Hydroxymethyl cyclohexylamines. RU patent 2514192.

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), having affinity to the µ-opioid receptor and the to the ORL1 receptor, a medicinal agent containing said compounds and use thereof to obtain a medicinal agent for treating pain and other diseases. In general formula (1), Y₁, Y₁', Y₂, Y₂', Y₃, Y₃', Y₄ and Y₄' denote -H; R₁ and R₂ independently denote -CH₃; R₃ denotes R₀, where R₀ denotes C_1-8-alkyl; aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR₀, where R₀ denotes -C_1-3-alkyl; unsubstituted heteroaryl, selected from a 5-member heteroaryl with one S atom as a heteroatom; R₄ denotes R₀, where R₀ denotes aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR₀, where R₀ denotes -C_1-3-alkyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, mono-substituted with -S(O)₂-phenyl; unsubstituted -dihydroisoindolyl or unsubstituted -indolyl; or R₄ denotes -OR₀ or -SR₀, where R₀ denotes a cycloaliphatic group selected from -C_5-6-cycloalkyl; aryl, selected from unsubstituted phenyl; C_1-2-alkylaryl, where aryl denotes phenyl, which is unsubstituted or mono-substituted with -OR₀, where R₀ denotes -C_1-3-alkyl; and R₅ denotes -H or -CH₃.

EFFECT: obtaining a medicinal agent for treating pain and other diseases.

7 cl, 3 tbl, 22 ex

The present invention relates to gidroksietiltselljuloza that have affinity for mu-opioid receptor and to ORL1-receptor, for the way they are received, to medicines that contain these compounds, and the use of these compounds for obtaining of medicinal the funds.

Cyclohexane derivatives, which have an affinity for mu-opioid receptor and receptor ORL1 known from the prior art. In this regard, in full, you can make a link, for example, WO 2002/090317, WO 2002/90330, WO 2003/008370, WO 2003/008731, WO 2003/080557, WO 2004/043899, WO 2004/043900, WO 2004/043902, WO 2004/043909, WO 2004/043949, WO 2004/043967, WO 2005/063769, WO 2005/066183, WO 2005/110970, WO 2005/110971, WO 2005/110973, WO 2005/110974, WO 2005/110975, WO 2005/110976, WO 2005/110977, WO 2006/018184 WO 2006/108565, WO 2007/079927, WO 2007/079928, WO 2007/079930, WO 2007/079931, WO 2007/124903, WO 2008/009415 and WO 2008/009416.

However, the known connections in some respect are not satisfactory. Thus, known connections sometimes they do not always optimal affinity for receptor ORL1. In General, you can assume that with the increasing affinity connection to the receptor ORL1 reduced the required dose to cause similar pharmacological effect. Below is a necessary dose, the less is the possibility of unwanted side effects.

In addition known connection suitable analyses linking sometimes demonstrate some affinity to hERG-ion channel, to calcium ion channel L-type (sites linking fenilalkilamina, benzodiazepine, digidropiridina), respectively for sodium channel in VTH-analysis (batrachotoxin), each case can be explained as symptoms of cardiovascular side effects. Further, many of them known compounds have very little soluble in water media, which, in particular, can have a negative effect on the bioavailability. In addition, is often insufficient chemical stability of known compounds. Thus, sometimes the connection does not show enough pH stability, resistance to UV, respectively resistance to oxidation, which, in particular, can affect stability during storage, and also on oral bioavailability. Next, known connections partially have adverse PK/PD (pharmacokinetics/pharmacodynamics) profile, which can be manifested, for example, the length of time steps.

Also requires improvements metabolic stability of known compounds. Improved metabolic stability may indicate an increased bioavailability. Weak or absent interaction with molecules that transmit involved in the admission and selection of drugs, should be regarded as indicating improved bioavailability and, in any case, minor drug interactions.

Then how can more minor must be interaction with enzymes involved in the breakdown and excretion of drugs, such as test results are equally indicate that, in any case, we should expect insignificant or even absent drug interactions the funds.

There is a need for the other compounds that bind to the receptor ORL1. Connections must be possible, at least, comparable, mainly higher affinity for receptor ORL1. Additional linking to other receptors (e.g., mu-opioid receptor Delta-opioid receptor), respectively additional antagonistic effect on other receptors (for example, BIR-receptor) may lead to additional benefits.

In addition, whenever possible, the connection must be comparable, but mainly best solubility in water environments.

The basis of the invention lies with the task to provide connections that are suitable for pharmaceutical purposes, and have the advantages compared with the level connection of equipment.

This problem can be solved thanks to the object of the claims. Suddenly it was discovered that can be obtained substituted derivatives of cyclohexane, which have an affinity for mu-opioid receptor and receptor ORL1.

Connection refers to compounds of General formula (1),

in which

Y 1 , Y 1 ', Y 2 , Y 2 ', Y 3 , Y 3 ', Y 4 and Y 4 ' every time independently apart selected from the group consisting of the-H, -F, Cl, Br, I, CN, NO 2 , -SNO, -R, 0 , -C(=O)R 0 , -C(=O)H, -C(=O)-HE-C(=O)OR 0 , -C(=O)NH 2 , -C(=O)other 0-C(=O)N(R 0 ) 2 , -IT, -OR, 0 , -OS(=O)H, -OC(=O)R 0 , -OC(=O)OR 0 , -OC(=O)other 0 , -OC(=O)N(R 0 ) 2 , -SH-SR 0 , -S(=O) 1-2 R 0 , -S(=O) 1-2 OH, -S(=O) 1-2'oro, -S(=O) 1-2 NH 2 , -S(=O) 1-2 other 0 or-S(=O) 1-2 N(R 0 ) 2 , -NH 2 , -other 0 , N(R 0 ) 2 , N + (R, 0 ) 3 , -N + (R 0 ) 2 O - , -NHC(=O)R 0 , -NHC(=O)OR 0 , -NHC(=O)NH 2 , -NHC(=O)other 0 , -NHC(=O)N(R 0 ) 2 ; mostly every time independently from each other selected from the group, consisting of the-S, -F, -Cl CN and C 1-8-Halifat; or Y-1 and Y 1 ', or Y 2 and Y 2 ', or Y 3 and Y 3 ', or Y 4 and Y 4 ' together mean =O;

R 0 every time independent means-C 1-8-Halifat-3-12-cycloolefin, -aryl-heteroaryl-1-8-Halifat-3-12-cycloolefin, -C 1-8-Halifat-aryl-C 1-8-Halifat-heteroaryl-3-8-cycloolefin-1-8-Halifat-3-8-cycloolefin-aryl or-3-8-cycloolefin-heteroaryl;

R 1 and R 2 are independent from each other mean-N or-C 1-8-Halifat, and R 1 and R 2 are mostly not both mean ' N; or R 1 and R 2 together form a ring and means -(CH 2 ) 2 to 4;

R 3 means-R 0 ;

R 4 means-S, -F, Cl, Br, -I, -R, 0 , -C(=O)H, -C(=O)R 0 , -C(=O)OR 0 , CN, -C(=O)NH 2 , -C(=O)other 0-C(=O)N(R 0 ) 2 , -IT, -OR, 0 , -OC(=O)H, -OC(=O)R 0 , -OC(=O)OR 0 , -OC(=O)OTHER 0 , -OC(=O)-N(R 0 ) 2 , -NH 2 , -OTHER 0 , N(R 0 ) 2 , N + (R, 0 ) 3 , -N + (R 0 ) 2 O - , -NHC(=O)R 0 , -NHC(=O)OR 0 , -NHC(=O)other 0 , -NHC(=O)-N(R 0 ) 2 , NO 2 , -SH-SR 0 , -S(=O) 1-2 R o-S(=O) 1-2 OH, -S(=O) OR 1-2 0 , -S(=O) 1-2 NH 2 , -S(=O) 1-2 Other 0 , -S(=O) 1-2 N(R 0 ) 2 , -OS(=O) 1-2 R 0 , -OS(=O) 1-2 OH, -OS(=O) OR 1-2 0 , -OS(=O) 1-2 NH 2 , -OS(=O) 1-2 other 0 or-OS(=O) 1-2 N(R 0 ) 2 ;

R 5 means-H, -R, 0 , -C(=O)H, -C(=O)R 0 , -C(=O)OR 0 , CN, -C(=O)NH 2 , -C(=O)other 0 or

-C(=O)N(R 0 ) 2 ;

"Halifat" every time a branched or unbranched, saturated or monounsaturated or polyunsaturated, unsubstituted or monosubstituted or polytheny, aliphatic hydrocarbon residue;

"cycloolefin" every time is a saturated or monounsaturated or polyunsaturated, unsubstituted or monosubstituted or polytheny, alicyclic monocyclic or multicyclone hydrocarbon residue the number of cyclic carbon atoms of which is primarily in the specified limit (i.e. "With 3-8 -"cycloolefin has mainly 3, 4, 5, 6, 7 or 8 cyclic carbon atoms);

and as for "Halifat" and "cycloolefin", under "monosubstituted or polyamidine" is a one time or multiple substitution of one or more hydrogen atoms, such as single, double, triple or complete replacement, deputies, independently from each other selected from the group consisting of-F, Cl, Br, I, CN, NO 2 , -SNO, =O, -R, 0 , -C(=O)R 0-C(=O)H, -C(=O)HE, -C(=O)OR 0 , -C(=O)NH 2 , -C(=O)OTHER 0-C(=O)N(R 0 ) 2 , -IT, -OR, 0 , -OC(=O)H, -OC(=O)R 0 , -OC(=O)OR 0 , -OC(=O)OTHER 0 , -OC(=O)-N(R 0 ) 2 , -SH-SR 0 , -SO 3 H, -S(=O) 1-2-R 0 , -S(=O) 1-2 NH 2 , -NH 2 , -other 0 , N(R 0 ) 2 , N + (R, 0 ) 3 , -N + (R 0 ) 2 O-, -NHC(=O)R 0 , -NHC(=O)OR 0 , -NHC(=O)NH 2 , -NHC(=O)-other 0 , -NH-C(=O)N(R 0 ) 2 , a-Si(R 0 ) 3 , -PO(OR 0 ) 2 ;

"aryl" every time independently means carbocyclic circular system with at least one aromatic ring, but without heteroatoms in the ring-and aryl remains, if necessary, can be condensed to other rich, (partially) unsaturated or aromatic ring systems, which on its part may have one or more of heterocyclic atoms, each time independently from each other selected from N, O and S, and each aryl the balance can be loose or monosubstituted or polyamidine, and aryl substituents may be the same or different in any and possible provision of aryl;

"heteroaryl" means 5-, 6 - or 7-membered cyclic aromatic balance, which contains a 1, 2, 3, 4 or 5 heteroatoms, and heteroatoms equally or different are nitrogen, oxygen or sulfur, and a heterocycle may be loose or monosubstituted or polyamidine; and in the case of substitution of the heterocycle deputies may be the same or different in any and possible position heteroaryl; and with a heterocycle can also be part of bicyclic or polycyclic systems;

and as for the "aryl and heteroaryl", under "monosubstituted or polyamidine " refers to single or multiple substitution of one or more hydrogen atoms ring system deputies selected from the group consisting of the-F, -Cl, Br, I, CN, NO 2 , -SNO, =O, -R, 0 , -C(=O)R 0-C(=O)H, -C(=O)HE, -C(=O)OR 0 , -C(=O)NH 2 , -C(=O)other 0-C(=O)-N(R 0 ) 2 , -IT, -O(CH 2 ) 1-2 O-, OR 0 , -OS(=O)H, -OC(=O)R 0 , -OC(=O)OR 0 , -OC(=O)other 0 , -OC(=O)N(R 0 ) 2 , -SH-SR 0 , -SO 3 H, -S(=O) 1-2-R 0 , -S(=O) 1-2 NH 2 , -NH 2 , -Other 0 , N(R 0 ) 2 , N + (R, 0 ) 3 , -N + (R 0 ) 2 O-, -NHC(=O)R 0 , -NHC(=O)OR 0 , -NH-C(=O)NH 2 , -NHC(=O)other 0 , -NHC(=O)N(R 0 ) 2 , a-Si(R 0 ) 3 , -PO(OR 0 ) 2 ; and when having available N-ring atoms each time can be oxidized (N-oxide);

in separate stereoisomer or his mixture of free compounds and/or their physiologically compatible salts and/or the solvate.

The synthesis of various residues, such as R 1 and R 2 , as well as the compilation of balances to their substitutes, such as, for example, -OR, 0 , -OC(=O)R 0 , -OC(=O)other 0 , one Deputy, for example, R 0 , for two or multiple residues, for example-OR 0 , -OC(=O)R 0 , -OC(=O)other 0 , within a single connection can have various values.

Connection according to the invention show good binding to the receptor ORL1 and mu-opioid receptor.

In one of the preferred form of communication according to the invention has a ratio ORLI/mu-affinity of at least 0.1. ORL1/mu-ratio is defined as 1/[K i(ORL1) /K i(u) ]. Especially preferably ORLI/mu-ratio is at least 0.2 or at least 0,5, it is preferable, at least, 1.0, or at least a 2.0, even preferable, at least a 3.0 or, at least, 4,0, most preferably at least 5.0 or at least 7.5 and particularly at least 10 or, at least 15. In one of the preferred form of implementation ORL1/mu-ratio is in the range from 0.1 to 30, preferable from 0.1 to 25.

In another preferred form of communication according to the invention has a ratio ORL1/mu-affinity of more than 30, preferably at least 50, even preferable, at least 100, it is most preferable, at least 200 and particularly at least 300.

Connection according to the invention preferably has a K i value in mu-opioid receptors at most 500 nm, preferably at most 100 nm, even preferable 50 nm, most preferably at most 10 nm and especially most of 1.0 nm.

Methods for determination K i-values in mu-opioid receptors known specialist in the art. Preferably definition is as described in connection with examples.

Connection according to the invention preferably has a K i value ORL1-receptor at most 500 nm, preferably at most 100 nm, even preferable 50 nm, most preferably at most 10 nm and especially most of 1.0 nm.

Methods for determination K i-values in ORL1-receptor known specialist in the art. Preferably definition is as described in connection with examples.

Unexpectedly discovered that the connection with affinity to ORL1-receptor and mu-opioid receptors, in which certain by 1/[K i(ORL1) /K i(u) ] ratio ORL1 to mu is in the range from 0.1 to 30, mainly from 0.1 to 25, have pharmacological profile, which has clear advantages compared with other ligand opioid receptor:

1. Connection according to the invention demonstrate efficacy in models of acute pain, which sometimes comparable with common stage-3 opioids. But at the same time they differ clearly improved compatibility in terms of classical mu-opioid.

2. In contrast to the common phase-3 opioids connections according to the invention clearly demonstrate higher efficiency models mononeuropathies pain and polyneuropathies pain, because of the synergy ORL1 - and mu-opioid component.

3. In contrast to the common phase-3 opioids connections according to the invention in neuropathic animals show a significant, preferably full, division antiallergicheskie, respectively antihyperalgesic actions and antinociceptive effect.

4. In contrast to common stage-3 opioids connections according to the invention in animal models for chronic pain (in particular, carrageenan-induced or CFA-induced hyperalgesia, visceral inflammatory pain) show a visible strengthening actions against acute pain.

5. In contrast to the common phase-3 opioids typical of mu-opioid side effects (in particular, respiratory depression caused by opioid hyperalgesia, physical dependence/breaking mental addiction/obsession) in connection according to the invention in therapeutically the effective range of the dose is clearly diminished, respectively largely not observed.

On the basis of reduced mu-opioid side effects with one hand and increased efficiency in chronic, preferably neuropathic pain from the other side so mixed ORL1/mu-agonists differ clearly growing intervals of security compared to net mu-opioid. It follows clearly increased "therapeutic window" in the treatment of painful conditions, preferably chronic pain, even preferable neuropathic pain.

Preferred Y 1 , Y 1 ', Y 2 , Y 2 ', Y 3 , Y 3 ', Y 4 and Y 4 ', every time independently from each other selected from the group consisting of the-H, -F, Cl, Br, I, -CN-NH 2 , -NH-C 1-6-Halifat, -NH-3-8-cycloolefin, -NH-C 1-6-Halifat-HE-N(1-6-alipac) 2 , -N(3-8 C-cycloolefin) 2 , -N(1-6-Halifat-IT) 2 , NO 2 , -NH-1-6 -Halifat-3-8-cycloolefin, -NH-1-6-Halifat-aryl -,- NH-C 1-6-Halifat-heteroaryl, -NH-aryl -,- NH-heteroaryl, -SH-S-C 1-6-Halifat, -S-3-8-cycloolefin, -S,-1-6-Halifat-3-8-cycloolefin, -S, - C 1-6-Halifat-aryl-S-C 1-6-Halifat-heteroaryl, -S-aryl-S-heteroaryl, -HE-O-C 1-8-Halifat, -O-3-8 -cycloolefin, -About-1-6-Halifat-HE-O-1-6-Halifat-3-8-cycloolefin, -About-1-6-Halifat-aryl-O-C 1-6-Halifat-heteroaryl, -O-aryl-O-heteroaryl, -O-C(=O)1-6-Halifat, -O-C(=O)From 3-8-cycloolefin, -O-C(=O)1-6-Halifat-HE-O-(=O)1-6-Halifat-3-8-cycloolefin, -O-C(=O)C 1-6-Halifat-aryl-O-C(=O)1-6-Halifat-heteroaryl, -O-C(=O)aryl-O-C(=O)heteroaryl, -1-6 C-Halifat-3-8-cycloolefin-1-6-Halifat-3-8-cycloolefin, -1-6 C-Halifat-aryl, -1-6 C-Halifat-heteroaryl, -aryl-heteroaryl-C(=O)1-6-Halifat-C(=O)From 3-8-cycloolefin-C(=O)1-6-Halifat-3-8-cycloolefin-C(=O)1-6 -Halifat-aryl, -C(=O)C 1-6-Halifat-heteroaryl-C(=O)aryl-C(=O)heteroaryl, -CO 2 H, -CO 2-1-6-Halifat, -CO 2-3-8-cycloolefin, -CO 2-1-6-Halifat-3-8-cycloolefin, -CO 2-1-6-Halifat-aryl, -CO 2-1-6-Halifat-heteroaryl, -CO 2-aryl, -2-heteroaryl; or Y-1 and Y 1 ', or Y 2 and Y 2 'or Y 3 and Y 3 ', or Y 4 and Y 4 ' together mean =O. Preferred Y 1 , Y 1 ', Y 2 , Y 2 ', Y 3 , Y 3 ', Y 4 and Y 4 ', every time independently from each other selected from the group consisting of the-H, -F, Cl, Br, I, -CN-NH 2 and HE.

