Fluorine-containing tevinol and orvinol derivatives and methods of their obtaining (versions)

FIELD: chemistry.

SUBSTANCE: invention relates to tevinol and orvinol derivatives of general formula I where R=OH; R1=H, CF3, C1-C4 alkyl, aryl, or (R+R1) stands for O=; R2=H, CH3; R3=H, CH3; R4=CH3, cyclopropylmethyl, allyl; Z~Z=CH2CH2, CH=CH. Invention also relates to method of obtaining formula I derivatives. Method lies in trifluoromethylation of respective aldehyde with formation of 21,21,21-trifluorotevinol, further oxidation of formed fluorine-containing alcohol with formation of respective ketone, which under influence of reagent, selected from the group, including R1Li, R1MgX, CF3Si(CH3)3, results in obtaining formula I tevinol derivatives. Orvinol derivatives are obtained by demethylation of tevinols.

EFFECT: formula I derivatives as ligands of opioid receptors with wide possibilities of varying their hydrophilic-hydrophobic balance.

9 cl, 16 ex

 

The invention relates to new compounds containing cyclic system an-8,9c-aminoadamantane[4,5-b,c,d] furan, condensed with carbocyclic ring, more precisely, with the bridge group at positions 6 and 14, consisting of only two carbon atoms, namely, the fluorine-containing derivative of thevenon, terminal and arinola and their pharmaceutically acceptable salts, specifically derivatives containing fluorine atoms in position With(21), the General formula

,

where R=OH; R1=N, CF3C1-C4is alkyl or aryl; R2=N, CH3; R3=H, CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2CH=CH,

and to methods for their preparation.

The claimed compounds, their properties and methods of obtaining not described in literature. Not previously known fluorine-containing compounds described by General formula I.

The claimed compounds are fluorinated derivatives elenasamarthanka and most effectively can be used (in the form of pharmaceutically acceptable salts as drugs, mechanism of action of which is based on agonistic and/or antagonistic interaction with opioid receptors. Opioid system in human and animal modulate a number of physiological and behavioral processes, such as vospriiatiia, response to stress, immune response, neuroendocrine function [Aldrich, J.V.; Vigil-Cruz, S.. Narcotic Analgesics. In Burger''s Medicinal Chemistry and Drug Discovery; Abraham, PAUL, Ed.; John Wiley & Sons: New York, 2003; Vol.6, Chapter 7, pp 329-481]. For this reason, the compounds exhibiting the ability to bind to opioid receptors (ligands of opioid receptors), are used as the beginning of the current drugs used in particular for treating pain, drug addiction, alcoholism, certain types of shock, diarrhea.

The most similar structure to the claimed compounds are known for their counterparts that do not contain fluorine, the formula

,

where R=OH; R1=H, alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, or another organic group; R2=N, CH3; R3=N, CH3; R4=H, alkyl, allyl, propargyl, cycloalkylation, or another organic group.

The famous "tevion" (17-methyl-3,6-dimethoxy-7α-acetyl-4,5α-epoxy-6α,14α-heterosomatina) formula

,

which is widely used as a precursor of a variety not containing fluorine derivatives aminoethanol formula (II). Thevenon IIa represents the previously described adduct of thebaine and vinylethylene [VE Allen, ET Jarvi, D.J. Kalota, J.R. Meyer, K.G. Tomazi, A. Mannmo, B. Orr. //WO 2010/039220 A1 (2010)], [C. Zhong, Z. Gong, Y. Wang, Y Liu. // Application for U.S. patent US 2005/70564 A1 (2005)]. Common name "tevion" is the basis of brief items of this class of compounds [K.W. Bentley, D.G. Hardy, C. Meek. Novel Analgesics and Molecular Rearrangements in the Morphine-Thebaine Group. II. Alcohols Derived from 6,14-endo-Etheno - and 6,14-endo-Ethanotetrahydrothebaine. // J. Amer. Chem. Soc., 89 (13), 3273-3280 (1967)], according to which its counterpart containing three atoms of fluorine in position 21 of the formula (Ia), should be called 21,21,21-triptoreline.

It is known that thevenon (IIa) is a key starting compound to obtain compounds of the formula (II)belonging to the class of talinolol formula

,

where R1=CH3; R2=H, alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, or another organic group; R3=CH3; R4=CH3; Z~Z=CH=CH, CH2CH2and onlinelow (derived from talinolol) formula

,

where R2=H, alkyl, Alchemilla, Alchemilla, cycloalkyl, aryl, or another organic group; R4=H, alkyl, allyl, propargyl, cycloalkylation, or another organic group; Z~Z=CH=CH, CH2CH2[A.F. Casy, R.. Parfitt. Opioid Analgesics: Chemistry and Receptors. Plenum Press: New York, London, 1986], [K.W. Bentley. Brit. Pat. 1136214 (1968). Chem. Abstr., 70: 78218s (1969)], [.S. Park, NO Lee, U.N. in. Kim, J.K. Park, Zvartau E.E., N. Lee. A highly selective κ-opioid receptor agonist with low addictive potential and dependence liability. // Bioorg. Med. Chem. Lett., 16, (13), 36093613 (2006)].

It is known that divinely are precursors of onlinelow, which are demetilirovanie derivatives talinolol and contain a hydroxyl group in position 3 of the heterocyclic system.

Orginaly represent one of the most important types of highly effective ligands for opioid receptors [.F. Casy, R.T. Parfitt. Opioid Analgesics: Chemistry and Receptors. Plenum Press: New York, London, 1986], [G.R. Lenz. S.M. Evans, D.E. Walters, A.J. Hopfinger, in: Opiates, Academic Press, Orlando London. 1986] and are the substances of drugs, widely used in medicine (buprenorphine, dihydroetorphine) and veterinary (Etorphine, diprenorphine) as analgesics for the treatment of acute and chronic pain of high intensity and for the treatment of drug addiction, as well as to Immobilise large animals out of this condition and treatment of acute overdose of narcotic analgesics.

Known teviron is a common key precursor compounds of the formula II (R=OH). A high level of mutual structural similarity of the compounds of formulas I and II (R=OH), the presence of the same cyclic system an-8,9c-aminoadamantane[4,5-b,c,d] furan with bridge group positions 6 and 14, consisting of only two carbon atoms, makes the ability to bind to opioid receptors, known for compounds II, General property this is Lassa connections

The size of the fluorine atom is not very different from the size of a hydrogen atom. In particular, the van der Waals radii of the groups CH3and CF3equal to 1.29 and 1.35 A, respectively, which can largely save the geometrical parameters of the molecule with partial replacement of hydrogen atoms by fluorine. It is known that the introduction of molecules into pharmacologically active compounds of fluorine atoms affects their pharmacological activity, in particular, by increasing lipophilicity, improve their transport in vivo and greater stability relations of the C-F to the metabolism of [S.V. Druzhinin, E.S. Balenkova, V.G. Nenajdenko. Recent advances in the chemistry of α,β-unsaturated trifluoromethylketones. // Tetrahedron, 63 (33), 7753-7808 (2007)].

Opioid receptors are widely distributed in both the Central and peripheral nervous system.

Substitution in the compounds of General formula II (R=OH) some of the hydrogen atoms by fluorine atoms, would lead to opioid ligands of General formula I (where R=OH) with reduced hydrophilicity and, as a consequence, with an enhanced ability to overcome the blood-brain barrier and to facilitate access to opioid receptors in the Central nervous system.

Stimulation of opioid receptors in the Central nervous system leads to analgesia, which, however, often accompanied by a number of negative side effects (respiratory depression, sedation,tolerance, physical dependence, the effects on the gastrointestinal tract). Meanwhile, clinically significant analgesia, as well as several other useful therapeutic effects can be achieved by activating opioid receptors in the peripheral nervous system [E.K. Ryu, Zh. Wu, K. Chen, L.H. Lazarus, E.D. Marczak, Y. Sasaki, A. Ambo, S. Salvadori, C. Ren, H. Zhao, G. Balboni, X. Chen. Synthesis of a Potent and Selective18F-Labeled δ-Opioid Receptor Antagonist Derived from the Dmt-Tic pharmacophore doesn for Positron Emission Tomography Imaging. // J. Med. Chem., 51 (6), 1817-1823 (2008)], [S. Stein, M. Schäfer, H. Machelska, Attaching pain at its source: new perspectives on opioids. Nat. Med., 9, (8), 1003-1008 (2003)], [S. Furst, P. Riba, T. Friedmann, J. Timar, M. Al-Khrasani, I. Obara, W. Makuch, M. Spetea, J. Schutz, R. Przewlocki, B. Przewlocka, H. Schmidhammer. Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. J. Pharmacol. Exp. Ther., 312, (2), 609-618 (2005)]. Therefore, for medical purposes is necessary not only to opioid ligands and receptors of the Central nervous system, with reduced levels of undesirable side effects, and opioid ligands, focused on the selective interaction with receptors of the peripheral nervous system, in order to minimize the activation of Central opioid receptors that are associated with unwanted side effects and thus improve the safety of opioid drugs. [I. Obara, W. Makuch, M. Spetea, J. Schutz, H. Schmidhammer, R. Przewlocki, B. Przewlocka. Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives ininflammatory and neuropathic pain in the rat. // Eur. J. Pharm., 558 (1), 60-67 (2007)], [L. DeHaven-Hudkins, R.E. Dolle, Peripherally restricted opioid agonists as novel analgesic agents, Curr. Pharm. Des., 10, (7), 743-757 (2004)], [S. Stein, M. Schafer, H. Machelska, Attaching pain at its source: new perspectives on opioids. Nat. Med., 9, (8), 1003-1008 (2003)].

