2,70 (1H, m), 2,70-of 2.50 (2H, m), 2,50 to 2.35 (1H, m), 2,30-of 1.95 (2H, m), 1,95-to 1.60 (3H, m), 1.60-to a 1.45 (4H, m).

IR (pure): 3450 cm-1.

Example 12.

2-(3,4-Dichlorophenyl)-N-[1-(S)-(4-forfinal) ethyl-2-(3-(S)-hydroxypyrrolidine-1-yl)]-N-hydroxyacetamido.

This compound was obtained from 2-(R)-(4-forfinal)-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 3,4-dichlorophenylamino acid with a yield of 52.8% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,41-7,26 (4H, m), 7,12 (1H, DD, J=1,8, 8.1 Hz), of 6.99 (2H, DD, J=8,4, 8,8 Hz), the ceiling of 5.60 (1H, DD, J=5,1, and 11.0 Hz), 4,35-of 4.25 (1H, m), 3,82 (1H, d, J=a 13.9 Hz), and 3.72 (1H, d, J=14,3 Hz), 3,10 (2H, m), 1,65-of 1.55 (1H, m).

IR (pure): 3200, 1640 cm-1.

MS m/z: 426 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H21Cl2FN2O3HCl 0,7 H2O: C, 50,43; H, OF 4.95; N, 5,88.

Obtained: C, 50,80; H, 4,96; N, The 5.45.

Example 13.

2-(4-Bromophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 4-bromoferrocene acid with the release of 44.6% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,50-7,14 (9H, m), 5,61 (1H, DD, J=5,1, and 11.0 Hz), 4,28-4,22 (1H, m), 3,90 (1H, d, J=13,6 Hz), 3,70 (1H, d, J=a 13.9 Hz), to 3.33 (1H, DD, J=11,0, 12,5 Hz), 2,92-2,82 (1H, m), 2,72-of 2.64 (2H, m), 2,50 (1H, DD, J=5,5, a 10.6 Hz), 2,38-of 2.28 (1H, m), of 2.20 (2H, user. C), 2,16 is 2.01 (1H, m), 1.60-to 1,50 (1H, m).

IR (pure): 3200, 1630 cm-1.

MS m/z: 418 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H23BrN2O3HCl 0.5 H2O: C, 51,68; H, 5,42; N, 6,03.

Obtained: C, Won With 51.75; H, The 5.51; N, 5,71.

Example 14.

2-(3-Bromophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

1H NMR (270 MHz, CDCl3) 7,51-to 7.15 (9H, m), 5,62 (1H, DD, J=5,5, and 11.0 Hz), 4,28-4,20 (1H, m), of 3.94 (1H, d, J=a 13.9 Hz), 3,70 (1H, d, J=13,6 Hz), the 3.35 (1H, DD, J=11,4, 12,5 Hz), 2,92-and 2.83 (1H, m), 2,70-2,62 (2H, m), of 2.51 (1H, DD, J=5,1, a 10.6 Hz), 2,42 (2H, user. C), 2,38-of 2.28 (1H, m), 2,18-2,03 (1H, m), 1.60-to of 1.46 (1H, m).

IR (pure): 3200, 1630 cm-1.

MS m/z: 418 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H23BrN2O3HCl H2O: C, 50,70; H, OF 5.53; N, 5,91.

Obtained: C, 50,57; H, To 5.58; N, 5,90.

Example 15.

2-(4-Forfinal)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 4-florfenicol acid with a yield of 23.6% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,40-7,22 (7H, m), 7,10-to 6.95 (2H, m), 5,67-5,61 (1H, m), 4,34-4,22 (1H, m), 3,92 (1H, d, J=13,6 Hz), to 3.73 (1H, d, J= a 13.9 Hz), to 3.36 (1H, DD, J=10,6, 12,5 Hz), 2,96-of 2.86 (1H, m), was 2.76-2,62 (2H, m), 2,58-2,48 (1H, m), 2,40-of 2.28 (1H, m), 2,24 is 1.70 (3H, m), 1,64 is 1.48 (1H, m).

IR (pure): 3400, 1630 cm-1.

MS m/z: 358 (M+).

Hydrochloride: amorphous solid.

Anal. the,88.

Example 16.

2-(3,4-Acid)-N-hydroxy-N-[2-(3- (S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 3,4-dimethoxyphenylacetic acid with the release of 10.6% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,40-7,22 (5H, m), 6,95-of 6.78 (3H, m), 5,70-the ceiling of 5.60 (1H, m), 4,25-to 4.15 (1H, m), 3,91 (1H, d, J=a 13.9 Hz), 3,88 (3H, s), a 3.87 (3H, s), 3,68 (1H, d, J=a 13.9 Hz), to 3.33 (1H, DD, J=11,4, 11.7 Hz), 2,90-2,78 (1H, m), 2,74-2,60 (2H, m), 2,47 (1H, DD, J=5,1, to 10.6 Hz), 2,34-of 2.20 (1H, m), 2,14-to 1.98 (1H, m), 1,90 (2H, user. C) 1,50-of 1.36 (1H, m).

IR (pure): 3400, 1640 cm-1.

MS m/z: 400 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C22H28N2O5HCl 2,7 H2O: C, 54,42; H, 7,14; N, 5,77.

Obtained: C, 54,31; H, 6,77; N, Of 5.92.

Example 17.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl] -2-(3-triptoreline)ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 3-triftormetilfullerenov acid with the release of 18.9% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

m), 2,84-to 2.40 (6H, m), 2,20-to 2.06 (1H, m), 1.70 to 1.55V (1H, m).

IR (pure): 3350, 1630 cm-1.

MS m/z:408 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C21H23F3N2O3HCl 1,9 H2O: C, 54,70; H, 5,64; N, BETWEEN 6.08.

Obtained: C, 54,83; H, 5,97; N, 6,21.

Example 18.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl] -2-(4-triptoreline)ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 4-triftormetilfullerenov acid with a yield of 35.4% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,56 (2H, d, J=8.1 Hz), 7,44 (2H, d, J=8.1 Hz), 7,33-7,26 (5H, m), the 5.65 (1H, DD, J=5,9, and 11.0 Hz), 4,35-4,20 (1H, m), 3,99 (1H, d, J=14,3 Hz), 3,85 (1H, d, J=a 13.9 Hz), to 3.41 (1H, DD, J=12.1 is a 12.5 Hz), 3,00-2,90 (1H, m), 2,82-2,02 (7H, m), 1,64 of 1.50 (1H, m).

IR (pure): 3100, 1650 cm-2.

MS m/z: 408 (M+).

Hydrochloride: so pl. 142,5-144,2oC.

Anal. Calc. for C21H23F3N2O3HCl 0,2 H2O: C, 56,24; H, OF 5.48; N, 6,25.

Obtained: C, 56,27; H, 5,61; N, Between 6.08.

Example 19.

2-(4-Biphenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ACE and 4-biphenyloxy acid with access to 38.8% in accordance with the methodology similar to the one described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,60-7,26 (14H, m), to 5.66 (1H, DD, J=5,1, and 11.0 Hz), 4,20-to 4.14 (1H, m), Android 4.04 (1H, d, J=13,6 Hz), 3,76 (1H, d, J=13,2 Hz), the 3.35 (1H, DD, J= 10,3, to 13.6 Hz), 2,90 is 2.80 (1H, m), 2,73-2,63 (2H, m), 2,55 at 2.45 (1H, m), 2,35-2,22 (1H, m), 2,10 is 1.96 (1H, m), 1,90 (2H, user. C) a 1.50 and 1.35 (1H, m).

MS m/z: 417 (M+H)+.

Hydrochloride: so pl. 163,8-165,5oC.

Anal. Calc. for C26H28N2O3HCl 0.5 H2O: C, 67,60; H, 6,55; N, 6,06.

Obtained: C, 67,77; H, 6.42 Per; N, 5,76.

Example 20.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl] -2-(4-nitrophenyl)ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 4-nitrophenylarsonic acid with a yield of 11.6% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) to 8.14 (2H, d, J=8,8 Hz), 7,44 (2H, d, J=8,8 Hz), 7,35-7,16 (5H, m), 5,74 (1H, DD, J=4,8, or 10.3 Hz), 4,46-to 4.38 (1H, m), a 4.03 (1H, d, J=15,0 Hz), of 3.96 (1H, d, J=15,0 Hz), 3,64-3,50 (1H, m), 3,20-3,10 (1H, m), 2,96 (1H, user. d, J=10.3 Hz), 2,90-to 2.74 (3H, m) to 2.66 (2H, user. C) 2,30-of 2.16 (1H, m), 1,84 is 1.70 (1H, m).

IR (pure): 3400, 1630 cm-1.