In one of the preferred form of the implementation of one of the remnants Y 1 , Y 1 ', Y 2 , Y 2 ', Y 3 , Y 3 ', Y 4 and Y 4 ' not equal to ' N and rest the remains of the mean-N.

Especially preferably Y 1 , Y 1 ', Y 2 , Y 2 ', Y 3 , Y 3 ', Y 4 and Y 4 ' every time mean-N.

R 0 preferably every time independent means-C 1-8-Halifat-3-12-cycloolefin, -aryl-heteroaryl, -C 1-8-Halifat-3-12-cycloolefin, -C 1-8-Halifat-aryl or-C 1-8-Halifat-heteroaryl. At the same time-With 1-8-Halifat-3-12-cycloolefin, -C 1-8-Halifat-aryl or-C 1-8-Halifat-heteroaryl mean that remains-3-12-cycloolefin, -aryl or heteroaryl every time connected through bivalent bridge-C 1-8-Halifat-. Preferred examples for C 1-8-Halifat-aryl are-CH 2 6 N 5 , CH 2 CH 2 6 N 5-CH=CH-6 N 5 .

R 1 and R 2 are independent from each other mean-N; -1-5-Halifat; or the remains R 1 and R 2 together form a ring and means -(CH 2 ) 2 -, -(CH 2 ) 3 or(CH 2 ) 4 -.

Preferably R 1 and R 2 are independent from each other every time mean-N, CH 3 or CH 2 CH 3 , or R 1 and R 2 together form a ring and mean-CH 2 CH 2 - or CH 2 CH 2 CH 2. Especially the preferred connection, where R 1 and R 2 are independent from each other mean-CH 3 or-N, and R 1 and R 2 are not at the same time mean-N. In one of the preferred form of the implementation of R 1 =R 2 . In another preferred form of the implementation of R 1 warranty R 2 . Preferably R 1 and R 2 together with the nitrogen atom to which they are bound, form one of the following functional groups:

Preferably R 3 means-C 1-8-Halifat-3-8-cycloolefin, -aryl-heteroaryl; or each time through-C 1-3-Halifat-a group linked-aryl-heteroaryl or-3-8-cycloolefin.

Preferably R 3 means-ethyl-propyl, -butyl-pencil, -hexyl-heptyl,

-cyclopentyl, -cyclohexyl, - phenyl, -naphthyl, -anthracene-difenil,

-benzotiofen, - furyl-thienyl, -thiazolyl-benzofuranyl, -benzodioxole,

-indolyl-indanol, -benzodioxane, -pyrrolyl, -pyridyl, pirimidil or

-pyrazinyl, every time unsubstituted or monosubstituted or polytheny; through the rich, single-path -C 1-3-Halifat-a group linked-cyclopentyl,

-cyclohexyl, - phenyl-naphthyl, -anthracene-difenil-benzotiofen, -furyl,

-thienyl, -thiazolyl-benzofuranyl, -benzodioxole, -indolyl-indanol,

-benzodioxane, -pyrrolyl, -pyridyl, pirimidil or pyrazinyl, every time unsubstituted or monosubstituted or polytheny.

Preferable R 3 means-ethyl-propyl, -butyl-pencil, -hexyl-heptyl,

-cyclopentyl, -cyclohexyl, -phenyl-benzyl-naphthyl, -anthracene-difenil,

-benzotiofen, -furyl-thienyl, -thiazolyl-benzofuranyl, - benzodioxole,

-indolyl-indanol, -benzodioxane, -pyrrolyl, -pyridyl, pirimidil or

-pyrazinyl, every time unsubstituted or monosubstituted or polytheny; through the rich, single-path-C 1-3-Halifat group associated With 5-6-cycloolefin, -phenyl-naphthyl, -anthracene-difenil-benzotiofen, -pyridyl,

-furyl-thienyl, -thiazolyl-benzofuranyl, -benzodioxole, -indolyl-indanol,

-benzodioxane, -pyrrolyl, pirimidil, -triazolyl or pyrazinyl, every time unsubstituted or monosubstituted or polytheny.

Preferable R 3 means-propyl, -butyl-pencil, -hexyl, -phenyl-difenil,

-furyl-thienyl, -thiazolyl, -naphthyl, -benzyl-benzofuranyl, -indolyl-indanol,

-benzodioxane, -benzodioxole, -pyridyl, pirimidil-pyrazinyl, -triazolyl or benzotiofen, every time unsubstituted or monosubstituted or polytheny; through the rich, non-branched

-C 1-3-Halifat-a group linked -phenyl, -furyl-thienyl or thiazolyl, every time unsubstituted or monosubstituted or polytheny.

Still preferable R 3 means-propyl, -butyl-pencil, -hexyl, -phenyl,

-phenethyl-difenil, -pyridyl, -triazolyl-benzotiofen or-benzyl, every time substituted or vacant, especially preferably means-propyl,

-3-methoxypropyl, -butyl-pencil, -hexyl, -phenyl, -3-were, -3-torfanil,

-benzo[1,3]-dioxolan-thienyl-benzotiofen, -4-Chlorobenzyl, -benzyl, -3-Chlorobenzyl-4-methylbenzyl, -2-Chlorobenzyl-4-feranil, -3-methylbenzyl, -2-methylbenzyl, -3-feranil, -2-tormentil, -1-methyl-1,2,4-triazole or fenatel.

Highly preferable R 3 means-butyl-ethyl-3-methoxypropyl,

-benzotiofen, -phenyl, -3-were, -3-torfanil, -benzo[1,3]-dioxolan,

-benzyl, -1-methyl-1,2,4-triazole-thienyl or fenatel.

Preferably R 3 means-phenyl-benzyl or fenatel, every time unsubstituted or in the ring monosubstituted or polytheny; -1-5 C - Halifat,

-With 4-6-cycloolefin, -pyridyl-thienyl, -thiazolyl-imidazolyl, -1,2,4-triazole

-benzimidazole, unsubstituted or monosubstituted or polytheny.

In particular, preferably R 3 means-phenyl-benzyl-phenethyl-thienyl,

-pyridyl, -thiazolyl-imidazolyl, -1,2,4-triazolyl, -benzimidazole or-benzyl, unsubstituted or monosubstituted or polytheny through-F, Cl, Br,

-CN-HF 3 , From 2 N 5 , -NH 2 ,NO 2 , -SH-CF 3 , -IT, -DOS 3 , -OC 2 H 5 or-N(CH 3 ) 2 ; -ethyl, n-propyl, -2-propyl-allyl, -n-butyl, -ISO-butyl-Deut.-butyl, tert.-butyl, -n-pentyl,

-out-of pencil, -neo-pencil, -n-hexyl-cyclopentyl or-cyclohexyl, every time unsubstituted or monosubstituted or polytheny through-HE-DOS 3 or OS 2 N 5 , predominantly-thienyl, -pyridyl, -thiazolyl-imidazolyl,

-1,2,4 triazolyl and-benzimidazole are unsubstituted.

In one of the preferred form of the implementation of R 3 means-1-6 C-Halifat, -aryl (preferably-phenyl) or heteroaryl (preferably-thienyl, -thiazolyl or-pyridyl), and-aryl-and-heteroaryl each time are loose or monosubstituted or polyamidine deputies, independently from each other selected from a-F, Cl, Br, I, CH 3 , -DOS 3 and HE.

In particular, preferably R 3 means-phenyl, unsubstituted or monosubstituted through F-Cl-CN-CH 3 ; -thienyl; -ethyl, n-propyl or - n-butyl, unsubstituted or monosubstituted or polytheny by-DOS 3-IT-or-OC 2 H 5 , notably through-DOS 3 .

Preferably R 4 means-S, -F, Cl, Br, I, C 1-8-Halifat-3-12-cycloolefin, -aryl-heteroaryl-1-8-Halifat-3-12-cycloolefin, -C 1-8-Halifat-aryl-C 1-8-Halifat-heteroaryl-C(=O)H, -C(=O)-1-8-Halifat-C(=O)-3-12-cycloolefin-C(=O)-aryl-C(=O)-heteroaryl-C(=O)-1-8-Halifat-3-12-cycloolefin-C(=O)-1-8-Halifat-aryl-C(=O)-1-8-Halifat-heteroaryl-C(=O)O-1-8-Halifat-C(=O)O-3-12-cycloolefin-C(=O)O-aryl-C(=O)O-heteroaryl-C(=O)O-1-8-Halifat-3-12-cycloolefin-C(=O)O-1-8-Halifat-aryl-C(=O)O-1-8-Halifat-heteroaryl, -CN-C(=O)NH 2-C(=O)-NH-1-8-Halifat,

-C(=O)NH-3-12-cycloolefin-C(=O)NH-aryl-C(=O)NH-heteroaryl-C(=O)-NH-1-8-Halifat-3-12-cycloolefin-C(=O)NH-1-8-Halifat-aryl, -C(=O)NH-C 1-8-Halifat-heteroaryl-C(=O)N(1-8-alipac) 2 - (=O)N(3-12-cycloolefin) 2- (=O)N(aryl) 2 ,

-C(=O)N-(heteroaryl) 2- (=O)N(1-8-Halifat-3-12-cycloolefin) 2 , -C(=O)N(C 1-8-Halifat-aryl) 2- (=O)-N(1-8-Halifat-heteroaryl) 2 , -IT, -OC 1-8-Halifat, -OS 3-12-cycloolefin,

-Oeil-Heteroaryl, -OS 1-8-Halifat-3-12-cycloolefin, -OC 1-8-Halifat-aryl, -OC 1-8-Halifat-heteroaryl, -OS(=O)H, -OS(=O)-1-8-Halifat, -OS(=O)-3-12-cycloolefin,

-OS(=O)-aryl, -OS(=O)-heteroaryl, -OS(=O)-1-8-Halifat-3-12-cycloolefin, -OS(=O)-1-8-Halifat-aryl, -OS(=O)-1-8-Halifat-heteroaryl, -OC(=O)O-C 1-8-Halifat, -OS(=O)O-3-12-cycloolefin, -OS(=O)O-aryl, -OS(=O)-O-heteroaryl, -OS(=O)O-1-8-Halifat-3-12-cycloolefin, -OS(=O)O-1-8-Halifat-aryl, -OS(=O)-O-C 1-8-Halifat-heteroaryl,

-OS(=O)NH-1-8-Halifat, -OS(=O)NH-3-12-cycloolefin, -OS(=O)NH-aryl, -OS(=O)NH-heteroaryl, -OS(=O)NH-1-8-Halifat-3-12-cycloolefin, -OC(=O)NH-C 1-8-Halifat-aryl,

-OS(=O)NH-1-8-Halifat-heteroaryl, -OS(=O)N(1-8-alipac) 2 , -OS(=O)N(3-12-cycloolefin) 2 , -OS(=O)N(aryl) 2 , -OS(=O)-N(heteroaryl) 2 , -OC(=O)N(C 1-8-Halifat-3-12-cycloolefin) 2 , -OS(=O)N(1-8-Halifat-aryl) 2 , -OS(=O)N(1-8-Halifat-heteroaryl) 2 , -NH 2 , NO 2 , -NH-C 1-8-Halifat, -NH-3-12-cycloolefin, -NH-aryl -,- NH-heteroaryl, -NH-1-8-Halifat-3-12-cycloolefin, -NH-C 1-8-Halifat-aryl -,- NH-C 1-8-Halifat-heteroaryl, -N(C 1-8-alipac) 2 , -N(3-12-cycloolefin) 2 , -N(aryl) 2 , -N(heteroaryl) 2 , -N(1-8-Halifat-3-12-cycloolefin) 2 , -N( 1-8-Halifat-aryl) 2 , -N(1-8 -Halifat-heteroaryl) 2 , -NHC(=O)-1-8-Halifat, -NHC(=O)-3-12-cycloolefin, -NHC(=O)-aryl, -NHC(=O)-heteroaryl,

-NHC(=O)-1-8-Halifat-3-12-cycloolefin, -MTL(=O)-1-8-Halifat-aryl, -

NHC(=O)-1-8-Halifat-heteroaryl, -NHC(=O)O-1-8-Halifat, -NHC(=O)O-3-12-cycloolefin,

-NHC(=O)O-aryl, -NHC(=O)O-heteroaryl, -NHC(=O)O-1-8-Halifat-3-12-cycloolefin,

-NHC(=O)O-1-8-Halifat-aryl, -NHC(=O)O-1-8-Halifat-heteroaryl, -NHC(=O)NH-1-8-Halifat, -NHC(=O)NH-3-12-cycloolefin, -NHC(=O)NH-aryl,

-NHC(=O)-NH-heteroaryl, -NHC(=O)NH-1-8-Halifat-3-12-cycloolefin, -NHC(=O)NH-1-8 -Halifat-aryl,

-NHC(=O)NH-1-8-Halifat-heteroaryl, -NHC(=O)N(1-8-alipac) 2 ,-NHC(=O)N(3-12-cycloolefin) 2 , -NHC(=O)N(aryl) 2 , -NHC(=O)-N(heteroaryl) 2 , -NHC(=O)N(C 1-8-Halifat-3-12-cycloolefin) 2 , -NHC(=O)N(1-8 -Halifat-aryl) 2 , -NHC(=O)N(C 1-8-Halifat-heteroaryl) 2 , -SH-SC 1-8 -Halifat, -SC 3-12-cycloolefin, -S, -S, -SC 1-8-Halifat-3-12-cycloolefin, -SC 1-8-Halifat-aryl-the SC 1-8-Halifat-heteroaryl, -S(=O) 1-2 With 1-8-Halifat, -S(=O) 1-2 With 3-12-cycloolefin, -S(=O) 1-2 aryl, -S(=O) 1-2 heteroaryl, -S(=O) 1-2 With 1-8-Halifat-3-12-cycloolefin, -S(=O) 1-2 C 1-8 -Halifat-aryl-S(=O) 1-2 With 1-8-Halifat-heteroaryl, -S(=O) 1-2 OH, -S(=O) 1-2 OC 1-8-Halifat, -S(=O) 1-2 OC 3-12-cycloolefin, -S(=O) 1-2 Auril,

-S(=O) 1-2 Heteroaryl, -S(=O) 1-2 OC 1-8-Halifat-3-12-cycloolefin, -S(=O) 1-2 OC 1-8-Halifat-aryl-S(=O) 1-2 OC 1-8-Halifat-heteroaryl, -S(=O) 1-2 NH 2 , -S(=O) 1-2 NHC 1-8-Halifat, -S(=O) 1-2 NHC 3-12-cycloolefin, -S(=O) 1-2 NH, -S(=O) 1-2 NH, -S(O) 1-2 NHC 1-8-Halifat-3-12-cycloolefin, -S(=O) 1-2 NHC 1-8-Halifat-aryl-S(=O) 1-2 NHC 1-8-Halifat-heteroaryl, -S(=O) N 1-2(1-8 -alipac) 2 , -S(=O) N 1-2(3-12-cycloolefin) 2 , -S(=O) N 1-2(aryl) 2 , -S(=O) N 1-2(heteroaryl) 2 , -S(=O) N 1-2(1-8-Halifat-3-12-cycloolefin) 2 , -S(=O) N 1-2(C 1-8-Halifat-aryl)2, - S(=O) N 1-2(1-8-Halifat-heteroaryl) 2 , -OS(=O) 1-2 With 1-8-Halifat, -OS(=O) 1-2 With 3-12-cycloolefin, -OS(=O)1-aryl, -OS(=O) 1-2 heteroaryl, -OS(=O) With 1-2 1-8-Halifat-3-12-cycloolefin, -OS(=O) 1-2 With 1-8-Halifat-aryl, -OS(=O) 1-2 With 1-8-Halifat-heteroaryl, -OS(=O)1-2OH, -OS(=O) 1-2 OC 1-8-Halifat, -OS(=O) 1-2 OC 3-12-cycloolefin, -OS(=O) 1-2 Auril, -OS(=O) 1-2 O heteroaryl, -OS(=O) 1-2 OC 1-8 -Halifat-3-12-cycloolefin, - OS(=O) 1-2 OC 1-8-Halifat-aryl, -OS(=O) 1-2 OC 1-8-Halifat-heteroaryl, -OS(=O) 1-2 NH 2 , -OS(=O) 1-2 NHC 1-8-Halifat, -OS(=O) 1-2 NHC 3-12-cycloolefin, -OS(=O) 1-2 NH, -OS(=O) 1-2 NH,

-OS(=O) 1-2 NHC 1-8-Halifat-3-12-cycloolefin, -OS(=O) 1-2 NHC 1-8-Halifat-aryl,- OS(=O) 1-2 NHC 1-8-Halifat-heteroaryl, -OS(=O) N 1-2(1-8-alipac) 2 ,-OS(=O) N 1-2(3-12-cycloolefin) 2 , -OS(=O) N 1-2(aryl) 2 , -OS(=O) N 1-2(heteroaryl) 2 , -OS(=O) N 1-2(C 1-8-Halifat-3-12-cycloolefin) 2 , -OS(=O) N 1-2(1-8-Halifat-aryl) 2 or-OS(=O) N 1-2(1-8-Halifat-heteroaryl) 2 .