One way to reduce access of opioid ligands in the Central nervous system is chemical modification to improve hydrophilicity, preventing overcoming the blood-brain barrier [J. Schutz, W. Brandt, M. Spetea, K. Wurst, G. Wunder, H. Schmidhammer. Synthesis of 6-amino acid substituted derivatives of the highly potent analgesic 14-O-methyloxymorphone. Helv. Chim. Acta, 86, (6), 2142-2148 (2003)], [M. Spetea, T. Friedmann, P. Riba, J. Schutz, G. Wunder, T. Langer, H. Schmidhammer, S. Furst. In vitro opioid activity profiles of 6-amino acid substituted derivatives of 14-O-methyloxymorphone. Eur. J. Pharmacol., 483, (2-3), 301-308 (2004)]. [M. Al-Khrasani, M. Spetea, T. Friedmann, P. Riba, K. Kiraly, H. Schmidhammer, S. Furst. DAMGO and 6β-substituted glycine 14-O-methyloxymorphone but not morphine show peripheral, preemptive antinociception after systemic administration in a mouse visceral pain model and high intrinsic efficacy in the isolated rat vas deferens. // Brain Res. Bull., 74, 369-375 (2007)].

The transition from compounds of General formula I (where R=OH; R3=CH3to 6-O-demetilirovanny derivative of General formula I (where R=OH; R3=H) increases the hydrophilicity of the molecules, while retaining substantially their geometrical parameters, which should facilitate the interaction of fluorine-containing ligands of the formula I (where R=OH; R3=H) with opioid receptors of the peripheral nervous system.

A method of obtaining not containing fluorine Academy of Sciences of the log of the inventive compounds of General formula II (where R=HE; R1=H, substituted or unsubstituted alkyl, Alchemilla or Alchemilla group containing up to 8 carbon atoms, or cycloalkyl group with the number of carbon atoms from 4 to 8; R2=N, CH3CnH2n+1CO (n=1-3), With6H5WITH nicotinoyl; R3=SN3; R4=H, alkyl, Alchemilla or Alchemilla group containing up to 8 carbon atoms, or cycloalkylation methyl group, the total number of carbon atoms is from 4 to 8; Z~Z=CH2CH2) [K.W. Bentley. The UK patent GB 1136214, C07D 99/04 (1968). Chem. Abstr., 70: 78218s (1969)], of teminon IIa, which is subjected to the action of the Grignard reagent R1gX with subsequent hydrolysis of the resulting magnesium alcoholate.

However, to obtain a similar way fluorinated devinely I (where R=OH; R1=H, alkyl, aryl, or another organic group; R2=Me; R3=Me; R4=Me; Z~Z=CH=CH, CH2CH2) is not possible due to the extreme instability of ORGANOMETALLIC compounds CF3MgX (where X=halogen) [R.N. Haszeldine. Neuere Chemie des Fluors. Organometall - und Organometalloid-Acidic des Fluors. Angew. Chem., 66, (22), 693-701 (1954)], [R.N. Hasseldine. Perfluoroalkyl Grignard and Grignard-type Reagents. Part IV. Trifluoromethylmagnesium Iodide. J. Chem. Soc., 1273-1279 (1954)], [AT McBee, R.D. Battershell, E.G. Braendlin. A New Synthesis of Perfluoroalkylmagnesium Halides. J. Org. Chem., 28, (4), 1131-1133 (1963)], [K.J. Klabunde, .F. Efner, L. Satek and W. Donley. Preparation of an extremely active magnesum slurry for Grignard reagent preparations by metal atom-solvent condensation. J. Organometal. Chem., 71, 309-313 (1974)] and CF3Li [R.N. Haszeldine. Neuere Chemie des Fluors. Organometall - und Organometalloid-Acidic des Fluors. Angew. Chem., 66, (22), 693-701 (1954)], [O.R. Pierce, E.T. McBee, G.F. Judd. Preparation and reactions of perfluoroalkyllithiums. J. Amer. Chem. Soc., 76, (2), 474-478 (1954)].

The present invention is to obtain previously unknown fluorinated derivatives of teverola and ordinola, which would be a new type of ligands of opioid receptors with the wide possibilities of variation of their hydrophilic-hydrophobic balance and the development of methods for such compounds, based on a small number of predecessors.

The problem is solved by the new compounds of fluorinated derivatives of teverola and ordinola formula I in which R represents a group HE; R1selected from the group N, CF3C1-C4alkyl, aryl, or (R+R1) denotes O=; R2and R3represent hydrogen atoms or a metal of the group Z~Z selected from the group CH=CH or CH2CH2and R4selected from the group of CH3cyclopropylmethyl, allyl, and their pharmaceutically acceptable salts, and methods of making compounds of formula (I).

The method of obtaining compounds of formula (I), where R=OH; R1=N, CF3C1-C4alkyl, aryl, or (R+R1)=O; R2=CH3; R3=CH3; R4=CH3Z~Z=SN=SN presented in figure 1 vkluchaetsia stages:

(a) triptoreline aldehyde of formula (III)

with the formation of 21,21,21-triptoreline (7α-(1-hydroxy-2,2,2-triptorelin)-17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-elenasamarthanka) Ib;

(b) oxidation of the resulting triptoreline IB product of interaction of oxalicacid and DMSO, with subsequent processing of the substrate and formation of the corresponding ketone Ia;

(C) the interaction of the resulting ketone or (i) with an appropriate organolithium compound of the formula R1Li, or (ii) with a Grignard reagent of formula R1MgX, or (iii) CF3Si(CH3)3and the subsequent allocation of fluorinated products of known techniques presented on the following scheme 1.

Scheme 1

The second method of obtaining compounds of formula I, where R=OH; R1=N, CF3C1-C4alkyl, aryl, or (R+R1)=O; R2=R3=CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2, SN=SN, presented in figure 2, lies in the interaction triptoreline agent such as CF3Si(CH3)3with derivatives of teminon formula (II)in which R+R1=O, R2R2=CH3; R3=CH3; R4=CH3cyclopropylmethyl, allyl, Z-Z=CH2CH2, SN=SN, subsequent processing of the reaction is ionic mixture of acid and the selection of appropriate talinolol:

Scheme 2

Another variant of the method of obtaining compounds of formula I is shown in figure 3, the method is designed to obtain a fluorine-containing derivatives of ordinola formula I, where R=OH; R1=CH3, CF3C1-C4alkyl, aryl, R2=H; R3=N, CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2, CH=CH, and is the demethylation of talinolol received two above methods (schemes 1 and 2), where R=OH; R1=N, CF3With1-C4alkyl, aryl, R2=CH3; R3=CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2, CH=CH, and the selection of target products by the known methods.

Demethylation of these talinolol formula I perform the action of BBr3or HBr (Scheme 3).

Scheme 3

The first stage (a) of the method according to scheme 1 is the interaction of the aldehyde of formula (III) with a reagent Rupert-Prakash [CF3Si(CH3)3] in the presence of the source of F-such as tetrabutylammonium, in a solvent such as tetrahydrofuran, and then the reaction mixture is treated with acid and emit secondary fluorinated alcohol 1b (21,21,21-triptoreline) (example 1).

As starting materials for the production of fluorine-containing secondary Speer is and 1b use commercially available Me 3SiCF3[I.Ruppert, .Schlich, W.Volbach. Tetrahedron Lett, 25, (21), 2195-2198 (1984)], [G.K.S.Prakash, R.Krishnamurti, G.A.Olah. J.Amer. Chem. Soc, 111, (7), 393-395 (1989)]). and the aldehyde (III), which is accessible connection: it easily and with high yield gain in one stage from natural raw materials (thebaine) [J.J.Kopcho, J.C.Schaeffer. Selective O-Demethylation of 7-α-(Aminomethyl)-6,14-endo-ethenotetrahydrothebaine. // J: Org. Chem., 51(9), 1620-1622 (1986)].

At the next stage (b) of this method (scheme 1) fluorine-containing secondary alcohol 1b, obtained in stage (a), oxidizing the product of the interaction of oxalicacid and dimethyl sulfoxide at a temperature of from -70°C to -78°C, then treated reaction mixture with a base, such as triethylamine. The result is the corresponding fluorinated ketone (17-methyl-3,6-dimethoxy-7α-(TRIFLUOROACETYL)-4,5α-epoxy-6α,14α-heterosomatina (21,21,21-triptoreline) of the formula I, where R+R1=O, R2=R3=R4=CH3; Z~Z=SN=SN, called Ia (examples 2-1, 2-2).

It should be noted that fluorine similar secondary alcohol IIb can oxidize the action of potassium permanganate and to obtain the corresponding ketone-thevenon, but expect a similar reaction with fluorine-containing alcohol 1b under the action of potassium permanganate does not occur.

At the stage (C) of the method presented in figure 1, the interaction obtained in stage (b) fluorine-containing ketone Ia reagent, select the authorized group, includes R1Li (i, 10), R1MgX (ii, example 11), CF3Si(CH3)3(iii, example 5), which allows to vary the substituents R1in position 20 of the heterocyclic system; this makes it possible expansion of the range obtained in this way talinolol and further products of their demethylation.

The second variant of the method of obtaining new compounds of the formula I presented in figure 2, allows you to get divinely directly from thevenon IIa (example 3), which is the easiest way to not get through the aldehyde (III), and without it, in one stage from the same natural materials - thebaine [.W.Bentley. The UK patent GB A) (1962)], or from the product of the hydrogenation of thevenon - dihydrothebainone (example 4), or N-necrosophic of thevenon (example 12) and dihydrothebainone (examples 13 and 14).