MS m/z: 385 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H is 21.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine - 1-yl)-1-(S)-phenylethyl] -2-(3-nitrophenyl)ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 3-nitrophenylarsonic acid with a yield of 11.6% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 8,17-8,08 (2H, m), 7,66-7,20 (7H, m), 5,64 (1H, DD, J=5,9, and 11.0 Hz), to 4.38-4,30 (1H, m), a 4.03 (1H, d, J=14,7 Hz), 3,90 (1H, d, J=14,3 Hz), 3,50-to 3.38 (1H, m), 3,06-to 2.94 (1H, m), 2,84-2,70 (2H, m), 2,66-of 2.56 (1H, m), 2,50 of-2.32 (1H, m), 2,20-2,04 (1H, m), a 1.96 (2H, user. s), 1.70 to a 1.50 (1H, m).

MS m/z: 386 (M+H)+.

Hydrochloride: so pl. 154,3-155,5oC.

Anal. Calc. for C20H23N3O5HCl 0,3 H2O: C, 56,22; H, 5,80; N, 9,83.

Obtained: C, 56,29; H, 5,80; N, Of 9.55.

Example 22.

2-(4-Chlorophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 4-chloranilic - susei acid with a yield of 49.4% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) ' 7,40-7,20 (9H, m), the 5.65 (1H, DD, J=5,1, and 11.0 Hz), 5,00-3,30 (2H, widely set of user. C), 4,35-of 4.25 (1H, m), 3,86 (1H, d, J=13,9 g was 2.25 (1H, m), 2,23-of 2.08 (1H, m), 1,65 of 1.50 (1H, m).

IR (pure): 3400, 1630 cm-1.

MS m/z: 374 (M+).

Hydrochloride: so pl. 146,5-147,3oC.

Anal. Calc. for C20H23ClN2O3HCl 0,3 H2O: C, 57,64; H, 5,95; N, 6,72.

Obtained: C, 57,87; H, 5,88; N Is 6.78.

Example 23.

2-(3-Chlorophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 3-chlorophenylalanine acid with the release of 29.6% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,34-7,20 (9H, m), 5,75-5,62 (1H, m), 4,35-of 4.25 (1H, m), of 3.94 (1H, d, J=a 13.9 Hz), 3,74 (1H, d, J=a 13.9 Hz), of 3.45 (1H, DD, J= 9,5, 12.1 Hz), 3,05 of 2.92 (1H, m), 2,80 (1H, user. d, J=a 10.6 Hz), 2.77-to 2,30 (3H, m), 3,80-of 2.30 (2H, almost flat peak), 2,23-to 2.06 (1H, m), 1,68-and 1.54 (1H, m).

IR (pure): 3350, 1630 cm-1.

MS m/z: 374 (M+).

Hydrochloride: so pl. of 113.2-114,3oC.

Anal. Calc. for C20H23ClN2O3HCl 0,4 H2O: C, 57,40; H, 5,97; N, 6,69.

Obtained: C, 57,79; H, Of 5.84; N, 6,74.

Example 24.

2-(2-Chlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl]ndimethylacetamide.

Bankislami with the release of 31.2% in accordance with the methodology similar to the one described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-7,16 (9H, m), 5,85-5,70 (1H, m), of 4.44-4,34 (1H, m), 4,14 (1H, d, J=16.1 Hz), 3,91 (1H, d, J=16.1 Hz), 3,68-2,48 (1H, m), 3,24-3,10 (1H, m), 2,98-to 2.40 (6H, m), 2,34-to 2.18 (1H, m), 1,86 is 1.70 (1H, m).

IR (pure): 3400, 1640 cm-1.

MS m/z: 374 (M+).

Hydrochloride: so pl. 146oC.

Anal. Calc. for C20H23ClN2O3HCl H2O: C, 55,95; H, 6,10; N, 6,52.

Obtained: C, 56,18; H; 6,00; N, 6,55.

Example 25.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl] -2-(2,3,5-trichlorophenyl)ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 2,3,5-trichlorophenylacetic acid with a yield of 51.6% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-7,22 (6H, m), 7,14 (1H, d, J=2.2 Hz), 5,70 (1H, DD, J=4,8, and 11.0 Hz), 4,48-4,30 (1H, m), 4,20 is 3.00 (2H, widely set of user. C) 4,06 (1H, d, J=16.5 Hz), 3,90 (1H, d, J=16.1 Hz), 3,50 (1H, DD, J=11,4, 12.1 Hz), 3,20-3,10 (1H, m), 2,86 (1H, user. d, J=10.3 Hz), 2,75 - 2,60 (2H, m), 2,55 to 2.35 (1H, m), 2,35-of 2.20 (1H, m), 1.85 to to 1.70 (1H, m).

IR (pure): 3400, 1640 cm-1.

MS m/z: 444 (M+).

Hydrochloride: amorphous solid.

Anal. In 5,17; N, 5,40.

Example 26.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl] -2-(2,4,6-trichlorophenyl)ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 2,4,6-trichlorophenylacetic acid with the release 14.0% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,50-7,26 (7H, m), the ceiling of 5.60 (1H, DD, J=4,8, and 11.4 Hz), 4,47-to 4.38 (1H, m), 4,19 (2H, s), 3,49 (1H, DD, J=11,7, 12.1 Hz), 3,25-3,10 (1H, m), 2,84 (1H, user. d, J=9.5 Hz), 2,75-2,60 (2H,m), 2,50 to 2.35 (2H, m), 2,35-of 2.20 (2H, m), 1,90 is 1.70 (1H, m).

IR (pure): 3450, 1640 cm-1.

MS m/z: 442 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H21Cl3N2O3HCl 0,2 H2O: C, 49,65; H, OF 4.67; N, 5,79.

Obtained: C, 49,42; H, 4,39; N, 5,96.

Example 27.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl] -2-(2,4,6-trimetilfenil)ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 2,4,6-trimethylpentane acid with a yield of 67.8% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-of 7.25 (5H, m),m), of 2.23 (3H, s) to 2.18 (6H, s), 1,90-of 1.65 (1H, m), 1,65 of 1.50 (1H, m).

IR (pure): 3250, 1630 cm-1.

MS m/z: 382 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C23H30N2O3HCl 0,2 H2O: C, 64,01; H, EUR 7.57; N, OF 6.49.

Obtained: C, 64,08; H, A 7.85; N, 6,61.

Example 28.

2-(2,3-Dichlorophenyl)-N-hydroxy-N-[2-(3- (S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 2,3-dichlorophenylamino acid with a yield of 56% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,50-7,05 (8H, m) 5,69 (1H, DD, J=5,1, and 11.4 Hz), 5,00-of 3.00 (2H, almost flat user. C), 4,45 is 4.35 (1H, m), 4,10 (1H, d, J= 16.1 Hz), 3,92 (1H, d, J=16.1 Hz), 3,48 (1H, DD, J=11,7, 12.1 Hz), 3,20-3,10 (1H, m), 2,82 (1H, d, J=10.3 Hz), 2,70 is 2.55 (2H, m), 2,45-of 2.20 (2H, m), 1,80 is 1.70 (1H, m).

IR (pure): 3200, 1640 cm-1.

MS m/z: 408 (M+).

Hydrochloride: so pl. was 155.3-158,1oC.

Anal. Calc. for C20H22Cl2N2O3HCl: C, 53,89; H, 5,20; N, 6,28.

Obtained: C, 53,72; H, 5,24; N, 6,16.

Example 29.

2-(2,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-phenyl-Christ.) of ethanol and 2.4-dichlorphenoxy acid with a yield of 56% in accordance with the methodology similar to the one described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-to 7.15 (8H, m) 5,69 (1H, DD, J=5,1, and 11.4 Hz), 6,50-4,50 (2H, almost flat user. C), 4,35-of 4.25 (1H, m) 4,00 (1H, d, J= 16.1 Hz), 3,86 (1H, d, J=16.1 Hz), 3,47 (1H, DD, J=11,7, 12.1 Hz), 3,20-3,10 (1H, m), and 2.83 (1H, d, J= a 10.6 Hz), 2,61 (2H, DD, J=5,5, 12.1 Hz), 2,45-of 2.20 (2H, m), 1,80-of 1.65 (1H, m).

IR (pure): 3200, 1635 cm-1.

MS m/z: 408 (M+).

Hydrochloride: so pl. 149-151,5oC.

Anal. Calc. for C20H22Cl2N2O3HCl 0,2 H2O: C, 53,46; H, A 5.25; N, 6,23.

Obtained: C, 53,46; H, 5,19; N Is 6.19.

Example 30.

2-(2,5-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(R)-phenyl-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethanol and 2.5-dichlorphenoxy acid with the release of 56.3 per cent in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-to 7.15 (8H, m) 5,69 (1H, DD, J=5,1, and 11.0 Hz), the ceiling of 5.60-4,50 (2H, almost flat user. C), 4,35-of 4.25 (1H, m), a 4.03 (1H, d, J=16.1 Hz), 3,86 (1H, d, J=16.1 Hz), 3,47 (1H, t, J=11.7 Hz), 3,20-3,10 (1H, m), 2,82 (1H, d, J=a 10.6 Hz), 2,63 (2H, DD, J=5,1, 12.1 Hz), 2,45-of 2.20 (2H, m), 1.85 to to 1.70 (1H, m).

