Derivatives of benzene, methods for their preparing and pharmaceutical compositions containing thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzene of the formula (I): wherein A represents a group taking among the following groups: -C≡C-, -CH=CH-, -CH2-CH2; n = 1 or 2; X represents hydrogen, chlorine or fluorine atom or methyl or methoxy-group; Y represents hydrogen, chlorine or fluorine atom; R1 represents cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with methyl group, phenyl group monosubstituted or disubstituted with fluorine or chlorine atom or methoxy-group, cycloheptyl, tert.-butyl, dicyclopropylmethyl, 4-tetrahydropyranyl or 1- or 2-adamantyl, or adamantine-2-ol group; or R1 represents phenyl group and in this case X and Y both represents chlorine atom; R2 represents hydrogen atom or (C1-C4)-alkyl group; R3 represents (C5-C7)-cycloalkyl, and salts of these compounds formed by addition of pharmaceutically acceptable acids, and their solvates and hydrates also. Also, invention relates to methods for preparing compounds of the formula (I) and to pharmaceutical composition able to interact with receptors sigma-2 based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for treatment of autoimmune states, disturbance on heart contraction frequency and control against proliferation of tumor cells.

EFFECT: improved preparing methods, valuable medicinal properties of compositions.

18 cl, 14 tbl, 78 ex

 

The present invention relates to the derivatives of benzene containing amine functional group, substituted alkyl group and cycloalkyl group that specifically bind to Sigma receptors, in particular with the receptors of the peripheral nervous system, to a method for producing these compounds and to their use in pharmaceutical compositions and, more specifically, as immunosuppressants.

Sigma receptors have been identified with several ligands. First of all, you can mention opiate compounds - 6,7-benzomorphan or SKF-10047-in particular the chiral compound (+) SKF-10047 (W.R. Martin et al., J. Pharmacol. Exp. Ther. 1976, 197, 517-532; B.R. Martin et al., J. Pharmacol. Exp. Ther. 1984, 231, 539-544). Of these compounds the most commonly used (+)N-hallinnollisiin, or (+)NAHM, and (+)pentazocine. Antipsychotic agent haloperidol is also a ligand of the Sigma receptor, and (+)3-(3-hydroxyphenyl)-1-propylpiperidine and (+)3-PPP (B. L. Largent et al., Proc. Nat. Acad. Sci. USA 1984, 81, 4983-4987).

In U.S. patent 4709094 described guanidine derivatives, which are highly active ligands that are specific in respect to the Sigma receptors, and we can mention, in particular, di-(O-tolyl)guanidine, or DTG. Anatomical distribution of Sigma receptors in the brain was established by autoradiography after tagging these receptors DTG according to E. Weber et al., Proc. Nat. Acad. Sci USA 1986, 83, 8784-8788 and ligands (+)SKF-10047 and (+)3-PPP according to C. L. Largent et al., J. Pharmacol. Exp. Ther. USA 1986, 238, 739-748. Autoradiographical study gave the opportunity to clearly identify the Sigma receptors in the brain and to distinguish them from other opioid receptors, as well as from phencyclidine receptors. In particular, Sigma receptors are distributed in the Central nervous system and is concentrated in the brain stem, the limbic system and the regions involved in the regulation of emotions. Sigma receptors are also found in various peripheral tissues. There are at least two types of Sigma receptors: receptors Sigma-1 and Sigma-2. The ligands of the type (+)SKF-10047 selectively bind to receptors Sigma-1, whereas other ligands, such as DTG, haloperidol or (+)3-PPP show significant affinity for both Sigma-1 and Sigma-2 receptors.

In the patent EP 461986 described compounds of the formula

which selectively bind to Sigma receptors and which have immunosuppressive activity.

In this series of compounds investigated specifically hydrochloride (Z)-[3-(3-chloro-4-cyclohexylphenol)allyl]cyclohexylethylamine formula

You can refer to, for example, in Biological Chemistry. 1997, 272 (43), 27107-27115; Immunopharmacology and Immunotoxicology. 1996, 18 (2), 179-191. However, the connection fo the mules (a) possess a specific property, which can be considered as a disadvantage. This property, which appears during metabolisation is dependent on cytochrome known as CYP 2D6.

In 1957, for the first time it has been suggested that genetic differences may be responsible for variations in the response to drug products. Oxidative metabolism demonstrates considerable variation between individuals and races. The study, which was conducted during the last 15 years have shown that variations in the functional expression of multigene families of cytochrome P450 (CYP) are the cause of these differences. Just some isoforms of cytochrome P450 from those that have already been identified in humans, involved in the oxidative metabolism of medicinal products (Xenobiotica, 1986, 16, 367-378). To date, on the basis of their clinical importance of the identified CYP 1A2, CYP 2A6, CYP 2C9, CYP 2D6, CYP 2C19, CYP 2E1 and CYP 3A4. Found that CYP 3A4, CYP 2D6 and CYP 2C9 are responsible (in varying degrees) for 90% of oxidative metabolism of medicinal products. Although the functional expression of these isoforms is regulated and influenced by a broad range of environmental and physiological factors, genetic factors have the most pronounced effect, which emphasizes the important role of the polymorphism in the oxidation of medicinal products. Some what of these polymorphisms have been studied (in particular, polymorphisms of CYP 2C19 and CYP 2D6). More specifically, we demonstrated the clinical significance of the polymorphism of CYP 2D6 in 4-hydroxylation debrisoquine (Clin. Pharmacol. Ther., 1991, 50, 233-238). Genetic polymorphism of CYP 2D6 responsible for problematic metabolism more than 30 important medicinal products and affects up to 10% of the Caucasian population (slow metabolite). Currently, it is shown that this isoform controls the biotransformation of drug products, such as anti-arrhythmic agents, β-blockers, antihypertensive agents, agents against angina, neuroleptics and antidepressants. With some exceptions, these medicinal products used in psychiatry and cardiovascular therapy for long-term treatment.

The pharmacokinetic results are the results of purely quantitative procedure: slowly metabolizing individuals have a level of unmodified product, which is higher than the rest. These quantitative differences have a significant clinical impact on molecules that have a low therapeutic index.

Thus, genetics is largely influenced by differences in efficacy and adverse effects observed among individuals. It is therefore important to determine whether the metabolism of the drug product bytessent in the case of a genetic deficiency of the enzyme or not.

In accordance with the present invention found new excellent benzene derivatives for Sigma receptors, in particular for Sigma receptors of the peripheral nervous system, which have immunosuppressive activity, but have a low metabolic rate and/or a low level or absence of involvement of CYP 2D6 in the oxidation process.

The compounds of this invention also possess antitumor activity and, in particular, they inhibit the proliferation of cancer cells.

Moreover, it is demonstrated that these new compounds have activity in the cardiovascular system, more specifically in controlling heart rate.

The compounds of this invention also have activity against apoptosis.

So, in one of its aspects the present invention relates to compounds of the formula

where a represents a group selected from the following:- ≡C-, -CH=CH-; -CH2-CH2-;

n is 1 or 2;

X represents a hydrogen atom, chlorine or fluorine or a methyl or methoxy group;

Y represents a hydrogen atom or chlorine atom or fluorine;

R1represents tsiklogeksilnogo group, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group; enelow group, monosubstituted or disubstituted by fluorine atom or chlorine or a methoxy group; cycloheptanol, tert-boutelou, Dicyclopentadiene, bicyclo[3.2.1]octanediol, 4-tetrahydropyranyl, 4-tetrahydropyranyl or 1-or 2-adamantanol or adamantane-2-Aulnay group; or R1represents a phenyl group, and it is clear that in this case X and Y are other than hydrogen;

R2represents a hydrogen atom or (C1-C4)alkyl group, possibly substituted triptorelin group;

R3is a (C5-C7)cycloalkyl;

and the salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

The term "alkyl" means a linear or branched saturated monovalent hydrocarbon radical.

The term "(1-C4)alkyl" means an alkyl radical comprising from 1 to 4 carbon atoms.

In accordance with another aspect of this invention relates to compounds of formula (I), where a is a group selected from the following:- ≡C-, -CH=CH-, -CH2-CH2-;

n is 1 or 2;

X represents a hydrogen atom, chlorine or fluorine or a methyl or methoxy group;

Y represents a hydrogen atom or chlorine atom or fluorine;

R1is abizacelna group, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group; phenyl group monosubstituted or disubstituted by fluorine atom or chlorine or a methoxy group; cypoheptadine, tert-boutelou, Dicyclopentadiene, bicyclo[3.2.1]octanediol, 4-tetrahydropyranyl, 4-tetrahydropyranyl or 1-or 2-adamantanol group; or R1represents a phenyl group, and it is clear that in this case X and Y are other than hydrogen;

R2is a (C1-C4)alkyl group, possibly substituted triptorelin group;

R3is a (C5-C7)cycloalkyl;

and the salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

In accordance with another aspect of this invention relates to compounds of the formula

where a represents a group selected from the following:- ≡C-, -CH=CH-, -CH2-CH2-;

X represents a hydrogen atom or chlorine;

Y represents a hydrogen atom or a chlorine atom;

R1represents cyclohexyl, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group; a phenyl group substituted by a chlorine atom, a methoxy group or one or two atoms is mi fluorine; tert-boutelou or 1-or 2-adamantanol group; or R1represents a phenyl group, and it is clear that in this case X and Y both represent chlorine atom;

R2is a (C2-C3)alkyl;

and the salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

In accordance with another aspect of this invention relates to compounds of formula (I) and (I.1)in which a represents a group-CH=CH-(Z) configuration, and the salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate. In accordance with another aspect of this invention relates to compounds as defined above in which X represents a chlorine atom, and Y represents a hydrogen atom or chlorine, and the salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

In accordance with another aspect of this invention relates to compounds as defined above in which R1represents 3,3,5,5-tetramethylcyclopentadienyl, or 3.3-dimethylcyclohexyl, or 4,4-dimethylcyclohexyl group; phenyl group monosubstituted or disubstituted by fluorine atom, or substituted in position 4 by an atom is Laura; or 1-or 2-adamantanol group; and the salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

The following connections:

[(Z)-3-(4-adamantane-2-yl-3-chlorophenyl)propen-2-yl]cyclohexylethylamine;

[(Z)-3-(4-adamantane-2-ylphenyl)propen-2-yl]cyclohexylethylamine;

{(Z)-3-[4-(4,4-dimethylcyclohexyl)-2-chlorophenyl]propen-2-yl}-cyclohexylethylamine;

[(Z)-3-(4-(adamantane-1-yl-3-chlorophenyl)propen-2-yl]cyclohexylethylamine;

[(Z)-3-(4-adamantane-2-yl-3,5-dichlorophenyl)propen-2-yl]cyclohexylethylamine;

[(Z)-3-(4-adamantane-2-yl-3,5-dichlorophenyl)propen-2-yl]cyclohexyl(2-methylethyl)amine;

and also their salts, formed by joining pharmaceutically acceptable acids, their solvate and hydrate constitute another aspect of the present invention.

In particular, this invention relates to [(Z)-3-(4-adamantane-2-yl-3,5-dichlorophenyl)propen-2-yl]cyclohexylethylamine, as well as its salts, formed by the joining of pharmaceutically acceptable acids, solvate and hydrate.

Salts of the compounds according to this invention receive by methods well known to specialists in this field of technology.

Salts of compounds of formula (I) according to the present invention include salts with inorganic or organic acids which allow the division or the appropriate crystallization joint is of the formula (I), as well as pharmaceutically acceptable salts.

Suitable acids which may be mentioned are picric acid, oxalic acid or an optically active acid such as tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid and acids, which form physiologically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrosulfate, dihydrophosphate, maleate, fumarate, 2-naphthalenesulfonate or para-toluensulfonate. Hydrochloride are the most preferred salts of compounds of formula (I). In the case where the connection according to this invention contains one or more than one asymmetric carbon atom, optical isomers of this compound are an integral part of the present invention. If the connection according to this invention takes stereoisomer, such as axial-Equatorial-type or Z-E type, this invention includes all stereoisomers of this compound.

The present invention includes compounds of formula (I) in the form of pure isomers, as well as in the form of a mixture of isomers in any proportion. The compound (I) is isolated in the form of pure isomers traditional methods of separation. For example, you can use fractional recrystallization of the salt racemic mixture with an optically active acid and base, the principle being well known, or standard chromatographic methods on a chiral stationary phase or organization of the achiral stationary phase; for example, you can use the separation on silica gel or C18-grafted silica gel, elwira compounds, such as chlorinated solvents/alcohol. The above compounds of formula (I) also include compounds in which one or more than an atom of hydrogen, carbon, or halogen, in particular chlorine or fluorine, replaced by their radioactive isotope, for example tritium or carbon-14. Such labeled compounds are suitable for studies of metabolism or pharmacokinetics in biochemical tests as ligands of the receptor.

Functional groups that may be present in the molecule of the compounds of formula (I) and intermediate compounds can be protected, permanently or temporarily, protective groups, which provide the final synthesis of the expected compounds. Response the introduction and removal of the protective groups is carried out by methods well-known to specialists in this field of technology. The expression "temporary protective group for amines, alcohols, fenoterol or carboxylic acid" means a protective group such as the groups described in Protective Groups in Organic Synthesis, Greene T. W. and Wuts P. G. M., ed. John Willey and Sons, 1991, and in Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag. Specialist in sostenibilitat suitable protective group. The compounds of formula (I) may contain groups precursor of other functional groups, which are sequentially formed on one or more than one stage.