Getting porpoising of ordinola formula I, from talinolol obtained by schemes 1 and 2, the method presented in scheme 3, by demethylation of talinolol under the action of HBr (example 7) or BBr3(examples 6, 8, 9, and 15) makes it possible to carry out the demethylation of talinolol 6 position and obtain the derivatives of onlinelow, containing not only triptorelin group, but additional hydroxyl group in position 6, which may determine the occurrence of unexpected properties of these ligands.

The invention is illustrated by specific examples of the implementation, below.

Example 1. Getting 21,21,21-triptoreline [7α-(1-hydroxy-2,2,2-triptorelin)-17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-elenasamarthanka] (1b).

To a solution of 0.45 g (1.22 mmol) of the aldehyde of formula (III) in 10 ml anhydrous THF added 0.36 ml (2.45 mmol) of (CH3)3SiCF3. The reaction mixture is cooled to 0-10°C and with stirring was added a solution of 0.01 g of three-hydrate (h-Bu)4NF in 2 ml of THF. The cooling bath is removed, the reaction mixture was allowed to warm to room temperature, the mixture is then incubated for another 1 hour, add 5 ml of 20% aqueous HCl and intensively stirred for 20 minutes. To the mixture is added 15 ml of chloroform and bring the pH of the aqueous layer to 10, adding 25% aqueous ammonia solution. The organic layer is separated, the aqueous layer was extracted with chloroform (3×10 ml). The organic layer and extracts are combined, dried over anhydrous Na2S04 and the solvent is distilled off in vacuum. Obtain 0.36 g (67%) of the compounds of formula 1b in the form of a mixture of (20R)-and (20S)-isomers in the ratio 17:1, representing a clear yellowish oil. Individual (20R)- and (20S)-isomers from the mixture obtained allocate chromatography on a column of silica gel [eluent -25%aqueous ammonia solution: CH3OH:CHCl=1:15:1600 (by volume)]. Both isomers are butter yellow color.

(20R)-isomer: Mass spectrum (electrospray) (m/z): 438 [M+1]+. Range 1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.51 (DD,2J=13.2 Hz,3J=6.7 Hz, 1H, H-8α), 1.86 (DD, 1H, H-15EC), 2.00-2.05 (m, 1H, H-15AK), 2.21 (m, 1H, H-7β), 2.39 (s, 3H, NCH3), 2.35-2.44 (m, 2H, H-10α+N-16AK), 2.56 (DD, 1H, H-16EC), 2.85 (DD,2J=13.2 Hz,3J=9.6 Hz, 1H, H-8β), 3.21-3.24 (m, 2H, H-9, H-10β), 3.59 (s, 3H, 6-OCH3), 3.81 (s, 3H, 3-och3), 4.45 (q, 1H, H-20), 4.57 (d, 1H, H-5), 5.50 (d, J18,19)=8.7 Hz, 1H, H-19), 5.83 (ush. d, 1H, H-18), 6.62+6.53 (AB system, JAB=8.3 Hz, 2H, N-1+N-2). Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): - 76.44 (d, J=8.0 Hz, 3F, CF3).

(20S)-isomer: Mass spectrum (electrospray) (m/z): 438 [M+1]+.

Range1H NMR (CDC13, δ, ppm, relative to the (CH3)4Si): 1.00-1.07 (m, 1H, H-8A), 1.83 (DD, 1H, H-15EC), 1.95-2.06 (m, 1H, H-15AK), 2.11-2.19 (m, 1H, H-7β), 2.35 (s, 3H, NCH3), 2.35-2.43 (m, 2H, H-10α+N-16AK), 2.51 (DD, 1H, H-16EC), 2.89 (DD,2J=13.5 Hz,3J=9.1 Hz, 1H, H-8β), 3.14 (d, 1H, H-9), 3.21 (d, 1H,2J=18.5 Hz, H-10β), 3.76 (s, 3H, 6-och3), 3.81 (s, 3H, 3-och3), 3.74-3.83 (m, 1H, H-20), 4.57 (d, 1H, H-5), 5.59 (d, J18,19=8.9 Hz, 1H, H-19), 5.95 (ush. d, 1H, H-18), 5.93 (ush. s, 1H, OH), 6.62+6.53 (AB system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): - 76.71 (d, J=8.0 Hz, 3F, CF3).

Example 2-1. Getting 21,21,21-triptoreline [3,6-dimethoxy-17-methyl-7α-(TRIFLUOROACETYL)-4,5α-epoxy-6α,14α-elenasamarthanka] (Ia).

To mix the solution is 0.42 ml (0.005 mol) of oxalicacid in CH 2Cl2(6 ml) at a temperature of from -70°C to -78°C is added dropwise over 20 minutes a solution of 0.76 ml (0.01 mol) of dimethyl sulfoxide in CH2Cl2(1 ml). The mixture is stirred for 30 minutes at the same temperature, add dropwise over 20 minutes a solution of 1.8 g (0.004 mol) of a mixture of (20R)- and (20S)-isomers of the alcohol 1b obtained in Example 1 in CH2CI2 (3 ml), stirred for 30 minutes at the same temperature, add 2.86 ml (0.02 mol) Et3N, and heated to a temperature of 20-25°C. To the reaction mixture are added water (10 ml) and stirred for 10 minotauromachy layer is separated, the aqueous layer was extracted with chloroform (2×20 ml). The organic layer and extracts are combined and dried over anhydrous Na2SO4. The solvent is distilled off and the residue is recrystallized from a mixture of benzene: hexane (1:3). Obtain 1.48 g (85%) of the compound (Ia). Melting point: 118-120°C.

Mass spectrum (electrospray) (m/z): 436 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.38 (DD,2J=12.7 Hz,3J=6.7 Hz, 1H, H-8A), 1.87-1.92 (m, 1H, H-15EC), 1.99-2.04 (m, 1H, H-15AK), 2.38 (s, 3H, NCH3), 2.42-2.48 (m, 2H, H-10ct+N-16AK), 2.55 (DD, 1H,2J=12.1 Hz,3J=5.2 Hz, H-16EC), 3.08 (DD,2J=12.6 Hz,3J 9.5 Hz, 1H, H-u), 3.22 (d,3J=6.4 Hz, 1H, H-9), 3.27 (d,2J=18.5 Hz, 1H, H-10β), 3.38 (DD, J7β,8α=6.7 Hz, J7β8β=9.5 Hz, 1H, H-7β), 3.63 (s, 3H, 6-och3), 3.84 (s, 3H 3-och 3), 4.60 (d,4J=1.2 Hz, 1H, H-5), 5.62 (d, J18,19=8.9 Hz, 1H, H-19), 6.01 (ush. d, 1H, H-18), 6.66+6.57 (AB-system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19F-NMR (CDC13, 8, ppm, relative to CFCl3): -78.83 (s, 3F, CF3).

Range13With NMR (CDCl3, S, ppm, relative to the (CH3)4Si): 22.60 (C-10), 31.64 (C-8), at 33.35 (C-15), 43.48 (NCH3), 44.79 (C-7), 45.41 (C-16), 47.48 (C-13), 54.45 (6-och3), 56.72 (3-OCH3), 59.90 (C-9), 82.22 (C-6), 95.85 (C-5), 113.83 (C-2), 115.24 (kV, CF3), 119.63 (s-1), 125.22 (C-18), 128.11 (C-11), 133.72 (C-12), 136.34 (C-19), 141.92 (C-3), 147.87 (C-4), 192.47 (kV).

IR-spectrum: νC=o 1760 cm-1(in tablets with KBR).

Example 2-2. Getting 21,21,21-triptoreline [3,6-dimethoxy-17-methyl-7α-(TRIFLUOROACETYL)-4,5α-epoxy-6,14α-elenasamarthanka] (Ia) of (20R)-isomer of the alcohol (Ib)

According to the method described in example 2-1, 0.23 ml (0.003 mol) of oxalicacid, 0.42 ml (0.006 mol) of dimethyl sulfoxide, 1.00 g (0.002 mol) of (20R)-isomer of the alcohol (Ib) and 1.59 ml (0.012 mol) Et3N obtain 0.82 g (82%) of compound (Ia), the properties of which are identical to the properties of the product, the receipt of which is described in example 2-1.

Example 3. Receipt of (20R)-17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-etheno-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye and (20S)-17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-etheno-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R1=HE; R1=CH3; R2=CH3; R3=CH3; R4=CH3; Z~Z=CH=CH.

.

To a solution of 5.00 g (13.12 mmol) of thevenon (R+R1=O; R2=CH3; R3=CH3; R4=CH3; Z~Z=SN=SN) in 60 ml anhydrous THF add 4.00 ml (26.24 mmol) (CH3)3SiCF3. The reaction mixture is cooled to 5-6°C and with stirring a solution of 0.08 g of three-hydrate (h-Bu)4NF in 2 ml of THF. The cooling bath is removed, the reaction mixture was allowed to warm to room temperature, and then incubated the mixture for another 1 hour, add 40 ml of 20%HCl solution and intensively stirred for 20 minutes. To the mixture is added 50 ml of chloroform and bring the pH of the aqueous layer to 10 25%ammonia solution or 2N NaOH solution. The organic layer is separated, the aqueous layer was extracted with chloroform (3×40 ml). The organic layer and extracts are combined dried over anhydrous Na2S04, the solvent is distilled off in vacuum and the residue is recrystallized from methanol. Obtain 3.70 g (63%) of (20R)-17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-etheno-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)-izomorfnye (I, R=OH; R1=CH3; R2=CH3; R3=CH3; R4=CH3; Z~Z=SN=SN).