Preferable R 4 is a-C 1-8-Halifat-3-12-cycloolefin, -aryl,

- heteroaryl, -O-C 1-8-Halifat, -About-3-12-cycloolefin, -O-aryl-O-heteroaryl, -NH-C 1-8-Halifat, -NH-3-12-cycloolefin, -NH-aryl -,- NH-heteroaryl, -N(C 1-8-alipac) 2 , -N(3-12-cycloolefin) 2 , -N(aryl) 2 , -N(heteroaryl) 2 , S-1-8-Halifat That-S-3-12-cycloolefin,

-S-aryl or-S-heteroaryl.

Still preferable R 4 means-3-12-cycloolefin, -aryl-heteroaryl, -O-C 1-8-Halifat, -About-3-12-cycloolefin, -O-aryl-O-heteroaryl, -NH-C 1-8-Halifat, -NH-3-12-cycloolefin, -NH-aryl -,- NH-heteroaryl, -N(1-8-alipac) 2 , -N(C 3-12 -cycloolefin) 2 ,

-N(aryl) 2 , -N(heteroaryl) 2 , -S-1-8-Halifat, -S-3-12-cycloolefin or-S-aryl or

-S-heteroaryl.

Especially preferably R 4 means-aryl (mainly phenyl, if necessary, replaced), -O-aryl (mainly-O-phenyl, if necessary, replaced or-heteroaryl (mainly-indolyl or-indanol, whenever you want replaced). In particularly the preferred form of the R 4 means-aryl-heteroaryl-3-12-cycloolefin, -O-aryl,

-C(=O)-1-8-Halifat-C(=O)-3-12-cycloolefin-C(=O)-aryl-C(=O)-heteroaryl-C(=O)-1-8-Halifat-3-12-cycloolefin-C(=O)-1-8-Halifat-aryl-C(O)-1-8-Halifat-heteroaryl-C(=O)O-1-8-Halifat, -C(=O)O-3-12-cycloolefin-C(=O)O-aryl-C(=O)O-heteroaryl-C(=O)O-With 1-8-Halifat-3-12-cycloolefin, -C(=O)O-C 1-8-Halifat-aryl,

-C(=O)O-1-8-Halifat-heteroaryl, -CN-C(=O)NH 2-C(=O)-NH-1-8-Halifat-C(=O)NH-3-12-cycloolefin-C(=O)NH-aryl-C(=O)NH-heteroaryl-C(=O)-NH-C 1-8-Halifat-3-12-cycloolefin-C(=O)NH-1-8-Halifat-aryl-C(=O)NH-1-8 -Halifat-heteroaryl,

-C(=O)N(1-8-alipac) 2- (=O)N(3-12-cycloolefin) 2- (=O)N(aryl) 2 , -C(=O)N-(heteroaryl) 2- (=O)N(1-8-Halifat-3-12-cycloolefin) 2- (=O)N(1-8-Halifat-aryl) 2 or-C(=O)-N(1-8-Halifat-heteroaryl) 2 .

Preferable R 5 selected from the-H, -C 1-8-Halifat, With 3-12 -cycloolefin, -C 1-8-Halifat-3-12-cycloolefin, -C 1-8-Halifat-aryl-C 1-8-Halifat-heteroaryl, -aryl-heteroaryl.

Preferred examples for R 5 warranty-N are shown below:

In one of the preferred form of the implementation of R 5 means.

Especially preferred form the implementation of the compounds according to the invention presented in the table below:

Preferably

Preferable

Even more preferably

-N or-C 1-8-Halifat

-N or-C 1-8-alkyl

-H or-CH 3

Preferably

Preferable

Even more preferably

-H or-C - 1-8-Halifat

-H or-C 1-8-alkyl

-H or-SN 3

-C - 1-8-Halifat; aryl, if necessary, replaced; or-heteroaryl, if necessary, replaced by

-C 1-8-alkyl; phenyl, if necessary, replaced; or-thienyl, if necessary, replaced by

-butyl, -phenyl, methoxy-phenyl or fluorine-phenyl

-aryl-O-aryl-S-aryl-heteroaryl, -O-C 1-8-Halifat-aryl-On-3-12-cycloolefin

-phenyl-O-phenyl-S-phenyl, whenever necessary, replaced; indolyl, if necessary, replaced; isoindole, if necessary, replaced; -O-3-12-cycloalkyl

-phenyl-O-phenyl-S-phenyl, whenever necessary, replaced; indolyl, if necessary, replaced; isoindole, if necessary, replaced; -O-3-12-cycloalkyl

Y 1 , Y 1 ', Y 2 , Y 2 ', Y 3 , Y 3 ', Y, 4 , Y 4 '

To describe hydrocarbon residues, on the one hand, subdivided into aliphatic hydrocarbon residues and, on the other hand, aromatic hydrocarbon residues.

Aliphatic hydrocarbon residues from its part is divided into acyclic aliphatic hydrocarbon residues, on the one hand (="Halifat"), and cyclic aliphatic hydrocarbon residues, i.e. acyclic hydrocarbon residues, on the other hand (="cycloolefin"). Cycloaliphatic can be monocyclic or multicyclone. Alicyclic hydrocarbons residues ("cycloolefin") cover as clean aliphatic carbocyclic and aliphatic compounds, i.e. - unless specifically - "cycloolefin" includes net aliphatic carbocyclic (for example, cyclohexyl), net aliphatic compounds (for example, piperidil or piperazin)and not aromatic, multicyclone, if necessary, mixed systems (for example, declines, decadrononline).

Aromatic hydrocarbons on its part is divided into carbocyclic aromatic hydrocarbons, on the one hand (="aryl"), and heterocyclic aromatic hydrocarbons, on the other hand (="heteroaryl").

Distribution multicyclonic at least partially aromatic systems mainly depends on whether at least one aromatic ring multisiliceous system, at least one heteroatom (usually N, or S) in the ring. If at least one such heteroatom this ring is available, it is preferable he is a "heteroaryl" (even if if necessary in the form of additionally available cycle multisiliceous system has another carbocyclic aromatic or not the aromatic ring with one heteroatom or without it); if no one or several aromatic rings multisiliceous system such heteroatom not present, preferably talking about "arilje" (even if in one, optionally available, not aromatic cycle multisiliceous system has one ring heteroatom).

Within multicyclonic deputies respectively in the distribution preferably given to the following priorities: heteroaryl > aryl > cycloolefin. So the next Deputy mainly understood as "aryl":

For a description of univalent and multivalent, such as ferrous, hydrocarbon residues conceptual not distinguish, i.e. "C 1-3-Halifat" includes, depending on the semantic relationships, such as-C 1-3-alkyl, -C 1-3-alkenyl and-C 1-3-quinil, and, for example, -C 1-3-alkilen -- 1-3-alcanilor - C 1-3-albinele-.

Preferably Halifat each time a branched or unbranched, saturated or monounsaturated or repeatedly unsaturated, unsubstituted or monosubstituted or polytheny aliphatic hydrocarbon residue. Because alipac is monosubstituted or polyamidine, Deputy independently from each other selected from the group consisting of-F, Cl, Br, I, CN, NO 2 , -SNO, =O, -R, 0 , -C(=O)R 0 ,

-C(=O)-HE-C(=O)OR 0 , -C(=O)NH 2 , -C(=O)OTHER 0-C(=O)N(R 0 ) 2 , -OH, -OR, 0 , -OC(=O)H,

-NHC(=O)NH 2 , -NHC(=O)other 0 , -NH-C(=O)N(R 0 ) 2 , a-Si(R 0 ) 3 , -PO(OR 0 ) 2 . Thus, "Halifat" includes acyclic saturated or unsaturated hydrocarbon residues, which may be branched or with direct chain, i.e. alcalali, alkenyl and ucinili. At the same time, alkenyl have at least one C=C double bond and ucinili at least one C=C-a triple bond. Preferred unsubstituted monovalent alipate cover-CH 3 ,

CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 ,

-With(CH 3 ) 3 , CH 2 CH 2 CH 2 CH 2 CH 3 and CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ; and-CH=CH 2-CN SN,

CH 2 CH=CH 2 , CH=SSN 3 , CH 2 With CN CN-CN CLO 3 & CH=SSN=CH 2 .

Preferred unsubstituted bivalent alipate cover-CH 2, CH 2 CH 2, CH 2 CH(CH 3 )-,

CH(CH 3 )CH 2 -, CH 2 CH 2 CH 2, CH(CH 3 )CH 2 CH 2, CH 2 CH(CH 3 )-CH 2, CH 2 CH 2 CH(CH 3 )-,

-CH-(CH 2 CH 3 )CH 2 CH 2 CH 2 CH 2 CH 2; and-CH=CH-, -C CN C-, CH 2 CH=CH-,CH=SSN 2 -, CH 2 With Inputs From and With inputs CLO 2 -. Preferred substituted monovalent alipate cover-CH 2 F-CHF 2 , -CF 3 , CH 2 CF 3 , A-2 CF CF 3 , CH 2 OH-CH 2 CH 2 OH,

CH 2 of SNONCE 3 , CH 2 OCH 3 and CH 2 CH 2 OCH 3 . Preferred substituted bivalent alipate cover-CF 2 -, -2 CF CF 2 -, -CH 2 CHOH-, -CHOHCH 2 and CH 2 of SNONCE 2 -. Especially preferred methyl, ethyl, n-propyl and n-butyl.

Preferably cycloolefin every time is a saturated or monounsaturated or repeatedly unsaturated, unsubstituted or monosubstituted or polytheny, aliphatic (i.e. non-aromatic), mono - or multicyclone hydrocarbon residue. The number of cyclic carbon atoms, is mostly in the specified range (i.e. "With 3-8 -"cycloolefin has mainly 3, 4, 5, 6, 7 or 8 cyclic carbon atoms). In order to describe "With 3-8-cycloolefin" preferably is a cyclic hydrocarbons with 3, 4, 5, 6, 7 or 8 cyclic carbon atoms, saturated or unsaturated, but not aromatic, and if necessary, one or two carbon atoms independently from each other substituted one heteroatom S, N, or Acting As cycloalkyl is monosubstituted or polyamidine, the deputies independently other selected from the group consisting of-F, Cl, Br, I, CN, NO 2 , -SNO,=O, -R, 0 , -C(=O)R 0 , -C(=O)OH, -C(=O)OR 0 , -C(=O)NH 2 , -C(=O)other 0-C(=O)N(R 0 ) 2 , -IT, -OR, 0 , -OC(=O)H, -OC(=O)R 0 , -OC(=O)OR 0 , -OC(=O)other 0 , -OC(=O)-N(R 0 ) 2 , -SH-SR 0 , -SO 3 H, -S(=O) 1-2-R 0 , -S(=O) 1-2 NH 2 , -NH 2 , -other 0 , N(R 0 ) 2 , N + (R, 0 ) 3 ,

-N + (R 0 ) 2 O - , -NHC(=O)R 0 , -NHC(=O)OR 0 , -NHC(=O)NH 2 , -NHC(=O)OTHER 0 , -NH-C(=O)N(R 0 ) 2 ,

-Si(R 0 ) 3 , -PO(OR 0 ) 2 . Mainly With 3-8-cycloolefin selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepten, cicloalchil, cyclopentenyl, cyclohexanol, cycloheptene and cyclooctene and tetrahydropyranyl, dioxanes, DIOXOLANYL, morpholinyl, piperidinyl, piperazinil, pyrazolinone and pyrrolidinyl. If cycloolefin replaced by R 0 and R 0 means aryl or heteroaryl, this aryl respectively heteroaryl Deputy through the connection may be tied to cycloaliphatic, but it can also be tied in two viszeralnah ring atom of cycloaliphatic, i.e. to be fused.

Preferably in connection with the "alfacom", respectively "cycloaliphatic" under "monosubstituted or polyamidine" refers to single or multiple substitution, such as single, double, triple or quadruple the substitution of one or more hydrogen atoms through-F, Cl, Br, I-HE,- OC 1-6-alkyl, -OS(=O)1-6-alkyl, -SH-NH 2 , -NHC 1-6-alkyl, -N(1-6-alkyl) 2- (=O)OS 1-6-alkyl or-C(=O)IT. The preferred connection, and the "Halifat substituted" or "cycloolefin substituted" means Halifat or cycloolefin substituted with-F, Cl, Br, I, CN, CH 3 , C 2 H 5 , -NH 2 , NO 2 , -SH-CF 3 , -IT, -DOS 3 , OS-2 N 5 or-N(CH 3 ) 2 . Especially preferred deputies are a-F, Cl, -IT, -SH-NH 2, and-C(=O)IT.

Under repeatedly replaced the remains should understand these residues, which are or in different or in the same atoms substituted many times, for example twice or three times, for example, three times in the same-the atom, as in the case-CF 3 or-CH 2 CF 3 , or in different places, as in the case-CH(OH)-CH=CH-CHCl 2 . Multiple substitution may occur same or different Deputy. If necessary, one Deputy from its part also may be replaced; thus, Halifat among other also includes-OCH 2 CH 2 O CH 2 CH 2 Oh. Preferably, if Halifat or cycloolefin replaced by a-F, Cl, Br, I, -CN-CH 3-2 N 5 , -NH 2 , NO 2 , -SH-CF 3 , -IT, -DOS 3 , -OS 2 N 5 or-N(CH 3 ) 2 . Highly preferable if Halifat or cycloolefin substituted through-HE-DOS 3 or OS 2 N 5 .

Preferably aryl every time independently means carbocyclic circular system with at least one aromatic ring, but without heteroatoms in the ring-and aryl remains, if necessary, can be condensed with other rich, (partially) unsaturated or aromatic ring systems, which on its part may have one or more of heterocyclic atoms, each time independently from each other selected from N, O and S, and each aryl the balance can be loose or monosubstituted or polyamidine, and aryl substituents may be the same or different in any and possible provision of aryl. Preferred arily represents phenyl, naphthyl, antracene, phenanthrene, Fiorentini, feranil, indanyl and tetralinyl. Especially preferred are phenyl and naphthyl. If aryl is monosubstituted or polyamidine, aryl substituents may be the same or different in any and possible provision of aryl, and independently from each other selected from the group consisting of-F, Cl, Br, I, CN, NO 2 , -SNO, =O, -R, 0 , -C(=O)R 0 , -C(=O)OH, -C(=O)OR 0 , -C(=O)-NH 2 ,

-C(=O)Other 0-C(=O)N(R 0 ) 2 , -OH, -O(CH 2 ) 1-2 O-, OR 0 , -OC(=O)H, -OC(=O)R 0 , -OC(=O)OR 0 ,

-OC(=O)-other 0 , -OC(=O)N(R 0 ) 2 , -SH-SR 0 , -SO 3 H, -S(=O) 1-2-R 0 , -S(=O) 1-2 NH 2 , -NH 2 , -other 0 , N(R 0 ) 2 , N + (R, 0 ) 3 , -N + (R 0 ) 2 O - , -NHC(=O)R 0 , -NHC(=O)OR 0 , -NHC(=O)NH 2 , -NHC(=O)OTHER 0 ,

-NH-C(=O)N(R 0 ) 2 , a-Si(R 0 ) 3 , -PO(OR 0 ) 2 . Preferred replaced by Allami are 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-debtor-phenyl, 2,4-debtor-phenyl, 3,4-debtor-phenyl, 2-chlorophenyl, 3-chloro-phenyl, 4-chlorophenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl and 3,4-dimethyl-phenyl.