The object of the present invention is also a method of obtaining compounds of formula (I), characterized in that:

1) when a represents a group-C≡C,

a) or, if n=1, conduct the reaction manniche between phenylacetylene derivative of the formula

where R1X and Y are as defined for (I), formaldehyde and an amine (1) HNR2R3and R2and R3are as defined for (I);

b) or carry out the Suzuki reaction mix between a compound of formula

where X, Y, n, R2and R3are as defined for (I), a, Z represents bromine, iodine or triftormetilfosfinov group (OTf), and boron derivative (2) of the formula R1-B(OR)2where R represents a hydrogen atom or an alkyl or aryl group, in the presence of a base and a metal catalyst;

b) or, when R1represents tsiklogeksilnogo group, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group; cycloheptyl, 4-tetrahydropyranyl, 4-tetrahydropyranyl or adamantly group, avodat the reaction mix between the compound (1A), in which Z represents an iodine atom or bromine, and the ketone (3)corresponding to R1presentedin the presence of a base to obtain the intermediate compounds of formula

where X, Y, n, R2and R3are as defined for (I); the specified connection (I’) then restore in selective conditions;

g) or carry out the reaction mix between the amine of the formula

where n, R2and R3are as defined for (I)and the compound of the formula

where R1X and Y are as defined for (I)and Z represents a bromine atom or iodine or triftormetilfullerenov group (triplet, or OTf);

2) when a represents a group-CH=CH-, carry out the hydrogenation, with hydrogen at the time of selection, or in the presence of cyclohexene, the compounds of formula (I), where a is an acetylene group-C≡C-, with the receipt of the ethylene compounds (I) in the form of a mixture of Z and E isomers, or that the hydrogenation is carried out in the presence of a metal catalyst on the carrier with the receipt of the ethylene compounds (I) in Z form, or, alternatively, compound (I)in which a represents an acetylene group-C≡ -, is subjected to the interaction with Geri the Ohm metal with obtaining the ethylene compounds (I) in the E form;

3) when a represents a group-CH2-CH2-conduct the hydrogenation of the compound (I)in which a represents a group-CH=CH-or-C≡C.

Stage 1A of the method according to the invention is carried out under heating, preferably at a temperature between 80°s and 90°With, in a polar solvent such as 1,2-dimethoxyethane or 1,4-dioxane. To promote the condensation reaction, it is possible to use a catalyst, for example a metal salt, such as chloride copper (II) or chloride of copper III.

At stage 1B of this method the reaction mix Suzuki preferably carried out between the compound (Ia)in which Z represents OTf, and boron derivative (2) of the formula R1-B(OH)2. The reaction is carried out in the presence of a base, such as hydroxide, alkoxide, phosphate, or carbonate of alkali or alkaline-earth metal, more specifically potassium phosphate or sodium carbonate. The reaction is carried out in the presence of a metal catalyst, such as catalyst based on copper, tin, or, preferably, palladium, such as tetrakis(triphenylphosphine)palladium, possibly with the use of halide such as lithium chloride, acting as socialization. The method is carried out by heating at a temperature between 60°s and 80°in an inert solvent, such as toluene or 1,2-dimethoxyethane, or, preferably, d is whatney environment toluene/water solution, perhaps with a bit of alcohol, such as ethanol. The reaction mix Suzuki investigated in many publications, such as, for example, Synth. Commun., 1981, 11 (7), 513-519 and J. Org. Chem., 1993, 58 (8), 2201-2208. Boranova acid (2) R1-B(OH)2are commercially available or synthesized by standard methods from the corresponding halogenated, preferably bromopropionic R1Br by effects such as trimethylboron in the presence of a base, such as tert-utility.

At stage 1B of the reaction mix is preferably carried out on the compound (Ia), where Z represents a bromine atom, in the presence of a base, such as n-utility, in an inert solvent, preferably diethyl ether, at low temperature, preferably in the range from -80°C to -70°C. Restore (I’) to (I) is carried out in selective conditions, for example in accordance with the method described in Tetrahedron, 1995, 51, 11043-11062 by exposure chlorotrimethylsilane and sodium iodide in a mixture of acetonitrile/chlorinated solvent, such as dichloromethane, followed by treatment with acetic acid in the presence of zinc, or, alternatively, by exposing iodomethane acid or by ionic hydrogenation under the influence of tetraborate sodium trifonovoj (triftormetilfullerenov) acid.

In stage 1 g of this method the reaction mix is avodat in the presence of a palladium catalyst, one or more than one tertiary amine and possibly lithium chloride. It is preferable to use the compound (III), where Z is triplet, and this process is carried out in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine)palladium, and possibly socializaton, such as copper iodide. When Z represents triflate, used for lithium chloride. This reaction mix is preferably carried out in the presence of triethylamine and pyridine at a temperature of reflux distilled reaction mixture. For this type of combination, a combination known as Sonogashira, you can refer to J. Org. Chem., 1993, 58, 7368-7376 and 1998, 63, 1109-1118; Syn. Lett., 1995, 1115-1116 and Synthesis, 1987, 981. To obtain the compounds (I), where a represents a group-CH=CH-, Z-form, the hydrogenation is usually carried out in the presence of cyclohexene and a metal catalyst on a carrier, such as palladium on barium sulfate or calcium carbonate, or Raney Nickel, or preferably, a Lindlar catalyst, in a solvent which is inert to this reaction medium, such as petroleum ether or alcohol solvent. To obtain the compounds (I) in the E-form is preferably used a metal hydride is diisobutylaluminum hydride (DIBALH) in an inert solvent, such as toluene.

the La obtain the compounds (I), where a represents a group-CH2-CH2-, the hydrogenation is usually carried out in alcohol, for example ethanol, in the presence of a catalyst such as platinum oxide or, preferably, palladium-on-charcoal grill.

Concerning methods of recovery of alkenes and alkynes used above, you can refer to the "Catalytic Hydrogenation. Techniques and Applications in Organic Chemistry", Robert L. Augustine, 1965, Narcel Dekker, Inc. New York.

General method of preparing compounds (I), where a is an acetylene group-C≡C is described in scheme 1, below.

SCHEME 1

Scheme 1 A=-≡ -, X, Y, n, R1, R2and R3are as defined for (I), R represents a hydrogen atom or an alkyl or aryl group, Z represents a bromine atom or iodine or triflate, and when Z represents a bromine or iodine, Z’ represents triflate, or Z’ represents a bromine atom or iodine. The importance of the nature of the substituents Z and Z’ in the reaction combinations indicated by the Path G, specified below.

The compound (II) obtained by processing chloroacrolein formula

where X, Y and R1are as defined for (I), the primary environment, preferably working with sodium hydroxide in a solvent such as tetrahydrofuran or, preferably, 1,4-dioxane, n and the temperature of reflux distilled solvent.

Chloroacrolein (IV) is obtained from acetophenone of the formula

where X, Y and R1are as defined for (I), influencing complex Vilsmeier. Use, for example, chloride (chlormethine)dimethylammonio representing commercial complex Vilsmeier, or complex of Vilsmeier derived from disubstituted formamide, combined with oxalylamino, phosphorus oxychloride or phosgene. This method is usually carried out in a chlorinated solvent or ether at a temperature between -20°s and 40°C. More specifically, using the complex of Vilsmeier obtained from dimethylformamide and oxalicacid in a solvent such as dichloromethane or 1,2-dimethoxyethane, at a temperature between -10°and 10°C.

For this type of reaction can be referenced, for example, in J. Chem. Soc. (C), 1970, 2484-2488 and Angew. Chem. Internat. Ed., 1963, 2, 98-99.

Acetophenone (V) are known or they are obtained by known methods such as methods described in Gazz. Chim. Ital., 1949, 79, 453-457 and J. Am. Chem. Soc., 1947, 69,1651-1652.

Scheme 2 illustrates the methods used to obtain the compounds (V).

SCHEME 2

In scheme 2, X, Y, and R1are as defined for (I), su is the same as defined for (I), Z represents a bromine atom or iodine, or OTf, R represents a hydrogen atom or Alki is inuu or aryl group, and P represents a protective group for a ketone functional group, such as methyl.

Compounds (V) can be obtained directly from the compounds (Va) by exposing the boron compound R1-B(OH)2(2)as described for the conversion of (Ia) to (I). Ketone functional group of the compound (Va) can also be protected in a traditional way, for example by influencing trialkylaluminium in the corresponding alcohol in the presence of acid, such as para-toluensulfonate acid.

Thus obtained compound (Vp) is subjected to interaction with ketoneunder the conditions described for the conversion of (Ia) to (I’). With a ketone functional group remove protection by hydrolysis in an acid medium to obtain the compound (V’). The specified connection (V’) then restore in mild conditions described for the conversion of (I’) in (I).

In some cases, for example when R1represents 4,4-dimethylcyclohexyl or 4-tetrahydropyranyloxy group, may form an intermediate compound of the formula

where X=O or-C(CH3)2that after the preliminary protection of the ketone functional group and hydrogenation, for example, in the presence of palladium-on-coal in methanol and subsequent removal of the protection keto is Noah functional group of the ketone gives the target compound (V).

The compound (V), where X and/or Y is other than hydrogen, can be obtained from the compounds (V), where X=Y=H, by methods well known to specialists in this field. For example, when X and/or Y represents an atom of chlorine, the chlorination of the aromatic nucleus through the action of gaseous chlorine in the presence of a Lewis acid, preferably of trichloride aluminum, in a chlorinated solvent such as dichloromethane, preferably at 0°C.

Compound (Va) is also available commercially or can be obtained by methods known to experts in this field.

For example, when Z is triplet, compound (Va) can be obtained, as shown in figure 3:

SCHEME 3

In scheme 3 X and Y are as defined for (I). Compounds (VIII) are commercially available or they are obtained by standard methods.

In accordance with yet another aspect the object of the present invention are also the compounds of formula (Ia)

where X, Y, n, R2and R3are as defined for (I)and Z represents a bromine atom, or iodine atom, or OTf. These compounds are new and are a key intermediate compounds in the synthesis of compounds (I).

The present invention also relates to a method for obtaining derivatives (I is), characterized in that:

or, when n=1, conduct the reaction manniche between phenylacetylene derivative of the formula

where X and Y are as defined for (I), a Z is a bromine atom, or iodine atom, or OTf, formaldehyde and an amine (1) HNR2R3;

any conduct the reaction mix between the amine of the formula

where R2, R3and n are as defined for (I), and derivative of the formula

where X and Y are as defined for (I), Z represents a bromine atom, or iodine, or triflate, and Z’ represents a bromine atom or iodine, if Z is triplet, otherwise Z’ represents triflate, in the presence of a palladium catalyst, one or more than one tertiary amine and possibly lithium chloride.

The reaction manniche carried out under the same conditions as the conditions described for the conversion of (II) in (I).

The reaction Sonogashira described for the combination of the compounds (III) and (4), is used for a combination of compounds (IIIa) and (4). When Z represents triflate, and Z’ represents a bromine atom or iodine, the method is carried out in the absence of lithium chloride. On the other hand, when Z represents a bromine atom or iodine, and Z’ represents triflate, which is about carried out in the presence of lithium chloride. The use of lithium chloride creates the possibility to control the reaction mix.

Propargylamine (4) (in the case when n=1) receive the traditional way, for example according to Tetrahedron Lett. 1989, 30 (13), 1679-1682, starting from amine (1) HNR2R3and 3-bromopropene by exposure to potassium carbonate in acetonitrile at a temperature between 50°s and 80°C.

Compound (III), where Z=OTf, usually traditionally receive from the corresponding alcohols of the formula

where X, Y and R1are as defined for (I), by exposure triftormetilfullerenov anhydride (triplecore anhydride in pyridine. Themselves alcohols (IX) are obtained from compounds of the formula

where Z represents a bromine atom or iodine, in the ways described earlier for the conversion of (Ia) to (I) or (Va) (V). Connection (A) are commercially available or obtained by methods that are well known to specialists in this field.

The compound (IIA) is obtained from chloroacrolein formula

where X and Y are as defined for (I)and Z represents a bromine atom or iodine, or OTf, which is itself derived from acetophenone of the formula

where X, Y and Z are as defined above for (IVa), the methods described for the conversion of (IV) (II) and (V) in (I).

Compounds according to the invention were subjected to biochemical and pharmacological studies. The compounds of formula (I) and their pharmaceutically acceptable salt, hydrate and solvate specifically associated with Sigma receptors, in particular with the Sigma receptors of the peripheral nervous system, also known as Sigma receptors-2.

The affinity of the receptor Sigma 1 was investigated in vitro on brain membrane of Guinea pigs using3H-(+)-3PPP as a ligand according to De Haven-Hudkins et al., Life Science, 1993, 53, 41-48. (+)-Pentazocine specifically binds with the receptor Sigma 1. A fragment of a membrane of the brain of Guinea pigs is prepared in the usual way. The preparation of membranes (0.3 mg protein/ml) incubated for 150 minutes at 37°in the presence of 0.5 nm [3H]-(+)-pentazocine. The nonspecific binding determined in the presence of 10 μm (+)-pentazocine. Membranes are filtered and washed 3 times. The filtered material is analyzed to determine specifically bound fraction [3H]-pentazocine. In these conditions, the compounds according to the invention, examples of which follow below, have the meanings IR50between 0.1 nm and 100 nm.

The ability of compounds according to the invention to interact with Sigma receptors-2 was tested in vitro on the membranes of the spleen in rats, using as ligand [3H]-DTG, with the under R. Paul et al. Journal of Neuroimmunology, 1994, 52, 183-192. The preparation of membranes (1 ml) incubated with 2 nm [3H]-DTG for 90 minutes at 20°C. the Amount of nonspecific binding estimate in the presence of 10 μm DTG or haloperidol. Membranes are filtered and washed twice, and the filtered material is analyzed to determine the amount of specifically bound [3H]-DTG. Compounds according to the invention possess activity towards the Sigma-2 between 1 nm and 500 nm.