Melting point: 162-163°C.

Mass spectrum (electrospray) (m/z): 452 [M+1]+

Range1H NMR (CDC13, 8, ppm, relative to the (CH3)4Si): 1.24-1.32 (m, 1H, H-8α), 1.33 (s, 3H, CH3), 1.82-1.88 (m, 1H, H-15EC), 1.88-.99 (m, 1H, H-15AK), 2.10 (m, 1H, H-7β), 2.36 (s, 3H, NCH3), 2.34-2.42 (m, 2H, H-10A+N-16AK), 2.51 (DD, 1H, H-16EC), 2.86 (DD,2J=12.5 Hz,3J=9.8 Hz, 1H, H-8β), 3.14 (d,3J=6.4 Hz, 1H, H-9), 3.20 (d,2J=18.7 Hz, 1H, H-10β), 3.77 (s, 3H, 6-och3), 3.81 (s, 3H, 3-Osns), 4.47 (d, 1H, H-5), 5.49 (d, J18,19=9.0 Hz, 1H, H-19), 5.94 (s, 1H, HE), 6.04 (ush. D., 1H, H-18), 6.62+6.52 (AB-system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19F-NMR (CDCIl3, δ, ppm, relative to the CFC13): -74.49 (s, 3F, CF3).

The solvent from the mother liquor is distilled off in vacuo, the residue chromatographic on a column of silica gel (eluent: chloroform/methanol/ammonia=1600:15:1). After recrystallization from methanol the selected chromatographic substances get 0.074 g (1.2%) of (20S)-17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-etheno-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3; R2=CH3; R3=CH3; R4

Melting point: 196-198°C.

Mass spectrum (electrospray) (m/z): 452 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.03-1.09 (m, 1H, H-8α), 1.18 (s, 3H, CH3), 1.81-1.86 (m, 1H, H-15EC), 1.96 (m, 1H, H-15AK), 2.27 (DD, 1H, H-7), 2.35 (s, 3H, NCH3), 2.33-2.41 (m, 2H, H-10A+N-16AK), 2.50 (DD, 1H, H-16EC), 2.90 (DD,2J=13.2 Hz,3J=9.0 Hz, 1H, H-8β, 3.13 (d,3J=6.5 Hz, 1H, H-9), 3.21 (d,2J=18.6 Hz, 1H, H-10β), 3.80 (s, 3H, 6-OCH3 ), 3.81 (s, 3H, 3-OCH3), 4.54 (d,4J=1.2 Hz, 1H, H-5), 5.52 (d, J18;19=8.9 Hz, 1H, H-19), 5.63 (s, 1H, OH), 5.95 (ush. D., 1H, H-18), 6.62+6.52 (AB-system, JAB=8.2 Hz, 2H, N-1+N-2).

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): -79.54 (s, 3F, CF3).

Example 4. Receipt of (20R)-17-methyl-3,6-dimethoxy-4,5A-epoxy-6α,14α-ethano-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3; R2=CH3; R3=CH3; R4=CH=CH3; Z~Z=CH2CH2

According to the method described in example 1 of 4.00 g (10.44 mmol) of II (where R+R1=O; R=CH3; R3=CH3; R4=CH3; Z~Z=CH2CH2and 3.00 ml (19.68 mmol) (CH3)3SiCF3obtain 2.72 g (60%) of compound I (R=OH; R1=CH3; R2=CH3; R3=CH3; R4=CH3; Z~Z=CH2CH2in the recrystallization from methanol.

Melting point: 151-152°C

Mass spectrum (electrospray) (m/z): 454 [M+1]+

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 0.67-0.78 (m, 1H, H-19l bottle), 1.03-1.13 (m, 1H, H-p), 1.41 (s, 3H, CH3), 1.52 (DD, 1H, H-8α), 1.61-2.01 (m, 4H, 2H-18+2N-15), 2.07 (DD, 1H, H-7β), 2.17-2.33 (m, 2H, H-16AK+H-10α), 2.30 (s, 3H, NCH3), 2.43 (DD, 1H,3J=5.4 Hz,2J=11.7 Hz, H-16EC), 2.65 (d, 1H,3J=6.4 Hz, H-9), 2.75-2.85 (m, 1H, H-8β, 3.10 (d,2J=18.2 Hz, 1H, H-10β), 3.51 (s, 3H, 6-och3), 3.87 (s, 3H, -och 3), 4.31 (d, 1H,4J=1.9 Hz, H-5), 5.88 (s, 1H, HE), 6.71+6.57 (AB system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): - 73.89 (s, 3F, CF3)

Example 5. Getting 17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-etheno-7α-[1-hydroxy-1-(trifluoromethyl)-2,2,2-triptorelin]izomorfnye (I, where R=OH; R1=CF3; R2=CH3; R3=CH3; R4=CH3; Z~Z=SN=SN).

According to the method described in example 1 from 1.50 g (3.44 mmol) Ia (R+R1=O; R=CH3; R3=CH3; R4=CH3; Z~Z=CH=CH) and 1.53 ml (10.30 mmol) (CH3)3SiCF3obtain 1.00 g (57%) of compound I (R=OH; R1=CF3; R2=CH3; R3=CH3; R4=CH3; Z~Z=CH=CH; Y=F) as a result of recrystallization from ethanol.

Melting point: 122-124°C

Mass spectrum (electrospray) (m/z): 506 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.47-1.53 (m, 1H, H-8α), 1.83-1.97 (m, 2H, H-15EC+H-15AK), 2.35 (s, 3H, NCH3), 2.34-2.45 (m, 3H, H-10α+H-16AK+H-7β), 2.51 (DD, 1H,2J=11.7 Hz, H-16EC), 2.92 (DD,2J=13.1 Hz,3J=9.8 Hz, 1H, H-8β, 3.16 (d,3J=6.5 Hz, 1H, H-9), 3.22 (d,2J=18.6 Hz, 1H, H-10β), 3.80 (s, 3H, 6-och3), 3.81 (s, 3H, 3-OCH3), 4.49 (d, J=1.3 Hz, 1H, H-5), 5.54 (d, J18,19=9.1 Hz, 1H, H-19), 6.03 (ush. d, 1H, H-18), 6.53+6.63 (AB system, JAB=8.1 Hz, 2H, N-1+N-2), 6.82, 1H, OH)

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): -70.34 (kV, J=9.9 Hz, 3F, CF3), -74.11 (kV, J=9.9 Hz, 3F, CF3)

Example 6. Receiving (20R)-3,6-dihydroxy-17-methyl-4,5α-epoxy-6α,14α-etheno-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3; R=H; R II: R4=CH3: Z~Z=CH=CH)

To a solution of 1.00 g (2.22 mmol) of I (R=OH; R1=CH3; R2=CH3; R3=CH3; R4=CH3; Z-Z=SN=SN) in dichloromethane (20 ml) at a temperature of from -70°C to -78°C for 10 minutes add 22.2 ml of 1 M solution of BBr3(22.2 mmol) in dichloromethane. The reaction mixture is left under stirring to warm to room temperature, then add methanol to bring the pH of the mixture until neutral 25%ammonia solution and extracted products with chloroform (3×50 ml). The organic extracts are combined dried over anhydrous Na2SO4the solvent is distilled off and the residue chromatographic on a column of silica gel (eluent: NH4OH:CH3HE: CHCl3=1:15:1600. The mass spectrum and NMR spectra registered for product I (R=OH; R1=CH3, R2=N, R3=N, R4=CH3Z~Z=CH=CH) in the form of foundations, obtained as a direct result chromatography in the form of a yellow oil. Mass spectrum (electrospray) (m/z): 424 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.31-1.35 (m, 1H, H-o), 1.37 (s, 3H, CH3), 1.88 (DD, 1H, H-15EC), 1.92-2.00 (m, 1H, H-15AK), 2.13 (m, 1H, H-70), 2.36 (s, 3H, NCH3), 2.34-2.42 (m, 2H, H-10α+N-16AK), 2.53 (DD, 1H,2J=11.7 Hz,3J=4.8 Hz, H-16EC), 2.86 (DD,2J=12.8 Hz,3J=9.8 Hz, 1H, H-8β), 3.16 (d,3J=7.4 Hz, 1H, H-9), 3.20 (d,2J=19.3 Hz, 1H, H-10β), 4.33 (s, 1H, H-5), 4.59 (s, 1H, OH), 5.38 (d, J18,19=8.7 Hz, 1H, H-19), 5.51 (s, 1H, OH), 5.63 (ush. d, 1H, H-18), 6.59+6.49 (AB-system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19P-NMR (CDCl3, δ, ppm, relative to CFCl3): -74.36 (s, 3F, CF3).

In the acidification and deposition from a mixture of ethanol/ether substance I (R=OH; R1=CH3, R2=N, R3=N, R4- CH3Z~Z=SN=SN) to obtain 0.43 g (46%) of product I (R=OH; R1=CH3, R2=N, R3=N, R4=CH3, Z-Z=CH=CH) hydrochloride with TPL 260°C (decomp.).