Preferably heteroaryl means of 5-, 6 - or 7-membered cyclic aromatic residue that contains 1,2,3,4 or 5 heteroatoms, and heteroatoms equally or differently are nitrogen, oxygen or sulfur, and a heterocycle may be loose or monosubstituted or polyamidine; and in the case of substitution of the heterocycle deputies can be same or different in any and possible position heteroaryl; and with a heterocycle can also be part of bicyclic or polycyclic system. Preferably "heteroaryl" selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, tienil (tofanil), benzothiasol, benzothiadiazole, benzoxazolyl, benzothiazole, benzoxazolyl, benzotriazole, benzodioxole, benzodioxane, phthalazine, pyrazolyl, imidazolyl, thiazolyl, oxazoles, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, piratini, Pirani, indazolin, purinol, indolizines, genolini, sochinyenii, chinazolinei, carbazolyl, phenazine, phenothiazines or oxadiazoles, the connection can be through any and possible ring member heteroaryl balance. If heteroaryl is monosubstituted or polyamidine, heteroaryl deputies may be the same or different and in any and possible position heteroaryl, and independently from each other selected from the group consisting of-F, Cl, Br, I, CN, NO 2 , -SNO, =O, -R, 0 , -C(=O)R 0 , -C(=O)OH, -C(=O)OR 0 , -C(=O)-NH 2 ,

-C(=O)other 0-C(=O)N(R 0 ) 2 , -OH, -O(CH 2 ) 1-2 O-, OR 0 , -OC(=O)H, -OC(=O)R 0 , -OC(=O)OR 0 ,

-OC(=O)other 0 , -OC(=O)-N(R 0 ) 2 , -SH-SR 0 , -SO 3 H, -S(=O) 1-2-R 0 , -S(=O) 1-2 NH 2 , -NH 2 , -other 0 , N(R 0 ) 2 , N + (O) 3 , -N + (R 0 ) 2 O - , -NH-C(=O)R 0 , -NHC(=O)OR 0 , -NHC(=O)NH 2 , -NHC(=O)OTHER 0 ,

-NH-C(=O)N(R 0 ) 2 , a-Si(R 0 ) 3 , -PO(OR 0 ) 2 .

As for the "aryl" or "heteroaryl", under "monosubstituted or polyamidine" understand single or multiple, for example, double, triple, quadruple or quintuple, the substitution of one or more hydrogen atoms in the ring system.

Especially preferred deputies of aryl and heteroaryl every time independently from each other selected from a-F, Cl, Br, I, -CN-SNO, -CO 2 H, -NH 2 , NO 2 ,

-OTHER 0 , N(R 0 ) 2 , N + (O) 3 , -N + (R 0 ) 2 O - , -SH-SR 0 , -IT, -OR, 0 , -C(=O)R 0 , -CO 2 R 0 , -C(=O)NH 2 ,

-C(=O)other 0-C(=O)N(R 0 ) 2 , -S(=O) 1-2 R 0 , -S(=O) 1-2 NH 2 , -SO 3 H, =O or-R 0 . Preferred deputies are a-F, Cl, Br, I, -IT, -OC 1-6-alkyl-O-C(=O)-1-6-alkyl, -SH-NH 2 , -NHC 1-6-alkyl, -N(1-6-alkyl) 2- (=O)OS 1-6-alkyl or-C(=O)IT. The preferred connection, and "aryl substituted" or "heteroaryl substituted" means aryl or heteroaryl, replaced by a-F, Cl, Br, I,

-CN-HF 3 , From 2 N 5 , -NH 2 , NO 2 , -SH-CF 3 , -IT, -DOS 3 , OS-2 N 5 or-N(CH 3 ) 2 . Especially preferred deputies are a-F, Cl, -IT, -SH-NH 2, and-C(=O)IT.

Connection according to the invention can be in the form of separate stereoisomer or its mixture of free compounds and/or their physiologically compatible salts and/or the solvate.

Connection according to the invention, depending on the sample of the Deputy may be chiral or achiral.

In the compounds according to the invention, depending on the substitution of relatively cyclohexane ring we can talk about the isomers, in which a sample of Deputy 1.4-position (1-position: > C(NR 1 R)R 3 ; 4-position: > COHR 5 CH 2 R 4 ) may also be indicated by blue/anti. "Sin/anti-isomers" are a subset of stereoisomers (configuration isomers).

If the connection according to the invention are chiral, then they are mainly in the form of a racemate or enriched in the form enantiomer. In one of the preferred form of implementation is the excess of the enantiomers (her) S-enantiomer of at least 50%of its preferred, at least 75%of it, even preferable, at least 90%of it, it is most preferable, at least 95%and in particular, at least 99%of it. In one other preferred form of the implementation of the excess of the enantiomers (her) R-enantiomer is at least 50%of its preferred, at least 75%of it, even preferable, at least 90%of it, it is most preferable, at least 95%and in particular, at least 99%of it.

Suitable methods of separation of enantiomers well-known specialist in the art. As examples can be called preparative HPLC on chiral stationary phases, and to transfer there diastereomers intermediate products. The transfer in diastereomers intermediate products can occur, for example, as the salt formation using chiral, enantiomerically pure acids. After the separation of the formed thus diastereomers salt then can be translated into a free basis or other salt.

Unless specifically, each reference to the connection according to the invention, includes all isomers (for example, the stereoisomers, diastereoisomers, enantiomers) in any mixing ratio.

Unless specifically, each reference to the connection according to the invention of the available connections (i.e. forms that are not in the form of salt) and all physiologically compatible salt.

To describe physiologically compatible salt compounds of the invention are in the form of salts with anions or acids appropriate connections with inorganic respectively organic acids, which are physiologically compatible - especially in the application of the person and/or mammal.

Examples of physiologically compatible salts certain acids are of salt: hydrochloric acid Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid, some saccharine acid, monomethilaniline acid, 5-oxo-Proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, α leonovoj acid, acetylglycine, acetylsalicylic acid, the hippuric acid and/or aspartic acid. Especially preferred are hydrochloride, citrate and polycitra.

Physiologically compatible salts with cations or grounds are the salt of the corresponding connection - as anion, with at least one, mainly inorganic, cation, which are physiologically compatible - especially in the application of the person and/or mammal. Especially preferred salts of alkaline and alkaline earth metals, and salts of ammonium, but especially salt (mono) or (di) sodium (mono) or (di) of potassium, magnesium or calcium. Further explains preferred in each case the form of the implementation of the compounds according to the invention. Unless specifically, then the all in each case explained earlier definition of deputies and respectively their respective preferred forms of exercise and are therefore not repeated.

Preferable form of implementation of the compounds according to the invention of General formula (1) have General formula(2), (3), (4), (5), (6), (7), (8) or (9):

where, if available,

R A means-S, -F, -Cl-CN-NO 2 or DOS 3 ; and

(heterosexual)aryl means heteroaryl or aryl, every time unsubstituted or monosubstituted or polytheny.

Connection according to the invention defined by the deputies, for example, through R 1 , R 2 and R 3 (Deputy of the 1st generation), who on their part, if necessary, replaced (deputies 2nd generation). Depending on the definition of these deputies deputies from our side can be re-substituted (deputies of the 3rd generation). If, for example, Y 1 =R 0 , and R 0 =-C 1-8-alipac (Deputy of the 1st generation), 1-8 C-Halifat on its part may be replaced, for example, using-OR 0 , and R 0 =-aryl (Deputy 2nd generation). Hence functional group-C 1-8-Halifat-Oeil. Then-aryl its part can be replaced, for example, through-Cl (Deputy of the 3rd generation). Then in General it follows functional group-1-8-Halifat-Oeil-Cl.

However, in one of the preferred form of the exercise of the deputies of the 3rd generation may not be re-substituted, i.e. in this case none of the Deputy of the 4th generation.

In another preferred form of the exercise of the deputies of the 2nd generation may not be re-substituted, i.e. in this case there is not already a Deputy of the 3rd generation. In other words, in the form of the functional group for R 0 R 5 if necessary each time can be replaced, but the respective deputies in this case, on its part may not be re-substituted.

In another preferred form of implementation are already deputies of the 1st generation may not be re-substituted, i.e. there is no Vice-no 2-generation, nor deputies of the 3rd generation. In other words, in the form of the functional group for R 0 R 5 every time can't be replaced,

Highly preferred connection from the group:

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenylethanol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-Phenoxyethanol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(1H-indole-1-yl)ethanol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(isoindol-2-yl)ethanol,

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(4-torfanil)ethanol;

- 1-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)-2-phenylethanol;

- 1-(4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-2-phenylethanol;

- 1-(4-(dimethylamino)-4-(thiophene-2-yl)cyclohexyl)-2-phenylethanol;

- 1-(4-butyl-4-(dimethylamino)cyclohexyl)-2-phenylethanol;

- 1-cyclopentyl-2-(4-(dimethylamino)-4-phenylcyclohexyl)-3-phenylpropane-2-ol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-2-(pyridine-4-yl)ethanol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylthio)ethanol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylsulfonyl)ethanol;

- 2-(cyclohexyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;

- 2-(benzyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-pentoxicated;

- 2-((1H-indol-3-yl)methoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;

- 2-(2-(1H-indol-3-yl)ethoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;

- 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-((2-(trimetilsilil)-1H-indol-3-yl)methoxy)ethanol;

- 1-(2-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)-2-hydroxyethyl)piperidine-2-he;

- 2-(4,4a-dihydro-1H-pyrido[3,4-b]indole-2(3H,N,an)-yl)-1-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)ethanol;

- 1-cynnamoyl-3-(2-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)-2-hydroxyethyl)tetrahydropyrimidine-2(1H)-it;

- 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenylpropane-2-ol;

- 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1,3-diphenylprop-2-ol;

- 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-2-yl)propan-2-ol;

- 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridine-3-yl)propan-2-ol and

- 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridine-4-yl)propan-2-ol

and their physiologically compatible salt and/or solvate. Other preferred compounds are

- 2-(9-(benzolsulfonat)-2,3,4,9-tetrahydro-1H-beta Carolin-2-yl)-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol;

- 2-(2,3-dihydro-1H-isoindole-2-yl)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol;

- 2-cyclohexyloxy-1-(4-dimethylamino-4-thiophene-2-illlogical)ethanol

- 2-(4-dimethylamino-4-phenylcyclohexyl)-1 fenoxi-propan-2-ol; and

- 3-((3S)-3-(4-dimethylamino-4-phenylcyclohexyl)-3-hydroxy-prop-1-inil)-1H-indole-1-carboxylic acid tert-butyl ether

and physiologically compatible salt.

Connection according to the invention affect, for example, on the relevant due to various diseases ORL1-receptor, so they are suitable as pharmaceutical active ingredient in medicine.

Therefore, another object of the invention refers to medicines that contain at least one connection according to the invention, and if necessary, suitable additives and/or auxiliary substances and/or, if required, other active ingredients.

Connection according to the invention have comparable affinity for mu-opioid receptors, respectively ORL1-receptor as compounds that are disclosed as an example of the connections in WO 2004043967. But compared with these compounds they have a higher solubility and therefore particularly suitable for drug development.

The amount of typing patients active substance vary depending on the weight of the patient, the type of application, indications and severity of the disease. Usually apply from 0,00005 up to 50 mg/kg, preferably from 0.001 to 0.5 mg/kg, at least one connection according to the invention.

For all the above forms of medicines according to the invention is especially desirable if the drug along with at least one connection according to the invention, contains one another active substance, in particular opioid, mainly stronger opioid, particularly morphine, or anesthetic, mainly hexobarbital or halothane.

In the preferred form of the medicinal product contained connection according to the invention is in the form of pure diastereoisomer and/or enantiomer.

In particular ORL1-receptor has been identified in pain. Accordingly connections according to the invention may be used for obtaining of medicinal products for the treatment of pain, particularly acute, or chronic neuropathic pain.

Therefore, another object of the invention refers to the application of connections according to the invention to obtain drugs for the treatment of pain, particularly acute, visceral, or chronic neuropathic pain.

Another object of the invention refers to the application of connections according invention to obtain medicines to treat conditions of fear, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, a General cognitive dysfunction, impaired learning and memory (as nootrop), withdrawal symptoms, abuse alcohol and/or drugs, and/or abuse of drugs and/or alcohol, drug, drug addiction, sexual dysfunction, cardiovascular disease, hypotension, hypertension, tinnitus, itching, headache, hearing loss, lack of mobility bowel disorders eating, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, incontinence, respectively, as a muscle relaxant, an anticonvulsant drug or anesthetic respectively for joint admission for treatment with opioid analgesic or pain, diuresis or antinatriuretic, anxiolysis, for modulation of motor activity, to modulate the distribution of neurotransmitters and treatment related neurodegenerative diseases, for treatment of withdrawal symptoms and/or to reduce the drug's potential opioids.

In one of the above applications may be preferable, if applicable, the connection is in the form of pure diastereoisomer and/or enantiomer in the form of a racemate or requiredno or equimolar mixture of diastereoisomers and/or enantiomers.

Another object of the invention refers to the method of treatment, especially when one of the above indications, inhuman mammal or a people or a need treatment pain, especially chronic pain, by introducing a therapeutically effective dose connections according to the invention, or medicinal funds according to the invention.

Another object of the invention refers to the manner of receipt of connections according to the invention, as indicated in the following description and examples. Especially when this is suitable way of receiving a single connection according to the invention, and compounds of General formula 1 can be obtained by joining fit of nucleophiles to fit carbonyl compounds. In the case when R 5 is not equal to N or R 5 or R 4-CH 2 - can be introduced in various sequences (scheme 1):

Ketones II, III respectively can be entered in the intermediate synthesis by attaching suitable carbon nucleophiles to aldehydes VI. Then the resulting alcohol V using well-known specialist in the art methods of oxidation can be translated into ketones II, III respectively. An alternative to this carbonyl compounds of the type amide Winneba (Weinreb) (IV) by substituting carbon nucleophiles can be translated into ketones (figure 2):

Getting amides Weinreb known specialist in the art.

If R 5 is identical to R 4 CH 2-compounds of General formula 1 can also be obtained by attaching at least 2 equivalents suitable carbon nucleophile to the corresponding esters of carboxylic acids or other suitable carbonyl compounds.

If R is equal to 5 " N, that fall intermediate stage V and VI.

An alternative way of obtaining compounds of General formula 1 is the replacement to the opening of a loop with a fit of nucleophiles containing R 4 in end epoxides VII (scheme 3). This benefits can come from protected by education acetal predecessors VIII, preferably ketals. With received by the replacement of disclosure cycle Catala VIII remove protection before receiving IX. In another stage impose suitable protective group to alcohol features, such as other acetal, obtained in compounds of General formula X. Received earlier ketone function well-known specialist in the art of ways transferred to amenasireli XI, who then in accordance with standard methods with carbon nucleophiles transferred to amines type XII. Then by removing acatalog protective groups in alcohol secrete compounds of General formula I.

Especially this method is advantageous for the case, when R 4 connected through heteroatom, i.e. R 4 begins with heteroatoms selected of N, S and O.

End epoxides type VII can be obtained under well-known specialist in the art methods, for example, by attaching Mejidov to fit carbonyl compounds III or, for example, through the epoxidation of relevant olefins XIV (figure 4):

On other details of the synthesis of compounds according to the invention in full may be referred WO 2002/090317, WO 2002/90330, WO 2003/008370, WO 2003/008731, WO 2003/080557, WO 2004/043899, WO 2004/043900, WO 2004/043902, WO 2004/043909, WO 2004/043949, WO 2004/043967, WO 2005/063769, WO 2005/066183, WO 2005/110970, WO 2005/110971, WO 2005/110973, WO 2005/110974, WO 2005/110975, WO 2005/110976, WO 2005/110977, WO 2006/018184, WO 2006/108565, WO 2007/079927, WO 2007/079928, WO 2007/079930, WO 2007/079931, WO 2007/124903, WO 2008/009415 and WO 2008/009416.

Examples

The following examples are for a more detailed explanation of the invention, however, should not be interpreted as limiting it.

The outputs of the obtained compounds are not optimized. All temperatures are not subject to adjustment. Specifying "a simple ether" means diethyl ether, "ITS" ethyl acetate and DCM dichloromethane. Specifying "equivalents" means the equivalent number of substances, "MP." melting point respectively region melting, "Different." decomposition, "KG" room temperature, "abs." absolute (anhydrous), "rat." racemic, "conc." concentrated, "min" minutes, "h" watch, "Dr." days, "vol%volume percentage, "m%" mass percentage and "M" is an indication of the concentration in mol/L.

As a stationary phase for column chromatography used silica gel 60 (0.040-0.063 mm) of the company that is Merck, Darmstadt. Research of thin-layer chromatography was performed using the finished plates WATCH, silica gel 60 F 254, company E. Merck, Darmstadt. The ratio of the components of the mixture of solvents for chromatography research is constantly shown in vol./vol.

1 H-NMR: Varian Mercury 400 BB, 400 MHz or Varian Mercury BB 300, 300 MHz;

13 C NMR: Varian Mercury 400 BB, 100 MHz or Varian Mercury 300 BB, 75 MHz; internal standard: TMS, chemical shifts in chastna million; br: wide signal;

19 F-NMR: Varian Mercury 400 BB, 376.8 MHz;

Internal standard: CFCl 3 ;

LC-MS: Agilent LC-MS 1200 Rapid Resolution with MSD6140;

gradient: time 0 min: 95% water (+1% formic acid)/5% methanol (+1% formic acid) - > time 5.4 min: 0% water/100% methanol (+1% formic acid);

the column temperature: 50 C; the amount of injection; 5 silt; the flow rate of 0.8 ml/min; fragmented voltage: 100 V [POS/neg]; detection: MM-ES+APCI+DAD (254 nm); column: SB-C18, 2.1 mm x 30 mm, 3.5 microns.

Methods №

Duration [min]

The flow rate [ml/min]

Table continued methods LC/MS

Methods №

Gradient

The pace. columns [°]

The wavelength [nm]

UV - scan.