The compound of example 44, below, were tested for binding to membranes derived from mammalian cells and yeast, expressively or Sigma-1, Sigma-2, or Sterol-isomerase man (Human sterol isomerase (HIS)). The results of these tests show that the compounds according to the invention show a very high affinity to receptors Sigma-1 and Sigma-2 and HIS. The following table presents data on the affinity of the compound of example 44 to these receptors and HIS compared with data known from the prior art ligands of Sigma receptors.

>1000


Ligands/receptors
Sigma-1 (nm)HIS (nm)Sigma-2 (nm)
The compound of example 440,40+/-0,040,29+/-0,0225+/-2
(+)pentazocine4,3+/-0,22900+/-500
(-)pentazocine62+/-3>100075+/-10
(+) 3-PPP31>1000158+/-11
DTG38+/-1>100038+/-3

The table shows that the affinity of a typical representative of the claimed compounds (compound of example 44) is much higher affinity of other classical ligands of Sigma receptors that are not associated with these three receptors simultaneously.

1 - Connection according to the invention was also tested in tests on immunosuppressive activity.

D-Galactosamine, SEB (enterotoxin In Staphylococcus) and LPS (lipopolysaccharide) were obtained from Sigma Chemical Co (St Louis, MO). SEB contains less 0,00029% of endotoxin (test lysate of amoebocytes limulus", Bioproduct, Walkersville, MD). These molecules are dissolved in a phosphate buffer solution; the compounds according to the invention is dissolved in a solution containing 5% ethanol, 5% tween 80 and 90% water.

Using female Balb/C mice aged 6 to 8 weeks, delivered from the nursery Charles River (France) and female mice C57BL/6 and B6D2F1 the age of 8 weeks, delivered from the nursery IFFA CREDO (Domaine des Oncins, BP 0109, 69592 L Arbresle Cedex, France).

Measurement of cytokines: 5 mice intraperitoneally injected compounds or one solvent for 30 minutes before injection of LPS (10 μg/mouse nutriv the NGOs) or orally 1 hour before LPS. Blood samples are taken by retro-orbital or cardiac puncture after 1 hour 30 minutes after the injection of LPS. The samples are centrifuged and get the serum. The serum stored at -80°until analysis. The content of TNF-α and IL-10 was determined by ELISA kit (Genzyme, Cambridge). Tests carried out according to the instructions for use.

Toxic shock syndrome: Compound injected intraperitoneally 10 animals. After 30 minutes, SEB (Staphylococcus enterotoxin B, Sigma St. Louis, MO) was injected in an amount of 10 μg/mouse intravenously, and enter D-galactosamine (20 mg/mouse, intraperitoneally).

Death observed after 48 hours.

Disease TNX (graft-versus-host): Test compound or solvent (control) injected female B6D2F1 (H2b× H2d) mice intraperitoneally. After 4 hours they injected 7,5×107C57BL/6 (H2b) mononuclear spleen cells of the mouse to initiate TNX. All animals kill one week after transplantation and measure the increase in mass of the spleen caused TNX. Expect the following figure:

Results expressed as follows:

where PS is the percentage of splenomegaly.

Measurement of T cell proliferation: cell Suspension is prepared using the spleen of mice Balb/C. Red blood those who, iza first are lysed during a brief hypotonic shock, achieved by using sterile distilled water. The remaining cells (white blood cells) twice washed with culture medium (RPMI 1640 containing 2% heat-inactivated serum of cow embryos, 2 mm L-glutamine, 1 mm sodium pyruvate, 100 U/ml penicillin, 100 μg/ml streptomycin, 15 mm PIPES (piperazine-N,N-bis(2-econsultancy acid)), advance brought to pH 6.6. Cell viability determined using Trypanosoma blue, always greater than 95% when this method of preparation. Splenocytes at a concentration of 6×106cells/ml were cultured with the test products in flat-bottomed 96-well plates (Falcon, Becton Dickinson, Lincoln Park, NJ) in the presence of 2 μg/ml SEB. Four wells prepared for each concentration of the tested products. Incubation was performed at 37°C incubator for cell cultures (atmosphere: 95% air + 5% CO2within 4 days. Then in each culture well add 2 µci titiraupenga thymidine (Amersham, Les Ullis, France). Four hours later the cells are harvested on glass fiber filters (Filtermat A, Wallac, Turku, Finland)using skadron (Pharmacia LKB, Piscataway, NJ). The radioactivity incorporated and connected to the filter, measured in a suitable liquid scintillation counter (Betaplate, Pharmacia LKB).

According to the results observed during these biochimicoistituto and behavioral tests compounds according to the invention exhibit immunosuppressive activity.

2 - Connection according to the invention were also subjected to the tests, demonstrating their ability to inhibit the proliferation of tumor cells and cancer cells.

Measurement of cell proliferation in MDA/MB231 (gormonozawisimogo breast cancer): Cells MDA/MB231 retain in vitro by serial transfers in the environment of the Needle, modified by Dulbecco (DMEM) (Gibco Laboratories, Grant Island, NY)containing 10% heat-inactivated serum of cow embryos, 1 mm sodium pyruvate, 100 U/ml penicillin and 100 μg/ml streptomycin.

To measure cell proliferation in a concentration of 2×105ml cultured with the test products in medium RPMI 1640 containing 10 μg/ml bovine insulin (Sigma) and 10 μg/ml apotransferrin (Sigma) in flat-bottomed 96-well plates (Falcon, Becton Dickinson, Lincoln Park, NJ). Three wells are prepared for each concentration of the tested products. Incubation was performed at 37°C incubator for cell cultures (atmosphere: 95% air + 5% CO2within 4 days. Then in each culture well add 2 µci titiraupenga thymidine (Amersham, Les Ullis, France). Twenty-four hours later the cells are separated using trypsin-EDTA (ethylenediaminetetraacetate) (Gibco)and harvested on glass fiber filters (Filtermat A, Wallac, Turku, Finland)using scutro the (Pharmacia LKB, Piscataway, NJ). The radioactivity incorporated and connected to the filter, measured in a suitable liquid scintillation counter (Betaplate, Pharmacia LKB).

3 Connection this invention were also subjected to the tests, demonstrating their value in the cardiovascular system.

Antiarrhythmic effects of the compounds according to the invention was tested on reinfusion arrhythmias have shot rats. The experiment was performed on male rats Sprague Dawley with normal blood pressure, weighing from 250 to 300, These animals were taken from the nursery IFFA CREDO. Animals were kept in standard laboratory conditions and fed standard food: AO4 (UAR). Water was given without restrictions. Method of occlusion and reperfusion used in this study corresponds to the methods described by Manning et al. (Circ. Res., 1984, 55, 545-548) and Kane et al. (Br. J. Pharmacol., 1984, 82, 349-357), modified slightly.

Animals were anestesiologi pentobarbital sodium at a dose of 60 mg/kg intraperitoneally, has made him a tracheotomy and was ventolinbuy ambient air (Harward respirator). The catheter (RE) were placed in the jugular vein for intravenous injection of the products tested. Needles for subcutaneous injections were placed on four paws animal to record the electrocardiogram (ECG), usually DII (Gould ES1000 or polygraph Astromed 7400). After performing a thoracotomy on the left anterior descending to the opened artery from the start incorporating a thread for ligature of the artery. The two ends of this yarn was passed through a plastic tube, which was placed on the heart surface directly above the coronary artery. The coronary artery was blocked, tightening the ends of the thread for 5 minutes, and were reinfusion, weakening the delay. The temperature of the animal was monitored and maintained at 37°using homeothermal blankets.

To study the intravenous route, the products were dissolved in a mixture of 75% PEG-400/distilled water and were injected with 5 minutes before the ligature of the artery. The products were injected with in a volume of 0.1 ml/100 g rat. The control group received the solvent. For studies with oral path products suspended in 0.6% methylcellulose and introduced animal, in consciousness, forced feeding for 120 minutes to ligature of the artery. The products were administered in a volume of 1 ml/100 g rat. The control group received the solvent.

The following types of arrhythmias were analyzed ECG (electrocardiography) during reinfused (study lasting 10 minutes) based on Lambevski agreements (Lambeth Conventions (Cardiovasc., Res., 1988, 22,447-355):

ventricular extrasystoles (GEN),

- ventricular tachycardia (VT), where VT is a sequence of at least four GEN,

- ventricular fibrillation (state),

and mortality due to fatal W is luchkovoj fibrillation or cardiac arrest.

These arrhythmias were expressed as the percentage of animals exhibiting this event (frequency).

Animals were divided into groups of 4-10 animals. Each animal received only one dose of the product. As with intravenous and oral administration of these products protect the animal from reinfusion arrhythmias, reducing or eliminating the mortality and the frequency of state. In addition, some products reduce and/or eliminate the frequency of state and GEN, when they are administered intravenously.

The involvement of CYP 2D6 can be demonstrated by the studies of metabolism in vitro microsomal fractions of human liver. The most frequently used concept is the inhibition of the enzyme to its specific inhibitor quinidine, used 20 times the value of its Kiandirepresents the absolute value of the inhibition constants of the active agent relative to the enzyme.

Different models allow us to demonstrate specific metabolic reactions involving CYP 2D6.

- You can use microsomal fractions of human liver which contains all of the liver isoform of human inkubirovanie in the presence of redox cofactor (NADPH) (nicotinamide adenine dinucleotide phosphate) and in the absence or in the presence of quinidine at 20 times the value of its Kiregarding CYP 2D6. The decrease is giving metabolism, observed in the presence of quinidine, can be associated with the inhibition of isoforms of CYP 2D6, thereby ensuring its possible involvement in the studied metabolic pathway(s). You can also use the microsomal fraction obtained from transfected cells that Express only one isoform of cytochrome P-450 person (GENTEST Corp.). You can also use human hepatocytes in primary culture, which is able to carry out metabolic reactions of phase I and II. In this case, the incubation is carried out kinetically within 24 hours in the presence and in the absence of quinidine, which is a powerful and specific inhibitor of CYP 2D6. To refer you to J. Pharm. Exp. Ther., 1996, 277. 321-332.

In particular, the compounds according to the invention was investigated as follows.

- The specified connection incubated with liver microsomal fractions of human and NADPH (redox cofactor), and in the presence or in the absence of quinidine. The degree of inhibition of b observed in the presence of quinidine, reflects the involvement of CYP 2D6 in metabolizing the specified connection. This approach can be used when the utilization on hepatic microsomal fractions has sufficient amplitude (i.e. greater than or equal to 10% of the original substrate).

When metabolizing pointed to by the first connection on the liver microsomes too small to serve to quantify inhibition, or when you need additional verification within 24 hours kinetically perform additional, more in-depth research on human hepatocytes in primary culture. The degree of involvement of CYP 2D6 in total hepatic metabolizing then reveal the reduction of the characteristic clearance specified connection, it is possible observed in the presence of quinidine.

- The results show that the compounds according to the invention have a low degree metabolize and/or a small degree of involvement of CYP 2D6 in the oxidation process.

It was also found that the bioavailability of the compounds according to the invention (in particular, the compounds of example 44) in animals and humans better than bioavailability similar in structure and activity are known (WO 9804251 and example 5 of EP 0376850) connection SR 31747. The exposure of the compound of example 44 and connection SR 31747 was assessed in the control group of mice in the collagen-induced model of arthritis. For the same dose, it was found that exposure of the compound of example 44 10 times higher than the exposure time of known compounds SR 31747. These results indicate the best suction and/or lower degree, b) the claimed compounds.

No signs of toxicity is not observed when using the years of compounds according to the invention in a pharmacologically active doses and their toxicity, thus, compatible with their use as medicinal products.

Compounds of the present invention is particularly useful, and can be usefully applied as medicinal products, in particular, for the treatment of conditions in which it is desirable reduction of immunological activity, as well as conditions associated with inflammatory disorders. As non-limiting examples can be mentioned condition with autoimmune components, such as, for example, rheumatoid arthritis, systemic lupus erythematosus, a condition caused by demyelination, such as multiple sclerosis, Crohn's disease, atopic dermatitis, diabetes, or reaction, transplant rejection, graft-versus-host status of organ transplant, or, alternatively, autoimmune uveitis, uveoretinitis, Behcet's disease, atherosclerosis, asthma, fibrotic disease, idiopathic lung fibrosis, cystic fibrosis, glomerulonephritis, some spondyloarthropathy, rheumatoid spondylitis, osteoarthritis, gout, bone resorption and cartilage, osteoporosis, Paget's disease, septic shock, septicemia, endotoxic shock, respiratory distress syndrome of adults, silicosis, asbestosis, pulmonary sarcoidosis, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease, Bo is esgn Parkinson, disseminated lupus erythematosus, hemodynamic shock, ischemic heart disease (myocardial infarction, myocardial ischemia, coronary artery spasm, angina, heart failure, heart attack), postischemic reinfusion attacks, malaria, mycobacterial infection, meningitis, leprosy, viral infections (human immunodeficiency virus (HIV), cytomegalovirus, herpes virus), AIDS-related opportunistic infections, tuberculosis, psoriasis, atopic dermatitis and contact dermatitis, cachexia and damage associated with radiation.

Compounds according to the invention can also be used in the treatment of any pathological process that causes the proliferation of tumor cells. This proliferation of the cells can be either hormone-sensitive or hormone-insensitive. More specifically, the clinical application for which can be shown the use of these compounds include state resulting from the proliferation of tumor cells, in particular glioblastoma, neuroblastoma, lymphoma, myeloma, melanoma, leukemia, carcinoma of the colon and rectal cancer, epithelial, liver, lung carcinoma, breast carcinoma, ovarian, pancreatic, bladder, or prostate. Thus, the compounds according to the invention with advantage can be used as the e of medicinal products, designed to combat the proliferation of tumor cells, in particular as anticancer agents or anticancer agents.