Example 7. Receiving (20R)-3,6-dihydroxy-17-methyl-4,5α-epoxy-6A,14α-ethano-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R=CH3; R=H; R=H; R4=CH3; Z-Z=CH2CH2) and (20R)-6-hydroxy-17-methyl-3-methoxy-4,5α-epoxy-6α,14α-ethano-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3; R2=H, R3=H, R4=CH3Z~Z=CH2CH2)

1.00 g (2.21 mol) of I (R=OH; R1=CH3; R2CH 3; R3=CH3; R4=CH3; Z-Z=CH2CH2) was dissolved in 20 ml of 48%aqueous HBr solution under heat and boil the reaction mixture for 15 minutes. After cooling to room temperature the mixture was diluted with water (10 ml), adjusted pH to 9-10 with 25%aqueous ammonia solution and extracted with chloroform (3×50 ml). The organic layer is dried over anhydrous Na2S04 and the solvent is distilled off in vacuum. The remainder chromatographic on a column of silica gel (eluent: NH4OH: CH3OH:CHCl3=1:15:1600) and get two main products: a) I (R=OH; R1=CH3; R2=CH3; R3=H; R4=CH3; Z~Z=CH2CH2) Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 0.60-0.67 (m, 1H, H-19 l), 1.01 - 1.09 (m, 1H, H-p), 1.27-1.35 (m, 1H, H-18), 1.44 (s, ZN, SN3), 1.56 (m, 1H, H-8A), 1.66-1.72 (m, 1H, H-15EC), 1.91-2.03 (m, 2H, H-15AK+H-18P airplanes), 2.11 (m, 1H,-7/J), 2.22 (DD, 1H, H-10A), 2.30 (s, 3H, NCH3), 2.29 to 2.35 (m, 1H, H-16AK), 2.46 (d, 1H, H-16EC), 2.68 (d, 1H, H-9), 2.81 (m, 1H, H-8β, 3.12 (d,2J=18.3 Hz, 1H, H-10β), 3.86 (s, 3H, 3-OCH3), 4.19 (s, 1H, H-5), 5.53 (s, 1H, OH), 6.72+6.60 (AB system, JAB=8.0 Hz, 2H, N-1+N-2).

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): -73.72 (s, 3F, CF3). After acidification of the obtained substances of concentrated hydrochloric acid and precipitation from a mixture of ethanol/ether floor is up 0.12 g (13%) of the hydrochloride of compound I (R=OH; R1=CH3; R2=CH3; R3=H; R4=CH3; Z~Z=CH2CH2in the form of colorless crystals with TPL 240°C (decomposition).

Mass spectrum (electrospray) (m/z): 440[M+1]+.

b) I (R=OH; R1=CH3; R2=H; R3-N; R4=CH3; Z-Z=CH2CH2)

Range1H NMR (CDCl3, 3, ppm, relative to the (CH3)4Si): 0.59-0.66 (m, 1H, H-19 l), 1.01-1.09 (m, 1H, H-p), 1.24-1.34 (m, 1H, H-18 l), 1.44 (s, 3H, CH3), 1.57-1.73 (m, 2H, H-8A+H-15EC), 1.91-2.03 (m, 2H, H-15AK+H-18P airplanes), 2.11 (DD, 1H, H-7D), 2.21 (DD, 1H,3J=5.8 Hz,2J=18.5 Hz, H-10β), 2.30 (s, 3H, NCH3), 2.31 to 2.35 (m, 1H, H-16AK), 2.46 (DD, 1H,3J=5.2 Hz,2J=12.3 Hz, H-16EC), 2.56 (USS, 1H, OH), 2.67 (d, 1H,3J=5.8 Hz, H-9), 2.78-2.85 (m, 1H,-S, 3.10 (d,2J=18.5 Hz, 1H, H-10β), 4.21 (s, 1H, H-5), 5.44 (s, 1H, OH), 6.69+6.55 (AB system, JAB=8.1 Hz, 2H, N-1+N-2);

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): -75.78 (s, 3F, CF3).

After acidification of the obtained substances of concentrated hydrochloric acid and precipitation from a mixture of ethanol/ether to obtain 0.26 g (28%) of the hydrochloride of the product I (R=OH; R1=CH3; R2=H; R3=H; R4=CH3; Z~Z=CH2CH2in the form of a white loose powder with TPL 239°C (decomposition). Mass spectrum (electrospray) (m/z): 426 [M+1]+.

Example 8. Obtaining ^S-3.6-dihydroxy-17-(cyclopropylmethyl)-4,5α-epoxy-6α,14α-etheno-7α-(1-HYDR the XI-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3: R2=H; R3- N; R4=cyclopropylmethyl: Z~Z=CH=CH)

According to the method described in example 6, from 0.83 g (1.70 mmol) of I (R=OH; R1=CH3; R2=CH3; R3=CH3; R4=cyclopropylmethyl; Z-Z=SN=SN) to obtain 0.30 g (38%) I (R=OH; R1=CH3; R2=H; R3=H; R4=cyclopropylmethyl; Z-Z=SN=SN) as a result of precipitation of the compound in the form of a hydrochloride salt of a mixture of ethanol/ether. Melting point: 255°C (hydrochloride melts with decomposition). The mass spectrum and NMR spectra were registered using I (R=OH; R1=CH3; R2=H; R3=H; R4=cyclopropylmethyl; Z~Z=CH=CH) in the form of foundations, obtained as a direct result chromatography in the form of a yellow oil.

Mass spectrum (electrospray) (m/z): 464 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 0.11-0.13 and 0.50-0.55 (m+m, 2H+2H, 2CH2(cyclo-C3H5), 0.82-0.87 (m, 1H, CH (cyclo-C3H5), 1.27-1.33 (m, 1H, H-8α), 1.38 (s, 3H, CH3), 1.74-1.77 (m, 1H, H-15EC), 1.88-1.95 (m, 1H, H-15AK), 2.13 (m, 1H, H-7β), 2.27-2.44 (m, 4H, H-10α+N-16AK+2N (cyclo-C3H3-CH2)), 2.69 (DD, 1H,2J=11.7 Hz,3J=4.7 Hz, H-16EC), 2.91 (DD,2J=12.9 Hz,3J=10.0 Hz, 1H, H-8β, 3.06 (d,2J=18.4 Hz, 1H, H-10β), 3.51 (d,3J=6.4 Hz, 1H, H-9), 4.31 (d, 1H, H-5), 5.37 (d, J 18,19=8.8 Hz, 1H, H-19), 5.62 (ush. d, 1H, H-18), 5.73 (s, 1H, OH), 6.60+6.46 (AB-system, JAB=8.0 Hz, 2H, N-1+N-2). Range

19F-NMR (CDCl3, δ, ppm, relative to CFCl3): -74.26 (s, 3F, CF3).

Example 9. Getting 3,6-dihydroxy-17-methyl-4,5α-epoxy-6α, 14α-etheno-7α-[1-hydroxy-1-(trifluoromethyl)-2,2,2-triftoratsetofenona (I, R=OH; R1=CF3; R2=N: R3=H; R4=CH3; Z~Z=CH=CH).

According to the method described in example 6, from 0.54 g (1.07 mmol) of I (R=OH; R1=CF3, R2=CH3, R3=CH3, R4=CH3, Z-Z=SN=SN) to obtain 0.39 g (76%) I (R=OH; R1=CF3; R2=H; R3=H; R4=CH3; Z-Z=SN=SN) as a result of precipitation of the compound in the form of a hydrochloride salt of a mixture of ethanol/ether.

Melting point: 280°C (hydrochloride melts with decomposition) Mass spectrum and NMR spectra were registered using I (R=OH; R1=CF3; R2=H; R3=H; R4=CH3; Z~Z=CH=CH) in the form of foundations, obtained as a direct result chromatography in the form of a yellow oil.

Mass spectrum (electrospray) (m/z): 478 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.53 (DD,2J=13.0 Hz,3J=7.9 Hz, 1H, H-8α), 1.80 (DD, 1H, H-15EC), 1.89-1.96 (m, 1H, H-15AK), 2.35 (s, 3H, NCH3), 2.34-2.40 (m, 2H, H-ExC+N-16AK), 2.44 (m, 1H, H-7D, 2.51 (DD, 1H, W16 EC), 2.91 (DD, 1H, H-8β), 3.17-3.21 (m, 2H, H-9+H-10β), 4.34 (s, 1H, H-5), 5.40 (d, J18,i9=8.8 Hz, 1H, H-19), 5.61 (ush. d, 1H, H-18), 6.50+6.60 (AB system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19P-NMR (CDCl3, ppm, relative to the CFC13): -70.09 (kV, J=9.9 Hz, 3F, CF3), -74.30 (kV, J=9.9 Hz, 3F, CF3).

Example 10. Receipt of (20S)-17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-etheno-7α-[1-hydroxy-1-(trifluoromethyl)butylhydroquinone (I, R=OH; R=; R=CN; R3=CH2; R4=CH3: Z~Z=CH=CH.

To the cooled from -70°C to -78°C solution of 1.00 g (2.3 mmol) of la (R+R1=O; R2=CH3; R3=CH3; R4=CH3; Z~Z=CH=CH) in THF (15 ml) was added dropwise 9 ml of a 0.34 M solution of n-PrLi in hexane. The cooling bath is removed, allow the reaction mixture to warm to room temperature and pour into saturated aqueous NH4CI solution (25 ml). The resulting mixture was extracted with chloroform (3×20 ml). The organic extracts are combined dried over anhydrous Na2S04 and the solvent argonautica recrystallization of the residue from methanol to obtain 0.60 g (54%) of product I (R=OH; R1=CH2CH2CH3; R2=CH3; R3=CH3; R4=CH3; Z~Z=SN=SN).