IR (pure): 3200, 1635 cm-1.

MS m/z: 408 (M+).

Hydrochloride: so; 's , 5.25; N, 6,23.

Obtained: C, 53,35; H, To 5.21; N, 6,14.

Getting 7.

2-(3-(S)-Methoxyethoxyethoxy-1-yl)-2- (R)-phenylethanol.

To a stirred solution of (S)-(-)-butanetriol (10,61 g, 0.1 mol) in pyridine (50 ml) portions was added p-toluensulfonate (38,13 g, 0.2 mol) at 0oC (ice bath). After stirring for 1 h the reaction mixture was poured into an aqueous solution of K-HCl containing ice, and acidified to pH 2. The mixture was extracted with ethyl acetate (100 ml x 3). The combined extract was washed with saline, dried (Na2SO4) and concentrated to obtain 36,22 g of a pale brown transparent oil. To a stirred solution of this crude of ditosylate (36,22 g) and matilla (50 ml) in CH2Cl2(50 ml) was added P2O5(20 g). After stirring for 1 h the reaction mixture was added 10 g of P2O5. After stirring for 2 h layer CH2Cl2was separated. The remaining dark brown solid was washed CH2Cl2. The combined layer of CH2Cl2washed in an aqueous solution of NaHCO3, dried (Na2SO4) and concentrated to obtain 38,51 g of brown viscous oil. A mixture of this oil (38,51 g, 84 mmol), (R)-(-)-2-FeNi is under stirring for 15 hours The solvent is evaporated and the residue was dissolved in CH2Cl2(200 ml), washed with aqueous solution of NaHCO3and brine, dried (Na2SO4) and concentrated to obtain 28,43 g of brown viscous oil. This oil was purified by the method of column chromatography (silica gel 200 g, CH2Cl2/methanol: from 40/1 to 20/1) to obtain the 9,74 g (48.4%) of transparent brown viscous oil.

1H NMR (270 MHz, CDCl3) 7,40-of 7.25 (5H, m), to 4.62 (1H, d, J=7,0 Hz), 4,58 (1H, d, J=6.6 Hz), 4.26 deaths-4,18 (1H, m) to 3.92 (1H, DD, J=6,2, and 11.0 Hz), 3,82 (1H, DD, J=5,5, and 11.0 Hz), of 3.54 (2H, t, J=5,9 Hz), to 3.33 (3H, s), with 2.93 (1H, user. C) 2,85-of 2.66 (3H, m), 2,56-2,47 (1H, m), 2,16-2,02 (1H, m), a 1.88-1.77 in (1H, m).

Example 31.

2-(2,6-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy-1-yl)- 2-(R)-phenylethanol and 2,6-dichlorophenylamino acid with the release of 47.2% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,50-of 7.25 (7H, m), 7,20-7,10 (1H, m), 5,71 (1H, DD, J=5,1, and 11.4 Hz), 5.40 to-3,70 (2H, almost flat user. C) 4,50-and 4.40 (1H, m), 4,25 (2H, s), 3,50 (1H, DD, J=11,0, 12,5 Hz), 3,28 is 3.15 (1H, m), 2,87 (1H, d, J= 10.3 Hz), 2,75 is 2.55 (2H, m), 2,50 was 2.25 (2H, m), 1,90 is 1.70 (1H, m).

IR (KBr): 3400, 1640 cm-1.

Cl2N2O3HCl 0.5 H2O: C, 52,82; H, 5,32; N, 6,16.

Obtained: C, 52,61; H, 5,13; N, 6,10.

Example 32.

2-(3,5-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy - 1-yl)-2-(R)-phenylethanol and 3.5-dichlorphenoxy acid with the release of 47.8% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-to 7.15 (8H, m), 5,63 (1H, DD, J=5,5, and 11.0 Hz), 4,50-of 3.00 (2H, almost flat user. C), 4,40 - to 4.28 (1H, m), a 3.87 (1H, d, J= 14,3 Hz), 3,71 (1H, d, J=14,3 Hz), 3,39 (1H, DD, J=11,4, 12.1 Hz), 3,05-2,95 (1H, m), is 2.74 (1H, d, J=11,0 Hz), 2,65 (1H, DD, J=5,5, 12,5 Hz) to 2.54 (1H, DD, J= 5,5, to 10.6 Hz), 2,45-of 2.30 (1H, m), 2,25-2,10 (1H, m), 1.70 to 1.55V (1H, m).

IR (KBr): 3350, 1650 cm-1.

MS m/z: 408 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H22Cl2N2O3HCl 2H2O: C, 49,86; H THE 5.65; N, 5,81.

Obtained: C, 49,49; H, Of 5.53; N, 5,59.

Example 33.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine - 1-yl)-1-(S)-phenylethyl] -2-(2,3,6-trichlorophenyl)ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy-1-yl)-2-(R)-phenylethanol and 2,3,6-trichlorophenylacetic acid W (270 MHz, CDCl3) 7,45-7,20 (7H, m), 5,69 (1H, DD, J=4,8, and 11.0 Hz), 5,00-3,50 (2H, almost flat user. C) 4,50-and 4.40 (1H, m), the 4.29 (2H, s), 3,49 (1H, t, J=11.7 Hz), 3.25 to a 3.15 (1H, m), 2,85 (1H, d, J=10.3 Hz), 2,70-2,60 (2H, m), 2,45-of 2.20 (2H, m), 1,90 is 1.70 (1H, m).

IR (pure): 3400, 1640 cm-1.

MS m/z: 442 (M+).

Hydrochloride: so pl. 102-103oC.

Anal. Calc. for C20H21Cl3N2O3HCl H2O: C, 48,21; H, A 4.86; N, 5,62.

Obtained: C, 48,40; H, With 4.64; N, 5,52.

Example 34.

2-(Benzo[b] furan-4-yl)-N-hydroxy-N-[2-(3- (S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy-1-yl)-2-(R)-phenylethanol and 4-benzo[B]furoxone acid with a yield of 57.5% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) to 7.64 (1H, d, J=2.2 Hz), 7,50-of 7.25 (7H, m), 7,14 (1H, d, J=7,3 Hz), at 6.84 (1H, DD, J=0.7 and 2.2 Hz), 5,61 (1H, DD, J=5,5, and 11.4 Hz), 4,24 (1H, d, J=13,6 Hz), 4,05-of 3.95 (1H, m), 3,91 (1H, d, J=13,2 Hz) and 3.31 (1H, DD, J=11,7, 12.1 Hz), 2,75-to 2.65 (1H, m), 2,63-of 2.50 (2H, m), 2,30 (1H, DD, J=5,1, 10,3 Hz), 2,20-2,10 (1H, m), 2.00 in of 1.85 (1H, m).

IR (pure): 3400, 1635 cm-1.

MS m/z: 380 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C22H24N2O4HCl 1,1 H2O: C, is pyrrolidin-1 - yl)-1-(S)-phenylethyl] -2-(1-tetralone-6-yl)ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy-1-yl)- 2-(R)-phenylethanol and (1-tetralone-6-yl)acetic acid with the release of 59.4% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) of 7.96 (1H, d, J=8.1 Hz), 7,40-to 7.18 (7H, m), to 5.66 (1H, DD, J=5,5, and 11.0 Hz), 4,30-4,20 (1H, m), of 3.94 (1H, d, J=14,3 Hz), 3,81 (1H, d, J=a 13.9 Hz), 3,80 is 2.00 (2H, almost flat user. C), 3,40 (1H, DD, J= 11,7, 12.1 Hz), 3.00 and-to 2.85 (3H, m), 2,80-of 2.50 (5H, m), 2,45-of 2.30 (1H, m), 2,20-2,05 (3H, m), 1,65 of 1.50 (1H, m).

IR (pure): 3400, 1680, 1640 cm-1.

MS m/z: 408 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C24H28N2O4HCl 1,2 H2O: C, 61,78; H, IS 6.78; N, 6,00.

Obtained: C, 61,60; H, 6,59; N, 6,35.

Example 36.

2-(3,4-Dimetilfenil)-N-hydroxy-N-[2-(3- (S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy-1-yl)-2-(R)-phenylethanol and 3,4-dimethylphenylacetic acid with access to 66.8% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-of 7.25 (5H, m), 7,20-to 7.00 (3H, m), to 5.66 (1H, DD, J=5,1, and 11.4 Hz), 4,25-4,10 (1H, m), a 3.87 (1H, d, J=a 13.9 Hz), to 3.67 (1H, d, J=a 13.9 Hz), 3,37 (1H, DD, J=11,7, 12.1 Hz), 3.00 and-to 2.85 (1H, m), 2,71 (1H the (net): 3350, 1630 cm-1.