They can also be used in the cardiovascular field, more specifically for the treatment of disorders of the heart rate.

Compounds according to the invention can also be used in the treatment of any pathological process that causes the proliferation of tumor cells. This proliferation of the cells can be either hormone-sensitive or hormone-insensitive. More specifically, the clinical application for which can be shown the use of these compounds include state resulting from the proliferation of tumor cells, in particular glioblastoma, neuroblastoma, lymphoma, myeloma, melanoma, leukemia, carcinoma of the colon and rectal cancer, epithelial, liver, lung carcinoma, breast carcinoma, ovarian, pancreatic, bladder, or prostate. Thus, the compounds according to the invention with advantage can be used as medicinal products designed to combat the proliferation of tumor cells, in particular as anticancer agents or anticancer agents.

They can also be used in the cardiovascular field, more specifically for the treatment of disorders of the hour is the notes of heartbeats.

Compounds according to the invention can be also very useful due to their neuroprotective activity, and their activity against apoptosis.

The use of compounds according to the invention for the treatment of the above conditions, as well as for preparation of medicinal products intended for treatment of the above conditions is an essential part of this invention.

The object of the present invention, therefore, also are pharmaceutical compositions containing a compound of the invention or its pharmaceutically acceptable salt, MES or hydrate and suitable excipients.

These excipients are chosen according to the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, local, intratracheal, intranasal, transdermal, rectal or intraocular injection of the active principle of formula (I)above, or the possible salt, solvate or hydrate, you can enter animals and humans for the prophylaxis or treatment of the above disorders or conditions in a standard dosage forms, mixed with conventional pharmaceutical carriers. Appropriate standard forms for administration include peroral the s form, such as tablets, gel capsules, powders, granules and oral solutions or suspensions, forms for sublingual, transbukkalno, intratracheal and intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical use the compounds according to the invention can be used in creams, ointments, lotions or eye drops.

To obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary from 0.2 mg to 15 mg per kg of body weight per day.

Each standard dose may contain from 10 mg to 300 mg, preferably from 25 mg to 75 mg, of active ingredients in combination with a pharmaceutical carrier. This standard dose can be administered 1 to 5 times a day, so that put the daily dose ranged from 10 mg to 1500 mg, preferably from 25 mg to 375 mg

In the preparation of solid compositions in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic and the like. Tablets can be coated with sucrose, a derivative of cellulose, or other suitable substances, or, alternatively, they can be processed so as to have a prolonged or delayed activity and that n is discontinuously to release a predetermined amount of the active agent.

Medication in the form of gel capsules is obtained by mixing the active ingredient with the carrier and filling the mixture of soft and hard gel capsules. The drug is in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient together with a sweetener, preferably low-calorie sweetener, methylparaben and propylparaben as an antiseptic, as well as steering of taste and aroma and a suitable dye.

Dispersible in water powders or granules can contain the active ingredient mixed with dispersing agents, wetting agents or suspendresume agents such as polyvinylpyrrolidone, as well as with sweeteners or flavour enhancers and aroma.

For rectal use of suppositories, which are made using a binder, melting at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral administration using aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically acceptable dispersing agents and/or moisturizing agents, for example propylene glycol or butyleneglycol.

The active principle can also be prepared in the form of microcapsules, possibly using one or more chemodrug media or additives, or, alternatively, using a matrix such as a polymer or a cyclodextrin (patch form slow release).

Along with the products of formula (I)above or their pharmaceutically acceptable salts, solvate and hydrate, the compositions of the present invention can contain other active principle, which can be used to treat complications or conditions specified above.

Thus, an object of the present invention are also pharmaceutical compositions containing several active principles in combination, one of which is a compound according to the invention.

Preparation examples and examples below illustrate the invention but do not restrict it. The melting temperature measured by the method

The spectra of nuclear magnetic resonance obtained in dimethyl sulfoxide, if it is not specifically mentioned, at 200 MHz, and chemical shifts are expressed in million-1.

Abbreviations used below:

s=singlet; m=multiplet, d=doublet; t=triplet; q=Quartet.

The phenyl group in the compounds (I) standard numbered as follows:

Preparatory example 1

1-Bromo-4-(1,1-dimethoxymethyl)benzene, Vp connection

(Vp):X=Y=H; Z=Br; P=CH3

The mixture 19,905 g of 1-(4-br is mpanel)ethanone, 101,4 ml of methanol and 0.22 g of hydrate pair-toluensulfonate acid and 19.9 ml of triethylorthoformate stirred for 6 hours at room temperature. The solution is neutralized with 1% solution of potassium hydroxide in methanol and concentrated under reduced pressure. The oil obtained is transferred into petroleum ether, the precipitate is removed by filtration, and the filtrate evaporated under reduced pressure. Connection IVp purified by distillation; yield=96%; boiling point (BP.)=82°With (at a pressure of 0.03 mbar (3 PA)).

Preparatory example 2

4,4-Dimethylcyclohexanone, the connection 3.1

(a) 4,4-Dimethylcyclohex-2-Aenon

1 ml of concentrated sulphuric acid are added at room temperature to 81 ml but-3-EN-2-she and 88 ml of 2-methylpropionamidine in 450 ml of benzene, after which the reaction mixture is refluxed for 13 hours to remove water by azeotropic entrainment. After cooling to room temperature the reaction mixture was washed with saturated aqueous sodium bicarbonate and then with water. The organic phase is dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. After distillation allocate 31.1 g of the expected compound; BP.=82°With (at a pressure of 22 mbar (2200 PA)).

b) 31.1 grams of 4,4-dimethylcyclohex-2-Aenon in 100 ml of pentane hydronaut in an autoclave at a pressure of 5 bar (500 PA) in the presence of 1.6 g of 5% palladium-the-corner. The reaction mixture is filtered and the solvent is evaporated under reduced pressure.

Preparatory example 3

4-Bromo-3,5-dichlorphenol, the connection IXa.1

a) N-(3,5-Dichlorophenyl)ndimethylacetamide

200 ml of pyridine are added dropwise to 100 g of 3,5-dichlorophenylamino in 3000 ml of chloroform, and then add 90 ml of acetic anhydride. The reaction mixture is stirred for 12 hours at room temperature. The solvent is evaporated under reduced pressure and the resulting residue is recrystallized from 1000 ml of ethyl acetate; melting point (TPL)=182°C.

b) N-(4-Bromo-3,5-dichlorophenyl)ndimethylacetamide

21,3 ml of bromine dissolved in 82 ml of acetic acid, add 6 hours to 84,86 g of N-(3,5-dichlorophenyl)ndimethylacetamide and 34 g of sodium acetate in 420 ml of acetic acid. After 12 hours at room temperature the reaction mixture is heated for 5 hours at 50°C. the Solvent is evaporated under reduced pressure. The obtained residue is recrystallized from isopropanol; TPL=224°C.

b) 4-Bromo-3,5-dichlorophenylamino

202 g of N-(4-bromo-3,5-dichlorophenyl)ndimethylacetamide and 220 g of sodium hydroxide (50% aqueous solution) in 670 ml of ethylene glycol is stirred for 5 hours at 120°and then for 12 hours at room temperature. Add 3000 ml of water, the mixture is filtered, the organic phase is dried over magnesium sulfate and the solvent is evaporated PR is the reduced pressure. The obtained residue is recrystallized from cyclohexane; TPL=132°C.

g) 100 g of 4-Bromo-3,5-dichlorophenylamino under stirring at 5°add to a mixture of 125 ml of water and 90 ml of concentrated sulfuric acid. The reaction mixture was added 230 g of crushed ice, and then 29 g of sodium nitrite in 70 ml of water and this reaction mixture is allowed to mix for 15 minutes. The reaction mixture was quickly added to a mixture of 280 ml of concentrated sulfuric acid and 200 ml of water, heated to 160°and this reaction mixture is allowed to mix at 160°C for 1 hour. The reaction mixture is poured on water/crushed ice and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silikagelevye column, elwira a mixture ciclohexane/dichloromethane 4/6 (about./vol.).

1H NMR: 10,5 (s,1H); 7,0 (s,2H).

Preparatory example 4

1-[4-(1-Hydroxy-3,3,5,5-tetramethylsilane)phenyl]Etalon, the connection V'.1

27.5 ml of 1.6 M solution of n-utility in hexane are added dropwise at -78°to a solution of 10 g of 1-bromo-4-(1,1-dimethoxymethyl)benzene (compound Vp) in 100 ml of tetrahydrofuran. The reaction mixture is stirred for 2 hours at this temperature. Within 20 minutes, add the solution 6,92 ml 3,3,5,5-tetramethylcyclopentadiene in 20 ml of tetrahydrofuran, and this reaction mixture is stirred for 1 hour at -78°C. After warming to room temperature, add 140 ml of a saturated aqueous solution of ammonium chloride. After separation the aqueous phase is extracted with diethyl ether, the combined organic phases are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting oil purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 95/5 (about./vol.); yield=88%; TPL=135°C.

The following compounds are obtained in the same way:

1-[4-(Hydroxy-3,3-dimethylcyclohexyl)phenyl]Etalon, the connection V'.2

TPL=99°C.

1-[4-(Hydroxyadamantane-2-yl)phenyl]Etalon, the connection V’.3

1H NMR: 7,9 (d, 2H); and 7.6 (d, 2H); and 4.8 (s, 1H); 2,6-1,4 (m, 18H).

1-[4-(Hydroxy-4,4-dimethylcyclohexyl)phenyl]Etalon, the connection V’.4

TPL=88°C.

Preparatory example 5

1-[4-(3,3,5,5-Tetramethylsilane)phenyl]Etalon, the connection V.1

38,1 ml of chlorotrimethylsilane within 45 minutes added to a solution 40,45 g of 1-[4-(hydroxy-3,3,5,5-tetramethylsilane)phenyl]ethanone (compound V'.1) and 56,21 g of sodium iodide in 230 ml of anhydrous acetonitrile. During the addition the temperature of the support is between 35&x000B0; S and 40°C. After stirring for 2 hours, add 40 ml of acetonitrile and 39.4 ml of acetic acid. Then portions with stirring at room temperature add to 29.4 g of powdered zinc. The mixture is refluxed with vigorous stirring for 4 hours. After cooling to room temperature, the reaction medium is filtered through celite and then washed with saturated aqueous sodium bicarbonate. The organic phase is concentrated under reduced pressure and the resulting oil purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 95/5 (about./about); TPL=54°C.

The following compounds are obtained in the same way:

1-[4-(3,3-Dimethylcyclohexyl)phenyl]Etalon, the connection V.2

1H NMR: 7,8 (d, 2H); to 7.2 (d, 2H); to 2.7 (m, 1H); 2,5 (s, 3H); 1,8-1,1 (m, 8H); 1,0 (s, 3H); 0,9 (s, 3H).

1-(4-Adamantane-2-ylphenyl)Etalon, the connection V.3

TPL=75°C.

Preparatory example 6

1-[4-(4,4-Dimethylcyclohex-1-enyl)phenyl]Etalon, the connection VI.1

a) 1-[4-(1,1-Dimethoxymethyl)phenyl]-4,4-dimethylcyclohexane 328 ml of a 1.6 M solution of utility in cyclohexane is added at -78°to 117 g of 1-bromo-4-(1,1-dimethoxymethyl)benzene in 1100 ml of tetrahydrofuran and the reaction mixture stirred at -78°C for 2 hours. 66 g of 4-dimethylcyclohexane, dissolved in 210 ml of tetrahydrofuran added at the same temperature and the reaction mixture is stirred for 1 hour at -78°C. the Reaction mixture was hydrolized by adding crushed ice. The organic phase is separated after separation of the phases, it is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The compound obtained is recrystallized from 500 ml of n-hexane; TPL=88°C.

b) 99,32 g of 1-[4-(1,1-Dimethoxymethyl)phenyl]-4,4-dimethylcyclohexanone in 300 ml of dichloromethane and 151 g of sodium iodide is added to 600 ml of acetonitrile in an inert atmosphere and the reaction mixture is heated to 30°C. Add 102 ml chlorotrimethylsilane, and then portions at 65°With a mixture of 300 ml of acetonitrile and 47 ml of acetic acid and this reaction mixture is stirred for 12 hours at room temperature. The reaction mixture was filtered and extracted with dichloromethane. The resulting residue is purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 99/1 (about./vol.).

Preparatory example 7

1-[4-(4,4-Dimethylcyclohexyl)phenyl]Etalon, the connection V.4

a) 1-(1,1-Dimethylethyl)-4-(4,4-dimethylcyclohex-1-enyl)benzene

36,13 g of 1-[4-(4,4-dimethylcyclohex-1-enyl)phenyl]ethanone (compound VI.1) in 250 ml of methanol is stirred for 12 hours at room temperature in the presence of 0.5 g of para-toluolsulfonic acid (PTSA) and 13 ml of trimethyl-ortho-formate. The solvent was partially evaporated under reduced pressure. Add 50% solution of potassium hydroxide in methanol and the solvent then evaporated under reduced pressure. The resulting residue is transferred in diisopropyl ether and the solvent is then evaporated under reduced pressure.

b) Obtained in (a) compound in 250 ml of methanol hydronaut in the presence of 3 g of 5% palladium-on-charcoal grill. The reaction mixture is filtered, the solvent is evaporated under reduced pressure and the resulting residue is transferred in dichloromethane. The reaction mixture is stirred for 12 hours in the presence of silicon dioxide and filtered, the solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 99/1 (about./vol.); TPL=60°C.