Masses limit

Fragmentation [V]

Example 1:

1-(4-dimethylamino-4-(3-fluoro-phenyl)cyclohexyl)-2-phenyl-ethanol

Stage 1:

4-dimethylamino-4-(3-torfanil)cyclopentanecarboxaldehyde

Suspension chloride methoxymethylacetanilide (2.18 g 6.36 mmol) in tetrahydrofuran, anhydrous (5 ml) and anhydrous N,N-dimethylformamide (5 ml) under argon mixed with 60% of the variance of the hydride sodium mineral oil (254 mg, 6.36 mmol). Mix 2 h stirred at room temperature. Then within 30 minutes was added dropwise solution 4-dimethylamino-4-(3-torfanil)cyclohexanone (1.0 g, 4.24 mmol) in tetrahydrofuran, anhydrous (5 ml) and anhydrous N,N-dimethylformamide (5 ml) and during the night was stirred at room temperature. Then when cooled ice was added dropwise 2 M hydrochloric acid (25 ml) and 5 h stirred at room temperature. After that the mixture were extracted with ethyl acetate (5 x 20 ml) and diethyl ether (3 x 20 ml). The aqueous phase with 4 M sodium hydroxide solution was set up to pH 11 and were extracted with ethyl acetate (4 x 20 ml). The combined organic extracts from alkaline solution, dried sodium sulfate and concentrated in vacuum. Output: 1.49 g (>100%), brown oil

1 H NMR (DMSO-d6): there is a mixture of diastereoisomers. You can identify all distinctive signals.

Stage 2:

1-(4-dimethylamino-4-(3-fluoro-phenyl)cyclohexyl)-2-phenyl-ethanol

1 H NMR (DMSO-d6): 0.56-1.10 (m, 2H); 1.20-1.60 (m, 4H); 1.74 (brd, 1H, J=13.0 Hz); 1.91 (s, 6H); 2.46 (m, 1H imposed from DMSO-signal); 2.56-2.70 (m, 3H); 3.27 (m, 1H); 4.23 (d, 1H, J=6.0 Hz); 7.02-7.25 (m, 8H); 7.41 (dd, 1H, J=7.9 and 14.5 Hz).

13 C NMR (DMSO-d6): 23.2; 25.8; 32.4; 32.7; 37.9; 40.7; 42.8; 61.0; 74.5; 112.8 (d, J=21 Hz); 114.6 (d, J=21 Hz); 123.9; 125.3; 127.8; 129.2; 140.2; 162.2 (d, J=242 Hz).

Example 2:

1-(4-butyl-4-dimethylaminoethoxy)-2-phenylethanol

By replacing the 4-dimethylamino-4-(3-torfanil)cyclohexanone 4-butyl-4-dimetilaminoetanol in example 1, stage 1 and subsequent similar interaction in stage 2 were received example 2:

1 H-NMR (CDCl 3 ): 0.90 (3H, t, J=7.1 Hz); 1.14-1.49 (N, m); 1.56-1.82 (6H, m); 2.28 (6H, s); 2.63 (1H, dd, J=8.9, 13.6 Hz); 2.88 (1H, dd, J=4.7, 13.6 Hz); 3.66 (1H, m); 7.16-7.22 (3H, m); 7.27-7.29 (2H, m). OH-proton was impossible to identify.

13 C NMR (CDCl 3 ): 14.0; 21.8; 23.5; 23.7 (2C); 26.7 (2C); 31.1; 31.7; 31.8; 37.0 (2C); 41.0; 42.3; 76.4; 126.0; 128.3 (2C); 129.3 (2C); 139.3. LC-MS method (8): [M+H] + : m/z=304.3, R, t =2.4 min

Example 3 Example 4

(1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylethanol hydrochloride, non-polar diastereoisomer)

(1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylethanol, polar diastereoisomer)

By replacing the 4-dimethylamino-4-(3-torfanil)cyclopentanecarboxaldehyde 4-dimethylamino-4-phenylcyclohexylamine in example 1, stage 2 received similar to the examples 3 and 4:

1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylethanol (non-polar

diastereoisomer)

Output: 170 mg (16%), yellowish oil

1 H NMR (CDCl 3 ): 1.35-1.90 m, 6H); 2.05 (s, 6H); 2.58-2.72 (m, MN); 2.94-3.06 (m, 1H); 3.42-3.50 (m, 1H); 3.72 (s br, 1H); 4.20-4.23 (m, 1H); 7.02-7.95 (m, 10H).

1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylethanol (polar diastereoisomer)

Output: 142 mg (14%), white solid

Melting point: 161-166°

1 H NMR (CDCl 3 ): 0.99-1.16 (m 2N); 1.46-1.78 (m, 5H); 1.89-1.98 (m, 1H); 2.07 (s, 6H); 2.49 (dd, 1H, J=9.5 and 13.5 Hz); 2.76 (brd, 1H, J=12.5 Hz); 2.80 (dd, 1H, J=13.7, 3.2 Hz); 3.40 (ddd, 1H, J=9.6, 6.4, 3.3 Hz); 7.11-7.43 (m, 10H).

Stage 2 (1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylethanol hydrochloride, non-polar diastereoisomer)

1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylethanol (non-polar diastereoisomer, 140 mg, 0.41 mmol) was mixed with 7.5 M solution of hydrogen chloride in diethyl ether (25 ml). Pop-up solution decantation, sludge is dried in a vacuum desiccator over potassium hydroxide.

Output: 80 m g (51%), white solid

Melting point: 235°

1 H NMR (AMCO-d6): 1.29-1.44 (m, 3H); 1.76-1.90 m, 1H); 1.92-2.04 (m, 1H); 2.24-2.38 (m 2N); 2.43 (t, 6H, J=5.3 Hz); 2.45-2.58 (m, 3H, partly imposed from DMSO-signal); 2.90 (dd, 1H, J=3.1 and 13.7 Hz); 3.80-3.88 (m, 1H); 4.44 (s, 1H); 7.13-7.19 (m, 1H); 7.22-7.29 (m, 4H); 7.47-7.55 (m, 3H); 7.66-7.71 (m 2N); 10.48 (s,1H).

Example 5

1-(4-dimethylamino-4-phenylcyclohexyl)-2-(4-torfanil)ethanol

By replacing chloride benslimane chloride 4-tormentillae in example 3 and 4 stage 1 similarly received example 5:

Melting point: 75? C

1 H NMR(CDCl 3 ): 1.32-1.56 (m, MN); 1.58-1.84 (m, 6H); 2.05 (s, 6H); 2.66 (m, 2H); 2.95 (d, 1H, J=13.8 Hz); 3.68 (m, 1H); 6.96-7.05 (m, 2H); 7.18-7.40 (m, 7H). 13C NMR (DMSO-d6): 23.1; 24.1; 32.8; 32.9; 37.8; 40.3; 42.5; 58.9; 76.4; 115.2 (d, J=21 Hz); 126.4; 126.6; 127.2; 130.7 (d, J=8 Hz); 134.9; 139.6; 161.6 (d, J=244 Hz). LC-MS method (8): [M+H]+: m/z=342.3, Rt=2.4 min

Example 6 Example 7

1-(4-dimethylamino-4-thiophene-2-Il-cyclohexyl)-2-phenylethanol (polar the diastereoisomer) and 1-(4-dimethylamino-4-thiophene-2-Il-cyclohexyl)-2-phenylethanol (non-polar diastereoisomer)

Stage 1:

1-(1,4-dioxaspiro[4.5]Oct-8-yl)-2-phenylethanol

The solution 1,4-dioxaspiro[4,5]Dean-8-carbaldehyde (4.42 g, 25.9 mmol) in tetrahydrofuran, anhydrous (30 ml) at cooling by ice dropwise mixed with 2 M solution of chloride benslimane (26 ml, 52 mmol). The mixture was stirred for overnight at room temperature. Then when the ice cooling the reaction mixture was mixed with a saturated solution of ammonium chloride (10 ml) and water (10 ml). The solvent is concentrated in vacuum. The remainder was extracted with diethyl ether (3 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 2.23 g (32%), white solid

Melting point: 86 degrees With

1 H NMR (DMSO-d6); 1.15 to 1.85 (m, N); 2.54 (dd, 1H, J=13.6, 8.4 Hz); 2.72 (dd, 1H, J=13.6, 4.2 Hz); 3.45 (m, 1H); 3.83 (s, 4H); 4.38 (d, 1H; J=6.0 Hz); 7.10-7.30 (m, 5H).

In a similar compositions from 3 to 48,11 mmol when using 2 to 4 of molar equivalent chloride benslimane achieved outputs from 26 to 47%.

Stage 2:

4-(1-hydroxy-2-phenylethyl)cyclohexanone

Sodium 1-(1,4-dioxaspiro[4.5]Oct-8-yl)-2-phenylethanol (2.98 g, 11.3 mmol) in tetrahydrofuran (30 ml) was added 2 M hydrochloric acid (30 ml). The solution was stirred for the night at 50 degrees C. The mixture was podlachian 4 M sodium hydroxide solution, the phases were separated and the aqueous phase was extracted with dichloromethane (3 x 20 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. Output: 2.52 g (100%), colorless oil

1 H NMR (DMSO-d6): 1.40-1.80 (m, 3H); 1.90 (m, 1H); 2.08 (m, 1H); 2.14-2.42 (m, 4H); 2.61 (dd, 1H, J=8.2 and 13.6 Hz); 2.76 (dd, 1H, J=4.6 and 13.6 Hz); 3.59 (m, 1H); 4.57 (d, 1H, J=5.9 Hz); 7.13-7.32 m, 5H).

Stage 3:

4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanone

Solution 4-(1-hydroxy-2-phenylethyl)cyclohexanone (2.52 g, 11.5 mmol) in anhydrous dichloromethane (50 ml) was mixed with ethylvanillin ether (998 mg, 1.32 ml, 13.8 mmol) and tosilata pyridinium (44 mg 0.17 mmol) and during the night was stirred at room temperature. The mixture was mixed with dichloromethane (20 ml) and washed with water, 5% solution of sodium bicarbonate and sodium chloride solution (50 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 2.93 g, oil orange

1 H NMR (DMSO-d6): Range contains all the expected signals.

There is a mixture of two diastereoisomers.

Stage 4:

1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclopentanecarbonitrile

A mixture of 4 M hydrochloric acid (2.61 ml) and methanol (1.56 ml) at cooling by ice mixed with 40% aqueous solution dimethylamine (6.05 ml 47.9 mmol). This mixture is added to the solution 4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanone (2.91 g, 10.0 mmol) in methanol (6 ml) and tetrahydrofuran (3 ml). After that to a mix added potassium cyanide (1.56 g, 24.1 mm), during the night was stirred at room temperature, then mixed with water (150 ml) and was extracted with diethyl ether (4 x 50 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The remainder resuspendiruetsa in dichloromethane (50 ml) and washed with water (30 ml). The organic phase again dried sodium sulfate and concentrated in vacuum. Output: 3.18 g, oil orange

1 H NMR (DMSO-d6): Range contains all the expected signals. There is a mixture of diastereoisomers.

Stage 5:

{4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]-1-thiophene-2-Il-cyclohexyl}dimethylamine

Sodium 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclopentanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml) at cooling by ice and under argon atmosphere of 1 M was let dropwise bromide solution 2-titimania in tetrahydrofuran (9.25 ml, 9.25 mmol). The mixture was stirred for 48 hours at room temperature and then mixed with water and with a saturated solution of ammonium chloride (10 ml). The phases were separated and the aqueous phase was extracted with diethyl ether (3 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. Output: 1.12 g, yellowish oil

1 H NMR (DMSO-d6): Range contains all the expected signals. There is a mixture of diastereoisomers

Stage 6:

1-(4-dimethylamino-4-thiophene-2-Il-cyclohexyl)-2-phenylethanol

The solution {4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]-1-thiophene-2-Il-cyclohexyl}dimethylamine (1.10 g 2.73 mmol) in tetrahydrofuran (20 ml) was added 2 M hydrochloric acid (20 ml) and the reaction mixture during the night was stirred at room temperature. Then podlachian 4 M sodium hydroxide solution and was extracted with dichloromethane (4 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (956 mg) was purified by flash chromatography with cyclohexane / ethyl acetate (3:2), and methanol. Both underlined fraction of the product each time resuspendiruetsa in diethyl ether and mixed with 2 M hydrochloric acid (20 ml). The phases were separated. Acidic aqueous phase was extracted with diethyl ether (3 x 10 ml) and after that was podlachian with 4 M sodium hydroxide solution. The aqueous phase was extracted with dichloromethane (4 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum.

Polar diastereoisomer

Output: 466 mg (46% in terms of used stage 2), solid beige

Melting point: 85 degrees With

1 H NMR (DMSO-d6): 1.22-1.75 (m, 7H); 2.01 (s, 6H); 2.40-2.46 (m, 2H); 2.55 (dd, 1H, J=and 13.6 8.6 Hz); 2.75 (dd, 1H, J=13.6 and 4.0 Hz); 3.45 (m, 1H); 4.35 (d, 1H, J=6.1 Hz); 6.90 (d, 1H, J=3.5 Hz); 7.03 (dd, 1H, J=3.5 5.1 Hz); 7.14-7.30 (m, 5H); 7.37 (d, 1H,J=5.1 Hz).

13 C NMR (DMSO-d6): 22.1; 23.9; 35.1; 35.3; 37.5; 40.6; 42.8; 58.1; 75.1; 122.8; 123.5; 125.3; 126.0; 127.7; 129.3; 140.4; 145.2. LC-MS (method 7): [M+H]+: m/z=330.3, Rt=2.8 minutes

Non-polar diastereoisomer

Output: 16 mg (1% in terms of used stage 2), yellow oil

1 H NMR (CDCl 3 ): 1.43-1.82 (m, 8H); 2.12 (s, 6H); 2.51 (d, 2H, J=13.8 Hz); 2.63 (dd, 1H, J=and 13.6 9.5 Hz); 2.97 (dd, 1H, J=3.4 and 13.6 Hz); 3.70 (m, 1H); 6.87 (dd, 1H, J=1.1 and 3.4 Hz); 7.03 (dd, 1H, J=3.6 and 5.1 Hz); 7.20-7.27 (m, 4H); 7.30-7.36 (m, 2H). LC-MS (method 1): [M+H]+: m/z=330.3, Rt=3.3 min

Example 8

1-(4-butyl-4-dimethylaminoethoxy)-2-phenylethanol

In similar conduct to obtain example 6 and 7 with the application stage 4 and replacing bromide titimania on bromide butylamine in stage 5 received example 8.

Stage 5:

{1-butyl-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexyl}dimethylamine To a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclopentanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml) at cooling by ice and under argon atmosphere let dropwise 2 M solution of chloride n-butylamine in tetrahydrofuran (4.62 ml, 9.25 mmol). The mixture 48 h stirred at room temperature and then mixed with water and with a saturated solution of ammonium chloride (10 ml). The phases were separated and water was extracted with diethyl ether (3 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. Output: 1.12 g, yellowish oil

1 H NMR (DMSO-d6): Range contains all the expected signals.

There is a mixture of diastereoisomers.

Stage 6:

1-(4-butyl-4-dimethylaminoethoxy)-2-phenylethanol

The solution {1-butyl-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexyl}dimethylamine (1.09 g 2.90 mmol) in tetrahydrofuran, anhydrous (20 ml) was mixed with 2 M hydrochloric acid (20 ml) and 3 days. mixed at room temperature. Tetrahydrofuran was removed in vacuo, acidic aqueous solution was extracted with diethyl ether (3 x 10 ml) and after that was podlachian with 4 M sodium hydroxide solution. Alkaline aqueous phase was extracted with dichloromethane (4 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (646 mg) was purified by flash chromatography with dichloromethane / methanol(9:1→8:2→0:1). Underlined product was hydrochloride. Resuspendiruetsa in dichloromethane and suspension washed saturated solution of potassium carbonate. Organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 306 mg (35% in terms of used stage 2), yellowish oil

13 C NMR (DMSO-d6): 13.9; 21.6; 23.4; 23.5; 26.4; 30.8; 32.0; 32.1; 36.8; 40.6; 43.0; 55.5; 75.3; 125.4; 127.8; 129.1; 140.3. LC-MS (method 7): [M+H]+; m/z=304.5, Rt=2.9 minutes

Example 9

1-[4-dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

In similar conduct to obtain example 6 and 7 with the application stage 4 and replacing bromide titimania on bromide 3-methoxybenzylamine in stage 5 received example 9.

Stage 5:

[4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]-1-(3-methoxyphenyl)cyclohexyl]dimethylamine

Sodium 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclopentanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml) at cooling by ice and under argon atmosphere let dropwise 1 M bromide solution 3-methoxybenzylamine in tetrahydrofuran (9.25 ml, 9.25 mmol). The mixture 48 hours stirred at room temperature and then mixed with water and with a saturated solution of ammonium chloride (10 ml). The phases were separated and water was extracted with diethyl ether (3 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. Output: 1.56 g, yellowish oil

1 H NMR (DMSO-d6): Range contains all the expected signals.

There is a mixture of diastereoisomers.

Stage 6:

1-[4-dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

The solution WW561 (1.54 g, 3.61 mmol) in tetrahydrofuran, anhydrous (20 ml) was mixed with 2 M hydrochloric acid (20 ml) and 2 days. mixed at room temperature. Tetrahydrofuran was removed in vacuo, acidic aqueous solution was extracted with diethyl ether (3 x 10 ml) and after that was podlachian with 4 M sodium hydroxide solution. Alkaline aqueous phase was extracted with dichloromethane (4 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (670 mg) was purified by flash chromatography with cyclohexane / acetate (3:2 Chicago time)dichloromethane / methanol (9:1).