MS m/z: 368 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C22H28N2O3HCl 1,8 H2O: C, 60,42; H, 7,51; N, 6,41.

Obtained: C, 60,51; H, 7,71; N, 6,29.

Example 37.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy-1-yl)- 2-(R)-phenylethanol and 3,4-dichlorophenylamino acid with the release of 32.8% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-of 7.25 (7H, m), 7,13 (1H, DD, J=1.5 and 8.1 Hz), 5,61 (1H, DD, J=5,5, to 10.6 Hz), 5,00-3,90 (2H, almost flat user. C), 4,45 is 4.35 (1H, m), 3,85 (1H, d, J=14,7, Hz) of 3.77 (1H, d, J=14,3 Hz), 3,37 (1H, DD, J=11,0, 12,5 Hz), 2,89 (1H, DD, J=4,7, and 8.4 Hz), 2,80-2,60 (3H, m), 2,45 to 2.35 (1H, m), 2,15-2,00 (1H, m), 1,80-of 1.65 (1H, m).

IR (KBr): 3450, 3250, 1650 cm-1.

MS m/z: 408 (M+).

So pl. output reached 125.5-126,0oC.

[]D= -95,4 (=0,218, methanol).

Anal. Calc. for C20H22Cl2N2O3: C, 58,69; H, 5,42; N, 6,84.

Obtained: C, 58,51; H, 5,42; N, 6,70.

Example 38.

2-(3,4-Differenl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

1H NMR (270 MHz, CDCl3) 7,40-of 7.25 (5H, m), 7.18 in-to 6.95 (3H, m), the 5.65 (1H, DD, J-5,5, and 11.4 Hz), 5,00-3,90 (2H, almost flat user. C), 4,35-of 4.25 (1H, m), 3,82 (1H, d, J=14,3 Hz), 3,74 (1H, d, J=14,3 Hz), 3,40 (1H, DD, J= 10,6, 13,2 Hz), 2,95 (1H, dt, J=4,4, 8,8 Hz) of 2.75 (1H, d, J=a 10.6 Hz), 2,61 (1H, DD, J=5,1, 12,5 Hz), of 2.51 (1H, DD, J=5,5, a 10.6 Hz), 2.40 a is 2.10 (2H, m), 1.70 to a 1.50 (1H, m).

IR (KBr): 3350, 3250, 1630 cm-1.

MS m/z: 376 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H22F2N2O3HCl 0.5 H2O: C, 56,94; H, 5,73; N, 6,64.

Obtained: C, 57,21; H, 6,07; N, 6,63.

Example 39.

2-(Benzo[b] thiophene-4-yl)-N-hydroxy-N-[2- (3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy - 1-yl)-2-(R)-phenylethanol and (benzo[b] thiophene-4-yl)acetic acid with the release of 48.8% in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,79 (1H, d, J=7,7 Hz), 7,66 (1H, d, J=5.5 Hz), 7,50-7,20 (8H, m), the ceiling of 5.60 (1H, DD, J=5,5, and 11.4 Hz), 4,60-3,20 (2H, almost flat user. C), 4,32 (1H, d, J=13,6 Hz) to 4.01 (1H, d, J=13,6 Hz), 4,00-are 3.90 (1H, m), 3,30 (1H, DD, J=11,7, 12.1 Hz), 2,70 at 2.45 (3H, m), 2,28 (1H, DD, J= 5,1, 10,3 Hz), 2,20-2,10 (1H, m), 1,95-of 1.80 (1H, m), 1,20-of 1.05 (1H, m).

IR (net who="ptx2">

Anal. Calc. for C22H24N2O3S HCl 0.5 H2O: C, 59,79; H, TO 5.93; N, 6,34.

Obtained: C, 59,85; H, 6,09; N, 6,27.

Example 40.

N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidine-1 - yl)-1-(S)-phenylethyl] -2-(3,4-methylenedioxyphenyl)ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy - 1-yl)-2-(R)-phenylethanol and 3,4-methylenedioxyphenylacetic acid with the release of 59.7 per cent in accordance with methods similar to those described in the Getting 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,45-of 7.25 (5H, m), 6,85-6,70 (3H, m), of 5.92 (2H, s), to 5.66 (1H, DD, J=5,5, and 11.4 Hz), 4,50-3,30 (2H, almost flat user. C) 4,30-4,20 (1H, m), 3,86 (1H, d, J=13,6 Hz) to 3.64 (1H, d, J=a 13.9 Hz), 3,39 (1H, t, J=12.1 Hz), 3,05-2,95 (1H, m), 2,72 (1H, d, J=10.3 Hz), 2,59 (1H, DD, J=5,5, 12,5 Hz), 2,48 (1H, DD, J=5,5, 10,3 Hz), 2,35 is 2.10 (2H, m), 1,65 of 1.50 (1H, m).

IR (pure): 3400, 3250, 1630 cm-1.

MS m/z: 384 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C21H24N2O5HCl 1,4 H2O: C, 56,54; H, 6,28; N, 6,28.

Obtained: C, 56,74; H, 6,38; N, Of 5.89.

Example 41.

2-(3,5-Differenl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy-1 - yl)-2-(R)-phenyl is attachment 4, Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,40-of 7.25 (5H, m), PC 6.82 (2H, d, J=8.1 Hz), 6,72-only 6.64 (1H, m), the 5.65 (1H, DD, J=5,1, and 11.0 Hz), and 5.30-4,20 (2H, almost flat user. C), 4,40-4,30 (1H, m), 3,86 (1H, d, J=14,3 Hz), 3,74 (1H, d, J= 14,3 Hz) to 3.41 (1H, DD, J=11,7, 12.1 Hz), 3,10-2,95 (1H, m), was 2.76 (1H, d, J= a 10.6 Hz), 2,61 (1H, DD, J=5,1, 12,5 Hz), 2,52 (1H, DD, J=5,5, to 10.6 Hz), 2,40 is 2.10 (2H, m), 1.70 to 1.55V (1H, m).

IR (pure): 3350, 3200, 1630 cm-1.

MS m/z: 376 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H22F2N2O3HCl 0.5 H2O: C, 56,94; H, 5,73; N, 6,64.

Obtained: C, 57,01; H, To 5.93; N, 6,45.

Getting 8.

1-Benzyl-3-(R)-tetrahydropyranyloxy.

To a stirred solution of (R)-(+)-1-benzyl-3-pyrrolidinone (5,00 g, 28 mmol) and D-camphor-10-sulfonic acid (6,97 g, 30 mmol) in CH2Cl2(10 ml) was added 3,4-dihydro-2H-Piran (20 ml) at room temperature and the reaction mixture was stirred for 14 h (in most cases the reaction was completed, when faded exothermic reaction). The reaction mixture was diluted with CH2Cl2(100 ml), washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated to obtain a brown oil. It was purified by the method column of the HRO is in the form of a brown oil.

1H NMR (270 MHz, CDCl3) 7,34-7,22 (5H, m), br4.61 (0.5 H, DD, J=2,9, 4,4 Hz), of 4.54 (1H, DD, J=2,9, 4,4 Hz), 4,42-or 4.31 (1H, m), 3,90-with 3.79 (1H, m) to 3.67 (1H, d, J=12,8 Hz) and 3.59 (0.5 H, d, J=12,8 Hz) to 3.58 (0.5 H, d, J=12,8 Hz), 3,50 is 3.40 (1H, m), 2,88 (0.5 H, DD, J=6,6, 10,3 Hz), 2,74-2,45 (3,5 H, m), 2,25-2,05 (1H, m), 1,95-1,45 (7H, m).

9.

3-(R)-Tetrahydropyranyloxy.

A mixture of 1-benzyl-C-(R)-tetrahydropapaveroline (8,78 g and 27.3 mmol) and Pearlman catalyst (3.50 g) in MeOH (100 ml) was stirred in hydrogen atmosphere at room temperature for 4 h After removal of the catalyst by filtration through celite, the filtrate was concentrated to obtain 5,74 g transparent light brown oil. It was used in further reactions without purification.

1H NMR (270 MHz, CDCl3) to 4.62 (1H, user. C), 4,45-4,30 (1H, m), 3,90-of 3.80 (1H, m), 3,55 is-3.45 (1H, m), 3,20 is 2.80 (5H, m), 2.00 in of 1.40 (8H, m).

10.

1-(S)-Phenyl-2-(3-(R)- tetrahydropyranyloxy-1-yl)ethanol and 2-(R)-Phenyl-2- (3-(R)-tetrahydropyranyloxy-1-yl)ethanol.

A mixture of 3-(R)-tetrahydropapaveroline (1,43 g, 8,32 mmol) and (S)-(-)-steralised (1,00 g, 8,32 mmol) in EtOH (10 ml) was heated under reflux with stirring for 1 h Evaporation of the solvent gave 3,098 g of brown oil, which was purified maniam 1.68 g (69.3 percent) transparent light brown oil in the form of a mixture of compounds, specified in the ratio of approximately 2 to 1, where 1-(S)-phenyl-2-(3-(R)- tetrahydropyranyloxy-1-yl)ethanol was predominant.