Preparatory example 8

1-[3-Chloro-4-(3,3,5,5-tetramethylsilane)phenyl]Etalon, the connection V.5

40,25 aluminium chloride are added at 0°in an inert atmosphere to 350 ml of dichloromethane, and then add 5 g of 1-[4-(3,3,5,5-tetramethylsilane)phenyl]ethanone (connection V.1), dissolved in dichloromethane. After stirring for 2 hours at 0°through the reaction mixture bubbled and 17.1 ml of gaseous gas (d=1,565 measured in a liquid state at -78°). After heating to room rate is atory to the reaction mixture is added a mixture of water/ice. The resulting mixture is extracted with dichloromethane, after separation of the phases are separated and the organic phase is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified on silikagelevye column, elwira with a mixture of cyclohexane/dichloromethane 7/3 (about./vol.); yield=74%; TPL=64°C. the Following dichloroethylene also emit chromatography:

1-[3,5-Dichloro-4-(3,3,5,5-tetramethylsilane)phenyl]Etalon, the connection V.6

1H NMR: 7,9 (1H, s); 7,8 (s, 1H); 3.9 to (m, 1H); 2,5 (s, 3H); 2,1 (m, 2H); 1,2 (m, 4H); 1,0 (s, 6H); 0,9 (s, 6H).

1-[3,6-Dichloro-4-(3,3,5,5-tetramethylsilane)phenyl]Etalon, the connection V.7

1H NMR: 7,6 (s, 1H); to 7.2 (s, 1H); 3,3 (m, 1H); 2,6 (s, 3H); 1,5 (m, 2H); 1,2 (m, 4H); 1,1 (s, 6N); 0,9 (s, 6N).

According to the method described for compound V.5, identified the following connections:

1-[3-Chloro-4-(3,3-dimethylcyclohexyl)phenyl]Etalon, the connection V.8

1H NMR: 7,9 (1H, s); 7,8 (d, 1H); to 7.4 (d, 1H); 3,1 (m, 1H); 2,5 (s, 3H); 1,8-1,1 (m, 8H); 0,9 (s, 3H); 0,8 (s, 3H).

1-(3-Chloro-4-tert-butylphenyl)Etalon, the connection V.9

1H NMR: 7,8 (s, 1H), and 7.7 (d, 1H); 7.5 (a d, 1H); 2,5 (s, 3H); 1,4 (s, 9H).

1-(3,5-Dichloro-4-cyclohexylphenol)Etalon, the connection V.10

1-[3-Chloro-(4,4-dimethylcyclohexyl)phenyl]Etalon, the connection V.11

1H NMR: 7,9 (s, 1H); 7,8 (d, 1H); 7.5 (a d, 1H); 2,8 (m, 1H); 2,5 (s, 3H); 1,8-1,1 (m, 8H); of 0.95 (s, 3H); 0,9 (s, 3H).

Preparation example 9

1-[(3-Chloro-4-hydroxy)phenyl]alanon, compound VII.1

(VII.1):X=3-Cl; Y=H

167 g of trichloride aluminum is added in an inert atmosphere to 63.5 ml of 2-chloro-1-methoxybenzene in 500 ml of 1,2-dichloroethane, and then added dropwise 167 g acetylchloride dissolved in 200 ml of 1,2-dichloroethane. The reaction mixture is heated at 45°C for 48 hours. The reaction mixture was poured into a mixture of water/ice and extracted with dichloromethane, the solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 90/10 (vol./vol.). Connection VII.1 recrystallized from cyclohexane; TPL=107°C.

Preparatory example 10

Cyclohexylprop-2-ynylamine, connection (4.1)

20 ml of 80% 3-bromopropene added dropwise to the 30.3 ml cyclohexylethylamine and 29.7 g of potassium carbonate in 300 ml of acetonitrile. The reaction mixture is heated at 50°C for 12 hours and at 80°C for 6 hours. The resulting mixture was filtered and the solvent is evaporated under reduced pressure.

Connection V.1 purified by distillation.

1H NMR: 3,3 (s, 2H); 3,0 (s, 1H); 2,5 (q, 2H); 2,4 (m, 1H); 1,8-1,1 (m, 10H); and 1.0 (t, 3H).

The following connections get in the same way:

Cyclohexylmethyl the ROP-2-ynylamine, connection 4,2

Cyclohexylprop-2-ynylamine, the connection 4,3

Preparatory example 11

Cyclohexylethyl-3-enylamine, connection (4,4)

a) but-3-in(4-were)sulfonate

74,8 g taillored added to 36 ml of pyridine at 80°C. the Reaction mixture is cooled to 15°and then add 25 g of but-3-in-1-ol. The reaction mixture was stirred at room temperature for 12 hours, and then at 15°add 70 ml of water. The resulting mixture was extracted with diethyl ether and the organic phase is then washed with dilute aqueous sulfuric acid solution, and then saturated aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure.

1H NMR: 7,8 (d, 2H); to 7.4 (d, 2H); 4.0 a (t, 2H); and 3.8 (s, 1H); 2,5 (t, 2H)and 2.4 (s, 3H)

b) to 57.9 g of compound obtained in stage (a), and 21.7 g of sodium bicarbonate and 35.7 ml cyclohexylethylamine in 100 ml of dimethylformamide is refluxed for 12 hours. The reaction mixture is poured into water and extracted with diethyl ether. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. After distillation produce the expected amine;

BP.=92-94°With (at a pressure of 13 mbar (1300 PA)).

Preparation example 12

4-Acetyl-2-chlorophenyl-triftorbyenzola is, connection Va.1

(Va.1):X=3-Cl; Y=H; Z=OTf

26,2 ml triplecore anhydride are added dropwise at 0°C to 26.7 g of 1-[(3-chloro-4-hydroxy)phenyl]ethanone (compound 1) in 700 ml of pyridine. The reaction mixture was stirred at 0°within 36 hours, the solvent is evaporated under reduced pressure and the residue is transferred in 0.1 n hydrochloric acid in dichloromethane. After separation of the phases are separated, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 95/5 (about./vol.).

1H NMR: 8,2 (s, 1H); 8.0 a (d, 1H); 7,8 (d, 1H).

The following connections get in the same way:

4-Acetyl-2,6-dichlorophenyl-triftorbyenzola, the connection Va.2

(Va.2): X=3-Cl; Y=6-Cl; Z=OTf

1H NMR: 8,2 (s, 2H); 2,6 (s, 3H).

4-Bromo-2-chlorophenyl-triftorbyenzola, the connection IIIa.1, starting with 4-bromo-2-chlorophenol.

(IIIa.1):X=3-CL; Y=H

1H NMR: 8,1 (s, 1H), and 7.7 (d, 1H); and 7.6 (d, 1H).

Preparation example 13

2-Chloro-4-[3-(cyclohexylethylamine)prop-1-inyl]phenyl-triftorbyenzola, the connection A

2.14 g of cyclohexylprop-2-ynylamine (compound 1) is added in an inert atmosphere to 4 g of 4-bromo-3-chlorophenyl-triftoratsetata (connection IIIa.1), 0.06 g of copper iodide, 10 ml of pyrid is on and 20 ml of triethylamine, then add 0,413 g catalyst - dichlorobis(triphenylphosphine)VI. The reaction mixture is refluxed for 2 hours, and then incubated at room temperature for 12 hours. The resulting mixture was filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silikagelevye column, elwira a mixture of dichloromethane/ethanol gradient from 100/0 to 99/1 (about./vol.). The compound obtained is transferred into dichloromethane and filtered and the solvents evaporated under reduced pressure; yield=76%.

1H NMR: 7,8 (s, 1H); and 7.6 (d, 1H); 7.5 (a d, 1H); 3,6 (s, 2H); 2,6 (q, 2H); 2,4 (m, 1H); 1,9-1,1 (m, 10H); and 0.9 (t,3H).

Preparation example 14

1-[3-Chloro-4-(4-forfinal)phenyl]Etalon, the connection V.12

of 19.7 g of 4-acetyl-2-chlorophenyl-triftoratsetata (connection C), 10 g of 4-ferbinteanu acid, 2 g of tetrakis(triphenylphosphine)palladium, 17.9 g of sodium carbonate in 84,5 ml of water, 591 ml of toluene, 200 ml of ethanol and the 5.51 g of lithium chloride is stirred in an inert atmosphere at 60°C for 8 hours. The reaction mixture is then stirred for 12 hours at room temperature. The resulting mixture was filtered and the solvent is evaporated from the filtrate under reduced pressure. The resulting residue is purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/etelaat is 97/3 (about./vol.); yield=94%.

1H NMR: 8,0 (s, 1H); 7.9 in (d, 1H); 7.5 (a m, 3H); to 7.3 (m, 2H); 2,6 (s, 3H).

Connection with V.13 for V.17 below in table 1, in the same way.

Table 1
ConnectionR11H NMR
V.13of 8.1 (s, 1H); 7.9 in (d, 1H); 7.5 (a m, 2H); to 7.2 (m, 3H); 2,6 (s, 3H)
V.14to 8.0 (s, 1H); 7.9 in (d, 1H); to 7.6 (m, 3H); to 7.3 (m, 1H); 2,6 (s, 3H)
V.15to 8.0 (s, 1H); 7.9 in (d, 1H); and 7.6 (d, 1H); between 7.4 and 7.1 (m, 3H), and 2.6 (s, 3H)
V.16to 8.0 (s, 1H); 7.9 in (d, 1H); 7.5 (a m, 5H); 2,6 (s, 3H)
V.17to 8.0 (s, 1H); 7.9 in (d, 1H); 7.5 (a d, 1H); to 7.4 (m, 2H); 7,0 (m, 2H); and 3.8 (s, 3H); 2,6 (s, 3H)

1-(2,6-Dichlorobiphenyl-4-yl)Etalon, V.18 connection

1H NMR: 8,0 (s, 2H); to 7.4 (m, 3H); to 7.2 (m, 2H); 2,6 (s, 3H).

1-(2,6-Dichloro-4’-forbiden-4-yl)Etalon, the connection V.19

1H NMR: 8,0 (s, 2H); and 7.3 (m, 4H); 2,6 (s, 3H).

Preparation example 15

3-Chloro-3-[3-chloro-4-(3,,5,5-tetramethylsilane)phenyl]-propenal, connection IV.1

3,51 ml oxalicacid added dropwise at a temperature between -5°s and 2°With the solution and 3.72 ml of dimethylformamide and 20 ml of anhydrous dichloromethane and the reaction mixture was then stirred at room temperature for 30 minutes. Then quickly add to 3.92 g of 1-[3-chloro-4-(3,3,5,5-tetramethylsilane)phenyl]ethanone (connection V.6), dissolved in 10 ml of dichloromethane, after which the reaction mixture is stirred at room temperature for 12 hours. The reaction mixture was poured into a mixture of water/ice, and then add 20 ml of water 2.84 M solution ethylate sodium. The resulting mixture was washed with 50 ml of a solution of sodium bicarbonate and 50 ml of water, after separation of the phases are separated, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting oil purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 97/3 (about./vol.).

1H NMR: 10,2 (d, 1H), and 7.7 (s, 1H); 7.5 (a d, 1H); and 7.3 (d, 1H); and 6.6 (d, 1H); 3,4 (m, 1H); 1,5 (m, 2H); 1,3 (m, 4H); 1,1 (s, 6H); 0,9 (s, 6H).

Connection IV.2 on IV.17 below in tables 2 and 3, in the same way.

Table 2
ConnectionR 1XTPL, °, or1H NMR
IV.2Nthe 10.1 (d, 1H); 7,8 (m, 2H); to 7.4 (m, 2H); to 6.9 (m, 1H); 2,9 (m, 1H); 1,4-0,8 (N)
IV.3N146
IV.4N 
IV.5N 
IV.6Cl10,0 (d, 1H); 7,8 (s, 1H), and 7.7 (d, 1H); to 7.4 (d, 1H); 7,0 (d, 1H); 3,1 (m, 1H); 1,8-1,1 (m, 8H); 1,0 (s, 3H); 0,9 (s, 3H)

Continued table 2
7Cl 
IV.8Cl139
9Cl 
IV.10Cl 
IV.11Cl 
IV.12 Cl 
IV.13Clthe 10.1 (d, 1H); 8.0 a (s, 1H); 7.9 in (d, 1H); of 7.6 to 7.3 (m, 3H); and 7.1 (m, 2H); 7,0 (d, 1H); and 3.8 (s, 3H).
IV.14Cl10 (d, 1H); 7,9 (s, 1H); 7,8 (d, 1H); 7.5 (a d, 1H); 7,0 (d, 1H); and 4.8 (m, 1H); 1,7-1,1 (m, 8H); of 0.95 (s, 3H); 0,9 (s, 3H).

Table 3
ConnectionR1YTPL, °, or1H NMR
IV.155-Clthe 10.1 (d, 1H); 8.0 a (s, 1H); 7,9 (s, 1H); and 7.1 (d, 1H); 3.9 to (m, 1H); 2,1 (m, 2H); 1,3 (m, 4H); 1,1 (s, 6H); 0,9 (s, 6H)
IV.166-Cl10,0 (d, 1H); 7,8-of 7.4 (m, 2H); and 6.6 (d, 1H); 3,2 (m, 1H); 1,6-1,2 (m, 6H); 1,0 (s, 6H); 0,9 (s, 6H)
IV.175-Cl108

Preparation example 16

3-Chloro-4-(3,3,5,5-tetramethylsilane)venilation, the connection II.1

to 5.3 g of sodium hydroxide dissolved in 150 ml of water in an inert atmosphere with vigorous stirring. Add 80 ml 1.4-dioxane and this is mesh heated to a temperature of reflux distilled. Quickly add 15 g of 3-chloro-3-[3-chloro-4-(3,3,5,5-tetramethylsilane)phenyl]propenal (compound IV.1), dissolved in 130 ml of 1,4-dioxane and the reaction mixture is support at the temperature of reflux distilled for 1 hour. After cooling to room temperature the reaction mixture was poured into a large volume of dichloromethane. After separation of the phases are separated, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silikagelevye column, elwira cyclohexane; yield=80%.