Output: 163 mg (15% in terms of stage 3), white solid

Melting point: 75? C

1 H NMR (DMSO-d6): 1.15-1.52 (m, 7H); 1.95 (s, 6H); 2.52-2.68 (m, 3H); 2.77 (dd, 1H, J=3.7 and 13.6 Hz); 3.45 (m, 1H); 3.74 (s, 3H); 4.33 (d, 1H, J=6.1 Hz); 6.78-6.84 (m, 2H); 6.89 (d, 1H, J=7.9 Hz); 7.11-7.30 (m, 6H).

13 C NMR (DMSO-d6); 22.2; 24.2; 32.8; 32.9; 37.6; 40.5; 42.9; 58.2; 75.0; 110.9; 112.9; 118.8; 125.3; 127.7; 127.9; 129.3; 140.5; 141.5; 158.6.

The other faction with a contaminated product (350 mg) again cleansed by flash chromatography with dichloromethane / methanol (95:5), which received 90 mg 1-[4-dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol (8% in terms of stage 3), white solid

Melting point: 72°

Example 10

1-[4-dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

Stage 1:

4-dimethylamino-4-beta-methoxyphenyl)cyclopentanecarbonitrile

Solution 4-(dimethylamino)-4-beta-methoxyphenyl)cyclohexanone (2.47 g, 10 mmol) and dosimetrician (2.54 g, 13 mmol) in anhydrous 1,2-dimethoxyethane (40 ml) and anhydrous ethanol (2 ml) was cooled to-30o C. Then added dropwise solution tert-butyl potassium (2.70 g, 24 mmol) in tetrahydrofuran, anhydrous (20 ml) so that the internal temperature did not rise above 5 degrees C. The mixture was stirred for 1 h at 0 C, 24 h at room temperature and then 5 hours boiling in the flask under reflux. The reaction mixture was cooled to room temperature and filtered. The filter residue washed 1,2-dimethoxyethane. The filtrate was concentrated in vacuum, sludge resuspendiruetsa in diethyl ether and the solution is washed with water (3 x 20 ml)and a saturated solution of sodium chloride (20 ml). Organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (1.76 g) was purified by flash chromatography with ethyl acetate and then the ethyl acetate / methanol(9:1→8:2).

Non-polar diastereoisomer

Output: 401 mg (15%), yellowish oil

1 H NMR (DMSO-d6): 1.60-1.90 m, 6H); 1.94 (s, 6H); 2.22-2.34 (m, 2H); 2.81 (m, 1H); 3.74 (s, 3N); 6.78-6.90 (m, 3H); 7.27 (t, 1H, J=7.9 Hz).

13 C NMR (DMSO-d6): 24.7; 26.3; 30.5; 37.4; 54.9; 58.7; 111.3; 113.2; 119.3; 122.9; 128.4; 139.2; 158.8.

LC-MS method (8): [M+H]+; m/z=259.3, Rt=0.9 min

Polar diastereoisomer

Output: 505 mg (19%), yellowish oil

1 H NMR (DMSO-d6): 1.33-1.52 (m, 2H); 1.92 (s, 6H); 1.93-2.18 (m, 6H); 2.92 (m, 1H); 3.76 (s, 3N); 6.80-6.94 (m, 3H); 7.30 (t, 1H, J=7.9 Hz).

13 C NMR (DMSO-d6): 24.9; 26.4; 30.3; 37.7; 54.8; 59.2; 111.4; 113.6; 119.4; 122.8; 128.4; 138.7; 158.8.

LC-MS method (8): [M+H]+: m/z=259.2, Rt=1.0 min

Stage 2:

1-[4-dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

The solution of the polar diastereoisomer (240 mg, 0.9 mmol) in tetrahydrofuran, anhydrous (5 ml) at cooling by ice mixed with 2 M solution of chloride benslimane in tetrahydrofuran (1.4 ml, 2.8 mmol) and 3 days. mixed at room temperature. The reaction mixture was mixed with a saturated solution of ammonium chloride (8 ml) and water (5 ml). The solvent was removed in vacuo, and aqueous suspension was extracted with diethyl ether (3 x 20 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product was purified by flash chromatography with dichloromethane / methanol (95:5). Output: 120 mg (36%), yellowish oil

1 H NMR (CDCl3): 1.33-1.46 (m, 2H); 1.72 (t, 2H, J=14.5 Hz); 1.87 (d, 2H, J=11.1 Hz); 2.13 (s, 6H); 2.56 (m, 1H); 2.70 (d, 2H, J=12.5 Hz); 3.69 (s, 2H); 3.85 (s, 3N); 6.82-6.94 (m, 4Hz); 7.16 (d, 1H, J=7.1 Hz); 7.22-7.38 (m, 4H).

Stage 3:

1-[4-dimethylamino-4-(3-methoxyphenyl)cyclohexyl]-2-phenylethanol

A solution of the product from the stage 2(112 mg, 0.3 mmol) in anhydrous methanol (5 ml) at 0 C mixed with sodium borohydride (24 mg, 0.6 mmol) and 3 h stirred at room temperature. Then added additional sodium borohydride (12 mg, and 0.3 mmol) and a further 2 hours stirred at room temperature. The mixture is mixed with water (20 ml). The solvent was removed in vacuo, and aqueous suspension were extracted with ethyl acetate (3 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (76 mg) was purified by flash chromatography (10 grams, 20 x 1.1 cm) dichloromethane / methanol [(95:5)+1% ammonia solution (30% in the H 23 (O)].

Output: 57 mg (50%), yellowish solid

Melting point: 120 C

1 H NMR (DMSO-d6): 0,84-1.12 (m, 2H); 1.18-1.58 (m, 6H); 1.72 (d, 1H, J=12.5 Hz); 1.91 (s, 6H); 2.40-2.50 (m, 1H); 2.54-2.70 (m, 2H); 3.26 (m, 1H); 3.75 (s, 3N); 4.20 (d, 1H, J=6.0 Hz); 6.79-6.92 (m, 3H); 7.10-7.33 (m, 6H).

13 C NMR (DMSO-d6): 23.5; 25.9; 32.5; 32.7; 37.9; 40.7; 42.9; 61.1; 74.6; 110.7; 114.4; 120.3; 125.3; 127.8; 128.4; 129.1; 138.4; 140.1; 158.9.

Example 11:

1-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)-2-(5-(phenylsulfonyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-yl)ethanol

Stage 1:

Benzyl ether 1,3,4,9-tetrahydro-b-carboline-2-carboxylic acid

Suspension 2,3,4,9-tetrahydro-1H-beta-carboline (4.43 g, 25.7 mmol) and 4-N,N-dimethylaminopyridine (266 mg) in tetrahydrofuran, anhydrous (30 ml) at cooling by ice mixed with solution of N-(benzyloxycarbonyloxy)succinimide (9.61 g, 38.6 mmol) in tetrahydrofuran, anhydrous (30 ml). Suspension 16 h stirred at room temperature and then tetrahydrofuran removed in a vacuum. The residue was dissolved in ethyl acetate (20 ml) and wash (2 x 20 ml). Organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (11.0 g) was purified by flash chromatography with cyclohexane / acetate (4:1).

Output: 6.64 g (84%), white solid

1 H NMR (DMSO-d6): 2.71 (t, 2H, J=5.6 Hz); 3.76 (t, 2H, J=5.3 Hz); 4.64 (brs, 2H); 5.14 (s, 2H); 6.96 (ddd, 1H, J=8.0, 7.1 and 1.1 Hz); 7.04 (ddd, 1H, J=8.2, 7.1 and 1.2 Hz); 7.25-7.44 (m, 7H); 10.78 and 10.84 (2 s, 1H).

Stage 2:

Benzyl ether 9-benzolsulfonat-1,3,4,9-tetrahydro-b-carboline-2-carboxylic acid

The solution of the product from stage 1 (6.61 g, 21.6 mmol) in anhydrous dichloromethane (100 ml) was mixed with powdered sodium hydroxide (1.73 g, 43.3 mmol) and hydrosulfate Tetra-n-butylamine (111 mg) and 1 h mixed in room temperature. To suspension at cooling by ice were added benzosulphochloride (4.21 g, 3.07 ml, 23.8 mmol). A mixture of 16 hours stirred at room temperature and then mixed with water and dichloromethane (50 ml). The organic phase is separated and washed with a solution of sodium chloride (40 ml). Organic phase was dried sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography with cyclohexane / ethyl acetate (4:2).

Output: 5.66 g (58%), white solid

Melting point: 153°

1 H NMR (DMSO-d6): 2.67 (t, 2H, J=5.5 Hz); 3.73 (t, 2H, J=4.7 Hz); 4.97 (s br, 2H); 5.16 (s, 2H); 7.26 (dt, 1H, J=7.4 1.0 Hz); 7.31-7.94 (m, 12H); 8.01 (brd, J=8.1 Hz).

Stage 3:

9-benzolsulfonat-2,3,4,9-tetrahydro-1H-b-carboline

The suspension of the product from the stage 2 (4.14 g, 9.27 mmol) in glacial acetic acid (20.7 ml) was mixed with 33% hydrogen bromide in glacial acetic acid (20.7 ml) and 1 h stirred at room temperature. The mixture is poured in diethyl ether (500 ml). Dropped out in a Deposit hydrobromide been pumped out, washed diethyl ether and dried in a desiccator over potassium hydroxide. Salt (3.60 g) mixed with a saturated solution of potassium carbonate (100 ml) and the resulting mixture was extracted with dichloromethane (3 x 25 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 2.51 g (86%), white solid

Melting point: 190-195°

1 H NMR (DMSO-d6): 2.53 (t, 2H, J=5.5 Hz); 2.91 (t, 2H, J=5.5 Hz); 4.11 (s, 2H); 7.20-7.33 (m, 2H); 7.40-7.43 (m, 1H); 7.52-7.60 (m, 2H); 7.62-7.70 (m, 1H); 7.84-7.90 (m, 2H); 7.96-8.04 (m, 1H).

Stage 4:

2-(9-benzolsulfonat-1,3,4,9-tetrahydro-b-carboline-2-yl)-1-(1,4-dioxaspiro[4.5]Oct-8-yl)ethanol

A solution of the product from the stage 3 (2.51 g, 8.05 mmol) and 8-oxiranyl-1,4-dioxaspiro[4.5]Dean (1.34 g, 7.30 mmol) in tetrahydrofuran, anhydrous (50 ml) was mixed with triftoratsetata calcium (1.22 g, 3.60 mmol) and 48 h stirred at room temperature. Tetrahydrofuran removed in a vacuum. The remainder resuspendiruetsa in dichloromethane (40 ml) and washed 25% solution of potassium carbonate (2 x 25 ml). Organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (4.31 g) was purified by flash chromatography (with cyclohexane / acetate (1:2).

Output: 2.33 g (64%), white solid

Melting point: 158 degrees With

1 H NMR (DMSO-d6): 1.22-1.48 (m, 5H); 1.57 (s, 1H); 1.62-1.78 (m, 3H); 2.48-2.68 (m, 4H); 2.72-2.90 (m, 2H); 3.51 (m, 1H); 3.83 (s, 4H); 3.95 (d, 1H, J=17.0 Hz); 4.03 (d, 1H, J=17.0 Hz); 4.38 (d, 1H, J=4.4 Hz); 7.25 (dt, 1H, J=7.3 and 1.2 Hz); 7.31 (ddd, 1H, J=8.4, 7.3 and 1.5 Hz); 7.40-7.45 (m, 1H); 7.51-7.60 (m, 2H); 7.64-7.71 (m, 1H); 7.82-7.89 (m, 2H); 7.99-8.03 (m, 1H).

Stage 5:

4-[2-(9-benzolsulfonat-1,3,4,9-tetrahydro-(3-Carolin-2-yl)-1-hydroxyethyl]cyclohexanone

A solution of the product from the stage 4 (748 mg, 1.50 mmol) in tetrahydrofuran (30 ml) was mixed with 2 M hydrochloric acid (30 ml), and 16 h stirred at room temperature. The mixture was podlachian 4 M sodium hydroxide solution and were extracted with ethyl acetate (3 x 35 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 658 mg (96%), solid beige

Melting point: 174°

1 H NMR (DMSO-d6): 1.40-1.64 (m, 2H); 1.76-1.98 (m, 2H); 2.02 (m, 1H); 2.15-2.26 (m, 2H); 2.27-2.45 (m, 2H); 2.54-2.70 (m, 4H); 2.77-2.93 (m, 2H); 3.64 (m, 1H); 3.98 (d, 1H, J=17.0 Hz); 4.06 (d, 1H, J=17.0 Hz); 4.56 (d, 1H, J=4.4 Hz); 7.25 (dt, 1H, J=7.3 and 1.1 Hz); 7.32 (ddd, 1H, J=8.6, 7.3 and 1.4 Hz); 7.44 (m, 1H); 7.52-7.60 (m, 2H); 7.67 (m, 1H); 7.83-7.89 (m, 2H); 8.02 (brd, 1H, J=7.8 Hz).

The solution of the product from stage 6 (553 mg, 1.22 mmol), antifungals (250 mg, 3.66 mmol) and tert-butyldimethylchlorosilane (275 mg, 1.83 mmol) in anhydrous N,N-dimethylformamide (20 ml) 48 hours stirred at room temperature. The reaction mixture was concentrated in vacuum. The remainder was mixed with a 25% solution of potassium carbonate (30 ml) and was extracted with dichloromethane (3 x 35 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (1.3 g) was purified by flash chromatography (85 grams, 20 x 3.8 cm) with cyclohexane / ethyl acetate (2:1).

Output: 588 mg (85%), white solid

Melting point; 150-152°

1 H NMR (DMSO-d6): 0.03 (s, 3N); 0.04 (s, MN); 0.85 (s, 9H); 1.44-1.66 (m, 2H); 1.86-2.06 (m, 3H); 2.14-2.25 (m, 2H); 2.28-2.47 (m, 2H); 2.55-2.70 (m, 4H); 2.71-2.92 (m, 2H); 3.83 (m, 1H); 3.89 (d, 1H, J=16.8 Hz); 4.00 (d, 1H, J=16.8 Hz); 7.26 (dt, 1H, J=7.3 and 1.2 Hz); 7.32 (ddd, 1H, 8.6, 7.3 and 1.4 Hz); 7.42-7.48 (m, 1H); 7.52-7.60 (m, 2H); 7.64-7.72 (m, 1H); 7.80-7.88 (m, 2H); 8.00-8.06 (m, 1H).

Stage 7:

4-[2-(9-benzolsulfonat-1,3,4,9-tetrahydro-b-carboline-2-yl)-1-(tert-butyldimethylsiloxy)ethyl]-1-dimethylamino-cyclopentanecarbonitrile

Mix 4 M hydrochloric acid (256 ml) and methanol (153 RL) at cooling by ice mixed with 40% aqueous solution dimethylamine (596 µm, 4.73 mmol). To the mixture was added to a solution of the product from the stage 6 (557 mg, 0.98 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml). Then add the potassium cyanide (153 mg, 2.36 mmol) and water (2 ml). The suspension was stirred for the night at room temperature and after that water (20 ml) was diluted. The mixture was extracted with diethyl ether (5 x 20 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. Output: 609 mg (100%), yellowish oil. There is a mixture of diastereoisomers.

1 H NMR (DMSO-d6): range contains all the expected signals.

[4-[2-(9-benzolsulfonat-1,3,4,9-tetrahydro-b-carboline-2-yl)-1-(tert-butyldimethylsiloxy)ethyl]-1-(3-torfanil)cyclohexyl]dimethylamine

The solution of the product from stage 7 (521 mg, 0.84 mmol) in tetrahydrofuran, anhydrous (20 ml) with cooled with ice and under argon was mixed with 1 M solution bromide 3-performane in tetrahydrofuran (2.5 ml 2.5 mmol) and 2 days. mixed at room temperature. Then the reaction mixture was mixed with a saturated solution of ammonium chloride and water (10 ml) and the phases were separated. The aqueous phase was extracted with diethyl ether (2 x 30 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The remainder (491 mg) was purified by flash chromatography with cyclohexane / acetate (4:1), which received more polluted 3-ftorhinolon product (211 mg). Which again was purified by flash chromatography with cyclohexane / tert-butyl methyl ether (4:1).

Output: 149 mg (25%), white solid

1 H NMR (DMSO-d6): 0.01 (s, 3N); 0.04 (s, 3N); 0.88 (s, 9H); 1.15-1.80 (m, 7H); 1.92 (s, 6H); 2.56-2.56 (m, 6H); 2.56-2.95 (m, 2H); 3.65-3.73 (m, 1H); 3.86 (d, 1H, J=16.9 Hz); 3.99 (d, 1H, J=17.0 Hz); 7.00-7.15 m, 2H); 7.20-7.45 (m, 5H); 7.50-7.59 (m, 2H); 7.62-7.70 (m, 1H); 7.80-7.87 (m, 2H); 8.01 (d, 1H, J=8.2 Hz).