Melting point: 193-196°C. Mass spectrum (electrospray) (m/z): 480 [M+1]+.

Range1H NMR (CDC3, δ, ppm, relative to the (CH3)4Si): 0.86 (t, ZN, SN3 2CH2), 1.08-1.14 (m, 1H, H-8A), 1.27-1.34 and 1.52-1.66 (m+m, 2H+2H, CH3CH2CH2), 1-83 (m, 1H, H-15EC), 1.95 (m, 1H, H-15AK), 1.28 (m, 1H, K-7β), 2.35 (s, 3H, NCH3), 2.32-2.40 (m, 2H, H-10α+N-16AK), 2.50 (DD, 1H,2J=11.6 Hz,3J=5.2 Hz, H-16EC), 2.89 (DD,2J=13.1 Hz,3J=9.3 Hz, 1H, H-8β, 3.12 (d,3J=6.4 Hz, 1H, H-9), 3.21 (d,2J=18.5 Hz, 1H, H-10β), 3.79 (s, 3H, 6-OCH3), 3.81 (s, 3H, 3-och3), 4.54 (d,4J=1.0 Hz, 1H, H-5), 5.30 (s, 1H, HE), 5.49 (d, J8,i9=8.9 Hz, 1H, H-19), 5.94 (ush. d, 1H, H-18), 6.62+6.52 (AB-system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): -74.09 (s, 3F, CF3).

Example 11. Getting 17-methyl-3,6-dimethoxy-4,5α-epoxy-6α,14α-etheno-7α-(1-hydroxy-1-phenyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=C6H5; R2=CH3; R3=CH3; R4=CH3; Z~Z=CH=CH.

To a solution of 0.20 g (0.46 mmol) Ia (R+R1=O; R2=CH3; R3=CH3; R4=CH3; Z-Z=SN=SN) in THF (15 ml) was added dropwise 1.63 ml of 0.56 M solution (to 0.92 mmol) PhMgBr in THF. The mixture is stirred for 16 h, poured it into a saturated aqueous solution of NH4Cl (25 ml), add water (25 ml) and the resulting mixture extracted with ether (3×20 ml). The organic extracts are combined dried over anhydrous Na2SO4and the solvent is distilled off. The product is separated by chromatography on Colo is ke silica gel [eluent - petroleum ether/ethyl acetate (1:1)]. After recrystallization of the residue from methanol to obtain 0.09 g (37%) of product I (R=OH; R1=C6H5; R2=CH3; R3=CH3; R4=CH3; Z~Z=SN=SN).

Melting point: 213-219°C (decomposition).

Mass spectrum (electrospray) (m/z): 514 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.36 (DD,2J=13.0 Hz,3J=7.8 Hz, 1H, H-8A), 1.65-1.71 (m, 1H, H-15EC), 1.73-1.76 (m, 1H, H-15AK), 2.13-2.39 (m, 6N), 2.23 (s, 3H, NCH3), 3.08 (d,3J=6.4 Hz, 1H, H-9), 3.16 (d,2J=18.6 Hz, 1H, H-10β), 3.82 (s, 3H, och3), 3.83 (s, 3H, och3), 4.48 (d, 1H, H-5), 5.55 (d, J18jl9=9.1 Hz, 1H, H-19), 6.13 (ush. D., 1H, H-18), 6.52+6.63 (AB-system, JAB=8.2 Hz, 2H, N-1+N-2), 6.66 (s, 1H, OH), 7.30-7.40 (m, 3H, 1Hn-+2nm-From6H5), 7.61 (d,3J=7.7, 2H, 2H of o-, C6H5).

Range19F-NMR (CDCl3, δ, ppm, relative to CFCl3): - 68.46 (s, 3F, CF3).

Example 12. Receiving (20R)-3,6-dimethoxy-17-(propen-2-yl-1)-4,5α-epoxy-6α,14α-etheno-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3; R2=CH3; R3=CH3; R4=CH2-CH=CH2; Z~Z=CH=CH.

According to the method described in example 1, 1.6 g (3.93 mmol) of II (R+R=O; R=CH3; R=CH3; R4=CH2-CH=CH2; Z~Z=CH=CH) and 2.4 ml (16.23 mol) (CH3)3SiCF3after a time the population of the reaction product by chromatography on a column of silica gel (eluent -25%aqueous solution of NH 3: CH3HE: SNS3: hexane=1:15:800:800) obtain 0.50 g (26.7%) I (R=OH; R1=CH3; R2=CH3; R3=CH3; R4=CH2-CH=CH2; Z~Z=SN=SN) as a yellow oil.

Mass spectrum (electrospray) (m/z): 478 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 1.23-1.29 (m, 1H, H-8A), 1.33 (s, 3H, CH3), 1.83-1.87 (m, 1H, H-15EC), 1.88-1.95 (m, 1H, H-15AK), 2.11 (m, 1H, H-7β), 2.35-2.43 (m, 2H, H-16AK+H-10α), 2.60 (DD,2J=12.4 Hz,3J=4.4 Hz, 1H, H-16AK), 2.90 (DD, 1H,2J=12.6 Hz,3J=9.9 Hz, H-8β), 3.11-3.15 (m, 3H, H-10β+CH2(allyl)), 3.27 (d,3J=6.4 Hz, 1H, H-9), 3.77 (s, 3H, 6-OCH3), 3.81 (s, 3H, 3-och3), 4.47 (USS, 1H, H-5), 5.14 (d, J=10.1 Hz, 1H, Hallyl, (CH2-CH=CH2(cis)), 5.21 (DD, J=17.1 Hz, 1H, Hallyl(-CH2-CH=CH2(trans)), 5.47 (d, J18,19=9.1 Hz, 1H, H-19), 5.77-5.87 (m, 1H, Hallyl(-CH2-CH=CH2), 5.94 (s, 1H, OH), 6.03 (ush. d, 1H, H-18), 6.62+6.51 (AB-system, JAB=8.2 Hz, 2H, N-1+N-2)

Range19F-NMR (CDCl3, δ, ppm, relative to the CFC13): -74.49 (s, 3F, CF3).

Example 13. Receiving (20R)-3,6-dimethoxy-17-(propen-2-yl-1)-4,5α-epoxy-6α,14α-ethano-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3; R2=CH3: R3=CH3; R4=CH2-CH=CH2; Z~Z=CH2CH2).

According to the method described in example 1, from 0.80 g (1.96 mmol) of I (R+R=O; R=CH3; R=CH3; R4=CH2-CH=CH2; Z~Z=CH2CH2) and 1.30 ml (8.79 mmol) of (CH3)3SiCF3obtain 0.50 g (53%) I (R=OH; R1=CH3; R2=CH3; R3=CH3; R4=CH2-CH=CH2; Z-Z=CH2CH2) as colorless crystals after recrystallization from methanol.

Melting point: 119-120°c.

Mass spectrum (electrospray) (m/z): 480 [M+1]+.

Range1H NMR (CDCl3, 8, ppm, relative to the (CH3)4Si): 0.67-0.73 (m, 1H, H-19 l), 1.04-1.09 (m, 1H, H-p), 1.42 (s, 3H, CH3), 1.49 (DD,2J=13.0 Hz,3J=9.8 Hz, 1H, H-8β), 1.68 (DD,2J=13.0 Hz,3J=2.52 Hz, 1H, H-15EC), 1.70-1.75 (m, 1H, H-18 l), 1.80-1.85 (m, 1H, H-18P airplanes), 1.92-1.97 (m, 1H, H-15AK), 2.08 (m, 1H, H-7β), 2.22 (DD,2J=18.3 Hz,3J=6.4 Hz, 1H, H-10α), 2.28-2.32 (m, 1H, H-16AK), 2.52 (DD,2J=12.2 Hz,3J=7.7 Hz, 1H, H-16AK), 2.78 (d,3J=6.4 Hz, 1H, H-9), 2.82-2.87 (m, 1H, H-8β), 3.01-3.06 (m, 3H, H-10β+2Hallyl(-CH2-CH=CH2)), 3.51 (s, 3H, 6-Osns), 3.87 (s, 3H, 3-och3), 4.32 (d,4J=2.3 Hz, 1H, H-5), 5.11 (DD,2J=10.0 Hz3J=1.3 Hz, 1H, Hallyl(-CH2-CH=CH2(cis)), 5.17 (DD,2J=17.2 Hz,3J=1.9 Hz, 1H, Hallyl(-CH2-CH=CH2(trans)), 5.74-5.81 (m, 1H, Hallyl(-CH2-CH=CH2), 5.87 (s, 1H, OH), 6.71+6.56 (AB-system, JAB=8.0 Hz, 2H, N-1+N-2). Range19P-NMR (CDCI3, 8, ppm, relative to CFCl3): -73.89 (s, 3F, CF3).

Example 14 Receive (20R)-3,6-dimethoxy-17-(cyclopropylmethyl)-4,5α-epoxy-6α,14α-ethano-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3: R2=CH3; R3=CH3; R4=cyclopropylmethyl: Z~Z=CH2CH2).