1H NMR: 7,5 (s, 1H); and 7.3 (m, 2H); 4,2 (s, 1H); 3,2 (m, 1H); 1,4 (m, 2H); 1,2 (m, 4H); 1,0 (s, 6H); 0,9 (s, 6H).

Connection II.2 on II.15 below in tables 4 and 5, in the same way.

Table 4
ConnectionR1XTPL, °C, or1H NMR
II.2Hof 7.3 (d, 2H); to 7.2 (d, 2H); to 4.1 (s, 1H); 2,9 (m, 1H); 1,5-1,1 (m, 6H); 1,0 (s, 6N); 0,9 (s, 6H)
II.3H 
II.4Clof 7.4 (s, 1H); 7,3 (, 1H); to 7.2 (d, 1H); 4.0 a (s, 1H); 3,0 (m, 1H); 1,7-1,0 (m, 8H); 0,9 (s, 3H); 0,8 (s, 3H)
II.5Clto 7.4 (m, 3H); 4,2 (s, 1H); 1,3 (s, 9H)

II.6Clof 7.6 (s, 1H); to 7.4 (m, 6H); 4,3 (s, 1H)
II.7Clto 7.7 (s, 1H); 7.5 (a m, 3H); to 7.3 (m, 3H); 4,3 (s, 1H)
II.8Clto 7.7 (s, 1H); 7.5 (a m, 4H); and 7.3 (m, 1H); 4,3 (s, 1H)
II.9Cl 
II.10Cl78
II.11Clof 7.6 (s, 1H); to 7.4 (d, 1H); and 7.3 (m, 3H); 7,0 (d, 2H); 4,3 (s, 1H); and 3.8 (s, 3H)
II.12Clto 7.5 (s, 1H); to 7.4 (m, 2H); 4,2 (s, 1H); 2,8 (m, 1H); 1,7-1,2 (m, 8H); of 0.95 (s, 3H); 0,9 (s, 3H)

Table 5
ConnectionR1YSo on the., °C, or1H NMR
II.135-Clof 7.6 (s, 1H); 7.5 (a s, 1H); 4,4 (s, 1H); 3.9 to (m, 1H); 2,0 (t, 2H); 1,2 (m, 4H); 1,1 (s, 6H); 0,9 (s, 6H)
II.146-Clof 7.6 (s, 1H); to 7.4 (s, 1H); 4,6 (s, 1H); 3,2 (m, 1H); 1,5-1,1 (m, 6H); 1,0 (s, 6H); 0,9 (s, 6H)
II.155-Clto 7.7 (s, 2H); to 7.4 (m, 3H); to 7.2 (d, 2H); 4.5 m (s, 1H)

Preparation example 17

3,5-Differentvarieties acid, compound 2.1

91,5 ml of tert-utility at -78°added to 20 g of 1-bromo-3,5-diferently in 300 ml of diethyl ether. The reaction mixture is stirred for 1 hour at -78°and then add to 14.2 ml trimethylborane. The reaction mixture is stirred for 1 hour at -78°and then for 12 hours at room temperature. Add 200 ml of 1N. an aqueous solution of hydrochloric acid. The resulting mixture was extracted with diethyl ether, the organic phase is washed with a saturated solution of sodium bicarbonate and dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is transferred in cyclohexane and the precipitate are filtered.

1H NMR: 7,4 (m, 3H); to 7.2 (m, 2H).

Preparation example 18

4-Bromo-3-chloracetophenone, the connection Va.3

(Va.3); X=3-Cl; Y=H; Z=Br

A solution of 100 g of 4-bromoacetophenone in 250 ml of dichloromethane are added dropwise at 0°to 133,34 g of aluminium chloride in 600 ml of dichloromethane. After stirring for 2 hours at 0°With this Wednesday at 0°bubbled With 28,3 ml pre-frozen (-75° (C) chlorine. The reaction mixture was stirred at room temperature for 12 hours, and then hydrolyzing. After separation of the phases are separated, the aqueous phase is extracted with dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The obtained residue is recrystallized from hexane; yield=57%; TPL=80°C.

Preparation example 19

3-Chloro-3-(4-bromo-3-chlorophenyl)propenal, the connection IVa.1

(IVa.1):X=3-Cl; Y=H; Z=Br

15,08 ml oxalicacid added at a temperature between 3°and 6°With vigorous stirring to 16 ml of dimethylformamide in 200 ml of dichloromethane. After heating to room temperature, the mixture is stirred for 30 minutes, then add a solution of 13.4 g of 4-bromo-3-chloracetophenone (connection Va.3) in 40 ml of dichloromethane. The reaction mixture is stirred for 12 hours at room temperature, and then hydrolyzing the addition of a solution of 18.9 g of sodium acetate in 50 ml of water. After stirring for 30 minutes at room temperature, after separation of the phases are separated, the aqueous phase extragere the t dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The obtained residue is recrystallized from cyclohexane; yield=87%; TPL=134°C.

Preparation example 20

[3-(4-Bromo-3-chlorophenyl)prop-2-inyl]cyclohexylethylamine, the connection Ia.2

a) 1-Bromo-2-chloro-4-ethynylbenzene

40 g of sodium hydroxide dissolved in inert atmosphere in 230 ml of water, add 120 ml of 1,4-dioxane and the reaction mixture is heated to 80°C. Type of 17.5 g of 3-chloro-3-(4-bromo-3-chlorophenyl)propenal dissolved in 400 ml of 1,4-dioxane, and the reaction mixture is stirred for 30 minutes at 80°C. the Reaction mixture is allowed to cool to room temperature, and then add 2300 ml of dichloromethane. After separation of the phases are separated and the organic phase is washed with water and dried over magnesium sulfate. Compound, dissolved in a mixture of dichloromethane/1,4-dioxane use in its current form in the next stage.

b)[3-(4-Bromo-3-chlorophenyl)prop-2-inyl]cyclohexylethylamine 36% aqueous formaldehyde solution is added to 10,36 ml ethylcyclohexylamine in 400 ml of 1,2-dimethoxyethane. This solution is added to a solution of the compound, obtained above, in the presence of 0.54 g of chloride dihydrate, copper (II. The reaction mixture is stirred for 4 hours at boiling reverse Kholodilin the com, and then left to stand at room temperature. The resulting mixture was filtered, the solvent is evaporated under reduced pressure and the resulting residue is then purified by chromatography on silikagelevye column, elwira a mixture of dichloromethane/ethanol 99/1 (about./vol.). The compound obtained is transferred into diethyl ether and through it bubbled hydrogen chloride. The precipitate is filtered off and dried to obtain compound in the form of hydrochloride.

1H NMR: 7,7 (d, 1H); and 7.6 (s, 1H); to 7.2 (d, 1H); 3,5 (s, 2H); 2,6 (q, 2H); 2,4 (m, 1H); 1,8-1,1 (m, 10H); and 0.9 (t, 3H).

Preparation example 21

2-Chloro-4-(4,4-dimethylcyclohexyl)phenol, compound IX.1

a) 2-Chloro-4-(1-hydroxy-4,4-dimethylcyclohexyl)phenol

100 ml of a 1.6 M solution of n-utility in hexane added at -78°to of 15.1 g of 4-bromo-2-chlorophenol in 150 ml of tetrahydrofuran and the reaction mixture stirred at -78°C for 1 hour. Added to 10.1 g of 4,4-dimethylcyclohexanone (compound 3.1) and the reaction mixture stirred at -78°C for another 30 minutes and then at room temperature for 12 hours. The reaction mixture was hydrolized 1H. hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The obtained solid is purified by chromatography on silikagelevye column, elwira mix cyclohex the an/ethyl acetate gradient from 98/2 to 90/10 (vol./vol.). Get to 11.8 g of solid substance.

1H NMR: 7,4 (s, 1H); to 7.2 (d, 2H); to 6.9 (d, 2H); 4.5 m (s, 1H); 1,9-1,1 (m, 8H): 0,9 (s, 6H)

b) 50 l 57% aqueous solution iodomethane acid is added to an 11.8 g of 2-chloro-4-(1-hydroxy-4,4-dimethylcyclohexyl)phenol in 200 ml of acetic acid. The reaction mixture is refluxed for 3 hours and the solvent is evaporated under reduced pressure. Add 40% aqueous sodium hydroxide solution, aqueous sodium carbonate solution and then an aqueous solution of sodium hydrosulphate and the resulting mixture extracted with diethyl ether. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The compound obtained purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate 95/5 (about./vol.).

1H NMR: 9,8 (s, 1H); and 7.1 (s, 1H); 7 (d, 1H); to 6.9 (d, 1H); 1,9 (m, 1H); 1,6-1,2 (m, 8H); 0,9 (s, 6H)

Connection 2 on IX.4 obtained in the same way:

4-(Adamantane-2-yl) - for 3,5-dichlorphenol, compound 2, obtained from the compound He and adamantane-2-it

1H NMR: a 10.1 (s, 1H); 6.8 cm (s, 2H); 3,4 (s, 1H); 2,4 (s, 2H); 2,3-1,4 (m, 12H)

4-(Adamantane-2-yl)phenol, compound IX.3

1H NMR: 9,1 (s, 1H); and 7.1 (d, 2H); 6,7 (d, 2H); 2,8 (s, 1H); 2,4 (s, 2H); 1,9-1,4 (m, 12H)

4-(Adamantane-2-yl)-3-chlorophenol, connection IX.4

1H NMR: 9,8 (s, 1H); and 7.1 (s, 1H); 7,0 (d, 1H); to 6.9 (d, 1H); 2,8 (s, 1H); 2,3 (m, 2H); 1,9 (m, 5H); and 1.7 (m, 5H); 1,5 (m, 2H)

Preparatory PR the measures 22

4-(Tetrahydropyran-4-yl)phenol, compound H

a) 4-(3,6-Dihydropyran-4-yl)phenol

A solution of 100 ml of 1.6 m utility in hexane, then to 8.1 g of 4-tetrahydropyranol added at -40°to 12.7 g of 4-bromophenol in 150 ml of tetrahydrofuran. At the same temperature to the reaction mixture was added 100 ml of 1.6 M utility in hexane, then add to 8.1 g of 4-tetrahydropyranol. The reaction mixture was left to mix for 18 hours at room temperature, and then hydrolyzing 1H. the hydrochloric acid. The resulting mixture was repeatedly extracted with diethyl ether, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The obtained solid is purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate gradient from 90/10 to 80/20 (vol./vol.).

1H NMR: 9,4 (s, 1H); to 7.2 (d, 1H); 6,7 (d, 1H); 6,0 (t, 1H); to 4.1 (d, 2H); 3,7 (t, 2H); 2,4 (t, 2H)

b) 5.5 g of 4-(3,6-dihydropyran-4-yl)phenol hydronaut in the presence of 550 mg of 10% palladium-on-coal in 100 ml of methanol for 3 hours. The mixture is filtered and the solvent then evaporated under reduced pressure.

1H NMR: 9,1 (s, 1H); 7 (d, 2H); and 6.6 (d, 2H); 3.9 to (m, 2H); 3,4 (m, 2H); 2,6 (m, 1H); 1,6 (m, 4H)

The following compound is obtained in the same way:

4-(4,4-Dimethylcyclohexyl)phenol, compound H

1H NMR: 9 (s, 1H); 7 (d, 2H); 6,7 (d, 2H); 2,2 (m, 1H); 1,6-1,2 (m, 8H); 0,9 (s, 6H)

On hotovely example 23

4-(Adamantane-2-yl) - for 3,5-diferena. connection IX.7

a) 2-(2,6-Debtor-4-methoxyphenyl)adamantane-2-ol

Obtained from 4-bromo-3,5-debtorganisation ether in the presence of one equivalent of n-utility according to the method described in preparation example 22 (a).

b) 19 g of the product obtained in the above stage, 200 ml iodomethane acid and 200 ml of acetic acid is stirred overnight at a temperature of reflux distilled. After cooling to room temperature the reaction mixture was poured into a mixture of crushed ice/NaS3. After neutralization with 1N. the sodium hydroxide solution the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvents are then evaporated under reduced pressure.

Preparation example 24

2-Chloro-4-(4,4-dimethylcyclohexyl)phenyl-triftorbyenzola, the connection III.1

8,2 ml triplecore anhydride type 5°to 9.7 g of 2-chloro-4-(4,4-dimethylcyclohexyl)phenol (compound IX. 1) in 60 ml of pyridine and the reaction mixture is allowed to stand at 0°C for 30 minutes and then stirred at room temperature for 12 hours. The reaction mixture was hydrolized and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is transferred in Tolu is l and the solvent then evaporated under reduced pressure. The resulting residue is purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate gradient from 100/0 to 99/1 (about./vol.). Receive 15 g connection.

1H NMR: 7,7 (s, 1H); 7.5 (a d, 1H); to 7.4 (d, 1H); 2,5 (m, 1H); 1,6-1,2 (m, 8H); to 0.92 (s, 3H); 0,86 (s, 3H).