13 C NMR (DMSO-d6): -5.1; -4.9; -4.0; -3.8; 17.9; 20.5; 24.1; 25.8; 25.9; 32.6; 32.7; 37.4; 49.7; 51.6; 58.3; 61.3; 71.3; 74.1; 111.6 (d, J=22 Hz); 112.6 (d, J=21 Hz); 113.1; 113.7; 117.1; 118.6; 120.7 (br); 122.4; 122.5; 123.6; 124.4; 126.0; 128.8 (d, J=8 Hz); 129.3; 129.8; 132.9; 134.5; 135.3; 137.4; 143.1 (d, J=6 Hz); 161.9 (d, J=242 Hz).

LC/MS method (8): [M+H]+: m/z=691.4, Rt=4.2 minutes

Stage 9:

2-(9-benzolsulfonat-1,3,4,9-tetrahydro-b-carboline-2-yl)-1-[4-dimethylamino-4-(3-torfanil)cyclohexyl]ethanol

A solution of the product from the stage 8 (176 mg, 0.255 mm) in tetrahydrofuran (20 ml) was mixed with 2 M hydrochloric acid (20 ml) and 1 days. mixed at room temperature. Then the reaction mixture 15 h mixed at 50C and then the next 16 h at room temperature. Then the mixture was podlachian 2 M sodium hydroxide solution (30 ml) and the phases were separated. The aqueous phase was extracted with diethyl ether (3 x 10 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (151 mg) was purified by flash chromatography with dichloromethane / methanol (97:3).

Output: 35 mg (22%), colorless oil

1 H NMR (CDCl 3 ): 1.35-1.78 (m, 7H); 1.85 (brd, 1H, J=12.4 Hz); 2.04 (s, 6H); 2.48-2.66 (m, 3H); 2.50-2.86 (m, 4H); 3.05 (m, 1H); 3.65 (t, 1H, J=7.8 Hz); 4.02 (d, 1H, J=16.4 Hz); 4.13 (d, 1H, J=16.4 Hz); 6.95 (t, 1H, J=8.1 Hz); 7.01 (dd, 1H, J=11.5 and 1.4 Hz); 7.09 (d, 1H, J=7.5 Hz); 7.20-7.46 (m, 6H); 7.52 (m, 1H); 7.77 (m, 2H); 8.12 (d, 1H,J=8.1 Hz).

13 C NMR (CDCl 3 ): 20.8; 23.2; 23.8; 32.9; 37.6; 41.9; 49.5; 51.3; 58.7; 60.3; 70.1; 113.1 (d, J=20 Hz); 113.6 (d, J=21 Hz); 114.2; 117.3; 118.2; 122.4; 123.6; 124.3; 126.2; 128.5 (d, J=8 Hz); 129.3; 129. 6; 132.6; 133.6; 136.1; 138.7; 143.0 (br); 162 (d, J=245 Hz).

LC-MS (method 7): [M+H]+: m/z=576.3, Rt=2.4 min

Example 12

2-(1,3-dihydrothieno-2-yl)-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol

Stage 1:

2-(1,3-dihydrothieno-2-yl)-1-(1,4-dioxaspiro[4.5]Oct-8-yl)ethanol

Solution 8-oxiranyl-1,4-dioxaspiro[4.5]Dean (1.41 g 7.66 mmol), isoindoline (1.00 g, 8.43 mmol) and triftoratsetata calcium (1.29 g, 3.8 mmol) in acetonitrile, anhydrous (60 ml) during the night was stirred at room temperature. The solvent is then concentrated in vacuum. The remainder resuspendiruetsa in ethyl acetate (50 ml) and the solution is washed 25% solution of potassium carbonate (3 x 50 ml). The aqueous phase were extracted with ethyl acetate (3 x 40 ml), United organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 2.04 g (88%), solid beige

1 H NMR (DMSO-d6): 1.24-1.48 (m, 5H); 1.59 (s br, 1 H); 1.64-1.74 (m, 3H); 2.56 (dd, 1H, J=7.4, 12.2 Hz); 2.70 (dd, 1H, J=4.7, 12.2 Hz); (m, 2H); 3.44 (m, 1H); 3.83 (s, 4H); 3.83-3.94 (m, 4H); 4.30 (d, 1H, J=4.4 Hz); 7.15-7.26 (m, 4 H).

Stage 2:

4-[2-(1,3-dihydrothieno-2-yl)-1-hydroxyethyl]cyclohexanone

Output: 1.12 g (64%), solid beige

Melting point: 136°

1 H NMR (DMSO-d6): 1.40-1.68 (m, 2H); 1.82-2.10 (m, 3H); 2.14-2.24 (m, 2H); 2.28-2.46 (m, 2H); 2.70 (dd, 1H, J=7.1, 12.3 Hz); 2.77 (dd, 1H, J=5.2 Hz); 3.58 (m, 1H); 3.85-3.97 (m, 4H); 4.54 (brs, 1H); 7.15-7.25 (m, 4H).

Stage 3:

4-[2-(1,3-dihydrothieno-2-yl)-1-hydroxyethyl]-1-dimethylaminoacetonitryl

It cooled to 0 C 4 M hydrochloric acid (706 l) in methanol (785 l) was added 40% aqueous solution of dimethylamine (1.72 ml 12.5 mmol). Then, the solution was added to the 4-[2-(1,3-dihydrothieno-2-yl)-1-hydroxyethyl]cyclohexanone (732 mg, 2.82 mmol) in methanol (4 ml) and tetrahydrofuran (6 ml). The mixture is then mixed with potassium cyanide (445 mg, 6.67 mmol) and during the night was stirred at room temperature.

The reaction mixture is then mixed with water (80 ml) and was extracted with diethyl ether (3 x 20 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 672 mg (76%), white solid

1 H NMR (DMSO-d6): 1.20-1.50 (m, 7H); 1.60-1.90 m, 2H); 2.22 and 2.33 (2 s, 6H); 2.63-2.75 (m, 2H); 3.45 (m, 1H); 3.82-3.94 (m, 4H); 4.36 and 4.45 (2 days" 1H, J = every time 4.7 Hz); 7.15-7.24 (m, 4H).

Received a mixture of diastereoisomers in the ratio of approx. 4.5:1.

Stage 4:

2-(1,3-dihydrothieno-2-yl)-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol

2 M saline vinilmania in tetrahydrofuran (4.25 ml, 8.49 mmol) at cooling by ice on drops mixed with solution of 4-[2-(1,3-dihydrothieno-2-yl)-1-hydroxyethyl]-1-dimethylaminoacetonitryl (666 mg, 2.12 mmol) in tetrahydrofuran, anhydrous (30 ml) and during the night was stirred at room temperature. The mixture is then at cooling by ice on drops mixed with a saturated solution of ammonium chloride and water each time (10 ml). Tetrahydrofuran drove away in a vacuum and the precipitate was extracted with diethyl ether (3 x 30 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (761 mg) was purified by flash chromatography with chloroform / methanol (9:1). Re-flash chromatography with chloroform (with 25% water saturated solution of ammonia) / methanol (95:5) has given out to 83 mg (10%), solid beige

Melting point:130-135°

1 H NMR (CDCl 3 ): 1.26 (s, 1H); 1.40-1.90 m, 7H); 2.05 (s, 6H); 2.58-2.70 (m, 2H); 2.79 (dd, 1H, J=10.2, 11.8 Hz); 2.84 (dd, 1H, J=3.5, 11.8 Hz); 3.63 (m, 1H); 3.93 (d, 2H, J=11.1 Hz); 4.12 (d, 2H, J=11.1 Hz); 7.21-7.29 (m, 5H); 7.30-7.39 (m, 4H).

Received a mixture of diastereoisomers in the ratio of approx. 4:1.

Example 13 and 14

(1-(4-dimethylamino-4-phenylcyclohexyl)-2-Phenoxyethanol, non-polar diastereoisomer)

(1-(4-dimethylamino-4-phenylcyclohexyl)-2-Phenoxyethanol, polar diastereoisomer)

Stage 1:

8-oxiranyl-1,4-dioxaspiro[4.5]Dean

60%variance hydride sodium mineral oil (1.78 g, at 44.59 mmol) resuspendiruetsa in dimethyl sulfoxide (25 ml) and was mixed with iodide trimethylsulfoxonium (9.80 g, 44.6 mmol). The mixture 45 min stirred at room temperature. Then to the mixture was added to a solution of 1,4-dioxaspiro[4,5]Dean-8-carbaldehyde (7.59 g, 44.6 mmol) in dimethyl sulfoxide (20 ml). The reaction mixture 18 h mixed at 60 C. After cooling the mixture was poured in water (100 ml) and diethyl ether (4 x 20 ml) were extracted. The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (4.64 g) was purified by flash chromatography with cyclohexane / acetate (4:1).

Output: 1.09 g (13%), colorless oil

1 H NMR (DMSO-d6): 1.10-1.85 (m, 8H); 2.50 (2N imposed from DMSO-signal); 2.64 (dd, 1H, J=5.0, 4.0 Hz); 2.71 (add, 1H, J=6.6, 4.0, 2.7 Hz); 3.84 (s, 4H).

Likewise received the following volumes:

a) from 1.16 g 1,4-dioxaspiro[4,5]Dean-8-carbaldehyde 247 mg, 20% d. Th.

b) from 2.99 g 1,4-dioxaspiro[4,5]Dean-8-carbaldehyde 560 mg, 17% d. Th.

C) from 7.6 g 1,4-dioxaspiro[4,5]Dean-8-carbaldehyde 7.34 g, and this party contained large quantities of dichloromethane and cyclohexane. The content of the product the maximum was approx. 30% d. Th.

Stage 2:

1-(1,4-dioxaspiro[4.5]Oct-8-yl)-2-Phenoxyethanol

60%variance hydride sodium mineral oil (834 mg, 20.7 mmol) resuspendiruetsa in anhydrous N,N-dimethylformamide (10 ml) and was mixed with phenol (1.96 g, 20.8 mmol). The mixture for 15 minutes stirred at room temperature, then added solution 8-oxiranyl-1,4-dioxaspiro[4.5]Dean (2.62 g, the content of approx. 30%approx. 4 mmol) in N,N-dimethylformamide (6 ml). The reaction mixture is 5.5 hours stirred at 120 C, then cooled to room temperature, mixed with water (1 ml) and concentrated in vacuum. The remainder re-mixed with toluene and every once again concentrated in a vacuum. The crude product (2.9 g) was purified by flash chromatography (200 g, 20 x 5.6 cm) with cyclohexane / acetate (4:1).

Output: 1.01 g (approx. 90%), colorless oil

1 H NMR (DMSO-d6): 1.30-1.80 (m, 9H); 3.59 (m, 1H); 3.82-3.88 (s, 4H, imposed from dd, 1H); 3.93 (dd, 1H, J=4.2, 9.9 Hz); 4.79 (d, 1H, J=5.4 Hz); 6.88-6.95 (m, 3H); 7.24-7.30 (m, 2H).

Stage 3:

4-(1-hydroxy-2-phenoxyethyl)cyclohexanone

Solution 1-(1,4-dioxaspiro[4.5]Oct-8-yl)-2-Phenoxyethanol (1.25 g, 4.5 mmol) in acetone (30 ml) was mixed with 2 M hydrochloric acid and 48 h stirred at room temperature. Solvent was removed in vacuo, the pH-value of water balance were podlachian 2 M sodium hydroxide solution and water balance was extracted with dichloromethane (4 x 20 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. Output: 928 mg (88%), yellowish oil

1 H NMR (DMSO-d6): 1.45-1.65 (m, 2H); 1.88-2.13 (m, 3H); 2.15-2.26 (m, 2H); 2.31-2.45 (m, 2H); 3.72 (m, 1H); 3.90 (dd, 1H, J=6.2, 9.9 Hz); 3.99 (dd, 1H, J=4.4, 9.9 Hz); 4.96 (d, 1H, J=5.4 Hz); 6.90-6.98 (m, 3H); 7.25-7.32 m, 2H).

Stage 4:

4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanone

Solution 4-(1-hydroxy-2-phenoxyethyl)cyclohexanone (919 mg, 3.92 mmol) in anhydrous dichloromethane (20 ml) was mixed with tosilata pyridinium (15 mg, 0.06 mmol) and ethylvanillin ether (339 mg, 450 l, 4.70 mmol) and during the night was stirred at room temperature. The mixture is then mixed with dichloromethane (20 ml) and with water, washed with 5%solution of sodium bicarbonate, and a saturated solution of sodium chloride (50 ml). Organic phase was dried sodium sulfate and concentrated in vacuum.

The crude product (1.09 g) was purified by flash chromatography with cyclohexane / acetate (4:1).

Output: 929 mg (77%), colorless oil

1 H NMR (DMSO-d6): 1.02-1.13 (m, 3H); 1.21 (dd, 3H, J=5.2, 9.1 Hz); 1.44-1.70 (m, 3H); 1.90-2.30 (m, 4H); 2.32-2.47 (m, 2H); 3.38-3.64 (m, 2H); 3.71-3.88 (m, 1H); 3.94-4.15 (m, 2H); 4.90 4.80 and (2 q's, 1H, J=5.3 Hz); 6.90-6.94 (m OZ); 7.29 (t, 2H, J=8.0 Hz).

The product has obtained as a mixture of diastereoisomers.

Stage 5:

1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclopentanecarbonitrile

A mixture of 4 M hydrochloric acid (747 l) and methanol (448 l) at cooling by ice mixed with 40% aqueous solution dimethylamine (1.73 ml, 13.7 mmol) was added to the 4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanone (880 mg, 2.87 mmol), before he added potassium cyanide (448 mg, 6.88 mg). As an agent of dissolution were added tetrahydrofuran (3 ml). The reaction mixture is 6 hours stirred at room temperature, then mixed with water (50 ml) and was extracted with diethyl ether (4 x 30 ml). The combined organic phase concentrated in vacuum, sludge resuspendiruetsa in dichloromethane (30 ml) and washed with water (30 ml).

Organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 877 mg (84%), colorless oil

1 H NMR (DMSO-d6): 1.00-1.12 (m, 3H); 1.16-1.24 (m, 3H); 1.30-2.00 (m, 8H); 2.10-2.30 (m, 7H); 3.40-3.70 (m, 3H); 4.00-4.10 (m, 2H); 4.74-4.90 (m, 1H); 6.90-6.99 (m, 3H); 7.25-7.32 m, 2H).

The product was in the form of a mixture of diastereoisomers.

Stage 6:

{4-[1-(1 etoxi-ethoxy)-2-phenoxyethyl]-1-phenylcyclohexyl}dimethylamine

To 2 M to the solution of chloride vinilmania in tetrahydrofuran (3.6 ml, 7.3 mmol) at cooling by ice was added dropwise solution 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclopentanecarbonitrile (871 mg, 2.4 mmol) in anhydrous tetrahydrofuran (15 ml). The mixture was stirred for overnight at room temperature and then mixed with a saturated solution of ammonium chloride and water (each 5 ml). The phases were separated and the aqueous phase was extracted with diethyl ether (3 x 20 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 946 mg (99%), yellowish oil

1 H NMR (DMSO-d6): 0.90-1.26 (m, 6H); 1.26-1.80 (m, 9H); 1.93 (s, 6H); 2.61-2.71 (m, 1H); 3.40-3.69 (m, 2H); 3.93-4.14 (m, 2H); 4.71-4.92 (m, 1H); 6.70-7.70 (m, 10H).

The product has obtained as a mixture of diastereoisomers.

Stage 7:

1-(4-dimethylamino-4-phenylcyclohexyl)-2-Phenoxyethanol

The solution {4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]-1-phenylcyclohexyl}dimethylamine (892 mg, 2.16 mmol) in acetone (30 ml) was mixed with 2 M hydrochloric acid (10 ml) and during the night was stirred at room temperature. Then the pH-value of the mixture was podlachian with 0.5 M sodium hydroxide solution and then was extracted with dichloromethane (3 x 30 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (1.26 g) was purified by flash chromatography with ethyl acetate / methanol (9:1→0:1). 1-(4-dimethylamino-4-phenylcyclohexyl)-2-Phenoxyethanol (non-polar diastereoisomer)

Output: 317 mg (43%), yellowish oil

1 H NMR (DMSO-d6): 1.22-1.38 (m, 2H); 1.40-1.74 (m, 5H); 1.92 (s, 6H); 2.58-2.74 (m, 2H); 3.56-3.65 (m, 1H); 3.88 (dd, 1H, J=10.0, 6.3 Hz); 3.98 (dd, 1H, J=10.0, 4.0 Hz); 4.78 (d, 1H, J=5.5 Hz); 6.88-6.97 (m, 3H); 7.18-7.37 (m, 7H).

1-(4-dimethylamino-4-phenylcyclohexyl)-2-Phenoxyethanol (polar diastereoisomer)

Output: 41 mg (5%), yellowish solid

Melting point:145-147°

1 H NMR (DMSO-d6): 0.80-1.10 (t,2N); 1.38-1.54 (t, 4N); 1.72(brd, 1H, J=12.8 Hz); 1.89 (s, 6H); 2.58-2.74 (t, 2H); 3.40-3.52 (t, 1H); 3.77 (dd, 1H, J=9.9, 6.1 Hz); 3.84 (dd, 1H, J=9.9, 4.4 Hz); 4.67 (brs, 1H); 6.84-6.92 (m, 3H); 7.20-7.40 (m, 7H).