1H NMR (270 MHz, CDCl3) 7,40-of 7.24 (5H, m), 4.72, and 4,68 (in the amount of 0.67 H, each approximately d, J=2,6 Hz, OCHO), 4,63-4,55 (1H, m, PhCHOH and OCHO), 4,43-of 4.25 (1H, m, OCHCH2N), 3,89-3,81 (1,67 H, m), 3,52-of 3.46 (1,33 H, m), 2,88-2,47 (5,33 H, m), 2,15-1,90 (2H, m), 1,86-of 1.66 (3H, m), 1,58-is 1.51 (4H, m).

Example 42.

2-(3,4-Dichlorophenyl)-N-[1-(S)-phenyl-2-(3- (R)-tetrahydropyranyloxy-1-yl)ethyl]-N - tetrahydropyranyloxy.

To a stirred solution of 1-(S)- Phenyl-2-(3-(R)-tetrahydropyranyloxy-1-yl)ethanol (1,67 g, 5,73 mmol) and Et3N (of 0.96 ml, 5,73 mmol) in CH2Cl2(20 ml) was added dropwise methylchloride (of 0.53 ml, to 6.88 mmol) at 0oC. the Reaction mixture was stirred at room temperature for 16 hours, the Reaction mixture was washed with saturated aqueous NaHCO3and with the left solution, dried (Na2SO4) and concentrated to obtain 2,02 g of brown oil. This oil was used in further reactions without purification.

1H NMR (270 MHz, CDCl3) 7,42-7,30 (5H, m), 4,94 (1H, DD, J=5,9, 8,1 Hz, PhCHCl), 4,60 and to 4.52 (total 1H, each m, OCHO), 4,35-or 4.31 (1H, m, OCHCH2N), 3,88-3,82 (1H, m), 3,48 is-3.45 (1H, m), 3,25-3,17 (1H, m), 3,02-2,69 (3H, hydroporini)hydroxylamine (0,806 g, to 6.88 mmol) in EtOH (10 ml) was heated under reflux with stirring for 0.5 hours the Reaction mixture was concentrated, diluted with CH2Cl2(30 ml), washed with saturated aqueous NaHCO3and brine, dried (Na2SO4) and concentrated to obtain 2,59 g of brown oil. This oil was used in further reactions without purification.

A mixture of the above crude amine derivative (2,59 g, 5,73 mmol), 3,4-dichlorophenylamino acid (1,41 g, to 6.88 mmol) and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (abbreviated as WRC, 1,32 g, to 6.88 mmol) in CH2Cl2(15 ml) was stirred at room temperature for 0.5 hours, the Reaction mixture was washed with saturated aqueous NaHCO3and brine, dried (Na2SO4) and concentrated to obtain 4.12 g of brown oil. This oil was purified by the method of column chromatography (silica gel: 100 g, CH2Cl2/MeOH from 50/1 to 40/1 as eluent) to obtain the 2,22 g (67,1%) pale yellow oil.

Example 43.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3- (R)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl]ndimethylacetamide.

The mixture of the above amide derivative (2.20 g, 3,81 mmol) and containing the listed, was podslushivaet aqueous solution of the NHs and was extracted with CH2Cl2(30 ml). The extract was washed with saline, dried (Na2SO4) and concentrated to obtain a light brown powder. It was collected by filtration and washed with hexane to obtain 1,117 g (71,6%) of light brown powder.

1H NMR (270 MHz, CDCl3) 7,41-7,28 (7H, m), 7,13 (1H, DD, J=1,8, and 8.4 Hz), 5,61 (1H, DD, J=5,5, to 10.6 Hz), 4,50-3,50 (2H, almost flat user. C), 4,40-of 4.35 (1H, m), a-3.84 (1H, d, J=14,7 Hz), of 3.77 (1H, d, J=14,3 Hz) to 3.38 (1H, DD, J=11,0, 12.1 Hz), 2,94-to 2.85 (1H, m), 2,74-2,63 (3H, m), 2,44 to 2.35 (1H, m), 2,15 for 2.01 (1H, m), 1,80-of 1.65 (1H, m).

IR (KBr): 3250, 1650 cm-1.

MS m/z: 408 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H22Cl2N2O HCl 0,8 H2O: C, 52,20; H, OF 5.39; N, 6,09.

Obtained: C, 52,22; H, Of 5.39; N, 6,12.

Example 44.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(R) -hydroxypyrrolidine-1-yl)-1-(R)-phenylethyl]ndimethylacetamide.

This compound was obtained from 3-(R)-tetrahydropapaveroline and (R)-(+)-steralised with the release of 33.3% in accordance with methods similar to those described in Examples 3 through 5.

1H NMR (270 MHz, CDCl3) 7,38 (1H, d, J=8,4 Hz), of 7.36-of 7.25 (6H, m), 7,13 (1H, DD, J=1,8, 8.1 Hz), 5,64 (1H, DD, J=5,1, and 11.0 Hz), 5,00-3,50 (2H, 0.3 Hz), 2,62 (1H, DD, J=5,1, 12,5 Hz), of 2.51 (1H, DD, J= 5,5, to 10.6 Hz), 2,40 was 2.25 (1H, m), 2,25-2,10 (1H, m), 1.70 to 1.55V (1H, m).

IR (KBr): 3400, 3200, 1640 cm-1.

MS m/z: 408 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C20H22Cl2N2O3HCl 0.5 H2O: C, 52,82; H, 5,32; N, 6,16.

Obtained: C, 52,71; H, 5,59; N, 6,15.

Receipt 11.

(S)-1-(3-Were)-1,2-ethanediol.

A mixture of 3-methylstyrene (1,69 ml, 12.7 mmol) and AD-mix- (17,78 g, 12.7 mmol) in water (65 ml) and tert-BuOH (65 ml) was stirred at 0oC for 3.5 h In this reaction mixture was added Na2SO3(20 g) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was extracted with ethyl acetate. The extract was washed with saline, dried (Na2SO4) and concentrated to obtain 2,07 g of light brown oil, which was purified by the method of column chromatography (silica gel: 110 g, ethyl acetate/hexane: 3/2) to give 1.89 g (98%) of the desired compound as a light brown oil.

1H NMR (270 MHz, CDCl3) of 7.24 (1H, DD, J=7,3, 7,7 Hz), 7,19-to 7.09 (3H, m), of 4.77 (1H, DD, J=3,7, 8.1 Hz), 3,74 (1H, DD, J=3,7, and 11.4 Hz), the 3.65 (1H, DD, J=8,1, to 11.4 Hz), 2,82 (1H, user. C) to 2.35 (3H, s), 1.77 in (1H, user. C).

Getting 12.

(S)-1-(3-1,7 mmol) in pyridine (35 ml) was added p-toluensulfonate (2,46 g, 12.9 mmol) and 4-dimethylaminopyridine (1,58 g, 12.9 mmol) at 0oC and the reaction mixture was stirred at 0oC to room temperature for 17 hours, the Reaction mixture was acidified 6H aqueous solution of HCl and was extracted with the addition of CH2Cl2. The extract was washed with water and brine, dried (Na2SO4) and concentrated with getting to 3.02 g of yellow oil, which was purified by the method of column chromatography (silica gel 100 g, ethyl acetate/hexane: 1/9 to 1/3) to obtain the 2,63 g (73%) of the desired product as a pale yellow oil. Its optical purity was 97% of ei according to GHUR using chiral stationary phase (Chiral pak AS, Daicel Chemical Industries, suirable n-hexane/EtOH: 98/2; detection time: 55 min for (R)-isomer, 59 min for (S)-isomer).

1H NMR (270 MHz, CDCl3) to 7.77 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8.1 Hz), 7,22 (1H, DD, J=7,7, 8.1 Hz), 7,15-7,05 (3H, m), 4,94 (1H, DDD, J=2,9, 2,9, and 8.4 Hz), 4,15 (1H, DD, J=2,9, 10,3 Hz), Android 4.04 (1H, DD, J=8,4, 10,3 Hz) to 2.54 (1H, user. d, J=2,9 Hz), a 2.45 (3H, s), of 2.33 (3H, s), 1,58 (3H, s).

13.

2-(3-(S)-Methoxyethoxyethoxy-1-yl)-1-(S)-(3-were) ethanol and 2-(3-(S)-methoxyethoxyethoxy-1-yl)-2-(R)-(3 - were)ethanol.