Connection III.2 on 7 obtained in the same way:

4-(Adamantane-2-yl) - for 3,5-dichlorophenyl-triftorbyenzola, the connection III.2

1H NMR: 7,7 (d, 1H); and 7.6 (d, 1H); 3,6 (m, 1H); 3,0-1,0 (m, 14H)

4-(Adamantane-2-yl)phenyl-triftorbyenzola, the connection III.3

1H NMR: 7,5 (d, 2H); to 7.4 (d, 2H); 3,0 (s, 1H); 2,4 (s, 2H); 1,9 (m, 5H); 1,8-1,5 (m, 7H)

4-(Adamantane-2-yl)-3-chlorophenyl-triftorbyenzola, the connection III.4

1H NMR: about 7.6 to 7.4 (m, 3H); 3,0 (s, 1H); 2,4 (m, 2H); 1,9 (m, 5H); 1,8-1,4 (m, 7H)

4-(Adamantane-1-yl)phenyl-triftorbyenzola, the connection III.5

1H NMR: 7,5 (d, 2H); and 7.3 (d, 2H); 2,1 (m, 3H); 1.8 m (m, 6H); and 1.7 (m, 6H)

4-(Tetrahydropyran-4-yl)phenyl-triftorbyenzola, the connection III.6

1H NMR: 7,4 (s, 4H); 3.9 to (m, 2H); 3,4 (m, 2H); 2,8 (m, 1H); to 1.7 (m, 4H)

4-(4,4-Dimethylcyclohexyl)phenyl-triftorbyenzola, the connection 7

1H NMR: between 7.4 and 7.3 (m, 4H); 2,6 (m, 1H); 1,6-1,2 (m, 8H); 0,93 (s, 3H); from 0.90 (s, 3H)

Compounds of the examples presented below, except where mentioned specifically, are compounds of formula (I), where:

Example 1

[3-(4-Adamantane-2-ylphenyl)prop-2-inyl]cyclohexylethyl the amine hydrochloride

8.6 ml of 36% formaldehyde is added to 11,2 ml cyclohexylethylamine in 100 ml of 1,2-dimethoxyethane and stirring is continued at room temperature for 2 hours. This solution is added to a mixture of 16 g of 2-(4-ethylphenyl)adamantane (compound II.3) and of 0.58 g of chloride dihydrate, copper (II 400 ml of 1,2-dimethoxyethane. The reaction mixture is refluxed for 2 hours and the solvent then evaporated under reduced pressure. The compound obtained is transferred into diethyl ether, and through him bubbled hydrogen chloride, and the precipitate is filtered off and dried; TPL=124°C (HCl·0.5 H2O).

The compounds of examples 2 through 12 below, in the same way.

Example 2

{3-[4-(3,3,5,5-Tetramethylsilane)phenyl]prop-2-inyl}-cyclohexylethylamine hydrochloride

TPL=150°C (Hcl·0,1 H2O).

Table 6
ExampleR1so pl., °With (salt, hydrate)
399

HCl
4137

HCl
5156

HCl

0.1 g2O
6148

HCl

0,2 N2O

7130

HCl

0,2 N2About
8of 0.96 (t, 3H); to 1.2-1.8 (m, 11H); 2,6 (q, 2H); 3,6 (s, 1H); and 7.1 to 7.4 (m, 5H); and 7.6 (s, 1H)
9172

HCl
1050 (viscous)

HCl

0,7 N2O
11(a)

HCl

(a)1H NMR: 7,4 (m, 2H); and 7.3 (d, 1H); 3.6 (s, 2H); 3,4 (m, 1H); 2,8 (m, 1H); 2,6 (q, 2H); 1,3-0,9 (m, 27H)

Example 12

[3-(2,6-Dichlorobiphenyl-4-yl)prop-2-inyl]cyclohexylethylamine hydrochloride

TPL=205°C (HCl).

Example 13

The connection is identical to the compound of example 7, but obtained by other methods.

3-(2-Chloro-3’-forbiden-4-yl)prop-2-inyl]cyclohexylethylamine hydrochloride

3.4 g of 2-chloro-4-[3-(cyclohexylethylamine)prop-1-inyl]phenyl-triftoratsetata (connection A), 1,23 g 3-f is urbansurvival acid, 2.2 g of sodium carbonate 10.4 ml of water, of 0.68 g of lithium chloride, 75 ml of toluene, 25 ml of ethanol and 0.7 g of tetrakis(triphenylphosphine)palladium stirred in an inert atmosphere while boiling under reflux for 4 hours. The resulting mixture was filtered, the solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on silikagelevye column, elwira a mixture of dichloromethane/ethanol 99/1 (about./vol.). The compounds obtained is transferred into diethyl ether and through it bubbled hydrogen chloride. The resulting mixture was filtered and the solvent is evaporated under reduced pressure; TPL=130°C(Hcl·0,2 H2O).

The compounds of examples 14 and 15 below, in the same way:

Table 7
ExampleR1TPL, °With (salt, hydrate)
14155

HCl
15139

HCl

0,3 H2O

Example 16

[3-(4-Adamantane-2-yl-3-chlorophenyl)prop-2-inyl]cyclohexyl-ethylamine hydrochloride

a) 2-{2-chloro-4-[3-(temporarilly)prop-inyl]phenyl}-adamantane-2-ol

[3-(4-Bromo-3-chlorophenyl)propen-2-inyl]cyclohexylethylamine hydrochloride is treated with 1 N. the sodium hydroxide solution in ether with obtaining grounds. 30,5 ml of 15% solution of n-utility in hexane at -75°add to 17,5 g of [3-(4-bromo-3-chlorophenyl)-propene-2-inyl]cyclohexylethylamine in 200 ml of diethyl ether and stirring is continued at -75°C for 1 hour and 30 minutes. Further, when -75°add 7.51 g of adamantane-2-it in 100 ml of diethyl ether and the reaction mixture is then stirred for 2 hours at -75°C.

The reaction mixture was left to warm to room temperature and stirring is continued for 1 hour. The reaction mixture was hydrolized and extracted with diethyl ether, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silikagelevye column, elwira a mixture of dichloromethane/ethanol gradient from 100/0 to 99/1 (about./vol.). The compound obtained is used directly in the next stage.

b) 9,78 g of sodium iodide is added to 11,12 g of the above compound in 50 ml of acetonitrile and 25 ml of dichloromethane, and then add 6,63 ml of chlorotrimethylsilane. The reaction mixture was stirred at 30°C for 2 hours followed by the addition of 25 ml of acetonitrile, 5,12 g of zinc powder and 2,99 ml of acetic acid. React the mixture was heated at 80° C for 3 hours, allow to cool to room temperature, filtered, washed with diethyl ether and extracted with dichloromethane and the solvent then evaporated under reduced pressure. The resulting residue is purified by chromatography on silikagelevye column, elwira a mixture of toluene/ethanol 97/3 (about./vol.), and then with a mixture of cyclohexane/ethyl acetate 92,5/7,5 (about./vol.). The compound obtained is transferred into diethyl ether. Hydrochloride get barbotine through him, hydrogen chloride, and the precipitate is filtered off and dried; TPL=110°C (Hcl·0,3H2O).

Example 17

{3-[4-(4,4-Dimethylcyclohexyl)-2-chlorophenyl]prop-2-inyl}-cyclohexylethylamine hydrochloride

1.42 g of dichlorobis(triphenylphosphine)palladium is added in an inert atmosphere to 8,03 g tikaexception-2-ynylamine (compound 4.1), 15 g of [4-(4,4-dimethylcyclohexyl)-2-chlorophenyl]triftoratsetata (compound 1), 0,19 g of copper iodide, 3.4 g of lithium chloride in 200 ml of triethylamine and 100 ml of pyridine. The reaction mixture is refluxed for 12 hours. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on silikagelevye column, elwira with a mixture of cyclohexane/ethyl acetate gradient from 95/5 to 90/10 (vol./vol.). The resulting residue is transferred in diethyl ether. Hydrochloride Department shall have the filter and then through it bubbled hydrogen chloride. The obtained residue is recrystallized from ethyl acetate.

1H NMR: 11 (s, 11N); and 7.6 to 7.4 (m, 2H); and 7.3 (d, 1H); 4,3 (s, 2H); 3,2 (m, 2H); 1,5 (m, 1H); 2,2-1,1 (m, 22H); 0,9 (d, 6H)

The compounds of examples 18 to 28 below, get in the same way:

Example 18

[4-(4-Adamantane-2-yl-2-chlorophenyl)but-3-inyl]cyclohexylethylamine hydrochloride

1H NMR: 7,5 (d, 1H); to 7.4 (s, 1H); and 7.3 (d, 1H); 3,4-3,2 (m, 4H); 3,1 (m, 2H); 3,0 (s, 1H); 2,4 (s, 2H); 2,0-2,1 (m, 26H).

Table 8
ExampleR1XYTPL, °C, or1H NMR (salt, hydrate)
193-Cl5-Clto 7.5 (d, 1H); to 7.2 (d, 1H); 4,3 (s, 2H); 3,3 (m, 3H); 2,6-1,1 (m, 28H) HCl

20HH186

HCl

0,8 H2O
21HH134
22HH152

HCl
23 3-Cl6-Cl196

HCl
243-F5-F132

HCl
253-Cl5-Cl210

HCl
(a)obtained according to the same scheme of the synthesis, the compound of example 17 using 4-bromo-3-methoxyphenol as the original substance (J. Am. Chem. Soc. 1926,48, 3129).

Table 9
ExampleXYSol1H NMR
26NNHClto 10.3 (s, 1H); to 7.4 (m, 4H); 4,3 (s, 2H); and 3.8 (m, 1H); 2,4 (s, 2H); 2.1 to 1,1 (m, N)
272-CLNHClof 10.4 (s, 1H); and 7.6 (d, 1H); 7.5 (a s, 1H); to 7.4 (d, 1H); 4,4 (s, 2H); and 3.8 (m, 1H); 3,4 (m, 1H); 2,9 (s, 1H); 2,4 (s, 2H); 2,1-1,2 (m, 28H)
283-CLCLHClto 10.3 (s, 1H); 7,6 (s, 2H); 4,3 (s, 2H); 3,5-1,0 (m, 32H)

Example 29

{(Z)-3-[3-Chloro-4-(3,3,5,5-tetramethylsilane)phenyl]propen-2-yl}cyclohexylethyl is on hydrochloride

3 g of compound of example 3 in 50 ml of petroleum ether hydronaut in an inert atmosphere at atmospheric pressure in the presence of 3 ml of cyclohexene and 0.3 g of palladium on calcium carbonate, poisoned 3.5% lead (Lindlar catalyst). The reaction mixture was filtered through celite, the solvent is evaporated and the resulting residue purified by chromatography on silikagelevye column, elwira a mixture of dichloromethane/ethanol 95/5 (about./vol.). The obtained oily residue is transferred in diethyl ether and through it bubbled hydrogen chloride. The precipitate is filtered off and dried under reduced pressure. The compound of example 29 emit exit 83%; TPL=158°C(Hcl·0.1 g2O).

The compounds of examples 30 through 54 below, get in the same way:

Table 10
ExampleR1TPL, °With (salt, hydrate)
30170

HCl
31182

HCl
32138

HCl

0,3 H2O
33 152
34162

HCl

Table 11
ExampleR1XYTPL, °With (salt, hydrate)
353-CLN155

HCl
363-CLN114

HCl

0.5 H2O
373-ClN144

HCl

0,3 H2O
383-CLN105

HCl

1,1 N2O
393-ClN108

HCl

0.6 N2O
403-ClN138

HCl

41 3-ClN160

HCl
423-ClN70

HCl

0,7 H2O
433-ClN102

HCl

0,4 H2O
44(a)3-Cl5-Cl188

HCl
45(b)3-ClN161

HCl
462-ClN195

HCl

(a)fumarate received, starting with the Foundation, as follows:

1 g of the base are dissolved in 50 ml of isopropanol. 0.26 g of fumaric acid dissolved in 50°With 100 ml of isopropanol. The solution containing starting material, poured into a warm solution of fumaric acid. The reaction mixture is stirred for 15 minutes at room temperature and the solvent then evaporated under reduced pressure. The resulting crystals are washed with ethyl ether and then recrystallized from acetonitrile; TPL=158° (fumarate). Maleate receive the same is the procedure: TPL=166° (Maleate).

(b)fumarate obtained from the corresponding base; TPL=104° (fumarate).

Table 12
ExampleXYNR2TPL, °With (salt, hydrate)
47NN1-CH(CH3)2(a) HCl
483-ClN1-CH(CH3)2HCl

0,75 H2O
493-Cl5-Cl1-CH(CH3)2226

HCl
502-ClN1-CH(CH3)2162

HCI; H2O
51(b)3-Cl5-Cl1-CH3204

HCl
523-Cl5-Cl2-CH2CH390

HCI; 0,2

H2O
(a) mass spectrometry, electrospray ionization ES+: 392,4 (MN+); 251,3 and 135,3

(b) obtained by the same procedure of synthesis, as the compound of example 44 using connection 4.2V as the starting material.

Example 53

[(Z)-3-(2,6-Dichlorobiphenyl-4-yl)propen-2-yl]cyclohexylethylamine hydrochloride

TPL=120°C (HCl).

Example 54

[(Z)-4-(4-Adamantane-2-yl-3-chlorophenyl)but-3-inyl]cyclohexyl-ethylamine hydrochloride

TPL=178°C (HCl).

Compounds in table 13, below, obtained according to the same scheme of the synthesis, the compound of example 44:

Table 13
ExampleXYR1R2so pl., °With (salt, hydrate)
553-F5-F-C2H5182

HCl

56(and)3-och3N-C2H5Resin

NOSE(O)CF3
573-Cl5-Cl-C2H5210

Cl

0,2 N2About
583-Cl6-Cl-C2H5165

HCl
593-Cl-N-C2H5140

HCl
60(b)2-Cl6-Cl-C2H5174

HCl
61-N-N-C2H5142

HCl
622-Cl-N-C2H5208

HCl
633-Cl5-Cl-N152

HCl
(a)using 4-bromo-3-methoxyphenol as the original substance (J. Am. Chem. Soc. 1926, 48, 3129)

(b)using 4-bromo-2,6-dichlorophenol as the original substance (J. Am. Chem. Soc. 1933, 55, 2125-2126).