According to the method described in example 1 of 3.20 g (7.30 mmol) of II (R+R1=O; R2=CH3; R3=CH3; R4=cyclo-C3H5CO; Z~Z=CH2CH2) and 3.23 ml (22.0 mol) (CH3)3SiCF3obtain 3.54 g of the product containing mainly I (R=OH; R1=CH3; R2=CH3; R3=SN3, R4=cyclo-C3H5CO; Z~Z=CH2CH2), which was dissolved in THF (25 ml). The resulting solution under vigorous stirring is added dropwise to a suspension of 1.10 g (0.03 mol) LiAlH4in THF (20 ml) for 30 minutes and then the mixture is stirred for further 10 minutes Into it cautiously dropwise with constant stirring, a saturated solution of ammonium chloride (20 ml). The organic layer is separated, the aqueous extracted with ether (3×50 ml). The organic solution and the extracts are combined and dried over anhydrous Na2S04. The solvent is distilled off to dryness, the residue chromatographic on a column of silica gel (eluent - 25%-aqueous solution of NH3:CH3HE:CHCl3:hexane=1:15:1600:1600). Get 3.00 g (83%) of product I (R=OH; R1=CH3; R2=CH3; R3=CH3; R4=cyclopropylmethyl; Z~Z=CH2CH2in the form of a yellowish oil.

Mass is the range (electrospray) (m/z): 494 [M+1] +.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 0.07-0.11 and 0.43-0.52 (m+m, 2H+2H, 2CH2(cyclo-C3H5)), 0.61-0.68 (m, 1H, H-19 l), 0.78-0.87 (m, 1H, CH (cyclo-C3H5)), 1.07-1.15 (m, 1H, H-p), 1.30-1.35 (m, 1H, H-18 l), 1.61-1.66 (m, 1H, H-8A), 1.70 (s, 3H, CH3), 1.71-1.78 (m, 1H, H-18P airplanes), 1.92 (DD, 1H, H-15EC), 2.01-2.09 (m, 2H, H-16AK+H-15AK), 2.22-2.31 (m, 4H, 2N (cyclo-C3H5-CH2)+H-10α+H-7β), 2.62-2.71 (m, 2H, H-16EC+H-8β, 3.01 (d,3J=6.4 Hz, 1H, H-9), 2.97 (d,2J=18.4 Hz, 1H, 10β), 3.38 (s, 3H, 6-och3), 3.86 (s, 3H, 3-OCH3), 4.43 (d,4J=1.9 Hz, 1H, H-5), 6.67+6.54 (AB-system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19F-NMR (CDCl3, δ, ppm, relative to the CFC13): -76.78 (s, 3F, CF3)

Example 15. Receiving (20R)-3,6-dihydroxy-17-(propen-2-yl-1)-4,5α-epoxy-6α,14α-ethano-7α-(1-hydroxy-1-methyl-2,2,2-triptorelin)izomorfnye (I, R=OH; R1=CH3; R2=H; R3=H; R4=CH?-CH=CH2; Z~Z=CH-CH2-CH2)

According to the method described in example 6, from 0.40 g (0.84 mmol) of I (R=OH; R1=Snz; R2=CH3; R3=CH3; R4=CH2-CH=CH2; Z-Z=CH2-CH2) obtain 0.33 g (88%) I (R=OH; R1=CH3; R2=H; R3=H; R4=CH2-CH=CH2; Z~Z=CH2-CH2in the deposition of the compound in the form of a hydrochloride salt of a mixture of ethanol/ether.

Melting point: 246°C (hydrochloride melts with decomposition).

The mass spectrum and NMR spectra were registered using I (R=OH; R1=CH3; R2=H; R3=H; R4=CH2-CH=CH2; Z~Z=CH2-CH2in the form of foundations, obtained as a direct result chromatography in the form of a yellow oil.

Mass spectrum (electrospray) (m/z): 452 [M+1]+.

Range1H NMR (CDCl3, δ, ppm, relative to the (CH3)4Si): 0.56-0.62 (m, 1H, H-19l bottle), 0.98-1.06 (m, 1H, H-p), 1.27-1.35 (m, 1H, 2H-18), 1.45 (s, 3H, CH3), 1.47-1.54 (m, 1H, H-8A), 1.86-1.96 (m, 2H, H-15EC+H-15AK), 2.07-2.12 (m, 1H, H-7β), 2.20 (DD,2J=18.6 Hz,3J=6.4 Hz, 1H, H-10A), 2.21-2.29 (m, 1H, H-16AK), 2.50 (DD,2J=11.5 Hz,3J=4.6 Hz, 1H, H-1 tank), 2.78 (d, J=6.5 Hz, 1H, H-9), 2.78-2.85 (m, 1H, H-8β), 2.98-3.05 (m, 3H, H-10β+2Hallyl(-CH2-CH=CH2)), 4.16 (d,4J=2.3 Hz, 1H, H-5), 5.11 (USD,2J=10.0 Hz, 1H, Ha11yl(-CH2-CH=CH2(cis)), 5.17 (USD,2J=17.2 Hz, 1H, Hallyl(-CH2-CH=CH2(trans)), 5.69-5.81 (m, 1H, Hallyl(-CH2-CH=CH2), 5.69 (s, 1H, HE), 6.71+6.53 (AB-system, JAB=8.1 Hz, 2H, N-1+N-2).

Range19P-NMR (CDCl3, δ, ppm, relative to CFCl3): -73.63 (s, 3F, CF3).

The technical result of the invention is to provide a first fluorinated derivatives aminomorpholine, which belong to the class of ligands of opioid receptors and is and are precursors of such compounds, structure which allows further chemical modification to obtain products with desired properties, containing triptorelin group. The methods of obtaining onlinelow and their predecessors provide an introduction triptorelin group in the available source connection, and the presence of other reaction centers makes it possible directed the introduction of substituents to obtain porpoising of teverola and ordinola exhibiting the properties of ligands for opioid receptors.

An advantage of the claimed compounds of formula I in comparison with not containing fluorine analogues is the increased possibility of varying the hydrophilic-hydrophobic balance of the molecule opioid ligand in accordance with the need to achieve the desired biological target (opioid receptor, localized in the Central or peripheral nervous system) without significant changes in the geometric parameters of the molecule.

All of the inventive fluorine-containing compounds can be obtained on the basis of several available precursors: thevenon (I, R+R1=O; R2=CH3; R3=CH3; R4=CH3; Z~Z=CH=CH; Y=H), synthesized from natural alkaloid thebaine in one stage [.W.Bentley. Brit. Pat. GB 902659(A) (1962)] or longer [N. Saxena. Autospid. The USSR 1362734 (1987)]; l the Bo on the basis of 18,19-dihydrothebainone (I, R+R1=O; R2=CH3; R3=CH3; R4=CH3; Z~Z=CH2CH2; Y=H), obtained by hydrogenation of teminon [K.W.Bentley. Brit. Pat. 1136214 (1968). Chem. Abstr., 70: 78218s (1969)]; or on the basis of 21,21,21-triptoreline (I, R+R1=O; R2=CH3; R3=CH3; R4=Snz; Z~Z=CH=CH; Y=F), which is also derived from natural raw materials (thebaine).

1. Fluorinated derivatives of teverola and ordinola General formula
,
where R=OH; R1=H, CF3C1-C4alkyl, aryl, or (R+R1) denotes O=; R2=H, CH3; R3=H, CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2CH=CH and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, where R=OH; R1=H, CF3C1-C4alkyl, aryl; R2=H; R3=H, CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2CH=CH, as a fluorine-containing ligands of opioid receptors.

3. Method of preparing compounds according to claim 1, where R=OH; R1=H, CF3C1-C4alkyl, aryl, or (R+R1)=O; R2=CH3; R3=CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH=CH, including
(a) triptoreline aldehyde of the formula

with the formation of 21,21,21-triptoreline;
(b) oxidation of the obtained 21,21,21-triptoreline formula

where R=OH, R1=H, R2=R3=R4=CH3, the product of the interaction of oxalicacid and dimethyl sulfoxide at a temperature of from -70°C to -78°C, followed by treating the reaction mixture with a base, such as triethylamine, and the formation of the corresponding ketone (21,21,21-thevenon) of the formula I, where R+R1=O, R2=R3=R4=CH3; Z~Z=CH=CH;
(C) obtaining derivatives of teverola according to claim 1 interaction obtained in stage (b) ketone or (i) with an appropriate organolithium compound of the formula R1Li, or (ii) with a Grignard reagent of formula R1MgX, or (iii) CF3Si(CH3)3and the subsequent allocation of the target products by the known methods.

4. Method of preparing compounds according to claim 1, where R=OH; R1=H, CF3C1-C4alkyl, aryl, or (R+R1)=O; R2=R3=CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2CH=CH, which consists in the interaction triptoreline agent derivative of teminon formula (II)

where R+R1=O, R2=CH3; R3=CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2CH=CH, then treating the reaction mixture with acid and the selection of appropriate talinolol formula I by known methods.

5. The method according to claim 3, in which the Tr is formatierung agent use CF 3Si(CH3)3.

6. The method according to claim 4, in which as triptoreline agent use CF3Si(CH3)3.

7. Method of preparing compounds according to claims 1 and 2, where R=OH; R1=CF3C1-C4alkyl, aryl, R2=H; R3=H, CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2CH=CH, involves demethylation of compounds according to claim 1, where R=OH; R1=H, CF3C1-C4alkyl, aryl, R2=CH3; R3=CH3; R4=CH3cyclopropylmethyl, allyl; Z~Z=CH2CH2CH=CH, obtained by the methods PP and 4, and the selection of target products by the known methods.