A mixture of (S)-1-(3-were)-1,2-ethanediol-2-tosilata (2,63 g, 8,59 mmol), (S)-3-methox what holodilniki with stirring for 2 hours After removal of the solvent by evaporation, the residue was diluted with water and was extracted with CH2Cl2. The extract was washed with saline, dried (Na2SO4) and concentrated to obtain 2,11 g of brown oil, which was purified by the method of column chromatography (silica gel: 110 g, CH2Cl2/MeOH: 15/1 to 10/1) to obtain the 1,72 g (76%) of a mixture of the desired products in a ratio of 3 to 2 in the form of a light brown oil.

1H NMR (270 MHz, CDCl3) 7,26-7,05 (4H, m), 4,68 (0,6 H, DD, J=2,9, a 10.6 Hz, PhCHOH), 4,67 (0,6 H, d, J= 7,0 Hz, OCH2O), 4,63 (0,6 H, d, J=6,6 Hz, OCH2O), 4,62 (0,4 H, d, J=7,0 Hz, OCH2O), 4,59 (0,4 H, d, J=7,0 Hz, OCH2O), 4,34-4,24 (0,6 H, m, OCHCH2N), 4,24-4,16 (0,4 H, m, OCHCH2N), 3,88 (0,4 H, DD, J= 6,2, to 10.6 Hz, CHCH2OH), 3,79 (0,4 H, DD, J=5,8, and 11.0 Hz, CHCH2OH), 3,47 (0,4 H, DD, J=5,8, 6,2 Hz, NCHPh), 3,38 (1,8 H, s), 3.33 and (1,2 H, s), 3,05-2,92 (1,2 H, m), 2,82-to 2.40 (4H, m) to 2.35 (3H, s), 2,25-of 1.50 (3H, m).

Example 45.

2-(3,4-Dichlorophenyl)-N-[2-(3-(S)- methoxyethoxyethoxy-1-yl)-1-(S)-(3-were)ethyl]- N-tetrahydropyranyloxy.

This compound was obtained from a mixture of 2-(3-(S)-methoxyethoxyethoxy-1-yl)-1-(S)-(3 - were)ethanol and 2-(3-(S)-methoxyethoxyethoxy-1-yl) -2-(R)-(3-were) ethanol with a yield of 60% in accordance with the method similar to that described in Example (0.5 H, DD, J= 5,1, to 11.4 Hz, PhCHN), 5,52 (0.5 H, DD, J=4,8, and 11.0 Hz, PhCHN), and 5.30-5,20 (1H, m, NOCHO), with 4.64 (0.5 H, d, J=6,6 Hz, OCH2O), 4,63 (0.5 H, d, J=7,0 Hz, OCH2O), br4.61 (0.5 H, d, J=6,6 Hz, OCH2O) 4,60 (0.5 H, d, J=6,6 Hz, OCH2O), 4,30-4,20 (0.5 H, m, OCHCH2N) 4,06-of 3.85 (3H, m), 3,56-3,36 (1,5 H, m), 3,35 (1,5 H, s, OMe), 3,34 (1,5 H, s, OMe), 3,24-3,10 (0.5 H, m), 3,01 is 2.80 (2H, m), 2,66-to 2.40 (3H, m), 2,34 (1,5 H, s), 2,28 (1,5 H, s), 2,15-of 1.15 (8H, m).

Example 46.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)- methoxyethoxyethoxy-1-yl)-1-(S)-(3-were)ethyl]ndimethylacetamide.

This compound was obtained from 2-(3,4-dichlorophenyl)-N-[2- (3-(S)-methoxyethoxyethoxy-1-yl)-1-(S)-(3-were) ethyl] -N-tetrahydropyranyloxy exit 77% in accordance with the method similar to that described in Example 5.

1H NMR (270 MHz, CDCl3) 7,42-7,05 (7H, m), 5,59 (1H, DD, J=5,1, and 11.0 Hz, PhCHN), 4,35-of 4.25 (1H, m, CHOH), 3,85 (1H, d, J=14,3 Hz, COCH2Ph), 3,74 (1H, d, J=15,8 Hz, COCH2Ph), 3,50-of 2.50 (2H, almost flat user. s, HE x 2), to 3.38 (1H, DD, J=11,7, 12.1 Hz), 3.00 and-2,90 (1H, m), 2,73 (1H, user. d, J=a 10.6 Hz), 2,62 (1H, DD, J=5,1, 12,5 Hz), 2,53 (1H, DD, J=5,5, to 10.6 Hz), 2,40 was 2.25 (4H, m, including 3H, s at 2,30 M. D.), 2,23-2,07 (1H, m), 1,65-of 1.55 (1H, m).

IR (pure): 3350, 1650 cm-1.

MS m/z: 422 (M+).

Hydrochloride: amorphous solid.

Anal. Calc. for C21H24F2N2O3HCl for 1.5 H2O: C, 51,81; H, 5 is pyrrolidin-1-yl)-2-(3,4-dichlorophenyl)-N-hydroxyacetamido.

This compound was obtained from 4-chloresterol and 3-(S)-methoxymethamphetamine with the release of 12% in accordance with methods similar to those described in Examples 7 through 11.

1H NMR (270 MHz, CDCl3) 7,40 (1H, d, J=2.2 Hz), was 7.36 (1H, d, J=8,4 Hz), 7,30-7,20 (4H, m), 7,14 (1H, DD, J=2,2, 8.1 Hz), to 5.58 (1H, DD, J=5,1, and 11.0 Hz, PhCHN), 5,00-of 3.00 (2H, almost flat user. s, HE x 2), 4,35-of 4.25 (1H, m, CHOH), 3,85 (1H, d, J=14,3 Hz, COCH2Ph), and 3.72 (1H, d, J=a 13.9 Hz, COCH2Ph) to 3.33 (1H, t, J=11.7 Hz), 3.00 and-to 2.85 (1H, m), is 2.74 (1H, user. d, J= 10.3 Hz), 2,65 (1H, DD, J=5,1, 12,5 Hz), 2,60 at 2.45 (1H, m), 2,45 was 2.25 (1H, m), 2,25-2,05 (1H, m), 1.70 to a 1.50 (1H, m).

Hydrochloride: amorphous solid.

IR (KBr): 3400, 3100, 1650 cm-1.

MS m/z: 443 (M+N)+.

Anal. Calc. for C20H21Cl3N2O3HCl 0,7 H2O: C, 48,74; H, 4,79; N, 5,68.

Obtained: C, 49,15; H, To 5.21; N, 5,58.

Example 48.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(S)-(4-methoxyphenyl)ethyl] ndimethylacetamide and 2-(3,4-dichlorophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidine-1-yl)-1-(R)-(4-methoxyphenyl)ethyl]ndimethylacetamide.

This compound was obtained from 4-methoxystyrene and 3-(S)-methoxymethamphetamine with the release of 12% in accordance with methods similar to those described in Examples 7 through 11.

In this case occurred raceme THPONH2and acylation).

1H NMR (270 MHz, CDCl3) 7,40 (1H, d, J=2.2 Hz), was 7.36 (1H, d, J=8,4 Hz), 7,40-7,26 (4H, m), 7,12 (0.5 H, DD, J=2,2, 8,4 Hz), 7,11 (0.5 H, DD, J= 2,6, and 8.4 Hz), at 6.84 (2H, d, J=8,4 Hz), 5,70-the ceiling of 5.60 (1H, m, PhCHN), 4,50-4,40 (0.5 H, m, CHOH), 4,50-of 3.00 (2H, almost flat user. s, HE x 2), 4,40-4,30 (0.5 H, m, CHOH), a-3.84 (1H, d, J=14,3 Hz, COCH2Ph), with 3.79 (3H, s), of 3.73 (1H, d, J=14,7 Hz, COCH2Ph), 3,65 is 3.40 (1H, m), 3,15-of 3.00 (1H, m), 2,90-to 2.40 (4H, m), 2,30-2,10 (1H, m), 1,90-1,78 (0.5 H, m), 1,78-1,60 (0.5 H, m).

Hydrochloride: amorphous solid.

IR (KBr): 3400, 3150, 1650 cm-1.

MS m/z: 438 (M+).

Anal. Calc. for C21H24Cl2N2O4HCl for 2.5 H2O: C, 48,43; H, OF 5.81; N, 5,38.

Obtained: C, 48,21; H, Of 5.75; N, 5,35.

Example 49.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-(4-triptoreline)ethyl]ndimethylacetamide.

This compound was obtained from 4-trifloromethyl and 3-(S)-methoxymethamphetamine with access to 25.3% in accordance with methods similar to those described in Examples 7 through 11.

1H NMR (270 MHz, CDCl3) 7,60-to 7.35 (6H, m), 7,20-7,10 (1H, m), the 5.65 (1H, DD, J= 5,5, and 11.0 Hz, PhCHN), 4,40-4,30 (1H, m, CHOH), 3,90 (1H, d, J= a 13.9 Hz, COCH2Ph), to 3.73 (1H, d, J=12,5 Hz, COCH2Ph) to 3.34 (1H, DD, J=11,0, 12,5 Hz), 3.00 and-2,90 (1H, m), 2,75-to 2.65 (2H, m), of 2.54 (1H, DD, J=5,1, to 10.6 Hz), 2,50 is 2.00 (4H, m), 1.70 to 1.55V (1H, m).