Example 15:

2-benzyloxy-1-(4-dimethylamino-4-phenylcyclohexyl)ethanol

Stage 1:

When replacing on phenol benzyl alcohol in example 13 and 14, stage 2 and the subsequent interaction received example 15;

1 H NMR (DMSO-d6): 1.15-1.68 (m, 8H); 1.92 (s, 6H); 2.52-2.70 (m, 2H); 3.35-3.50 (m, 2H); 4.49 (m, 3H); 7.18-7.40 (m, 10 H).

13 C NMR (DMSO-d6): 22.3; 23.7; 32.6; 32.7; 37.5; 58.1; 72.1; 72.7; 72.9; 126.1 (br); 126.3 (br); 127.1 (br); 127.4; 128.1; 138.7; 139.7. Been allocated only a single diastereoisomer.

Example 16

2-(cyclohexyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol

At replacement of phenol on the cyclohexanol in example 13 and 14, phase 2 and subsequent similar interaction received example 16:

1H-NMR (DMSO-d6): 1.10-1.57 (m, 16H); 1.80 (m, 2H); 1.92 (s, 6H); 2.63 (brd, 2H, J=13.9 Hz); 3.22 (m, 1H); 3.28-3.45 (m, 3H); 4.31 (d, 1H, J=4.7 Hz); 7.23 (m, 1H); 7.28-7.35 (m, 4H).

13C NMR (DMSO-d6): 22.7; 23.2; 23.7; 25.3; 31.7; 32.6; 37.4; 58.3; 70.2; 73.0; 76.4; 126.1; 126.5; 127.0; 139.6.

Been allocated only a single diastereoisomer.

Example 17:

2-cyclohexyloxy-1-(4-dimethylamino-4-thiophene-2-Il-cyclohexyl)ethanol

In similar conduct to obtain example 16 replacing chloride vinilmania on bromide 2-titimania in stage 6 received example 17.

1 H NMR (DMSO-d6): 1.10-1.57 (m, 15H); 1.80 (m, 2H); 1.99 (s, 6H); 2.42 (d, 2H, J=13.7 Hz); 3.21 (m, 1H); 3.27-3.44 (m, 3H); 4.34 (d, 1H, J=4.7 Hz); 6.89 (dd, 1H, J=1.1 and 3.4 Hz); 7.02 (dd, 1H, J=3.4 and 5.1 Hz); 7.37 (dd, 1H, J=1.1 and 5.1 Hz).

13 C NMR (DMSO-d6): 22.2; 23.2; 23.6; 25.3; 31.7; 35.1; 37.3; 58.1; 70.1; 72.9; 76.4; 122.8; 123.5; 126.0; 145.2.

Been allocated only a single diastereoisomer.

Example 18

1-(4-dimethylamino-4-phenylcyclohexyl)-2-indole-1-Il-ethanol

At replacement of phenol on indole in example 13 and 14, phase 2 and subsequent similar interaction received example 18:

1-(4-dimethylamino-4-phenylcyclohexyl)-2-phenylsulfonylacetone

At replacement of phenol on thiophenol in example 13 and 14, phase 2 and subsequent similar interaction received example 19:

1 H NMR (CDCl 3 ): 1.48-1.64 (m, 4H); 1.66-1.82 (m, 4H); 2.10 (s, 6 H); 2.60-2.72 (m, 2H); 2.94 (dd, 1H, J=8.8 13.6 Hz); 3.29 (dd, 1H, J=3.4 and 13.6 Hz) 3.64 (m, 1H); 7.21 (m, 1H); 7.25-7.43 (m, 9H).

LC-MS method (8): [M+H]+: m/z=356.2, Rt=2.6 minutes

Example 20:

2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenoxypropan-2-ol

As in example 13 and 14 received a stage 7, proceeding from which, as described in further, followed synthesis example 20:

1-(4-dimethylamino-4-phenylcyclohexyl)-2-Phenoxyethanol

Solution 1-(4-dimethylamino-4-phenylcyclohexyl)-2-Phenoxyethanol (800 mg, 2.35 mmol) in anhydrous dichloromethane (25 ml) was mixed with 15% solution periodinane dessa-Martin dichloromethane (22.9 g, 8.10 mmol). Mix 4 h stirred at room temperature and then 1,5 h at 40 C and then mixed with diethyl ether (100 ml). Suspension washed 25% solution of potassium carbonate, 5% solution of sodium bicarbonate, 1 M sodium thiosulfate solution and water (50 ml). Organic phase was dried sodium sulfate and concentrated in vacuum.

Output: 931 mg (>100%), yellowish solid

1 H NMR (DMSO-d6): 1.40-1.53 (m, 2H); 1.62-1.72 (m, 2H); 1.75-1.88 (m, 2H); 1.95 (s, 6H); 2.58-2.70 (m, 3H); 4.94 (s, 2H); 6.86-6.90 (m, 2H); 6.91-6.96 (m, 1H); 7.25-7.30 (m, 3H); 7.33-7.37 (m, 4H).

Stage 9:

2-(4-dimethylamino-4-phenylcyclohexyl)-1-phenoxypropan-2-ol

The suspension of the product from stage 7 (raw product, 300 mg, Max. 0.89 mmol) in tetrahydrofuran, anhydrous (30 ml) under argon and ice cooling mixed with 3 M solution bromide Metalmania in diethyl ether (8.8 ml, 26.7 mmol) and 3 h stirred at room the temperature. The mixture is then at cooling by ice on drops mixed with a saturated solution of ammonium chloride and water (10 ml) and was extracted with diethyl ether (3 x 20 ml). The combined organic phase was dried sodium sulfate and concentrated in vacuum. The crude product (167 mg) was purified by flash chromatography (20 g 20 x 2.0 cm) with ethyl acetate / methanol (9:1).

Output: 102 mg (32% in recalculation on stage 6), colorless oil

1 H NMR (DMSO-d6): 1.15 (8, MN); 1.20-1.30 (m 2N); 1.50-1.70 (m, 5H); 1.92 (s, 6H); 2.71 (br, Nam., 2N, J=14.3 Hz); 3.76 (d, 1H, J=9.3 Hz); 3.83 (d, 1H, J=9.3 Hz); 4.38 (s, 1H); 6.88-6.97 (m, 3H); 7.18-7.40 (m, 7H).

LC-MS (method 7): [M+H]+: m/z=354.3, Rt=3.3 min

A comparative example 1

3-{3-[4-(dimethylamino)-4-phenylcyclohexyl]-3-hydroxygon-1-inil}-1H-indole-1-carboxylic acid tert-butyl ether

The synthesis of this compound, and the following data of biological activity described in the literature (WO 04/043900).

A comparative example 2

(4-(dimethylamino)-4-phenyl-4',9'-dihydro-3 N-Spiro[cyclohexane-1,1'-piano[3,4-b]indole]-2-yl)methanol

Stage 1:

4-(dimethylamino)-4-phenyl-4',9'-dihydro-3 N-Spiro[cyclohexane-1,1'-piano[3,4-b]indole]-2-yl)methanol (one of the 4 possible racemic vapor of diastereoisomeric)

Methyl ester of 2-(4-(dimethylamino)-4-phenyl-4',9'-dihydro-3 N-Spiro[cyclohexane-1,1'-piano[3,4-b]indole]-2-yl)acetic acid (190 mg, 0,44 mmol) was dissolved in a mixture of 2N HCl (20 ml) and ethanol (20 ml) and 18 h mixed with KT. For processing ethanol drove away in a vacuum, water balance was neutralized with NaHCO 3 and using 2N NaOH sharply podlachian. The aqueous solution was extracted with ethyl acetate (3 x 10 ml). The combined organic phase was dried over MgSO 4 and then concentrated. Received solid residue was one of four possible diastereoisomers the desired alcohol in pure form. Thus, the obtained product with access to 153 mg (89%) with a melting point in 219-233 C (from propan-2-ol).

13 C NMR (101 MHz, DMSO-d 6 , δ frequent. in million): 22.1, 27.9, 30.5, 31.0, 37.9, 43.9, 59.1, 60.8, 61.6, 73.8, 106.5, 111.0, 117.3, 118.2, 120.4, 126.2, 126.3, 127.59, 127.63, 135.9, 136.6, 137.4

Research on the effectiveness of the compounds according to the invention

Measurement ORL1-linking

Compounds have been investigated in the analysis of binding of receptors with 3 H-nociceptin/orphanin FQ with membranes recombinant CHO-ORL1 cells. This test system was carried out according to the method presented in Ardati etal. (Mol. Pharmacol., 51, 1997, her. 816-824). Concentration 3 H-nociceptin/orphanin FQ when this study was 0.5 nm. Analyses linking were conducted with 20 µg membrane protein 200 l composition 50 mm HEPES, pH 7.4, 10 mm MgCl 2 and 1 mm EDTA. Linking ORL1-receptor was determined using 1 MrWGA-SPA of beads (Beads) (Amersham-Pharmacia, Freiburg), by a one-hour incubation composition at room temperature and subsequent measurement in scintillation counter Trilux (Waltac, Finland). Affinity are listed in table 1 as nanomolar K i value or % inhibition at s=1 flash off.

Measurement mu-linking

Affinity receptor for human mu-opioid receptor defined in homogeneous composition in microtiter plates. To do this within 90 minutes at room temperature incubated series dilution every time the test connection with the receptor membrane drug (15-40 µg protein 250 l incubation composition) Cho-K1 cells that Express human mu-opioid receptor (RB-HOM-receptor membrane drug company NEN, Zaventem, Belgium) in the presence of 1 nmol/l radioactive ligand [ 3h]-naloxone (NET719, the company NEN, Zaventem, Belgium), as well as 1 mg WGA-SPA-Beads (Wheat germ agglutinin SPA Beads company Amersham/Pharmacia, Freiburg, Germany) in the total volume of 250 l. As incubation buffer used 50 mmol/l Tris-HCl, supplemented 0,05% by weight sodium azide and 0.06% by weight serum albumin cattle. To identify nonspecific binding additionally added 25 mol/l naloxone. After the end of the ninety-minutes long incubation period microtiter tablets for 20 minutes at 1000 g was separated by centrifugation and radioactivity was measured on the beta-counter (Microbeta-Trilux, the company PerkinElmerWallac, Freiburg, Germany). Set the interest eviction of radioactive ligand from its binding to human mu-opiate receptors at a concentration of control of substances in 1 mol/l and indicated as a percentage inhibition (% inhibition) of specific binding. Partially based on a percentage of displacement due to different concentrations of the control and compounds of General formula IIC 50 , expected inhibiting concentration, which contributed 50% to the displacement of radioactive ligand.

By recounting using equation Cheng-Prusoff (Cheng-Prusoff) received K i-values for controlling emissions. In some cases refused to identify K i-values and is defined only inhibition test in a concentration of 1 µm.

Check analgesia in the test "OTDELENIE tail (Tail-Flick) in rats

Analgezirutee the subjects connection example 3 explored in the focal beam using a test "otdergivanija tail (Tail-flick) on rats in accordance with the method of D'amour and Smith (J. Pharm. Exp.Ther. 72, 74 79 (1941). This used the female rats Sprague Dawley with weight from 134 to 189, Animals individually placed in a special cell for testing and tail were subjected focusing thermal radiation lamp (Tail-flick Tour 50/08/1 .be, Labtec, Dr. Hess). The light intensity is installed so that the time from the lamp to the sudden otdergivanija tail (pain latency) in animals who have not undergone processing, was 2.5 to 5 seconds. Before the introduction of the tested compounds animals twice previously tested for 30 minutes and the average of these measurements was calculated as the average of the pre-test. The measure of pain was conducted in 20, 40 and 60 minutes after intravenous infusion. Analgesic action is defined as an increase in pain latency (% MPE), determined according to the following formula:

[(T 1-T 0 )/(T 2-T 0 )]x 100.

While T 0 is a latent period before and T 1 - latent period after the introduction of substances, T 2 is the maximum shutter speed (12 sec).

Whether the actions of the dose applied the appropriate test the connection in 3-5 logarithmically increasing doses that every time included limit and maximum effective dose, and values ED 50 were determined using regression analysis. Calculation ED 50 was carried out at the maximum effect, 20 minutes after intravenous injection of a substance.

Values a study of solubility (phosphate buffer pH 7.4):

This method examines the solubility of a substance when specified concentrations (1 flash off, 3 µm, 10 flash off, flash off 30 and 100 flash off) 10 mm of the test phosphate buffer at pH 7.4.

Originally required 10 mm mortar substances in DMSO, of which 100-multiples of the basic solutions of the above concentration levels again in DMSO, end DMSO concentration in the studied composition is 1% (v/v). The experiment is carried out with multiple definition. After adding DMSO basic solutions to the buffer composition incubated for 2 h at 37 C, before coming to the definition of absorption at 620 nm. Absorbance rises above a clean solution buffer/DMSO, it is an indicator of sedimentation. Lower limit solubility ("lower bound") is a concentration that precedes the first sediment (for example, 3 flash off, if the sediment was found at 10 flash off).

Comparative studies

% inhibition (ORL1)[1 flash off]

Ki (ORL1) environments. [nm]

% inhibition (u) [1 µm]

Ki(n) environments. [mm]

TF rat ED 50 i.v. [µg/kg]

Solubility (pH 7) [mol/l]

Example 1

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 12

Example 13

Example 15

Example 16

Example 17

Example 18

Ranking of 1

Comparison of 2

1. Connection with the General formula (1)

where Y 1 , Y 1 ', Y 2 , Y 2 ', Y 3 , Y 3 ', Y 4 and Y 4 ' mean-N; R 1 and R 2 are independent from each other mean-CH 3 ; R 3 R means 0 , where R 0 means - C 1-8-alkyl; - aryl selected from phenyl that is loose or monosubstituted-F, Cl, Br, I, CN or 0 , where R 0 is-1-3 C-alkyl; - unsubstituted heteroaryl selected from the 5-membered heteroaryl with one atom of S as of heteroatom; R 4 means R 0 R 0 means - aryl selected from phenyl that is loose or monosubstituted -F, Cl, Br, I, CN or 0 , where R 0 is-1-3 C-alkyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolil, monosubstituted-S(O) 2-phenyl; unsubstituted-dihydroisoquinolyl or unsubstituted-indolyl; or R 4 means-OR 0 or-SR 0 , where R 0 means cycloaliphatic group, selected from -5-6-cycloalkyl; - aryl selected from unsubstituted phenyl; - 1-2 C-alkylaryl where aryl means phenyl that is loose or monosubstituted-OR 0 , where R 0 is-1-3 C-alkyl; and R 5 means-N or-CH 3 ; where "alkyl" in each case is a branched or unbranched, rich, unsubstituted aliphatic hydrocarbon residue and cycloalkyl" in each case is a rich, unsubstituted, alicyclic monocyclic hydrocarbon residue; as separate stereoisomer or mixtures thereof, in the form of free compounds and/or their physiologically compatible salts.

2. Compound according to claim 1, where R 5 means.

3. Compound according to claim 1, which has the General formula(4), (5), (6), (7), (8) or (9)

where R is A means-S, -F, -Cl CN or-DOS 3 .

4. Compound according to claim 1, which is selected from the group, including: - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-phenylethanol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-Phenoxyethanol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(1H-indole-1-yl)ethanol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(isoindol-2-yl)ethanol - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(4-torfanil)ethanol; - 1-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)-2-phenylethanol; - 1-(4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-2-phenylethanol; - 1-(4-(dimethylamino)-4-(thiophene-2-yl)cyclohexyl)-2-phenylethanol; - 1-(4-butyl-4-(dimethylamino)cyclohexyl)-2-phenylethanol; - 1-cyclopentyl-2-(4-(dimethylamino)-4-phenylcyclohexyl)-3-phenylpropane-2-ol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-2-(pyridine-4-yl)ethanol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylthio)ethanol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-(phenylsulfonyl)ethanol; - 2-(cyclohexyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol; - 2-(benzyloxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-pentoxicated; - 2-((1H-indol-3-yl)methoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol; - 2-(2-(1H-indol-3-yl)ethoxy)-1-(4-(dimethylamino)-4-phenylcyclohexyl)ethanol; - 1-(4-(dimethylamino)-4-phenylcyclohexyl)-2-((2-(trimetilsilil)-1H-indol-3-yl)methoxy)ethanol; - 1-(2-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)-2-hydroxyethyl)piperidine-2-he; - 2-(4,4-dihydro-1H-pyrido[3,4-b]indole-2(3H,N,an)-yl)-1-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)ethanol; - 1-cynnamoyl-3-(2-(4-(dimethylamino)-4-(3-torfanil)cyclohexyl)-2-hydroxyethyl)tetrahydropyrimidine-2(1H)-it; - 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenylpropane-2-ol; - 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1,3-diphenylprop-2-ol; - 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridin-2-yl)propan-2-ol; - 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridine-3-yl)propan-2-ol and - 2-(4-(dimethylamino)-4-phenylcyclohexyl)-1-phenyl-3-(pyridine-4-yl)propan-2-ol and his physiologically compatible salt.

5. A drug that has affinity for ORL1-receptor and mu-opioid receptor that contains a therapeutically efficient quantity of at least one connection on any one of claims 1 to 4 as separate stereoisomer or mixtures thereof, in the form of free compounds and/or their physiologically compatible salts, and also suitable additives or excipients.

6. The use of connections on any one of claims 1 to 4 as separate stereoisomer or their mixtures, of a loose connection and/or their physiologically compatible salts, to obtain drugs for the treatment of pain.