Example 64

{(E)-3-[3-Chloro-4-(3,3,5,5-tetramethylsilane)phenyl]propen-2-yl}cyclohexylethylamine hydrochloride

24.3 ml 1M solution diisobutylaluminum hydride (DIBALH) in toluene are added dropwise in an inert atmosphere to a solution of 4 g of compound of example 4 in 40 ml of toluene. The reaction mixture was stirred at 40°C for 1 hour and then poured into a mixture of water/ice and add the sodium hydroxide to until the pH reaches 7. The resulting mixture is extracted with dichloromethane, after separation of the phases are separated, the organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is transferred in diethyl ether and through it bubbled hydrogen chloride. The precipitate is filtered off and dried: TPL=169°C (HCl·0,2 H2O).

Compounds of examples 65 to 67, below, obtained by the method described for example 64.

Example 65

{(E)-3-[4-(3,3,5,5-tetramethylsilane)phenyl]propen-2-yl}cyclohexylethylamine hydrochloride

TPL=200°C (HCl).

Example 66

{(E)-3-[4-(2-Substituted)phenyl]propen-2-yl}cyclohexylethylamine hydrochloride

TPL=200°C (Hcl)

Example 67

{(E)-3-[4-(2-Substituted)for 3,5-dichlorophenyl]propen-2-yl}cyclohexylethylamine hydrochloride

TPL=224°C (Hcl)

Example 68

{3-[3-Chloro-4-(3,3,5,5-tetramethylsilane)phenyl]propyl}-cyclohexylethylamine Hydra is chloride

4 g of the compound of example 3 hydronaut in the presence of 0.4 g of 10% palladium-on-coal and 50 ml of ethanol. The reaction mixture is filtered, the filtrate evaporated under reduced pressure and the resulting residue purified on silikagelevye column, elwira a mixture of toluene/ethanol 97/3 (about./vol.). The obtained oily residue is transferred in diethyl ether and through it bubbled hydrogen chloride. The precipitate is filtered off and dried; TPL=154°C (HCl).

Compounds of examples 69 to 78 below, get in the same way.

Table 14
ExampleR1XTPL; °With (salt, hydrate)
69H170

HCl

0,2 N2O
70H182

HCl

0.6 N2O
71Cl129

HCl
72Cl184

HCl
73 Cl102

HCl

1,2 H2O
74Cl104

HCl



75
Cl88

HCl

0,7 N2O
76H228

HCl

Example 77

[3-(2,6-Dichlorophenyl-4-yl)propyl]cyclohexylethylamine hydrochloride

(I): R1=; X=3-Cl; Y=6-CL; A=-CH2-CH2

TPL=128°C(Hcl)

Example 78

{3-[4-(2-Substituted)for 3,5-dichlorophenyl]propyl}cyclohexylethylamine hydrochloride

(I): R1=; X=3-Cl; Y=5-Cl; A=-CH2-CH2-

TPL F=220°C (HCl)

The example of the pharmaceutical composition

tr>
TabletQuantity (mg/tablet)
Ingredients 
The connection according to the invention50,0
Mannitol223,75
The sodium crosscarmelose6,0
Maize starch15,0
The hypromellose2,25
Magnesium stearate3,0

The ingredients are thoroughly mixed and tablets compressed on a tablet machine.

1. Derivatives of benzene of the formula

where

A represents a group selected from the following:- ≡C-, -CH=CH-; -CH2-CH2-;

n is 1 or 2;

X represents a hydrogen atom, chlorine or fluorine or a methyl or methoxy group;

Y represents a hydrogen atom or chlorine atom or fluorine;

R1represents tsiklogeksilnogo group, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group; phenyl group monosubstituted or disubstituted by fluorine atom or chlorine or a methoxy group; cycloheptanol, tert-boutelou, Dicyclopentadiene, 4-tetrahydropyranyl or 1 - or 2-adamantanol or adamantane-2-Aulnay group; or R1represents a phenyl group, and in this case X and Y both represent chlorine atom;

R2represents a hydrogen atom or (C1-C4)alkyl group;

R3is a (C5-C7)cycloalkyl;

and salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

2. Made in the benzene derivative according to claim 1, where

A represents a group selected from the following: -C≡C-, -CH=CH-; -CH2-CH2-;

n is 1 or 2;

X represents a hydrogen atom, chlorine or fluorine or a methyl or methoxy group;

Y represents a hydrogen atom or chlorine atom or fluorine;

R1represents tsiklogeksilnogo group, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group;

phenyl group monosubstituted or disubstituted by fluorine atom or chlorine or a methoxy group; cycloheptanol, tert-boutelou, Dicyclopentadiene, 4-tetrahydropyranyl or 1 - or 2-adamantanol group; or R1represents a phenyl group, and in this case X and Y both represent chlorine atom;

R2is a (C1-C4)alkyl;

R3is a (C5-C7)cycloalkyl;

and salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

3. Derivatives of benzene according to claim 1 or 2 formula

where

A represents a group selected from the following:- ≡C-, -CH=CH-; -CH2-CH2-;

X represents a hydrogen atom or chlorine;

Y not only is em a hydrogen atom or a chlorine atom;

R1represents cyclohexyl, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group; a phenyl group substituted by a chlorine atom, a methoxy group or one or two fluorine atoms; tert-boutelou or 1 - or 2-adamantanol group; or R1represents a phenyl group, and in this case X and Y both represent chlorine atom;

R2is a (C2-C3)alkyl;

and salts of these compounds formed by joining pharmaceutically acceptable acids, as well as their solvate and hydrate.

4. Compounds according to any one of claims 1 to 3, where a represents a group-CH=CH - (Z) configuration.

5. Compounds according to any one of claims 1 to 4, where X represents a chlorine atom, a Y is a hydrogen atom or chlorine.

6. Compounds according to any one of claims 1 to 5, where R1represents 3,3,5,5-tetramethylcyclopentadienyl or 3.3-dimethylcyclohexyl or 4,4-dimethylcyclohexyl group, phenyl group monosubstituted or disubstituted by fluorine atom, or substituted in position 4 by a chlorine atom; or 1 - or 2-adamantanol group.

7. Compounds according to claim 1, chosen from:

[(Z)-3-(4-adamantane-2-yl-3-chlorophenyl)propen-2-yl]cyclohexylethylamine;

[(Z)-3-(4-adamantane-2-ylphenyl)propen-2-yl]cyclohexylethylamine;

{(Z)-3-[4-(4,4-dimethyl logical)-2-chlorophenyl]propen-2-yl}cyclohexylethylamine;

[(Z)-3-(4-adamantane-2-yl-3,5-dichlorophenyl)propen-2-yl]cyclohexylethylamine;

[(Z)-3-(4-adamantane-2-yl-3,5-dichlorophenyl)propen-2-yl]cyclohexyl(2-methylethyl)amine;

and also their salts, formed by joining pharmaceutically acceptable acids, or their solvate and hydrate.

8. [(Z)-3-(4-Adamantane-2-yl-3,5-dichlorophenyl)propen-2-yl]-cyclohexylethylamine, as well as its salts, formed by joining pharmaceutically acceptable acids, their solvate and hydrate according to claim 7.

9. A method of obtaining a compound according to claim 1, where a represents a group-C≡ -, wherein, if n=1, conduct the reaction manniche between the derivative of phenylacetylene formula

where R1X and Y are as defined for (I), formaldehyde and an amine (1) HNR2R3and R2and R3are as defined for (I).

10. A method of obtaining a compound according to claim 1, where a represents a group-C≡ -, wherein conducting the Suzuki reaction mix between a compound of formula

where X, Y, n, R2and R3are as defined for (I), a, Z represents bromine, iodine or triftormetilfosfinov group (OTf), and boron derivative (2) of the formula R1-B(OR)2where R represents an atom bodoro is a or an alkyl or aryl group, in the presence of a base and a metal catalyst.

11. A method of obtaining a compound according to claim 1, where a represents a group-C≡ -, wherein, when R1represents tsiklogeksilnogo group, monosubstituted, disubstituted, tizamidine or Tetra-substituted methyl group; cycloheptyl, 4-tetrahydropyranyloxy or adamantly group, conduct the reaction mix between the compound (Ia), where Z represents an iodine atom or bromine, and the ketone (3)corresponding to R1presentedin the presence of a base to obtain the intermediate compounds of formula

where X, Y, n, R2and R3are as defined for (I); and the specified connection (I') then restore in selective conditions.

12. A method of obtaining a compound according to claim 1, where a represents a group-C≡ -, wherein conducting the reaction mix between the amine of the formula

where n, R2and R3are as defined for (I)and the compound of the formula

where R1X and Y are as defined for (I), a, Z represents a bromine atom or iodine or triftormetilfullerenov group (trif is at, or OTf).

13. A method of obtaining a compound according to claim 1, where a represents a group-CH=CH-, wherein conducting the hydrogenation, with hydrogen at the time of selection, or in the presence of cyclohexene, the compounds of formula (I), where a is an acetylene group-C≡C-, with the receipt of the ethylene compounds (I) in the form of a mixture of Z and E isomers, or that the hydrogenation is carried out in the presence of a metal catalyst on the carrier with the receipt of the ethylene compounds (I) in Z form, or, alternatively, compound (I), where But is an acetylene group-C≡ -, is subjected to the interaction with the metal hydride to obtain the ethylene compounds (I) in the E form.

14. A method of obtaining a compound according to claim 1, where a represents a group-CH2-CH2-, wherein conducting the hydrogenation of the compound (I), where a represents a group-CH=CH - or-C≡With-.

15. The pharmaceutical composition capable of interacting with receptors of the Sigma-2, containing as active principle a compound according to any one of claims 1 to 8.

16. The compound according to any one of claims 1 to 8 for preparing a medicinal product intended for the treatment of conditions in which it is desirable reduction of immunological activity, in particular autoimmune conditions such as rheumatoid arthritis.

17. The compound according to any one of p is.1-8 for the preparation of a medicinal product, designed to combat the proliferation of tumor cells.

18. The compound according to any one of claims 1 to 8 for preparing a medicinal product intended for treating disorders of the heart rate.



 

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22 cl, 2 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: medicine, genetic engineering.

SUBSTANCE: invention relates to applying genetic engineering approaches for treatment of autoimmune diseases, in particular, for treatment of cerebrospinal sclerosis. This is achieved by incorporation of one or some recombinant genes encoding autoantigens that represent a target for autoimmune response. In particular, invention claims a method for designation of gene encoding encephalitogenous epitope of proteolipid protein and expression of gene product in vivo by using the recombinant retroviral vector. Expression and secretion of encephalitogenous epitope improves histopathological and clinical indices in experimental autoimmune encephalomyelitis in mice that is used as a model of cerebrospinal sclerosis. The advantage of invention involves the development of a method for recovery the tolerance in treatment of cerebrospinal sclerosis being without suppression of immune system.

EFFECT: improved and valuable method for treatment.

6 cl, 13 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: a patient with systemic lupus erythematosus (SLE) should be prescribed to apply efficient quantity of pharmaceutically active form of dehydroepiandrosterone (DHEA) and then, after prescription it is necessary to detect the values for disease activity and total symptoms of the process that characterizes SLE-patient's state, such as: index of SLE activity (IASLE), degree of SLE activity (DSLE), patient's visual analog scale (VAS) and coefficient of Krupp's severity degree (CSDK) to determine the difference between these above-mentioned values obtained before treatment and those taken during therapy, moreover, the decrease of three out of these four values or either the decrease of stabilization or the increase being not higher than by 5% in the fourth value shows that patients reacts to the intake of DHEA.

EFFECT: higher efficiency of therapy.

13 cl, 1 dwg, 8 tbl

FIELD: animal science.

SUBSTANCE: on should apply a 3-fold selenopyran injection of prolonged form containing 300 mg active substance at the age of 6, 12 and 15 mo and per 500 IU vitamin E, 400000 IU vitamin D and 2000000 IU vitamin A/animal, perorally at the same period of time. The innovation enables to increase the values of growth and inspecific resistance.

EFFECT: higher efficiency.

1 ex, 2 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):

or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.

EFFECT: valuable medicinal properties of compounds and composition.

9 cl, 2 sch, 2 tbl, 29 ex

FIELD: medicine, phytotherapy, pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing agent eliciting immunocorrecting and anti-inflammatory activity. Method for preparing the phytopreparation eliciting immunocorrecting and anti-inflammatory activity involves milling common horse radish fresh roots, extraction of raw by maceration method in the definite ratio of ratio raw : extractant for definite time at room temperature, at periodic stirring, clarification of extract under definite conditions and filtration. Method provides preparing the phytopreparation from common horse radish roots for carrying out pharmacotherapy of immune deficient states and inflammatory diseases.

EFFECT: improved preparing method, valuable medicinal properties of preparation.

4 tbl, 3 ex

FIELD: medicine, immunology.

SUBSTANCE: invention is designated for treatment and prophylaxis of diseases associated with the immune system insufficiency in chronic relapsing inflammatory diseases, in cases of insufficient effectiveness of antibacterial and anti-inflammatory therapy. Agent eliciting the immunostimulating effect comprises dropwort (Filipendula ulmaria L.) dried, milled, above-ground part, dropwort (Filipendula ulmaria L. Maxim.) dry an aqueous or dry alcoholic extract prepared in the definite ratio of raw : extractant.

EFFECT: valuable medicinal properties of agent.

4 cl, 4 tbl, 4 ex

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