IR (S="ptx2">

Anal. Calc. for C21H21Cl2F3N2O3HCl 2H2O: C, 45; 88; H, OF 4.77; N, 5,10.

Obtained: C, 45,90; H, A 4.83; N, 4,71.

Getting 14.

(S)-1-(4-Were)-1, 2-ethanediol-2-tosylate.

This compound was obtained from 4-trifloromethyl with a total yield of 75% in accordance with methods similar to those described in Examples 7 and 8. Optical purity was 98.3% of ei according to HPLC analysis.

1H NMR (270 MHz, CDCl3) to 7.77 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8,4 Hz), 7,20 (2H, d, J=8.1 Hz), 7,14 (2H, d, J=8.1 Hz), 5,00-of 4.90 (1H, m), 4,13 (1H, DD, J=3.3V, 10,3 Hz), a 4.03 (1H, DD, J=8,4, 10,3 Hz), 2.49 USD (1H, d, J=2,9 Hz), of 2.45 (3H, s) of 1.57 (3H, s).

Get 15.

(S)-4-Methylsterols.

A mixture of (S)-1-(4-were)-1,2-ethanediol-2-tosilata (4,13 g, 13.5 mmol) and 50% aqueous NaOH solution (5 ml) in THF (25 ml) was stirred at room temperature for 1 h and at 50oC for 2 h After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4) and concentrated to obtain 1,59 g (88%) of the desired compound as a pale brown oil. This oil was used in further reactions without purification.

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Getting 16.

2-(3-(S)-Methoxyethoxyethoxy-1-yl)- 1-(S)-(4-were)ethanol and 2-(3-(S)- methoxyethoxyethoxy-1-yl)-2-(R)-(4-were)ethanol.

A mixture of (S)-4-methyltyrosine (1,59 g, to 11.9 mmol) and 3-(S)-methoxymethamphetamine (1.55 g, to 11.9 mmol) in isopropanol (25 ml) was heated under reflux for 7 hours, the Solvent evaporated and the residue was purified by the method of column chromatography (silica gel: 150 g, CH2Cl2/MeOH from 50/1 to 15/1) to obtain the 2,39 g (76%) of the desired product as a pale brown oil. They represented a mixture of compounds of the header in the proportion of 3 to 2.

1H NMR (270 MHz, CDCl3) 7,26 (1,2 H, d, J=8.1 Hz), 7,21-7,10 (2,8 H, m), 4.75 V-4,55 (2,6 H, m, including 0,6 H, d, J=6,6 Hz 4,66 M. D., of 0.6 H, d, J=7,0 Hz 4,63 M. D., 0,4 H, d, J=7,0 Hz 4,62 M. D., 0,4 H, d, J=7,0 Hz 4,58 M. D. ), 4,35-to 4.23 (0,6 H, m, OCHCH2N), 4,23-4,15 (0,4 H, m, OCHCH2N), a 3.87 (0,4 H, DD, J= 6,2, to 10.6 Hz, CHCH2OH), of 3.77 (0,4 H, DD, J=5,9, a 10.6 Hz, CHCH2OH), 3,49 (0,4 H, DD, J=5,9, 6,2 Hz, NCHPh), 3,38 (1,8 H, s), 3.33 and (1,2 H, s), 3,05-2,90 (1,2 H, m), 2,80-to 2.40 (5H, m), of 2.34 (3H, s), 2,25-2,00 (1H, m), 1,95 is 1.75 (1H, m).

Example 50.

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S) -hydroxypyrrolidine-1-yl)-1-(S)-(4-were)ethyl]ndimethylacetamide.

This compound was obtained from 2-(3-(S)-methoxyethoxyethoxy - 1-yl)-1-(S)-(4-METHYLPHENOL technique similar to that described in Examples 10 and 11.

1H NMR (270 MHz, CDCl3) 7,40-7,30 (2H, m), 7.23 percent (2H, approx. d, J=8.1 Hz), 7,11 (3H, approx. d, J=7,7 Hz), 5,64 (1H, DD, J=5,1, to 11.4 Hz, PhCHN), 5,00-of 3.00 (2H, almost flat user. s, HE x 2), 4,40-4,30 (1H, m, CHOH), a-3.84 (1H, d, J=14,7 Hz, COCH2Ph), to 3.73 (1H, d, J=14,3 Hz, COCH2Ph), of 3.46 (1H, DD, J= 11,4, 12.1 Hz), 3,10-2,95 (1H, m), and 2.83 (1H, user. d, J=11,0 Hz), of 2,75 2,40 (3H, m), 2,32 (3H, s), 2,25-2,10 (1H, m), a 1.75-to 1.60 (1H, m).

Hydrochloride: amorphous solid.

MS m/z: 422 (M+).

IR (KBr): 3420, 3180, 1650 cm-1.

Anal. Calc. for C21H24Cl2N2O3HCl 0.5 H2O: C, 58,30; H, 5,59; N, 5,98.

Obtained: C, 53,51; H, 5,67; N, 6,04.

Receipt 11.

(S)-1-(3-Were)-1,2-ethanediol.

This compound was obtained from 3-methoxyethoxymethyl (obtained by methoxyethylamine 3-hydroxystyrene standard method) in quantitative yield according to the procedure similar to that described in Example 7.

1H NMR (270 MHz, CDCl3) of 7.24 (1H, DD, J=7,7, 8.1 Hz), 7,03 (1H, d, J= 1,8 Hz), 6,98-6,92 (2H, m), of 5.15 (2H, s, OCH2OMe), 4,74 (1H, DD, J=3.3V, 8,1 Hz, ArCHOH), 3,71 (1H, user. d, J=9.9 Hz, CHCH2OH), 3,65-3,55 (2H, m, including 1H, DD, J=8,1, 11,0 Hz by 3.61 M. D., CHCH2OH), 3,44 (3H, s, OCH2OMe), 3,14 (1H, user. with IT).

Getting 18.

1H NMR (270 MHz, CDCl3) ' to 7.77 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8.1 Hz), 7,25 (1H, DD, J=7,7, and 8.4 Hz), 7,00-6,92 (3H, m), of 5.15 (2H, s), of 4.95 (1H, DDD, J= 3.3V, 3.3V, and 8.4 Hz, ArCHOH), is 4.15 (1H, DD, J=3.3V, 10,3 Hz, CHCH2OTs), a 4.03 (1H, DD, J=8,4, 10,3 Hz, CHCH2OTs), of 3.46 (3H, s, OCH2OMe), 2,65 (1H, d, J=3.3 Hz, ArCHOH), a 2.45 (3H, s, PhMe).

Example 51.

2-(3,4-Dichlorophenyl)-N-[1-(S)-(3 - methoxyethoxymethyl)-2-(3-(S)-tetrahydropyranyloxy - 1-yl)ethyl]-N-tetrahydropyranyloxy.

This compound was obtained from (S)-1-(3 - methoxyethoxymethyl)-1,2-ethanediol-2-tosilata with a total yield of 52% in accordance with methods similar to those described in Examples 9 and 10.

1H NMR (270 MHz, CDCl3) 7,42-6,91 (7H, m), 5,65 (0.5 H, DD, J=3.3V, 9.9 Hz, PhCHN), 5,54 (0.5 H, DD, J=4,4, and 11.0 Hz, PhCHN), 5,35-a 5.25 (1H, m, NOCHO), 5,19 (0.5 H, d, J=6,6 Hz, OCH2O) 5,15 (0.5 H, d, J=6,6 Hz, OCH2O) 5,14 (0.5 H, d, J=7,0 Hz, OCH2O), 5,10 (0.5 H, d, J=7,0 Hz, OCH2O) and 4.65-4,55 (1H, m, CHOCHO), 4,40-4,30 (0.5 H, m, OCHCH2N), 4,30-4,20 (0.5 H, m, OCHCH2N), 4,10-of 3.85 (4H, m, including 0.5 H, d, J=16.5 Hz on 4,06 M. D., 0.5 H, d, J=16.5 Hz on 3,92 M. D. and 1H, on 3,92 M. D., COCH2Ph), 3,68 is 3.15 (6H, m, including 1.5 H, C, 3,47, and of 3.46 M. D., OMe), 3,02 is 2.80 (2H, m), 2,66 to 2.35 (3H, m), 2,20-1,15 (14H, m).

Example 52.

2-(3,4-Dichlorophenyl)-N-hydro is 2-(3,4-dichlorophenyl)-N-[1- (S)-(3-methoxyethoxymethyl)-2-(3-(S)- tetrahydropyranyloxy-1-yl)ethyl] -N - tetrahydropyranyloxy with a total yield of 46% in accordance with the methodology similar to that described in Example 11.