8. The method according to claim 7, where demethylation is performed by the action of an aqueous solution of HBr.

9. The method according to claim 7, where demethylation carry out the action of BBr3.



 

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SUBSTANCE: invention relates to a novel compound - 7α-(1-hydroxy-2,2,2-trifluoroethyl)-17-methyl-3,6-dimethoxy-4;5α-epoxy-6α,14α-ethenoisomorphinane of formula (1) which is a precursor of fluorine-containing tevinol, tevinols and orvinols, and can be used in production thereof, as well as a method of producing a compound of formula (1) in form of a mixture of (20R)- and (20S)-isomers, which involves reacting an aldehyde of formula with a Ruppert-Prakash reagent [CF3Si(CH3)3], in the presence of a fluoride ion source such as tetrabutylammonium fluoride, in a solvent such as tetrahydrofuran, followed by treatment with and acid and separating the end product using known techniques. Separate (20R)- and (20S)-isomers are separated chromatographically.

EFFECT: improved method.

3 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 17-methyl-3,6-dimethoxy-7α-(trifluoroacetyl)-4,5α-epoxy-6α, 14α- ethenoisomorphinane of formula (I) The invention also relates to a method of producing said compound, which involves reacting an aldehyde of formula with a Ruppert-Prakash reagent [CF3Si(CH3)3] in the presence of an F- source and oxidising the obtained fluorine-containing alcohol of formula with a product of reacting oxalyl chloride and dimethylsulphoxide at low temperature in methylene chloride, followed by treating the reaction mixture with a base and separating the end product (I) using standard techniques.

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4 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a combination for the prevention, correction and therapy of pain related to neurodegeneration and/or associated with somatoform disorders, characterised by the fact that it consists of buspirone and doxepin taken in therapeutically effective amounts.

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5 cl, 2 ex, 2 tbl

FIELD: medicine.

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EFFECT: invention ensures prolonged anesthetisation in early post operational period within 3 days, due to reduction of introduced narcotic analgesic (morphine) dose, which makes it possible to reduce probability of development of addiction and development of side effects in patients.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (hetero)arylcyclohexane derivatives of formula , where values of Y1, Y1', Y2, Y2', Y3, Y3', Y4, Y4', R1-R3 are given in the first claim, having affinity for the µ- opioid receptor and ORL 1-receptor.

EFFECT: enabling use of the derivatives in drugs for treating pain.

10 cl, 2 tbl, 40 ex

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14 cl, 73 ex

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17 cl, 9 tbl, 8 dwg, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted quinoxaline-type bridge piperidine compounds of formula

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or pharmaceutically acceptable derivatives thereof, where: a equals 0; b is an integer selected from 0 or 1; each R5 is independently selected from -H; R1 is -(C9-C14)bicycloalkyl, each substituted with 1 or 2 independently selected R3 groups; each R3 independently selected from -(C1-C4)alkyl. The invention also relates to a pharmaceutical composition, capable of modulating ORL-1 receptor function, based on said compound.

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27 cl, 2 tbl, 19 ex

FIELD: chemistry.

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13 cl, 1 ex

FIELD: medicine, pharmaceutics.

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EFFECT: obtaining novel compounds.

10 cl, 36 ex

Drug form // 2493830

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form, preferably, to pill for per oral application, for pain treatment with controlled release of pharmacologically active composition (A), which it contains. Drug form contains pharmacologically active composition (A), which is potential for abuse, representing opioid or opioid derivative, and hydrophilic polymer (C). Part of surface of drug form by invention is convex, and the other part of its surface is concave. Drug form has tensile strength B1, at least, 500 H in direction of tension E1 and has tensile strength B2 lower than 500 H in direction of tension E2.

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16 cl, 21 dwg, 6 ex

FIELD: biotechnologies.

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EFFECT: hemihydrate of naltrexone base with high solvability in organic solvents, simplified and cheap method for obtaining polymorph of naltrexone base, method for obtaining microspheres with reduced toxic properties and improved profile of naltrexone release.

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10 cl, 11 ex, 4 tbl, 20 dwg

FIELD: medicine, pharmaceutics.

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47 cl, 4 ex, 4 tbl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular, to surgery and can be applied for prolonged anesthetisation in early post operational period of patients with haemorrhoids of III-IV stage. For this purpose 1% solution of morphine in dose 0.1 ml per 10 kg of weight is introduced one time per day in peridural space between vertebras L2-L3 , or L3-L4 through catheter. Said quantity is diluted with 6 ml of physiological solution. Such volume of narcotic medicine ensures effective anesthetisation within 18-20 hours. After that, after said time expiry, 6.0 ml of 2% solution of lidocaine are additionally introduced, which ensures anesthetisation effect within 4 hours. Claimed procedure is repeated on 2 and 3 day in the same succession.

EFFECT: invention ensures prolonged anesthetisation in early post operational period within 3 days, due to reduction of introduced narcotic analgesic (morphine) dose, which makes it possible to reduce probability of development of addiction and development of side effects in patients.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented versions of pharmaceutical compositions able to resist the recovery of a pharmaceutical substance containing alkaloids if used for non-medical purposes and to prevent the recreational misuse. They contain at least one pharmaceutical substance (PS) of alkaloid with the properties of an anxiolytic, an anti-depressant, a hypnotic, or a psychotropic, or an anti-cold in the acid form; polyphenol able to bind to the acid form of the PS to form a complex resistant to the common recovery, and an ingredient able to bind selectively to polyphenol, and thereby release the PS from the complex. What is presented is an additive for preventing the commercial and recreational misuse of the pharmaceutical substance containing: polyphenol - the first ingredient able to bind to the acid form of the PS to form the complex resistant to the common recovery, and the second ingredient able to bind selectively to polyphenol thereby releasing the PS from the complex. There are presented the methods for preparing the above pharmaceutical compositions and the additive, and also the method for administering the PS.

EFFECT: provided resistant properties of the pharmaceutical compositions to the recreational misuses have been shown.

28 cl, 12 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gastroenterology, laser therapy. The method involves administering the drugs: a proton pump inhibitor and a prokinetic accompanied by laser therapy. The proton pump inhibitor is presented by Controloc 20 mg 2 times a day. Gaviscon is administered in a dose of 2 tablets 3 times a day daily. Trimedat 200 mg is administered 3 times a day. The laser therapy is differentiated. That involves taking into account a severity of gastroesophageal reflux disease, a degree of manifestation of endothelial dysfunction and a severity of upper gastrointestinal motor dysfunction. The manifestation of endothelial dysfunction is shown by the contents of nitrogen oxide, pro-inflammatory, namely IL-1β, IL-6, TNF-α and anti-inflammatory, namely IL-4 cytokines. The degree of upper gastrointestinal motor dysfunction is shown by a stomach/duodenum ratio Pi/P(i+1). A mild degree of gastroesophageal reflux disease implying the levels of nitrogen oxide 35.2±2.7 mcmole/l and more, IL-1β 1.5±0.3 pg/ml or more, IL-6 1.8±0.8 pg/ml or more, TNF-α 2.78±0.35 pg/ml or more, IL-4 4.4±0.42 pg/ml or less, the ratio Pi/P(i+1) of 11.2±5.6% or less requires 6-7 daily procedures of the intravenous laser blood irradiation. The exposure length is 15 minutes at wave length 0.405 mcm, end face output density 1-1.5 mWt, pulse frequency 80 Hz, in a continuous mode. The moderate or severe gastroesophageal reflux disease with the levels of nitrogen oxide less than 35.2.2±2.7 mcmole/l, IL-1β 1.83±0.3 pg/ml or less, IL-6 1.98±0.8 pg/ml or less, TNF-α 10.04±2.84 pg/ml or less, IL-4 3.15±0.43 pg/ml or more, the ratio Pi/P(i+1) of 12.3±4.8% or more requires 9-10 daily procedures of the intravenous laser blood irradiation. The exposure length is 15 minutes at wave length 0.405 mcm, end face output density 1-1.5 mWt, pulse frequency 80 Hz, in a continuous mode.

EFFECT: method reduces the drug-induced load, reduces the length of treatment.

3 tbl, 3 ex

Nalmefene prodrugs // 2495042

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to ester prodrug forms of nalmefene of formula (I) wherein R1 means C6-16alkyl or C8-12alkylamino; or a pharmaceutically acceptable acid additive salt thereof. Also the invention claims the pharmaceutical compositions possessing action of an opioid receptor agonist containing a pharmaceutically acceptable salt and a therapeutically acceptable amount of the compound of formula (I).

EFFECT: invention describes the chemical methods for preparing the above compounds and using them in treating substance abuse disorders, such as abuse of alcohol and alcohol dependence, and pulse control disorders, such as compulsive gambling and shopping addiction.

14 cl, 5 ex, 1 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds, namely nalmefene prodrugs of formula (I) wherein R1 means C16-20alkyloxycarbonylC2-4alkyl, as well as to pharmaceutical compositions containing the above compounds, as well as to a method for preparing the above compounds.

EFFECT: compounds possess action of an opioid receptor antagonist and may be used for treating substance abuse disorders, wherein the above disorder represents abuse of alcohol and alcohol dependence.

8 cl, 1 tbl, 2 ex

Drug form // 2493830

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form, preferably, to pill for per oral application, for pain treatment with controlled release of pharmacologically active composition (A), which it contains. Drug form contains pharmacologically active composition (A), which is potential for abuse, representing opioid or opioid derivative, and hydrophilic polymer (C). Part of surface of drug form by invention is convex, and the other part of its surface is concave. Drug form has tensile strength B1, at least, 500 H in direction of tension E1 and has tensile strength B2 lower than 500 H in direction of tension E2.

EFFECT: drug form by invention is stable to rupture and stable against abuse.

16 cl, 21 dwg, 6 ex

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