1H NMR (270 MHz, CDCl3) 7,56 (1H, PhOH), 7,40 (1H, d, J=1,8 Hz), 7,37 (1H, d, J=8,4 Hz), 7,17 (1H, DD, J=1,8, 8.1 Hz), 7,11 (1H, DD, J=1,8, 8.1 Hz), 6.90 to-6,70 (3H, m) to 5.56 (1H, DD, J=5,1, to 10.6 Hz, PhCHN), 4,30-4,20 (1H, m, CHOH), are 3.90 (1H, d, J=15,0, COCH2Ph), 3,74 (1H, d, J=14.5 M, COCH2Ph), 4,50-of 2.50 (2H, almost flat user. s, HE x 2), of 3.32 (1H, DD, J=11,4, 11.7 Hz), 3.00 and-to 2.85 (1H, m), 2,75-to 2.55 (3H, m, including 1H, DD, J=5,1, and 11.0 Hz), 2.40 a-2,30 (1H, m), 2,15-2,00 (1H, m), 1,80-to 1.60 (1H, m).

IR (KBr): 3350, 3200, 1630 cm-1.

MS m/z: 424 (M+).

Free Amin: so pl. USD 151.6-153,1oC.

Anal. Calc. for C20H22Cl2N2O47H2O: C, 54,85; H, OF 5.39; N, 6,40.

Obtained: C, 54,70; H, 4,99; N, 6.42 Per.

The chemical structure of the compounds obtained in Examples 1 to 52, are summarized in the table.

1. Pyrrolidinone derivatives of hydroxamic acids of formula I

< / BR>
and its salts,

where a represents hydrogen, hydroxy or OY where Y is hydroxyamino group;

Ar represents phenyl, optionally substituted by one or more substituents selected from halogen, hydroxy, C1-C4of alkyl, C1-C4alkoxy, CF3C1-C4alkoxy-C1-C4alkyloxy;

X represents sigil, and these groups are optionally substituted by substituents in the number to three, selected from halogen, C1-C4of alkyl, C1-C4alkoxy, hydroxy, NO2, CF3, SO2CH3;

R represents hydrogen, C1-C4-alkyl or hydroxyamino group.

2. Connection on p. 1, where a represents hydrogen or hydroxy and R is hydrogen or C1-C4alkyl.

3. Connection on p. 2, where Ar represents phenyl.

4. Connection on p. 3, where X represents phenyl, substituted with substituents in the number to three, selected from chlorine, methyl and CF3and R represents hydrogen.

5. Connection on p. 4, where X represents 3,4-dichlorophenyl.

6. Connection on p. 4, selected from the group consisting of:

2-(3,4-dichlorophenyl)-N-hydroxy-N-/1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl/ndimethylacetamide;

N-hydroxy-N-/1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl/-2-(2,3,6-trichlorophenyl)ndimethylacetamide;

N-hydroxy-N-/1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl/-2-(4-triptoreline)ndimethylacetamide;

N-hydroxy-N-/1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl/-2-(2,4,6-trimetilfenil)ndimethylacetamide;

2-(3,4-dichlorophenyl)-N-hydroxy-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-femilet the XI-N/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/-2-(4-triptoreline)ndimethylacetamide;

2-(4-chlorophenyl)-N-hydroxy-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-(phenylethyl/ndimethylacetamide;

2-(2,3-dichlorophenyl)-N-hydroxy-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/ndimethylacetamide;

2-(2,3-dichlorophenyl)-N-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/ndimethylacetamide;

2-(2,5-dichlorophenyl)-N-hydroxy-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/ndimethylacetamide;

2-(2,6-dichlorophenyl)-N-hydroxy-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/ndimethylacetamide;

N-hydroxy-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/-2-(2,3,6-trichlorophenyl)ndimethylacetamide;

2-(3,4-dichlorophenyl)-N/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/ndimethylacetamide, and

2-(3,4-dimetilfenil)-N-hydroxy-N-/2-(3-(S)-hydroxypyrrolidine-1-yl)-1-(S)-phenylethyl/ndimethylacetamide.

7. Connection on p. 1, where a represents the OY and R represents hydroxyamino group and where hydroxyamine group selected from benzyl, tetrahydropyranyl.

8. The method of obtaining compounds of General formula I on p. 1, characterized in that the compound of formula II

where a And Ar have the abovementioned meanings;

R is hydroxyamino group

subjected to interaction with the carboxylic acid of the formula

CCI2COOH,

where X has the above meaning,

remove if necessary.

9. The intermediate compound of General formula II

< / BR>
and its salts,

where a represents hydrogen, hydroxy or OY where Y is hydroxyamino group;

Ar represents phenyl, optionally substituted by one or more substituents selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, CF3WITH1-C4alkoxy-C1-C4alkyloxy;

R represents hydrogen, C1-C4-alkyl or hydroxyamino group.

10. The method of obtaining compounds of General formula II under item 9, characterized in that ethanolamine compound of formula III

< / BR>
where Ar has the above meaning,

subjected to interaction with a hydroxylamine of the formula IV

< / BR>
where AI- H or a protected hydroxyl;

L is a leaving group,

obtaining the compounds of formula V

< / BR>
and then, the resulting compound of formula V is subjected to interaction with methanesulfonamide in the presence of base followed by the addition of the protected hydroxylamine and, if necessary, removing the protective group.

11. The method of obtaining compounds of General formula II under item 9, characterized in that pyrrolidinyl soinam or unsubstituted phenyloxazol formula VIII

< / BR>
where the symbol (Q)pdenotes the substituents specified in Ar

obtaining a mixture of the compounds of formula IX and a compound of the formula X

< / BR>
< / BR>
and then the resulting mixture is subjected to interaction with methanesulfonamide in the presence of base followed by the addition of protective hydroxylamine and, if necessary, removing the protective group.

12. A method of treating a pathological condition in use of the tool, having agonistic activity towards To opioid receptors in the subject is a mammal, wherein the mammal is administered the compounds of General formula I on p. 1 at a dose of from 0.01 to 1 mg per 1 kg of body weight per day.

 

Same patents:

The invention relates to a new vysokomernoa tritium compound -(2-propylene-4,6-dimethyl-8-oxymethyl)octyl-(3-hydroxy-4,5,6-trimethyl-6-ene)heptylene General formula I

< / BR>
which finds application in biochemical and biomedical studies, and to a method thereof, which lies in the interaction of the parent substance of General formula I with tritium water, by introducing into the reactor the initial substance, РdO or a mixture РdО with 5% РdО/Al2O3, the evacuation of the reactor filled with gaseous tritium and heated at local cold by freezing its upper part, then the reactor re-vacuum, heated to 65 - 85oC, then give him dioxane or a mixture of dioxane with triethylamine

The invention relates to new biologically active compound from a number of heterocyclic compounds of the formula I, showing the property activator germination of wheat seeds

The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, possibly substituted C1-C8-alkyl; R3- peloid in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt

The invention relates to compounds which inhibit the protease encoded by human immunodeficiency virus, or their pharmaceutically acceptable salts, and such compounds are used for the prevention of infection by HIV, treating infection by HIV and the treatment of acquired as a result immunodeficiency syndrome (AIDS)

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

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The invention relates to a new series of 4-phenylpiperazine, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridine

The invention relates to 4-amino-1-piperidinecarbonitrile formula (I):

< / BR>
where R1and R2each independently of one another denote H, A, Ph, Ph-ALK, CO-A, CO-Het, or known of the chemistry of protective peptides for amino group;

R1and R2together also denote alkylene with 4-5 C atoms, and one or two CH2- groups may be replaced by-O-, -S-, -CO-, -NH-, -NA - and/or N-CH2-Ph and, if necessary, the benzene ring may be precondensation so that the formed dihydroindole, tetrahydropyrimidines, tetrahydroisoquinolinium or dehydrobenzperidol the rest;

R3and R4each independently of one another denote H, A, Gal, -X-R5, CN, NO2, CF3CH2-CF3, SOn-R7or SO2-NR5R6;

R5denotes H, A, CF3CH2-CF3Ph, Ph-alk, C5-C7- cycloalkyl or C5-C7-cycloalkyl-alk;

R6denotes H or A, or

R5and R6together also denote alkylene with 4-5 C atoms, and one CH2group can be replaced by-O-, -S-, -NH-or-N-CH2-Ph;

R7denotes A or Romani;

Gal denotes F, Cl, Br or I;

Ph denotes unsubstituted or one-or two-, or three times substituted by A, OA, Gal, CF3, NH2, NHA or NA2phenyl;

Het denotes a saturated or unsaturated five - or six-membered heterocyclic residue with 1 to 4 atoms of nitrogen, oxygen and/or sulfur; and

"n" represents 1 or 2;

and their physiologically acceptable salts

The invention relates to applicable in medicine new derived aminotriazole or its hydrate and its pharmaceutically acceptable salts
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